When a virus expressing the proapoptotic gene Bc1-xs (Clarke et al., Proc. View details for Web of Science ID A1994PC47400008. Treatment of these T-cells with 5-azacytidine resulted in the induction of DR surface antigen expression, the appearance of DR alpha mRNA, and the partial demethylation of the DR alpha DNA sequences. 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. The mammary epithelium undergoes several rounds of extensive proliferation during the female reproductive cycle. We review the biological basis and the therapeutic implications of the stem cell model of cancer. Using 2 independent analyses, we identified multiple pathways that are aberrantly regulated in leukemic stem cells compared with normal HSC. Although neither the visual interpretation nor SUVlean differentiated mature teratoma from necrosis or scar, there were statistically significant differences in the kinetic rate constants K1 and K between mature teratoma and necrosis or scar as follows: K1, 0.113 mL/min/g +/- 0.026 versus 0.036 mL/min/g +/- 0.005 (P < .05); K, 0.005 mL/min/g +/- 0.003 versus 0.0008 mL/min/g +/- 0.0001 (P < .05).FDG PET with kinetic analysis appears to be a promising method for management of disease in patients with GCT after treatment. Liu, H., Shimono, Y., Bockhorn, J., Olopade, F., Greene, G., Clarke, M. F. Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models. Analysis of patient tumor and matched adjacent normal (nontumor) tissue revealed that CD47 is overexpressed on cancer cells. The prognostic role of a gene signature from tumorigenic breast-cancer cells. Increased levels of Bcl-XL were found in a subset of primary human breast carcinomas, as well as in the breast cancer line, T47D. Professor Michael Clarke, Director of the Royal United Services Institute and a graduate of the Department of International Politics, was honoured as Fellow of Aberystwyth University on Tuesday 10 July. The tumorigenic subpopulation could be serially passaged: each time cells within this population generated new tumors containing additional CD44(+)CD24(-/low)Lineage(-) tumorigenic cells as well as the phenotypically diverse mixed populations of nontumorigenic cells present in the initial tumor. The simulation demonstrates that removal of stem cells is a possible mechanism leading to culture decline. Ayash, L. J., Clarke, M., Adams, P., Ferrara, J., Ratanatharathorn, V., Reynolds, C., Roessler, B., Silver, S., Strawderman, M., Uberti, J., Wicha, M. Double dose-intensive chemotherapy with autologous stem cell support for relapsed and refractory testicular cancer: the University of Michigan experience and literature review. Bmi-1 was expressed at its highest levels in undifferentiated leukemia cells. 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. X-ray irradiated cells expressing wtp53 displayed microscopic and biochemical characteristics consistent with cell death due to apoptosis. 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. Box 270211 Rochester, NY 14627. Deletion of MYD88 or TLR2 in the intestinal epithelium markedly reduces DSS-induced colitis regeneration and spontaneous tumour development in mice. Furthermore, the oxygenation of arachidonic acid requires little of the oxygen consumed by phagocytosing alveolar macrophages. Orthologs of these differentially expressed genes predicted survival of human breast cancer patients from two different study groups. Parashurama, N., Lobo, N. A., Ito, K., Mosley, A. R., Habte, F. G., Zabala, M., Smith, B. R., Lam, J., Weissman, I. L., Clarke, M. F., Gambhir, S. S. Effect of stimulation of natural killer cells with an anti-CD137 mAb on the efficacy of trastuzumab, cetuximab, and rituximab. Dr. Michael F. Clarke is the Karel and Avice Beekhuis Professor in Cancer Biology and Associate Director of the Stanford Institute for Stem Cell and Regenerative Medicine. Northstar is a useful tool to assign known and novel cell type and states in the age of cell atlases. The reasons for the limited longevity are unknown. Hisamori, S., Dalerba, P., Shimono, Y., Rothenberg, M. E., Zabara, M., Cai, S., Qian, D., Clarke, M. F. Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer. 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. MicroRNAs (miRNAs) are important regulators of stem and progenitor cell functions. These chemically reactive forms of biotin produced derivatives biotinylated at amine or carboxyl groups, respectively. The presence of the concentrated conditioned medium (conCM) enhanced the production of nonadherent cells three-fold compared with control over an eight week culture period. 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. In contrast, C5-bGM-CSF binding above background fluorescence could not be detected using this system, suggesting that this derivative could bind to and activate the receptor, but not simultaneously bind fluorescein-conjugated avidin. [2] Isobe, T., Zarnegar, M. A., Abdel-Wahab, O., Clarke, M. F. A CD47-associated super-enhancer links pro-inflammatory signalling to CD47 upregulation in breast cancer. The DR alpha genes in both cell lines are hypermethylated relative to the same genes in T-cell lines infected with human T-cell leukemia virus (HTLV) and derived from patients with adult T-cell leukemia/lymphoma (ATL). A., Clarke, M. F., Weissman, I. L. MicroRNAs regulate breast cancer stem cells and spontaneous metastases in orthotopic xenograft models. View details for Web of Science ID A1984SP90200011. Michael Clarke was the original drummer of the Byrds, appearing on their first five albums before leaving around the end of 1967.Clarke was the least talented of the five members that were on the Byrds' 1965-1967 recordings, as unlike the others as could be, since he did almost no songwriting. 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. ALTERATION OF P53 CONFORMATION AND INDUCTION OF APOPTOSIS IN A MURINE ERYTHROLEUKEMIA CELL-LINE BY DIMETHYLSULFOXIDE, C-MYC AND BCL-2 MODULATE P53 FUNCTION BY ALTERING P53 SUBCELLULAR TRAFFICKING DURING THE CELL-CYCLE. Amine-derivatized analogues of 1.2 and 3.8 mol of biotin/mol of protein (N1-bGM-CSF and N4-bGM-CSF) and a carboxyl-modified analogue of 4.6 mol of biotin/mol of protein (C5-bGM-CSF) were synthesized. Three seminoma patients remain progression-free. [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. Using this system, we have generated AdEHT2 and AdEHE2F, two conditionally replicative adenoviruses for the treatment of breast cancer. His writingson justice, ethics, democracy, and markets--have been translated into 27 languages. Yoo, S., Chandhasin, C., Del Rosario, J., Chen, Y. K., Stafford, J., Perabo, F., Clarke, M. F. Inhibition of histone lysine demethylases with TACH101, a first-in-class pan-inhibitor of KDM4. View details for Web of Science ID A1984TY56600006. Finally, we show that the different gene-expression programs linked to multilineage differentiation are strongly associated with patient survival. We describe the construction and characterization of a hybrid promoter for transcriptional targeting of breast cancer. We then determined the effects of intratumoral injection of bcl-xs adenovirus on solid MCF-7 tumors in nude mice. Multiple cell lines expressing variable levels of exogenous temperature-sensitive p53 were generated. View details for DOI 10.1634/stemcells.2006-0229, View details for Web of Science ID 000247722100006. We have developed an in vitro cultivation system that allows for propagation of human mammary epithelial cells (HMECs) in an undifferentiated state, based on their ability to proliferate in suspension, as nonadherent mammospheres. For more information, please contact Ruth Lira, 650-723-1367. These tools should lead to new insights into the cellular and molecular mechanisms that drive human breast cancer growth and invasion. The human RGS18 ortholog has a tissue-specific expression pattern similar to that of mouse RGS18. LEFTY1 binds BMPR2 to suppress BMP7-induced activation of SMAD5, and this LEFTY1-BMPR2 interaction is specific to tumor-initiating cells in triple-negative breast cancer xenografts that rely on LEFTY1 for growth. Dalerba, P., Sahoo, D., Paik, S., Guo, X., Yothers, G., Song, N., Wilcox-Fogel, N., Forgo, E., Rajendran, P. S., Miranda, S. P., Hisamori, S., Hutchison, J., Kalisky, T., Qian, D., Wolmark, N., Fisher, G. A., van de Rijn, M., Clarke, M. F. CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer. Investigator:Michael Clarke (CI) Rural Industries Research & Development Corporation, 2016, $130,500 Development of honeybee products from a biodiversity hotspot Katherine Hammer, Connie Locher, Michael Clarke (CI) MS Research Australia, 2014, $180,000 Project Title: Vitamin D metabolites and risk of multiple sclerosis in the Ausimmune Study This cell line contains a wild-type p53 gene and is an ideal model for studying the mechanism of IR resistance in this disease. Therefore, infection with this virus preferentially kills estrogen receptor-positive breast cancer cells, or cells growing under hypoxic conditions. Mark Malloch Brown, Baron Malloch-Brown (* 1953), Politiker und stellvertretender Generalsekretr der Vereinten Nationen. To see if a limited sampling of tumor tissue from human subjects is a feasible way to gather In contrast, AdEHE2F was attenuated in nontransformed quiescent cells growing under normoxic conditions, suggesting that an intact pRB pathway with low levels of E2F transcription factors acts as a negative modulator for the virus. Hosen, N., Yamane, T., Muijtjens, M., Pham, K., Clarke, M. F., Weissman, I. L. Phenotypic characterization of human colorectal cancer stem cells. In 2007, he became the Director of the Royal United Services Institute. Infection with this vector induced apoptosis in vitro. 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. Here we describe a role for cell-intrinsic toll-like receptor-2 (TLR2; which is involved in inflammatory response) signalling in normal intestinal and mammary epithelial cells and oncogenesis. One of the best candidate genes involved in conferring self-renewal capacity is Bmi-1, which has been proven to be essential for the maintenance of both normal adult hematopoietic and leukemia stem cells, as well as adult neural stem cells. Thus, the predicted transforming product, a protein of 27,281 daltons, may be the actual precursor for normal human platelet-derived growth factor chain A. In this report, we have used intravital multiphoton microscopy to visualize the different migration patterns of human breast tumor cells in live primary tumors. View details for Web of Science ID 000178077600006. The mechanism of leukaemogenic transformation by human T-cell leukaemia/lymphoma virus (HTLV), a retrovirus implicated in the aetiology of certain adult T-cell leukaemias and lymphomas, is unknown but is conceivably associated with the expression of the cellular analogues of retroviral oncogenes. In this report we explore the role of Bcl-XL overexpression in protecting cancer cells from p53-mediated apoptosis. 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. Professor Clarke was presented by Professor Len Scott from the Department of International Politics. In Down's Syndrome (DS), triplication of Usp16 dampens the activation of the Wnt pathway. Other pathways have not been previously implicated in the regulation of cancer stem cell functions, including Ribosome and T Cell Receptor Signaling pathway. To understand the regulation of p53 cellular trafficking, we have previously identified two p53 domains involved in its localization. A Quiescent Bcl11b High Stem Cell Population Is Required for Maintenance of the Mammary Gland. At present, neither the role that the stromal cell extra-cellular matrix (ECM) plays in influencing stroma behavior is well understood nor are the effects of stroma aging. Reya, T., Morrison, S. J., Clarke, M. F., Weissman, I. L. Clinical protocol. View details for Web of Science ID A1984SY22400007. BMI1 has been demonstrated to play a role in self-renewal in other stem cell types and to be involved in tumorigenesis. AKR/J mice had significantly higher frequencies and numbers of both HSCs and restricted progenitors in their bone marrow than C57BL/Ka-Thy-1.1 mice. View details for DOI 10.1016/j.jviromet.2011.02.015, View details for Web of Science ID 000290836400014, View details for PubMedCentralID PMC3086718, View details for DOI 10.1158/1538-7445.AM2011-1582, View details for Web of Science ID 000209701302286, View details for Web of Science ID 000289796200068. Microarray analysis comparing Thy1+CD24+ tumor cells to not-Thy1+CD24+ cells identified a list of differentially expressed genes. Additionally, it facilitated the identification of quiescent stem cells and revealed genes that contribute to breast tumorigenesis. Human T cell lymphoma proviral (HTLV) sequences were demonstrated in both cell lines. We will discuss the important implications of this mammary tumour stem-cell model. Limiting dilution transplantations of breast epithelial cells devoid of TLR2 or MYD88 revealed a significant decrease in mammary repopulating unit frequency compared with the control. View details for DOI 10.1038/sj.onc.1207947, View details for Web of Science ID 000223998800013, View details for Web of Science ID 000223225500005. This will allow the characterization of crucial signaling pathways involved in processes such as self-renewal that are critical for tumor formation by the cancer cells within de novo tumors. miR-200c inhibited the clonal expansion of breast cancer cells and suppressed the growth of embryonal carcinoma cells in vitro. He is a board certified oncologist with extensive training in molecular biology and stem cell biology. This transcriptomic atlas-which we denote Tabula Muris Senis, or 'Mouse Ageing Cell Atlas'-provides molecular information about how the most important hallmarks of ageing are reflected in a broad range of tissues and cell types. Growing evidence suggests that pathways that regulate the self-renewal of normal stem cells are deregulated in cancer stem cells resulting in the continuous expansion of self-renewing cancer cells and tumor formation. Email: charlotte.clarke@ed.ac.uk. He was Director General of the Royal United Services Institute from 2017-2015 and is now a Distinguished Fellow at RUSI. In a pooled database of all patient cohorts, the rate of 5-year disease-free survival was higher among 23 patients with stage II CDX2-negative tumors who were treated with adjuvant chemotherapy than among 25 who were not treated with adjuvant chemotherapy (91% vs. 56%, P=0.006). Moreover, the inherent ability of residual CoCSC to generate tumors appears preserved. Chen, E. C., Karl, T. A., Kalisky, T., Gupta, S. K., O'Brien, C. A., Longacre, T. A., van de Rijn, M., Quake, S. R., Clarke, M. F., Rothenberg, M. 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