tbuckley/cabot-search huggingface dataset:
Abstract 11757: Telomerase Treatment Restores Transcriptional Profile and Epigenetic Landscape in Progeria Vascular Cells
Authors: Anahita Mojiri, Qiu Xu, Luay Boulahouache, Elisa Morales, Guangyu Wang, John P Cooke
Journal: Circulation (2021)

Hutchinson-Gilford progeria syndrome (HGPS) is a model of accelerated vascular aging caused by a de novo mutation of a single nucleotide in the Lamin A gene. The accumulation of abnormal lamin A (progerin) in the nuclear envelope induces a nuclear dysmorphology associated with global gene dysregulation, increased expression of inflammatory cytokines, impaired vascular function, and accelerated telomere erosion. These individuals succumb to myocardial infarction or stroke in their mid-teens. We hypothesized that restoration of telomere length might reverse some of the observed derangements in cell function, transcriptional profile and epigenetic alterations. Accordingly, we generated iPSC-derived endothelial cells (ECs) from HGPS children and their unaffected parents. By comparison to the parental controls, HGPS ECs have severely impaired replicative capacity, cellular functions (e.g. NO synthesis, acLDL uptake, network formation, cytokine secretion) and severe telomere shortening. We observed that transient transfection with mRNA encoding human telomerase (hTERT) increases telomere length, restores cellular replicative capacity and improves HGPS-EC functions. Notably, RNAseq studies revealed that that approximately 1200 genes were dysregulated in Progeria, most of which were improved by hTERT treatment, among which approximately 250+ genes were fully normalized. Intriguingly, hTERT treatment reduces DNA damage signals (γH2Ax) and reverses the aberrant chromatin accessibility observed in HGPS-ECs, as assessed by a reduction in the activating histone mark H3K4me3; an increase in the suppressive mark H3K4me3; and normalizes the level of heterochromatin markers HP1, Histone H1 and H3. Preliminary results from ChIPseq studies targeting histone marks characteristic of activators, repressors and enhancers as well as chromatin remodeling proteins; together with Hi-C analyses indicate that there are global changes in topologically associated domains (TADs) and other features of the chromatin landscape in HGPS ECs, which are partially restored by hTERT treatment. We conclude that hTERT treatment has surprisingly global effects on transcriptional profile and epigenetic landscape in addition to telomere extension.
Abstract 10515: Deep Phenotyping of Heart Failure with Machine Learning: An Echocardiographic Community Study
Authors: Nicholas B Larson, Susan Weston, Hector I Michelena, Suzette J Bielinski, Ruoxiang Jiang, Jungnam Joo, Sheila M Manemann, Alanna M Chamberlain, Veronique L Roger
Journal: Circulation (2021)

Introduction: Heart failure (HF) is a clinical syndrome with high mortality. Left ventricular ejection fraction (EF) determines clinical phenotyping and HF is classified most often as preserved (HFpEF) or reduced (HFrEF) EF. The importance of expanding phenotyping beyond EF is recognized. We hypothesized that machine learning applied to echocardiography will provide information important for deep phenotyping. Methods: We collected clinical and echo data in a HF community cohort between 2013 and 2017. Unsupervised clustering was applied to 23 echo variables using partitioning around medoids (PAM), with Gower dissimilarity used to address the mixed variable types. Proportional hazards regression examined the association between cluster assignment and death. Results: We identified 4978 persons with HF [mean age 73.9 years (SD 13.9), 47% women] with echocardiography within 6 months of diagnosis. We identified 2 primary clusters using echo variables, as depicted using t-Distributed Stochastic Neighbor Embedding (t-SNE) applied to the dissimilarity matrix (Figure). Diastolic function variables exhibited the largest differences by clusters as shown by absolute standardized differences (Table). After 3.2 + 1.9 years of follow up, 2001 deaths occurred. Assignment to cluster 2 was associated with a near 20% excess risk of death independent of age, sex, comorbidity, and EF [HR 1.17 (1.07, 1.28) p&lt;0.001]. Conclusions: Unsupervised clustering applied to echocardiography in a large community HF cohort identified 2 distinct clusters, which defined HF subgroups with different characteristics and were independently associated with risk of death.
Corrigendum to “Multifunctional nanoparticles based on a polymeric copper chelator for combination treatment of metastatic breast cancer” [Biomaterials 195 (2019) 86–99]
Authors: Ping Zhou, Jiaqi Qin, Ce Zhou, Guoyun Wan, Yuanyuan Liu, Mingming Zhang, Xiaoying Yang, Ning Zhang, Yinsong Wang
Journal: Biomaterials (2021)
QOLP-34. EVALUATING ADJUSTMENT DISORDER AND POST-TRAUMATIC STRESS DISORDER IN BRAIN TUMOR PATIENTS
Authors: Alec Gibson, Jerome Graber
Journal: Neuro-Oncology (2021)

Abstract Patients with primary and metastatic brain tumors are particularly susceptible to psychiatric comorbidities. Adjustment disorder (AD) and post-traumatic stress disorder (PTSD) are particularly prevalent in cancer patients and benefit from focused treatment; however, few studies have assessed these conditions in both brain tumor patients and their caregivers. This study aims to evaluate the prevalence of cancer-related AD and PTSD in both brain tumor patients and caregivers, including patients with gliomas, meningiomas, metastases and other brain tumor types. Patients and caregivers at the University of Washington’s Alvord Brain Tumor Center completed modified ADNM-20 and PCL-5 questionnaires to screen for cancer-related AD and PTSD, respectively. Cutoff scores for a positive screen were set at 47.5 for the ADNM-20 and 33 for the PCL-5. A total of 11 patients and 5 caregivers completed both surveys between December 2019 and May 2021. Two caregivers (40%) screened positive for AD, while none of the brain tumor patients met the cutoff score. One brain tumor patient (9%) screened positive for PTSD, while no caregivers had a positive score. Mean ADNM-20 scores were 34.9 (± 8.8) for brain tumor patients and 34.2 (± 14.8) for caregivers (p = 0.890, Mann-Whitney test). Mean PCL-5 scores were 15.3 (± 10.5) for brain tumor patients and 16.6 (± 11.2) for caregivers (p = 0.681, Mann-Whitney test). Mean scores for ADNM-20 and PCL-5 did not differ between groups, confirming that both caregivers and patients are psychologically affected, and 2 out of 5 caregivers screened positive for AD while 1 out of 11 brain tumor patients screened positive for PTSD. These results demonstrate that cancer-related AD and PTSD can be identified in these populations and suggest a difference in these psychiatric conditions between patients and caregivers. Identifying patients and their caregivers with AD and PTSD could improve their quality of life.
Elucidating the Characteristics of Two Tumor Cell Populations in Small Cell Variant of Anaplastic Lymphoma Kinase-Positive Anaplastic Large Cell Lymphoma
Authors: Kazuhiro Noguchi, Yasuhiro Ikawa, Mika Takenaka, Yuta Sakai, Toshihiro Fujiki, Rie Kuroda, Taizo Wada
Journal: Blood (2021)
Abstract 13936: Cardiac Beta3-Adrenergic Receptors Increase Pentose Phosphate Pathway Flux And Protect Against Hypertrophic Remodeling By Reducing Oxidative Stress
Authors: Lauriane Michel, esfahani hrag, Veronique Roelants, Christophe Beauloye, Luc Bertrand, Balligand Jean-Luc
Journal: Circulation (2021)

Introduction: Cardiac beta3-adrenergic receptors (β3AR) mediate effects opposite to those of β1AR and β2AR and are upregulated during the development of hypertrophy or heart failure (HF). We previously showed that upon hemodynamic or neurohormonal stress β3AR confer protection against cardiac fibrosis and hypertrophic remodeling, two key components of the progression towards HF. Hypothesis: We tested the hypothesis that modulations of cardiac metabolism are implicated in the myocardial protection by β3AR Results: In a transgenic mouse model with cardiac-specific expression of the human β3AR (TG; compared to their wild-type littermates (WT)) myocardial glucose uptake is enhanced both in vivo ( 18 Fluoro-deoxy-glucose by PET-CT) and in isolated adult cardiac myocytes exposed to hemodynamic stress by transverse aortic constriction for 9 weeks (TAC). In addition, a decrease in glycaemia during insulin tolerance test as well as an increase in Glut4 transporter in TG post-TAC suggest an insulin-dependency, as well as sensitization underlying the accrued glucose entry. Targeted metabolomics on cardiac tissue from TG (vs. WT) revealed a significant increase of several intermediates of the pentose phosphate pathway (PPP) post-TAC. Transcriptional expression from isolated cardiac myocytes showed an upregulation of several key enzymes of the pathway, that correlate with an elevation of NADPH levels, a major product of the PPP, with no modifications in nucleotides levels, implying a re-entry via the lower glycolysis. Consistent with an upregulated PPP, we found an increase in the ratio of reduced-to-oxidized Glutathione and a decrease in several indicators of oxidative stress (ROS production, MetO) both indicating a reduced oxidative stress. Conclusion: β3AR mediate an increased flux through the PPP, sustained by an enhanced glucose uptake, in cardiac myocytes upon prolonged hemodynamic stress. The associated renewal of the NADPH pool and cellular detoxification of ROS may contribute to the protective role of β3AR against hypertrophic remodeling. As β3AR agonists are currently used in clinical practice for urological indications, these original cardiac protective mechanisms may offer immediate perspectives for the prevention or treatment of HF.
Bleeding Complications in Patients with Cancer and COVID 19- Analysis from the COVID 19and Cancer Consortium (CCC19) Registry
Authors: Surbhi Shah, Shuchi Gulati, Ang Li, Julie Fu, Vaibhav Kumar, Rebecca Zon, Amit Kulkarni, Pankil Shah, Peter D. Byeff, Ryan Nguyen, Gayathri Nagaraj, Matthew Puc, Clara Hwang, Rana McKay, Benjamin French, Cassandra Hennessy, Jeremy L. Warner, Jean M. Connors, Dimpy P. Shah, Rachel P. Rosovsky
Journal: Blood (2021)
Abstract 14445: Quality Assessment of Transcatheter Aortic Valve Replacement Meta Analysis: Is It Worth Reading?
Authors: yasar sattar, David Song, Maria Riasat, Gurpal Singh, Rajendra Shah, Islam Y Elgendy, Anoosha Mehmood, Tanveer Mir, Mohamed Zghouzi, Waqas Ullah, Mahboob Alam, Anees Khan, M C Alraies
Journal: Circulation (2021)

Introduction: Multiple meta-analyses have been performed since Transcatheter Aortic Valve Replacement (TAVR) and quality of the rapidly publishing data on TAVR is debatable. Methods: Descriptive statistics was performed on pooled samples of quality assessment statistics including heterogeneity I2, Q-statistics ,Tau, and Cochrane. An approach to high heterogeneity was reviewed in this meta-analysis to review the quality of content published online. We reported total n, average numbers and percentages. Continuous data with normal distribution was reported as mean with standard deviation (SD). Results: A total of 231 meta-analyses done on TAVR were included in our study. The total of 1365 outcomes were reported in all of the meta-analyses. The total outcomes with heterogeneity I2&lt; 75% and I2 &gt;75% were 1125 and 244 respectively. The average number of outcomes with I2 &lt;75% was 5, while the outcomes with I2&gt;75% was 1.19. Tau, H statistics, and Cochrane statistics were reported for 79, 1 and 42 outcomes respectively. The subgrouping was performed in 87 outcomes. The mean number of subgroups was 1 ± SD 0.06, Odds ratios, relative risk and standard mean difference were used as an effect size in 93, 63, and 36 studies respectively. The random effect model, fixed effect model, or combine models were used in 180, 67, and 53 outcomes respectively. Sensitivity analysis was performed in 109 outcomes. Meta-regression was performed in 55 outcomes with an average of 0.27 studies. 46 outcomes were able to report I2&lt;75% after meta regression, and subgroup analysis. Trend (n) of outcomes with heterogeneity I2&gt;75% across different studies is shown in figure 1. Conclusion: TAVR heterogeneity was high in up to 18% of meta analysis outcomes in all meta analysis performed. Meta regression was performed in 22% with high heterogeneity, and 18% of the outcomes were able to fix the high heterogeneity in the data.
Systematic Review and Meta-analysis: The Role of Diet in the Development of Nonalcoholic Fatty Liver Disease
Authors: Elena Tsompanaki, Kessarin Thanapirom, Margarita Papatheodoridi, Pathik Parikh, Yasmin Chotai de Lima, Emmanuel A. Tsochatzis
Journal: Clinical Gastroenterology and Hepatology (2021)
PATH-10. MULTI-OMICS PROFILING AND MACHINE LEARNING PROPOSE A REFINED MOLECULAR CLASSIFICATION SYSTEM FOR GLIOMA
Authors: Cheng Zhou, zhaoming Zhou, Lei Wen, Mingyao Lai, Linbo Cai
Journal: Neuro-Oncology (2021)

Abstract Accurate molecular stratification of glioma patients is key to an optimal design of therapeutic strategy to maximize patient survival. Here we leveraged multi-omics analysis of glioma and detailed clinical follow-up to build a refined classification system for glioma patients using support vector machines. The model input included the number of non-synonymous mutations in cancer driver genes, the number of non-synonymous mutations in cancer related genes, the transcriptomic grouping information, the immune infiltrations predicted by RNA-seq dataset, the site of tumor occurrence, as well as other well-known markers including IDH mutation status and 1p19q co-deletion status. We validated key model predictions using TCGA and CGGA datasets. Our refined classification system outperforms current state-of-the-art framework used in clinic. Taken together, we propose a refined molecular classification for glioma combining multi-omics profiling and machine learning approaches.
Food choice in transition: adolescent autonomy, agency, and the food environment
Authors: Lynnette M Neufeld, Eduardo B Andrade, Ahna Ballonoff Suleiman, Mary Barker, Ty Beal, Lauren S Blum, Kathrin M Demmler, Surabhi Dogra, Polly Hardy-Johnson, Anwesha Lahiri, Nicole Larson, Christina A Roberto, Sonia Rodríguez-Ramírez, Vani Sethi, Teresa Shamah-Levy, Sofia Strömmer, Alison Tumilowicz, Susie Weller, Zhiyong Zou
Journal: The Lancet (2021)
Characterization of a Novel Missense <i>CXCR4</i> Mutation in a Patient with WHIM-like Syndrome
Authors: Sumit Pawar, Katarina Zmajkovicova, Svetlana Sharapova, Ivana Wiest, Chi Nguyen, Halenya Monticelli, Sabine Maier-Munsa, Christoph Geier, Neal Sondheimer, Boglarka Ujhazi, Sumai Gordon, Maryssa Ellison, Jolan E. Walter, Arthur G. Taveras, Adriana Badarau, Teresa Tarrant
Journal: Blood (2021)
Abstract 11230: Coordinate Cistrome Regulation by Reprogramming Factors During Direct Human Cardiac Reprogramming
Authors: Yawen Tang, Xinyue Zhou, Jianyi Zhang, Rui Lu, Yang Zhou
Journal: Circulation (2021)

Introduction: Direct cardiac reprogramming of somatic cells into induced cardiomyocytes (iCMs) through overexpressing cardiac enriched transcription factors is considered as a promising strategy for regenerative medicine and an important cell model to study cell fate determination. In addition to our published cocktail using MEF2C, GATA4, and TBX5 and microRNA miR-133 (MGT133), we found that addition of TBX20 significantly enhanced cardiac reprogramming and generated human iCMs (hiCMs) more similar to functional cardiomyocyte identity. However, it is largely unknown how the reprogramming factors coordinately regulate direct lineage conversion. Methods: To determine the regulatory networks orchestrated by transcription factors, we performed CUT&amp;TAG or CUT&amp;RUN for MEF2C, GATA4, TBX5, TBX20 and histone marks H3K27me3, H3K27ac and H3K4me3 in hiCMs generated with MGT133 or MGT133+TBX20. We also performed time course RNA-seq and ATAC-seq analyses to profile transcriptome and chromatin accessibility changes during reprogramming process. Results: We mapped the genome wide binding of each reprogramming factor and determined the co-occupancy of TBX20 and MGT at a majority of cardiac gene promotors, especially at genes related to cardiac cell structure and contractility, such as MYBPC3, SCN5A and MYH7. Interestingly, TBX20 itself is not able to target cardiac genes unless is expressed together with MGT. Meanwhile, expression of TBX20 led to significantly increased chromatin occupation of MGT factors and upregulation of cardiac-specific genes. Our immunoprecipitation assay further confirmed the physical interaction of TBX20 with MGT. Intriguingly, in addition to targeting cardiac-lineage genes, TBX20 also binds to many fibroblast-specific genes, such as LAMB1 and IGFN1. While binding of TBX20 augments chromatin accessibility at cardiac-specific genes loci, it decreases the chromatin openness at fibroblast genes. Conclusions: TBX20 cooperates with MEF2C, GATA4, and TBX5 to target cardiac-specific genes and facilitate gene transcription and serves as a transcription repressor of non-cardiac lineage genes. These results provided significant insight into cistrome regulation during human direct cardiac reprogramming.
Abstract 13900: Ex vivo Evaluation of Vascular Toxicity of Tobacco Products
Authors: Lexiao Jin, Daniel J Conklin
Journal: Circulation (2021)

Introduction: Tobacco smoke is the single most significant modifiable risk factor of cardiovascular disease (CVD), yet the contribution of electronic cigarettes (e-cig) to CVD risk is uncertain. Objective: The purpose of this study was to test an ex vivo approach for evaluation of vascular toxicity of tobacco products including e-cig aerosols. Methods: The assay relies on 2 facts of aortic function: 1) it is a biomarker of endothelial dysfunction; and, 2) it is nearly 100% dependent on endothelial-derived nitric oxide synthase (eNOS). To assess real-time eNOS function, phenylephrine-precontracted (PE) murine aortas were incubated with L-nitroargininemethylester (L-NAME) that subsequently increased tension and blocked (&gt;99%) acetylcholine-induced relaxation (ACh %). The ‘L-NAME PE Contraction Ratio’ (PECR) was calculated as: ‘PE Tension post-L-NAME’ divided by ‘PE Tension pre-L-NAME’, and regressed vs ACh % relaxation. Results: Validation 1: PECR and ACh % values of naïve aortas were strongly and positively correlated (PECR vs ACh %, r 2 =0.91, n=7). Validation 2: Retrospective analyses of published PECR and ACh % data of aortic function of female mice exposed to air, propylene glycol:vegetable glycerin (PG:VG), formaldehyde (FA), or acetaldehyde (AA) for 4d, 6h/d showed that the PECR in air-exposed mice (PECR=1.42±0.04, n=16) correlated positively with the ACh % (r 2 =0.40) as in naïve aortas. Similarly, PECR values were significantly decreased in aortas with endothelial dysfunction yet retained positive regression coefficients (PG:VG r 2 =0.54; FA r 2 =0.55). Unlike other toxicants, AA exposure significantly increased both PECR and ACh % values yet diminished regression (r 2 =0.09). Validation 3: Naïve aortas were incubated (1h) with particles of either mainstream cigarette smoke (MCS) or PG:VG, and the PECR was significantly increased by MCS (1.97±0.17; p&lt;0.05) yet not by PG:VG (1.34±0.05) compared with controls (1.48±0.05) indicating MCS induced vascular toxicity. Conclusions: Because the PECR reflects eNOS function directly, it is a robust tool for evaluating tobacco toxicity and predicting endothelial dysfunction. Thus, it strongly complements and extends insights gained using ex vivo measures of vascular toxicity.
Abstract 11369: Leveraging an Artificial Intelligence-Enabled Ecg Algorithm for Atrial Fibrillation Detection to Predict Long-Term Ischemic Stroke and Cardiovascular Mortality in the Community
Authors: Jose R Medina-inojosa, Zachi Attia, Peter A Noseworthy, Konstantinos Siontis, Abraham Baez, Michal Shelly, Paul Friedman, Francisco Lopez-jimenez
Journal: Circulation (2021)

Background: Artificial intelligence (AI)-based analysis of the electrocardiogram (ECG) can estimate the probability of having atrial fibrillation (AF) while in sinus rhythm. We evaluated the association between the probability of AF using AI-ECG and incident ischemic stroke (I-Stroke) and cardiovascular (CV) mortality. Methods: We evaluated a community-based cohort of consecutive patients that sought primary care in Olmsted County, MN, from the years 1998 to 2000 followed-up through March 2016. Inclusion criteria were ages 40-79, an electrocardiogram within 2 years and complete CHA2DS2-VASc data. We excluded those with known atherosclerotic CV disease or AF. The AI network was developed in 180,000 patients (649,931 ECG). The primary endpoint was incident I-Stroke; secondary endpoint was I-Stroke or CV mortality; validated in duplicate. Multivariate cox models adjusted for age, sex, history of hypertension, diabetes, heart failure, and in CHA2DS2-VASc Score subgroups (categorized as low=0, moderate=1, and high risk ≥2). Results: We included 14,601 patients, mean age 53.2±13.08 (51% women, 95% whites), CHA2DS2-VASc score 1.3±1.2, median follow-up of 16.3 years, IQR 14.5-17.5, 727 (4.9%) had an I-Stroke and 1309 (8.9%) had I-Stroke or died from CV causes. When comparing the 5 th vs the 1 st quintile, those with high AI-ECG AF probability had increased risk for I-Stroke (HR 3.25, 95%CI 2.55-4.14, P-for trend &lt;.0001 Figure-A ) and ischemic stroke or CV mortality (HR 5.73, 95%CI 4.69-6.99, P-for trend &lt;.0001 Figure-B ). This remained significant after adjustments. Furthermore, AI-ECG AF probability was associated with I-Stroke across CHA2DS2-VASc risk levels (HR 2.43 for high, 2.33 for moderate, 1.98 for low CHA2DS2-VASc risk, all P&lt;0.01). Conclusion: The AI-ECG AF algorithm predicts long-term I-Stroke and CV mortality and may refine CHA2DS2-VASc. These results highlight the utility of the AI enabled ECG when estimating I-Stroke or CV mortality risk.
Design and <i>in Vitro</i> Evaluation of a CAR-T Prototype (ARI-0003) Targeting CD123 for Acute Myeloid Leukemia
Authors: Alex Bataller Torralba, Néstor Tirado, Diego Sánchez-Martínez, Talía Velasco-Hernández, Aina Oliver-Caldés, Sandra Castaño-Díez, Francesca Guijarro, Marina Diaz-Beyá, Manel Juan, Pablo Engel, Clara Bueno, Pablo Menendez, Álvaro Urbano-Ispizua, Jordi Esteve
Journal: Blood (2021)