tbuckley/cabot-search huggingface dataset:
Abstract P3-06-12: Genetic heterogeneity of DCIS is a predictor of invasive cancer
Authors: A Fortunato, D Mallo, L King, T Hardman, A Hall, JR Marks, S Hwang, CC Maley
Journal: Cancer Research (2019)

Abstract Background: Heterogeneity is a hallmark of human cancers that is apparent both between and within individual tumors. Intra-tumor heterogeneity provides the genetic fuel for natural selection in clonal evolution and cancer progression. Tumors with high levels of genetic heterogeneity are hypothesized to be more likely to progress to invasion and metastasis Methods: We measured the mutational loads from separate areas of pure DCIS and compared this to genetic heterogeneity in DCIS lesions that co-exist with invasive cancer, as a surrogate for progression. Cases of pure DCIS and DCIS diagnosed concurrent with invasive cancer were identified. Two areas of DCIS from each case a minimum of 0.8 cm apart and control tissues were macro-dissected and the DNA extracted from FFPE samples. To analyze the data, we developed new bioinformatics methods that allowed analysis of small amounts of degraded DNA extracted from FFPE samples across multiple regions. Our bioinformatics pipeline was optimized on a series of 28 independent technical replicates of the same DNA sample sequenced twice, as training tools to find the best filtering parameters. Results: Whole exome sequencing was performed on two geospatially separated blocks for each case (41 pure DCIS and 30 DCIS adjacent to invasive disease). Minimum coverage for inclusion in this study was 40X over at least 50% of the exome. We used the ratio of private mutations (only in 1 area) to public (found in both areas) mutations as a measure of intra-tumor heterogeneity. Overall mutational load of DCIS was not a significant predictor to progression; however notably, DCIS adjacent to invasive disease patients had a higher ratio of private/public mutations (heterogeneity) in coding domains (Mann-Whitney p=0.016. Functional analysis of mutated coding genes (DAVID 6.8) shows a statistically significant enrichment in signal transduction, olfactory receptors (G-protein-coupled receptors) and cell-matrix interactions in both tumor types, after FDR correction. DCIS adjacent to invasive disease had an enrichment of mutated genes involved in additional cellular functions such as microtubule activity (fold enrichment =7.6, FDR=0.002), protein-protein interactions (fold enrichment =3.65, FDR=5.11E-04) and extracellular matrix remodeling (fold enrichment =8.3, FDR=0.02). Conclusion: We present an approach to measure clonal heterogeneity using a bulk sequencing strategy applied to geospatially distinct foci of DCIS. Our findings suggest that functional heterogeneity may play an important evolutionary role as a driver for invasive progression. Citation Format: Fortunato A, Mallo D, King L, Hardman T, Hall A, Marks JR, Hwang S, Maley CC. Genetic heterogeneity of DCIS is a predictor of invasive cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-06-12.
DIFFERENCES IN CARDIAC REMODELING, HEMODYNAMIC RESPONSE, AND PREDICTORS OF OUTCOMES AFTER TRANSCATHETER AORTIC VALVE REPLACEMENT IN PATIENTS WITH LOW-FLOW, LOW-GRADIENT AORTIC STENOSIS AND NORMAL-FLOW, LOW-GRADIENT AORTIC STENOSIS: RESULTS FROM THE LARGEST SINGLE-CENTER EXPERIENCE
Authors: Jeffrey Tyler, Tarun Chakravarty, Faizan Malik, Chinar Patel, Takahiro Shiota, Siddharth Singh, Sabah Skaf, Robert Siegel, Sung-Han Yoon, Tomoki Ochiai, Takahiro Nomura, Matthias Raschpichler, Wen Cheng, Raj Makkar
Journal: Journal of the American College of Cardiology (2019)
Cholesterol-tuned liposomal membrane rigidity directs tumor penetration and anti-tumor effect
Authors: Hangyi Wu, Miaorong Yu, Yunqiu Miao, Shufang He, Zhuo Dai, Wenyi Song, Yuan Liu, Sha Song, Ejaj Ahmad, Dongkai Wang, Yong Gan
Journal: Acta Pharmaceutica Sinica B (2019)

Recently, liposomes have been widely used in cancer therapeutics, but their anti-tumor effects are suboptimal due to limited tumor penetration. To solve this problem, researchers have made significant efforts to optimize liposomal diameters and potentials, but little attention has been paid to liposomal membrane rigidity. Herein, we sought to demonstrate the effects of cholesterol-tuned liposomal membrane rigidity on tumor penetration and anti-tumor effects. In this study, liposomes composed of hydrogenated soybean phospholipids (HSPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2000) and different concentrations of cholesterol were prepared. It was revealed that liposomal membrane rigidity decreased with the addition of cholesterol. Moderate cholesterol content conferred excellent diffusivity to liposomes in simulated diffusion medium, while excessive cholesterol limited the diffusion process. We concluded that the differences of the diffusion rates likely stemmed from the alterations in liposomal membrane rigidity, with moderate rigidity leading to improved diffusion. Next, the in vitro tumor penetration and the in vivo anti-tumor effects were analyzed. The results showed that liposomes with moderate rigidity gained excellent tumor penetration and enhanced anti-tumor effects. These findings illustrate a feasible and effective way to improve tumor penetration and therapeutic efficacy of liposomes by changing the cholesterol content, and highlight the importance of liposomal membrane rigidity.
PROGNOSTIC VALUE OF THE C-REACTIVE PROTEIN/ALBUMIN RATIO IN PATIENTS UNDERGOING TRANSCATHETER AORTIC VALVE IMPLANTATION
Authors: Derk Frank, Hatim Seoudy, Tim Kujat, Johanne Frank, Georg Lutter, Ashraf Y. Rangrez, Christian Kuhn, Norbert Frey
Journal: Journal of the American College of Cardiology (2019)
Noninvasive Genotyping and Monitoring of Classical Hodgkin Lymphoma
Authors: Michael C. Jin, Joseph G Schroers-Martin, David M. Kurtz, Lieselot Buedts, Mohammad S Esfahani, Charles Macaulay, Brian Sworder, Joanne Soo, Cynthia Glover, Mark Roschewski, Wyndham H. Wilson, Ulrich Dührsen, Andreas Hüttmann, Davide Rossi, Gianluca Gaidano, Jason R. Westin, Lauren S. Maeda, Ranjana H Advani, Peter Vandenberghe, Maximilian Diehn, Arash A. Alizadeh
Journal: Blood (2018)
Physiological conditioning of human cardiomyocyte progenitor cells driven by electrical stimulation
Authors: Aida Llucia-Valldeperas, B. Sanchez, C. Soler-Botija, C. Galvez-Monton, J. Rossell-Ferrer, R. Bragos, A. Bayes-Genis
Journal: European Journal of Heart Failure (2014)
Self-Monitoring of Blood Glucose in Youth-Onset Type 2 Diabetes: Results From the TODAY Study
Authors: Ruth S. Weinstock, Barbara H. Braffett, Paul McGuigan, Mary E. Larkin, Nisha B. Grover, Natalie Walders-Abramson, Lori M. Laffel, Christine L. Chan, Nancy Chang, Beth E. Schwartzman, Rose Ann Barajas, Nicole Celona-Jacobs, Morey W. Haymond
Journal: Diabetes Care (2019)

OBJECTIVE To determine whether self-monitoring of blood glucose (SMBG) is associated with lower HbA1c in youth with type 2 diabetes taking oral medications only or after starting insulin for persistently elevated HbA1c. RESEARCH DESIGN AND METHODS Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study participants (n = 699) taking oral medications were asked to perform SMBG twice daily. After reaching primary outcome (PO) (HbA1c ≥8% [64 mmol/mol]) over 6 months or an inability to wean from temporary insulin because of metabolic decompensation), insulin glargine was started. HbA1c and percent of SMBG (SMBG%) (percent days when the meter was used one or more times) before and after PO were analyzed. RESULTS SMBG declined over time and was inversely related to HbA1c (P &amp;lt; 0.0001). Of 298 youth who reached PO and started insulin, 282 had SMBG data. At PO, mean ± SD age was 15.8 ± 2.3 years, BMI 35.5 ± 7.9 kg/m2, and HbA1c 9.6 ± 2.0% (81 ± 21.9 mmol/mol); 65.3% were female. Median SMBG% was 40% at PO, which increased to 49% after 6 months and fell to 41% after 1 year on insulin. At PO, 22% of youth checked ≥80% of days, which increased to 25% and fell to 19% after 6 and 12 months using insulin, respectively. At PO, compared with those who checked &amp;lt;80%, youth who checked ≥80% were younger and with a lower BMI, HbA1c, and blood pressure. SMBG ≥80% was associated with ≥1% reduction in HbA1c at 6 and 12 months after insulin initiation. CONCLUSIONS Low SMBG adherence was common and associated with higher HbA1c. Optimal SMBG frequency in youth using or not using insulin, and whether less frequent SMBG is a marker for overall worse self-care, require further study.
Abstract 16950: Paradoxical Effect of Obstructive Sleep Apnea on Survival Outcomes After In-hospital Cardiac Arrest
Authors: Rafath Ullah, Vaibhav Gupta, Tadele W Mengesha, Amina Adil, Beneet Pandey, Indrajit Choudhuri, M. Eyman Mortada, Vikram Nangia, Imran Niazi, Atul Bhatia, Jasbir Sra, Arshad Jahangir
Journal: Circulation (2017)

Background: Obstructive Sleep Apnea (OSA) is associated with higher prevalence of cardiac arrhythmias, yet recurrent hypoxemia that induces cardioprotective responses may improve survival outcomes after cardiac arrest. Methods: Using the Nationwide Inpatient Sample database, adult patients undergoing resuscitation for in-hospital cardiac arrest (IHCA) from 2005 to 2008 were identified and patients with OSA were 1:1 propensity matched (age, sex and major comorbidities) with no OSA group. Differences in hospital mortality in patients with ventricular fibrillation (VF) and non-VF-related IHCA were determined. Logistic regression model was used to identify independent predictors of mortality. Results: Out of 75,099 patients who experienced IHCA, 1260 patients had OSA and were 1:1 matched with non-OSA patients. Of the 2520 patients in the matched group, 1687 (67%) patients died after IHCA; overall survival was significantly better in those who had VF cardiac arrest than in those with non-VF arrest (38.7% vs 32...
Integrated DNA/RNA microarray profiling of hormone-refractory clinical prostate cancers and metastases indicates deregulation of several pathways, including androgen/AR, Hedgehog, MAPK and neuroactive ligand/receptor signalling
Authors: M K Wolf, H Edgren, I Mills, A Carles, O Poch, S Kilpinen, M Peltola, R Autio, D Neal, B Wasylyk, J Schalken, O Kallioniemi
Journal: Cancer Research (2006)
LOWER DIASTOLIC BLOOD PRESSURE AFTER TRANSCATHETER OR SURGICAL AORTIC VALVE REPLACEMENT IS COMMON AND ASSOCIATED WITH INCREASED MORTALITY
Authors: Brian L. Lindman, Kashish Goel, Javier Bermejo, Joshua Beckman, Clayton Allen Kaiser, Jared O'Leary, Colin Barker, Joao L. Cavalcante, Sammy Elmariah, Jian Huang, Graeme L. Hickey, David Adams, Jeffrey Popma, Michael Reardon
Journal: Journal of the American College of Cardiology (2019)
ADDING CORONARY CALCIUM SCORE TO EXERCISE TREADMILL TEST: AN ALTERNATIVE TO BETTER RISK STRATIFY PATIENTS WITH SYMPTOMATIC CHEST PAIN AT AN OUTPATIENT SETTING
Authors: Yue Wang, Weiting Huang, Natalie Koh, Zijuan Huang, Lohendran Baskaran, Swee Yaw Tan
Journal: Journal of the American College of Cardiology (2019)
30-DAY UNPLANNED READMISSIONS AFTER ADMISSION WITH A PRIMARY DIAGNOSIS OF NON-SPECIFIC CHEST PAIN: INSIGHTS FROM THE NATIONWIDE READMISSION DATABASE
Authors: Chun Shing Kwok, Purvi Parwani, David Fischman, Ritu Thamman, Jassim al Suwaidi, Mohamed Mohamed, Josip A. Borovac, Yoon K. Loke, Evangelos Kontopantelis, David Brown, Mamas A. Mamas
Journal: Journal of the American College of Cardiology (2019)
Abstract 353: Nucleolar Enlargement and Perturbed Ribosome Biogenesis Are Cellular Hallmarks of Cardiac Aging
Authors: Collin Matsumoto, Trang Hua, Mark Sussman, Nirmala Hariharan
Journal: Circulation Research (2018)

Introduction: Cardiac Aging manifests as structural and functional impairment of the heart and is associated with several changes in the cellular architecture. Of the many alterations in organelle structure and function that occur during aging, changes in the nucleolus and ribosome remain least studied in the cardiac context. The nucleolus functions as a stress sensor and is critical for ribosome biogenesis. Hypothesis: This study hypothesizes that perturbations in nucleolar architecture and ribosome biogenesis result in accumulation of free ribosomal proteins that stabilize p53 and trigger cardiac aging. Methods and Results: Using animal models of chronological (CA) and biological aging (BA), we observed that nucleolar size is dramatically increased in senescent myocardial cells (1.75 fold) as well as in aged hypertrophied hearts. Nucleolar enlargement is accompanied by significant increase in pre-ribosomal RNA levels (2 fold, p&lt;0.01 in CA hearts; 9 fold in BA hearts) indicating increased ribosome biogenesis. Synthesis of ribosomal proteins (RP) in equimolar amounts to ribosomal RNA that occurs under normal conditions is disrupted in the aged heart, resulting in increased expression of RPL11 (50% in BA heart, 33% in CA heart) that is a component of the 60S large ribosomal subunit. Accumulation of RPL11 coincides with increased p53 expression (2 fold, p&lt;0.05 in BA heart; 5.4 fold in CA heart) suggesting a role for RPL11 in mediating p53 stability in the aged heart. Conclusion: Collectively our data demonstrate nucleolar enlargement as a cellular hallmark of cardiac aging and uncover a molecular mechanism involving perturbed ribosome biogenesis and accumulation of free RPs that contribute to age-associated afflictions in the heart.
Dysregulation of Splicing in Multiple Myeloma: The Splicing Factor SRSF1 Supports MM Cell Proliferation Via Splicing Control
Authors: Mariateresa Fulciniti, Michael A Lopez, Anil Aktas Samur, Eugenio Morelli, Hervé Avet-Loiseau, Mehmet Kemal Samur, Nikhil Munshi
Journal: Blood (2018)
SPONTANEOUS CORONARY ARTERY DISSECTION: SIMULTANEOUS CONSERVATIVE AND INTERVENTIONAL MANAGEMENT
Authors: Khawaja A. Bashir, Sundeep Kumar, Hiren Patel, Jovan Gayle, Kirolus Sourial, Ruthvik Srinivasamurthy, Jooby John, Sayed Hussain
Journal: Journal of the American College of Cardiology (2019)
Abstract 513: Lower Nadir Cd4 T-cell Count is a Strong Predictor of Endothelial Dysfunction in HIV Infected Patients
Authors: Emad Mogadam, Kevin King, Kimberly Shriner, Karen Chu, Anders Sondergaard, Darlene Royal, Kristal Young, Robert Kloner
Journal: Circulation Research (2018)

Background: Nadir CD4 T-cell count is a predictor of negative outcomes in HIV -infected patients and strongly correlates with WHO disease staging. There is lack of data pertaining the relationship between vascular function and nadir CD4 in patients without risk factors of hypertension and diabetes. Therefore we investigated the association between low nadir CD4 T-cells and endothelial function in these otherwise cardiovascular healthy patients. Methods: We conducted a study of 19 HIV-infected men on antiretroviral therapy with undetectable plasma RNA levels without hypertension or diabetes. Vascular reactivity index (VRI), a marker for vascular endothelial function, was measured via VENDYS technique using temperature rebound in response to hyperemic blood flow and vasodilation to the forearm following a 5-minute cuff occlusion of the brachial artery. Results: VRI showed a significant correlation with low nadir CD4 count (p = 0.019) (Figure 1). Lower CD4 counts were associated with significant endothelial dysfunction. We examined the effect of potential mediators on such association. No significant correlation was found with LDL-C (p=0.60), HDL-C (p=0.59), systolic and diastolic blood pressures (p=0.12 and 0.13) or history of smoking (p=0.55) with VRI in the studied HIV cohort. Conclusion: Low nadir CD4 count remained independently associated with vascular reactivity index and thus a significant clinical predictor of endothelial dysfunction in HIV infected patients with no history of hypertension or diabetes even before clinical evidence of cardiovascular disease. Vascular Reactivity Index vs CD4 Nadir(Figure1).
Abstract 517: Pathogenic Mechanism of a Catecholaminergic Polymorphic Ventricular Tachycardia Causing-Mutation in Cardiac Calcium Release Channel RyR2
Authors: Zheng Liu
Journal: Circulation Research (2018)

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a condition that is characterized by an abnormal heart rhythm in response to physical or emotional stress. The majority CPVT patients carry mutations in the RYR2 gene that encodes the calcium release channel/ryanodine receptor (RyR2) in cardiomyocytes. The pathogenic mechanisms that account for the clinical phenotypes of CPVT are still elusive. We have identified a de novo mutation, A165D, from a CPVT patient. A knock-in mouse model that expresses an A165D point mutation was generated using CRISPR/Cas9 technology. Echocardiogram, electrocardiography, and histological analysis were performed on mutant mice. We found that ventricular tachycardia was readily induced by exercise and pharmacological challenges. Functional properties of the mutant RyR2 channel were evaluated in isolated cardiomyocytes. The mutant RyR2 channels enhanced SR Ca 2+ release, triggered delayed afterdepolarization in cardiomyocytes. These recapitulated CPVT phenotypes in both animal models and cardiomyocytes indicated that RyR2 A165D is a CPVT-causing mutation. Furthermore, we pinpointed the 3D localization of the mutation site in the structures determined by cryo-electron microscopy. It revealed that the A165D mutation change the electric charge of the residue, disrupted conformational stability of the RyR2 tetramer structure, and promoted a closed-to-open state transition. Moreover, the location of the A165D mutation is in a loop that harbors several other mutations, and, like A165D, most these mutations result in changes in the electrostatic charge of the side chains of the residues. This demonstrated a common molecular mechanism of CPVT-causing RyR2 mutations. Our data illustrated disease-relevant functional defects and provide a deeper mechanistic understanding of a life-threatening cardiac arrhythmia.
LONG-TERM THERAPY BAY 1142524, A CHYMASE-1 INHIBITOR, NORMALIZES PLASMA BIOMARKERS IN DOGS WITH CORONARY MICROEMBOLIZATION-INDUCED HEART FAILURE
Authors: Hani N. Sabbah, Ramesh C. Gupta, Vinita Singh-Gupta, Kefei Zhang
Journal: Journal of the American College of Cardiology (2019)
AN ISOLATED URINARY SODIUM/POTASSIUM RATIO IS A BETTER PREDICTOR OF PROGRESSION OF HYPERTENSION THAN THE ESTIMATED DAILY INTAKE OF SALT IN THE CHILEAN POPULATION: THE ASSOCIATION IS HIGHER IN WOMEN
Authors: Giovanna Valentino, Rodrigo Tagle, Jorge Quitral, Lorena Orellana, Marcela Adasme, Pamela Illanes, Fernando Baraona, Carlos Navarrete, Monica Acevedo
Journal: Journal of the American College of Cardiology (2019)
Abstract 16172: Post-Cardiac Surgery Delirium and In-Out Fluid Balance: Results From a Retrospective Case-Control Study
Authors: Tanya Mailhot, Sylvie Cossette, Jean Lambert, Marc-André Maheu-Cadotte, Guillaume Fontaine, Aymen Benkreira, Beaubien-Souligny William, Alexis Cournoyer, Josée Bouchard, Yoan Lamarche, Antoine Rochon, Eileen O’Meara, André Denault
Journal: Circulation (2017)

Introduction: Cardiac surgery patients in the intensive care unit are one of the most at risk for delirium, reflecting acute brain dysfunction. Post-cardiac surgery delirium could result from an in...
A NOVEL APPROACH TO QUANTIFYING RISK OF MAJOR CARDIOVASCULAR EVENTS IN PATIENTS 1-3 YEARS POSTMYOCARDIAL INFARCTION: INSIGHTS FROM THE GLOBAL PROSPECTIVE TIGRIS REGISTRY
Authors: Stuart J. Pocock, David Brieger, John Gregson, Ji Yan Chen, Mauricio G. Cohen, Shaun G. Goodman, Christopher B. Granger, Richard Grieve, Jose C. Nicolau, Tabassome Simon, Dirk Westermann, Satoshi Yasuda, Katarina Hedman, Kirsten L. Rennie
Journal: Journal of the American College of Cardiology (2019)
ULTRA-LOW-DOSE 70-KV CORONARY COMPUTED TOMOGRAPHY ANGIOGRAPHY USING DUAL- SOURCE COMPUTED TOMOGRAPHY
Authors: Sei Komatsu, Satoru Takahashi, Mitsuhiko Takewa, Tomoki Ohara, Chikao Yutani, Kazuhisa Kodama
Journal: Journal of the American College of Cardiology (2019)
Abstract 479: The ER Unfolded Protein Response Effector, ATF6, Promotes Proliferation and Maintains Pluripotency in Cardiac Stem Cells
Authors: Winston T Stauffer, Shirin Doroudgar, Hailey N Stephens, Erik A Blackwood, Christopher C Glembotski
Journal: Circulation Research (2018)

Recent studies have suggested that multipotent stem cells residing in the adult heart, called cardiac stem cells (CSCs), mitigate damage in the infarcted or failing heart. Investigating the factors governing CSC proliferation and differentiation is key to understanding what role these cells play in the heart and in future therapeutic strategies. Additionally, activating transcription factor 6 (ATF6), an effector of the endoplasmic reticulum (ER) unfolded protein response (UPR), plays critical roles in development, as well as in the differentiation of certain stem cell types, though it has not been studied in this regard in the heart. Our lab has demonstrated that ATF6 in cardiac myocytes is cardioprotective in vivo during ischemia/reperfusion partly by virtue of its ability to induce an antioxidant gene program that reduces damaging reactive oxygen species (ROS). However, ATF6, and its involvement in antioxidant gene induction, have not been studied in CSCs. Therefore, here we hypothesized that activation of the ATF6 branch of the UPR in CSCs is important for their proliferation and differentiation, given that ROS is known to be essential for these processes. To address this hypothesis, we subjected cultured mouse CSCs to simulated ischemia and observed increased ATF6 target gene mRNA levels. This demonstrates that, despite their undifferentiated status, CSCs have a functional UPR, which can be activated in response to ischemic stress. ATF6 loss of function (LOF) in CSCs, via RNAi or chemical inhibitor, yielded a basal decrease in cell viability and an increase in several differentiation markers, similar to the effect of dexamethasone differentiation stimulus. Increased ROS was also observed in an ATF6 LOF model. Strikingly, cotreatment with a chemical ROS inhibitor significantly rescued cell viability and reduced markers of differentiation in CSCs with reduced ATF6 function. These results suggest that CSCs require a basal level of ATF6 activity to maintain their proliferation and pluripotentcy in vitro and that this is mediated by the role of ATF6 in the mitigation of ROS. This is an important finding given that stem cell expansion in vitro is a critical step in the characterization of stem cells and their use in many therapeutic treatment strategies.