tbuckley/cabot-search huggingface dataset:
Abstract 14101: CES1 Deficiency is Associated With Oxidative Stress and Endoplasmic Reticulum/Mitochondrial Injury in Pulmonary Endothelial Cells
Authors: Stuti Agarwal, Ananya Chakraborty, David Condon, Elya Shamskhou, Hiral Patel, Lichao Liu, James West, Karthik Suresh, Bruce D Hammock, Marlene Rabinovitch, Joseph C Wu, Mark Nicolls, Vinicio A Dejesus Perez
Journal: Circulation (2021)

Background: Pulmonary Arterial Hypertension (PAH) is a life-threatening disease characterized by loss of pulmonary microvessels and vascular remodeling. BMPR2 insufficiency in PAH is associated with oxidative stress and mitochondrial dysfunction but mechanism remain incompletely understood. We recently identified CES1 as a downstream target of BMPR2 and key mediator of EC survival. Carboxylesterase1 (CES1) is an endoplasmic reticulum(ER) enzyme responsible for lipid metabolism, cellular detoxification and redox balance. Here, we explore the consequences of CES1 deficiency and its link to EC dysfunction in PAH. Hypothesis: Loss of CES1 promotes EC dysfunction through oxidative stress and disruption of ER-mitochondrial homeostasis. Methods: PECs were transfected with siRNA/plasmid to knockdown/overexpress CES1. To induce oxidative stress, we used Luperox (100 μM). Chronic hypoxia (10% O 2 for 3 weeks) studies were carried out with male wild type and CRISPR-CES1 KO mice. Hemodynamic measurement and vessel morphometry was performed to assess right ventricular (RV) and vascular remodeling. Mitochondrial and ER structure and function was assessed by confocal microscopy and WB assays. Results: Both BMPR2 and CES1-deficient PECs have higher rates of apoptosis in the context of increased ROS production and mitochondrial fragmentation. Lipid staining with OilRedO demonstrated accumulation of lipid droplets in the cytoplasm of CES1-deficient PECs suggesting disruption in lipid metabolism. CES1-deficient PECs also showed an increase in ER stress markers (CHOP, BiP, IRE-1) compared to controls. Overexpression of CES1 was able to protect PECs against ROS accumulation and apoptosis while increasing tube formation in Matrigel assay. Compared to WT, CRISPR-CES1 KO mice demonstrated higher RV systolic pressures, RV and pulmonary microvessel remodeling in normoxia and with chronic hypoxia. Analysis of CES1-KO lung tissue demonstrates high lipid peroxidation, oxidative damage and reduced number of alveolar vessels. Conclusions: CES1 expression is crucial for PMVEC survival by preventing ROS and maintaining mitochondria/ER homeostasis. Therapeutic interventions to restore CES1 expression could serve as novel treatment approaches for PAH.
EPCO-07. HYBRID NEURO-GLIAL CELLULAR ARCHITECTURE IN HIGH-GRADE GLIOMA DRIVEN BY H3-G34R MUTATION
Authors: Julie Laffy, Masashi Nomura, Chen He, Lillian Bussema, Michal Slyper, Laura Hover, Simon Gritsch, Aviv Regev, Suzanne Baker, Itay Tirosh, Mario Suva
Journal: Neuro-Oncology (2021)

Abstract High-grade gliomas (HGG) with histone H3.3 G34R mutation are rare intractable tumours in the cerebral hemispheres that preferentially affect adolescents and young adults, but have unknown mechanisms of neuroanatomical specificity and tumourigenesis. Here, we performed single-nucleus RNA-sequencing of twenty patient samples, encompassing twelve tumours with G34R mutation and eight H3.3 wildtype HGGs, age- and location-matched. Both classes of HGG were heterogeneous, with malignant cells in multiple states, recapitulating neural and glial developmental trajectories. G34R HGG is distinguished by lack of malignant cells in the oligodendroglial lineage, and aberrant expression of neuronal programs superimposed over cellular states, resulting in hybrid glio-neuronal malignant programs. Singe-cell barcoding supports plasticity between cellular states in HGG with multiple possible transitions. CRISPR-correction of G34R in HGG models followed by scRNA-seq supports that the G34R mutation directly drives these aberrant programs. Our study provides a framework for studying the origin and tumourigenesis of paediatric gliomas.
Reply to Wei Zhang So, Ziting Wang, and Ho Yee Tiong’s Letter to the Editor re: Anna Lantz, David Bock, Olof Akre, et al. Functional and Oncological Outcomes After Open Versus Robot-assisted Laparoscopic Radical Prostatectomy for Localised Prostate Cancer: 8-Year Follow-up. Eur Urol 2021;80:650–60
Authors: Anna Lantz, David Bock, Olof Akre, Eva Angenete, Anders Bjartell, Stefan Carlsson, Katarina Koss Modig, Martin Nyberg, Karin Stinesen Kollberg, Gunnar Steineck, Johan Stranne, Peter Wiklund, Eva Haglind
Journal: European Urology (2021)
Abstract 10580: Health Care Utilization After First-Line Cryoablation for Atrial Fibrillation
Authors: Giulio Zucchelli, Julian K Chun, Surinder Kaur Khelae, Csaba Földesi, Fred Kueffer, Kelly van Bragt, Fernando Scazzuso, Young-Keun On, Fawzia Al-Kandari, Ken Okumura
Journal: Circulation (2021)

Background: Cryoablation is superior to antiarrhythmic drugs (AAD) for the prevention of arrhythmia recurrence in drug naïve (first-line) patients with paroxysmal atrial fibrillation (AF). The adoption and outcomes of first-line cryoablation in a real-world setting are unknown. Purpose: To describe global usage, safety, efficacy, and healthcare utilization outcomes in patients treated with cryoablation for first-line management of AF. Methods: Cryo Global Registry (NCT02752737) is an ongoing, prospective, multicenter registry. AF patients with an index cryoballoon ablation performed according to local standards of care at 58 centers in 26 global countries were included. Subjects undergoing first-line cryoablation were compared to patients with prior failed AAD usage and/or taking AADs at baseline. Serious procedure-related complication rates, 12-month freedom from a ≥30sec AF/atrial flutter (AFL)/atrial tachycardia (AT) recurrence after a 90-day blanking period, and healthcare utilization were compared. Results: Of 1,394 total patients, 433 (31.1%) were treated with first-line cryoablation. The proportion of first-line enrollments varied widely by world region and country. AAD-refractory patients failed a mean of 1.2 ± 0.5 AADs prior to cryoablation. Freedom from AF/AFL/AT after cryoablation in first-line and AAD-refractory was 90.0% (95% CI: 86.4-92.7%) vs 84.4% (95% CI: 81.5-86.8%) in paroxysmal AF and 72.9% (95% CI: 58.6-83.0%) vs 70.2% (95% CI: 62.9-76.4%) in persistent AF (overall p=0.02), respectively. Serious adverse event rates were not statistically different between first-line and AAD-refractory patients (2.3% vs 3.4%; p=0.32), with highest rates being groin-site complications (0.7% vs 0.5%), respectively. Freedom from repeat ablations in first-line vs AAD-refractory was 95.5% (95% CI: 92.7 - 97.2%) vs 93.1% (95% CI: 91.0 - 94.7%) in paroxysmal AF and 84.7% (95% CI: 71.8 - 92.1%) vs 88.2% (95% CI: 82.5 - 92.2%) in persistent AF (overall p=0.35), respectively. Conclusion: The current data support cryoablation as an early intervention strategy for treatment of patients with AF.
Abstract 14483: Correlating Blood Type, Infection Risk, and Illness Severity in Patients With COVID-19
Authors: Vikas Yellapu, Shani V Daniel, Naif L Hindosh, Douglas Corwin, Richard Snyder, mathai chalunkal
Journal: Circulation (2021)

Introduction: There have been over 13 million cases of COVID-19 cases with a 2% mortality rate [1]. Over the past year there has been a significant progress in the understanding and management of COVID-19 infections. There are still many factors and complications of COVID-19 that have yet to be elucidated. There have been multiple studies looking at the possible link between ABO group type and increased risk of mortality. Many studies from China, Europe and Canada indicate that blood group “O” had lower risk of susceptibility and severe infection[2-4]. We wanted to identify weather this trend was applicable within our hospital network in Eastern Pennsylvania. We wanted to identify through retrospective analysis if there is an association between ABO type, Race, Gender, and mortality at 30-day or 90 days. Methods: We identified n=568 patients between February 2020 to June 2020 that were admitted to the hospital for treatment of COVID-19 that also had historical data regarding ABO grouping. Demographics, length of stay, intubations, and smoking history. Once data was collected, statistical analysis was conducted with SPSS for means, standard deviations, and Chi-squared test for non-parametric testing. Results: The breakdown of blood groups in our populations was [ A: 35.1%, B: 11.6%, AB: 7.9%, O:45.3% ]. The average age of patients by blood group was [A:70.9±6 , B: 68.6±15, AB:66.3±12, O: 65±17], The percentage of females in each group is [A:45%, B: 35%, AB:67%, O:50%]. The mean BMI for all groups were 31±7 (p&gt;0.05) and there was no significant difference between blood groups with length of stay [A:8±6.1 , B: 10.5±9.6, AB:8.3±6.7, O: 9±8 (p&gt;0.05)] There was no significant difference in mortality rate among the blood groups during admission [ A: 26%, B: 16%, AB: 13%, O:24% (p=0.17)] or the rate of intubation [ A: 10%, B: 15%, AB: 11%, O:12% (p=0.72)]. Conclusion: Our findings indicate there is no significant difference between mortality, inpatient length of stay, or proportion of intubations between different blood groups. Our population of blood groups was distributed close to distribution of blood group in the general population. While there have been studies that indicate there is a protective nature of type O blood group, we did not see this in our cohort.
Abstract 13612: An mPGES-1 Inhibitor Halts Abdominal Aortic Aneurysm Formation in Mice
Authors: Lauren M Weaver, Madeline J Stewart, Kai Ding, Shuo Zhou, Charles Loftin, Fang Zheng, Chang-Guo Zhan
Journal: Circulation (2021)

Background: Abdominal aortic aneurysm (AAA) is a deadly, permanent balloon of the aortic artery. Surgery is the only option available to patients, but it is risky. In addition, there are currently no FDA-approved pharmacological treatments for AAA available. Notably, microsomal prostaglandin E 2 synthase-1 (mPGES-1) is recognized as a promising target for development of a next generation of anti-inflammatory drugs. Through computational modeling and in vitro experiments, we have recently discovered a novel type of mPGES-1 inhibitors as possible anti-inflammatory drug candidates. Objectives: The purpose of this study was to assess the capability of an mPGES-1 inhibitor to alter the growth of AAA in the angiotensin (Ang)-II induced mouse model. Methods: For 28 days, 12-week-old male ApoE-/- were infused with Ang-II (1,000 ng/kg/min) plus either an mPGES-1 inhibitor (UK4b) starting day 7 (10 mg/kg SC, BID; N = 6) or no drug (control group, N = 9). Maximal aortic diameter was measured by ultrasound (Vevo 3100) on day 0 (baseline), 2, 5, 7, 12, 16, 21, and 28. Aorta tissues were collected after sacrifice on day 28 and measured. Results: On day 28, there was a significant difference between the maximal aortic diameters of the control and drug treated groups (2.08±0.22 mm, 1.34±0.02 mm; p &lt; 0.005). Comparing day 28 in vivo and ex vivo measurements of aortas, there was no significant difference ( p = 0.898), validating the use of ultrasound as an in vivo measurement method in this study. Conclusions: In summary, the mPGES-1 inhibitor UK4b, was able to halt the progression of AAA in these mice. There was a significant difference in the size of aortas between the two groups which was validated by ex vivo assessment. These preliminary results show promise for the use of an mPGES-1 inhibitor in the treatment of AAA.
Abstract P385: Sarcolipin Reduction Prevents Mitochondrial Dysfunction In Dystrophic Myocardium
Authors: Satvik Mareedu, Nadezhda Fefelova, Lai-hua Xie, Gopal J Babu
Journal: Circulation Research (2021)

Rationale &amp; Hypothesis: Sarcolipin (SLN), an inhibitor of sarco/endoplasmic reticulum Ca 2+ ATPase (SERCA) is abnormally high and enriched in the mitochondrial associated membrane (MAM) fractions of dystrophic hearts. We, therefore, hypothesized that in the dystrophic cardiomyocytes, SLN upregulation causes abnormal elevation of intracellular Ca 2+ (Ca 2+ i ) including Ca 2+ mishandling in the MAM region, resulting in sustained elevation of mitochondrial Ca 2+ (Ca 2+ m ) , which in turn affects mitochondrial structure and function. Approach: We chose dystrophin mutant and utrophin deficient, mdx:utr -/- mice for our studies and generated SLN haploinsufficient mdx:utr -/- (mdx:utr -/- :sln +/- ) mice. Single-cell Ca 2+ transients and Ca 2+ m efflux were measured in isolated cardiomyocytes to determine Ca 2+ i handling and Ca 2+ m content, respectively. Mitochondrial membrane potential was assessed with membrane-permeant dyes in isolated cardiomyocytes followed by confocal imaging. Mitochondrial respiration was measured using Complex activity assays and Seahorse metabolic profiling in ventricular tissue lysates and isolated mitochondria respectively. Mitochondrial structure, number, and area were evaluated using electron micrographs. Results: Heterozygous deletion of the SLN gene normalized SLN expression and improved Ca 2+ i cycling and prevented Ca 2+ m overload in dystrophic cardiac myocytes. Furthermore, reducing SLN expression prevents loss of membrane potential and improves mitochondrial respiration in the dystrophic cardiac myocytes. Transmission electron microscopic analyses of the dystrophic heart revealed significant cristae loss in the mitochondria globally as well as in the MAM-associated mitochondria. On the other hand, the reduction in SLN expression prevents these changes. Conclusions: In conclusion, reduction in SLN expression preserves the SR-mitochondrial interface and restores the mitochondrial function by mitigating the Ca 2+ overload, membrane potential loss, and structural damage. These changes improve cardiac function and prevent the development of cardiomyopathy in mdx:utr -/- mice. Our findings suggest that SLN reduction could be a potential therapeutic strategy for the treatment of Duchenne muscular dystrophy and associated cardiomyopathy.
Abstract 9819: Real World Data: Off-Label Metformin in Patients with Prediabetes is Associated with Improved Cardiovascular Outcomes
Authors: Jaime E Murillo, Chace McNeil, Kathryn Van Nest, Jamie Schaeffer, Lynn Polingo, Solomon Adjei, Victoria Shapiro, Ben Wiegand, Vojta Deneen
Journal: Circulation (2021)

Background: Metformin is not FDA-approved for prediabetes but it is being prescribed off-label for this condition. Per the American Diabetes Association (ADA), metformin “should be considered” for prediabetes patients with a BMI &gt; 35. Prediabetes is associated with a higher risk of cardiovascular disease (CVD). We report on real-world, off-label use of metformin and its association with lower incidence of CVD in a large population with prediabetes, by age, BMI, and race. Methods: This analysis used insurance claims linked to electronic health records from Jan 2016 to Sept 2020. Patients in the metformin cohort had &gt; 180-day supply: &gt; 90 days pre- and &gt; 90 days post diagnosis of prediabetes. All had continuous enrollment for &gt; 24 months. We excluded age &lt;25; FDA-approved metformin indications; type 1 DM; CVD; CKD; or gestational diabetes. Inclusion criteria: Prediabetes ICD-10 code R73, or HbA1c 5.7-6.4, or fasting glucose 100-125 mg/dL or OGTT 140-199 mg/dL. Results: Of 149,654 patients with prediabetes, 8,624 (5.8%) were prescribed metformin. Table 1 describes metformin and non-metformin patients. At a 2.8-year mean follow-up, 24% of prediabetes patients developed CVD. Table 2 describes metformin use and CVD outcomes by BMI, gender, race, and age. As a whole and by gender, a BMI &gt; 35 was associated with lower CVD. A similar effect was seen for AA &gt; 65 with a BMI &gt; 35 Conclusion: Patients with BMI &gt; 35 showed an association between metformin use and lower incidence of CVD, including African Americans older than age 65. The data suggest that morbidly obese patients with prediabetes may benefit from the use of metformin as recommended by the ADA.
Abstract 13683: Corticosteroids and the Risk of Atrial Fibrillation in Hospitalized COVID-19 Patients
Authors: Yi Lee, Qasim Jehangir, Laila Poisson, Katie Latack, Geetha Krishnamoorthy, Anupam Sule, Shiyi Song, Dinesh Reddy Apala, Abdul R Halabi, Kirit Patel, Dee Dee Wang
Journal: Circulation (2021)

Introduction: Some studies suggest an increased incidence of atrial fibrillation (AF) in patients receiving corticosteroids, whereas others suggest a preventive effect of steroids. Data on the impact of steroids on the incidence of new-onset AF in hospitalized COVID-19 patients is lacking. Methods: This retrospective, multicenter cohort study included patients ≥ 18 years admitted to one tertiary care and five community hospitals for treatment of COVID-19 infection between 3/1/2020 and 3/31/2021. Subjects were stratified based on steroid exposure during hospitalization: group 1 (full-dose) received cumulative dosage including dexamethasone ≥ 6 mg/day, methylprednisolone ≥ 80 mg/day or hydrocortisone ≥ 50 mg/day for ≥ 3 days, group 2 (low-dose) did not receive the aforementioned dosage, and group 3 had no steroid usage. Patients with a history of AF and length of stay &lt; 3 days were excluded. Results: Among 4578 (1556 in group 1, 1046 in group 2, 2156 in group 3) patients (mean age 65.4 ± 61 years, 50.4 % females), 542 patients developed new-onset AF. 523 (24.3%) patients in group 1, 97 (9.3%) in group 2, and 125 (8%) in group 3 died during hospitalization. In multivariable logistic regression models adjusted for hypoxia and significant baseline demographics (age, sex, body mass index, hypertension, pulmonary disease, chronic kidney disease, liver disease, and cerebrovascular accident), we found that group 1 had a higher incidence of AF compared to group 3 (adjusted relative risk [aRR] 1.59; 95% CI 1.27 - 1.99; p &lt; 0.001) and group 2 (aRR 1.39; 95% CI 1.09 - 1.77; p = 0.007). The group 2 vs group 3 (aRR 1.14; 95% CI 0.87 - 1.50; p = 0.347) comparison did not reach statistical significance (Figure). Conclusions: Corticosteroids, the mainstay of treatment of hypoxic COVID-19 patients, are associated with an increased risk of developing AF. This suggests that steroids have a potential direct arrhythmogenic effect in COVID-19 patients.
From response to transformation: how countries can strengthen national pandemic preparedness and response systems
Authors: Victoria Haldane, Anne-Sophie Jung, Rachel Neill, Sudhvir Singh, Shishi Wu, Margaret Jamieson, Monica Verma, Melisa Tan, Chuan De Foo, Salma M Abdalla, Pami Shrestha, Alvin Qijia Chua, Anders Nordström, Helena Legido-Quigley
Journal: BMJ (2021)

<b>Victoria Haldane and colleagues</b> delve into the characteristics of national responses to covid-19. They suggest actionable steps at a national level that can guide states to achieve the independent panel's recommendations for making this the last pandemic
Abstract 13959: Topographical Impedance Patterns Within Epicardial Ventricular Scar
Authors: Iwanari Kawamura, Vivek Y Reddy, Mohit Turagam, Daniel Musikantow, Edward Chu, Marc Miller, William Whang, Srinivas Dukkipati, jacob s Koruth
Journal: Circulation (2021)

Introduction: During pericardial electroanatomical mapping of the ventricles, impedance changes within regions of epicardial scar can be observed, but their extent and relevance are not well understood. We aimed to characterize the impedance maps within the epicardial scar of patients who underwent first-time epicardial scar ablation. Methods: In this retrospective single center analysis, we identified 69 consecutive patients with structural heart disease that underwent successful first-time pericardial mapping with an irrigated contact force-sensing catheter (ThermoCool ST; Biosense Webster Inc) between 2015-2020. Among them, 37 patients were included as they had both available voltage map with epicardial scar regions and its compatible impedance map. Characteristics of impedance variations with the epicardial low voltage zone (0.5-1.5 mV) were analyzed. Abrupt impedance increases ( AIi ) were defined as impedance delta of &gt;100Ω increase between points &lt;1 cm apart. Results: Among 37 patients (61.4 ± 14.5 years old, male 94.6%, LVEF 38.2±14.2% and ischemic cardiomyopathy 32.4%), AIi was observed in 11 of 37 patients (29.7%). Baseline characteristics of those with AIi was similar to those without. Lateral right ventricle and apical locations demonstrated AIi more frequently compared to other sites (P&lt;0.01). The maximum impedance was significantly higher at sites with AIi than without (425.5±58.6 vs 242.9±60.8 Ω, P&lt;0.01) despite similar average contact force. However, impedance at sites of ablation were noted to be not significantly different between those with and without AIi, in consequence of avoiding ablation in the regions of high impedance. Conclusion: This study identified different topographical characteristics of the impedance over the ventricular epicardium. This epicardial impedance variation within low voltage regions needs to be further characterized and its clinical implications better understood.
CTNI-33. METRONOMIC TEMOZOLOMIDE THERAPY IN HEAVILY PRETREATED PATIENTS WITH RECURRENT GLIOBLASTOMA: A LARGE MONO-INSTITUTIONAL RETROSPECTIVE STUDY
Authors: Alberto Bosio, Giulia Cerretti, Marta Padovan, Mario Caccese, Valentina Guarneri, Vittorina Zagonel, Giuseppe Lombardi
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Despite advances in surgical and first-line treatment, all glioblastoma pts relapse. The aim of this study is to evaluate the benefit of metronomic temozolomide (mTMZ) for recurrent glioblastoma. METHODS 120 pts treated at Veneto Institute of Oncology from September 2013 to March 2021 were retrospectively reviewed. Major inclusion criteria were: first-line therapy with Stupp protocol, relapse after first or subsequent line of therapy, treatment with mTMZ schedule (50mg/m2 continuously), hystologically confirmed diagnosis. RESULTS mFollow-up was 15.6ms, mAge 59ys (range 18-81), ECOG PS 0-2 in 107pts (89%) and 3 in 11 (9%). MGMT was methylated in 66 of 105 (62%) evaluable pts, IDH mutated in 9 of 106 (8%). mNumber of prior lines of treatment was 2 (range 1-7); 41% of pts received mTMZ beyond the third line. mTime between last standard TMZ (sTMZ) cycle and mTMZ administration was 6ms (range 1-50); 40% of pts started mTMZ after 3ms from sTMZ. All pts were evaluable for response: 3 (2%) and 48 (40%) showed PR and SD. mOS from the start of mTMZ was 5.4ms (95% CI 4.3-6.4), mPFS 2.6ms (95% CI 2.3-2.8). On univariate analysis, MGMTmet and MGMTunmet pts had a mOS of 5.6 and 4.4ms (p= 0.03); mOS for pts with ECOG PS &amp;gt; or ≤ 2 was 2.3 and 6.0ms (p&amp;lt; 0.001). On multivariate analysis, MGMTmet status (HR= 2.3, 95% CI, p= 0.004) and ECOG PS (HR= 0.5, 95% CI, p= 0.017) remained significant for PFS; ECOG PS (HR= 0.4, 95% CI, p= 0.001) was the only factor significantly associated with OS. The most common grade 3-4 hematologic toxicities were lymphopenia (10%) and thrombocytopenia (3%). Grade 3-4 nonhematologic toxicities were uncommon. CONCLUSIONS Rechallenge with mTMZ can be a well tolerated treatment option for recurrent glioblastoma, even in heavily pretreated pts. Pts with MGMTmet and good ECOG PS might report the major benefit.