tbuckley/cabot-search huggingface dataset:
CSIG-18. HYPERMETHYLATION OF SLIT-ROBO PATHWAY GENES RESULTS IN INACTIVATION IN GLIOMA PROGRESSION
Authors: Amber Kerstetter-Fogle, Peggy Harris, Harry Hoffman, Anthony Sloan, Theresa Elder, Marta Couce, Jill Barnholtz-Sloan, Andrew Sloan
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Glioblastomas (GBM) are the most common and malignant primary brain tumors. Their rapid growth and invasion into neuronal parenchyma is devastating, with limited treatment options. Genomic alterations have been extensively studied in gliomas tumors, including aberrations of the Slit-Robo pathway genes. The Slit family of secreted proteins modulates migration of somatic cells during development and mediate their effect by binding to its receptor Roundabout (Robo). Genes in the Slit-Robo pathways have been shown to be inactivated by promoter hypermethylation in a number of human cancers. We hypothesize that Slit-Robo signaling pathways are modulated via promotor methylation, controlling GBM malignancy and regulating the invasive capacity of glioma stem cells (GSCs). METHODS We characterized expression of mRNA and protein via real-time PCR and Western blots in primary GBM tissue. We then assessed whether epigenetic alterations correlate with Slit-Robo expression by conducting in vitro demethylation assays in patient derived GSCs followed by real-time PCR. We conducted invasion assays to elucidate the role of Slit in GSC invasion. RESULTS The Cancer Genome Atlas indicates a negative correlation between Robo2 expression and glioma patient survival (17.1 months versus 37.4 months; p &amp;lt; 1.4E-4). We discovered differential expression of the Slit (1-3) and Robo (2, 3) genes and protein of up to 8-fold between grades 3 and 4 astrocytomas (8.34 versus 4.73 density). Treating patient derived glioma stem cells with 5-aza-2-deoxycytidine results in induction in Slit-Robo gene expression ranging from 5 – 40-fold (p &amp;lt; 0.01). Addition of Slit 2 and 3 in an invasion assay induced migration of GSCs in a differential and concentration dependent manner of 10 - 25% (p &amp;lt; 0.05). CONCLUSIONS Our results suggest that promoter methylation and gene expression of the Slit-Robo genes correlates with protein expression, tumor invasiveness, and prognosis and a potential therapeutic target.
Abstract 11887: High Agreement Between 2D and 3D Echocardiography in Measuring Dimensions of the Patent Ductus Arteriosus in Infants
Authors: Stephan Juergensen, Christine Springston, Michael J Bunker, Phillip Moore, Shafkat Anwar
Journal: Circulation (2021)

Introduction: The patent ductus arteriosus (PDA) is a common lesion in infants. Two-dimensional echocardiography (2DE) is standard for PDA imaging. Three-dimensional echocardiography (3DE) is often used for complex anatomy and for procedural planning. Very limited data exist on use of 3DE of the PDA in infants despite its value in planning interventions. We aim to determine the agreement between 2DE and 3DE in measuring PDAs in infants. Hypothesis: Significant agreement exists between 2DE and 3DE for PDA measurements. Methods: Infants with a known PDA underwent 2DE and 3DE imaging by an IRB-approved protocol. Subjects were &lt;1 year old, &gt;32 weeks corrected gestation (CGA), &gt;1kg, and clinically stable. Parasternal short axis (PSAX) and suprasternal notch (SSN) PDA images were taken. Two blinded observers measured the pulmonic (PA) and aortic (Ao) end of the PDA. Interobserver variability was assessed by interclass correlation (ICC), Bland-Altman (BA), and coefficient of variability (COA). 2DE to 3DE agreement was assessed by BA. Results: For 19 subjects acquired, median CGA 38.0 weeks (IQR 35.6-39.1), median weight 3.07kg (IQR 2.83-4.34). ICC for 2DE and 3DE in all views was &gt;0.98 with narrow limits of agreement (LOA) (Table 1). BA showed low bias and narrow LOA. COA was &lt;3.6%. Paired 2DE-3DE comparison had low bias and narrow LOA (Table 2). Conclusions: PDA measures by 2DE and 3DE have strong interobserver agreement. Paired 2DE-3DE measures show low bias and variability. A larger cohort will test agreement with variable subject size, ductal size &amp; type, and compare to angiography. Preliminary data show promise for 3DE in future use for PDA procedural planning.
Abstract 13311: A Novel Senolytic Drug, Seno-7284 Ameliorates Age-Related Cardiometabolic Diseases
Authors: Goro Katsuumi, Masayoshi Suda, Ippei Shimizu, Yohko Yoshida, Yung-Ting Hsiao, Chien Lun Hsiao, Ryo Furuuchi, Tohru Minamino
Journal: Circulation (2021)

Cellular senescence plays a pivotal role in aging and age-related disorders. Recently, it was shown that elimination of senescent cells, so-called "senolysis" has the potential to become a next generation therapy for age-related disorders including cardio-metabolic diseases. However, currently there is no senolytic drug available in clinical settings. The present study was aimed to identify a novel senolytic reagent effective for cardiometabolic diseases in compounds already available in clinical settings. We demonstrate a compound called "Seno-7284" exhibits senolytic effect in murine models of type 2 diabetes, atherosclerosis, progeroid and chronological aged mice. Seno-7284 reduced the accumulation of senescent cells in visceral adipose tissue of diabetic mice as senescence-associated-beta-galactosidase (SA-beta-gal) staining exhibits. This associated with the suppression in systemic glucose intolerance, and adipose tissue inflammation in four weeks after the administration of Seno-7284. Administrating Seno-7284 for two weeks also suppressed the progression of atherosclerosis in ApoE-KO mice. This drug significantly improved the lifespan of Zm-KO mice by administering it from 12 weeks old. Administration of Seno-7284 from 50 week-old for 20 weeks improves physical function in chronological aged mice. Further analysis including single cell RNA-seq suggested that Seno-7284 stimulates endogenous senolytic function of NK cells and CD8+ T cells. Our results indicate Seno-7284 mediates its biological effects by inducing senolysis in murine aging models. Seno-7284 would become promising therapies for age-related disorders.
Abstract 13024: Excessive Slow Flow and Thick Boundary Layers Cause Non ST Segment Elevation in Patients With Patent Coronary Arteries
Authors: Thach N Nguyen, Phuc X Le, Thoa Le, Nghi V Tran, Le H Minh, Thu Q Nguyen, Thinh Cao, Gianluca Rigatelli, Dung T Ho, Hung N Pham, Nghia T Nguyen Thuong, Marco Zuin
Journal: Circulation (2021)

Introduction: Many patients arrived to emergency room with atypical chest pain, borderline ST segment elevation, troponin level significantly elevated however the coronary angiogram was normal. Why? Hypothesis: Based on damages by flow disturbances in pipes, our research is built on the hypothesis that flow abnormalities disrupt delivery of oxygenated blood to the myocardium. Our strategy is to use today’s practice of fluid mechanics to unlock the mechanism of non-ST Segment elevation myocardial infarction (non-NSTEMI) and patent coronary arteries. What coronary flow abnormalities were the culprit? Methods: Patients with non-STEMI were enrolled if the coronary arteries were patent. In our new dynamic angiographic protocol, contrast was injected until the index coronary artery was completely opacified. Once the manual injection stopped, the blood moved in, displacing the contrast. The movements and directions of the blood flow in “white” color on top of a “black contrast” background could be clearly analyzed. The main focuses were the types of flows and their duration, direction and length. Results: 12 patients with non-STEMI and patent coronary arteries were enrolled. 100% patients had severe slow flow with prolonged arterial phase (&gt;1.8secs) compared with historical control (0.72 secs) (p&lt;0.05). 83% patients had retention flow with thick stagnant boundary layers at the proximal and mid segment of right coronary artery. The retrograde flow was short (0.18secs). Two patients showed excessive contraction of left ventricle. 4 patients revealed history of intense emotional stress however no sign of adrenergic excess (elevated blood pressure, heart rate or extreme peripheral vasoconstriction). All patients recovered and remained asymptomatic after one year follow-up. Conclusions: In non-STEMI and patent coronary arteries, severe slow flow and prolonged retention of thick boundary layers were the culprits. Besides the ischemia caused by delayed delivery of new blood to myocardium, the prolonged retention of thick boundary layers could prevent the intima from absorbing new oxygenated blood and provoked local ischemia. These new discoveries open new management and preventive options for patients with non-STEMI and patent coronary arteries.
Abstract 11917: Reduced Left Atrial Strain Can Predict Higher Risk of Long-Term Major Adverse Cardiovascular Events Post-Myocardial Infarction: A Meta-Analysis
Authors: Sonali Sachdeva, Rupak Desai, Harshwardhan Khandait, TAHA SAEED, Sneha Gupta, Shihla Shireen Kanamgode, Siddharth Bajaj, VARSHA NANDWANA, Zeeshan Gulam Hussain, Ankit Vyas
Journal: Circulation (2021)

Background: Risk stratification after acute myocardial infarction (AMI) is essential to plan management and reduce mortality. Deformation imaging of the left atrium (LA) has tremendous prognostic importance following AMI. LA dilation and larger LA volumes are associated with poor patient outcomes post-MI. LA strain is a more sensitive indicator that can be used to assess major adverse cardiovascular events (MACE) in post-MI patients, however, pooled data exploring its use in predicting long-term outcomes remain limited. Methods: A systematic literature search of PUBMED, Google Scholar, and SCOPUS databases was performed to identify studies reporting the association of MACE and LA strain. Data on the odds ratio (OR) with 95% confidence interval (CI) were collected and pooled to compute the pooled odds ratio using random-effects models. Heterogeneity was assessed using the I 2 test. I 2&gt; 75% was considered a moderate inter-study variation. P&lt;0.05 was considered statistically significant. Results: A total of 6 studies were included with 2931 AMI patients. Baseline characteristics of included studies are shown in Table 1 . The median follow-up in the studies ranged from 6 months to 4 years. Meta-analysis of included studies using random-effects models showed that reduced LA strain was predictive of long-term adverse cardiovascular events following MI (Pooled Odds ratio: 0.93 (0.90-0.96, p=&lt;0.001, I 2 =48%) (Figure 1) . Conclusion: Reduced LA strain is associated with higher major adverse cardiovascular events in post-myocardial infarction patients and can be used in addition to LVEF to evaluate MACE.
Abstract 10772: Telemedicine in a Pediatric Lipid Clinic: Feasibility, Acceptability, and Health Care Disparities
Authors: Julie A Brothers, Katherine Houng, Jared Minetola, Sansanee Craig, Kate Fuller, Tamar J Preminger
Journal: Circulation (2021)

Introduction: During the COVID-19 pandemic, telemedicine became an essential way to provide patient care. We assessed the feasibility, acceptability, and initial impact on health care disparities of using telemedicine in a large pediatric lipid clinic. Methods: Data were collected from a telemedicine (TM) cohort between 4/1/20-3/31/21 and compared to an in-person (IP) cohort between 1/1/19-3/13/20. Families participated in telemedicine visits through an online patient portal. Interpreter services were available. Family surveys were sent after each telemedicine visit; providers were surveyed monthly. We evaluated family and provider satisfaction, cancellation rates, travel-related time and costs, and visit duration (check-in to check-out). Data were analyzed using standard descriptive summaries and student’s t-test. Results: Five providers completed 784 lipid telemedicine visits, accounting for 79% of total visit volume between 4/1/20-3/31/21. Average age was 14 years (+/- 3.8 yrs) and 366 (46.7%) were male. Interpreters were used in 11 (1.4%) visits. Payor mix (Medicaid vs. commercial) was comparable between TM (19.9%) and IP cohorts (22.4%). Of 98 completed telemedicine family surveys, 18 (18.4%) noted technical difficulties; however, nearly all families were interested in future telemedicine visits. Sixteen monthly provider surveys were completed: 31% reported technical difficulties and rated telemedicine 9.1/10. The 48-hour cancellation rate decreased from 11% to 7% (IP and TM cohort, respectively, P &lt; 0.018), with a decrease from 25% to 5% for Non-Hispanic Black patients ( P &lt; .001). No show rates were consistent between cohorts at 2%. Total driving distance saved was 20,800 miles with an estimated travel-related savings of $11,440. Average visit time for IP cohort was 87.5 minutes compared to 39.5 minutes for the TM cohort. Conclusion: We found that using telemedicine in a pediatric lipid clinic is feasible, time efficient, and associated with travel-related time and cost savings. There was a significant decrease in 48-hour cancellation rates overall, most notably for Non-Hispanic Black patients. Future studies utilizing telemedicine in our clinic will evaluate the effect on long term cardiovascular risk and health care delivery.
Abstract 11241: Longitudinal Myocardial Mechanics in Covid-19 Survivors with Normal Left Ventricular Ejection Fraction, a Single Center Study
Authors: Vaibhav Jain, Juan Quintero-Martinez, Sandra C Madera, Katie Young, Garvan Kane, Patricia A Pellikka, Hector I Michelena, Sorin Pislaru, Hector R Villarraga
Journal: Circulation (2021)

Introduction: Subclinical cardiovascular involvement in COVID-19 patients has not been well described. 2D-Speckle Tracking Echocardiography derived global longitudinal strain (GLS) and systolic and early diastolic strain rate (SRs, SRe) measurements are more sensitive than standard echocardiographic parameters to diagnose subclinical mechanical dysfunction in patients with normal Left Ventricle Ejection Fraction (LVEF). Hypothesis: Evaluate subclinical myocardial mechanical function and reserve in active COVID-19 systemic disease patients with normal LVEF vs controls and between survivors and non survivors of COVID-19 in the longitudinal domain of contractility. Methods &amp; Results: 166 adult patients with active COVID 19 having normal LVEF were included and compared to 89 healthy volunteers. Baseline parameters were recorded. Peak GLS, SRs and SRe, were measured offline. Mean age was 62.53 ± 18.96 years and 87 (52%) were males and Mean LVEF was 62±5%. COVID-19 patients had higher GLS compared to controls (-20.93%±0.30 vs. -18.48%±0.40; p value &lt;0.0001), SRs was similar (-0.97 s -1 ±0.10 vs. -0.98 s -1 ±0.02, p value 0.2528) and SRe was lower (0.85 s -1 ±0.0 vs. 1.05 s -1 ±0.02; p value &lt;0.0001) respectively. After adjusting for age and sex, GLS, SRs and SRe was significant (p&lt;0.001). GLS, SRs and SRe were similar in survivors vs. non survivors (p NS), both groups had elevated biomarkers (cardiac troponin, NT-pro BNP, CRP), but non survivors had higher levels (3.22±0.18 vs 3.62±0.28, p = 0.2371, 5.86±0.19 vs 7.15±0.27, p = 0.0004, 3.75±0.14 vs 4.31±0.21, p = 0.0422, 7.64±0.17 vs 8.26±0.25, p=0.0487 respectively) (Table 1). Conclusions: In our cohort, COVID-19 patients had better systolic reserve and abnormal relaxation compared to controls. There was no significant difference in strain (GLS) and strain rate (SRs &amp; SRe) amongst survivors and non survivors in the longitudinal domain of contractility despite of higher inflammatory biomarkers in non-survivors.
Abstract 9781: Electromechanical Optical Mapping in Beating, <i>in Situ</i> Swine Hearts
Authors: Hanyu Zhang, Haley N Patton, Garrett A Wood, Greg P Walcott, Jack M Rogers
Journal: Circulation (2021)

Introduction: Optical mapping is a powerful method for imaging cardiac propagation but is traditionally limited to motion-arrested, ex vivo preparations. Extending the method to beating, in situ preparations will enable study of bidirectional electromechanical interactions and physiological coupling between the heart and the animal. Challenges in adapting optical mapping to this setting include motion artifact, loading of voltage sensitive dye (VSD), and absorption of excitation and emission light by blood. Here, we outline a system to simultaneously image electrical propagation and contraction of intact beating hearts in an in vivo swine model. Methods: Fifteen pigs weighting 25-35 kg were anesthetized. Hearts were exposed via median sternotomy. We glued 20-30 fiducial markers (2 mm, ~1 cm spacing) to the anterior LV epicardium. We injected 14 ml of 50 uM di-4-ANEQ(F)PTEA into a catheter placed in the LAD. Blood flow in the artery was blocked during and for 1 min following the injection. This VSD works at longer wavelengths than commonly used VSDs and is therefore less affected by blood. Fluorescence was excited with alternating amber (602 nm) and green (526 nm) LEDs. Emission was long pass filtered (&gt;700 nm) and recorded at 750 Hz with a pair of video cameras (SciMedia MiCAM03-N256) fitted with 35 mm, f/1.4 lenses . We analyzed marker motion to (1) quantify contraction and (2) partially correct motion artifact in membrane potential ( Vm ) signals. We also computed the ratio of green- to amber-elicited fluorescence on alternate frames to further correct motion artifact. Results and Conclusions: The method successfully images Vm and deformation. The figure shows an isochronal activation map of a paced beat (A), bars aligned with systolic principal strain (B), and Vm and shortening strain signals from selected sites (C). The method can be used to investigate coupled electromechanics and arrhythmogenesis in a more physiologically realistic setting than previous techniques.
Abstract 11425: Vascular Organ-Chips Made from Blood
Authors: Tanmay Mathur, James J Tronolone, Abhishek Jain
Journal: Circulation (2021)

Introduction: Organ-on-chip technology has accelerated in vitro preclinical research of the vascular system, and a key strength of this platform is its promise to impact personalized medicine by providing a primary human cell-culture environment where endothelial cells are directly biopsied from individual tissue or differentiated through stem cell biotechniques. But these methods are difficult to adopt in labs and limit the power of organ-chips in making accurate physiological predictions. Hypothesis: In this study, we report Blood Outgrowth Endothelial Cells as a suitable alternative to primary and iPSC-derived endothelial cells. Through organ-chip and RNA sequencing, we further demonstrate that patient-blood derived BOECs are disease-specific and can differentiate sickle cell disease (SCD) patients. Methods: We isolate BOECs from healthy blood samples and compare their genotype, phenotype and organ-chip functional characteristics against commercially available and most commonly used HUVECs and iPSC-derived endothelial cells. To study patient-specificity, we isolate BOECs from two clinically distinct SCD patients and compare the presence of proinflammatory and endothelial activation pathways as predicted by RNA sequencing of autologous BOECs. Finally, we study the differences in thromboinflammation and endothelial activation between patient BOECs through vessel-chips. Results: Blood-derived endothelial cells exhibit the gold-standard hallmarks of typical endothelial cells. BOECs exhibit the classic endothelial “cobblestone” morphology in vitro and exhibit growth rates, migration abilities, de novo vessel formation, response to fluid shear and exogenous cytokine stimulation in a manner comparable to HUVECs and iECs. When isolated from SCD patients, BOECs exhibit an activated state as predicted by differential gene expression (DGE) and pathway analysis. Finally, real-time healthy whole blood perfusion through endothelialized vessel-chips with BOECs from more severe SCD patient yielded higher platelet adhesion compared to patient with mild severity. Conclusions: Blood-derived endothelial cells may be employed in preclinical research for developing more robust and personalized next-generation disease models.
Abstract 12011: Left Ventricular Hypertrophy Detected by Echocardiogram in Women With HIV
Authors: Karla Inestroza, Bertrand Ebner, Vanessa Hurtado, Sanjana Satish, Ryan Severdija, Quentin Loyd, Louis T Vincent, Jelani Grant, Claudia Martinez
Journal: Circulation (2021)

Introduction: Left ventricular hypertrophy (LVH) is an independent predictor of major cardiovascular events. People with HIV have an increased risk of cardiovascular disease (CVD), and a higher prevalence of LVH has been reported in this population. Women with HIV (WWH) have a higher CVD risk than their male counterparts. We sought to evaluate the current prevalence and characteristics of LVH in WWH. Methods: We performed a retrospective chart review (n=1,202) of patients seen at the University of Miami/Jackson Memorial Hospital Special Immunology clinic between 2017-2019. Of the 547 charts of WWH, 148 had available transthoracic echocardiogram. Data regarding demographic, clinical, imaging, and laboratory results was obtained. Results: The estimated prevalence of LVH in WWH was 25%. The mean age was 56.2 years. WWH with LVH were significantly older (60.7 vs. 54.9 years old, p=0.002), had higher systolic blood pressure (144 mmHg vs. 132 mmHg, p= 0.031), and left ventricle mass (169.2g vs. 128.7g, p&lt;0.001). Those who had LVH had a higher prevalence of diastolic dysfunction (68.8% vs. 40.3%, p=0.007), diabetes (47.4% vs. 18.7%, p=0.001), hypertension (76.3% vs. 54.2%, p=0.017), heart failure (23.7% vs. 7.5% p=0.012), and CVD (47.4% vs. 24.3%, p=0.008). We found no significant difference in those with and without LVH regarding race, ethnicity, body mass index, ejection fraction, statin use, alcohol use, smoking, or HIV-related factors (CD4 count and an undetectable viral load). Conclusions: These findings suggest that WWH have a higher prevalence of LVH in the current era when compared to previous reports (15% in 2009). Furthermore, consistent with prior reports, WWH with LVH had a higher prevalence of CVD in this cohort. These findings emphasize the need to further assess risk and mechanisms for the development of LVH in WWH to help reduce CVD risk in this population.