Digital Commons Network^™

Sucroferric Oxyhydroxide For Hyperphosphatemia: A Review Of Real-World Evidence, Daniel W Coyne, Stuart M Sprague, Marc Vervloet, Rosa Ramos, Kamyar Kalantar-Zadeh

2020-Current year OA Pubs

Hyperphosphatemia is a common complication in dialysis-dependent patients with chronic kidney disease. Most dialysis-dependent patients need oral phosphate binder therapy to control serum phosphorus concentrations. Most phosphate binders have a high daily pill burden, which may reduce treatment adherence and impair phosphorus control. Sucroferric oxyhydroxide is a potent iron-based phosphate binder approved for use in dialysis-dependent patients in 2013. A randomized controlled trial of sucroferric oxyhydroxide demonstrated its efficacy for reduction of serum phosphorus with a lower pill burden than sevelamer carbonate. Clinical trials carefully select patients, monitor adherence, and routinely titrate medications to a protocol-defined goal. Consequently, trials may …

Efficacy And Safety Outcomes With Diroximel Fumarate After Switching From Prior Therapies Or Continuing On Drf: Results From The Phase 3 Evolve-Ms-1 Study, Sibyl Wray, Robert T Naismith, Et Al.

2020-Current year OA Pubs

INTRODUCTION: Diroximel fumarate (DRF) is an oral fumarate for relapsing multiple sclerosis (MS) with the same active metabolite as dimethyl fumarate (DMF). DRF has a safety/efficacy profile similar to DMF but with improved gastrointestinal (GI) tolerability and low (< 1%) treatment discontinuation due to GI adverse events (AEs). Efficacy and safety outcomes in patients who switched to DRF from other disease-modifying therapies (DMTs) have not been evaluated.

METHODS: EVOLVE-MS-1 is an ongoing, 2-year, open-label, phase 3 study of DRF in adults with relapsing-remitting MS. Patients either entered as newly enrolled to DRF trials, or from the 5-week, randomized, head-to-head, phase 3 EVOLVE-MS-2 study of DRF and DMF. This analysis evaluated safety and GI tolerability in patients continuing on DRF (DRF-rollover) or switching from DMF (DMF-rollover) following EVOLVE-MS-2. Safety …

A Study Examining The Usefulness Of A New Measure Of Research Engagement, Deborah J Bowen, Nicole Ackermann, Vetta Saunders Thompson, Andrea Nederveld, Melody Goodman

2020-Current year OA Pubs

INTRODUCTION: Engagement of relevant stakeholders' ideas, opinions, and concerns is critical to the success of modern research projects. We have developed a tool to measure stakeholder engagement, called the Research Engagement Survey Tool (REST). The purpose of this paper is to present the implementation and uptake of the stakeholder engagement measure REST among research teams, including the assessment of barriers and facilitating factors for use of the new research engagement measure in practice.

METHODS: In this implementation study, project team members participated in baseline and follow-up web-based surveys. Web-based interviews were conducted with a subset of project teams that implemented …

Association Of Prenatal Exposure To Early-Life Adversity With Neonatal Brain Volumes At Birth, Regina L Triplett, Rachel E Lean, Amisha Parikh, J Philip Miller, Dimitrios Alexopoulos, Sydney Kaplan, Dominique Meyer, Christopher Adamson, Tara A Smyser, Cynthia E Rogers, Deanna M Barch, Barbara Warner, Joan L Luby, Christopher D Smyser

2020-Current year OA Pubs

Importance: Exposure to early-life adversity alters the structural development of key brain regions underlying neurodevelopmental impairments. The association between prenatal exposure to adversity and brain structure at birth remains poorly understood.

Objective: To examine whether prenatal exposure to maternal social disadvantage and psychosocial stress is associated with neonatal global and regional brain volumes and cortical folding.

Design, Setting, and Participants: This prospective, longitudinal cohort study included 399 mother-infant dyads of sociodemographically diverse mothers recruited in the first or early second trimester of pregnancy and their infants, who underwent brain magnetic resonance imaging in the first weeks of life. Mothers were …

Fluvoxamine For Outpatient Management Of Covid-19 To Prevent Hospitalization: A Systematic Review And Meta-Analysis, Todd C Lee, Simone Vigod, Émilie Bortolussi-Courval, Ryan Hanula, David R Boulware, Eric J Lenze, Angela M Reiersen, Emily G Mcdonald

2020-Current year OA Pubs

Importance: Widely available and affordable options for the outpatient management of COVID-19 are needed, particularly for therapies that prevent hospitalization.

Objective: To perform a meta-analysis of the available randomized clinical trial evidence for fluvoxamine in the outpatient management of COVID-19.

Data Sources: World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov.

Study Selection: Studies with completed outpatient trials with available results that compared fluvoxamine with placebo were included.

Data Extraction and Synthesis: The PRISMA 2020 guidelines were followed and study details in terms of inclusion criteria, trial demographics, and the prespecified outcome of all-cause hospitalization were extracted. Risk of …

Narratives Bridge The Divide Between Distant Events In Episodic Memory, Brendan I Cohn-Sheehy, Angelique I Delarazan, Jordan E Crivelli-Decker, Zachariah M Reagh, Nidhi S Mundada, Andrew P Yonelinas, Jeffrey M Zacks, Charan Ranganath

2020-Current year OA Pubs

Many studies suggest that information about past experience, or episodic memory, is divided into discrete units called "events." Yet we can often remember experiences that span multiple events. Events that occur in close succession might simply be linked because of their proximity to one another, but we can also build links between events that occur farther apart in time. Intuitively, some kind of organizing principle should enable temporally distant events to become bridged in memory. We tested the hypothesis that episodic memory exhibits a narrative-level organization, enabling temporally distant events to be better remembered if they form a coherent narrative. …

Reach And Adoption Of A Geriatric Emergency Department Accreditation Program In The United States, Maura Kennedy, Adriane Lesser, Juhi Israni, Shan W Liu, Ilianna Santangelo, Nicole Tidwell, Lauren T Southerland, Christopher R Carpenter, Kevin Biese, Surriya Ahmad, Ula Hwang

2020-Current year OA Pubs

STUDY OBJECTIVE: The objectives of this study were to describe the reach and adoption of Geriatric Emergency Department Accreditation (GEDA) program and care processes instituted at accredited geriatric emergency departments (EDs).

METHODS: We analyzed a cross-section of a cohort of US EDs that received GEDA from May 2018 to March 2021. We obtained data from the American College of Emergency Physicians and publicly available sources. Data included GEDA level, geographic location, urban/rural designation, and care processes instituted. Frequencies and proportions and median and interquartile ranges were used to summarize categorical and continuous data, respectively.

RESULTS: Over the study period, 225 …

Digital Interventions To Address Mental Health Needs In Colleges: Perspectives Of Student Stakeholders, Naira Topooco, Lauren A Fowler, Ellen E Fitzsimmons-Craft, Bianca Depietro, Melissa M Vázquez, Marie-Laure Firebaugh, Peter Ceglarek, Grace Monterubio, Michelle G Newman, Daniel Eisenberg, Denise E Wilfley, C Barr Taylor

2020-Current year OA Pubs

OBJECTIVE: The need for clinical services in U.S. colleges exceeds the supply. Digital Mental health Interventions (DMHIs) are a potential solution, but successful implementation depends on stakeholder acceptance. This study investigated the relevance of DMHIs from students' perspectives.

METHODS: In 2020-2021, an online cross-sectional survey using mixed methods was conducted with 479 students at 23 colleges and universities. Respondents reported views and use of standard mental health services and DMHIs and rated the priority of various DMHIs to be offered through campus services. Qualitative data included open-ended responses.

FINDINGS: Among respondents, 91% reported having experienced mental health problems, of which …

Clinical Validation Of Guardant360 Cdx As A Blood-Based Companion Diagnostic For Sotorasib, Joshua M Bauml, Bob T Li, Vamsidhar Velcheti, Ramaswamy Govindan, Alessandra Curioni-Fontecedro, Christophe Dooms, Toshiaki Takahashi, Andrew W Duda, Justin I Odegaard, Fernando Cruz-Guilloty, Liming Jin, Ying Zhang, Abraham Anderson, Ferdinandos Skoulidis

2020-Current year OA Pubs

OBJECTIVES: Effective therapy for non-small-cell lung cancer (NSCLC) depends on morphological and genomic classification, with comprehensive screening for guideline-recommended biomarkers critical to guide treatment. Companion diagnostics, which provide robust genotyping results, represent an important component of personalized oncology. We evaluated the clinical validity of Guardant360 CDx as a companion diagnostic for sotorasib for detection of KRAS p.G12C, an important oncogenic NSCLC driver mutation.

MATERIALS AND METHODS: KRAS p.G12C was tested in NSCLC patients from CodeBreaK100 (NCT03600833) in pretreatment plasma samples using Guardant360 CDx liquid biopsy and archival tissue samples using therascreen® KRAS RGQ polymerase chain reaction (PCR) kit tissue testing. …

Soluble Trem2 In Csf And Its Association With Other Biomarkers And Cognition In Autosomal-Dominant Alzheimer's Disease: A Longitudinal Observational Study, Estrella Morenas-Rodríguez, Yan Li, Chengjie Xiong, Anne M. Fagan, Stephanie Schultz, Brian A. Gordon, Tammie L. S. Benzinger, Jason Hassenstab, Eric Mcdade, Celeste M. Karch, John C. Morris, Randall J. Bateman, Et Al.

2020-Current year OA Pubs

BACKGROUND: Therapeutic modulation of TREM2-dependent microglial function might provide an additional strategy to slow the progression of Alzheimer's disease. Although studies in animal models suggest that TREM2 is protective against Alzheimer's pathology, its effect on tau pathology and its potential beneficial role in people with Alzheimer's disease is still unclear. Our aim was to study associations between the dynamics of soluble TREM2, as a biomarker of TREM2 signalling, and amyloid β (Aβ) deposition, tau-related pathology, neuroimaging markers, and cognitive decline, during the progression of autosomal dominant Alzheimer's disease.

METHODS: We did a longitudinal analysis of data from the Dominantly Inherited …

Suppressing Fatty Acid Synthase By Type I Interferon And Chemical Inhibitors As A Broad Spectrum Anti-Viral Strategy Against Sars-Cov-2, Saba R. Aliyari, Xiaochao Wei, Clay F. Semenkovich, Et Al.

2020-Current year OA Pubs

SARS-CoV-2 is an emerging viral pathogen and a major global public health challenge since December of 2019, with limited effective treatments throughout the pandemic. As part of the innate immune response to viral infection, type I interferons (IFN-I) trigger a signaling cascade that culminates in the activation of hundreds of genes, known as interferon stimulated genes (ISGs), that collectively foster an antiviral state. We report here the identification of a group of type I interferon suppressed genes, including fatty acid synthase (FASN), which are involved in lipid metabolism. Overexpression of FASN or the addition of its downstream product, palmitate, increased …

Clinical Outcomes From The Assessing Donor-Derived Cell-Free Dna Monitoring Insights Of Kidney Allografts With Longitudinal Surveillance (Admiral) Study, Lihong Bu, Haris Murad, Tarek Alhamad, Et Al.

2020-Current year OA Pubs

The use of routine monitoring of donor-derived cell-free DNA (dd-cfDNA) after kidney transplant may allow clinicians to identify subclinical allograft injury and intervene prior to development of clinically evident graft injury. To evaluate this, data from 1092 kidney transplant recipients monitored for dd-cfDNA over a three-year period was analyzed to assess the association of dd-cfDNA with histologic evidence of allograft rejection. Elevation of dd-cfDNA (0.5% or more) was significantly correlated with clinical and subclinical allograft rejection. dd-cfDNA values of 0.5% or more were associated with a nearly three-fold increase in risk development of de novo donor-specific antibodies (hazard ratio 2.71) …

Soluble Trem2: Innocent Bystander Or Active Player In Neurological Diseases?, Fabia Filipello, Claire Goldsbury, Shih Feng You, Alberto Locca, Celeste M Karch, Laura Piccio

2020-Current year OA Pubs

Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed by macrophages and microglia in the central nervous system (CNS). TREM2 has attracted a lot of interest in the past decade for its critical role in modulating microglia functions under homeostatic conditions and in neurodegenerative diseases. Genetic variation in TREM2 is sufficient to cause Nasu-Hakola disease, a rare pre-senile dementia with bone cysts, and to increase risk for Alzheimer's disease, frontotemporal dementia, and other neurodegenerative disorders. Beyond the role played by TREM2 genetic variants in these diseases, TREM2 engagement is a key step in microglia activation …

Depression Interventions For Individuals With Coronary Artery Disease - Cost-Effectiveness Calculations From An Irish Perspective, Samira Barbara Jabakhanji, Jan Sorensen, Robert M Carney, Chris Dickens, Martin Dempster, Jonathan Gallagher, Isabela Caramlau, Frank Doyle

2020-Current year OA Pubs

BACKGROUND: A substantial proportion of individuals with coronary artery disease experience moderate or severe acute depression that requires treatment. We assessed the cost-effectiveness of four interventions for depression in individuals with coronary artery disease.

METHODS: We assessed effectiveness of pharmacotherapy, psychotherapy, collaborative care and exercise as remission rate after 8 and 26 weeks using estimates from a recent network meta-analysis. The cost assessment included standard doses of antidepressants, contact frequency, and staff time per contact. Unit costs were calculated as health services' purchase price for pharmaceuticals and mid-point staff salaries obtained from the Irish Health Service Executive and validated by …

Implementation And Early Experience Of A Pediatric Electrophysiology Telehealth Program, Jonathan Schweber, Lisa Roelle, Juliana Ocasio, Aarti S Dalal, Nathan Miller, George F Van Hare, Jennifer N Avari Silva

2020-Current year OA Pubs

BACKGROUND: Telehealth (TH) visits have been growing with exponential increased utilization during the COVID-19 pandemic. The aim of this manuscript is to describe the implementation and early experience of a pediatric electrophysiology (EP) TH program implemented during the pandemic, assessing patient satisfaction, patient equity and inclusion (measured by geographical outreach), and sustainability.

METHODS: A retrospective chart review study was performed and data were collected from the medical record, including demographic, testing, and billing data from scheduled TH encounters between March and August 2020 of a single pediatric EP group in the Midwest. Patients were called to complete satisfaction surveys.

RESULTS: …

Deglutarylation Of Glutaryl-Coa Dehydrogenase By Deacylating Enzyme Sirt5 Promotes Lysine Oxidation In Mice, Dhaval P Bhatt, C Allie Mills, Kristin A Anderson, Bárbara J Henriques, Tânia G Lucas, Sara Francisco, Juan Liu, Olga R Ilkayeva, Alexander E Adams, Shreyas R Kulkarni, Donald S Backos, Michael B Major, Paul A Grimsrud, Cláudio M Gomes, Matthew D Hirschey

2020-Current year OA Pubs

A wide range of protein acyl modifications has been identified on enzymes across various metabolic processes; however, the impact of these modifications remains poorly understood. Protein glutarylation is a recently identified modification that can be nonenzymatically driven by glutaryl-CoA. In mammalian systems, this unique metabolite is only produced in the lysine and tryptophan oxidative pathways. To better understand the biology of protein glutarylation, we studied the relationship between enzymes within the lysine/tryptophan catabolic pathways, protein glutarylation, and regulation by the deglutarylating enzyme sirtuin 5 (SIRT5). Here, we identify glutarylation on the lysine oxidation pathway enzyme glutaryl-CoA dehydrogenase (GCDH) and show …

When Reboa Grows Wings: Resuscitative Endovascular Balloon Occlusion Of The Aorta To Facilitate Aeromedical Transport, Jason A Snyder, Douglas J E Schuerer, Grant V Bochicchio, Mark H Hoofnagle

2020-Current year OA Pubs

BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a helpful adjunct in the control of non-compressible truncal hemorrhage. Concerns regarding ischemia time limits its applicability in transfer. We describe the first reported case of civilian transfer via aeromedical transport to a higher level of care with a zone 3 REBOA catheter deployed.

CASE REPORT: We present the case of a patient in hemorrhagic shock with a complex pelvic fracture exceeding the capability of a rural level-two trauma center requiring the use of REBOA catheter to permit aeromedical transport to a level-one trauma center for definitive embolization.

CONCLUSION: Deployment …

Joanne Knight Breast Health Cohort At Siteman Cancer Center, Graham A Colditz, Debbie L Bennett, Jennifer Tappenden, Courtney Beers, Nicole Ackermann, Ningying Wu, Jingqin Luo, Sarah Humble, Erin Linnenbringer, Kia Davis, Shu Jiang, Adetunji T Toriola

2020-Current year OA Pubs

PURPOSE: The Joanne Knight Breast Health Cohort was established to link breast cancer risk factors, mammographic breast density, benign breast biopsies and associated tissue markers, and blood markers in a diverse population of women undergoing routine mammographic screening to study risk factors and validate models for breast cancer risk prediction.

METHODS: Women were recruited from November 2008 to April 2012 through the mammography service at the Joanne Knight Breast Health Center at Washington University in St. Louis, Missouri. Baseline questionnaire risk factors, blood, and screening mammograms were collected from 12,153 women. Of these, 1,672 were excluded for prior history of …

Phase 1b Trial Of Anti-Vegf/Pdgfr Vorolanib Combined With Immune Checkpoint Inhibitors In Patients With Advanced Solid Tumors, Nusayba A Bagegni, Haeseong Park, Katlyn Kraft, Maura O-Toole, Feng Gao, Saiama N Waqar, Lee Ratner, Daniel Morgensztern, Siddhartha Devarakonda, Manik Amin, Maria Q Baggstrom, Chris Liang, Giovanni Selvaggi, Andrea Wang-Gillam

2020-Current year OA Pubs

PURPOSE: Vorolanib is a multi-target tyrosine kinase inhibitor with anti-angiogenic properties. This study aimed to evaluate the tolerability, safety and efficacy of vorolanib when added to checkpoint inhibitors (CPIs) in patients with advanced solid tumors.

METHODS: We conducted a phase 1b study of vorolanib (300 or 400 mg orally once daily) plus pembrolizumab or nivolumab using a standard 3 + 3 design to determine the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). The endpoints included safety, toxicity and objective response rate, according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1).

RESULTS: …

High-Throughput Methodology To Identify Crispr-Generated Danio Rerio Mutants Using Fragment Analysis With Unmodified Pcr Products, Sarah Colijn, Ying Yin, Amber N Stratman

2020-Current year OA Pubs

Targeted mutagenesis in zebrafish, fruit flies, and C. elegans has been significantly improved over the years through CRISPR technology. CRISPR enables researchers to efficiently examine cellular pathways by inducing small, targeted mutations in vivo. Though these mutations are commonly random insertions or deletions (indels), they often result in functionally disrupted alleles of a target gene if the CRISPR components are appropriately designed. However, current protocols used to identify the presence of CRISPR-generated indels are often labor intensive, time-consuming, or expensive. Here, we describe a straightforward, high-throughput method for identifying the presence of mutations by using a fragment analyzer platform which …

Better Together: Integrating Biomedical Informatics And Healthcare It Operations To Create A Learning Health System During The Covid-19 Pandemic, Philip R O Payne, Adam B Wilcox, Peter J Embi, Christopher A Longhurst

2020-Current year OA Pubs

The growing availability of multi-scale biomedical data sources that can be used to enable research and improve healthcare delivery has brought about what can be described as a healthcare "data age." This new era is defined by the explosive growth in bio-molecular, clinical, and population-level data that can be readily accessed by researchers, clinicians, and decision-makers, and utilized for systems-level approaches to hypothesis generation and testing as well as operational decision-making. However, taking full advantage of these unprecedented opportunities presents an opportunity to revisit the alignment between traditionally academic biomedical informatics (BMI) and operational healthcare information technology (HIT) personnel and …

First-In-Human, Open-Label, Phase 1/2 Study Of The Monoclonal Antibody Programmed Cell Death Protein-1 (Pd-1) Inhibitor Cetrelimab (Jnj-63723283) In Patients With Advanced Cancers, Enriqueta Felip, Daniel Morgensztern, Et Al.

2020-Current year OA Pubs

PURPOSE: To assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of cetrelimab (JNJ-63723283), a monoclonal antibody programmed cell death protein-1 (PD-1) inhibitor, in patients with advanced/refractory solid tumors in the phase 1/2 LUC1001 study.

METHODS: In phase 1, patients with advanced solid tumors received intravenous cetrelimab 80, 240, 460, or 800 mg every 2 weeks (Q2W) or 480 mg Q4W. In phase 2, patients with melanoma, non-small-cell lung cancer (NSCLC), and microsatellite instability-high (MSI-H)/DNA mismatch repair-deficient colorectal cancer (CRC) received cetrelimab 240 mg Q2W. Response was assessed Q8W until Week 24 and Q12W thereafter.

RESULTS: In phase 1, 58 patients …

An International Survey On Nasal Nitric Oxide Measurement Practices For The Diagnosis Of Primary Ciliary Dyskinesia, Nicole Beydon, Thomas Ferkol, Et Al.

2020-Current year OA Pubs

Nasal nitric oxide (nNO) measurements are used in the assessment of patients suspected of having primary ciliary dyskinesia (PCD), but recommendations for performing such measurements have not focused on children and do not include all current practices. To guide the development of a European Respiratory Society-supported technical standard for nNO measurement in children, an international online survey was conducted to better understand current measurement practices among providers involved in PCD diagnostics. 78 professionals responded, representing 65 centres across 18 countries, mainly in Europe and North America. Nearly all centres measured nNO in children and more than half performed measurements before …

Parent-Of-Origin Effects Propagate Through Networks To Shape Metabolic Traits, Juan F Macias-Velasco, Celine L St Pierre, Jessica P Wayhart, Li Yin, Larry Spears, Mario A Miranda, Caryn Carson, Katsuhiko Funai, James M Cheverud, Clay F Semenkovich, Heather A Lawson

2020-Current year OA Pubs

Parent-of-origin effects are unexpectedly common in complex traits, including metabolic and neurological traits. Parent-of-origin effects can be modified by the environment, but the architecture of these gene-by-environmental effects on phenotypes remains to be unraveled. Previously, quantitative trait loci (QTL) showing context-specific parent-of-origin effects on metabolic traits were mapped in the F

Differential Function And Maturation Of Human Stem Cell-Derived Islets After Transplantation, Kristina G Maxwell, Michelle H Kim, Sarah E Gale, Jeffrey R Millman

2020-Current year OA Pubs

Insulin-producing stem cell-derived islets (SC-islets) provide a virtually unlimited cell source for diabetes cell replacement therapy. While SC-islets are less functional when first differentiated in vitro compared to isolated cadaveric islets, transplantation into mice has been shown to increase their maturation. To understand the effects of transplantation on maturation and function of SC-islets, we examined the effects of cell dose, transplantation strategy, and diabetic state in immunocompromised mice. Transplantation of 2 and 5, but not 0.75 million SC-islet cells underneath the kidney capsule successfully reversed diabetes in mice with pre-existing diabetes. SQ and intramuscular injections failed to reverse diabetes at …

Computationally Driven Discovery Of Sars-Cov-2 M Pro Inhibitors: From Design To Experimental Validation, Léa El Khoury, Jay W Ponder, Et Al

2020-Current year OA Pubs

We report a fast-track computationally driven discovery of new SARS-CoV-2 main protease (M

Stronger Microstructural Damage Revealed In Multiple Sclerosis Lesions With Central Vein Sign By Quantitative Gradient Echo Mri, Victoria A Levasseur, Biao Xiang, Amber Salter, Dmitriy A Yablonskiy, Anne H Cross

2020-Current year OA Pubs

BACKGROUND: Multiple sclerosis (MS) lesions typically form around a central vein that can be visualized with FLAIR* MRI, creating the central vein sign (CVS) which may reflect lesion pathophysiology. Herein we used gradient echo plural contrast imaging (GEPCI) MRI to simultaneously visualize CVS and measure tissue damage in MS lesions. We examined CVS in relation to tissue integrity in white matter (WM) lesions and among MS subtypes.

OBJECTIVE: We aimed to determine if CVS positive lesions were specific to MS subtype, if CVS can be detected consistently among readers using the GEPCI method, and if there were differences in tissue …

Btla Signaling In Conventional And Regulatory Lymphocytes Coordinately Tempers Humoral Immunity In The Intestinal Mucosa, Caroline Stienne, Richard Virgen-Slane, Lisa Elmén, Marisol Veny, Sarah Huang, Jennifer Nguyen, Elizabeth Chappell, Mary Olivia Balmert, Jr-Wen Shui, Michelle A Hurchla, Mitchell Kronenberg, Scott N Peterson, Kenneth M Murphy, Carl F Ware, John R Šedý

2020-Current year OA Pubs

The Btla inhibitory receptor limits innate and adaptive immune responses, both preventing the development of autoimmune disease and restraining anti-viral and anti-tumor responses. It remains unclear how the functions of Btla in diverse lymphocytes contribute to immunoregulation. Here, we show that Btla inhibits activation of genes regulating metabolism and cytokine signaling, including Il6 and Hif1a, indicating a regulatory role in humoral immunity. Within mucosal Peyer's patches, we find T-cell-expressed Btla-regulated Tfh cells, while Btla in T or B cells regulates GC B cell numbers. Treg-expressed Btla is required for cell-intrinsic Treg homeostasis that subsequently controls GC B cells. Loss of …

Rationally Designed Immunogens Enable Immune Focusing Following Sars-Cov-2 Spike Imprinting, Blake M Hauser, Maya Sangesland, Kerri J St Denis, Evan C Lam, James Brett Case, Ian W Windsor, Jared Feldman, Timothy M Caradonna, Ty Kannegieter, Michael S Diamond, Alejandro B Balazs, Daniel Lingwood, Aaron G Schmidt

2020-Current year OA Pubs

Eliciting antibodies to surface-exposed viral glycoproteins can generate protective responses that control and prevent future infections. Targeting conserved sites may reduce the likelihood of viral escape and limit the spread of related viruses with pandemic potential. Here we leverage rational immunogen design to focus humoral responses on conserved epitopes. Using glycan engineering and epitope scaffolding in boosting immunogens, we focus murine serum antibody responses to conserved receptor binding motif (RBM) and receptor binding domain (RBD) epitopes following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike imprinting. Although all engineered immunogens elicit a robust SARS-CoV-2-neutralizing serum response, RBM-focusing immunogens exhibit increased …

Prospectively Defined Patterns Of Apobec3a Mutagenesis Are Prevalent In Human Cancers, Rachel A Deweerd, Eszter Németh, Ádám Póti, Nataliya Petryk, Chun-Long Chen, Olivier Hyrien, Dávid Szüts, Abby M Green

2020-Current year OA Pubs

Mutational signatures defined by single base substitution (SBS) patterns in cancer have elucidated potential mutagenic processes that contribute to malignancy. Two prevalent mutational patterns in human cancers are attributed to the APOBEC3 cytidine deaminase enzymes. Among the seven human APOBEC3 proteins, APOBEC3A is a potent deaminase and proposed driver of cancer mutagenesis. In this study, we prospectively examine genome-wide aberrations by expressing human APOBEC3A in avian DT40 cells. From whole-genome sequencing, we detect hundreds to thousands of base substitutions per genome. The APOBEC3A signature includes widespread cytidine mutations and a unique insertion-deletion (indel) signature consisting largely of cytidine deletions. This …