tbuckley/cabot-search huggingface dataset:
Abstract 9414: Utilization of Antithrombotic Therapies in Patients With Atrial Fibrillation Across the Spectrum of Stroke Risk
Authors: Xiaoxi Yao, Ken Cohen, Omar Latif, Konstantinos Siontis, Holly Van Houten, Bernard J Gersh, Neena Abraham, Paul A FRIEDMAN, Peter A Noseworthy
Journal: Circulation (2021)

Introduction: OAC are recommended for AF patients with CHA 2 DS 2 -VASc ≥2 in men or ≥3 in women (high-risk group), may be considered in patients with CHA 2 DS 2 -VASc 1 in men or 2 in women (medium-risk group), and are reasonable to omit in patients with CHA 2 DS 2 -VASc 0 in men or 1 in women (low-risk group). Furthermore, NOACs are recommended over warfarin in most AF patients. This study aimed to investigate AF stroke prevention treatment patterns in patients managed in routine practice, in particular, the under-use of OAC in the high-risk group and over-use in the low-risk group. Methods: Adult patients with AF were identified using de-identified claims for commercial and Medicare Advantage enrollees in the OptumLabs Data Warehouse. Prescription fills were assessed within 90 days of a patient’s AF encounter between 1/1/2016-12/31/2020. Patients with other indications for OAC, such as VTE, recent joint replacement, prior mechanical or bioprosthetic valve replacement, rheumatic mitral stenosis, and patients who underwent LAAO were excluded. Results: Among the 339,197 AF patients, 4.4%, 8.0%, and 87.6% were in the low-, medium-, and high-risk groups, respectively. The mean age was 51.2 ±10.5 yr, 59.9 ±9.4 yr, and 75.1 ±8.8 yr. In the low-risk group, 29.6% were treated with OAC, whereas in the high-risk group, 40.3% were not treated with any antithrombotic therapy and 7.5% used thienopyridine only. Although 71% of patients on OAC were on a NOAC, the proportion of patients on NOAC decreased from 91% in the low-risk group to 69% in the high-risk group. Conclusions: There are potentially both under-use of guideline-recommended stroke prevention therapies in the high-risk patients and over-use in the low-risk group. Because patients at a high risk of stroke are also at a high risk of major and intracranial bleeding who might benefit from NOACs, the decreased use of NOAC in high-risk patients might highlight the need for future quality improvement efforts.
Abstract 11855: Disruption of β-arrestin-2 Signaling Resulted in Impaired Systolic and Diastolic Function During Aging
Authors: Paola C Rosas, Andrielle E Capote, Chad M Warren, Shamim Chowdhury, Beata M Wolska, R J Solaro
Journal: Circulation (2021)

Introduction: Angiotensin II (ang II) signaling at ang II receptor type 1 (AT1R), which is a G-protein coupled receptor (GPCR), promotes both G-protein signaling as well as β-arrestin-2 signaling. β-arrestin-2 participates in GPCR desensitization, internalization, but also acts a scaffold for adaptive signal transduction that may occur independently or in parallel to G-protein signaling. Hypothesis: We tested the hypothesis that β-arrestin-2 is an important element in the preservation of cardiac function during aging. Methods: We tested this hypothesis by aging β-arrestin-2 knock-out (KO) mice, and wild-type equivalent (WT) to 12-16 months. We performed echocardiography studies, and Western blot analysis. Results: By echocardiography we found that compared to controls aged KO mice exhibited enlarged left atria (2.2±0.1 vs 2.5±0.1 mm) and left ventricular diameters (4.2±0.2 vs 4.5 ±0.1mm) as well as depressed contractility parameters such as s’ (23.2±1.4 vs 21.4±0.8 mm/s) and decreased circumferential fiber shortening velocity (5.5±0.4 vs 4.5±0.2) with preserved ejection fraction (EF&gt;50%). Aged KO also exhibited depressed relaxation parameters such as e’ (29.2±1.4 vs 21.4±0,6 mm/s) and E/e’ (27.4±1.6 vs 35.6±2.0) when compared to WT controls at the same age. Cardiac dysfunction in aged KO mice was correlated with decreased phosphorylation of RLC and increased phosphorylation of cMyBP-C at Ser302. Among other kinases, cMyBP-C phosphorylation at Ser302 is a PKCε target which activation is negatively regulated by β-arrestin-2 signaling. To determine the direct effects of PKCε over-activation on cMyBP-C phosphorylation, we used mice that over-expresses constitutively active PKC ε in the heart. We found that similarly to our aged KO mice, PKCε overexpression model exhibited significantly higher levels of cMyBP-C phosphorylation at Ser302, when aged to 12 - 15 months. Conclusions: Deletion of β-arrestin-2 signaling in KO mice affected aged mice, resulting in changes in the phosphorylation of myofilament proteins consisting of decreased phosphorylation of RLC and increased phosphorylation of cMyBP-C at Ser302 through the unrestricted activity of PKCε. These changes negatively affected systolic and diastolic function in aged KO mice.
Orchestration of the circadian clock and its association with Alzheimer's disease: Role of endocannabinoid signaling
Authors: Deepak Kumar, Ashish Sharma, Rajeev Taliyan, Maiko T. Urmera, Oscar Herrera-Calderon, Thomas Heinbockel, Shafiqur Rahman, Rohit Goyal
Journal: Ageing Research Reviews (2021)
ARRAY CGH ABERRATIONS IN NON-BRCA1/2 FAMILIAL BREAST CANCER
Authors: M. Didraga, E. van Beers, K. Brandwijk, S. Joosse, F. Hogevorst, L. Wessels, S. Verhoef, P. Devilee, P.M. Nederlof
Journal: Annals of Oncology (2010)
Abstract 9888: Ischemic Heart Disease and Type 2 Diabetes Complications Are Associated with Glycemic Variability Measured by Continuous Glucose Monitoring
Authors: Jeffrey K Hertzberg, Ciara Janer, An-Ting Jhuang, Alix J Santos, Nathan Kibanoff, Deneen Vojta, Ben Wiegand, Jaime Murillo
Journal: Circulation (2021)

Introduction: The management of type 2 diabetes mellitus (DM) has focused on achieving normal glucose levels in order to prevent cardiovascular disease (CVD) and other DM-related complications. Some have suggested that glucose variability (GV) may be associated with DM complications. Other studies, using manual glucose testing, failed to prove it. In our retrospective study using a large administrative database and thousands of patients wearing continuous glucose monitors (CGM), we evaluated the association between various glucose parameters and CVD and DM complications. Methods: Of 15,815 people enrolled in a T2DM program who ordered a CGM device, 58.2% actually used it. The final cohort had 4,530 CGM users with &gt; 30 days of CGM data within 90 days. Metrics included mean glucose and GV measures such as SD, IQ range, % coefficient of variation (%CV), mean amplitude of glycemic excursions (MAGE) and time in range. A multivariable regression analysis tested for the association between these metrics and the occurrence of CVD and DM complications based on claims from Jan 2016 through April 2021. Results: The mean age was 53, with a 1:1 gender ratio. Mean glucose level was 157 (SD + 32). At least one CVD condition or DM complication (nephro-, retino-, neuropathy, skin ulcer/gangrene, circulatory problems) was present in 84% of subjects. The 2 most frequent were ischemic heart disease (IHD) in 15.7% and DM kidney disease in 9.5%. Subjects with IHD or DM complications had significantly higher mean glucose and GV measures (p&lt;0.001). However, there was a 10-fold difference between a marker of variability (%CV) and the mean glucose level: for every % point increase in %CV there was a 7% increased likelihood of DM complications, compared with only a 0.7% increase for every additional 1 mg/dl of mean glucose. Conclusions: In a relatively young cohort of persons with T2DM wearing CGM, glycemic variability, as measured by %CV, was more strongly associated with IHD and diabetic complications than mean glucose level. This suggests that management of diabetes should focus more on glycemic variability than absolute glucose levels. Wider adoption of CGM may more effectively detect persons with high glycemic variability at risk for ischemic heart disease and other diabetic complications.
Transcriptional profiling of breast cancer cells exposed to soy phytoestrogens after knockdown of BRCA1 with a whole human genome microarray approach
Authors: Dominique Gallon-Bernard, Samir Satih, Nassera Chalabi, Nadege Rabiau, Yves-Jean Bignon
Journal: Cancer Research (2008)

1716  To study the role of BRCA1 loss-of-function in breast cancer and the possible links existing with soy isoflavones metabolism, we generated conditional BRCA1 knockdown using specific siRNA associated to phytoestrogen treatment. This study assayed two human breast cancer cell lines (MCF-7, MDA-MB-231), and a fibrocystic breast cell line (MCF-10a) transfected with siRNA BRCA1-specific and treated with 18.5 µM genistein or 78.5 µM daidzein for 72h. To define differential gene expression, a competitive hybridization was performed between Cy5-labeled transfected/treated RNA and Cy3-labeled control RNA.  Initial feature extraction and Cy3/Cy5 intensities for each individual gene were performed using GenePix Pro 6 software (Axon®). Signal intensities ratios of each gene were converted into a logarithmic value (log2) with LimmaGUI 1.7.0 software using R 2.2.0 software. Normalizations were performed within and between array via a global lowess method. Hierarchical clusters were obtained with TIGR MeV version 4.0.0 software using complete-linkage Pearson correlation clustering method according to the estrogen receptor status or the malignancy status of cell lines.  Results showed that BRCA1 knockdown altered significantly expression of genes correlated to important molecular pathways directly involved in carcinogenesis such as apoptosis (BAX, BCL2, IκB, PTPN13), cell communication (CAV1), xenobiotic metabolism (CYP2B6, CYP1B1), or sterol metabolism (HSD17B1), and suggested that genistein and daidzein treatments could partially reverse or limit the BRCA1 knockdown alterations. These findings provide evidence supporting that BRCA1 tumor suppressor gene is a molecular target for soy phytoestrogens and suggested that these phytochemicals could act as preventive dietary elements in mammary carcinogenesis.
Abstract 6941: Cardiac Repair With Echocardiography-Guided Multiple Percutaneous Left Ventricular Intramyocardial Injection of Human Induced Pluripotent Stem Cell Derived Cardiomyocytes After Myocardial Infarction
Authors: Xun Wu, Di Wang, Kele Qin, CHUKWUEMEKA DANIEL D IROEGBU, Kun Xiang, Yuanjing Zhou, Qing Guan, Jun Peng, Jinfu Yang, Chengming Fan
Journal: Circulation (2021)

Objective: To investigate the cardiac repair potency with echocardiography-guided multiple percutaneous left ventricular intramyocardial injection of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) after myocardial infarction. Methods: The surgically induced myocardial infarcted mice were randomly divided into three groups (8 in each) and were injected with echocardiography-guided percutaneous left ventricular infarcted border zone of one shot hiPSC-CMs (single dose, 10ul of 3x10 5 cells), medium, or repeated delivery of hiPSC-CMs at post-MI week 1 and 2 (multiple dose). The sham group of animals underwent all surgical procedures necessary for MI induction except for the ligation step. 4 weeks after the MI, heart function was measured by the transthoracic echocardiography. The engraftment size was evaluated through the detection of human specific cardiac troponin T. Infarcted size and collagen volume were calculated by sirius-red and fast green staining. Angiogenesis was evaluated by the staining of isolectin B4. Cardiac remodeling was evaluated by the cardiomyocyte minimal fiber diameter in the infarcted border zone. Apoptosis was detected via tunel staining in cardiomyocyte from the infarcted border zone. Results: No death was detected with echocardiography-guided percutaneous left ventricular intramyocardial injection. The number of hiPSC-CMs was about 9-fold higher in multiple dose group at week 4 compaired to single dose group. The multiple dose transplantation was associated with significant improvement in left ventricular function, infarct size, angiogenesis, cardiac remodeling, and cardiomyocyte apoptosis. Conclusions: Echocardiography-guided multiple percutaneous left ventricular intramyocardial injection is a feasible, satisfactory, repeatable, relatively less invasive and effective delivery method for cell therapy and the delivery of hiPSC-CMs indicate a novel therapy for myocardial infarction.
Abstract 9375: Melatonin and Metformin Exert Cardioprotection Against Trastuzumab-induced Cardiotoxicity Through Modulating Cardiac Mitochondrial Dynamics in Rats
Authors: Apiwan Arinno, Chayodom Maneechote, Thawatchai Khuanjing, Titikorn Chunchai, Nanthip Prathumsap, Busarin Arunsak, Sasiwan Kerdphoo, Krekwit Shinlapawittayatorn, Siriporn Chattipakorn, Nipon Chattipakorn
Journal: Circulation (2021)

Introduction: The combination of doxorubicin (Dox) and trastuzumab (Trz) in patients with metastatic human epidermal growth factor receptor 2 (HER2) positive tumors is limited by cardiotoxicity, as manifested by cardiac dysfunction. Although several pharmacological interventions including melatonin and metformin have been shown cardioprotection in several cardiovascular diseases, their roles in Trz-induced cardiotoxicity and the underlying mechanisms have never been tested. Hypothesis: We hypothesized that either melatonin or metformin exerts cardioprotection against Trz-induced cardiac injury through attenuating cardiac mitochondrial dysfunction. Methods: Twenty male Wistar rats were randomly divided into control group (n=5) and Trz group (n=15). Trz-treated rats were intraperitoneally injected with 4 mg/kg/day of Trz for 7 consecutive days, while control rats were injected with normal saline. Then, Trz-treated rats were equally subdivided into 3 co-treatment groups to receive normal saline, melatonin (10 mg/kg/day), or metformin (250 mg/kg/day) via oral gavage. Left ventricular (LV) function was performed using echocardiography, and the hearts were rapidly removed to determine cardiac mitochondrial function and mitochondrial dynamic proteins. Results: Trz induced excessive mitochondrial oxidative stress and mitochondrial dynamics imbalance, eventually leading to LV dysfunction (Fig. 1A-D). Treatment with either melatonin or metformin similarly improved contractile function (Fig. 1A), reduced mitochondrial ROS production (Fig. 1B) and mitochondrial dynamic index (Drp1/Mfn2) (Fig. 1C &amp; D), resulting in improved LV function. Conclusions: Melatonin and metformin equally exerted cardioprotection against Trz-induced cardiotoxicity. Our findings suggested that either melatonin or metformin can be used as a concomitant intervention for cardioprotection in patients with metastatic HER2 positive tumors being treated with Trz.
Abstract 12437: Network-Based Identification of Tissue-Specific Regulators and Drug Repurposing Candidates for Coronary Artery Disease
Authors: Jenny Cheng, Montgomery Blencowe, Aldons J Lusis, Xia Yang
Journal: Circulation (2021)

Coronary artery disease (CAD) is the leading cause of mortality worldwide. Recent genomic studies in human populations and mouse models have revealed numerous novel genetic loci that may affect pathways and gene networks in CAD relevant tissues. In this study, we aim to use network-based systems biology approaches to identify regulators and drug repurposing candidates based on CAD gene networks. Through integration of multiomics datasets encompassing genetic association studies, transcriptomic profiles, and tissue-specific gene regulation from human and mouse populations, we previously modeled gene networks in vascular and liver tissues that are affected by CAD genetic loci in both species. Based on the shared CAD gene networks between human and mouse, we predicted candidate key regulatory genes and further examined multiple single-cell RNA sequencing datasets of vascular and liver tissues to pinpoint the specific cell types and molecular pathways in each tissue through which the top predicted regulators function. We further used network-based drug repositioning approaches to predict drugs targeting the CAD networks in each tissue, revealing both currently used medications and potential novel therapeutic agents. The cross-species networks, predicted key regulatory genes, their cellular and tissue context, and the network-based drug repositioning analyses offer tissue and cell-type specific targets and potential existing drugs that can be repurposed for CAD treatment.
Abstract 12915: Machine Learning Models Show That Age, Functional Status, and TNF-α Accurately Predicts Multimorbidity in Acute Coronary Syndrome
Authors: Katherine Breen, Jesse Coultas, Holli A Devon
Journal: Circulation (2021)

Introduction: Increasing prevalence of multimorbidity (&gt;2 conditions) put individuals, especially older adults, at increased risk for acute coronary syndrome (ACS). Machine learning techniques provide an opportunity to identify clinical factors associated with multimorbidity that may aid in identifying subgroups of multimorbid patients that are at higher risk for ACS. Our primary objective was to use machine learning techniques to identify factors associated multimorbidity in individuals presenting to the emergency department (ED) for potential ACS. Hypothesis: Markers of chronologic and physiologic aging are associated with multimorbidity and vary by functional status and inflammatory profiles. Methods: This was a secondary analysis of data collected from a large multi-site study aimed at characterizing sex differences in symptoms suggestive of ACS in the ED. Variables of interests were measured with the Charlson Comorbidity Index, the Duke Activity Status Index, and serum cytokines (TNF-α, IL-6, and IL-18). A logistic regression model was applied to a sample of 414 patients utilizing a 70/30 test/train split to determine if biomarkers, functional status, sex, and age were associated with multimorbidity. Results: Patients were predominantly male (62.5%), white (73.0%), and had a mean age of 58.9 years. The accuracy of the model in predicting multimorbidity was 86.8% in the training set (n=290). In validation testing, accuracy was 73.0% (n=124). Functional status (OR .960, 95% CI .94-.206, p&lt;0.000), age (OR 1.10, 95% CI 1.04-1.10, p&lt;0.000), and TNF- α (OR 2.21, 95% CI 1.17-4.45, p&lt;0.000), were associated with multimorbidity. The overall model was significant with a χ 2 (286, N=71.1) = 6, p&gt;0.05. A responder operator curve was run on the individual variables and age, functional status, and TNF- α and showed significant discrimination levels (c-statistic 0.74, 0.73, and 0.65, respectively). Conclusions: Multimorbidity increases the risk for ACS. TNF-α, functional status, and age improved models of ACS risk stratification in a heterogeneous sample of multimorbid patients. Machine learning methodologies exhibit utility in identifying potential clinical markers of multimorbidity.
Time Since Last Anti-CD20 Treatment Is a Major Determinant of Sars-Cov-2 Vaccine Response in a Large Cohort of Patients with B-Cell Lymphoma
Authors: Tanaya Shree, Vishnu Shankar, Debra K. Czerwinski, Gladys Rodriguez, Sara Beygi, Joseph G Schroers-Martin, Ranjana Advani, Lauren S. Maeda, Neel K. Gupta, Michael S. Khodadoust, David M. Kurtz, Karen S. Corbelli, Etelka Gabriel, Alyssa M. Kanegai, Ash A. Alizadeh, Ronald Levy
Journal: Blood (2021)
DDRE-48. COMPARTMENT LOCKED IL-12 - INCREASED TISSUE RETENTION AND MINIMAL PERIPHERAL EXPOSURE ALLOW HIGHER TREATMENT EFFICACY AND TOLERABILITY IN LOCAL GLIOBLASTOMA THERAPY
Authors: Michal Beffinger, Linda Schellhammer, Tala Shekarian, Sereina Deplazes, Ivan Zimmermann, Pascal Egloff, Thorsten Buch, Markus Seeger, Gregor Hutter, Johannes Vom Berg
Journal: Neuro-Oncology (2021)

Abstract Recent clinical studies in glioblastoma (GBM) highlight the potential of local IL-12 therapy, but they also bring back tolerability concerns due to leakage into the periphery. This leakage might thus hamper exploiting the full potential of local IL-12 therapy. Fusion with an IgG4 Fc portion increases the tissue retention of IL-12; but could also confer export into the blood and subsequent systemic recycling through the neonatal Fc receptor (FcRn), ultimately leading to potentially toxic IL-12 serum levels. We assessed the expression of FcRn in human and murine GBM and its role in IL-12Fc tissue retention and systemic exposure upon local delivery. Human or murine IL-12Fc was injected in GBM-bearing or naïve wt or FcRn-humanized mice continuously or as bolus via convection-enhanced delivery (CED). We screened combinations of amino-acid substitutions at the (IL-12)Fc:FcRn binding interface to abolish this interaction. Brain and blood concentrations were assessed via ELISA or cytokine bead arrays. FcRn affinity was measured by SPR/ELISA and bioactivity tested on PBMCs and human GBM explant cultures. Treatment efficacy and immunological correlates were assessed in GBM bearing mice. FcRn is upregulated in human and mouse GBM and contributes to brain export and subsequent peripheral recycling of IL-12Fc in the blood. IL-12Fc with abrogated FcRn binding due to a unique set of substitutions is fully functional and appears brain compartment locked (CL IL-12) as it exhibits enhanced tissue retention and reduced serum levels upon local injection, reaching up 100x higher brain to serum concentration ratios than regular IL-12. Compared to its non-modified counterpart, murine CL IL-12 shows significantly higher treatment efficacy at negligible systemic footprint in late stage murine GBM. In patient explant cultures, human CL IL-12 leads to successful inflammatory conditioning. Compartment locked IL-12 should thus allow a wide dosing window to fully harness its therapeutic potential for local GBM therapy.
Abstract 12154: Exploring Differences in Race and Ethnicity in Sudden Death in the Young, 2015-2019
Authors: Austin Whitted, Heather MacLeod, Beverly Yashar, Esther Shaw, Alexa Erck Lambert
Journal: Circulation (2021)

Background: In 2015, the National Institutes of Health and Centers for Disease Control and Prevention collaborated to create the Sudden Death in the Young (SDY) Case Registry, a population-based surveillance and research initiative. The Registry monitors SDY incidence and identifies characteristics to inform data-driven prevention efforts. Previous analyses using 2015-2017 data identified differences in SDY by race/ethnicity. Further investigation into SDY demographics and the circumstances at death by race/ethnicity may help identify reasons for disparities and priority areas for future research. Objective: To explore racial/ethnic differences in SDY by demographic and circumstantial characteristics. Methods: We analyzed sudden and unexpected deaths that occurred during 2015-2019 among infants (&lt;1 year old) and children (1-18 years old) in the 13 states/jurisdictions participating in the Registry. We excluded cases with explained causes including explained suffocation, motor vehicle accidents and drownings, and those missing race/ethnicity (n=15). We reported percentages and performed χ 2 tests to assess differences in demographic and circumstantial characteristics by race/ethnicity. Results: Among 1,370 SDY cases included, 46% were non-Hispanic White (NHW), 35% non-Hispanic Black (NHB), 10% Hispanic, and 9% non-Hispanic other (NHO). Most occurred among infants (68%), and most infants (92%) were sleeping at the time of the incident. Among children, sleeping at the time of the incident ranged from 45% for NHW to 29% for Hispanic (P&lt;0.0073). More NHW infants/children had metabolic and genetic testing than infants/children of other race/ethnicities. Metabolic testing ranged from 52% for NHW to 36% for NHB (p&lt;0.0001). Genetic testing ranged from 11% for NHW to 5% for NHB (p&lt;0.0056). Conclusion: Our findings show that among SDY, there are key demographic and circumstantial differences by race/ethnicity: NHW children were more likely to be sleeping at the time of the incident, and NHW infants/children more commonly had metabolic and genetic testing. This analysis contextualizes the racial/ethnic differences in SDY, offering focus for further research and prevention efforts.