tbuckley/cabot-search huggingface dataset:
Abstract 10194: Pacing Site- and Rate-Dependent Shortening of Retrograde Conduction Time Over the Slow Pathway After Atrial Entrainment of Fast-Slow Atrioventricular Nodal Reentrant Tachycardia
Authors: Yoshiaki Kaneko, Tadashi Nakajima, Shuntaro Tamura, Hiroshi Hasegawa, Hasegawa Hiroshi
Journal: Circulation (2021)

Introduction: The entrainment rule by which the site of entrainment has no effect on the orthodromic conduction time across the reentry circuit immediately after cessation of pacing has not been unequivocally verified in atypical atrioventricular nodal reentrant tachycardia (AVNRT). We have recently observed a unique electrophysiological response upon atrial induction of fast-slow (F/S-) AVNRT, characterized by a shortening of the retrograde conduction time across the slow pathway (SP) (retro-SP-time). Hypothesis: Atrial entrainment pacing (EP) of a) the common-type (com-) F/S-AVNRT using a typical SP, or b) the superior-type (sup-) F/S-AVNRT using a superior SP, both might modify the retro-SP-time immediately after termination of EP. Methods: In 16 patients of com-F/S-AVNRT and 11 patients of sup-F/S-AVNRT in whom successful EP from the high right atrium (EP-HRA) and the proximal coronary sinus (EP-CS) was obtained at 2±2 rates, we evaluated the difference in the His-atrial (HA) interval measured immediately after cessation of each EP attempt (HA difference) between EP-HRA and EP-CS (HA[1]-HRA and HA[1]-CS, respectively) and also measured atrial-His and HA intervals in the 1st and 2nd cycles immediately after the EP, and during tachycardia stabilized. Results: &gt;20 ms HA difference, defined as an atypical difference, at ≥1 rates of EP was observed in 16 patients (56%), including 7 with com- and 9 with sup-F/S-AVNRT. Irrespective of the EP rate, the atypical response of com-F/S-AVNRT was always due to a shorter HA[1]-CS than HA[1]-HRA, with a 39±22 ms HA difference, whereas the atypical response of sup-F/S-AVNRT was always due to a longer HA[1]-CS than HA[1]-HRA, with a 51±26 ms HA difference. Moreover, the atypical response disappeared within 2 cycles after the cessation of EP. The atypical difference, although its exact mechanism remains unclear, might attribute to a shortening of the retro-SP-time according to decremental properties of the SP with deeper antidromic penetration during EP provoked depending on the site and rate of pacing. Conclusions: We have identified a little-known pacing site- and pacing rate-dependent shortening of the retro-SP-time. This phenomenon may affect an interpretation of post-pacing interval after EP of F/S-AVNRT.
Abstract 11305: Protective Effects of Homoarginine on Cardiovascular Function in a Mouse Model of Chronic Kidney Disease
Authors: Billy Ding, Anisa Raidah, Eric Schram, Neil Kaungumpillil, Mohnish Singh, Olga V Savinova
Journal: Circulation (2021)

Introduction: The level of homoarginine (hArg) in plasma correlates inversely with cardiovascular and renal disease. However, the cardioprotective mechanism of hArg in renal disease is currently unknown. In this study, we assessed hArg’s effects on cardiovascular function in mice with chronic kidney disease (CKD). Hypothesis: We have previously reported that hArg reduces fibrosis and helps preserve ejection fraction in a model of coronary artery disease. We now hypothesize that hArg supplementation will 1) decrease cardiac and renal fibrosis and inflammation in a model of CKD, 2) preserve cardiac geometry and function, 3) increase renal artery blood flow, and 4) increase survival. Methods: The mice used in this study had a mutation in the low density lipoprotein receptor on the C57BL/6 genetic background. Mice of both sexes (n=28) were fed a standard rodent diet supplemented with 0.1% (F) and 0.2% (M) adenine to induce CKD. Mice were randomly assigned to 14 μg/ml hArg (in drinking water) or placebo (PBO). Cardiac structure and function as well as renal blood flow were measured via high frequency ultrasound (Vevo 3100, VisualSonics). Results: LV geometry data of hArg treated male mice showed increased left ventricular (LV) mass (p&lt;0.05) with normal LV internal diameter and increased LV wall thickness (p&lt;0.01). In terms of cardiac function, ejection fraction (EF, p&lt;0.05), fractional shortening (p&lt;0.01), and cardiac output (p&lt;0.01) were also increased in hArg treated male mice compared to placebo. No differences in renal blood flow were observed. Survival was not affected by hArg. Additionally, we observed decreased food consumption (p&lt;0.01) and fecal output (p&lt;0.001) in hArg treated mice with no difference in urine output compared with placebo. Conclusion: hArg treated male mice developed physiologic cardiac hypertrophy with preserved EF in the absence of LV dilation. Additionally, hArg affected the metabolic state of treated mice reflected in food consumption.
Abstract 13546: Putative Titin Mutations Associated With Both Long QT Syndrome and Left Ventricular Noncompaction
Authors: Alexander M Greiner, Margaret Freese, Gabriel Kringlen, Edward M Powers, Rebecca A Gutmann, Barry London
Journal: Circulation (2021)

Introduction: Inherited long QT Syndrome (LQTS) is characterized by prolonged QTc intervals on electrocardiogram (EKG), ventricular arrhythmias and sudden death (SCD), and is caused by mutations in ion channel or ion-channel related genes. Inherited forms of dilated cardiomyopathy (DCM) and left ventricular noncompaction (LVNC), on the other hand, are caused by mutations in sarcomeric and structural genes including titin. Methods: Two unrelated families with histories of SCD presented to us for clinical evaluation of LQTS. Clinical genetic testing covering arrhythmia and cardiomyopathy genes was performed on each proband, with carrier testing on other family members. Results (Figure): The proband of family 1 had a strong family history of SCD, carried the clinical diagnosis of LQTS treated with propranolol, and had normal cardiac function by echocardiography. Following chemotherapy with adriamycin for breast cancer, evaluation showed a QTc of 514 ms on EKG, non-sustained VT on Holter, and LVNC with an LVEF=43% on cardiac MRI (cMRI). Genetic testing identified a likely pathogenic nonsense TTN variant (p.W18202*) along with a benign TTN polymorphism (p.E689K). Her clinically normal daughter did not carry the p.W18202* variant. The proband of family 2 had a strong family history of LQTS and SCD and was diagnosed with LQTS in her 20s after her mother suffered a cardiac arrest. Evaluation showed a QTc of 500 ms on EKG and biventricular LVNC with an LVEF=48% on cMRI. Genetic testing identified a likely pathogenic frameshift TTN variant (p.E18038Rfs*47). Three of her children carried the variant and had borderline or prolonged QTc intervals; one had hypertrabeculation on cMRI. Conclusion: We have identified two truncating TTN variants in close proximity to each other in unrelated families with overlapping LQTS/LVNC/DCM syndromes. Mutations in TTN may play a previously unappreciated role in the pathogenesis of inherited arrhythmia syndromes.
Abstract 10960: Genetic Overlap of Acute Myocarditis and Inherited Cardiomyopathy
Authors: Amrit S Lota, Mark Hazebroek, Pantazis Theotokis, Rebecca Wassall, Sara Salmi, Brian Halliday, Upasana Tayal, Job Verdonschot, Devendra Meena, Antonio de Marvao, Alma Iacob, Daniel Hammersley, Richard Jones, Rick Wage, Rachel Buchan, Momina Yazdani, Michela Noseda, Tarun Mittal, Joyce Wong, Jan Lukas Robertus, John Baksi, Vassilios Vassiliou, Ioanna Tzoulaki, Antonios Pantazis, John Cleland, Paul J Barton, stuart cook, Dudley J Pennell, Pablo Garcia-Pavia, Leslie T Cooper, Stephane Heymans, James S Ware, Sanjay K Prasad
Journal: Circulation (2021)

Background: Myocarditis may predispose to dilated cardiomyopathy (DCM) and sudden cardiac death (SCD). Familial data indicate a potential genetic susceptibility shared with arrhythmogenic cardiomyopathy (ACM). We present the first large-scale genotype-phenotype study of adults with acute myocarditis. Methods: A cohort comprising 336 consecutive patients with acute myocarditis was enrolled in London and Maastricht. All participants underwent targeted DNA sequencing for well-characterised cardiomyopathy-associated genes. The burden of rare protein altering variants (PAV) in ACM genes, DCM genes, and TTN specifically, were compared with local healthy controls sequenced on the same platform (n=1053). Case ascertainment was assessed against national hospital admission data. Results: We identified rare protein-altering variants in 23% of cases compared to 16% in controls (Δ+6.8%; p=0.021), with rare truncating variants (tv) in 6% of cases compared to &lt;1% of controls ((Δ+5%; p=0.0097). In London (n=230; median left ventricular ejection fraction (LVEF) 63%), which was representative of national myocarditis admissions, 4.8% of cases carried rare tv, particularly within ACM genes (3% cases vs 0% controls; odds ratio 8.2; p=0.001). This was predominantly driven by desmoplakin (DSP)-tv in patients with normal LVEF. In Maastricht (n=106; median LVEF 30%), rare tv in DCM genes were enriched, particularly TTN-tv found in 7% (all with LVEF&lt;50%) compared to 1% in controls (OR 3.6; p=0.0116). During a median follow-up of 1.9 years, all-cause mortality was greatest in those with a DCM variant (18% vs 4% with no variant; OR 5.0; p=0.004). Conclusion: We identified enrichment of cardiomyopathy gene variants in acute myocarditis patients, dominated by DSP-tv in those with normal LVEF and TTN-tv in those with reduced LVEF. Incorporation of genetic testing may be beneficial to identify such high-risk individuals and guide family screening in acute myocarditis patients.
Abstract 12836: Predictors of Recurrent Pericardial Effusion in Cancer Patients Requiring Pericardiocentesis
Authors: TALHA AHMED, Ayesha Safdar, Juhee Song, Jose Banchs, Peter Kim, Nicolas L Palaskas, Cezar Iliescu
Journal: Circulation (2021)

Introduction: Pericardial effusion (PE) is a common manifestation of various malignancies and tends to recur in a subset of patients requiring recurrent PC. Hypothesis: We sought to evaluate the factors determining the recurrence of PE in certain subsets of patients. Methods: All data pertaining to PC for large PE in a cancer patient population performed and enrolled over a decade 2010-2020 in a Cancer Center Pericardiocentesis Registry were analyzed. Patient characteristics were summarized using descriptive statistics (Mean (SD) for continuous variables and frequency (%) for categorical variables. Time to first recurrent PC was defined as time interval from index PC to first recurrent PC. Fine-Gray models were used to identify risk factors associated with incidence of recurrent PC while Cox regression models were used to identify risk factors associated with risk of death. Results: Data set included 418 subjects with index PC and 65 (16%) had recurrent PC while 353 (84%; 286 died without recurrent PC and 67 were alive without recurrent PC) did not have recurrent PC. Descriptive statistics for the entire group are described in table 1. Younger age, elevated creatinine, non-colon cancer, established advanced-stage cancer, presence of cardiac metastasis, and non-colon cancer (P=&lt;0.05) were associated with increased incidence of recurrence of pericardiocentesis. The risk of death was higher in patients with older age, malignant effusion by cytology, no use of anti-inflammatory agents, and primary lung cancer (p=&lt;0.05). The cumulative incidence of recurrent pericardiocentesis at 12 months was 15 % and did not differ much at 60 (16 %). Conclusions: Patients with advanced-stage cancer are more likely to present with recurrent pericardial effusion and tamponade. Pericardiocentesis appears to have a palliative role in this population with increased disease and treatment-related mortality.
Abstract 11333: Muscle Specific MicroRNA-499-5p Impairs Angiogenesis in Ischemic Hindlimb of Diabetic Micehindlimb of Diabetic Mice
Authors: Zhongjian Cheng, May Truongcao, Chunlin Wang, Carolina Gonzalez, Grace Huang, Maria Cimini, Vandana Mallaredy, Anna M Lucchese, Cindy Benedict, jessica Ibetti, Venkata Garikipati, Suresh K Verma, Walter J Koch, Raj Kishore
Journal: Circulation (2021)

Introduction: Limb ischemia is one of the most prevalent cardiovascular complications in diabetic patients. The underlying mechanisms remain incompletely understood. Previously, we have reported that microvascular endothelial cells (MVECs) play an important role in angiogenesis. Recent study demonstrated that skeletal muscle cells (SKMCs) regulate angiogenesis process via paracrine signals; level of miR-499, a muscle specific miR, was enhanced in diabetic hearts/cardiomyocytes and overexpression of miR-499 impaired MVEC function. We observed that level of miR-499-5p, but not -3p, was increased in skeletal muscle cells (SKMCs), MVECs and SKMC-derived extracellular vehicles (SKMC-EVs) in db/db mice. Hypothesis: SKMC-EVs-derived miR-499-5p impairs MVEC function in diabetes. Methods: MVECs and SKMCs, and SKMC-EVs were isolated from 8-10-week male db/+ and db/db mice. Ischemic hind limb (IHL) surgery was conducted in 8-10-week male wildtype C57BL/6J, diabetic db/db and non-diabetic db/+ mice. Results: Level of miR-499-5p was increased in SKMCs and MVECs from db/db mice. Overexpression of miR-499-5p impaired tube formation and migratory activity of MVECs. Intramuscular injection of anti-miR-499-5p lentivirus ameliorated blood perfusion and capillary density in IHL of db/db mice. Mechanistically, miR-499-5p level was increased in diabetic SKMC-EVs. Inhibition of EV formation/section by GW4869 ameliorated diabetic SKMCs-enhanced miR-499-5p level in MVECs. Local injection of diabetic SKMC-EVs impaired blood perfusion and capillary density in C57BL/6J mice. Moreover, diabetic SKMC-EVs-impaired tube formation and migratory activity of MVECs was ameliorated by silencing of miR-499-5p in the diabetic SKMCs ameliorated. Level of sex-determining region Y-box 6 (SOX6), the most attractive gene targeted by miR-499-5p, was decreased in MVECs of db/db mice. Finally, silencing of SOX6 impaired tube formation, migration and pro-angiogenic factor secretion from MVECs. Conclusions: miR-499-5p impairs angiogenic property of MVECs in diabetic mice via SKMC-EV/miR-499-5p/SOX6/proangiogenic factors cascades. miR-499-5p and SOX6 may be novel targets for prevention/therapeutics of ischemic limb injury in diabetic patients.
Abstract 13074: Impact of Adrenergic Receptor Polymorphisms on Incident Ventricular Fibrillation During Acute Myocardial Ischemia: The MAP-MI Study
Authors: Philippe Chevalier, Pascal Roy, Benedicte Ankou, Elodie Morel, Gilles MILLAT, Gina Morgan, Indrani Holder, Barry London, Wayne Minobe, Dobromir Slavov, Antoine Deliniere, Ian Carroll, Michael R Bristow
Journal: Circulation (2021)

Rationale: During acute coronary syndromes (ACS) adrenergic receptor (AR) signaling may have major effects on cardiac arrhythmias including VF. AR gene products are highly polymorphic, and minor variants exhibit potentially important pharmacologic differences compared to receptors encoded by major allele homozygotes ( mah ). Objective: We tested the general hypothesis that polymorphic variants in the ADRB1 , ADRB2 or ADRA2C genes affect incident VF during ACS. Methods and Results: We recruited 953 subjects with a proven MI and no previous history of AC. In a case-control design 477 VF patients were compared to 476 controls without VF who did not differ in baseline characteristics. DNA collection and subsequent genotyping for ADRB1 389/49, ADRB2 27/16 and ADRA2C 322-325 Ins/Del were available in 718-779 patients. Results were expressed as Odds Ratios (OR) for VF vs. No-VF subjects by comparing each mah to minor allele monotype genotypes, genotype combinations or haplotypes. The entire cohort OR (95% CI) for patients receiving (41%) vs. not receiving beta-blockade (BB) was (0.70 (0.53, 0.93), P=0.014), dictating a BB adjustment in the genotype-VF analyses. No minor allele genotype was associated with increased incident VF. Monotypes with statistically significant ORs and their mah comparators were: ADRB2 monotypes and ADRB1 or ADRB2 haplotypes were not associated with VF reduction. Two of 3 ADRB1 and 3 of 4 ADRB2 monotypes or genotype combinations associated with VF reduction encoded ARs that exhibit increased agonist-induced internalization. Conclusions: In acute MI AR variants associated with reduced incident VF are those that mediate increased adrenergic drive ( ADRA2 C Del) and beta-AR internalization. This combination would be predicted to redirect beta-AR signaling from canonical pathways to "biased" EGFR and ERK1/2 mediated cardioprotection.
Combination of Ras Modulator and Azacitidine Impacts Innate Immune Signaling Pathway in MDS-L Cell Line
Authors: Richa Rai, Foramben Patel, Jonathan Feld, Stella Melana, Shyamala C. Navada, Rosalie Odchimar-Reissig, Erin P. Demakos, E. Premkumar Reddy, Lewis R. Silverman
Journal: Blood (2021)
LncRNA PKMYT1AR promotes cancer stem cell maintenance in non-small cell lung cancer via activating Wnt signaling pathway
Authors: Yaomei He, Xiulin Jiang, Lincan Duan, Qiuxia Xiong, Yixiao Yuan, Peishen Liu, Liping Jiang, Qiushuo Shen, Song Zhao, Cuiping Yang, Yongbin Chen
Journal: Molecular Cancer (2021)

Non-small cell lung cancer (NSCLC) is the most common type of human lung cancers, which has diverse pathological features. Although many signaling pathways and therapeutic targets have been defined to play important roles in NSCLC, limiting efficacies have been achieved.Bioinformatics methods were used to identify differential long non-coding RNA expression in NSCLC. Real-time RT-PCR experiments were used to examine the expression pattern of lncRNA PKMYT1AR, miR-485-5p. Both in vitro and in vivo functional assays were performed to investigate the functional role of PKMYT1AR/miR-485-5p/PKMYT1 axis on regulating cell proliferation, migration and tumor growth. Dual luciferase reporter assay, fluorescent in situ hybridization (FISH), immunoblot, co-immunoprecipitation experiments were used to verify the molecular mechanism.Here, we identify a human-specific long non-coding RNA (lncRNA, ENST00000595422), termed PKMYT1AR (PKMYT1 associated lncRNA), that is induced in NSCLC by Yin Yang 1 (YY1) factor, especially in cancerous cell lines (H358, H1975, H1299, H1650, A549 and SPC-A1) compared to that in normal human bronchial epithelium cell line (BEAS-2B). We show that PKMYT1AR high expression correlates with worse clinical outcome, and knockdown of PKMYT1AR inhibits tumor cell proliferation, migration and xenograft tumor formation abilities. Bioinformatic analysis and a luciferase assay demonstrate that PKMYT1AR directly interacts with miR-485-5p to attenuate the inhibitory role on its downstream oncogenic factor PKMYT1 (the protein kinase, membrane-associated tyrosine/threonine 1) in NSCLC. Furthermore, we uncover that miR-485-5p is downregulated in both cancerous cell lines and peripheral blood serum isolated from NSCLC patients compared to reciprocal control groups. Consistently, forced expression of miR-485-5p inhibits the proliferation and migration abilities of tumor cells. Moreover, we provide evidence showing that PKMYT1AR targeting antisense oligonucleotide (ASO) dramatically inhibit tumor growth in vivo. Mechanistic study shows that PKMYT1AR/ miR-485-5p /PKMYT1 axis promotes cancer stem cells (CSCs) maintenance in NSCLC via inhibiting β-TrCP1 mediated ubiquitin degradation of β-catenin proteins, which in turn causes enhanced tumorigenesis.Our findings reveal the critical role of PKMYT1AR/miR-485-5p /PKMYT1 axis during NSCLC progression, which could be used as novel therapeutic targets in the future.
Targeting Control of Cell Cycle Enhances the Activity of Conventional Chemotherapy in Chemotherapy-Resistant Acute Myeloid Leukemia
Authors: Victoria Y Ling, Sebastien Jacquelin, Jasmin Straube, Rohit Haldar, Yashaswini Janardhanan, Leanne T Cooper, Claudia Bruedigam, Emily Cooper, William Godfrey, Siok-Keen Tey, Lars Bullinger, Marco J Herold, Jonathan Baell, Megan Bywater, Steven W Lane
Journal: Blood (2021)
CSIG-12. THE ROLE OF HYPOXIA SIGNALING AS AN ONCOGENIC EFFECTOR IN ACVR1-MUTANT DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Elinn Johansson, Alexander Pietras
Journal: Neuro-Oncology (2021)

Abstract Diffuse intrinsic pontine gliomas (DIPG) are aggressive and highly treatment resistant pediatric tumors of the brainstem. The majority of the DIPG tumors (60-80%) carry somatic histone H3 mutations resulting in a global reduction of H3K27 trimethylation and subsequently a unique epigenetic landscape. Moreover, activating mutations in ACVR1 – the gene encoding for the BMP receptor ALK2 – were recently described in a large subset of DIPGs, suggestive of an oncogenic role of signaling from this receptor. Potential mechanisms of ACVR1-driven oncogenesis, however, remain poorly understood. Similar and overlapping ACVR1 mutations have been described in the rare disorder Fibrodysplasia Ossificans Progressiva (FOP), and evidence from FOP models have suggested several links between hypoxia signaling, BMP signaling, and FOP pathogenesis. We used cultured DIPG cells and adult glioma cells respectively to test the activity of the hypoxia pathway using a hypoxia-responsive elements (HRE)-luciferase reporter assay. Intriguingly, DIPG but not glioma cells overexpressing a mutant ACVR1 construct significantly elevated hypoxia signaling at hypoxia. BMP ligand stimulation resulted in a dose-dependent increase of hypoxia signaling in DIPG cells. By querying clinical gene expression data, we found elevated hypoxia signature scores in pediatric gliomas with mutant ACVR1 as compared to those with wildtype ACVR1. Finally, ACVR1 mutations frequently co-occur with Histone 3.3 and 3.1 mutations, and the hypoxia signature score was significantly higher than baseline only in tumors also harboring these Histone 3.3 or 3.1 mutations. Together, these data support the notion that hypoxia signaling is elevated downstream of ACVR1 specifically in pediatric gliomas and prompts for evaluation of hypoxia signaling as potential therapeutical target in DIPG.