tbuckley/cabot-search huggingface dataset:
Abstract 9785: A Very-Low Carbohydrate Content in a High-Fat Diet Modifies the Plasma Metabolome and Alleviates Experimental Atherosclerosis
Authors: Courtney Whalen, Karel Kalecky, Sean Gullette, Neil K Huang, Vishal Singh, Kristina Peterson, Thomas Neuberger, A Catharine Ross, Teodoro Bottiglieri, Rita Castro
Journal: Circulation (2021)

Background: A healthy diet is a cornerstone of CVD prevention and management. The vascular impact of very-low-carbohydrate (CHO), high-fat diets, or ketogenic diets (KD), remains unclear. Hypothesis: A KD will be protective against atherogenesis compared to a moderate-CHO, high-fat diet (HFD). Methods: Seven-week-old male apoE -/- mice, a model for human atherosclerosis, were fed two casein-based diets ad libitum for 12 weeks (Kcal%, CHO/fat/protein): KD (1/81/18) or HFD (42/40/18). Animals (6-8/group) were weighed weekly, and plasma was collected for quantification of beta-hydroxybutyrate (BHB) by a colorimetric assay, the inflammatory cytokines MCP1 and TNFα by immunoassays, and targeted metabolites by LC-MS/MS. Aortic atherosclerotic lesions were quantified ex-vivo by MRI on a 14-tesla-system. Results: KD mice weighed significantly less than HFD mice, reflecting the anti-obesogenic effect of the KD diet. Relative to HFD mice, the BHB level was markedly higher, and cytokines were significantly lower in the KD group, confirming the presence of ketosis in KD mice that alleviated the well-established fat-induced systemic inflammation. Several changes in the plasma metabolome driven by KD included a significant decrease in lipophilic metabolites, with increases in hydrophilic ones. Despite the higher fat content of KD versus HFD, KD mice presented significantly lower levels of several lipid metabolites including phosphatidylcholines, cholesterol esters, sphingomyelins, and ceramides. Consistent with the shift in energy metabolism toward fatty acid oxidation caused by the KD, the ratio of acyl-carnitines to free carnitine was significantly higher in KD than in HFD mice. Mice under nutritional ketosis displayed a distinct plasma amino acid profile evidencing a KD-induced alteration in protein metabolism. These included increased levels of the constituents of the major antioxidant glutathione, suggesting a more favorable redox status in the animals under nutritional ketosis. Lastly, the aortic plaque burden was significantly lower in the KD (4.8t±2.4 vol%) versus the HFD (12.8±6.72 vol%) group. Conclusion: Nutritional ketosis induced by the KD was associated with specific metabolic changes and an atheroprotective phenotype versus HFD.
TIM3+<i> TRBV11-2</i> T cells and IFNγ signature in patrolling monocytes and CD16+ NK cells delineate MIS-C
Authors: Levi Hoste, Lisa Roels, Leslie Naesens, Victor Bosteels, Stijn Vanhee, Sam Dupont, Cedric Bosteels, Robin Browaeys, Niels Vandamme, Kevin Verstaen, Jana Roels, Karel F.A. Van Damme, Bastiaan Maes, Elisabeth De Leeuw, Jozefien Declercq, Helena Aegerter, Leen Seys, Ursula Smole, Sofie De Prijck, Manon Vanheerswynghels, Karlien Claes, Veronique Debacker, Gert Van Isterdael, Lynn Backers, Kathleen B.M. Claes, Paul Bastard, Emmanuelle Jouanguy, Shen-Ying Zhang, Gilles Mets, Joke Dehoorne, Kristof Vandekerckhove, Petra Schelstraete, Jef Willems, Julie Willekens, Heidi Schaballie, Sabine Van daele, Laure Dierickx, Sara David, Evelyn Dhont, Ann Verrijckt, Annick de Jaeger, Emma Beel, Inge Matthijs, Aurélie Minne, Karin Decaestecker, Jijo John, Thomas E.M. Crijnen, Muriel Koninckx, Joery Verbruggen, Goele Nys, Samira Akhnikh, Koen Vanlede, Annelien Coppens, Joke Thijs, Ilse Ryckaert, Annick Covents, Els L.I.M. Duval, Ann Verschelde, Linde De Keyzer, Tine Van Ackere, Astrid Verbist, Charlotte Daeze, Caroline Becue, Justine De Paepe, Jo Keepers, Bruno Bruylants, Sabine Kuypers, Siel Daelemans, Jutte van der Werff ten Bosch, Gerlant van Berlaer, Alexandra Dreesman, Benoit Florkin, Catherine Heijmans, Jean Papadopoulos, Patrick Stordeur, Sophie Janssens, Rudi Beyaert, Yvan Saeys, Jean-Laurent Casanova, Bart N. Lambrecht, Filomeen Haerynck, Simon J. Tavernier
Journal: The Journal of Experimental Medicine (2021)

In rare instances, pediatric SARS-CoV-2 infection results in a novel immunodysregulation syndrome termed multisystem inflammatory syndrome in children (MIS-C). We compared MIS-C immunopathology with severe COVID-19 in adults. MIS-C does not result in pneumocyte damage but is associated with vascular endotheliitis and gastrointestinal epithelial injury. In MIS-C, the cytokine release syndrome is characterized by IFNγ and not type I interferon. Persistence of patrolling monocytes differentiates MIS-C from severe COVID-19, which is dominated by HLA-DRlo classical monocytes. IFNγ levels correlate with granzyme B production in CD16+ NK cells and TIM3 expression on CD38+/HLA-DR+ T cells. Single-cell TCR profiling reveals a skewed TCRβ repertoire enriched for TRBV11-2 and a superantigenic signature in TIM3+/CD38+/HLA-DR+ T cells. Using NicheNet, we confirm IFNγ as a central cytokine in the communication between TIM3+/CD38+/HLA-DR+ T cells, CD16+ NK cells, and patrolling monocytes. Normalization of IFNγ, loss of TIM3, quiescence of CD16+ NK cells, and contraction of patrolling monocytes upon clinical resolution highlight their potential role in MIS-C immunopathogenesis.
Abstract 14000: Identification of Circulating Surrogate Biomarkers for Risk Prediction of Breast Cancer Treatment-Related Cardiotoxicity
Authors: Tarun Pant, Matea Juric, Jacek Zielonka, Ivor J Benjamin, Zeljko J Bosnjak
Journal: Circulation (2021)

Introduction: Although anthracyclines, including doxorubicin (DOX), are among the most effective anticancer drugs to date, they cause dose-related cardiotoxicity that can lead to heart failure in a subset of patients. At present, it is not possible to predict which patients will be affected by doxorubicin-induced cardiotoxicity (DIC). We utilized patient-specific PBMC/Neutrophils to prospectively assess patient-and tissue-specific effects of high-risk therapeutic regimens and compare the results with patient outcomes after receiving chemotherapy for breast cancer. Hypothesis: We hypothesized that the PBMC/Neutrophils could recapitulate the predisposition of the patients towards DIC. Methods: The PBMC/Neutrophils were isolated from breast cancer patients with and without cardiotoxicity, and exposed to varying concentrations of doxorubicin (DOX). The in vitro DIC in breast cancer patients specific PBMC/Neutrophils after 24 hrs was assessed via analysis of: (a) Cytotoxicity determined via Alamar Blue cell viability assay kit; (b) Cytotoxicity determined using ATP based luminescence assay; (c) Oxygen consumption rate (OCR); and (d) Genome wide transcriptomic analysis of PBMCs. Results: Patient specific PBMC/Neutrophils recapitulate the predilection of the patients towards DIC. The PBMC/Neutrophils derived from breast cancer patients who experienced clinical doxorubicin-induced cardiotoxicity were more sensitive to doxorubicin toxicity depicting: (1) An increased response to DOX with neutrophils being more sensitive to DOX at lower concentrations than PBMCs; (2) Decreased ATP production indicating lower cellular viability; and (3) Lower OCR associated with basal mitochondrial respiration, ATP production, maximal respiration and spare respiratory capacity (representing mitochondrial function), as compared to breast cancer patients without cardiotoxicity. Conclusions: Together, our data indicate that this in vitro approach may represent a fast, cost-effective, and high throughput means to assess the future cardiotoxic effects of chemotherapy drugs. Furthermore, it offers the opportunity to understand the on-target and off-target molecular mechanisms to optimize the efficacy and safety of the cancer drugs.
Abstract 12653: Cardiologist Perspectives on Cardiac Point-of-Care Ultrasound
Authors: Linda Liu, Andrew Pattock, Cooper Kersey, Gary Huang, Sula Mazimba, Brandon Wiley, james kirkpatrick, Younghoon Kwon
Journal: Circulation (2021)

Background: The use of cardiac point-of-care ultrasound (c-POCUS) for patient care has been on the rise in many non-cardiology specialties. Perspectives on c-POCUS by cardiologists, the predominant user of comprehensive echocardiograms, have not been explored. Methods: A 19-item online survey was developed to evaluate respondents’ echocardiography experience as well as their current practices and perspectives on various aspects of c-POCUS. The survey was distributed to attending cardiologists at quaternary academic medical centers. Results: A total of 96 survey responses were collected from participants at 13 institutions. Majority of the respondents worked in an inpatient setting (97.9%) and formally practiced echocardiography (72.6%). C-POCUS use was common, with 37.9% of cardiologists using it more than twice per inpatient week. Cardiologists that practiced echocardiography used c-POCUS at higher frequency (43% vs. 23%, p=0.07). About half of respondents (47.9%) agreed that c-POCUS changed their clinical management. However, more than half agreed that c-POCUS should be further incorporated in practice (68.1%) and in formal fellowship education (71.3%). Few expressed time and labor intensiveness or impact on volume of comprehensive echocardiograms as major concerns. Major barriers to c-POCUS implementation included device availability, image documentation infrastructure, and reimbursement. Conclusion: This study demonstrates that the rising enthusiasm for c-POCUS also extends to cardiology. However, several barriers remain to more thorough utilization of this rapidly adopted diagnostic tool by cardiologists. Interventions to overcome these barriers would likely encourage further integration of c-POCUS use in clinical practice and fellowship training.
Abstract 14308: Lamotrigine Inhibits the Inward Fast Sodium Current (INa) in Epileptic Rat Cardiomyocytes
Authors: Juan Antonio Contreras Vite, Robert Dumaine
Journal: Circulation (2021)

Introduction: Lamotrigine (LTG) is widely prescribed to treat neurological disorders such as migraine, neurophatic pain, and epilepsy. Recently, LTG has been linked to Brugada sindrome (BrS) ECG as...
Abstract 10361: Cardiovascular Risk Factor Control and Treatment Across the Spectrum of Patients with Atherosclerotic Cardiovascular Disease: The Precision Medicine Initiative - All of Us Study
Authors: Yufan Gong, Nathan D Wong
Journal: Circulation (2021)

Objective: The 2018 Multisociety Cholesterol Guideline categorized patients with atherosclerotic cardiovascular disease (ASCVD) according to very high risk status, but there are few reports of recent medication use and risk factor control by risk group. We examined in a current cohort of US adults the extent of ASCVD risk factor control and treatment by these ASCVD groups. Methods: The NIH Precision Medicine Initiative (All of Us Study) is an ongoing program aiming to enroll &gt; 1 million adults across the US. Since May 2018, &gt;315,000 participants have been recruited from &gt;340 sites nationwide, oversampling underrepresented groups. We studied adults age &gt; 18 years with prior ASCVD, classified based on the 2018 guideline as 1) very high risk with &gt; 2 major ASCVD events, 2) very high risk with 1 major event and &gt; 2 major ASCVD conditions, or 3) ASCVD not at very high risk. We examined proportions at recommended therapies (high intensity statin, blood pressure [BP] and diabetes [DM] medication, and aspirin) and desired levels of risk factors (LDL-C, BP, HbA1c, and non-smoking status) across ASCVD risk categories. Results: Our 34,195 participants with ASCVD included 49% female, 20.5% non-Hispanic Black and 12.9% Hispanic or Latino adults, with an overall age of 66.0 + 12.4 years. 44.6% were classified as very high risk, of which 10.8% had &gt; 2 prior ASCVD evets. The table shows the proportion of each risk group on recommended therapies and risk factor targets. Across ASCVD risk groups use of high intensity statins (10-14%) and attainment of acceptable LDL-C levels (17-27%) and BP levels (42-47%) are markedly suboptimal. Across risk groups only 3-8% were on all 4 recommended therapies and &lt;5% were at all desired levels of all 4 risk factors. Conclusions: Improved efforts are needed to communicate the importance of multiple risk factor control and recommended therapies across the spectrum of ASCVD patients, and especially those at very high risk.
Abstract 11936: Macrophage-Specific DNase II Deficiency Stimulates Atherosclerosis in Apolipoprotein E-deficient Mice
Authors: Kumiko Suto, Daiju Fukuda, Masataka Sata
Journal: Circulation (2021)

Background: Atherosclerosis is a chronic inflammatory disease of the walls of blood vessels. Macrophage activated by endogenous ligands plays an important role in chronic inflammation of blood vessels. Endogenous DNA fragments derived from vascular cells in the presence of various risk factors attract much attention because endogenous DNA fragments, as well as exogenous DNA fragments induce inflammatory responses through the activation of DNA sensor, including Toll-like receptor 9 (TLR9). We hypothesized that DNase II (DN2) in macrophages degradates incorporated DNA fragments, suppressing pro-inflammatory activation of this cell-type and vascular inflammation. Therefore, we investigated the role of DN2 in macrophages in atherogenesis in apolipoprotein e-deficient (ApoE KO). Methods and Results: Macrophage-specific DN2 deleted ApoE KO mice were generated by cross breeding of DN2-flox mice, LysMCre mice, and ApoE KO mice. Mice obtained by cross breeding of DN2-flox mice and ApoE KO mice were used as the control. All mice were fed a western-type diet from 7 weeks of age and received subcutaneous angiotensin II infusion (1000 ng/kg per minute) from 8 weeks of age for 4 weeks. Macrophage-specific DNase II deletion significantly accelerated atherosclerotic lesion development in the aortic arch in ApoE KO mice (P &amp;lt; 0.05), accompanied with the increase in the expression of MMP-9 and TNF-α (P &amp;lt; 0.05, respectively) in the aorta. DN2-deletion significantly promoted the expression of inflammatory molecules such as MCP-1 (P &amp;lt; 0.01) in macrophages in the response to CpG-ODN 1826, a TLR9 agonist, or mitochondrial DNA. mtDNA promoted IkBα degradation in DN2-deficient macrophages, suggesting that NF-kB signal was related to DNA-induced macrophage activation. Conclusion: Our results suggested that macrophage-specific DN2 deletion accelerated pro-inflammatory activation of macrophages in the response to DNA fragments, leading to the development of atherogenesis in ApoE KO mice. DN2 may be a potential therapeutic target for atherosclerosis.
Abstract 13619: Obese Patients With New Onset Atrial Fibrillation/Flutter Have Higher Rates of Hospitalization, Cardioversion, and Ablation
Authors: Jonathan Norton, Andrew Foy, Gerald Naccarelli
Journal: Circulation (2021)

Atrial fibrillation (AF) is the most common arrhythmia and can lead to frequent healthcare encounters. Obesity is a rapidly growing epidemic, and greater than one third of all adults in the USA are obese. Additionally, obese patients have over twice the prevalence of AF compared to the non-obese. Despite the frequency of these conditions, there is limited research assessing the relationship between obesity and healthcare resource utilization (HRU) in AF patients. We hypothesized that obese patients with new onset atrial fibrillation/flutter (AFL) would have higher AF/AFL related hospitalizations and procedures compared to non-obese patients. We utilized MarketScan® claims data to select patients with new onset atrial fibrillation or atrial flutter in 2017 and 2018 and classified them according to diagnosis codes as obese or non-obese. We then stratified by the diagnosis of obesity. There were 95,314 patients with new onset atrial fibrillation/flutter, which included 72,218 (76%) who were non-obese and 23,096 (24%) who were obese. There were significantly more males than females (64.4% vs. 35.6%). The average age was similar at 54.4 (+/- 0.04) in the non-obese and 54.6 (+/- 0.06) in the obese cohort. The rate of hospitalizations (35.9% vs. 24.8%, p&lt;0.001), cardioversions (16% vs. 10%, p&lt;0.001), and ablation procedures (10% vs. 7%, p&lt;0.0001) were significantly higher in the obese versus non-obese cohort. Obese patients with new onset AF/AFL had significantly higher HRU than non-obese patients. This increased health resource utilization increases the cost of care in such patients and future studies should concentrate on understanding the reasons for this difference.
Abstract 12611: Demographics and Readmissions of Patients With Congestive Heart Failure and Adverse Social Determinants of Health
Authors: Appesh N Mohandas, Holly Rodin, Katherine D Vickery, Gautam R Shroff
Journal: Circulation (2021)

Background: Safety Net Community Hospitals (SNCH) account for 1/3 of all US inpatient admissions. The congestive heart failure (CHF) population at our SNCH has high rates of adverse social and behavioral determinants of health (SBDH), but this high-risk population is not well represented in randomized clinical trials of CHF. We sought to determine whether differences in prescriptions of guideline-directed medical therapy (GDMT) for CHF explained worse outcomes in individuals with CHF and adverse SBDH. Methods: We performed a retrospective review of patients diagnosed with CHF (using ICD codes) in 2018, 2019 at Hennepin Healthcare, a SNCH in downtown Minneapolis. We obtained baseline demographics, comorbidities, insurance status, and outcomes from electronic health record. We compared these variables among those without and with adverse SBDH (homelessness, incarceration, substance abuse) using paired t-tests. Results: CHF patients with at least 1 adverse SBDH were more likely to be younger, male, black, with higher prevalent mental illness (Table). They were less likely to have commercial insurance or Medicare, more likely to have Medicaid. The prescription for GDMT for each of the individual categories was high; prescription patterns of GDMT were statistically similar or superior for CHF patients with vs. without adverse SBDH. Patients in SNCH with adverse SBDH had significantly higher hospitalizations and emergency department (ED) visits compared to those without adverse SBDH. Conclusions: CHF patients with adverse SBDH are demographically different from those without adverse SBDH. CHF in the presence of ≥1 adverse SBDH is associated with significantly higher rates of hospitalization and ED visits, without significant differences in prescriptions of GDMT for CHF. The disproportionate demographic burden of adverse SBDH in SNCH as well as causes underlying worse outcomes in CHF patients with adverse SBDH need further research.
TMOD-04. T-TYPE CALCIUM CHANNELS DRIVE GLIOBLASTOMA INITIATION AND PROGRESSION
Authors: Collin Dube, Ying Zhang, Myron Gibert Jr, Elizabeth Mulcahy, Matteo Ottolini, Esther Xu, Aditya Sorot, Edward Perez-Reyes, Swapnil Sonkusare, Roger Abounader
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma is the most common primary malignant brain tumor with a dismal median survival of 15 months. Calcium signaling regulates a plethora of cellular processes making it an ideal target for therapeutic intervention. Our group identified T-type calcium channels (TTCCs) as upregulated in GBM cells, stem cells and human tumors. Analysis of the Cancer Genome Atlas (TCGA) demonstrates for the first time that &amp;gt;20% of GBM patients exhibit mutation, amplification or mRNA upregulation of TTCCs. TCGA and Chinese Glioma Genome Atlas (CGGA) data analyses demonstrate that patients with alterations in TTCC trend toward worse survival compared to normal TTCC expression. Our group utilized an FDA repurposed TTCC blocker Mibefradil to demonstrate inhibition of TTCCs decreases cancer associated signaling, transcription, malignancy parameters and in vivo tumor growth. Mibefradil treatment sensitized Gliomas stem like cells (GSC) xenografts to temozolomide (TMZ) chemotherapy and radiotherapy. To elucidate the roles of the individual TTCCs in vivo we created RCAS/Tva-shTTCC mice for silencing of Cav3.1 and Cav3.2. The silencing of the TTCCs individually decreased tumor growth as measured by MRI and H&amp;E staining. Silencing of TTCCs extended survival of mice in vivo. Silencing of TTCC decreases proliferation (Ki67) and increases apoptosis (Caspase 3). Our findings suggest T-type calcium channels contribute to tumor initiation and progression.
Leukemic Cells Expressing <i>ETV6-Frk</i> Identified in a Refractory B-ALL Patient Are Sensitive to Dasatinib <i>in Vitro</i>
Authors: Azusa Mayumi, Hideki Yoshida, Kouhei Mitsuno, Nozomi Nishida, Shinya Osone, Takahiko Yasuda, Toshihiko Imamura
Journal: Blood (2021)
Abstract 10496: Cardiac Function in Postmenopausal Women Are Unaltered by Two Decades of Different Physical Activity Levels
Authors: Mads Fischer, Andrea S Tamariz-Ellemann, Ylva Hellsten, Lasse Gliemann
Journal: Circulation (2021)

Rationale: In women, the risk of coronary heart disease increases significantly after the onsetof menopause. Exercise and active lifestyle have known benefits such as a significantly reducedrisk of heart failure. To date, most of the knowledge on physical activity induced changes incardiac function in older individuals are based on males and with a sparsity of data from healthypostmenopausal women with differing physical activity and fitness. Aim: The aim was to determine the impact of more than twenty years of differing physicalactivity levels and maximal oxygen consumption on cardiac morphology and function inpostmenopausal women. Method: The study design was cross-sectional with age-matched non-smoking, non-medicatedhealthy women divided in to three groups based on their self-reported physical activity levelwith regard to intensity and volume over the past two decades. Forty-one women was included(age of 61 ± 1 years; 11 ± 2 postmenopausal years; body mass index 23 ± 3 kg • m 2 ) and dividedinto groups based on activity level categorized as sedentary (SED; ≤1 h exercise weekly; n=14);Moderate (MOD; ≥2 ≤6h low/moderate intensity exercise weekly; n=12) and high (HIGH; &lt;4h of moderate/high intensity exercise weekly; n=15). Cardiac function and dimensions wereassessed with transthoracic echocardiography and maximal pulmonary oxygen uptake wasdetermined by graded bike ergometer exercise to exhaustion. Results: The three groups displayed significantly different levels of maximum oxygen uptake(24.9 ± 5.8; 30.5 ± 5.8; 38.4 ± 4.4 ml/kg, for SED, MOD and HIGH respectively) (p &lt; 0.01).No differences were observed in resting left ventricular (LV) morphology (LVmass, LVmassindex) systolic function (EF%, GLS and mitral valve S′), diastolic function (E/A ratio, IVRT)or right ventricular function (TAPSE and tricuspid annular velocity S’) between the threegroups. Conclusions: These data show that the level of lifelong physical activity and correspondingdifferences in maximal oxygen consumption, may have less impact on left ventricularmorphology and systolic/diastolic function in healthy postmenopausal women than previouslyexpected.