tbuckley/cabot-search huggingface dataset:
Abstract 10346: Peripheral Vascular Disease Hospitalizations with Cardiovascular Disease Risk and Major Adverse Cardiac and Cerebrovascular Events Occur at Increasingly Younger Age Across Two Nationwide Cohorts Selected 10-Years Apart
Authors: Rupak Desai, Srija Shanker, Ashish Nepal, Tanvi Singla, Aamer Mohammad, Deepu Joseph, Bushra Fatima, Mir Zeeshan Ali Khan, Ankit Vyas
Journal: Circulation (2021)

Introduction: There have been increasing hospitalizations among young adults for peripheral vascular disease (PVD) in the last decade. We compared the mean age of young PVD admissions with cardiovascular comorbidities and major adverse cardiac and cerebrovascular events (MACCE) across two national cohorts 10-years apart. Methods: Two nationwide cohorts from 2007 and 2017 were analyzed for mean age at presentation with CVD risk factors and MACCE in young (18-44 years) PVD hospitalizations. Age at admission was reported as Mean± SD and compared between two groups using student’s t-test. Results: A total of 37,099 admissions in 2007 and 46,760 admissions in 2017 were identified for PVD among young adults. Total admissions increased from 0.4% to 0.5%.The 2017 cohort showed that non-elective PVD admissions occurred at significantly younger age (mean 35 vs 38 years) compared to 2007 cohort. Patients with PVD had comorbid risk factors including hypertension, diabetes mellitus, smoking, obesity, and congestive heart failure (CHF) with a mean age of 39±5 years at presentation in 2007 which decreased to 38±6 years for hypertension and diabetes, 36±6 years for smoking and 37±6 years for CHF and obesity (p&lt;0.001) in 2017. Mean age for MACCE in PVD was 39±5 years in 2007 cohort which significantly reduced to 36±7 years in 2017 (p&lt;0.001) (Table 1). Acute myocardial infarction, cardiogenic shock and PCI procedures were recorded at a younger age in 2017 PVD cohort vs. 2007 PVD cohort. Similarly, the 2017 PVD cohort included relatively younger patients experiencing ventricular tachyarrhythmias and stroke. Conclusions: This study from two young cohorts selected 10-years apart shows increasing trends in PVD hospitalizations occurring at a significantly younger age with associated cardiovascular comorbidities and MACCE in recent years. The link between young age and complicated/severe PVD admissions with frequent comorbidities should be further investigated.
Abstract 12348: Urine Albumin to Creatinine Ratio on Admission Predicts Early Rehospitalization in Patients With Acute Decompensated Heart Failure
Authors: Yuki Matsumoto, Masanori Asakura, Kyung-Duk Min, Isamu Sunayama, Kouhei Azuma, Koichi Nishimura, Yoshiro Naito, Akiko Goda, Masaharu Ishihara
Journal: Circulation (2021)

Introduction: Detecting high-risk patients for early rehospitalization is crucial in heart failure patient care. An association of albuminuria with cardiovascular events is well known. However, its predictive impact on rehospitalization for acute decompensated heart failure (ADHF) remains unknown. Hypothesis: The aim of this study was to clarify the utility of urine albumin to creatinine ratio (UACR) in ADHF patients. Methods: Two hundred and sixty consecutive patients who were admitted due to ADHF between December 2017 and April 2019 were enrolled. Further investigated were 140 patients from whom UACR was measured with spot urine samples on admission. The association between UACR and rehospitalization due to HF during 1 year after discharge was evaluated. Results: The mean age of 140 participants was 77.6 years and 55% were men. Only 18% (n=25) of patients presented with normoalbuminuria (UACR&amp;lt:30mg/g·creatinine), whereas 59% (n=83) and 23% (n=32) showed microalbuminuria (UACR30-300mg/g·creatinine) and macroalbuminuria (UACR&amp;gt:300 mg/g·creatinine), respectively. The level of UACR on admission was correlated with the risk of subsequent rehospitalization due to HF (p=0.017). The Receiver operating characteristic analysis indicated that the best cut-off values for the UACR and B-type natriuretic peptide (BNP) levels to predict ADHF rehospitalization were 50 mg/g·creatinine and 824 pg/ml, respectively. When the patients were divided into four groups using both cut-off values, the individual predictive impacts of UACR and BNP on rehospitalization were comparable. In the patients with both elevated UACR and BNP levels, the rehospitalization rate due to HF was higher than those with elevated BNP levels alone (p=0.041). Conclusions: The UACR is useful, when combined with BNP levels, to predict the risk for HF rehospitalization.
Abstract 12334: Concerns About the Use of Digoxin in Acute Coronary Syndromes
Authors: Edina Cenko, Maria Bergami, Jinsung Yoon, Mihaela van der Schaar, Sasko Kedev, Chris P Gale, Zorana Vasiljevic, Davor Milicic, Marija Zdravkovic, Gordana Krljanac, Lina Badimon, Olivia Manfrini, Raffaele Bugiardini
Journal: Circulation (2021)

Introduction: The use of digitalis has been plagued by controversy since its initial use. Previous observations have shown that digoxin can be safely used in patients with chronic heart failure (HF), but concern remains about the effects of digoxin on mortality in patients with incident HF in the acute setting, especially in those with myocardial infarction. Hypothesis: We aimed to determine the relationship between digoxin use and outcomes in hospitalized patients with acute coronary syndromes (ACS) complicated by HF accounting for sex difference and prior heart diseases. Methods: We analyzed information on 88,774 patients presenting with acute HF (Killip class ≥2) in the International Survey of Acute Coronary Syndromes (ISACS)-Archives (NCT04008173) registry, 4,722 (18.7%) who received digoxin on hospital admission. Patients with pre-existing nonischemic congestive cardiomyopathy and without HF were excluded, leaving a final study population of 25,187 patients. The main outcome measure was all-cause 30-day mortality. Estimates were evaluated by inverse probability of treatment weighting models. Results: Women who received digoxin had a higher rate of death than women who did not receive it (33.8% vs. 29.2 %; relative risk [RR] ratio:1.24;95 % confidence interval [CI]: 1.12-1.37). Similar odds for mortality with digoxin were observed in men (28.5 % vs. 24.9 %; RR ratio 1.20; 95% CI:1.10-1.32). Comparable results were obtained in patients with no prior coronary heart disease (RR ratios:1.26; 95 % CI: 1.10 to 1.45 in women and RR:1.21; 95 % CI: 1.06 to 1.39 in men) and those in sinus rhythm at admission (RR ratios:1.34; 95% CI 1.15 to 1.54 in women and 1.26; 95% CI 1.10 to 1.45 in men). Conclusions: Digoxin therapy is associated with an increased risk of early death among women and men with ACS complicated by HF. This finding highlights the need for re-examination of digoxin use in the clinical setting of ACS.
Abstract 12802: Intron-Mediated Enhancement of <i>Titin</i> ( <i>TTN</i> ) Regulates Sarcomere Formation and Function
Authors: Yuri Kim, Seongwon Kim, Meraj Neyazi, Manuel Schmid, Justin Letendre, Jourdan Ewoldt, Feng Xiao, Paige Cloonan, Arun Sharma, Lauren Wasson, Christopher Toepfer, Angela Tai, Joshua Gorham, Gavin Y Oudit, William T Pu, Diane Dickel, Christopher S Chen, Christine E Seidman, Jonathan Seidman
Journal: Circulation (2021)

Background: Heterozygous truncating variants in the sarcomere protein titin (TTN) are the most common genetic cause of heart failure, a major cause of morbidity and mortality. This causality indicates that even two-fold changes in the amount of TTN can profoundly disturb cardiac physiology. Although a critical role of TTN in sarcomere formation and cardiomyocyte contractility is well established, the mechanisms regulating transcription of the TTN gene remain poorly understood. Methods: We performed bioinformatics analysis to identify a putative transcriptional enhancer of TTN . Next, we created biallelic deletion of the enhancer in human induced pluripotent stem cell derived cardiomyocytes and performed enhancer reporter assays both in vitro and in vivo to demonstrate necessity and sufficiency of the enhancer in TTN gene expression, respectively. Furthermore, we performed massive parallel reporter assay to define critical transcriptional factors of the TTN enhancer activity and analyzed whole genome sequencing (WGS) data of human patients with unexplained dilated cardiomyopathy (DCM). Results: We identified an intron mediated enhancer that promotes cardiac-specific TTN expression. Global deletion of this element downregulated TTN expression in cardiomyocytes and impaired sarcomere development, while transgenic expression promoted cardiac expression in mice. Using mutational scanning we defined key transcription factor binding sites, including NKX2-5 and MEF2 motifs that promote TTN expression in cardiomyocytes. Consistent with these functions, analyses of WGS data in 69 patients with unexplained DCM revealed one rare variant that disrupted the conserved MEF2 transcriptional factor binding motif. Conclusions: Discovery of a TTN enhancer advances our understanding of cardiomyocyte development, provides an opportunity to modulate TTN transcriptional activity, and ultimately develop therapeutic strategies to treat dilated cardiomyopathy caused by TTN haploinsufficiency.
Abstract 9706: Sex Differences in Symptoms During Arrhythmias
Authors: Andrea M Russo, Marek J Dziubinski, Natan Napiorkowski, Olga Witkowska, Agnieszka Grotek, Magdalena E Slusarczyk, Linda Johnson
Journal: Circulation (2021)

Introduction: Prior studies have reported sex differences in symptoms and quality of life in patients (pts) with atrial fibrillation (AF). It is currently unclear if this is also true for other arrhythmias or if symptoms occurring at the time of arrhythmia recordings differ by sex. Hypothesis: We hypothesized that women may be more symptomatic than men during atrial and ventricular arrhythmias and that differences may be associated with differences in heart rate (HR). Methods: We examined 27,203 pts (58% women) with up to 30-day ECGs recorded using the PocketECG (MediLynx), which transmits a 3-lead ambulatory ECG and uses an algorithm based on rhythm and morphology. VT and SVT were defined as 3 or more beats, and AV block included 2nd- or 3rd-degree block. A sustained arrhythmia was ≥30s. The rhythm occurring 30 s prior to symptoms was analyzed. Chi2 tests were used to compare women to men. Results: Men were older than women (68.9 ± 13.9 vs 67.7 ±15.6, 95% CI of the difference: [-1.55; -0.84]). Mean HR in SR was faster in women than in men (73.1 ± 10.3 vs. 70.2 ± 10.3 bpm, [2.64; 3.16]). Women were more likely to have SVT (76 vs. 74%) and less likely to have AF (15% vs. 21%), VT (23% vs. 41%), PVCs (45% vs. 61%), PACs (55% vs. 57%) or AV block (21% vs. 28%). Women were more likely than men to report symptoms (66.4% vs. 55.6%, p&lt;0.001), including greater frequency of palpitations, chest discomfort, and shortness of breath (p&lt;0.001 for all). (Figure 1) Women were more likely to report symptoms during PACs and SVT while men were more likely to report symptoms during AF (p &lt;0.001 for all). Mean HR in AF is faster in women (106.5 ± 26.6 vs. 98.7 ± 27.4, 95% CI: [6.29 ; 9.36]). (Figure 2) Conclusions: Symptoms experienced during arrhythmias differ by sex. Reasons for these differences are currently unclear but could be related to ventricular function, underlying heart disease or medications, and are not clearly related to HR. Further study is needed to help identify reasons for differences in symptoms.
QOLP-25. PERFORMANCE STATUS OF PEDIATRIC PATIENTS WITH CENTRAL NERVOUS SYSTEM TUMORS TREATED IN A TERTIARY CENTER IN MEXICO, A SINGLE-CENTER EXPERIENCE
Authors: Claudia Madrigal-Avila, Rafael Ruvalcaba-Sanchez, Alfonso Perez-Bañuelos, Gabriela Escamilla-Asiain, Andrea Ellis, Lourdes Vega-Vega
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Central nervous system (CNS) tumors are the most common solid neoplasms in the pediatric age. Despite this, there are no reports of results focused on the performance status of pediatric patients who are treated in a multidisciplinary setting. OBJECTIVE Describe the Performance Status of CNS pediatric patients after being treated with a multidisciplinary approach in a tertiary center. METHODS We review the chart of the pediatric patients at the Teleton Children Oncology Hospital from December 2014 to December 2019. The performance status was evaluated either using ECOG, Karnofsky, or Lansky scores. The multidisciplinary approach at our hospital includes: A Well-Equipped Diagnostic Center, integrated by a CAP-accredited laboratory, a Molecular Biology Unit, and the Imaging Unit, including a high-quality 2 tesla MRI. The surgical equipment comprises a surgical microscope, bipolar coagulation equipment, microsurgical instruments, and craniotomy equipment. For deep biopsies or functional surgery, we use Frame-Based Stereotactic Systems (FBSS) and neuronavigation systems. We provide first-line chemotherapy protocols and have a radiotherapy unit that can start treatment within a week. We have an Intensive Care Unit for oncologic patients with a 93% of overall survival. We provide ludic therapy and cognitive behavioral therapy, as well as emotional support. The Physical Rehabilitation Clinic uses the Bobath concept, proprioceptive and neuromuscular techniques as well as follow-up visits according to needs. RESULTS Of the 56 patients treated, 35 were evaluated with ECOG/Lansky performance status scale during the last follow up visit, resulting in 74.2% with a fully active performance, able to carry on all pre-disease activities without restriction. CONCLUSION A multidisciplinary approach is essential in the management of pediatric patients with CNS tumors. Efforts should be aimed at reducing post-surgical morbidity and early rehabilitation to reintegrate patients into society in the long term as we described many of them have an excellent performance status.
Pif1 Helicases and the Evidence for a Prokaryotic Origin of <i>Helitrons</i>
Authors: Pedro Heringer, Gustavo C S Kuhn
Journal: Molecular Biology and Evolution (2021)

Helitrons are the only group of rolling-circle transposons that encode a transposase with a helicase domain (Hel), which belongs to the Pif1 family. Because Pif1 helicases are important components of eukaryotic genomes, it has been suggested that Hel domains probably originated after a host eukaryotic Pif1 gene was captured by a Helitron ancestor. However, the few analyses exploring the evolution of Helitron transposases (RepHel) have focused on its Rep domain, which is also present in other mobile genetic elements. Here, we used phylogenetic and nonmetric multidimensional scaling analyses to investigate the relationship between Hel domains and Pif1-like helicases from a variety of organisms. Our results reveal that Hel domains are only distantly related to genomic helicases from eukaryotes and prokaryotes, and thus are unlikely to have originated from a captured Pif1 gene. Based on this evidence, and on recent studies indicating that Rep domains are more closely related to rolling-circle plasmids and phages, we suggest that Helitrons are descendants of a RepHel-encoding prokaryotic plasmid element that invaded eukaryotic genomes before the radiation of its major groups. We discuss how a Pif1-like helicase domain might have favored the transposition of Helitrons in eukaryotes beyond simply unwinding DNA intermediates. Finally, we demonstrate that some examples in the literature describing genomic helicases from eukaryotes actually consist of Hel domains from Helitrons, a finding that underscores how transposons can hamper the analysis of eukaryotic genes. This investigation also revealed that two groups of land plants appear to have lost genomic Pif1 helicases independently.
Minimal Residual Disease (MRD) Data in Hematologic Malignancy Drug Applications and Prescribing Information: FDA Analysis
Authors: Maryam Sarraf Yazdy, Andrea C. Baines, Theresa Carioti, Rachel Ershler, Emily Y. Jen, Bindu Kanapuru, Yvette L. Kasamon, Ashley Lane, Nicholas Richardson, Marc Theoret, Nicole J. Gormley
Journal: Blood (2021)
Risk of Major Bleeding with Ibrutinib in Patients with Thrombocytopenia - a Retrospective Single-Center Canadian Study
Authors: Mina Dehghani, Taylor Dear, Anthony Quint, Martha L Louzada, Selay Lam, Chai Wye Phua, Joy Mangel, Kang Howson-Jan, Michael J. Kovacs, Alejandro lazo-Langer, Anargyros Xenocostas, Cyrus C. Hsia
Journal: Blood (2021)
Abstract P429: Aldehyde Dehydrogenase 2 Regulates Angiogenesis Of Coronary Microvascular Endothelial Cells Via A Novel Signaling Pathway
Authors: Bipradas Roy, Guodong Pan, Suresh Palaniyandi
Journal: Circulation Research (2021)

Coronary microvascular endothelial cell (CMECs) damage is implicated in diabetes-mediated heart failure with preserved ejection fraction (HFpEF). 4-hydroxy-2-nonenal (4HNE), a reactive aldehyde that is increased in diabetic heart, decreases angiogenesis in cultured mouse CMECs by decreasing the mRNA and protein levels of vascular endothelial growth factor receptor (VEGFR)2. Nuclear factor-kappa B (NF-kB), a transcription factor, was shown to transcribe VEGFR2. Thus, we presume 4HNE modulates NF-kB-mediated VEGFR2 transcription and regulates angiogenesis in CMECs. Aldehyde dehydrogenase (ALDH) 2, a mitochondrial enzyme that detoxifies 4HNE and confers cryoprotection. However, ALDH2 activity was reduced in the diabetic hearts which results in the augmentation of 4HNE-induced cardiotoxicity. Thus, we hypothesize that ALDH2 in CMECs reduces 4HNE-mediated cell signaling aberrations, and thereby, preserves coronary angiogenesis. We treated the cultured mouse CMECs with disulfiram (DSF) (2.5 μM), an ALDH2 inhibitor, alda1 (10 μM), an ALDH2 activator and prostratin (1 μM), an NF-κB activator prior to challenging the CMECs with 4HNE (75 μM). Our tube-formation angiogenesis assay revealed that pretreatment with DSF exacerbated a 4HNE-induced decrease in CMECs angiogenesis (P&lt;0.0005 vs con and P&lt;0.05 vs both 4HNE &amp; DSF alone) while pretreatments with alda1 and prostratin attenuated a 4HNE-induced decrease in CMEC angiogenesis (P&lt;0.05 vs 4HNE alone). DSF pretreatment exacerbated 4HNE mediated decrease in ALDH2 (P&lt;0.005 vs con), phospho-IKBα (P&lt;0.0005 vs con and P&lt;0.05 vs both 4HNE and DSF alone), NF-κB levels, and nuclear translocation (P&lt;0.0005 vs con and P&lt;0.05 vs both 4HNE &amp; DSF alone) and VEGFR2 (P&lt;0.0005 vs con and P&lt;0.05 vs both 4HNE and DSF alone) levels in cultured CMECs. Pretreatment with both prostratin and alda1 increased ALDH2 (P&lt;0.0005 vs con), VEGFR2 (P&lt;0.05 vs con) and NF-κB (P&lt;0.005 vs con) levels in CMECs. The cardiac tissue samples of db/db mice when they manifest HFpEF showed increased 4HNE adducts, decreased NF-kB and VEGFR2 levels in CD31+ CMECs besides exhibiting low CMEC density. In conclusion, ALDH2 attenuates 4HNE-mediated decrease in coronary angiogenesis by decreasing VEGFR2 levels via low NF-κB mediated transcription.
BIOM-14. METABOLIC BIOMARKERS OF TERT-TARGETED THERAPY FOR HUMAN GLIOBLASTOMA DETECTED BY MAGNETIC RESONANCE SPECTROSCOPY
Authors: Noriaki Minami, Donghyun Hong, Nicholas Stevers, Georgios Batsios, Anne Marie Gillespie, Russell Pieper, Joseph Costello, Pavithra Viswanath, Sabrina Ronen
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND TERT promoter mutations that result in TERT expression are observed in over 80% of GBM. Moreover, the upstream transcription factor GABPB1 was recently identified as an ideal therapeutic target for tumors with TERT promoter mutations. In that context, non-invasive reliable biomarkers that can help detect TERT expression are needed. The aim of this research was to assess the value of MRS-detectable metabolic changes as biomarkers of TERT expression and TERT-targeted therapy in GBM. METHODS Genetically engineered GBM cells (NHARas/TERT) treated with TERT siRNA were compared to siCtrl-treated cells, and stable TERT and GABPB1 knock down GBM cells (U251, GBM1) were compared to shCtrl. 1H-MRS and 13C-MRS metabolic data was acquired from cell extracts using a Bruker 500MHz scanner. Hyperpolarized MRS studies of live cells used a HyperSense DNP polarizer and data was acquired using a Varian 500MHz scanner. Spectra were analyzed using Mnova and Matlab software. Multivariate data analysis was performed using SIMCA software. RESULTS Unbiased PCA analysis of 1H-MRS metabolic data showed separation of TERT or GABPB1 knock down and control cells. VIP predictive scores revealed that lactate and GSH were the top altered metabolites with a significant drop observed in both metabolites in every model following TERT silencing. Consistent with the reduction in GSH, spectrophotometric assays showed a significant drop in NADPH and NADH. 2-13C glucose flux analysis revealed that both glycolysis and PPP-related metabolites were reduced in TERT knock down cells. Hyperpolarized [1-13C]-pyruvate flux to lactate was also reduced, confirming that the glycolytic pathway was altered following TERT knock down. CONCLUSION 1H MRS-detectable lactate and GSH, combined with hyperpolarized 13C MRS-detectable metabolic fluxes, could serve as metabolic biomarkers of TERT-targeted therapy for human GBM with TERT promoter mutations. These biomarkers could be translated to the clinical, improve the monitoring of GBM patients and advance precision medicine.
Abstract 9782: Disruption of Notch1 and Gata5 in Mice Results in Clinically Relevant Aortic Valve Disease
Authors: Jun Yasuhara, Yukie Ueyama, Sara Adamczak, Emily Cameron, Vidu Garg
Journal: Circulation (2021)

Congenital malformations of the aortic valve are the most common type of congenital heart defect, but the underlying mechanisms of congenital aortic valve disease (AVD) remain poorly understood. NOTCH1 mutations are associated with AVD, and we previously reported that Notch1;Nos3 mutant mice display AVD. However, this mouse model has limitations since ~65% mutant mice suffer neonatal lethality. GATA5 is also implicated in human AVD, and Gata5 -/- mice display bicuspid aortic valve, with an associated reduction in Notch signaling. We hypothesized that interaction of Notch1 and Gata5 was critical for aortic valve morphogenesis, and generated novel murine models by intercrossing Notch1 and Gata5 heterozygote mice. We characterized the cardiac phenotype in mice that are heterozygous for Notch1 and Gata5 ( Notch1 +/- ;Gata5 +/- ) and also those that are heterozygous for Notch1 and null for Gata5 ( Notch1 +/- ;Gata5 -/- ). While normal Mendelian ratios were present at 6 weeks and 4 months of age, echocardiography demonstrated an increased incidence of aortic stenosis/regurgitation in Notch1 +/- ;Gata5 +/- mice (52%: 11/21) and Notch1 +/- ;Gata5 -/- mice (86%: 6/7). Histological examination revealed thickened, dysmorphic aortic valve cusps and left ventricular hypertrophy in Notch1 +/- ;Gata5 +/- and Notch1 +/- ;Gata5 -/- mice compared to wild-type, Notch1 +/- , Gata5 +/- , and Gata5 -/- mice. In addition, 1 year old Notch1 +/- ;Gata5 +/- mice displayed 100% incidence of aortic valve stenosis/regurgitation with thickened valve cusps. At postnatal day 10, the aortic valve cusps of Notch1 +/- ;Gata5 +/- and Notch1 +/- ;Gata5 -/- mice were significantly larger than controls consistent with a neonatal phenotype. Interestingly, Notch1 +/- ;Gata5 -/- mice displayed significantly thickened aortic valve cusps compared to Notch1 +/- ;Gata5 +/- mice. Further examination at embryonic day 18.5 demonstrated thickened, malformed aortic valves in Notch1;Gata5 mutant embryos. In conclusion, our findings demonstrate a novel genetic interaction of Notch1 and Gata5 necessary for the proper remodeling of aortic valves. Our new mouse models display highly penetrant congenital AVD without lethality, allowing for studying disease progression to identify novel therapeutic targets.
Abstract 12567: Glucose-6-Phosphate Dehydrogenase Deficiency in Pulmonary Arterial Hypertension
Authors: Cody A Eccles, Sergey Kurdyukov, Ankit A Desai, Manuel Gonzalez-Garay, Jason X Yuan, Joe G Garcia, Olga Rafikova, Ruslan Rafikov
Journal: Circulation (2018)

Introduction: Pulmonary Arterial Hypertension (PAH) is a fatal disorder with limited treatment options and reduced life expectancy after diagnosis. Complex genetic backgrounds in PAH complicates id...