tbuckley/cabot-search huggingface dataset:
Digoxin targets low density lipoprotein receptor-related protein 4 and protects against osteoarthritis
Authors: Kai-di Wang, Xiang Ding, Nan Jiang, Chao Zeng, Jing Wu, Xian-yi Cai, Aubryanna Hettinghouse, Asya Khleborodova, Zi-Ning Lei, Zhe-Sheng Chen, Guang-hua Lei, Chuan-ju Liu
Journal: Annals of the Rheumatic Diseases (2021)

Objectives Dysregulated chondrocyte metabolism is closely associated with the pathogenesis of osteoarthritis (OA). Suppressing chondrocyte catabolism to restore cartilage homeostasis has been extensively explored, whereas far less effort has been invested toward enhancing chondrocyte anabolism. This study aimed to repurpose clinically approved drugs as potential stimulators of chondrocyte anabolism in treating OA. Methods Screening of a Food and Drug Administration-approved drug library; Assays for examining the chondroprotective effects of digoxin in vitro; Assays for defining the therapeutic effects of digoxin using a surgically-induced OA model; A propensity-score matched cohort study using The Health Improvement Network to examine the relationship between digoxin use and the risk of joint OA-associated replacement among patients with atrial fibrillation; identification and characterisation of the binding of digoxin to low-density lipoprotein receptor-related protein 4 (LRP4); various assays, including use of CRISPR-Cas9 genome editing to delete LRP4 in human chondrocytes, for examining the dependence on LRP4 of digoxin regulation of chondrocytes. Results Serial screenings led to the identification of ouabain and digoxin as stimulators of chondrocyte differentiation and anabolism. Ouabain and digoxin protected against OA and relieved OA-associated pain. The cohort study of 56 794 patients revealed that digoxin use was associated with reduced risk of OA-associated joint replacement. LRP4 was isolated as a novel target of digoxin, and deletion of LRP4 abolished digoxin’s regulations of chondrocytes. Conclusions These findings not only provide new insights into the understanding of digoxin’s chondroprotective action and underlying mechanisms, but also present new evidence for repurposing digoxin for OA.
Abstract 13700: Combined Landscape of Single-Nucleotide Variants and Copy-Number Alterations in Clonal Hematopoiesis and Their Impact on Hematological and Cardiovascular Outcomes
Authors: Ryunosuke Saiki, Yukihide Momozawa, Yasuhito Nannya, Masahiro M Nakagawa, Yotaro Ochi, Tetsuichi Yoshizato, Chikashi Terao, Yutaka Kuroda, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Atsushi Niida, Seiya Imoto, Koichi Matsuda, Takayuki Morisaki, Yoshinori Murakami, Yoichiro Kamatani, Shuichi Matsuda, Michiaki Kubo, Satoru Miyano, Hideki Makishima, Seishi Ogawa
Journal: Circulation (2021)

Background: Clonal hematopoiesis (CH) in apparently healthy individuals has recently been highlighted and implicated in the development of hematological malignancies (HM) and cardiovascular diseases. In previous studies, CH has been investigated through detecting either single-nucleotide variants and indels (SNVs/indels) or copy number alterations (CNAs), but not both. Methods: Here, we performed a combined analysis of CH-related SNVs/indels and CNAs in 11,234 individuals with a median age of 70, including 672 with subsequent HM events, to delineate their relationships and impacts on clinical outcomes. Results: Overall, CH-related SNV/indels or CNAs were detected in 40% of the subjects, and they significantly cooccurred in 16% of the CH-positive subjects. In addition to the largest effect of age on the prevalence of CH, male gender and cigarette smoking were also significantly associated with variable CH-related SNV/indels and CNAs while alcohol drinking was associated only with del(20q). As for clinical impacts, CH-related SNVs/indels and CNAs coordinately affected blood cell counts and the mortality from HM, depending on the maximum clone size and total number of both lesions (Figure 1). In particular, as is the case with those in myeloid neoplasms, SNVs/indels and CNAs affecting DNMT3A , TET2 , JAK2 , and TP53 significantly co-occurred, predicting a high HM mortality. CH-related SNV/indels were also associated with the risk of cardiovascular mortality and independently predicted the presence of hypertension in multivariate modeling (Figure 2). The association with cardiovascular mortality was more prominent when SNVs/indels were combined with CNAs (Figure 3), even though the effect of CNAs alone was not evident. Conclusion: These findings provided novel insight into the interplay between SNVs/indels and CNAs in CH, highlighting the importance of detecting both types of lesions in estimating the impact of CH on hematological and cardiovascular outcomes.
Expanded cells in monoclonal TCR-{alpha}{beta}+/CD4+/NKa+/CD8-/+dim T-LGL lymphocytosis recognize
Authors: A. Rodríguez-Caballero, A.C. García-Montero, P. Bárcena, J.M.M. Almeida, F. Ruiz-Cabello, Tabernero, P. Garrido, S. Muñoz-Criado, Y. Sandberg, A.W. Langerak, M. González, A. Balanzategui, A. Orfao
Journal: Blood (2008)
Abstract 12455: Comparison of Clinical Symptoms and Bioimpedance to Pulmonary Capillary Wedge Pressure in Heart Failure
Authors: Bret Alvis, Monica Polcz, Meghan Breed, Marisa Case, Jessica H Huston, Philip Leisy, Jeffrey Schmeckpeper, Colleen Brophy, Joann Lindenfeld, Kyle Hocking
Journal: Circulation (2021)

Introduction: Clinical symptoms of heart failure commonly include fatigue, edema, and shortness of breath. Unfortunately, clinical monitoring has proven to be unreliable for the assessment of congestion and predicting the need for hospitalization. Biosensing wearables have been developed as a potential adjunct to clinical signs and symptoms. Hypothesis: This report hypothesis a correlation between clinicians’ signs and symptoms of heart failure along with bioimpedance measurements (ZOE ® ), and pulmonary capillary wedge pressure (PCWP). Methods: One hundred and fifty-five subjects undergoing right heart catheterization (RHC) at Vanderbilt University Medical Center (VUMC) were prospectively enrolled. A Zo value (ohms) was obtained, jugular venous pressure (JVP) was estimated, edema graded, and dyspnea assessed in all subjects. RHC was performed by scheduled cardiologist per routine. One-way ANOVA was performed to assess relationship between dependent and independent variables. A Pearson correlation coefficient was used to compare Zo value and PCWP. Results: Neither estimated JVP (cmH 2 O) (p = 0.65, n=110) nor edema scores (p = 0.12, n=110) demonstrated a significant relationship to PCWP (Figure 1). The presence of subjective SOB also did not demonstrate significant association with PCWP (p = 0.99, n=110; Figure 1). There was no correlation between ZOE ® and PCWP (r = -0.08, p = 0.56, n=56; Figure 2). Conclusions: These findings support the idea that traditional measures for monitoring heart failure patients are limited.
Abstract 11331: Economic and Social Challenges Faced by People Living with Rheumatic Heart Disease in a Resource Limited Setting
Authors: Jafesi Pulle, JENIFER ATALA, Hadija Nalubwama, Rebecca Namara, Emma Ndagire, Emmy Okello, Rachel Sarnacki, Andrea Z Beaton, Craig A Sable, David Watkins
Journal: Circulation (2021)

Introduction: Rheumatic heart disease (RHD) has nearly been eradicated in wealthy nations but remains a significant public health concern in low-resource countries like Uganda. Many people living with RHD (PLWRHD) is these settings have not been diagnosed and many who are diagnosed have late-stage disease. Objectives: To explore the social and economic challenges faced by PLWRHD in a resource limited setting. Methods: This was a qualitative study. We conducted in depth interviews on a sample of 36 RHD patients randomly selected from a computer-generated list from RHD registries in the Northern, Central, and South-western regions. The selected participants were interviewed by trained qualitative research staff. All interviews were tape recorded and transcribed verbatim. Data were analyzed by thematic content analysis and useful codes were generated by both inductive and deductive approaches. Generated codes were collapsed into themes. Coding was done by 3 independent researchers who compared their results and agreed on one codebook which was updated iteratively. Results: Of the 36 interviewed participants, 18 had congestive heart and another 18 had no congestive heart failure, a complication of RHD. Economic challenges faced by PLWRHD included financial burdens to family, debts incurred to meet treatment costs, selling off assets and loss of jobs. Social challenges entailed poor support at schools for RHD patients, school drop outs, family instability, poor social relations and poor community perception of RHD. Conclusion: Understanding challenges faced will enable designing of interventions that improve the quality of life of PLWRHD and significantly influence future policies on RHD management.
A Phase 1 Dose Escalation Study of Dual PI3K and DNA PK Inhibitor, BR101801 in Adult Patients with Advanced Hematologic Malignancies
Authors: Tae Min Kim, Dok Hyun Yoon, Ahmad H. Mattour, Jorge M. Chaves, Emily Curran, Yoon Kyung Jeon, Bong-Seog Kim, Seok Jin Kim
Journal: Blood (2021)
Abstract 14294: Quantification Correction for Rapid Myocardial T1ρ Mapping in Mice Using the T1ρ* Relaxation Pathway
Authors: Maximilian Gram, Daniel Gensler, Patrick Winter, Anahi-Paula Arias-Loza, Peter M Jakob, Peter Nordbeck
Journal: Circulation (2021)

Introduction: Cardiac MRI offers detailed tissue characterization and high sensitivity to macromolecules using T 1ρ based imaging. However, fast and accurate T 1ρ mapping in the myocardium is still a major challenge in small animal models. The sequence design based on prospective triggering and breath gating causes a corruption of T 1ρ relaxation leading to quantification errors in the in vivo experiment. In this study, we present a T 1ρ quantification correction using the T 1ρ * relaxation pathway. Methods: A new signal equation was derived by analytical means describing spin-lock prepared fast gradient echo readouts: S(t SL ) = S 0 / [ exp(t SL /T 1ρ ) - cos(α) NR exp(-(N R T R +T rec )/T 1 ) ] The equation was validated in phantom experiments and used in vivo for corrected T 1ρ mapping in mice. Here, the correlation of T 1ρ and the breath dependent spin recovery time T rec was examined. The results were compared to the conventional monoexponential T 1ρ fitting. Results: In the phantom study, the novel signal equation provided improved quantification accuracy compared to monoexponential fitting. The mean quantification error could be reduced from -7.4% to -0.97%. In vivo, a correlation of T 1ρ with the respiratory cycle was observed for monoexponential fitting (PCC=0.804). Using the new correction method, this correlation was reduced (PCC=0.495) and the standard deviation was decreased from ±4.2% to ±1.3%. Conclusions: Our corrected formalism enables fast and accurate T 1ρ quantification for small animals and can improve the comparability of study results. The new technique thus offers a reasonable tool for assessing myocardial diseases. Besides, the derived signal equation could be used for sequence optimization or for subsequent correction of study results.
NR2F2 controls malignant squamous cell carcinoma state by promoting stemness and invasion and repressing differentiation
Authors: Federico Mauri, Corentin Schepkens, Gaëlle Lapouge, Benjamin Drogat, Yura Song, Ievgenia Pastushenko, Sandrine Rorive, Jeremy Blondeau, Sophie Golstein, Yacine Bareche, Marie Miglianico, Erwin Nkusi, Milena Rozzi, Virginie Moers, Audrey Brisebarre, Maylis Raphaël, Christine Dubois, Justine Allard, Benoit Durdu, Floriane Ribeiro, Christos Sotiriou, Isabelle Salmon, Jalal Vakili, Cédric Blanpain
Journal: Nature Cancer (2021)
PATH-41. POLYMORPHOUS LOW-GRADE NEUROEPITHELIAL TUMOR OF THE YOUNG WITH FGFR3-TACC3 FUSION MIMICKING HIGH-GRADE GLIOMA: CASE REPORT AND SERIES OF HIGH-GRADE CORRELATES
Authors: Danielle Golub, Peter C Pan, Benjamin Liechty, Cheyanne Slocum, Tejus Bale, David J Pisapia, Rupa Juthani
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently-described entity that can occasionally histologically and molecularly mimic high-grade glioma. The histologic and molecular features that predict aggressive behavior in FGFR3-TACC3 altered tumors are unclear. CASES We present a rare case of an indolent neuroepithelial neoplasm in a 59-year-old female with imaging initially suggestive of high-grade glioma and analyze common molecular features between this case and a series of high-grade gliomas. After total resection, pathology of the case patient revealed predominantly low-grade cytomorphology, abundant microcalcifications, unusual neovascularization, and a low proliferation index. The lesion was diffusely CD34 immunoreactive and harbored both an FGFR3-TACC3 fusion and a TERT promoter mutation. Based on the overall histologic and molecular profile, a diagnosis of PLNTY was favored. The patient was thereafter observed without adjuvant therapy with no evidence of progression at 15-month follow-up. In contrast, a series of eight adult patients with glioblastomas harboring FGFR3-TACC3 fusions and correspondingly aggressive clinical courses are also presented. Common molecular findings included IDH-wildtype status, absence of 1p19q codeletion, and CDKN2A loss. TERT promoter mutations and lack of MGMT promoter methylation were also frequently observed. These patients demonstrated a median 15-month overall survival and a 6-month progression-free survival. CONCLUSIONS PLNTY is a rare low-grade entity that can display characteristics of high-grade glioma, particularly in adults. The potential for a unique entity mimicking PLNTY which may act as a precursor lesion for a more malignant phenotype should be considered in cases with FGFR3-TACC3 fusions and other high-grade features.
Abstract MP244: Deciphering The Mechanism Of Elevation Of Mir34a And Its Attenuation Via Corm A1 And Subsequent Improvement In Mitochondrial Status In Atherogenic Mdms
Authors: Hitarthi Vyas, Ranjitsinh Devkar
Journal: Circulation Research (2021)

Elevated levels of miR34a and its association with macrophage polarization is reported in atherosclerosis but the underlying mechanism that upregulates miR34a lacks clarity. Herein, the mechanism of miR34a elevation in atherogenic human monocyte derived macrophages (MdMs) and subsequent changes in mitochondria were monitored. Further, CO supplementation (via Carbon monoxide Releasing Molecule A1; CORM A1) to atherogenic (OxLDL treated) MdMs was used to achieve downregulation of miR34a. Herein, we also hypothesize that lowering of miR34a in atherogenic MdMs improves the cellular health and mitochondrial function. Transcriptional factors (P53, NF-κb), transcriptional inhibitors (Zeb1, snai1, stat3) and epigenetic modification (methylation) in promoter region of miR34a were evaluated. OxLDL treated MdMs recorded significant decrement in mRNA levels of the said transcription inhibitors whereas; the same were reversed in CORM A1 co-treated group. Further, hypomethylation was recorded in the promotor region of miR34a on oxLDL treatment but methylation status was reverted to the control levels following CORM A1 co-supplementation. The mRNA levels of transcription factors showed non-significant changes in all the experimental groups. In silico docking studies had shown that CO effectively binds to the DNA binding domains of p53 that possibly prevents subsequent binding to their respective miR34a promotor regions. Positive docking of miR34a to 3’UTR of SIRT-1 supported our observation on lowered SIRT-1 and PGC-1α levels in oxLDL group that were found to be restored in CORM A1 co-treated group. Poor indices of mitochondrial biogenesis (SIRT-1, PGC1α, Nrf-1, Drp1, Mito Tracker Red staining), function (ATP assay), mitochondrial membrane potential (JC-1) and mitochondrial antioxidants (SOD2 and TrxR2), cellular ROS (DCFDA) following oxLDL treatment was found to be restored by CORM A1 co-treatment. In conclusion, atherogenic elevation of miR34a is as a result of hypomethylation in its promotor region and lowered mRNA transcripts of its inhibitors (Zeb1, snai1, stat3). Further, lowering of miR34a by CORM A1, improves atherogenic status of MdMs as evidenced by an improved cellular and mitochondrial health.
Abstract 11736: Anatomic Repair of Congenitally Corrected Transposition of the Great Arteries is Associated With Risk of Heart Block and ECMO, but Not Mortality
Authors: Bethan A Lemley, Felina Mille, Katsuhide Maeda, Michael L Obyrne, Meryl S Cohen
Journal: Circulation (2021)

Introduction: Congenitally corrected transposition of the great arteries (CC-TGA) is characterized by atrioventricular and ventriculoarterial discordance with circulation remaining in series. The double switch operation and atrial switch with Rastelli are anatomic repairs of CC-TGA, achieving a systemic morphologic left ventricle. In contrast, physiologic repair (addressing associated lesions like ventricular septal defects and pulmonary stenosis) or no repair leave the right ventricle in the systemic position. Anatomic repair may confer superior longevity with increased upfront risk. We sought to determine if anatomic repair was associated with increased short-term risk of mortality, heart block, or extracorporeal membrane oxygenation (ECMO). Methods: Single-center retrospective cohort study of CC-TGA patients from 1990-2017. Cox proportional hazard analyses and Fisher’s exact test were performed. Results: Inclusion criteria were met by 54 patients, 21 anatomic repair and 33 physiologic/no repair. Median follow-up was 8.9 years (IQR 1.4-18.0) with no difference between cohorts (p=0.38). The anatomic repair cohort was more likely to have ventricular septal defects, 86% versus 33% (p&lt;0.001) and pulmonary stenosis, 43% versus 15% (p=0.02). Mortality was low and did not differ significantly between cohorts (p=0.07). Probability of developing complete heart block was higher in the anatomic repair cohort (p=0.006), with no significant difference after adjusting for anatomy (HR 3.8, 95% CI 0.7-20.5). The anatomic repair cohort had an increased risk of ECMO (p=0.006). There was no difference in quantity of iterative operations (p=0.64). Conclusions: Anatomic repair of CC-TGA conferred a higher short-term risk of heart block and ECMO compared to the physiologic/no repair cohort, though risk of heart block was linked with anatomy. This upfront risk did not result in higher mortality in the anatomic repair cohort but long-term risk remains unknown.
Abstract 9731: Improved Risk Stratification with Vendor Independent Coronary Calcium Scores: Data from the Multi-Ethnic Study of Atherosclerosis (mesa)
Authors: Magdalena M Dobrolinska, Niels van der Werf, Marcel J Greuter, Martin J Willemink, Dominik Fleischmann, Riemer Slart, Matthew Budoff, Tim Leiner
Journal: Circulation (2021)

Introduction: Coronary calcium score (CCS) plays a role in cardiovascular disease (CVD) risk calculators, but also reclassifies patients when considering statin therapy. However, CCS is still calculated following the Agatston methodology as developed on electron beam tomography (EBT) in the early 1990s. EBT has been replaced by multidetector computed tomography (MDCT). It is known that CCS differs substantially between MDCT-systems from different manufacturers, which can lead to risk reclassifications for 6.5% of examined individuals Aims: Our first aim was to identify CT system specific conversion factors to calculate a vendor-neutral Agatston score (rCCS). Second, we aimed to validate rCCS risk stratification for participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Methods: As a first step, we calculated conversion factors between six state-of the-art CT systems and the reference EBT system used in the MESA study. For this purpose, we scanned two calcium-containing inserts, which were placed in a small and large anthropomorphic thorax phantom. Linear regression was used to find a model which converts vendor-specific CCS to vendor-independent rCCS. As a second step, we recalculated the non-zero Agatston scores of 550 MESA participants. Following the Youden method, we calculated an optimal cut-off point for rCCS. Results: The linear model for each CT system allowed for prediction of Agatston scores as measured on the EBT system (p=0.001). rCCS for GE LightSpeed, used in MESA, was calculated as rCCS=0.049+1.97xMESA Agatston score and rCCS=1.903+1.37xMESA Agatston score for small and large size, respectively. The median MESA Agatston score was 100.5 (26.3-379.5), and the median rCCS was 135.8 (35.6-508.6). Participants were assigned to a high Agatston category with Agatston scores exceeding 100 (50.2%) and 187 (43.1%) for CCS and rCCS, respectively. The hazard ratio for CVD of individuals with high Agatston scores increased from 1.88 (95%CI: 1.31-2.68, p=0.001) with MESA scores to 2.15 (95%CI: 1.52-3.05, p=0.001) with rCCS. rCCS reclassified 39 participants into the lower risk group, without statin therapy. Conclusions: In conclusion, based on these preliminary results, rCCS may improve patient classification for statin therapy.
Abstract 12138: Cell Senescence Associated H3K9me3 Decline Sensitizes Aortic Valve Cell for Osteogenic Response
Authors: Su Shuwen, Li Shunyi, Zeng Jingxin, Xian Gaopeng, Yang Xi, Xie Kaiji, Zhan Qiong, Xu Dingli, Qingchun Zeng
Journal: Circulation (2021)

Introduction: Cell senescence has been identified as an impact etiological factor in cardiovascular diseases, as well as calcific aortic valve disease (CAVD) . In our previous experiment results, We found that a large number of senescent aortic valve interstitial cells (AVIC) accumulated in the calcific aortic valve tissues, especially around the calcification sites. But the role and mechanism of cellular senescence in the development of calcified aortic stenosis have not been clarified. We hypothesized valvular interstitial cell senescence sensitize interstitial cell for osteogenic response through enhancing cell senescence associated epigenetic modification. Methods and Results: Representative immunofluorescence results of the clinical samples show that p16INK4A positive cells in the calcific aortic valve expressed more osteogenic associated factors, such as Runx2 and BMP2. And RAS system hyperactivation seemed to be an impact association with aortic valve calcification. Then we found Angiotensin II (1μM, 72h) chronic irritation induces valve interstitial cell senescence associated secretion phenotype (SASP) and activates osteogenic response through ERK1/2 and NF-κB pathway. ChIP-qPCR results demonstrated H3K9Me3 modifications on the promoters of Runx2, ACTA2(also known as α-SMA), IL-6, IL-8, MCP-1 were significantly decreased in angiotensin II pretreated AVIC. Blockage of angiotensin II and ABT-263 pretreatment inhibited valvular interstitial cell to convert into osteoblast-like phenotype induced by Angiotensin II, as well as attenuating senescence associated secretion phenotype factors yield. Blockage of angiotensin II receptor and p16 INK4A knockdown contributed to recover H3K9me3 modification on the promoters of those gene in angiotensin II pretreated AVIC through attenuating angiotensin II-induced ubiquitination degradation of SUV39H1. Conclusion: p16 INK4A mediated H3K9me3 decline sensitizes aortic valvular interstitial cell for osteogenic response, which impacts on aortic valve homeostasis and aortic valve calcification. Taken together, p16 INK4A positive senescent cells would be the potential target on prevention and treatment of calcific aortic valve disease.