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Masamitsu Honma, Airi Kitazawa, Alex Cayley, Richard V Williams, Chris Barber, Thierry Hanser, Roustem Saiakhov, Suman Chakravarti, Glenn J Myatt, Kevin P Cross, Emilio Benfenati, Giuseppa Raitano, Ovanes Mekenyan, Petko Petkov, Cecilia Bossa, Romualdo Benigni, Chiara Laura Battistelli, Alessandro Giuliani, Olga Tcheremenskaia, Christine DeMeo, Ulf Norinder, Hiromi Koga, Ciloy Jose, Nina Jeliazkova, Nikolay Kochev, Vesselina Paskaleva, Chihae Yang, Pankaj R Daga, Robert D Clark, James Rathman
The International Conference on Harmonization (ICH) M7 guideline allows the use of in silico approaches for predicting Ames mutagenicity for the initial assessment of impurities in pharmaceuticals. This is the first international guideline that addresses the use of quantitative structure-activity relationship (QSAR) models in lieu of actual toxicological studies for human health assessment. Therefore, QSAR models for Ames mutagenicity now require higher predictive power for identifying mutagenic chemicals. To increase the predictive power of QSAR models, larger experimental datasets from reliable sources are required...
October 23, 2018: Mutagenesis
Alex Cayley, Adrian Fowkes, Richard V Williams
While high-level performance metrics generated from the validation of quantitative structure-activity relationship (QSAR) systems can provide valuable information on how well these models perform and where they need to be improved, they require appropriate interpretation. There is no universal performance metric which will answer all of the questions a user might ask relating to a model, and therefore, a combination of metrics should usually be considered. Furthermore, results may vary according to the chemical space being used to validate a model, and, in some cases, it may be the validation data which is lacking or ambiguous rather than the prediction being made...
October 20, 2018: Mutagenesis
Suman K Chakravarti, Roustem D Saiakhov
This article describes a method to generate molecular fingerprints from structural environments of mutagenicity alerts and calculate similarity between them. This approach was used to improve classification accuracy of alerts and for searching structurally similar analogues of an alerting chemical. It builds fingerprints using molecular fragments from the vicinity of the alerts and automatically accounts for the activating and deactivating/mitigating features of alerts needed for accurate predictions. This study also demonstrates the usefulness of transfer learning in which a distributed representation of chemical fragments was first trained on millions of unlabelled chemicals and then used for generating fingerprints and similarity search on smaller data sets labelled with Ames test outcomes...
October 20, 2018: Mutagenesis
Rachael E Tennant, Sébastien J Guesné, Steven Canipa, Alex Cayley, William C Drewe, Masamitsu Honma, Kenichi Masumura, Takeshi Morita, Susanne A Stalford, Richard V Williams
As part of the hazard and risk assessment of chemicals in man, it is important to assess the ability of a chemical to induce mutations in vivo. Because of the commonalities in the molecular initiating event, mutagenicity in vitro can correlate well to the in vivo endpoint for certain compound classes; however, the difficulty lies in identifying when this correlation holds true. In silico alerts for in vitro mutagenicity may therefore be used as the basis for alerts for mutagenicity in vivo where an expert assessment is carried out to establish the relevance of the correlation...
October 3, 2018: Mutagenesis
Romualdo Benigni, Cecilia Bossa
With the aim of providing faster, more economical, animal-free tools to predict toxicity, quantitative structure-activity relationships (QSAR) approaches are increasingly applied to the chemical risk assessment-in particular genotoxicity and carcinogenicity. The more recent period of time has witnessed refinements of the predictive systems, with the collection of larger training sets and continued fine-tuning, together with an increased interest for the use of QSAR by regulatory authorities. This literature review provides an updated snapshot of the present state of the art in the evaluation of QSAR methods as applied to genotoxicity...
September 26, 2018: Mutagenesis
(no author information available yet)
No abstract text is available yet for this article.
September 21, 2018: Mutagenesis
Azeddine Elhajouji, Dagmara Vaskova, Stephen D Dertinger, Hansjeorg Martus
5-(2-Chloroethyl)-2'-deoxyuridine (CEDU) was developed as an antiviral drug. It has been studied in a number of in vitro and in vivo genotoxicity assays and is considered an unusual nucleoside analogue owing to its potent mutagenic potential, with little to no measurable clastogenic activity. Given this atypical profile, CEDU represented an interesting compound for evaluating the in vivo Pig-a gene mutation assay, a test that is undergoing extensive validation for regulatory safety applications. The current report describes two studies with 7-week-old male Wistar Han rats, one that exposed animals to several dose levels of CEDU for 5 consecutive days, the other for 28 consecutive days...
September 15, 2018: Mutagenesis
Jatin R Verma, Danielle S G Harte, Ume-Kulsoom Shah, Huw Summers, Catherine A Thornton, Shareen H Doak, Gareth J S Jenkins, Paul Rees, John W Wills, George E Johnson
Use of imaging flow cytometry to assess induced DNA damage via the cytokinesis block micronucleus (CBMN) assay has thus far been limited to radiation dosimetry in human lymphocytes using high end, 'ImageStream X' series imaging cytometers. Its potential to enumerate chemically induced DNA damage using in vitro cell lines remains unexplored. In the present manuscript, we investigate the more affordable FlowSight® imaging cytometry platform to assess in vitro micronucleus (MN) induction in the human lymphoblastoid TK6 and metabolically competent MCL-5 cells treated with Methyl Methane Sulfonate (MMS) (0-5 µg/ml), Carbendazim (0-1...
September 11, 2018: Mutagenesis
Antonella Russo, Eugenia Cordelli, Tullia Salvitti, Elisa Palumbo, Francesca Pacchierotti
Rad54 protein is a key player of the homologous recombination pathway, required for deposition and stabilisation of Rad51 foci at double strand breaks. Its role at the meiotic prophase, when double strand breaks are physiologically introduced to allow recombination, is well described. However, the hypothesis that Rad54 deficiency affect chromosome integrity of germ cells in unirradiated and irradiated animals has not been tested yet. In this study, the occurrence of spontaneous and X-ray-induced chromosome aberrations was assessed by analysis of spermatocyte MI spreads or by application of micronucleus assay in early spermatids isolated from wild type and Rad54/Rad54B knockout (KO) mice...
September 11, 2018: Mutagenesis
Alexander Amberg, Lennart T Anger, Joel Bercu, David Bower, Kevin P Cross, Laura Custer, James S Harvey, Catrin Hasselgren, Masamitsu Honma, Candice Johnson, Robert Jolly, Michelle O Kenyon, Naomi L Kruhlak, Penny Leavitt, Donald P Quigley, Scott Miller, David Snodin, Lidiya Stavitskaya, Andrew Teasdale, Alejandra Trejo-Martin, Angela T White, Joerg Wichard, Glenn J Myatt
(Quantitative) structure-activity relationship or (Q)SAR predictions of DNA-reactive mutagenicity are important to support both the design of new chemicals and the assessment of impurities, degradants, metabolites, extractables and leachables, as well as existing chemicals. Aromatic N-oxides represent a class of compounds that are often considered alerting for mutagenicity yet the scientific rationale of this structural alert is not clear and has been questioned. Because aromatic N-oxide-containing compounds may be encountered as impurities, degradants and metabolites, it is important to accurately predict mutagenicity of this chemical class...
September 5, 2018: Mutagenesis
Fengge Wang, Shuxiong Chen, Yanwen Jiang, Yun Zhao, Liting Sun, Biaobiao Zheng, Lu Chen, Zhuo Liu, Xue Zheng, Kangle Yi, Chunjin Li, Xu Zhou
Ammonia, produced mainly from the deamination of amino acids and glutamine, is one of the major toxic components in blood and tissues that may affect bovine health. However, the physiological and pathological roles of ammonia in the mammary glands are not understood clearly. In the present study, the bovine mammary epithelial cell line (MAC-T) was utilised as an in vitro model to determine the effects of ammonia on bovine mammary gland. We demonstrated that ammonia stimulated the production of intracellular reactive oxygen species, decreased mitochondrial membrane potential, interrupted intracellular calcium ion (Ca2+) homeostasis and induced cell apoptosis...
September 4, 2018: Mutagenesis
Hiroyuki Kamiya, Tetsuaki Makino, Tetsuya Suzuki, Miwako Kobayashi, Ichiro Matsuoka
Reactive oxygen species generate 8-oxo-7,8-dihydroguanine (GO, 8-hydroxyguanine), which induces G:C→T:A transversion mutations. The knockdowns of the protein responsible for Werner syndrome (WRN), a cancer-associated DNA helicase, and DNA polymerase (pol) λ, a WRN-interacting DNA pol, cause untargeted base-substitution mutations (action-at-a-distance mutations). To examine the consequences of the dual reductions of WRN and pol λ for the mutations caused by GO, siRNAs against both proteins were introduced into human U2OS cells...
August 23, 2018: Mutagenesis
Shunlan Yu, Junkang Quan, Xiaozhe Wang, Xiangyu Sun, Xianli Zhang, Yang Liu, Chenying Zhang, Shuguo Zheng
Autosomal-dominant hypocalcification amelogenesis imperfecta (ADHCAI) is characterized by soft enamel that easily disintegrates and exposed dark dentin. ADHCAI is caused by mutations in a gene called family with sequence similarity 83 member H (FAM83H). To investigate the molecular genetics of ADHCAI, a Chinese family in which three generations exhibited ADHCAI was recruited. The enamel ultrastructure was analysed by environmental scanning electron microscopy (ESEM), which showed altered enamel rod (prism) structures in ADHCAI patients compared to the structures in healthy controls...
October 11, 2018: Mutagenesis
Laura E Wohak, Ann-Christin Baranski, Annette M Krais, Heinz H Schmeiser, David H Phillips, Volker M Arlt
The tumour suppressor p53, encoded by TP53, is a key player in a wide network of signalling pathways. We investigated its role in the bioactivation of the environmental carcinogen 3-nitrobenzanthrone (3-NBA)found in diesel exhaust and its metabolites 3-aminobenzanthrone (3-ABA) and N-hydroxy-3-aminobenzanthrone (N-OH-3-ABA) in a panel of isogenic human colorectal HCT116 cells differing only with respect to their TP53 status [i.e. TP53(+/+), TP53(+/-), TP53(-/-), TP53(R248W/+) or TP53(R248W/-)]. As a measure of metabolic competence, DNA adduct formation was determined using 32P-postlabelling...
October 11, 2018: Mutagenesis
Jennifer E May, Craig Donaldson, Liana Gynn, H Ruth Morse
Mesenchymal stem/stromal cells (MSCs) within the bone marrow (BM) are vitally important in forming the micro-environment supporting haematopoiesis after myeloablative chemotherapy. MSCs are known to be damaged phenotypically and functionally by chemotherapy; however, to the best our knowledge, the persistence of genotoxic effects of chemotherapy on the BM micro-environment has not been studied. We therefore aimed to evaluate genotoxic effects of chemotherapy on the BM both in vitro and in vivo, using the comet and micronucleus assays, focussing on the persistence of DNA lesions that may contribute to complications in the patient...
September 17, 2018: Mutagenesis
Priti Singh, Lalit Mohan Aggarwal, Stephen A Parry, Mercy J Raman
Accurate quantification of DNA double strand breaks (DSB) in testicular germ cells is difficult because of cellular heterogeneity and the presence of endogenous γH2AX. Here, we used confocal microscopy to quantify DNA damage and repair kinetics following γ-irradiation (0.5-4 Gy) in three major mouse male germ cell stages, early and late pachytene spermatocytes and round spermatids (RSs), following a defined post irradiation time course. Dose-response curves showing linear best fit validated γH2AX focus as a rapid biodosimetric tool in these substages in response to whole body in vivo exposure...
September 17, 2018: Mutagenesis
Ashutosh Kumar, Mojgan Najafzadeh, Badie K Jacob, Alok Dhawan, Diana Anderson
No abstract text is available yet for this article.
September 17, 2018: Mutagenesis
Ana Cecilia Damiao Gouveia, Astrid Skovman, Annie Jensen, Ismo Kalevi Koponen, Steffen Loft, Martin Roursgaard, Peter Møller
Particles from burning candles contribute to the overall indoor exposure to particulate matter (PM). However, little is known about the effects of indoor sources of particles on cardiovascular disease endpoints. This study investigated the effect of pulmonary exposure to particles from combustion of candles and progression of atherosclerosis. Telomere shortening was assessed in tissues due to its relationship to risk of cardiovascular diseases. The particles were collected from burning candles and used for toxicological studies in cultured endothelial cells and apolipoprotein E (ApoE) knockout mice...
September 17, 2018: Mutagenesis
Héloïse Proquin, Carolina Rodríguez-Ibarra, Carolyn Moonen, Ismael M Urrutia Ortega, Jacob J Briedé, Theo M de Kok, Henk van Loveren, Yolanda Irasema Chirino
No abstract text is available yet for this article.
September 17, 2018: Mutagenesis
Huaxiang Zhao, Mengqi Zhang, Wenjie Zhong, Jieni Zhang, Wenbin Huang, Yunfan Zhang, Weiran Li, Peizeng Jia, Taowen Zhang, Zhonghao Liu, Jiuxiang Lin, Feng Chen
Non-syndromic cleft lip with or without cleft palate (NSCLP) is the most common congenital craniofacial malformation, and its harmful influence on affected individuals is apparent. Despite many studies, the causative genes and their mechanisms are not completely clear. We recruited a Han Chinese NSCLP family and explored the causative variant in this pedigree. We performed whole-exome sequencing on two patients. Bioinformatics screening and analysis were used to identify the mutation. We also performed species conservation analysis, mutation function predictions, and homology protein modelling to evaluate the influence of the mutation...
September 17, 2018: Mutagenesis
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