Digital Commons Network^™

Tauroursodeoxycholic Acid Ameliorates Renal Injury Induced By Col4a3 Mutation, Shuwen Yu, Teija Suhas, Meei-Hua Lin, Jeffrey H Miner, Et Al.

2020-Current year OA Pubs

COL4A3/A4/A5 mutations have been identified as critical causes of Alport syndrome and other genetic chronic kidney diseases. However, the underlying pathogenesis remains unclear, and specific treatments are lacking. Here, we constructed a transgenic Alport syndrome mouse model by generating a mutation (Col4a3 p.G799R) identified previously from one large Alport syndrome family into mice. We observed that the mutation caused a pathological decrease in intracellular and secreted collagen IV α3α4α5 heterotrimers. The mutant collagen IV α3 chains abnormally accumulated in the endoplasmic reticulum and exhibited defective secretion, leading to persistent endoplasmic reticulum stress in vivo and in vitro. RNA-seq analysis revealed …

Dynamic Changes In Circulating Tumor Fraction As A Predictor Of Real-World Clinical Outcomes In Solid Tumor Malignancy Patients Treated With Immunotherapy, Ryan D Gentzler, Aadel A Chaudhuri, Et Al.

2020-Current year OA Pubs

INTRODUCTION: A dynamic molecular biomarker that can identify early efficacy of immune checkpoint inhibitor (ICI) therapy remains an unmet clinical need. Here we evaluate if a novel circulating tumor DNA (ctDNA) assay, xM, used for treatment response monitoring (TRM), that quantifies changes in ctDNA tumor fraction (TF), can predict outcome benefits in patients treated with ICI alone or in combination with chemotherapy in a real-world (RW) cohort.

METHODS: This retrospective study consisted of patients with advanced cancer from the Tempus de-identified clinical genomic database who received longitudinal liquid-based next-generation sequencing. Eligible patients had a blood sample ≤ 40 days prior …

Comparison Of Outcomes Of Abdominoperineal Resection Vs Low Anterior Resection In Very-Low Rectal Cancer, Roberta L Muldoon, Alva J Bethurum, Adriana C Gamboa, Kevin Zhang, Fei Ye, Scott E Regenbogen, Sherif Abdel-Misih, Aslam Ejaz, Paul E Wise, Matthew Silviera, Jennifer Holder-Murray, Glen C Balch, Alexander T Hawkins

2020-Current year OA Pubs

BACKGROUND: The management of very-low rectal cancer is one of the most challenging issues faced by general and colorectal surgeons. Many feel compelled to pursue abdominoperineal resection (APR) over low anterior resection (LAR) to optimize oncologic outcomes. This study aimed to determine differences in long-term oncologic outcomes between patients undergoing APR or LAR for very-low rectal cancer.

METHODS: The United States Rectal Cancer Consortium (2010-2016) was queried for adults who underwent either APR or LAR for stage I-III rectal cancers < 5 cm from anorectal junction and met inclusion criteria. The primary outcome was disease-free survival. Secondary outcomes included overall survival, length of stay, complications, recurrence location, and perioperative factors.

RESULTS: A total of 431 patients with very-low rectal cancer who underwent APR or LAR were identified; 154 (35.7%) underwent …

An Interpretable Machine Learning-Based Cerebrospinal Fluid Proteomics Clock For Predicting Age Reveals Novel Insights Into Brain Aging, Justin Melendez, Yun Ju Sung, Miranda Orr, Andrew Yoo, Suzanne Schindler, Carlos Cruchaga, Randall Bateman

2020-Current year OA Pubs

Machine learning can be used to create "biologic clocks" that predict age. However, organs, tissues, and biofluids may age at different rates from the organism as a whole. We sought to understand how cerebrospinal fluid (CSF) changes with age to inform the development of brain aging-related disease mechanisms and identify potential anti-aging therapeutic targets. Several epigenetic clocks exist based on plasma and neuronal tissues; however, plasma may not reflect brain aging specifically and tissue-based clocks require samples that are difficult to obtain from living participants. To address these problems, we developed a machine learning clock that uses CSF proteomics to …

Genetic Risk Accentuates Dietary Effects On Hepatic Steatosis, Inflammation And Fibrosis In A Population-Based Cohort, Vincent L Chen, Xiaomeng Du, Antonino Oliveri, Yanhua Chen, Annapurna Kuppa, Brian D Halligan, Michael A Province, Elizabeth K Speliotes

2020-Current year OA Pubs

BACKGROUND & AIMS: Steatotic liver disease (SLD), characterized by elevated liver fat content (LFC), is influenced by genetics and diet. However, whether diet has a differential effect based on genetic risk is not well-characterized. We aimed to determine how genetic factors interact with diet to affect SLD in a large national biobank.

METHODS: We included UK Biobank participants with dietary intake measured by 24-hour recall and genotyping. The primary predictors were dietary pattern, PNPLA3-rs738409-G, TM6SF2-rs58542926-T, a 16-variant hepatic steatosis polygenic risk score (PRS), and gene-environment interactions. The primary outcome was LFC, and secondary outcomes were iron-controlled T1 time (cT1, a …

Evaluation Of Knowledge-Based Planning Models For Male Pelvic Cbct-Based Online Adaptive Radiotherapy On Conventional Linear Accelerators, Riley C Tegtmeier, Edward L Clouser, Brady S Laughlin, Diego A Santos Toesca, Mattison J Flakus, Sara Bashir, Christopher J Kutyreff, Dean Hobbis, Daniel P Harrington, Jennifer L Smetanick, Nathan Y Yu, Carlos E Vargas, Sarah E James, Jean-Claude M Rwigema, Yi Rong

2020-Current year OA Pubs

PURPOSE: To assess the practicality of employing a commercial knowledge-based planning tool (RapidPlan) to generate adapted intact prostate and prostate bed volumetric modulated arc therapy (VMAT) plans on iterative cone-beam computed tomography (iCBCT) datasets.

METHODS AND MATERIALS: Intact prostate and prostate bed RapidPlan models were trained utilizing planning data from 50 and 44 clinical cases, respectively. To ensure that refined models were capable of producing adequate clinical plans with a single optimization, models were tested with 50 clinical planning CT datasets by comparing dose-volume histogram (DVH) and plan quality metric (PQM) values between clinical and RapidPlan-generated plans. The RapidPlan tool …

A Damaging Col6a3 Variant Alters The Mir31hg-Regulated Response Of Chondrocytes In Neocartilage Organoids To Hyperphysiologic Mechanical Loading, Niek Gc Bloks, Zainab Harissa, Giorgia Mazzini, Shaunak S Adkar, Amanda R Dicks, Ghazaleh Hajmousa, Nancy Steward, Roman I Koning, Aat Mulder, Berend B R De Koning, Margreet Kloppenburg, Rodrigo Coutinho De Almeida, Yolande Fm Ramos, Farshid Guilak, Ingrid Meulenbelt

2020-Current year OA Pubs

The pericellular matrix (PCM), with its hallmark proteins collagen type VI (COLVI) and fibronectin (FN), surrounds chondrocytes and is critical in transducing the biomechanical cues. To identify genetic variants that change protein function, exome sequencing is performed in a patient with symptomatic OA at multiple joint sites. A predicted damaging variant in COL6A3 is identified and introduced by CRISPR-Cas9 genome engineering in two established human induced pluripotent stem cell-derived in-vitro neocartilage organoid models. The downstream effects of the COL6A3 variant on the chondrocyte phenotypic state are studied by a multi-omics (mRNA and lncRNA) approach in interaction with hyper-physiological mechanical loading …

Expert Panel Curation Of 31 Genes In Relation To Limb Girdle Muscular Dystrophy, Shruthi Mohan, Kelly Macalalad, Amanda R Clause, Conrad C Weihl, Et Al.

2020-Current year OA Pubs

OBJECTIVE: Limb girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous autosomal conditions with some degree of phenotypic homogeneity. LGMD is defined as having onset >2 years of age with progressive proximal weakness, elevated serum creatine kinase levels and dystrophic features on muscle biopsy. Advances in massively parallel sequencing have led to a surge in genes linked to LGMD.

METHODS: The ClinGen Muscular Dystrophies and Myopathies gene curation expert panel (MDM GCEP, formerly Limb Girdle Muscular Dystrophy GCEP) convened to evaluate the strength of evidence supporting gene-disease relationships (GDR) using the ClinGen gene-disease clinical validity framework to evaluate 31 …

"Allowing Space For Voice…All Our Voices:" Understanding Ho'ouna Pono Implementation Through Educational Leadership Perspectives In Rural Hawai'i Schools, Kelsie H Okamura, Tessa Palafu, Katlyn An, Sarah Momilani Marshall, Steven Keone Chin, Kelly A Stern, Byron J Powell, Sara J Becker, David S Mandell, Scott K Okamoto

2020-Current year OA Pubs

Epidemiological research over the past two decades has highlighted substance use disparities that affect Native Hawaiian and Pacific Islander youth, and the lack of effective approaches to address such disparities (Okamoto et al., 2019). The Ho'ouna Pono curriculum is a culturally grounded, teacher-implemented, video-enhanced substance use prevention program that has demonstrated efficacy in rural Hawai'i in a large-scale trial (Okamoto et al., 2019). Despite its potential to ameliorate health disparities and address youth substance use, prevention programs such as Ho'ouna Pono have been poorly disseminated and implemented across Hawai'i, raising the question:

Mutant Nrf2e79q Enhances The Promotion And Progression Of A Subset Of Oncogenic Ras Keratinocytes And Skin Tumors, John G Witherspoon, Jonathan R Hall, Dereje Jima, Hannah M Atkins, Nathan T Wamsley, Michael B Major, Bernard E Weissman, Robert C Smart

2020-Current year OA Pubs

Squamous cell carcinomas (SCCs), including lung, head & neck, bladder, and skin SCCs often display constitutive activation of the KEAP1-NRF2 pathway. Constitutive activation is achieved through multiple mechanisms, including activating mutations in NFE2L2 (NRF2). To determine the functional consequences of Nrf2 activation on skin SCC development, we assessed the effects of mutant Nrf2

Echocardiograms And Bed Placement In Patients With Multisystem Inflammatory Syndrome In Children, Hafsa Lodhi, Emma Singer, Mary Claire Mcglynn, Jinli Wang, Erik Hoefgen, Mythili Srinivasan, William B. Orr

2020-Current year OA Pubs

BACKGROUND: Understanding of multisystem inflammatory syndrome in children (MIS-C) continues to evolve with extensive evaluations, including echocardiograms, obtained in emergency departments (EDs) to assist with clinical decision making and bed allocation. We assessed the utility of obtaining echocardiograms in the ED to assist in determining bed placement for this patient population.

METHODS: This 2-year retrospective single-center study of patients 0-21 years old without underlying cardiac disease hospitalized for MIS-C focused on individuals whose initial evaluation occurred in the institution's ED and whose echocardiogram was obtained either in the ED or within 24 hours of admission. Patients were placed in two …

Regulatory Transposable Elements In The Encyclopedia Of Dna Elements, Alan Y Du, Jason D Chobirko, Xiaoyu Zhuo, Cédric Feschotte, Ting Wang

2020-Current year OA Pubs

Transposable elements (TEs) comprise ~50% of our genome, but knowledge of how TEs affect genome evolution remains incomplete. Leveraging ENCODE4 data, we provide the most comprehensive study to date of TE contributions to the regulatory genome. We find 236,181 (~25%) human candidate cis-regulatory elements (cCREs) are TE-derived, with over 90% lineage-specific since the human-mouse split, accounting for 8-36% of lineage-specific cCREs. Except for SINEs, cCRE-associated transcription factor (TF) motifs in TEs are derived from ancestral TE sequence more than expected by chance. We show that TEs may adopt similar regulatory activities of elements near their integration site. Since human-mouse divergence, …

Loss Of Periostin Function Impairs Ligament Fibroblast Activity And Facilitates Ros-Mediated Cellular Senescence, Muhammad Farooq Rai, Xin Duan, Mingming Yan, Robert H Brophy, Lei Cai

2020-Current year OA Pubs

Anterior cruciate ligament (ACL) injuries pose a significant challenge due to their limited healing potential, often resulting in premature arthritis. The factors and mechanisms contributing to this inadequate healing process remain elusive. During the acute phase of injury, ACL tissues express elevated periostin levels that decline over time. The functional significance of periostin in ligament biology remains understudied. In this study, we investigated the functional and mechanistic implications of periostin deficiency in ACL biology, utilizing ligament fibroblasts derived from patients and a murine model of ACL rupture. Our investigations unveiled that periostin knockdown compromised fibroblast growth characteristics, hindered the egress …

Association Between Growth Differentiation Factor-15 And Adverse Outcomes Among Patients With Heart Failure: A Systematic Literature Review, Ali Javaheri, Mualla Ozcan, Lauren Moubarak, Karen E Smoyer, Michelle I Rossulek, James H Revkin, John D Groarke, Lisa C Tarasenko, Mikhail N Kosiborod

2020-Current year OA Pubs

Growth differentiation factor-15 (GDF-15) is an emerging biomarker in several conditions. This SLR, conducted following PRISMA guidelines, examined the association between GDF-15 concentration and range of adverse outcomes in patients with heart failure (HF). Publications were identified from Embase® and Medline® bibliographic databases between January 1, 2014, and August 23, 2022 (congress abstracts: January 1, 2020, to August 23, 2022). Sixty-three publications met the eligibility criteria (55 manuscripts and 8 abstracts; 45 observational studies and 18 post hoc analyses of randomized controlled trials [RCTs]). Of the 19 outcomes identified, the most frequently reported longitudinal outcomes were mortality (n = 32 …

Histone H3.3 Lysine 9 And 27 Control Repressive Chromatin At Cryptic Enhancers And Bivalent Promoters, Matteo Trovato, Daria Bunina, Umut Yildiz, Nadine Fernandez-Novel Marx, Michael Uckelmann, Vita Levina, Yekaterina Perez, Ana Janeva, Benjamin A Garcia, Chen Davidovich, Judith B Zaugg, Kyung-Min Noh

2020-Current year OA Pubs

Histone modifications are associated with distinct transcriptional states, but it is unclear whether they instruct gene expression. To investigate this, we mutate histone H3.3 K9 and K27 residues in mouse embryonic stem cells (mESCs). Here, we find that H3.3K9 is essential for controlling specific distal intergenic regions and for proper H3K27me3 deposition at promoters. The H3.3K9A mutation resulted in decreased H3K9me3 at regions encompassing endogenous retroviruses and induced a gain of H3K27ac and nascent transcription. These changes in the chromatin environment unleash cryptic enhancers, resulting in the activation of distinctive transcriptional programs and culminating in protein expression normally restricted to …

Brief Report: Incidence And Outcomes Of Pediatric Tracheal Intubation-Associated Cardiac Arrests In The Icu-Resus Clinical Trial, Akira Nishisaki, Stuart H Friess, Arushi Manga, Et Al.

2020-Current year OA Pubs

BACKGROUND: Tracheal intubation (TI)-associated cardiac arrest (TI-CA) occurs in 1.7% of pediatric ICU TIs. Our objective was to evaluate resuscitation characteristics and outcomes between cardiac arrest patients with and without TI-CA.

METHODS: Secondary analysis of cardiac arrest patients in both ICU-RESUS trial and ancillary CPR-NOVA study. The primary exposure was TI-CA, defined as cardiac arrest occurred during TI procedure or within 20 min after endotracheal tube placement. The primary outcome was survival to hospital discharge with favorable neurological outcome (Pediatric Cerebral Performance Category score 1-3 or unchanged).

RESULTS: Among 315 children with cardiac arrests, 48 (15.2%) met criteria for TI-CA. …

Cognitive Effects Of Simulated Galactic Cosmic Radiation Are Mediated By Apoe Status, Sex, And Environment In App Knock-In Mice, Laura Wieg, Jason C Ciola, Caroline C Wasén, Fidelia Gaba, Brianna R Colletti, Maren K Schroeder, Robert G Hinshaw, Millicent N Ekwudo, David M Holtzman, Takashi Saito, Hiroki Sasaguri, Takaomi C Saido, Laura M Cox, Cynthia A Lemere

2020-Current year OA Pubs

Cosmic radiation experienced during space travel may increase the risk of cognitive impairment. While simulated galactic cosmic radiation (GCRsim) has led to memory deficits in wildtype (WT) mice, it has not been investigated whether GCRsim in combination with genetic risk factors for Alzheimer's disease (AD) worsens memory further in aging mice. Here, we investigated the central nervous system (CNS) effects of 0 Gy (sham) or 0.75 Gy five-ion GCRsim or 2 Gy gamma radiation (IRR) in 14-month-old female and male APP

Novel Framework Of Financial Hardship In Childhood Cancer: Incorporating Stakeholder Perspectives, Julie Ritter, Sara M Malone, Et Al.

2020-Current year OA Pubs

PURPOSE: Although financial hardship in childhood cancer contributes to poor outcomes, no standardized tool to assess its impact exists. Existing methods are heterogeneous and designed using high-income country (HIC), adult perspectives. This project aimed to construct a stakeholder-informed conceptual framework of financial hardship in childhood cancer with global relevancy.

METHODS: Group concept mapping, a participatory mixed-methods approach, was used. Participants were parents or caregivers of a child with cancer, childhood cancer survivors, and clinical or nonclinical support personnel, fluent in English, Spanish, or Portuguese. A representative panel established a comprehensive list of relevant items. Participants individually sorted these items into …

West Nile Virus Triggers Intestinal Dysmotility Via T Cell-Mediated Enteric Nervous System Injury, Hana Janova, Fang R. Zhao, Pritesh Desai, Matthias Mack, Larissa B. Thackray, Thaddeus S. Stappenbeck, Michael S. Diamond

2020-Current year OA Pubs

Intestinal dysmotility syndromes have been epidemiologically associated with several antecedent bacterial and viral infections. To model this phenotype, we previously infected mice with the neurotropic flavivirus West Nile virus (WNV) and demonstrated intestinal transit defects. Here, we found that within 1 week of WNV infection, enteric neurons and glia became damaged, resulting in sustained reductions of neuronal cells and their networks of connecting fibers. Using cell-depleting antibodies, adoptive transfer experiments, and mice lacking specific immune cells or immune functions, we show that infiltrating WNV-specific CD4+ and CD8+ T cells damaged the enteric nervous system (ENS) and glia, which led to …

Structural Basis For Mouse Lag3 Interactions With The Mhc Class Ii Molecule I-Ab, Qianqian Ming, Daniel Antfolk, David A Price, Anna Manturova, Elliot Medina, Srishti Singh, Charlotte Mason, Timothy H Tran, Keiran S M Smalley, Daisy W Leung, Vincent C Luca

2020-Current year OA Pubs

The immune checkpoint protein, Lymphocyte activation gene-3 (LAG3), binds Major Histocompatibility Complex Class II (MHC-II) and suppresses T cell activation. Despite the recent FDA approval of a LAG3 inhibitor for the treatment of melanoma, how LAG3 engages MHC-II on the cell surface remains poorly understood. Here, we determine the 3.84 Å-resolution structure of mouse LAG3 bound to the MHC-II molecule I-A

Diet-Induced Obesity Induces Transcriptomic Changes In Neuroimmunometabolic-Related Genes In The Striatum And Olfactory Bulb, Rosario B Jaime-Lara, Claudia Colina-Prisco, Marcel De Jesus Vega, Sarah Williams, Ted Usdin, Bridget Matikainen-Ankney, Alayna Kinkead, Brianna Brooks, Yupeng Wang, Alexis T Franks, Alexxai Kravitz, Paule V Joseph

2020-Current year OA Pubs

The incidence of obesity has markedly increased globally over the last several decades and is believed to be associated with the easier availability of energy-dense foods, including high-fat foods. The reinforcing hedonic properties of high-fat foods, including olfactory cues, activate reward centers in the brain, motivating eating behavior. Thus, there is a growing interest in the understanding of the genetic changes that occur in the brain that are associated with obesity and eating behavior. This growing interest has paralleled advances in genomic methods that enable transcriptomic-wide analyses. Here, we examined the transcriptomic-level differences in the olfactory bulb and striatum, regions …

Signaling Modulation Mediated By Ligand Water Interactions With The Sodium Site At Μor, Rohini S Ople, Nokomis Ramos-Gonzalez, Sarah M Bernhard, Kevin Appourchaux, Sashrik Sribhashyam, Balazs R Varga, Susruta Majumdar, Et Al.

2020-Current year OA Pubs

The mu opioid receptor (μOR) is a target for clinically used analgesics. However, adverse effects, such as respiratory depression and physical dependence, necessitate the development of alternative treatments. Recently we reported a novel strategy to design functionally selective opioids by targeting the sodium binding allosteric site in μOR with a supraspinally active analgesic named

Nonreciprocity In Chikv And Mayv Vaccine-Elicited Protection, Whitney C Weber, Takeshi F Andoh, Craig N Kreklywich, Zachary J Streblow, Michael Denton, Magdalene M Streblow, John M Powers, Gauthami Sulgey, Samuel Medica, Igor Dmitriev, David T Curiel, Nicole N Haese, Daniel N Streblow

2020-Current year OA Pubs

Chikungunya virus (CHIKV) is a pathogenic arthritogenic alphavirus responsible for large-scale human epidemics for which a vaccine was recently approved for use. Mayaro virus (MAYV) is a related emerging alphavirus with epidemic potential with circulation overlap potential with CHIKV. We previously reported the ability of a non-replicating human adenovirus (AdV)-vectored vaccine expressing the MAYV structural polyprotein to protect against disease in mice following challenge with MAYV, CHIKV and UNAV. Herein, we evaluated mouse immunity and protective efficacy for an AdV-CHIKV full structural polyprotein vaccine in combination with heterologous AdV-MAYV prime/boost regimens versus vaccine coadministration. Heterologous prime/boost regimens skewed immunity toward …

Kmt2c Restricts G-Csf-Driven Hsc Mobilization And Granulocyte Production In A Methyltransferase-Independent Manner, Helen C Wang, Ran Chen, Wei Yang, Yanan Li, Rohini Muthukumar, Riddhi M Patel, Emily B Casey, Elisabeth Denby, Jeffrey A Magee

2020-Current year OA Pubs

Granulocyte colony-stimulating factor (G-CSF) is widely used to enhance myeloid recovery after chemotherapy and to mobilize hematopoietic stem cells (HSCs) for transplantation. Unfortunately, through the course of chemotherapy, cancer patients can acquire leukemogenic mutations that cause therapy-related myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). This raises the question of whether therapeutic G-CSF might potentiate therapy-related MDS/AML by disproportionately stimulating mutant HSCs and other myeloid progenitors. A common mutation in therapy-related MDS/AML involves chromosome 7 deletions that inactivate many tumor suppressor genes, including KMT2C. Here, we show that Kmt2c deletions hypersensitize murine HSCs and myeloid progenitors to G-CSF, as evidenced …

Baf155 Controls Hematopoietic Differentiation And Regeneration Through Chromatin Priming, Jun Wu, Changxu Fan, Ashraf Ul Kabir, Karen Krchma, Minseo Kim, Yoojung Kwon, Xiaoyun Xing, Ting Wang, Kyunghee Choi

2020-Current year OA Pubs

Chromatin priming promotes cell-type-specific gene expression, lineage differentiation, and development. The mechanism of chromatin priming has not been fully understood. Here, we report that mouse hematopoietic stem and progenitor cells (HSPCs) lacking the Baf155 subunit of the BAF (BRG1/BRM-associated factor) chromatin remodeling complex produce a significantly reduced number of mature blood cells, leading to a failure of hematopoietic regeneration upon transplantation and 5-fluorouracil (5-FU) injury. Baf155-deficient HSPCs generate particularly fewer neutrophils, B cells, and CD8

A Rad18-Ubc13-Palb2-Rnf168 Axis Mediates Replication Fork Recovery In Brca1-Deficient Cancer Cells, Emily Cybulla, Sierra Wallace, Alice Meroni, Jessica Jackson, Sumedha Agashe, Mithila Tennakoon, Mangsi Limbu, Annabel Quinet, Elena Lomonosova, Hollie Noia, Stephanie Tirman, Matthew Wood, Alessandro Vindigni, Et Al.

2020-Current year OA Pubs

BRCA1/2 proteins function in genome stability by promoting repair of double-stranded DNA breaks through homologous recombination and by protecting stalled replication forks from nucleolytic degradation. In BRCA1/2-deficient cancer cells, extensively degraded replication forks can be rescued through distinct fork recovery mechanisms that also promote cell survival. Here, we identified a novel pathway mediated by the E3 ubiquitin ligase RAD18, the E2-conjugating enzyme UBC13, the recombination factor PALB2, the E3 ubiquitin ligase RNF168 and PCNA ubiquitination that promotes fork recovery in BRCA1- but not BRCA2-deficient cells. We show that this pathway does not promote fork recovery by preventing replication fork reversal …

Dual Color Optogenetic Tool Enables Heart Arrest, Bradycardic, And Tachycardic Pacing In Drosophila Melanogaster, Elena Gracheva, Yuxuan Wang, Jiantao Zhu, Fei Wang, Abigail Matt, Matthew Fishman, Hongwu Liang, Chao Zhou

2020-Current year OA Pubs

In order to facilitate cardiovascular research to develop non-invasive optical heart pacing methods, we have generated a double-transgenic Drosophila melanogaster (fruit fly) model suitable for optogenetic pacing. We created a fly stock with both excitatory H134R-ChR2 and inhibitory eNpHR2.0 opsin transgenes. Opsins were expressed in the fly heart using the Hand-GAL4 driver. Here we describe Hand > H134R-ChR2; eNpHR2.0 model characterization including bi-directional heart control (activation and inhibition) upon illumination of light with distinct wavelengths. Optical control and real-time visualization of the heart function were achieved non-invasively using an integrated light stimulation and optical coherence microscopy (OCM) system. OCM produced high-speed …

Evaluating The Impact Of Laboratory-Based Eligibility Criteria By Race/Ethnicity In First-Line Clinical Trials Of Dlbcl, Arushi Khurana, Brad S Kahl, Et Al.

2020-Current year OA Pubs

Underrepresentation of racial and ethnic subgroups in cancer clinical trials remains a persistent challenge. Restrictive clinical trial eligibility criteria have been shown to exacerbate this problem. We previously identified that up to 24% of patients treated with standard immunochemotherapy would have been excluded from recent first-line trials in diffuse large B-cell lymphoma (DLBCL) based on 5 laboratory-based criteria. These ineligible patients had worse clinical outcomes and increased deaths related to lymphoma progression, suggesting the potential exclusion of patients who could have benefited most from the novel therapies being evaluated. Using data from the prospectively enrolled Lymphoma Epidemiology Outcomes cohort study, …

Single-Cell Analysis Of Chromatin And Expression Reveals Age- And Sex-Associated Alterations In The Human Heart, David F Read, Yiing Lin, Et Al.

2020-Current year OA Pubs

Sex differences and age-related changes in the human heart at the tissue, cell, and molecular level have been well-documented and many may be relevant for cardiovascular disease. However, how molecular programs within individual cell types vary across individuals by age and sex remains poorly characterized. To better understand this variation, we performed single-nucleus combinatorial indexing (sci) ATAC- and RNA-Seq in human heart samples from nine donors. We identify hundreds of differentially expressed genes by age and sex and find epigenetic signatures of variation in ATAC-Seq data in this discovery cohort. We then scale up our single-cell RNA-Seq analysis by combining …

Heart Failure With Reduced Ejection Fraction Polypill Implementation Strategy In India: A Convergent Parallel Mixed Methods Study, Anubha Agarwal, Raji Devarajan, Salva Balbale, Aashima Chopra, Dorairaj Prabhakaran, Mark D Huffman, Lisa R Hirschhorn, Padinhare P Mohanan

2020-Current year OA Pubs

INTRODUCTION: A polypill-based implementation strategy has been proposed to increase rates of guideline-directed medical therapy (GDMT) in patients with heart failure with reduced ejection fraction. This has the potential to improve mortality and morbidity in India and undertreated populations globally.

METHODS: We conducted a convergent parallel mixed methods study integrating quantitative data from stakeholder surveys using modified implementation science outcome measures and qualitative data from key informant in-depth interviews. Our objective was to explore physician, nurse, pharmacist, and patient perspectives on a HFrEF polypill implementation strategy in India from January 2021 to April 2021. Quantitative and qualitative data were integrated …