tbuckley/cabot-search huggingface dataset:
Abstract 13730: In-Hospital Outcomes for Takotsubo Cardiomyopathy Among Patients With Psychiatric Diagnosis
Authors: Gauravpal S Gill, Isaac Burright, Ryan Walters, Venkata Alla
Journal: Circulation (2021)

Background: Takotsubo (or stress) cardiomyopathy (TC) is a transient regional systolic dysfunction, clinically and echocardiographically resembling acute coronary syndrome (ACS) in the absence of obstructive coronary artery disease. The prevalence of psychiatric disorders is high in TC. However, it is unclear whether presence of underlying psychiatric condition impacts outcomes of TC. Methods: Hospitalizations for TC from 2012 to 2018 were identified using the National Inpatient Sample (NIS) and stratified by presence or absence of concomitant psychiatric diagnoses (major depression, dysthymia, anxiety, bipolar, substance abuse). Outcomes of interest included mortality, cardiac arrest, cardiogenic shock, intra-aortic balloon pump (IABP), mechanical ventilation, and length of stay. Differences in outcome rates were compared using the Rao-Scott chi-square test; length of stay was compared using a lognormal regression model. All analyses accounted for the NIS sampling design. Results: A total of 51,625 hospital discharges with TC were identified, of which 21,690 (42%) carried a psychiatric diagnosis. There were no statistically significant differences in mortality (1.2% vs. 1.6%; p=0.087), cardiac arrest (1.5% vs. 1.5%; p=0.853), cardiogenic shock (4.6% vs. 4.9%; p=0.427), IABP use (1.6% vs. 1.7%; p=0.695), mechanical ventilation (4.9% vs. 4.2%; p=0.113) for patients with and without psychiatric diagnosis, respectively. The length of stay among patients with psychiatric diagnosis, was marginally higher (median 3.7, IQR [3.6-3.8] days vs. 3.5 [3.4-3.6] days; p&lt;0.01). Conclusion: Our analysis demonstrates that in-hospital mortality and complications of TC patients with and without psychiatric illness are statistically similar.
Abstract 14183: Oxidized Phospholipids Promote NETosis and Arterial Thrombosis in LNK(SH2B3) Deficiency
Authors: Huijuan Dou
Journal: Circulation (2021)

Background and Objective: GWAS have shown association of a common SNP (R262W) in LNK with neutrophilia, thrombocytosis and coronary artery disease (CAD). We have shown that LNK(R262W) reduces LNK function and that LNK deficient mice display prominent platelet-neutrophil aggregates, accelerated atherosclerosis and thrombosis. Platelet-neutrophil interactions can promote neutrophil extracellular trap (NET) formation. The goals of this study were to assess the role of neutrophil extracellular traps (NETs) in atherosclerosis and thrombosis in mice with hematopoietic Lnk deficiency and to evaluate the role of LNK in atherothrombosis in humans and mice bearing a gain of function variant in JAK2 (JAK V617F ). Methods and Results: We bred mice with combined deficiency of Lnk and the NETosis-essential enzyme peptidylarginine deiminase4 (PAD4); their bone marrow was transplanted into Ldlr-/- mice. There was accelerated carotid artery thrombosis with prominent NETosis in Lnk deficient mice with complete reversal by PAD4 deficiency. In contrast, PAD4 deficiency abrogated increased NETosis in plaques but did not alter plaque size or morphology. Thrombin-activated Lnk -/- platelets promote NETosis when incubated with Lnk -/- neutrophils compared to WT platelets or WT neutrophils. This involved increased surface exposure and release of oxidized phospholipids (oxPL) from Lnk -/- platelets, as well as increased priming and response of Lnk -/- neutrophils to oxPL. To counteract the effects of oxPL, we introduced a transgene expressing the single-chain variable fragment of E06 (E06-scFv). E06-scFv reversed accelerated NETosis, atherosclerosis and thrombosis in Lnk -/- mice. Using data from UK Biobank we showed that individuals with the JAK2 VF mutation only showed increased CAD when also carrying the LNK R262W allele. Mice with hematopoietic Lnk +/- and Jak2 VF clonal hematopoiesis, showed accelerated arterial thrombosis but not atherosclerosis compared to Jak2 VF Lnk +/+ controls. Conclusions: Increased NETosis in hematopoietic LNK deficiency promotes arterial thrombosis in an oxPL-dependent fashion. Reduced LNK function may increase CAD in humans carrying JAK2 VF mutations possibly reflecting increased arterial thrombotic risk.
Germline <i>MPO</i> Variants Predispose to Myeloid Neoplasia: Potential Mechanisms Suggested By In Vivo and in Vitro Studies
Authors: Sunisa Kongkiatkamon, Laila Terkawi, Vera Adema, Yihong Guan, Metis Hasipek, Tatiana Dombrovski, Milo Co, Wencke Walter, Cassandra M Kerr, Yasunobu Nagata, Hassan Awada, Yvonne Parker, Stephan Hutter, Simona Pagliuca, Carmelo Gurnari, Manja Meggendorfer, Daniel Lindner, Valeria Visconte, Torsten Haferlach, Thomas LaFramboise, Babal K. Jha, Jaroslaw P. Maciejewski
Journal: Blood (2021)
EXTH-18. IL-12 ARMORED CAR T CELL THERAPY FOR HETEROGENEOUS GLIOBLASTOMA
Authors: Steven Shen, Jessica Reedy, Carter Suryadevara, Kelly Hotchkiss, David Snyder, Luis Sanchez-Perez, John Sampson
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Glioblastoma (GBM) is a lethal primary malignant brain tumor with a median survival of &amp;lt; 20 months. Our next generation immunotherapy utilizes chimeric antigen receptor (CAR) T cells targeted to GBM-specific overexpression of epidermal growth factor receptor variant III (EGFRvIII), “armored” with IL-12, a stimulatory cytokine that enhances T cell persistence and function, to treat orthotopic heterogeneous GBM. METHODS C57Bl/6 mice were intracranially implanted with 5 x 105 of either CT2AvIII tumor cells or a 1:1 mixture of CT2AvIII and CT2A parental tumor cells. Seven days post-implant, mice were treated with 2 x 106 IL-12 CARvIII and monitored for survival. For endogenous T cell activity assessment, TCRα -/- mice were intracranially implanted with either CT2AvIII cells or a 1:1 mixture of CT2AvIII:CT2A parental cells and treated 7 days post implant with intracranial IL-12 CARvIII therapy. RESULTS IL-12 CARvIII therapy was curative in the treatment of CT2AvIII homogeneous tumors and confers a long-term survival in 50% of CT2AvIII:CT2A mice. Furthermore, IL-12 CARvIII therapy successfully eradicated the homogeneous CT2AvIII tumors in TCRα-/- mice but failed to produce any efficacy against the heterogeneous CT2AvIII:CT2A parental tumors, suggesting that endogenous T cells are required for IL-12 CARvIII therapeutic success against heterogeneous tumors. CONCLUSIONS Our findings suggest that IL-12 CARvIII may be an effective treatment against heterogeneous glioma. Furthermore, this data provides insight on treatment against the immunosuppressive tumor microenvironment and applications against other solid tumors. In anticipation of translating this therapy into a phase I clinical trial, we are also investigating adjuvant therapies such irradiation to improve antitumor efficacy of IL-12 CARvIII against heterogeneous glioma.
Abstract 11129: Long-Term Success Rate of Intramural PVC Ablation
Authors: Sanghamitra Mohanty, John Burkhardt, CHINTAN G TRIVEDI, William Zagrodzky, Domenico G Della Rocca, Carola Gianni, Bryan MacDonald, Angel Mayedo, Mohamed Bassiouny, Jorge Romero, G Gallinghouse, Rodney Horton, Luigi Di Biase, Amin Al-ahmad, Andrea Natale
Journal: Circulation (2021)

Introduction: Intramural PVCs are identified by equal but not remarkably early activation on at least two separate sites. The site of origin of these foci is typically determined by a deductive approach using extensive mapping in the surrounding areas. Ablation of the intramural VT is particularly challenging, since conventional ablation strategies often fail to obtain transmural lesion formation. We report the long-term success rate of ablation of the intramural PVCs at our center. Methods: Consecutive patients undergoing VT ablation at our center were screened and 73 patients with intramural PVCs identified by activation mapping and pace mapping were included in the analysis. Pace-mapping was performed at a pacing cycle length equal to the coupling interval of the spontaneous PVCs. If these PVCs could not be eliminated by conventional ablation, bipolar ablation or ablation from multiple sides or ablation using half-normal saline (HNS) was performed. Standardized RF power settings (up to 40W) were used during the procedure. Ablation was performed using 4-mm irrigated tip catheter guided by 3-D mapping system and intra-cardiac echocardiography. Patients were followed with remote monitoring as well as ICD interrogations and office visits every 3 months for 3 years. Results: A total of 73 patients were included in the analysis (mean age 56.2±8.6 years, 69.8% male, LVEF 54±12%). The intramural focus was effectively ablated by bipolar ablation or ablation from multiple sides in 51 (69.8%) and with the use of HNS in the remaining 22 patients. Median RF time was 11.14±8.7 minutes. Acute success (non-inducibility of the VT) was achieved in 71 (97.2%) patients. At 3 years follow-up, 66 (90.4%) remained arrhythmia-free. Conclusion: Intramural PVCs could be successfully ablated using bipolar or multiple-side ablations or utilizing half-normal saline with high long-term success rate.
Abstract 13012: A Novel Risk Score For Predicting Atrial Fibrillation Ablation Outcomes
Authors: Anjali A Wagle, Nino Isakadze, Usama Daimee, David D Spragg, Hugh G Calkins, Seth S Martin
Journal: Circulation (2021)

Introduction: Pre-procedural predictors of atrial fibrillation (AF) ablation have focused largely on non-modifiable risk factors. This study aimed to identify a risk score derived entirely from modifiable risk factors. Such a predictive model can permit optimization of these risk factors prior to ablation procedures. Methods: We evaluated 160 patients who underwent their first AF ablation from 2014 through 2018. We derived a novel ABCs ( A lcohol use, B MI, B lood pressure, b lood glucose, C igarette smoking, c holesterol, s leep apnea) model consisting of modifiable AF risk factors by receiver operating characteristic curve analysis to predict AF recurrence at 1 year after AF ablation (Table 1). Each risk factor was assigned a score of 0-2, and the total ABC score ranged from 0-14, with 0-4 indicating poor, 5-9 intermediate and 10-14 being ideal. Results: Among 160 study participants, the mean age was 63.1 + 9.6 years, and 33% were women. There were 55 (41%) patients with AF recurrence. Mean ABCs score was 9.2 + 1.9 among those without AF recurrence and 7.9 + 1.5 among those with recurrence (p &lt; 0.01). The ABCs AUC was 0.70 and the CHA 2 DS 2 -VASc was 0.61 (Figure 1). A cut-off value of &gt; 9 displayed the highest discrimination for AF recurrence (sensitivity = 64.8%, specificity 61.8%). Conclusions: The novel ABCs risk score consisting of modifiable AF risk factors has superior predictive capacity for AF recurrence compared with CHA 2 DS 2 -VASC score. This may allow for risk factor optimization prior to ablation. External validation of ABCs score is needed to further evaluate its predictive capability.
Abstract 11521: Mitochondrial Metabolism is Regulated by the Type III Transforming Growth Factor Beta Receptor
Authors: David Trykall, Vineet Agrawal, James West, Joey V Barnett
Journal: Circulation (2021)

Introduction: In adults myocardial injury activates an epicardial process initiating epicardial cell epithelial-mesenchymal transformation (EMT) contributing epicardial-derived cells that become vascular smooth muscle, cardiac fibroblasts, or produce factors that support myocardial repair. The Type III Transforming Growth Factor Beta Receptor (TGFβR3) is an important mediator of EMT; a process influenced by metabolism. Here we probed wild type and TGFβR3-deficient metabolism in murine epicardial cells to determine if TGFβR3 regulates mitochondrial function. Hypothesis: Does TGFβR3 regulate mitochondrial metabolism in epicardial cells? Methods: Cultured murine epicardial cells were analyzed. Gene constructs were transduced by adenovirus. Mitochondrial function was assessed by Seahorse XFe96 and immunostaining or electron microscopy. Results: Loss of a single allele of Tgfbr3 significantly decreased the oxygen consumption rate; an effect enhanced by loss of both alleles. Decreased mitochondrial function is associated with reduced mitochondrial number and abnormal morphology. These alterations coincide with dysregulated expression of genes involved with mitochondrial biogenesis: Ppargc1a , Ppargc1b , Erra , Errb , and Errg . Addition of TGFβR3 and TGFβ2 or BMP2, but not TGFβ1, to Tgfbr3 null cells partially restored mitochondrial function and morphology. Expression of a constitutively active receptor rescues mitochondrial function, while expression of TGFβR3 lacking either the cytoplasmic domain or the three C-terminal amino acids that bind the scaffolding protein GIPC failed to rescue. Further, rescue of Tgfb r3 null cells by TGFβR3 and BMP2 was blocked by GIPC targeted siRNAs. Conclusions: These results demonstrate that the loss of a single allele of Tgfbr3 significantly alters mitochondrial function. Both the cytoplasmic domain of TGFβR3 and GIPC are required for the regulation of mitochondrial function.
Abstract 11014: Circulating Endothelin-1 Levels Are Not Elevated in Atherosclerotic Coronary Artery Disease and Coronary Microvascular Dysfunction Defined Using [ <sup>15</sup> O]h2o Pet Perfusion, Invasive Ffr and Coronary Ct Angiography
Authors: Ruurt Jukema, Ruben de Winter, Pepijn van Diemen, Roel Driessen, Jan H Danser, Ingrid Garrelds, Pieter Raijmakers, Peter van de Ven, Paul Knaapen, Ibrahim Danad, Guus De Waard
Journal: Circulation (2021)

Introduction: Endothelin-1 (ET-1), the most potent cardiovascular vasoconstrictor in humans, is increasingly being linked to coronary microvascular dysfunction (CMD) and atherosclerosis, thus providing a therapeutically modifiable target. In this study we investigated whether increased ET-1 levels are related to atherosclerosis, high risk plaque (HRP), myocardial perfusion and CMD in chest pain patients. Methods: Serum ET-1 was measured by ELISA in 205 patients (64% men; age 58 ± 9 years) with suspected coronary artery disease. All patients underwent 256-slice coronary CT angiography for (quantitative) plaque analysis and coronary artery calcium (CAC) scoring, [ 15 O]H2O PET perfusion imaging and invasive FFR measurements in all coronary arteries. A total of 585 vessels were stratified upon four categories based on [ 15 O]H2O PET perfusion (hyperemic MBF 2.3 ml/min/g) and invasive pressure measurements (FFR 0.80). Vessels with a FFR &gt;0.80 but with an ischemic hyperemic MBF below 2.3 ml/min/g were defined as CMD. Results: In univariable analysis, ET-1 was not related to the CAC score, total plaque volume (TPV) or perfusion (p=0.33; p=0.55; p=0.75, respectively). Also, patients with HRP did not show higher levels of ET-1 (mean logarithmic ET-1 0.29 vs 0.30; p=0.83). ET-1 levels were equally distributed across the four vessel categories and were not elevated in CMD patients (p=0.31). Conclusions: Our findings indicate that circulating ET-1 levels are not elevated in stable patients with either atherosclerotic coronary artery disease or coronary microvascular dysfunction, suggesting that ET-1 may not be a useful therapeutic target in these disease states. Figure 1. A typical case example of a CMD patient with non-flow limiting coronary arteries (A) and an ischemic perfusion (B). ET-1 depicted for the four vessels categories. (C) The upper and lower whiskers represent the 10th and 90th percentile.
Abstract 13563: Acute Effects of Inspiratory Loads and Pursed Lips Breathing on Non-Linear Heart Rate Variability in Young Health Subjects
Authors: Joceline Sa, Vanessa Resqueti, Cibele Therezinha Dias, Fernando A Dias, Guilherme Fregonezi
Journal: Circulation (2021)

Introduction: Inspiratory muscle loads and breathing exercises are recognized tools used to improve the rehabilitation process. Hypothesis: Inspiratory loads and pursed lips breathing have different effects on the heart rate variability in young healthy subjects. Methods: Twenty-nine subjects were studied (15 male), aged 22.6 ± 2.9 years and BMI: 22.8 ± 2.7 Kg/m 2 , without respiratory and cardiac-related diseases. Subjects were randomized into three experimental groups: 20% PImax inspiratory load (IL 20%group ), 50% inspiratory load (IL 5 0% group ), and pursed lips breathing (PLB group ). Heart rate variability was measure before and while subjects breathing using different load's intensity or pursed lips breathing technique. Results: A significant change in autonomic balance was found, with greater parasympathetic modulation on the heart during pursed lips breathing and increased sympathetic activity during moderate inspiratory load (Table 1). Conclusion: Acute effects of moderate inspiratory load improves sympathetic activation and may influence the behavior of heart rate when used in patients with arrhythmias or other heart clinical conditions. Also, pursed lips breathing can be considered as a breathing exercise that could be promoter the cardioprotective effect. in memoriam Fernando Henrique de Macedo
EXTH-10. EXPLORATION OF A NOVEL TOXIN-INCORPORATING CAR T CELL: HOW DOES CHLOROTOXIN RECOGNIZE GLIOBLASTOMA CELLS?
Authors: Maryam Aftabizadeh, Lovish Bawa, Simiao Wang, Blake Brewster, Dongrui Wang, Xin Wang, Christine Brown, Michael Barish
Journal: Neuro-Oncology (2021)

Abstract Chlorotoxin, a peptide toxin component of scorpion venom, binds selectively to glioblastoma and other neuroepithelial tumors, with minimal binding to non-malignant cells. We have recently developed a CAR T cell incorporating chlorotoxin (CLTX) as its target recognition domain, and CLTX-CAR T cells are now in clinical trial for recurrent glioblastoma (NCT04214392). We determined in preclinical studies that surface MMP-2 was required for CLTX-CAR T cell killing. However, the precise composition and structure of the cell surface complex recognized by CLTX-CAR T cells remains an unresolved question of increasing importance. Previous investigations have variously proposed matrix metalloprotease-2 (MMP-2), ClC-3 chloride channels, regulators of MMP-2, annexin A2, and neuropilin-1, as receptors, or components of receptors, for CLTX. To approach this question, we have visualized bound Cy5.5-conjugated CLTX peptide (CLTX.Cy5.5) or biotin-conjugated CLTX peptide (CLTX.biotin) on tumor cells in fixed sections of patient resections, on tumor cells in organotypic cultures of patient resections, and on cells of cultured patient-derived glioblastoma tumor lines. At tissue- and cell-level spatial resolution, we saw good correlation of CLTX binding with MMP-2 expression in patient tumor samples and on cultured GBM cells, and between CLTX binding and tumor cell death (cleaved caspase-3) in organotypic GBM cultures. However, at subcellular resolution, surface binding of CLTX was related to, but not precisely overlapping, with MMP-2 or other putative receptors. Rather, on fixed PBT003, PBT030 and PBT106 cells in monolayer cultures, MMP-2 staining was clustered, with diffuse loosely associated CLTX.biotin staining. Diffuse distribution of CLTX.Cy5.5 was also seen in fixed xenograft sections of PBT003-4, PBT1206, PBT030-2, PBT051 and PBT138 tumor cells, and not obviously associated with more discrete staining for IL13Rα2 and EGFR. Ongoing experiments are further examining association of CLTX with other putative components of CLTX receptor complexes, and their redistribution during binding by CLTX and CLTX-CAR T cells.
Abstract 12529: Sex-Specific Mortality Associated With High Left Ventricular Ejection Fraction After ST-segment Elevation Myocardial Infarction
Authors: Ilias Nikolakopoulos, Santiago Garcia, Timothy D Henry, Scott W Sharkey, Christian Schmidt, Brynn Okeson, Odayme Quesada, Mario Goessl, Courtney Baechler, Judit Karacsonyi, Spyridon Kostantinis, Evangelia Vemmou, Bavana V Rangan, Emmanouil S Brilakis
Journal: Circulation (2021)

Introduction: Using sex-specific cutoffs, high left ventricular ejection fraction (LVEF) is associated with increased mortality in women but not in men with chronic coronary syndromes. Purpose: To explore the association between LVEF and mortality after an acute coronary syndrome in women and men. Methods: Using population-derived sex-specific LVEF cutoffs, we compared characteristics and outcomes of 1,953 ST-segment Elevation Myocardial Infarction (STEMI) patients (1,399 men and 554 women) presenting at Minneapolis Heart Institute between 2003 and 2020. Patients who had a follow-up LVEF measurement available within 2 months of the index hospitalization were included in the analysis. Sex specific cutoffs for post STEMI LVEF were a) for men, &gt;70% (high), 47-70% (normal), &lt;47% (low); b) for women, &gt;72% (high), 50-72% (normal), &lt;50% (low). Standard cutoffs were: &gt;65% (high), 55-65% (normal), &lt;55% (low). Results: When comparing high vs normal vs low LVEF, 1-year mortality was 0% vs 0.8% vs 4.4% in men ( P log-rank &lt;0.001) and 13.3% vs 2.2% vs 3.4% in women ( P log-rank =0.03) (Figure). Five-year mortality was 0% vs 5.1% vs 12% in men ( P log-rank &lt;.001) and 13.3% vs 11.4% vs 19.9% in women ( P log-rank =0.18). The findings were not replicated when standard LVEF cutoffs were used (1-year mortality in women was 6.1% vs 2.5% vs 2.5%, P log-rank =0.33). After adjustment for baseline variables and comorbidities (age, diabetes, dyslipidemia, hypertension, history of MI, door-to-balloon time less than 90 minutes, and the presence of congestive heart failure), high LVEF was associated with 1-year mortality when compared with normal LVEF in women (HR, 10.83; 95% CI, 1.94-60.57, P =0.007). Landmark analysis showed that among women alive beyond 1 year, 5-year mortality was 0% vs 9.4% vs 16.1%, P log-rank =0.31. Conclusion: High LVEF after STEMI using sex-specific cutoffs is associated with lower 1-year survival in women but not in men.
Initial Clinical Presentation and Predictors of Thrombotic Thrombocytopenic Purpura in Quebec
Authors: Emmanuelle Pépin, Clémence Merlen, Ousmane Barry, Anik Cormier, Caroline Dubois, Anne-Laure Lapeyraque, Stephan Troyanov, Georges-Etienne Rivard, Arnaud Bonnefoy
Journal: Blood (2021)
Exosomes derived from immunogenically dying tumor cells as a versatile tool for vaccination against pancreatic cancer
Authors: Wenxi Zhou, Xinli Chen, Yu Zhou, Si Shi, Chen Liang, Xianjun Yu, Hongyi Chen, Qin Guo, Yiwen Zhang, Peixin Liu, Chao Li, Yongchao Chu, Yifan Luo, Yu Wang, Zheng Zhou, Zhenhao Zhao, Qinjun Chen, Tao Sun, Chen Jiang
Journal: Biomaterials (2021)