U.S.A. 1995;92:11024-11028) is used in combination with Ad5ERE2, the ability of both viruses to induce cell death is dramatically increased, and the effect can be modulated by addition of the antiestrogen tamoxifen. Human tumors where evidence of cancer stem cells has been published include tumors of the breast, brain, pancreas, head and neck, and colon. Similar to TWF1, VIM also regulates F-actin formation, a key component of cellular transition to a more invasive mesenchymal phenotype. However, attempts to develop stable long-term human bone marrow cultures have been unsuccessful. We have designed a microfluidic device to perform sensitive ChIP analysis on low cell numbers in a rapid, automated fashion while preserving the specificity of the assay. [1] Clarke is a former Deputy Vice-Principal and Director of Research Development at King's College London, where he remains a Visiting Professor of Defence Studies. Finally, the laboratory is actively pursuing how cancer stem cells self-renew to maintain themselves and escape the genetic constraints on unlimited self-renewal that regulate normal stem cell numbers. Thomas Jeffrey Hanks ( Concord, California; 9 de julio de 1956) es un actor y director de cine estadounidense. View details for DOI 10.1016/j.jcmgh.2017.01.006. Bmi-1-green fluorescent protein (GFP)-knock-in mice reveal the dynamic regulation of Bmi-1 expression in normal and leukemic hematopoietic cells. 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. Reitz, M. S., Mann, D. L., Eiden, M., Trainor, C. D., Clarke, M. F. METHYLATION OF HUMAN T-CELL LEUKEMIA-VIRUS PROVIRAL DNA AND VIRAL-RNA EXPRESSION IN SHORT-TERM AND LONG-TERM CULTURES OF INFECTED-CELLS. Bcl-XS overexpressed in MCF-7 cells by stable transfection does not affect viability by itself but induces a marked increase in chemosensitivity to VP-16 or taxol. We confirm that CSC drive tumorigenesis, suggesting a link between CSC and remodeling. Bockhorn, J., Dalton, R., Nwachukwu, C., Huang, S., Prat, A., Yee, K., Chang, Y., Huo, D., Wen, Y., Swanson, K. E., Qiu, T., Lu, J., Park, S. Y., Dolan, M. E., Perou, C. M., Olopade, O. I., Clarke, M. F., Greene, G. L., Liu, H. MicroRNA-30c targets cytoskeleton genes involved in breast cancer cell invasion. We performed in vivo imaging of changes in fluorescent, endogenous duct architecture as a metric for remodeling. Cell-free RNA from liquid biopsies can be analyzed to determine disease tissue of origin. Only a small minority of cancer cells had the capacity to form new tumors in a xenograft model. We were able to distinguish the tumorigenic (tumor initiating) from the nontumorigenic cancer cells based on cell surface marker expression. View details for Web of Science ID A1991GV58400008. We have developed a new in vitro culture system that permits, for the first time, the propagation of mammary stem and progenitor cells in an undifferentiated state, which should facilitate the elucidation of pathways that regulate normal mammary stem-cell self-renewal and differentiation. In the validation data set, which included 314 patients, the rate of 5-year disease-free survival was lower among the 38 patients (12.1%) with CDX2 protein-negative colon cancers than among the 276 (87.9%) with CDX2 protein-positive colon cancers (hazard ratio, 2.42; 95% CI, 1.36 to 4.29; P=0.003). And while one former spy chief predicted that Putin would eventually be replaced by someone more "extreme", professor Michael Clarke, former director-general of the Royal United Services. The effect of these changes on protein function is currently unknown. In many tissues, a cellular hierarchy exists in which a small population of stem cells is responsible for the production of the mature cells of the organ. Cai, S., Kalisky, T., Sahoo, D., Dalerba, P., Feng, W., Lin, Y., Qian, D., Kong, A., Yu, J., Wang, F., Chen, E. Y., Scheeren, F. A., Kuo, A. H., Sikandar, S. S., Hisamori, S., van Weele, L. J., Heiser, D., Sim, S., Lam, J., Quake, S., Clarke, M. F. Targeted chromatin ligation, a robust epigenetic profiling technique for small cell numbers. Amy Smith Berylson Professor of Materials Science and Professor of Chemistry & Chemical Biology. Understanding and reproducing the molecular interactions between bone marrow stromal cells and stem cells in tissue culture models is therefore the critical step in successful bone marrow tissue culture. Tumor kinetic rate constants (K1, k2, k3) and net rate of FDG phosphorylation (K = [K1.k3]/[k2 + k3]) in tumors were calculated from the dynamic data by means of a three-compartment model, assuming k4 = 0.Viable tumors (n = 10) showed intense FDG uptake and could easily be differentiated visually from mature teratoma (n = 6) and necrosis or scar (n = 10). However, inferring both the state and direction of differentiation is challenging. We used immunostaining and fluorescence-activated cell sorting analyses with in vivo administration of a Notch inhibitor and in vitro organoid cultures to characterize different cell types.Multicolor fluorescence-activated cell sorting could isolate distinct regions of colonic crypts. Many cancers overexpress a member of the bcl-2 family of inhibitors of apoptosis. Limited viral replication facilitates greater penetration of virions into tissue and can improve gene transfer. 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. View details for Web of Science ID A1995TF89100042. Adjunct Senior Lecturer Dr Urs Wermuth. We performed the first genome-wide expression analysis directly comparing the expression profile of highly enriched normal human hematopoietic stem cells (HSC) and leukemic stem cells (LSC) from patients with acute myeloid leukemia (AML). Li, C., Heidt, D. G., Dalerba, P., Burant, C. F., Zhang, L., Adsay, V., Wicha, M., Clarke, M. F., Simeone, D. M. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. View details for DOI 10.1007/s10549-012-2346-4, View details for Web of Science ID 000313201100005, View details for PubMedCentralID PMC3583223. Gulati, G. S., Sikandar, S. S., Wesche, D. J., Manjunath, A. n., Bharadwaj, A. n., Berger, M. J., Ilagan, F. n., Kuo, A. H., Hsieh, R. W., Cai, S. n., Zabala, M. n., Scheeren, F. A., Lobo, N. A., Qian, D. n., Yu, F. B., Dirbas, F. M., Clarke, M. F., Newman, A. M. Ageing hallmarks exhibit organ-specific temporal signatures. Subsequently, the majority of tumors adapt to the withdrawal of KrasG12D expression and return. This decrease in survival began 48 h following radiation. We developed a new technique that replaces immunoprecipitation with a simplified chromatin fragmentation and proximity ligation step that eliminates bead purification and washing steps. CD137 activation, which was dependent on NK cell expression of the FcRIII receptor, occurred both in vitro and in the peripheral blood of women with HER2-expressing breast cancer after trastuzumab treatment. While the majority of the cancer cells have a limited ability to divide, a population of cancer stem cells that has the exclusive ability to extensively proliferate and form new tumors can be identified based on marker expression. Professor Michael Clarke is a British security analyst. When combined with the prognostic criteria of the National Institutes of Health, the IGS was used to stratify patients with high-risk early breast cancer into prognostic categories (good or poor); among patients with a good prognosis, the 10-year rate of metastasis-free survival was 81%, and among those with a poor prognosis, it was 57%. Liu, H., Bockhorn, J., Dalton, R., Olopade, O. F., Clarke, M. F., Greene, G. L. MicroRNAs regulating breast cancer stem cells and metastasis. RRV replication was significantly rescued in IFN types I and II, as well as STAT1 (IFN types I, II, and III) deficient mice in contrast to EW, which was only modestly sensitive to IFNs I and II. Ryan, J. J., Prochownik, E., Gottlieb, C. A., Apel, I. J., Merino, R., Nunez, G., Clarke, M. F. CELL-CYCLE ANALYSIS OF P53-INDUCED CELL-DEATH IN MURINE ERYTHROLEUKEMIA-CELLS. Here, a systematic approach using bioinformatics and array hybridization techniques to analyze gene expression profiles in HSCs is described. Moreover, the inherent ability of residual CoCSC to generate tumors appears preserved. Wild-type p53 plays a crucial role in the control of apoptosis following ionizing radiation (IR); conversely, mutant p53 is associated with IR resistance. By examining the pathways upstream and downstream of Bmi1, hence the molecular pathways that regulate self-renewal, his laboratory found that USP16, a protein that dampens Bmi1 signals, causes a stem cell defect in various stem cells in Downs syndrome, including neural stem cells. 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. He is especially known for his research into the evolution of cooperative breeding in honeyeaters, particularly the genus Manorina and for his work on the response of fauna and flora to wildfire (Clarke 2008, Clarke et al. View details for Web of Science ID 000076744000010. Major conclusions of the symposium were that the flow cytometry of multiple markers in fresh tissue would remain the standard technique of evaluating cancer-initiating cells and that surrogates need to be developed for both experimental and clinical use. 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 10.1172/JCI200420800, View details for Web of Science ID 000188195600005, View details for Web of Science ID 000187068700011. Despite rapid advances over recent years, many of the molecular and cellular processes that underlie the progressive loss of healthy physiology are poorly understood2. Professor Michael Clarke write a piece in The Sun saying time was running out for Putin. By complementation of the E1a protein in trans, Ad5ERE2 allows restricted replication of a conventional E1a-deleted adenoviral vector. 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. These experiments demonstrate the feasibility of using bcl-xs gene therapy to induce apoptosis in human breast tumors. View details for Web of Science ID 000166430900009. 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. Imatinib inhibited growth of KIT(+) colon cancer organoids in culture and growth of xenograft tumors in mice. We extend this concept to identify cell types of origin using the Tabula Sapiens transcriptomic cell atlas as well as individual tissue transcriptomic cell atlases in combination with the Human Protein Atlas RNA consensus dataset. Metastasis remains a significant challenge in treating cancer. He was on the senior staff of the S We observed an almost universal loss of gene expression with age that is largely mimicked by parabiosis: aged blood reduces global gene expression, and young blood restores it in select cell types. One such cDNA clone, KT1, was isolated and its nucleotide sequence was determined. 2010). When a virus expressing the proapoptotic gene Bc1-xs (Clarke et al., Proc. Thus, the ECMs used did not significantly influence the cell productivity of LTHBMCs. Breast cancers contain a minority population of cancer cells characterized by CD44 expression but low or undetectable levels of CD24 (CD44+CD24-/low) that have higher tumorigenic capacity than other subtypes of cancer cells.We compared the gene-expression profile of CD44+CD24-/low tumorigenic breast-cancer cells with that of normal breast epithelium. Transformed mammary stem or progenitor cells undergo aberrant differentiation processes that result in generation of the phenotypic heterogeneity found in human and rodent breast cancers. In six of seven tumors examined, Thy1+CD24+ cancer cells, which constituted approximately 1%-4% of tumor cells, were highly enriched for cells capable of regenerating new tumors compared with cells of the tumor that did not fit this profile ("not-Thy1+CD24+"). However, the consequences of the underlying gene-dosage imbalance on adult tissues remain poorly understood. Research Expertise and Interests In this study we describe the effect on murine erythroleukemia cells, transfected with a temperature-sensitive mutant p53, of exposure to the differentiating agent dimethylsulfoxide (DMSO). Knockdown of endogenous miR-142 effectively suppressed organoid formation by BCSCs and slowed tumor growth initiated by human BCSCs in vivo. Clinical and Therapeutic Implications of Cancer Stem Cells. View details for Web of Science ID A1995RY96700021. Michael Sandel teaches political philosophy at Harvard University. Here we show that normal mammary epithelial stem cells contain lower concentrations of ROS than their more mature progeny cells. He has published internationally on the ecology and conservation biology of birds, reptiles, mammals, fish and plants. These results suggest that in some tumors, miR-142 regulates the properties of BCSCs at least in part by activating the WNT signaling pathway and miR-150 expression. Isobe, T., Zarneger, M. A., Matsubara, J., Abdel-Wahab, O., Clarke, M. F. Usp16 modulates Wnt signaling in primary tissues through Cdkn2a regulation. His interest is in Stem Cell Biology. Hosen, N., Clarke, M. F., Weissman, I. L. Cancer stem cells--perspectives on current status and future directions: AACR Workshop on cancer stem cells. Our metastatic cancer models, combined with noninvasive imaging techniques, constitute an integrated approach that could be applied to dissect the molecular mechanisms underlying the dissemination of metastatic CSCs (MCSCs) and to explore therapeutic strategies targeting MCSCs in general or to evaluate individual patient tumor cells and predict response to therapy. Sorted cells were then injected into recipient background FVB/NJ female syngeneic mice. In the absence of Bmi-1, the cyclin-dependent kinase inhibitor gene p16Ink4a is upregulated in neural stem cells, reducing the rate of proliferation. Specifically, in the presence of CSC, we identified an increased number of branches, branch points, ducts which have greater than 40 branches (5/33 for CSC and 0/39 for non-CSC), and histological evidence of increased branching. View details for Web of Science ID 000227329300006. Hematopoietic stem cells (HSCs) have self-renewal capacity and multilineage developmental potentials. Dalerba, P., Dylla, S. J., Park, I., Liu, R., Wang, X., Cho, R. W., Hoey, T., Gurney, A., Huang, E. H., Simeone, D. M., Shelton, A. Notably, these gene sets show similar expression across tissues, differing only in the amplitude and the age of onset of expression. Here, using molecular clones of HTLV and human major histocompatibility antigen DNA, we have shown homology between the envelope gene region of HTLV and the region of an HLA-B locus gene which codes for the extracellular portion of a class I histocompatibility antigen. We have introduced this construct into Friend erythroleukemia (F-MEL) cells and have isolated a number of clones which contain intact and transcriptionally active human c-myb sequences. With the growing evidence that cancer stem cells exist in a wide array of tumors, it is becoming increasingly important to understand the molecular mechanisms that regulate self-renewal and differentiation because corruption of genes involved in these pathways likely participates in tumor growth. Il neo-ateismo ritiene che la superstizione, la religione e l'irrazionalismo non dovrebbero essere tollerati, e si propone di contrastarli . In addition to his clinical duties in the division of Oncology, Dr . Okamoto, T., Reitz, M. S., Clarke, M. F., JAGODZINSKI, L. J., WONGSTAAL, F. Sequence-specific interaction of histones with the simian virus 40 enhancer region in vitro. We report that Bcl-XL, which functions like Bcl-2 to inhibit apoptosis, is highly expressed in MCF-7 human breast carcinoma cells. Cai, S., Kalisky, T., Dalerba, P., Clarke, M., Stanford Univ. 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