tbuckley/cabot-search huggingface dataset:
Abstract 9603: Polycomb Group Protein Cbx7 Represses Cardiomyocyte Proliferation via Modulation of the Tardbp/Rbm38 Axis
Authors: Kyuwon Cho, Andrade Mark, SeongHo Bae, Sangsung Kim, Jin Eyun Kim, Er Yearn Jang, Ahsan Husain, R L Sutliff, John W Calvert, Changwon Park, Young-sup Yoon
Journal: Circulation (2021)

Introduction: Cardiomyocyte (CM) proliferation notably decreases during the perinatal period. Regulatory mechanisms for this loss of proliferative capacity are poorly understood. CBX7, a polycomb group (PcG) protein, regulates the cell cycle but its role in CM proliferation is unknown. Methods: We profiled CBX7 expression in the mouse hearts via qRT-PCR, western blotting, and immunohistochemistry. We overexpressed CBX7 in neonatal mouse CMs via adenoviral transduction. We knocked down CBX7 by using constitutive and inducible conditional knockout mice (Myh6-cre;Cbx7 fl/+ and Myh6-MCM;Cbx7 fl/fl , respectively). We measured CM proliferation by immunostaining of proliferation markers such as Ki67, phospho-histone 3, and cyclin B1. We examined the mechanism of CBX7-mediated repression of CM proliferation via co-immunoprecipitation, mass spectrometry, and other molecular techniques. Results: The mRNA expression of Cbx7 was increased at the perinatal stage and sustained in the postnatal heart (fold increase of adult vs. prenatal: 32.1 ± 3.3, P &lt; 0.01). Overexpression of CBX7 in neonatal mouse CMs reduced CM proliferation (% of Ki67 + CMs: Ad-Mock, 22.3 ± 1.7 vs. Ad-CBX7, 7.7 ± 0.7, P &lt; 0.001). The haplodeficiency of CBX7 (Tnnt2-Cre;Cbx7 fl/+ ) enhanced proliferation of neonatal CMs in vivo (% of Ki67 + CMs: wild-type, 7.9 ± 0.9% vs. mutants, 24.7 ± 1.2%, P &lt; 0.01), leading to increased myocardial wall thickness, cardiomegaly and neonatal lethality. Genetic deletion of CBX7 in CMs (Myh6-MCM;Cbx7 fl/fl ) at P1 resulted in increased CM proliferation (% of Ki67 + CMs: vehicle, 9.5 ± 1.4% vs. tamoxifen, 18.3 ± 1.8%, P &lt; 0.01), leading to cardiomegaly at 3 months. Mechanistically, CBX7 interacted with TAR DNA-binding protein 43 (TARDBP) and positively regulated its downstream target, RNA Binding Motif Protein 38 (RBM38). Rbm38 was perinatally upregulated in the mouse hearts and overexpression of RBM38 reduced proliferation of neonatal CMs. Conclusions: CBX7 expression is perinatally increased in the mouse hearts and inhibits proliferation of CMs by controlling TARDBP/Rbm38 pathway. This is the first study to demonstrate the role of CBX7 in regulation of CM proliferation and CBX7 could be an important target for cardiac regeneration.
TAMI-53. CYSTEINE IS A LIMITING FACTOR FOR GLIOMA PROLIFERATION AND SURVIVAL
Authors: Victor Ruiz Rodado, Tyrone Dowdy, Jinkyu Jung, Ana Dios-Esponera, Adrian Lita, Tamalee Kramp, Kevin Camphausen, Mark Gilbert, Mioara Larion
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Little is known about the mechanisms that render cancer cells dependent on certain nutrients from the microenvironment. Cysteine is a non-essential amino acid, since it can be synthetized from methionine through the transsulfuration pathway; moreover, cysteine is also uptake from the diet as cystine. We have investigated the metabolism of cysteine in glioma cell lines, and how cysteine/cystine-deprivation alters their antioxidant response in addition to the effect of this nutrient restriction to viability and proliferation in vitro and in vivo. METHODS Cysteine metabolism was investigated through LCMS-based 13C-tracing experiments and the expression levels of key enzymes in the transsulfuration pathway were also explored. Finally, a mouse model of IDH1 mutant glioma was subjected to a cysteine/cystine-free diet and tumor metabolism was analyzed by LCMS. RESULTS Herein, we report the dependence of glioma cells on exogenous cysteine/cystine, despite this amino acid being nonessential. Using several 13C-tracers and analysis of cystathionine synthase and cystathioninase levels, we revealed that glioma cells were not able to upregulate the transulfuration pathway cysteine, which allows methionine to be converted to cysteine in cysteine/cystine deprived conditions. We demonstrated that exogenous cysteine/cystine are crucial for glutathione synthesis, and impact growth and viability. Therefore, we explored the nutritional deprivation in a mouse model of glioma. Animals subjected to a cysteine/cystine-free diet survived longer, with concomitant reductions in glutathione and cysteine plasma levels. At the endpoint higher levels of oxidative stress were detected despite the systemic recovery of cysteine-related metabolites in the plasma. CONCLUSION The results presented herein reveal an alternative therapeutic approach combining cysteine/cysteine-deprivation diets and treatments involving ROS production by limiting the ability of glioma cells to quench oxidative stress through dietary interventions. Our study highlights a time window where cysteine deprivation can be exploited for additional therapeutic strategies.
Role of the Gut in the Temporal Changes of β-Cell Function After Gastric Bypass in Individuals With and Without Diabetes Remission
Authors: Malini Prasad, Victoria Mark, Chanel Ligon, Roxanne Dutia, Nandini Nair, Ankit Shah, Blandine Laferrère
Journal: Diabetes Care (2021)

OBJECTIVE The role of the gut in diabetes remission after Roux-en-Y gastric bypass (RYGB) is incompletely understood. We assessed the temporal change in insulin secretory capacity after RYGB, using oral and intravenous (IV) glucose, in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS Longitudinal, prospective measures of β-cell function were assessed after oral glucose intake and graded glucose infusion in individuals with severe obesity and diabetes studied at 0, 3 (n = 29), 12 (n = 24), and 24 (n = 20) months after RYGB. Data were collected between 2015 and 2019 in an academic clinical research center. RESULTS The decreases in body weight, fat mass, waist circumference, and insulin resistance after surgery (all P &amp;lt; 0.001 at 12 and 24 months) did not differ according to diabetes remission status. In contrast, both the magnitude and temporal changes in β-cell glucose sensitivity after oral glucose intake differed by remission status (P = 0.04): greater (6.5-fold; P &amp;lt; 0.01) and sustained in those in full remission, moderate and not sustained past 12 months in those with partial remission (3.3-fold; P &amp;lt; 0.001), and minimal in those not experiencing remission (2.7-fold; P = not significant). The improvement in β-cell function after IV glucose administration was not apparent until 12 months, significant only in those in full remission, and only ∼33% of that observed after oral glucose intake. Preintervention β-cell function and its change after surgery predicted remission; weight loss and insulin sensitivity did not. CONCLUSIONS Our data show the time course of changes in β-cell function after RYGB. The improvement in β-cell function after RYGB, but not changes in weight loss or insulin sensitivity, drives diabetes remission.
A Comprehensive Cancer Center Experience with Hyper-CVAD Plus Ponatinib As Frontline Therapy for Adult Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
Authors: Tamer Othman, Benjamin Moskoff, Matthew Tenold, Tali Azenkot, Margaret Krackeler, Samantha C Fisch, Laura A. Potter, Paul R. Kaesberg, Jeanna Welborn, Ted Wun, Naseem Esteghamat, Rasmus T. Hoeg, Aaron S. Rosenberg, Mehrdad Abedi, Joseph Tuscano, Brian A. Jonas
Journal: Blood (2021)
Abstract 14378: Implantable Cardioverter-Defibrillator Use in Nonischemic Cardiomyopathy - A Bayesian Analysis
Authors: Joonseok Kim, Vibhu Parcha, Peng Li, Vijawant Brar, Jingnan Han, Garima Arora, Pankaj Arora
Journal: Circulation (2021)

Background: Prophylactic implantable Cardioverter-Defibrillator (ICD) therapy has been a cornerstone of sudden cardiac death prevention in patients with left ventricular systolic failure. While the benefit of ICD in ischemic cardiomyopathy has been well established, its benefit in nonischemic cardiomyopathy (NICM) is debated. Methods: We conducted a post-hoc Bayesian analysis of the DANISH randomized clinical trial (N=1,116) to estimate the probability of clinical benefit of ICD compared with medical therapy (control) to reduce all-cause mortality among participants with NICM and who were not on cardiac resynchronization therapy (N=471). Bayesian modeling was used to ascertain the posterior probability of a reduction in all-cause mortality of ICD compared with medical therapy using 1) a noninformative prior (Beta[1,1] distribution), and 2) using an informative prior (derived from the random-effect meta-analysis comparing ICD versus control in the NICM cohorts of the SCD-HeFT, CAT, and DEFINITE trials, N=1,354). Results: Using a noninformative Beta[1,1] prior, Bayesian analysis of the DANISH trial indicates that there is a 74.2% probability of a reduction in all-cause mortality (ARR [absolute risk reduction]: -2.6% [-10.5 to 5.3%]; RRR [relative risk reduction]: 0.90 [0.67-1.22]) among NICM patients receiving an ICD compared with control. Using an informative prior, Bayesian analysis of the DANISH trial indicates a 99.7% probability of a reduction in all-cause mortality (ARR: -5.2% [-9.0 to -1.4%]; RRR: 0.80 [0.67-0.95]) and a 98.6% probability of an ARR&lt;1% among NICM patients who received an ICD compared with control. Conclusion: Using a Bayesian approach, our post-hoc analysis of the DANISH trial provides probabilities of reducing the all-cause mortality in NICM patients using ICD compared with medical therapy.
Abstract 13019: Association of Histopathologic Phenotypes With Demographics and Cardiovascular Risks in People With Clinically Diagnosed Heart Failure
Authors: Sarah Kim, Meghna Gaddam, Ashwin Sunderraj, Arjun Sinha, Sanjiv J Shah, Don Lloyd-jones, Edward B Thorp, Jon W Lomasney, Matthew J Feinstein
Journal: Circulation (2021)

Introduction: Heart failure phenotypes are often defined based on imaging diagnoses and clinical risk factors without corroborative tissue-level investigation. Defining clinical factors associated with specific tissue phenotypes among people with HF may yield important insights. Methods: We analyzed cardiac autopsies performed on people with clinical diagnoses of HF (N=526) at a large urban medical center between 4/6/2002 and 04/01/2021. We determined whether or not patients had histopathologic evidence of the following: (1) cardiomegaly; (2) atherosclerosis (any); (3) severe/obstructive coronary atherosclerosis; (4) remote MI; (5) acute/recent MI (&lt;14 days old pathologically); (6) myocardial fibrosis; and/or (7) myocardial inflammation. We determined associations of demographics and clinical factors with histopathologic phenotypes among people with a clinical diagnosis of HF using Chi-square and ANOVA. A Bonferroni-corrected p-value of &lt;0.00102 was considered statistically significant to correct for multiple comparisons. Results: We observed significant differences by sex and several clinical factors in cardiac histopathology among patients with clinical diagnoses of HF (Table). Men were significantly more likely than women to have histopathologically-defined fibrosis (73% vs. 59%; p=0.0008) and cardiomegaly (76% vs. 60%; p=0.0002). HF patients with atrial fibrillation were significantly more likely to have cardiac fibrosis than those without atrial fibrillation (73% vs. 58%; p=0.0005). HF patients with LVEF &gt;=50% were significantly less likely to have pathologic evidence of prior MI than patients with LVEF 40 to &lt;50% and LVEF &lt;40% (respectively, 24%, 50%, and 48% of patients in these groups; p&lt;0.00001). Conclusions: Among patients with HF, sex, atrial fibrillation, and LVEF were associated with distinct cardiac histopathology at autopsy. Future tissue-level analyses in humans to define underlying mechanisms are needed.
INNV-04. A MULTI-INSTITUTIONAL CLINICAL AND MRI REPOSITORY OF NEUROFIBROMATOSIS TYPE 1-ASSOCIATED PERIPHERAL NERVE SHEATH TUMORS
Authors: Ina Ly, Angela Hirbe, Justin Jordan, Olivia Michaels, Daniel Kwon, Dana Borcherding, Divya Srihari, Eva Dombi, Brigitte Widemann, Kai Pollard, Christine Pratilas, Demetrius Boswell, Peter de Blank, Mairim Melecio-Vázquez, Ping Chi, Johannes Salamon, Viktor Mautner, Zachary Mulder, Matthew Steensma, Shernine Lee, Bruce Korf, Jaishri Blakeley, Scott Plotkin
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Individuals with neurofibromatosis type 1 (NF1) frequently have peripheral nerve sheath tumors (PNST), including plexiform neurofibromas (PNF), atypical neurofibromas (ANF), and malignant peripheral nerve sheath tumors (MPNST). These tumors reflect a histologic spectrum from benign to malignant. Various clinical and MRI-based features are proposed as risk factors for MPNST development based on small single-institution studies. A major barrier to study these risk factors is collation and annotation of multi-center serial MRIs. To address this, we created a standardized database of clinical data and longitudinal MRIs from NF1-associated PNST from nine international NF1 referral centers. METHODS Clinical data from NF1 patients are collected in Research Electronic Data Capture databases housed at Massachusetts General Hospital and Washington University, including demographic information, genotype, disease course, treatment history, and survival. ANF and MPNST require histologic confirmation whereas a diagnosis of PNF can also be made based on clinical/radiographic stability. Longitudinal MRIs predating the histologic diagnosis are uploaded to a HIPAA-compliant cloud-based system. RESULTS Data from 200 patients (87 females, 113 males) with 217 tumors (75 PNF, 40 ANF, 102 MPNST) have been collected. 280 regional and 108 whole-body MRIs have been identified. Median age at the time of histologic diagnosis is 30 years (range 5-64). All tumors are histologically confirmed except for 6 PNF which remained stable over time. Median follow-up time is 32 months. Of 147 patients with available survival data, 32 (21.7%) have died from MPNST progression; estimated median overall survival is 20 months. CONCLUSIONS In this ongoing work, we have assembled one of the largest systematically annotated clinical and MRI repositories of NF1-associated PNST from pediatric and adult NF1 patients. The data will be accessible to outside researchers which will promote interdisciplinary and multi-center collaborations. Active efforts include the identification of radiomic MRI features to differentiate between PNF and MPNST.
Abstract 13266: Prognostic Impact Of Low On-treatment Diastolic Blood Pressure On The First Episode Of Stroke/Systemic Embolism In Japanese Patients With Atrial Fibrillation: The Fushimi AF Registry
Authors: Syuhei Ikeda, Moritake Iguchi, Hisashi Ogawa, Kimihito Minami, Kenjiro Ishigami, KOSUKE DOI, Yasuhiro Hamatani, Takashi Yoshizawa, Yuya Ide, Akiko Fujino, MITSURU ISHII, Nobutoyo Masunaga, Masahiro Esato, Hiromichi Wada, Koji Hasegawa, Mitsuru Abe, Masaharu Akao
Journal: Circulation (2021)

Background: Atrial fibrillation (AF) is associated with an increased risk of cardioembolic stroke and systemic embolism (SE). A secondary analysis of the Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that low diastolic blood pressure (DBP) was not related to risk of the first episode of stroke in hypertensive patients who received prescription of any antihypertensive agents. However, data regarding the impact of low on-treatment DBP on the first episode of stroke or SE in AF patients are limited. Methods: The Fushimi AF Registry is a community-based prospective survey of AF patients in Fushimi-ku, Kyoto, Japan. Follow-up data were available in 4,472 patients, and hypertensive patients who received prescription of any antihypertensive agents, and without prior stroke or SE were examined (n=1,934).We divided these patients into four groups based on the quartile of DBP; Q1 (DBP&amp;lt; 63 mmHg, n=463), Q2 (63 mmHg≤DBP&amp;lt;71 mmHg, n=463), Q3 (71 mmHg≤DBP&amp;lt;80 mmHg, n=484), Q4 (80 mmHg≤DBP, n=524), and compared the clinical background and the incidence of clinical events. Results: Patients in Q1 group were older (Q1 vs. Q2 vs. Q3 vs. Q4; 77.2±0.45 vs. 74.2±0.45 vs. 73.6±0.44 vs. 71.0±0.42; p&amp;lt;0.01), and had lower systolic blood pressure (SBP, 113.9±0.73 mmHg vs. 124.4±0.73 vs. 130.2±0.71 vs. 141.3±0.68; p&amp;lt;0.01). During the median follow-up of 3,005 days, the incidence rates of stroke/SE were higher in patients in Q1 group, and other groups were comparable (Q1: 1.7% per person-year vs. Q2: 1.1% vs. Q3: 1.0% vs. Q4: 1.1%; p&amp;lt;0.01). Multivariate Cox proportional hazards regression analysis revealed that lower DBP(&amp;lt;63 mmHg) was an independent determinant of the incidence of stroke/SE (adjusted hazard ratio: 1.47, 95% confidence interval: 1.05-2.06). Conclusion: In Japanese AF patients without prior stroke or SE, low on-treatment DBP was associated with the incidence of stroke or SE.
Abstract 11252: Transferrin Predicts Trimethlamine-N-Oxide Levels and is a Potential Cardiovascular Disease Biomarker
Authors: Lamuel Bean, Jeffrey J Wing, Michael W Milks
Journal: Circulation (2021)

Introduction: Trimethlamine-N-oxide (TMAO) is a circulating biomarker associated with atherosclerotic cardiovascular disease (CVD) risk and results from metabolism of micronutrients choline and L-carnitine, present in foods such as red meat and eggs. Hypothesis: The investigators sought to predict serum TMAO quartile levels among healthy individuals at increased risk of CVD, using clinical and dietary consumption data via an ordinal logistic model. Methods: Data from patients (n=127) enrolled in a longitudinal observational study on CVD were used to build a predictive model for TMAO using ordinal logistic regression with demographic variables and 40 other variables considered related to CVD risk. First, univariate models for each covariate were run (with serum TMAO quartiles as the dependent variable), and only variables with p &lt;0.30 were evaluated further. Second, demographic variables (age, gender, white vs. non-white race) were included in a multivariable model with each previously identified independent variable controlling for potential confounding. Last, the final model included fixed demographics and candidates from the confounder-adjusted model with p &lt;0.10. Results: Eight candidate variables were included in the final model, with only transferrin and HDL cholesterol with significant associations with TMAO (Table) . Patients had 0.16 (Q2), 0.31 (Q3), and 0.20 (Q4) times the odds to be in a higher TMAO quartile compared with patients in the lowest transferrin quartile. Patients in the second quartile of HDL had 2.68 times higher odds to be in a higher TMAO quartile compared with patients in the lowest HDL quartile. Non-Whites had 2.92 times higher odds of being in the highest TMAO quartile as compared to whites in this cohort. Conclusions: Transferrin showed the strongest association with TMAO; thus, transferrin may represent a novel potential biomarker of increased CVD risk worthy of further study.
Abstract 12114: Endothelial Extracellular Signal-Regulated Kinase 2 Contributed to the Development of Pulmonary Arterial Hypertension in Mice Through the Impairment of Endothelial Nitric Oxide Synthase Function
Authors: Yusuke Yumita, Kazuki Kagami, Yuki Ishinoda, Midori Iwashita, Risako Yasuda, Takumi Toya, Yukinori Ikegami, Takayuki Namba, Nobuyuki Masaki, Yasuo Ido, Yuji Nagatomo, Takeshi Adachi
Journal: Circulation (2021)

Introduction: Pulmonary arterial hypertension (PAH) is a progressive disease, characterized by abnormal muscularization and endothelial dysfunction in pulmonary artery (PA). Previous study showed that endothelial extracellular signal-regulated kinase 2 (eERK2) released vasoconstrictive factors and decreased NO bioactivity resulting in obese-induced hypertension and endothelial dysfunction. However, the role of eERK2 in the pathogenesis of PAH remains to be elucidated. Hypothesis: We hypothesized eERK2 impaired eNOS function and progressed the pathogenesis of PAH. Methods and Results: We generated eERK2 knock out mice (EE2KO) crossing Tie2-Cre mice and ERK2 flox mice and induced PAH by exposing mice to chronic hypoxia (10%) for 4 weeks. The littermate ERK2 flox mice without Cre expression were used as Control (Ctr). Immuno-histochemical staining showed the deficiency of eERK2 expression in the PA of EE2KO. We assessed the medial thickness of pulmonary arteries (MTPA) and measured right ventricular systolic pressure (RVSP). Although Ctr exhibited the progression of PA muscularization with an increase in MTPA, EE2KO revealed the significantly attenuated MTPA under hypoxic condition. Moreover, we found the lower RVSPs in EE2KO than those in Ctr under hypoxia in spite of similar RVSPs in normoxia. In RT-PCR, lung endothelin1 (ET1) gene expression was significantly lower in EE2KO than Ctr under hypoxia. Interestingly, hypoxia increased eNOS protein expression both in Ctr and EE2KO with Western blot analysis. The phosphorylation of AMPKα and eNOS were up-regulated in the lungs of EE2KO relative to Ctr under hypoxia. In addition, eNOS dimer/monomer ratios with non redusing SDS-PAGE was significantly increased in EE2KO compared to the Ctr under hypoxia (1.29±0.10 vs. 0.87±0.02, P=0.02, dimer / monomer ratios), suggesting improved eNOS uncoupling. Conclusions: These findings suggest that hypoxia increased eNOS expression and function, and that eERK2 impaired eNOS function by decreasing the phosphorylation of AMPKα and eNOS, and inducing eNOS uncoupling. In addition, ET1 synthesis through eERK2 might contribute to these pathogenesis of PAH with hypoxia.
Abstract 10629: Effect of Empagliflozin on Blood Volume Redistribution in Patients with Chronic Heart Failure and Reduced Ejection Fraction
Authors: Massar Omar, Jesper Jensen, Daniel Burkhoff, Peter H Frederiksen, Caroline N Kistorp, Lars Videbaek, Mikael Kjaer Poulsen, Finn Gustafsson, Lars Kober, Barry A Borlaug, Morten Schou, Jacob Moller
Journal: Circulation (2021)

Background: The relationship between blood volume and pressure in the vascular system can be described in terms of unstressed and stressed blood volume. Stressed blood volume determines venous pressure and provides preload back to the heart, which regulates the generation of cardiac output (CO) via the Frank-starling mechanism. Whether sodium-glucose cotransporter-2 (SGLT2i) favorably modifies stressed blood volume is not known. Hypothesis: To investigate the effect of SGLT2i (empagliflozin) on the hemodynamic estimated stressed blood volume (eSBV) in HFrEF patients compared to placebo. Methods: A post hoc analysis of investigator-initiated, double-blinded, placebo-controlled, randomized trial. Seventy patients were assigned to empagliflozin of 10 mg or matching placebo once daily for 12 weeks. Patients underwent right heart catheterization at rest and during exercise at baseline and follow-up. Outcome was change in eSBV after 12 weeks of empagliflozin treatment at each level of exercise. We conducted computer-modelling simulations based on invasive hemodynamic assessment to measure eSBV. Results: HFrEF patients with mean age was 57 years, mean ejection fraction 27%, 47 (71%) on diuretics were randomized. After 12 weeks treatment exercise eSBV was significantly reduced at 0 watt, 25 watt and 25 % of maximal exercise watt, compared to placebo [(0 watt; –258 mL, 95% CI –476 to –39, p=0.021); (25 watt; –301 mL, 95% CI –561 to –40, p=0.024); and (25% of peak exercise watt; –262 mL, 95% CI –490 to –34, p=0.024)]. There was no effect on rest, or at peak exercise eSBV [(Rest; –75 ml, 95% confidence interval [CI] –279 to 130; p=0.47); and (Peak; –96 mL, 95% CI –444 to 251, p=0.59)]. This was consistent among patients with and without type 2 diabetes, etiology of HFrEF, and diuretic usage (Figure 1). Conclusion: Empagliflozin may contribute to shift blood from the effective circulatory beds to the venous reservoir in reducing filling pressure and eSBV, but maintaining CO.