University of Duisburg-Essen

About: University of Duisburg-Essen is a education organization based out in Essen, Nordrhein-Westfalen, Germany. It is known for research contribution in the topics: Population & Transplantation. The organization has 16072 authors who have published 39972 publications receiving 1109199 citations.

Randomized, controlled trial of telcagepant for the acute treatment of migraine

Abstract: Connor et al.1 report that the use of 150 mg of telcagepant results in pain relief at 2 hours in 54% of patients with migraine compared to 33% of patients achieving this endpoint with placebo. Merck Research Laboratories funded this study and all the authors were employees of Merck or had financial ties to Merck or other large pharmaceutical companies. The publication of this trial raises serious concerns. Triptans are the standard care for moderate to severe migraine. Sumatriptan 50 mg, now available as a generic, results in pain relief at 2 hours in 50% to 59% of patients with migraine compared to 17% to 26% for placebo.2 The relevant question for patients and physicians is whether telcagepant offers any advantage over sumatriptan. The authors justify comparing telcagepant to placebo—rather than to active treatment— because it may be used in patients with coronary artery or cerebrovascular disease, in whom triptans are contraindicated. However, if this is the population of interest for telcagepant, it should be tested in this population. There are sufficient preliminary data supporting the superiority of telcagepant to placebo. A placebo-controlled trial in the population of patients eligible for triptan treatment before a trial in the clinically …

MIFlowCyt-EV: a framework for standardized reporting of extracellular vesicle flow cytometry experiments

Abstract: Extracellular vesicles (EVs) are small, heterogeneous and difficult to measure. Flow cytometry (FC) is a key technology for the measurement of individual particles, but its application to the analysis of EVs and other submicron particles has presented many challenges and has produced a number of controversial results, in part due to limitations of instrument detection, lack of robust methods and ambiguities in how data should be interpreted. These complications are exacerbated by the field's lack of a robust reporting framework, and many EV-FC manuscripts include incomplete descriptions of methods and results, contain artefacts stemming from an insufficient instrument sensitivity and inappropriate experimental design and lack appropriate calibration and standardization. To address these issues, a working group (WG) of EV-FC researchers from ISEV, ISAC and ISTH, worked together as an EV-FC WG and developed a consensus framework for the minimum information that should be provided regarding EV-FC. This framework incorporates the existing Minimum Information for Studies of EVs (MISEV) guidelines and Minimum Information about a FC experiment (MIFlowCyt) standard in an EV-FC-specific reporting framework (MIFlowCyt-EV) that supports reporting of critical information related to sample staining, EV detection and measurement and experimental design in manuscripts that report EV-FC data. MIFlowCyt-EV provides a structure for sharing EV-FC results, but it does not prescribe specific protocols, as there will continue to be rapid evolution of instruments and methods for the foreseeable future. MIFlowCyt-EV accommodates this evolution, while providing information needed to evaluate and compare different approaches. Because MIFlowCyt-EV will ensure consistency in the manner of reporting of EV-FC studies, over time we expect that adoption of MIFlowCyt-EV as a standard for reporting EV- FC studies will improve the ability to quantitatively compare results from different laboratories and to support the development of new instruments and assays for improved measurement of EVs.

Identification of new functional inhibitors of acid sphingomyelinase using a structure-property-activity relation model.

Abstract: Some organic weak bases induce a detachment from inner lysosomal membranes and subsequent inactivation of acid sphingomyelinase (ASM) and thus work as functional ASM inhibitors. The aim of the present investigation was to develop a structure−property−activity relation (SPAR) model in order to specify the structural and physicochemical characteristics of probes capable of functionally inhibiting ASM. High pKa and high log P values are necessary but not sufficient preconditions for functional inhibition of ASM. The experimental data supported the requirement of an additional factor, which is necessary for functional inhibition of ASM. This factor k is related to the steric hindrance of the most basic nitrogen atom and presumably modulates the free presentation of a protonated nitrogen atom at the inner lysosomal surface. During the course of the study, we characterized 26 new functional ASM inhibitors, including doxepine 63, fluoxetine 104, maprotiline 109, nortriptyline 114, paroxetine 118, sertraline 124,...

Endolysosomal sorting of ubiquitylated caveolin-1 is regulated by VCP and UBXD1 and impaired by VCP disease mutations

Abstract: VCP (also called p97) recognizes and interacts with ubiquitylated cargo molecules that are destined for proteasomal degradation. Meyer and colleagues show that VCP, together with its cofactor UBXD1, sorts ubiquitylated caveolin-1 to the endolysosome system. Mutations in VCP that are associated with human degenerative diseases lack this ability. The AAA-ATPase VCP (also known as p97) cooperates with distinct cofactors to process ubiquitylated proteins in different cellular pathways1,2,3. VCP missense mutations cause a systemic degenerative disease in humans, but the molecular pathogenesis is unclear4,5. We used an unbiased mass spectrometry approach and identified a VCP complex with the UBXD1 cofactor, which binds to the plasma membrane protein caveolin-1 (CAV1) and whose formation is specifically disrupted by disease-associated mutations. We show that VCP–UBXD1 targets mono-ubiquitylated CAV1 in SDS-resistant high-molecular-weight complexes on endosomes, which are en route to degradation in endolysosomes6. Expression of VCP mutant proteins, chemical inhibition of VCP, or siRNA-mediated depletion of UBXD1 leads to a block of CAV1 transport at the limiting membrane of enlarged endosomes in cultured cells. In patient muscle, muscle-specific caveolin-3 accumulates in sarcoplasmic pools and specifically delocalizes from the sarcolemma. These results extend the cellular functions of VCP to mediating sorting of ubiquitylated cargo in the endocytic pathway and indicate that impaired trafficking of caveolin may contribute to pathogenesis in individuals with VCP mutations.