tbuckley/cabot-search huggingface dataset:
Abstract 11320: Ablation of Sam68 in Cardiomyocytes Attenuates Cardiac Hypertrophy but Exacerbates Heart Failure
Authors: Ying Jiang, Shiyue Xu, Junlan Zhou, Chan Boriboun, Chaoshan Han, Wenxia Ma, Aijun Qiao, Gangjian Qin
Journal: Circulation (2021)

Background &amp; Hypothesis: Src-associated-in-mitosis-of-68-kDa (Sam68) is a pleotropic adaptor protein shown to regulate signal transduction, RNA splicing, cell cycle, differentiation, and energy metabolism. Its function in the heart has never been studied. We hypothesize that Sam68 regulates cardiac hypertrophy and heart failure. Methods &amp; Results: Pressure overload was induced by Ang II infusion (via osmotic pump) in 12-week-old male Sam68 -/- , Sam68 +/- , and WT littermates, followed by weekly assessments with echocardiography; Sam68 -/- mice displayed attenuated left ventricular (LV) wall thickness compared to Sam68 +/- or WT littermates. We then generated Sam68 floxed mice and, by crossing with α-MHC-Cre transgenic (Cre Tg ) mice, obtained cardiomyocyte-specific Sam68 knockout (Sam68 CM-KO ) mice. Consistently, Ang II-induced LV wall thickening was attenuated in Sam68 CM-KO mice compared to Cre Tg littermates, confirming an autonomous role of Sam68 in promoting cardiac hypertrophy. Interestingly, in the surgically-induced transverse-aortic-constriction (TAC) model, Sam68 CM-KO mice, while had an overall lesser LV wall hypertrophy over the course of 6 weeks, displayed higher rates of immediate post-surgery mortality and later-stage LV dilation and ejection-fraction drop, than Cre Tg littermates. The Sam68 CM-KO mouse hearts showed smaller cross section area, fibrosis area, and cardiomyocyte size than Cre Tg mouse hearts. To gain mechanistic insights, we engineered a lentiviral vector coding for a Sam68 shRNA, which knocked down Sam68 protein expression in H9C2 cells (H9C2 Sam68KD ) by more than 90% (after selection). Sam68 knockdown led to a marked reduction in the expression of Raptor (by &gt;50%), Rictor (by &gt;50%), and ATG13 (by &gt;80%) proteins, but no change in the level of mTOR protein or the mRNA expression of Raptor, Rictor, and ATG13. Furthermore, in H9C2 Sam68KD , starvation-induced autophagy flux was increased as shown by elevated LC3II/LC3I ratio with Bafilomycin A treatment. Conclusions: Sam68 promotes cardiac hypertrophy and protects against heart failure likely through the activity of mTOR complexes.
Abstract 11720: Loss of Vascular Smooth-Muscle Activity During Moderate Physical Activity as a Hallmark of Aging in Human Subjects
Authors: Vladimir Shusterman, Stacy Hoffman, Barry London
Journal: Circulation (2021)

Studies have shown a higher risk of adverse outcomes after cardiac surgery in patients with reduced complexity of arterial-pressure dynamics (APD). We hypothesized that this effect is caused by age-related loss of vascular smooth-muscle activity (VSMA). This hypothesis was tested using data from 30 humans and a validated, large-scale theoretical model of circulation with VSMA blocked (T-model). The results were also verified in a realistic physical model of circulation (P-model, Fig.1). Methods: ECG and APD data were recorded using a high-fidelity system (APEX, PinMed, Inc.) during moderate physical activity (handgrip followed by leg lifts) in 30 subjects (age: 46±10y, 53% female; pressure ranges for systolic, diastolic, and mean: 90-210, 49-116, and 67-147mm, respectively). Results: T-model accurately predicted APD in older subjects ≥48y (n=13, r 2 =0.74; Fig.2); this effect was preserved in both females and males, but not in younger subjects (n=17, r 2 =0.13). The difference between the older and younger subjects was pronounced (40%) and significant (p=0.01, F-test). In P-model, changes in cardiac force produced changes in central arterial pressure that were in excellent agreement with those observed in humans ≥48y (r 2 =0.93, Fig.3). Conclusions: Loss of VSMA during physical activity could serve as an important prognostic/diagnostic indicator of cardiovascular aging and disease.
Abstract 11554: Measures of High-Density Lipoprotein Function and Composition in Men and Women with Severe Aortic Valve Stenosis
Authors: Anouar Hafiane, Elda Favari, Anna E Bortnick
Journal: Circulation (2021)

Introduction and Hypothesis: Aortic valve calcification (AVC), is the intrinsic mechanism of valvular obstruction in severe aortic stenosis (AS), sharing similarities with atherosclerosis. There are differences in AVC by sex, with women having a lower burden of calcification than men, but the mechanism for this is unclear. Improved HDL functionality has been associated with protection against coronary artery calcification, but its relationship to AVC is less studied. Methods: We evaluated measures of high-density lipoprotein (HDL) functionality in 46 patients with severe AS, n= 30 men, n=16 women. ATP-Binding Cassette A1 (ABCA1) mediated cholesterol efflux capacity (CEC) was measured from human cultured Tamm-Horsfall protein 1 (THP-1) macrophages to apoB-depleted patient plasma samples. Lipid profile, lecithin-cholesterol acyltransferase activity (LCAT), fast protein liquid chromatography (FPLC), HDL size, and small pre-β1 and α-HDL particles, were measured in apolipoprotein B-depleted patient plasma. Proteomic analysis was used to explore sex-based differences in the HDL proteome. Results: Women with severe AS had higher ABCA1-mediated CEC, as compared to men (n=46, p=0.04). We found differences in FPLC profiles between sexes in severe AS along with a reduction in preβ and α-particles in men vs women by spectral counts, (preβ-HDL, 15661.74±789.00 vs 20298.29±1076.15, p=0.002), and (α-HDL, 50447.00± 546.52 vs 63006.35±756.81, p=0.03). Conversion of free cholesterol into cholesteryl esters by LCAT was decreased in men vs. women (12.00±8.07 %/h vs 16.44±9.11 %/h, p=0.03). We identified 108 HDL-associated proteins in a representative man and woman, of which, 15 were found only in the female sample Conclusions: Sex-specific differences in measures of HDL functionality were found in patients with severe AS. Future studies should consider whether sex-based differences in HDL functionality might account for the decreased burden of calcification in women vs. men with severe AS.
Abstract 12444: Smooth Muscle-Specific Deletion of Perk Prevents Atherosclerotic Plaque Formation in Mice
Authors: Abhijnan Chattopadhyay, Suravi Majumder, Pujun Guan, Chen Zhang, Anita Kaw, Zhen Zhou, Kaveeta Kaw, Callie Kwartler, Scott A Lemaire, Ying H Shen, Dianna M Milewicz
Journal: Circulation (2021)

Introduction: Lineage tracing and single cell RNA sequencing (scRNA-Seq) studies have identified a subset of phenotypically modulated vascular smooth muscle cells (SMCs) that appear with atherosclerotic plaque formation in hyperlipidemic mice. These modulated SMCs (mSMCs) are de-differentiated, and increase expression of macrophage, fibroblast and stem cell markers. We previously showed that SMCs exposed to free cholesterol in vitro activate an endoplasmic reticulum unfolded protein response (UPR) and assume an mSMC phenotype, and blocking Perk specifically abolishes this SMC modulation. Methods: Here, we sought to define the role of Perk in atherosclerotic plaque formation using SMC-specific Perk knockout in C57BL6 mice ( Perk SMC-KO ) and inducing hyperlipidemia by PSCK9 DY overexpression and a high fat diet for 12 weeks. Results: Aortic Oil Red O staining and en face aortic analysis revealed no plaque formation in the Perk SMC-KO aorta, with the exception of some small plaques in the root, whereas the wild-type (WT) aortas had extensive plaque, especially in the aortic arch (N = 10, p&lt;0.0001, Fig. 1A ). scRNA-Seq analysis of aortic tissue from the root to the arch from these mice showed no major differences in cell clusters between Perk SMC-KO and WT mice at baseline ( Fig. 1B ). In hyperlipidemic WT mice, SMC-derived cluster 8 expands and a new cluster 7 appears (circled in red, Fig. 1B ). In Perk SMC-KO mice, cluster 8 is similarly expanded with hyperlipidemia, while cluster 7 is completely absent ( Fig. 1B , bottom right). Cluster 7 in the WT atherosclerotic aortas is the only cluster with Perk expression and has significantly increased expression of macrophage markers and a subset of fibroblast-specific markers when compared to cluster 8. Conclusions: These data indicate that SMC phenotypic modulation plays a major role in atherosclerotic plaque formation and Perk is a key regulator of the SMC modulation that specifically contributes to atherosclerotic plaque burden.
Abstract 10116: Sex and Race Disparities in Mitral Regurgitation Related Mortality Rates Among Older Adults; Data from CDC Wonder 1999-2019
Authors: Abdul Minhas, Robert Ariss, SALIK NAZIR, Waqas Ullah, Muhammad Osama Muslim, Marat Fudim, Khurram Nasir
Journal: Circulation (2021)

Mitral regurgitation (MR) is the second most common valvular heart disease in the United States with recent improvements in the management of MR including percutaneous therapies. However, MR-related mortality may vary across sex and race groups in the elderly population. Methods: We used CDC Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) to access National Vital Statistics System data from 1999 to 2019. MR related deaths, age ≥75 years were identified from multiple causes of death and were represented as age-adjusted mortality rates (AAMR) per 100,000 population. Joinpoint regression was used to examine changes in trend and annual percentage change (APC) overall and stratified by sex and race groups. Results: AAMR related to MR decreased from 29.0 in 1999 to 15.4 in 2012 and then increased to 16.4 in 2019 (2012-2019 APC 1.2 [95% CI, 0.5 to 2.0]). AAMR was higher in women (19.6) compared with men (18.6). Among the race groups, AAMR was highest in non-Hispanic whites (NHWs) (20.8) followed by non-Hispanics Others (NH Others) (includes American Indian or Alaska Natives and Asian or Pacific Islanders) (12.7), non-Hispanic blacks (NHBs) (10.5) and lastly Hispanics (10.1). AAMR was highest in NHW females (21.1). After an initial decline, APC in AAMR increased in both men (1.4) and women (1.0) since 2012 and NHWs (0.9) since 2011. AAMR decreased in NHBs (APC -5.0) till 2009 and Hispanics (APC -4.6) until 2013 and remained stable thereafter. APC in AAMR decreased in NH-Others (-1.9) during the entire study period. Conclusion: After initial decline, MR related mortality has been increasing recently. Significant disparities exist across various sex and race subgroups. Further studies are needed to understand these trends and address the underlying causes of the disparities and increasing mortality in this patient population.
A Phase I/II Study of Bosutinib in Pediatric Patients with Resistant/Intolerant or Newly Diagnosed Philadelphia Chromosome-Positive Chronic Myeloid Leukemia, Study ITCC (Innovative Therapies for Children with Cancer European Consortium) 054 and COG (Children's Oncology Group Consortium) AAML1921: Results from the Phase I Trial in Resistant/Intolerant Patients
Authors: Edoardo Pennesi, Erica Brivio, Marieke E. Willemse, Alwin D. R. Huitema, Saurabh Chandra, Ashwini Vijayakumar, Vincent H.J. Van Der Velden, H. Berna Beverloo, Chandra Durairaj, Andrea Viqueira, Antonella Ingrosso, Franco Locatelli, Jayashree Motwani, Jean-Pierre Bourquin, Francisco J. Bautista Sirvent, Carmelo Rizzari, Arnaud Petit, Donna Lancaster, Markus Metzler, Yves Bertrand, Laura Murillo-Sanjuán, Andrew J. Bukowkinski, Julie Krystal, Inge M. Van Der Sluis, Michael E. Roth, Harm Van Tinteren, Nobuko Hijiya, Christian M. Zwaan
Journal: Blood (2021)
TMOD-06. CREATION OF PATIENT-DERIVED LOWER GRADE GLIOMA ORGANOID MODELS FOR PERSONALIZED TREATMENT RESPONSE ASSESSMENT
Authors: Kalil Abdullah, Joseph Buehler, Cylaina Bird, MIlan Savani, Alex Sternisha, Michael Levitt, Kimmo Hatanpaa, Timothy Richardson, Samuel McBrayer
Journal: Neuro-Oncology (2021)

Abstract Creating in vitro models of lower grade glioma represents a major challenge in neuro-oncology research. There are few such models that are tractable and widely used, which has hindered understanding of the biology of these tumors. Recently, substantial progress has been made in generating patient-derived in vitro organoid models of high grade glioma, but modeling lower grade disease remains difficult. Based on our experience creating neurosphere cultures of lower grade astrocytomas from genetically engineered mice, we hypothesized that modifying patient-derived organoid generation protocols to incorporate physiological oxygen levels would allow establishment and propagation of lower grade glioma organoids. In this study, we show that this approach supports efficient organoid model generation from primary glioma specimens across all histological subtypes and tumor grades (WHO Grade I-IV, n = 20). These organoid models retain key characteristics of their respective parental tumors, including IDH mutations and other genetic alterations, metabolite profiles, intratumoral heterogeneity, cellular composition, and cytoarchitectural features. Importantly, lower grade glioma organoids can be cultured for months and reanimated after biobanking. Our high success rate ( &amp;gt;90%) in establishing organoid models from primary lower grade glioma tissue samples further highlighted opportunities for treatment response assessments. To perform longitudinal measurements of therapy-induced changes in glioma organoid viability, we designed a novel, non-invasive imaging assay (termed rapid apex imaging) to determine real-time treatment response in low and high grade gliomas. We evaluated longitudinal responses of glioblastoma and IDH1 R132H-positive Grade II astrocytoma organoids to temozolomide and olaparib with and without radiation treatment. We quantified topological changes in organoid structure by building a bioinformatics tool to translate imaging data into a cellularity metric as a biomarker of organoid response. Our work unveils an effective new method to create in vitro, personalized models of lower grade glioma that supports elucidation of treatment sensitivity profiles.
Use of contact tracing, isolation, and mass testing to control transmission of covid-19 in China
Authors: Yibiao Zhou, Honglin Jiang, Quanyi Wang, Meixia Yang, Yue Chen, Qingwu Jiang
Journal: BMJ (2021)

<b>Qingwu Jiang and colleagues</b> discuss China's experience of contact tracing, isolation, and quarantine of infected people and their contacts, and mass nucleic acid testing in the second phase of the covid-19 epidemic
Abstract 11236: Preserved Cardiac Reserve and Cardiorespiratory Fitness in Patients with De Novo versus Acute on Chronic HFrEF
Authors: Marco Del Buono, Virignia Mihalick, Juan Ignacio Damonte, Hayley Billingsley, Alessandra Vecchie, Cory R TRANKLE, Dinesh Kadariya, George F Wohlford, Ai-Chen Ho, Azita Talasaz, Salvatore Carbone, ROSHANAK MARKLEY, Jeremy Turlington, Juan Lu, Emily Federmann, Ross Arena, Benjamin W VAN TASSELL, Antonio Abbate, Justin M Canada
Journal: Circulation (2021)

Hypothesis: There is limited understanding on the potential differences in the pathophysiology between de-novo heart failure with reduced ejection fraction (HFrEF) and acute on chronic HFrEF. Objective: the aim of this study was to assess differences in cardiorespiratory fitness (CRF) parameters between de-novo heart failure and acute on chronic HFrEF using cardiopulmonary exercise testing (CPX). Methods: We retrospectively analyzed CPX data measured within 2 weeks of discharge following acute hospitalization for HFrEF. The predicted peak oxygen consumption (VO 2 ) was calculated using the FRIEND formula. Circulatory power, a measure of cardiac reserve, was calculated as the product of peak VO 2 and peak systolic blood pressure. Peak O 2 pulse, a surrogate measure of exercise stroke volume, was calculated by dividing peak VO 2 by the maximum heart rate (HR). Left ventricular ejection fraction (LVEF) was calculated using Simpson method during echocardiography. Data are reported as median and interquartile range or frequency and percentage (%). Results: We included 102 patients: 32 (31%) women, 81 (79%) Black, 57.0 [ 51-64] years of age, BMI of 34 [29-39] Kg/m 2 . Of these, 26 (25%) had de-novo HFrEF and 76 (75%) had acute on chronic HFrEF. When compared with acute on chronic, patients with de-novo HFrEF had a significantly higher peak VO 2 (16.5 [12.2-19.4] vs 12.8 [10.15-15.32] mL·kg -1 ·min -1 , p &lt;0.001), %-predicted peak VO 2 (58% [51-75] vs 49% [42-59]) p =0.012), peak HR (134 [117-147] vs 117 [104-136] bpm, p =0.004), peak O 2 pulse (12.2 [10.5 -15.5] vs 9.9 [8.0-13.1] mL/beat, p =0.022) and circulatory power (2823 [1973-3299] vs 1902 [1372-2512] mmHg·mL·kg -1 ·min -1 , p=0.002). No significant difference in resting LVEF was found between groups. Conclusion: Patients with de-novo HFrEF patients have better CRF parameters than those with acute on chronic HFrEF. These differences are not explained by resting left ventricular systolic function but may be related to greater preservation in cardiac reserve during exercise in de-novo HFrEF patients.
Abstract 11953: Hemorrhagic Insults And Secondary Takotsubo Syndrome: A New In-vitro Model
Authors: Carola Y Forster, Serge C Thal
Journal: Circulation (2021)

Introduction: Hemorrhagic insults result in very devastating forms of cerebral damage. The effects on the blood-brain barrier are so far examined only ex vivo and show reduced integrity. Hypothesis: There is a connection between hemorrhagic bleeding and secondary takotsubo syndrome (TTS), leading to a poor outcome in comorbidity. Our hypothesis is that through the elevated catecholamine levels and proinflammatory cytokine leves demonstrated to be present in the serum of TTS patients, BBB integrity will be impaired by TTS blood exposure more pronounced and/or early than by control group blood exposure (potentially fueling cardiac arrhythmia/ TTS at the brain-heat axis). Methods: Our study aims to establish an in-vitro cell culture model of blood exposure from heathy and TTS patients and measure the time-dependent effect on integriy of brain capillary cell monolayers as a basis to further examine the connection between hemorrhagic insults and TTS. We perfomed blood and serum exposure from healthy and TTS subjects to murine brain microvascular endothelial cells (cerebEND) derived from the cerebellum as an established model of the blood brain barrier and evaluated effects on barrier components by PCR and western blot. Results: Decreased monolayer integrity was readily detectable, reduced levels of Claudin-5 and Occludin were confirmed by RT-qPCR and Westernblot. Both tight-junction proteins show a time-dependent reduction. Conclusions: the development of the model seems successful, as ex-vivo studies previously showed matching results. Exposure of monolayer to TTS patient blood clearly showed a faster and more pronounced disintegration of brain endothelial monolayer.
Abstract 12391: Association of Left Ventricular Global Longitudinal Strain With Poor Clinical Outcome in COVID-19: A Systemic Review and Meta-Analysis
Authors: Nath Limpruttidham, Tanawan Riangwiwat, Narut Prasitlumkum
Journal: Circulation (2021)

Introduction: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was declared a global pandemic by the World Health Organization (WHO) in March 2020. Although left ventricular global longitudinal strain (LV-GLS) has been validated as a prognostic marker in other disease processes, the utility of LV-GLS in risk stratification of coronavirus disease 2019 (COVID-19) remains controversial. This study aimed to investigate the prognostic value of echocardiographic findings, including LV-GLS in patients with COVID-19. Hypothesis: LV-GLS is associated with poor clinical outcomes in patients with COVID-19. Methods: We comprehensively searched the databases of MEDLINE and EMBASE from inception to June 2021. Included studies were published observational studies that reported an association between echocardiographic findings and prognostic valve in COVID-19. Data from each study were combined with random-effects, generic inverse variance method of DerSimonian and Laird to calculate pooled odds ratios and their 95% confidence intervals at 0.05 significance level. Sensitivity analysis and funnel plot were assessed for the validity of the results. Results: Six observational studies from August 2020 to May 2021 were included in this meta-analysis. The pooled odds ratio for COVID-19 mortality for each 1% change in LV-GLS was 1.452 (95% confidence interval 1.186 to 1.778, P &lt; 0.001). There was moderate heterogeneity with an I-square value of 49.9%. Sensitivity analysis showed no significant deviation from pooled odds ratios. There was no evidence of publication bias from the funnel plot and Egger’s test. Conclusions: LV-GLS measurement has prognostic value in risk stratification among COVID-19 patients. Low LV-GLS is independently associated with poor clinical outcomes.
NIMG-56. USING RADIOMIC FEATURES FROM DAILY MAGNETIC RESONANCE IMAGING TO PREDICT RESPONSE TO RADIATION THERAPY IN GLIOBLASTOMA PATIENTS: A PILOT STUDY
Authors: Kaylie Cullison, Garrett Simpson, Danilo Maziero, Kolton Jones, Radka Stoyanova, Tejan Diwanji, Gregory Azzam, Macarena De la Fuente, John Ford, Eric Mellon
Journal: Neuro-Oncology (2021)

Abstract A dilemma in treating glioblastoma is that MRI after chemotherapy and radiation therapy (chemoRT) shows areas of presumed tumor growth in up to 50% of patients. These areas can represent true progression (TP), tumor growth with tumors non-responsive to treatment, or pseudoprogression (PP), edema and tumor necrosis with favorable treatment response. On imaging, TP and PP are usually not discernable. Patients in this study undergo six weeks of chemoRT on a combination MRI/RT device, receiving daily MRIs. The goal of this study is to explore the correlation of radiomics features with progression. The tumor lesion and surrounding areas of growth/edema were manually outlined as regions of interest (ROIs) for each daily T2-weighted MRI scan. The ROIs were used to calculate texture features: statistical features based on the gray-level co-occurrence matrix (GLCM), the gray-level zone size matrix (GLZSM), the gray-level run length matrix (GLRLM), and the neighborhood gray-tone difference matrix (NGTDM). Each of these matrix classes describe the probability of spatial relationships of gray levels occurring within the ROI. Daily texture features were averaged per week of treatment for each patient. Patient response was retrospectively defined as no progression (NP), TP, or PP. A Kruskal-Wallis test was performed to identify texture features that correlated most strongly with patient response. Forty texture features were calculated for 12 patients (19 treated, 7 excluded due to no T2 lesion or progression status unknown, 6 NP, 3 TP, 3 PP). There was a trend of more texture features correlating significantly with response in weeks 4-6 of treatment, compared to weeks 1-3. A particular texture feature, GLSZM Small Zone Low Gray-Level Emphasis, showed increasing difference between PP and TP over time, with significant difference during week 6 of treatment (p=0.0495). Future directions include correlating early outcomes with greater numbers of patients and daily multiparametric MRI.