ABSTRACT
Quantitative structure-activity relationship (QSAR) models are powerful in silico tools for predicting the mutagenicity of unstable compounds, impurities and metabolites that are difficult to examine using the Ames test. Ideally, Ames/QSAR models for regulatory use should demonstrate high sensitivity, low false-negative rate and wide coverage of chemical space. To promote superior model development, the Division of Genetics and Mutagenesis, National Institute of Health Sciences, Japan (DGM/NIHS), conducted the Second Ames/QSAR International Challenge Project (2020-2022) as a successor to the First Project (2014-2017), with 21 teams from 11 countries participating. The DGM/NIHS provided a curated training dataset of approximately 12,000 chemicals and a trial dataset of approximately 1,600 chemicals, and each participating team predicted the Ames mutagenicity of each trial chemical using various Ames/QSAR models. The DGM/NIHS then provided the Ames test results for trial chemicals to assist in model improvement. Although overall model performance on the Second Project was not superior to that on the First, models from the eight teams participating in both projects achieved higher sensitivity than models from teams participating in only the Second Project. Thus, these evaluations have facilitated the development of QSAR models.
Subject(s)
Mutagens , Quantitative Structure-Activity Relationship , Mutagens/toxicity , Mutagens/chemistry , Mutagenicity Tests , Mutagenesis , JapanSubject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Cell Proliferation , Humans , Receptors, Notch , Signal TransductionABSTRACT
The transcription factor Snail is a master regulator of cellular identity and epithelial-to-mesenchymal transition (EMT) directly repressing a broad repertoire of epithelial genes. How chromatin modifiers instrumental to its activity are recruited to Snail-specific binding sites is unclear. Here we report that the long non-coding RNA (lncRNA) HOTAIR (for HOX Transcript Antisense Intergenic RNA) mediates a physical interaction between Snail and enhancer of zeste homolog 2 (EZH2), an enzymatic subunit of the polycomb-repressive complex 2 and the main writer of chromatin-repressive marks. The Snail-repressive activity, here monitored on genes with a pivotal function in epithelial and hepatic morphogenesis, differentiation and cell-type identity, depends on the formation of a tripartite Snail/HOTAIR/EZH2 complex. These results demonstrate an lncRNA-mediated mechanism by which a transcriptional factor conveys a general chromatin modifier to specific genes, thereby allowing the execution of hepatocyte transdifferentiation; moreover, they highlight HOTAIR as a crucial player in the Snail-mediated EMT.
Subject(s)
Carcinoma, Hepatocellular/pathology , Chromatin/genetics , Enhancer of Zeste Homolog 2 Protein/metabolism , Epithelial-Mesenchymal Transition , Gene Expression Regulation, Neoplastic , RNA, Long Noncoding/genetics , Snail Family Transcription Factors/metabolism , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Cell Transdifferentiation , Cells, Cultured , Enhancer of Zeste Homolog 2 Protein/genetics , Epigenesis, Genetic , Genomics , Hepatocytes/metabolism , Hepatocytes/pathology , Humans , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Signal Transduction , Snail Family Transcription Factors/geneticsABSTRACT
BACKGROUND: Formic acid 85% constitutes the active substance of a new wart removal agent marketed in France under the name of Objectif ZeroVerrue(®), a product sold over-the-counter for adults and children aged over four years, and on a doctor's recommendation for children aged under four years. Its mechanism of action may involve cellular destruction through dehydration. PATIENTS AND METHODS: Herein we report two cases of cutaneous necrosis following application of formic acid 85%. One case was severe, affecting the extremity of the middle finger and involving the underlying extensor apparatus in a girl aged 3 and a half years. This necrosis required the creation of a pedicled fasciocutaneous flap and temporary arthroereisis. DISCUSSION: The precautions for use set out in the information leaflet for this preparation based on formic acid must be strictly adhered to by patients. In particular, only one application should be made per week, taking care to avoid adjacent skin. It is essential to suspend treatment if the skin is still erythematous after the previous application, and the treated area must not be occluded with bandages. Doctors must be aware of the risk of necrosis, since their recommendation is required for children under the age of four years.
Subject(s)
Burns, Chemical/etiology , Caustics/toxicity , Fingers/pathology , Formates/toxicity , Skin/pathology , Child , Child, Preschool , Female , Humans , Male , NecrosisABSTRACT
Thirty-seven polychlorobiphenyl (PCB) congeners and seven polybromodiphenylether (PBDE) congeners were measured in human milk samples collected in Rome between 2005 and 2007. The comparison of results with two previous studies performed in Rome in 1984 and in 2000-2001 indicates a 64% decrease of PCB levels, still in progress; profile differences with time were also evident as lighter congeners are less relevant now; data are in good agreement with recent European studies. PBDE contamination profiles were different in individual samples and a similar variability was observed in data from different countries, suggesting different exposure pathways and profiles.
