tbuckley/cabot-search huggingface dataset:
Genomic Landscapes and Clonality of De Novo AML
Authors: John Brewin, Gillian Horne, Timothy Chevassut
Journal: New England Journal of Medicine (2013)

We agree that it is important to understand whether mutations are responsible for the initiation of AML or cooperate with initiating mutations to cause disease progression or relapse.1,2 Whereas initiating mutations may be more likely to appear in founding clones, cooperating mutations might appear either in founding clones or subclones derived from founding clones. In our study, it was not possible to define the clonal architecture for all samples, both because AML genomes harbor a comparatively small number of mutations and because for 150 of 200 samples, only exome sequencing was performed. Nevertheless, we have used the data in Table S6 (available with the full text of our article at NEJM.org) to identify variants in significantly mutated genes that can be assigned with high confidence to either a founding clone or a subclone.

Mutations in some genes appear almost exclusively in founding clones, which suggests that they are disease initiators. These genes include RUNX1 (9 of 9 mutations in founding clones), NPM1 (3 of 3), U2AF1 (5 of 5), DNMT3A (38 of 40), IDH2 (13 of 14), IDH1 (15 of 17), and KIT(5 of 6). In contrast, mutations in NRAS (1 of 12 in founding clones), TET2 (13 of 18), KRAS(4 of 6), CEBPA (3 of 5), WT1 (3 of 6), PTPN11 (4 of 8), and FLT3 (6 of 13), are often found in subclones, suggesting that they are often cooperating mutations. Many additional genomes will need to be tested to make these tentative assignments more definitive.
Abstract 13479: AMP-activated Protein Kinase Mediates Vascular Protective Effects During Exercise Training
Authors: Swenja Schuhmacher, Philip Wenzel, Matthias Oelze, Andreas Daiber, Benoit Viollet, Thomas Munzel, Eberhard Schulz
Journal: Circulation (2010)

Background: Regular physical activity is known to protect the vasculature by antioxidative effects and upregulation of endothelial nitric oxide synthase. During skeletal muscle contraction, the AMP...
Abstract 19088: Synstatin: A Peptide-Based Switch to Alter the Phenotype of Vascular Smooth Muscle Cells
Authors: Somali Chaterji, Kimberly Pham, Seung Choe, Christoffer Lam, Aaron Baker
Journal: Circulation (2013)

Introduction: Vascular proliferative diseases such as primary atherosclerosis, postangioplasty restenosis, and transplant vasculopathy reduce the likelihood of success in vascular interventions. The ability of activated vascular smooth muscle cells (vSMCs) to contribute to the vascular lesion mass and to the inflammatory state of the vessel wall after injury is well known. An understanding of the mechanistic basis of vSMC activation can result in more effective therapies for improving vascular outcomes. Hypothesis: Prior work has suggested that loss of the transmembrane receptor, syndecan-1, can de-differentiate vSMCs. Given the extended reach of the glycosaminoglycan chains of syndecan-1, we hypothesized that the interaction of syndecan-1 with other receptors and matrix molecules can affect vSMC phenotype. It has been identified that the ectodomain of syndecan-1 can regulate the activation of α v β 3 and α v β 5 integrins on mammary carcinoma cells, fibroblasts, and endothelial cells. Further, the peptide synstatin (SSTN) has been found to inhibit this interaction of syndecan-1 with the α v β 3 and α v β 5 integrins. Thus, we further hypothesized that SSTN could modulate vSMC phenotype, affording mechanistic insights into syndecan-1’s role in vSMC differentiation. Findings: We performed gene expression studies for studying the effect of SSTN addition on the differentiation of primary human aortic SMCs. Real time PCR (n=4) indicated lower levels of smooth muscle-specific differentiation markers [[Unable to Display Character: –]] smooth muscle α-actin, calponin, and smoothelin in SSTN-treated vSMCs. Further, higher levels of the inflammatory markers [[Unable to Display Character: –]] IL-6, ICAM-1, and VCAM-1, and of heparanase, an endoglycosidase which cleaves heparan sulfate (GAG) chains, were observed. This indicates that an SSTN-based tumor stopper, as proposed in literature, could potentially result in vSMC activation and increase the inflammatory state of the blood vessel wall. Conclusion: Taken together, our results support a positive role for syndecan-1 in promoting vSMC differentiation, reducing the chances of intimal hyperplasia after vascular injury. It also indicates that the interaction of syndecan-1 with the integrins α v β 3 and α v β 5 may be a necessary condition for the differentiation of vSMCs.
Abstract 3162: Dynamic mortality modeling in PCI-treated ST-elevation Myocardial Infarction: Implications for Clinical Decision Making
Authors: Cynthia M Westerhout, Kerry L Lee, Stefan K James, Frans Van de Werf, William W O’Neill, Torsten Toftegaard Nielsen, W D Weaver, Christopher B Granger, Paul W Armstrong
Journal: Circulation (2007)

Background: Baseline factors predict adverse events after acute myocardial infarction (AMI), whereas dynamic risk modeling captures its evolving nature using continuous temporal profile updating. This refinement may guide medical decisions. Methods: APEX AMI trial tested pexelizumab efficacy in 5745 STEMI pts undergoing primary PCI; no treatment effect was observed. Four multivariable Cox models predicted 90-day mortality from key time points: baseline, 30-min post-PCI, 24 hrs, 96 hrs. % ST-resolution 30-min post-PCI, TIMI Flow pre-and post-PCI were measured. Complications included shock, CHF, re-MI, recurrent ischemia, stroke, renal failure, severe bleeding and major cardiac rhythm disturbances. The relative covariate contribution was quantified as the % of the ∑individual X 2 ’s. Results: Ninety-day mortality was 4.7%; 22% and 40% of deaths occurred &lt; 24 hrs and 4 days, respectively. The figure (left ) shows decreasing relative contributions of age, systolic BP/heart rate and other factors over time to 90d mortality, and incremental influence of in-hospital complications, TIMI flow and post-PCI ST-resolution. As time elapsed, the % of “low risk” pts increased. (Right panel) At 96 hrs, a possible early discharge point for low risk pts, 44.0% of survivors had been discharged. This discharge rate decreased with increasing risk: Low: 53.3%; Moderate: 35.3%; High: 20.4% (p &lt; 0.001). If early discharge depended on risk, the remaining 46.7% of low risk pts might have been discharged early. Conclusions: This novel approach demonstrates the dynamic nature of STEMI risk over time and may be used to guide early clinical decision-making.
Abstract 5464: The Cell Proliferative Effect of LRP6 Mutation is Mediated by Increased PDGF Dependent Cyclin D1 Expression
Authors: Ali R Keramati, Wenzhong Liu, Timothy Nottoli, Saeed Faramarzi, George Tellides, Arya Mani
Journal: Circulation (2009)

We recently identified a disease causing mutation (R611C) at a highly conserved residue of the LDL receptor like protein 6 (LRP6) in a family with early onset coronary artery disease (CAD), and metabolic syndrome. This finding signifies the effect of a single gene defect in LRP6 on development of atherosclerosis and underscores emerging evidence implicating effect of altered Wnt signaling on atherosclerosis. The exact mechanisms linking LRP6 mutation with atherosclerosis are not well understood. mRNA expression analysis in cells from LRP6 mutation carriers has demonstrated that LRP6 mutation has a heterogeneous effect on Wnt signaling. Strikingly, cyclin D1, a target of Wnt signaling and a cell cycle activator is expressed at significantly higher levels in the mutant compared to the wildtype cells. Smooth muscle cell proliferation is a major component in the process of atherosclerosis development. We therefore dissected Wnt signaling and examined cell proliferation in aortic smooth muscle cell (SMC) cultures isolated from LRP6 R593C knock-in and LRP6 +/− knockout mice. The proliferation rate of LRP6 R593C SMCs was highest and those of the wildtype littermates were the lowest among the three, indicating that both haploinsufficiency as well as impaired LRP6 function result in cell cycle activation. GSK3 β is an intermediate peptide of the Wnt signaling pathway that inhibits cyclin D1expression. PDGF inactivates GSK3 β and promotes cellular proliferation by increasing the expression levels of cyclin D1. Our experiments showed that GSK3 β is at baseline more activated in cells expressing the mutant vector compared to the wildtype cells. However, after stimulation with PDGF, GSK3 β activation in the mutant cells diminishes to levels significantly lower than wildtype cells. This effect was mediated by higher expression levels of PDGF receptor in the mutant compared to the wildtype cells. Our result signifies the important role of LRP6 and its interaction with PDGF in the process of smooth cell proliferation and identifies LRP6 and GSK3 β as potential targets for both prevention and pharmacotherapy of atherosclerosis.
Abstract 4843: Furosemide-induced Diuresis With Matched Replacement of Intravascular Volume Compared to Standard Hydration for Contrast-induced Nephropathy Prevention: The Mythos Trial
Authors: Giancarlo Marenzi, Cristina Ferrari, Emilio Assanelli, Ivana Marana, Gianfranco Lauri, Monica De Metrio, Marco Grazi, Giovanni Teruzzi, Daniela Trabattoni, Antonio L Bartorelli
Journal: Circulation (2009)

Hypothesis. We investigated the effect of a new preventive strategy strategy for contrast-induced nephropathy (CIN) based on a dedicated device (RenalGuard; PLC Medical System Inc., USA). The system is capable of delivering i.v. saline solution to a patient in an amount matched to the volume of urine produced after an i.v. bolus of furosemide. The aim of the study was to evaluate if furosemide-induced high-volume diuresis with concurrent maintenance of intravascular volume may prevent CIN. Methods . To date, 63 chronic kidney disease (CKD) patients (eGFR&lt;60 ml/min/1.73 m 2 ) undergoing percutaneous coronary interventions (PCI) were enrolled in the MYTHOS trial. They were randomized to matched hydration (RenalGuard group, n=30) or to i.v. isotonic saline hydration (control group; n=33) at a rate of 1 ml/kg/hour for 12 hours before and after PCI. Matched fluid replacement was started approximately 90 minutes pre-PCI, maintained during catheterization, and for up to 4 hours afterwards. Patients were given an initial i.v. bolus of 250 ml of normal saline over 30 minutes and then an i.v. bolus of furosemide (0.5 mg/kg). The RenalGuard measures the patient’s urine volume and then automatically adjusts the infusion pump rate to precisely replace the measured urine output in real time. When a &gt;300 ml/hour urine output rate was obtained, patients underwent PCI. CIN was defined as a ≥0.5 mg/dl or ≥25% rise in serum creatinine over baseline. Results . Overall, the mean eGFR was 40±9 ml/min/1.73 m 2 . The mean contrast volume was 190±92 ml in RenalGuard group and 212±118 ml in controls (P=0.4). In RenalGuard group, urine output ranged from 319 to 1788 ml/hr (mean 830±322 ml/hr). There were no serious device-or therapy-related complications, including clinically significant electrolyte changes (asymptomatic ipokalemia was corrected in 1 case). CIN occurred in no patient (0%) of the RenalGuard group and in 5 (15%) controls (P=0.03). Two controls (6%) required temporary renal replacement therapy. Conclusions. These preliminary results indicate that furosemide-induced high urine output with maintenance of intravascular volume through matched hydration can be safely obtained with the RenalGuard system and may reduce the risk of CIN in CKD patients undergoing PCI.
Abstract 154: Serum Biomarkers of Brain Injury Predict Outcome After Pediatric Cardiac Arrest
Authors: Ericka L Fink, Rachel P Berger, Robert S Clark, Robert S Watson, Derek C Angus, Ashok Panigrahy, Clifton W Callaway, Michael J Bell, Patrick M Kochanek
Journal: Circulation (2011)

Morbidity and mortality in children with return of pulses after cardiac arrest (CA) largely result from neurologic failure. Serum biomarkers of brain injury can potentially measure injury to neuron...
Age at onset of panic disorder: influence of familial liability to the disease and of childhood separation anxiety disorder
Authors: M Battaglia, S Bertella, E Politi, L Bernardeschi, G Perna, A Gabriele, L Bellodi
Journal: American Journal of Psychiatry (1995)

The authors investigated the relation of age at onset of panic disorder to liability to panic disorder and agoraphobia.Two hundred thirty-one outpatients with panic disorder were compared with 131 surgical outpatients on demographic variables and familial risk of psychiatric disorders. The distribution of patients' ages at onset of panic disorder and several covariates were entered in a stepwise survival analysis.The patients with panic disorder had a significantly higher rate of childhood separation anxiety disorder and higher familial risks of panic disorder/panic disorder with agoraphobia and alcoholism. A family history of panic disorder with agoraphobia and the presence of childhood separation anxiety disorder influenced age at onset of panic disorder.Age at onset of panic disorder may reflect genetic penetrance, and separation anxiety disorder may be an individual predictor of earlier onset of panic disorder.
Prognostic value of circulating Bcl-2/IgH levels in patients with follicular lymphoma receiving first-line immunochemotherapy
Authors: Fabian Zohren, Ingmar Bruns, Sabrina Pechtel, Thomas Schroeder, Roland Fenk, Akos Czibere, Georg Maschmeyer, Dorothea Kofahl-Krause, Norbert Niederle, Gerhard Heil, Christoph Losem, Manfred Welslau, Wolfram Brugger, Ulrich Germing, Ralf Kronenwett, Juergen Barth, Mathias J. Rummel, Rainer Haas, Guido Kobbe
Journal: Blood (2015)
Abstract 1144: Successful Surface-Aminated Nanofiber Expansion of Human Umbilical Cord-Derived CD133+ Cells Leads to Augmentation of Angiogenic Functionality <i>In Vitro</i> and <i>In Vivo</i>
Authors: Hiranmoy Das, Matthew Joseph, Nasreen Abdulhameed, Hai-Quan Mao, Vincent J Pompili
Journal: Circulation (2007)

Background: Umbilical cord blood (UCB) and marrow-derived CD133+ cells have been shown to mediate encouraging effects on therapeutic angiogenesis in both animal models and early clinical trials. Low numbers of CD133+ cells derived from a single donor have been a limitation of use of these cells in cardiovascular therapy. We hypothesized that an ex vivo aminated nanofiber system combined with cytokine supplementation would provide optimized topographical and biochemical signals to allow the expansion and potential functional augmentation of CD133+ cells without promoting terminal differentiation. Methods and Results: Human UCB derived CD133+ progenitor cells were isolated by MACS sorting and ex vivo expanded on aminated nanofiber plates with cytokine rich media. Cells harvested 10 days after expansion demonstrated a 225X increase in total number. Flow cytometric analysis demonstrated CD133–24%, CD34–93%, CXCR4–97%, LFA-97% surface expression. The expanded cells can uptake AcLDL efficiently and demonstrate a 2.3X increase in transwell migration to SDF-1 as compared to fresh UCB CD133+ cells. In vitro analysis revealed that expanded cells have potential to differentiate into endothelial or smooth muscle phenotype as demonstrated with CD31, vWF, VCAM-1 and F-pholloidin, α-actin, and SM myosin heavy chain immunocytochemistry when re-cultured for 14d in EGM2 or SMBM respectively. RT-QPCR analysis of 1% O 2 exposed (hypoxic) cells demonstrated a 2X increase in VEGF and 3X increase in IL-8 gene expression compared to normoxic control. In vivo functionality in a NOD/SCID mouse hind limb ischemic model demonstrated that mice treated with 5 x 10 6 expanded cells (n=7) augmented blood flow ratio (ischemic/control limb) as compared to mice treated with CD133+ cells (n=7) and control (n=7) at 28d. (control 0.32±.02 vs. UCB133+ 0.37±.02 vs. expanded cells 0.50±.04 p&lt;0.01) Capillary density in ischemic hind-limb was increased at 28d (control 62.5±5.4 vs. expanded cell 97.6±2.5 p&lt; 0.01) Conclusions: These studies demonstrate successful high level expansion of UCB derived CD133+ cells into functionally potent stem cells which have the capacity to differentiate into vascular cells and promote in vivo neovascularization.
Discussion of Structure-Reactivity Relationships of Halo-Ether Carcinogenicity
Authors: B. L. Van Duuren, B. M. Goldschmidt
Journal: JNCI Journal of the National Cancer Institute (1973)

Journal Article Discussion of Structure-Reactivity Relationships of Halo-Ether Carcinogenicity Get access B. L. Van Duuren, B. L. Van Duuren Laboratory of Organic Chemistry and Carcinogenesis Institute of Environmental Medicine New York University Medical Center New York, New York Search for other works by this author on: Oxford Academic PubMed Google Scholar B. M. Goldschmidt B. M. Goldschmidt Laboratory of Organic Chemistry and Carcinogenesis Institute of Environmental Medicine New York University Medical Center New York, New York Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 50, Issue 5, May 1973, Page 1411, https://doi.org/10.1093/jnci/50.5.1411 Published: 01 May 1973
Abstract 2060: Enhanced in situ Recellularization by Fibronectin and Stromal Cell Derived Factor-1alpha Coating of Heart Valves Acquires a Quasi-Native Valve Composition of Cell Phenotypes.
Authors: Geofrey De Visscher, Helga Blockx, Ilse Vranken, Eric Verbeken, Hans Van Oosterwyck, Marie-Christine Herregods, Bart Meuris, Willem Flameng
Journal: Circulation (2007)
Abstract 14853: Ischemic Preconditioning Protects Mitochondria Against Respiratory Failure Secondary To Ischemia-reperfusion Independently Of Cytosolic Signaling And Permeability Transition. Role Of Connexin43.
Authors: Celia Fernandez-Sanz, Elisabet Miro-Casas, Antonio Rodriguez-Sinovas, Estefania Nunez, Marisol Ruiz-Meana, Jesus Vazquez, David Garcia-Dorado
Journal: Circulation (2011)

Ischemic preconditioning (IP) protects against reperfusion injury. Several membrane receptor-triggered cascades involving kinase pathways that ultimately prevent mitochondrial permeability transiti...
Abstract 17732: Combination of B-Type Natriuretic Peptide and Minute Ventilation Carbon Dioxide Production Slope Improves Risk Stratification in Patients with Diastolic Heart Failure
Authors: Jing Yan, Li Li, Shi-jin Gong, Hai-wen Dai, Jin Chen, Yi-hua Yu, Qiang-hong Xv, Guo-long Cai
Journal: Circulation (2011)

Objectives To investigate the prognostic values of the minute ventilation/carbon dioxide production slope (VE/VCO 2 ) and peak oxygen consumption (VO 2 ) for cardiovascular and all-cause mortality in diastolic heart failure. Background Recent studies have demonstrated that VE/VCO 2 was more powerfully predicted mortality, hospitalization, or both than VO 2 in systolic heart failure. Methods and Results The outpatients previously diagnosed as diastolic heart failure were recruited from April 2006 to March 2007, and underwent cardiopulmonary exercise testing and echocardiographic examination. Plasma BNP concentration was measured. Total of 224 patients were enrolled. During a mean follow-up of 30 months, 57 patients died (36 from cardiovascular death). Univariate Cox regression analysis showed that age, New York Heart Association function class, atrial fibrillation, diabetes mellitus, left ventricular diastolic dysfunction, peak VO 2 , VE/VCO 2 , and plasma BNP were significantly associated with mortality risk. Multivariate analysis revealed that plasma BNP, VE/VCO 2 , and age remained independent predictors for both cardiovascular and all-cause mortality, with the strongest prognostic values of plasma BNP (chi square =35.9 vs 39.8; P&lt;0.001). In addition to clinical risk factors and plasma BNP, The VE/VCO 2 could provided incremental and independently prognostic information of cardiovascular (chi square =60.6 vs 51.7; P=0.009) and all-cause mortality (chi square =62.8 vs 54.2; P=0.015) with increased chi square value of Cox regression model. Conclusion In patients with diastolic heart failure, plasma BNP is the strongest predictor of mortality risk, and VE/VCO 2 , but not peak VO 2 , provides addictive independent prognostic information, which suggests that combination of plasma BNP and VE/VCO 2 can improve risk stratification.
Abstract 13695: Prevalence of Mechanical Dyssynchrony in Hypertrophic Cardiomyopathy
Authors: Aurelio Pinheiro, Veronica Dimaano, Miguel Santaularia-Tomas, Lars Sorensen, Hsin-Yueh Liang, Sivajothi Kanagalingam, Blaid Mbiyangandu, Sourabh Verma, Roselle Abraham, Theodore Abraham
Journal: Circulation (2011)

BACKGROUND. Dyssynchrony has been extensively studied in LV systolic dysfunction, properly selecting patients for CRT. The present study has the objective to analyze the prevalence of dyssynchrony ...
Immunologic Studies in von Willebrand's Disease
Authors: Bruce Bennett, Oscar D. Ratnoff, Jack Levin
Journal: Journal of Clinical Investigation (1972)

Antihemophilic globulin (AHF, factor VIII) levels were measured by a standard coagulation assay and by an immunological technique before and serially after infusion of fresh frozen plasma or cryoprecipitate into patients with von Willebrand's disease. Initial levels of AHF, measured both as procoagulant and as antigen, were low. Immediately after transfusions, the rise in levels of AHF-like antigen was compatible with the quantity of antigen present in the infused plasma or cryoprecipitate. Thereafter, levels of antigen declined rapidly and reached preinfusion values in approximately 24 hr. In contrast, procoagulant activity remained elevated, and sometimes continued to rise, for longer periods of time. One possible explanation of this finding is that the AHF molecule produced by patients with von Willebrand's disease, in response to transfusion of as yet unidentified factors, lacks the antigenic site associated with the normal AHF molecule or the inactive molecule produced by patients with hemophilia A.