tbuckley/cabot-search huggingface dataset:
Genome-Wide Association Analyses Identify <i>CATSPERE</i> as a Mediator of Colorectal Cancer Susceptibility and Progression
Authors: Yixuan Meng, Mulong Du, Dongying Gu, Chen Li, Shuwei Li, Qiuyi Zhang, Shuai Ben, Qiuyuan Zhu, Junyi Xin, Zhengdong Zhang, Zhibin Hu, Hongbing Shen, Kewei Jiang, Meilin Wang
Journal: Cancer Research (2022)

Abstract Genome-wide association studies (GWAS) have revealed numerous genetic loci associated with colorectal cancer risk, but the mechanisms underlying these loci have not been comprehensively elucidated. In this study, we performed a GWAS meta-analysis with a two-stage replication strategy by combining eight colorectal cancer cohorts encompassing 7,186 cases and 8,512 controls in Chinese populations, accompanied by an evaluation encompassing 29,832 cases and 406,694 controls in European populations. The genetic variant rs505706 A&amp;gt;G, located at chr1q44 in the upstream region of catsper channel auxiliary subunit epsilon (CATSPERE), was associated with colorectal cancer risk and exhibited genome-wide significance (OR, 0.73; 95% confidence interval, 0.67–0.80; P = 9.75 × 10–12). Cell line and animal models were applied to assess the biological function of the genetic risk variant and the corresponding susceptibility gene. Genetically, the G allele of rs505706 resulted in long-range regulatory effects, reducing the binding affinity of POU2F1 for the CATSPERE promoter and thus abolishing the inhibitory effect of POU2F1 on CATSPERE transcription. Phenotypically, CATSPERE upregulation attenuated tumor growth in both colorectal cancer cells and xenograft models. Mechanistically, CATSPERE promoted calcium ion influx and apoptotic pathway activity. In zebrafish models, CATSPERE exerted pleiotropic effects, enhancing the progression of colorectal cancer. Collectively, these findings highlight a colorectal cancer susceptibility locus that acts to remotely modulate the activity of CATSPERE, a gene that mediates multiple functions involved in colorectal tumorigenesis and progression. Significance: A GWAS meta-analysis identifies a novel susceptibility locus harboring a genetic risk variant that mediates pleiotropic biological effects in colorectal tumorigenesis and progression.
Abstract EP19: Obesity And Diabetes Risk According To Age Groups; An Analysis Of The National Health Screening Program For The People In Transition In Korea
Authors: Tae Kyung Yoo, Eun-Jung Rhee, Satoshi Miyashita, Farideh Davoudi, Kyung-Do Han, Won-Young Lee
Journal: Circulation (2022)

Objective: The prevalence of type 2 diabetes mellitus (DM) and obesity is increasing among young population. However, the effect of obesity on the development of diabetes in different age groups is unclear. Therefore, we assessed the risk of development of future DM in two different age groups without diabetes at baseline, according to baseline body mass index (BMI) and waist circumference (WC). Research Design and Methods: The Korean National Health Insurance Service record, a nationwide population-based cohort was used to retrospectively analyze 4,145,321 Korean adults without DM, who had national health screening in Korea between 2009 and 2014. We included participants with mean age of 40 (n=2,905,752) and 66 (n=1,239,569) years old. Participants were categorized into 5, and 6 groups based on their BMI and WC, respectively. Each participant was followed either until 2017 or until the new diagnosis of DM was made. We assessed the risk of developing DM based on BMI and WC. Obesity (O) was defined as BMI≥25. Abdominal obesity (AO) was defined as WC ≥ 90cm for men, and ≥85cm for women. Multiple confounding factors were adjusted for multivariable analysis. Results: The median duration of follow-up was 5.6 years. In a multivariable analysis, higher BMI and WC among subjects with a mean age of 40 were associated with a higher risk of developing DM in the future. There was a linear association between BMI, WC, and the risk of DM (BMI&lt;18.5, ref; BMI≥30, HR 10.35, P trend &lt;0.001; WC 75-80 cm, ref; WC≥100 cm, HR 3.23, P trend &lt;0.001). A similar pattern was observed among patients with mean age 66 years old (BMI&lt;18.5, ref; BMI≥30, HR 3.16, P trend &lt;0.001; WC 75-80cm, ref; WC≥100, HR 1.98, P trend &lt;0.001). When participants were categorized based on the presence of O and AO, AO had a stronger impact on the development of DM than O in the 66 years old group (O(-)/AO(-), ref; O(-)/AO(+), HR 1.55; O(+)/AO(-), HR 1.45; O(+)/AO(+), HR 2.09). At the same time, O had a stronger impact on DM development than AO in the 40 years old group. (O(-)/AO(-), ref; O(-)/AO(+), HR 2.18; O(+)/AO(-), HR 2.62; O(+)/AO(+), HR 4.94). Conclusions: Regardless of age, both obesity and abdominal obesity increase the risk of DM. Among younger people, obesity was associated with a higher impact on the risk of DM. In older adults, the presence of abdominal obesity might have a greater effect on the development of DM in the future.
Abstract 10095: Beneficial Effects of Intensive Blood Pressure Control on Cardiovascular Outcomes Are Seen in Cohabitating Black Individuals but Not in Those Living Alone
Authors: Kosuke Inou, Karol E Watson, Naoki Kondo, Tamara B Horwich, William Hsu, Alex Bui, Obidiugwu Duru
Journal: Circulation (2021)

Introduction: Living alone, a key proxy of social isolation, is a risk factor for cardiovascular disease. In addition, Black race is associated with less optimal blood pressure (BP) control than in other racial/ethnic groups. However, it is not clear whether living arrangement modifies the beneficial effects of intensive BP control on reduction in cardiovascular events among Black individuals. We aimed to examine whether the effects of intensive BP control on cardiovascular events differ by living arrangement among Black and non-Black individuals in the Systolic Blood Pressure Intervention Trial (SPRINT). Methods: This secondary analysis of the SPRINT trial included 9,361 participants (30% Black individuals; 29% living alone) who were randomized to a systolic BP target of either &lt;120mmHg (intensive treatment group) or &lt;140mmHg (standard treatment group). Cox proportional hazards model was used to estimate the effect of intensive treatment on the composite cardiovascular outcome according to living arrangement (i.e., living alone or living with others) among Black and non-Black individuals. Results: At a median follow-up of 3.2 years, the intensive treatment group showed a significantly lower rate of the composite cardiovascular outcome than the standard treatment group among cohabitating Black individuals (hazard ratio [HR], 0.53 [95%CI, 0.33-0.85]) but not among those living alone (HR, 1.07 [95%CI, 0.66-1.73]; p-for-interaction, 0.04). A significant reduction of the composite cardiovascular outcome was observed among non-Black individuals regardless of living arrangement status. Conclusion: Intensive BP control was beneficial to reduce cardiovascular events among Black individuals living with others and non-Black individuals but not among Black individuals living alone. Our findings highlight a potentially important role of assessing living arrangements in tailored approaches to improve cardiovascular health among Black individuals.
Psychological stress disrupts intestinal epithelial cell function and mucosal integrity through microbe and host-directed processes
Authors: Jacob M. Allen, Amy R. Mackos, Robert M. Jaggers, Patricia C. Brewster, Mikaela Webb, Chia-Hao Lin, Chris Ladaika, Ronald Davies, Peter White, Brett R. Loman, Michael T. Bailey
Journal: Gut Microbes (2022)

Psychological stress alters the gut microbiota and predisposes individuals to increased risk for enteric infections and chronic bowel conditions. Intestinal epithelial cells (IECs) are responsible for maintaining homeostatic interactions between the gut microbiota and its host. In this study, we hypothesized that disruption to colonic IECs is a key factor underlying stress-induced disturbances to intestinal homeostasis. Conventionally raised (CONV-R) and germ-free (GF) mice were exposed to a social disruption stressor (Str) to ascertain how stress modifies colonic IECs, the mucosal layer, and the gut microbiota. RNA sequencing of IECs isolated from CONV-R mice revealed a robust pro-inflammatory (Saa1, Il18), pro-oxidative (Duox2, Nos2), and antimicrobial (Reg3b/g) transcriptional profile as a result of Str. This response occurred concomitant to mucus layer thinning and signs of microbial translocation. In contrast to their CONV-R counterparts, IECs from GF mice or mice treated with broad spectrum antibiotics exhibited no detectable transcriptional changes in response to Str. Nevertheless, IECs from Str-exposed GF mice exhibited an altered response to ex vivo bacterial challenge (increased dual Oxidase-2 [Duox2] and nitric oxide synthase-2 (Nos2)), indicating that STR primes host IEC pro-oxidative responses. In CONV-R mice stress-induced increases in colonic Duox2 and Nos2 (ROS generating enzymes) strongly paralleled changes to microbiome composition and function, evidencing Str-mediated ROS production as a primary factor mediating gut-microbiota dysbiosis. In conclusion, a mouse model of social stress disrupts colonic epithelial and mucosal integrity, a response dependent on an intact microbiota and host stress signals. Together these preclinical findings may provide new insight into mechanisms of stress-associated bowel pathologies in humans.
THE ATLAS INITIATIVE AND HOW TO IMPROVE ACCESS FOR PATIENTS
Authors: Kate Morgan
Journal: HemaSphere (2022)

Myeloma Patients Europe (MPE) is an umbrella organisation of patient groups representing myeloma and AL amyloidosis patients. MPE currently has 48 members in 30 European countries. The Myeloma Access Atlas is an online platform designed to provide myeloma and AL amyloidosis patient advocates with information needed to work effectively on access issues. It provides country specific and comparative information on European health systems, including data on system performance (as well as stakeholder perceptions on this topic) and on access to treatment and care. Through the Myeloma Access Atlas, MPE has worked with industry, physicians and its members to map national access to 26 drugs and drug combinations approved by the European Medicines Agency (EMA) across geographical Europe. This presentation will focus on the process and results of this mapping exercise, alongside key findings on European access inequalities. MPE ideas for solutions to address these inequalities will also be presented.
11P Results of a phase II study investigating eftilagimod alpha (soluble LAG-3 protein) and pembrolizumab in second-line PD-1/PD-L1 refractory metastatic non-small cell lung carcinoma pts
Authors: M.G. Krebs, M. Majem Tarruella, M. Forster, J.A. Peguero, T. Clay, E. Felip, W. Iams, P. Roxburgh, B. Doger de Spéville, P. Bajaj, C. Mueller, F. Triebel
Journal: Annals of Oncology (2022)
Abstract 057: Trends In Blood Pressure Diagnosis, Treatment, And Control Among Nursing Home Residents, 2007-2018
Authors: Michelle C Odden, Yongmei Li, Laura Graham, Michael Steinman, Sei Lee, Zachary Marcum, Christine Liu, Bocheng Jing, Kathy Fung, Carmen A Peralta
Journal: Circulation (2022)

Inadequate treatment of high blood pressure (BP) can lead to preventable adverse events in nursing home residents, while excessive treatment can lead to associated harms. In this study, we describe the prevalence, pharmacologic treatment, and control of hypertension over time among older adults residing in Veterans Affairs (VA) nursing homes from October 2006 through September 2018 (FY2007-2018). Data were extracted from the VA electronic health record and Bar Code Medication Administration system on 40,079 long-term care residents aged 65 years and older. Hypertension prevalence at admission was identified by one or more ICD code(s) in the year prior, and antihypertensive medication use was considered present if administered ≥50% of days in the nursing home. BP measures were obtained from the electronic health record and averaged over 2 year epochs. The age-standardized prevalence of hypertension diagnosis at admission increased over time from 75.2% in FY2007-2008 to 85.1% in FY2017-2018 (p-value for trend &lt;0.001). Rates of BP treatment and control among residents with hypertension at admission declined slightly over time (all p-values for trend &lt;0.001), but remained high (80.3% of residents treated in FY2017-2018 and 80.1% with average BP &lt;140/90 mmHg). (Figure) The age-adjusted prevalence of chronic low BP, defined as average BP &lt;90/60 mmHg, also declined over this period from 11.1% in FY2007-2008 to 4.7% in FY2017-2018 (p-value for trend &lt;0.001). Persons identified in their health records as being of Black race or Hispanic ethnicity and those with a history of diabetes, stroke, and renal disease were less likely to have average BP &lt;140/90 mmHg. In summary, hypertension is well controlled in VA nursing homes, and recent trends of less intensive BP control were accompanied by lower prevalence of chronic low BP. Nonetheless, some high-risk populations have average BP levels &gt;140/90 mmHg. Future research is needed to better understand the ratio of benefits to harms of BP control in nursing home residents.
Abstract P146: A Report On The Outcomes Of The Cleveland Clinic Community Care Health Challenges Project 2018 To 2019.
Authors: Chete Eze-Nliam, Jonathan Holmes, Jacqueline Bailey, Nazleen Bharmal, Umesh Khot
Journal: Circulation (2022)

Healthy Community Initiatives is a means of directly impacting the health and well-being of the cities and communities served by the Cleveland Clinic. The Health Challenge is the signature program of the Cleveland Clinic Healthy Community Initiatives. It is a collaborative effort between Cleveland Clinic and community partners to engage individuals in the community to help manage chronic conditions and promote a healthier lifestyle. The population is the Cleveland Clinic Central region and other nearby neighborhoods impacting 59 zip codes. Each Health Challenge lasted 8 weeks. Neighborhood participants representing each area acquired points by attending health and wellness classes and events held at the Cleveland Clinic community center and partner locations. Individuals are awarded points for participation and improvement in biometric results and/or completion of a clinical appointment. Data was collected by summing up scores received from the different events in the health challenges as noted : Pre-Program Health Screening (1 point), Post-Program Health Screening (1 point), Decrease in BMI at End of Program (1 Point), Decrease in Blood Pressure at End of Program (1 point), Attend classes, programs, or exercise sessions at partner organizations (1 point), Attend classes, programs, or exercise sessions (2 points), mammography (5 points) and Women's Clinic Appointment (5 points) at the Cleveland Clinic Community Center. The winner of individual health challenge was determined by a point system based on participation and completion percentage. There were 17 eight week Health Challenges held in 2018 and 2019 in which a total of 1889 participants enrolled. Average age was 60 years. Average participant attended 9.4 classes/programs or exercise sessions during the 8 week program - total number attended by all the participants was 7,433. The completion percentage was 47.6%. From 2018 to 2019, enrollment increased by 24.9%, weight (by pounds) decreased by 27.7% (a net total of 2,133.7 pounds lost). However, completion rate decreased by 6.6%. Blood pressure abnormality (number of participants with stage 2 blood pressure abnormality decreased from 33% to 23% (national average 28.3%) ; initial lack of physical activity decreased from 51.2% to 32.2% (national average 25.4%) , initial lack of sleep decreased from 50.2% to 41% (national average 29.2%). The main objective of this report is to show how community health interventions such as these have positive impact on the health and well-being of both individuals and community at large. It is anticipated that dissemination of the positive outcomes of these community health interventions will encourage and consolidate healthy behaviors. It may also create incentives for both community and institutional investment and support in such beneficial health focused activities at the grassroots level.
Single-Cell Immune Mapping of Melanoma Sentinel Lymph Nodes Reveals an Actionable Immunotolerant Microenvironment
Authors: Kavitha Yaddanapudi, Bryce F. Stamp, Priyanka B. Subrahmanyam, Andrei Smolenkov, Sabine J. Waigel, Rahul Gosain, Michael E. Egger, Robert C.G. Martin, Robert Buscaglia, Holden T. Maecker, Kelly M. McMasters, Jason A. Chesney
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Improving our understanding of the immunologic response to cancer cells within the sentinel lymph nodes (SLN) of primary tumors is expected to identify new approaches to stimulate clinically meaningful cancer immunity. Experimental Design: We used mass cytometry by time-of-flight (CyTOF), flow cytometry, and T-cell receptor immunosequencing to conduct simultaneous single-cell analyses of immune cells in the SLNs of patients with melanoma. Results: We found increased effector-memory αβ T cells, TCR clonality, and γδ T cells selectively in the melanoma-bearing SLNs relative to non–melanoma-bearing SLNs, consistent with possible activation of an antitumor immune response. However, we also observed a markedly immunotolerant environment in the melanoma-bearing SLNs indicated by reduced and impaired NK cells and increased levels of CD8+CD57+PD-1+ cells, which are known to display low melanoma killing capabilities. Other changes observed in melanoma-bearing SLNs when compared with non–melanoma-bearing SLNs include (i) reduced CD8+CD69+ T cell/T regulatory cell ratio, (ii) high PD-1 expression on CD4+ and CD8+ T cells, and (iii) high CTLA-4 expression on γδ T cells. Conclusions: Our data suggest that these immunologic changes compromise antimelanoma immunity and contribute to a high relapse rate. We propose the development of clinical trials to test the neo-adjuvant administration of anti–PD-1 antibodies prior to SLN resection in patients with stage III melanoma. See related commentary by Lund, p. 1996
Anterior–Lateral Versus Anterior–Posterior Electrode Position for Cardioverting Atrial Fibrillation
Authors: Anders Sjørslev Schmidt, Kasper Glerup Lauridsen, Dorthe Svenstrup Møller, Per Dahl Christensen, Karen Kaae Dodt, Hans Rickers, Bo Løfgren, Andi Eie Albertsen
Journal: Circulation (2021)

Background: Smaller randomized studies have reported conflicting results regarding the optimal electrode position for cardioverting atrial fibrillation. However, anterior–posterior electrode positioning is widely used as a standard and believed to be superior to anterior–lateral electrode positioning. Therefore, we aimed to compare anterior–lateral and anterior–posterior electrode positioning for cardioverting atrial fibrillation in a multicenter randomized trial. Methods: In this multicenter, investigator-initiated, open-label trial, we randomly assigned patients with atrial fibrillation scheduled for elective cardioversion to either anterior–lateral or anterior–posterior electrode positioning. The primary outcome was the proportion of patients in sinus rhythm after the first shock. The secondary outcome was the proportion of patients in sinus rhythm after up to 4 shocks escalating to maximum energy. Safety outcomes were any cases of arrhythmia during or after cardioversion, skin redness, and patient-reported periprocedural pain. Results: We randomized 468 patients. The primary outcome occurred in 126 patients (54%) assigned to the anterior–lateral electrode position and in 77 patients (33%) assigned to the anterior–posterior electrode position (risk difference, 22 percentage points [95% CI, 13–30]; P &lt;0.001). The number of patients in sinus rhythm after the final cardioversion shock was 216 (93%) assigned to anterior–lateral electrode positioning and 200 (85%) assigned to anterior–posterior electrode positioning (risk difference, 7 percentage points [95% CI, 2–12]). There were no significant differences between groups in any safety outcomes. Conclusions: Anterior–lateral electrode positioning was more effective than anterior–posterior electrode positioning for biphasic cardioversion of atrial fibrillation. There were no significant differences in any safety outcome. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03817372.
Reply to Zhao <i>et al.</i>: Integrated Biomarkers for Indeterminate Pulmonary Nodules: Is 2-Year Imaging Follow-Up Enough for Suspected Benign Lesions?
Authors: Michael N. Kammer, Fabien Maldonado, Steve A. Deppen, Anna Baron, Eric L. Grogan
Journal: American Journal of Respiratory and Critical Care Medicine (2022)
Five-Year Outcomes of the Partial Oral Treatment of Endocarditis (POET) Trial
Authors: Mia M Pries-Heje, Christoffer Wiingaard, Nikolaj Ihlemann, Sabine U Gill, Niels E Bruun, Hanne Elming, Jonas A Povlsen, Trine Madsen, Kaare T Jensen, Kurt Fursted, Martin Schultz, Lauge Østergaard, Jens J Christensen, Ulrik Christiansen, Flemming Rosenvinge, Jannik Helweg-Larsen, Emil L Fosbøl, Lars Køber, Christian Torp-Pedersen, Niels Tønder, Claus Moser, Kasper Iversen, Henning Bundgaard
Journal: New England Journal of Medicine (2022)
FAK Activation Promotes SMC Dedifferentiation via Increased DNA Methylation in Contractile Genes
Authors: Kyuho Jeong, James M. Murphy, Jung-Hyun Kim, Pamela Moore Campbell, Hyeonsoo Park, Yelitza A.R. Rodriguez, Chung-Sik Choi, Jun-Sub Kim, Sangwon Park, Hyun Joon Kim, Jonathan G. Scammell, David S. Weber, Richard E. Honkanen, David D. Schlaepfer, Eun-Young Erin Ahn, Ssang-Taek Steve Lim
Journal: Circulation Research (2021)

Rationale: Vascular smooth muscle cells (SMCs) exhibit remarkable plasticity and can undergo dedifferentiation upon pathological stimuli associated with disease and interventions. Objective: Although epigenetic changes are critical in SMC phenotype switching, a fundamental regulator that governs the epigenetic machineries regulating the fate of SMC phenotype has not been elucidated. Methods and Results: Using SMCs, mouse models, and human atherosclerosis specimens, we found that FAK (focal adhesion kinase) activation elicits SMC dedifferentiation by stabilizing DNMT3A (DNA methyltransferase 3A). FAK in SMCs is activated in the cytoplasm upon serum stimulation in vitro or vessel injury and active FAK prevents DNMT3A from nuclear FAK-mediated degradation. However, pharmacological or genetic FAK catalytic inhibition forced FAK nuclear localization, which reduced DNMT3A protein via enhanced ubiquitination and proteasomal degradation. Reduced DNMT3A protein led to DNA hypomethylation in contractile gene promoters, which increased SMC contractile protein expression. RNA-sequencing identified SMC contractile genes as a foremost upregulated group by FAK inhibition from injured femoral artery samples compared with vehicle group. DNMT3A knockdown in injured arteries reduced DNA methylation and enhanced contractile gene expression supports the notion that nuclear FAK-mediated DNMT3A degradation via E3 ligase TRAF6 (TNF [tumor necrosis factor] receptor-associated factor 6) drives differentiation of SMCs. Furthermore, we observed that SMCs of human atherosclerotic lesions exhibited decreased nuclear FAK, which was associated with increased DNMT3A levels and decreased contractile gene expression. Conclusions: This study reveals that nuclear FAK induced by FAK catalytic inhibition specifically suppresses DNMT3A expression in injured vessels resulting in maintaining SMC differentiation by promoting the contractile gene expression. Thus, FAK inhibitors may provide a new treatment option to block SMC phenotypic switching during vascular remodeling and atherosclerosis.