tbuckley/cabot-search huggingface dataset:
Abstract 11391: Association Between Smoking History and Response to Rhythm Control Therapy in Atrial Fibrillation Patients Across Race-Ethnicity
Authors: Bahaa Al-azzam, Ishita Aggarwal, Miles Barney, Annette Diaz, Pranati Sreepathy, Katherine Shapiro, Dawood Darbar
Journal: Circulation (2021)

Introduction: Although smoking is associated with increased risk of developing atrial fibrillation (AF) and stroke, whether it also predicts response to rhythm control therapy across race-ethnicity remains unclear. Hypothesis: We hypothesize that smokers are less likely to respond to rhythm control therapy for AF than non-smokers. Methods: In this cohort study, patients managed with rhythm control strategy at the time of enrollment to the study were prospectively enrolled in an AF multi-center clinical-DNA biorepository. Rhythm control includes antiarrhythmic drugs (AADs) and\or catheter ablation. Successful response was defined as continuation of the same AAD for at least 6 months and/or successful catheter ablation without recurrence of AF for 12 months. Results: Of the 362 enrolled, 132 (36.4%) were European American, 155 (42.8%) were African- American and 75 (20.7%) were Hispanic American. 125 patients were smokers and 237 patients were non-smokers. Baseline clinical characteristics were similar in both groups (Table 1). Compared to nonsmokers, smokers were less likely to respond to rhythm control strategy (odds ratio [OR] 1.36, 95% confidence interval [CI]: 0.88-2.11, P-value: 0.07). Adjusted for the type of rhythm control, smokers were more likely to have a recurrence of AF catheter ablation as compared with nonsmokers ([OR] 1.38, 95% [CI]: 1.031-2.348, P-value: 0.044). However, there was no significant difference between smokers and non-smokers in terms of response to AADs ([OR] 1.25, 95% [CI]: 0.560-2.809, P-value: 0.292). Conclusions: Patients with a smoking history were less likely to respond rhythm control therapy as compared to nonsmokers. After adjusting for the type of rhythm treatment, smokers were more likely to have a recurrence of AF when compared to non-smokers but there was no difference in response to AADs between the two groups.
Abstract P444: Inflammation Resolution And Transition Of Macrophages Are Dependent On Ikke
Authors: Hyang Hee Cho, Yong Sook Kim, Dong Im Cho, Meeyoung Cho, Youngkeun Ahn
Journal: Circulation Research (2021)

Rationale: Myocardial infarction (MI) is a major cause of death and inflammation mainly contributes to pathological progress. Expression of IKKe is induced in inflammatory macrophages, but the pathophysiological roles in cardiac injury remain unclear. Objective: We aimed to investigate the role of IKKe in macrophages in the IKKe knockout (KO) MI mouse model. Methods and Results: MI was induced by coronary artery ligation, then cardiac macrophages and bone marrow-derived macrophages were isolated for further comparison studies.The IKKe KO group showed poor survival rate, high circulating IL-6 level, large cardiac fibrosis (14.7±4.8% vs. 31.1±10.2%, p&lt;0.05), and low ejection fraction (34.02±5.5% vs. 30.33±5.3% vs. p&lt;0.05) compared with the wild type (WT) group.Next, we investigated the inflammatory and fibrotic responses to understand the relevant mechanism. Flow cytometry and phosphorylated protein array showed that IKKe-deficient macrophages exhibited lower phosphorylated p38 and higher inflammatory markers.Moreover, we identified macrophage-myofibroblast transition (MMT) by detecting aSMA expression in macrophages, and found that the number of cells under MMT was 2.0-fold higher in the IKKe KO group than in the WT group.In parallel to the increase in MMT, the transition of CD206(+) anti-inflammatory macrophages to myofibroblasts was 2.16-fold greater in the IKKe KO mice.Macrophages with chemical or genetic interfering of p38 displayed the remarkable increases in both MMT and inflammatory phenotype. Conclusions: Our results suggest that IKKe-p38 axis may potentially induce the inflammation resolution and limit MMT in macrophages in response to MI. Mechanistical understanding of IKKe signaling offers novel therapeutic pathways to treat MI.
Abstract P362: Gata4 Dimerization May Be A Target For Heart Failure Therapy
Authors: Satoshi Shimizu, Kodai Hara, Asami Hishiki, Yoichi Sunagawa, Yasufumi Katanasaka, Yusuke Miyazaki, Masafumi Funamoto, nurmila sari, Kana Shimizu, Koji Hasegawa, Hiroshi Hashimoto, Tatsuya Morimoto
Journal: Circulation Research (2021)

Introduction: Cardiac hypertrophy is regulated by activation of GATA4. Although GATA4 post-translational modification such as acetylation by p300 is well examined, the details of the activation mechanism of GATA4 are still unclear. The purpose of this study is to investigate whether GATA4 dimerization involved in transcriptional activation and cardiomyocyte hypertrophic responses. Methods and Results: A GST pull-down assay using GST fusion GATA4 full-length and deletion mutants demonstrated that GATA4 308-326, including the acetylation site, was required for the dimerization of GATA4. A DNA pull down assay showed that the C-zinc finger motif (256-295) and the acetylation site were required for the DNA binding capacity of GATA4. IP-WB using nuclear extract from HEK293T cells expressing FLAG- or HA-tagged GATA4 showed that co-expression of p300 increased the formation of the homo-dimer as well as acetylation of GATA4. The GATA4 homo-dimer was disrupted by both acetyl-deficient GATA4 and HAT-deficient p300. This result indicates that acetylation of GATA4 is important for dimerization of GATA4. Overexpression of the deletion mutant containing a GATA4 308-326 (G4D) prevented p300-induced GATA4 dimerization but not the p300 binding nor acetylation of GATA4. ChIP assay and DNA pulldown assay showed that G4D did not inhibit the p300-induced DNA binding of GATA4. In cardiomyocytes, the G4D inhibited phenylephrine-induced ANF and ET-1 promoter activities and cardiomyocyte hypertrophy. To perform the X-ray crystal structure analysis, recombinant GATA4 fragment including GATA4 308-326 was highly purified. The X-ray diffraction data of obtained crystals was collected. Resolution of the crystal was 3.1Å, which was insufficient for phase determine. To obtain a high-quality crystal, GATA4 fragment was crystallized in international space station, in collaboration with JAXA. Resolution of the crystal was 3.16Å, which was similar to the best data before obtained. Conclusions: These results suggest that GATA4 dimerization may play an important role in hypertrophy-response gene transcription. It is expected to elucidate the GATA4 dimerization mechanism and targeted this dimerization will lead to the development of a noble heart failure therapy.
Abstract MP243: Detection Of Mesenchymal Stem Cells In Mobilized Autologous Peripheral Blood Transplantation From Patients With Ischemic Heart Disease
Authors: Hadyanto Lim, Umar Zein, Ilham Hariaji
Journal: Circulation Research (2021)

Background: Mesenchymal stem cells (MSCs) improve the cardiac function and remodeling in patients with ischemic heart disease. However, their presence in the circulating peripheral blood and post-transplantation has not been fully elucidated. We aimed to investigate the effects of intravenous transplantation of mobilized autologous peripheral blood on the number of MSCs in patients with ischemic heart disease. Methods: Granulocyte-colony stimulating factor (G-CSF, 5.0 μg/kg/day) was given subcutaneously once a day for five days to 7 patients (4 women and 3 men, aged 54-69 years) with ischemic heart disease. Leukapheresis procedure was started on the day 5 of G-CSF using the Spectra Optia cell separator. Circulating and intravenous transplantation of autologous MSCs after leukapheresis were analyzed by flow cytometry. MSCs were identified on the basis of dual positive cells (CD73 + /CD105 + or CD90 + /CD73 + or CD90 + /CD105 + ) and detected as MSCs if a cluster of at least 10 cells could be found. Results: MSCs in the circulating peripheral blood and after transplantation were detected in 2 (28%) and 6 (85%) patients, respectively. The frequency of intravenous peripheral blood MSCs increased significantly after transplantation (from 32.57 ± 22.76 x10 -4 % to 58.57 ± 28.49 x 10 -4 % , p&lt;0.001). Moreover, there were significant rise in the total white blood cells count (from 10.25 ± 4.86 x 10 3 /μl to 35.81 ± 7.07 x 10 3 /μl, p&lt;0.001) and the levels of CD34 + cells (from 1.17 ± 0.93 cells/μL to 138.30 ± 11.26 cells/μL, p&lt;0.001) after the infusion. Conclusions: The results show that intravenous transplantation of mobilized autologous peripheral blood increases the number of MSCs in patients with ischemic heart disease. Leukapheresis product of peripheral blood MSCs could therefore be a potential source for autologous transplantation in ischemic heart disease.
Abstract 11589: Hemodynamic Assessment of Inhalational Epoprostenol for Post-Operative Right Ventricular Dysfunction in Cardiac Surgery Patients
Authors: harsh shah, Alexander I Papolos, Benjamin Kenigsberg
Journal: Circulation (2021)

Introduction: Right ventricular (RV) dysfunction after cardiac surgery presents a significant challenge. Epoprostenol (EPO) is a pulmonary vasodilator that can be administered via inhalation and is often used in patients with post-operative RV dysfunction. However, the effects of EPO on RV performance have not been well studied. Furthermore, EPO is generally contraindicated in WHO Group 2 pulmonary hypertension. The purpose of this study is to describe the hemodynamic consequences of weaning inhaled epoprostenol (iEPO) in post-operative RV dysfunction and potentially identify any predictive markers for successful weaning. Methods: This is a single-center case series of patients receiving iEPO after cardiac surgery identified by convenience sampling. Inclusion criteria included post-cardiac surgery patients, &gt;18 years, and receiving iEPO for RV dysfunction. Exclusion criteria included pregnancy, open chest, SARS-COV-2 pneumonia, left ventricular assist device use, extracorporeal membrane oxygenation use, heart transplantation, or receiving iEPO for refractory hypoxia. A paired two sample t-test compared the hemodynamic parameters collected pre and post iEPO weaning. Results: EPO weaning was associated with a decrease in mean pulmonary artery pulsatility index (PAPi) (pre-wean 1.81 vs post-wean 1.57, p=0.04) and increase in pulmonary artery systolic pressure (PASP) (46.5mmHg vs 55.1mmHg, p=0.01). Cardiac index and right atrial pressure were not significantly different (p=0.35 and p=0.26 respectively). Case 5 had EPO weaning failure and had the lowest baseline PAPi in the cohort. Conclusion: iEPO weaning is associated with dynamic changes in PASP and PAPI in post-operative cardiac surgery patients. This finding supports the conceptual role of iEPO in improving post-operative RV-PA coupling and RV performance. Baseline PAPi may be a predictive marker to guide the weaning process. However, larger cohorts are needed to confirm these findings.
Abstract 11102: Ginsenoside Rb2 Alleviated Atherosclerosis Progression by Inhibiting M1 Macrophages Polarization Induced by Microrna-216a
Authors: Shuting Wang, Shujun YANG, Yutong Chen, Yu Chen, Weili Zhang
Journal: Circulation (2021)

Background: It has been reported that microRNA-216a (miR-216a) advanced atherosclerosis progression by promoting macrophage polarization to M1 pro-inflammation phenotype. Ginsenoside Rb2 (Rb2) is the major pharmacologically active compound extracted from ginseng. Bioinformatics predicted that Rb2 had a high affinity with miR-216a. In the present study, we aimed to investigate the effect of Rb2 on macrophages in atherosclerosis progression induced by miR-216a. Methods: ApoE -/- mice with miR-216a adenovirus infection and Rb2 intraperitoneal injection were used to explore the effect of Rb2 on miR-216a-mediated atherosclerosis development in vivo. Oil red O, Hematoxylin-Eosin (HE) and Masson's trichrome staining were performed to assess the thoracic aortic plaque progression and stability. Immunohistochemical staining was used to detect the M1 macrophages in plaque. Furthermore, macrophages transfected with miR-216a and treatment with Rb2 were used to explore the mechanism of Rb2 on M1 polarization in vitro. Neutral red phagocytic experiment and cholesterol efflux assay were performed to assess the role of Rb2 in lipid accumulation of M1 macrophages. Results: The results in ApoE -/- mice showed that Rb2 alleviated miR-216a-mediated atherosclerosis lesion area by 33%, and promoted plaque stability with a lipid accumulation decrease by 55% and a collage content increase by 250%. We further observed that Rb2 inhibited M1 macrophages in plaque by 76%. Mechanistically, the data from macrophages revealed that Rb2 reserved miR-216a-mediated Smad3 and IκBα protein expression to inhibit NF-κB-responsive genes, including M1 maker monocyte chemotactic protein-1 (MCP1) and tumor necrosis factor alpha (TNFα), and Rb2 attenuated miR-216a-mediated lipid deposit in M1 macrophages by decreasing lipid uptake and promoting cholesterol efflux. Conclusion: Our results first time showed that Rb2 alleviated atherosclerosis progression and stability induced by miR-216a. By inhibiting M1 macrophage polarization through Smad3/IκBα, Rb2 decreases lipid accumulation and increases collage content increase in plaque. The Rb2 could serve as a potential small molecule drug for atherosclerosis associated M1 polarization.
Abstract 13950: 5-years Mortality Of Heart Failure With Preserved, Mild Reduced, And Reduced Ejection Fractionin A 4880 Chinese Cohort
Authors: Zhidong Huang, Yanfang Yang, Liling Chen, Jin Liu, Yong Liu, shiqun Chen
Journal: Circulation (2021)

Introduction: There are limited data on the distribution and long-term prognosis in heart failure (HF) patients categorized by ejection fraction (EF) in China. Furthermore, available evidence conflicts with the outcome of HF patients with preserved EF (HFpEF), mild reduced EF (HFmrEF), and reduced EF (HFrEF). We aimed to characterize the 5-year prognosis in 3 HF phenotypes according to EF in a cohort of hospitalized HF patients in southern China. Methods: From January 2007 to December 2014, hospitalized patients who complicated with HF were enrolled in the Cardiorenal ImprovemeNt cohort study (CIN, ClinicalTrials.gov NCT04407936). HF types were defined as HFpEF (EF ≥50%), HFmrEF (EF 40%~49%) and HFrEF (EF &lt;40%). Kaplan-Meier and Cox proportional hazards models were constructed to examine differences in 5-year prognosis in HF patients with different phenotypes. Results: A total of 4880 HF patients (mean age: 61.8±10.3, male: 64.7%) were included: 2768 (57%) had HFpEF, 1015 (21%) had HFmrEF, and 1097 (22%) had HFrEF. With 5 years of follow-up through the end of December 2019, 1624 (27.6%) patients died. After full adjustment, HFrEF was associated with an 85% risk increased in 5-year mortality than HFpEF and with a 32% risk increased in 5-year mortality than HFmrEF. HFmrEF was associated with a 40% increased risk of 5-year mortality compared to HFpEF. (HFrEF 25.2% vs. HFpEF 13.4%, adjusted hazard ratio (aHR): 1.85[95% confidence interval (CI): 1.45- 2.35]; HFmrEF 18.1% vs. HFpEF 13.4%, aHR: 1.4 [95% CI: 1.08 - 1.81]; in addition, HFrEF25.2% vs. HFmrEF 18.1%, aHR: 1.32[95% CI: 1.02 - 1.71]). When compared with other countries and regions, the distribution of HFrEF is relatively smaller. Conclusions: In this Chinese cohort, patients with HFrEF accounts for more than a fifth of HF patients. Lower EF category was independently associated with an increased risk of mortality. Further studies in prevention and intervention are needed for all of 3 HF phenotypes.
Dual Targeting Bcl-2 By Venetoclax and Mcl-1 By AZD5991 to Overcome Therapeutic Resistance in Aggressive R/R Mantle Cell Lymphoma
Authors: Yijing Li, Yang Liu, Yuxuan Che, Alexa A Jordan, Joseph McIntosh, Angela Leeming, Courtney L Andersen, Justin Cidado, Jingling Jin, Vivian Changying Jiang, Michael Wang
Journal: Blood (2021)
Bullous Sweet syndrome following SARS‐CoV‐2 Oxford AstraZeneca vaccine
Authors: T. Žagar, N. Hlača, I. Brajac, L. Prpić‐Massari, S. Peternel, M. Kaštelan
Journal: British Journal of Dermatology (2021)

Journal Article Bullous Sweet syndrome following SARS‐CoV‐2 Oxford AstraZeneca vaccine Get access T. Žagar, T. Žagar Department of Dermatovenereology Clinical Hospital Centre Rijeka Rijeka Croatia Search for other works by this author on: Oxford Academic Google Scholar N. Hlača, N. Hlača Department of Dermatovenereology Clinical Hospital Centre Rijeka Rijeka CroatiaFaculty of Medicine University of Rijeka Rijeka Croatia Correspondence: Nika Hlača. Email: nika.hlaca@uniri.hr https://orcid.org/0000-0002-0517-5462 Search for other works by this author on: Oxford Academic Google Scholar I. Brajac, I. Brajac Department of Dermatovenereology Clinical Hospital Centre Rijeka Rijeka CroatiaFaculty of Medicine University of Rijeka Rijeka Croatia Search for other works by this author on: Oxford Academic Google Scholar L. Prpić‐Massari, L. Prpić‐Massari Department of Dermatovenereology Clinical Hospital Centre Rijeka Rijeka CroatiaFaculty of Medicine University of Rijeka Rijeka Croatia Search for other works by this author on: Oxford Academic Google Scholar S. Peternel, S. Peternel Department of Dermatovenereology Clinical Hospital Centre Rijeka Rijeka CroatiaFaculty of Medicine University of Rijeka Rijeka Croatia https://orcid.org/0000-0001-8590-0451 Search for other works by this author on: Oxford Academic Google Scholar M. Kaštelan M. Kaštelan Department of Dermatovenereology Clinical Hospital Centre Rijeka Rijeka CroatiaFaculty of Medicine University of Rijeka Rijeka Croatia Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 186, Issue 3, 1 March 2022, Page e110, https://doi.org/10.1111/bjd.20876 Published: 01 March 2022
PATH-04. LEPTOMENINGEAL DISEASE IN PATIENTS WITH HISTONE-MUTANT GLIOMAS
Authors: Maria Diaz, Carlos Eduardo Silva Correia, Andrew Lin, Alexandra Miller, Elena Pentsova
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION The 2016 WHO classification describes a subtype of midline gliomas harboring histone 3 (H3) K27M mutations, and the upcoming 2021 edition may include a new subtype of hemispheric diffuse gliomas with H3 G34R/V mutations. Since we began to perform molecular profiling at Memorial Sloan Kettering Cancer Center (MSKCC) we have observed an increased prevalence of leptomeningeal disease (LMD) in this population. However, the incidence and clinical behavior of LMD has not been well defined. METHODS This is a retrospective study of patients with H3-mutant gliomas at MSKCC diagnosed from 01/2012 to 02/2021, either by tumor biopsy or by cerebrospinal fluid (CSF). Histone mutations were identified through next-generation sequencing (NGS). RESULTS We found 40 patients (pts) harboring H3 mutations (K27M mutations in 31 pts, G34R/V in 8, and both in one), with 2/40 (5%) mutations identified through CSF NGS only and rest in tumor tissue. Median age was 20.5 years (4-70); 25 were male. Tumor location was midline for K27M-mutant tumors (thalamus [N=15], brainstem [N=10], spine [N=5], pineal gland [N=1]) and hemispheric for G34R/V-mutant tumors; tumor with both mutations was thalamic. LMD was diagnosed in 22/40 (55%) pts radiographically, including 19/31 (61%) of K27M-mutant pts and 3/8 (38%) of G34R/V-mutant pts (patient with both mutations did not develop LMD). At analysis, 10 patients remain alive. Median time from diagnosis to LMD was 8.8 months (0-44.4), with median OS of 6.5 months (0.3-34) after LMD diagnosis. CONCLUSION More than half of patients with histone-mutant gliomas develop LMD, including over a third of patients with G34R/V mutations. Neuroaxis imaging should be performed in conjunction with CSF studies in histone-mutant gliomas. Besides, CSF NGS represents an important tool to identify molecular profile of tumors when biopsy is not feasible or there is limited tissue for analysis.
Abstract 9633: Caveolin-3 Nitrative Modification Exacerbates Ischemic Heart Failure in Pre-Diabetic Mice by Disassembling Cardioprotective Signalosomes
Authors: Zhijun Meng, Jianli Zhao, Peng Yao, Zhen Zhang, jumpei tsukuda, Theodore Christopher, Jonathan Koa, Bernard L Lopez, Erhe Gao, Harry Ischiropoulos, Walter J Koch, Xin Ma, Yajing Wang
Journal: Circulation (2021)

Rationale: Diabatic heart is “universally” resistant to protective interventions, including insulin, adiponectin exacerbating ischemic heart failure (HF). Caveolin (Cav) serves as scaffolding regulator, coordinating signal transduction in cell survival. However, whether and how diabetes alter Cav3-centered signalosome integrity, contributing to diabetic ischemic HF remains unclear.We hypothesized that preserving Cav3 signalosome integrity restore cardioprotective signaling, protecting against diabetic exacerbation of ischemia HF. Methods and Results: Mice with normal diet (ND) or high-fat-diet (HFD) were subjected to myocardial ischemia and reperfusion (MI/R). Administration of insulin or adiponectin markedly attenuated MI injury (60 minutes MI/24 hours reperfusion) in ND mice, an effect lost in diabetic animals (12 weeks HFD, n=18-20/group). Interestingly, cardioprotective effect of insulin and adiponectin was blunted as early as 4 weeks of HFD (pre-diabetes). In ND heart, Cav3 interacts with AdipoR1 and insulin receptor-β (IRβ), forming signalosomes. Those complexes were significantly reduced in pre-diabetic heart. However, the level of Cav3, AdipoR1, AdipoR2, and IRβ remain unchanged. Among multiple post-translational modifications, Cav3 nitration was the dominant in pre-diabetic heart. SIN-1 (a nitration donor) reduced Cav3/AdipoR1 and Cav3/IRβ complex, and blocked their transmembrane signaling. Mass spectrometry identified Tyr 73 is the site modified in pre-diabetic cardiomyocytes. Phenylalanine substitution of Tyr 73 (Cav3 Y73F ) blocked SIN-1 induced Cav3 nitration, restored signalosome assembling, and rescued insulin and adiponectin transmembrane signaling in diabetic cardiomyocytes. Finally, AAV9-mediated cardiomyocyte specific Cav3 Y73F re-expression blocked HFD-induced Cav3 nitration, restored transmembrane signaling, rescued the protective action against ischemic HF. Conclusion: Nitration of Cav3 at Tyr 73 and complex dissociation is responsible for cardiac insulin/adiponectin resistance in pre-diabetic heart, contributing to ischemic HF progression. Early intervention preserving Cav3-centered signalosome integrity is an effective novel strategy against diabetic ischemic HF.