Medicine and Health Sciences Commons^™

Simulation-Guided Pan-Cancer Analysis Identifies A Novel Regulator Of Cpg Island Hypermethylation Heterogeneity, Xianglin Zhang, Wei Zhang, Jinyi Zhang, Xiuhong Lyu, Haoran Pan, Tianwei Jia, Ting Wang, Xiaowo Wang, Haiyang Guo

2020-Current year OA Pubs

CpG island hypermethylation, a hallmark of cancer, exhibits substantial heterogeneity across tumors, presenting both opportunities and challenges for cancer diagnostics and therapeutics. While this heterogeneity offers potential for patient stratification to predict clinical outcomes and personalize treatments, it complicates the development of robust biomarkers for early detection. Understanding the mechanisms driving this heterogeneity is essential for advancing biomarker design. Here, simulation-based analyses demonstrate that tumor purity and the high prevalence of low epi-mutation samples significantly obscure the identification of negative, rather than positive, regulators of CpG island hypermethylation, limiting a comprehensive understanding of heterogeneity sources. By addressing these confounders, we …

Multiregional Implementation Initiative's Impact On Guideline-Based Performance Measures For Patients Hospitalized With Heart Failure: Implement-Hf, Andrew J. Sauer, Nancy Sweitzer, Et Al.

2020-Current year OA Pubs

BACKGROUND: Despite randomized data for survival benefit (with class 1 recommendations) for treating heart failure (HF) with reduced ejection fraction using quadruple medical therapy (QMT)-defined as evidence-based β-blockers, sodium-glucose cotransporter 2 inhibitor, preferably angiotensin receptor/neprilysin inhibitor, and mineralocorticoid receptor antagonist-it is underutilized. IMPLEMENT-HF is a multiregional HF quality improvement initiative to improve care and outcomes for patients with HF by enhancing the use of QMT in routine practice.

METHODS: This analysis of HF with reduced ejection fraction treatment in patients from hospitals participating in the American Heart Association's Get With The Guidelines-HF who volunteered to participate in IMPLEMENT-HF in 7 …

Widespread Pain Phenotypes Impact Treatment Efficacy Results In Randomized Clinical Trials For Interstitial Cystitis/Bladder Pain Syndrome: A Multidisciplinary Approach To The Study Of Chronic Pelvic Pain Network Study, John T. Farrar, Siobhan Sutcliffe, Et Al.

2020-Current year OA Pubs

Pain clinical trials are notoriously complex and often inefficient in demonstrating efficacy, even for known efficacious treatments. A major issue is the difficulty in the a priori identification of specific phenotypes to include in the study population. Recent work has identified the extent of widespread pain as an important determinant of the likelihood of response to therapy, but it has not been tested in clinical trials for the treatment of interstitial cystitis/bladder pain syndrome (IC/BPS). We explored this hypothesis using data from 3 previously published trials testing treatments for IC/BPS, which suggested modest benefits but did not meet a priori …

The Multiverse Of Cd46 And Oncologic Interactions, M. Kathryn Liszewski, John P. Atkinson

2020-Current year OA Pubs

Initially identified as a regulator of complement activation on host cells, the known roles of CD46 (membrane cofactor protein [MCP]) have expanded. We now know that this ancient molecule is expressed on almost all nucleated cells as a family of four predominant isoforms. It also is involved in human reproduction, modulation of T cell activation and immunoinflammatory effector functions, autophagy, and the newly identified intracellular complement system (complosome). CD46 is also known as a "pathogen" magnet, being a port of entry for at least seven bacteria and five viruses. Moreover, CD46 has recently emerged as a key player in cancer …

Safety And Efficacy Of Stereotactic Cardiac Radio-Ablation For Ventricular Tachycardia In Patients At High Risk Of Mortality, Calum J Redpath, Andrew M Crean, Pablo B Nery, Girish M Nair, Mehrdad Golian, Simon Hansom, Connor Haberl, Robert Dekemp, Phillip S Cuculich, Clifford G Robinson, Katie S Lekx-Toniolo, David Tiberi, Graham Cook

2020-Current year OA Pubs

BACKGROUND: Patients who have recurrent ventricular tachycardia (VT) despite receiving antiarrhythmic drugs (AADs), implantable cardioverter defibrillator placement, and catheter ablation (CA) are at significant risk of morbidity and mortality.

METHODS: We offered completely noninvasive cardiac radio-ablation (CRA) on a "compassionate use" basis for patients who were unable or unwilling to undergo CA for recurrent VT despite their having received treatment with AADs and placement of an implantable cardioverter defibrillator. All patients who were referred to the CRA program were entered into a prospective registry and followed indefinitely thereafter.

RESULTS: A total of 20 patients were referred for CRA, and 10 …

Plasma P-Tau217 And Tau-Pet Predict Future Cognitive Decline Among Cognitively Unimpaired Individuals: Implications For Clinical Trials, Rik Ossenkoppele, Tammie L S Benzinger, Suzanne E Schindler, Randall J Bateman, Et Al.

2020-Current year OA Pubs

Plasma p-tau217 and tau positron emission tomography (PET) are strong prognostic biomarkers in Alzheimer's disease (AD), but their relative performance in predicting future cognitive decline among cognitively unimpaired (CU) individuals is unclear. In a head-to-head comparison study including nine cohorts and 1,474 individuals, we show that plasma p-tau217 and medial temporal lobe tau-PET signal display similar associations with cognitive decline on a global cognitive composite test (R

Automated Extraction Of Functional Biomarkers Of Verbal And Ambulatory Ability From Multi-Institutional Clinical Notes Using Large Language Models, Levi Kaster, Ethan Hillis, Inez Y Oh, Bhooma R Aravamuthan, Virginia C Lanzotti, Casey R Vickstrom, Brain Gene Registry Consortium, Christina A Gurnett, Philip R O Payne, Aditi Gupta

2020-Current year OA Pubs

BACKGROUND: Functional biomarkers in neurodevelopmental disorders, such as verbal and ambulatory abilities, are essential for clinical care and research activities. Treatment planning, intervention monitoring, and identifying comorbid conditions in individuals with intellectual and developmental disabilities (IDDs) rely on standardized assessments of these abilities. However, traditional assessments impose a burden on patients and providers, often leading to longitudinal inconsistencies and inequities due to evolving guidelines and associated time-cost. Therefore, this study aimed to develop an automated approach to classify verbal and ambulatory abilities from EHR data of IDD and cerebral palsy (CP) patients. Application of large language models (LLMs) to clinical …

Synergies, Partnership Outcomes, And Lessons Learned: A Qualitative Evaluation Of Cancer Center-Coalition Engagement, Aubrey Villalobos, Sarah Chavez, Bettina Drake, Et Al.

2020-Current year OA Pubs

BACKGROUND: Nine National Cancer Institute-Designated Cancer Centers received supplemental funding to expand community outreach and engagement activities through a partnership with Centers for Disease Control and Prevention-funded comprehensive cancer control coalitions. This article reports on an evaluation of these awards focused on organizational relationships and partnership outcomes.

METHODS: The National Cancer Institute, community outreach and engagement, and coalition representatives co-designed the evaluation, which involved document review and 18 semistructured interviews with 16 community outreach and engagement and 19 coalition representatives. Artificial intelligence-generated interview transcripts were dual-coded in NVivo, version 20/R1, software.

RESULTS: The funding generated a diverse collection of projects …

Histidine-Rich Enantiomeric Peptide Coacervates Enhance Antigen Sequestration And Presentation To T Cells, Ushasi Pramanik, Anirban Das, Elise M Brown, Heather L Struckman, Huihao Wang, Samuel Stealey, Macy L Sprunger, Abdul Wasim, Jonathan Fascetti, Jagannath Mondal, Jonathan R Silva, Silviya P Zustiak, Meredith E Jackrel, Jai S Rudra

2020-Current year OA Pubs

Peptides and peptidomimetics that self-assemble through LLPS have recently emerged as vital building blocks for creating functional biomaterials, thanks to their unique physicochemical properties and dynamic nature. One of life's most distinctive features is its selectivity for chiral molecules. To date, coacervates comprised of d-amino acids have not been reported. Here, we demonstrate that histidine-rich repeats of (GHGXY)

A Secretome Atlas Of Cardiac Fibroblasts From Healthy And Infarcted Mouse Hearts, Jasmin Bahr, Junedh M Amrute, Kory J Lavine, Et Al.

2020-Current year OA Pubs

Cardiac fibroblasts (CF) are key players after myocardial infarction (MI), but their signaling is only incompletely understood. Here we report a first secretome atlas of CF in control (cCF) and post-MI mouse hearts (miCF), combining a rapid cell isolation technique with SILAC and click chemistry. In CF, numerous paracrine factors involved in immune homeostasis are identified. Comparing secretome, transcriptome (SLAMseq), and cellular proteome disclose protein turnover. In miCF at day 5 post-MI, significantly upregulated proteins include SLIT2, FN1, and CRLF1 in mouse and human samples. Comparing the miCF secretome at days 3 and 5 post-MI reveals the dynamic nature of …

Distinct Oxytocin Signaling Pathways Synergistically Mediate Rescue-Like Behavior In Mice, Feng-Rui Zhang, Juan Liu, Jieqi Wen, Zi-Yan Zhang, Yijia Li, Eric Song, Li Hu, Zhou-Feng Chen

2020-Current year OA Pubs

Spontaneous rescue behavior enhances the well-being and survival of social animals, yet the neural mechanisms underlying the recognition and response to conspecifics in need remain unclear. Here, we report that observer mice experience distress when encountering anesthetized conspecifics, prompting spontaneous rescue-like behavior toward the unconscious mice. This behavior facilitates the earlier awakening of anesthetized mice while simultaneously alleviating stress in the helper mice. Our findings reveal that endogenous oxytocin (OXT) release from the hypothalamic paraventricular nucleus (PVN) to the oxytocin receptor (OXTR) in the central nucleus of the amygdala (CeA) regulates the emotional component of rescue-like behavior. In contrast, OXT …

Patient-Generated Health Data: Impact On Promoting Patient-Centered Point Of Care Tobacco Treatment In Patients With Cancer, Jessica Liu, Jingling Chen, Nina Smock, Nicholas B Griffith, Ramaswamy Govindan, Paula Goldberg, Jodi Thole, Kristin Daly, James Reddy, Alex T Ramsey, Laura J Bierut, Aimee James, Robert A Schnoll, Ross C Brownson, Li-Shiun Chen, Et Al.

2020-Current year OA Pubs

INTRODUCTION: Guideline-based tobacco treatment is infrequently offered. Electronic health record-enabled patient-generated health data (PGHD) has the potential to increase patient treatment engagement and satisfaction.

METHODS: We evaluated outcomes of a strategy to enable PGHD in a medical oncology clinic from July 1, 2021 to December 31, 2022. Among 12,777 patients, 82.1% received a tobacco screener about use and interest in treatment as part of eCheck-in via the patient portal.

RESULTS: We attained a broad reach (82.1%) and moderate response rate (30.9%) for this low-burden PGHD strategy. Patients reporting current smoking (

DISCUSSION: PGHD via patient portal appears to be a …

Functional Connectivity Between The Visual And Salience Networks And Autistic Social Features At School-Age, Jessica B Girault, Tomoyuki Nishino, Muhamed Talović, Margaret Reynolds, Abraham Z Snyder, Kelly N Botteron, Natasha Marrus, Robert C Mckinstry, Alexandre A Todorov, John R Pruett Jr, Et Al.

2020-Current year OA Pubs

BACKGROUND: Autism spectrum disorder (ASD) is highly heritable and phenotypically variable. Neuroimaging markers reflecting variation in behavior will provide insights into circuitry subserving core features. We examined functional correlates of ASD symptomology at school-age, while accounting for associated behavioral and cognitive domains, in a longitudinal sample followed from infancy and enriched for those with a genetic liability for ASD.

METHODS: Resting state functional connectivity MRIs (fcMRI) and behavioral data were analyzed from 97 school-age children (8.1-12.0 years, 55 males, 15 ASD) with (n = 63) or without (n = 34) a family history of ASD. fcMRI enrichment analysis (EA) was …

Place-Based Harms And Hidden Strengths: A Qualitative Study Exploring Facets Of Neighborhood Disinvestment Driving Opioid Overdose Among Black Individuals, Kaytryn D Campbell, Rachel P Winograd, Maria E Paschke, Alex Duello, Devin E Banks

2020-Current year OA Pubs

BACKGROUND: Despite significant efforts to address the opioid overdose crisis, Black people who use drugs (PWUD) face unabating, disproportionate increases in opioid overdose death (OOD) rates. These inequities persist in treatment admissions, utilization of medication for opioid use disorder, and treatment retention. Research has linked neighborhood disinvestment - a process of urban decline driven by policy-related changes in neighborhood demand and desirability leading to decreased population, physical and economic erosion, and poorer quality of life for residents - to increased rates of OOD. However, given recent increases in OOD inequities, more research is needed to determine the specific aspects of …

Perspectives On The Current Diagnostic And Treatment Paradigms In Secondary Hemophagocytic Lymphohistiocytosis (Hlh), Leonard Naymagon, Jeffrey Bednarski, Et Al.

2020-Current year OA Pubs

Improved awareness of hemophagocytic lymphohistiocytosis (HLH) among clinicians has led to an increase in its diagnosis. Often diagnosis is made based on the HLH- 2004 criteria. While these criteria have considerable strengths, they lack specificity and may be fulfilled in the setting of many pro-inflammatory disorders. Genetic defects affecting cellular cytotoxicity cause familial (primary) HLH. On the other hand, secondary HLH is more a pathophysiologic process common to many conditions, rather than a singular disease entity. Improved genetic, immunologic, and functional testing have changed not only the way we diagnose HLH, but also how we treat it. In 2004, there …

Functional Screening Identifies Kinesin Spindle Protein Inhibitor Filanesib As A Potential Treatment Option For Hepatoblastoma, Ruth Nousiainen, Katja Eloranta, Jani Saarela, Antti Hassinen, Tamara J Luck, Stefano Cairo, Emilie Indersie, Swapnil Potdar, Michaela J Feodoroff, Jouko Lohi, Lassi Paavolainen, David B Wilson, Vilja Pietiäinen, Markku Heikinheimo, Marjut Pihlajoki

2020-Current year OA Pubs

Hepatoblastoma is a rare pediatric liver malignancy usually treated with surgery and chemotherapy. To explore new treatment options for hepatoblastoma, drug screening was performed using six cell models established from aggressive hepatoblastoma tumors and healthy pediatric primary hepatocytes. Of the 527 screened compounds, 98 demonstrated cancer-selective activity in at least one hepatoblastoma model. The kinesin spindle protein (KSP) inhibitor filanesib was effective in all models and was further evaluated. Filanesib induced G2/M arrest and apoptosis in hepatoblastoma cells at concentrations tolerable to primary hepatocytes. Prominent nuclear fragmentation was observed in filanesib-treated hepatoblastoma cells. Genes participating in cell cycle regulation were …

Development And Evaluation Of A Non-Invasive Brain-Spine Interface Using Transcutaneous Spinal Cord Stimulation, Carolyn Atkinson, Lorenzo Lombardi, Meredith Lang, Rodolfo Keesey, Rachel Hawthorn, Zachary Seitz, Eric C Leuthardt, Peter Brunner, Ismael Seáñez

2020-Current year OA Pubs

Motor rehabilitation is a therapeutic process to facilitate functional recovery in people with spinal cord injury (SCI). However, its efficacy is limited to areas with remaining sensorimotor function. Spinal cord stimulation (SCS) creates a temporary prosthetic effect that may allow further rehabilitation-induced recovery in individuals without remaining sensorimotor function, thereby extending the therapeutic reach of motor rehabilitation to individuals with more severe injuries. In this work, we report our first steps in developing a non-invasive brain-spine interface (BSI) based on electroencephalography (EEG) and transcutaneous spinal cord stimulation (tSCS). The objective of this study was to identify EEG-based neural correlates of …

Comparative Efficacy And Acceptability Of Interventions For Universal, Selective And Indicated Prevention Of Eating Disorders: Study Protocol For A Systematic Review And Network Meta-Analysis, Sandra Schlegl, Felicitas Hirler, Andreas Gerich, Mikkel Højlund, Eric Stice, Tracey Wade, Denise Wilfley, James Downs, Ulrich Voderholzer, Jasmine Perry, Verena Haas, Marco Solmi, Christoph Correll

2020-Current year OA Pubs

BACKGROUND: Eating disorders (EDs) are severe psychiatric conditions, with prevalence rates ranging from 5.5 to 17.9% in women and 0.6 to 2.4% in men. EDs carry a high risk of chronicity and mortality, highlighting the need for effective prevention strategies. Primary prevention can target the entire population (universal), high-risk groups (selective), or individuals with early signs (indicated). Despite substantial research, prior reviews often show limitations, such as single-author data extraction, lack of quality assessment, reliance on endpoint data, exclusion of obesity prevention programs, or outdated findings. No review has yet evaluated the comparative effectiveness of multiple interventions across risk groups. …

Adipose-Derived Leptin And Complement Factor D Mediate Osteoarthritis Severity And Pain, Kelsey H Collins, Kristin L Lenz, Hope D Welhaven, Erica Ely, Luke E Springer, Sophie Paradi, Ruhang Tang, Lauryn Braxton, Antonina Akk, Huimin Yan, Bo Zhang, Xiaobo Wu, John P Atkinson, Arin K Oestreich, Ron K June, Christine T N Pham, Farshid Guilak

2020-Current year OA Pubs

Obesity is a risk factor for osteoarthritis (OA), and leptin is among the adipokines implicated in obesity-induced OA. However, the specific role of leptin in OA severity and pain is not known. Using lipodystrophic (LD) mice, we show that fat-secreted factors are required for knee OA development, implicating a fat-cartilage cross-talk. Fat pad implantation or systemic leptin restoration in LD mice reintroduced structural OA and pain, whereas implantation of leptin-deficient fat pad did not change OA susceptibility. Isochronic parabiosis and spatial transcriptomics confirmed that a fat-joint cross-talk likely occurred via soluble mediators. Global unsupervised multiomics of conditioned media from fat …

Deciphering Distinct Genetic Risk Factors For Ftld-Tdp Pathological Subtypes Via Whole-Genome Sequencing, Cyril Pottier, Carlos Cruchaga, Et Al.

2020-Current year OA Pubs

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with only a limited number of risk loci identified. We report our comprehensive genome-wide association study as part of the International FTLD-TDP Whole-Genome Sequencing Consortium, including 985 patients and 3,153 controls compiled from 26 institutions/brain banks in North America, Europe and Australia, and meta-analysis with the Dementia-seq cohort. We confirm UNC13A as the strongest overall FTLD-TDP risk factor and identify TNIP1 as a novel FTLD-TDP risk factor. In subgroup analyzes, we further identify genome-wide significant loci specific to each of the three …

Implementation Of The Extension For Community Healthcare Outcomes Model For Hypertension Education Of Frontline Health Care Workers In The Federal Capital Territory, Nigeria: Explanatory Sequential Mixed Methods Evaluation, Abigail S Baldridge, Mark D Huffman, Et Al.

2020-Current year OA Pubs

BACKGROUND: The Extension for Community Healthcare Outcomes (ECHO) model was adapted for hypertension education of community health extension workers in the Federal Capital Territory, Nigeria, and delivered as a 7-part series.

OBJECTIVE: This study aims to evaluate implementation outcomes of the hypertension ECHO series mapped to the first 3 levels of the Kirkpatrick model. Outcomes included reach, appropriateness (level 1), effectiveness (level 2), and penetration (level 3).

METHODS: From August 2022 to April 2023, 7 hypertension ECHO sessions were delivered via Zoom (Zoom Video Communications, Inc) to a health care worker audience including targeted community health extension workers at 12 …

Induction Of Cardiac Fibulin-4 Protects Against Pressure Overload-Induced Cardiac Hypertrophy And Heart Failure, E D Van Deel, C M Halabi, Et Al.

2020-Current year OA Pubs

The prevailing view of fibulin-4 deficient mice is that the cardiac phenotype is the result of aortic and/or valvular disease. In the present study, we have tested whether the cardiac phenotype is, at least in part, the consequence of primary cardiac effects of fibulin-4. We have found fibulin-4 expression to be activated throughout the myocardium in wildtype (fibulin-4

Disuse-Driven Plasticity In The Human Thalamus And Putamen, Roselyne J Chauvin, Dillan J Newbold, Ashley N Nielsen, Ryland L Miller, Samuel R Krimmel, Athanasia Metoki, Anxu Wang, Andrew N Van, David F Montez, Scott Marek, Vahdeta Suljic, Noah J Baden, Nadeshka Ramirez-Perez, Kristen M Scheidter, Julia S Monk, Forrest I Whiting, Babatunde Adeyemo, Jarod L Roland, Abraham Z Snyder, Benjamin P Kay, Marcus E Raichle, Timothy O Laumann, Evan M Gordon, Nico U F Dosenbach

2020-Current year OA Pubs

Subcortical plasticity has mainly been studied using invasive electrophysiology in animals. Here, we leverage precision functional mapping (PFM) to study motor plasticity in the human subcortex during 2 weeks of upper-extremity immobilization with daily resting-state and motor task fMRI. We found previously that, in the cortex, limb disuse drastically impacts disused primary motor cortex functional connectivity (FC) and is associated with spontaneous fMRI pulses. It remains unknown whether disuse-driven plasticity pulses and FC changes are cortex specific or whether they could also affect movement-critical nodes in the thalamus and striatum. Tailored analysis methods now show spontaneous disuse pulses and FC …

Samd9 Senses Cytosolic Double-Stranded Nucleic Acids In Epithelial And Mesenchymal Cells To Induce Antiviral Immunity, Gaopeng Hou, Wandy Beatty, Juhee Son, Yinxing Zhu, Qingyu Sheng, Wanyi Huang, Dian Li, Constin Liu, Chen Shen, L David Sibley, Siyuan Ding, Et Al.

2020-Current year OA Pubs

Sensing of cytosolic, double-stranded (ds) DNA or dsRNA molecules derived from microbial or endogenous sources triggers cell-intrinsic innate immunity, but sensors recognizing both cytosolic dsDNA and dsRNA are sparsely reported. Here we find that full-length human SAMD9 protein directly binds to synthetic or viral dsDNA or dsRNA. Overexpression of SAMD9 from various vertebrate species leads to robust production of interferons and pro-inflammatory cytokines. By contrast, loss of endogenous SAMD9 impairs the interferon responses to cytosolic dsDNA and dsRNA stimulation in multiple cell types and enhances the infectivity of pathogenic dsDNA and dsRNA viruses. Mice lacking Samd9l, the human SAMD9 homolog, …

Sars-Cov-2 N Protein And Anti-Spike Serologies: Insights Into Covid-19 Disease Severity And Mortality-A Secondary Analysis Of The Activ-1 Trial, Alfredo J Mena Lora, Kimi Enders, Huimin Wu, Luis Parra-Rodriguez, Christopher Palma, Katy Saliba, Sylvain Laverdurre, P Brian Smith, Kevin J Anstrom, Samuel A Bozzette, William G Powderly

2020-Current year OA Pubs

BACKGROUND: Understanding factors that predict progression to severe COVID-19 is critical. Antibodies targeting SARS-CoV-2 spike protein confer protection, while the N protein of SARS-CoV-2 plays roles in viral replication and immune dysfunction. This study explores the significance of N protein and anti-spike antibodies on disease severity, progression, and mortality.

OBJECTIVES: To evaluate the relationship between SARS-CoV-2 N protein and anti-spike antibody levels with disease severity, clinical outcomes, and mortality in hospitalized patients with COVID-19.

DESIGN: A secondary analysis of serologic data from participants in the ACTIV-1 randomized clinical trial, which evaluated immunomodulators for the treatment of hospitalized patients with COVID-19. …

Center-Ing Black Voices: Incorporating Lived Experience Across The Research Process To Advance Equity In Drug Treatment And Outcomes, Devin E Banks, Maria E Paschke, Kaytryn D Campbell, Daje D Bradshaw-Glenn, Rashmi Ghonasgi, Burton Barr, Arial Collins, Gerald Dennis, Keith Lofton, Alfred Long, Harriet Montgomery, Andreas Prince, Rachel P Winograd

2020-Current year OA Pubs

BACKGROUND: Black people in the United States face persistent and increasing inequities in addiction treatment access and drug overdose death. Incorporating people with lived experience through community based participatory research (CBPR) approaches can improve understanding of drivers of and solutions to such inequities. However, practical and systemic challenges limit incorporating Black people with lived experience with substance use across each step of the research process. This paper describes the methods, recommendations, and lessons learned from a research team and Black-led community advisory board (CAB) working together across the research process to promote equity in harm reduction and addiction treatment.

METHODS: …

Enhancement Of The Endocannabinoid System Through Monoacylglycerol Lipase Inhibition Relieves Migraine-Associated Pain In Mice, Elizaveta Mangutov, Yaseen Awad-Igbaria, Kendra Siegersma, Francois Gastambide, Ayodeji A Asuni, Amynah A A Pradhan

2020-Current year OA Pubs

BACKGROUND: Migraine affects over 1 billion people worldwide and is a leading cause of disability. Targeting the cannabinoid system offers a promising approach for pain and migraine relief. This study evaluated a novel monoacylglycerol lipase (MAGL) inhibitor to prolong endocannabinoid action in acute and chronic mouse models of migraine. It also examined MAGL and cannabinoid receptor 1 (CB

METHODS: C57BL6/J male and female mice received the human migraine trigger nitroglycerin (NTG) acutely or every other day for 9 days. Allodynia was assessed by von Frey hair stimulation of the periorbital area. A single dose of MAGL inhibitor (ABD-1970) was tested …

Injured Tubular Epithelia-Derived Ccn1 Promotes The Mobilization Of Fibroblasts Toward Injury Sites After Kidney Injury, Tomohiro Nakata, Benjamin D Humphreys, Et Al.

2020-Current year OA Pubs

Humoral factors that prompt fibroblasts to migrate to an injury site at an appropriate time point are deemed indispensable for repair after kidney injury. We herein demonstrated the pivotal roles of injured tubule-derived cellular communication network factor 1 (CCN1) in the mobilization of fibroblasts to the injury site after kidney injury. Based on analyses of ligand-receptor interactions

Mechanism Of Dna Replication Fork Breakage And Parp1 Hyperactivation During Replication Catastrophe, Pedro Ortega, Elodie Bournique, Junyi Li, Ambrocio Sanchez, Gisselle Santiago, Brooke R Harris, Josefine Striepen, John Maciejowski, Abby M Green, Rémi Buisson

2020-Current year OA Pubs

Ataxia telangiectasia and Rad3-related (ATR) inhibition triggers a surge in origin firing, resulting in increased levels of single-stranded DNA (ssDNA) that rapidly deplete all available RPA. This leaves ssDNA unprotected and susceptible to breakage, a phenomenon known as replication catastrophe. However, the mechanism by which unprotected ssDNA breaks remains unclear. Here, we reveal that APOBEC3B is the key enzyme targeting unprotected ssDNA at replication forks, initiating a reaction cascade that induces fork collapse and poly(ADP-ribose) polymerase 1 (PARP1) hyperactivation. Mechanistically, we demonstrate that uracils generated by APOBEC3B at replication forks are removed by UNG2, resulting in abasic sites that are …

Mendelian Randomization Study Of Sleep Traits And Risk Of Colorectal Cancer, Olympia Dimopoulou, Yin Cao, Et Al.

2020-Current year OA Pubs

A potential association of endogenous circadian rhythm disruption with risk of cancer development has been suggested, however, epidemiological evidence for the association of sleep traits with colorectal cancer (CRC) is limited and often contradictory. Here we investigated whether genetically predicted chronotype, insomnia and sleep duration are associated with CRC risk in males, females and overall and according to CRC anatomical subsites using Mendelian randomization (MR). The two-sample inverse variance weighted (IVW) method was applied using summary-level data in up to 58,221 CRC cases and 67,694 controls and genome-wide association data of genetic variants for self-reported sleep traits. Secondary analyses using …