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Bibliography on: Publications by FHCRC Researchers

RJR-3x

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

RJR: Recommended Bibliography 28 Sep 2021 at 01:43 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: 2021-09-27

Bardi E, Mulder RL, van Dalen EC, et al (2021)

Late hepatic toxicity surveillance for survivors of childhood, adolescent and young adult cancer: Recommendations from the international late effects of childhood cancer guideline harmonization group.

Cancer treatment reviews, 100:102296 pii:S0305-7372(21)00144-4 [Epub ahead of print].

BACKGROUND: Survivors of childhood, adolescent and young adult (CAYA) cancer may develop treatment-induced chronic liver disease. Surveillance guidelines can improve survivors' health outcomes. However, current recommendations vary, leading to uncertainty about optimal screening. The International Late Effects of Childhood Cancer Guideline Harmonization Group has developed recommendations for the surveillance of late hepatotoxicity after CAYA cancer.

METHODS: Evidence-based methods based on the GRADE framework were used in guideline development. A multidisciplinary guideline panel performed systematic literature reviews, developed evidence summaries, appraised the evidence, and formulated recommendations on the basis of evidence, clinical judgement, and consideration of benefits versus the harms of the surveillance while allowing for flexibility in implementation across different health care systems.

RESULTS: The guideline strongly recommends a physical examination and measurement of serum liver enzyme concentrations (ALT, AST, gGT, ALP) once at entry into long-term follow-up for survivors treated with radiotherapy potentially exposing the liver (moderate- to high-quality evidence). For survivors treated with busulfan, thioguanine, mercaptopurine, methotrexate, dactinomycin, hematopoietic stem cell transplantation (HSCT), or hepatic surgery, or with a history of chronic viral hepatitis or sinusoidal obstruction syndrome, similar surveillance for late hepatotoxicity once at entry into LTFU is reasonable (low-quality evidence/expert opinion, moderate recommendation). For survivors who have undergone HSCT and/or received multiple red blood cell transfusions, surveillance for iron overload with serum ferritin is strongly recommended once at long-term follow-up entry.

CONCLUSIONS: These evidence-based, internationally-harmonized recommendations for the surveillance of late hepatic toxicity in cancer survivors can inform clinical care and guide future research of health outcomes for CAYA cancer survivors.

RevDate: 2021-09-27

Simon S, Bugos G, Salter AI, et al (2021)

Synthetic receptors for logic gated T cell recognition and function.

Current opinion in immunology, 74:9-17 pii:S0952-7915(21)00121-7 [Epub ahead of print].

Adoptive cell therapy with T cells engineered with customized receptors that redirect antigen specificity to cancer cells has emerged as an effective therapeutic approach for many malignancies. Toxicity due to on target or off target effects, antigen heterogeneity on cancer cells, and acquired T cell dysfunction have been identified as barriers that can hinder successful therapy. This review will discuss recent advances in T cell engineering that have enabled the application of logic gates in T cells that can mimic the integration of natural signaling pathways and act in a cell intrinsic or extrinsic fashion to precisely target tumor cells and regulate effector functions, potentially overcoming these barriers to effective therapy.

RevDate: 2021-09-27

Dahlberg A, Kurtzberg J, Boelens J, et al (2021)

Guidelines for Pediatric Unrelated Cord Blood Transplantation-Unique Considerations.

Cord blood (CB) is the stem cell source of choice for approximately 30% of pediatric patients undergoing hematopoietic cell transplantation. Cord blood is readily available and is a particularly appealing stem cell source for patients who lack appropriate HLA matched related or unrelated donors. Pediatric cord blood transplant (CBT) recipients have low rates of disease relapse in the malignant setting and very low rates of chronic GVHD. In addition, CB has unique properties that make it the stem cell source of choice for some non-malignant conditions such as metabolic disorders. This review provides evidence-based and experience-based pediatric specific guidelines for CBT including considerations for infectious disease management, CB unit selection and infusion, conditioning regimen selection, and GVHD management. In addition, it covers unique bedside considerations for pediatric patients and CB banking. In concert with the other topic specific CB guidelines previously published in this series, it provides a comprehensive overview of the clinical management of pediatric CBT.

RevDate: 2021-09-27

Liese AD, Reboussin BA, Kahkoska AR, et al (2021)

Inequalities in Glycemic Control in Youth with Type 1 Diabetes Over Time: Intersectionality Between Socioeconomic Position and Race and Ethnicity.

Annals of behavioral medicine : a publication of the Society of Behavioral Medicine pii:6376461 [Epub ahead of print].

BACKGROUND: Racial/ethnic health inequities have been well-documented among youth and young adults with type 1 diabetes (T1D), yet little is known about how socioeconomic position (SEP) intersects with the risk marker of race/ethnicity to predict inequities in longitudinal glycemic control.

PURPOSE: To identify patterns of SEP, race/ethnicity, and clinical characteristics that differentiate hemoglobin A1c (HbA1c) trajectories among youth and young adults after T1D diagnosis.

METHODS: The SEARCH for Diabetes in Youth cohort includes youth with diabetes diagnosed from 2002 to 2006 and 2008 who were followed through 2015. We analyzed data from 1,313 youth and young adults with T1D with ≥3 HbA1c measures. Classification tree analysis identified patterns of baseline demographic, SEP, and clinical characteristic that best predicted HbA1c trajectories over an average of 8.3 years using group-based trajectory modeling.

RESULTS: Two HbA1c trajectories were identified: Trajectory 1 (77%) with lower baseline HbA1c and mild increases (from mean 7.4% to 8.4%) and Trajectory 2 (23%) with higher baseline HbA1c and major increases (from 8.5% to 11.2%). Race/ethnicity intersected with different SEP characteristics among non-Hispanic white (NHW) than in non-whites. Public health insurance predicted high-risk Trajectory 2 membership in non-whites, whereas parental education, household structure, diagnosis age and glucose checking frequency predicted membership for NHW youth and young adults. Two characteristics, race/ethnicity and parental education alone identified 80% of the Trajectory 2 members.

CONCLUSIONS: Race/ethnicity intersects with multiple SEP and clinical characteristics among youth and young adults with T1D, which is associated with particularly high risk of poor long-term glycemic control.

RevDate: 2021-09-27

Ali MF, Latimer AJ, Wang Y, et al (2021)

Met is required for oligodendrocyte progenitor cell migration in Danio rerio.

G3 (Bethesda, Md.), 11(10):.

During vertebrate central nervous system development, most oligodendrocyte progenitor cells (OPCs) are specified in the ventral spinal cord and must migrate throughout the neural tube until they become evenly distributed, occupying non-overlapping domains. While this process of developmental OPC migration is well characterized, the nature of the molecular mediators that govern it remain largely unknown. Here, using zebrafish as a model, we demonstrate that Met signaling is required for initial developmental migration of OPCs, and, using cell-specific knock-down of Met signaling, show that Met acts cell-autonomously in OPCs. Taken together, these findings demonstrate in vivo, the role of Met signaling in OPC migration and provide new insight into how OPC migration is regulated during development.

RevDate: 2021-09-27

Beauchamp EM, Leventhal M, Bernard E, et al (2021)

ZBTB33 is mutated in clonal hematopoiesis and myelodysplastic syndromes and impacts RNA splicing.

Blood cancer discovery, 2(5):500-517.

Clonal hematopoiesis results from somatic mutations in cancer driver genes in hematopoietic stem cells. We sought to identify novel drivers of clonal expansion using an unbiased analysis of sequencing data from 84,683 persons and identified common mutations in the 5-methylcytosine reader, ZBTB33, as well as in YLPM1, SRCAP, and ZNF318. We also identified these mutations at low frequency in myelodysplastic syndrome patients. Zbtb33 edited mouse hematopoietic stem and progenitor cells exhibited a competitive advantage in vivo and increased genome-wide intron retention. ZBTB33 mutations potentially link DNA methylation and RNA splicing, the two most commonly mutated pathways in clonal hematopoiesis and MDS.

RevDate: 2021-09-27

Abou-El-Enein M, Elsallab M, Feldman SA, et al (2021)

Scalable Manufacturing of CAR T cells for Cancer Immunotherapy.

Blood cancer discovery, 2(5):408-422.

As of April 2021, there are five commercially available chimeric antigen receptor (CAR) T cell therapies for hematological malignancies. With the current transition of CAR T cell manufacturing from academia to industry, there is a shift toward Good Manufacturing Practice (GMP)-compliant closed and automated systems to ensure reproducibility and to meet the increased demand for cancer patients. In this review we describe current CAR T cells clinical manufacturing models and discuss emerging technological advances that embrace scaling and production optimization. We summarize measures being used to shorten CAR T-cell manufacturing times and highlight regulatory challenges to scaling production for clinical use.

As the demand for CAR T cell cancer therapy increases, several closed and automated production platforms are being deployed, and others are in development.This review provides a critical appraisal of these technologies that can be leveraged to scale and optimize the production of next generation CAR T cells.

RevDate: 2021-09-25

Msaouel P, Grivas P, T Zhang (2021)

Adjuvant Systemic Therapies for Patients with Renal Cell Carcinoma: Choosing Treatment Based on Patient-level Characteristics.

Motivated by recent presentation of the KEYNOTE-564 interim results for adjuvant pembrolizumab in clear-cell renal cell carcinoma, we discuss concepts that can guide patient-specific decision-making in selecting individuals for whom adjuvant therapies should be offered.

RevDate: 2021-09-24

Yong MK, Shigle TL, Kim YJ, et al (2021)

American Society of Transplantation and Cellular Therapy Series: #4 - Cytomegalovirus treatment and management of resistant or refractory infections after hematopoietic cell transplantation.

The Practice Guidelines Committee of the American Society of Transplantation and Cellular Therapy (ASTCT) partnered with its Transplant Infectious Disease Special Interest Group (TID-SIG) to update its 2009 compendium-style infectious disease guidelines for hematopoietic cell transplantation (HCT). A new approach was employed with the goal of better serving clinical providers by publishing each standalone topic in the infectious diseases series as a concise format of frequently asked questions (FAQ), tables, and figures. Adult and pediatric infectious diseases and HCT content experts developed and answered FAQs. Topics were finalized with harmonized recommendations that were made by assigning an A through E strength of recommendation paired with a level of supporting evidence graded I through III. The fourth topic in the series focuses on the management and treatment of cytomegalovirus (CMV) resistant and refractory infections. The diagnosis, definitions of resistant and refractory CMV, risk factors, virological genotypes and treatment algorithms are reviewed.

RevDate: 2021-09-24

Aljedani SS, Liban TJ, Tran K, et al (2021)

Structurally related but genetically unrelated antibody lineages converge on an immunodominant HIV-1 Env neutralizing determinant following trimer immunization.

PLoS pathogens, 17(9):e1009543 pii:PPATHOGENS-D-21-00745 [Epub ahead of print].

Understanding the molecular mechanisms by which antibodies target and neutralize the HIV-1 envelope glycoprotein (Env) is critical in guiding immunogen design and vaccine development aimed at eliciting cross-reactive neutralizing antibodies (NAbs). Here, we analyzed monoclonal antibodies (mAbs) isolated from non-human primates (NHPs) immunized with variants of a native flexibly linked (NFL) HIV-1 Env stabilized trimer derived from the tier 2 clade C 16055 strain. The antibodies displayed neutralizing activity against the autologous virus with potencies ranging from 0.005 to 3.68 μg/ml (IC50). Structural characterization using negative-stain EM and X-ray crystallography identified the variable region 2 (V2) of the 16055 NFL trimer to be the common epitope for these antibodies. The crystal structures revealed that the V2 segment adopts a β-hairpin motif identical to that observed in the 16055 NFL crystal structure. These results depict how vaccine-induced antibodies derived from different clonal lineages penetrate through the glycan shield to recognize a hypervariable region within V2 (residues 184-186) that is unique to the 16055 strain. They also provide potential explanations for the potent autologous neutralization of these antibodies, confirming the immunodominance of this site and revealing that multiple angles of approach are permissible for affinity/avidity that results in potent neutralizing capacity. The structural analysis reveals that the most negatively charged paratope correlated with the potency of the mAbs. The atomic level information is of interest to both define the means of autologous neutralization elicited by different tier 2-based immunogens and facilitate trimer redesign to better target more conserved regions of V2 to potentially elicit cross-neutralizing HIV-1 antibodies.

RevDate: 2021-09-24

Angenendt L, Wöste M, Mikesch JH, et al (2021)

Calcitonin receptor-like (CALCRL) is a marker of stemness and an independent predictor of outcome in pediatric AML.

Blood advances pii:477031 [Epub ahead of print].

We have recently identified the G protein-coupled neuropeptide receptor Calcitonin receptor-like (CALCRL) as an independent prognostic biomarker and a therapeutic target in more than 1500 adult patients with acute myeloid leukemia (AML). Here, we confirmed CALCRL expression as a prognostic factor in a cohort of 284 pediatric patients with AML. High CALCRL expression was independently associated with event free survival (EFS) (hazard ratio [HR], 1.87; 95% confidence interval [CI], 1.36-2.57; P=0.0001), overall survival (OS) (HR, 1.55; 95% [CI], 1.06-2.27; P=0.025) and cumulative incidence of relapse (CIR) (HR, 2.10; 95% CI, 1.49-1.96; P<0.0001) when adjusting for age, white blood cell count and genetic risk. Despite its association with leukemia stem cell (LSC) signatures, CALCRL expression remained associated with all endpoints when compared to the LSC17 score. The strong association of CALCRL expression with the risk of relapse also in the pediatric population supports its role as novel age-independent master regulator of relapse-initiating drug-tolerant AML cells in humans.

RevDate: 2021-09-24

Moon JY, Hua S, Qi Q, et al (2021)

Association of Sugar-sweetened Beverage Consumption with Prediabetes and Glucose Metabolism Markers in Hispanic/Latino Adults in the United States: Results from HCHS/SOL.

The Journal of nutrition pii:6374868 [Epub ahead of print].

BACKGROUND: Diabetes mellitus and consumption of sugar-sweetened beverages is high in the Hispanic/Latino population in the United States. The associations between consumption of sugar-sweetened beverages, artificially sweetened beverages, and 100% fruit juice with prediabetes and glucose metabolism markers in the diverse Hispanic/Latino population in the US are unknown.

OBJECTIVE: To examine the cross-sectional associations between consumption of sugar-sweetened beverages, artificially sweetened beverages, and 100% fruit juice with prediabetes and glucose metabolism markers such as fasting glucose and insulin, 2-hour oral glucose tolerance test (OGTT) glucose, HOMA index for insulin resistance (HOMA-IR), HOMA index for β-cell function (HOMA-B), and hemoglobin A1C (HbA1c) among US Hispanic/Latino adults.

METHODS: Using baseline data from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL; 2008-2011), beverage consumption was ascertained using two 24-hour dietary recalls and the Food Propensity Questionnaire. Diabetes/prediabetes status was defined by self-report, antihyperglycemic medication use, and American Diabetes Association laboratory criteria. Among 9965 individuals without diabetes (5194 normoglycemia, 4771 prediabetes) aged 18-74 years, the associations of beverage consumption with prediabetes and glucose metabolism markers were analyzed using logistic and linear regressions, respectively, accounting for complex survey design.

RESULTS: Compared with individuals who consumed < 1 serving/day (<240 mL/day) of sugar-sweetened beverages, individuals who consumed > 2 servings/day (>480 mL/day) had 1.3 times greater odds of having prediabetes (95% confidence interval = 1.06-1.61) and higher glucose metabolism markers including fasting glucose, fasting insulin, HOMA-IR, and HbA1c. Consumption of artificially sweetened beverages showed an inverse association with β-cell function (HOMA-B). 100% fruit juice intake was not significantly associated with prediabetes nor with glucose metabolism markers.

CONCLUSIONS: Among US Hispanic/Latino adults, higher sugar-sweetened beverage consumption was associated with an increased odds of prediabetes and higher glucose metabolism markers. Public health initiatives to decrease sugar-sweetened beverage consumption could potentially reduce the burden of diabetes among Hispanics/Latinos in the US.

RevDate: 2021-09-23

Hastie KM, Li H, Bedinger D, et al (2021)

Defining variant-resistant epitopes targeted by SARS-CoV-2 antibodies: A global consortium study.

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

[Figure: see text].

RevDate: 2021-09-23

Storb R (2021)

Commentary on the 1962 Transfusion paper by Don Thomas and Joe Ferrebee.

Transfusion [Epub ahead of print].

RevDate: 2021-09-23

Wang T, Ling W, Plantinga AM, et al (2021)

Testing microbiome association using integrated quantile regression models.

Bioinformatics (Oxford, England) pii:6374494 [Epub ahead of print].

MOTIVATION: Most existing microbiome association analyses focus on the association between microbiome and conditional mean of health or disease-related outcomes, and within this vein, vast computational tools and methods have been devised for standard binary or continuous outcomes. However, these methods tend to be limited either when the underlying microbiome-outcome association occurs somewhere other than the mean level, or when distribution of the outcome variable is irregular (e.g., zero-inflated or mixtures) such that conditional outcome mean is less meaningful. We address this gap by investigating association analysis between microbiome compositions and conditional outcome quantiles.

RESULTS: We introduce a new association analysis tool named MiRKAT-IQ within the Microbiome Regression-based Kernel Association Test framework using Integrated Quantile regression models to examine the association between microbiome and the distribution of outcome. For an individual quantile, we utilize the existing kernel machine regression framework to examine the association between that conditional outcome quantile and a group of microbial features (e.g., microbiome community compositions). Then, the goal of examining microbiome association with the whole outcome distribution is achieved by integrating all outcome conditional quantiles over a process, and thus our new MiRKAT-IQ test is robust to both the location of association signals (e.g.,mean, variance, median) and the heterogeneous distribution of the outcome. Extensive numerical simulation studies have been conducted to show the validity of the new MiRKAT-IQ test. We demonstrate the potential usefulness of MiRKAT-IQ with applications to actual biological data collected from a previous microbiome study.

AVAILABILITY: R codes to implement the proposed methodology is provided in the MiRKAT package, which is available on CRAN.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

RevDate: 2021-09-23

Little A, Hu Y, Sun Q, et al (2021)

Whole genome sequence analysis of platelet traits in the NHLBI trans-omics for precision medicine initiative.

Human molecular genetics pii:6365133 [Epub ahead of print].

Platelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing from NHLBI's Trans-Omics for Precision Medicine Initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We identified and replicated secondary signals at MPL (rs532784633) and PECAM1 (rs73345162), both more common in African ancestry populations. We also observed rare variation in Mendelian platelet related disorder genes influencing variation in platelet traits in TOPMed cohorts (not enriched for blood disorders). For example, association of GP9 with lower PLT and higher MPV was partly driven by a pathogenic Bernard-Soulier syndrome variant (rs5030764, p.Asn61Ser), and the signals at TUBB1 and CD36 were partly driven by loss of function variants not annotated as pathogenic in ClinVar (rs199948010 and rs571975065). However, residual signal remained for these gene-based signals after adjusting for lead variants, suggesting that additional variants in Mendelian genes with impacts in general population cohorts remain to be identified. Gene-based signals were also identified at several GWAS identified loci for genes not annotated for Mendelian platelet disorders (PTPRH, TET2, CHEK2), with somatic variation driving the result at TET2. These results highlight the value of whole genome sequencing in populations of diverse genetic ancestry to identify novel regulatory and coding signals, even for well-studied traits like platelet traits.

RevDate: 2021-09-25

Bellettiere J, Nguyen S, Eaton CB, et al (2021)

The short physical performance battery and incident heart failure among older women: the OPACH study.

American journal of preventive cardiology, 8:100247.

Objective: Reduced functional capacity is a hallmark of early pre-clinical stages of heart failure (HF). The Short Physical Performance Battery (SPPB) is a valid measure of lower extremity physical function, has relatively low implementation burden, and is associated with cardiovascular disease and mortality. However, the SPPB-HF association is understudied in older women among whom HF burden is high.

Methods: Women (n = 5325; mean age 79 ± 7 years; 34% Black, 18% Hispanic, and 49% White) without prior HF completed the SPPB consisting of standing balance, strength, and walking tests that were summarized as a composite score from 0 (lowest) to 12 (highest), categorized as very low (0-3), low (4-6), medium (7-9), or high (10-12). Participants were followed for up to 8 years for incident HF (306 cases identified). Cox proportional hazards regression estimated hazard ratios (HR) adjusting for age, race/ethnicity, education, smoking, alcohol, diabetes, hypertension, COPD, osteoarthritis, depression, BMI, systolic blood pressure, lipids, glucose, and accelerometer-measured moderate-vigorous physical activity (MVPA) and sedentary time.

Results: Incident HF cases (crude rate per 1000 person-years) in the four SPPB categories (very low to high) were 34 (26.0), 79 (14.5), 128 (9.3), and 65 (5.6). Corresponding multivariable-adjusted HRs (95% CIs) were 2.22 (1.34-3.66), 1.63 (1.11-2.38), 1.39 (1.00-1.94), and 1.00 (referent; P-trend<0.001). Higher HF risk was associated with lower SPPB in women with major modifiable HF risk factors including obesity (HR per 3-unit SPPB decrement: present HR = 1.41, absent HR = 1.41), hypertension (present HR = 1.45, absent HR = 1.30), diabetes (present HR = 1.32, absent HR = 1.44), and lower accelerometer-measured MVPA (<45 min/day HR = 1.29, ≥45 min/day HR = 1.60); all P-interaction>0.10.

Conclusion: Lower SPPB scores were associated with greater risk of incident HF in older women even after accounting for differences in HF risk factors and objectively measured PA. Implementing the SPPB in clinical settings could potentially enhance individual-level HF risk assessment, which should be further explored.

RevDate: 2021-09-25

Peng T, Phasouk K, Sodroski CN, et al (2021)

Tissue-Resident-Memory CD8+ T Cells Bridge Innate Immune Responses in Neighboring Epithelial Cells to Control Human Genital Herpes.

Frontiers in immunology, 12:735643.

Tissue-resident-memory T cells (TRM) populate the body's barrier surfaces, functioning as frontline responders against reencountered pathogens. Understanding of the mechanisms by which CD8TRM achieve effective immune protection remains incomplete in a naturally recurring human disease. Using laser capture microdissection and transcriptional profiling, we investigate the impact of CD8TRM on the tissue microenvironment in skin biopsies sequentially obtained from a clinical cohort of diverse disease expression during herpes simplex virus 2 (HSV-2) reactivation. Epithelial cells neighboring CD8TRM display elevated and widespread innate and cell-intrinsic antiviral signature expression, largely related to IFNG expression. Detailed evaluation via T-cell receptor reconstruction confirms that CD8TRM recognize viral-infected cells at the specific HSV-2 peptide/HLA level. The hierarchical pattern of core IFN-γ signature expression is well-conserved in normal human skin across various anatomic sites, while elevation of IFI16, TRIM 22, IFITM2, IFITM3, MX1, MX2, STAT1, IRF7, ISG15, IFI44, CXCL10 and CCL5 expression is associated with HSV-2-affected asymptomatic tissue. In primary human cells, IFN-γ pretreatment reduces gene transcription at the immediate-early stage of virus lifecycle, enhances IFI16 restriction of wild-type HSV-2 replication and renders favorable kinetics for host protection. Thus, the adaptive immune response through antigen-specific recognition instructs innate and cell-intrinsic antiviral machinery to control herpes reactivation, a reversal of the canonical thinking of innate activating adaptive immunity in primary infection. Communication from CD8TRM to surrounding epithelial cells to activate broad innate resistance might be critical in restraining various viral diseases.

RevDate: 2021-09-23

Verstovsek S, Mesa R, Talpaz M, et al (2021)

Retrospective analysis of pacritinib in patients with myelofibrosis and severe thrombocytopenia.

Haematologica [Epub ahead of print].

Thrombocytopenia is common in patients with myelofibrosis and is a well-established adverse prognostic factor. Both of the approved Janus kinase (JAK) inhibitors, ruxolitinib and fedratinib, can worsen thrombocytopenia and have not been evaluated in patients with severe thrombocytopenia (.

RevDate: 2021-09-24

Dotan E, Walter LC, Browner IS, et al (2021)

NCCN Guidelines® Insights: Older Adult Oncology, Version 1.2021.

Journal of the National Comprehensive Cancer Network : JNCCN, 19(9):1006-1019 pii:jnccnglins1909.

The NCCN Guidelines for Older Adult Oncology address specific issues related to the management of cancer in older adults, including screening and comprehensive geriatric assessment (CGA), assessing the risks and benefits of treatment, preventing or decreasing complications from therapy, and managing patients deemed to be at high risk for treatment-related toxicity. CGA is a multidisciplinary, in-depth evaluation that assesses the objective health of the older adult while evaluating multiple domains, which may affect cancer prognosis and treatment choices. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines providing specific practical framework for the use of CGA when evaluating older adults with cancer.

RevDate: 2021-09-24

Brown PA, Shah B, Advani A, et al (2021)

Acute Lymphoblastic Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

Journal of the National Comprehensive Cancer Network : JNCCN, 19(9):1079-1109 pii:jnccnGLS1909.

The NCCN Guidelines for Acute Lymphoblastic Leukemia (ALL) focus on the classification of ALL subtypes based on immunophenotype and cytogenetic/molecular markers; risk assessment and stratification for risk-adapted therapy; treatment strategies for Philadelphia chromosome (Ph)-positive and Ph-negative ALL for both adolescent and young adult and adult patients; and supportive care considerations. Given the complexity of ALL treatment regimens and the required supportive care measures, the NCCN ALL Panel recommends that patients be treated at a specialized cancer center with expertise in the management of ALL This portion of the Guidelines focuses on the management of Ph-positive and Ph-negative ALL in adolescents and young adults, and management in relapsed settings.

RevDate: 2021-09-24

El Sahly HM, Baden LR, Essink B, et al (2021)

Efficacy of the mRNA-1273 SARS-CoV-2 Vaccine at Completion of Blinded Phase.

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

BACKGROUND: At interim analysis in a phase 3, observer-blinded, placebo-controlled clinical trial, the mRNA-1273 vaccine showed 94.1% efficacy in preventing coronavirus disease 2019 (Covid-19). After emergency use of the vaccine was authorized, the protocol was amended to include an open-label phase. Final analyses of efficacy and safety data from the blinded phase of the trial are reported.

METHODS: We enrolled volunteers who were at high risk for Covid-19 or its complications; participants were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo, 28 days apart, at 99 centers across the United States. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The data cutoff date was March 26, 2021.

RESULTS: The trial enrolled 30,415 participants; 15,209 were assigned to receive the mRNA-1273 vaccine, and 15,206 to receive placebo. More than 96% of participants received both injections, 2.3% had evidence of SARS-CoV-2 infection at baseline, and the median follow-up was 5.3 months in the blinded phase. Vaccine efficacy in preventing Covid-19 illness was 93.2% (95% confidence interval [CI], 91.0 to 94.8), with 55 confirmed cases in the mRNA-1273 group (9.6 per 1000 person-years; 95% CI, 7.2 to 12.5) and 744 in the placebo group (136.6 per 1000 person-years; 95% CI, 127.0 to 146.8). The efficacy in preventing severe disease was 98.2% (95% CI, 92.8 to 99.6), with 2 cases in the mRNA-1273 group and 106 in the placebo group, and the efficacy in preventing asymptomatic infection starting 14 days after the second injection was 63.0% (95% CI, 56.6 to 68.5), with 214 cases in the mRNA-1273 group and 498 in the placebo group. Vaccine efficacy was consistent across ethnic and racial groups, age groups, and participants with coexisting conditions. No safety concerns were identified.

CONCLUSIONS: The mRNA-1273 vaccine continued to be efficacious in preventing Covid-19 illness and severe disease at more than 5 months, with an acceptable safety profile, and protection against asymptomatic infection was observed. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.).

RevDate: 2021-09-25

Menghrajani K, Gomez-Arteaga A, Madero-Marroquin R, et al (2021)

Risk classification at diagnosis predicts post-HCT outcomes in intermediate-, adverse-risk, and KMT2A-rearranged AML.

Blood advances pii:S2473-9529(21)00604-2 [Epub ahead of print].

Little is known about whether risk classification at diagnosis predicts post-hematopoietic cell transplantation (HCT) outcomes for acute myeloid leukemia (AML) patients. We evaluated 8709 AML patients from the CIBMTR database and, after selection and manual curation of cytogenetics data, 3779 patients in CR1 were included in the final analysis: 2384 with intermediate-risk, 969 with adverse-risk, and 426 with KMT2A-rearranged disease. An adjusted multivariable analysis compared to intermediate-risk patients detected an increased risk of relapse for KMT2A-rearranged and adverse-risk patients (HR 1.27, p = 0.01 and HR 1.71, p < 0.001, respectively). Leukemia-free survival (LFS) was similar for KMT2A and adverse-risk patients (HR 1.26, p = 0.002 and HR 1.47, p < 0.001), as was overall survival (OS) (HR 1.32, p < 0.001 and HR 1.45, p < 0.001). No differences in outcome could be detected when patients were stratified by KMT2A fusion partner. This is the largest study conducted to date on post-HCT outcomes in AML using manually curated cytogenetics for risk stratification. Our work demonstrates that risk classification at diagnosis remains predictive of post-HCT outcomes in AML. It also highlights the critical need to develop novel treatment strategies for patients with KMT2A rearrangements and adverse-risk disease.

RevDate: 2021-09-22

Duggan C, Yu M, Willbanks AR, et al (2021)

Exercise effects on DNA methylation in EVL, CDKN2A (p14, ARF), and ESR1 in colon tissue from healthy men and women.

Epigenetics [Epub ahead of print].

Physical activity reduces risk of colon cancer persons by 20-30%. Aberrant methylation patterns are common epigenetic alterations in colorectal adenomas and cancers, and play a role in cancer initiation and progression. Alterations have been identified in normal colon tissue potentially representing a "field cancerization" process, where the normal colon is primed for carcinogenesis. Here, we investigate methylation patterns in three genes -Ena/VASP-like (EVL), (CDKN2A (p14, ARF)), and Estrogen Receptor-1 (ESR1)-in normal colon tissue collected at baseline and 12-months from 202 sedentary men and women, 40-75 years, enrolled in a randomized controlled trial testing an exercise intervention vs. control (http://clinicaltrials.gov/show/NCT00668161). Participants were randomized to moderate-to-vigorous intensity exercise, 60 minutes/day, 6 days/week for 12 months, or usual lifestyle. Sigmoid colon biopsies were obtained at baseline and 12-months, DNA extracted, and bisulphite converted. Droplet digital methylation-specific PCR was performed for EVL, p14ARF, and ESR1. Generalized estimating equations modification of linear regression were used to model relationships between intervention effects and candidate gene methylation levels, adjusting for possible confounders.There were no statistically significant differences between methylation patterns at 12-months between exercisers and controls. ESR1 methylation patterns differed by sex: women -10.58% (exercisers) +11.10% (controls); men +5.54% (exercisers), -8.16% (controls); (P=0.05), adjusting for BMI and age. There were no statistically significant changes in methylation patterns in any gene stratified by change in VO2max, or by minutes/week of exercise.While no statistically significant differences were found in gene methylation patterns comparing exercises vs. controls, 12-month exercise effects on ESR1 methylation differed by sex, warranting further study.

RevDate: 2021-09-22

Becht E, Tolstrup D, Dutertre CA, et al (2021)

High-throughput single-cell quantification of hundreds of proteins using conventional flow cytometry and machine learning.

Science advances, 7(39):eabg0505.

[Figure: see text].

RevDate: 2021-09-22

Kessler RC, A Luedtke (2021)

Pragmatic Precision Psychiatry-A New Direction for Optimizing Treatment Selection.

JAMA psychiatry pii:2784467 [Epub ahead of print].

Importance: Clinical trials have identified numerous prescriptive predictors of mental disorder treatment response, ie, predictors of which treatments are best for which patients. However, none of these prescriptive predictors is strong enough alone to guide precision treatment planning. This has prompted growing interest in developing precision treatment rules (PTRs) that combine information across multiple prescriptive predictors, but this work has been much less successful in psychiatry than some other areas of medicine. Study designs and analysis schemes used in research on PTR development in other areas of medicine are reviewed, key challenges for implementing similar studies of mental disorders are highlighted, and recent methodological advances to address these challenges are described here.

Observations: Discovering prescriptive predictors requires large samples. Three approaches have been used in other areas of medicine to do this: conduct very large randomized clinical trials, pool individual-level results across multiple smaller randomized clinical trials, and develop preliminary PTRs in large observational treatment samples that are then tested in smaller randomized clinical trials. The third approach is most feasible for research on mental disorders. This approach requires working with large real-world observational electronic health record databases; carefully selecting samples to emulate trials; extracting information about prescriptive predictors from electronic health records along with other inexpensive data augmentation strategies; estimating preliminary PTRs in the observational data using appropriate methods; implementing pragmatic trials to validate the preliminary PTRs; and iterating between subsequent observational studies and quality improvement pragmatic trials to refine and expand the PTRs. New statistical methods exist to address the methodological challenges of implementing this approach.

Conclusions and Relevance: Advances in pragmatic precision psychiatry will require moving beyond the current focus on randomized clinical trials and adopting an iterative discovery-confirmation process that integrates observational and experimental studies in real-world clinical populations.

RevDate: 2021-09-24

Dong J, Zost SJ, Greaney AJ, et al (2021)

Genetic and structural basis for SARS-CoV-2 variant neutralization by a two-antibody cocktail.

Nature microbiology [Epub ahead of print].

Understanding the molecular basis for immune recognition of SARS-CoV-2 spike glycoprotein antigenic sites will inform the development of improved therapeutics. We determined the structures of two human monoclonal antibodies-AZD8895 and AZD1061-which form the basis of the investigational antibody cocktail AZD7442, in complex with the receptor-binding domain (RBD) of SARS-CoV-2 to define the genetic and structural basis of neutralization. AZD8895 forms an 'aromatic cage' at the heavy/light chain interface using germ line-encoded residues in complementarity-determining regions (CDRs) 2 and 3 of the heavy chain and CDRs 1 and 3 of the light chain. These structural features explain why highly similar antibodies (public clonotypes) have been isolated from multiple individuals. AZD1061 has an unusually long LCDR1; the HCDR3 makes interactions with the opposite face of the RBD from that of AZD8895. Using deep mutational scanning and neutralization escape selection experiments, we comprehensively mapped the crucial binding residues of both antibodies and identified positions of concern with regards to virus escape from antibody-mediated neutralization. Both AZD8895 and AZD1061 have strong neutralizing activity against SARS-CoV-2 and variants of concern with antigenic substitutions in the RBD. We conclude that germ line-encoded antibody features enable recognition of the SARS-CoV-2 spike RBD and demonstrate the utility of the cocktail AZD7442 in neutralizing emerging variant viruses.

RevDate: 2021-09-22

Rocha V, Arcuri LJ, Seber A, et al (2021)

Impact of mother donor, peripheral blood stem cells and measurable residual disease on outcomes after haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide in children with acute leukaemia.

Bone marrow transplantation [Epub ahead of print].

Haploidentical hematopoietic-cell transplantation using post-transplant cyclophosphamide(Haplo-PTCy) is a feasible procedure in children with haematologic malignancies. However, data of a large series of children with acute leukaemia(AL) in this setting is missing. We analysed 144 AL Haplo-PTCy paediatric recipients; median age was 10 years. Patients had acute lymphoblastic(ALL; n = 86) or myeloblastic leukaemia(AML; n = 58) and were transplanted in remission(CR1: n = 40; CR2: n = 57; CR3+: n = 27) or relapse (n = 20). Bone marrow was the graft source in 57%; donors were father (54%), mother (35%), or sibling (11%). Myeloablative conditioning was used in 87%. Median follow-up was 31 months. At day +100, cumulative incidence (CI) of neutrophil recovery and acute GVHD (II-IV) were 94% and 40%, respectively. At 2-years, CI of chronic GVHD and relapse, were 31%, 40%, and estimated 2-year overall survival (OS), leukaemia-free survival (LFS) and graft-versus-host-relapse-free survival (GRFS) were 52%, 44% and 34% respectively. For patients transplanted in remission, positive measurable residual disease (MRD) prior to transplant was associated with decreased LFS (p = 0.05) and GRFS (p = 0.003) and increased risk of relapse (p = 0.02). Mother donor was associated with increased risk of chronic GVHD (p = 0.001), decreased OS (p = 0.03) and GRFS (p = 0.004). Use of PBSC was associated with increased risk of chronic GVHD (p = 0.04). In conclusion, achieving MRD negativity pre-transplant, avoiding use of mother donors and PBSC as graft source may improve outcomes of Haplo-PTCy in children with AL.

RevDate: 2021-09-22

Zou Q, Wang X, Ren D, et al (2021)

DNA methylation-based signature of CD8+ tumor-infiltrating lymphocytes enables evaluation of immune response and prognosis in colorectal cancer.

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

BACKGROUND: Tumor-infiltrating lymphocytes (TILs), especially CD8+ TILs, can be used for predicting immunotherapy responsiveness and survival outcome. However, the evaluation of CD8+ TILs currently relies on histopathological methodology with high variability. We therefore aimed to develop a DNA methylation signature for CD8+ TILs (CD8+ MeTIL) that could evaluate immune response and prognosis in colorectal cancer (CRC).

METHODS: A CD8+ MeTIL signature score was constructed by using CD8+ T cell-specific differentially methylated positions (DMPs) that were identified from Illumina EPIC methylation arrays. Immune cells, colon epithelial cells, and two CRC cohorts (n=282 and 335) were used to develop a PCR-based assay for quantitative analysis of DNA methylation at single-base resolution (QASM) to determine CD8 + MeTIL signature score.

RESULTS: Three CD8+ T cell-specific DMPs were identified to construct the CD8+ MeTIL signature score, which showed a dramatic discriminability between CD8+ T cells and other cells. The QASM assay we developed for CD8+ MeTIL markers could measure CD8+ TILs distributions in a fully quantitative, accurate, and simple manner. The CD8+ MeTIL score determined by QASM assay showed a strong association with histopathology-based CD8+ TIL counts and a gene expression-based immune marker. Furthermore, the low CD8+ MeTIL score (enriched CD8+ TILs) was associated with MSI-H tumors and predicted better survival in CRC cohorts.

CONCLUSIONS: This study developed a quantitative DNA methylation-based signature that was reliable to evaluate CD8+ TILs and prognosis in CRC. This approach has the potential to be a tool for investigations on CD8+ TILs and a biomarker for therapeutic approaches, including immunotherapy.

RevDate: 2021-09-24

Jiao B, Gulati R, Katki HA, et al (2021)

A Quantitative Framework to Study Potential Benefits and Harms of Multi-cancer Early Detection Testing.

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-21-0380 [Epub ahead of print].

BACKGROUND: Multi-cancer tests offer screening for multiple cancers with one blood draw, but the potential population impact is poorly understood.

METHODS: We formulate mathematical expressions for expected numbers of (1) individuals exposed to unnecessary confirmation tests (EUC), (2) cancers detected (CD), and (3) lives saved (LS) given test performance, disease incidence and mortality, and mortality reduction. We add colorectal, liver, lung, ovary, and pancreatic cancer to a test for breast cancer, approximating prevalence at ages 50, 60, or 70 using incidence over the next 5 years and mortality using corresponding probabilities of cancer death over 15 years in the Surveillance, Epidemiology, and End Results registry.

RESULTS: EUC is overwhelmingly determined by specificity. For a given specificity, EUC/CD is most favorable for higher-prevalence cancers. Under 99% specificity and sensitivities as published for a 50-cancer test, EUC/CD is 1.1 for breast+lung versus 1.3 for breast+liver at age 50. Under a common mortality reduction associated with screening, EUC/LS is most favorable when the test includes higher-mortality cancers (e.g., 19.9 for breast+lung versus 30.4 for breast+liver at age 50 assuming a common 10% mortality reduction).

CONCLUSIONS: Published multi-cancer test performance suggests a favorable tradeoff of EUC to CD, yet the full burden of unnecessary confirmations will depend on the post-test work-up protocol. Harm-benefit tradeoffs will be improved if tests prioritize more prevalent and/or lethal cancers for which curative treatments exist.

IMPACT: The population impact of multi-cancer testing will depend not only on test performance but also on disease characteristics and efficacy of early treatment.

RevDate: 2021-09-22

Helms EJ, Berry MW, Chaw RC, et al (2021)

Mesenchymal Lineage Heterogeneity Underlies Non-Redundant Functions of Pancreatic Cancer-Associated Fibroblasts.

Cancer discovery pii:2159-8290.CD-21-0601 [Epub ahead of print].

Cancer-associated fibroblast (CAF) heterogeneity is increasingly appreciated, but the origins and functions of distinct CAF subtypes remain poorly understood. The abundant and transcriptionally diverse CAF population in pancreatic ductal adenocarcinoma (PDAC) is thought to arise from a common cell of origin, pancreatic stellate cells (PSCs), with diversification resulting from cytokine and growth factor gradients within the tumor microenvironment. Here we analyzed the differentiation and function of PSCs during tumor progression in vivo. Contrary to expectations, we found that PSCs give rise to a numerically minor subset of PDAC CAFs. Targeted ablation of PSC-derived CAFs within their host tissue revealed non-redundant functions for this defined CAF population in shaping the PDAC microenvironment, including production of specific extracellular matrix components and tissue stiffness regulation. Together, these findings link stromal evolution from distinct cells of origin to transcriptional heterogeneity among PDAC CAFs, and demonstrate unique functions for CAFs of a defined cellular origin.

RevDate: 2021-09-21

Huang BJ, Smith J, Wang J, et al (2021)

CBFB-MYH11 Fusion Transcripts Distinguish Acute Myeloid Leukemias with Distinct Molecular Landscapes and Outcomes.

Blood advances pii:476984 [Epub ahead of print].

Patients with inv(16)/CBFB-MYH11 AML are considered favorable risk, however, nearly one-third relapse despite intensive therapy. Despite efforts to define risk groups within this favorable risk cohort, CBFB-MYH11 AML patients continue to be treated as a uniform cohort. Through transcriptome sequencing of 186 patients with inv(16) AML, we demonstrate that fusion junction breakpoints (exon 5-exon 33 versus other) are highly associated with outcome. The presence of exon 17 KIT mutations provides additional prognostic significance. Additionally, we provide insights into the transcriptional landscapes that differentiate these distinct CBFB-MYH11 AML subtypes. Children's Oncology Group trials include CCG-2961 (registered at www.clinicaltrials.gov as NCT00002798), AAML03P1 (NCT00070174), AAML0531 (NCT00372593), and AAML1031 (NCT01371981).

RevDate: 2021-09-21

Shaukat A, Marsh TL, Crockett SD, et al (2021)

Low prevalence of screen-detected colorectal cancer in an average-risk population: the new normal.

Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association pii:S1542-3565(21)00977-0 [Epub ahead of print].

RevDate: 2021-09-21

Dembitz V, Lalic H, Tomic B, et al (2021)

All-trans retinoic acid induces differentiation in primary acute myeloid leukemia blasts carrying an inversion of chromosome 16.

International journal of hematology [Epub ahead of print].

All-trans retinoic acid (ATRA)-based therapy for acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia (AML), is the most successful example of differentiation therapy. Although ATRA can induce differentiation in some non-APL AML cell lines and primary blasts, clinical results of adding ATRA to standard therapy in non-APL AML patients have been inconsistent, probably due to use of different regimens and lack of diagnostic tools for identifying which patients may be sensitive to ATRA. In this study, we exposed primary blasts obtained from non-APL AML patients to ATRA to test for differentiation potential in vitro. We observed increased expression of differentiation markers, indicating a response to ATRA, in four out of fifteen primary AML samples. Three samples in which CD11b increased in response to ATRA had an inversion of chromosome 16 as well as the CBFB-MYH11 fusion gene, and the fourth sample was from a patient with KMT2A-rearranged, therapy-related AML. In conclusion, we identified a subgroup of non-APL AML patients with inv(16) and CBFB-MYH11 as the most sensitive to ATRA-mediated differentiation in vitro, and our results can help identify patients who may benefit from ATRA treatment.

RevDate: 2021-09-21

Flores Ramos S, Brugger SD, Escapa IF, et al (2021)

Genomic Stability and Genetic Defense Systems in Dolosigranulum pigrum, a Candidate Beneficial Bacterium from the Human Microbiome.

mSystems [Epub ahead of print].

Dolosigranulum pigrum is positively associated with indicators of health in multiple epidemiological studies of human nasal microbiota. Knowledge of the basic biology of D. pigrum is a prerequisite for evaluating its potential for future therapeutic use; however, such data are very limited. To gain insight into D. pigrum's chromosomal structure, pangenome, and genomic stability, we compared the genomes of 28 D. pigrum strains that were collected across 20 years. Phylogenomic analysis showed closely related strains circulating over this period and closure of 19 genomes revealed highly conserved chromosomal synteny. Gene clusters involved in the mobilome and in defense against mobile genetic elements (MGEs) were enriched in the accessory genome versus the core genome. A systematic analysis for MGEs identified the first candidate D. pigrum prophage and insertion sequence. A systematic analysis for genetic elements that limit the spread of MGEs, including restriction modification (RM), CRISPR-Cas, and deity-named defense systems, revealed strain-level diversity in host defense systems that localized to specific genomic sites, including one RM system hot spot. Analysis of CRISPR spacers pointed to a wealth of MGEs against which D. pigrum defends itself. These results reveal a role for horizontal gene transfer and mobile genetic elements in strain diversification while highlighting that in D. pigrum this occurs within the context of a highly stable chromosomal organization protected by a variety of defense mechanisms. IMPORTANCE Dolosigranulum pigrum is a candidate beneficial bacterium with potential for future therapeutic use. This is based on its positive associations with characteristics of health in multiple studies of human nasal microbiota across the span of human life. For example, high levels of D. pigrum nasal colonization in adults predicts the absence of Staphylococcus aureus nasal colonization. Also, D. pigrum nasal colonization in young children is associated with healthy control groups in studies of middle ear infections. Our analysis of 28 genomes revealed a remarkable stability of D. pigrum strains colonizing people in the United States across a 20-year span. We subsequently identified factors that can influence this stability, including genomic stability, phage predators, the role of MGEs in strain-level variation, and defenses against MGEs. Finally, these D. pigrum strains also lacked predicted virulence factors. Overall, these findings add additional support to the potential for D. pigrum as a therapeutic bacterium.

RevDate: 2021-09-23

Bhatt NS, Meyer C, Mau LW, et al (2021)

Return to School Practices for Pediatric Hematopoietic Cell Transplant Recipients During COVID-19 Pandemic.

Transplantation and cellular therapy [Epub ahead of print].

While organizations such as Centers for Disease Control and Prevention and American Academy of Pediatrics have published guidelines favoring resumption of in-person schooling during COVID-19 pandemic, there is no specific guidance on hematopoietic cell transplant (HCT) recipients' safety of returning to school. We conducted a cross-sectional survey of pediatric HCT physician members of the Pediatric Transplantation and Cellular Therapy Consortium (PTCTC) practicing in the United States (US) to describe current return to school practices during the COVID-19 pandemic for HCT recipients. A total of 122 respondents (response rate 30.6%) from 60 transplant centers in 32 US states completed the survey. The majority of respondents (76%) recommend that HCT recipients should consider remote or hybrid school option at this time, if possible. If not possible, physicians recommended return to in-person school as long as they are at least 12 months post-transplant or off immune suppression while taking school safety measures and local COVID-19 cases into account. These results provide valuable guidance to the HCT community, patients, and caregivers, regarding important topics to consider while making return-to-school decisions.

RevDate: 2021-09-20

Yung RL, NE Davidson (2021)

Optimal adjuvant endocrine therapy for breast cancer.

The Lancet. Oncology pii:S1470-2045(21)00420-4 [Epub ahead of print].

RevDate: 2021-09-23

Pal S, Myburgh J, Bansil P, et al (2021)

Reference and point-of-care testing for G6PD deficiency: Blood disorder interference, contrived specimens, and fingerstick equivalence and precision.

PloS one, 16(9):e0257560.

Certain clinical indications and treatments such as the use of rasburicase in cancer therapy and 8-aminoquinolines for Plasmodium vivax malaria treatment would benefit from a point-of-care test for glucose-6-phosphate dehydrogenase (G6PD) deficiency. Three studies were conducted to evaluate the performance of one such test: the STANDARD™ G6PD Test (SD BIOSENSOR, South Korea). First, biological interference on the test performance was evaluated in specimens with common blood disorders, including high white blood cell (WBC) counts. Second, the test precision on fingerstick specimens was evaluated against five individuals of each, deficient, intermediate, and normal G6PD activity status. Third, clinical performance of the test was evaluated at three point-of-care settings in the United States. The test performed equivalently to the reference assay in specimens with common blood disorders. High WBC count blood samples resulted in overestimation of G6PD activity in both the reference assay and the STANDARD G6PD Test. The STANDARD G6PD Test showed good precision on multiple fingerstick specimens from the same individual. The same G6PD threshold values (U/g Hb) were applied for a semiquantitative interpretation for fingerstick- and venous-derived results. The sensitivity/specificity values (95% confidence intervals) for the test for G6PD deficiency were 100 (92.3-100.0)/97 (95.2-98.2) and 100 (95.7-100.0)/97.4 (95.7-98.5) for venous and capillary specimens, respectively. The same values for females with intermediate (> 30% to ≤ 70%) G6PD activity were 94.1 (71.3-99.9)/88.2 (83.9-91.7) and 82.4 (56.6-96.2)/87.6(83.3-91.2) for venous and capillary specimens, respectively. The STANDARD G6PD Test enables point-of-care testing for G6PD deficiency.

RevDate: 2021-09-21

Song Q, Kong X, Martin PJ, et al (2021)

Murine Models Provide New Insights Into Pathogenesis of Chronic Graft-Versus-Host Disease in Humans.

Frontiers in immunology, 12:700857.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative therapy for hematologic malignancies, but its success is complicated by graft-versus-host disease (GVHD). GVHD can be divided into acute and chronic types. Acute GVHD represents an acute alloimmune inflammatory response initiated by donor T cells that recognize recipient alloantigens. Chronic GVHD has a more complex pathophysiology involving donor-derived T cells that recognize recipient-specific antigens, donor-specific antigens, and antigens shared by the recipient and donor. Antibodies produced by donor B cells contribute to the pathogenesis of chronic GVHD but not acute GVHD. Acute GVHD can often be effectively controlled by treatment with corticosteroids or other immunosuppressant for a period of weeks, but successful control of chronic GVHD requires much longer treatment. Therefore, chronic GVHD remains the major cause of long-term morbidity and mortality after allo-HCT. Murine models of allo-HCT have made great contributions to our understanding pathogenesis of acute and chronic GVHD. In this review, we summarize new mechanistic findings from murine models of chronic GVHD, and we discuss the relevance of these insights to chronic GVHD pathogenesis in humans and their potential impact on clinical prevention and treatment.

RevDate: 2021-09-26

Smith SK, Somers TJ, Kuhn E, et al (2021)

A SMART approach to optimizing delivery of an mHealth intervention among cancer survivors with posttraumatic stress symptoms.

Contemporary clinical trials, 110:106569 pii:S1551-7144(21)00305-0 [Epub ahead of print].

BACKGROUND/AIMS: Many cancer survivors who received intensive treatment such as hematopoietic stem cell transplantation (HCT) experience posttraumatic stress disorder (PTSD) symptoms. PTSD is associated with lower quality of life and other symptoms that require clinical treatment. The iterative treatment decisions that happen in clinical practice are not adequately represented in traditional randomized controlled trials (RCT) of PTSD treatments. The proposed stepped-care SMART design allows for evaluation of initial response to the Cancer Distress Coach mobile app; adaptive stepped-care interventions; and precision treatment strategies that tailor treatment selection to patient characteristics.

METHODS/DESIGN: HCT survivors (N = 400) reporting PTSD symptoms are being recruited at two cancer centers and randomly assigned to: 1) Cancer Distress Coach app or 2) Usual Care. The app includes educational and cognitive behavioral therapy (CBT)-based activities. Four weeks post-randomization, participants re-rate their PTSD symptoms and, based on intervention response, non-responders are re-randomized to receive video-conferenced sessions with a therapist: 3) coaching sessions in using the mobile app; or 4) CBT specific to HCT survivors. Participants complete outcome measures of PTSD, depression, and anxiety after Months 1, 3, and 6. Participant characteristics moderating intervention responses will be examined.

CONCLUSIONS: This novel adaptive trial design will afford evidence that furthers knowledge about optimizing PTSD interventions for HCT survivors. To our knowledge, this study is the first SMART design evaluating PTSD symptom management in cancer survivors. If successful, it could be used to optimize treatment among a range of cancer and other trauma survivors.

RevDate: 2021-09-20

Amonoo HL, Topping CE, Clay MA, et al (2021)

Distress in a Pandemic - The Association of the Coronavirus Disease-2019 (COVID-19) Pandemic with Distress and Quality of Life in Hematopoietic Stem Cell Transplantation (HSCT).

Transplantation and cellular therapy [Epub ahead of print].

BACKGROUND: The global coronavirus disease 2019 (COVID-19) pandemic has drastically disrupted cancer care, potentially exacerbating patients' distress levels. Patients undergoing HSCT may be especially vulnerable to this pandemic stress. However, the associations of the COVID-19 pandemic with distress, fatigue, and QOL are not well understood in this population.

METHOD: In a cross-sectional analysis of data from 205 patients undergoing HSCT enrolled in a supportive care trial, we compared baseline pre-HSCT distress (depression, anxiety, and posttraumatic stress disorder [PTSD]) symptoms, fatigue, and QOL between enrollees pre- (i.e., 03/2019-01/2020) and during (i.e., 03/2020-01/2021) the COVID-19 pandemic. We used linear regression models adjusting for sociodemographics and cancer diagnosis to examine the associations between enrollment period and patient-reported outcomes. We used semi-structured qualitative interviews in 20 allogeneic HSCT recipients who were ≥3-months post-HSCT to understand the impact of the COVID-19 pandemic on their recovery post-HSCT.

RESULTS: Prior to COVID-19, 124 participants enrolled, while 81 participants enrolled during the pandemic. The cohorts had similar baseline demographics and disease risk factors. In multivariate regression models, enrollment during COVID-19 was not associated with pre-HSCT symptoms of depression, anxiety, PTSD, fatigue, or QOL impairment. COVID-19-era participants reported themes of negative (e.g., increased isolation) and positive (e.g., engagement with meaningful activities) implications of the pandemic on HSCT recovery.

CONCLUSIONS: We found no differences in pre-HSCT distress, fatigue or QOL in patients undergoing HSCT prior to or during the COVID-19 pandemic. Patients in early recovery post-HSCT, however, report both negative and positive implications of the COVID-19 pandemic on their lives.

RevDate: 2021-09-18

Kordahi MC, Stanaway IB, Avril M, et al (2021)

Genomic and functional characterization of a mucosal symbiont involved in early-stage colorectal cancer.

Cell host & microbe pii:S1931-3128(21)00389-9 [Epub ahead of print].

Colorectal cancer is a major health concern worldwide. Growing evidence for the role of the gut microbiota in the initiation of CRC has sparked interest in approaches that target these microorganisms. However, little is known about the composition and role of the microbiota associated with precancerous polyps. Here, we found distinct microbial signatures between patients with and without polyps and between polyp subtypes using sequencing and culturing techniques. We found a correlation between Bacteroides fragilis recovered and the level of inflammatory cytokines in the mucosa adjacent to the polyp. Additional analysis revealed that B. fragilis from patients with polyps are bft-negative, activate NF-κB through Toll-like receptor 4, induce a pro-inflammatory response, and are enriched in genes associated with LPS biosynthesis. This study provides fundamental insight into the microbial microenvironment of the pre-neoplastic polyp by highlighting strain-specific genomic and proteomic differences, as well as more broad compositional differences in the microbiome.

RevDate: 2021-09-20

Ahuno ST, Doebley AL, Ahearn TU, et al (2021)

Circulating tumor DNA is readily detectable among Ghanaian breast cancer patients supporting non-invasive cancer genomic studies in Africa.

NPJ precision oncology, 5(1):83.

Circulating tumor DNA (ctDNA) sequencing studies could provide novel insights into the molecular pathology of cancer in sub-Saharan Africa. In 15 patient plasma samples collected at the time of diagnosis as part of the Ghana Breast Health Study and unselected for tumor grade and subtype, ctDNA was detected in a majority of patients based on whole- genome sequencing at high (30×) and low (0.1×) depths. Breast cancer driver copy number alterations were observed in the majority of patients.

RevDate: 2021-09-25

Pidala J, Onstad L, Martin PJ, et al (2021)

Initial therapy of chronic graft vs. host disease: Analysis of practice variation and failure-free survival.

Blood advances pii:S2473-9529(21)00580-2 [Epub ahead of print].

Prior clinical trials largely considered prednisone 1mg/kg/day with or without calcineurin inhibitor as standard initial therapy for chronic graft vs. host disease (cGVHD) but uncertainty remains regarding the extent of practice variation and whether this affects subsequent outcomes. We assembled a cohort of 745 cGVHD patients treated with initial systemic immune suppressive (IS) therapy from three prior Chronic GVHD Consortium observational studies. Initial therapy was defined as first IS therapy started for cGVHD or prednisone increased to ≥ 0.4mg/kg/day from lower doses within 30 days before cGVHD diagnosis to any time afterward. Initial therapies were non-prednisone IS therapies (n=137, 18%), prednisone alone (n=411, 55%), or prednisone plus other IS therapy (n=197, 26%). In multivariate analysis, initial therapy group was not associated with FFS (failure-free survival, a composite of death, relapse, new IS therapy), overall survival (OS) or non-relapse mortality (NRM). Among the prednisone-based approaches, steroid dose (mg/kg/day) was <0.25 (9%), 0.25-0.74 (36%), 0.75-1.25 (42%), or >1.25 (13%). Prednisone dose within the steroid-treated patients was not significantly associated with FFS, OS, or NRM. No significant interactions were detected between overall cGVHD severity and either initial therapy group or prednisone dose for the outcomes of FFS, OS, or NRM. These observational data document heterogeneity in more contemporary cGVHD initial treatment practices, including prednisone dose and use of non-steroid approaches. This variation was not associated with FFS, OS, or NRM. Prospective trials are needed to verify efficacy of reduced-dose prednisone or prednisone-free initial therapy approaches.

RevDate: 2021-09-25

Martin PJ, Storer BE, Levine DM, et al (2021)

Genetic Variants Associated with Inflammatory Bowel Disease and Gut Graft-versus-host Disease.

Blood advances pii:S2473-9529(21)00584-X [Epub ahead of print].

Previous studies have identified genetic variants associated with inflammatory bowel disease (IBD). We tested the hypothesis that some of these variants are also associated with the risk of moderate to severe gut graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). Associations were evaluated initially in a discovery cohort of 1980 HCT recipients of European ancestry with HLA-matched related or unrelated donors. Associations discovered in this cohort were tested for replication in a separate cohort of 1294 HCT recipients. Among the 296 single nucleotide polymorphisms SNPs and 26 HLA alleles tested, we found that the recipient rs1260326 homozygous T allele in GCKR was associated with a higher risk of stage 2-4 gut GVHD. No other candidate variants were associated with stage 2-4 gut GVHD. The rs1260326 variant resides in an IBD-associated locus containing FNDC4, a gene that encodes a secreted anti-inflammatory factor that dampens macrophage activity and improves colitis in mice. Our results suggest that targeting inflammatory macrophages with recombinant FNDC4 offers an attractive avenue of clinical investigation for management of IBD and gut GVHD.

RevDate: 2021-09-17

Keyes-Elstein L, Pinckney A, Goldmuntz E, et al (2021)

Clinical and Molecular Findings after Autologous Stem Cell Transplantation or Cyclophosphamide for Scleroderma: Handling Missing Longitudinal Data.

Arthritis care & research [Epub ahead of print].

OBJECTIVE: Among individuals with systemic sclerosis (SSc) randomized to cyclophosphamide (CYC, n=34) or hematopoietic stem cell transplantation (HSCT, n=33), we examined longitudinal trends of clinical, pulmonary function and quality of life measures while accounting for the influence of early failures on treatment comparisons.

METHODS: Assuming data were missing at random, mixed effects regression models were used to estimate longitudinal trends for clinical measures when comparing treatment groups. Results were compared to observed means and to longitudinal trends estimated from shared parameter models, assuming data were missing not at random. Longitudinal trends for SSc intrinsic molecular subsets defined by baseline gene expression signatures (normal-like, inflammatory and fibroproliferative signatures) were also studied.

RESULTS: Available observed means for pulmonary function tests appeared to improve over time in both arms. However, after accounting for participant loss, forced vital capacity in HSCT recipients increased by 0.77 percentage points/year but worsened by -3.70/yr for CYC (P=0.004). Similar results were found for DLCO and quality of life indicators. Results for both analytic models were consistent. HSCT recipients in the inflammatory (n=20) and fibroproliferative (n=20) subsets had superior long-term trends compared to CYC for pulmonary and quality of life measures. HSCT was also superior for Rodnan skin scores in the fibroproliferative subset. For the normal-like subset (n=22), superiority of HSCT was less apparent.

CONCLUSIONS: Longitudinal trends estimated from two statistical models affirm the efficacy of HSCT over CYC in severe SSc. Failure to account for early loss of participants may distort estimated clinical trends over the long-term.

RevDate: 2021-09-17

Shangguan S, Ehrenberg PK, Geretz A, et al (2021)

Monocyte-derived transcriptome signature indicates antibody-dependent cellular phagocytosis as a potential mechanism of vaccine-induced protection against HIV-1.

eLife, 10: pii:69577 [Epub ahead of print].

A gene signature previously correlated with mosaic adenovirus 26 vaccine protection in simian immunodeficiency virus (SIV) and SHIV challenge models in non-human primates (NHP). In this report we investigated presence of this signature as a correlate of reduced risk in human clinical trials and potential mechanisms of protection. The absence of this gene signature in the DNA/rAd5 human vaccine trial, which did not show efficacy, strengthens our hypothesis that this signature is only enriched in studies that demonstrated protection. This gene signature was enriched in the partially effective RV144 human trial that administered the ALVAC/protein vaccine, and we find that the signature associates with both decreased risk of HIV-1 acquisition and increased vaccine efficacy. Total RNA-seq in a clinical trial that used the same vaccine regimen as the RV144 HIV vaccine implicated antibody-dependent cellular phagocytosis (ADCP) as a potential mechanism of vaccine protection. CITE-seq profiling of 53 surface markers and transcriptomes of 53,777 single cells from the same trial showed that genes in this signature were primarily expressed in cells belonging to the myeloid lineage, including monocytes, which are major effector cells for ADCP. The consistent association of this transcriptome signature with vaccine efficacy represents a tool both to identify potential mechanisms, as with ADCP here, and to screen novel approaches to accelerate development of new vaccine candidates.

RevDate: 2021-09-19

Hannan M, Ricardo AC, Cai J, et al (2021)

Sedentary Behavior and Change in Kidney Function: The Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

Kidney360, 2(2):245-253.

Background: There is accumulating evidence linking prolonged sedentary time to adverse health outcomes. The effect of sedentary behavior on kidney function has not been evaluated in US Hispanics/Latinos, a population disproportionately affected by CKD.

Methods: We evaluated the association between accelerometer-measured (1 week) sedentary time at baseline and kidney function among 7134 adults without CKD at entry in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), who completed a baseline visit with accelerometry (2008-2011) and a follow-up visit (2014-2017). Outcomes included: (1) change in kidney function (eGFR and urine albumin-to-creatinine ratio, ACR), (2) incident low eGFR (eGFR <60 ml/min per 1.73 m2 and eGFR decline ≥1 ml/min per year), and (3) incident albuminuria (ACR ≥17 mg/g in men or ≥25 mg/g in women). Linear regression using survey procedures was used to evaluate change in kidney function (eGFR and ACR), and Poisson regression with robust variance was used to evaluate incident low eGFR and albuminuria.

Results: The median sedentary time was 12 hours/d. Over a median follow-up of 6.1 years, the mean relative change in eGFR was -0.50% per year, and there were 167 incident low eGFR events. On multivariable analysis, each 1 hour increase in sedentary time was associated with a longitudinal decline in eGFR (-0.06% per year, 95% CI, -0.10 to -0.02). There was a significant interaction with sex, and on stratified analyses, higher sedentary time was associated with eGFR decline in women but not men. There was no association between sedentary time and the other outcomes.

Conclusions: Sedentary time was associated with a small longitudinal decline in eGFR, which could have important implications in a population that experiences a disproportionate burden of CKD but further investigation is needed.

RevDate: 2021-09-18

Lewitus E, Sanders-Buell E, Bose M, et al (2021)

RV144 vaccine imprinting constrained HIV-1 evolution following breakthrough infection.

Virus evolution, 7(2):veab057.

The scale of the HIV-1 epidemic underscores the need for a vaccine. The multitude of circulating HIV-1 strains together with HIV-1's high evolvability hints that HIV-1 could adapt to a future vaccine. Here, we wanted to investigate the effect of vaccination on the evolution of the virus post-breakthrough infection. We analyzed 2,635 HIV-1 env sequences sampled up to a year post-diagnosis from 110 vaccine and placebo participants who became infected in the RV144 vaccine efficacy trial. We showed that the Env signature sites that were previously identified to distinguish vaccine and placebo participants were maintained over time. In addition, fewer sites were under diversifying selection in the vaccine group than in the placebo group. These results indicate that HIV-1 would possibly adapt to a vaccine upon its roll-out.

RevDate: 2021-09-21

Cardozo-Ojeda EF, AS Perelson (2021)

Modeling HIV-1 Within-Host Dynamics After Passive Infusion of the Broadly Neutralizing Antibody VRC01.

Frontiers in immunology, 12:710012.

VRC01 is a broadly neutralizing antibody that targets the CD4 binding site of HIV-1 gp120. Passive administration of VRC01 in humans has assessed the safety and the effect on plasma viremia of this monoclonal antibody (mAb) in a phase 1 clinical trial. After VRC01 infusion, the plasma viral load in most of the participants was reduced but had particular dynamics not observed during antiretroviral therapy. In this paper, we introduce different mathematical models to explain the observed dynamics and fit them to the plasma viral load data. Based on the fitting results we argue that a model containing reversible Ab binding to virions and clearance of virus-VRC01 complexes by a two-step process that includes (1) saturable capture followed by (2) internalization/degradation by phagocytes, best explains the data. This model predicts that VRC01 may enhance the clearance of Ab-virus complexes, explaining the initial viral decay observed immediately after antibody infusion in some participants. Because Ab-virus complexes are assumed to be unable to infect cells, i.e., contain neutralized virus, the model predicts a longer-term viral decay consistent with that observed in the VRC01 treated participants. By assuming a homogeneous viral population sensitive to VRC01, the model provides good fits to all of the participant data. However, the fits are improved by assuming that there were two populations of virus, one more susceptible to antibody-mediated neutralization than the other.

RevDate: 2021-09-17

Liao JB, Gwin WR, Urban RR, et al (2021)

Pembrolizumab with low-dose carboplatin for recurrent platinum-resistant ovarian, fallopian tube, and primary peritoneal cancer: survival and immune correlates.

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

BACKGROUND: Anti-programmed death 1 (PD1)/programmed cell death ligand 1 (PD-L1) therapies have shown modest activity as monotherapy in recurrent ovarian cancer. Platinum chemotherapies induce T-cell proliferation and enhance tumor recognition. We assessed activity and safety of pembrolizumab with carboplatin in recurrent platinum-resistant ovarian cancer.

PATIENTS AND METHODS: This phase I/II, single-arm clinical trial studied concurrent carboplatin and pembrolizumab in recurrent platinum-resistant ovarian, fallopian tube, and primary peritoneal cancer. Primary platinum refractory patients were excluded. Patients were treated after progression on subsequent non-platinum systemic therapy after becoming platinum resistant or refractory. Pembrolizumab 200 mg was given on day 1 and carboplatin area under the curve 2 on days 8 and 15 of a 3-week cycle until progression. Imaging was assessed by blinded independent review. PD-L1 expression was assessed by immunohistochemistry. Flow cytometry on peripheral blood mononuclear cells was performed for CD3, CD4, CD8, PD1, CTLA4 and Ki67.

RESULTS: The most common treatment-related adverse events were lymphopenia (18%) and anemia (9%) with most being grade 1 or 2 (93%). Of 29 patients treated, 23 patients were evaluable for best objective response: 10.3% (95% CI 2.2 to 27.4) had partial response (PR), 51.7% (95% CI 32.5 to 70.6) had stable disease (SD). 56.5% of patients had decreases in target lesions from baseline. All PD-L1-positive patients achieved PR (3/7, 42.8%) or SD (4/7, 57.2%). Median progression-free survival was 4.63 months (95% CI 4.3 to 4.96). Median OS was 11.3 months (95% CI 6.094 to 16.506). Peripheral CD8+PD1+Ki67+ T cells expanded after 3 (p=0.0015) and 5 (p=0.0023) cycles. CTLA4+PD1+CD8+ T cells decreased through the course of treatment up to the 12th cycle (p=0.004). When stratified by ratio of peripheral CD8+PD1+Ki67+ T cells to tumor burden at baseline, patients with a ratio ≥0.0375 who had a significantly longer median OS of 18.37 months compared with those with a ratio <0.0375 who had a median OS of 8.72 months (p=0.0099). No survival advantage was seen with stratification by tumor burden alone (p=0.24) or by CD8+PD1+Ki67+ T cells alone (p=0.53).

CONCLUSIONS: Pembrolizumab with carboplatin was well-tolerated and active in recurrent platinum-resistant ovarian cancer. A ratio of peripheral T-cell exhaustion to radiographic tumor burden may identify patients more likely to benefit from this chemoimmunotherapy.

TRIAL REGISTRATION NUMBER: NCT03029598.

RevDate: 2021-09-17

Douglas J, Mendes FK, Bouckaert R, et al (2021)

Phylodynamics reveals the role of human travel and contact tracing in controlling the first wave of COVID-19 in four island nations.

Virus evolution, 7(2):veab052.

New Zealand, Australia, Iceland, and Taiwan all saw success in controlling their first waves of Coronavirus Disease 2019 (COVID-19). As islands, they make excellent case studies for exploring the effects of international travel and human movement on the spread of COVID-19. We employed a range of robust phylodynamic methods and genome subsampling strategies to infer the epidemiological history of Severe acute respiratory syndrome coronavirus 2 in these four countries. We compared these results to transmission clusters identified by the New Zealand Ministry of Health by contact tracing strategies. We estimated the effective reproduction number of COVID-19 as 1-1.4 during early stages of the pandemic and show that it declined below 1 as human movement was restricted. We also showed that this disease was introduced many times into each country and that introductions slowed down markedly following the reduction of international travel in mid-March 2020. Finally, we confirmed that New Zealand transmission clusters identified via standard health surveillance strategies largely agree with those defined by genomic data. We have demonstrated how the use of genomic data and computational biology methods can assist health officials in characterising the epidemiology of viral epidemics and for contact tracing.

RevDate: 2021-09-16

Yu C, Jordahl KM, Bassett JK, et al (2021)

Smoking methylation marks for prediction of urothelial cancer risk.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:1055-9965.EPI-21-0313 [Epub ahead of print].

BACKGROUND: Self-reported information may not accurately capture smoking exposure. We aimed to evaluate whether smoking-associated DNA methylation markers improve urothelial cell carcinoma (UCC) risk prediction.

METHODS: Conditional logistic regression was used to assess associations between blood-based methylation and UCC risk using two matched case-control samples, N=404 pairs from the Melbourne Collaborative Cohort Study (MCCS) and N=440 pairs from the Women's Health Initiative (WHI) cohort, respectively. Results were pooled using fixed-effects meta-analysis. We developed methylation-based predictors of UCC and evaluated their prediction accuracy on two replication datasets using the area under the curve (AUC).

RESULTS: The meta-analysis identified associations (P<4.7×10-5) for 29 of 1,061 smoking-associated methylation sites, but these were substantially attenuated after adjustment for self-reported smoking. Nominally significant associations (P<0.05) were found for 387 (36%) and 86 (8%) of smoking-associated markers without/with adjustment for self-reported smoking, respectively, with same direction of association as with smoking for 387 (100%) and 79 (92%) markers. A Lasso-based predictor was associated with UCC risk in one replication dataset in MCCS (N=134, odds ratio per SD [OR]=1.37, 95%CI=1.00-1.90) after confounder adjustment; AUC=0.66, compared with AUC=0.64 without methylation information. Limited evidence of replication was found in the second testing dataset in WHI (N=440, OR=1.09, 95%CI=0.91-1.30).

CONCLUSIONS: Combination of smoking-associated methylation marks may provide some improvement to UCC risk prediction. Our findings need further evaluation using larger datasets.

IMPACT: DNA methylation may be associated with UCC risk beyond traditional smoking assessment and could contribute to some improvements in stratification of UCC risk in the general population.

RevDate: 2021-09-22

Dignum T, Varnum-Finney B, Srivatsan SR, et al (2021)

Multipotent progenitors and hematopoietic stem cells arise independently from hemogenic endothelium in the mouse embryo.

Cell reports, 36(11):109675.

During embryogenesis, waves of hematopoietic progenitors develop from hemogenic endothelium (HE) prior to the emergence of self-renewing hematopoietic stem cells (HSCs). Although previous studies have shown that yolk-sac-derived erythromyeloid progenitors and HSCs emerge from distinct populations of HE, it remains unknown whether the earliest lymphoid-competent progenitors, multipotent progenitors, and HSCs originate from common HE. In this study, we demonstrate by clonal assays and single-cell transcriptomics that rare HE with functional HSC potential in the early murine embryo are distinct from more abundant HE with multilineage hematopoietic potential that fail to generate HSCs. Specifically, HSC-competent HE are characterized by expression of CXCR4 surface marker and by higher expression of genes tied to arterial programs regulating HSC dormancy and self-renewal. Taken together, these findings suggest a revised model of developmental hematopoiesis in which the initial populations of multipotent progenitors and HSCs arise independently from HE with distinct phenotypic and transcriptional properties.

RevDate: 2021-09-16

Generalova O, Roy M, Hall E, et al (2021)

Implementation of a cloud-based electronic patient-reported outcome (ePRO) platform in patients with advanced cancer.

Journal of patient-reported outcomes, 5(1):91.

BACKGROUND: Patient reported outcomes (PROs) have been associated with improved symptom management and quality of life in patients with cancer. However, the implementation of PROs in an academic clinical practice has not been thoroughly described. Here we report on the execution, feasibility and healthcare utilization outcomes of an electronic PRO (ePRO) application for cancer patients at an academic medical center.

METHODS: We conducted a randomized trial comparing an experimental ePRO arm to standard of care in patients with advanced cancer in the thoracic, gastrointestinal, and genitourinary oncology groups at Stanford Cancer Center from March 2018 to November 2019. We describe the pre-implementation, implementation, and post-implementation phases of the ePRO arm, technological barriers, electronic health record (EHR) integration, clinician burden, and patient data privacy and security. Feasibility was pre-specified to be at least 70% completion of all questionnaires. Acceptability was based on patient and clinician feedback. Ambulatory healthcare utilization was assessed by reviewing numbers of phone messages, electronic portal messages, and referrals for supportive care.

RESULTS: Of 617 ePRO questionnaires sent to 72 patients, 445 (72%) were completed. Most clinicians (87.5%) and patients (93%) felt neutral or positive about the ePRO tool's ease of use. Exposure to ePRO did not cause a measurable change in ambulatory healthcare utilization, with a median of less than two phone messages and supportive care referrals, and 5-6 portal messages.

CONCLUSIONS: Web-based ePRO tools for patients with advanced cancer are feasible and acceptable without increasing clinical burden. Key lessons include the importance of pilot testing, engagement of stakeholders at all levels, and the need for customization by disease group. Future directions for this work include completion of EHR integration, expansion to other centers, and development of integrated workflows for routine clinical practice.

RevDate: 2021-09-18

Hart JE, Hohensee C, Laden F, et al (2021)

Long-Term Exposures to Air Pollution and the Risk of Atrial Fibrillation in the Women's Health Initiative Cohort.

Environmental health perspectives, 129(9):97007.

BACKGROUND: Atrial fibrillation (AF) is associated with substantial morbidity and mortality. Short-term exposures to air pollution have been associated with AF triggering; less is known regarding associations between long-term air pollution exposures and AF incidence.

OBJECTIVES: Our objective was to assess the association between long-term exposures to air pollution and distance to road on incidence of AF in a cohort of U.S. women.

METHODS: We assessed the association of high resolution spatiotemporal model predictions of long-term exposures to particulate matter (PM10 and PM2.5), sulfur dioxide (SO2), nitrogen dioxide (NO2), and distance to major roads with incidence of AF diagnosis, identified through Medicare linkage, among 83,117 women in the prospective Women's Health Initiative cohort, followed from enrollment in Medicare through December 2012, incidence of AF, or death. Using time-varying Cox proportional hazards models adjusted for age, race/ethnicity, study component, body mass index, physical activity, menopausal hormone therapy, smoking, diet quality, alcohol consumption, educational attainment, and neighborhood socioeconomic status, we estimated the relative risk of incident AF in association with each pollutant.

RESULTS: A total of 16,348 incident AF cases were observed over 660,236 person-years of follow-up. Most exposure-response associations were nonlinear. NO2 was associated with risk of AF in multivariable adjusted models [Hazard Ratio (HR)=1.18; 95% confidence interval (CI): 1.13, 1.24, comparing the top to bottom quartile, p-for-trend=<0.0001]. Women living closer to roadways were at higher risk of AF (e.g., HR=1.07; 95% CI: 1.01, 1.13 for living within 50m of A3 roads, compared with ≥1,000 m, p-for-trend=0.02), but we did not observe adverse associations with exposures to PM10, PM2.5, or SO2. There were adverse associations with PM10 (top quartile HR=1.10; 95% CI: 1.05, 1.16, p-for-trend=<0.0001) and PM2.5 (top quartile HR=1.09; 95% CI: 1.03, 1.14, p-for-trend=0.002) in sensitivity models adjusting for census region.

DISCUSSION: In this study of postmenopausal women, NO2 and distance to road were consistently associated with higher risk of AF. https://doi.org/10.1289/EHP7683.

RevDate: 2021-09-25

DeFilipp Z, Alousi A, Pidala J, et al (2021)

Non-relapse mortality among patients diagnosed with chronic GVHD: An updated analysis from The Chronic GVHD Consortium.

Blood advances pii:S2473-9529(21)00552-8 [Epub ahead of print].

Chronic graft-versus-host disease (GVHD) is the leading cause of late morbidity and mortality after allogeneic hematopoietic cell transplantation. To better understand patients at highest risk for non-relapse mortality (NRM), we analyzed patient, transplant, and chronic GVHD-related variables, risk factors, and causes of non-relapse deaths in an updated cohort of 937 subjects enrolled on two prospective, longitudinal observational studies through the Chronic GVHD Consortium. The median follow-up of survivors was 4 years (0.1 months - 12.5 years). Relapse accounted for 25% of the 333 deaths. The cumulative incidence of NRM was 22% at 5 years and increased over time with a projected 40% (95%CI, 30-50) at 12 years. Centers reported that chronic GVHD (37.8%) was the commonest cause of NRM and was associated with organ failure, infection, or additional cause not otherwise specified. The next most frequent causes without mention of chronic GVHD were infection (17%) and respiratory failure (10%). In multivariate analysis, an increased risk for NRM was significantly associated with the use of reduced intensity conditioning, higher total bilirubin, NIH skin score 2-3, NIH lung score 1-3, worse modified HAP adjusted activity score, and decreased distance on walk test. In conclusion, chronic GVHD NRM does not plateau but increases over time and is most commonly attributed to GVHD or infection, presumably associated with immunocompromised status. Severe skin and lung chronic GVHD remain challenging manifestations associated with increased NRM, for which novel therapeutic options are needed that do not predispose patients to infections.

RevDate: 2021-09-25

Nieuwlaat R, Wiercioch W, Brożek JL, et al (2021)

How to write a guideline: a proposal for a manuscript template that supports the creation of trustworthy guidelines.

Blood advances pii:S2473-9529(21)00555-3 [Epub ahead of print].

Trustworthy health guidelines should provide recommendations, document the development process, and highlight implementation information. Our objective was to develop a guideline manuscript template to help authors write a complete and useful report. The McMaster Grading of Recommendations Assessment, Development and Evaluation (GRADE) centre collaborated with the American Society of Hematology (ASH) to develop guidelines for the management of venous thromboembolism. A template for reporting the guidelines was developed based on prior approaches and refined using input from other key stakeholders. The proposed guideline manuscript template includes: 1) title for guideline identification; 2) abstract, including a summary of key recommendations; 3) overview of all recommendations [executive summary]; 4) the main text, providing sufficient detail on the entire process including objectives, background, and methodological decisions from panel selection and conflict of interest management to criteria for updating, as well as supporting information such as links to online (interactive) tables. The template further allows for tailoring to the specific topic, using examples. Initial experience with the ASH guideline manuscript template was positive, and challenges included drafting descriptions of recommendations involving multiple management pathways, tailoring the template for a specific guideline, and choosing key recommendations to highlight. Feedback from a larger group of guideline authors and users will be needed to evaluate its usefulness and refine. The proposed guideline manuscript template is the first detailed template for transparent and complete reporting of guidelines. Consistent application of the template may simplify preparing an evidence-based guideline manuscript and facilitate its use.

RevDate: 2021-09-16

Mulenga H, Musvosvi M, Mendelsohn SC, et al (2021)

Longitudinal Dynamics of a Blood Transcriptomic Signature of Tuberculosis.

American journal of respiratory and critical care medicine [Epub ahead of print].

Objectives We evaluated longitudinal kinetics of an 11-gene blood transcriptomic tuberculosis (TB) signature, RISK11, and effects of TB preventative therapy (TPT) and respiratory organisms on RISK11 signature score, in HIV-uninfected and HIV-infected individuals. Methods RISK11 was measured in a longitudinal study of RISK11-guided TPT in HIV-uninfected adults, a cross-sectional respiratory organisms cohort or a longitudinal study in people living with HIV (PLHIV). HIV-uninfected RISK11+ participants were randomised to TPT or no TPT; RISK11- participants received no TPT. PLHIV received standard-of-care ART and TPT. In the cross-sectional respiratory organisms cohort, viruses and bacteria in nasopharyngeal and oropharyngeal swabs were quantified by RT-qPCR. Measurements and Main Results RISK11+ status was transient in most of the 128 HIV-negative participants with longitudinal samples; >70% of RISK11+ participants reverted to RISK11- by 3 months, irrespective of TPT. By comparison, reversion from a RISK11-positive state was less common in 645 PLHIV (42.1%). Non-HIV viral and non-tuberculous bacterial organisms were detected in 7.2% and 38.9% of the 1,000 respiratory organisms cohort participants, respectively, and among those investigated for TB, 3.8% had prevalent disease. Median RISK11 scores (%) were higher in participants with viral organisms alone (46.7%), viral and bacterial organisms (42.8%), or prevalent TB (85.7%), than those with bacterial organisms other than TB (13.4%), or no organisms (14.2%). RISK11 could not discriminate between prevalent TB and viral organisms. Conclusions Positive RISK11 signature status is often transient, possibly due to intercurrent viral infection, highlighting potentially important challenges for implementation of these biomarkers as new tools for TB control. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

RevDate: 2021-09-17
CmpDate: 2021-09-17

Hill JA (2021)

Humoral Immunity After mRNA SARS-CoV-2 Vaccination in Allogeneic HCT Recipients-Room for Improvement and Much to Learn.

JAMA network open, 4(9):e2127454 pii:2784062.

RevDate: 2021-09-15

Boe LA, Tinker LF, PA Shaw (2021)

An approximate quasi-likelihood approach for error-prone failure time outcomes and exposures.

Statistics in medicine, 40(23):5006-5024.

Measurement error arises commonly in clinical research settings that rely on data from electronic health records or large observational cohorts. In particular, self-reported outcomes are typical in cohort studies for chronic diseases such as diabetes in order to avoid the burden of expensive diagnostic tests. Dietary intake, which is also commonly collected by self-report and subject to measurement error, is a major factor linked to diabetes and other chronic diseases. These errors can bias exposure-disease associations that ultimately can mislead clinical decision-making. We have extended an existing semiparametric likelihood-based method for handling error-prone, discrete failure time outcomes to also address covariate error. We conduct an extensive numerical study to compare the proposed method to the naive approach that ignores measurement error in terms of bias and efficiency in the estimation of the regression parameter of interest. In all settings considered, the proposed method showed minimal bias and maintained coverage probability, thus outperforming the naive analysis which showed extreme bias and low coverage. This method is applied to data from the Women's Health Initiative to assess the association between energy and protein intake and the risk of incident diabetes mellitus. Our results show that correcting for errors in both the self-reported outcome and dietary exposures leads to considerably different hazard ratio estimates than those from analyses that ignore measurement error, which demonstrates the importance of correcting for both outcome and covariate error.

RevDate: 2021-09-23

Koup RA, Donis RO, Gilbert PB, et al (2021)

A government-led effort to identify correlates of protection for COVID-19 vaccines.

Nature medicine, 27(9):1493-1494.

RevDate: 2021-09-17

Buas MF, Drescher CW, Urban N, et al (2021)

Quantitative global lipidomics analysis of patients with ovarian cancer versus benign adnexal mass.

Scientific reports, 11(1):18156.

Altered lipid metabolism has emerged as an important feature of ovarian cancer (OC), yet the translational potential of lipid metabolites to aid in diagnosis and triage remains unproven. We conducted a multi-level interrogation of lipid metabolic phenotypes in patients with adnexal masses, integrating quantitative lipidomics profiling of plasma and ascites with publicly-available tumor transcriptome data. Using Sciex Lipidyzer, we assessed concentrations of > 500 plasma lipids in two patient cohorts-(i) a pilot set of 100 women with OC (50) or benign tumor (50), and (ii) an independent set of 118 women with malignant (60) or benign (58) adnexal mass. 249 lipid species and several lipid classes were significantly reduced in cases versus controls in both cohorts (FDR < 0.05). 23 metabolites-triacylglycerols, phosphatidylcholines, cholesterol esters-were validated at Bonferroni significance (P < 9.16 × 10-5). Certain lipids exhibited greater alterations in early- (diacylglycerols) or late-stage (lysophospholipids) cases, and multiple lipids in plasma and ascites were positively correlated. Lipoprotein receptor gene expression differed markedly in OC versus benign tumors. Importantly, several plasma lipid species, such as DAG(16:1/18:1), improved the accuracy of CA125 in differentiating early-stage OC cases from benign controls, and conferred a 15-20% increase in specificity at 90% sensitivity in multivariate models adjusted for age and BMI. This study provides novel insight into systemic and local lipid metabolic differences between OC and benign disease, further implicating altered lipid uptake in OC biology, and advancing plasma lipid metabolites as a complementary class of circulating biomarkers for OC diagnosis and triage.

RevDate: 2021-09-14

Bickett TE, Knitz M, Darragh LB, et al (2021)

FLT3L release by NK cells enhances response to radioimmunotherapy in preclinical models of HNSCC.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-21-0971 [Epub ahead of print].

PURPOSE: Natural Killer (NK) cells are type 1 innate lymphoid cells that are known to secrete cytokines and for their role in killing virally infected cells or cancer cells through cytotoxicity. In addition to direct tumor cell killing, NK cells are known to play fundamental roles in the tumor microenvironment through secretion of key cytokines such as FMS-like tyrosine kinase 3 ligand (FLT3L). Although radiation therapy (RT) is the mainstay treatment most cancers, the role of radiation therapy on NK cells is not well characterized.

EXPERIMENTAL DESIGN: This study combines radiation, immunotherapies, genetic mouse models, and antibody depletion experiments to identify the role of NK cells in overcoming resistance to RT in orthotopic models of head and neck squamous cell carcinoma.

RESULTS: We have found that NK cells are a crucial component in the development of an anti-tumor response, as depleting them removes efficacy of the previously successful combination treatment of RT, anti-CD25 and anti-CD137. However, in the absence of NK cells, the effect can be rescued through treatment with FLT3L. But neither RT with FLT3L therapy alone nor RT with anti-NKG2A yields any meaningful tumor growth delay. We also identify a role for IL-2 in activating NK cells to secrete FLT3L. This activity is mediated through CD122, the intermediate affinity IL-2 receptor and can be targeted with anti-CD25.

CONCLUSIONS: These findings highlight the complexity of using radio-immunotherapies to activate NK cells within the tumor microenvironment, and the importance of NK cells in activating dendritic cells for increased tumor surveillance.

RevDate: 2021-09-17

Hu Y, Bien SA, Nishimura KK, et al (2021)

Correction to: Multi-ethnic genome-wide association analyses of white blood cell and platelet traits in the Population Architecture using Genomics and Epidemiology (PAGE) Study.

BMC genomics, 22(1):656.

RevDate: 2021-09-14

Su W, Sia SF, Schmitz AJ, et al (2021)

Neutralizing Monoclonal Antibodies That Target the Spike Receptor Binding Domain Confer Fc Receptor-Independent Protection against SARS-CoV-2 Infection in Syrian Hamsters.

mBio [Epub ahead of print].

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein is the main target for neutralizing antibodies. These antibodies can be elicited through immunization or passively transferred as therapeutics in the form of convalescent-phase sera or monoclonal antibodies (MAbs). Potently neutralizing antibodies are expected to confer protection; however, it is unclear whether weakly neutralizing antibodies contribute to protection. Also, their mechanism of action in vivo is incompletely understood. Here, we demonstrate that 2B04, an antibody with an ultrapotent neutralizing activity (50% inhibitory concentration [IC50] of 0.04 μg/ml), protects hamsters against SARS-CoV-2 in a prophylactic and therapeutic infection model. Protection is associated with reduced weight loss and viral loads in nasal turbinates and lungs after challenge. MAb 2B04 also blocked aerosol transmission of the virus to naive contacts. We next examined three additional MAbs (2C02, 2C03, and 2E06), recognizing distinct epitopes within the receptor binding domain of spike protein that possess either minimal (2C02 and 2E06, IC50 > 20 μg/ml) or weak (2C03, IC50 of 5 μg/ml) virus neutralization capacity in vitro. Only 2C03 protected Syrian hamsters from weight loss and reduced lung viral load after SARS-CoV-2 infection. Finally, we demonstrated that Fc-Fc receptor interactions were not required for protection when 2B04 and 2C03 were administered prophylactically. These findings inform the mechanism of protection and support the rational development of antibody-mediated protection against SARS-CoV-2 infections. IMPORTANCE The ongoing coronavirus disease 2019 (COVID-19) pandemic, caused by SARS-CoV-2, has resulted in the loss of millions of lives. Safe and effective vaccines are considered the ultimate remedy for the global social and economic disruption caused by the pandemic. However, a thorough understanding of the immune correlates of protection against this virus is lacking. Here, we characterized four different monoclonal antibodies and evaluated their ability to prevent or treat SARS-CoV-2 infection in Syrian hamsters. These antibodies varied in their ability to neutralize the virus in vitro. Prophylactic administration of potent and weakly neutralizing antibodies protected against SARS-CoV-2 infection, and this effect was Fc receptor independent. The potent neutralizing antibody also had therapeutic efficacy and eliminated onward aerosol transmission. In contrast, minimally neutralizing antibodies provided no protection against infection with SARS-CoV-2 in Syrian hamsters. Combined, these studies highlight the significance of weakly neutralizing antibodies in the protection against SARS-CoV-2 infection and associated disease.

RevDate: 2021-09-15

Sokolova AO, Marshall CH, Lozano R, et al (2021)

Efficacy of systemic therapies in men with metastatic castration resistant prostate cancer harboring germline ATM versus BRCA2 mutations.

The Prostate [Epub ahead of print].

BACKGROUND: Among men with metastatic prostate cancer, about 10% have germline alterations in DNA damage response genes. Most studies have examined BRCA2 alone or an aggregate of BRCA1/2 and ATM. Emerging data suggest that ATM mutations may have distinct biology and warrant individual evaluation. The objective of this study is to determine whether response to prostate cancer systemic therapies differs between men with germline mutations in ATM (gATM) and BRCA2 (gBRCA2).

METHODS: This is an international multicenter retrospective matched cohort study of men with prostate cancer harboring gATM or gBRCA2. PSA50 response (≥50% decline in prostate-specific antigen) was compared using Fisher's exact test.

RESULTS AND LIMITATIONS: The study included 45 gATM and 45 gBRCA2 patients, matched on stage and year of germline testing. Patients with gATM and gBRCA2 had similar age, Gleason grade, and PSA at diagnosis. We did not observe differences in PSA50 responses to abiraterone, enzalutamide, or docetaxel in metastatic castration resistant prostate cancer between the two groups; however, 0/7 with gATM and 12/14 with gBRCA2 achieved PSA50 response to PARPi (p < .001). Median (95% confidence interval) overall survival from diagnosis to death was 10.9 years (9.5-not reached) versus 9.9 years (7.1-not reached, p = .07) for the gATM and gBRCA2 cohorts, respectively. Limitations include the retrospective design and lack of mutation zygosity data.

CONCLUSIONS: Conventional therapies can be effective in gATM carriers and should be considered before PARPi, which shows limited efficacy in this group. Men with gATM mutations warrant prioritization for novel treatment strategies.

RevDate: 2021-09-13

Kirk PS, Zhu K, Zheng Y, et al (2021)

Treatment in the absence of disease reclassification among men on active surveillance for prostate cancer.

Cancer [Epub ahead of print].

BACKGROUND: Maintaining men on active surveillance for prostate cancer can be challenging. Although most men who eventually undergo treatment have experienced clinical progression, a smaller subset elects treatment in the absence of disease reclassification. This study sought to understand factors associated with treatment in a large, contemporary, prospective cohort.

METHODS: This study identified 1789 men in the Canary Prostate Cancer Active Surveillance Study cohort enrolled as of 2020 with a median follow-up of 5.6 years. Clinical and demographic data as well as information on patient-reported quality of life and urinary symptoms were used in multivariable Cox proportional hazards regression models to identify factors associated with the time to treatment RESULTS: Within 4 years of their diagnosis, 33% of men (95% confidence interval [CI], 30%-35%) underwent treatment, and 10% (95% CI, 9%-12%) were treated in the absence of reclassification. The most significant factor associated with any treatment was an increasing Gleason grade group (adjusted hazard ratio [aHR], 14.5; 95% CI, 11.7-17.9). Urinary quality-of-life scores were associated with treatment without reclassification (aHR comparing "mostly dissatisfied/terrible" with "pleased/mixed," 2.65; 95% CI, 1.54-4.59). In a subset analysis (n = 692), married men, compared with single men, were more likely to undergo treatment in the absence of reclassification (aHR, 2.63; 95% CI, 1.04-6.66).

CONCLUSIONS: A substantial number of men with prostate cancer undergo treatment in the absence of clinical changes in their cancers, and quality-of-life changes and marital status may be important factors in these decisions.

LAY SUMMARY: This analysis of men on active surveillance for prostate cancer shows that approximately 1 in 10 men will decide to be treated within 4 years of their diagnosis even if their cancer is stable. These choices may be related in part to quality-or-life or spousal concerns.

RevDate: 2021-09-13

Belitškin D, Pant SM, Munne P, et al (2021)

Hepsin regulates TGFβ signaling via fibronectin proteolysis.

EMBO reports [Epub ahead of print].

Transforming growth factor-beta (TGFβ) is a multifunctional cytokine with a well-established role in mammary gland development and both oncogenic and tumor-suppressive functions. The extracellular matrix (ECM) indirectly regulates TGFβ activity by acting as a storage compartment of latent-TGFβ, but how TGFβ is released from the ECM via proteolytic mechanisms remains largely unknown. In this study, we demonstrate that hepsin, a type II transmembrane protease overexpressed in 70% of breast tumors, promotes canonical TGFβ signaling through the release of latent-TGFβ from the ECM storage compartment. Mammary glands in hepsin CRISPR knockout mice showed reduced TGFβ signaling and increased epithelial branching, accompanied by increased levels of fibronectin and latent-TGFβ1, while overexpression of hepsin in mammary tumors increased TGFβ signaling. Cell-free and cell-based experiments showed that hepsin is capable of direct proteolytic cleavage of fibronectin but not latent-TGFβ and, importantly, that the ability of hepsin to activate TGFβ signaling is dependent on fibronectin. Altogether, this study demonstrates a role for hepsin as a regulator of the TGFβ pathway in the mammary gland via a novel mechanism involving proteolytic downmodulation of fibronectin.

RevDate: 2021-09-13

Buonerba C, Grivas P, G Di Lorenzo (2021)

Perioperative Immune Checkpoint Inhibitors in Renal Cell and Urothelial Carcinomas: An Exciting New Paradigm under Investigation?.

RevDate: 2021-09-22

Edwards TC, Heike CL, Kapp-Simon KA, et al (2021)

Infant with Clefts Observation Outcomes Instrument (iCOO): A New Outcome for Infants and Young Children with Orofacial Clefts.

The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association [Epub ahead of print].

OBJECTIVE: We evaluated the measurement properties for item and domain scores of the Infant with Clefts Observation Outcomes Instrument (iCOO).

DESIGN: Cross-sectional (before lip surgery) and longitudinal study (preoperative baseline and 2 days and 2 months after lip surgery).

SETTING: Three academic craniofacial centers and national online advertisements.

PARTICIPANTS: Primary caregivers with an infant with cleft lip with or without cleft palate (CL ± P) scheduled to undergo primary lip repair. There were 133 primary caregivers at baseline, 115 at 2 days postsurgery, and 112 at 2 months postsurgery.

MAIN OUTCOME MEASURE(S): Caregiver observation items (n = 61) and global impression of health and function items (n = 8) across eight health domains.

RESULTS: Mean age at surgery was 6.0 months (range 2.7-11.8 months). Five of eight iCOO domains have scale scores, with Cronbach's alphas ranging from 0.67 to 0.87. Except for the Facial Skin and Mouth domain, iCOO scales had acceptable intraclass correlation coefficients (ICCs) ranging from 0.76 to 0.84. The internal consistency of the Global Impression items across all domains was 0.90 and had acceptable ICCs (range 0.76-0.91). Sixteen out of 20 (nonscale) items had acceptable ICCs (range 0.66-0.96). As anticipated, iCOO scores 2 days postoperatively were generally lower than baseline and scores 2 months postsurgery were consistent with baseline or higher. The iCOO took approximately 10 min to complete.

CONCLUSIONS: The iCOO meets measurement standards and may be used for assessing the impact of cleft-related treatments in clinical research and care. More research is needed on its use in various treatment contexts.

RevDate: 2021-09-12

Alblas M, Peterse EFP, Du M, et al (2021)

Cost-effectiveness of prophylactic hysterectomy in first-degree female relatives with Lynch syndrome of patients diagnosed with colorectal cancer in the United States: a microsimulation study.

Cancer medicine [Epub ahead of print].

BACKGROUND: To evaluate the cost-effectiveness of prophylactic hysterectomy (PH) in women with Lynch syndrome (LS).

METHODS: We developed a microsimulation model incorporating the natural history for the development of hyperplasia with and without atypia into endometrial cancer (EC) based on the MISCAN-framework. We simulated women identified as first-degree relatives (FDR) with LS of colorectal cancer patients after universal testing for LS. We estimated costs and benefits of offering this cohort PH, accounting for reduced quality of life after PH and for having EC. Three minimum ages (30/35/40) and three maximum ages (70/75/80) were compared to no PH.

RESULTS: In the absence of PH, the estimated number of EC cases was 300 per 1,000 women with LS. Total associated costs for treatment of EC were $5.9 million. Offering PH to FDRs aged 40-80 years was considered optimal. This strategy reduced the number of endometrial cancer cases to 5.4 (-98%), resulting in 516 quality-adjusted life years (QALY) gained and increasing the costs (treatment of endometrial cancer and PH) to $15.0 million (+154%) per 1,000 women. PH from earlier ages was more costly and resulted in fewer QALYs, although this finding was sensitive to disutility for PH.

CONCLUSIONS: Offering PH to 40- to 80-year-old women with LS is expected to add 0.5 QALY per person at acceptable costs. Women may decide to have PH at a younger age, depending on their individual disutility for PH and premature menopause.

RevDate: 2021-09-12

Chan KCG, Gao F, F Xia (2021)

Discussion on "Causal mediation of semicompeting risks" by Yen-Tsung Huang.

Biometrics [Epub ahead of print].

RevDate: 2021-09-15

Giraldi L, Collatuzzo G, Hashim D, et al (2021)

Infection with Human Papilloma Virus (HPV) and risk of subsites within the oral cancer.

Cancer epidemiology, 75:102020 pii:S1877-7821(21)00137-5 [Epub ahead of print].

BACKGROUND: The aim of this study was to investigate the relationship between high-risk genotypes of Human Papilloma Virus (HPV) and cancer of different subsites of the oral cavity.

MATERIAL AND METHODS: A pooled analysis of five studies included on the International Head and Neck Cancer Epidemiology (INHANCE) Consortium was conducted. HPV 16 and HPV 18 were considered. Adjusted odds ratios (ORs) and corresponding 95 % confidence intervals (CIs) for HPV and each oral cavity subsites were simultaneously estimated using multinomial logistic regression models.

RESULTS: The analysis included 1157 cases and 3272 controls. This study showed a slightly higher prevalence of HPV infection among oral cancer cases than controls. In particular, an increased risk of other and not otherwise specified (NOS) sites within the oral cavity, oral tongue, palate and floor of mouth cancer was observed for overall HPV16 positivity (OR = 1.66, 95 % CI: 1.01-2.72; OR = 1.97, 95 % CI: 1.36-2.85; OR = 2.48, 95 % CI: 1.50-4.11; OR = 2.71, 95 % CI: 1.06-6.95, respectively). In particular, HPV16E7 was related to cancer of floor of mouth, oral cavity NOS and palate (OR = 2.71, 95 % CI: 1.06-6.95; OR = 3.32, 95 % CI:1.53-7.19; OR = 3.34, 95 % CI:1.38-8.06). Results were inconsistent for HPV18 due to low prevalence of infection.

CONCLUSION: Our study suggests that HPV16 infection may increase the risk of developing floor of mouth, gum, tongue, and palate cancers.

CLINICAL RELEVANCE: Subjects with HPV infection have a higher risk of cancer from all sites of the oral cavity.

RevDate: 2021-09-11

Qayed M, Bleakley M, NN Shah (2021)

Role of chimeric antigen receptor T-cell therapy: bridge to transplantation or stand-alone therapy in pediatric acute lymphoblastic leukemia.

Current opinion in hematology pii:00062752-900000000-99117 [Epub ahead of print].

PURPOSE OF REVIEW: To discuss the curative potential for chimeric antigen receptor T-cell (CAR-T) therapy, with or without consolidative hematopoietic stem cell transplantation (HCT) in the treatment of children and young adults with B lineage acute lymphoblastic leukemia (B-ALL).

RECENT FINDINGS: CAR-T targeting CD19 can induce durable remissions and prolong life in patients with relapsed/refractory B-ALL. Whether HCT is needed to consolidate remission and cure relapse/refractory B-ALL following a CD19 CAR-T induced remission remains controversial. Preliminary evidence suggests that consolidative HCT following CAR-T in HCT-naïve children improves leukemia-free survival. However, avoiding HCT-related late effects is a desirable goal, so identification of patients at high risk of relapse is needed to appropriately direct those patients to HCT when necessary, while avoiding HCT in others. High disease burden prior to CAR-T infusion, loss of B-cell aplasia and detection of measurable residual disease by flow cytometry or next-generation sequencing following CAR-T therapy associate with a higher relapse risk and may identify patients requiring consolidative HCT for relapse prevention.

SUMMARY: There is a pressing need to determine when CD19 CAR-T alone is likely to be curative and when a consolidative HCT will be required. We discuss the current state of knowledge and future directions.

RevDate: 2021-09-10

Peeken JC, Asadpour R, Specht K, et al (2021)

MRI-based Delta-Radiomics predicts pathologic complete response in high-grade soft-tissue sarcoma patients treated with neoadjuvant therapy.

Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology pii:S0167-8140(21)06717-7 [Epub ahead of print].

PURPOSE: In high-grade soft-tissue sarcomas (STS) the standard of care encompasses multimodal therapy regimens. While there is a growing body of evidence for prognostic pretreatment radiomic models, we hypothesized that temporal changes in radiomic features following neoadjuvant treatment ("delta-radiomics") may be able to predict the pathological complete response (pCR).

METHODS: MRI scans (T1-weighted with fat-saturation and contrast-enhancement (T1FSGd) and T2-weighted with fat-saturation (T2FS)) of patients with STS of the extremities and trunk treated with neoadjuvant therapy were gathered from two independent institutions (training: 103, external testing: 53 patients). pCR was defined as < 5% viable cells. After segmentation and preprocessing, 105 radiomic features were extracted. Delta-radiomic features were calculated by subtraction of features derived from MRI scans obtained before and after neoadjuvant therapy. After feature reduction, machine learning modeling was performed in 100 iterations of 3-fold nested cross-validation. Delta-radiomic models were compared with single timepoint models in the testing cohort.

RESULTS: The combined delta-radiomic models achieved the best area under the receiver operating characteristic curve (AUC) of 0.75. Pre-therapeutic tumor volume was the best conventional predictor (AUC 0.70). The T2FS-based delta-radiomic model had the most balanced classification performance with a balanced accuracy of 0.69. Delta-radiomic models achieved better reproducibility than single timepoint radiomic models, RECIST or the peri-therapeutic volume change. Delta-radiomic models were significantly associated with survival in multivariate Cox regression.

CONCLUSION: This exploratory analysis demonstrated that MRI-based delta-radiomics improves prediction of pCR over tumor volume and RECIST. Delta-radiomics may one day function as a biomarker for personalized treatment adaptations.

RevDate: 2021-09-17

Lemos MP, Nandi V, Dragavon J, et al (2021)

HIV-1 Nucleic Acids Identify Rectal HIV Exposures in Self-Collected Rectal Swabs, Whereas Y-Chromosome Single Tandem Repeat Mixtures Are Not Reliable Biomarkers of Condomless Receptive Anal Intercourse.

Journal of acquired immune deficiency syndromes (1999), 88(2):138-148.

BACKGROUND: To focus interventions, biomarkers of HIV-1 exposure could help in identifying subpopulations at highest risk of acquisition. We assessed whether Y-chromosome single tandem repeat (YSTR) mixtures obtained from rectal swabs could serve as a biomarker of condomless receptive anal intercourse (CRAI) among men who have sex with men and transgender women and evaluated the feasibility of detecting HIV-1 virions to assess exposures.

METHODS: Twenty-nine sexually active HIV-seronegative men who have sex with men and one transgender woman from New York City answered on-site and mobile app sexual behavior questionnaires. They were randomized to collecting self-administered rectal swabs every morning or after receptive anal intercourse (RAI). YSTR profiles were assessed from blood sample and swabs; HIV-1 exposure was measured by conducting quantitative polymerase chain reaction in swabs.

RESULTS: After 2 months, the daily mobile survey had 135%-201% more instances of anal sex acts and 170%-193% more RAI than on-site surveys. Daily mobile reporting had 11%-35% less CRAI events than those reported on-site (Pdaily = 0.001; Pper-sex = 0.047). The daily swabbing arm reported less RAI (P < 0.001) and CRAI (P < 0.038) and had 2.95 lower odds of detecting YSTR mixtures (P = 0.021) than the per-sex-event arm. Surprisingly, YSTR detection was not significantly modified by report of bowel movements and lubricant, enema, or condom use. No participant became HIV-1 infected, yet HIV-1 total nucleic acids were detected in 6 independent episodes of CRAI in 2 participants taking pre-exposure prophylaxis.

CONCLUSIONS: YSTR mixtures demonstrated 80% specificity but only 30% sensitivity as a biomarker of CRAI in self-collected rectal swabs. However, detection of HIV-1 exposures in self-collected swabs may help in identifying those needing further HIV risk reduction strategies.

RevDate: 2021-09-10

Chen J, Ali MW, Yan L, et al (2021)

Prioritization and functional analysis of GWAS risk loci for Barrett's esophagus and esophageal adenocarcinoma.

Human molecular genetics pii:6367976 [Epub ahead of print].

Genome-wide association studies (GWAS) have identified ~ 20 genetic susceptibility loci for esophageal adenocarcinoma (EAC), and its precursor, Barrett's esophagus (BE). Despite such advances, functional/causal variants and gene targets at these loci remain undefined, hindering clinical translation. A key challenge is that most causal variants map to non-coding regulatory regions such as enhancers, and typically, numerous potential candidate variants at GWAS loci require testing. We developed a systematic informatics pipeline for prioritizing candidate functional variants via integrative functional potential scores consolidated from multi-omics annotations, and used this pipeline to identify two high-scoring variants for experimental interrogation: chr9q22.32/rs11789015 and chr19p13.11/rs10423674. Minimal candidate enhancer regions spanning these variants were evaluated using luciferase reporter assays in two EAC cell lines. One of the two variants tested (rs10423674) exhibited allele-specific enhancer activity. CRISPR-mediated deletion of the putative enhancer region in EAC cell lines correlated with reduced expression of two genes-CREB-regulated transcription coactivator 1 (CRTC1) and Cartilage oligomeric matrix protein (COMP); expression of five other genes remained unchanged (CRLF1, KLHL26, TMEM59L, UBA52, RFXANK). Expression quantitative trait locus (eQTL) mapping indicated that rs10423674 genotype correlated with CRTC1 and COMP expression in normal esophagus. This study represents the first experimental effort to bridge GWAS associations to biology in BE/EAC, and supports the utility of functional potential scores to guide variant prioritization. Our findings reveal a functional variant and candidate risk enhancer at chr19p13.11, and implicate CRTC1 and COMP as putative gene targets, suggesting that altered expression of these genes may underlie the BE/EAC risk association.

RevDate: 2021-09-10

Curran C, Adib E, Kazakova V, et al (2021)

Outcomes of metastatic urothelial carcinoma following discontinuation of enfortumab-vedotin.

Clinical genitourinary cancer pii:S1558-7673(21)00159-2 [Epub ahead of print].

BACKGROUND: Enfortumab vedotin (EV) is approved to treat metastatic urothelial carcinoma (mUC) following platinum and PD1/L1 inhibitors. Since the outcomes and patterns of therapy of patients following discontinuation of EV are unknown, we conducted a retrospective study to assess this issue.

METHODS: Data were retrospectively obtained from patients with mUC following discontinuation of EV after prior platinum-based chemotherapy and PD1/L1 inhibitors. Objective response rate (ORR) was evaluated in those who received therapy post-EV. Statistical analyses were performed to describe the overall survival (OS) and compare patient characteristics and outcomes of those who did or did not receive treatment post-EV.

RESULTS: Data were available for 63 patients from 6 institutions: 46 (73%) were male and median age was 68 years (range 43-83). The median OS was 32 weeks. Thirty-two patients (51%) received therapy after EV. The OS of those who did vs. did not receive post-EV therapy was significantly different (median 43.1 vs. 16.9 weeks, P = .015). Longer duration of prior EV therapy was associated with receipt of post-EV therapy (P = .0437) as well as OS in both the treated (P = .045) and untreated groups (P = .012). Objective response was observed in 3 of 32 patients (9.4%) who received therapy post-EV.

CONCLUSION: Outcomes of patients with mUC following discontinuation of EV are dismal and only 51% received therapy after discontinuation of EV. This study identifies benchmarks for the interpretation of activity of new agents following EV and raises the hypothesis for duration of EV as a potential prognostic factor following discontinuation of EV.

RevDate: 2021-09-10

Cooley LF, Emeka AA, Meyers TJ, et al (2021)

Factors Associated with Time to Conversion from Active Surveillance to Treatment for Prostate Cancer in a Multi-Institutional Cohort.

The Journal of urology [Epub ahead of print].

PURPOSE: We examined the demographic and clinicopathological parameters associated with the time to convert from active surveillance to treatment among men with prostate cancer.

MATERIALS AND METHODS: A multi-institutional cohort of 7,279 patients managed with active surveillance had data and biospecimens collected for germline genetic analyses.

RESULTS: Of 6,775 men included in the analysis, 2,260 (33.4%) converted to treatment at a median followup of 6.7 years. Earlier conversion was associated with higher Gleason grade groups (GG2 vs GG1 adjusted hazard ratio [aHR] 1.57, 95% CI 1.36-1.82; ≥GG3 vs GG1 aHR 1.77, 95% CI 1.29-2.43), serum prostate specific antigen concentrations (aHR per 5 ng/ml increment 1.18, 95% CI 1.11-1.25), tumor stages (cT2 vs cT1 aHR 1.58, 95% CI 1.41-1.77; ≥cT3 vs cT1 aHR 4.36, 95% CI 3.19-5.96) and number of cancerous biopsy cores (3 vs 1-2 cores aHR 1.59, 95% CI 1.37-1.84; ≥4 vs 1-2 cores aHR 3.29, 95% CI 2.94-3.69). Patients with high-volume GG1 tumors had a shorter interval to conversion than those with low-volume GG1 tumors and behaved like the higher-risk patients. We found no significant association between the time to conversion and self-reported race or genetic ancestry.

CONCLUSIONS: A shorter time to conversion from active surveillance to treatment was associated with higher-risk clinicopathological tumor features. Furthermore, patients with high-volume GG1 tumors behaved similarly to those with intermediate and high-risk tumors. An exploratory analysis of self-reported race and genetic ancestry revealed no association with the time to conversion.

RevDate: 2021-09-10

Cooley LF, Emeka AA, Meyers TJ, et al (2021)

Reply by Authors.

The Journal of urology [Epub ahead of print].

RevDate: 2021-09-09

Doucette K, Percival ME, Williams L, et al (2021)

Hypoalbuminemia as a prognostic biomarker for higher mortality and treatment complications in acute myeloid leukemia.

Hematological oncology [Epub ahead of print].

Older age and poor performance status lead to worse outcomes in acute myeloid leukemia (AML) patients. Hypoalbuminemia is a negative predictor of morbidity and mortality in several malignancies. We evaluated the relationship between baseline serum albumin levels on treatment-related complications, as well as short-term mortality and overall survival (OS) in 756 newly diagnosed AML patients. We conducted a retrospective multicenter study to examine treatment-related complications and OS according to pretreatment serum albumin levels: normal albumin ≥3.5 g/dl, marked hypoalbuminemia <2.5 g/dl, and hypoalbuminemia 2.5-3.4 g/dl. In an adjusted multivariate analysis, a lower baseline albumin was independently associated with a higher number of grade ≥3 complications when adjusting for age, secondary AML, sex and intensive treatment. When comparing normal to markedly low albumin levels, the estimated mean number of complications increases by a factor of 1.35. Patients who had a normal baseline albumin had a 30 day-mortality rate of 4.8%, which was significantly lower compared with patients with hypoalbuminemia (16.5%) and marked hypoalbuminemia (33.9%; p < 0.01). Similarly, 60-day mortality rate was significantly higher in the hypoalbuminemia group (24.0%) and marked hypoalbuminemia group (45%) compared with normal albumin group (8.3%; p < 0.01). Patients with lower baseline albumin levels have increased treatment-related morbidity and mortality, suggesting that pre-treatment serum albumin is an important independent prognostic marker.

RevDate: 2021-09-23

Cranston RD, Brown E, Bauermeister J, et al (2021)

A Randomized, Double Blind, Placebo-Controlled, Phase 1 Safety and Pharmacokinetic Study of Dapivirine Gel (0.05%) Administered Rectally to HIV-1 Seronegative Adults (MTN-026).

AIDS research and human retroviruses [Epub ahead of print].

INTRODUCTION: Dapivirine (DPV), formulated as vaginal ring, demonstrated HIV risk reduction. MTN-026 explored DPV, formulated as rectal gel, for safety, pharmacokinetics, and acceptability.

METHODS: HIV-uninfected men and women aged 18-45 years were enrolled at United States and Thailand sites and randomized 2:1 to receive DPV 0.05% or placebo gel via rectal applicator. A single dose phase was followed by 7 observed daily doses. Plasma, and fluid and tissue from both rectum and cervix were collected at baseline and after the final dose over 72 hours for pharmacokinetics, ex-vivo HIV-1 biopsy challenge, histology, and flow cytometry.

RESULTS: 28 participants were randomized; 2 terminated early; 9 were female and 19 male; 12 were white, 11 Asian, 4 black and 1 other race/ethnicity. Mean age was 28.5 and 34.2 years in the DPV and placebo arms, respectively. Thirty adverse events occurred (all Grade 1 or 2, except one unrelated Grade 3) without study arm differences. DPV rectal tissue concentrations (median [interquartile range]) 0.5-1 and 2 hours after a single dose were 256 ng/gm (below limit of quantitation [BLQ], 666) and BLQ (BLQ, 600), respectively, then BLQ (BLQ, BLQ) from 24-72 hours; concentrations following multiple doses were similar. The largest median DPV plasma concentrations were 0.33 ng/mL (0.15, 0.48) after one dose and 0.40 (0.33, 0.49) after seven doses.

CONCLUSIONS: The DPV rectal gel was acceptable and without safety concerns. While DPV plasma concentrations were similar to the vaginal ring, rectal tissue concentrations were well below vaginal ring tissue concentrations, suggesting need for reformulation.

RevDate: 2021-09-09

Salvucci M, Crawford N, Stott K, et al (2021)

Patients with mesenchymal tumours and high Fusobacteriales prevalence have worse prognosis in colorectal cancer (CRC).

Gut pii:gutjnl-2021-325193 [Epub ahead of print].

OBJECTIVES: Transcriptomic-based subtyping, consensus molecular subtyping (CMS) and colorectal cancer intrinsic subtyping (CRIS) identify a patient subpopulation with mesenchymal traits (CMS4/CRIS-B) and poorer outcome. Here, we investigated the relationship between prevalence of Fusobacterium nucleatum (Fn) and Fusobacteriales, CMS/CRIS subtyping, cell type composition, immune infiltrates and host contexture to refine patient stratification and to identify druggable context-specific vulnerabilities.

DESIGN: We coupled cell culture experiments with characterisation of Fn/Fusobacteriales prevalence and host biology/microenviroment in tumours from two independent colorectal cancer patient cohorts (Taxonomy: n=140, colon and rectal cases of The Cancer Genome Atlas (TCGA-COAD-READ) cohort: n=605).

RESULTS: In vitro, Fn infection induced inflammation via nuclear factor kappa-light-chain-enhancer of activated B cells/tumour necrosis factor alpha in HCT116 and HT29 cancer cell lines. In patients, high Fn/Fusobacteriales were found in CMS1, microsatellite unstable () tumours, with infiltration of M1 macrophages, reduced M2 macrophages, and high interleukin (IL)-6/IL-8/IL-1β signalling. Analysis of the Taxonomy cohort suggested that Fn was prognostic for CMS4/CRIS-B patients, despite having lower Fn load than CMS1 patients. In the TCGA-COAD-READ cohort, we likewise identified a differential association between Fusobacteriales relative abundance and outcome when stratifying patients in mesenchymal (either CMS4 and/or CRIS-B) versus non-mesenchymal (neither CMS4 nor CRIS-B). Patients with mesenchymal tumours and high Fusobacteriales had approximately twofold higher risk of worse outcome. These associations were null in non-mesenchymal patients. Modelling the three-way association between Fusobacteriales prevalence, molecular subtyping and host contexture with logistic models with an interaction term disentangled the pathogen-host signalling relationship and identified aberrations (including NOTCH, CSF1-3 and IL-6/IL-8) as candidate targets.

CONCLUSION: This study identifies CMS4/CRIS-B patients with high Fn/Fusobacteriales prevalence as a high-risk subpopulation that may benefit from therapeutics targeting mesenchymal biology.

RevDate: 2021-09-12

Leeman J, Rohweder C, Lee M, et al (2021)

Aligning implementation science with improvement practice: a call to action.

Implementation science communications, 2(1):99.

BACKGROUND: In several recent articles, authors have called for aligning the fields of implementation and improvement science. In this paper, we call for implementation science to also align with improvement practice. Multiple implementation scholars have highlighted the importance of designing implementation strategies to fit the existing culture, infrastructure, and practice of a healthcare system. Worldwide, healthcare systems are adopting improvement models as their primary approach to improving healthcare delivery and outcomes. The prevalence of improvement models raises the question of how implementation scientists might best align their efforts with healthcare systems' existing improvement infrastructure and practice.

MAIN BODY: We describe three challenges and five benefits to aligning implementation science and improvement practice. Challenges include (1) use of different models, terminology, and methods, (2) a focus on generalizable versus local knowledge, and (3) limited evidence in support of the effectiveness of improvement tools and methods. We contend that implementation science needs to move beyond these challenges and work toward greater alignment with improvement practice. Aligning with improvement practice would benefit implementation science by (1) strengthening research/practice partnerships, (2) fostering local ownership of implementation, (3) generating practice-based evidence, (4) developing context-specific implementation strategies, and (5) building practice-level capacity to implement interventions and improve care. Each of these potential benefits is illustrated in a case study from the Centers for Disease Control and Prevention's Cancer Prevention and Control Research Network.

CONCLUSION: To effectively integrate evidence-based interventions into routine practice, implementation scientists need to align their efforts with the improvement culture and practice that is driving change within healthcare systems worldwide. This paper provides concrete examples of how researchers have aligned implementation science with improvement practice across five implementation projects.

RevDate: 2021-09-08

Adair JE, Androski L, Bayigga L, et al (2021)

Towards access for all: 1st Working Group Report for the Global Gene Therapy Initiative (GGTI).

Gene therapy [Epub ahead of print].

The gene and cell therapy field saw its first approved treatments in Europe in 2012 and the United States in 2017 and is projected to be at least a $10B USD industry by 2025. Despite this success, a massive gap exists between the companies, clinics, and researchers developing these therapeutic approaches, and their availability to the patients who need them. The unacceptable reality is a geographic exclusion of low-and middle-income countries (LMIC) in gene therapy development and ultimately the provision of gene therapies to patients in LMIC. This is particularly relevant for gene therapies to treat human immunodeficiency virus infection and hemoglobinopathies, global health crises impacting tens of millions of people primarily located in LMIC. Bridging this divide will require research, clinical and regulatory infrastructural development, capacity-building, training, an approval pathway and community adoption for success and sustainable affordability. In 2020, the Global Gene Therapy Initiative was formed to tackle the barriers to LMIC inclusion in gene therapy development. This working group includes diverse stakeholders from all sectors and has set a goal of introducing two gene therapy Phase I clinical trials in two LMIC, Uganda and India, by 2024. Here we report on progress to date for this initiative.

RevDate: 2021-09-26

Rane MS, Rohani P, ME Halloran (2021)

Durability of protection after 5 doses of acellular pertussis vaccine among 5-9 year old children in King County, Washington.

Vaccine, 39(41):6144-6150.

PURPOSE: Waning of immunity after vaccination with the acellular Pertussis (aP) vaccine has been proposed as one of the main reasons for pertussis resurgence in the US. In this study, we estimated time-varying vaccine effectiveness after 5 doses of aP vaccine.

METHODS: We conducted a retrospective cohort study among children 5-9 years old (born between 2008 and 2012) living in King County, Washington, USA, who participated in the Washington State Immunization Information System. We estimated time-varying vaccine effectiveness after 5 doses of aP using smoothed scaled Schoenfeld residuals obtained from fitting Cox proportional hazards models to the data as well as piecewise constant Poisson regression.

RESULTS: There were 55 pertussis cases in this cohort, of whom 22 (40%) were fully-vaccinated and 33 (60%) were under-vaccinated. Vaccine effectiveness (VE) remained high for up to 42 months after the fifth dose (VE(t) = 89%; 95% CI: 64%, 97%) as estimated using survival analysis methods and up to 4 years (VE(t) = 93%; 95% CI: 67%, 98%) as estimated using Poisson regression.

CONCLUSION: We did not find evidence for waning of vaccine effectiveness for up to four years after 5 doses of aP among 5 -9 years old children in King County, WA.

RevDate: 2021-09-11

Maloney DG, Kuruvilla J, Liu FF, et al (2021)

Matching-adjusted indirect treatment comparison of liso-cel versus axi-cel in relapsed or refractory large B cell lymphoma.

Journal of hematology & oncology, 14(1):140.

BACKGROUND: In the absence of randomized studies directly comparing chimeric antigen receptor T cell therapies, this study used matching-adjusted indirect comparisons (MAIC) to evaluate the comparative efficacy and safety of lisocabtagene maraleucel (liso-cel) versus axicabtagene ciloleucel (axi-cel) in patients with relapsed or refractory large B cell lymphoma (LBCL).

METHODS: Primary data sources included individual patient data from the TRANSCEND NHL 001 study (TRANSCEND [NCT02631044]; N = 256 for efficacy set, N = 269 for safety set) for liso-cel and summary-level data from the ZUMA-1 study (NCT02348216; N = 101 for efficacy set, N = 108 for safety set) for axi-cel. Inter-study differences in design, eligibility criteria, baseline characteristics, and outcomes were assessed and aligned to the extent feasible. Clinically relevant prognostic factors were adjusted in a stepwise fashion by ranked order. Since bridging therapy was allowed in TRANSCEND but not ZUMA-1, the initial efficacy and safety analyses included bridging therapy use as a matching factor (TRANSCEND patients who received bridging therapy were removed). Subsequent sensitivity analyses excluded this matching factor.

RESULTS: The initial analysis showed similar MAIC-weighted efficacy outcomes between TRANSCEND and ZUMA-1 for overall and complete response rates (odds ratio [95% confidence interval (CI)], 1.40 [0.56-3.49] and 1.21 [0.56-2.64], respectively) and for overall survival and progression-free survival (hazard ratio [95% CI], 0.81 [0.44-1.49] and 0.95 [0.58-1.57], respectively). MAIC-weighted safety outcomes favored liso-cel, with significantly lower odds of all-grade and grade ≥ 3 cytokine release syndrome (odds ratio [95% CI], 0.03 [0.01-0.07] and 0.08 [0.01-0.67], respectively) and study-specific neurological events (0.16 [0.08-0.33] and 0.05 [0.02-0.15], respectively). Efficacy and safety outcomes remained similar in sensitivity analyses, which did not include use of bridging therapy as a matching factor.

CONCLUSIONS: After matching and adjusting for clinically relevant prognostic factors, liso-cel demonstrated comparable efficacy and a more favorable safety profile compared with axi-cel in patients with third- or later-line relapsed or refractory LBCL.

TRIAL REGISTRATION: NCT02631044 and NCT02348216.

RevDate: 2021-09-23

Janes H, Gao F, A Luedtke (2021)

Discussion on "Estimating vaccine efficacy over time after a randomized study is unblinded" by Anastasios A. Tsiatis and Marie Davidian.

Biometrics [Epub ahead of print].

RevDate: 2021-09-22

Lin MJ, Haynes AM, Addetia A, et al (2021)

Longitudinal TprK profiling of in vivo and in vitro-propagated Treponema pallidum subsp. pallidum reveals accumulation of antigenic variants in absence of immune pressure.

PLoS neglected tropical diseases, 15(9):e0009753 pii:PNTD-D-21-00926 [Epub ahead of print].

Immune evasion by Treponema pallidum subspecies pallidum (T. pallidum) has been attributed to antigenic variation of its putative outer-membrane protein TprK. In TprK, amino acid diversity is confined to seven variable (V) regions, and generation of sequence diversity within the V regions occurs via a non-reciprocal segmental gene conversion mechanism where donor cassettes recombine into the tprK expression site. Although previous studies have shown the significant role of immune selection in driving accumulation of TprK variants, the contribution of baseline gene conversion activity to variant diversity is less clear. Here, combining longitudinal tprK deep sequencing of near clonal Chicago C from immunocompetent and immunosuppressed rabbits along with the newly developed in vitro cultivation system for T. pallidum, we directly characterized TprK alleles in the presence and absence of immune selection. Our data confirm significantly greater sequence diversity over time within the V6 region during syphilis infection in immunocompetent rabbits compared to immunosuppressed rabbits, consistent with previous studies on the role of TprK in evasion of the host immune response. Compared to strains grown in immunocompetent rabbits, strains passaged in vitro displayed low level changes in allele frequencies of TprK variable region sequences similar to that of strains passaged in immunosuppressed rabbits. Notably, we found significantly increased rates of V6 allele generation relative to other variable regions in in vitro cultivated T, pallidum strains, illustrating that the diversity within these hypervariable regions occurs in the complete absence of immune selection. Together, our results demonstrate antigenic variation in T. pallidum can be studied in vitro and occurs even in the complete absence of immune pressure, allowing the T. pallidum population to continuously evade the immune system of the infected host.

RevDate: 2021-09-25

Hullar MAJ, Jenkins IC, Randolph TW, et al (2021)

Associations of the gut microbiome with hepatic adiposity in the Multiethnic Cohort Adiposity Phenotype Study.

Gut microbes, 13(1):1965463.

Nonalcoholic fatty liver disease (NAFLD) is a risk factor for liver cancer and prevalence varies by ethnicity. Along with genetic and lifestyle factors, the gut microbiome (GM) may contribute to NAFLD and its progression to advanced liver disease. Our cross-sectional analysis assessed the association of the GM with hepatic adiposity among African American, Japanese American, White, Latino, and Native Hawaiian participants in the Multiethnic Cohort. We used MRI to measure liver fat and determine nonalcoholic fatty liver disease (NAFLD) status (n = 511 cases) in 1,544 participants, aged 60-77 years, with 12-53% overall adiposity (BMI of 17.8-46.2 kg/m2). The GM was measured by 16S rRNA gene sequencing and, on a subset, by metagenomic sequencing. Alpha diversity was lower overall with NAFLD and in certain ethnicities (African Americans, Whites, and Latinos). In models regressing genus on NAFLD status, 62 of 149 genera (40%) exhibited a significant interaction between NAFLD and ethnicity stratified analysis found 69 genera significantly associated with NAFLD in at least one ethnic group. No single genus was significantly associated with NAFLD across all ethnicities. In contrast, the same bacterial metabolic pathways were over-represented in participants with NAFLD regardless of ethnicity. Imputed secondary bile acid and carbohydrate pathways were associated with NAFLD, the latter of which was corroborated by metagenomics, although different genera in different ethnicities were associated with these pathways. Overall, we found that NAFLD was associated with altered bacterial composition and metabolism, and that bacterial endotoxin, assessed by plasma lipopolysaccharide binding protein (LBP), may mediate liver fat-associated systemic inflammation in a manner that seems to vary by ethnicity.

RevDate: 2021-09-07

Tagawa ST, P Grivas (2021)

Reply to T. Powles et al.

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

RevDate: 2021-09-07

Gooley TA (2021)

Two Biologic-Assignment Studies Evaluating the Efficacy of Hematopoietic Cell Transplant Among Older Patients With High-Risk Myelodysplastic Syndrome.

RevDate: 2021-09-11

Schoenbeck KL, Atallah E, Lin L, et al (2021)

Patient-Reported Functional Outcomes in Patients with Chronic Myeloid Leukemia after Stopping Tyrosine Kinase Inhibitors.

Journal of the National Cancer Institute pii:6365943 [Epub ahead of print].

Treatment-free remission (TFR) is a goal for patients with chronic myeloid leukemia (CML). Functional outcomes after discontinuing Tyrosine Kinase Inhibitor (TKI) treatment have not been described. PROMIS patient-reported outcome measures (PROMs) of social, physical, cognitive, and sexual function were assessed over 36 months in 172 adult patients with chronic phase CML from 14 sites at baseline (on TKI) and after discontinuation. Linear mixed-effects models described the average trajectories for each PROM after discontinuation and in those who restarted TKI. Of 112 patients in TFR at 12 months, 103 (92.0%) had a ≥ 3-point improvement in social function, 80 (71.4%) in social isolation, 11 (9.8%) in satisfaction with sex life, 4 (3.6%) in physical function, and no patients had a ≥ 3-point improvement in cognitive function or interest in sexual activity. Patients' scores worsened after restarting TKI. This novel information on functional outcomes in TFR can help guide patient and clinician decision-making.

RevDate: 2021-09-08

Teshima T, GR Hill (2021)

The Pathophysiology and Treatment of Graft-Versus-Host Disease: Lessons Learnt From Animal Models.

Frontiers in immunology, 12:715424.

Allogeneic hematopoietic cell transplantation (HCT) is a curative treatment for hematologic malignancies, bone marrow failure syndromes, and inherited immunodeficiencies and metabolic diseases. Graft-versus-host disease (GVHD) is the major life-threatening complication after allogeneic HCT. New insights into the pathophysiology of GVHD garnered from our understanding of the immunological pathways within animal models have been pivotal in driving new therapeutic paradigms in the clinic. Successful clinical translations include histocompatibility matching, GVHD prophylaxis using cyclosporine and methotrexate, posttransplant cyclophosphamide, and the use of broad kinase inhibitors that inhibit cytokine signaling (e.g. ruxolitinib). New approaches focus on naïve T cell depletion, targeted cytokine modulation and the inhibition of co-stimulation. This review highlights the use of animal transplantation models to guide new therapeutic principles.

RevDate: 2021-09-07

Lee JW, Su Y, Baloni P, et al (2021)

Integrated analysis of plasma and single immune cells uncovers metabolic changes in individuals with COVID-19.

Nature biotechnology [Epub ahead of print].

A better understanding of the metabolic alterations in immune cells during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may elucidate the wide diversity of clinical symptoms experienced by individuals with coronavirus disease 2019 (COVID-19). Here, we report the metabolic changes associated with the peripheral immune response of 198 individuals with COVID-19 through an integrated analysis of plasma metabolite and protein levels as well as single-cell multiomics analyses from serial blood draws collected during the first week after clinical diagnosis. We document the emergence of rare but metabolically dominant T cell subpopulations and find that increasing disease severity correlates with a bifurcation of monocytes into two metabolically distinct subsets. This integrated analysis reveals a robust interplay between plasma metabolites and cell-type-specific metabolic reprogramming networks that is associated with disease severity and could predict survival.

RevDate: 2021-09-07

Liechti T, Weber LM, Ashhurst TM, et al (2021)

An updated guide for the perplexed: cytometry in the high-dimensional era.

Nature immunology [Epub ahead of print].

RevDate: 2021-09-06

Roelofs EJ, Dengel DR, Wang Q, et al (2021)

The role of FSH in body composition in hematopoietic cell transplant recipients.

Pediatric transplantation [Epub ahead of print].

BACKGROUND: Childhood cancer survivors who received a hematopoietic cell transplantation (HCT) are at increased risk for follicle-stimulating hormone (FSH) abnormalities, which may have a significant negative impact on bone health and body composition. This study's purpose was to examine FSH and body composition in HCT recipients, non-HCT recipients and healthy controls.

METHODS: The study included HCT recipients (n = 24), non-HCT recipients (n = 309), and a control group of healthy siblings (n = 211) all aged 9-18 years. A fasting blood sample was collected to measure FSH. All participants underwent a dual X-ray absorptiometry scan to assess total and regional percent fat, lean mass (LM), fat mass (FM), bone mineral content (BMC), bone mineral density (BMD), and visceral adipose tissue (VAT) mass.

RESULTS: FSH was significantly higher in HCT recipients compared to non-HCT recipients and healthy controls. HCT recipients had significantly lower total body weight, total LM, arm and leg LM, BMC and BMD compared to non-HCT recipients and healthy controls (p < .05). Non-HCT recipients had significantly higher total, trunk, android, gynoid, arm and leg FM compared to healthy controls. Also, healthy controls had significantly lower VAT mass compared to non-HCT recipients.

CONCLUSIONS: This study's results show that HCT recipients have significant reductions in BMD, worse body composition, and abnormal FSH levels compared to non-HCT recipients and healthy controls.

RevDate: 2021-09-20
CmpDate: 2021-09-20

Chan M, Vijay S, McNevin J, et al (2021)

Machine learning identifies molecular regulators and therapeutics for targeting SARS-CoV2-induced cytokine release.

Molecular systems biology, 17(9):e10426.

Although 15-20% of COVID-19 patients experience hyper-inflammation induced by massive cytokine production, cellular triggers of this process and strategies to target them remain poorly understood. Here, we show that the N-terminal domain (NTD) of the SARS-CoV-2 spike protein substantially induces multiple inflammatory molecules in myeloid cells and human PBMCs. Using a combination of phenotypic screening with machine learning-based modeling, we identified and experimentally validated several protein kinases, including JAK1, EPHA7, IRAK1, MAPK12, and MAP3K8, as essential downstream mediators of NTD-induced cytokine production, implicating the role of multiple signaling pathways in cytokine release. Further, we found several FDA-approved drugs, including ponatinib, and cobimetinib as potent inhibitors of the NTD-mediated cytokine release. Treatment with ponatinib outperforms other drugs, including dexamethasone and baricitinib, inhibiting all cytokines in response to the NTD from SARS-CoV-2 and emerging variants. Finally, ponatinib treatment inhibits lipopolysaccharide-mediated cytokine release in myeloid cells in vitro and lung inflammation mouse model. Together, we propose that agents targeting multiple kinases required for SARS-CoV-2-mediated cytokine release, such as ponatinib, may represent an attractive therapeutic option for treating moderate to severe COVID-19.

RevDate: 2021-09-07

Lalish KM, Stromholt S, Curtis N, et al (2021)

Explorers Virtual Internship: Fostering Rightful Presence and Sense of Belonging in an Online High School Internship Program.

Journal of STEM outreach, 4(2):.

This paper describes the "Explorers Virtual Internship" (EVI), which was designed and presented in the 2020-21 school year by the Fred Hutchinson Cancer Research Center. Despite our initial wariness about creating a virtual internship, the shift helped us make valuable innovations to our programming. EVI paired 11 high school interns with mentors to work on individual research projects. We designed our program to foster a sense of belonging and "rightful presence" in biomedical research among the interns, all of whom came from backgrounds underrepresented in science. In addition to the research experience, we also focused on ethical issues, career awareness, community building, identity/belonging, and leadership/agency. Interns reported increases in their perceptions of the overlap of their identity and those of STEM professionals. They also reported increases in their knowledge of STEM concepts and capacity to demonstrate STEM skills (n=10). Open-ended survey responses indicated that students' uptake of scientific practices and sense of belonging were interrelated with their relationship with their mentors, and that students felt a sense of community with other students despite being in a virtual environment. We also provided programming for mentors, who indicated that learning and thinking about rightful presence and belonging was helpful for their role.

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RJR Experience and Expertise

Researcher

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

Educator

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

Administrator

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

Technologist

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

Publisher

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

Speaker

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

Facilitator

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

Designer

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

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

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Collection of publications by R J Robbins

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

Research Gate page for R J Robbins

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Curriculum Vitae for R J Robbins

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