@article {326, title = {A new platform for ultra-high dose rate radiobiological research using the BELLA PW laser proton beamline.}, journal = {Sci Rep}, volume = {12}, year = {2022}, month = {2022 01 27}, pages = {1484}, abstract = {

Radiotherapy is the current standard of care for more than 50\% of all cancer patients. Improvements in radiotherapy (RT) technology have increased tumor targeting and normal tissue sparing. Radiations at ultra-high dose rates required for FLASH-RT effects have sparked interest in potentially providing additional differential therapeutic benefits. We present a new experimental platform that is the first one to deliver petawatt laser-driven proton pulses of 2\ MeV energy at 0.2\ Hz repetition rate by means of a compact, tunable active plasma lens beamline to biological samples. Cell monolayers grown over a 10\ mm diameter field were exposed to clinically relevant proton doses ranging from 7 to 35\ Gy at ultra-high instantaneous dose rates of 10\ Gy/s. Dose-dependent cell survival measurements of human normal and tumor cells exposed to LD protons showed significantly higher cell survival of normal-cells compared to tumor-cells for total doses of 7\ Gy and higher, which was not observed to the same extent for X-ray reference irradiations at clinical dose rates. These findings provide preliminary evidence that compact LD proton sources enable a new and promising platform for investigating the physical, chemical and biological mechanisms underlying the FLASH effect.

}, keywords = {Cell Line, Humans, Lasers, Monte Carlo Method, Neoplasms, Proton Therapy, Radiation Oncology, Radiobiology, Radiometry, Radiotherapy Dosage, Synchrotrons}, issn = {2045-2322}, doi = {10.1038/s41598-022-05181-3}, author = {Bin, Jianhui and Obst-Huebl, Lieselotte and Mao, Jian-Hua and Nakamura, Kei and Geulig, Laura D and Chang, Hang and Ji, Qing and He, Li and De Chant, Jared and Kober, Zachary and Gonsalves, Anthony J and Bulanov, Stepan and Celniker, Susan E and Schroeder, Carl B and Geddes, Cameron G R and Esarey, Eric and Simmons, Blake A and Schenkel, Thomas and Blakely, Eleanor A and Steinke, Sven and Snijders, Antoine M} } @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} } @article {301, title = {Machine Learning in Multimodal Medical Imaging.}, journal = {Biomed Res Int}, volume = {2017}, year = {2017}, month = {2017}, pages = {1278329}, keywords = {Animals, Humans, Image Processing, Computer-Assisted, Machine Learning}, issn = {2314-6141}, doi = {10.1155/2017/1278329}, author = {Xia, Yong and Ji, Zexuan and Krylov, Andrey and Hang Chang and Cai, Weidong} } @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 {26, title = {Integrated profiling of three dimensional cell culture models and 3D microscopy}, journal = {Bioinformatics}, volume = {29}, year = {2013}, pages = {3087{\textendash}3093}, doi = {10.1093/bioinformatics/btt535}, url = {http://dx.doi.org/10.1093/bioinformatics/btt535}, author = {Cemal Cagatay Bilgin and Sun Kim and Elle Leung and Hang Chang and Bahram Parvin} } @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 {87, title = {Molecular predictors of 3D morphogenesis by breast cancer cell lines in 3D culture}, journal = {PLoS Comput Biol}, volume = {6}, year = {2010}, month = {2010 Feb}, pages = {e1000684}, abstract = {

Correlative analysis of molecular markers with phenotypic signatures is the simplest model for hypothesis generation. In this paper, a panel of 24 breast cell lines was grown in 3D culture, their morphology was imaged through phase contrast microscopy, and computational methods were developed to segment and represent each colony at multiple dimensions. Subsequently, subpopulations from these morphological responses were identified through consensus clustering to reveal three clusters of round, grape-like, and stellate phenotypes. In some cases, cell lines with particular pathobiological phenotypes clustered together (e.g., ERBB2 amplified cell lines sharing the same morphometric properties as the grape-like phenotype). Next, associations with molecular features were realized through (i) differential analysis within each morphological cluster, and (ii) regression analysis across the entire panel of cell lines. In both cases, the dominant genes that are predictive of the morphological signatures were identified. Specifically, PPARgamma has been associated with the invasive stellate morphological phenotype, which corresponds to triple-negative pathobiology. PPARgamma has been validated through two supporting biological assays.

}, keywords = {Biological, Biomarkers, Breast Neoplasms, Cell Culture Techniques, Cell Line, Computer-Assisted, ErbB-2, Female, Gene Expression Profiling, Histocytochemistry, Humans, Image Processing, Models, Phenotype, PPAR gamma, Receptor, Reproducibility of Results, Tumor}, issn = {1553-7358}, doi = {10.1371/journal.pcbi.1000684}, author = {Han, Ju and Hang Chang and Giricz, Orsi and Lee, Genee Y and Baehner, Frederick L and Gray, Joe W and Bissell, Mina J and Kenny, Paraic A and Parvin, Bahram} } @article {296, title = {Active mask segmentation of fluorescence microscope images.}, journal = {IEEE Trans Image Process}, volume = {18}, year = {2009}, month = {2009 Aug}, pages = {1817-29}, abstract = {

We propose a new active mask algorithm for the segmentation of fluorescence microscope images of punctate patterns. It combines the (a) flexibility offered by active-contour methods, (b) speed offered by multiresolution methods, (c) smoothing offered by multiscale methods, and (d) statistical modeling offered by region-growing methods into a fast and accurate segmentation tool. The framework moves from the idea of the "contour" to that of "inside and outside," or masks, allowing for easy multidimensional segmentation. It adapts to the topology of the image through the use of multiple masks. The algorithm is almost invariant under initialization, allowing for random initialization, and uses a few easily tunable parameters. Experiments show that the active mask algorithm matches the ground truth well and outperforms the algorithm widely used in fluorescence microscopy, seeded watershed, both qualitatively, as well as quantitatively.

}, keywords = {Algorithms, Automated, Computer-Assisted, Cytological Techniques, Fluorescence, HeLa Cells, Humans, Image Processing, Microscopy, Pattern Recognition}, issn = {1057-7149}, doi = {10.1109/TIP.2009.2021081}, author = {Srinivasa, Gowri and Fickus, Matthew C and Yusong Guo and Linstedt, Adam D and Kovacevi{\'c}, Jelena} }