University of Münster

About: University of Münster is a education organization based out in Münster, Germany. It is known for research contribution in the topics: Population & Catalysis. The organization has 35609 authors who have published 69059 publications receiving 2278534 citations. The organization is also known as: University of Munster & University of Muenster.

Heparanase, Hyaluronan, and CD44 in Cancers: A Breast Carcinoma Perspective

Abstract: Glycosaminoglycans are major constituents of the cancer cell surface and the tumor stroma. The heparan sulfate degrading enzyme heparanase, hyaluronan, and its receptor CD44 are up-regulated in breast cancer, generating a microenvironment that promotes tumor progression and metastasis. Recent experimental and clinical evidence shows that heparanase, hyaluronan, and CD44 regulate cancer cell proliferation, migration, and invasion, as well as tumor-associated angiogenesis and are correlated with patient survival. These findings suggest that they may be used as prognostic factors and targets for breast cancer treatment.

Effect of fish oil on ventricular tachyarrhythmia and death in patients with implantable cardioverter defibrillators: The Study on Omega-3 Fatty acids and ventricular Arrhythmia (SOFA) randomized trial

Abstract: ContextVery-long-chain n-3 polyunsaturated fatty acids (omega-3 PUFAs) from fish are thought to reduce risk of sudden death, possibly by reducing susceptibility to cardiac arrhythmia.ObjectiveTo study the effect of supplemental fish oil vs placebo on ventricular tachyarrhythmia or death.Design, Setting, and PatientsThe Study on Omega-3 Fatty acids and ventricular Arrhythmia (SOFA) was a randomized, parallel, placebo-controlled, double-blind trial conducted at 26 cardiology clinics across Europe. A total of 546 patients with implantable cardioverter-defibrillators (ICDs) and prior documented malignant ventricular tachycardia (VT) or ventricular fibrillation (VF) were enrolled between October 2001 and August 2004. Patients were randomly assigned to receive 2 g/d of fish oil (n = 273) or placebo (n = 273) for a median period of 356 days (range, 14-379 days).Main Outcome MeasureAppropriate ICD intervention for VT or VF, or all-cause death.ResultsThe primary end point occurred in 81 (30%) patients taking fish oil vs 90 (33%) patients taking placebo (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.64-1.16; P = .33). In prespecified subgroup analyses, the HR was 0.91 (95% CI, 0.66-1.26) for fish oil vs placebo in the 411 patients who had experienced VT in the year before the study, and 0.76 (95% CI, 0.52-1.11) for 332 patients with prior myocardial infarctions.ConclusionOur findings do not indicate evidence of a strong protective effect of intake of omega-3 PUFAs from fish oil against ventricular arrhythmia in patients with ICDs.Trial Registrationclinicaltrials.gov Identifier: NCT00110838

VE‐PTP and VE‐cadherin ectodomains interact to facilitate regulation of phosphorylation and cell contacts

Abstract: VE-cadherin is the essential adhesion molecule in endothelial adherens junctions, and the regulation of protein tyrosine phosphorylation is thought to be important for the control of adherens junction integrity. We show here that VE-PTP (vascular endothelial protein tyrosine phosphatase), an endothelial receptor-type phosphatase, co-precipitates with VE-cadherin, but not with beta-catenin, from cell lysates of transfected COS-7 cells and of endothelial cells. Co-precipitation of VE-cadherin and VE-PTP required the most membrane-proximal extracellular domains of each protein. Expression of VE-PTP in triple-transfected COS-7 cells and in CHO cells reversed the tyrosine phosphorylation of VE-cadherin elicited by vascular endothelial growth factor receptor 2 (VEGFR-2). Expression of VE-PTP under an inducible promotor in CHO cells transfected with VE-cadherin and VEGFR-2 increased the VE-cadherin-mediated barrier integrity of a cellular monolayer. Surprisingly, a catalytically inactive mutant form of VE-PTP had the same effect on VE-cadherin phosphorylation and cell layer permeability. Thus, VE-PTP is a transmembrane binding partner of VE-cadherin that associates through an extracellular domain and reduces the tyrosine phosphorylation of VE-cadherin and cell layer permeability independently of its enzymatic activity.

An Innovative Phase I Clinical Study Demonstrates Inhibition of FLT3 Phosphorylation by SU11248 in Acute Myeloid Leukemia Patients

Abstract: Purpose: Obtaining direct and rapid proof of molecular activity in early clinical trials is critical for optimal clinical development of novel targeted therapies. SU11248 is an oral multitargeted kinase inhibitor with selectivity for fms-related tyrosine kinase 3/Flk2 (FLT3), platelet-derived growth factor receptor α/β, vascular endothelial growth factor receptor 1/2, and KIT receptor tyrosine kinases. FLT3 is a promising candidate for targeted therapy in acute myeloid leukemia (AML), because activating mutations occur in up to 30% of patients. We conducted an innovative single-dose clinical study with a primary objective to demonstrate inhibition of FLT3 phosphorylation by SU11248 in AML. Experimental Design: Twenty-nine AML patients each received a single dose of SU11248, escalated from 50 to 350 mg, in increments of 50 mg and cohorts of three to six patients. FLT3 phosphorylation and plasma pharmacokinetics were evaluated at seven time points over 48 h after SU11248 administration, and FLT3 genotype was determined. Study drug-related adverse events occurred in 31% of patients, mainly grade 1 or 2 diarrhea and nausea, at higher dose levels. Results: Inhibition of FLT3 phosphorylation was apparent in 50% of FLT3–wild-type (WT) patients and in 100% of FLT3-mutant patients. FLT3 internal tandem duplication (ITD) mutants showed increased sensitivity relative to FLT3-WT, consistent with preclinical predictions. The primary end point, strong inhibition of FLT3 phosphorylation in >50% patients, was reached in 200 mg and higher dose cohorts. Downstream signaling pathways were also inhibited; signal transducer and activator of transcription 5 (STAT5) was reduced primarily in internal tandem duplication patients and at late time points in FLT3-WT patients, whereas extracellular signal-regulated kinase (ERK) activity was reduced in the majority of patients, independent of FLT3 inhibition. Conclusions: This novel translational study bridges preclinical models to the patient setting and provides the first evidence of anti-FLT3 activity in patients. Proof of target inhibition accomplishes a crucial milestone in the development of novel oncology therapeutics.

The Vibronic Structure of Electronic Absorption Spectra of Large Molecules: A Time-Dependent Density Functional Study on the Influence of “Exact” Hartree−Fock Exchange

Abstract: The functional dependence of excited-state geometries and normal modes calculated with time-dependent density functional theory (TDDFT) is investigated on the basis of vibronic structure calculations of the absorption spectra of large molecules. For a set of molecules covering a wide range of different structures including organic dyes, biological chromophores, and molecules of importance in material science, quantum mechanical simulations of the vibronic structure are performed. In total over 40 singlet−singlet transitions of neutral closed-shell compounds and doublet−doublet transitions of neutral radicals, radical cations, and anions are considered. Calculations with different standard density functionals show that the predicted vibronic structure critically depends on the fraction of the “exact” Hartree−Fock exchange (EEX) included in hybrid functionals. The effect can been traced back to a large influence of EEX on the geometrical displacement upon excitation. On the contrary, the dependence of the r...