tbuckley/cabot-search huggingface dataset:
Abstract 14032: Racial Differences in Clinical Manifestations and Events in Fibromuscular Dysplasia: A Report of the United States Registry for FMD
Authors: Kajal Shah, Heather L Gornik, Xiaokui Gu, Pamela D Mace, Eva M Kline-rogers, Michael Bacharach, Natalia Fendrikova Mahlay, James B Froehlich, Kamal gupta, Bruce Gray, Esther Kim, Bryan Wells, Ido Weinberg, Jeffrey W Olin, Aditya M Sharma
Journal: Circulation (2021)

Introduction: Fibromuscular dysplasia (FMD) is a non-inflammatory vasculopathy associated with arterial stenosis, aneurysm, dissection, and tortuosity. We investigated racial differences in clinical manifestations and events of multifocal FMD. Methods: Demographics, medical history, presenting signs and symptoms, and major vascular events were queried from the US Registry for FMD and stratified into White or Black based on self-identified race. Results: Of the 1897 female patients (pts) with multifocal FMD and race reported from 14 sites as of 12/23/2020, there were 1697 (89.5 %) White, 123 (6.5 %) Black, 52 (2.7%) Hispanic, and 25 (1.3%) pts of other races. Given a small number of pts in other groups, analysis was only performed between White and Black pts. Age at diagnosis and at first sign/symptom was similar between the two groups. Black pts were more likely to have a history of hypertension (p=0.009), stroke (p=0.002), and subarachnoid hemorrhage (p&lt;0.001) than White pts. While Black pts were less likely to have had any arterial dissection (p=0.010), a higher percentage had aortic dissection (p=0.015). Family history of FMD was less common among Black pts (p=0.018). There were differences in the distribution of vascular bed involvement and aneurysms between Black and White pts, though not all patients underwent comprehensive vascular imaging. Conclusion: We noted a low number of Black patients enrolled in the US Registry for FMD at FMD specialty centers. There were differences in clinical manifestations, events, and pattern of vascular involvement among Black and White patients enrolled in US Registry, the mechanisms for which require additional study.
Abstract 10820: Atrial Fibrillation Catheter Ablation Reduces the Risk of Dementia: A Systematic Review and Meta-Analysis
Authors: Siddharth Shah, Kuldeep Shah, Mohit K Turagam, Rahul Bhardwaj, Tahmeed Contractor, Ravi Mandapati, Andrea Natale, Dhanunjaya Lakkireddy, Jalaj Garg
Journal: Circulation (2021)

Introduction: Although atrial fibrillation (AF) has a risk of cognitive dysfunction, it is not clear whether AF catheter ablation impacts cognitive function. Catheter ablation for AF prolongs the duration of sinus rhythm, thereby improving the quality of life and theoretically reducing the risk of dementia. Objective: We investigated the association of catheter ablation for AF with the occurrence of any dementia. Methods: A systematic search using electronic databases was performed from inception until January 15, 2021. Mantel-Haenszel risk ratio (RR) random-effects model (DerSimonian and Laird method) was used to summarize data. The primary outcome was occurrence of dementia during the follow-up period. Statistical analysis was performed using a meta-package for R version 4.0 and Rstudio version 1.2. Results: A total of 3 eligible studies (retrospective and prospective) consisting of 34,360 patients [Catheter ablation = 10,862 and medical therapy (antiarrhythmic drugs or rate-control drugs) = 23,498] were included in the meta-analysis. Patients in the ablation group were younger compared to medical therapy (59.6 ± 10.4 vs 60.3 ± 10.6 years; p&lt;0.001). Hypertension (55% vs 54.4%, p = 0.31), heart failure (23.7% vs 22.1%, p = 0.001), diabetes (14% vs 15.2%, p = 0.004), cerebrovascular accident (11% vs 10%, p = 0.005) and myocardial infarction (7.5% vs 6.5%, p&lt;0.001) were most common comorbidities, respectively. There was a lower incidence of dementia in AF patients treated with catheter ablation compared to medical therapy (2% vs 3.5%, RR 0.39, 95% CI 0.22-0.70, p&lt;0.01) during a mean follow-up period of 5.44 years. Conclusion: AF ablation patients have a significantly lower risk of dementia in comparison to AF patients without ablation.
Abstract 13273: Late Senolytic Therapy Improves Cerebrovascular Endothelial Function but Not Cognition in Middle-Aged Severely Atherosclerotic Mice
Authors: Melanie Lambert, Geraldine Miquel, Nathalie Thorin-Trescases, Eric Thorin
Journal: Circulation (2021)

Introduction: Age-related and atherosclerosis-related vascular dysfunction contributes to neuro-vascular uncoupling, which induces neuronal damage and leads to precocious cognitive loss. This dysfunction could be partially explained by the accumulation of senescent cells (SnC) that remain metabolically active and release many pro-inflammatory factors. Hypothesis: Targeted elimination of SnC with a senolytic restores cerebrovascular function, maintains neuro-vascular coupling and slows cognitive decline. Methods and Results: Nine-month old male atherosclerotic mice (ATX, LDLR -/- ;hApoB +/+ ) were treated (n=13), or not (n=11), for 3 months with navitoclax (50mg/kg), a Bcl2 inhibitor that stimulates global elimination of SnC overexpressing this antiapoptotic pathway. Twelve-month old vehicle-treated ATX mice developed atheroma plaques up to the upper neck portion of the carotid arteries, but not in the cerebral circulation. Three months treatment with navitoclax reduced aortic plaques size (-32%, p&lt;0.001) from 40±2% in vehicle-treated mice to 27±2% in navitoclax mice. At 12 months, endothelial dysfunction was severe in vehicle-treated ATX mice, as evidenced by a strong reduction in flow-mediated dilation (FMD) of pressurized posterior cerebral arteries ex vivo ; navitoclax improved endothelium-dependent dilatation by 50% (for example, FMD at 20 dyn/cm 2 : 58±10%) compared to vehicle-treated mice (FMD: 29±7%; p&lt;0.05). Two cognitive tests were performed: the Y-maze and the novel object recognition tests, to assess exploratory behavior and executive function, respectively. A gradual decline of both exploratory and executive memory was observed from 3 to 6, 9 and 12 months in vehicle-treated ATX mice; navitoclax, however, did not prevent this cognitive decline. Conclusion: Global elimination of SnC slowed atherosclerotic plaque development and restored cerebral endothelial function, demonstrating that senescence contributes to vascular dysfunction. The absence of cognitive improvement with navitoclax suggests an irreversible state of neuronal damage that could not be affected by the late senolytic treatment. To demonstrate the role of SnC in cognitive impairment, an earlier senolytic therapy will be needed.
Abstract 111: Conjoining Gene Expression And Cell Organization With Imaging To Explore Cell States In Hipsc-derived Cardiomyocytes
Authors: Ruwanthi Gunawardane
Journal: Circulation Research (2021)

The Allen Institute for Cell Science is developing a state space of stem cell structural signatures to study changes in cellular organization of human induced pluripotent stem cells (hiPSCs) and other cell states through differentiation. Towards this goal, we have used CRISPR/Cas9 to generate a collection of ~50 endogenous fluorescently tagged hiPSC lines (www.allencell.org), each expressing a monoallelic EGFP-tagged protein that localizes to a particular cellular structure or organelle. In this study, we focuson hiPSC-derived cardiomyocytes and compare the relationship between sarcomeric structural organization and gene expression signatures at large scale. We developed several tools and novel quantitative approaches to achieve this: 1) scarless GFP-tagging of cardiac genes such as ACTN2 to study the organization and morphogenesis of the contractile apparatus; 2) a robust protocol for differentiation of hiPSCs into cardiomyocytes and methods for preparing cells for imaging; and 3) a quantitative, image-based platform for the systematic and automated classification of subcellular organization in single cells. We use these approaches to quantify subcellular organization and gene expression in &gt;30,000 individual human induced pluripotent stem cell-derived cardiomyocytes, producing a publicly available dataset that describes the population distributions of local and global sarcomere organization, mRNA abundance, and correlations between these traits. While the mRNA abundance of some phenotypically important genes correlates with subcellular organization (e.g., MYH7), these two cellular metrics are heterogeneous and often uncorrelated, which suggests that geneexpression alone is not sufficient to classify cell states. Instead, we posit thatcell state should be defined by observing full distributions of quantitative, multidimensional traits in single cells that also account for space, time, and function. This platform provides a multidimensional approach to classify hiPSC-derived cardiomyocytes based on structural organization and gene expression in single cells.
Abstract 9695: <i>RASA3</i> as a Novel Candidate Gene in Sickle Cell Disease-associated Pulmonary Hypertension and Pulmonary Arterial Hypertension
Authors: Clare C Prohaska, Xu Zhang, Tae-Hwi Schwantes-An, Robert Stearman, Micheala A Aldred, Katie Lutz, Michael Pauciulo, Bill Nichols, Ankit A Desai, Victor Gordeuk, Roberto F MacHado
Journal: Circulation (2021)

Introduction: Sickle cell disease (SCD)-associated PH is associated with increased mortality when tricuspid regurgitant jet velocity (TRV) is ≥2.5m/s and mPAP is ≥25mmHg on right heart catheterization. RASA3, a ubiquitously expressed GTPase-activating protein, is integral to angiogenesis and maintenance of endothelial barrier function. Hypothesis: Loss of RASA3 leads to the development of PH in patients with SCD-associated PH and PAH. Methods: Cis-eQTLs were queried for RASA3 using whole genome genotype arrays and gene expression profiles from PBMCs of subjects with SCD from 3 cohorts. Genome-wide SNPs near or in the RASA3 gene that may associate with lung RASA3 expression were identified using data from the Genotype-Tissue Expression project, reduced to 9 tagging SNPs for RASA3 and associated with TRV≥2.5m/s and RHC hemodynamics. Associations between the top RASA3 SNP and RHC hemodynamics were tested using whole genome genotype data from subjects in the PAH Biobank. PAECs collected from explanted lungs from patients with IPAH or control lungs were cultured with RASA3 expression evaluated on Western blot. Results: PBMC-derived RASA3 expression was significantly lower in patients with SCD-associated PH using TRV≥2.5m/s and RHC hemodynamics, with significantly higher mortality (Figure 1). The risk allele (T) at rs9525228, an eQTL for RASA3, correlated with PH risk, higher TRV and higher PVR among PBMCs associated with decreased RASA3 expression in patients with SCD-associated PH. The T allele at rs9525228 was significantly associated with increased mPAP (p=0.014), PVR (p=0.041) and mean right atrial pressure (p=0.04) in patients from the PAH Biobank. RASA3 expression was significantly lower in PAECs from patients with IPAH compared to control. Conclusions: RASA3 is a novel candidate gene in SCD-associated PH and PAH, with RASA3 expression appearing to be protective. Further studies are ongoing to delineate the role of RASA3 in PH.
INNV-08. LOW AND INTERMEDIATE GRADE GLIOMA UMBRELLA STUDY OF MOLECULAR GUIDED THERAPIES (LUMOS) STUDY
Authors: Benjamin Kong, Hao-Wen Sim, Benhur Amanuel, Bryan Day, Michael Buckland, Roel Verhaak, Sonia Yip, Terrance Johns, Zarnie Lwin, Mark Rosenthal, Anna K Nowak, Elizabeth H Barnes, Andrew M Scott, Jonathon Parkinson, Rosalind Jeffree, Richard De Abreu Lourenco, Peter Lau, James Whittle, Elizabeth Hovey, Lawrence Cher, Ganessan Kichendasse, Merryn Hall, Cleo Robinson, Marc Thomas, Tindaro Giardina, Emily Tu, Mustafa Khasraw, Eng-Siew Koh, Hui Gan
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Grade 2 and 3 (G2/3) gliomas are the second largest group of brain tumors in adults. Although the prognosis for G2/3 gliomas at the time of relapse mirror those of glioblastoma, there are few trials in this space. METHODS LUMOS was a national multi-center pilot study for patients with relapsed G2/3 gliomas designed to match contemporaneous tissue obtained at the time of disease progression with subsequent targeted therapies. The objective was to establish the feasibility of a precision oncology, umbrella approach to obtain and type tissue within a useful timeframe. As a key feature of LUMOS, a multidisciplinary Molecular Tumor Advisory Panel (MTAP) with subspecialty neuro-oncology expertise was formed to interpret the complex genomic information and provide a simplified recommendation to the treating physician. RESULTS Ten patients (median age 42: range 32-62; four G2 astrocytoma, one G3 astrocytoma, three G2 oligoendroglioma, one G3 oligodendroglioma, one mixed tumor) were enrolled in the study. Eight patients had biopsies within 6 months of study entry whilst two underwent a biopsy during the study. All patients had potentially targetable alterations (10 IDH, 3 FGFR, 2 PIK3K, CCND3, NRAS, CDK4, PRPRZ1-MET fusion and MET amplification). Matched therapies were delivered for two patients via compassionate access outside the study. The median turnaround time (TAT) of MTAP reports was 6.2 weeks (range 4.2-9.7 weeks) but 4.6 weeks when lag time for shipping was removed. CONCLUSION LUMOS confirmed that this design was feasible with good turnaround times. The MTAP facilitated education and support for treating physicians. Thes findings support moving to a larger study using contemporaneous and longitudinal tissue samples matched with targeted therapies as part of a comprehensive umbrella study design. Delivery and interpretation of molecular data is a challenge shared across oncology which may be mitigated with a neuro-oncology specific molecular tumor board.
Real-time alerting system for COVID-19 and other stress events using wearable data
Authors: Arash Alavi, Gireesh K. Bogu, Meng Wang, Ekanath Srihari Rangan, Andrew W. Brooks, Qiwen Wang, Emily Higgs, Alessandra Celli, Tejaswini Mishra, Ahmed A. Metwally, Kexin Cha, Peter Knowles, Amir A. Alavi, Rajat Bhasin, Shrinivas Panchamukhi, Diego Celis, Tagore Aditya, Alexander Honkala, Benjamin Rolnik, Erika Hunting, Orit Dagan-Rosenfeld, Arshdeep Chauhan, Jessi W. Li, Caroline Bejikian, Vandhana Krishnan, Lettie McGuire, Xiao Li, Amir Bahmani, Michael P. Snyder
Journal: Nature Medicine (2021)

Abstract Early detection of infectious diseases is crucial for reducing transmission and facilitating early intervention. In this study, we built a real-time smartwatch-based alerting system that detects aberrant physiological and activity signals (heart rates and steps) associated with the onset of early infection and implemented this system in a prospective study. In a cohort of 3,318 participants, of whom 84 were infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), this system generated alerts for pre-symptomatic and asymptomatic SARS-CoV-2 infection in 67 (80%) of the infected individuals. Pre-symptomatic signals were observed at a median of 3 days before symptom onset. Examination of detailed survey responses provided by the participants revealed that other respiratory infections as well as events not associated with infection, such as stress, alcohol consumption and travel, could also trigger alerts, albeit at a much lower mean frequency (1.15 alert days per person compared to 3.42 alert days per person for coronavirus disease 2019 cases). Thus, analysis of smartwatch signals by an online detection algorithm provides advance warning of SARS-CoV-2 infection in a high percentage of cases. This study shows that a real-time alerting system can be used for early detection of infection and other stressors and employed on an open-source platform that is scalable to millions of users.
Understanding and targeting prostate cancer cell heterogeneity and plasticity
Authors: Dean G. Tang
Journal: Seminars in Cancer Biology (2021)

Prostate cancer (PCa) is a prevalent malignancy that occurs primarily in old males. Prostate tumors in different patients manifest significant inter-patient heterogeneity with respect to histo-morphological presentations and molecular architecture. An individual patient tumor also harbors genetically distinct clones in which PCa cells display intra-tumor heterogeneity in molecular features and phenotypic marker expression. This inherent PCa cell heterogeneity, e.g., in the expression of androgen receptor (AR), constitutes a barrier to the long-term therapeutic efficacy of AR-targeting therapies. Furthermore, tumor progression as well as therapeutic treatments induce PCa cell plasticity such that AR-positive PCa cells may turn into AR-negative cells and prostate tumors may switch lineage identity from adenocarcinomas to neuroendocrine-like tumors. This induced PCa cell plasticity similarly confers resistance to AR-targeting and other therapies. In this review, I first discuss PCa from the perspective of an abnormal organ development and deregulated cellular differentiation, and discuss the luminal progenitor cells as the likely cells of origin for PCa. I then focus on intrinsic PCa cell heterogeneity in treatment-naïve tumors with the presence of prostate cancer stem cells (PCSCs). I further elaborate on PCa cell plasticity induced by genetic alterations and therapeutic interventions, and present potential strategies to therapeutically tackle PCa cell heterogeneity and plasticity. My discussions will make it clear that, to achieve enduring clinical efficacy, both intrinsic PCa cell heterogeneity and induced PCa cell plasticity need to be targeted with novel combinatorial approaches.
Abstract 12940: Shared Senescence Pathophysiology in Preeclampsia and Peripartum Cardiomyopathy
Authors: Jason D Roh, Andy Yu, Sarosh Rana, Sajid SHAHUL, Claire Castro, Michael Honigberg, Melanie Ricke-Hoch, Ashish Yeri, Robert Kitchen, Ryan Hobson, Vinita Chaudhari, Bliss Chang, Amy Sarma, James Kirkland, Ananth Karumanchi, John Gorcsan, Sugahara Masataka, Julie B Damp, Karen Hanley-Yanez, Zoltan Arany, Dennis M McNamara, Denise Hilfiker-Kleiner, Anthony Rosenzweig
Journal: Circulation (2021)

Introduction: Peripartum cardiomyopathy (PPCM) is a rare form of pregnancy-related heart failure associated with preeclampsia. Our understanding of their shared pathophysiology is limited as are treatment options. Hypothesis: We hypothesized that plasma proteomic profiling would identify deleterious circulating proteins and provide insights into shared mechanisms driving preeclampsia and PPCM. Methods: We performed serum proteomic case-control studies in women with preeclampsia or PPCM to identify biological processes common to both conditions. The top candidate was validated in independent preeclampsia (n=58) and PPCM (n=114) cohorts. Preeclamptic placenta was examined as a potential source of circulating proteins. Therapeutic targeting the top candidate was examined in an animal model of PPCM. Results: Paradoxically, we found the senescence-associated secretory phenotype (SASP), a marker of biological aging, to be the most upregulated process in relatively young women with preeclampsia (normalized enrichment score [NES]=3.3;p adj =4.0x10 -6 ) or PPCM (NES=3.2;p adj =1.9x10 -5 ). 28 circulating proteins contributed to this common signal, and were strongly enriched in preeclamptic placenta, which expressed markers of increased senescence. The TGFb family member, Activin-A, was the most highly upregulated SASP gene in preeclamptic placentas (5-fold;p&lt;0.001). Circulating Activin-A was elevated in preeclampsia (2.9-fold) and PPCM (2.5-fold) validation cohorts (p&lt;0.001) and correlated with impaired left ventricular global longitudinal strain (r=0.3-0.5;p&lt;0.001). In PPCM, Activin-A increased with worsening heart failure, reflected by NYHA class and BNP levels (p&lt;0.05), and cardiac FSTL3 expression, an indicator of Activin-A signaling, was increased (2.2-fold;p=0.005). Inhibition of Activin-A receptors with a monoclonal antibody improved systolic function and adverse cardiac remodeling in a murine PPCM model. Conclusions: These data implicate placental senescence in the increased deleterious circulating proteins seen in preeclampsia and PPCM. We identify multiple new circulating factors associated with these diseases and demonstrate that targeting SASP proteins, such as Activin-A, can mitigate PPCM in mice.
Abstract 10982: The Impact of Successful Electrical Cardioversion for Atrial Fibrillation in Patients with Heart Failure and Preserved Ejection Fraction
Authors: Kosuke Tsuda, Yumiko Kanzaki, Kazushi Sakane, Tomohiro Fujisaka, Masaaki Hoshiga
Journal: Circulation (2021)

Background: Although atrial fibrillation (AF) is the major comorbid condition in heart failure with preserved ejection fraction (HFpEF), the evidence, which supports the efficacy of rhythm control for AF in HFpEF is limited. Hypothesis: Electrical cardioversion (EC) of AF for maintenance of sinus rhythm (SR) improves recovery in patients with HFpEF. Methods: We analyzed 162 subjects hospitalized for acute decompensated heart failure which were documented AF on admission and left ventricular ejection fraction ≥ 50%. We defined the conservative treatment (CT) group as not attempting cardioversion during hospitalization and EC groups as successful EC of AF and maintenance of SR until discharge. Clinical characteristics, composite event of cardiovascular death and heart failure rehospitalization were compared between the two groups. Results: Among all patients with AF on admission, 24 subjects (14.8%) were succeeded in restoring and maintaining SR by EC. They exhibited younger (70.8 years vs. 80.3 years, p &lt; 0.01) and a lower level of BNP (88.3 ng/L vs. 156.0 ng/L, p &lt; 0.01) than the CT group (n = 111). The findings from echocardiography demonstrated a smaller left atrial dimension (44.7 mm vs. 55.7 mm, p &lt; 0.01) and lower E wave levels (81.5 cm/s vs. 110.0 cm/s) in the EC group. Concerning medical therapy, the rate of using anti-arrhythmia drugs in the EC group was higher (41.7% vs. 5.2%, p &lt; 0.01). During the observational period (median = 1.6 years), successful restoration of SR was associated with a less frequent incidence of a composite event of cardiovascular death and heart failure rehospitalization (hazard ratio = 0.19, 95% confidence interval = 0.06 - 0.60, p &lt; 0.01). Conclusions: Our findings highlight those patients with HFpEF, and AF treated with rhythm control by EC may improve, healthwise. Randomized controlled studies should evaluate the efficacy of EC and the effect of rhythm control for AF about atrial remodeling in HFpEF.