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1دورية أكاديمية
المؤلفون: Kim, Olga, Park, Eun Young, Klinkebiel, David L, Pack, Svetlana D, Shin, Yong-Hyun, Abdullaev, Zied, Emerson, Robert E, Coffey, Donna M, Kwon, Sun Young, Creighton, Chad J, Kwon, Sanghoon, Chang, Edmund C, Chiang, Theodore, Yatsenko, Alexander N, Chien, Jeremy, Cheon, Dong-Joo, Yang-Hartwich, Yang, Nakshatri, Harikrishna, Nephew, Kenneth P, Behringer, Richard R, Fernández, Facundo M, Cho, Chi-Heum, Vanderhyden, Barbara, Drapkin, Ronny, Bast, Robert C, Miller, Kathy D, Karpf, Adam R, Kim, Jaeyeon
المصدر: PLoS genetics. 16(6)
مصطلحات موضوعية: Cell Line, Tumor, Animals, Mice, Knockout, Humans, Mice, Cystadenocarcinoma, Serous, Peritoneal Neoplasms, Ovarian Neoplasms, Neoplasm Metastasis, Disease Models, Animal, Chromosomal Instability, Ribonuclease III, Antineoplastic Agents, Drug Screening Assays, Antitumor, Feasibility Studies, DNA Repair, Drug Resistance, Neoplasm, Mutation, Female, Tumor Suppressor Protein p53, PTEN Phosphohydrolase, DEAD-box RNA Helicases, Primary Cell Culture, Neoplasm Grading, Developmental Biology, Genetics
الوصف: Metastasis is responsible for 90% of human cancer mortality, yet it remains a challenge to model human cancer metastasis in vivo. Here we describe mouse models of high-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), the most common and deadliest human ovarian cancer type. Mice genetically engineered to harbor Dicer1 and Pten inactivation and mutant p53 robustly replicate the peritoneal metastases of human HGSC with complete penetrance. Arising from the fallopian tube, tumors spread to the ovary and metastasize throughout the pelvic and peritoneal cavities, invariably inducing hemorrhagic ascites. Widespread and abundant peritoneal metastases ultimately cause mouse deaths (100%). Besides the phenotypic and histopathological similarities, mouse HGSCs also display marked chromosomal instability, impaired DNA repair, and chemosensitivity. Faithfully recapitulating the clinical metastases as well as molecular and genomic features of human HGSC, this murine model will be valuable for elucidating the mechanisms underlying the development and progression of metastatic ovarian cancer and also for evaluating potential therapies.
وصف الملف: application/pdf
الوصول الحر: https://escholarship.org/uc/item/04x8d69rTest
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2دورية أكاديمية
المؤلفون: Scholler, Nathalie, Perbost, Regis, Locke, Frederick L., Jain, Michael D., Turcan, Sarah, Danan, Corinne, Chang, Edmund C., Neelapu, Sattva S., Miklos, David B., Jacobson, Caron A., Lekakis, Lazaros J., Lin, Yi, Ghobadi, Armin, Kim, Jenny J., Chou, Justin, Plaks, Vicki, Wang, Zixing, Xue, Allen, Mattie, Mike, Rossi, John M., Bot, Adrian, Galon, Jérôme
المصدر: Nature Medicine ; volume 28, issue 9, page 1872-1882 ; ISSN 1078-8956 1546-170X
مصطلحات موضوعية: General Biochemistry, Genetics and Molecular Biology, General Medicine
الوصف: Axicabtagene ciloleucel (axi-cel) is an anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for relapsed/refractory large B cell lymphoma (LBCL) and has treatment with similar efficacy across conventional LBCL subtypes. Toward patient stratification, we assessed whether tumor immune contexture influenced clinical outcomes after axi-cel. We evaluated the tumor microenvironment (TME) of 135 pre-treatment and post-treatment tumor biopsies taken from 51 patients in the ZUMA-1 phase 2 trial. We uncovered dynamic patterns that occurred within 2 weeks after axi-cel. The biological associations among Immunoscore (quantification of tumor-infiltrating T cell density), Immunosign 21 (expression of pre-defined immune gene panel) and cell subsets were validated in three independent LBCL datasets. In the ZUMA-1 trial samples, clinical response and overall survival were associated with pre-treatment immune contexture as characterized by Immunoscore and Immunosign 21. Circulating CAR T cell levels were associated with post-treatment TME T cell exhaustion. TME enriched for chemokines (CCL5 and CCL22), γ-chain receptor cytokines (IL-15, IL-7 and IL-21) and interferon-regulated molecules were associated with T cell infiltration and markers of activity. Finally, high density of regulatory T cells in pre-treatment TME associated with reduced axi-cel–related neurologic toxicity. These findings advance the understanding of LBCL TME characteristics associated with clinical responses to anti-CD19 CAR T cell therapy and could foster biomarker development and treatment optimization for patients with LBCL.
الإتاحة: https://doi.org/10.1038/s41591-022-01916-xTest
https://www.nature.com/articles/s41591-022-01916-x.pdfTest
https://www.nature.com/articles/s41591-022-01916-xTest -
3دورية أكاديمية
المؤلفون: Chang, Edmund C, Liu, Hao, West, John A, Zhou, Xiaoou, Dakhova, Olga, Wheeler, David A, Heslop, Helen E, Brenner, Malcolm K, Dotti, Gianpietro
المصدر: Molecular Therapy ; volume 24, issue 4, page 736-745 ; ISSN 1525-0016
مصطلحات موضوعية: Drug Discovery, Pharmacology, Genetics, Molecular Biology, Molecular Medicine
الإتاحة: https://doi.org/10.1038/mt.2015.217Test
https://api.elsevier.com/content/article/PII:S1525001616309972?httpAccept=text/plainTest
https://api.elsevier.com/content/article/PII:S1525001616309972?httpAccept=text/xmlTest -
4دورية أكاديمية
المؤلفون: Nguyen, Tuan Minh, Chang, Edmund C., Rosen, Jeffrey M.
المصدر: The FASEB Journal ; volume 27, issue S1 ; ISSN 0892-6638 1530-6860
الوصف: The cancer stem cell (CSC) theory hypothesizes a subset of the tumorigenic cells able to self‐renew and wholly reconstitute original tumors by lineage restriction. We developed a lentiviral barcoding system as a means of genetic lineage tracing of cell subpopulations sorted by surface marker expression to investigate the proliferation kinetics, plasticity and clonality of tumor‐initiating cells (TICs). The abundance of each barcode in the reconstituted tumor reflects the frequency of TIC progeny in individual cell fractions. We determined that the CD29 H /CD24 H subfraction consistently out‐competes other subfractions while forming populations of different immune‐profiles, indicating that this subfraction retains the two cardinal features of self‐renewal and ability to give rise to progeny through lineage restriction ascribed to TICs, and suggests that not a lot of plasticity happens between non‐TICs and TICs. Also, iPCR was successfully applied into the lentiviral barcoding system, enabling the analysis of the TIC's clonality over serial transplant passages to understand the CSC's hierarchy. This novel lentiviral barcoding strategy provides future framework for defining specific biomarkers and evaluating therapeutics directed towards CSCs. This lineage tracing methodology should be applicable not only to genetically engineered mouse models but also to primary human breast cancer xenografts.
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5دورية أكاديمية
المؤلفون: Chang, Edmund C., Liu, Hao, West, John A, Zhou, Xiaoou, Dakhova, Olga, Wheeler, David A, Heslop, Helen E, Brenner, Malcolm K, Dotti, Gianpietro
المصدر: Molecular Therapy, 24(4)
مصطلحات موضوعية: Humans, Transplantation, Homologous, T-Lymphocytes, Organic Chemicals, Immunotherapy, Transgenes, Hematopoietic Stem Cell Transplantation, Promoter Regions, Genetic, Graft vs Host Disease, Chromatin, Virus Integration, Caspase 9, Genome, Human
الوصف: Safety switches are becoming relevant for the clinical translation of T-cell-based immunotherapies. In patients receiving an allogeneic hematopoietic stem cell transplant, the inducible caspase-9 gene (iC9) safety switch expressed by donor-derived T lymphocytes efficiently controls acute graft versus host disease (GvHD). However, in vivo elimination of iC9-T cells by the chemical inducer of dimerization (CID) that activates the iC9 protein is incomplete. To study this effect, we characterized the clonal diversity and dynamics of vector insertion sites (VIS) in iC9-T cells pre- and post-CID administration in four patients who developed GvHD. We identified 3,203 VIS among four patients and followed their in vivo clonal dynamics up to 161 days post-CID. VIS were categorized by their proximity to host genome elements, gene associations, and cis-modulatory relationship to mapped promoters. We found that VIS are preferentially located near open chromatin and promoter regions; furthermore, there was no evidence for selection bias among VIS surviving the CID treatment. The majority of iC9-T cells with high normalized VIS copy number at the time of GvHD onset were eliminated by CID, while iC9-T cells detectable post-CID generally have low normalized VIS copy number. We propose that suboptimal iC9 transgene expression is responsible for the incomplete elimination of iC9-T cells and illustrate here by simple model how cis-modulatory influences of local genome context and T-cell receptor activation status at time of CID treatment contribute to stochastic sparing of iC9-T cells.
العلاقة: https://doi.org/10.17615/t3ap-kz12Test; https://cdr.lib.unc.edu/downloads/rv043063t?file=thumbnailTest; https://cdr.lib.unc.edu/downloads/rv043063tTest
الإتاحة: https://doi.org/10.17615/t3ap-kz12Test
https://cdr.lib.unc.edu/downloads/rv043063t?file=thumbnailTest
https://cdr.lib.unc.edu/downloads/rv043063tTest -
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المؤلفون: Liu, Hao, Dotti, Gianpietro, Heslop, Helen E, Brenner, Malcolm K, Dakhova, Olga, Wheeler, David A, Chang, Edmund C., West, John A, Zhou, Xiaoou
الوصف: Safety switches are becoming relevant for the clinical translation of T-cell-based immunotherapies. In patients receiving an allogeneic hematopoietic stem cell transplant, the inducible caspase-9 gene (iC9) safety switch expressed by donor-derived T lymphocytes efficiently controls acute graft versus host disease (GvHD). However, in vivo elimination of iC9-T cells by the chemical inducer of dimerization (CID) that activates the iC9 protein is incomplete. To study this effect, we characterized the clonal diversity and dynamics of vector insertion sites (VIS) in iC9-T cells pre- and post-CID administration in four patients who developed GvHD. We identified 3,203 VIS among four patients and followed their in vivo clonal dynamics up to 161 days post-CID. VIS were categorized by their proximity to host genome elements, gene associations, and cis-modulatory relationship to mapped promoters. We found that VIS are preferentially located near open chromatin and promoter regions; furthermore, there was no evidence for selection bias among VIS surviving the CID treatment. The majority of iC9-T cells with high normalized VIS copy number at the time of GvHD onset were eliminated by CID, while iC9-T cells detectable post-CID generally have low normalized VIS copy number. We propose that suboptimal iC9 transgene expression is responsible for the incomplete elimination of iC9-T cells and illustrate here by simple model how cis-modulatory influences of local genome context and T-cell receptor activation status at time of CID treatment contribute to stochastic sparing of iC9-T cells.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::3ebcd2c86552421e28a1a3d67bfd5a6aTest
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7دورية أكاديمية
المؤلفون: Chang, Edmund C
المساهمون: BAYLOR COLL OF MEDICINE HOUSTON TX
المصدر: DTIC
مصطلحات موضوعية: Anatomy and Physiology, Medicine and Medical Research, CANCER, STEM CELLS, BREAST CANCER, CELLS(BIOLOGY), GROWTH(PHYSIOLOGY), HYPOTHESES, KINETICS, NEOPLASMS, POPULATION, RESISTANCE, LINEAGE TRACING, LENTIVIRAL BARCODING
الوصف: In order to characterize the TIC population, we are developing a unique lentiviral barcode strategy to examine the growth kinetics and lineage of tumor cells. These studies are based on the hypothesis that TICs represent a limited subpopulation in breast cancers that give rise to tumor heterogeneity, and that these cells are intrinsically resistant to radiation and chemotherapy. In the first 12 months of the award period, we have successfully completed the first of our two specific aims. ; The original document contains color images.
وصف الملف: text/html
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8دورية
المؤلفون: Chang, Edmund C, Liu, Hao, West, John A, Zhou, Xiaoou, Dakhova, Olga, Wheeler, David A, Heslop, Helen E, Brenner, Malcolm K, Dotti, Gianpietro
المصدر: Molecular Therapy; April 2016, Vol. 24 Issue: 4 p736-745, 10p
مستخلص: Safety switches are becoming relevant for the clinical translation of T-cell–based immunotherapies. In patients receiving an allogeneic hematopoietic stem cell transplant, the inducible caspase-9 gene (iC9) safety switch expressed by donor-derived T lymphocytes efficiently controls acute graft versus host disease (GvHD). However, in vivoelimination of iC9-T cells by the chemical inducer of dimerization (CID) that activates the iC9 protein is incomplete. To study this effect, we characterized the clonal diversity and dynamics of vector insertion sites (VIS) in iC9-T cells pre- and post-CID administration in four patients who developed GvHD. We identified 3,203 VIS among four patients and followed their in vivoclonal dynamics up to 161 days post-CID. VIS were categorized by their proximity to host genome elements, gene associations, and cis-modulatory relationship to mapped promoters. We found that VIS are preferentially located near open chromatin and promoter regions; furthermore, there was no evidence for selection bias among VIS surviving the CID treatment. The majority of iC9-T cells with high normalized VIS copy number at the time of GvHD onset were eliminated by CID, while iC9-T cells detectable post-CID generally have low normalized VIS copy number. We propose that suboptimal iC9 transgene expression is responsible for the incomplete elimination of iC9-T cells and illustrate here by simple model how cis-modulatory influences of local genome context and T-cell receptor activation status at time of CID treatment contribute to stochastic sparing of iC9-T cells.
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9دورية
المؤلفون: Chang, Edmund C., Charn, Tze Howe, Park, Sung-Hee, Helferich, William G., Komm, Barry, Katzenellenbogen, John A., Katzenellenbogen, Benita S.
المصدر: Molecular Endocrinology; May 2008, Vol. 22 Issue: 5 p1032-1043, 12p
مستخلص: Estrogen receptors and β (ER and ERβ) mediate the actions of estrogens in a variety of normal and cancer target cells. Estrogens differ in their preference for these ERs, and many phytoestrogens bind preferentially to ERβ. To investigate how phytoestrogens such as genistein impact ER-regulated gene expression, we used adenoviral gene delivery of ERβ coupled with ER depletion with small interfering RNA to generate human breast cancer (MCF-7) cells expressing four complements of ER and ERβ. We examined the dose-dependent effects of genistein on genome-wide gene expression by DNA microarrays and monitored the recruitment of ERs and coregulators to responsive regions of estrogen-regulated genes. At a low (6 nM) concentration, genistein regulated gene expression much more effectively in cells coexpressing ER and ERβ than in cells expressing ER alone, whereas at high concentration (300 nM), genistein induced transcriptome changes very similar to that of 17β-estradiol. We demonstrate that ERβ is preferentially activated by genistein and is recruited to estrogen-responsive genomic sites and that differential occupancy of ER and ERβ by genistein and 17β-estradiol in turn influences the recruitment patterns of coregulators such as steroid receptor coactivator 3 (SRC3) and receptor-interacting protein 140 (RIP140). Our observations indicate that genistein is a potency-selective ligand for gene expression regulation by ER and ERβ and that the ability of ER and ERβ to serve as determinants of gene expression is greatly influenced by the nature of the ligand, by ligand dose, and by the differential abilities of ligand-ER complexes to recruit different coregulators at ER binding sites of hormone-regulated genes.
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المؤلفون: Chang, Edmund Chi-Ru
مصطلحات موضوعية: Biology, Molecular.
الوصف: Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2007.
Source: Dissertation Abstracts International, Volume: 68-11, Section: B, page: 7110. Adviser: Benita Katzenellenbogen. Includes bibliographical references. Available on microfilm from Pro Quest Information and Learning.
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