ASAM : Automatic Architecture Synthesis and Application Mapping; dl. 2.2: Report on initial version of the hierarchical application model

No abstract

The Rise of Three Rs Centres and Platforms in Europe*

Public awareness and discussion about animal experiments and replacement methods has greatly increased in recent years. The term 'the Three Rs', which stands for the Replacement, Reduction and Refinement of animal experiments, is inseparably linked in this context. A common goal within the Three Rs scientific community is to develop predictive non-animal models and to better integrate all available data from in vitro, in silico and omics technologies into regulatory decision-making processes regarding, for example, the toxicity of chemicals, drugs or food ingredients. In addition, it is a general concern to implement (human) non-animal methods in basic research. Toward these efforts, there has been an ever-increasing number of Three Rs centres and platforms established over recent years - not only to develop novel methods, but also to disseminate knowledge and help to implement the Three Rs principles in policies and education. The adoption of Directive 2010/63/EU on the protection of animals used for scientific purposes gave a strong impetus to the creation of Three Rs initiatives, in the form of centres and platforms. As the first of a series of papers, this article gives an overview of the European Three Rs centres and platforms, and their historical development. The subsequent articles, to be published over the course of ATLA's 50th Anniversary year, will summarise the current focus and tasks as well as the future and the plans of the Three Rs centres and platforms. The Three Rs centres and platforms are very important points of contact and play an immense role in their respective countries as 'on the ground' facilitators of Directive 2010/63/EU. They are also invaluable for the widespread dissemination of information and for promoting implementation of the Three Rs in general

The Current Status and Work of Three Rs Centres and Platforms in Europe*

The adoption of Directive 2010/63/EU on the protection of animals used for scientific purposes has given a major push to the formation of Three Rs initiatives in the form of centres and platforms. These centres and platforms are dedicated to the so-called Three Rs, which are the Replacement, Reduction and Refinement of animal use in experiments. ATLA's 50th Anniversary year has seen the publication of two articles on European Three Rs centres and platforms. The first of these was about the progressive rise in their numbers and about their founding history; this second part focuses on their current status and activities. This article takes a closer look at their financial and organisational structures, describes their Three Rs focus and core activities (dissemination, education, implementation, scientific quality/translatability, ethics), and presents their areas of responsibility and projects in detail. This overview of the work and diverse structures of the Three Rs centres and platforms is not only intended to bring them closer to the reader, but also to provide role models and show examples of how such Three Rs centres and platforms could be made sustainable. The Three Rs centres and platforms are very important focal points and play an immense role as facilitators of Directive 2010/63/EU 'on the ground' in their respective countries. They are also invaluable for the wide dissemination of information and for promoting the implementation of the Three Rs in general

Adaptation to acetaminophen exposure elicits major changes in expression and distribution of the hepatic proteome.

Acetaminophen overdose is the leading cause of acute liver failure. One dose of 10-15 g causes severe liver damage in humans, whereas repeated exposure to acetaminophen in humans and animal models results in autoprotection. Insight of this process is limited to select proteins implicated in acetaminophen toxicity and cellular defence. Here we investigate hepatic adaptation to acetaminophen toxicity from a whole proteome perspective, using quantitative mass spectrometry. In a rat model, we show the response to acetaminophen involves the expression of 30% of all proteins detected in the liver. Genetic ablation of a master regulator of cellular defence, NFE2L2, has little effect, suggesting redundancy in the regulation of adaptation. We show that adaptation to acetaminophen has a spatial component, involving a shift in regionalisation of CYP2E1, which may prevent toxicity thresholds being reached. These data reveal unexpected complexity and dynamic behaviour in the biological response to drug-induced liver injury

Effect of Chemical Mutagens and Carcinogens on Gene Expression Profiles in Human TK6 Cells

Characterization of toxicogenomic signatures of carcinogen exposure holds significant promise for mechanistic and predictive toxicology. In vitro transcriptomic studies allow the comparison of the response to chemicals with diverse mode of actions under controlled experimental conditions. We conducted an in vitro study in TK6 cells to characterize gene expression signatures of exposure to 15 genotoxic carcinogens frequently used in European industries. We also examined the dose-responsive changes in gene expression, and perturbation of biochemical pathways in response to these carcinogens. TK6 cells were exposed at 3 dose levels for 24 h with and without S9 human metabolic mix. Since S9 had an impact on gene expression (885 genes), we analyzed the gene expression data from cells cultures incubated with S9 and without S9 independently. The ribosome pathway was affected by all chemical-dose combinations. However in general, no similar gene expression was observed among carcinogens. Further, pathways, i.e. cell cycle, DNA repair mechanisms, RNA degradation, that were common within sets of chemical-dose combination were suggested by clustergram. Linear trends in dose–response of gene expression were observed for Trichloroethylene, Benz[a]anthracene, Epichlorohydrin, Benzene, and Hydroquinone. The significantly altered genes were involved in the regulation of (anti-) apoptosis, maintenance of cell survival, tumor necrosis factor-related pathways and immune response, in agreement with several other studies. Similarly in S9+ cultures, Benz[a]pyrene, Styrene and Trichloroethylene each modified over 1000 genes at high concentrations. Our findings expand our understanding of the transcriptomic response to genotoxic carcinogens, revealing the alteration of diverse sets of genes and pathways involved in cellular homeostasis and cell cycle control

Using crisis theory to explain the quality of life of organ transplant patients

To evaluate the literature on the stress, coping, and quality of life of organ transplant candidates and recipients, and to place previous research within a theoretical context. CINAHL database, Proquest database, Google Scholar; references from articles were also reviewed to identify additional data. Qualitative and quantitative research studies and meta-analyses pertinent to the stress, coping, and quality of life of transplant candidates and recipients were selected. Stressors associated with the transplantation process, coping strategies of transplant patients, and quality of life or transplant patients have been well researched for many years. Patients typically use problem-focused coping strategies in response to various stressors. Transplant recipients typically report a higher quality of life than do transplant candidates; however, posttransplant quality of life does not typically equal the quality of life of healthy nonpatients. The relationship between stress, coping, and quality of life of transplant patients has not yet been systematically investigated from a theoretical perspective. Recommendations for further research are provided

Internationale activiteiten gericht op het verminderen van LC50 testen voor het vaststellen van acute toxiciteit in vissen : International efforts to reduce the use of acute toxicity tests in fish

Om de veiligheid van stoffen voor het milieu te beoordelen is informatie nodig over de mate waarin stoffen giftig zijn. Deze informatie wordt gedeeltelijk via dierproeven verkregen, zoals in vissen. Om zo min mogelijk dierproeven in te hoeven zetten, wordt gezocht naar alternatieven. In dat verband heeft het RIVM in kaart gebracht welke internationale activiteiten zijn ondernomen om het proefdiergebruik te verminderen voor studies naar de acute giftigheid van chemische stoffen voor vissen. Op dit moment vinden de meeste activiteiten hiervoor plaats bij de OESO (Organisatie voor Economische Samenwerking en Ontwikkeling) die zorgt voor uniforme testrichtlijnen en bij ECHA (Europees Agentschap voor Chemische Stoffen) in het kader van de Europese stoffenwetgeving REACH. Bij de acute giftigheidstesten voor vissen wordt gezocht bij welke concentratie 50 procent van de vissen sterft (zogeheten LC50-methode). Deze testen zijn in principe verboden, omdat de dieren veel ongerief ondervinden. Ze worden alleen met ontheffing ingezet als er geen alternatieve methoden mogelijk zijn. Een van de alternatieven is om visembryo's voor deze test te gebruiken; een methode die is geaccepteerd door de OESO en onder bepaalde condities voor REACH mag worden gebruikt. Visembryo's worden tot vijf dagen na bevruchting niet als proefdier aangemerkt, omdat ze dan nog niet zelfstandig kunnen eten en geen pijn en ongerief kunnen ervaren. Implementatie van deze test in de wettelijke richtlijnen kan het proefdiergebruik verminderen. Het is niet mogelijk dierproeven hiermee volledig te vervangen, doordat het gebruik van vissenembryo's niet voor alle (klassen van) chemische stoffen geschikt is. De OESO schrijft nu nog meerdere concentraties voor in de test met volwassen vissen. Het aantal proefdieren kan ook worden verminderd door de huidige test uit te voeren met één concentratie van de stof. Hiervoor wordt bij de OESO momenteel een strategie ontwikkeld.In order to assess the environmental safety of chemical substances, information must be obtained about their toxicity. Such information is partly derived tests performed in animals. Researchers are currently looking for alternative methods to reduce the reliance on animal testing. The Dutch National Institute for Public Health and the Environment (RIVM) has surveyed international efforts to reduce the number of animals in studies examining the acute toxicity of chemical substances to fish. At present, most activities in this area are being undertaken under the auspices of the Organization for Economic Cooperation and Development (OECD), who develop harmonized test guidelines and the European Chemicals Agency (ECHA) for REACH (Registration, Evaluation, Authorization and Restriction of Chemicals). Acute toxicity tests in fish seek to determine the concentration at which 50 percent of the fish die (the so-called 'LC50 test'). In principle, such tests are prohibited because of their large impact on animal welfare. They may only be performed under an exemption when no alternative research methods are available. One alternative is to use fish embryos for this toxicity test. This method has been authorized by the OECD and can be used for REACH purposes. Fish embryos up to five days after fertilization do not fall into the regulatory frameworks dealing with animal experimentation. One reason is that in this early life stage the embryos cannot eat independently or experience pain or discomfort. Implementation of the Fish Embryo Toxicity (FET) tests in the applicable regulatory guidelines may therefore reduce the number of experimental animals for acute toxicity testing. However, FET tests cannot completely replace animal testing because they are not suitable for all (classes of) chemical substances. The OECD guideline currently prescribes multiple concentrations in the fish acute toxicity test. The number of test animals used can also be reduced by performing acute toxicity tests in fish using a single concentration of the substance being studied. The OECD is currently developing a strategy for this.Ministerie van E

Explaining the quality of life of organ transplant patients with crisis theory

Context - Ubiquitous findings regarding the quality of life (QOL) of transplant patients have yet to be explained from a theoretical perspective. Objective - To investigate transplant patients' QOL by using the conceptual framework of crisis theory. Design - Cross-sectional study to explore differences in transplant patients' experiences of stress, coping, and QOL. Regression analysis was used to test crisis theory in relation to QOL, stress, and coping. Participants - A total of 226 participants representing transplant candidates, transplant recipients, and nontransplant individuals participated via survey-based data collection. Results - Results showed that transplant candidates experience lower QOL than transplant recipients and nontransplant individuals. No significant differences were detected regarding stress levels or coping styles. Stress made a significant contribution to patients' QOL. Conclusions - Current findings suggest important QOL benefits of organ transplant. Using a theoretical model is an effective way to investigate the QOL of people experiencing chronic illness such as end-stage organ failure. Further investigation is required to reach a conclusive understanding of the complex interaction between transplant patients' QOL, stress, and coping