tbuckley/cabot-search huggingface dataset:
Abstract 9892: Proteomic Profiling of Cardiometabolic Phenotypes: A Comparison of Aptamer-Based and Antibody-Based Affinity Platforms
Authors: Daniel H Katz
Journal: Circulation (2021)

Introduction: High-throughput proteomics with novel affinity reagents for detection of specific proteins is used increasingly in cardiovascular cohort studies and clinical trials. Hypothesis: A detailed comparison of aptamer- vs antibody-based platforms and their associations with cardiometabolic traits (e.g. cholesterol, HbA1c, BMI, blood pressure, atherosclerotic risk) will highlight critical platform differences. Methods: We first compare SomaScan ® 1.3K (“Soma1.3K”, N=1301 reagents) and Olink ® Explore (“Olink”, N=1472 reagents) platforms in 568 adults from the Jackson Heart Study. We also compare Olink to the expanded SomaScan ® 5K (“Soma5K”, N=4979 reagents) in 209 participants from the HERITAGE study. Results: When comparing reagents from each platform that target the same protein, 234/616 such matched reagents are highly correlated, implying accuracy. We alternatively assess accuracy by leveraging whole genome sequencing data: Olink reagents associate with variants near the coding gene ( cis protein quantitative trait loci) for a greater proportion of their protein targets — 40% versus 28% for Soma1.3K (Figure). Principal components analysis reveals 95% of total variance is explained using fewer components on Olink, suggesting Soma1.3K covers more axes of variation. Finally, Olink demonstrates more protein associations (false discovery rate &lt; 5%) with cardiometabolic phenotypes. When limited to matched reagents, Olink identifies more cardiometabolic associations, particularly when measurements are poorly correlated with Soma1.3K. However, on the expanded Soma5K, we identify significantly more proteins associated with cardiometabolic traits. Notably, Olink still finds more associations among poorly correlated, matched reagents. Conclusions: Our data show that antibody-based proteomics may provide greater accuracy and phenotypic associations while aptamers have higher precision and breadth of protein coverage.
Abstract 13999: Atrial-Specific BetaM Protein is a Novel Transcriptional Regulator of Cardiac Hypertrophic Response and Myogenesis
Authors: Nisar Ahmad, Xiaoming Fan, Prabhatchandra Dube, Shungang Zhang, Esha Kashaboina, Eshita Kashaboina, Nikolay Pestov, Rajesh Gupta, saqib masroor, David J Kennedy, Steven Haller, Nikolai Modyanov
Journal: Circulation (2021)

Background: The ability to appropriately repair or regenerate functional cardiac tissue is the major force determining adverse outcomes after cardiac injury. We previously discovered an evolutionary transformation of the Na,K-ATPase BetaM-subunit (encoded by Atp1b4 gene) into a muscle specific transcriptional regulator where it resides in the inner nuclear membrane and regulates the TGF-β signaling pathway through direct interaction with nuclear transcriptional co-regulator Ski-interacting protein (SKIP) and augmentation of inhibitory Smad7 expression. We hypothesized that BetaM is a novel transcriptional regulator of genes involved in cardiac hypertrophy and myogenesis. Methods/Results: RT-PCR and western blot analyses demonstrated that cardiac BetaM is expressed exclusively in intact rat atrial myocytes. Using luciferase reporter assays, we demonstrated that expression of exogenous BetaM in C2C12 cells up-regulates cardiac transcription factors such as myocyte enhancer factor-2 (Mef2, 2 fold), Nkx2.5 (6 fold) and atrial natriuretic factor (ANF, 2 fold). Notably, BetaM also up-regulated endogenous MyoD (a master regulator of myogenesis) mRNA and protein. Furthermore, luciferase reporter assays showed that BetaM up-regulates the MyoD reporter activity (3 fold) in a dose dependent manner. Using chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assays (EMSA) in rat neonatal skeletal muscle, BetaM was identified as a component MyoD-transcriptional complex bound to specific E-box and CArG elements of the distal regulatory region (DRR) region of the MyoD promoter. To further characterize BetaM function in vivo, transcriptome analysis by RNA Seq was performed in myocytes from newborn Atp1b4 KO and WT mice and revealed strong changes in expression of components of the Ca 2+ -Calcineurin – NFATc2 signaling cascade involved in pathological cardiac remodeling and heart failure. Conclusion: Our studies reveal that BetaM regulates the activity of essential cardiac hypertrophic response genes and master regulators of myogenesis indicating that BetaM is a hitherto unknown transcriptional regulator of cardiac hypertrophic response and myogenesis and may represent a novel therapeutic target for cardiac disease.
Abstract 8885: Exercise Capacity as a Prognostic Marker in Renal Transplant Cardiovascular Assessment
Authors: Sean Tan, Yi Wen Thang, William R Mulley, Kevan Polkinghorne, Satish Ramkumar, Kevin Cheng, Adam Brown, Stuart Moir, James D Cameron, Thomas Marwick, Stephen Nicholls, Philip Mottram, Nitesh Nerlekar
Journal: Circulation (2021)

Introduction: Pharmacological stress testing is routinely performed for cardiovascular assessment in kidney transplant candidates due to perceived poor exercise capacity in such patients. Although exercise stress testing is feasible, the prognostic utility of exercise capacity in this patient population has not been investigated. Hypothesis: We hypothesize that exercise capacity predicts long term cardiovascular risk in kidney transplant candidates undergoing exercise stress echocardiography (ESE) for pre-transplant cardiovascular assessment. Methods: We prospectively evaluated 898 patients with stage 4/5 chronic kidney disease from 2013 to 2020 who performed symptom limited treadmill ESE. Exercise capacity was calculated as age and sex predicted metabolic equivalents (METs). The primary outcome was incident major adverse cardiovascular events (MACE), defined as a composite of cardiac death, non-fatal myocardial infarction and stroke. Cox proportional hazard multivariable modelling was performed to identify predictors of MACE, with transplantation treated as a time-varying covariate. Results: There were 106 MACE. During follow up, 525 (58%) received a kidney transplant. Achievement of predicted METs (hazard ratio (HR) 0.49, 95% confidence interval (CI) 0.29-0.82, p=0.007) and transplantation (HR 0.52, 95% CI 0.30-0.91, p=0.02) were independently associated with less incident MACE. Patients who achieved predicted METs had similar rates of MACE irrespective of subsequent transplantation ( Figure 1 , HR 0.78, 95% CI 0.32-1.92, p=0.59). Patients who achieved predicted METs and were not transplanted had similar outcomes to those that did not achieve predicted METs and received a kidney transplant ( Figure 1 , HR 0.97, 95% CI 0.42-2.25, p=0.95). Conclusions: Exercise capacity is associated with reduced MACE in kidney transplant candidates. Achievement of predicted METs confers excellent prognosis independent of subsequent transplantation.
QOLP-11. WORKING MEMORY TRAINING FOR ADULTS WITH GLIOMA
Authors: Sarah Braun, Farah aslanzadeh, Autumn Lanoye, Ashlee Loughan
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND CogMed Working Memory Training (CWMT) is a computer-based program shown to improve working memory (WM) among those with cognitive impairment. No study to date has investigated its feasibility, acceptability, and satisfaction in adult patients with glioma, despite the well-documented incidence of WM impairment in this population. METHODS Twenty patients with glioma and objective and/or perceived WM deficits enrolled in the study: 52% high-grade, 57% female, Mage=47 (range=21-72 years). Adverse events were monitored to determine safety. Feasibility and acceptability were assessed based on established metrics. Satisfaction was explored by exit-interviews. Neurocognitive tests and measures of psychological distress were administered pre-/post-CWMT to assess preliminary efficacy. RESULTS Of 20 enrolled patients, 16 completed the study protocol (80% retention rate). Reasons for withdrawal included time burden (n=2); tumor-related fatigue (n=1) or lost to follow-up (n=1). No adverse events were determined to be study-related. Adherence was 69%. The perceived degree of benefit was only moderate. Pre- to post-CWMT assessments showed medium to large effects on near-transfer tasks (h p 2 =.35, p=.01 and h p 2 =.25, p=.04) and far-transfer tasks (h p 2 =.20, p=.07 and h p 2 =.16, p=.12) but small to no effects on perceived WM (h p 2 =.01, p=.79) and psychological distress (h p 2 =.01-.06, p=.35-.79). CONCLUSION CWMT was found to be safe and acceptable in adult patients with glioma. Enrollment, retention rates, and treatment adherence were all adequate, yet only moderate perceived benefit was reported. Given that objective measures of WM improved but psychological distress did not, it may be worth considering a less burdensome CWMT protocol, perhaps investigating a less time intensive intervention with respect to both frequency and length of training sessions.
Abstract 13429: Intercalated Disk Nanoscale Structure and Ion Channel Distribution Regulate Cardiac Conduction
Authors: Nicolae Moise, Heather Struckman, Rengasayee Veeraraghavan, Seth Weinberg
Journal: Circulation (2021)

The intercalated disk (ID) is a specialized subcellular region that provides electrical and mechanical connections between myocytes in the heart. The ID has a clearly defined passive role in cardiac tissue, transmitting mechanical forces and electrical currents between cells. Recent studies have shown that Na+ channels, the primary current responsible for cardiac excitation, are preferentially localized at the ID, particularly within nanodomains such as the gap junction-adjacent perinexus and mechanical junction-associated adhesion-excitability nodes, and that perturbations of ID structure, such as those that appear in disease states like heart failure or atrial fibrillation, alter cardiac conduction. This suggests that the ID may play an important, active role in regulating conduction. However, no systematic investigation of how ID nanostructure influences cardiac conduction in health or disease has yet been done. Based on our previously published work, we develop an approach to integrate the distribution of ion channels within the ID and ID nanoscale structure in a realistic finite element model, based on experimental measurements from transmission electron microscopy (TEM) and stochastic optical reconstruction microscopy (STORM) images. Tissue-scale simulations demonstrated that ID structural heterogeneity leads to significant spatial variation in electrical polarization within the intercellular cleft. Importantly, we find that this heterogeneous cleft polarization regulates conduction by desynchronizing the activation of post-junctional Na+ currents. Further, we find that disruption of local ID nanodomains can lead to either conduction slowing or enhancing, depending on gap junctional coupling strength. Overall, our study demonstrates that ID nanoscale structure and ion channel distribution can play a significant role in regulating cardiac conduction.
Abstract 10374: Ankle and Toe-Brachial Index for Peripheral Artery Disease Identification: Unlocking Clinical Data Through Novel Methods
Authors: Julia Friberg, Abdul H Qazi, BRENDEN BOYLE, Carrie Franciscus, Mary Vaughan-Sarrazin, Dax Westerman, Olga V Patterson, Sharidan K Parr, Michael E Matheny, Shipra ARYA, Kim G Smolderen, BRIAN LUND, Glenn T Gobbel, Saket Girotra
Journal: Circulation (2021)

Objectives: Develop a natural language processing (NLP) system for identification of patients with peripheral artery disease (PAD). Background: Despite its high prevalence and clinical impact, research on PAD remains limited due to poor accuracy of billing codes. Ankle and toe-brachial index (ABI, TBI) can be used to identify PAD patients with high accuracy using electronic health record (EHR) data. Methods: A random sample of 800 ABI test reports from 94 Veterans Affairs (VA) facilities during 2015-2017 were selected and annotated by clinical experts. We trained the NLP system using random forest models and optimized it through sequential iterations of 10-fold cross validation and error-analysis on 600 test reports and evaluated its final performance on a separate set of 200 reports. We also assessed the accuracy of NLP-extracted ABI and TBI values for identifying patients with PAD in a separate cohort undergoing ABI testing. Results: The NLP system had an overall precision (positive predictive value) of 0.85, recall (sensitivity) of 0.93 and F1-measure (overall accuracy) of 0.89 to correctly identify ABI/TBI values and laterality. Among 261 patients with ABI testing (49% PAD), the NLP system achieved a positive predictive value of 92.3%, sensitivity of 83.1% and specificity of 93.1% to identify PAD when compared to a structured chart review (Table). The above findings were consistent in a range of sensitivity analysis (Table). Conclusion: We successfully developed and validated an NLP system for identifying patients with PAD within the VA’s EHR. Our findings have broad implications for PAD research and quality improvement efforts.
Abstract 14297: Spatially Synchronized Electrogram Islands Within Atrial Fibrillation Predict Termination by Ablation
Authors: Prasanth Ganesan, Brototo Deb, neal bhatia, Miguel Rodrigo, Ruibin Feng, Mahmood Alhusseini, Albert J Rogers, David Krummen, Paul L Clopton, Wouter-Jan Rappel, Sanjiv M Narayan
Journal: Circulation (2021)

Introduction: It is unclear how persistent atrial fibrillation (AF) terminates by any spatial arrangement of ablation lesions. Hypothesis: We hypothesized that AF that exhibits spatial organization with islands of 1:1 synchronized electrograms within the disordered milieu and, specifically, that patients with larger area islands may be more likely to terminate than those without. Methods: We recruited n=60 patients (72% male, age 63±10 years) in whom AF terminated by ablation (n=30; “Term”) or did not (n=30, “Non-term”). Unipolar AF electrograms were recorded by 64-pole basket catheters in both atria. For all possible 2X2 electrode grids, synchronization was assessed by correlation (repeating shapes + relative timings, coefficient, Fig A). Ablation targeted organized sites (rotational/ focal), then pulmonary vein isolation. Results: Fig A shows (top) AF EGMs in a Term patient showing 1:1 patterns at D2-D3-E2-E3 over time (correlation&gt;0.9). For the entire left atrium, there was a large synchronized island &gt;25% of mapped atria (Fig B, red). Bottom panels show less synchronization in a Non-term patient (Fig A), with &lt;5% area (Fig B). For all patients, synchronized islands (with correlation &gt;0.8) were larger for Term (black) than Non-term (gray) patients over a range of time durations (Fig C, p&lt;0.01 ANOVA). Area of synchronized regions predicted AF termination with c-statistic 0.68, and the optimum cut-point provided sensitivity 87% (specificity 43%). Conclusions: Persistent AF shows organized islands of synchronized electrograms, whose size and duration predict the likelihood of termination by ablation. Future studies should investigate the pathophysiology of synchronized islands in AF.
NCOG-25. REVISITING THE PIGNATTI RISK SCORE IN LOW-GRADE GLIOMA PATIENTS IN THE MOLECULAR ERA
Authors: Christine Jungk, Mara Gluszak, Philip Dao Trong, Andreas von Deimling, Christel Herold-Mende, Andreas Unterberg
Journal: Neuro-Oncology (2021)

Abstract Until now, the Pignatti risk score has been used to guide treatment decisions after histological diagnosis of diffuse glioma WHO grade 2. However, its prognostic value was derived from a historic cohort that has been diagnosed by morphologic rather than molecular criteria. We re-challenged the Pignatti score in a contemporary, molecularly characterized cohort. From our institutional cohort of 422 diffuse gliomas WHO grade 2, 202 patients were identified for whom IDH mutation status was known and 1p/19q co-deletion or loss of ATRX expression unambiguously classified tumors into astrocytoma or oligodendroglioma. Patients with IDH wildtype astrocytoma (n=9), multifocal lesions or brainstem involvement were excluded. Potential prognostic factors including the individual items of the Pignatti score (astrocytoma; age ≥40 years; neurologic deficit; maximum tumor diameter ≥6cm; tumor crossing midline) were correlated with progression-free survival (PFS) by univariate log-rank und multivariate Cox regression analysis. 165 patients with astrocytoma or oligodendroglioma were analysed of whom 109 (66%) did not receive adjuvant radio- or chemotherapy. 94 untreated patients with a minimum follow-up of 24 months entered survival analysis. These patients were classified as “high-risk” (Pignatti 3-5) and “low-risk” (Pignatti 0-2) in 15% and 85% and did not differ with regard to potential prognostic factors (gender; resection vs. biopsy; tumor recurrence) other than the individual Pignatti score items. Diameter ≥6 cm (p=0.006; HR=2.18) and midline crossing (p=0.003; HR=3.54) were identified as independent prognostic factors of PFS. Noteworthy, prognostic factors coincided when all patients (n=144) with a minimum follow-up of 24 months, regardless of adjuvant treatment, were analysed. In IDH mutant, molecularly characterized diffuse gliomas WHO grade 2, the Pignatti risk score as a whole no longer seems to be of prognostic relevance. Instead, outcome seems to be determined by tumor burden.
Abstract 14114: Role of Toxic Protein Sequestration by Aggregates in Cardiac Myocytes in Ischemic Cardiomyopathy
Authors: Moydul Islam, David Rawnsley, Xiucui Ma, Layla Foroughi, Chen Zhao, John Murphy, Meredith Jackrel, Carla Weinheimer, Attila Kovacs, Ali Javaheri, Babak Razani, Abhinav Diwan, Kartik Mani
Journal: Circulation (2021)

Introduction: Proteotoxic aggregation causes cardiomyopathy (CMP) associated with rare genetic mutations. The role of protein aggregates in ischemic cardiomyopathy is unclear. Hypothesis: Cardiac myocyte protein aggregation is deleterious in cardiomyopathy. Methods: Human (ischemic) and murine (ischemic and proteotoxic) CMP models were profiled by immunohistochemistry (IHC) and proteomic characterization of the detergent-insoluble fraction. Aggregates were evaluated by immunocytochemistry in p62 deficient neonatal mouse cardiac myocytes (NMCMs) with adenoviral transduction of mutant alpha-B crystallin (CRYABR120G). Mice with cardiac myocyte selective p62 deficiency (p62ckO) were generated and characterized (echocardiography, myocardial structure, autophagic flux, mitophagy, and biochemical analyses). p62cKO and floxed controls were subjected to closed-chest ischemia (90 minutes) or sham followed by reperfusion (IR) and evaluated 4 weeks later. Cardiac selective (AAV9-cTnT) reconstitution of p62, its aggregation-deficient K7R mutant or GFP, was performed. Wild-type mice transduced with a fungal disaggregase (AAV9-Hsp104 or control) were modeled for IR as above. Results: Protein aggregation increases in ischemic CMP, but not controls, with increased insoluble CRYAB with phosphorylation at serine 59 (pS59CRYAB). p62-deficient NMCMs are unable to form aggregates following CRYABR120G transduction, indicating the necessity of p62 in protein aggregation. p62cKO mice show preserved baseline cardiac structure/function, without significantly decreased mitophagy or autophagic flux. Compared to controls, p62cKO mice (post-IR) show infarct expansion and impaired LV remodeling at 4 weeks, associated with decreased sequestration of pS59CRYAB in insoluble fraction. Reconstitution with AAV9 p62, but not aggregation-deficient K7R, shows partial functional rescue after IR. Finally, disruption of protein aggregation by AAV9 Hsp104 (but not controls) results in decreased sequestration of pS59CRYAB, and decreased function post-IR. Conclusions: Contrary to the hypothesis, preventing or disrupting protein aggregation, associated with decreased pS59CRYAB sequestration, is maladaptive in ischemic cardiomyopathy.
DDRE-45. HIGH-THROUGHPUT SCREENING OF EPIGENETIC COMPOUNDS FOR THE TREATMENT OF CHORDOMA IDENTIFIES POTENTIAL NOVEL THERAPEUTICS
Authors: Tadeusz Wroblewski, Philip Tatman, Anthony Fringuello, Sam Scherer, William Foreman, Denise Damek, Samy Youssef, Kevin Lillehei, David Ormond, Michael Graner
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Chordoma is a rare malignant tumor with few treatment options. While surgical resection is deemed the most effective treatment, the 5-year overall survival rate is 61% and 5-year recurrence free survival rate is approximately 50%. To date, no FDA approved pharmacotherapies exist for the treatment of chordoma, and adjuvant therapy remains highly debated. This necessitates the need for further research to provide clinicians with more options to treat this patient population. METHODS In this study, we conducted a high-throughput 139-compound epigenetic inhibitor screen against 12 chordoma patient-derived cell lines; 4 were resected at our institution and 8 were graciously donated by the Chordoma Foundation. RESULTS 8 tumors were located in the sacrum, 3 were located in the mobile spine, and 1 tumor was located in the clivus. 5 tumors were primary, 5 were recurrent, and 2 were metastatic. 6 tumors came from female patients and 6 tumors came from male patients. The top three most effect compounds across the cohort were the G9a inhibitor UNC0631 (cell viability = 64.5% +/-25.1SD; p=1.53x10-9), the KDM inhibitor JIB-04 (cell viability = 68.4% +/-27.2SD; p=9.81x10-8), and the G9a inhibitor BIX01294 (cell viability = 68.6% +/-27.9SD; p=1.27x10-7). No single compound significantly reduced viability in every tumor in the cohort, although the HDAC inhibitor HC Toxin significantly reduced viability in 9 tumors (cell viability = 69.7% +/-16.6SD; p=2.6x10-12). The most effective compound for sacral tumors was UNC0631 (viability = 68.6% +/-22.1SD; p=4x10-7), UNC0631 was also the most effective for spinal tumors (viability = 54.4% +/-32.1SD; p=2.72x10-3), and notably, no significant compounds were identified for the single clival tumor. CONCLUSIONS Based on our drug screen results, epigenetic inhibition, particularly methyltransferase inhibition, may be a promising therapeutic avenue for the treatment of chordomas.