tbuckley/cabot-search huggingface dataset:
Abstract 12542: Prevalence and Characterization of Occult Coronary Atherosclerotic Disease Among Middle Aged Individuals Free of Clinical Cardiovascular Disease - Results From Miami Heart Study (MiHeart) at Baptist Health South Florida
Authors: Khurram Nasir, Miguel Cainzos Achirica, Matthew Budoff, Ricardo C Cury, Javier Valero Elizondo, Shozab S Ali, Lara Arias, Michael D Shapiro, Michael J Blaha, Ron Blankstein, Jack A Ziffer, Theodore Feldman, Jonathan Fialkow
Journal: Circulation (2021)

Introduction: While prior population-based cohorts have extensively described burden of coronary artery calcification (CAC) among asymptomatic individuals, there is paucity of occult coronary atherosclerotic disease (CAD) assessment with coronary computed tomography angiography (CCTA) in the general population. The aims were to determine prevalence, burden and coronary plaque characteristics in the ongoing prospective Miami Heart Study (MiHeart) using both CAC and CCTA. Methods: MiHeart enrolled 2,549 middle-aged 40-65 years free of clinical cardiovascular disease participants (49% females, mean age 53, 47% Hispanic/Latino) from general population of Greater Miami Area (Florida, USA). Final study consisted of 2491 (98%) among whom non- cardiac-gated CT for CAC testing and contrast-enhanced CCTA cardiac-gated were performed. Results: In this study 58% had CAC=0, 13% had CAC≥100, and 45% had detectable plaque on CCTA. 143 (6%) participants had significant (≥50%) stenosis and 44 (2%) had severe (≥70%) stenosis. Overall, 26% participants had exclusive non-calcified plaque whereas 7% demonstrated high-risk plaque features (HRP) with positive remodeling being most frequently observed (5%). Among participants with CAC=0, 15% had any plaque on CCTA (62% in 1 segment); 1% had obstructive CAD and 2% any HRP, respectively. Burden of CAD (plaque segmental score, subtype, stenosis) as well as HRP on CCTA was strongly associated with increasing CAC scores (table). Overall, 31% and 20% with CAC≥100 had significant stenosis and HRP, respectively. Conclusions: In the first US general population based CCTA study, we demonstrate high burden of diverse coronary atherosclerotic plaque features in a middle-aged general population free of established CVD. Future studies in MiHeart will focus on biological associations and clinical implications of of coronary atherosclerotic disease severity and features on CCTA among asymptomatic individuals.
Abstract 10437: “Explainable Artificial Intelligence (ai) in Cardiology”: A Tool to Provide Personalized Predictions on Cardiac Health States Among Older Adults Engaged in Physical Activity
Authors: De Rong Loh, Si Yong Yeo, Ru San Tan, Fei Gao, Angela S Koh
Journal: Circulation (2021)

Introduction: As a prevention strategy, the effect of physical activity on older adults is likely heterogeneous against a background of individual ageing trajectories. While machine learning models that combine various systemic signals may aid in predictive modeling, the inability to rationalize predictions at a patient personalized level is a major shortcoming in AI. Methods: We applied a novel approach using Shapley Additive Explanations (SHAP) methodology on a dataset of older adults whose physical activity levels were studied in conjunction with changes in left ventricular (LV) structure. The SHAP approach provided intelligible visualization on the magnitude of the impact of the features in their physical activity levels on their LV structure. Results: As proof of concept, we studied n = 86 older adults (mean age 72±4 years). Using repeated K-cross validation on the train set (n = 68), we found the Random Forest Regressor with the most optimal hyperparameters, which achieved the lowest mean squared error. With the trained model, we evaluated its performance by reporting its mean absolute error and plotting the correlation on the test set (n = 18) (Fig 1). A collective force plot for individually numbered patients (horizontal axis) showing magnitude (i.e., effect) of physical parameters (higher in red; lower in blue) towards prediction of LV structure (Fig 2). For example, for patient number 6, basal metabolic rate was the predominant positive factor on LV structure, outweighing other weaker positive factors and negative factor contributed by body fat mass (Figure 3). In contrast, LV structure in patient number 11 was predicted jointly by several weaker positive factors without any single predominant factor (Figure 4). Conclusions: As a tool that identified specific features in physical activity that predicted cardiac structure on a per patient level, our findings support a role for explainable AI to be incorporated into personalized cardiology strategies.
INNV-24. METASTATIC HEMANGIOPERICYTOMA TO THE LIVER: DEFINING THE IMPORTANCE OF NAB-STAT2 FUSION
Authors: Megan Sefler, Simon Khagi
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Meningeal hemangiopericytoma (HPC) is a rare and aggressive vascular tumor which typically occurs in younger adults and has a tendency for local recurrence with delayed metastases outside the CNS. HPC is considered a variant of solitary fibrous tumor (SFT), and is associated with the presence of the fusion oncoprotein NAB2-STAT6. This fusion results in over-expression of the EGR1 gene and results in tumorigenesis. CASE REPORT We present a case of a 49 y/o female with a remote history of left occipital lobe HPC, initially treated with resection and radiotherapy in 2007, who presented with symptoms of right upper quadrant abdominal pain. She was found to have a hypervascular 7 cm mass in the right upper lobe of the liver on magnetic resonance imaging (MRI) studies and subsequently underwent hepatectomy for removal of the mass. Histopathological findings revealed metastatic HPC with features consistent with her primary meningeal tumor that was removed over 13 years agoearlier. Presence of the NAB2-STAT6 fusion was confirmed by targeted genomic analysis. MRI revealed a small focus of nodular enhancement abutting the confluence of the superior sagittal sinus and transverse sinus. This was considered her source of disease and possible dissemination. She was treated with stereotactic radiosurgery to target the lesion. DISCUSSION Given the rarity and often remote medical history of the primary intracranial HPC, this report suggests that 1) long term follow up of HPC is essential and 2) detection of the NAB2-STAT6 fusion can identify and confirm recurrent HPC at metastatic sites. In regards to the latter, distinguishing HPCs from other more benign spindle cell tumors that may mimic SFT (such as fibroblastic meningiomas) is also of therapeutic significance as HPCs typically require adjuvant treatment, (i.e. radiotherapy) as opposed to surgical resection alone.
Abstract 13300: Does Mechanical Dyssynchrony in Addition to QRS Area Ensure Sustained Response to Cardiac Resynchronization Therapy?
Authors: Philippe C Wouters, Wouter van Everdingen, Kevin Vernooy, Bastiaan Geelhoed, Cornelis Allaart, Michiel Rienstra, Alexander H Maass, Marc A Vos, Frits W PRINZEN, Mathias Meine, Maarten J Cramer
Journal: Circulation (2021)

Introduction: Judicious patient selection for CRT may further enhance treatment response. Progress has been made by using improved markers of electrical dyssynchrony and mechanical discoordination, using QRS AREA , and systolic rebound stretch of the septum (SRSsept) or systolic stretch index (SSI), respectively. Hypothesis: We hypothesize that the presence of combined electrical and mechanical dysfunction are of added benefit in predicting a sustained CRT-response. Methods: A total of 240 CRT patients were prospectively enrolled from six centers. Patients underwent standard 12-lead electrocardiography, and echocardiography, at baseline, 6 month, and 12 month follow-up. QRS AREA was derived using vectorcardiography, and SRSsept and SSI were measured using strain-analysis. Reverse remodelling was measured as the relative decrease in left ventricular end-systolic volume, indexed to body surface area (ΔLVESVi). Sustained response was defined as ≥ 15% decrease in LVESVi, at both 6 and 12 month follow-up. Presence of left bundle branch block (LBBB) was determined according to strict American Heart Association criteria. Results: QRS AREA and SRSsept were both strong, multivariably adjusted, predictors of reverse remodelling. The presence of SRSsept ≥ 2.5%, in addition to QRS AREA ≥ 120 μVs, significantly increased the extent of reverse remodelling when compared to high QRS AREA alone (ΔLVESVi 38±21 versus 22±21%). As a result, 100% of LBBB-patients and 74% of non-LBBB patients with combined electrical and mechanical dysfunction were sustained volumetric responders, as opposed to 53% and 46% with high QRS AREA alone, respectively. Conclusions: In patients with high QRS AREA , concomitant presence of high SRSsept significantly increases 6-month remodelling after CRT. Combined presence of high SRSsept and QRS AREA , but not high QRS AREA alone, is of importance in order to ensure a sustained response after CRT in LBBB patients.
Abstract 12296: Clinical and Functional Genetic Characterization of the Role of Cardiac Calcium Channel Variants in the Early Repolarization Syndrome
Authors: Hector Barajas-martinez, Charles N Antzelevitch, Dan Hu
Journal: Circulation (2021)

Introduction: Early repolarization syndrome (ERS) is an inherited sudden cardiac death syndrome. Hypothesis: In this study we test the role of genetic variants in cardiac calcium channel genes in the pathogenesis of ERS and probes the underlying mechanisms. Methods: PCR-based next-generation sequencing was carried out using a targeted gene approach. Unrelated ERS probands carrying calcium channel variants were evaluated clinically and compared with matched healthy controls. Wild type (WT) and mutant CACNA1C genes were co-expressed with CACNB2b and CACNA2D1 in HEK293 cells and studied using whole-cell patch-clamp and confocal fluorescence microscope . Results: Among 104 ERS probands, 16 carried pathogenic variants in calcium channel genes (32.2±14.6 years old, 87.5% male). The symptoms at diagnosis included syncope (56.3%), ventricular tachycardia/fibrillation (VT/VF, 62.5%), sudden cardiac death (SCD, 56.3%). Three cases (18.8%) had a family history of SCD or syncope. Eight patients (50.0%) had a single calcium gene rare variant. The other half carried rare variants in other ERS susceptible genes. Compared with controls, the heart rate was slower (72.7±8.9 vs. 65.6±16.1 bpm), QTc interval was shorter (408.2±21.4 vs. 386.8±16.9 ms) and Tp-e/QT was longer (0.22±0.05 vs.0.28±0.04) in calcium mutation carriers. Electrophysiological analysis of one mutation, CACNA1C -P817S revealed that the density of I Ca was reduced by approximately 84.6% compared to WT (-3.1±2.5 vs. -20.5±3.6 pA/pF, n=11 and 15, respectively). Heterozygous expression of mutant channels was associated with a 51.3% reduction of I Ca . Steady-state inactivation was shifted to more negative potentials and significantly accelerated. Confocal microscopy revealed trafficking impairment of CACNA1C -P817S (peripheral/central intensity: 0.94±0.1 in WT vs. 0.33±0.1 in P817S, n=10 and 9, respectively). Conclusions: ERS associated with loss of function (LOF) genetic defects in genes encoding the cardiac calcium channel represents a unique clinical entity characterized by decreased heart rate and QTc, as well as increased transmural dispersion of repolarization. In the case of CACNA1C -P817S impaired trafficking of the channel to the membrane contributes to the LOF.
Abstract P302: Alpha-1A Adrenergic Receptor Activation Increases Electron Transport Chain Activity In The Uninjured Mouse Heart
Authors: Peyton B Sandroni, Matthew R Vander Ploeg, Wei Huang, Brian C Jensen
Journal: Circulation Research (2021)

Decreased electron transport chain (ETC) activity in cardiac mitochondria is a hallmark of heart failure. Gain- and loss-of-function studies define the benefits of alpha-1A adrenergic receptor (α1A-AR) activation in the failing heart, such as increased cardiac contractility. However, the mechanisms behind these effects are unknown, and α1A-AR activation as a method of ETC regulation has not been studied. Here, we assessed the hypotheses that decreased α1A-AR activation reduces ETC enzyme activity, whereas increased α1A-AR activation enhances ETC enzyme activity. We profiled citrate synthase and ETC complex I-IV activities in isolated cardiac mitochondria from (1) wild-type (WT) CL57Bl/6J mice or global α1A-AR knockout mice (10-12 wks) and (2) WT mice (10-12 wks) treated with vehicle (0.9% saline) or the selective α1A-AR agonist A61603 (10 ng/kg/d, 3 d). Citrate synthase, a key enzyme in the citric acid cycle, fuels ETC activity and is a commonly used marker for mitochondrial mass. Global α1A-AR knockout increased citrate synthase activity in male mice compared to WT controls (5,292 ± 275 vs. 4,198 ± 339 nmol/min/mg, n = 5 each group, p = 0.04) (mean ± SEM) (Panel A). When normalized to citrate synthase activity, global α1A-AR knockout decreased complex I (37 ± 10% vs. 64 ± 5%, p = 0.02) (1,786 ± 421 vs. 2,766 ± 422 nmol/min/mg) and complex II (25 ± 9% vs. 50 ± 13%, p = 0.01) (1,332 ± 219 vs. 2,032 ± 213 nmol/min/mg) activities with a trend toward decreased complex IV activity (33 ± 13% vs. 49 ± 17%, p = 0.07) (1,707 ± 201 vs. 2,000 ± 238 nmol/min/mg) (Panel B). A61603 treatment led to a trend towards decreased citrate synthase activity in female mice compared to vehicle controls (6,662 ± 501 vs. 7,701 ± 421 nmol/min/mg, n = 3 each group, p = 0.09) (Panel C). When normalized to citrate synthase activity, A61603 increased complex I (27 ± 3% vs. 17 ± 2%, p = 0.03) (1,736 ± 92 vs. 1,326 ± 156 nmol/min/mg), complex III (61 ± 6% vs. 37 ± 5%, p = 0.02) (3,993 ± 258 vs. 2,894 ± 531 nmol/min/mg), and complex IV (70 ± 6% vs. 48 ± 6%, p = 0.03) (4,631 ± 100 vs. 3,676 ± 533 nmol/min/mg) activities (Panel D). In conclusion, we show that global α1A-AR knockout decreases ETC enzyme activity, while treatment with an α1A-AR agonist increases ETC enzyme activity. These findings may identify a novel mechanism through which α1A-AR activation protects the injured and failing heart.
Upgrade of an old drug: Auranofin in innovative cancer therapies to overcome drug resistance and to increase drug effectiveness
Authors: Tania Gamberi, Giovanni Chiappetta, Tania Fiaschi, Alessandra Modesti, Flavia Sorbi, Francesca Magherini
Journal: Medicinal Research Reviews (2021)

Abstract Auranofin is an oral gold(I) compound, initially developed for the treatment of rheumatoid arthritis. Currently, Auranofin is under investigation for oncological application within a drug repurposing plan due to the relevant antineoplastic activity observed both in vitro and in vivo tumor models. In this review, we analysed studies in which Auranofin was used as a single drug or in combination with other molecules to enhance their anticancer activity or to overcome chemoresistance. The analysis of different targets/pathways affected by this drug in different cancer types has allowed us to highlight several interesting targets and effects of Auranofin besides the already well‐known inhibition of thioredoxin reductase. Among these targets, inhibitory‐κB kinase, deubiquitinates, protein kinase C iota have been frequently suggested. To rationalize the effects of Auranofin by a system biology‐like approach, we exploited transcriptomic data obtained from a wide range of cell models, extrapolating the data deposited in the Connectivity Maps website and we attempted to provide a general conclusion and discussed the major points that need further investigation.
Abstract MP217: Nuclease-deficient Cas9 Transcription Factors Restore <i>Krueppel-like Factor 15</i> Expression In Stressed Mouse And Human Cardiomyocytes
Authors: Eric Schoger, Kim Rosa, Cheila Rocha, Mareike Jassyk, Shirin Doroudgar, Oliver Mueller, Lukas Cyganek, Wolfram H Zimmermann, Laura C Zelarayan
Journal: Circulation Research (2021)

Transcriptional changes in cardiomyocytes drive heart failure progression, however, precise control over endogenous gene expression remains challenging. The expression of Krueppel-like factor 15 ( KLF15 ), an evolutionary conserved nuclear and cardiomyocyte specific inhibitor of WNT/CTNNB1 signalling in the heart, is lost upon cardiac remodelling, and accompanied by aberrantly active WNT/CTNNB1 resulting in heart failure progression. We investigated KLF15 expression dynamics employing CRISPR/Cas9-based tools in mouse cardiomyocytes in vivo and in human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM) under the hypothesis that re-establishment of KLF15 levels in myocardial stress conditions prevents heart failure progression. Using a mouse model expressing enzymatically inactive Cas9 (dCas9) fused to transcriptional activators (VPR) under Myh6 -promoter control, we activated Klf15 in a murine pressure overload model by transverse aortic constriction. Delivery of Klf15 gRNAs targeted to the Klf15 promoter region via AAV9 induced Klf15 expression sufficiently to re-normalize Klf15 expression to transcript levels comparable to sham surgery hearts. This was accompanied by reduced decrease of fractional shortening as well as reduced cardiomyocyte hypertrophy in stressed Klf15 re-activated hearts compared to non-trageted (NT) gRNA hearts (n=3-8 per group, echo data from 4 and 8 weeks post-surgery). We achieved titratable KLF15 activation in dCas9VPR transgenic hiPSC-CM by selection of single and multiple gRNAs (n=3-4 replicates) and used these cells to generate human engineered myocardium by combining hiPSC-CM and fibroblasts which we subjected to isometric contractions in order to induce mechanical stress, which resulted in KLF15 expressional decrease in line with our in vivo data. This transcriptional loss was rescued in CRISPR/dCas9VPR hiPSC-CM targeted to the KLF15 locus compared to controls (n=6-9/2/4 tissues per group/casting sessions/differentiations). Additionally, TGFB1 induced cardiomyocyte stress resulted in decreased KLF15 expression levels in 2D hiPSC-CM cultures which were rescued by dCas9VPR- KLF15 targeting (n=3 experiments). In conclusion, we report controllable gene activity by CRISPR/dCas9VPR to restore the loss of KLF15 in stressed mouse and human cardiomyocytes. We furthermore evaluate the potential to gain full control over gene dose titratability with these models to validate and define novel therapeutic targets for the prevention of heart failure progression.
Management of Acne Vulgaris
Authors: Dawn Z. Eichenfield, Jessica Sprague, Lawrence F. Eichenfield
Journal: JAMA (2021)

<h3>Importance</h3> Acne vulgaris is an inflammatory disease of the pilosebaceous unit of the skin that primarily involves the face and trunk and affects approximately 9% of the population worldwide (approximately 85% of individuals aged 12-24 years, and approximately 50% of patients aged 20-29 years). Acne vulgaris can cause permanent physical scarring, negatively affect quality of life and self-image, and has been associated with increased rates of anxiety, depression, and suicidal ideation. <h3>Observations</h3> Acne vulgaris is classified based on patient age, lesion morphology (comedonal, inflammatory, mixed, nodulocystic), distribution (location on face, trunk, or both), and severity (extent, presence or absence of scarring, postinflammatory erythema, or hyperpigmentation). Although most acne does not require specific medical evaluation, medical workup is sometimes warranted. Topical therapies such as retinoids (eg, tretinoin, adapalene), benzoyl peroxide, azelaic acid, and/or combinations of topical agents are first-line treatments. When prescribed as a single therapy in a randomized trial of 207 patients, treatment with tretinoin 0.025% gel reduced acne lesion counts at 12 weeks by 63% compared with baseline. Combinations of topical agents with systemic agents (oral antibiotics such as doxycycline and minocycline, hormonal therapies such as combination oral contraception [COC] or spironolactone, or isotretinoin) are recommended for more severe disease. In a meta-analysis of 32 randomized clinical trials, COC was associated with reductions in inflammatory lesions by 62%, placebo was associated with a 26% reduction, and oral antibiotics were associated with a 58% reduction at 6-month follow-up. Isotretinoin is approved by the US Food and Drug Administration for treating severe recalcitrant nodular acne but is often used to treat resistant or persistent moderate to severe acne, as well as acne that produces scarring or significant psychosocial distress. <h3>Conclusions and Relevance</h3> Acne vulgaris affects approximately 9% of the population worldwide and approximately 85% of those aged 12 to 24 years. First-line therapies are topical retinoids, benzoyl peroxide, azelaic acid, or combinations of topicals. For more severe disease, oral antibiotics such as doxycycline or minocycline, hormonal therapies such as combination oral conceptive agents or spironolactone, or isotretinoin are most effective.
Biological Significance and Prognostic Value of Cytogenetics in 160 Patients with Multiple Myeloma: Predictivity of 13 and/or 14 Monosomies
Authors: Jolanda Donatella Vincelli, Antonio Scopelliti, Angela Violi, Corrado Mammi', Maria Grazia D'Errigo, Irene Bova, Bianca Oliva, Cristina Garreffa, Massimo Martino, Stefania Ciolli, Bruno Martino
Journal: Blood (2021)
Corrigendum to ‘Dietary carbohydrate intake and new-onset diabetes: A Nationwide Cohort Study in China’ [Metab Clin Exp 123 (2021) 154865]
Authors: Chun Zhou, Zhuxian Zhang, Mengyi Liu, Yuanyuan Zhang, Huan Li, Panpan He, Qinqin Li, Chengzhang Liu, Xianhui Qin
Journal: Metabolism (2021)
RTID-08. MACHINE LEARNING TO UNCOVER SIGNATURES OF VULNERABILITY IN GLIOBLASTOMA UMBRELLA SIGNATURE TRIAL (GUST)
Authors: Sen Peng, Matthew Lee, Nanyun Tang, Manmeet Ahluwalia, Ekokobe Fonkem, Karen Fink, Jeffrey Raizer, Christopher Walker, Harshil Dhruv, Michael Berens
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma is characterized by intra- and inter-tumoral heterogeneity. A glioblastoma umbrella signature trial (GUST) posits multiple investigational treatment arms based on corresponding biomarker signatures. A contingency of an efficient umbrella trial is a suite of orthogonal signatures to classify patients into the likely-most-beneficial arm. Assigning optimal thresholds of vulnerability signatures to classify patients as “most-likely responders” for each specific treatment arm is a crucial task. We utilized semi-supervised machine learning, Entropy-Regularized Logistic Regression, to predict vulnerability classification. By applying semi-supervised algorithms to the TCGA GBM cohort, we were able to transform the samples with the highest certainty of predicted response into a self-labeled dataset and thus augment the training data. In this case, we developed a predictive model with a larger sample size and potential better performance. Our GUST design currently includes four treatment arms for GBM patients: Arsenic Trioxide, Methoxyamine, Selinexor and Pevonedistat. Each treatment arm manifests its own signature developed by the customized machine learning pipelines based on selected gene mutation status and whole transcriptome data. In order to increase the robustness and scalability, we also developed a multi-class/label classification ensemble model that’s capable of predicting a probability of “fitness” of each novel therapeutic agent for each patient. Such a multi-class model would also enable us to rank each arm and provide sequential treatment planning. By expansion to four independent treatment arms within a single umbrella trial, a “mock” stratification of TCGA GBM patients labeled 56% of all cases into at least one “high likelihood of response” arm. Predicted vulnerability using genomic data from preclinical PDX models correctly placed 4 out of 6 models into the “responder” group. Our utilization of multiple vulnerability signatures in a GUST trial demonstrates how a precision medicine model can support an efficient clinical trial for heterogeneous diseases such as GBM. Surgical Therapies