95038 research outputs found
Sort by
Women's Rugby As An NCAA Emerging Sport
Get PDFThis study examines the current state of women’s collegiate rugby in the UnitedStates, focusing on the transition from club teams to NCAA varsity status. Despite theclassification of women's rugby as an NCAA Emerging Sport, only 27 of over 405 club teamshave achieved varsity status since 2002. Through surveys of club leaders, this research soughtto understand their interest in NCAA affiliation, awareness of the application process, andperceptions of benefits and challenges related to NCAA affiliation. The study alsoinvestigated the role of team culture, leadership, and Title IX in shaping the future ofwomen’s rugby. Findings aim to inform strategies for promoting NCAA involvement,fostering the sport's growth, and enhancing gender equity in athletics. By examining thesefactors, the research identifies barriers to expansion and offers insights into how this sportcan better align with the evolving landscape of women’s collegiate athletics.Master of Art
Lipid Nanoparticle-encapsulated Dnai1 mRNA rescues ciliary activity in primary ciliary dyskinesia mouse cell models.
Get PDFPrimary ciliary dyskinesia (PCD) is a rare, genetically heterogenous disorder resulting from dysfunctional motile cilia that is characterized by chronic, progressive lung disease with currently no corrective therapies available. Here, we test the efficacy of selective organ targeting lipid nanoparticles (SORT-LNPs) that were optimized for potency and delivery to respiratory cells containing an mRNA coding for an axonemal protein to rescue ciliary activity in a murine culture model of PCD. Utilizing murine nasopharyngeal epithelial cell cultures (mNPEC) isolated from a conditional Dnai1 knockout mouse model of the known human PCD-associated gene DNAI1 homolog, we tested if SORT-LNPs containing an optimized Dnai1 mRNA could rescue ciliary activity. Treatment of differentiating and well-differentiated Dnai1 knockout mNPEC with SORT-LNP-Dnai1 mRNA led to a dose-dependent increase in levels of DNAI1 protein and incorporation into ciliary axonemes, resulting in rescued ciliary activity with normal ciliary beat frequency that persisted for over three weeks. These data support further clinical development of an mRNA-based therapeutic with LNP-mediated delivery as a treatment for PCD patients with disease-causing DNAI1 mutations
Distribution of methane-cycling archaea in buried ridge flank sediment: community zonation, activity, and potential environmental drivers
Get PDFSubseafloor sediments harbor Earth’s biggest reservoir of methane, with most of this methane being produced biologically by methanogenic archaea (methanogens). Yet, little is known about the controls on in situ abundances, community structure, and biochemical pathways of methanogens, and closely related anaerobic methane oxidizing archaea (ANMEs), in these environments. Here we examine the vertical distribution of methane-cycling archaea at Integrated Ocean Drilling Program Site U1301, an offshore drilling site on the eastern flank of the Juan de Fuca Ridge, that was previously characterized with respect to its in situ temperature profile, sediment provenance, geochemical gradients, and general microbial community structure. We integrate (1) functional gene analyses (mcrA) to analyze methane-cycling archaeal abundances and community structure with (2) sediment porewater concentration profiles of sulfate, methane, Mn2+, and Fe2+ to shed light on the distributions of dominant microorganisms and processes involved in subseafloor methane cycling. These analyses indicate that sediments from the cold seafloor (2 °C) to the hot basement (64 °C), across zones of sulfate reduction (SR), anaerobic oxidation of methane (AOM), and methanogenesis (MG), were dominated by two phylogenetic clusters. These belonged to the family Methanoperedenaceae, which couples the oxidation of methane to the reduction of nitrate or metals, and the candidate order Methanophagales (group ANME-1a-b). The latter has mainly been linked to sulfate-dependent AOM, although a facultative methanogenic metabolism has also been proposed. Other groups of methane-cycling archaea (ANME-2c, -3, Methanothrix, Methanocellales, Candidatus Nezhaarchaeales) were only detected in single samples from the upper and lower AOM zones and the MG zone. No stimulation of methanogenic activity was evident at the deep sediment-basement interface; however, the dominant Methanoperedenaceae and Methanophagales phylotypes throughout the sediment column cluster phylogenetically with those previously detected in underlying basalt, suggesting dispersal and similar selective forces on methane-cycling archaea across this major lithological boundary. Based on the observed dominance of Methanoperedenaceae and porewater geochemical profiles which indicate decoupling between measured sulfate and methane concentrations in sediments with methane oxidation, we propose that a significant portion of AOM in the iron- and manganese-rich sediments of the Juan de Fuca Ridge Flank proceeds through the reduction of iron (III) and manganese (IV)
Mechanisms Involved in the Adverse Cardiovascular Effects of Selective Cyclooxygenase-2 Inhibitors
Get PDFNonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for managing inflammation, but they are associated with gastrointestinal and renal toxicity upon long-term use. Selective cyclooxygenase-2 (COX-2) inhibitors, or coxibs, were developed to avoid these adverse effects while maintaining anti-inflammatory efficacy. However, accumulating evidence indicates that coxibs may increase the risk of cardiovascular complications. This review explores the pathophysiological mechanisms underlying adverse cardiovascular effects in patients treated with COX-2 inhibitors. These mechanisms include an imbalance between prothrombotic and antithrombotic factors, an altered endocannabinoid metabolism, and downregulation of PPARδ, contributing to thrombosis. Additionally, COX-2 inhibition disrupts renal prostaglandin synthesis, particularly PGE2 and prostacyclins, reduces EP4 receptor expression in macrophages, promotes chemotaxis, and elevates arterial pressure via increased iNOS, ADMA, and L-NMMA activity. At the molecular level, genetic polymorphisms, matrix metalloproteinases, signaling cross-talk, and direct cardiomyocyte injury are implicated. Collectively, these alterations promote a prothrombotic state, fluid retention, enhanced vasoconstriction, impaired vasodilation, myocardial injury, cell death, and cardiac fibrosis. Despite these risks, coxibs are often prescribed without adequate cardiovascular assessment, particularly in patients with pre-existing cardiovascular risk factors. Greater awareness of these mechanisms is essential to optimize the benefit–risk ratio in clinical decision-making involving selective COX-2 inhibitors
The associations of premorbid social isolation and social support with self-rated health and heart failure outcomes in the atherosclerosis risk in communities (ARIC) Study
Get PDFWe assessed whether social isolation (SI), social support (SS), and subtypes of SS were associated with self-rated health trajectories and clinical heart failure (HF) outcomes among participants with incident HF hospitalizations. We included 2967 Atherosclerosis Risk in Communities study participants with incident HF hospitalization after Visit 2 (1990–1992). SI, SS, and subtypes of SS were measured at Visit 2. We identified incident HF hospitalization as ICD-9 code 428 and physician adjudicated events; on average HF occurred 17 (SD 8) years after Visit 2. We assessed associations with trajectories of annually measured self-rated health in the 4 years prior to and after incident HF hospitalization (excellent/good self-rated health on a 0–100 scale), using linear mixed effects models. We calculated hazard ratios (HR) and 95% confidence intervals (CIs) for associations with time to first all-cause rehospitalization and all-cause mortality using Cox proportional hazard models. Low overall SS had a 5.8 point (95% CI 7.8, 3.8) lower self-rated health value over time than high SS; associations of subtypes of SS with this outcome were similar. Low belonging SS was associated with greater days to first rehospitalization (HR 0.85; 95% CI 0.79, 0.96) compared to the highest tertile; however, belonging SS was not associated with mortality (HR 1.05; 95% CI 0.95, 1.17). Being socially isolated/high risk for SI was associated with greater hazard of all-cause mortality among females (HR 1.57; 95% CI 1.20, 2.06) but not males (HR 0.95; 95% CI 0.75, 1.19), compared to low SI. SI and SS were not associated with number of hospitalizations in the first year or percent of first year spent at home
Racial Disparities in the Prescribing of Guideline‐Recommended Medications for Metastatic Prostate Cancer: A Retrospective Cohort Study
Get PDFProstate cancer is the second leading cause of cancer death among men, with a disproportionate burden on Black men. Racial disparities in care delivery for early‐stage disease are well documented but less is known about racial gaps in advanced prostate cancer care, a stage where effective therapies can prolong life for years. We sought to evaluate potential treatment disparities among Black and White men with metastatic prostate cancer. We performed a retrospective cohort study of patients with metastatic prostate cancer receiving treatment at a large public tertiary care health system between 2015 and 2020 using electronic health record data. We estimated the prevalence ratio (PR) of being prescribed each of the recommended treatment options for metastatic prostate cancer as per National Comprehensive Care Network guidelines, including androgen receptor pathway inhibitors (ARPIs) and other antiandrogens, chemotherapy, and bone protection, comparing Black men to White men. We identified 1166 patients with metastatic prostate cancer treated with androgen deprivation therapy (ADT); 370 (32%) were Black. Prescribing of systemic treatments did not differ by race, notably including ARPI (PR: 0.98 95% CI: 0.98–1.1, p = 0.8). About 30% of both Black and White patients interacted with our patient navigation team, a group of oncology nurses focused on ensuring patients receive recommended care. In a large public tertiary care health system, we did not observe racial disparities in the prescribing of guideline‐recommended therapies for metastatic prostate cancer. High rates of insurance, a robust patient navigation program, and a well‐developed pharmacy assistance program may have helped mitigate racial disparities in care. Future studies should prospectively evaluate the delivery of prostate cancer therapies across health systems and the influence of navigation and pharmacy assistance programs
Experimentally Testing the Hypothesis That Hybrid Fitness Can Increase Evolutionarily: An Example in Spadefoot Toads
Get PDFHybrids often have reduced fitness because of genetic incompatibilities. If populations contain variation at loci involved in these genetic incompatibilities, then selection can disfavor alleles involved in incompatibilities, thereby reducing their frequency within the parent-lineages' gene pools in the hybridizing population. Such selection can concomitantly increase hybrid fitness in populations over evolutionary time. This hypothesis predicts that hybrid fitness should be higher in populations where species have hybridized for longer periods (or where hybridization is more frequent) versus in populations where species have hybridized for a shorter duration (or where hybridization is less frequent). We tested this prediction in spadefoot toads, Spea bombifrons and Spea multiplicata. Spea bombifrons has expanded its range into that of S. multiplicata; consequently, regions of sympatry differ in the length of time during which hybridization has occurred. We used a “space for time substitution” experiment to contrast hybrid fitness, as measured by development time and body size, in different regions of sympatry. We found that hybrids derived from “Old sympatry” were larger and had faster development than hybrids derived from “New sympatry.” Despite limits in our study design, our results suggest that selection can reduce incompatibilities and increase hybrid fitness evolutionarily. We discuss means for best evaluating whether selection can evolutionarily reduce genetic incompatibilities. Doing so is important to better understand ecological and evolutionary processes ranging from speciation to hybridization's role in adaptive evolution and species range expansion
Digital health technologies in the accelerating medicines Partnership® Schizophrenia Program
Get PDFAlthough meta-analytic studies have shown that 25-33% of those at Clinical High Risk (CHR) for psychosis transition to a first episode of psychosis within three years, less is known about estimating the risk of transition at an individual level. Digital phenotyping offers a novel approach to explore the nature of CHR and may help to improve personalized risk prediction. Specifically, digital data enable detailed mapping of experiences, moods and behaviors during longer periods of time (e.g., weeks, months) and offer more insight into patterns over time at the individual level across their routine daily life. However, while novel digital health technologies open up many new avenues of research, they also come with specific challenges, including replicability of results and the adherence of participants. This paper outlines the design of the digital component of the Accelerating Medicines Partnership® Schizophrenia Program (AMP SCZ) project, a large international collaborative project that follows individuals at CHR for psychosis over a period of two years. The digital component comprises one-year smartphone-based digital phenotyping and actigraphy. Smartphone-based digital phenotyping includes 30-item short daily self-report surveys and voice diaries as well as passive data capture (geolocation, on/off screen state, and accelerometer). Actigraphy data are collected via an Axivity wristwatch. The aim of this paper is to describe the design and the three goals of the digital measures used in AMP SCZ to: (i) better understand the symptoms, real-life experiences, and behaviors of those at CHR for psychosis, (ii) improve the prediction of transition to psychosis and other health outcomes in this population based on digital phenotyping and, (iii) serve as an example for replicable and ethical research across geographically diverse regions and cultures. Accordingly, we describe the rationale, protocol and implementation of these digital components of the AMP SCZ project. **Link to video interview: https://vimeo.com/1060935583*
Gene signatures derived from transcriptomic-causal networks stratify colorectal cancer patients for effective targeted therapy
Get PDFBackgroundGene signatures derived from transcriptomic-causal networks offer potential for tailoring clinical care in cancer treatment by identifying predictive and prognostic biomarkers. This study aimed to uncover such signatures in metastatic colorectal cancer (CRC) patients to aid treatment decisions.MethodsWe constructed transcriptomic-causal networks and integrated gene interconnectivity into overall survival (OS) analysis to control for confounding genes. This integrative approach involved germline genotype and tumor RNA-seq data from 1165 metastatic CRC patients. The patients were enrolled in a randomized clinical trial receiving either cetuximab or bevacizumab in combination with chemotherapy. An external cohort of paired CRC normal and tumor samples, along with protein-protein interaction databases, was used for replication.ResultsWe identify promising predictive and prognostic gene signatures from pre-treatment gene expression profiles. Our study discerns sets of genes, each forming a signature that collectively contribute to define patient subgroups with different prognosis and response to the therapies. Using an external cohort, we show that the genes influencing OS within the signatures, such as FANCI and PRC1, are upregulated in CRC tumor vs. normal tissue. These signatures are highly associated with immune features, including macrophages, cytotoxicity, and wound healing. Furthermore, the corresponding proteins encoded by the genes within the signatures interact with each other and are functionally related.ConclusionsThis study underscores the utility of gene signatures derived from transcriptomic-causal networks in patient stratification for effective therapies. The interpretability of the findings, supported by replication, highlights the potential of these signatures to identify patients likely to benefit from cetuximab or bevacizumab
B7-H3 and CSPG4 co-targeting as Pan-CAR-T cell treatment of triple-negative breast cancer
Get PDFPURPOSE: Chimeric antigen receptor T (CAR-T) cell therapy is under clinical investigation in patients with metastatic triple-negative breast cancer (TNBC). However, the identification of targetable antigens remains a high priority to avoid toxicity and prevent tumor escape. EXPERIMENTAL DESIGN: Here we analyzed the gene expression of B7-H3 (CD276) and chondroitin sulfate proteoglycan 4 (CSPG4) in 98 TNBC samples identified in the AURORA US Network and Rapid Autopsy RNA sequencing data set at University of North Carolina (UNC). We then performed immunohistochemistry analysis for B7-H3 and CSPG4 protein expression in 151 TNBC samples collected at UNC. Finally, the validity of the proposed B7-H3 and CSGP4 co-targeting was tested in clinically relevant TNBC patient derived xenograft (PDX) models. RESULTS: We observed that CD276 and CSPG4 genes are broadly and comparably expressed in TNBC samples, and gene expression is generally conserved in tumor metastases. None of the TNBC analyzed met the criteria for simultaneous low expression of CSPG4 and CD276 genes. Immunohistochemistry analysis showed a median H-score of 138 (105-168, lower and upper quartile, respectively) for B7-H3 expression and a median H-score of 33 (14-78 lower and upper quartile, respectively) for CSPG4 expression. Notably, 49% of the TNBC cores with B7-H3 H-score ≤105 exhibited a CSPG4 H-score exceeding its median value, and 37% and 18% of the TNBC cores with low B7-H3 expression scored CSPG4 expression above its median H-score or exceeded its upper quartile, respectively, confirming that at least one of these two proteins is expressed in 94% of the analyzed tumors. Finally, optimized dual-specific B7-H3 and CSPG4 CAR-T cells eradicated tumors with mixed antigen expression in TNBC PDX models. CONCLUSIONS: These data highlight the clinical potential of the proposed approach that could be applicable to the great majority of patients with TNBC as well as most of patients with breast cancer in general