Stem cells are the most sensitive screening tool to identify toxicity of GATA4-targeted novel small-molecule compounds

Safety assessment of drug candidates in numerous in vitro and experimental animal models is expensive, time consuming and animal intensive. More thorough toxicity profiling already in the early drug discovery projects using human cell models, which more closely resemble the physiological cell types, would help to decrease drug development costs. In this study we aimed to compare different cardiac and stem cell models for in vitro toxicity testing and to elucidate structure-toxicity relationships of novel compounds targeting the cardiac transcription factor GATA4. By screening the effects of eight compounds at concentrations ranging from 10 nM up to 30 µM on the viability of eight different cell types, we identified significant cell type- and structure-dependent toxicity profiles. We further characterized two compounds in more detail using high-content analysis. The results highlight the importance of cell type selection for toxicity screening and indicate that stem cells represent the most sensitive screening model, which can detect toxicity that may otherwise remain unnoticed. Furthermore, our structure-toxicity analysis reveals a characteristic dihedral angle in the GATA4-targeted compounds that causes stem cell toxicity and thus helps to direct further drug development efforts towards non-toxic derivatives

Impact of CT-apelin and NT-proBNP on identifying non-responders to cardiac resynchronization therapy

CONTEXT: Assessment of response to cardiac resynchronization therapy (CRT) is essential. OBJECTIVE: To assess the predictive value of CT-apelin together with NT-proBNP in patients undergoing CRT. METHODS: Serum CT-apelin and NT-proBNP were measured by ELISA before, and 6-month after CRT. Primary endpoint was non-response (<4% increase in LVEF) after 6-month. RESULTS: From 81 patients, 15 proved to be non-responders. Six-month CT-apelin was superior compared to NT-proBNP in identifying non-responders by multivariate ROC (CT-apelin:p = 0.01, NT-proBNP:p = 0.13) and by logistic regression (CT-apelin:p = 0.01, NT-proBNP:p = 0.41) analyzes. CONCLUSION: Six-month CT-apelin might be valuable novel biomarker in identifying non-responders to CRT that was superior to NT-proBNP

Radical Right Populist Politics in Hungary: Reinventing the Magyars through Sport

Given the contemporary growth of ‘populist’ political parties and movements in a number of highly-developed democratic states in Europe and North America, there has been a resurgence in academic interest around the various causes for the groundswell of support for political populism. Given this broader political context, this paper explores the interconnection between sport and populist politics in Hungary, with a particular emphasis on the appropriation of sport by ‘right-wing’ populist political actors. In particular, this paper will examine the politics – sport interconnection by discussing Victor Orbán’s, Hungary’s Prime Minister, use of football, and sport more broadly, and the ways in which the Hungarian government have attempted to reinvent a strong nation and national identity through sport and related political populism. These attempts have been influenced by the interaction between forces of Westernisation and the country’s continuing post-communist transition, with the view to (re)inventing the Hungarian nation

Geographical and temporal distribution of SARS-CoV-2 clades in the WHO European Region, January to June 2020

We show the distribution of SARS-CoV-2 genetic clades over time and between countries and outline potential genomic surveillance objectives. We applied three available genomic nomenclature systems for SARS-CoV-2 to all sequence data from the WHO European Region available during the COVID-19 pandemic until 10 July 2020. We highlight the importance of real-time sequencing and data dissemination in a pandemic situation. We provide a comparison of the nomenclatures and lay a foundation for future European genomic surveillance of SARS-CoV-2.Peer reviewe