tbuckley/cabot-search huggingface dataset:
Targeting the prevention of plaque rupture as a new strategy for prevention of acute arterial cardiovascular events
Authors: M. Levi, E. Stroes
Journal: Cardiovascular Research (2008)

Acute arterial cardiovascular disease is usually caused by the sudden thrombotic occlusion of a vessel that is critical for maintaining adequate tissue perfusion and that contains an atherosclerotic plaque. Due to a myriad of processes within this plaque, rupture of its fibrous cap may occur, thereby exposing highly procoagulant material to the circulating blood, leading to occlusive thrombus formation and subsequent ischemia or infarction. In particular, inflammatory cells bearing tissue factor at their surface play a pivotal role in this mechanism, as tissue factor has been found to be the principal activator of the coagulation cascade, leading to the generation of thrombin and subsequent conversion of fibrinogen to fibrin. Hence, pharmacological strategies aimed at the prevention and treatment of acute cardiovascular disease thus far mainly focus on the reduction of atherosclerotic burden (e.g. by preventative strategies towards risk factors for atherosclerosis or by administration of statins) or on the inhibition of coagulation activation (e.g. by anticoagulants or anti-platelet agents). Besides these strategies, which have indeed been proven to be effective, stabilization of the atherosclerotic plaque could theoretically prevent plaque rupture and its … 

*Corresponding author. Tel: +31 20 5662171; fax: +31 20 6919658. E-mail address : m.m.levi{at}amc.uva.nl
Heart Failure, Saxagliptin, and Diabetes Mellitus: Observations from the SAVOR-TIMI 53 Randomized Trial
Authors: Benjamin M. Scirica, Eugene Braunwald, Itamar Raz, Matthew A. Cavender, David A. Morrow, Petr Jarolim, Jacob A. Udell, Ofri Mosenzon, KyungAh Im, Amarachi A. Umez-Eronini, Pia S. Pollack, Boaz Hirshberg, Robert Frederich, Basil S. Lewis, Darren K. McGuire, Jaime Davidson, Ph. Gabriel Steg, Deepak L. Bhatt
Journal: Circulation (2014)

Diabetes mellitus and heart failure frequently coexist. However, few diabetes mellitus trials have prospectively evaluated and adjudicated heart failure as an end point.A total of 16 492 patients with type 2 diabetes mellitus and a history of, or at risk of, cardiovascular events were randomized to saxagliptin or placebo (mean follow-up, 2.1 years). The primary end point was the composite of cardiovascular death, myocardial infarction, or ischemic stroke. Hospitalization for heart failure was a predefined component of the secondary end point. Baseline N-terminal pro B-type natriuretic peptide was measured in 12 301 patients. More patients treated with saxagliptin (289, 3.5%) were hospitalized for heart failure compared with placebo (228, 2.8%; hazard ratio, 1.27; 95% confidence intercal, 1.07-1.51; P=0.007). Corresponding rates at 12 months were 1.9% versus 1.3% (hazard ratio, 1.46; 95% confidence interval, 1.15-1.88; P=0.002), with no significant difference thereafter (time-varying interaction, P=0.017). Subjects at greatest risk of hospitalization for heart failure had previous heart failure, an estimated glomerular filtration rate ≤60 mL/min, or elevated baseline levels of N-terminal pro B-type natriuretic peptide. There was no evidence of heterogeneity between N-terminal pro B-type natriuretic peptide and saxagliptin (P for interaction=0.46), although the absolute risk excess for heart failure with saxagliptin was greatest in the highest N-terminal pro B-type natriuretic peptide quartile (2.1%). Even in patients at high risk of hospitalization for heart failure, the risk of the primary and secondary end points were similar between treatment groups.In the context of balanced primary and secondary end points, saxagliptin treatment was associated with an increased risk or hospitalization for heart failure. This increase in risk was highest among patients with elevated levels of natriuretic peptides, previous heart failure, or chronic kidney disease.http://www.clinicaltrials.gov. Unique identifier: NCT01107886.
Non-surgical management of uterine fibroids
Authors: G. Tropeano, S. Amoroso, G. Scambia
Journal: Human Reproduction Update (2008)

Efforts to develop alternatives to surgery for management of symptomatic uterine fibroids have provided new techniques and new medications. This review summarizes the existing literature on uterine artery embolization (UAE) and investigational studies on four newer approaches.PubMed, Cochrane and Embase were searched up to December 2007. Studies reporting side-effects and complications and presenting numerical data on at least one outcome measure were included.Case studies report 50-60% reduction in fibroid size and 85-95% relief of symptoms following UAE. The largest of these studies reported an in-hospital complication rate of 2.7% (90 of 3041 patients) and a post-discharge complication rate of 26% (710 of 2729 patients). Eight studies compared UAE with conventional surgery. Best evidence suggested that UAE offered shorter hospital stays (1-2 days UAE versus 5-5.8 days surgery, 3 randomized controlled trials (RCTs)) and recovery times (9.5-28 days UAE versus 36.2-63 days surgery, 3 RCTs) and similar major complication rates (2-15% UAE versus 2.7-20% surgery, 3 RCTs). Four studies analysing cost-effectiveness found UAE more cost-effective than surgery. There is insufficient evidence regarding fertility and pregnancy outcome after UAE. Five feasibility studies after transvaginal temporary uterine artery occlusion in 75 women showed a 40-50% reduction in fibroid volume and two early studies using magnetic resonance guided-focused ultrasound showed symptom relief at 6 months in 71% of 109 women. Two small RCTs assessing mifepristone and asoprisnil showed promising results.Good quality evidence supports the safety and effectiveness of UAE for women with symptomatic fibroids. The current available data are insufficient to routinely offer UAE to women who wish to preserve or enhance their fertility. Newer treatments are still investigational.
Human and Mouse <i>VEGFA</i>-Amplified Hepatocellular Carcinomas Are Highly Sensitive to Sorafenib Treatment
Authors: Elad Horwitz, Ilan Stein, Mariacarla Andreozzi, Julia Nemeth, Avivit Shoham, Orit Pappo, Nora Schweitzer, Luigi Tornillo, Naama Kanarek, Luca Quagliata, Farid Zreik, Rinnat M. Porat, Rutie Finkelstein, Hendrik Reuter, Ronald Koschny, Tom Ganten, Carolin Mogler, Oren Shibolet, Jochen Hess, Kai Breuhahn, Myriam Grunewald, Peter Schirmacher, Arndt Vogel, Luigi Terracciano, Peter Angel, Yinon Ben-Neriah, Eli Pikarsky
Journal: Cancer Discovery (2014)

Death rates from hepatocellular carcinoma (HCC) are steadily increasing, yet therapeutic options for advanced HCC are limited. We identify a subset of mouse and human HCCs harboring VEGFA genomic amplification, displaying distinct biologic characteristics. Unlike common tumor amplifications, this one seems to work via heterotypic paracrine interactions; stromal VEGF receptors (VEGFR), responding to tumor VEGF-A, produce hepatocyte growth factor (HGF) that reciprocally affects tumor cells. VEGF-A inhibition results in HGF downregulation and reduced proliferation, specifically in amplicon-positive mouse HCCs. Sorafenib-the first-line drug in advanced HCC-targets multiple kinases, including VEGFRs, but has only an overall mild beneficial effect. We found that VEGFA amplification specifies mouse and human HCCs that are distinctly sensitive to sorafenib. FISH analysis of a retrospective patient cohort showed markedly improved survival of sorafenib-treated patients with VEGFA-amplified HCCs, suggesting that VEGFA amplification is a potential biomarker for HCC response to VEGF-A-blocking drugs.Using a mouse model of inflammation-driven cancer, we identified a subclass of HCC carrying VEGFA amplification, which is particularly sensitive to VEGF-A inhibition. We found that a similar amplification in human HCC identifies patients who favorably responded to sorafenib-the first-line treatment of advanced HCC-which has an overall moderate therapeutic efficacy.
PET-adapted sequential salvage therapy with brentuximab vedotin followed by augmented ifosamide, carboplatin, and etoposide for patients with relapsed and refractory Hodgkin's lymphoma: a non-randomised, open-label, single-centre, phase 2 study
Authors: Alison J Moskowitz, Heiko Schöder, Joachim Yahalom, Susan J McCall, Stephanie Y Fox, John Gerecitano, Ravinder Grewal, Paul A Hamlin, Steven Horwitz, Rachel Kobos, Anita Kumar, Matthew Matasar, Ariela Noy, M Lia Palomba, Miguel-Angel Perales, Carol S Portlock, Craig Sauter, Neerav Shukla, Peter Steinherz, David Straus, Tanya Trippett, Anas Younes, Andrew Zelenetz, Craig H Moskowitz
Journal: The Lancet Oncology (2015)
Molecular Analysis of Non–Small Cell Lung Cancer Identifies Subsets with Different Sensitivity to Insulin-like Growth Factor I Receptor Inhibition
Authors: Antonio Gualberto, Marisa Dolled-Filhart, Mark Gustavson, Jason Christiansen, Yu-Fen Wang, Mary L. Hixon, Jennifer Reynolds, Sandra McDonald, Agnes Ang, David L. Rimm, Corey J. Langer, Johnetta Blakely, Linda Garland, Luis G. Paz-Ares, Daniel D. Karp, Adrian V. Lee
Journal: Clinical Cancer Research (2010)

Abstract Purpose: This study aimed to identify molecular determinants of sensitivity of non–small cell lung cancer (NSCLC) to anti–insulin-like growth factor receptor (IGF-IR) therapy. Experimental Design: A total of 216 tumor samples were investigated, of which 165 consisted of retrospective analyses of banked tissue and an additional 51 were from patients enrolled in a phase II study of figitumumab, a monoclonal antibody against IGF-IR, in stage IIIb/IV NSCLC. Biomarkers assessed included IGF-IR, epidermal growth factor receptor, IGF-II, IGF-IIR, insulin receptor substrate 1 (IRS-1), IRS-2, vimentin, and E-cadherin. Subcellular localization of IRS-1 and phosphorylation levels of mitogen-activated protein kinase and Akt1 were also analyzed. Results: IGF-IR was differentially expressed across histologic subtypes (P = 0.04), with highest levels observed in squamous cell tumors. Elevated IGF-IR expression was also observed in a small number of squamous cell tumors responding to chemotherapy combined with figitumumab (P = 0.008). Because no other biomarker/response interaction was observed using classical histologic subtyping, a molecular approach was undertaken to segment NSCLC into mechanism-based subpopulations. Principal component analysis and unsupervised Bayesian clustering identified three NSCLC subsets that resembled the steps of the epithelial to mesenchymal transition: E-cadherin high/IRS-1 low (epithelial-like), E-cadherin intermediate/IRS-1 high (transitional), and E-cadherin low/IRS-1 low (mesenchymal-like). Several markers of the IGF-IR pathway were overexpressed in the transitional subset. Furthermore, a higher response rate to the combination of chemotherapy and figitumumab was observed in transitional tumors (71%) compared with those in the mesenchymal-like subset (32%; P = 0.03). Only one epithelial-like tumor was identified in the phase II study, suggesting that advanced NSCLC has undergone significant dedifferentiation at diagnosis. Conclusion: NSCLC comprises molecular subsets with differential sensitivity to IGF-IR inhibition. Clin Cancer Res; 16(18); 4654–65. ©2010 AACR.
Increased surface tension favors pulmonary edema formation in anesthetized dogs' lungs.
Authors: R K Albert, S Lakshminarayan, J Hildebrandt, W Kirk, J Butler
Journal: Journal of Clinical Investigation (1979)

The possibility that surface tension may affect the hydrostatic transmural pressure of pulmonary vessels and the development of pulmonary edema was studied in anesthetized, open-chested dogs. Isogravimetric pressure (the static intravascular pressure at which transmural osmotic and hydrostatic pressures are balanced such that net fluid flux is zero and lung weight is constant) was measured in nine animals under three conditions: (a) control, normal surface tension, at an alveolar pressure of 30 cm H2O with the apenic lung at room temperature; (b) after increasing surface tension by cooling and ventilating at a low functional residual capacity, at an alveolar pressure sufficient to produce the same lung volume present during control measurements; and (c) after restoring surface tension by rewarming while holding the lung at a high inflation volume, again at the control lung volume. Lung volumes were established from external dimensions and confirmed +/- 10% by deflation spirometry. The isogravimetric pressure (relative to alveolar pressure) was significantly less with increased surface tension than during either the initial control condition (P less than 0.01), or when the surface tension has been restored (P less than 0.01). Similar changes occurred in each of three additional studies performed with control alveolar pressures of 10 cm H2O. Thus, increased surface tension favors fluid leakage presumably because it increases the microvascular transmural pressure.
Effect of Massachusetts healthcare reform on racial and ethnic disparities in admissions to hospital for ambulatory care sensitive conditions: retrospective analysis of hospital episode statistics
Authors: D. McCormick, A. D. Hanchate, K. E. Lasser, M. G. Manze, M. Lin, C. Chu, N. R. Kressin
Journal: BMJ (2015)

<b>Objectives</b> To examine the impact of Massachusetts healthcare reform on changes in rates of admission to hospital for ambulatory care sensitive conditions (ACSCs), which are potentially preventable with good access to outpatient medical care, and racial and ethnic disparities in such rates, using complete inpatient discharge data (hospital episode statistics) from Massachusetts and three control states. <b>Design</b> Difference in differences analysis to identify the change, overall and according to race/ethnicity, adjusted for secular changes unrelated to reform. <b>Setting</b> Hospitals in Massachusetts, New York, New Jersey, and Pennsylvania, United States. <b>Participants</b> Adults aged 18-64 (those most likely to have been affected by the reform) admitted for any of 12 ACSCs in the 21 months before and after the period during which reform was implemented (July 2006 to December 2007). <b>Main outcome measures</b> Admission rates for a composite of all 12 ACSCs, and subgroup composites of acute and chronic ACSCs. <b>Results</b> After adjustment for potential confounders, including age, race and ethnicity, sex, and county income, unemployment rate and physician supply, we found no evidence of a change in the admission rate for overall composite ACSC (1.2%, 95% confidence interval −1.6% to 4.1%) or for subgroup composites of acute and chronic ACSCs. Nor did we find a change in disparities in admission rates between black and white people (−1.9%, −8.5% to 5.1%) or white and Hispanic people (2.0%, −7.5% to 12.4%) for overall composite ACSC that existed in Massachusetts before reform. In analyses limited to Massachusetts only, we found no evidence of a change in admission rate for overall composite ACSC between counties with higher and lower rates of uninsurance at baseline (1.4%, −2.3% to 5.3%). <b>Conclusions</b> Massachusetts reform was not associated with significantly lower overall or racial and ethnic disparities in rates of admission to hospital for ACSCs. In the US, and Massachusetts in particular, additional efforts might be needed to improve access to outpatient care and reduce preventable admissions.
Cardiovascular medication use in patients with undiagnosed obstructive sleep apnoea
Authors: K Otake
Journal: Thorax (2002)

Background: A study was undertaken in patients with undiagnosed sleep apnoea/hypopnoea syndrome (OSAS) to document the use of prescribed medications, especially those used in cardiovascular diseases, in the year before the OSAS diagnosis was confirmed. Methods: A total of 549 patients with OSAS (401 men of mean age 47.2 years, mean body mass index (BMI) 35.5 kg/m<sup>2</sup>, mean apnoea/hypopnoea index (AHI) 47.2 and148 women of mean age 50.2 years, BMI 39.6 kg/m<sup>2</sup>, AHI 32.6) were each matched to one general population control by age, sex, geographical location, and family physician. Medication use was evaluated for patients and controls using a database containing information about all prescriptions completed in the province of Manitoba, Canada. Results: In the year before OSAS was diagnosed, prescribed medication costs were $155.91 (Can) (95 % CI $91.34 to $220.49) greater for cases than for controls. Cases were dispensed 3.3 (95% CI 1.5 to 5.2) more prescriptions, were on 1.2 (95% CI 0.8 to 1.6) more medications, and were supplied with 157.4 (95% CI 95.9 to 218.8) more daily doses of medication. The odds ratio of OSAS cases being on a prescribed medication was 1.88 relative to controls (95% CI 1.38 to 2.54, p&lt;0.0001). In the same year 36.6% of cases and 19.7% of controls were using medications for cardiovascular disease (OR 2.82, 95% CI 2.05 to 3.89, p&lt;0.0001), consuming 79.4 (95% CI 48.9 to 109.8) more daily doses of medication, having been dispensed 1.7 (95% CI 1.0 to 2.4) more prescriptions, and at a $75.26 (95% CI $44.03 to $106.50) greater cost. The odds ratio of patients with OSAS being on medications indicated for the treatment of systemic hypertension was 2.71 (95% CI 1.96 to 3.77) relative to controls; however, such medications might also be prescribed for other indications such as angina pectoris and congestive heart failure, and for the secondary prevention of myocardial infarction. The use of medications indicated for the treatment of systemic hypertension was predicted significantly by age (odds ratio (OR) 1.10 per year), BMI (OR 1.05 per unit), and AHI (OR 1.01 per unit). Conclusions: In the year before OSAS was diagnosed, patients with OSAS were heavy users of medications, particularly those used to treat cardiovascular diseases.
Mast cells and fibroblasts work in concert to aggravate pulmonary fibrosis: Role of transmembrane SCF and PAR-2/PKCα/Raf-1/p44/42 signaling pathway
Authors: Malgorzata Wygrecka, Bhola D. Dahal, Djuro Kosanovic, Frank Petersen, Brigitte Taborski, Susanne von Gerlach, Miroslava Didiasova, Dariusz Zakrzewicz, Klaus T. Preissner, Ralph T. Schermuly, Philipp Markart
Journal: European Respiratory Journal (2013)

Mast cell (MC) accumulation has been demonstrated in the lungs of idiopathic pulmonary fibrosis (IPF) patients. Mediators released from MC may regulate tissue remodelling processes thereby, contributing to IPF pathogenesis. Here, we investigated the role of MC-fibroblast interaction for the progression of lung fibrosis. Increased number of activated MC, located in close proximity to fibroblast foci and alveolar type II cells, was observed in IPF lungs. Correspondingly, elevated tryptase levels were detected in IPF lung tissue samples. Co-culture of human lung MC with human lung fibroblasts (HLF) induced MC activation as evidenced by tryptase release, and stimulated HLF proliferation with IPF fibroblasts exhibiting a significantly higher growth rate compared to control fibroblasts. Tryptase stimulated HLF growth in a PAR-2/PKCα/Raf-1/p44/42 dependent manner and potentiated ECM production, however, independently of PKCα, Raf-1, and p44/42 activities. Proproliferative properties of tryptase were attenuated by knockdown or pharmacological inhibition of PAR-2, PKCα, Raf-1, or p44/42. Expression of transmembrane, but not soluble, SCF was elevated in IPF lung tissue and fibroblasts isolated from IPF lungs. Co-culture of IPF lung fibroblasts with MC enhanced MC survival and proliferation. These effects were cell contact dependent and could be inhibited by application of anti-SCF antibody or CD117 inhibitor. Collectively, fibroblasts and MC appear to work in concert to perpetuate fibrotic processes and thus contribute to lung fibrosis progression.
Functional Activity of the OCT-1 Protein Is Predictive of Long-Term Outcome in Patients With Chronic-Phase Chronic Myeloid Leukemia Treated With Imatinib
Authors: Deborah L. White, Phuong Dang, Jane Engler, Amity Frede, Stephanie Zrim, Michael Osborn, Verity A. Saunders, Paul W. Manley, Timothy P. Hughes
Journal: Journal of Clinical Oncology (2010)

Organic cation transporter-1 (OCT-1) activity (OA), a measure of the OCT-1-mediated influx of imatinib into CML mononuclear cells (MNCs), is predictive of major molecular response (MMR) at 12 and 24 months in patients with untreated CML. We now report the impact of OA on loss of response, disease transformation, and survival after 5 years of imatinib.OA is defined as the difference in intracellular concentration of carbon-14-imatinib with and without OCT-1 inhibition. OA was measured in blood from 56 patients with untreated chronic-phase CML.More patients who had high OA (ie, > median OA value) achieved MMR by 60 months compared with patients who had low OA (89% v 55%; P = .007). A low OA was associated with a significantly lower overall survival (87% v 96%; P = .028) and event-free survival (EFS; 48% v 74%; P = .03) as well as a higher kinase domain mutation rate (21% v 4%; P = .047). These differences were highly significant in patients who averaged less than 600 mg/d of imatinib in the first 12 months but were not significant in patients averaging >/= 600 mg/d. Patients with very low OA (ie, quartile 1) were the only group who developed leukemic transformation (21% in quartile 1 v 0% in all other quartiles; P = .002).Measurement of OA pretherapy is a predictor for the long-term risk of resistance and transformation in patients with imatinib-treated CML. Early dose-intensity may reduce the negative prognostic impact of low OA. We propose that OA could be used to individualize dosage strategies for patients with CML to maximize molecular response and optimize long-term outcome.
Biomimetic Materials: Peptide‐Directed Spatial Organization of Biomolecules in Dynamic Gradient Scaffolds (Adv. Healthcare Mater. 9/2014)
Authors: Lesley W. Chow, Astrid Armgarth, Jean‐Philippe St‐Pierre, Sergio Bertazzo, Cristina Gentilini, Claudia Aurisicchio, Seth D. McCullen, Joseph A. M. Steele, Molly M. Stevens
Journal: Advanced Healthcare Materials (2014)

Peptide-polymer conjugates that specifically and dynamically bind glycosaminoglycans are used to functionalize the surface of biodegradable electrospun fiber scaffolds. The versatile platform presented by L. W. Chow, M. M. Stevens, and colleagues on page 1381 can be used to recreate gradients of ECM-like biomolecule organization within scaffolds to achieve more functional and clinically relevant tissue-engineered constructs.