tbuckley/cabot-search huggingface dataset:
Abstract 11565: Revascularization Prior to Renal Transplantation is Not Superior to Medical Therapy Alone in Reducing Mortality in Patients with Coronary Artery Disease
Authors: Muhammad U Siddiqui, Joey Junarta, Gregary D Marhefka
Journal: Circulation (2021)

Introduction: Coronary artery disease (CAD) is a common cause of mortality in end stage renal disease and is highly prevalent in patients with chronic kidney disease. Therefore, patients with end stage renal disease are routinely screened for heart disease prior to renal transplant. The role of revascularization remains unclear in this process. Hypothesis: There is no difference in all-cause and cardiovascular (CV) mortality in renal transplant patients with coronary artery disease who underwent revascularization prior to transplant when compared to those who were treated with optimum medical therapy (OMT). Methods: Medline, Scopus and Cochrane Central Register of Controlled Trials were systematically searched to identify relevant studies. Primary outcomes of interest were all-cause mortality, CV mortality and major adverse cardiovascular events (MACE). Results: We included six studies for this metanalysis. There was no significant difference in all-cause mortality (RR 1.16; 95% CI 0.63 - 2.12), CV mortality (RR 0.71; 95% CI 0.24 - 2.09) or MACE (RR 0.78; 95% CI 0.30 - 2.07) in renal transplant patients with CAD who underwent revascularization prior to renal transplant compared to those who were on OMT alone for CAD. Conclusions: Studies suggest that revascularization is not superior to OMT for CAD in patients undergoing renal transplant therapy.
TAMI-73. GLIOBLASTOMA CELL POPULATIONS WITH DISTINCT ONCOGENIC PROGRAMS RELEASE PODOPLANIN AS PROCOAGULANT EXTRACELLULAR VESICLES
Authors: Nadim Tawil, Rayhaan Bassawon, Brian Meehan, Laura Montermini, Ali Nehme, Dongsic Choi, Cristiana Spinelli, Lata Adnani, Abdulshakour Mohammadnia, Charles Couturier, Kevin Petrecca, Janusz Rak
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Vascular anomalies, including thrombosis, are a hallmark of glioblastoma (GBM) and an aftermath of dysregulated cancer cell genome and epigenome. Up-regulation of podoplanin (PDPN) by cancer cells has recently been linked to an increased risk of venous thromboembolism in glioblastoma patients. Thus, regulation of this platelet activating protein by transforming events and release from cancer cells is of considerable interest. AIMS I. Investigate the pattern of PDPN expression and characterize PDPN-expressing cellular populations in GBM. II. Evaluate the contribution of oncogenic drivers to PDPN expression in GBM models. III. Investigate the potential involvement of extracellular vesicles (EVs) as a mechanism for systemic dissemination of PDPN and tissue factor (TF). IV. Examine the role of PDPN in intratumoral and systemic thrombosis. METHODS Bioinformatics (single-cell and bulk transcriptome data mining), GBM cell lines and stem cell lines, xenograft models in mice, ELISA assays for PDPN and TF, platelet (PF4) and clotting activation markers (D-dimer), EV electron microscopy, density gradient fractionation, and nano-flow cytometry. RESULTS PDPN is expressed by distinct glioblastoma cell subpopulations (mesenchymal) and downregulated by oncogenic mutations of EGFR and IDH1 genes, via changes in chromatin modifications (EZH2) and DNA methylation, respectively. GBM cells exteriorize PDPN and/or TF as cargo of exosome-like EVs shed both in vitro and in vivo. Injection of glioma PDPN-EVs activates platelets. Increase of platelet activation (PF4) or coagulation markers (D-dimer) occurs in mice harboring the corresponding glioma xenografts expressing PDPN or TF, respectively. Co-expression of PDPN and TF by GBM cells cooperatively increases tumor microthrombosis. CONCLUSION Distinct cellular subsets drive multiple facets of GBM-associated thrombosis and may represent targets for diagnosis and intervention. We suggest that the preponderance of PDPN expression as a risk factor in glioblastoma and the involvement of platelets may merit investigating anti-platelets for potential inclusion in thrombosis management in GBM.
Abstract 11497: Echocardiographic Features of Severe Mitral Stenosis in Three Different Etiologies
Authors: Shunsuke Kagawa, Omori Taku, Goki Uno, Florian Rader, Robert J Siegel, Takahiro Shiota
Journal: Circulation (2021)

Background: In our Heart Center, the cause of mitral stenosis (MS) is usually classified into 3 different categories/etiologies, namely, rheumatic disease, degenerative disease with annular or leaflet calcification, and MS as a consequence of a transcatheter mitral repair with clips for mitral regurgitation. However, differences in the morphology and echocardiographic evaluation among the three etiologies have not been fully elucidated. The aim of this study is therefore to investigate differences in echocardiographic features of these three etiologies of MS. Method: We retrospectively studied 157 patients who underwent three-dimensional transesophageal echocardiography (3D TEE) at Cedars-Sinai Medical Center between January 2012 and December 2020, and had severe mitral stenosis defined as 3D TEE derived mitral valve orifice area (MVA) of ≤ 1.0 cm 2 .These patients also had a mean transmitral pressure gradient of ≥ 5 mmHg on transthoracic echocardiography which was performed within 6 months before and after TEE. Other clinical and echocardiographic characteristics were obtained from medical records. Result: Of 157 patients, 37 patients had rheumatic MS, 60 patients had degenerative calcific MS and 60 patients had post-clip MS. There was no significant difference among the three groups in 3D TEE derived MVA (Table). Despite comparable 3D derived MVA, patients with post-clip MS had significantly lower mean transmitral pressure gradient than those with other 2 types of MS. Patients with rheumatic MS had larger indexed left atrial volume than patients with other 2 types of MS. Patients with degenerative calcific MS and those with post-clip MS had larger MVA both by pressure half time and by continuity equation than patients with rheumatic MS. Conclusion: There were distinct differences in echocardiographic features among the three MS etiologies. The optimal evaluation method and multi-parameter determined grading of MS severity may differ depending on the etiology.
Abstract 13641: High Precordial Leads Increase the Detection of Brugada-Like Electrocardiographic Changes in Arrhythmogenic Right Ventricular Cardiomyopathy Patients and Healthy Controls
Authors: Lauren A Yee, Charles M Pearman, Zachary W Laksman, Brianna Davies, Andrew D Krahn
Journal: Circulation (2021)

Introduction: Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) relies on the 2010 Task Force Criteria (TFC), known to have high specificity and low sensitivity. Diagnosis is complicated by variable phenotypic expression, potentially fatal first presentation of disease, and modest yield of genetic testing. Phenotypic overlap has been described between ARVC and Brugada Syndrome (BrS), while high precordial lead positioning increases the sensitivity for BrS diagnosis. Purpose: To explore the scope and nature of ECG changes in high precordial leads in ARVC. Methods: Patients seen in the Inherited Arrhythmia Clinic in Vancouver, Canada between 2013-2020 had high precordial lead ECGs recorded and were enrolled in the Canadian ARVC/HiRO Registry (www.heartsinrhythm.ca). ECGs of cases and matched healthy controls were interpreted blinded to phenotype/genotype. We defined 10 ECG variables, including features of the TFC and novel markers. We compared standard vs. high leads within-patient, and cases vs. controls in standard and high lead positions. Results: There were 58 ARVC patients (age 41±14, 48% male, TFC 3.6±1.7) and 58 controls (age 47±15, 43% male) included. Brugada-like ECG changes were seen in 5 patients (4.3%), exclusively in high leads (p&lt;0.001 compared to standard leads). No type 1 pattern was detected. Type 2 pattern was seen in 1 ARVC patient (0.9%) in high lead V2. Type 3 pattern was seen in 2 ARVC patients (1.7%) and 2 controls (1.7%) in the high leads position, with no difference between cases and controls (p=NS). Epsilon waves were observed in 2 ARVC patients (1.7%). The SAECG was positive for late potentials in one patient, and the other negative. Both patients had an epsilon wave in a standard lead, and in one patient epsilon waves were seen in a further 2 high leads. No sex-differences were evident. Conclusions: High precordial leads increase detection of Brugada-like ECG changes to a similar extent in ARVC patients and controls. Our study supports the finding that Type 3 pattern is a benign finding in healthy individuals. High precordial leads do not substantially increase the sensitivity for detection of epsilon waves. Further investigation is warranted into novel diagnostic methods that improve sensitivity for ARVC diagnosis.
Abstract 12691: Comparison of Deep Learning and Radiomic Features to Differentiate Non-Ischemic and Ischemic Cardiomyopathy Using Cardiac MRI Cine Imaging
Authors: Makiya Nakashima, David Chen, Ramesh Basnet, Mitchel Benovoy, Tae Hyun Hwang, Robert Geschke, Richard A Grimm, Samir R Kapadia, Lars G Svensson, Brian P Griffin, Scott D Flamm, Wai Hong W Tang, Deborah H Kwon
Journal: Circulation (2021)

Introduction: Cardiac magnetic resonance (CMR) is frequently utilized to characterize etiology of cardiomyopathy (CM), but there is need for improved disease classification, standardization in the interpretation of findings, and throughput in analysis. Radiomics has been shown to classify disease in a semi-automated manner. Alternatively, deep learning (DL) provides the ability to identify unknown features in image data. Therefore, we sought to compare DL and radiomic approaches to differentiate ischemic vs non-ischemic cardiomyopathy (ICM vs NICM), using cardiac magnetic resonance (CMR) short axis cine images. Methods: We selected 291 patients with cardiomyopathy (CM) who underwent a CMR exam at Cleveland Clinic between 2008 and 2018, of which 249 had NICM (positive label) based on expert review of the CMR exam and electronic medical record documentation. We compared a radiomic and end-to-end DL approach to identify CM etiology from short axis cine images. Automatically generated radiomic features describing myocardial shape, texture, thickness, and motion in the cine images were used to train several machine learning classifiers. In the DL approach, we directly used the cine images to train several DL classifiers, without extracting radiomic features. We evaluated the classifiers through 5-fold cross validation using the area under the curve (AUC), F1-score, and accuracy metrics. Statistical significance was evaluated using paired 2-tailed t-test at 0.05 level. Results: Support vector machine (SVM) and DenseNet121 achieved the best metrics for radiomic and DL approaches respectively. The radiomic and DL approach achieved similar AUCs of 0.852 and 0.858 respectively, but DL approach achieved statistically significant higher F1-score of 0.758 vs 0.585 of the radiomic approach. Conclusions: An end-to-end DL approach more accurately identified NICM vs ICM compared to a radiomics approach, using only cine CMR images.
Abstract P367: ‘Youthful’ Phenotype Of C-kit+ Cardiac Fibroblasts
Authors: Fareheh Firouzi, Oscar H Echeagaray, Carolina Y Esquer, Natalie A Gude, Mark A Sussman
Journal: Circulation Research (2021)

Introduction: Fibroblasts are critical contributors to myocardial development, tissue homeostasis and remodeling. Cardiac fibroblast population heterogeneity and plasticity present a challenge for categorization of biological and functional properties. Distinct molecular markers and associated signaling pathways provide valuable insight for cardiac fibroblast biology and interventional strategies to influence injury response and remodeling. Receptor tyrosine kinase c-Kit mediates cell survival, proliferation, migration, and is activated by pathological injury. However, the biological significance of c-Kit within cardiac fibroblast population has not been addressed. Approach: An inducible c-Kit reporter mouse detects promoter activation with Green Fluorescent Protein (GFP) expression in cardiac interstitial cells (CICs). Coincidence of GFP and c-Kit with the DDR2 fibroblast marker was confirmed at protein level using flow cytometry and immunohistochemistry. Subsequently, cardiac fibroblasts expressing DDR2 with or without c-Kit were isolated and characterized in vitro . Results: A subset of DDR2 + cardiac fibroblasts also express c-Kit with coincidence in ~8% of total CICs. Pathological injury induces coincidence as well as expression of c-Kit and DDR2. Cultured cardiac DDR2+ fibroblasts that are c-Kit+ exhibit youthful morphological and functional phenotypes compared to c-Kit- cells including 1) significantly smaller size, 2) higher cellular motility, 3) enhanced proliferation, 4) less multinucleation, 5) decreased senescence-associated β-galactosidase staining, and 6) down-regulation of p53 senescence marker. Mechanistically, c-Kit expression correlates with signaling implicated in proliferation and cell migration including phospho-ERK and pro-Caspase 3. Conclusion: The phenotype of c-kit+ on DDR2+ cardiac fibroblasts correlates with multiple characteristics of ‘youthful’ cells. To our knowledge, this represents the first evaluation of c-Kit biology within DDR2+ cardiac fibroblast population and provides a fundamental basis for future studies to influence myocardial biology, cardiac remodeling, and response to pathological injury.
Abstract 12848: Patient-Specific <i>in silico</i> Models Demonstrate Hemodynamic Effect of LAMPOON in Transcatheter Mitral Valve Replacement
Authors: Keshav Kohli, Zhenglun Alan Wei, Emily Perdoncin, Vahid Sadri, Andrew W Siefert, Philipp Blanke, Adam Greenbaum, Jaffar Khan, Robert Lederman, Vasilis Babaliaros, Ajit P Yoganathan, John N Oshinski
Journal: Circulation (2021)

Introduction: The purpose of this study was to investigate the hemodynamic impact of LAMPOON (Laceration of the Anterior Mitral leaflet to Prevent Outflow ObstructioN) in transcatheter mitral valve replacement (TMVR) using patient-specific in silico modeling. Methods: Eight subjects from the LAMPOON investigational device exemption trial were included. All subjects were at prohibitive risk of outflow tract obstruction from TMVR based on computed tomography (CT), and underwent successful LAMPOON immediately followed by TMVR. A validated computational fluid dynamics (CFD) model was used to compare simulated hemodynamics and 3D flow patterns between two modeled conditions: 1) TMVR with LAMPOON and 2) TMVR without LAMPOON. Using the post-procedure CT scans, anatomical models of TMVR with LAMPOON were created for each subject. The open transcatheter valve cells were then virtually closed to model TMVR without LAMPOON for each subject. Finally, CFD was performed for each condition to simulate the systolic flow fields. Results: As compared to TMVR without LAMPOON, TMVR with LAMPOON resulted in lower peak velocity, lower peak LVOT gradient, and higher peak LVOT effective orifice area by 13 ± 6% (p=0.004), 28 ± 14% (p=0.008), and 15 ± 8% (p=0.002), respectively. LAMPOON provided flow communication through exposed cells of the transcatheter valve, thereby decreasing the flow constriction and reducing flow stasis in the vicinity of the neo-LVOT (Figure). The hemodynamic benefit of LAMPOON was observed to be greater in subjects with a smaller neo-LVOT area measured post-implant (p&lt;0.001). Conclusions: In silico modeling allowed for a quantitative patient-specific comparison of TMVR with and without LAMPOON, which is impossible to study clinically. The LAMPOON procedure improved simulated hemodynamics in all subjects, with a greater hemodynamic impact observed in subjects with a smaller post-implant neo-LVOT area.
EXTH-11. COLD ATMOSPHERIC PLASMA SELECTIVELY INDUCES APOPTOSIS AND FERROPTOSIS THROUGH REACTIVE OXYGEN SPECIES IN HIGH-GRADE GLIOMA
Authors: Sophie Peeters, Zhitong Chen, Richard Obenchain, Blake Haist, Robert Prins, Linda Liau, Richard Wirz, Anthony Wang
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Cold atmospheric plasma (CAP) selectively induces reactive oxygen and nitrogen species (ROS/RNS) in many types of cancerous cells. ROS-mediated lipid peroxidation is thought to induce ferroptosis, apoptosis, and autophagy. We hypothesize that ferroptosis and apoptosis are key mechanisms of CAP-mediated cytotoxicity in high-grade glioma (HGG). METHODS B16, U87, GL261, EPD-210FHTC and human astrocyte NHA hTERT cells were treated with CAP for 10, 30, 60, 90, and 180 seconds. Proliferation and propidium iodide (PI)/annexin V flow cytometry assays were employed to quantify cytotoxicity, cell cycle phases and apoptosis. Mitochondrial superoxide concentration was measured using MitoSOX Red. Cells were pre-treated with ferroptosis inhibitors Ferrostatin-1 and Deferoxamine (DFO) in rescue assays. RESULTS Survival of GL261 and U87 cells after 90 seconds of CAP treatment was 3.7% and 7%, respectively, compared to 62% in NHA cells. A CAP dose-dependent increase in mitochondrial superoxide concentration was observed in GL261 and NHA (R2=0.88 and 0.99, respectively). A shift of EPD and NHA cells into G0 phase was noted after 180 seconds of treatment, compared to baseline (55.4% versus 1.2%, 100% vs. 27.5% respectively). Early apoptosis was more prominent in NHA cells (79% of dead cells), and late apoptosis in EPD cells after 60 seconds of treatment (86% of dead cells). DFO pre-treatment significantly reduced CAP cytotoxicity in GL261 (93% vs. 58% after 10 seconds) and U87 cells (85% vs. 13% after 60 seconds). DFO pre-treatment had no effect on NHA response to CAP. CONCLUSION CAP treatment induces dose-dependent increases in ROS and apoptosis in HGG lines tested more significantly than in NHA cells. CAP induces G1-phase cell cycle arrest in treated HGG cells and G0 arrest in non-cancerous cells. CAP-mediated cytotoxicity was significantly mitigated with DFO pre-treatment in HGG cells, suggesting that ferroptosis plays a critical role in the mechanism of CAP treatment in HGG.
Abstract 98: The Assessment and Value of Bystander Cardio Pulmonary Resuscitation (by-CPR)
Authors: Ingela Hasselqvist-Ax, Johan Herlitz, Mårten Rosenqvist, Jacob Hollenberg, Per Nordberg, Mattias Ringh, Martin Jonsson, Christer Axelsson, Jonny Lindqvist, Leif Svensson
Journal: Circulation (2013)

Background: 3 million people in Sweden are educated in CPR and the value of this has been questioned if this leads to increased By-CPR and survival. Aim: To describe different aspects and effect on survival after OHCA depending if bystander CPR (By-CPR) was performed or not, and if the bystander was Lay or Medical educated. Also to explore the effects from CPR training on times to CPR, alarm and on outcome, when a medical educated bystander perform CPR versus when a Lay person act. Methods: Patients in the Swedish Cardiac Arrest Registry receiving bystander CPR 1990-2011 were included and divided into: No-ByCPR , and By-CPR . By-CPR was further divided in Lay-ByCPR and Med-ByCPR when CPR was performed by professionals in terms of medical educated bystanders. Crew witnessed cases were excluded. Results: In all 61 704 patients are included in the registry, and among them 30 188 bystander witnessed cases (49 %) were included in this survey. By-CPR have over the years continuously increased from 40% to 68% and 30 days survival increased from 3.8% 1990 to 10.7% 2011. Survival was 4.0% in No-ByCPR, 10.6% in By-CPR, 9.4% in Lay-ByCPR and 13.7% in Med-ByCPR. Various aspects on delay to treatment were independently associated with survival to one month: Collapse-call for EMS (OR 0.70;95% CI 0.64-0.77); collapse-start of CPR (OR 0.72;95% CI 0.68-0.76); call for arrival of EMS (OR 0.41;95% CI 0.36-0.46). (Adjusted for age, gender, place and etiology) Lay-ByCPR was significant better than No-ByCPR (OR 2.49) in all patients. Med-ByCPR had even better outcome compared to No-ByCPR (OR 2.84). When comparing Med-ByCPR vs. Lay-ByCPR bystanders, there were non- significant differences, OR 1.18 (CI:0.98-1.41). Conclusion: Increased By-CPR correlate to increased survival and can more than double survival rate compared to No-ByCPR. Collapse to call, start of CPR, call-arrival EMS were independently associated with survival to one month. Lay-ByCPR were better than no ByCPR and as good as Med-ByCPR.
Abstract 13618: Novel Fumarate Prodrug Rescues Cardiomyopathy and Motor Function in Friedreich’s Ataxia
Authors: Claire B Montgomery, Veronica Flores, Landon Sims, Phung N Thai, Nipavan Chiamvimonvat, Gino Cortopassi, Elena N Dedkova
Journal: Circulation (2021)

Background: Friedreich ataxia (FA) is a monogenic recessive ataxia caused by reduction of a single mitochondrial protein, frataxin (FXN), for which there is no approved therapy. Although the name of FA refers to the neurodegenerative ataxia, the lethal event is cardiomyopathy, caused by deficient FXN expression in the heart. Through a drug discovery screening program, we identified that bioactive fumarates are protective in FA cell models. We have subsequently developed a novel monomethyl fumarate precursor which has a higher retention time in the gut and also releases nicotinamide ( NAD + ). Hypothesis: To test the hypothesis that novel NAD + and fumarate precursor IMF provides more efficient protection against development of lethal cardiomyopathy in the inducible mouse model of FA (FXNKD) compared to a known fumarate precursor dimethyl fumarate (DMF, also known as Tecfidera). Methods: To suppress FXN expression, FXNKD mice were fed doxycycline chow and cardiac function was examined by in-vivo echocardiography. Aconitase activity, used as a surrogate measure of frataxin’s iron-sulfur biogenesis function, complex I and II activities, NAD + /NADH levels were measured by biochemical assays. Results: FXNKD and CTL mice were given vehicle, DMF or IMF daily for 8 weeks at concentrations that match the equimolar amount of monomethyl fumarate (MMF) released by the drugs. After 4 weeks of doxycycline treatment, FXNKD mice developed significant balance and locomotor deficits as assessed by the rotarod, 16 mm balance beam and open field tests. All neurobehavior parameters were improved after 8 weeks of treatment with IMF but not with DMF. Echocardiography revealed a significant increase in left ventricular wall thickness, and a decrease in LV internal diameter, stroke volume, and cardiac output, hallmarks of clinical cardiomyopathy in FA patients. IMF but not DMF prevented a decline in cardiac function in FXNKD mice. FXNKD mice treated with IMF showed increase in FXN expression levels, NAD + /NADH, aconitase and complex I and II activities. Conclusions: Because cardiomyopathy is the usual lethal event in FA, we suggest that nicotinamidated monomethyl fumarate is more potent drug compared to DMF and could improve the quality of life in FA affected individuals.
Treatment Responses, Toxicity and Survival in Patients with Classical Hodgkin Lymphoma Aged 50 Years and Older: A Single-Center Experience over 2 Decades
Authors: Simay Çokgezer, Tuğrul Elverdi, Ayşe Salihoğlu, Muhlis Cem Ar, Şeniz Öngören, Zafer Başlar, Ahmet Emre Eşkazan
Journal: Blood (2021)