tbuckley/cabot-search huggingface dataset:
Detecting Genetic Ancestry and Adaptation in the Taiwanese Han People
Authors: Yun-Hua Lo, Hsueh-Chien Cheng, Chia-Ni Hsiung, Show-Ling Yang, Han-Yu Wang, Chia-Wei Peng, Chun-Yu Chen, Kung-Ping Lin, Mei-Ling Kang, Chien-Hsiun Chen, Hou-Wei Chu, Chiao-Feng Lin, Mei-Hsuan Lee, Quintin Liu, Yoko Satta, Cheng-Jui Lin, Marie Lin, Shu-Miaw Chaw, Jun-Hun Loo, Chen-Yang Shen, Wen-Ya Ko
Journal: Molecular Biology and Evolution (2020)

The Taiwanese people are composed of diverse indigenous populations and the Taiwanese Han. About 95% of the Taiwanese identify themselves as Taiwanese Han, but this may not be a homogeneous population because they migrated to the island from various regions of continental East Asia over a period of 400 years. Little is known about the underlying patterns of genetic ancestry, population admixture, and evolutionary adaptation in the Taiwanese Han people. Here, we analyzed the whole-genome single-nucleotide polymorphism genotyping data from 14,401 individuals of Taiwanese Han collected by the Taiwan Biobank and the whole-genome sequencing data for a subset of 772 people. We detected four major genetic ancestries with distinct geographic distributions (i.e., Northern, Southeastern, Japonic, and Island Southeast Asian ancestries) and signatures of population mixture contributing to the genomes of Taiwanese Han. We further scanned for signatures of positive natural selection that caused unusually long-range haplotypes and elevations of hitchhiked variants. As a result, we identified 16 candidate loci in which selection signals can be unambiguously localized at five single genes: CTNNA2, LRP1B, CSNK1G3, ASTN2, and NEO1. Statistical associations were examined in 16 metabolic-related traits to further elucidate the functional effects of each candidate gene. All five genes appear to have pleiotropic connections to various types of disease susceptibility and significant associations with at least one metabolic-related trait. Together, our results provide critical insights for understanding the evolutionary history and adaption of the Taiwanese Han population.
Abstract 14902: The Impact of Bicuspid Pulmonary Valve in Aortic Position After Arterial Switch for Transposition of the Great Arteries onNeoaortic Root and Neoaortic Valve Function; Propensity Score Matched Analysis
Authors: Bobae Jeon, Eun Seok Choi, Bo Sang Kwon, Tae-Jin Yun, Chun Soo Park
Journal: Circulation (2020)

Objective: Neoaortic valve regurgitation which might be related to root dilatation is one of the major concerns following arterial switch operation (ASO) for transposition of the great arteries (TGA). This study investigated the effect of bicuspid neoaortic valve on neoaortic root morphology, function, and the long-term clinical outcomes after ASO for TGA using propensity score matching (PSM). Methods: From 1997 to 2018, 442 patients underwent ASO for TGA. Patients who underwent staged repair (n=15), were repaired at extremely old age (&gt; 1 year, n=9), and died before discharge (n=46), and were lack of echocardiographic data at discharge (n=20) were excluded. Among a total of 352 eligible patients, 18 patients (5.1%) had a BPV. After PSM (1:4), 15 patients with BPV and 60 corresponding patients with tricuspid pulmonary valve were enrolled for analysis. Results: Baseline characteristics in both groups were similar. The median duration of follow-up was 9.9 years (4 months ~ 22.3 years). There was one late death. Freedom from reoperation at 10 years was 93.3 ± 6.4 % in bicuspid group and 88.7 ± 4.4 % in tricuspid group ( p =0.84). Reoperation for aortic valve or aortic root was rarely required during follow-up. Indexed dimension (z-score) of neoaortic annulus was not increased in both groups ( p =0.57) (Figure 1A), although there was a little increasing tendency in z-score of neoaortic sinus without intergroup difference ( p =0.69) (Figure 1B). Deterioration in neoaortic valve function was more prominent in bicuspid group (common odds ratio; 1.40 in bicuspid group [ p &lt;0.01], and 1.12 in tricuspid group [ p =0.03], p =0.03) (Figure 1C). Conclusions: Arterial switch operation could be a safe option in selected patients with TGA associated with BPV without increasing the risk of reoperation. Deterioration of aortic valve function was more prominent in bicuspid group, which suggests that the neoaortic valve function would be deteriorated mainly by valve itself not root pathology.
dbCNS: A New Database for Conserved Noncoding Sequences
Authors: Jun Inoue, Naruya Saitou
Journal: Molecular Biology and Evolution (2020)

Abstract We developed dbCNS (http://yamasati.nig.ac.jp/dbcns), a new database for conserved noncoding sequences (CNSs). CNSs exist in many eukaryotes and are assumed to be involved in protein expression control. Version 1 of dbCNS, introduced here, includes a powerful and precise CNS identification pipeline for multiple vertebrate genomes. Mutations in CNSs may induce morphological changes and cause genetic diseases. For this reason, many vertebrate CNSs have been identified, with special reference to primate genomes. We integrated ∼6.9 million CNSs from many vertebrate genomes into dbCNS, which allows users to extract CNSs near genes of interest using keyword searches. In addition to CNSs, dbCNS contains published genome sequences of 161 species. With purposeful taxonomic sampling of genomes, users can employ CNSs as queries to reconstruct CNS alignments and phylogenetic trees, to evaluate CNS modifications, acquisitions, and losses, and to roughly identify species with CNSs having accelerated substitution rates. dbCNS also produces links to dbSNP for searching pathogenic single-nucleotide polymorphisms in human CNSs. Thus, dbCNS connects morphological changes with genetic diseases. A test analysis using 38 gnathostome genomes was accomplished within 30 s. dbCNS results can evaluate CNSs identified by other stand-alone programs using genome-scale data.
Differences in Allogeneic Product T-Cell Subsets According to Donor Age: Associations with Immune Reconstitution and Acute Graft Versus Host Disease (aGVHD) in Haploidentical (HI) Hematopoietic Stem Cell Transplantation (HSCT)
Authors: Jason Chen, Jonathan Pan, John L. Wagner, Michael Sun, Onder Alpdogan, Matthew Carabasi, Joanne Filicko-O'Hara, Sameh Gaballa, Margaret Kasner, Thomas Klumpp, Neil Palmisiano, Ubaldo Martinez-Outschoorn, Pierluigi Porcu, Neal Flomenberg, Dolores Grosso
Journal: Blood (2017)
Abstract 13201: Atrial Fibrillation Detection in Community Ischemic Stroke Patients is Improved With Implantable Cardiac Monitors
Authors: Jia Guo, James R Brorson, Andrew Beaser, Zaid A Aziz, Cevher Ozcan, Roderick Tung, Hemal Nayak, Gaurav A Upadhyay
Journal: Circulation (2020)

Introduction: Although implantable cardiac monitors (ICM) improve atrial fibrillation (AF) detection relative to Holters or other extended ambulatory cardiac monitors (EACMs) (e.g., 30-day event monitors or outpatient telemetry) in clinical trials, data are limited on their performance in the community setting. We investigated AF detection in ischemic stroke patients and subsequent initiation of oral anticoagulation (OAC) in a real-world setting. Methods: We identified patients with ischemic stroke (2010-2015) in IBM MarketScan, a national prospectively acquired data set in whom Holters, EACMs, or ICMs were ordered. We further selected patients with no prior history of AF or OAC and continuous database enrollment 6 mos pre- and 24 mos post monitoring. Propensity score matching (PSM) was used to adjust for baseline characteristics differences between monitoring types. Logrank test was used to compare the Kaplan-Meier (KM) curves for AF detection and OAC initiation in patients with AF. Results: A total of 6,287 patients were analyzed: 4,107 Holter (age 63±14 yrs, 46% female, 28% coronary artery disease [CAD], 71% hypertension [HTN]), 1,829 EACM (age 61±14 yrs, 49% female, 27% CAD, 73% HTN), and 351 implanted with ICM (age 63±13 yrs, 51% female, 38% CAD, 82% HTN). After 1:1 PSM, the Holter-ICM cohort comprised of 664 patients and the EACM-ICM cohort comprised of 676 patients. In the Holter-ICM pair, 2 yr AF diagnoses rate was 14.5% for Holter vs 38.3% for ICM (logrank p&lt;0.01, Panel A). In the EACM-ICM pair, 2 yr AF diagnoses rate was 15.4% for EACM vs 38.2% for ICM (logrank p&lt;0.01, Panel B). Initiation of OAC in AF patients by 2 yrs was 41.7% for Holters vs 49.6% for ICMs (logrank p=0.30, Panel C) and 61.5% for EACM vs 49.6% for ICM (logrank p=0.16, Panel D). Conclusion: In community patients with ischemic stroke with no history of AF or prior OAC, rates of OAC initiation are comparable between monitoring types when AF is detected, and ICM outperforms Holter and EACM for the detection of AF.
Abstract 16710: <i>CYP2C19</i> Polymorphisms and Clinical Outcomes Following Percutaneous Coronary Intervention (PCI) in the Million Veterans Program (MVP)
Authors: Catherine Chanfreau-Coffinier, Tori Anglin-Foote, Kyung Min Lee, Zhenyu Lu, julie lynch, Mary E Plomondon, Scott L DuVall, Kevin A Friede, Deepak Voora, Jason L Vassy, Stephen W Waldo, John H Cleator, Thomas M Maddox, Scott M Damrauer, Daniel J Rader, Themistocles L Assimes, Christopher O'Donnell, Jay Giri, Philip S Tsao, Kyong-Mi Chang, Sony Tuteja
Journal: Circulation (2020)

Introduction: CYP2C19 reduced function (RF) alleles (*2, *3) have been shown to impair clopidogrel effectiveness following percutaneous coronary intervention (PCI) in the setting of acute coronary syndromes (ACS); however, this association has not been explored in the Veterans Health Administration. Hypothesis: CYP2C19 RF alleles are associated with major adverse cardiac events (MACE) in patients treated with clopidogrel Methods: MACE and CYP2C19 genotype were determined in MVP participants who underwent PCI between 2009-2017 with 1 year follow-up. Age was restricted to &lt;65 years of age to exclude Veterans likely receiving care outside VHA. DNA extracted from whole blood was genotyped using a customized array and imputed to the 1000 Genomes reference panel. MACE, encompassing all-cause mortality, myocardial infarction and ischemic stroke, was ascertained in VA electronic health records using ICD 9/10 codes. Time to first MACE was determined in the whole cohort and in the subgroup with ACS and stable coronary disease using Kaplan-Meier estimators and Cox proportional hazard models adjusted for clinical covariates and clopidogrel exposure modeled as a time-varying covariate. Results: Among 4,490 Veterans (age 59.1 ± 5 years, 18% African American, 6% Hispanic, 44% ACS) who were prescribed clopidogrel following PCI, 1,261 (28%) had RF CYP2C19 alleles. The overall MACE rate was 7.0%. MACE was associated with ACS as initial presentation, diagnosis of diabetes, chronic kidney disease, peripheral vascular disease, congestive heart failure, history of stroke, prior MI. Among the subgroup presenting with ACS, the adjusted risk of MACE was greater in participants with RF alleles compared to those with wildtype alleles (HR 1.38, 95% CI 1.002-1.916). There was no impact of RF alleles on MACE risk in those in the non-ACS group (HR 1.00, 95% CI 0.702-1.429). Conclusions: These data from the largest integrated health system in the US demonstrate that in Veterans presenting with ACS undergoing PCI, there was a higher risk of MACE in CYP2C19 RF carriers prescribed clopidogrel vs. wildtype carriers. The impact of the CYP2C19-clopidogrel interaction was not observed in the non-ACS patients. Further studies should explore the role of pharmacogenetic testing in Veterans.
Abstract 14055: Impact of a Boxed Meal Facilitated Plant-based Diet on Cardiometabolic Endpoints: A Clinical Trial
Authors: Amanda L Keller, Sanaz Ziad, Allison M Stephens, Elizabeth A Tesch, Joseph Sky, Eric Shih, Kirbee A Brooks, Vina E Howarth, Sachin A Shah
Journal: Circulation (2020)

Background: Plant-based diets (PBD) are increasingly recommended to reduce the risk of cardiovascular disease. Boxed meal-delivery services are a growing market facilitating consumer convenience; however, their effects on health require further study. We compared cardiometabolic changes between a boxed meal facilitated PBD (f-PBD) and Standard Omnivorous Diet (f-SOD). Methods: A prospective, controlled, parallel-designed trial assessing the impact of a f-PBD (n=16) to a f-SOD (n=16) on cardiometabolic endpoints was conducted in military beneficiaries. Participants with a BMI &gt;25 kg/m 2 consuming a standard omnivorous diet volunteered to adopt a f-PBD or f-SOD for a 4-week period. Participants had the option to consume breakfast and lunch according to their adopted diet at the military dining facility. Dinner was facilitated by shipping a commercially available plant-based or standard omnivorous boxed meal kit to participants as appropriate. Lipid parameters were monitored at baseline and at 4 weeks. Weight, blood pressure (BP) and other clinical endpoints were assessed weekly. The primary endpoints were change from baseline at 4 weeks in calculated low-density lipoproteins (LDL-c) and weight. A student’s t-test was performed to assess differences between groups using the intention-to-treat methodology. Results: A total of 32 participants were enrolled in the f-PBD and f-SOD groups. Average age of participants was 33.3±7.8 years, BMI was 29.6±3.5 kg/m 2 and 50% were male. Change in LDL-c from baseline in the f-PBD and f-SOD groups were -9.41±21.7 mg/dl and +5.63±15.9 mg/dl, respectively (p=0.033). The change in weight from baseline in the f-PBD and f-SOD groups were -3.82±4.4 pounds and +0.87±2.7 pounds, respectively (p=0.001). Systolic BP decreased non-significantly in the f-PBD group (-4.88±5.4 mmHg vs -0.38±9.2 mmHg for f-PBD and f-SOD, respectively, p=0.103). Conclusion: Incorporating a meal-delivery f-PBD significantly reduced LDL-c and weight over a 4-week period. Plant-based meal kits could serve as a novel dietary intervention in the optimization of cardiovascular disease burden.
M2 Macrophage-Derived Exosomes Promote Angiogenesis and Growth of Pancreatic Ductal Adenocarcinoma by Targeting E2F2
Authors: Yuhan Yang, Zengya Guo, Weiwei Chen, Xiaofeng Wang, Meng Cao, Xuan Han, Kundong Zhang, Buwei Teng, Jun Cao, Weidong Wu, Peng Cao, Chen Huang, Zhengjun Qiu
Journal: Molecular Therapy (2020)

Pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive tumors all over the world, has a generally poor prognosis, and its progression is positively correlated with the density of blood vessels. Recently, tumor-associated macrophages (TAMs) were proven to be beneficial for angiogenesis, but their mechanism of action remains unclear. Our study indicated that M2 macrophages were positively correlated with the microvessel density (MVD) of PDAC tissues, and M2 macrophage-derived exosomes (MDEs) could promote the angiogenesis of mouse aortic endothelial cells (MAECs) in vitro. At the same time, the M2 MDEs could also promote the growth of subcutaneous tumors and increase the vascular density of mice. Moreover, we also found that miR-155-5p and miR-221-5p levels in the M2 MDEs were higher than those in M0 MDEs, and they could be transferred into MAECs, as demonstrated by RNA sequencing (RNA-seq) and qPCR analysis. Our data confirmed the interaction between TAMs and the angiogenesis of PDAC by exosomes. Additionally, targeting the exosomal miRNAs derived from TAMs might provide diagnostic and therapeutic strategies for PDAC. Pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive tumors all over the world, has a generally poor prognosis, and its progression is positively correlated with the density of blood vessels. Recently, tumor-associated macrophages (TAMs) were proven to be beneficial for angiogenesis, but their mechanism of action remains unclear. Our study indicated that M2 macrophages were positively correlated with the microvessel density (MVD) of PDAC tissues, and M2 macrophage-derived exosomes (MDEs) could promote the angiogenesis of mouse aortic endothelial cells (MAECs) in vitro. At the same time, the M2 MDEs could also promote the growth of subcutaneous tumors and increase the vascular density of mice. Moreover, we also found that miR-155-5p and miR-221-5p levels in the M2 MDEs were higher than those in M0 MDEs, and they could be transferred into MAECs, as demonstrated by RNA sequencing (RNA-seq) and qPCR analysis. Our data confirmed the interaction between TAMs and the angiogenesis of PDAC by exosomes. Additionally, targeting the exosomal miRNAs derived from TAMs might provide diagnostic and therapeutic strategies for PDAC.
RNA interference-mediated gene silencing of signal transducer and activator of transcription 3 (STAT3) induces apoptosis in breast cancer cells
Authors: Sateesh Kunigal, Sajani Lakka, Norman Estes, Roger Geiss, Jasti Rao
Journal: Cancer Research (2008)

2282  STAT3, a member of the signal transducer and activator of transcription family, has the potential to mediate cell survival, growth and differentiation. STAT3 is constitutively activated in numerous cancers including more than 50% of breast cancer types. Previous studies have demonstrated that constitutively activated STAT3 plays an important role in the development and progression of breast cancer by promoting cell proliferation and inhibiting apoptosis. The present study was designed to investigate the potential use of RNA interference (RNAi) to block STAT3 expression and activation as well as any subsequent effect on the growth of human breast cancer cells. We identified a small interfering RNA (siRNA) specific for STAT3. Here, we show that blockade of STAT3 activation by the STAT3 siRNA suppressed STAT3-mediated gene expression and the growth of human breast cancer cells while also inducing apoptotic cell death. These results demonstrate that targeting STAT3 signaling using siRNA may serve as a novel therapeutic strategy for the treatment of breast cancer cells that express constitutively activated STAT3.
Beyond the clot: perfusion imaging of the pulmonary vasculature after COVID-19
Authors: Ranju T Dhawan, Deepa Gopalan, Luke Howard, Angelito Vicente, Mirae Park, Kavina Manalan, Ingrid Wallner, Peter Marsden, Surendra Dave, Howard Branley, Georgina Russell, Nishanth Dharmarajah, Onn M Kon
Journal: The Lancet Respiratory Medicine (2020)

A compelling body of evidence points to pulmonary thrombosis and thromboembolism as a key feature of COVID-19. As the pandemic spread across the globe over the past few months, a timely call to arms was issued by a team of clinicians to consider the prospect of long-lasting pulmonary fibrotic damage and plan for structured follow-up. However, the component of post-thrombotic sequelae has been less widely considered. Although the long-term outcomes of COVID-19 are not known, should pulmonary vascular sequelae prove to be clinically significant, these have the potential to become a public health problem. In this Personal View, we propose a proactive follow-up strategy to evaluate residual clot burden, small vessel injury, and potential haemodynamic sequelae. A nuanced and physiological approach to follow-up imaging that looks beyond the clot, at the state of perfusion of lung tissue, is proposed as a key triage tool, with the potential to inform therapeutic strategies.
Abstract 15567: Residual Cholesterol and Cardiovascular Events in Patients With Coronary Artery Disease Under Different Glucose Metabolism Status
Authors: Jian-jun Li, Yexuan Cao, Hui-Wen Zhang, Jing-Lu Jin, Yan Zhang, Rui-Xia Xu, Yuan-Lin Guo, Na-Qiong Wu, Cheng-Gang Zhu
Journal: Circulation (2020)

Introduction: The atherogenicity of residual cholesterol (RC) has been underlined by recent guidelines, which was linked to coronary artery disease (CAD), especially for patients with diabetes mellitus (DM). Hypothesis: This study aimed to examine the prognostic value of plasma RC, clinically presented as triglyceride-rich lipoprotein-cholesterol (TRL-C) or remnant-like lipoprotein particles-cholesterol (RLP-C), in CAD patients with different glucose metabolism status. Methods: Fasting plasma TRL-C and RLP-C levels were directly calculated or measured in 4331 patients with CAD. Patients were followed for incident MACEs for up to 8.6 years and categorized according to both glucose metabolism status [DM, pre-DM, normal glycaemia regulation (NGR)] and RC levels. Cox proportional hazards model was used to calculate hazard ratios (HRs) with 95% confidence intervals. Results: During a mean follow-up of 5.1 years, 541 (12.5%) MACEs occurred. The risk for MACEs was significantly higher in patients with elevated RC levels after adjustment for potential confounders. No significant difference in MACEs was observed between pre-DM and NGR groups (p&gt;0.05). When stratified by status of glucose metabolism and RC levels, highest levels of RLP-C, calculated and measured TRL-C were significant and independent predictors of developing MACEs in pre-DM (HR: 2.10, 1.98, 1.92, respectively; all p&lt;0.05) and DM (HR: 2.25, 2.00, 2.16, respectively; all p&lt;0.05). Conclusions: In this large cohort study with long-term follow-up, data firstly demonstrated that higher RC levels were significantly associated with the worse prognosis in DM and pre-DM patients with CAD, suggesting RC might be a target for patients with impaired glucose metabolism.
Abstract 16449: Sex Differences in Myocardial Injury and Outcomes of Covid-19 Infection
Authors: Nina Talmor, Amrita Mukhopadhyay, Yuhe Xia, Samrachana Adhikari, Claudia Pulgarin, Eduardo Iturrate, Leora I Horwitz, Judith S Hochman, Jeffrey S Berger, Glenn I Fishman, Andrea B Troxel, Harmony Reynolds
Journal: Circulation (2020)

Background: Myocardial injury is associated with higher mortality of COVID-19 and more complicated disease course. Little is known about sex differences in COVID-19-associated myocardial injury. We hypothesized that sex modifies the relationship between myocardial injury and severe COVID-19 infection. Methods: This is a cross-sectional study of all hospitalized patients with COVID-19 at a large health system in New York City between 3/2/20 - 5/12/20. We defined severe COVID-19 infection as ICU admission, mechanical ventilation, discharge to hospice, or death. Using multivariable logistic regression, we assessed whether sex modified the effect of peak troponin on the odds of severe COVID-19 infection, adjusting for demographics, co-morbidity, and laboratory values, and did the same for D-dimer. Results: Among 2,746 patients hospitalized with COVID-19, 650 (23.7%) required ICU admission, 648 (23.7%) required mechanical ventilation, and 680 (24.8%) died or were discharged to hospice. Peak troponin was higher in men than women (median 0.06, interquartile range [IQR] 0.01- 0.10 vs. 0.05 [IQR 0.01-0.10], p=0.02). Men were more likely to be admitted to the ICU and to receive mechanical ventilation (Table). After adjustment for demographics, medical history and other laboratory values, peak troponin level was associated with higher odds of severe COVID-19 illness: OR 1.51 per ng/mL, 95% CI 1.27-1.88, p&lt;0.001. This association was modified by sex: the OR for severe COVID-19 per ng/mL peak troponin was 1.30 in women (95% CI 1.11-1.65) and 1.92 (95% CI 1.42-2.78) in men, p-interaction=0.047. There was no interaction between sex and D-dimer on severe COVID-19. Conclusions: Sex modifies the relationship between myocardial injury and severe COVID-19, with men having higher odds of severe COVID-19 infection associated with increasing peak troponin. Sex differences in myocardial injury may play a role in poorer outcome among men.