tbuckley/cabot-search huggingface dataset:
Decreased adipose tissue oxygenation associates with insulin resistance in individuals with obesity
Authors: Vincenza Cifarelli, Scott C. Beeman, Gordon I. Smith, Jun Yoshino, Darya Morozov, Joseph W. Beals, Brandon D. Kayser, Jeramie D. Watrous, Mohit Jain, Bruce W. Patterson, Samuel Klein
Journal: Journal of Clinical Investigation (2020)

BACKGROUNDData from studies conducted in rodent models have shown that decreased adipose tissue (AT) oxygenation is involved in the pathogenesis of obesity-induced insulin resistance. Here, we evaluated the potential influence of AT oxygenation on AT biology and insulin sensitivity in people.METHODSWe evaluated subcutaneous AT oxygen partial pressure (pO2); liver and whole-body insulin sensitivity; AT expression of genes and pathways involved in inflammation, fibrosis, and branched-chain amino acid (BCAA) catabolism; systemic markers of inflammation; and plasma BCAA concentrations, in 3 groups of participants that were rigorously stratified by adiposity and insulin sensitivity: metabolically healthy lean (MHL; n = 11), metabolically healthy obese (MHO; n = 15), and metabolically unhealthy obese (MUO; n = 20).RESULTSAT pO2 progressively declined from the MHL to the MHO to the MUO group, and was positively associated with hepatic and whole-body insulin sensitivity. AT pO2 was positively associated with the expression of genes involved in BCAA catabolism, in conjunction with an inverse relationship between AT pO2 and plasma BCAA concentrations. AT pO2 was negatively associated with AT gene expression of markers of inflammation and fibrosis. Plasma PAI-1 increased from the MHL to the MHO to the MUO group and was negatively correlated with AT pO2, whereas the plasma concentrations of other cytokines and chemokines were not different among the MHL and MUO groups.CONCLUSIONThese results support the notion that reduced AT oxygenation in individuals with obesity contributes to insulin resistance by increasing plasma PAI-1 concentrations and decreasing AT BCAA catabolism and thereby increasing plasma BCAA concentrations.TRIAL REGISTRATIONClinicalTrials.gov NCT02706262.FUNDINGThis study was supported by NIH grants K01DK109119, T32HL130357, K01DK116917, R01ES027595, P42ES010337, DK56341 (Nutrition Obesity Research Center), DK20579 (Diabetes Research Center), DK052574 (Digestive Disease Research Center), and UL1TR002345 (Clinical and Translational Science Award); NIH Shared Instrumentation Grants S10RR0227552, S10OD020025, and S10OD026929; and the Foundation for Barnes-Jewish Hospital.
Abstract 12729: Impact of Chilli-pepper Intake on All-cause and Cardiovascular Mortality - A Systematic Review and Meta-analysis
Authors: Manpreet Kaur, Beni R Verma, Leon Zhou, Simrat Kaur, Yasser Sammour, Hassan Mehmood Lak, Bo Xu
Journal: Circulation (2020)

Background: Chilli-pepper (CP) is well known for its anti-inflammatory, antioxidant, anticancer, and blood glucose regulation effects. However, the impact of CP on all-cause and cardiovascular mortality is not clear. Methods: A comprehensive search was performed using Ovid, Cochrane, Medline, Embase, and Scopus. We screened the studies from inception till January 16, 2020, and reported the outcomes of our interest after consumption of CP (Figure1a). The inclusion criteria were: all observational and randomized controlled trials reporting the outcomes of interest, and pediatric, animal studies, letters/case reports, reviews, abstracts, and book chapters were excluded. All-cause mortality was studied as the primary endpoint. Cardiovascular, cerebrovascular, and cancer-related deaths were studied as secondary outcomes. Results: From 4729 studies screened, four studies including 570,762 subjects met the inclusion criteria. Random-effects pooled analysis showed that there was a 25% reduction in the relative risk of all-cause mortality for regular CP consumers, compared to non-consumers (relative risk (RR): 0.75; 95% confidence intervals (CI): 0.64-0.88, p = 0.0004, Figure1b). Furthermore, there were a 26% and 23% reduction in the RR of death due to cardiovascular causes (RR: 0.74; 95% CI: 0.62-0.88, p=0.0006, Figure1c) and cancer (RR: 0.77; 95% CI: 0.71-0.84, p=0.0001, Figure 1d), respectively. However, there were no statistically significant differences in cerebrovascular accidents (RR: 0.76; 95% CI: 0.36-1.60, p=0.47). Conclusion: In a contemporary meta-analysis of 570,762 subjects, regular CP consumption was associated with a significant reduction in all-cause, cardiovascular, and cancer-related mortalities. Future studies are needed to better understand the potential mechanisms of the mortality benefits of CP consumption.
Fidelity of human ovarian cancer patient-derived xenografts in a partially humanized mouse model for preclinical testing of immunotherapies
Authors: Adekunle Odunsi, A J Robert McGray, Anthony Miliotto, Yali Zhang, Jianming Wang, Adebukola Abiola, Cheryl Eppolito, Ruea-Yea Huang
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Immune checkpoint blockers (ICBs) have been approved by the Food and Drug Administration to be used alone in front-line therapies or in combination with other regimens for certain advanced cancers. Since ICB only works in a subset of patients and has limited efficacy in treating ovarian cancer (OVC), developing preclinical models that help to understand which patients may derive benefit from ICB would be of tremendous benefit in OVC. Methods Here, we generated preclinical human OVC models from freshly resected tumors, which include six patient-derived xenografts (PDXs) from six different patient tumors, three transplantable OVC PD spheroid lines (PD-sphs), and 3 cell lines (PD-CLs). We tested the therapeutic combination of anti-PD1/CTLA4 antibodies with (1) autologous tumor-associated leukocytes (TALs) on the growth of PD-sphs in a coculture system in vitro, (2) with adoptively transferred autologous peripheral blood mononuclear cells or TALs in patient-derived OVC models using partially humanized mice, NSG-HHDxSGM3 (N-HSGM3). Results We show that PD-1 and CTLA-4 dual blockade when combined with autologous TALs effectively reduced PD-sph number in a co-culture system and led to regression of established PD-CLs and PDXs in the N-HSGM3 mice. Combinatorial PD-1 and CTLA-4 blockade increased the frequency and function of tumor-specific CD8 T cells. These CD8 T cells persisted in the tumor microenvironment, exhibited memory phenotype and protected animals from tumor growth on tumor rechallenge. Gene expression analysis of tumors resistant to dual PD1/CTLA4 blockade treatment identified upregulation of antigen processing and presentation pathways and downregulation of extracellular matrix organization genes. Conclusions These findings describe a novel platform for developing patient-derived preclinical tumor models suitable for rationally testing combinatorial ICB in the context of autologous tumor-reactive T cells. This platform can be further developed for testing additional targeted therapies relevant to OVC.
Abstract PR-005: Tumor intrinsic p53 mutation drives accumulation of neutrophils in the pancreatic tumor microenvironment promoting resistance to immunotherapy
Authors: Despina Siolas, Emily Vucic, Emma Kurz, Cristina Hajdu, Dafna Bar-Sagi
Journal: Cancer Research (2020)

Abstract Intratumoral genetic alterations can cause remodeling of local immune cell populations through distinct cellular mechanisms. After oncogenic KRAS, TP53 is the gene most frequently mutated in pancreatic ductal adenocarcinoma (PDAC). These mutations in TP53 are neomorphic and confer phenotypes distinct from those due to homozygous TP53 deletion. We sought to evaluate the non-cell-autonomous role of mutant p53 protein in the immune microenvironment by studying KrasG12D-mutated mouse pancreatic ductal epithelial cells (PDEC) engineered using CRISPR/Cas gene editing to express the Trp53R172H gain-of-function mutation. We found distinct immune profiles associated with orthotopically implanted tumors derived from KrasG12D;Trp53R172H PDEC, characterized by an influx of intratumoral CD11b+Ly6G+ neutrophils and concomitant decreases in CD3+ T cells, CD8+ T cells, and CD4+ T helper 1 (Th1) cells. Analysis of publicly available human PDAC cohorts revealed enrichment of genes in neutrophil-related pathways in TP53-mutated tumors. Knockdown of CXCL2, a neutrophil chemoattractant, in the tumor epithelial compartment of KrasG12D;Trp53R172H PDEC tumors reversed the neutrophil phenotype. Depleting neutrophils in mice bearing KrasG12D;Trp53R172H PDEC tumors augmented sensitivity to combined CD40 immunotherapy and chemotherapy. Collectively, these data link mutant p53 to the presence of intratumoral neutrophils in pancreatic cancer and suggests that tumor genotypes could inform patient selection for immunotherapy. Citation Format: Despina Siolas, Emily Vucic, Emma Kurz, Cristina Hajdu, Dafna Bar-Sagi. Tumor intrinsic p53 mutation drives accumulation of neutrophils in the pancreatic tumor microenvironment promoting resistance to immunotherapy [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PR-005.
A versatile toolkit for CRISPR-Cas13-based RNA manipulation in Drosophila
Authors: Nhan Huynh, Noah Depner, Raegan Larson, Kirst King-Jones
Journal: Genome biology (2020)

Abstract Advances in CRISPR technology have immensely improved our ability to manipulate nucleic acids, and the recent discovery of the RNA-targeting endonuclease Cas13 adds even further functionality. Here, we show that Cas13 works efficiently in Drosophila , both ex vivo and in vivo. We test 44 different Cas13 variants to identify enzymes with the best overall performance and show that Cas13 could target endogenous Drosophila transcripts in vivo with high efficiency and specificity. We also develop Cas13 applications to edit mRNAs and target mitochondrial transcripts. Our vector collection represents a versatile tool collection to manipulate gene expression at the post-transcriptional level.
Nick Foster: founder member of the East Midlands Immediate Care Scheme
Authors: Rebecca Wallersteiner
Journal: BMJ (2020)

Photo credit: Gillian Wilmot

Nick Foster, who co-founded emergency response group EMICS and was the first doctor on the scene of the Kegworth air disaster in 1989, has died at the age of 65.

Foster was born in Leicester in 1955, an only child and raised in Hong Kong where his father, John, was a Church of England dean. Foster’s parents met during the war. His mother, Margaret, was in the Wrens, and John in the Leicester Yeomanry, and they married in 1943. In his youth, Foster adored animals and according to his family was always rescuing “mutts” from the streets in Hong Kong, where he attended a local school. As a child, he underwent many operations—he was born deaf in his left ear. He returned to England as a boarder at Loughborough Grammar School. He was told he was not bright enough to be a doctor but in time became an exceptional medical practitioner.

Foster initially studied dentistry at Sheffield University and qualified as a dentist in 1978. Afterwards he read medicine. He worked briefly in maxillofacial reconstructive surgery and anaesthetics before opting for general practice. He trained …
Abstract 120: Artesunate Reduces the Severity of Post-Resuscitation Myocardial and Cerebral Dysfunction
Authors: Hui Li, Cheng Cheng, Lian Liang, Tao Jin, Guozhen Zhang, Jennifer Bradley, Mary Ann A Peberdy, Joseph P Ornato, Wanchun Tang
Journal: Circulation (2020)

Introduction: Artesunate (ART) possesses anti-inflammatory activity, which can mitigate the systemic inflammatory response in poor outcomes of cardiac arrest (CA). We investigated the effects of ART on myocardial and cerebral function, duration of survival, and inflammation in a rat model of CA and cardiopulmonary resuscitation (CPR). Hypothesis: ART reduces the severity of post resuscitation myocardial and cerebral dysfunction by alleviating inflammation in a rat model of CA and CPR. Methods: 30 male Sprague-Dawley rats weighing between 450g-550g were randomized into 3 groups: Sham (S), Control (C), and Artesunate (A). C and A were divided into subgroups: survival and non-survival (n=6). Ventricular fibrillation (VF) was induced and untreated for 6 min. A 4J defibrillation was attempted after 8 min of CPR. Phosphate buffer (1ml/kg, pH 7.9-8.1) or ART (2.4mg/kg), was administered at return of spontaneous circulation (ROSC). Myocardial function was measured at baseline and every hour for 4h post ROSC. Plasma levels of IL-6, TNF-α and cTnI were detected at baseline and 4h after ROSC. Survival animals were observed for an additional 72h. Neurologic deficit scores were recorded daily. Results: ART reduced the severity of post-resuscitation myocardial dysfunction compared to C. It attenuated IL-6, TNF-α and cTnI plasma levels 4h after ROSC (p&lt;0.05) (Fig. 1). Post-resuscitation cerebral function and survival rate also improved significantly (p&lt;0.05) (Fig. 2). Conclusion: ART reduces the severity of post-resuscitation myocardial and cerebral dysfunction, improves survival rate and attenuates inflammation in a rat of model of CA and CPR.
Abstract 13551: Identifying Left Main Coronary Artery Disease Using Coronary Artery Calcium Scans
Authors: Joel E Money, Joseph B Muhlestein, Steve M Mason, Tami L Bair, Kirk U Knowlton, Jeffrey L Anderson
Journal: Circulation (2020)

Introduction: The ISCHEMIA trial tested an invasive vs. an initial medical strategy in patients (pts) with stable coronary disease and evidence of ischemia. No significant difference between strategies in cardiovascular events was found at 3.2 years. However, pts were screened before randomization by coronary CT angiography (CCTA) to exclude ≥50% left main coronary stenosis (LMCS). CCTA adds complexity to routine medical practice, including time delays, expense, and safety concerns. We tested whether a coronary artery calcium scan (CACS), a simpler, less expensive test, could replace CCTA to exclude significant LMCS. Methods: We hypothesized that pts with ≥50% LMCS would have a LM CACS score&gt;0. As a corollary, we postulated that a LM CACS=0 would exclude pts with LMCS. To test this, we searched Intermountain Healthcare’s electronic medical records database for all adult pts who had undergone non-contrast cardiac CT for quantitative CACS scoring prior to selective coronary angiography (SCA) and were found to have a LMCS ≥50%. Pts aged &lt;50 and those with a heart transplant were excluded. Cases with incomplete (qualitative) angiographic reports for LMCS and those with incomplete or discrepant LM CACS results were reviewed and reassessed blinded to CACS or SCA findings, respectively. Results: Among 674 candidate pts with CACS followed by SCA, 24 qualifying pts were identified who had a quantitative CACS score and LMCS ≥50%. Their age averaged 71 ± 11 years, and 83% were men. Angiographic LMCS averaged 77% (range 50%-99%). A heavy burden of both total CAC and LM CAC was typically present. Total CACS score averaged 2,545 Agatston Units (AU), range 571-6,636. LM CACS score averaged 214 AU, range 47-610. Importantly, no LMCS pt had a LM CACS score of 0 vs. 57% (368/650) of non-LMCS controls (p&lt;0.00001). Conclusions: Our results support the hypothesis that an easily administered, inexpensive, low radiation CACS can identify a large subset of pts with a very low risk of LMCS without the need for routine CCTA. Using CACS to exclude LMCS may efficiently allow for safe implementation of an initial medical therapy strategy in clinical practice for ISCHEMIA trial-like pts with at least moderate ischemia on stress testing. These promising results deserve validation in larger data sets.
Abstract 17186: Molecular Mechanisms Underlying Sex-Related Differences in Mitochondrial Response to Myocardial Ischemia/Reperfusion
Authors: Meijing Wang, Susan Scott, Qing Yu, Kanhaiya Singh, Chandan Sen, Mark Turrentine
Journal: Circulation (2020)

Introduction: Cardiac dysfunction adversely impacts patient outcomes following surgically induced myocardial ischemia/reperfusion (I/R). Maintaining mitochondrial activity is crucial to reducing myocardial I/R. Inflammation and oxidative stress triggered by I/R impair mitochondria. Our group has shown sex differences in myocardial functional recovery after I/R. Here, we determined whether sex disparity in mitochondrial response to inflammatory mediator - TNFα and to reactive oxygen species - H 2 O 2 is responsible for sex differences in cardiac dysfunction. Given the key role of mitochondrial connexin43 (Cx43) in cardiac protection initiated by ischemic preconditioning, we also investigated the implication of Cx43 in sex-related mitochondrial response. Methods: Cardiomyocytes (male &amp; female; C57BL/6 &amp; doxycycline inducible Tnnt2-controlled Cx43 knockout) were subjected to simulated I/R (20’ I/60’ R), TNFα (10ng/ml), or H 2 O 2 (50 μM), +/- 17β-estradiol (E2).Mitochondrial membrane potential (ΔΨm) analyzed by JC1 red to JC1 green fluorescence intensity ratio (Fig. A) and mitochondrial respiration capacity by Seahorse XF Cell Mito Stress Test were determined.Cx43 was assessed in mitochondria by Western blots and Immunoelectron microscopy. Results: Improved ΔΨm (Fig. B) and preserved mitochondrial respiratory capacity were observed in female cardiomyocytes than in male ones following simulated I/R, TNFα, or H 2 O 2 .E2 restored mitochondrial activity in cardiomyocytes (Fig. C, D). In addition, E2 increased Cx43 content and phosphorylation in cardiac mitochondria. Ablation of cardiac Cx43 abolished E2-mediated mitochondrial protection during TNFα or H 2 O 2 challenge (Fig. E). Conclusions: Female cardiomyocytes were more resistant to I/R, TNFα, or H 2 O 2 stimulation than age-matched males, with greater protective role of mitochondrial Cx43 in female hearts. E2 usage regulated mitochondrial Cx43 and preserved cardiac mitochondrial performance.
Abstract 17251: Knockdown of NOX2 Reduces Rotational Drivers in AF - A New Gene Therapy Approach for Atrial Fibrillation?
Authors: Markus Rottmann, Anna Pfenniger, Shin Yoo, David Johnson, Gail Elizabeth Geist, Mandava Suman, Burrell Amy, Andrew Wasserstrom, Bradley P Knight, Rod S Passman, Rishi Arora
Journal: Circulation (2020)

Introduction: Oxidative Stress (OS) is thought to be a mediator of atrial fibrillation (AF). However, the precise role of OS in electrical remodeling in AF is unknown. We assessed the effect of a novel gene-based strategy by performing knockdown of NOX2 in a clinically relevant large animal on the maintenance of rotational drivers in AF. Hypothesis: We hypothesized that the gene-based strategy by performing knockdown of NOX2 reduces rotational activities in AF. Methods: 1 week after pacemaker implantation, open-chest sub-epicardial gene injection of NOX2 shRNA was performed in the LA (PLA, LAFW, LAA), to significantly knockdown NOX2 in 6 dogs and 10 controls were also used. Epicardial high-density mapping was performed (117 electrodes, inter-elec.-distance 2.5mm) at day1 (gene injection) and at terminal day (up to 12weeks RAP) in 6 atrial regions. Number and stability of rotational activities were detected based on activation maps and CL was analyzed. Results: AF developed in controls (&gt;30 min) in 4-9 days, compared to &gt;21 days in NOX2 shRNA animals (p&lt;0.01). The stability of observed rotational drivers decreased (baseline gene delivery vs terminal day) in all left atrial regions: in the LAA (315.88±123.53ms, median 300.00ms vs 282.55±175.04ms, median 270ms), PLA (462.46±477.04ms, median 360ms vs 280.39±101.55ms, median 240ms), LAFW (416.67±162.50ms, median 405ms vs 241.67±92.63ms, median 195ms) (Figure A). Number of rotational activities reduced by 36.58% (P=0.14) after gene delivery. CL increased in the PLA from (93.74±30.11ms, median 85.00ms to 102.15±33.07ms, median 92.00ms after gene delivery (Figure C). Conclusions: Gene injection by NOX2 shRNA reduced the stability of rotational activities in AF. OS may be an important, dynamic mechanism underlying the formation and maintenance of the AF disease state. Targeted disruption of NOX2-dependent oxidative injury with a new gene therapy approach prevents onset as well as the perpetuation of AF.
Abstract 16597: Outcomes of a Randomized Controlled Trial of Integrated Cardiac Rehabilitation Among Heart Failure Patients in Kenya
Authors: G.Titus K Ngeno, Felix A Barasa, Edith Kwobah, Jemima Kamano, Rajesh Vedanthan, Brandon Knettel, Neelima Navuluri, Joseph R Egger, Nathan Thielman, Peter Kussin, William E Kraus, Gerald S Bloomfield
Journal: Circulation (2020)

Background: Cardiac rehabilitation (CR) is an evidence based, cost effective treatment for heart failure (HF). Globally, access to CR is limited, especially in low- and middle-income countries. An integrated model of institutional and home-based CR has been proposed as a solution to access barriers. However, the efficacy of integrated CR in this region is unknown. We performed a randomized controlled trial of integrated CR compared to usual care (no CR) among patients with stable HF in western Kenya. Methods: Patients with class II or III NYHA symptoms were enrolled from the Moi Teaching and Referral Hospital. Participants with arrhythmias, congenital heart disease, or stenotic valvular heart disease were excluded. Integrated CR comprised of counseling and supervised aerobic exercises 3 times a week for 1 month, followed by 2 months of monitored home-based exercises prescribed weekly via phone. Participants in both arms received health lifestyle education and wore triaxial hip pedometers. The primary outcome, change in 6-minute walk time distance (6MWTD), as well as weekly step counts were compared using the Student’s t-test. Results: Eighty-two participants were randomized (Figure). 6MWTD improved significantly more among the 41 patients receiving CR (45 ± 67m from baseline), compared to the usual care arm (18 ± 49m in, p&lt;0.05), (Table). There was no significant difference in change by age, gender, BMI, ejection fraction or reported HF cause. Conclusions: Integrated CR improves 6MWTD among patients with HF. The findings are limited to a single center. Future studies on long-term outcomes and mechanistic processes responsible for improvement are needed.