The 'service turn' in a new public management context: a street-level bureaucrat perspective
In: Public management review, S. 1-25
ISSN: 1471-9045
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In: Public management review, S. 1-25
ISSN: 1471-9045
In: Ecotoxicology and environmental safety: EES ; official journal of the International Society of Ecotoxicology and Environmental safety, Band 30, Heft 2, S. 164-170
ISSN: 1090-2414
In: Progress in nuclear energy: the international review journal covering all aspects of nuclear energy, Band 43, Heft 1-4, S. 57-66
ISSN: 0149-1970
In: Progress in nuclear energy: the international review journal covering all aspects of nuclear energy, Band 43, Heft 1-4, S. 35-41
ISSN: 0149-1970
Abstract CYP enzyme induction is a sensitive biomarker for phenotypic metabolic competence of in vitro test systems; it is a key event associated with thyroid disruption, and a biomarker for toxicologically relevant nuclear receptor-mediated pathways. This paper summarises the results of a multi-laboratory validation study of two in vitro methods that assess the potential of chemicals to induce cytochrome P450 (CYP) enzyme activity, in particular CYP1A2, CYP2B6, and CYP3A4. The methods are based on the use of cryopreserved primary human hepatocytes (PHH) and human HepaRG cells. The validation study was coordinated by the European Union Reference Laboratory for Alternatives to Animal Testing of the European Commission's Joint Research Centre and involved a ring trial among six laboratories. The reproducibility was assessed within and between laboratories using a validation set of 13 selected chemicals (known human inducers and non-inducers) tested under blind conditions. The ability of the two methods to predict human CYP induction potential was assessed. Chemical space analysis confirmed that the selected chemicals are broadly representative of a diverse range of chemicals. The two methods were found to be reliable and relevant in vitro tools for the assessment of human CYP induction, with the HepaRG method being better suited for routine testing. Recommendations for the practical application of the two methods are proposed.
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The recent advent of microphysiological systems – microfluidic biomimetic devices that aspire to emulate the biology of human tissues, organs and circulation in vitro – promises to enable a global paradigm shift in drug development. An extraordinary US government initiative and various dedicated research programs in Europe and Asia recently have led to the first cutting-edge achievements of human single-organ and multi-organ engineering based on microphysiological systems. The expectation is that test systems established on this basis will model various disease stages and predict toxicity, immunogenicity, ADME profiles and treatment efficacy prior to clinical testing. Consequently, this technology could significantly affect the way drug substances are developed in the future. Furthermore, microphysiological system-based assays may revolutionize our current global programs of prioritization of hazard characterization for any new substances to be used, for example, in agriculture, food, ecosystems or cosmetics, thus replacing the use of laboratory animal models. Here, thirty-six experts from academia, industry and regulatory bodies present the results of an intensive workshop (held in June 2015, Berlin, Germany). They review the status quo of microphysiological systems available today against industry needs, and assess the broad variety of approaches with fit-for-purpose potential in the drug development cycle. Feasible technical solutions to reach the next levels of human biology in vitro are proposed. Furthermore, key organ-on-a-chip case studies as well as various national and international programs are highlighted. Finally, a roadmap into the future towards more predictive and regulatory-accepted substance testing on a global scale is outlined.
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A search for dark matter linelike signals iss performed in the vicinity of the Galactic Center by the H.E.S.S. experiment on observational data taken in 2014. An unbinned likelihood analysis iss developed to improve the sensitivity to linelike signals. The upgraded analysis along with newer data extend the energy coverage of the previous measurement down to 100 GeV. The 18 h of data collected with the H.E.S.S. array allow one to rule out at 95% C.L. the presence of a 130 GeV line (at l=-1.5°, b=0° and for a dark matter profile centered at this location) previously reported in Fermi-LAT data. This new analysis overlaps significantly in energy with previous Fermi-LAT and H.E.S.S. RESULTS: No significant excess associated with dark matter annihilations was found in the energy range of 100 GeV to 2 TeV and upper limits on the gamma-ray flux and the velocity weighted annihilation cross section are derived adopting an Einasto dark matter halo profile. Expected limits for present and future large statistics H.E.S.S. observations are also given. ; The support of the Namibian authorities and of the University of Namibia in facilitating the construction and operation of H.E.S.S. is gratefully acknowledged, as is the support by the German Ministry for Education and Research (BMBF), the Max Planck Society, the German Research Foundation (DFG), the French Ministry for Research, the Centre National de la Recherche Scientifique-Institut National de Physique Nucléaire et de Physique des Particules and the Astroparticle Interdisciplinary Programme of the Centre National de la Recherche Scientifique, the United Kingdom Science and Technology Facilities Council (STFC), the Institute of Particle and Nuclear Physics of the Charles University, the Czech Science Foundation, the Polish Ministry of Science and Higher Education, the South African Department of Science and Technology and National Research Foundation, and the University of Namibia. We appreciate the excellent work of the technical support staff in Berlin, Durham, Hamburg, Heidelberg, Palaiseau, Paris, Saclay, and Namibia in the construction and operation of the equipment. R. C. G. Chaves Funded by European Union Seventh Framework Programme Marie Curie, Grant Agreement No. PIEF-GA-2012-332350. ; Peer-reviewed ; Publisher Version
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