tbuckley/cabot-search huggingface dataset:
Abstract 13106: Modulation of Mitochondrial Respiration During Early Reperfusion Using Amobarbital Decreases Cardiac Injury in Donation After Circulatory Death Hearts
Authors: Oluwatoyin E Akande, Qun Chen, Renee Cholyway, Stefano Toldo, Edward J Lesnefsky, Mohammed Quader
Journal: Circulation (2021)

Introduction: Hearts from donation after circulatory death (DCD) donors are becoming an important source for heart transplantation (HTx). However, DCD hearts undergo ischemia reperfusion injury (IRI) and manifest impaired cardiac function. Blockage of electron transport chain (ETC) with the reversible inhibitor amobarbital (AMO) may mitigate IRI. Since pretreatment is not allowed in the DCD donors, therapeutic interventions at reperfusion are critical to limit injury in DCD hearts. Hypothesis: Transient blockade of ETC using AMO at reperfusion can decrease IRI in the DCD heart. Methods: Sprague Dawley rat hearts were subjected to 25 min. in-vivo ischemia. Hearts were then treated with 2mM AMO or vehicle for the first 5 min. of reperfusion, followed by Krebs-Henseleit buffer perfusion at 37 0 C on a Langendorff setup for 55 or 85 minutes. Infarct size was measured in hearts reperfused for a total of 90 min. Subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM) were isolated from a separate set of hearts reperfused for a total of 60 min. to assess calcium retention capacity (CRC), a measurement of mitochondrial permeability transition pore (MPTP) susceptibility to opening, and H 2 O 2 generation. Control beating donor (CBD) hearts underwent similar evaluation except for the ischemia. Results: AMO treatment caused a significant 19% decrease in infarct size (Figure A) compared to vehicle treated DCD hearts (25±2 vs.31±2 % of the Left Ventricle; mean± SEM, p&lt;0.05). CRC was improved with AMO compared to vehicle treated DCD hearts (360±17 vs. 269±17nmol/mg in SSM; 485±19 vs. 388±26nmol/mg in IFM; p&lt;0.05. Figure B). H 2 O 2 generation was reduced in AMO treated DCD hearts, especially in SSM (37±4 vs.59± 5pmol/mg/min; p&lt;0.05. Figure C). Conclusions: Brief inhibition of mitochondrial respiration with AMO during early reperfusion decreases injury in DCD hearts. AMO is a promising approach to protect myocardium in DCD hearts.
Practical Recommendations on Quantifying and Interpreting Treatment Effects in the Presence of Terminal Competing Risks
Authors: Zachary R. McCaw, Brian Lee Claggett, Lu Tian, Scott D. Solomon, Otavio Berwanger, Marc A. Pfeffer, Lee-Jen Wei
Journal: JAMA Cardiology (2021)

In a comparative trial, the time to a clinical event is often a key end point. However, the occurrence of a terminal event, such as death or premature study discontinuation, may preclude observation of this outcome. Although various methods for handling competing risks are available, no specific recommendations have been made for scenarios encountered in practice, especially when the terminal event profiles of the study arms are dissimilar. Moreover, appropriate methods for a desirable outcome, such as live hospital discharge, have seldom been discussed.Several of the most commonly used methods are reviewed. The first regards the terminal event as censoring and applies standard survival analysis to the event of interest. The between-group difference is usually summarized by the cause-specific hazard ratio. This summary measure is inappropriate when the new therapy markedly prolongs time to the terminal event. Moreover, the corresponding Kaplan-Meier curve for the end point of interest is uninterpretable. The second method is to use the cumulative incidence curve, which is the probability of experiencing the event of interest by each time point, acknowledging that patients who have died will never experience the event. However, the resulting pseudo hazard ratio is difficult to interpret. With a proper alternative summary measure, this approach works well for a desirable outcome but may not for an undesirable outcome. The third method focuses on the event-free survival time by combining information from occurrences of the terminal event and the event of interest simultaneously. This clinically interpretable method naturally accounts for differences in terminal event rates when comparing treatments with respect to the time to an undesirable outcome.This article enhances our understanding of each method's advantages and shortcomings and assists practitioners in choosing appropriate methods for handling competing risk problems in practice.
Ibrutinib in Mantle Cell Lymphoma Patients: Analysis of the Czech Lymphoma Study Group
Authors: Aleš Obr, Pavel Klener, Andrea Janíková, Heidi Mocikova, David Belada, David Šálek, Alice Sýkorová, Andrea Jirkuvová, Tomáš Papajík, Marek Trněný
Journal: Blood (2021)
Abstract 10413: Clinical Outcomes with Metformin and Sulfonylurea Initiation Among Patients with Heart Failure and Diabetes: From Get with the Guidelines-Heart Failure
Authors: Mohammad S Khan, Nicole Solomon, Adam D Devore, Abhinav Sharma, G.Michael Felker, Adrian F Hernandez, Paul A Heidenreich, Roland Matsouaka, Jennifer B Green, Javed Butler, Clyde Yancy, Pamela Peterson, Gregg C Fonarow, Stephen J Greene
Journal: Circulation (2021)

Background: Metformin and sulfonylureas are frequently prescribed to patients with diabetes for glycemic control. The impact of these drugs on cardiovascular outcomes among patients with heart failure (HF) and diabetes is unclear. Methods: We evaluated Medicare beneficiaries hospitalized for HF in the Get With The Guidelines-HF Registry between 2006 and 2014 who had diabetes and Part D prescription coverage (n=29,181). Patients with glomerular filtration rate &lt;45 mL/min/1.73m 2 or prescribed metformin or sulfonylurea prior to admission were excluded. In separate analyses for metformin and sulfonylurea, patients filling new prescriptions for each therapy within 90 days of discharge were compared with patients not prescribed therapy. Multivariable models landmarked at 90 days evaluated associations between therapy and mortality and hospitalization for HF (HHF) outcomes over the following 12 months. Secondary analyses were stratified by ejection fraction (EF) ≤40% vs &gt;40%. Results: Of 5,852 patients, 454 (7.8%) were newly prescribed metformin and 504 (8.6%) were newly prescribed sulfonylurea. After adjustment, metformin prescription was associated with reduced risk of composite mortality/HHF, but not individual components (Table) . Associations with mortality/HHF and HHF endpoints were driven by reduced risk among patients with EF&gt;40% (all p for interaction ≤0.04). Sulfonylurea prescription was independently associated with increased risk of mortality, HHF, and the composite. Associations between sulfonylurea prescription and endpoints were consistent regardless of EF (all p for interaction &gt;0.12). Conclusion: Among US patients hospitalized for HF with comorbid diabetes, initiation of metformin was independently associated with improved clinical outcomes, driven by improvements among patients with preserved EF. In contrast, sulfonylurea initiation was associated with adverse clinical outcomes regardless of EF.
Abstract 10465: Prevalence, Predictors and Outcomes of Pericardial Tamponade In Influenza Virus Infection: A Nationwide Inpatient Analysis
Authors: Rupak Desai, Zainab Gandhi, , Neha, Naima Rahim, Arashpreet Chhina, Athul Raj Raju, Geethu Jnaneswaran, Rashmi Gawde, Akhil Jain
Journal: Circulation (2021)

Introduction: Pericardial Tamponade (PT) is a rare, yet fatal complication of influenza virus infection (IVI). Considering the pertaining data remaining limited to case reports, we evaluated the frequency of PT and associated demographic variations, predictors and outcomes of PT in IVI using national multicenter datasets. Methods: We identified adult IVI admissions complicated by PT using National Inpatient Sample (2015Oct-2017) and relevant ICD-10 codes. Primary outcomes for frequency and predictors of PT in IVI and secondary outcomes of all-cause in-hospital mortality and patient discharge were analyzed. The multivariable analysis was performed adjusting for confounders to assess the independent predictors of PT in IVI. Results: Of 380,730 admissions with IVI, 130 (0.03%) patients experienced PT. Overall, young, female, non-white patients more frequently suffered PT during admissions for IVI. Compared to IVI admissions without PT, admissions with PT had significantly nearly six times higher all-cause mortality (23.1% v. 3.4 %, p&lt;0.001). IVI-PT cohort had fewer routine discharges compared to those without PT (30.8% vs. 59.8%, p&lt;0.001). IVI-related admissions who were Hispanics (OR 2.85 [CI 1.66-4.89] p&lt;0.001) in highest income quartile (OR 4.02 [CI 2.40-6.74] p&lt;0.001) with comorbidities like metastatic cancer(OR 6.60 [CI 3.70-11.79] p&lt;0.001), peripheral vascular disease (OR 4.69 [CI 2.65-8.29] p&lt;0.001), prior radiation therapy (OR 3.66 [CI 1.38-9.70] p=0.009), congestive heart failure (OR 3.65 [CI 2.41-5.52] p&lt;0.001), pulmonary circulation disease (OR 3.23 [CI 1.30-8.02] p=0.011), and obesity (OR 2.41 [CI 1.56-3.72] p&lt;0.001) had higher odds of developing PT (Figure 1) . Conclusions: In this multicenter analysis, we found IVI-related admissions among non-whites, patients from high-income quartile with cardiometabolic and oncologic comorbidities had a higher prediction of PT on multivariate analysis.
NIMG-36. VISUALIZATION OF TUMOR HETEROGENEITY AND PREDICTION OF ISOCITRATE DEHYDROGENASE MUTATION STATUS FOR HUMAN GLIOMAS BY USING MULTIPARAMETRIC PHYSIOLOGIC AND METABOLIC MRI
Authors: Akifumi Hagiwara, Hiroyuki Tatekawa, Yao Jingwen, Catalina Raymond, Richard Everson, Kunal Patel, Sergey Mareninov, William Yong, Noriko Salamon, Whitney Pope, Phioanh Nghiemphu, Linda Liau, Timothy Cloughesy, Benjamin Ellingson
Journal: Neuro-Oncology (2021)

Abstract Preoperative prediction of isocitrate dehydrogenase mutation status is clinically meaningful, but remains challenging. This study aimed to predict the isocitrate dehydrogenase (IDH) status of gliomas by using the machine learning voxel-wise clustering method of multiparametric physiologic and metabolic magnetic resonance imaging (MRI) and to show the association of the created cluster labels with the glucose metabolism status of the tumors. Sixty-nine patients with diffuse glioma were scanned by pH-sensitive MRI, diffusion-weighted imaging, fluid-attenuated inversion recovery, and contrast-enhanced T1-weighted imaging at 3 T. An unsupervised two-level clustering approach, including the generation of a self-organizing map followed by the K-means clustering, was used for voxel-wise feature extraction from the acquired images. The logarithmic ratio of the labels in each class within tumor regions was applied to a support vector machine to differentiate IDH mutation status. Bootstrapping and leave-one-out cross-validation were used to calculate the area under the curve (AUC) of receiver operating characteristic curves, accuracy, sensitivity, and specificity for evaluating performance. Targeted biopsies were performed for 14 patients to explore the relationship between clustered labels and the expression of key glycolytic proteins determined using immunohistochemistry. The highest prediction performance to differentiate IDH status was found for 10-class clustering, with a mean AUC, accuracy, sensitivity, and specificity of 0.94, 0.91, 0.90, and 0.91, respectively. The tissues with labels 7 + 8 + 9 + 10 showed high expression levels of hypoxia-inducible factor 1-alpha, glucose transporter 3, and hexokinase 2, which are typical of IDH wild-type glioma, whereas those with labels 1 showed low expression of these proteins. Our machine learning model successfully predicted the IDH mutation status of gliomas, and the resulting clusters properly reflected the metabolic status of the tumors.
Abstract 10730: Vascular Smooth Muscle Cell Phenotypic Switch and Replication Stress as a Key Contributors in CVD in HGPS
Authors: Nuria Coll-bonfill, Urvashi Mahajan, Susana Gonzalo
Journal: Circulation (2021)

Hutchinson Gilford Progeria Syndrome is a premature aging disease caused by LMNA gene mutation and production of a truncated lamin A protein “progerin” that elicits cellular and organismal toxicity. Patients show severe aging phenotypes, including alopecia, reduced fat and bone density, and cardiovascular disease (CVD), which ultimately causes their death as teenagers. HGPS has no cure and clinical trials obtained only minor benefits. It is urgent to identify mechanisms of progerin toxicity to target therapeutically. Progerin accumulates preferentially in the vasculature, being especially toxic for vascular smooth muscle cells (VSMC). Patients' autopsies show that vessel stiffening and aortic atherosclerosis are accompanied by VSMCs depletion in the media, increased extracellular matrix (ECM), and adventitia thickening. Mechanisms whereby progerin causes massive VSMC loss and ECM accumulation are unknown. We previously demonstrated that progerin expression in fibroblasts hinders DNA replication, causes genomic instability, and triggers a phenotypic switch towards activated fibroblasts/myofibroblasts. These cells are known to promote tissue fibrosis by ECM deposition and release of inflammatory cytokines. VSMCs can also undergo phenotypic modulation or de-differentiation, a process whereby contractile cells revert to a synthetic/proliferative phenotype, leading to pathological accumulation of ECM and CVD. Here we show that progerin expression in VSMCs causes a switch towards the synthetic/proliferative phenotype. Similarly to fibroblasts, progerin represents a challenge for DNA replication in VSMC, triggering replication stress, genomic instability and ultimately VSMC death. Importantly, we found that calcitriol -hormonal active form of vitamin D- prevents VSMC switch and replication stress. Our data suggest that replication stress might be an underlying cause of VSMC loss in progeria and that preventing the phenotypic switch-induced replication stress with compounds such as calcitriol might prevent the massive loss of VSMC and the vascular stiffness in HGPS patients.
Abstract 11916: Patterns of Care and Outcomes of Lower Extremity Peripheral Endovascular Intervention in Peripheral Artery Disease: Insights From National Ambulatory Surgery Sample
Authors: Abhishek Chaturvedi, Zachary Gertz, Barbara D Lawson, Rahul Gupta, Ioannis Milioglou, Jonathan G Sung, Nihar R Desai, George W Vetrovec, Ajar Kochar, Avirup Guha
Journal: Circulation (2021)

Introduction: Over the past 2 decades, the use of peripheral endovascular intervention (PVI) has surpassed surgical revascularization as the primary treatment modality for patients with symptomatic peripheral artery disease (PAD) refractory to non-invasive interventions. Hypothesis: To examine the patterns of care and associated outcomes in patients with PAD undergoing ambulatory lower extremity PVI (LE-PVI) in the United States (US). Methods: Records for patients with PAD who underwent LE-PVI between 01/01/2016 and 12/31/2017 were identified using appropriate CPT codes in the National Ambulatory Surgery Sample, the largest ambulatory surgery database in the US. Patient demographics, comorbidities, socioeconomic status, hospital characteristics, periprocedural mortality and complications were computed using Stata 15.0. Results: Total 266,574 (weighted) LE-PVI encounters were identified during the study period. The cohort had a mean age of 68.9 years and 40.5% were female (Table 1). Most common comorbidities were hypertension (54.3%), ischemic heart disease (IHD) (36.3%) and diabetes (24.6%). Periprocedural mortality (PM) was 0.02%, mean charges per encounter were $56,500, and 97.6% patients were discharged home. Complication rate was low (3.3%) including distal emboli (1.8%), dissection (0.4%), periprocedural bleeding (0.3%) and acute kidney injury (0.3%). On multivariable analysis, age [OR(CI), p = 1.02 (1.003 to 1.04), 0.02], Midwest region [OR(CI), p = 1.9 (1.2 to 3.2), 0.01], Southern region [OR(CI), p = 2.2 (1.3 to 3.7), 0.002], IHD [OR(CI), p = 1.6 (1.2 to 2.2), 0.002], arrhythmia [OR(CI), p = 2.4 (1.7 to 3.4), &lt;0.001], valvular disease [OR(CI), p = 1.5 (1.01 to 2.3), 0.045], and coagulopathy [OR(CI), p = 2.6 (1.1 to 5.9), 0.03] were associated with higher odds of PM. Conclusion: Our nationally representative study demonstrates the overall safety of ambulatory LE-PVI in a real-world setting with low periprocedural complications and mortality.
Abstract 10321: Disrupting the Bag3-hsp70 Complex with the Proposed Cancer Therapeutic Jg-98 is Detrimental for Cardiomyocytes
Authors: Thomas G Martin, Christine Delligatti, Nitha Aima Muntu, Jonathan A Kirk
Journal: Circulation (2021)

The heat shock protein 70 (HSP70) co-chaperone Bcl-2-associated athanogene-3 (BAG3) is critical for cell viability through facilitating HSP70-dependent protein quality control (PQC). Unfortunately, the same vital functions of BAG3-HSP70 in healthy cells are known to promote cell survival and proliferation in various cancers. Recent promising studies found that disrupting BAG3-HSP70 with the small molecule JG-98 has potent anti-cancer effects in cultured cells and in vivo . However, it is unknown what impact this therapy has on other cell types such as cardiomyocytes, where BAG3-mediated PQC is important for function. Using neonatal rat ventricular myocytes (NRVMs), we assessed the impact of JG-98 on cardiomyocyte viability and found apoptosis increased, even at doses 10-100-fold lower than those used with cancer cells. Next, we measured autophagic flux using ammonium chloride to block lysosomal degradation and found flux was reduced with JG-98. To explore mechanism, we assessed expression of BAG3, HSP70, and three other proteins that assemble with the complex during autophagy (HSPB5, HSPB8, SYNPO2). We found BAG3, HSPB8, HSPB5, and SYNPO2 expression decreased at the protein and transcript level with JG-98, while HSP70 expression was not changed. Next, we tested whether the BAG3-HSP70 interaction was important for protein stability of the complex members by treating NRVMs with JG-98 in the presence of cycloheximide to block translation. JG-98 decreased the protein half-life of BAG3, HSPB8, and HSPB5, indicating that protein stability was reduced, while SYNPO2 and HSP70 half-lives were unaffected. As we previously showed BAG3-HSP70 was important for maintaining sarcomere PQC, we next assessed the impact of JG-98 on sarcomere structure. In agreement, we found here that JG-98 caused sarcomere structural disintegration, which was exacerbated with stress. Finally, the detrimental effects of JG-98 on cell viability and sarcomere structure could be partially ameliorated with autophagy induction by rapamycin. Taken together, our findings indicate the importance of BAG3-HSP70 in cardiomyocytes and caution against broadly targeting this complex therapeutically.
Abstract 11182: Reliability of Systolic Pulmonary Artery Pressure by Doppler Echocardiography Compared to Right Heart Catheterization in Patients with Congenital Heart Disease: Analysis in a Large Patient Population
Authors: Hai-Long Dai, Na Tong, Xue-Feng Guang
Journal: Circulation (2021)

Introduction: Pulmonary arterial hypertension (PAH) in patients with congenital heart disease (CHD) is associated with increased morbidity and mortality. While Doppler echocardiography (DE) has been a useful screening test in PAH, the presence of structural cardiac defects may affect the ability to reliably predict systolic pulmonary arterial pressure (sPAP).Therefore, this study was to analyze the reliability of sPAP assessment by DE compared to right heart catheterization (RHC) in a large CHD patient population. Methods: We retrospectively analyzed simple atrial septal defect (ASD) , ventricular septal defect (VSD) and patent ductus arteriosus (PDA) patients older than 14 years with matched examinations (within 1 months) from 2015 to 2020. Relationships between RHC- and DE-derived sPAP were assessed using the Pearson correlation. Bland-Altman analyses were performed to evaluate the agreement between DE and RHC measurements of sPAP. Results: 1937 ASD patients,188 VSD patients, 294 PDA patients were included in this study. In ASD patients, sPAP was 47.06±14.33 mmHg by DE and 39.42±13.18 mmHg by RHC(P&lt;0.001). There was moderate correlation between DE and RHC measurements of PASP (r = 0.585, P&lt;0.05). Bland-Altman analysis showed a bias of 7.6 mmHg for sPAP (95% limits of agreement -17.0 to 32.3 mmHg). In VSD patients, sPAP was 60.89±26.36 mmHg by DE and 64.39±35.79 mmHg by RHC(P&lt;0.001). There was highly correlation between DE and RHC measurements of PASP (r = 0.866, P&lt;0.05). Bland-Altman analysis showed a bias of -3.5 mmHg for sPAP (95% limits of agreement -39.7 to 32.7 mmHg). In PDA patients, sPAP was 49.96±19.53 mmHg by DE and 53.10±29.36 mmHg by RHC(P&lt;0.001). There was highly correlation between DE and RHC measurements of PASP (r=0.813, P&lt;0.05). Bland-Altman analysis showed a bias of -3.1 mm Hg for sPAP (95% limits of agreement -37.7 to 31.5 mmHg). Conclusions: DE estimates of sPAP are inaccurate in patients with CHD, a significant overestimation of the sPAP in ASD patients, significant underestimate of the sPAP in VSD and PDA patients.
DDRE-24. ARF4-MEDIATED RETROGRADE TRAFFICKING PROMOTES CHEMORESISTANCE IN GBM
Authors: Shreya Budhiraja, Shivani Baisiwala, Khizar Nandoliya, Gabriel Dara, Ella Perrault, Andrew Zolp, Li Chen, Crismita Dmello, Cheol Park, Adam Sonabend, Atique Ahmed
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma (GBM) is the most common type of adult malignant brain tumor, with a median survival of only 21 months. This is partly due to the high rate of resistance to conventional therapy, including temozolomide (TMZ), leading to recurrence rates close to 100%. To identify the unknown genes driving the development of this resistance, we performed a genome-wide CRISPR knockout screen comparing a DMSO-treated population with a TMZ-treated population over 14 days. Results showed significant enrichment of ~200 novel genes and pathways. From this list, we identified 4 previously unstudied genes showing significant elevations in RNA expression (p&amp;lt; 0.05) when comparing recurrent and primary tumors in patient datasets, along with significant survival benefits corresponding to low gene expression (p&amp;lt; 0.05). Validation experiments in vitro showed significant elevations in RNA and protein expression in multiple patient-derived xenografts (PDX) lines during TMZ-treated conditions, while knocking out these genes also resulted in significantly heightened sensitivity to TMZ (p&amp;lt; 0.01). We investigated one particularly enriched gene, ARF4, known to be involved in retrograde trafficking. With previous studies showing that ARF4 is upregulated under ER stress, we first confirmed the increased expression of ER stress markers during TMZ treatment to explain the increased expression of ARF4 during treatment. Further investigation via live-cell imaging also showed a consequent increase in retrograde trafficking in TMZ-treated cells, as evidenced by significantly increased trafficking of transferrin receptors, a retrograde transport marker, as well as EGFR, known to play a role in promoting chemoresistance through strengthened DNA repair response. ARF4-overexpressed GBM cells similarly showed increased trafficking of transferrin receptors and EGFR to the nucleus, while ARF4-knockdowns showed decreased trafficking and nuclear EGFR expression. Ultimately, our CRISPR-Cas9 screen has identified a promising therapeutic target, ARF4, which may drive GBM’s robust resistance to chemotherapy through increased retrograde trafficking of chemoresistance-promoting nuclear EGFR.