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Leiden, Netherlands

Kraushaar U.,Multi Channel Systems | Meyer T.,Reutlingen University | Hess D.,Institute for Safety Technology GmbH | Gepstein L.,Technion - Israel Institute of Technology | And 3 more authors.
Expert Opinion on Drug Safety | Year: 2012

Introduction: The field of cardiac safety pharmacology has been experiencing exciting changes over the recent years. Drug induced arrhythmia of the torsade des pointes types has been the reason for the denial of approval of novel drug candidates. The aim of cardiac safety pharmacology is to detect undesirable pharmacodynamic drug effects within and above the therapeutic range. A special focus is on the identification of potential arrhythmogenic effects within the drug discovery chain. Areas covered: Here, the authors discuss the relevance of induced pluripotent stem (iPS) cell derived cardiomyocytes for safety pharmacology. The technology of obtaining functional cardiomyocytes from somatic cells of healthy donors and patients with inherited diseases is the basis for diverse disease models in multi-level safety pharmacology screening. The reader will gain an overview of stem cell based technologies in cardiac safety pharmacology in cardiac and disease modeling by iPS cell derived cardiomyocytes from patients with an inherited cardiac syndrome. Expert opinion: iPS cell derived cardiomyocytes especially from patients with increased risk of cardiac arrhythmia are on the verge of offering new options for drug testing. More reliable assays can be expected to predict the arrhythmogenic risk of drug candidates in humans. However, this technology is still new and extensive validation studies are due. © 2012 Informa UK, Ltd.


Grant
Agency: Cordis | Branch: H2020 | Program: ECSEL-IA | Phase: ECSEL-02-2014 | Award Amount: 48.05M | Year: 2015

The goal of the InForMed project is to establish an integrated pilot line for medical devices. The pilot line includes micro-fabrication, assembly and even the fabrication of smart catheters. The heart of this chain is the micro-fabrication and assembly facility of Philips Innovation Services, which will be qualified for small/medium-scale production of medical devices. The pilot facility will be open to other users for pilot production and product validation. It is the aim of the pilot line: to safeguard and consolidate Europes strong position in traditional medical diagnostic equipment, to enable emerging markets - especially in smart minimally invasive instruments and point-of-care diagnostic equipment - and to stimulate the development of entirely new markets, by providing an industrial micro-fabrication and assembly facility where new materials can be processed and assembled. The pilot line will be integrated in a complete innovation value chain from technology concept to high-volume production and system qualification. Protocols will be developed to ensure an efficient technology transfer between the different links in the value chain. Six challenging demonstrators products will be realized that address societal challenges in: Hospital and Heuristic Care and Home care and well-being, and demonstrate the trend towards Smart Health solutions.


Colak S.,Center for Experimental Molecular Medicine | Zimberlin C.D.,Center for Experimental Molecular Medicine | Fessler E.,Center for Experimental Molecular Medicine | Hogdal L.,Dana-Farber Cancer Institute | And 5 more authors.
Cell Death and Differentiation | Year: 2014

Tumor heterogeneity is in part determined by the existence of cancer stem cells (CSCs) and more differentiated tumor cells. CSCs are considered to be the tumorigenic root of cancers and suggested to be chemotherapy resistant. Here we exploited an assay that allowed us to measure chemotherapy-induced cell death in CSCs and differentiated tumor cells simultaneously. This confirmed that CSCs are selectively resistant to conventional chemotherapy, which we revealed is determined by decreased mitochondrial priming. In agreement, lowering the anti-apoptotic threshold using ABT-737 and WEHI-539 was sufficient to enhance chemotherapy efficacy, whereas ABT-199 failed to sensitize CSCs. Our data therefore point to a crucial role of BCLXL in protecting CSCs from chemotherapy and suggest that BH3 mimetics, in combination with chemotherapy, can be an efficient way to target chemotherapy-resistant CSCs. © 2014 Macmillan Publishers Limited All rights reserved.


Davis R.P.,Leiden University | Davis R.P.,Netherlands Proteomics Center | van den Berg C.W.,Leiden University | Casini S.,Leiden University | And 4 more authors.
Trends in Molecular Medicine | Year: 2011

Recent advances in pluripotent stem cell biology now make it possible to generate human cardiomyocytes in vitro from both healthy individuals and from patients with cardiac abnormalities. This offers unprecedented opportunities to study cardiac disease development 'in a dish' and establish novel platforms for drug discovery, either to prevent disease progression or to reverse it. In this review paper, we discuss some of the genetic diseases that affect the heart and illustrate how these new paradigms could assist our understanding of cardiac pathogenesis and aid in drug discovery. In particular, we highlight the limitations of other commonly used model systems in predicting the consequences of drug exposure on the human heart. © 2011 Elsevier Ltd.


Dambrot C.,Leiden University | Braam S.R.,Pluriomics | Tertoolen L.G.J.,Leiden University | Birket M.,Leiden University | And 2 more authors.
Journal of Cellular and Molecular Medicine | Year: 2014

It has been known for over 20 years that foetal calf serum can induce hypertrophy in cultured cardiomyocytes but this is rarely considered when examining cardiomyocytes derived from pluripotent stem cells (PSC). Here, we determined how serum affected cardiomyocytes from human embryonic- (hESC) and induced pluripotent stem cells (hiPSC) and hiPSC from patients with hypertrophic cardiomyopathy linked to a mutation in the MYBPC3 gene. We first confirmed previously published hypertrophic effects of serum on cultured neonatal rat cardiomyocytes demonstrated as increased cell surface area and beating frequency. We then found that serum increased the cell surface area of hESC- and hiPSC-derived cardiomyocytes and their spontaneous contraction rate. Phenylephrine, which normally induces cardiac hypertrophy, had no additional effects under serum conditions. Likewise, hiPSC-derived cardiomyocytes from three MYBPC3 patients which had a greater surface area than controls in the absence of serum as predicted by their genotype, did not show this difference in the presence of serum. Serum can thus alter the phenotype of human PSC derived cardiomyocytes under otherwise defined conditions such that the effects of hypertrophic drugs and gene mutations are underestimated. It is therefore pertinent to examine cardiac phenotypes in culture media without or in low concentrations of serum. © 2014 The Authors.

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