tbuckley/cabot-search huggingface dataset:
Abstract MP236: PI3Kgamma-PP2A Axis In Regulation Of SERCA Function
Authors: Maradumane L Mohan, Conner P Witherow, Robert Papay, Yu Sun, Kate Stenson, Sathyamangla V Naga Prasad
Journal: Circulation Research (2021)

Genetic deletion of Phosphoinositide 3-kinase (PI3Kγ) in mice (PI3Kγ -/- ) results in increased cAMP levels and enhanced ventricular rate/contractility. We investigated whether PI3Kγ plays a role in cardiac contractility by altering intracellular calcium recycling. Caffeine treatment of adult cardiomyocytes from PI3Kγ -/- mice showed significantly reduced calcium reuptake by sarcoendoplasmic reticulum (SR) indicating that PI3Kγ locally regulates SR function. This resulted in elevated levels of intracellular calcium for prolonged period following caffeine. Our findings show that delayed re-uptake of calcium was caused by changes in phosphorylation of phospholamban (PLN), a major regulator of SR calcium reuptake. PI3Kγ -/- cardiomyocytes showed significantly reduced PLN phosphorylation due to increase in PLN-associated protein phosphatase (PP) activity as reflected by decreased demethylated-PP2A. Abrogation of PLN phosphorylation in the PI3Kγ -/- cardiomyocytes shows that the loss in the steady-state phosphorylation of PLN leads to increased inhibition of SERCA. This inhibition is reflected by the slow reuptake of calcium by the SR in the PI3Kγ -/- cardiomyocytes. Concomitantly, significant interaction was observed between SERCA and PLN in the PI3Kγ -/- hearts compared to the controls. Consistently, the altered calcium regulation in the cardiomyocytes of PI3Kγ -/- can be restored by inhibition of PP by okadaic acid. Unexpectedly, cardiomyocyte-specific overexpression of kinase-dead PI3Kγ (PI3Kγ inact ) in the global PI3Kγ -/- cardiomyocytes normalized caffeine induced calcium reuptake, restored PLN phosphorylation, and decreased PLN-associated PP activity reflected by increased demethylated-PP2A. These studies bring-to-fore an unrecognized kinase-independent regulation of PLN by PI3Kγ through PP2A with implications in deleterious cardiac remodeling as PI3Kγ is significantly upregulated following cardiac stress.
Abstract 11065: Continuation versus Discontinuation of Beta Blockers in Patients Admitted with Acute Decompensated Heart Failure Requiring Inotropes
Authors: Kirsten Raby, Charles A German, Austin Seals, Jiaqian Xu, Eric Crespo, Stan Green, Dion Banoian, Thomas Hilton, Kevin Goslen, Barbara A Pisani
Journal: Circulation (2021)

Introduction: Heart failure is one of the leading causes of morbidity and mortality globally. The use of beta blockers (BB) in patients with chronic heart failure is the cornerstone of guideline directed medical therapy and is recommended by national guidelines. However, BB are often discontinued when a patient is admitted to the hospital with ADHF, especially when inotropic support is needed. Little is known about the effects of continuing BB therapy in patients with ADHF requiring inotropes. This study sought to compare the effect of BB continuation vs discontinuation on in-hospital mortality among patients admitted to the hospital in ADHF requiring inotropic therapy. Methods: A single center, retrospective, non-blinded study was conducted in patients hospitalized with ADHF requiring inotropes over a three-year period. Inclusion criteria were patients ≥ 18 years of age admitted with ADHF and treated with inotropes (milrinone, dobutamine) from 1/1/2017-1/1/2020 at Wake Forest Baptist Medical Center. We assessed BB continuation and discontinuation on admission. Continuation of BB was defined as BB given at least 50% of patient’s hospitalization time. A time to event analysis framework was implemented using Cox proportional hazards models to analyze the effect of BB use on in-hospital mortality. Results: A total of 449 patients were admitted with ADHF requiring inotropes who met study criteria. Of those patients, 206 (45.9%) were admitted and continued on BB therapy. Continuation of BB therapy was associated with significant improvements in survival compared with patients whose BB was discontinued. Compared with the BB discontinuation group, a 70% reduction in the likelihood of in-hospital mortality was observed among individuals that continued BB therapy [HR 0.30, 95% Cl: 0.18-0.61, p&lt;0.002]. Conclusion: In our study, among patients admitted with ADHF requiring inotropes, those continued on BB therapy were 70% less likely to die during their hospitalization.
Abstract 9735: Cost Effectiveness of Screening for Valvular Heart Disease Using the Valvenet Deep Learning Electrocardiogram Model
Authors: Timothy J Poterucha, Pierre Elias, Rebecca T Hahn, Tamim Nazif, Mathew S Maurer, Andrew J Einstein, Martin B Leon, Adler Perotte, David J Cohen
Journal: Circulation (2021)

Background: Valvular heart disease (VHD) is an important contributor to CVD morbidity and mortality. The ValveNet model uses deep learning analysis of ECGs to detect moderate or severe left sided valve disease (LSVDz) including aortic stenosis (AS), aortic regurgitation (AR), and mitral regurgitation (MR) alone and in combination. A screening program using it may allow cost effective VHD screening. Methods: The ValveNet deep learning algorithm was tested on 26,606 ECGs from unique patients (pts) (LSVDz prevalence 8.6%) and demonstrated a sensitivity 81.3% and specificity 70.2% for LSVDz detection. We developed a decision analytic model to examine the cost-effectiveness of VHD screening using 3 approaches: (1) No screening, (2) ValveNet-assisted ECG with TTE in pts with positive ECGs (ValveNet Screen Strategy), and (3) up-front TTE (TTE Up-Front). Cost effectiveness was assessed as the incremental cost to detect a case of LSVDz. Costs were based on Medicare rates and assumed that ValveNet had negligible costs above a standard ECG. Sensitivity analyses were conducted across a range of prevalence levels and costs. Results: At a LSVDz prevalence of 5%, the ValveNet strategy was projected to identify significant LSVDz in 81% of prevalent cases at a cost of $175 per pt with an incremental cost-effectiveness ratio (ICER) of $4308/LSVDz detected compared with no screening. Compared with the ValveNet strategy, the ICER for TTE Up-Front was $34,169 per additional case of significant LSVDz detected and was highly prevalence-dependent (Figure). Additional multiway and fully probabilistic sensitivity analyses will be presented. Conclusions: A screening strategy using the ValveNet ECG model may detect a large proportion of significant LSVDz while providing cost savings compared with routine TTE screening. If ongoing studies demonstrate benefit of early treatment of asymptomatic valve disease, the ValveNet approach may be a cost-effective approach to community VHD screening.
Progression-Free Survival (PFS) According to the Presence of Adverse Cytogenetic Abnormalities in Patients (pts) with Multiple Myeloma (MM) Receiving Ixazomib (ixa)-Based vs Placebo (pbo)-Based Therapy: A Pooled Analysis of the TOURMALINE-MM1, MM2, MM3, and MM4 Phase 3 Studies
Authors: Wee-Joo Chng, Sagar Lonial, Gareth J. Morgan, Shinsuke Iida, Philippe Moreau, Shaji Kumar, Philip Twumasi-Ankrah, Arun Kumar, Ajeeta B. Dash, Alexander Vorog, Xiaoquan Zhang, Kaveri Suryanarayan, Richard Labotka, Meletios A. Dimopoulos, S. Vincent Rajkumar
Journal: Blood (2021)
Neurotoxicity of Axicabtagene Ciloleucel and Long-Term Outcomes - in a Minority Rich, Ethnically Diverse Real World Cohort
Authors: Ryann Quinn, Astha Thakkar, Sumaira Zareef, Richard Elkind, Karen Wright, Karen Fehn, Susan Sakalian, Michelly Abreu, Alyssa De Castro, Jennat Mustafa, Fariha Khatun, Amanda Lombardo, Latoya Townsend Nugent, Kira Gritsman, Mendel Goldfinger, Noah Kornblum, Aditi Shastri, Ioannis Mantzaris, Lizamarie Bachier Rodriguez, Lili Zhang, Katharine McNeill, Elizabeth Michell, Mark Milstein, Amit Verma, Ira Braunschweig, R. Alejandro Sica
Journal: Blood (2021)
Abstract 14448: National Adherence to Guideline-Directed Medical Management of Aortic Disease
Authors: William L Patrick, Fabliha Khurshan, Joseph E Bavaria, Peter W Groeneveld, Siddharth Yarlagadda, Jake Rosen, Josua C Grimm, Wilson Y Szeto, Nimesh D Desai
Journal: Circulation (2021)

Introduction: Guidelines for the medical management of aortic (AD) and coronary artery disease (CAD) recommend treatment for hypertension (HTN), hyperlipidemia (HLD), and tobacco use (TU) (Class 1). Hypothesis: Adherence to guidelines for the management of AD is low, and inferior to CAD. Methods: Adults in the Clinformatics Data Mart database diagnosed with AD or CAD and concomitant HTN, HLD, and/or TU between 2004 and 2019 were included. Those with less than six months of continuous enrollment or prior cardiovascular procedures were excluded. Adherence was calculated as the proportion of patients with a given comorbidity (or combination thereof) who received a prescription for the appropriate intervention. Any beta-blocker, ACEi, or ARB for HTN. Any statin for HLD. Bupropion, varenicline, or referral to counseling for TU. Composite adherence for patients with AD and CAD was compared using a Z-test. Temporal trends were analyzed using a Chi-square test for trend. Results: There were 354,851 patients with AD and 907,997 with CAD who met the inclusion criteria. Composite adherence was 50% for those with AD compared to 59% for CAD (p&lt;0.01). No clinically-significant changes in composite adherence overtime occurred for either group (Figure 1A). Among those with AD, adherence was highest among those with HTN alone (73%), followed by combined HTN/HLD (58%) and HLD alone (45%). Diagnosis of TU was associated with lower adherence across all risk factor combinations. There has been a significant improvement in adherence for TU overtime (p&lt;0.01) (Figure 1B). Conclusions: Adherence to guidelines for medical management of AD is low, and significantly lower than for CAD.
Abstract 11603: Pulmonary Artery Dilation in Submassive Acute Pulmonary Embolus and Chronic Thromboembolic Pulmonary Hypertension
Authors: Nupur Dandawate, Jasleen Minhas, Pietro Nardelli, Ruben San Jose Estepar, Gregory Piazza, George Washko, Raul San Jose Estepar, Farbod Rahaghi
Journal: Circulation (2021)

Introduction: CT imaging is the primary mode of diagnosis of acute pulmonary embolus. At initial presentation, both patients with acute PE and undiagnosed decompensated CTEPH may present with similar clinical findings of presence of clot and RV dysfunction. Extraction of markers of disease from CT scans at the point of diagnosis may help with clinical decision making. In this study we compare two CT markers of disease severity in patients with submassive PE and CTEPH. We hypothesized that higher pressures and thus increased dilation of the pulmonary artery would be hemodynamically tolerated in the chronic disease. Methods: We conducted a retrospective chart review study at Brigham and Women’s Hospital for patients with acute submassive PE between 2009-2017. Patients with adequate imaging and at least one positive right ventricular echocardiogram findings were included. The CTEPH cohort consisted of patients with CT imaging within one year of RHC proven CTEPH and patients from the submassive PE cohort found to have subsequently been diagnosed with CTEPH. The ratio of the main pulmonary artery (PA) to aorta (A) and RV to LV diameter ratio were measured by multiple operators to confirm reproducibility. All data collection was approved by the IRB at Mass General Brigham. Data was analyzed using R version 4.0.1 and Wilcoxon Rank-sum test with two-sided p-values for differences. Medians and interquartile ranges are reported. Results: 355 patients with the diagnosis of acute submassive PE and positive echo findings and 31 patients with CTEPH were included. Patients with acute PE were older (63 [53-73] vs 48 [41-67] p= 0.003) and had a similar fraction of females (190/355 vs 17/31). PAA was significantly higher in the CTEPH cohort (1.16 [0.97-1.32] vs 0.94 [0.85-1.04] p &lt; 0.0001) as was the RV/LV ratio (1.44 [1.34-1.57] vs 1.31 [1.16-1.46]; p = 0.0005). Conclusions: Patients with CTEPH have a higher PA/A ratio than patients with submassive PE and echocardiographic signs of RV dysfunction. This study is limited in part because of the time between imaging and diagnosis of CTEPH, and lack of definitive follow-up for all acute PE cases. Prospective data collection would help evaluate clinical utility of CT markers in identifying chronic disease.
Is Nature Truly Healing Itself? Spontaneous Remissions and Clonal Replacement in Paroxysmal Nocturnal Hemoglobinuria
Authors: Carmelo Gurnari, Simona Pagliuca, Tariq Kewan, Waled Bahaj, Ishani Nautiyal, Christopher Haddad, Minako Mori, Valeria Visconte, Jaroslaw P. Maciejewski
Journal: Blood (2021)
Abstract 13938: Multi-Chamber Strain Characterization Provides Incremental Prognostic Value to Cardiac Damage Staging in Significant Aortic Stenosis
Authors: Zi Ye, Li-Tan Yang, Maurice E Enriquez Sarano, Hector I Michelena
Journal: Circulation (2021)

Introduction: The survival impact of impaired multi-chamber longitudinal strain in significant tricuspid aortic valve stenosis(TAV-AS) and its relation to cardiac damage staging(CDS) is unknown. Hypothesis: Impaired strain improves prognostication of CDS in significant TAV-AS. Methods: We performed 2D-semi-automated strain analysis in a retrospective cohort of consecutive patients with TAV-AS with mean pressure gradient≥30mmHg on echocardiogram. The outcome was all-cause death. Cutoffs of impaired left-ventricular global longitudinal strain(
Abstract 14343: Predictive Value of Myocardial Strain for Chimeric Antigen Receptor T-cell Therapy Associated Cardiovascular Events
Authors: Nikita Patel, Prarthana Dalal, Gregory Cascino, Arjun Sinha, Ashwin Sunderraj, Matthew Feinstein, Nausheen Akhter
Journal: Circulation (2021)

Introduction: Cardiovascular events following Chimeric Antigen Receptor (CAR) T-cell therapy are increasingly recognized. Left ventricular systolic dysfunction and arrhythmias are the most common cardiac toxicities seen. Thus, cardiac risk stratification in this population is important, especially in adults with subclinical cardiac disease. Although left ventricular global longitudinal strain (LV-GLS) has demonstrated prognostic utility for other cancer therapy related cardiac dysfunction, less is known regarding predictors of adverse cardiac events following CAR T-cell therapy. We determined the association of baseline LV-GLS with adverse cardiovascular events in adults receiving CAR-T cell therapy. Methods: We identified 75 patients who had baseline LV-GLS measurements available within 6 months of initiating CAR T-cell therapy at a large urban medical center from 2016-2020. Demographics, malignancy history, treatment data, cardiovascular risk factors, echocardiographic measurements (LV-GLS and left ventricular ejection fraction (LVEF)), and cardiac events were retrospectively collected via chart review. Absolute value of LV-GLS was used for ease of interpretation. Multivariable logistic regression was used to determine the association of LV-GLS (per 1% rise) with cardiovascular events with adjustment for age, BMI, CAD, HTN, HLD, DM, and previous cardiotoxic chemotherapy. Results &amp; Conclusions: There were 10 CAR T-cell therapy-related cardiac events, including 1 death, 3 new/worsening cardiomyopathies, and 6 new/worsening arrythmias. Higher baseline LV-GLS (per 1% rise in absolute value) was associated with a significantly lower risk of cardiovascular events (OR 0.66, 95% CI 0.46, 0.96). These findings suggest LV-GLS may risk-stratify adults receiving CAR T-cell therapy for therapy-related cardiac toxicity. Additional prospective studies in other cohorts are needed to corroborate these findings.
Abstract 11460: Antibodies to Citrullinated Protein Antigens Are Associated with Inflammatory Markers in a Multi-Ethnic Community-Living Population: The Multi-Ethnic Study of Atherosclerosis
Authors: Maedha Begur, Simon Schenk, Michael H Criqui, Maripat P Corr, William Robinson, Jan M Hughes-austin
Journal: Circulation (2021)

Introduction: Individuals with antibodies to citrullinated protein antigens (ACPA) have higher risk for cardiovascular disease (CVD). Cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNFα), have been identified as pro-atherogenic. While the association between ACPA and cytokines has been studied in rheumatoid diseases, it has not been studied in the general population. We hypothesized that ACPA are positively associated with IL-6, c-reactive protein (CRP), and TNFα; and that gender and race/ethnicity modify this association. Methods: In 1743 Multi-Ethnic Study of Atherosclerosis participants without clinical CVD, we evaluated the association between number of ACPA and IL-6, CRP, and TNFα using multivariable linear regression. We adjusted for demographics, CVD risk factors, and medication use; and tested for interactions by gender and race/ethnicity. ACPA was measured as an array of 38 individual ACPA with the cut-off for positivity for each antibody set at the 95 th percentile. CRP, IL-6, and TNFα were measured in serum of fasting participants; values were log-transformed to reduce skewness. Results: Average age was 64.7±9.7 years; 50% were women, 40% Caucasian, 13% Chinese American, 21% African American, and 26% Hispanic American. Approximately 31% (537) had at least one positive ACPA. In the fully adjusted analysis, each additional ACPA was associated with 0.3±0.1% (p=0.005) higher serum IL-6 and 0.6±0.2% (p=0.007) higher CRP. ACPA was not associated with TNFα. Associations of ACPA with CRP were modified by gender (p interaction = 0.000) and race/ethnicity (p interaction = 0.000). In men, each additional ACPA was associated with 0.4±0.1% (p=0.015) higher IL-6 and 0.7±0.2% (p=0.007) higher CRP. In women, this association was not observed. In Hispanic participants, each additional ACPA was associated with 0.3±0.2% (p=0.049) higher IL-6 and 0.8±0.3% (p=0.010) higher CRP; in Caucasian participants, each additional ACPA was associated with 0.4±0.2% (p=0.014) higher IL-6 and 0.6±0.3% (p=0.026) higher CRP. This association was not observed in Chinese or African American participants. Conclusion: In a multi-ethnic community-dwelling population, higher number of ACPA was associated with higher IL-6 and CRP.
Engineering Tissues of the Central Nervous System: Interfacing Conductive Biomaterials with Neural Stem/Progenitor Cells
Authors: Rebecca D. Bierman‐Duquette, Gevick Safarians, Joyce Huang, Bushra Rajput, Jessica Y. Chen, Ze Zhong Wang, Stephanie K. Seidlits
Journal: Advanced Healthcare Materials (2021)

Conductive biomaterials provide an important control for engineering neural tissues, where electrical stimulation can potentially direct neural stem/progenitor cell (NS/PC) maturation into functional neuronal networks. It is anticipated that stem cell-based therapies to repair damaged central nervous system (CNS) tissues and ex vivo, "tissue chip" models of the CNS and its pathologies will each benefit from the development of biocompatible, biodegradable, and conductive biomaterials. Here, technological advances in conductive biomaterials are reviewed over the past two decades that may facilitate the development of engineered tissues with integrated physiological and electrical functionalities. First, one briefly introduces NS/PCs of the CNS. Then, the significance of incorporating microenvironmental cues, to which NS/PCs are naturally programmed to respond, into biomaterial scaffolds is discussed with a focus on electrical cues. Next, practical design considerations for conductive biomaterials are discussed followed by a review of studies evaluating how conductive biomaterials can be engineered to control NS/PC behavior by mimicking specific functionalities in the CNS microenvironment. Finally, steps researchers can take to move NS/PC-interfacing, conductive materials closer to clinical translation are discussed.
NIMG-08. A MULTI-CENTER RADIOMICS-BASED MODEL TO DIFFERENTIATE BETWEEN NEUROFIBROMATOSIS TYPE 1-ASSOCIATED PLEXIFORM NEUROFIBROMAS AND MALIGNANT PERIPHERAL NERVE SHEATH TUMORS
Authors: Ina Ly, Tianyu Liu, Wenli Cai, Daniel Kwon, Olivia Michaels, Miriam Bredella, Justin Jordan, Eva Dombi, Brigitte Widemann, Angela Hirbe, Dana Borcherding, Divya Srihari, Mairim Melecio-Vázquez, Ping Chi, Demetrius Boswell, Peter de Blank, Kai Pollard, Christine Pratilas, Johannes Salamon, Viktor Mautner, Zachary Mulder, Matthew Steensma, Shernine Lee, Bruce Korf, Jaishri Blakeley, Scott Plotkin
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Several MRI features are proposed to distinguish between plexiform neurofibromas (PNF) and malignant peripheral nerve sheath tumors (MPNST) in neurofibromatosis type 1 (NF1), including tumor size, margins, and degree of heterogeneity. However, most of these features are descriptive in nature, subject to intra-/interrater variability, and based on small single-institution studies. The goal of this study was to identify radiomic features that can differentiate between NF1-associated PNF and MPNST. METHODS 31 MPNSTs and 24 PNFs from five centers were segmented on short TI inversion recovery sequences using a semi-automated segmentation software (3DQI). Standard pre-processing was performed, including N4 bias field correction, intensity normalization (using a mean of 120 SI and standard deviation of 80 SI), and resampling to 1 mm3 voxel resolution. 1688 radiomic features were extracted from the tumor region of interest using PyRadiomics, an open-source Python radiomics package. To classify tumors as PNF or MPNST, we implemented the Boruta algorithm and correlation removal for selection of important features. A Random Forest model was built using the top ten selected features. Five-fold cross-validation was performed and repeated 100 times. Model performance was evaluated using the area under the ROC curve (AUC), sensitivity, specificity, accuracy, and confidence intervals. RESULTS The top ten features included in the model were five intensity features, two shape features, and three texture features. The model demonstrated an AUC of 0.891 (95% CI 0.882-0.899), sensitivity of 0.744, specificity of 0.847, and accuracy of 0.802 (95% CI 0.792-0.813). CONCLUSIONS Our machine learning model demonstrated high performance in classifying tumors as either PNF or MPNST in NF1 individuals. Inclusion of additional tumors for model training and testing on an independent dataset are underway. Ultimately, our model may enable improved differentiation between PNF and MPNST compared to descriptive MRI features, permit early patient risk stratification, and improve patient outcomes.