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D3.3.1 Toxicity gene expression signatures of reference compounds for murine ES cell-derived neuronal cells, spermatocytes and primary hepatocytes D3.4.1 Central core data repository & data extraction procedures D3.6.1b Periodic SP progress report (part of ESNATS periodic progress report) D4.1.1 Metabolic activities of mouse hepatocytes in transwell culture D4.2.1 Toxicity and genotoxicity data of the test substances (all data with & without metabolic activation) D4.3.2 Integrated approach of in vitro testing including metabolising system and PBPK modelling to be used to predict in vivo effect levels for reproduction toxicity & CNS toxicity D4.4.2 Report on expression profiling and metabolic activities of mES cell derived hepatocytelike cells D4.5.1b Periodic SP progress report (part of ESNATS periodic progress report) D0.6.3 Periodic Report for period 2 (M13-M24) The first toxicogenomics expression signatures of reference compounds for murine ES cell-derived neuronal cells & spermatocytes were generated & first conclusions derived from these experiments The core data repository was set up with the management of transcriptomics & proteomics experimental data A summary of the progress in SP3 was provided It was analysed whether hepatocyte sandwich cultures show a time-dependent formation of metabolites over an incubation period of 24h using diagnostic substrates An in vitro system with primary hepatocytes cultivated in collagen sandwiches that can serve as a metabolising system for neurotoxicity testing, has been established A two-step in silico approach to extrapolate in vitro toxicity data has been established, determined in in vitro assays for reproduction & neurotoxicity by other ESNATS partners in SP1 & SP2, to in vivo effect levels for these two toxic endpoints. Mouse ES cells were used to express a reporter/selection vector with the eGFP gene & a puromycin resistance (Pac) cassette driven by a common a- fetoprotein (AFP) gene promoter A summary of the progress in SP4 was provided The periodic report for the period 2 was submitted to the EC 80 PROGRESS REPORTS FROM EU-FUNDED PROJECTS Progress Report 2011 & AXLR8-2 Workshop Report
D0.3.2 Cell culture automation: concepts Requirements for an automated ES cell maintenance system were provided, based on the needs expressed in D0.3.1 & the results of numerous interviews with both ESNATS consortium members & other research institutions D1.4.4 Report on the most suitable hES cell lines for establishment of neuronal teratogenicity in vitro tests Data obtained with different ES cell lines in the in vitro neural teratogenicity test was compared, in particular cytotoxic & lineage-specific toxic effects of different compounds during the neural differentiation process of HUES1 & H9 cell lines D1.4.5 Report on the characterisation of hES cell derived cardiac cells & predictive endpoints Results of the differentiation of hES cells into cells corresponding to the cardiac compartment were described D0.4.5b Summer school The second ESNATS summer school was held in Tallinn, Estonia on 19-23 Sept. 2011 D0.5.6 Draft plan for using & disseminating knowledge The draft plan for disseminating knowledge was updated with the plan for using knowledge D1.6.6 Report on the universal applicability of the in vitro development model as determined by comparative testing of several Cellartis hES cell lines Several different Cellartis hES cell lines, developed either in a feeder-based or in a feeder-free system, were evaluated & compared; cells either seeded as clusters or as single cells with the possible survival effect of a ‘survival compound’ were evaluated D2.1.11 Optimised SOP for minibrains (modification after electrophysiological characterisation) The electrophysiological characteristics of spontaneous & evoked field potentials from neural networks derived from mouse ES cells were described D1.2.2 Expression profiles of hES cells after exposure to reference compounds & identification of pertinent toxicity biomarkers at the transcriptional level Pluripotent hES cells were treated with toxicants at sublethal concentrations (IC10) & the expression pattern of toxicity biomarkers after exposure to reference toxicants was analysed by semi quantitative RT-PCR & RT-qPCR PROGRESS REPORTS FROM EU-FUNDED PROJECTS Progress Report 2011 & AXLR8-2 Workshop Report 81
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ALTERNATIVE TESTING STRATEGIES PROG
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ALTERNATIVE TESTING STRATEGIES PROG
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TABLE OF CONTENTS 1. 2. EXECUTIVE S
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Update on EPA’s ToxCast Programme
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challenges, needs, and priorities f
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1INTRODUCTION It is the aim of the
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and progress of these multidiscipli
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Table 2. Members of the AXLR8 Scien
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• OECD Joint Meeting Special Sess
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ACuteTox Optimisation & Pre-Validat
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to robotic screening platforms; and
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ased on functional parameters inclu
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Table 1. Outliers identified by com
Page 30 and 31: showed that for some compounds the
Page 32 and 33: Computer-based prediction of metabo
Page 34 and 35: three reference compounds revealed
Page 36 and 37: a calibration curve constructed. Th
Page 38 and 39: cell lines) or 48 hours (A704 cells
Page 40 and 41: multivariate CART results did not c
Page 42 and 43: probability) ~50% of the substances
Page 44 and 45: Publications 2010-11 Hoffmann S, Ki
Page 46 and 47: Per Artursson Uppsala University Up
Page 48 and 49: their genotoxic and carcinogenic po
Page 50 and 51: Table 1. Overview of carcinoGENOMIC
Page 52 and 53: D12.23 3 monthly Project M42 √ Bo
Page 54 and 55: annual carcinoGENOMICS meeting in N
Page 56 and 57: M3.5 Decision of most M40 Postponed
Page 58 and 59: M3.4 Identification of most suitabl
Page 60 and 61: WP1 with input from other partners
Page 62 and 63: Partners Project Co-ordinator Jos K
Page 64 and 65: combine knowledge of critical proce
Page 66 and 67: defined and published in the form o
Page 68 and 69: WP6 is devoted to the setup of a so
Page 70 and 71: Partners Co-ordinator Bart van der
Page 72 and 73: obustness, comparing results obtain
Page 74 and 75: 6. Candéias S, Pons B, Viau M, et
Page 76 and 77: ESNATS Embryonic Stem Cell-Based No
Page 78 and 79: Table 1. List of deliverables due i
Page 82 and 83: Table 2. List of milestones due in
Page 84 and 85: Table 3. Test systems corresponding
Page 86 and 87: Publications 2010-11 1. Peters SJ,
Page 88 and 89: Marcel Leist Universität Konstanz
Page 90 and 91: The most significant achievements o
Page 92 and 93: Figure 3. The Sensor Dish Reader (S
Page 94 and 95: LIINTOP Optimisation of Liver & Int
Page 96 and 97: cells express most of the functions
Page 98 and 99: Figure 3. Scheme of lentivirus gene
Page 100 and 101: Figure 5. Co-culture set-up. Functi
Page 102 and 103: Figure 9. Phalloidin-TRITC staining
Page 104 and 105: Table 1. Values are expressed as pe
Page 106 and 107: formed with mannitol, atenolol, pro
Page 108 and 109: Figure 14. Comparison of Digoxin an
Page 110 and 111: By using the new technology of HCA
Page 112 and 113: Figure 17. (Left panel) Phalloidin-
Page 114 and 115: limited amount of data could be pro
Page 116 and 117: André Guillouzo Institut National
Page 118 and 119: Objectives The overall aim of this
Page 120 and 121: Table 2: Milestones achieved in 201
Page 122 and 123: detected iron (µg/ml) 80 70 6
Page 124 and 125: in the following order: uncoated ma
Page 126 and 127: analysis of leukocytes, expression
Page 128 and 129: 2011 the automated protocols will b
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OpenTox Promotion, Development, Acc
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Results The OpenTox Framework The O
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Figure 1. ToxPredict: OpenTox Appli
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scientifically sound manner, so as
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Figure 4. Creating a QPRF report wi
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Figure 7. MaxTox model-building app
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Figure 8. Bioclipse interaction wit
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and model predictions, which they m
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Publications 2010-11 1. Hardy B, Do
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In vitro toxicology using isolated
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(2C-Glo-CYP2C, 3A-Glo-CYP3A) while
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neuronal models 2D (primary culture
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10 and 14 days. The liver-specific
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Frédéric Bois Institut National d
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Figure 1. The Sens-it-iv sphere. 2.
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Figure 2. The updated modular struc
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Technology Module The aim of techno
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Table 1: The final compound list. R
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Table 2. The Sens-it-iv Toolbox. N
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Figure 4. A gene profile for identi
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Figure 7. In vitro T cell priming a
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sessions at congress and meetings (
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7. Gibbs S, van Montfrans C, Kroeze
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vitro assessment of allergens. Eds:
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S.F. Martin Universitätsklinikum F
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idging the gap to human volunteer s
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combinations of transcriptomics, me
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normal animals who usually exhibit
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Workshop proposals Concepts of data
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VITROCELLOMICS Reducing Animal Expe
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esulting of the project was the abi
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Figure 3. Four-compartment artifici
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embryonic stem cells differentiatin
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196 3AXLR8-2 WORKSHOP REPORT
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Workshop participants were divided
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08.45 - 09.15 ACuteTox Annette Kopp
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3.3 Workshop Presentations 202
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Table 1. A sampling of current toxi
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Table 2. EPA activities: a timeline
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Why is a Consortium Needed While th
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the development of new more relevan
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in particular for fundamental resea
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compared to controls. Most interest
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epidermis to known allergens and UV
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The Virtual Liver Spatial-Temporal
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A B C D E Figure 2. Tissue reconstr
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Figure 4. Mechanisms of how hepatoc
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in rat liver in vivo (Figure 5A). H
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The IMI eTOX Project Efforts to Dev
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deliverables, which can only be ach
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A series of publications related to
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Update on EPA’s ToxCast Programme
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Phase I of ToxCast involved the eva
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Endpoint Brief Description of Bioac
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includes approximately 150 chemical
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information. For each slice, distan
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Judson RS, Houck KA, Kavlock RJ, et
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Embryonic Stem Cell Approaches Towa
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perhaps be tested efficiently in al
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compared gene and protein expressio
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cost and time, allowing more chemic
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Toxicol Appl Pharmacol. 2011; 251,
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functions, establish relationships
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cellular behaviours are captured fr
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assay. PLoS One. 2011; 6, e18540. 7
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learning algorithm called Support V
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Compound Potency Vehicle Concentrat
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mediated inhibition of RXR function
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References Basketter DA, Evans P, F
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When considering consumer exposure,
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in the induction of skin sensitisat
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has reacted, when the peptide deple
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of presentations and discussions, t
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Contact Dermatitis. 2005; 53. 16. S
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the development of in vitro assays.
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Although the mechanisms underlying
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skin sensitisation, it will aid in
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Figure 3. Scatter plot of robust li
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7. De Smedt A, Van Den Heuvel R, Va
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The OECD Adverse Outcome Pathway Ap
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the AOP can be used in qualitative
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Table 1. Summary of the experimenta
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the significance of type 1 versus t
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plus the key events that occur acro
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Dimitrov, S.D., Low, L.K., Patlewic
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[Supporting information and databas
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Figure 1. Strategic R&D of chemical
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The Bhas 42 system can sensitively
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Table 1. Established reporter cell
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elated genes (Hand1, ADAM19, Cmyal,
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Publications Carcinogenicity Tanaka
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Case Study Approaches for Implement
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assay results together with CSBP mo
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them to support multi-day testing i
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CSBP models for both receptor-media
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Hamner Presentations in 2011 • Ch
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human health risk assessment. Risk
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There is a significant scientific c
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phototoxicity and eye irritation, f
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allergy risk assessment rather than
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‘toolbox’ of non-animal methods
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332 3.4 Breakout Group Reports
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Figure 1. An illustration of the me
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methods, and the generally poor und
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3.4.3. Break-Out Group 2: Reproduct
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- Deep-sequencing of birth defect p
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Figure 2. Specific stages of the ma
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3.4.4 Break-Out Group 3: Skin Sensi
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for further progress. Better tools
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sure doses is not straightforward.
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3.5 AXLR8 Scientific Panel Recommen
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Workshop participants underlined th
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could be co-ordinated in a focused
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focusing on scientific excellence a
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Directory of Projects & Co-ordinato
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Glossary of Terms 2D/3D 3Rs CARDAM/
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