tbuckley/cabot-search huggingface dataset:
Abstract 12075: Utility of Cardiac MRI for Assessment of Patients with Myocardial Infarction and Non-Obstructive Coronary Arteries: 5-Year Experience in a Tertiary Care Center in Latin-America
Authors: Sergio A Higuera, Oscar M Perez-Fernandez, Julian Forero, Claudia Jaimes, Daniel Isaza, Hector Medina
Journal: Circulation (2021)

Introduction: Acute myocardial infarction with non-obstructive coronary arteries (MINOCA) is a frequent condition caused by a wide array of diseases. Absence of a definitive diagnosis can difficult proper treatment and may worsen prognosis. Given its unique ability to achieve tissue characterization, cardiac magnetic resonance (CMR) can be extremely useful in these patients. We sought to describe the use of CMR in a tertiary care center in Latin-America for the evaluation of MINOCA and its impact in patient management. Methods: Cross-sectional study of all hospitalized patients with MINOCA undergoing CMR and impact in medical management at discharge based on its result. Results: A total of 3283 patients underwent CMR between 2016 and 2020 in our institution. Of these, 144 had MINOCA (without IVUS/OCT imaging) as the main indication for the study. Mean age was 50.7 ± 14.8 years and 56.9% were females. The most frequent diagnosis after CMR was myocarditis in 50% of cases (n=71) followed by AMI in 22% (n=31) and Tako-Tsubo Syndrome in 12% (n=17). Only 11% (n=15) of CMR were normal (Fig 1). There were significant changes in prescription before and after CMR of ASA, dual-antiplatelet therapy (DAPT), anticoagulants (AC), betablockers (BB), statins, colchicine and NSAIDs (Fig 2). Conclusions: CMR is critical for making a definitive diagnosis in a substantial proportion of MINOCA patients and its use has a significant impact in medical regimen optimization at discharge. Figure 1. Definite diagnosis achieved after CMR. AMI: Acute Myocardial Infarction. CMP: Cardiomyopathies. HCM: Hypertrophic Cardiomyopathy. TS: Takotsubo Syndrome.Figure 2. Changes in prescription before and after CMR.
CBIO-27. INTEGRATED FUNCTIONAL AND MOLECULAR CHARACTERIZATION OF THE INTRINSIC APOPTOTIC MACHINERY IDENTIFIES THERAPEUTIC VULNERABILITIES IN GLIOBLASTOMA
Authors: Elizabeth Fernandez, Wilson Mia, Nicholas Bayley, Henan Zhu, Christopher Tse, Linda Liau, Timothy Cloughesy, David Nathanson
Journal: Neuro-Oncology (2021)

Abstract Molecular profiling frequently fails to predict therapeutic outcomes in cancer. This is in part due to the myriad of genetic alterations comprising a tumor which enable rapid rewiring of cancer signaling pathways. Functional profiling ascertains signaling dynamics and has emerged as an alternative method to predict drug responses. It is unknown whether incorporating molecular with functional profiling offers superior insight into specific tumor dependencies and consequently therapeutic susceptibilities. Here we performed integrated molecular and functional characterization (via BH3 profiling) of the intrinsic apoptotic machinery in 50 GBM patient specimens. We found that treatment with standard of care (e.g., temozolomide or radiation) rewired the apoptotic machinery in a p53 dependent manner, eliciting an exclusive survival dependency on BCL-xL in a genetically defined subset of GBM tumors. However, functional BH3 profiling of ‘apoptotic priming’ was required to predict response to combined IR/TMZ and BCL-xL inhibition in p53 WT GBM tumors. Accordingly, a composite of genetic and functional profiling predicted the response of patient derived GBM models to IR/TMZ with a novel GBM specific BCLxL antagonist. Collectively, these studies identify the mechanisms of intrinsic apoptosis resistance in GBM and demonstrate how functional and molecular data can be complementary to robustly predict therapy-induced cell death.
Abstract 14443: Deep Learning to Identify Atrial Fibrillation Phenotypes in Individual Patientsbased on Rate, Variability, Electrogram Shape
Authors: Brototo Deb, AJ J Rogers, Prash Ganesan, Mahmood Alhusseini, Sanjiv M Narayan, Miguel Rodrigo
Journal: Circulation (2021)

Introduction: Automatic identification of atrial fibrillation (AF) from Flutter or Tachycardia (AFL/AT) is key to therapy, yet devices often group them as ‘high-rate events’. Hypothesis: We hypothesized that (a) convolutional neural networks (CNN) may separate AF from AFL/AT better than Electrogram (EGM) rate or rhythm, and (b) The physiology represented by CNN could be probed using novel methods including computer modelling. Methods: We developed custom CNN on N= 450,960 EGM tracings (4 sec), in 110 patients with AF(n=55) or AFL/AT (n=55) at ablation (31.8% female, 65±11Y). Training used 88 patients; validation used 22. We systematically probed CNN with 140,360 EGM sequences controlling rate (cycle length, CL), beat-to-beat variability (%) or shape (autocorrelation, %) (figs A-B) alone or in combination. Results: CNN differentiated AF from AFL with a c-statistic of 0.95. Individual variations in rate (N=572), CL variability (N=418), shape (N=462), or in combination (N=26,620) decreased the c-statistic of the CNN predictions to 0.66, 0.84, 0.88, 0.58 ( P &lt;0.05, Delong test) respectively, suggesting rate as the primary determinant of CNN decision (Figure 1, C). Conclusions: Machine learning of intracardiac EGMs separates AF from AFL/AT significantly better than electrogram rate, regularity or shape. Opening the ‘black-box’ of CNN showed that additional indices from Electrograms identify the physiology of AF in individual patients. Studies on the physiological signatures for AF between patients may identify important clinical phenotypes.
Abstract 14070: Epidemiology of Cardiomyopathy in Haitian Patients Seen in a United States Urban, Safety-Net, Academic Medical Center
Authors: Michel Ibrahim, Leili Behrooz, Garly Rushler Saint Croix, Berenice Loubeau, Maria I Barillas Lara, Ludwine Paul
Journal: Circulation (2021)

Introduction: Many studies have described the high incidence of Peripartum cardiomyopathy (PPCM) in Haiti. However, there are only been two known studies that report other causes of heart failure (HF) in Haitians, although these studies were limited by the lack of diagnostic tools available for the appropriate cardiomyopathy work up in Haiti. Haitians make up the second largest share of immigrants in Boston and Boston Medical Center provides health care for many immigrants where patients receive optimal cardiovascular care. Our study will help better characterize cardiomyopathies (CMP) in Haitian patients to help develop tailored diagnostic and treatment interventions. Methods: We performed a retrospective analysis on all adult patients of Haitian descent and/or Haitian Creole speaking patient who were evaluated at Boston Medical Center and whom had undergone optimal cardiomyopathy work up. Results: Among 88 Haitian patients, 65.9% had moved to the USA prior to 2010, 38.6% were diagnosed with an Ischemic CMP and 19.3% with hypertensive heart disease. Hypertension was prevalent in 80.7% of the population followed by dyslipidemia (59.1%) and diabetes (55.6%). 13.6% of patients are found to be active tobacco users. 69.3% have medical insurance listed. 20.45% died at 1 year. Conclusions: Cardiovascular disease (CVD) is the leading cause of mortality among Haitians. Our study is the first Haitian cardiovascular study in the literature to look at the epidemiology of cardiomyopathy in the afro-mentioned population utilizing the availability of optimal cardiovascular resources. We found that ischemic cardiomyopathy is most common etiology of cardiomyopathy contrary to 2 prior studies Haitian studies where non-ischemic cardiomyopathy was found to be more common. Future study will need to focus on collecting data on much larger scale of patient Haitian. patients.
Abstract 9024: Molecular Mechanism of Chronic Beta3-Adrenergic Receptor Antagonist Caused Regression of Diabetic Cardiomyopathy in a Murine Model With Type 2 Diabetes
Authors: Heng Cheng, Jing Cao, Xiaoqiang Sun, Yixi Liu, Tiankai Li, Dalane W Kitzman, David Zhao, Donald McClain, Che Ping Cheng
Journal: Circulation (2021)

Background: Diabetic cardiomyopathy (DCM) is a serious complication of diabetes (DM). As yet, no effective therapeutic strategies exist. Recently, we found that DM-induced LV dysfunction was prevented by chronic treatment with a β 3 -adrenergic receptor (AR) antagonist (β 3 ANT). However, the molecular mechanism is unclear. We hypothesized that reversal of DM-induced detrimental alterations on the expressions of cardiac SR Ca 2+ -ATPase (SERCA2a), β-ARs, nitric oxide synthase (NOS) by β 3 ANT may play a key role for its salutary role in DCM. Methods: The protein levels of myocyte β 1 - and β 3 - AR, SERCA2a, NOS and myocyte functional responses were determined in 3 groups (7/group) wild-type female mice over 14 weeks (W): Type 2 DM ( T2 ), 14 W fed a high-fat diet (HFD), but after HFD for 4 W receiving streptozotocin (STZ, 40 mg/kg/day, i.p. 5 days); T2β 3 ANT , T2 mice at 10 W received L-748,337, a selective β 3 ANT (10 -7 M/kg/day, mini-pump) for 4 W; and Vehicle controls (C). Results: Versus C, T2DM was induced in mice received HFD and low dose STZ with significantly elevated blood glucose (~340 to 380 mg/dl). Only T2 mice had significantly decreased protein levels of LV myocyte β 1 -AR (T2: 0.35 vs C: 0.49) and SERCA2a (0.19 vs 0.29), but increased β 3 -AR (0.25 vs 0.14) and iNOS (0.25 vs 0.15) without significant changes in eNOS (0.14 vs 0.13) and nNOS. These changes were followed by significantly reduced basal cell contraction (dL/dt max , 75.4 vs 133.7 μm/s), relaxation (dR/dt max , 59.6 vs 113.8 μ m/s) and [Ca 2+ ] iT (0.16 vs 0.21). The isoproterenol (ISO, 10 -8 M)-stimulated increases in dL/dt max (38% vs 58%), dR/dt max (34% vs 55%) and [Ca 2+ ] iT (19% vs 30%) were also significantly reduced. By contrary, versus C, T2β 3 ANT myocytes had similar protein levels of β 1 -AR (0.52), SERCA2a (0.75) and iNOS (0.36) with preserved normal basal cell contractility (127.8 μm/s), relaxation (109.4 μm/s) and [Ca 2+ ] iT (0.21). ISO caused increases in dL/dt max (57%), dL/dt max (52%), and [Ca 2+ ] iT (30%) were also closed to control values. Conclusions: Chronic β 3 ANT prevents DCM-caused downregulations of cardiac β 1 -ARs and SERCA2a, and normalized upregulations of iNOS and β 3 -AR, thus leading to the preservation of normal myocyte contractile function, [Ca 2+ ] iT , and β-adrenergic reserve in a mouse model of T2DM.
Abstract 11090: Therapeutic Effect of VEGF- and SDF-Nanoparticles in the Rat Monocrotaline Model of Pulmonary Hypertension
Authors: Victoria A Guarino, Bradley M Wertheim, Joseph Loscalzo, Yingyi Zhang
Journal: Circulation (2021)

Introduction: Pulmonary vascular endothelial cell injury, dysfunction, and apoptosis are associated with the development of pulmonary arterial hypertension (PAH). Improving endothelial function may be therapeutically beneficial in this disorder. In the present study, we examined the effect of vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1α (SDF-1α), proteins that support endothelial repair and tissue regeneration, in rats with monocrotaline-induced PAH. A polysaccharide nanoparticle was used as a carrier for VEGF and SDF-1α delivery, the formulation of which extends the retention time of the proteins in the lung by ~17-fold compared with free protein. Method: A crosslinked dextran sulfate-chitosan nanoparticle (XDSCS NP) was prepared as the carrier. Recombinant human VEGF and SDF-1α were incorporated in the XDSCS NP to generate VEGF-NP and SDF-NP, respectively. Athymic nude rats were injected with monocrotaline (50 mg/kg, IP) to induce PAH. Two weeks after the injection, VEGF-NP (8 μg/rat) and SDF-NP (4 μg/rat) were delivered to the lungs of rats via intratracheal aerosolization. At 4 weeks, catheterization of right and left heart was performed, and lung tissue collected for histological analysis. Results: Monocrotaline induced PAH in the nude rats, leading to right ventricular systolic pressure (RVSP) of 71±8 mmHg (mean±SD, n=8) vs. 29±2 mmHg in the untreated control rats. VEGF-NP and SDF-NP treatment reduced the RVSP to 48±13 mmHg. The Fulton indices of the three groups were 0.45±0.07, 0.22±0.01, and 0.25±0.06, respectively. The pulmonary vascular resistance indices of the groups were 3.2±0.7, 0.6±0.3, and 2.1±1.0 mmHg.min/ml/kg, respectively. Histological analysis showed monocrotaline-treated rats had prominent muscularization of precapillary vessels, which was markedly reduced by the VEGF-NP and SDF-NP treatment. Aerosolization of free VEGF and SDF-1α or of empty XDSCS NP carrier had no effect on monocrotaline-induce PAH. Conclusion: These data indicate that the delivery of VEGF and SDF to the lungs of rats in a NP-bound form had beneficial therapeutic effects in monocrotaline-induced PAH, and offer the potential for a novel therapeutic strategy for human pulmonary hypertensive disorders.
Nutrition in adolescent growth and development
Authors: Shane A Norris, Edward A Frongillo, Maureen M Black, Yanhui Dong, Caroline Fall, Michelle Lampl, Angela D Liese, Mariam Naguib, Ann Prentice, Tamsen Rochat, Charles B Stephensen, Chiwoneso B Tinago, Kate A Ward, Stephanie V Wrottesley, George C Patton
Journal: The Lancet (2021)
CBIO-03. A COMPREHENSIVE CHARACTERIZATION OF THE GBM LIPIDOME REVEALS A MOLECULARLY-DEFINED SUB-GROUP WITH HEIGHTENED SENSITIVITY TO FERROPTOSIS
Authors: Danielle Morrow, Jenna Minami, Nicholas Bayley, Kevin Williams, Robert Prins, Linda Liau, Timothy Cloughesy, Steven Bensinger, David Nathanson
Journal: Neuro-Oncology (2021)

Abstract Cancers, including the universally lethal glioblastoma (GBM), have reprogrammed lipid metabolism to fuel tumor growth. However, the molecular alterations responsible for aberrant lipid metabolism, and the potential for identifying new therapeutic opportunities are not fully understood. To systematically investigate the GBM lipidome, we performed integrated transcriptomic, genomic and shotgun lipidomic analysis of an extensive library of molecularly diverse patient-derived GBM tumors and model systems. Using this comprehensive approach, we discovered two GBM sub-groups defined by their combined molecular and lipidomic profile. Among the most significant differences between the two groups were lipid length and desaturation. As a consequence of this signature, a subset was more sensitive to lipid peroxidation and ferroptosis. Our findings suggest a novel association between specific molecular signatures of GBM, lipid metabolism and lipid peroxidation-induced cell death. This relationship may present a new therapeutic opportunity to target reprogrammed lipid metabolism in a molecularly-defined subset of GBMs.
Abstract 11524: Ezetimibe Consistently Reduces LDL-C with Little Interindividual Variability in 14,970 Patients Post-ACS
Authors: Siddharth M Patel, Christopher P Cannon, KyungAh Im, Michael A Blazing, Yale B Mitchel, Marc S Sabatine, Robert P Giugliano, Erin A Bohula
Journal: Circulation (2021)

Introduction: Ezetimibe (EZE) added to statin further reduces LDL-C and CV events. Prior studies demonstrated large inter-individual variability in LDL-C reduction with statins. Whether similar variability exists with EZE has not been reported in a large study. Methods: We assessed the placebo (PBO)-adjusted LDL-C reduction from randomization to 4 months in IMPROVE-IT, a double-blind RCT of EZE vs placebo (PBO) added to simvastatin (SIMVA) post-ACS. Inter-individual variation in % LDL-C reduction was calculated via rank-ordered subtraction of PBO/SIMVA from EZE/SIMVA. Patients not on study drug or with missing LDL-C values at either timepoint were excluded. Using the overall distribution of PBO-adjusted LDL-C reductions with EZE, we modelled the % of patients anticipated to achieve guideline-recommended LDL-C targets at 4 months with the addition of EZE across a range of baseline LDL-C values. Results: In 14,970 pts, the median baseline LDL-C in both groups was 80 mg/dL (IQR 65-96). The median change from baseline at 4 months was -37% (IQR -20% to -51%) in the EZE/SIMVA arm and -14% (IQR +7% to -31%) with PBO/SIMVA ( Panel A ). The PBO-adjusted median change in LDL-C at 4 months with EZE/SIM was -23% with low variability (IQR -19 to -27%; Panel A) . Based on this distribution, modelling predicts that fewer than half of patients would achieve the U.S. and European targets of &lt;70 and &lt;55 mg/dL when the baseline LDL-C is &gt;91 mg/dL and &gt;72 mg/dL, respectively, with the addition of EZE to statin therapy ( Panel B ). Conclusions: Addition of EZE to statin therapy results in a consistent median 23% reduction in LDL-C, with 75% of patients achieving at least a 19% reduction. The distribution of LDL-C reduction can be used to estimate how likely a patient will be to achieve guideline LDL-C targets with the addition of EZE to statin therapy.
Combining Arsenic Trioxide and Mitocans Selectively Disrupts Cellular Energetics in Acute Myeloid Leukemia
Authors: Nithya Balasundaram, Arvind Venkatraman, Yolanda Augustin, Hamenth Kumar Palani, Swathy Palanikumar, Nair Reeshma Radhakrishnan, Anu Korula, Uday Prakash Kulkarni, Poonkuzhali Balasubramanian, Eunice Sindhuvi, Biju George, Sanjeev Krishna, Vikram Mathews
Journal: Blood (2021)
COVID-19 recovery from the community perspective in Middlesbrough: a coproduction cross-sectional study
Authors: Andrew Divers, Catherine Parker, Parisa Diba, Clifford Johnson, Dorothy Newbury-Birch
Journal: The Lancet (2021)

BackgroundPeople younger than 65 years living in deprivation are nearly four times more likely to die of COVID-19 and, in Middlesbrough, life expectancy is 12·6 years lower than those in the least deprived areas of England. We aimed to examine COVID-19 recovery from the perspective of members of the local communities in Middlesbrough.MethodsIn this coproduction cross-sectional study, we used purposive, semi-structured interviews, with recruitment via social media and community groups. Interviews were conducted via telephone or Microsoft Teams. Participants needed to be a resident of Middlesbrough and aged 18 years or older. Particular engagement was sought amongst those aged 18–30 years (n=15), older than 50 years (n=20), and individuals identifying as Black, Asian, or minority ethnic (n=22), or those residing in a TS1 or TS3 postcode area (n=23), with both areas being associated with high rates of deprivation, and Middlesbrough ranking fifth highest according to the 2019 English Indices of Deprivation (ONS, 2019). Interviews were transcribed verbatim and subjected to thematic analysis, coded blind to eliminate bias. Ethical clearance was granted by the Teesside University Ethics Sub-Committee at which time recruitment commenced. Written and verbal consent was obtained by the research team before any interviews started.FindingsBetween Oct 1, 2020, and March 1, 2021, we recruited and interviewed 52 people (26 women, 25 men, and one non-binary person), generating over 50 h of interview transcripts. From analysis of these transcripts, eight primary themes emerged: authority, autonomy, community, economy, fairness, framing, future, and wellbeing. Participants spoke of feeling abandoned by authorities, mistrusting of official information, and worries around the ability of their communities to survive financially through lockdowns.InterpretationDevelopment of social capital is crucial to the development of a COVID-19 recovery strategy. Providing people with choices tailored to their local setting is fundamentally important. Mental health is a priority as we emerge from lockdown, particularly young people. Communication from authorities must be carefully framed, avoiding imperatives where possible. Better understanding is needed for the reasons behind mistrust of official information.FundingMiddlesbrough Council.
PATH-30. RAPID AND LOW-COST LIQUID BIOPSY-BASED METHOD FOR SCREENING AND MONITORING OF GBM BY MASTER REGULATORY GENE MARKERS IN GBM STEM-LIKE CELLS
Authors: David Tran, Tianyi Liu, Son Le
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Current liquid-based cancer screening relies on massive deep NGS to detect rare cancer-derived genetic materials - a costly method fraught with high false-negative and false-positive rates. We aim to develop a non-NGS-centered, AI-directed liquid-based detection of GBM stem-like cells (GSCs). METHODS Utilizing a robust AI suite, NETZEN, we defined a common master regulatory gene network (MRGN) of the GBM state in GSCs. Since master regulators (MRs) in MRGN are developmentally restricted, their chromosomal loci are accessible in GSCs but not in normal cells. Downstream factors in MRGN are massively overexpressed in GSCs compared to normal cells. Thus, we measured the following in PBMCs from healthy controls spiked with known quantities of GSCs and patients with GBM: 1) accessibility of MR genes using transposase/transposons carrying unique barcodes to be inserted into the MR’s predetermined accessible locations, and 2) expression of downstream factors using nested qRT-PCR. RESULTS We characterized 10 MRs in GSCs with ≥1 promoter region that is hypomethylated and accessible (by ATACseq) in GBM/GSCs per GSE70175-92460 (19 samples) and GSE67633-96088 (14 samples), or hypermethylated and inaccessible in lymphocytes/PBMCs per GSE98837 (6) and GSE74912 (13). Using barcoded transposons, we specifically disrupted 4 MR’s accessible foci only in GSCs, not in PBMCs. We also identified 50 downstream factors with the top 20 having 3 to 5-orders-of-magnitude higher mean expression in GSCs compared to PBMCs (GSE79362-86884, 451 samples). Currently our method has a detection limit of 0.2-1 GSC per 106 PBMCs. Using the first iteration, we detected MRGN of the GBM state in blood samples of 14 of 14 GBM patients before resection, compared to none of 15 healthy donors. CONCLUSIONS Chromosomal accessibility and signal amplification in MRGN of GSCs provide powerful substrates for a non-NGS, low-cost, liquid-based GBM detection system with high sensitivity and specificity. Further testing and optimization are ongoing.