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  • 1
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  Mainz//2011; 56. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie (gmds), 6. Jahrestagung der Deutschen Gesellschaft für Epidemiologie (DGEpi); 20110926-20110929; Mainz; DOC11gmds371 /20110920/
    Publication Date: 2011-09-20
    Keywords: Psychiatrie ; Telemedizin ; BSI-18 ; ddc: 610
    Language: German
    Type: conferenceObject
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  • 2
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  16. Deutscher Kongress für Versorgungsforschung (DKVF); 20171004-20171006; Berlin; DOCP029 /20170926/
    Publication Date: 2017-09-26
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 3
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  17. Deutscher Kongress für Versorgungsforschung (DKVF); 20181010-20181012; Berlin; DOC18dkvf171 /20181012/
    Publication Date: 2018-10-13
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 4
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  14. Deutscher Kongress für Versorgungsforschung; 20151007-20151009; Berlin; DOCFV54 /20150922/
    Publication Date: 2015-09-23
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 5
    Abstract: Short-term dynamic culture of rat testicular fragments was evaluated as a model to assess effects on steroidogenesis. A total of 11 compounds differentially affecting testosterone synthesis (aminoglutethimide, ketoconazole, danazol, flutamide, diethylstilbestrol, genistein, butylparaben, nonoxynol-9, dimethoate, RU 486, and cadmium chloride) were used to explore the performance of the assay. Testosterone secretion into the medium and testosterone retained in tissue fragments was determined as a measure of steroidogenesis. Three independent experiments per compound were performed. The known in vitro inhibitory properties of most compounds could be detected. Whenever significant inhibition of testosterone synthesis was observed, low effect concentrations for a given compound differed frequently only by a factor of 〈or=3.3, maximally by a factor of 10 from each other across the three experiments and besides a decrease of testosterone concentrations in the medium, corresponding reduction of testosterone levels in tissue fragment was obtained. On the other hand, despite the use of high concentrations, danazol and genistein were unexpectedly tested negative, and considerable variability of testosterone production within control and treatment groups of individual experiments were frequently observed. In contrast to cellular systems, specific assessment of cytotoxicity to the testosterone producing Leydig cells was not possible, effects requiring prolonged incubation times could be overlooked, and the observed variability of hormone production necessitates a considerable number of individual incubations per treatment group. On the whole, short-term dynamic culture of rat testicular fragments offers limited potential to assess effects on steroidogenesis by compounds of moderate to strong potency that directly interfere with steroidogenic enzymes or rapidly induce cytotoxicity.
    Type of Publication: Journal article published
    PubMed ID: 19897028
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  • 6
    Abstract: Despite more than a decade of research in the field of endocrine active compounds with affinity for the androgen receptor (AR), still no validated recombinant AR binding assay is available, although recombinant AR can be obtained from several sources. With funding from the European Union (EU)-sponsored 6th framework project, ReProTect, we developed a model protocol for such an assay based on a simple AR binding assay recently developed at our institution. Important features of the protocol were the use of a rat recombinant fusion protein to thioredoxin containing both the hinge region and ligand binding domain (LBD) of the rat AR (which is identical to the human AR-LBD) and performance in a 96-well plate format. Besides two reference compounds [dihydrotestosterone (DHT), androstenedione] ten test compounds with different affinities for the AR [levonorgestrel, progesterone, prochloraz, 17alpha-methyltestosterone, flutamide, norethynodrel, o,p'-DDT, dibutylphthalate, vinclozolin, linuron] were used to explore the performance of the assay. At least three independent experiments per compound were performed. The AR binding properties of reference and test compounds were well detected, in terms of the relative ranking of binding affinities, there was good agreement with published data obtained from experiments using recombinant AR preparations. Irrespective of the chemical nature of the compound, individual IC(50)-values for a given compound varied by not more than a factor of 2.6. Our data demonstrate that the assay reliably ranked compounds with strong, weak, and no/marginal affinity for the AR with high accuracy. It avoids the manipulation and use of animals, as a recombinant protein is used and thus contributes to the 3R concept. On the whole, this assay is a promising candidate for further validation.
    Type of Publication: Journal article published
    PubMed ID: 19833195
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  • 7
    Abstract: Despite more than a decade of research in the field of endocrine active compounds targeting the androgen receptor (AR), and although suitable cell lines can be obtained, no validated human stably transfected androgen sensitive transactivation assay is available. Bayer Schering Pharma (BSP) and the Flemish Institute for Technological Research (VITO), partners within the EU-sponsored 6th framework project ReProTect, made first steps towards such a validation. A standard operation protocol (SOP) developed at BSP based on the androgen sensitive PALM cell line was transferred to VITO and its performance and transferability were thoroughly studied. The investigation followed a generic protocol prepared for all reporter gene assays evaluated within ReProTect, and in both laboratories at least three independent experiments were performed. The highest concentration to be tested was limited to 10 microM, if needed. A few compounds, 17alpha-methyltestosterone (17alpha-MT), vinclozolin and linuron, were studied using a real world scenario, i.e., assuming that their interaction with the AR was not known: A prescreening for agonism and true, competitive antagonism was used to select conditions such as the appropriate mode of action, and the working range excluding cytotoxicity for the final screening. All other compounds were tested according to the generic protocol: Compounds screened for agonism were the reference androgen 17alpha-methyldihydrotestosterone (MDHT), levonorgestrel, norethynodrel, progesterone, o,p'-DDT, and dibutylphthalate (DBP), while compounds screened for antagonism were the reference anti-androgen flutamide, prochloraz, o,p'-DDT, progesterone, norethynodrel, and DBP. Cytotoxicity was assessed in parallel as lactate dehydrogenase release. The prescreen classified 17alpha-MT as androgenic, vinclozolin and linuron as anti-androgenic and compounds were tested accordingly. In the absence of cytotoxicity, appropriate androgenic properties of reference and test compounds were detected by both laboratories, o,p'-DDT and DBP had no androgenic activity. Across the two laboratories EC(50)-values for MDHT, 17alpha-MT, and levonorgestrel varied by not more than a factor of 3.4, for norethynodrel by a factor of 9.7. Progesterone effects could not fully be evaluated, as frequently concentration response curves were incomplete. In the absence of cytotoxicity anti-androgenic properties of reference and test compounds were also detected in both laboratories. DBP, the putative negative reference compound, was inactive, norethynodrel rather showed agonistic properties. Progesterone was an antagonist at low concentrations, but agonistic properties were observed in one laboratory at high concentrations. Since the highest test concentration was limited to 10 microM, for some compounds no complete concentration response curves were obtained and estimation of EC(50)-values was less robust. Our data demonstrated that the SOP was transferable, and that the assay was able to rank compounds with strong, weak, and without affinity for the AR and to discriminate agonists and antagonists. The sensitivity of the assay could be improved further, if the limit of solubility or beginning cytotoxicity was chosen as the highest test concentration. The assay avoids the use of tissues from laboratory animals, and thus contributes to the 3R concept. Furthermore, it could be adjusted to an intermediate/high throughput format. On the whole, this PALM assay is a promising candidate for further validation.
    Type of Publication: Journal article published
    PubMed ID: 19836445
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  • 8
    Keywords: IN-VITRO ; Germany ; IN-VIVO ; TOXICITY ; VITRO ; VIVO ; BIOLOGY ; TRIAL ; ASSAY ; PREDICTION ; in vitro tests ; FUTURE ; PROJECT ; SPRAGUE-DAWLEY RATS ; PROGRAM ; FRAMEWORK ; WEIGHT ; SCIENCE ; development ; methods ; PROFILES ; ANDROGEN RECEPTOR ; in vivo ; CHEMICALS ; in vitro assay ; PROFILE ; BREAST-CANCER CELLS ; FERTILITY ; in vitro ; DEVELOPMENTAL TOXICITY ; Alternative methods ; Reproductive toxicology ; ReProTect ; Alternative reproductive toxicity testing ; CONGENITAL DIAPHRAGMATIC-HERNIA ; DIETARY BISPHENOL-A ; Embryotoxicity ; Endocrine disruption ; ENDOCRINE DISRUPTOR VINCLOZOLIN ; ETHYLENE-GLYCOL MONOMETHYL ; GLUFOSINATE-AMMONIUM ; Hershberger assay ; Ring trial
    Abstract: ReProTect is a project within the 6th European Framework Program which has developed alternative methods aimed to reduce or replace animal experimentation in the field of reproductive toxicology. In its final year, a ring trial, named the "Feasibility Study", was conducted, in which 10 blinded chemicals with toxicologically well-documented profiles were analyzed by employing a test battery of 14 in vitro assays. EC(50) (half maximal effective concentration) or equivalent endpoints were determined and the test compounds were ranked relative to chemicals previously assayed in the tests of the battery. This comparative analysis together with a weight of evidence approach allowed a robust prediction of adverse effects on fertility and embryonic development of the 10 test chemicals in vivo. In summary, the vast majority of the predictions made based on the in vitro results turned out to be correct when compared to the whole animal data. The procedure used here, a nearest neighbor analysis coupled with a weight of evidence approach, may guide future activities in the field of alternative toxicity testing.
    Type of Publication: Journal article published
    PubMed ID: 20493943
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  • 9
    Keywords: OPTIMIZATION ; RECEPTOR ; CELLS ; Germany ; MODEL ; PROTEIN ; validation ; DOMAIN ; RAT ; CONTRAST ; BINDING ; BIOLOGY ; ALPHA ; ASSAY ; LENGTH ; RECEPTORS ; PROJECT ; AFFINITY ; ER ; FEATURES ; FRAMEWORK ; SCIENCE ; ESTROGEN ; BINDING DOMAIN ; ESTROGEN-RECEPTOR-ALPHA ; CONTRIBUTE ; Binding assay ; Screening for endocrine active compounds ; Full length human recombinant estrogen receptor alpha
    Abstract: Despite about two decades of research in the field of endocrine active compounds, still no validated human recombinant (hr) estrogen receptor-alpha (ER alpha) binding assay is available, although hr-ER alpha is available from several sources. In a joint effort, US EPA and Bayer Schering Pharma with funding from the EU-sponsored 6th framework project, ReProTect, developed a model protocol for such a binding assay. Important features of this assay are the use of a full length hr-ER alpha and performance in a 96-well plate format. A full length hr-ER alpha was chosen, as it was considered to provide the most accurate and human-relevant results, whereas truncated receptors could perform differently. Besides three reference compounds [17 beta-estradiol, norethynodrel, dibutylphthalate] nine test compounds with different affinities for the ER alpha [diethylstilbestrol (DES), ethynylestradiol, meso-hexestrol, equol, genistein, o,p'-DDT, nonylphenol, n-butylparaben, and corticosterone] were used to explore the performance of the assay. Three independent experiments per compound were performed on different days, and dilutions of test compounds from deep-frozen stocks, solutions of radiolabeled ligand and receptor preparation were freshly prepared for each experiment. The ER alpha binding properties of reference and test compounds were well detected. As expected dibutylphthalate and corticosterone were non-binders in this assay. In terms of the relative ranking of binding affinities, there was good agreement with published data obtained from experiments using a human recombinant ER alpha ligand binding domain. Irrespective of the chemical nature of the compound, individual IC50-values for a given compound varied by not more than a factor of 2.5. Our data demonstrate that the assay was robust and reliably ranked compounds with strong, weak, and no affinity for the ER alpha with high accuracy. It avoids the manipulation and use of animals, i.e., the preparation of uterine cytosol as receptor source from ovariectomized rats, as a recombinant protein is used and thus contributes to the 3R concept (reduce, replace, and refine). Furthermore, in contrast to other assays, this assay could be adjusted to an intermediate/high throughput format. On the whole, this assay is a promising candidate for further validation. (C) 2010 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 20074635
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  • 10
    Keywords: validation ; ANDROGEN RECEPTOR ; Binding assay
    Abstract: Concentration-response studies are performed to investigate the potency of the substance under investigation. Data are typically evaluated using non-linear regression. A common model is the log-logistic model which includes parameters for lower and upper boundary of mean response, EC50 and Hill slope. Often, response and/or concentration data are transformed before proceeding with the analysis of their relationship. This is motivated by practical reasons, including comparability of results across different assays. We prove mathematically that a linear transformation of data will not change the EC50 and Hill slope estimates and only results in an identical transformation of the estimated parameters for lower and upper boundary of mean response. However, fixing some of the parameters may lead to erroneous estimates. This is of practical relevance when data are corrected for background signal and normalized by background corrected solvent control and a reduced model is used in which the response range is fixed between 100% and 0%. Computer simulations and a real data example are used to illustrate the impact of data transformations on parameter estimation. We further shed light on some common problems arising in the analysis of concentration-response data. Recommendations for practical implementation in concentration-response analysis are provided.
    Type of Publication: Journal article published
    PubMed ID: 22828011
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