tbuckley/cabot-search huggingface dataset:
Abstract 14532: Computational Drug Repurposing Identifies a Piperlongumine Analog That Controls a Gstp1-iscu Pathogenic Axis in Pulmonary Hypertension
Authors: Jimin Yang
Journal: Circulation (2020)

Background and Hypothesis: Pulmonary arterial hypertension (PAH) is an incurable vascular disease for which chemotherapies are being considered for therapeutic development. There is no method reported to date for effective computational screening of these drugs for this disease. Big data analyses that leverage the molecular parallels between cancer and PH may define novel pathogenic mechanisms and facilitate repurposing of chemotherapies for PAH. More specifically, while functional deficiency of the iron-sulfur (Fe-S) biogenesis gene ISCU and oxidative metabolism in human pulmonary arterial endothelial cells (PAECs) is known to drive PAH, the pathogenic regulation of ISCU is not fully defined, and no tailored drugs have been identified to bolster ISCU activity. Methods and Results: We applied a computational algorithm EDDY (Evaluating Differential DependencY), which analyzes RNA sequencing data from 810 cancer cell lines exposed to 368 small molecules, in order to identify chemotherapeutics that depended upon rewired PH-related gene clusters. The top ranked drug was a piperlongumine (PL) analog (BRD2889) that was predicted to extensively rewire dependencies across PH gene clusters, mediated by ISCU. In vitro, coupling gain- and loss-of-function analyses of GSTP1 with BRD2889 exposure in PAECs, we found that BRD2889 inhibits glutathione S-transferase P1 (GSTP1), an enzyme which in turn catalyzes ISCU glutathionylation and increases its stability in hypoxia. Consequently, BRD2889 and GSTP1 knockdown phenocopy one another by increasing Fe-S-dependent Complex I activity and mitochondrial oxygen consumption while ameliorating pathogenic apoptosis. Consistent with these computational and in vitro results, in a mouse model of PAH (IL-6 transgenic mice in hypoxia), BRD2889 improved hemodynamic and molecular disease manifestations in vivo. Conclusions: Using a novel computational platform, we identified a coordinated connection between BRD342289 and GSTP1-ISCU axis, crucial to PAEC metabolism. This study offers insight to fundamental PH pathobiology and sets the stage for accelerated repurposing of chemotherapies such as BRD342289 in PH.
Neutrophils Extracellular Traps Induced By Lymphoma-Derived IL-8 Could Promote Diffuse Large B Cell Lymphoma Progression
Authors: Man Nie, Linbing Yang, Xiwen Bi, Yu Wang, Peng Sun, Hang Yang, Panpan Liu, Zhiming Li, Yi Xia, Wenqi Jiang, Wenyu Li
Journal: Blood (2017)
Abstract 16128: Association Between Timing of Readmission and Risk of 1-year Mortality Among Patients After Hospitalization for Heart Failure in China: Findings From the China-PEACE Prospective Heart Failure Study
Authors: YILAN Ge, Bin Wang, jing li, xin zheng
Journal: Circulation (2020)

Introduction: Although 30-day readmission has been used as a quality metric for treatment of patients hospitalized for heart failure (HF), the association between the timing of readmission with mortality after discharge has been scarcely investigated. Methods: We studied a national sample of 4875 patients admitted to 52 hospitals for HF between 2016 and 2018 who were discharged alive from the China PEACE-Heart Failure Study. The timing of readmission was defined as the timing of first readmission from all cause after discharge. Mortality analyses across the timing of readmission were performed using Kaplan-Meier curves and log-rank tests. The associations between the timing of readmission and 1-year all-cause mortality was determined using Cox models. Results: The median participant age was 67 (57-76) years, and 37.5% were female. The median duration from discharge to readmission was 88 (28-194) days. Kaplan-Meier analysis revealed 1-year mortality did not differ between patients admitted within 0-30 and 31-60 days, and between patients admitted within 61-90 and 91-180 days after discharge (Figure1A). Then we classified the timing of readmission as early (0-60 days), midrange (61-180 days) and late (181-365 days). The 1-year all-cause mortality for patients experiencing early, midrange and late readmission was 31.8%, 23.2% and 12.0%, respectively (Figure1B). After adjusting for patient characteristics and treatment during hospitalization, the HR for 1-year all-cause mortality was 2.89 (95% CI 2.22-3.77) for patients with early readmission, and 2.07 (95% CI 1.56-2.75) for patients with midrange readmission when compared with patients with late readmission, respectively. Conclusions: Earlier readmission are associated with increased risk for 1-year all-cause mortality. Not only 30-day readmission but also readmission within 60 days after discharge could be perceived as an alarming sign of higher risk of death in patients with hospitalized HF in China.
Abstract 14683: Central Nervous System Mediated Cardiac Bradyarrhythmia With Asystole That Required Permanent Pacemaker in a Young Woman With Anti- NMDAR Encephalitis
Authors: Yogamaya Mantha, Azeen Anjum, Anita G Holtz, Uday Tatiraju, Macym Rizvi, Mark Feldman
Journal: Circulation (2020)

Background: We report a young woman who presented with acute psychosis and autonomic dysfunction who was diagnosed with Anti-N-Methyl-D-Aspartate Receptor Encephalitis (anti-NMDARE). Her life-threatening autonomic instability was controlled only after the placement of a permanent cardiac pacemaker. Case Presentation: A 29-year-old woman presented with abnormal movements and depersonalization. Vital signs showed BP 132/94 mmHg, HR 110 beats/min, RR 26 cycles/min, temperature of 101 F and spO2 of 80 % on RA. She was emergently intubated. Laboratory evaluation showed elevated CRP 6.98 mg/dL and CK 3329 U/L. Brain MRI revealed an abnormality in the right amygdala and hippocampus. Infectious workup was negative; however, a high titer of CSF NMDAR antibody was present. CT abdomen and pelvis revealed a 1.1 cm cyst within the left ovary. With a diagnosis of anti-NMDARE, she was treated with plasmapheresis, methylprednisolone, and immunoglobulin G therapy and underwent bilateral salpingo-oophorectomy with pathology confirming a teratoma. Despite these treatments, she continued to display autonomic dysfunction. Telemetry showed tachycardia-bradycardia with asystole that remained refractory to treatment and required placement of a permanent pacemaker (PPM). She showed clinical improvement after PPM and treatment ( Figure ). Conclusion: This is a rare case of severe bradyarrhythmia in anti NMDARE that necessitated placement of a permanent cardiac pacemaker. Neural-mapping studies show that the amygdala and hippocampus strongly modulate autonomic control. Disruption of cortical circuitry related to autonomic tone likely lead to arrhythmias in our case. Class I indications for pacemakers in the ICU include asystole, symptomatic bradycardia with hypotension and/or unresponsive to atropine. Early recognition, cardiorespiratory support, multistep pharmacological care and sometimes early electrophysiological support in anti-NMDARE are paramount.
Abstract 284: Looking Back to Glance Ahead: The Impact of Last Minute's Qrs Width &amp; Frequency in Pulseless Electrical Activity
Authors: Anders Norvik, Eirik Unneland, Gunnar W Skjeflo, David Buckler, Unai Irusta, Elisabete Aramendi, Trygve Eftestol, Benjamin Abella, Daniel Bergum, Jan P Loennechen, Jan Terje Kvaloy, Eirik Skogvoll
Journal: Circulation (2020)

Background: Observed heart rate and QRS-width during CPR in Pulseless Electrical Activity (PEA) develop differently in patients who gain ROSC compared to those who do not. In this study we investigated the impact of heart rate and QRS width on the transition from PEA to ROSC. Method: Defibrillator data from 293 episodes of cardiac arrest at two US and one Norwegian hospital were reviewed. The files contained ECG, impedance signal and compression depth. In total 178 episodes containing PEA intervals were included. Episodes with excessive ECG noise and signs of an active pacemaker were excluded. The files were processed in a MATLAB graphical application, and the clinical states were determined based on clinical documentation and the visual appearance of the ECG. ROSC was defined as an organized rhythm lasting longer than 1 minute without ongoing compressions. During pauses in compressions, heart rate and QRS-width was automatically measured and averaged over the preceding minute until current time and controlled and corrected manually. The results were analyzed using Aalen’s additive model for time-to-event data, using R version 3.6.3. Results: The average transition intensity, corresponding to the probability of gaining ROSC in one minute, was about 0.20 per min of CPR peaking at approximately 7 min. An increase in the average heart rate by 10/min increased the transition intensity by 0.03/min (p &lt;0.01). Narrowing of the QRS in average by 100 milliseconds (ms) increased the transition intensity by 0.14/min (p &lt;0.01). Our figure shows QRS width and heart rate for one patient with PEA approaching ROSC (gray area), with smoothed curves overlaid. Conclusion: Higher heart rates and narrower QRS complexes during PEA are strongly and significantly associated with a transition from PEA to ROSC. These changes could indicate whether a patient responds to ongoing CPR. In addition, there is a potential for predicting the immediate outcome based on these ECG characteristics.
Abstract 13863: Outcomes of Hybrid Convergent Procedure in Patients With Persistent and Longstanding, Persistent Atrial Fibrillation
Authors: Karl Crossen, Lisa D Foley, James Stone, Edward Ferguson, David Talton, Edward Garrett, Judah Askew, Keith Kyker
Journal: Circulation (2020)

Introduction: The primary indications for AF ablation are to reduce symptoms, time in AF and burden of medical management. Catheter ablation has suboptimal outcomes in persistent/longstanding persistent AF, however the hybrid Convergent procedure (combined endocardial and epicardial ablation) has shown promising results. The study objective was to evaluate outcomes of Convergent hybrid procedure for AF. Methods: The Convergent procedure involves a cardiac surgeon ablating the pulmonary veins (PV) and left atrial posterior wall epicardially via subxyphoid or transdiaphragmatic access. The EP then endocardially isolates the pulmonary veins and other AF triggers evident during mapping. A retrospective analysis of outcomes at a mean follow up of one year after Convergent ablation was performed. The composite burden score, which is a summation of a) AF burden, b) frequency of symptoms, and c) AAD status was calculated at baseline and at various follow-up intervals (see Table 1). Results: Fifty-seven consecutive highly symptomatic AF patients received Convergent ablation between October 2014-March 2019 at a single center. Baseline parameters were mean age 65.9 ± 9.2 years, 39% female, 52% LVEF, 4.3±4.3 years in continuous AF. Primary safety events were similar to those reported with endocardial catheter ablation. Of 57 patients, 29 (51%) had continuous rhythm monitors and the rest received ECG every 3-6 months until last follow-up. At a mean follow up of 350±122 days, 77% patients either had no AF or were free from AF at least 95% of the time. The composite burden score significantly reduced during 1 year since Convergent ablation (p&lt;0.001, Figure 1). Conclusion: Convergent hybrid procedure is safe and reduces the burden of AF as shown by sustained improvement in AF symptoms, reduction in AAD usage and reduction in time in AF. A heart team approach where the cardiac surgeon and EP collaborate is effective in the treatment of persistent/long-standing persistent AF.
Abstract 13941: Temporal Trends and Outcomes of Transcatheter Mitral Valve Repair and Surgical Mitral Valve Interventions
Authors: Ayman Elbadawi, Islam Y Elgendy, Ahmed Mohamed, Mohamed Faher Almahmoud, Mohamed A Omer, Ahmed S Abuzaid, Ali E Denktas, David Paniagua, Subhash Banerjee, Hani Jneid
Journal: Circulation (2019)

Introduction: Little is known about the contemporary changes in the uptake and outcomes of transcatheter mitral valve repair (TMVR) and surgical mitral valve repair/replacement (SMVR). Methods: We ...
Abstract 15877: Chamber Volumes and Deformation Measures are Abnormal in Chemotherapy-Naïve Cancer Patients: Potential Implications for Surveillance and Definitions of Cardiotoxicity
Authors: Dina Labib, Alessandro Satriano, Steven Dykstra, Yoko Mikami, Zdenka Slavikova, Patricia Feuchter, Sandra Rivest, Rosa Sandonato, Jacqueline Flewitt, Andrew G Howarth, Bobak Heydari, Carmen Lydell, Brian Clarke, Louis Kolman, Edith Pituskin, Winson Cheung, Joon Lee, James White
Journal: Circulation (2020)

Background: Cancer Therapeutics-related Cardiac Dysfunction (CTRCD) is defined by an interval drop in contractile performance to below reference lower limits of normal. This definition assumes healthy reference data appropriately represent referral populations with active cancer. However, the influence of active cancer on cardiac chamber volumes and contractile performance has not been established. Using cardiac magnetic resonance (CMR), we studied chamber volume- and deformation-based markers in ~400 cancer patients with comparison to ~100 healthy controls. Methods: 394 active cancer patients referred for first-time anthracycline-based chemotherapy and 102 healthy volunteers (HV) were recruited. Both underwent identical CMR protocols with quantification of chamber volumes and ejection fraction (EF). Left ventricular (LV) mechanics were also assessed by 3D myocardial deformation analysis (3D-MDA), providing global longitudinal, circumferential, radial and principal peak-systolic strain amplitude and rate. Results: The mean age was 53.8±13 years (78% female), with 64% having breast cancer and 36% lymphoma. Table 1 summarizes CMR findings of cancer patients versus HV, stratified by sex. Chamber volumes were significantly smaller while LV mass was significantly greater versus HV. LV EF and global longitudinal (GLS) were similar. However, cancer patients demonstrated significantly higher radial, circumferential and maximal principal strain amplitude. Peak-systolic strain rates were also consistently elevated. Conclusion: Chemotherapy-naïve cancer patients have smaller chamber volumes, greater LV mass, and higher radial, circumferential, and maximal principal strain versus healthy subjects. LV EF and peak GLS remain similar, and therefore are most appropriate to define CTRCD. However, an altered state of cardiac health is apparent by all other CMR-based markers, reflecting a unique cardiac phenotype of patients with active cancer.
Artificial intelligence-based pathology for gastrointestinal and hepatobiliary cancers
Authors: Julien Calderaro, Jakob Nikolas Kather
Journal: Gut (2020)

Artificial intelligence (AI) can extract complex information from visual data. Histopathology images of gastrointestinal (GI) and liver cancer contain a very high amount of information which human observers can only partially make sense of. Complementing human observers, AI allows an in-depth analysis of digitised histological slides of GI and liver cancer and offers a wide range of clinically relevant applications. First, AI can automatically detect tumour tissue, easing the exponentially increasing workload on pathologists. In addition, and possibly exceeding pathologist’s capacities, AI can capture prognostically relevant tissue features and thus predict clinical outcome across GI and liver cancer types. Finally, AI has demonstrated its capacity to infer molecular and genetic alterations of cancer tissues from histological digital slides. These are likely only the first of many AI applications that will have important clinical implications. Thus, pathologists and clinicians alike should be aware of the principles of AI-based pathology and its ability to solve clinically relevant problems, along with its limitations and biases.
Failure on voxilaprevir, velpatasvir, sofosbuvir and efficacy of rescue therapy
Authors: Julia Dietz, Velia Chiara Di Maio, Adolfo de Salazar, Dolores Merino, Johannes Vermehren, Stefania Paolucci, Andreas E. Kremer, Magdalena Lara, Maria Rodriguez Pardo, Heinz Zoller, Elisabetta Degasperi, Kai-Henrik Peiffer, Laura Sighinolfi, Francisco Téllez, Christiana Graf, Valeria Ghisetti, Jonas Schreiber, Elisa Fernández-Fuertes, Lucio Boglione, Leopoldo Muñoz-Medina, Rudolf Stauber, William Gennari, Blanca Figueruela, Jesús Santos, Pietro Lampertico, Stefan Zeuzem, Francesca Ceccherini-Silberstein, Federico García, Christoph Sarrazin, Alessio Aghemo, Tiziano Allice, Massimo Andreoni, Mario Angelico, Fausto Baldanti, Silvia Barbaliscia, Ada Bertoli, Vanni Borghi, Vincenza Calvaruso, Giuseppe Cariti, Antonio Craxì, Simona Francioso, Carlo Federico Perno, Pietro Pozzoni, Pier Luigi Toniutto, Maurizio Zazzi, Ana Belén Pérez, Cristina Quilez, Juan Carlos Alados, Joaquin Cabezas, Juan Ignacio Arenas Ruiz-Tapiador, Miguel Jimenez, Juan Manuel Pascasio-Acevedo, Manuel Alberto Macias Rodriguez, Jose Miguel Rosales Zabal, Miguel García Deltoro, Ana María Martinez Sapiña, Ana Fuentes, Natalia Chueca, Christoph P. Berg, Andreas Herrmann, Andreas Stallmach, Kerstin Port, M. Katja Deterding, Heiner Wedermeyer, Markus Cornberg, Michael P. Manns, Christophe Moreno, Julian Schulze zur Wiesch, Felix Piecha, Ansgar Lohse, Jürgen Siebler, Nikolaus Kordecki, Lorenzo Magenta, Burkhard Jäger, Hjördis Möller, Renate Heyne, Tomas Beyer, Stephan Grunwald, Axels Baumgarten, Eva Jägel-Guedes, Wolfgang Schmidt
Journal: Journal of Hepatology (2020)
THE GLOBAL IMPACT OF COVID-19 ON GLOBAL AND REGIONAL HEPATITIS C ELIMINATION EFFORTS
Authors: S. Blach, L. A. Kondili, A. Aghemo, Z. Cai, E. Dugan, C. Estes, I. Gamkrelidze, S. Ma, J. M. Pawlotsky, D. Razavi-Shearer, H. Razavi, I. Waked, S. Zeuzem, A. Craxi
Journal: Hepatology (2020)

Background: COVID-19 has placed significant strain on national healthcare systems at a critical moment in the context of hepatitis elimination Mathematical models can be used to evaluate the possible impact of programmatic delays on hepatitis disease burden The objective of this analysis was to evaluate the incremental change in hepatitis C liverrelated deaths and liver cancer, following a 3-month, 6-month, or 1-year hiatus in hepatitis elimination program progress Methods: Previously developed models were adapted for 110 countries to include a status quo or “no delay” scenario and a “1-year delay” scenario assuming significant disruption in interventions (screening, diagnosis and treatment) in the year 2020 Annual, country-level, model outcomes were extracted, and weighted averages were used to calculate regional (WHO and World Bank Income Group) and global estimates from 2020 to 2030 The incremental annual change in outcomes was calculated by subtracting the “no-delay” estimates from the “1-year delay” estimates Results: The “1-year delay” scenario resulted in 44,800 (95% UI: 43,800 - 49,300) excess hepatocellular carcinoma (HCC) cases and 72,300 (95% UI: 70,600 - 79,400) excess liver-related deaths (LRDs), relative to the “no delay” scenario globally, from 2020-2030 Most missed treatments would be in lower-middle income countries, while most excess HCC and LRDs would be among high-income countries Under the “1-year delay” scenario, no regions were projected to reach the WHO targets for diagnosis, treatment or incidence, and only the highincome country group was projected to achieve the target for liver-related deaths Conclusion: The impact of COVID-19 extends beyond the direct morbidity and mortality associated with exposure and infection In order to mitigate the impact on viral hepatitis programming and reduce excess mortality from delayed treatment, policy makers should prioritize hepatitis programs as soon as it becomes safe to do so  (Table Presented)
Abstract 13772: Percent Predicted Peak Oxygen Pulse Predicts Vascular Responses to Exercise in HFpEF
Authors: Jason P Li, John Sbarbaro, Mark Schoenike, Matthew G Nayor, Jennifer E Ho, Gregory D Lewis, Rajeev Malhotra
Journal: Circulation (2020)

Introduction: Cardiopulmonary exercise testing (CPET) can help identify early stages of heart failure with preserved ejection fraction (HFpEF). We sought to determine if percent predicted peak oxygen pulse (%PredO 2 P, as defined by peak oxygen uptake/heart rate), a noninvasive measure combining stroke volume and peripheral oxygen extraction, could serve as a marker of the hemodynamic response to exercise in HFpEF patients. Methods: 154 consecutive patients who underwent maximal CPET (RER&gt;1.05) and were diagnosed with HFpEF (defined as LVEF&gt;50% and PCWP/CO &gt;2 mmHg*min/L or supine resting PCWP &gt;15 mmHg) were included. Exclusion criteria included patients who were taking AV nodal agents, were paced, or had atrial fibrillation. Peak O 2 P and percent predicted were calculated using the Wasserman equation for peak VO2 in conjunction with peak predicted heart rate (220-age). Results: Tertiles of %PredO 2 P were determined with first tertile at 42.1-76.2%, second tertile at 76.2-94.4%, and third tertile at 94.4-139.2%. Baseline parameters differed across %PredO 2 P tertiles ( Table 1 ) with BMI increasing (trend p=0.014). Peak cardiac output (1 st : 10.0±3.0 L/min, 2 nd : 11.1±2.4, 3 rd : 11.5±3.5; p=0.038) and peak stroke volume (1 st : 70.6±20.1 mL, 2 nd : 83.0±16.6, 3 rd : 92.7±20.1; p&lt;0.001) were higher across tertiles, whereas peak HR (1 st : 143±23 bpm, 2 nd : 135±25, 3 rd : 123±26; p&lt;0.001) and peak SVR (1 st : 959±304 dynes*s/cm 5 , 2 nd : 831±187, 3 rd : 810±321; p=0.009) were lower. Exercise PAP/CO slope (1 st : 4.5±2.1 mmHg*min/L, 2 nd : 3.6±1.6, 3 rd : 3.3±1.7; p=0.003) and PCWP/CO slope (1 st : 3.4±1.8 mmHg*min/L, 2 nd : 2.9±1.4, 3 rd : 2.8±2.0; p=0.015) were lower across tertiles of %PredO 2 P. Conclusions: %PredO 2 P is a noninvasive variable that associates with vascular responses to exercise in HFpEF patients. Higher %PredO 2 P was associated with improved vascular responses to exercise with lower SVR, PAP/CO and PCWP/CO slopes.