tbuckley/cabot-search huggingface dataset:
Abstract 12030: Impact of High-Resolution Epiaortic Ultrasonographic Imaging on Evaluating Aortic Wall Pathology
Authors: Soichiro Henmi, So Izumi, Reiko Kanno, Masato Hoshino, Kazunori NAKAGAWA, Yutaka Nakashima, Kenji Okada, Takuro Tsukube
Journal: Circulation (2021)

Introduction: Innovative imaging modality for preclinical diagnosis of aortic dissection (AD) has been awaited. Hypothesis: We previously reported that synchrotron radiation-based X-ray phase-contrast tomography (XPCT) imaging revealed densitometrical changes in the tunica media in the aortic wall (TM) of AD. To replicate XPCT findings in clinical practice, we investigated the application of high-resolution ultrasound in intraoperative epi-aortic scan (EAS) imaging. Methods: Twelve patients (normal aorta (5), chronic AD (3), acute type-A AD(4)) were selected. Before beginning cardiopulmonary bypass, the mid-ascending aorta was exposed and an EAS was conducted using EPIQ CVx and an eL18-4 transducer. After aortic repairs, the aortic samples of AD were fixed and applied XPCT, to compare ultrasonographic intensity (UI) of EAS and densitometric changes in XPCT in the same samples. Results: In normal aorta, UI remained unchanged throughout the TM (Figure-1A). In chronic AD, high linear changes in the UI in the middle of the TM was observed in the aorta that had not been dissected (yellow arrow in Figure-1B). In acute AD, high linear changes in the UI were clearly observed in the middle of TM, and aortic dissection was observed as an extension of those liner changes (Figure-1C). A line profile of the UI between the intima and the adventitia showed that the UI remained unchanged in normal aorta, and exhibited a high peak in the middle of the TM in chronic and acute AD (Figure-1A,B,C). These results indicated differences in the UI throughout the TM between normal and pathological aortas. These findings were well consistent with changes in the TM of patients with AD, which were obtained using XPCT (Figure-1D,E). Conclusions: High-resolution ultrasonographic imaging could replace XPCT findings in clinical settings and lead to significant improvements in the presymptomatic diagnosis of various aortic wall pathologies, including aortic dissection.
Abstract MP219: Hnrnpa2b1-dependent Selective Sorting Of Mir-486a-5p Into Msc-derived Exosomes Contributes To Cardioprotection
Authors: Keith Jones, Ahn Phan, Chongyu Zhang, Lauren Haar, Thomas Lynch
Journal: Circulation Research (2021)

Exosomes (Exo) are a class of extracellular vesicles and involvement of stem cell-derived Exo in cardiac repair and cardioprotection is thought to be an important in the heart. Our HYPOTHESIS Is that specific microRNAs (miRs) from mesenchymal stem cell (MSC)-derived exosomes are actively and selectively sorted into Exo by RNA binding proteins and motifs on the miR, to serve specific functions of the Exo, including Cardioprotection. Methods: We characterized the miR populations of parental MSCs and their Exo via RNA Seq and confirmed by QRT-PCR the subpopulation of miRs that is increased in Exo vs . MSC cells. We then used Multiple Em for Motif Elicitation (MEME) Version 5.3.3 and determined the predicted conserved motifs. From these, we predicted RNA binding protein sites from the literature. In parallel, we performed mass spectrometry and western blot analyses to determine RNA binding proteins in MSC and Exo. Predicting that hnRNPA2B1 was a likely RNA binding protein for the new motif, we knocked out the cognate gene (CRISPR) in MSC and evaluated the KO Exo vs. the WT Exo by RNA Seq and QRT-PCR. We performed protein and RNA pulldowns, and EMSA to validate binding of hnRNPA2B1 to several of the miRs, and investigated the effects of these miRs on cell survival after simIR and in an in vivo mouse model of MI. Results: We found a set of eight miRs that are selectively concentrated in the MSC Exo. MEME software predicted a conserved binding motif of gAGu, which is close to canonical sites for binding of hnRNPA2B1 and hnRNPA1. We determined hnRNPA2B1 was in MSC and Exo and showed KO hnRNPA2B1 cells and Exo had no compensatory perturbation of other RNA binding proteins. The KO MSC Exo show reduction of the selective sorting of the miRs of interest. Pulldowns and binding assay results verify binding of hnRNPA2B1 to both miR-486a-5p and miR-122a. Finally, we showed that miR-486a-5p is protective in H9C2 cells submitted to simIR and results in significant 68% reduction of infarct size (n=7, P=0.0175) in vivo in association with repression of PDCD4 expression and apoptosis. Conclusions: We determined that a set of miRs is selectively concentrated in MSC Exo and demonstrated the necessity of hnRNPA2B1 in that process. This appears to involve a conserved RNA sequence motif (mutational analysis underway). A major miR affected is miR-486a-5p, which is strongly cardioprotective. Our results support that miR-486a-5p is selectively concentrated in MSC Exo and contributes to cardioprotection by reducing PDCD4 activity in apoptosis.
Abstract 9809: Mortality, Hospitalization, and Cardiac Interventions in Atrial Fibrillation Patients Younger Than 65 Years
Authors: Aditya Bhonsale, Jianhui Zhu, Floyd W Thoma, Krishna Kancharla, Andrew Voigt, Jared W Magnani, N A Estes, Samir Saba, Suresh R Mulukutla, Sandeep Jain
Journal: Circulation (2021)

Introduction: The risk factor burden, and long-term outcome among atrial fibrillation (AF) patients under 65 years of age is unclear. Methods: The study population included 67,221 (mean age 72.4 ± 12.3, 45% female) adult patients with AF evaluated at the University of Pittsburgh Medical Center between 1/2010 and 12/2019. Hospital system wide electronic health records and administrative data using International Classification of Disease 9 and 10 revisions was utilized to ascertain risk factors, comorbidities, and subsequent mortality and hospitalization stratified according to age at initial evaluation. Association of AF with all-cause mortality among those &lt; 65 years was analyzed using an internal contemporary cohort of patients without AF (n=918,073). Results: 17,335 patients (26%) were less than 65 years of age (32% female, 92% white) with considerable cardiovascular risk factors (current smoker 16%, BMI 33.0 ± 8.3, hypertension 55%, Diabetes Mellitus 21%, congestive heart failure 20%, Coronary artery disease 19%, prior ischemic stroke 6%) and comorbidity burden (COPD 11%, Obstructive sleep apnea 18%, CKD 1.3 %). Over mean follow up of &gt; 5 years, 2084 (6.7% &lt;50 years; 13% 50-65 years) patients died. Proportion of patients with &gt;1 hospitalization for MI, HF and Ischemic stroke was 1.25%, 4.8%, and 1.05% for those &lt;50 years and 2.2%,7.4%, and 1.1% for the 50-65 years subgroup respectively. Multiple cardiac and non-cardiac risk factors were associated with increased mortality in younger AF patients with HF and hypertension demonstrating significant age-related interaction (p=0.007 and p=0.013 respectively). AF patients experienced significantly worse survival when compared to comorbidity adjusted patients without AF (Males &lt;50y HR 1.49 (1.24-1.79), 50-65y HR 1.34 (1.26-1.43); Females &lt;50y HR 2.4 (1.82-3.16), 50-65y HR 1.75 (1.6-1.92)). Conclusions: AF patient &lt;65 years of age have significant comorbidity burden and considerable long-term mortality. They are also at a significant increased risk of hospitalization for HF, stroke, and myocardial infarction. Cardiac and non-cardiac comorbidities are independently associated with worse outcome in these patients and warrant aggressive risk factor and comorbidity evaluation and management.
Global, regional, and national cancer incidence and death for 29 cancer groups in 2019 and trends analysis of the global cancer burden, 1990–2019
Authors: Longfei Lin, Zhiyong Li, Lei Yan, Yuling Liu, Hongjun Yang, Hui Li
Journal: Journal of Hematology & Oncology (2021)

Abstract Background and aims Cancer will soon become the leading cause of death in every country in the twenty-first century. This study aimed to analyze the mortality and morbidity of 29 types of cancer in 204 countries or regions from 1990 to 2019 to guide global cancer prevention and control. Methods Detailed information for 29 cancer groups was collected from the Global Burden of Disease Study in 2019. The age-standardized incidence rate (ASIR) and age-standardized death rate (ASDR) of the 29 cancer groups were calculated based on sex, age, region, and country. In addition, separate analyses were performed for major cancer types. Results In 2019, more than 10 million people died from cancer, which was approximately twice the number in 1990. Tracheal, bronchus, and lung (TBL) cancers collectively showed the highest death rate, and the ASDR of pancreatic cancer increased by 24%, which was cancer with the highest case fatality rate (CFR). The global cancer ASIR showed an increasing trend, with testicular cancer, thyroid cancer, and malignant skin melanoma showing a significant increase. The ASDR and ASIR of cancer in males were about 1.5 times higher than that in females. Individuals over 50 years had the highest risk of developing cancer, with incidences and deaths in this age group accounting for more than 85% of cancers in all age groups. Asia has the heaviest cancer burden due to its high population density, with esophageal cancer in this region accounting for 53% of the total fatalities related to this type of cancer in the world. In addition, the mortality and morbidity of most cancers increased with the increase in the development or socio-demographic index (SDI) in the SDI regions based on the World Bank's Human Development Index (HDI), with cancer characteristics varying in the different countries globally. Conclusions The global cancer burden continues to increase, with substantial mortality and morbidity differences among the different regions, ages, countries, gender, and cancer types. Effective and locally tailored cancer prevention and control measures are essential in reducing the global cancer burden in the future.
Human Endogenous Retrovirus Type K Promotes Proliferation and Confers Sensitivity to Antiretroviral Drugs in Merlin-Negative Schwannoma and Meningioma
Authors: Emmanuel A. Maze, Bora Agit, Shona Reeves, David A. Hilton, David B. Parkinson, Liyam Laraba, Emanuela Ercolano, Kathreena M. Kurian, C. Oliver Hanemann, Robert D. Belshaw, Sylwia Ammoun
Journal: Cancer Research (2021)

Deficiency of the tumor suppressor Merlin causes development of schwannoma, meningioma, and ependymoma tumors, which can occur spontaneously or in the hereditary disease neurofibromatosis type 2 (NF2). Merlin mutations are also relevant in a variety of other tumors. Surgery and radiotherapy are current first-line treatments; however, tumors frequently recur with limited treatment options. Here, we use human Merlin-negative schwannoma and meningioma primary cells to investigate the involvement of the endogenous retrovirus HERV-K in tumor development. HERV-K proteins previously implicated in tumorigenesis were overexpressed in schwannoma and all meningioma grades, and disease-associated CRL4DCAF1 and YAP/TEAD pathways were implicated in this overexpression. In normal Schwann cells, ectopic overexpression of HERV-K Env increased proliferation and upregulated expression of c-Jun and pERK1/2, which are key components of known tumorigenic pathways in schwannoma, JNK/c-Jun, and RAS/RAF/MEK/ERK. Furthermore, FDA-approved retroviral protease inhibitors ritonavir, atazanavir, and lopinavir reduced proliferation of schwannoma and grade I meningioma cells. These results identify HERV-K as a critical regulator of progression in Merlin-deficient tumors and offer potential strategies for therapeutic intervention. SIGNIFICANCE: The endogenous retrovirus HERV-K activates oncogenic signaling pathways and promotes proliferation of Merlin-deficient schwannomas and meningiomas, which can be targeted with antiretroviral drugs and TEAD inhibitors.
Abstract 13385: Prediction of Patient Comfort for Extravascular and Subcutaneous Implantable Cardioverter-Defibrillation Devices Using Modeling
Authors: Danielle Mathiesen, Varun Bhatia, Elizabeth Formosa, Bridget Portway
Journal: Circulation (2021)

Introduction: Implanted medical devices may exert pressure on patients’ tissues, generating discomfort. Depending on implant location and device design, the pressure generated will vary. The investigational extravascular implantable cardioverter-defibrillator (EV ICD) device volume is 33 cubic centimeters (cc), while the commercially available subcutaneous (SQ) ICD is 59 cc. The objective of this work is to compare the pressure on the subcutaneous and muscular tissue over a device in a tissue pocket through computer simulation. Method: Finite element modeling was performed for the EV ICD and SQ ICD in three implant locations: subcutaneous, submuscular, and intermuscular. A pocket condition was simulated with tissue above the device being displaced by the thickness of the device; the resulting pressures were calculated. Device contact pressure on the subcutaneous and muscular tissue above the device was used as a surrogate for potential patient discomfort caused by the device pushing against tissue. Results: In all three implant locations, the tissue pressure of the EV ICD was lower than that of the SQ ICD. Larger areas of high pressure were present on the tissue surface near the edges of the SQ ICD device compared to the EV ICD. The reduction observed in the EV ICD relative to the SQ ICD device was 24% in subcutaneous, 12% in submuscular, and 44% in intermuscular. See figure. Conclusion: Simulation shows that the EV ICD exerts less pressure on the tissue over the device than the SQ ICD across clinically relevant locations, with the potential to improve patient comfort.
Abstract 9556: Dipeptidyl Peptidase-4 Inhibitors Significantly Reduce the Incidence of First Cardiovascular Events in Diabetic Patients
Authors: Hirofumi Soejima, Takeshi Morimoto, Sadanori Okada, Chisa Matsumoto, Masafumi Nakayama, Hideaki Jinnouchi, Izuru Masuda, Masako Waki, Yoshihiko Saito, Hisao Ogawa
Journal: Circulation (2021)

Background: Many studies have reported that dipeptidyl peptidase (DPP)-4 inhibitors do not significantly reduce cardiovascular events (CVE). We sought to evaluate whether DPP-4 inhibitors effected the incidence of CVE in diabetic patients with no history of atherosclerotic events. Methods: The Japanese primary prevention of atherosclerosis with aspirin for diabetes (JPAD) trial was a multicenter, prospective, randomized, open label, blinded, end-point study done from 2002 to 2008. After completion of the JPAD trial, we followed up with the patients until 2019. We defined the cardiovascular events as the following: acute myocardial infarction; stable angina; unstable angina; sudden cardiac death; stroke; transient ischemic attack; heart failure requiring hospitalization; aortic disease; and peripheral artery disease. JPAD patients were divided into a DPP-4 Group and a non-DPP-4 Group based on whether or not they were taking DPP-4 inhibitors at the 2013 follow-up. We investigated the incidence of CVE in 1,107 JPAD patients who had had at least one follow-up by 2019. Results: During the observation period from 2013 to 2019, there were 37 (7%) CVE in the DPP-4 Group (n=520) and 66 (11%) in the non-DPP-4 Group (n=587). The incidence of CVE was significantly lower in the DPP-4 Group than in the non-DPP-4 Group (Log-Rank P=0.0074, Figure). Cox proportional hazards model analysis revealed that use of DPP-4 inhibitors (HR, 0.65: 0.43-0.98, P=0.04) was an independent factor after adjustment for age ≥65 years, hypertension, dyslipidemia, and, insulin usage (Figure). Conclusions: Our study demonstrated that the use of DPP-4 inhibitors was associated with a reduced incidence of CVE after adjustment in diabetic patients without a history of atherosclerotic events. It is necessary to be aware of the cardiovascular event-suppressing effect of DPP-4 inhibitors on diabetic patients.
Epidemiology of pre-existing multimorbidity in pregnant women in the UK in 2018: a cross-sectional study
Authors: Siang Ing Lee, Amaya Azcoaga-Lorenzo, Utkarsh Agrawal, Jonathan I Kennedy, Adeniyi Francis Fagbamigbe, Holly Hope, Anuradhaa Subramanian, Astha Anand, Beck Taylor, Catherine Nelson-Piercy, Christine Damase-Michel, Christopher Yau, Francesca Crowe, Gillian Santorelli, Kelly-Ann Eastwood, Zoe Vowles, Maria Loane, Ngawai Moss, Peter Brocklehurst, Rachel Plachcinski, Shakila Thangaratinam, Mairead Black, Dermot O'Reilly, Kathryn M Abel, Sinead Brophy, Krishnarajah Nirantharakumar, Colin McCowan
Journal: The Lancet (2021)
Abstract 10192: Circular RNA Formation in the Failing Heart is Enhanced by the Reduction of Adenosine-to-Inosine RNA Editing
Authors: Karoline Elizabeth Kokot, Jasmin M Kneuer, David John, Maximilian N Moebius-Winkler, Marion Müller, Michael Andritschke, Susanne Gaul, Bilal N Sheikh, Jan Haas, Holger Thiele, Florian Leuschner, Stefanie Dimmeler, Benjamin Meder, Ulrich Laufs, Jes-Niels Boeckel
Journal: Circulation (2021)

Introduction: Adenosine-to-Inosine (A-to-I) RNA editing is a post-transcriptional modification process regulating RNA stability and alternative splicing. A-to-I RNA editing is conducted by the enzymes ADAR1 and ADAR2 and mainly targets Alu elements, primate-specific elements which have been associated with the formation of circular RNA (circRNA). Although differential expression of circRNAs has been studied in heart failure (HF), the extent of A-to-I RNA editing and consequences in the human heart remain largely unknown. Methods and Results: We analyzed RNA editing in human heart samples of HF (n=20) patients and controls (n=10) using RNA sequencing. We found a reduction of A-to-I RNA editing in intronic Alu elements of protein-coding genes in HF patients compared to controls. The majority (96%) of regulated circRNAs were upregulated. The predicted back-splice sites (BSS) of 20 circRNAs were validated by qPCR. The circRNA candidates correlated with RNA editing (R=0.47, P=0.02). Among the upregulated circRNAs, we identified two circular transcripts (circAKAP13) derived from the AKAP13 gene, which showed reduced A-to-I RNA editing in HF (-70.7%, n=20). In HF, ADAR2 was reduced (-68.2%) and ADAR1 was increased (7.41±0.13 -fold) on protein level (n=3-6). The knockdown of ADAR1 did not alter circRNA levels, whereas the knockdown of ADAR2 led to significantly upregulated levels of circAKAP13 (1.88±0.42 -fold, n=6). Consistently, ADAR2 overexpression reduced circAKAP13 expression (-41%, n=3). Using two mini-genes containing exons 15-19 of the AKAP13 gene and flanking Alu elements, we found convergent Alu elements enhancing circAKAP13 expression. Conclusion: In conclusion, these data describe the A-to-I RNA editome in the human heart for the first time. Reduced A-to-I RNA editing in HF patients is associated with elevated circRNA levels. We propose a primate-specific splicing mechanism mediated by A-to-I RNA editing in the human heart. These findings contribute to a better mechanistic understanding of A-to-I RNA editing in cardiac diseases.
Abstract P457: Systems Analysis To Understand The Impact Of The CDK Module On Cardiomyocyte Proliferation
Authors: Bryana N Harris, Laura Woo, Jeffrey J Saucerman
Journal: Circulation Research (2021)

Rationale: Heart failure is caused by the inability of adult mammalian hearts to overcome the loss of cardiomyocytes (CMs). This is due partly to the limited proliferative capacity of CMs, which exit the cell cycle and do not undergo cell division. Current knowledge in cardiac regeneration lacks an understanding of the molecular regulatory networks that determine whether CMs will progress through the cell cycle to proliferate. Our goal is to use computational modeling to understand the expression and activation levels of the core cell cycle network, specifically cyclins and cyclin-cyclin-dependent kinase (CDK) complexes. Methods: A model of core cell cycle dynamics was curated using previously published studies of CM proliferation regulators. This model incorporates those regulators known to stimulate G1/S and G2/M transitions through the core CDKs. The activity of each of the 22 network nodes (22 reactions) was predicted using a logic-based differential equation approach. The CDK model was then coupled with a minimal ODE model of cell cycle phase distributions and validated based on descriptions and experimental data from the literature. To prioritize key nodes for experimental validation, we performed a sensitivity analysis by stimulating individual knockdown for every node in the network, measuring the fractional activity of all nodes. Results: Our model confirmed that the knockdown of p21 and Rb protein and the overexpression of E2F transcription factor and cyclinD-cdk4 showed an increase in cells going through DNA synthesis and entering mitosis. A combined knockdown of p21 and p27 showed an increase of cells entering mitosis. Cyclin D-cdk4 and p21 overexpression showed a decrease and increase of Rb expression, respectively. Of the 14 model predictions, 12 agreed with experimental data in the literature. A comprehensive knockdown of the model nodes suggests that E2F (a key transcription factor driving DNA synthesis) is positively regulated by cyclin D while negatively regulated by GSK3B, SMAD3, and pRB. Conclusion: This model enables us to predict how cardiomyocytes respond to stimuli in the CDK network and identify potential therapeutic regulators that induce cardiomyocyte proliferation.
Abstract 13246: Utility and Validity of Deep Learning Based Fully Automated Echocardiogram Interpretation in Patients With Congenital and Structural Heart Disease: Importance of Congenital Specific Algorithms
Authors: Maria Luisa Benesch Vidal, Gerhard Diller, Alicia Fischer, Helmut Baumgartner, Stefan Orwat
Journal: Circulation (2021)

Background: Automated echocardiographic image interpretation has the potential to transform clinical practice by improving efficiency and supporting serial assessment of structural abnormalities or cardiac function. We hypothesized that neural networks (NN) developed for image segmentation in general/non-congenital cohorts may underperform in the setting of abnormal cardiac anatomy and that deep learning (DL) algorithms trained specifically in this cohort may have superior precision in this setting. Methods: Consecutive patients with various forms of congenital or structural heart disease (CHD/SHD) were used to validate an existing convolutional NN trained on 14,035 echocardiograms for automated viewpoint classification (Zhang et al. Circulation 2018). In addition, a new specific deep convolutional network for viewpoint classification was trained and tested in patients with CHD/SHD. Results: Overall, 9,793 imaging files (8,363 GE Medical, 1,421 Philips Medical) from 262 patients with CHD/SHD (mean age 48 years, 59.5% male) and 62 normal controls (mean age 45 years, 50,0% male) were included. Congenital diagnoses included among others, Tetralogy of Fallot (30), Ebstein anomaly (18), transposition of the great arteries (TGA) (48), congenitally corrected TGA (34). Assessing correct view classification based on 284,250 individual frames revealed that the non-congenital model had an overall accuracy of 54.2% for correct view classification in patients with CHD/SHD (66.7% in normal controls), compared to 84% in the original derivation sample. In contrast our newly trained convolutional networks for echocardiographic view detection based on over 139,910 frames and tested on 35,614 frames from CHD/SHD patients achieved an accuracy comparable to the general cardiology model, exceeding 90% for standard view classification. Conclusions: The current study is the first to validate CHD/SHD specific echocardiographic DL networks and demonstrate its marked superiority compared to generic models which appear to have acceptable accuracy in general cardiology patients, only.