tbuckley/cabot-search huggingface dataset:
Abstract 10303: CRRL290: A Novel and Mechanism-Based Therapeutic Peptide Targeting the Crosstalk Between Angiotensin II and the Natriuretic Peptide System for Cardiorenal Disease
Authors: Xiao Ma, Seethalakshmi R Iyer, Shawn Reginauld, Shuchong Pan, Ye Zheng, Valentina Cannone, Jeson Sangaralingham, John C Burnett
Journal: Circulation (2021)

Introduction: Therapeutic strategies dual-targeting renin-angiotensin system (RAS) and natriuretic peptide system (NPS), such as Sacubitril/Valsartan, have been proven promising in treating cardiorenal disease (CRD). However, mechanisms behind the crosstalk between RAS and NPS remain to be fully elucidated. While angiotensin II (ANGII), the central RAS hormone, is thought to interact with NPS at multiple levels, whether and how it may influence the actions of particulate guanylyl cyclase A (pGC-A), the receptor activated by ANP and BNP to increase its second messenger cGMP, has not been investigated. Hypothesis: We hypothesize ANGII naturally suppresses pGC-A activity and inhibition of this ANGII mediated action can be a new strategy to combat CRD. Methods: Studies consist of biomarker analyses in plasma from healthy humans, drug infusions in normal rats, molecular characterization in human HEK293 cells, and in vitro assessment of CRRL290, an innovative dual-functional peptide designed to activate pGC-A and inhibit protein kinase C (PKC). Results: In 128 healthy humans, plasma cGMP was positively associated with ANP or BNP in low (≤ 4.5 pg/mL) but not those with high (&gt; 4.5 pg/mL) ANGII levels. Infusion of ANP (300 pmol/kg/min) in normal rats increased plasma and urinary cGMP, however ANP mediated cGMP generation was reduced in the presence of ANGII. Interestingly, suppression effect of ANGII on pGC-A was only recapitulated in HEK293 cell overexpressing both pGC-A and AT1R, but not in HEK293 cell overexpressing pGC-A alone. We also found PKC, a known downstream target of AT1R, was a key mediator as the suppression effect of ANGII was largely ablated by Go6983, a pan PKC inhibitor. Accordingly, we designed and synthesized CRRL290. Notably, CRRL290 had superior potency in cGMP generation compared to the currently best-in-class ANP-analog, MANP, in HEK293 cells. Conclusions: We demonstrate that ANGII is a natural suppressor of pGC-A via AT1R and PKC signaling. We also report for the first time that CRRL290, a novel bioengineered peptide that activates pGC-A receptor while inhibiting PKC signaling, potently generates cGMP. Our study provides new insights into the RAS-NPS interaction, and highlights a novel and mechanism-based therapeutic avenue for treating CRD.
Abstract 14287: Outcomes of Sudden Cardiac Arrest in Liquid vs Solid Cancers. A Nationwide Inpatient Sample Analysis
Authors: yasar sattar, David Song, Fawaduzzaman Syed, Fatir Murtaza, Sharaad Latchana, Mohamed Zghouzi, Waqas Ullah, M C Alraies
Journal: Circulation (2021)

Background: The comparative outcomes of Liquid and Solid cancer in Sudden cardiac arrest (SCA) population is not well studied in literature. Methods: The National inpatient sample database from the year 2015-2018 was used to compare liquid cancer and Solid cancer patients that underwent sudden cardiac arrest (SCA). Means and medians were calculated for continuous variables, p -value (&lt;0.05), and Pearson chi-square used to calculate weighted outcomes. Results: A total of 7,695.00 SCA patients (solid cancer n= 475.0 ; liquid cancer n=7,220.0) were included in our study analysis. Among participants, male and female percentages in Solid (65.3 % and 34.7%) and liquid cancers (61.9% and 38.1%) respectively. The median age of solid cancer with SCA was 67 years (IQR 51-77) while median age for liquid cancer with SCA was 70 years (IQR 58-79). The median length of stay of solid cancer with SCA is 8 days (IQR 3-20) whereas liquid cancer with SCA is 5 days (IQR 1-13). There was no statistical significant difference among solid or liquid cancer with SCA in terms of in-hospital mortality (76.6% vs 78.1%, p = 0.742), acute kidney injury (55.8% vs 61%, p = 0.319), major bleeding (5.3% vs 10.7%, p = 0.098), transfusion requirement (82.1% vs 81.2%, p = 0.837), and cardiogenic shock (3.2% vs 3.6%, p= 0.824) in sudden cardiac arrest (SCA) patients respectively. There was higher prevalence of cerebrovascular accidents (3% vs 7.4%, p= 0.024) and mechanical circulatory support use including ventricular assist devices (VAD) and Extracorporeal membrane oxygen (ECMO) in liquid cancer patients as compared to solid cancers in SCA (1.1% vs 3.3%, p = 0.001). Conclusion: Liquid cancers with SCA can have higher prevalence of stroke and mechanical circulatory support requirement as compared to solid cancers with SCA
High CRP-Albumin Ratio Predicts Poor Prognosis in Transplant Ineligible Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia
Authors: Hajime Senjo, Masahiro Onozawa, Daisuke Hidaka, Shota Yokoyama, Satoshi Yamamoto, Yutaka Tsutsumi, Yoshihito Haseyama, Takahiro Nagashima, Akio Mori, Shuichi Ota, Hajime Sakai, Toshimichi Ishihara, Takuto Miyagishima, Yasutaka Kakinoki, Mitsutoshi Kurosawa, Hajime Kobayashi, Hiroshi Iwasaki, Takeshi Kondo, Takanori Teshima
Journal: Blood (2021)
Abstract 9100: Two-Dimensional Speckle Tracking Echocardiography in Assessing the Subclinical Myocardial Dysfunction in Patients With Gestational Diabetes Mellitus
Authors: Wei Li, Ziyao Li, Wei Liu, Peng Zhao, Zhenzhen Wang
Journal: Circulation (2021)

Introduction and Hypothesis: Gestational diabetes mellitus (GDM) refers to impaired glucose tolerance first diagnosed during pregnancy, which may increase the risk of incident cardiovascular disease. Asymptomatic subclinical myocardial dysfunction already exists before the GDM diagnosis. In this study, we hypothesize that the two-dimensional speckle tracking echocardiography (2D-STE) may identify the subclinical impairment of GDM on the maternal left ventricular function. Methods: We prospectively enrolled 47 women with GDM and 62 healthy pregnant women (control group) at their 24~28 weeks of gestation who underwent transthoracic echocardiography (TTE). GDM diagnosis was in agreement with the IADPSG criteria. TTE was performed according to the recommendations of the American Society of Echocardiography. Conventional and 2D-STE parameters were compared between the two groups. Results: Age, gestational weeks, heart rate, and conventional echocardiographic parameters had no difference between the two groups. LV global longitudinal strain (LV-GLS) was lower in GDM (18.14 ± 2.53 vs. 22.36 ± 6.33, p&lt; 0.001). LA reservoir and conduit phasic strain also decreased in patients with GDM (32.71 ± 6.64 vs. 38.00 ± 7.06, 20.41 ± 5.69 vs. 25.56 ± 5.73, p&lt; 0.001). However, there was no significant difference regarding LA contractile function between the two groups. In multivariate regression analysis, the LV-GLS and LA conduit strain independently associated with GDM. Furthermore, the LA conduit strain may be a predominant parameter to illustrate subclinical myocardial deterioration in patients with GDM. Conclusions: Two-dimensional speckle tracking echocardiography may sensitively provide quantitative parameters, such as LV-GLS and LA conduit strain, to illuminate subclinical myocardial dysfunction in patients with GDM.
Effectiveness and Security of a Modified CALGB10403 in Adolescents and Young Adults with Acute Lymphoblastic Leukemia in Low-and-Middle-Income Countries: A Multicentric Experience in Central America
Authors: Juan Rangel-Patiño, Lee-Tsai Yu Ling, Victor Itaí Urbalejo Ceniceros, Maria Elena Monserrat Luna Perez, Karla Adriana Espinosa, Lauro Fabian Amador, Alvaro Cabrero Garcia, Carolina Balderas-Delgado, Sergio I Inclan-Alarcon, Yvette Neme Yunes, Luis Meillon-García, Jose Manuel Sanchez Albarran, Elia Ixel Apodaca, Roberta Demichelis
Journal: Blood (2021)
Impaired Mitochondrial Transcription Factor A Expression Promotes Mitochondrial Damage to Drive Fibroblast Activation and Fibrosis in Systemic Sclerosis
Authors: Xiang Zhou, Thuong Trinh‐Minh, Cuong Tran‐Manh, Andreas Gießl, Christina Bergmann, Andrea‐Hermina Györfi, Georg Schett, Jörg H. W. Distler
Journal: Arthritis & Rheumatology (2021)

Mitochondrial transcription factor A (TFAM) controls the transcription of core proteins required for mitochondrial homeostasis. This study was undertaken to investigate changes in TFAM expression in systemic sclerosis (SSc), to analyze mitochondrial function, and to evaluate the consequences for fibroblast activation.TFAM expression was analyzed by immunofluorescence and Western blotting. The effects of TFAM knockout were investigated in cultured fibroblasts and in murine models of bleomycin-induced skin fibrosis, bleomycin-induced lung fibrosis, and skin fibrosis induced by overexpression of constitutively active transforming growth factor β type I receptor (TGFβRΙ).TFAM expression was down-regulated in fibroblasts in SSc skin and in cultured SSc fibroblasts. The down-regulation of TFAM was associated with decreased mitochondrial number and accumulation of damaged mitochondria with release of mitochondrial DNA (mtDNA), accumulation of deletions in mtDNA, metabolic alterations with impaired oxidative phosphorylation, and release of the mitokine GDF15. Normal fibroblasts subjected to long-term, but not acute, exposure to TGFβ mimicked SSc fibroblasts, with down-regulation of TFAM and accumulation of mitochondrial damage. Down-regulation of TFAM promoted fibroblast activation with up-regulation of fibrosis-relevant Gene Ontology terms in RNA-Seq, partially in a reactive oxygen species-dependent manner. Mice with fibroblast-specific knockout of Tfam were prone to fibrotic tissue remodeling, with fibrotic responses even to NaCl instillation and enhanced sensitivity to bleomycin injection and overexpression of constitutively active TGFβRI. TFAM knockout fostered Smad3 signaling to promote fibroblast activation.Alterations in the key mitochondrial transcription factor TFAM in response to prolonged activation of TGFβ and associated mitochondrial damage induce transcriptional programs that promote fibroblast-to-myofibroblast transition and drive tissue fibrosis.
Abstract 10758: Individuals with Normal-Weight Obesity Exhibit Higher Postprandial Triglycerides, but Similar Endothelial Function and Inflammation Compared to Normal-Weight Controls
Authors: Bryant H Keirns, Samantha M Hart, Christina M Sciarrillo, Kara L Poindexter, Stephen L Clarke, Sam R Emerson
Journal: Circulation (2021)

Introduction: Normal-weight obesity (NWO) is defined as having a normal BMI yet high body fat % and is linked to increased cardiovascular disease (CVD) risk. However, the current understanding of NWO’s risk profile is incomplete and, in many cases, their clinical presentation is arguably unremarkable based on common risk factors. Hypothesis: We hypothesized that other indictors of CVD risk such as postprandial triglycerides (TG), flow-mediated dilation (FMD), and inflammatory cytokines would be elevated in NWO, consistent with their future CVD risk. Methods: Individuals were recruited into 3 groups (n = 10/ group): healthy controls (Con), NWO, and metabolic syndrome (MetS) based on results from a fasting metabolic panel, blood pressure, and DEXA. All participants underwent an abbreviated fat tolerance test where fasting TG were measured, a high-fat shake was consumed (9 kcal/kg; 73% fat), and then TG measured again 4 hrs later. Brachial FMD was measured during the fasted state and postprandially, and a high-sensitivity T cell cytokine bioplex (Millipore; Burlington, MA) was performed with fasting serum. Data were analyzed using one-way ANOVA followed by Fisher’s LSD. Results: NWO and MetS had similar body fat % and both were higher than Con ( p &lt; 0.01). All groups differed with respect to visceral adipose tissue mass, with MetS &gt; NWO &gt; Con ( p &lt; 0.01). Despite having similar fasting TG to Con, NWO (122.5 ± 46.4 mg/dL) had 4-hr TG intermediate to Con (73.7 ± 13.9 mg/dL) and MetS (178.3 ± 76.4 mg/dL; p &lt; 0.01). Across the entire sample, FMD decreased ( p &lt; 0.01) after the high-fat meal. MetS (3.3 ± 1.2 %) displayed lower fasting FMD than Con (5.1 ± 1.1 %), and NWO (4.5 ± 2.0 %) was similar to both groups ( p &lt; 0.05). No group differences were observed with postprandial FMD. The majority of cytokines assessed were not different across groups. However, MetS (7.8 ± 2.1 pg/mL) exhibited higher TNF-α than Con (4.8 ± 1.9 pg/mL; p &lt; 0.05), and NWO (6.6 ± 3.4 pg/mL) was not different from either group. Conclusions: In conclusion, NWO was associated with higher postprandial TG than Con, but displayed little evidence of impaired vascular health or inflammation. MetS had the greatest 4-hr TG, as well as impaired vascular function and signs of inflammation compared to Con.
Enhanced p53 Activation By Dual Inhibition of MDM2 and XPO1 Disrupts MYC Transcriptional Program and Restores Sensitivity to BCL-2 Inhibition in Ven/HMA Resistant AML
Authors: Yuki Nishida, Jo Ishizawa, Edward Ayoub, Tallie Patsilevas, Lauren Ostermann, Rafael Heinz Montoya, Muharrem Muftuoglu, Vivian Ruvolo, Po Yee Mak, Wenjing Tao, Bing Z Carter, Kensuke Kojima, Naval Daver, Arnaud Lesegretain, Takahiko Seki, Sharon Shacham, Marina Konopleva, Michael Andreeff
Journal: Blood (2021)
Therapeutic inhibition of RBM20 improves diastolic function in a murine heart failure model and human engineered heart tissue
Authors: Michael H. Radke, Victor Badillo-Lisakowski, Thiago Britto-Borges, Dieter A. Kubli, René Jüttner, Pragati Parakkat, Jacobo Lopez Carballo, Judith Hüttemeister, Martin Liss, Arne Hansen, Christoph Dieterich, Adam E. Mullick, Michael Gotthardt
Journal: Science Translational Medicine (2021)

Heart failure with preserved ejection fraction (HFpEF) is prevalent and deadly, but so far, there is no targeted therapy. A main contributor to the disease is impaired ventricular filling, which we improved with antisense oligonucleotides (ASOs) targeting the cardiac splice factor RBM20. In adult mice with increased wall stiffness, weekly application of ASOs over 2 months increased expression of compliant titin isoforms and improved cardiac function as determined by echocardiography and conductance catheter. RNA sequencing confirmed RBM20-dependent isoform changes and served as a sensitive indicator of potential side effects, largely limited to genes related to the immune response. We validated our approach in human engineered heart tissue, showing down-regulation of RBM20 to less than 50% within 3 weeks of treatment with ASOs, resulting in adapted relaxation kinetics in the absence of cardiac pathology. Our data suggest anti-RBM20 ASOs as powerful cardiac splicing regulators for the causal treatment of human HFpEF.
Abstract 12221: Reduction of Inappropriate Shocks Over Time in Hypertrophic Cardiomyopathy Patients With Subcutaneous Implantable Cardioverter-Defibrillators
Authors: Chockalingam Narayanan, William Gionfriddo, Srijan Shrestha, Benjamin Koethe, Benjamin Katcher, Ann Garlitski, Jonathan Weinstock, Munther Homoud, Barry Maron, Martin S Maron, Ethan J Rowin, Christopher Madias
Journal: Circulation (2021)

Introduction: Subcutaneous implantable cardioverter defibrillators (SICD) are an attractive option for sudden death (SCD) prevention in younger hypertrophic cardiomyopathy (HCM) patients. Conversely, SICDs have higher rate of inappropriate shock (IAS) when compared to transvenous devices. Objective: We characterize incidence of appropriate shock (AS) and IAS and analyze predictors of IAS in HCM SICD patients. Methods: Data was collected from HCM SICD patients from 2013 to 2021. We used multivariable logistic regression to assess for predictors of IAS in patients with &gt; 6 mo follow up. Results: 94 HCM patients (age 47 ± 15 years) underwent SICD implant with mean follow up of 3.7 ± 2.0 year. Maximal LV thickness 20.5 ± 5.8 mm with massive hypertrophy (&gt; 30 mm) in 10 patients (11.8%). Initial DFT with 65J was successful in 88 patients, with 5 more successful after device adjustment. 5 patients (5.9%) had 10 AS (3.2 AS per 100 pt-years). 10 patients (11.8%) had 19 IAS (6.0 IAS per 100 pt-years) due to T wave oversensing (n = 13), P wave oversensing (n = 2), atrial arrhythmia (n=2), and external noise (n = 1). IAS rate decreased over time, with IAS occurring in 8 patients of the initial half of the cohort and in only 2 of the second half. Time to IAS from implant was 11 ± 10.8 mo. QRS duration (OR 1.025, 95% CI 0.997-1.053; P = 0.084) showed trend to prediction of IAS, but no characteristic proved independently significant. Conclusions: This data adds to increasing evidence that in high-risk HCM patients, SICD represents a reliable treatment option for SCD prevention. IAS mainly due to cardiac oversensing, was seen in 11.8% of patients within this HCM cohort. IAS decreased over time, possibly due to improved patient selection, implant technique and device programming (SMART pass filter). A larger dataset is likely necessary to better understand this trend.
Abstract P353: Adipose-derived Stem Cells Contribute To Vascular Remodeling Via <i>Clec11a</i> + Subpopulation
Authors: Yongli Ji, Yunrui Lu, Jian Shen, Meixiang Xiang, Yao Xie
Journal: Circulation Research (2021)

Introduction: Recent researches identified the existence of perivascular adipose-derived stem cells (ADSCs) which could differentiate into vascular lineages and participate in vascular remodeling. Single-cell mRNA analysis revealed cellular heterogeneity of subcutaneous ADSCs in respect to cell clustering and cell differentiation. However, such analysis of perivascular ADSCs has not been investigated at a single-cell level. Hypothesis: There is a significant difference among perivascular ADSCs subpopulations in respect to vascular-lineage differentiation. Methods: We performed droplet-based single-cell profiling of subcutaneous and perivascular adipose stromal cells and compared ADSCs regarding their heterogeneity, gene ontology, and cell fate trajectory by applying single-cell analysis as well as in vitro and in vivo assays. Results: Single-cell analysis uncovered 4 perivascular ADSCs subpopulations including Dpp4+ , Col4a2+ / Icam1+ , Clec11a+ / Cpe+ and Sult1e1+ cells. Notably, the Clec11a + subpopulation comprised the bulk of perivascular ADSCs, while was hardly presented in subcutaneous ADSCs. Further gene-set enrichment analysis suggested Clec11a + ADSCs were potentially involved with TGF-β signaling pathways and pseudotemporal analysis predicted that Clec11a + subpopulation lay at the end of the differential trajectory towards smooth muscle cells (SMCs). In vitro assays displayed that perivascular ADSCs could differentiate into SMCs via CLEC11A regulation when treated by TGF-β1. To further elucidate the role of the Clec11a + subpopulation in SMCs differentiation, we labeled CLEC11A+ and CLEC11A- perivascular ADSCs by lentivirus transfection and isolated them by FACS assay. CLEC11A+ cells showed the greater capability of SMCs differentiation in response to TGF-β1 in vitro and enhanced neointima formation when transplanted to the adventitial side of guidewire injured arteries. Conclusions: The present study depicted the unique heterogeneity of perivascular ADSCs and the novel role of the Clec11a + subpopulation, providing a supplement for the relationship between perivascular ADSCs and vascular SMCs.
Clinical Characteristics and Late-Line Treatment Patterns of Patients with Chronic Myeloid Leukemia Who Received 2 Prior Lines of Tyrosine Kinase Inhibitor Therapy in US Community Oncology Practices
Authors: Pareshkumar Patel, Aditya Raju, Anna Coutinho, Rodrigo Maegawa, Orsolya Lunacsek, Kathryn Deyoung, Serban Iorga, Xiting Cao
Journal: Blood (2021)
Haplo-Identical Non-Gene Editing CD7 CAR T-Cells Induced Bone Marrow and Extramedullary Remission in a Pediatric Patient with <i> <i>TP53</i> </i> Mutated Relapsed and Refractory Early T-Cell Precursor Lymphoblastic Leukemia/Lymphoma after Haploidentical Hematopoietic Stem Cell Transplantation
Authors: Haiping Dai, Yang Lin, Huimin Meng, Qingya Cui, Wenjuan Zhu, Xiaowen Tang, Wei Cui, Depei Wu
Journal: Blood (2021)
Abstract 14141: Role of Pak1 in Sinus Node Function
Authors: Carlos H Pereira, Disha Varma, Kathrin Banach
Journal: Circulation (2021)

Introduction: Sinus node (SN) dysfunction (SND) and atrial arrhythmia frequently occur simultaneously with a hazard ratio of 4.2 for new onset atrial fibrillation (AF) in SND patients. We demonstrated previously that loss of p21-activated kinase 1 (Pak1), a serine/threonine kinase increases the propensity for AF by increasing cellular production of reactive oxygen species (ROS). Since pacemaker current (HCN4) is negatively regulated by cellular ROS we hypothesized that loss of Pak1 leads to attenuated SN function. Methods: Heart rate regulation was quantified in wild type (WT) and Pak1 deficient mice (Pak1 -/- ) in vivo and the isolated Langendorff perfused heart using ECGs, bipolar and multi-electrode array derived atrial electrograms. Unpaired t-test was used to compare means between groups. Results: In vivo WT and Pak1 -/- animals exhibited no difference in basal heart rate (WT: 450 ± 26 bpm, n=16; Pak1 -/- : 440 ± 24 bpm, n=13), but intrinsic HR after autonomic blockage, was reduced in Pak1 -/- (WT: 399 ± 32 bpm, n=16; Pak1 -/- : 365 ± 34 bpm, n=13, p&lt;0.05). The result was confirmed in the Langendorff configuration (WT: 359 ± 47 bpm, n=12; Pak1 -/- : 293 ± 47 bpm, n=21, p&lt;0.01) suggesting attenuated SN impulse generation. To determine the contribution of the Ca clock, hearts were perfused with cyclopiazonic acid (5 μM) a blocker of the sarcoplasmic reticulum Ca ATPase. CPA attenuated the HR in WT and Pak1 -/- (WT: -19.6 ± 6.6 % n=2 ; Pak1 -/- : -15.8 ± 7.5 %, n=5) but did not eliminate the difference in HR (WT: 320 ± 37 bpm, n=2; Pak1 -/- : 255 ± 26 bpm, n=5, p&lt;0.05). Block of HCN4 by ivabradine (3 μM), reduced the HR in WT and Pak1 -/- (WT: -45.1 ± 6.3 %, n=6; Pak1 -/- : -22.2 ± 8.6 %, n=7, p&lt;0.001) and eliminated differences in spontaneous activity (WT: 186 ± 43 bpm, n=6; Pak1 -/- : 234 ± 41 bpm, n=7). In vivo the change in HR in response to ß-blocker propranolol (WT: -13.5 ± 2.5 %, n=6; Pak1 -/- : -18.4 ± 1.5 %; n=4, p&lt;0.01) and muscarinic receptor blocker atropine (WT: 9.7 ± 5.0%, n=10; Pak1 -/- : 4.6 ± 4.4 %; n=9, p&lt;0.05) revealed that the attenuated SN impulse generation in Pak1 -/- mice was compensated by an increased sympathetic and attenuated parasympathetic tone. Conclusion: Attenuated Pak1 expression results in suppressed SN impulse generation likely by ROS dependent attenuation of HCN4 expression.