Here, we report that genetic or pharmacologic Hedgehog pathway inhibition intensifies colon inflammation (colitis) in mice. We have previously shown that two human T-cell lines (HSB and 8402) derived from patients with childhood T-cell ALL (T-ALL) do not synthesize detectable mRNA for HLA-DR alpha. Programmed cell death (PCD) plays an important role in normal and malignant hematopoieis. Search by Name. The lack of expression correlates with a lack of detectable HLA-DR mRNA. A basic domain, Lys(305)-Arg(306), is required for p53 nuclear import, and a carboxyl-terminal domain, namely the cytoplasmic sequestration domain (CSD) from residues 326-355, could block the nuclear import of Lys(305) or Arg(306) mutated p53. These tools should lead to new insights into the cellular and molecular mechanisms that drive human breast cancer growth and invasion. To determine the mechanism, by which this virus spares normal hematopoietic cells, we isolated normal mouse hematopoietic stem cells and infected them with an adenovirus that contains a beta-galactosidase minigene. All three analogues retained full agonist activity relative to the native protein (EC50 = 10-15 pM) when assayed for the stimulation of human bone marrow progenitor cell growth. Paneth cells contribute to the small intestinal niche of Lgr5(+) stem cells. Finally, we show how gene expression shifts in distinct tissues are highly correlated with corresponding protein levels in plasma, thus potentially contributing to the ageing of the systemic circulation. In this report we explore the role of Bcl-XL overexpression in protecting cancer cells from p53-mediated apoptosis. Join Facebook to connect with Michael Clarke and others you may know. Clarke, M. F., Clevers, H., Eaves, C. J., Weinberg, R. A., Rajasekhar, V. K. Quantitative assessment of single-cell RNA-sequencing methods. B., Lu, R., Attema, J. L., Lobo, N. A., Weissman, I. L., Clarke, M. F., Quake, S. R. Optimized imaging of the growth and metastasis of human breast cancer stem cells in immunodeficient mice. Emerson, S. G., Palsson, B. O., Clarke, M. F. INFLUENCE OF MEDIUM EXCHANGE SCHEDULES ON METABOLIC, GROWTH, AND GM-CSF SECRETION RATES OF GENETICALLY ENGINEERED NIH-3T3 CELLS. GSE professors bring the latest advances in the social sciences, technology and teacher preparation to the field of education. He earned a B.A. In several forms of human cancer, only a phenotypic subset of cancer cells, usually termed "cancer stem cells" (CSC), can initiate tumor growth when transplanted. Dylla, S. J., Beviglia, L., Park, I., Chartier, C., Raval, J., Ngan, L., Pickell, K., Aguilar, J., Lazetic, S., Smith-Berdan, S., Clarke, M. F., Hoey, T., Lewicki, J., Gurney, A. L. Characterizing metastatic cancer stem cells from human breast cancer. These results indicate that, similar to normal tissue stem cells, subsets of CSCs in some tumours contain lower ROS levels and enhanced ROS defences compared to their non-tumorigenic progeny, which may contribute to tumour radioresistance. Office Hours: Tuesday 12:00-1:00PM; Thursday 2:00-3:00PM; Friday 10:30-11:30AM. This functional subset of cancer cells is operationally defined as the "cancer stem cell" (CSC) subset. identify miR-22 as both a repressor of TET proteins and a powerful oncogene in the mammary epithelium and hematopoietic system. His group was the first to discover that the proto-oncogene Bmi-1 regulates stem cell self-renewal via an epigenetic mechanism. The miR-30c-VIM/TWF1 signaling cascade is also associated with clinical outcome in breast cancer patients. James H. Clarke, Michael P. Vandenbergh . Critically, we found that only streaming and not random migration of single cells was significantly correlated with proximity to vessels, with intravasation and with numbers of elevated circulating tumor cells in the bloodstream. We thus identify stromal cells as cellular coordinators of colon inflammation and suggest their pharmacologic manipulation as a potential means to treat colitis. He was Director of the Royal United Services Institute from 2007 to 2015. Under these conditions, the cultures produced as many cells as were inoculated every 2 weeks and led to a greater than 2.5-fold expansion in terms of the number of nonadherent cells produced over a 6- to 8-week period. A., Parmiani, G., Castelli, C., Clarke, M. F. Identification of pancreatic cancer stem cells. Unequivocal proof that stem cells exist in the haematopoietic system has given way to the prospective isolation of several tissue-specific stem and progenitor cells, the initial delineation of their properties and expressed genetic programmes, and the beginnings of their utility in regenerative medicine. Similarly, tumors contain a minority population of cancer stem cells that maintain the tumor. According to a story Tom Hanks told at. View details for Web of Science ID A1992JB22100010. Pharmacological depletion of ROS scavengers in CSCs markedly decreases their clonogenicity and results in radiosensitization. Lactate dehydrogenase-elevating virus (LDV) can infect transplantable mouse tumors or xenograft tumors in mice through LDV-contaminated mouse biological materials, such as Matrigel, or through mice infected with LDV. Lobo, N. A., Zabala, M., Qian, D., Clarke, M. F. Serially transplantable mammary epithelial cells express the Thy-1 antigen. Methods We used a new bioinformatics approach to search for biomarkers of colon epithelial differentiation across gene-expression arrays and then ranked candidate genes according to the availability of clinical-grade diagnostic assays. We found that adult and fetal mouse and adult human HSCs express the proto-oncogene Bmi-1. This has been recently shown in an in vivo model, where overexpression of Bcl-XL, is a crucial step in the progression from hyperplasia to neoplasia and is accompanied by a significant decrease in tumor apoptosis [56]. View details for Web of Science ID 000308928300005, View details for Web of Science ID 000318009801791. We confirm that CSC drive tumorigenesis, suggesting a link between CSC and remodeling. This model, first developed in human myeloid leukemias, is today being extended to solid tumors, such as breast and brain cancer. Eipers, P. G., Krauss, J. C., Palsson, B. O., Emerson, S. G., Todd, R. F., Clarke, M. F. BCL-X(L) PROTECTS CANCER-CELLS FROM P53-MEDIATED APOPTOSIS. This observation is traditionally explained by postulating variations in tumor microenvironment and coexistence of multiple genetic subclones, created by progressive and divergent accumulation of independent somatic mutations. Clarke, Clifton - Professor: Business Management Clement, Anthony E. - Associate Professor: Mathematics Cohen, Douglas - Lecturer/Doctoral Scholar: . Although these culture conditions still fall short of full reconstitution of functional human bone marrow, they provide an improved approach to hematopoietic cell culture that may permit the expansion and manipulation of progenitor cells in vitro. A., Beachy, P. A., Berdnik, D., Bilen, B., Brownfield, D., Cain, C., Chan, C. K., Chen, M. B., Clarke, M. F., Conley, S. D., Demers, A., Demir, K., de Morree, A., Divita, T., du Bois, H., Ebadi, H., Espinoza, F. H., Fish, M., Gan, Q., George, B. M., Gillich, A., Gomez-Sjoberg, R., Green, F., Genetiano, G., Gu, X., Gulati, G. S., Hahn, O., Haney, M. S., Hang, Y., Harris, L., He, M., Hosseinzadeh, S., Huang, A., Huang, K. C., Iram, T., Isobe, T., Ives, F., Jones, R. C., Kao, K. S., Karnam, G., Kershner, A. M., Khoury, N., Kim, S. K., Kiss, B. M., Kong, W., Krasnow, M. A., Kumar, M. E., Kuo, C. S., Lam, J., Lee, D. P., Lee, S. E., Lehallier, B., Leventhal, O., Li, G., Li, Q., Liu, L., Lo, A., Lu, W., Lugo-Fagundo, M. F., Manjunath, A., May, A. P., Maynard, A., McKay, M., McNerney, M. W., Merrill, B., Metzger, R. J., Mignardi, M., Min, D., Nabhan, A. N., Ng, K. M., Nguyen, P. K., Noh, J., Nusse, R., Patkar, R., Peng, W. C., Penland, L., Pollard, K., Puccinelli, R., Qi, Z., Rando, T. A., Rulifson, E. J., Segal, J. M., Sikandar, S. S., Sinha, R., Sit, R. V., Sonnenburg, J., Staehli, D., Szade, K., Tan, M., Tato, C., Tellez, K., Torrez Dulgeroff, L. B., Travaglini, K. J., Tropini, C., Tsui, M., Waldburger, L., Wang, B. M., van Weele, L. J., Weinberg, K., Weissman, I. L., Wosczyna, M. N., Wu, S. M., Xiang, J., Xue, S., Yamauchi, K. A., Yang, A. C., Yerra, L. P., Youngyunpipatkul, J., Yu, B., Zanini, F., Zardeneta, M. E., Zee, A., Zhao, C., Zhang, F., Zhang, H., Zhang, M. J., Zhou, L., Zou, J. Evidence from studies in murine and human embryonic stem cells indicates that Polycomb group proteins play a dynamic role in concert with master transcriptional regulators in actively maintaining an undifferentiated state, suggesting that this mechanism applies to multiple types of stem cell. Further investigation will reveal whether this translates to improved therapy in the future. Raised by his single mother, Jean, a house cleaner, on Chicago's South Side, Duncan grew up resisting drugs and alcohol, instead concentrating on school. Direct visualization of human tumor cells in vivo shows two patterns of high-speed migration inside primary tumors: (1) single cells and (2) multicellular streams (i.e., cells following each other in a single file but without cohesive cell junctions). View details for Web of Science ID A1986A778300041. Transplanted fetal liver and bone marrow cells obtained from Bmi-1-/- mice were able to contribute only transiently to haematopoiesis. View details for Web of Science ID 000168861600008. We performed multiplexed single-cell gene expression analysis with quantitative reverse transcriptase polymerase chain reaction followed by hierarchical clustering analysis to characterize distinct cell types. Coexpression of bcl-2 and c-myc can totally overcome p53-induced apoptosis and cell cycle arrest by altering the subcellular trafficking of p53 during the cell cycle: the p53 remains in the cytoplasm of the cotransfected cells during a critical period in G1. View details for DOI 10.1073/pnas.1121623109, View details for DOI 10.1158/1538-7445.AM2012-3331, View details for Web of Science ID 000209701505088, View details for DOI 10.1158/1538-7445.AM2012-1012, View details for Web of Science ID 000209701505194. This new model for cancer will have significant ramifications for the way we study and treat cancer. This study thus establishes a key RNA-based feature of developmental potential and a platform for delineation of cellular hierarchies. In contrast, normal hematopoietic progenitor cells and primitive cells capable of repopulating severe combined immunodeficient mice were refractory to killing by the bcl-xs adenovirus. Professor Clark is someone that should teach all students. Prior to coming to UK, Dr. Clark was the Chief Economist for the Kentucky Legislative Research . We therefore propose to initiate a phase I clinical trial to test the safety of this virus in women with breast cancer undergoing high does chemotherapy and autologous BMT. View details for Web of Science ID 000073794800011. View details for DOI 10.1016/j.stem.2007.08.012, View details for Web of Science ID 000251055200003. We describe the construction and characterization of a hybrid promoter for transcriptional targeting of breast cancer. Han, J. S., Qian, D. L., Wicha, M. S., Clarke, M. F. Targeting cancer cell death with a bcl-x(s) adenovirus. Pagination. Utilizing computer-assisted integration techniques, we have theoretically simulated culture cell production kinetics to help identify factors that may be responsible for culture decay, as well as to suggest possible means of improving culture longevity. In experiments on nude mice bearing HeLa ascites tumors, intraperitoneal injection of AdRSVlaclys/pE1 resulted in a significantly higher percentage of infected HeLa cells as compared with the PBS controls (p < 0.05) or the AdRSVlaclys/pUC19 controls (p < 0.01). To date, therapies targeting end-stage disease plaques, tangles, or inflammation have limited efficacy. The AKR/J chromosome 17 locus was not sufficient to increase HSC frequencies when bred onto a C57BL background. View details for DOI 10.1146/annurev.med.58.062105.204854, View details for Web of Science ID 000244461500018, View details for Web of Science ID 000242973400002, View details for Web of Science ID 000242440001597. CHUCK, A. S., Clarke, M. F., Palsson, B. O. bcl-x(s) gene therapy induces apoptosis of human mammary tumors in nude mice. The arrangement of this clone suggests that its RNA transcript was activated by provirus integration in cis, possibly by the activity of a downstream provirus enhancer. Adams, S., Upadhyaya, G., Clarke, M. F., Emerson, S. G. CONSTITUTIVE EXPRESSION OF A C-MYB CDNA BLOCKS FRIEND MURINE ERYTHROLEUKEMIA CELL-DIFFERENTIATION. Chandhasin, C., Yoo, S., Del Rosario, J., Chen, Y. K., Stafford, J., Perabo, F., Clarke, M. F. Depletion of Trp53 and Cdkn2a Does Not Promote Self-Renewal in the Mammary Gland but Amplifies Proliferation Induced by TNF-. A minority population of cancer cells is operationally defined as the `` cancer stem cells marrow cells obtained Bmi-1-/-! Discover that the proto-oncogene Bmi-1 chromosome 17 locus was not sufficient to increase HSC frequencies when bred a! Therapy in the future, therapies targeting end-stage disease plaques, tangles, inflammation. Expression analysis with quantitative reverse transcriptase polymerase chain reaction followed by hierarchical clustering analysis to characterize distinct cell.! 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