@article {335, title = {Clinical Significance and Molecular Annotation of Cellular Morphometric Subtypes in Lower Grade Gliomas discovered by Machine Learning.}, journal = {Neuro Oncol}, year = {2022}, month = {2022 Jun 18}, abstract = {

BACKGROUND: Lower grade gliomas (LGG) are heterogenous diseases by clinical, histological, and molecular criteria. We aimed to personalize the diagnosis and therapy of LGG patients by developing and validating robust cellular morphometric subtypes (CMS) and to uncover the molecular signatures underlying these subtypes.

METHODS: Cellular morphometric biomarkers (CMBs) were identified with artificial intelligence technique from TCGA-LGG cohort. Consensus clustering was used to define CMS. Survival analysis was performed to assess the clinical impact of CMBs and CMS. A nomogram was constructed to predict 3- and 5- year overall survival (OS) of LGG patients. Tumor mutational burden (TMB), and immune cell infiltration between subtypes were analyzed using the Mann-Whitney test. The double-blinded validation for important immunotherapy-related biomarkers were executed using immunohistochemistry (IHC).

RESULTS: We developed a machine learning pipeline to extract CMBs from whole slide images of tissue histology; identifying and externally validating robust CMS of LGGs in multi-center cohorts. The subtypes had independent predicted OS across all three independent cohorts. In the TCGA-LGG cohort, patients within the poor-prognosis subtype responded poorly to primary and follow-up therapies. LGGs within the poor-prognosis subtype were characterized by high mutational burden, high frequencies of copy number alterations, and high levels of tumor-infiltrating lymphocytes and immune checkpoint genes. Higher levels of PD-1/PD-L1/CTLA-4 were confirmed by immunohistochemical staining. In addition, the subtypes learned from LGG demonstrates translational impact on glioblastoma (GBM).

CONCLUSIONS: We developed and validated a framework (CMS-ML) for CMS discovery in LGG associated with specific molecular alterations, immune micro-environment, prognosis, and treatment response.

}, issn = {1523-5866}, doi = {10.1093/neuonc/noac154}, author = {Liu, Xiao-Ping and Jin, Xiaoqing and Ahmadian, Saman Seyed and Yang, Xu and Tian, Su-Fang and Cai, Yu-Xiang and Chawla, Kuldeep and Snijders, Antoine M and Xia, Yankai and van Diest, Paul J and Weiss, William A and Mao, Jian-Hua and Li, Zhi-Qiang and Vogel, Hannes and Chang, Hang} } @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 PPARĪ± 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 {309, title = {Genetic and metabolic links between the murine microbiome and memory.}, journal = {Microbiome}, volume = {8}, year = {2020}, month = {2020 04 17}, pages = {53}, abstract = {

BACKGROUND: Recent evidence has linked the gut microbiome to host behavior via the gut-brain axis [1-3]; however, the underlying mechanisms remain unexplored. Here, we determined the links between host genetics, the gut microbiome and memory using the genetically defined Collaborative Cross (CC) mouse cohort, complemented with microbiome and metabolomic analyses in conventional and germ-free (GF) mice.

RESULTS: A genome-wide association analysis (GWAS) identified 715 of 76,080 single-nucleotide polymorphisms (SNPs) that were significantly associated with short-term memory using the passive avoidance model. The identified SNPs were enriched in genes known to be involved in learning and memory functions. By 16S rRNA gene sequencing of the gut microbial community in the same CC cohort, we identified specific microorganisms that were significantly correlated with longer latencies in our retention test, including a positive correlation with Lactobacillus. Inoculation of GF mice with individual species of Lactobacillus (L. reuteri F275, L. plantarum BDGP2 or L. brevis BDGP6) resulted in significantly improved memory compared to uninoculated or E. coli DH10B inoculated controls. Untargeted metabolomics analysis revealed significantly higher levels of several metabolites, including lactate, in the stools of Lactobacillus-colonized mice, when compared to GF control mice. Moreover, we demonstrate that dietary lactate treatment alone boosted memory in conventional mice. Mechanistically, we show that both inoculation with Lactobacillus or lactate treatment significantly increased the levels of the neurotransmitter, gamma-aminobutyric acid (GABA), in the hippocampus of the mice.

CONCLUSION: Together, this study provides new evidence for a link between Lactobacillus and memory and our results open possible new avenues for treating memory impairment disorders using specific gut microbial inoculants and/or metabolites. Video Abstract.

}, issn = {2049-2618}, doi = {10.1186/s40168-020-00817-w}, author = {Mao, Jian-Hua and Kim, Young-Mo and Zhou, Yan-Xia and Hu, Dehong and Zhong, Chenhan and Hang Chang and Brislawn, Colin J and Fansler, Sarah and Langley, Sasha and Wang, Yunshan and Peisl, B Y Loulou and Celniker, Susan E and Threadgill, David W and Wilmes, Paul and Orr, Galya and Metz, Thomas O and Jansson, Janet K and Snijders, Antoine M} } @inbook {288, title = {Quantification of the Dynamics of DNA Repair to Ionizing Radiation via Colocalization of 53BP1 and {\^I}{\textthreesuperior}H2AX}, booktitle = {Video Bioinformatics: From Live Imaging to Knowledge}, year = {2015}, publisher = {Springer}, organization = {Springer}, isbn = {978-3-319-23723-7}, doi = {10.1007/978-3-319-23724-4}, author = {Groesser, Torsten and Fontenay, Gerald V. and Ju Han and Hang Chang and Janice Pluth and Bahram Parvin}, editor = {Bir Bhanu and Prue Talbot} } @article {76, title = {Stress signaling from human mammary epithelial cells contributes to phenotypes of mammographic density}, journal = {Cancer Res}, volume = {74}, year = {2014}, month = {2014 Sep 15}, pages = {5032-44}, abstract = {

Telomere malfunction and other types of DNA damage induce an activin A-dependent stress response in mortal nontumorigenic human mammary epithelial cells that subsequently induces desmoplastic-like phenotypes in neighboring fibroblasts. Some characteristics of this fibroblast/stromal response, such as reduced adipocytes and increased extracellular matrix content, are observed not only in tumor tissues but also in disease-free breast tissues at high risk for developing cancer, especially high mammographic density tissues. We found that these phenotypes are induced by repression of the fatty acid translocase CD36, which is seen in desmoplastic and disease-free high mammographic density tissues. In this study, we show that epithelial cells from high mammographic density tissues have more DNA damage signaling, shorter telomeres, increased activin A secretion and an altered DNA damage response compared with epithelial cells from low mammographic density tissues. Strikingly, both telomere malfunction and activin A expression in epithelial cells can repress CD36 expression in adjacent fibroblasts. These results provide new insights into how high mammographic density arises and why it is associated with breast cancer risk, with implications for the definition of novel invention targets (e.g., activin A and CD36) to prevent breast cancer.

}, keywords = {Antigens, Breast Neoplasms, CD36, DNA Damage, Epithelial Cells, Female, Human, Humans, Mammary Glands, Phenotype, Signal Transduction}, issn = {1538-7445}, doi = {10.1158/0008-5472.CAN-13-3390}, author = {DeFilippis, Rosa Anna and Fordyce, Colleen and Patten, Kelley and Hang Chang and Zhao, Jianxin and Fontenay, Gerald V and Kerlikowske, Karla and Parvin, Bahram and Tlsty, Thea D} } @article {81, title = {Breast fibroblasts modulate early dissemination, tumorigenesis, and metastasis through alteration of extracellular matrix characteristics}, journal = {Neoplasia}, volume = {15}, year = {2013}, month = {2013 Mar}, pages = {249-62}, abstract = {

A wealth of evidence has now demonstrated that the microenvironment in which a tumorigenic cell evolves is as critical to its evolution as the genetic mutations it accrues. However, there is still relatively little known about how signals from the microenvironment contribute to the early events in the progression to malignancy. To address this question, we used a premalignant mammary model to examine how fibroblasts, and the extracellular matrix (ECM) proteins they secrete, influence progression to malignancy. Their effect on metastatic malignant cells was also assessed for comparison. We found that carcinoma-associated fibroblasts, and the distinct aligned ECM they deposit, can cause both premalignant and malignant mammary epithelial cells to assume a mesenchymal morphology that is associated with increased dissemination and metastasis, while benign reduction mammoplasty fibroblasts favor the maintenance of an epithelial morphology and constrain early dissemination, tumor growth, and metastasis. Our results suggest that normalizing the organization of the ECM could be effective in limiting systemic dissemination and tumor growth.

}, keywords = {Animals, Breast, Cell Line, Cell Transformation, Coculture Techniques, Epithelial Cells, Experimental, Extracellular Matrix, Extracellular Signal-Regulated MAP Kinases, Female, Fibroblasts, Humans, Lung Neoplasms, Mammary Neoplasms, Neoplasm Metastasis, Neoplastic, Phenotype, Proto-Oncogene Proteins c-jun, rho GTP-Binding Proteins, Signal Transduction, Transforming Growth Factor beta, Tumor}, issn = {1476-5586}, author = {Dumont, Nancy and Liu, Bob and DeFilippis, Rosa Anna and Hang Chang and Rabban, Joseph T and Karnezis, Anthony N and Tjoe, Judy A and Marx, James and Parvin, Bahram and Tlsty, Thea D} } @article {82, title = {CD36 repression activates a multicellular stromal program shared by high mammographic density and tumor tissues}, journal = {Cancer Discov}, volume = {2}, year = {2012}, month = {2012 Sep}, pages = {826-39}, abstract = {

UNLABELLED: Although high mammographic density is considered one of the strongest risk factors for invasive breast cancer, the genes involved in modulating this clinical feature are unknown. Tissues of high mammographic density share key histologic features with stromal components within malignant lesions of tumor tissues, specifically low adipocyte and high extracellular matrix (ECM) content. We show that CD36, a transmembrane receptor that coordinately modulates multiple protumorigenic phenotypes, including adipocyte differentiation, angiogenesis, cell-ECM interactions, and immune signaling, is greatly repressed in multiple cell types of disease-free stroma associated with high mammographic density and tumor stroma. Using both in vitro and in vivo assays, we show that CD36 repression is necessary and sufficient to recapitulate the above-mentioned phenotypes observed in high mammographic density and tumor tissues. Consistent with a functional role for this coordinated program in tumorigenesis, we observe that clinical outcomes are strongly associated with CD36 expression.

SIGNIFICANCE: CD36 simultaneously controls adipocyte content and matrix accumulation and is coordinately repressed in multiple cell types within tumor and high mammographic density stroma, suggesting that activation of this stromal program is an early event in tumorigenesis. Levels of CD36 and extent of mammographic density are both modifiable factors that provide potential for intervention.

}, keywords = {Adipocytes, Animals, Antigens, Breast Neoplasms, CD36, Cell Differentiation, Female, Humans, Knockout, Mammography, Mice, Risk Factors, Signal Transduction, Stromal Cells}, issn = {2159-8290}, doi = {10.1158/2159-8290.CD-12-0107}, author = {DeFilippis, Rosa Anna and Hang Chang and Dumont, Nancy and Rabban, Joseph T and Chen, Yunn-Yi and Fontenay, Gerald V and Berman, Hal K and Gauthier, Mona L and Zhao, Jianxin and Hu, Donglei and Marx, James J and Tjoe, Judy A and Ziv, Elad and Febbraio, Maria and Kerlikowske, Karla and Parvin, Bahram and Tlsty, Thea D} } @article {179, title = {Progressive genomic instability in the FVB/Kras(LA2) mouse model of lung cancer.}, journal = {Mol Cancer Res}, volume = {9}, year = {2011}, month = {2011 Oct}, pages = {1339-45}, abstract = {

Alterations in DNA copy number contribute to the development and progression of cancers and are common in epithelial tumors. We have used array Comparative Genomic Hybridization (aCGH) to visualize DNA copy number alterations across the genomes of lung tumors in the Kras(LA2) model of lung cancer. Copy number gain involving the Kras locus, as focal amplification or whole chromosome gain, is the most common alteration in these tumors and with a prevalence that increased significantly with increasing tumor size. Furthermore, Kras amplification was the only major genomic event among the smallest lung tumors, suggesting that this alteration occurs early during the development of mutant Kras-driven lung cancers. Recurring gains and deletions of other chromosomes occur progressively more frequently among larger tumors. These results are in contrast to a previous aCGH analysis of lung tumors from Kras(LA2) mice on a mixed genetic background, in which relatively few DNA copy number alterations were observed regardless of tumor size. Our model features the Kras(LA2) allele on the inbred FVB/N mouse strain, and in this genetic background, there is a highly statistically significant increase in level of genomic instability with increasing tumor size. These data suggest that recurring DNA copy alterations are important for tumor progression in the Kras(LA2) model of lung cancer and that the requirement for these alterations may be dependent on the genetic background of the mouse strain.

}, keywords = {Animal, Animals, Cell Line, Chromosome Aberrations, Disease Models, Disease Progression, DNA, DNA Copy Number Variations, Gene Dosage, Gene Expression Regulation, Genes, Genomic Instability, Inbred C57BL, Lung Neoplasms, Mice, Neoplasm, Neoplastic, Proto-Oncogene Proteins p21(ras), ras, Tumor}, issn = {1557-3125}, doi = {10.1158/1541-7786.MCR-11-0219}, author = {To, Minh D and Quigley, David A and Jiang-Hua Mao and Del Rosario, Reyno and Hsu, Jeff and Hodgson, Graeme and Jacks, Tyler and Balmain, Allan} } @article {41, title = {Graphical methods for quantifying macromolecules through bright field imaging}, journal = {Bioinformatics}, volume = {25}, year = {2009}, pages = {1070{\textendash}1075}, doi = {10.1093/bioinformatics/btn426}, url = {http://dx.doi.org/10.1093/bioinformatics/btn426}, author = {Hang Chang and Rosa Anna DeFilippis and Thea D. Tlsty and Bahram Parvin} } @conference {46, title = {Scoring histological sections through immunohistochemistry}, booktitle = {Proceedings of the 2008 {IEEE} International Symposium on Biomedical Imaging: From Nano to Macro, Paris, France, May 14-17, 2008}, year = {2008}, doi = {10.1109/ISBI.2008.4541003}, url = {http://dx.doi.org/10.1109/ISBI.2008.4541003}, author = {Hang Chang and Rosa Anna DeFilippis and Thea D. Tlsty and Bahrain Parvin} }