@article {325, title = {Host genetics and gut microbiota cooperatively contribute to azoxymethane-induced acute toxicity in Collaborative Cross mice.}, journal = {Arch Toxicol}, volume = {95}, year = {2021}, month = {2021 03}, pages = {949-958}, abstract = {

Azoxymethane (AOM) is a widely used carcinogen to study chemical-induced colorectal carcinogenesis and is an agent for studying fulminant hepatic failure. The inter-strain susceptibility to acute toxicity by AOM has been reported, but its association with host genetics or gut microbiota remains largely unexplored. Here a cohort of genetically diverse Collaborative Cross (CC) mice was used to assess the contribution of host genetics and the gut microbiome to AOM-induced acute toxicity. We observed variation in AOM-induced acute liver failure across CC strains. Quantitative trait loci (QTL) analysis revealed three chromosome regions significantly associated with AOM toxicity. Genes located within these QTL, including peroxisome proliferator-activated receptor alpha (Ppara), were enriched for enzyme activator and nucleoside-triphosphatase regulator activity. We further demonstrated that the protein level of PPARα in liver tissues from sensitive strains was remarkably lower compared to levels in resistant strains, consistent with protective role of PPAR family in liver injury. We discovered that the abundance levels of gut microbial families Anaeroplasmataceae, Ruminococcaceae, Lactobacillaceae, Akkermansiaceae and Clostridiaceae were significantly higher in the sensitive strains\ compared to the resistant strains. Using a random forest classifier method, we determined that the relative abundance levels of these microbial families predicted AOM toxicity with the area under the receiver-operating curve (AUC) of 0.75. Combining the three genetic loci and five microbial families increased the predictive accuracy of AOM toxicity (AUC of 0.99). Moreover, we found that Ruminococcaceae and Lactobacillaceae acted as mediators between host genetics and AOM toxicity. In conclusion, this study shows that host genetics and specific microbiome members play a critical role in AOM-induced acute toxicity, which provides a framework for analysis of the health effects from environmental toxicants.

}, keywords = {Animals, Azoxymethane, Carcinogens, Chemical and Drug Induced Liver Injury, Collaborative Cross Mice, Gastrointestinal Microbiome, Liver Failure, Acute, Male, Mice, Quantitative Trait Loci, Species Specificity}, issn = {1432-0738}, doi = {10.1007/s00204-021-02972-x}, author = {Zhong, Chenhan and He, Li and Lee, Sun-Young and Chang, Hang and Zhang, Yuqing and Threadgill, David W and Yuan, Ying and Zhou, Fuling and Celniker, Susan E and Xia, Yankai and Snijders, Antoine M and Mao, Jian-Hua} } @article {300, title = {High-Dimensional Phenotyping Identifies Age-Emergent Cells in Human Mammary Epithelia.}, journal = {Cell Rep}, volume = {23}, year = {2018}, month = {2018 Apr 24}, pages = {1205-1219}, abstract = {

Aging is associated with tissue-level changes in\ cellular composition that are correlated with increased susceptibility to disease. Aging human mammary tissue shows skewed progenitor cell potency, resulting in diminished tumor-suppressive cell types and the accumulation of defective epithelial progenitors. Quantitative characterization of these age-emergent human cell subpopulations is lacking, impeding our understanding of the relationship between age and cancer susceptibility. We conducted single-cell resolution proteomic phenotyping of healthy breast epithelia from 57 women, aged 16-91 years, using mass cytometry. Remarkable heterogeneity was quantified within the two mammary epithelial lineages. Population partitioning identified a subset of aberrant basal-like luminal cells that accumulate with age and originate from age-altered progenitors. Quantification of age-emergent phenotypes\ enabled robust classification of breast tissues by age in healthy women. This high-resolution mapping highlighted specific epithelial subpopulations that\ change with age in a manner consistent with increased susceptibility to breast cancer.

}, issn = {2211-1247}, doi = {10.1016/j.celrep.2018.03.114}, author = {Pelissier Vatter, Fanny A and Schapiro, Denis and Hang Chang and Borowsky, Alexander D and Lee, Jonathan K and Parvin, Bahram and Stampfer, Martha R and LaBarge, Mark A and Bodenmiller, Bernd and Lorens, James B} } @article {204, title = {Hematein, a casein kinase II inhibitor, inhibits lung cancer tumor growth in a murine xenograft model.}, journal = {Int J Oncol}, volume = {43}, year = {2013}, month = {2013 Nov}, pages = {1517-22}, abstract = {

Casein kinase II (CK2) inhibitors suppress cancer cell growth. In this study, we examined the inhibitory effects of a novel CK2 inhibitor, hematein, on tumor growth in a murine xenograft model. We found that in lung cancer cells, hematein inhibited cancer cell growth, Akt/PKB Ser129 phosphorylation, the Wnt/TCF pathway and increased apoptosis. In a murine xenograft model of lung cancer, hematein inhibited tumor growth without significant toxicity to the mice tested. Molecular docking showed that hematein binds to CK2α in durable binding sites. Collectively, our results suggest that hematein is an allosteric inhibitor of protein kinase CK2 and has antitumor activity to lung cancer.

}, keywords = {Animals, Apoptosis, Blotting, Casein Kinase II, Cultured, Enzyme Inhibitors, Female, Hematoxylin, Humans, Immunoenzyme Techniques, Inbred BALB C, Lung Neoplasms, Mice, Phosphorylation, Proto-Oncogene Proteins c-akt, T Cell Transcription Factor 1, Tumor Cells, Western, Wnt Proteins, Xenograft Model Antitumor Assays}, issn = {1791-2423}, doi = {10.3892/ijo.2013.2087}, author = {Hung, Ming-Szu and Xu, Zhidong and Chen, Yu and Smith, Emmanuel and Jiang-Hua Mao and Hsieh, David and Lin, Yu-Ching and Yang, Cheng-Ta and Jablons, David M and You, Liang} }