دورية أكاديمية
أعرض في EDS

Predictions of genotoxic potential, mode of action, molecular targets, and potency via a tiered multiflow® assay data analysis strategy.

التفاصيل البيبلوغرافية
العنوان: Predictions of genotoxic potential, mode of action, molecular targets, and potency via a tiered multiflow® assay data analysis strategy.
المؤلفون: Dertinger SD; Litron Laboratories, Rochester, New York., Kraynak AR; Merck & Co., Inc., West Point, Pennsylvania., Wheeldon RP; Institute of Life Science, Swansea University Medical School, Swansea University, Swansea, Wales, United Kingdom., Bernacki DT; Litron Laboratories, Rochester, New York., Bryce SM; Litron Laboratories, Rochester, New York., Hall N; Litron Laboratories, Rochester, New York., Bemis JC; Litron Laboratories, Rochester, New York., Galloway SM; Merck & Co., Inc., West Point, Pennsylvania., Escobar PA; Merck & Co., Inc., West Point, Pennsylvania., Johnson GE; Institute of Life Science, Swansea University Medical School, Swansea University, Swansea, Wales, United Kingdom.
المصدر: Environmental and molecular mutagenesis [Environ Mol Mutagen] 2019 Jul; Vol. 60 (6), pp. 513-533. Date of Electronic Publication: 2019 Feb 27.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: Wiley-Liss Country of Publication: United States NLM ID: 8800109 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1098-2280 (Electronic) Linking ISSN: 08936692 NLM ISO Abbreviation: Environ Mol Mutagen Subsets: MEDLINE
أسماء مطبوعة: Publication: New York Ny : Wiley-Liss
Original Publication: New York, NY : Liss, c1987-
مواضيع طبية MeSH: Mutagens/*toxicity, Aneugens/toxicity ; Biological Assay/methods ; Biomarkers/metabolism ; Cell Line ; DNA Damage/drug effects ; Data Analysis ; Flow Cytometry/methods ; Histones/metabolism ; Humans ; Machine Learning ; Micronucleus Tests/methods ; Mutagenicity Tests/methods ; Phosphorylation/drug effects ; Tumor Suppressor Protein p53/metabolism
مستخلص: The in vitro MultiFlow® DNA Damage Assay multiplexes γH2AX, p53, phospho-histone H3, and polyploidization biomarkers into a single flow cytometric analysis. The current report describes a tiered sequential data analysis strategy based on data generated from exposure of human TK6 cells to a previously described 85 chemical training set and a new pharmaceutical-centric test set (n = 40). In each case, exposure was continuous over a range of closely spaced concentrations, and cell aliquots were removed for analysis following 4 and 24 hr of treatment. The first data analysis step focused on chemicals' genotoxic potential, and for this purpose, we evaluated the performance of a machine learning (ML) ensemble, a rubric that considered fold increases in biomarkers against global evaluation factors (GEFs), and a hybrid strategy that considered ML and GEFs. This first tier further used ML output and/or GEFs to classify genotoxic activity as clastogenic and/or aneugenic. Test set results demonstrated the generalizability of the first tier, with particularly good performance from the ML ensemble: 35/40 (88%) concordance with a priori genotoxicity expectations and 21/24 (88%) agreement with expected mode of action (MoA). A second tier applied unsupervised hierarchical clustering to the biomarker response data, and these analyses were found to group certain chemicals, especially aneugens, according to their molecular targets. Finally, a third tier utilized benchmark dose analyses and MultiFlow biomarker responses to rank genotoxic potency. The relevance of these rankings is supported by the strong agreement found between benchmark dose values derived from MultiFlow biomarkers compared to those generated from parallel in vitro micronucleus analyses. Collectively, the results suggest that a tiered MultiFlow data analysis pipeline is capable of rapidly and effectively identifying genotoxic hazards while providing additional information that is useful for modern risk assessments-MoA, molecular targets, and potency. Environ. Mol. Mutagen. 60:513-533, 2019. © 2019 Wiley Periodicals, Inc.
(© 2019 Wiley Periodicals, Inc.)
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معلومات مُعتمدة: R44 ES029014 United States ES NIEHS NIH HHS; R44ES029014 International National Institute of Health/National Institute of Environmental Health Sciences
فهرسة مساهمة: Keywords: TK6 cells; aneugen; benchmark dose; clastogen; mode of action; multiplexed; p53; γH2AX
المشرفين على المادة: 0 (Aneugens)
0 (Biomarkers)
0 (Histones)
0 (Mutagens)
0 (Tumor Suppressor Protein p53)
تواريخ الأحداث: Date Created: 20190201 Date Completed: 20191209 Latest Revision: 20191217
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC6880310
DOI: 10.1002/em.22274
PMID: 30702769
قاعدة البيانات: MEDLINE
الوصف
تدمد:1098-2280
DOI:10.1002/em.22274