All together, these findings link important stem cell regulators like Bmi1/Usp16 and Cdkn2a to Wnt signaling, and have implications for designing therapies for conditions, like DS, aging or degenerative diseases, where the Wnt pathway is hampered. 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. E. miR-142 regulates the tumorigenicity of human breast cancer stem cells through the canonical WNT signaling pathway. Clarke, M. F., Dick, J. E., Dirks, P. B., Eaves, C. J., Jamieson, C. H., Jones, D. L., Visvader, J., Weissman, I. L., Wahl, G. M. A self-renewal assay for cancer stem cells. Constitutive expression of mbm2, in contrast to c-myb, here resulted in enhanced differentiation of F-MEL cells. While cell lines expressing p53 alone rapidly died, those cells co-expressing Bcl-XL survived. Using a model in which human breast cancer cells were grown in immunocompromised mice, we found that only a minority of breast cancer cells had the ability to form new tumors. Until 2001 he was Deputy Vice-Principal and Director for Research Development at King's College London, where he remains a Visiting Professor of Defence Studies. The possible significance of this finding is discussed. These results suggest that radiation-induced cell death occurs by both p53-dependent and p53-independent pathways. Majetl, R., Becker, M. W., Tian, Q., Lee, T. M., Yan, X., Liu, R., Chiang, J., Hood, L., Clarke, M. F., Weissman, I. L. Identification of Conserved Gene Expression Programs in Epithelial Cancer Stem Cells. The ability to self-renew is essential for all kinds of stem cells regardless of tissue type. Effect of ASXL1 on the stemness of colorectal cancer initiating cells. Clones with various levels of c-sis expression were generated by transfecting NIH 3T3 cells with a plasmid that expressed the human c-sis cDNA and the TN5 neomycin-resistance gene. Three seminoma patients remain progression-free. When breast cancer cells mixed with hematopoietic cells were infected with the bcl-x(s) adenovirus, cancer cells were selectively killed by the suicide adenoviruses. Many cancers overexpress a member of the bcl-2 family of inhibitors of apoptosis. View details for DOI 10.1172/JCI200420800, View details for Web of Science ID 000188195600005, View details for Web of Science ID 000187068700011. To improve prognosis, patients entered a phase I/II tandem dose-escalation trial of carboplatin (1500-2100 mg/m(2)) and etoposide (1200-2250 mg/m(2)) with ABMT. Scheeren, F. A., Kuo, A. H., van Weele, L. J., Cai, S., Glykofridis, I., Sikandar, S. S., Zabala, M., Qian, D., Lam, J. S., Johnston, D., Volkmer, J. P., Sahoo, D., van de Rijn, M., Dirbas, F. M., Somlo, G., Kalisky, T., Rothenberg, M. E., Quake, S. R., Clarke, M. F. A cell-intrinsic role for TLR2 MYD88 in intestinal and breast epithelia and oncogenesis. View details for Web of Science ID A1984SV56900010. An alternately spliced c-myb mRNA encodes a truncated version of p75c-myb (mbm2) that includes the DNA binding region and nuclear localization signal present in the c-myb protein, but does not contain the transcriptional regulatory regions. Clinical and Therapeutic Implications of Cancer Stem Cells Reply, Solid tumor cancer stem cells: From bench to bedside, ASXL1 regulates cellular differentiation and initiates tumorigenesis in colon. An in vivo reconstitution assay revealed that the frequency of HSCs was 1/16 in Bmi-1high c-kit+ lin -Sca-1+ bone marrow (BM) cells and 1/49 in Bmi-1 high lin- BM cells, suggesting that Bmi-1 may serve as a marker for normal HSCs. View details for Web of Science ID A1995RY96700021. Intriguingly, overexpression of p53 could reverse the inherent IR resistance of Shep-1 cells. Three clusters, miR-200c-141, miR-200b-200a-429, and miR-183-96-182 were downregulated in human BCSCs, normal human and murine mammary stem/progenitor cells, and embryonal carcinoma cells. Differentially expressed genes were used to generate a 186-gene "invasiveness" gene signature (IGS), which was evaluated for its association with overall survival and metastasis-free survival in patients with breast cancer or other types of cancer.There was a significant association between the IGS and both overall and metastasis-free survival (P<0.001, for both) in patients with breast cancer, which was independent of established clinical and pathological variables. Parsels, L. A., Zellars, R. C., Loney, T. L., Parsels, J. D., Clarke, M. F., MERCHANT, A. K., Lawrence, T. S., Maybaum, J. Bcl-x(s) enhances adenoviral vector-induced apoptosis in neuroblastoma cells. However, DNA from HTLV-infected lymphocytes cultured for 48 hr (by which time increases in viral RNA expression are evident) did not differ detectably with respect to proviral DNA methylation from uncultured cells, suggesting that the increase in viral RNA expression after short-term culture is mediated by mechanisms independent of changes in DNA methylation. Here we show that normal mammary epithelial stem cells contain lower concentrations of ROS than their more mature progeny cells. Taken together, these results suggest that USP16 has an important role in antagonizing the self-renewal and/or senescence pathways in Down's syndrome and could serve as an attractive target to ameliorate some of the associated pathologies. X-ray irradiated cells expressing wtp53 displayed microscopic and biochemical characteristics consistent with cell death due to apoptosis. (Funded by the National Comprehensive Cancer Network, the National Institutes of Health, and others.). Conversely, genetic augmentation of Hedgehog response and systemic small-molecule Hedgehog pathway activation potently ameliorate colitis and restrain initiation and progression of colitis-induced adenocarcinoma. [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. We present a simple single tube proximity ligation technique, targeted chromatin ligation, that captures histone modification patterns with only 200 cells. We used Bcl-XS, a dominant negative inhibitor of Bcl-2 and Bcl-XL, to demonstrate the role of these genes in modulating chemotherapy-induced apoptosis. 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. This effect was associated with a loss of the G1 specificity of p53-mediated cell cycle arrest. Metastasis is the main cause of death in breast cancer patients. He is a board certified oncologist with extensive training in molecular biology and stem cell biology. Oncolytic adenoviruses with restricted replication can be produced if the expression of crucial transcription units of the virus is controlled by tissue- or tumor-specific promoters. Because of the unusual findings of apparently inappropriate HLA antigens in HTLV infected cells, we had previously looked for rearrangement of class I-related genes in HTLV infected cells but failed to find any. We examined the effect of this limited adenovirus replication in vitro and in vivo. 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. Ryan, J. J., Danish, R., Gottlieb, C. A., Clarke, M. F. C-MYB EFFECTS ON KINETIC EVENTS DURING MEL CELL-DIFFERENTIATION. View details for Web of Science ID A1995TF89100042. Pagination. The pattern of triple mutant multipotent progenitor response to growth factors resembles that of wild-type multipotent progenitors but not wild-type HSCs. CLARKE Michael Function : Distinguished Fellow, Royal United Services Institute (RUSI) Political Committee, Saturday 12 October Biography Professor Michael Clarke was Director General of the Royal United Services Institute from 2007-2015, where he remains a Distinguished Fellow. It kills tumor cells by several mechanisms, including antibody-dependent cellular cytotoxicity (ADCC). In Down's Syndrome (DS), triplication of Usp16 dampens the activation of the Wnt pathway. The bcl-xs adenovirus vector may prove useful in killing cancer cells contaminating the bone marrow of patients undergoing autologous bone marrow transplantation. A novel regulator of G-protein signaling (RGS) has been isolated from a highly purified population of mouse long-term hematopoietic stem cells, and designated RGS18. Here we describe a method for the rapid incorporation of exogenous promoters into the E1A and E4 regions of the human adenovirus type 5 genome. With the use of subgroup analysis involving independent and retrospective cohorts of patients with stage II or stage III colon cancer, the top candidate gene was tested for its association with disease-free survival and a benefit from adjuvant chemotherapy. Dr Michael Clarke is an internationally recognised expert on the history and politics of the Xinjiang Uyghur Autonomous Region, People's Republic of China (PRC), Chinese foreign policy in Central Asia, Central Asian geopolitics, nuclear proliferation and non-proliferation and American grand strategy and foreign policy. Kohrt, H. E., Houot, R., Weiskopf, K., Goldstein, M. J., Scheeren, F., Czerwinski, D., Colevas, A. D., Weng, W., Clarke, M. F., Carlson, R. W., Stockdale, F. E., Mollick, J. Here, we report a mouse model that, in the absence of p53 and the presence of oncogenic KrasG12D , develops breast tumors. Hernandez-Alcoceba, R., Pihalja, M., Nunez, G., Clarke, M. F. Molecular cloning and characterization of a novel regulator of G-protein signaling from mouse hematopoietic stem cells. Michael Clarke is a British academic who specialises in defence studies. 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. Profiles. [2] [3] Biography [ edit] Palovics, R., Keller, A., Schaum, N., Tan, W., Fehlmann, T., Borja, M., Kern, F., Bonanno, L., Calcuttawala, K., Webber, J., McGeever, A., Tabula Muris Consortium, Luo, J., Pisco, A. O., Karkanias, J., Neff, N. F., Darmanis, S., Quake, S. R., Wyss-Coray, T., Almanzar, N., Antony, J., Baghel, A. S., Bakerman, I., Bansal, I., Barres, B. He also carries out research into the cellular responses to anti-cancer drugs. At the molecular level, Usp16 affects Rspo-mediated phosphorylation of LRP6. We screened for genetic polymorphisms that were linked to differences between mouse strains in the numbers of long-term reconstituting HSCs or restricted progenitors in the bone marrow. Zarnegar, M. A., Reinitz, F. n., Newman, A. M., Clarke, M. F. CDX2 as a Prognostic Biomarker in Colon Cancer. We developed northstar, a computational approach to classify thousands of cells based on published data within seconds while simultaneously identifying and highlighting new cell states such as malignancies. Cancer is often viewed as a caricature of normal developmental processes, but the extent to which its cellular heterogeneity truly recapitulates multilineage differentiation processes of normal tissues remains unknown. He is an adviser to two Parliamentary Committees and Associate Director of the Strategy and Security Institute at the University of Exeter. View details for Web of Science ID A1997YA26800007. However, at later times X-ray irradiated parental DP16-1 cells also had decreased survival compared to the unirradiated control. Michael Clarke is a UK academic and "terror expert". View details for Web of Science ID 000308928300005, View details for Web of Science ID 000318009801791. View details for Web of Science ID A1995TE58500016. Although a major commonly deleted region (CDR) has been delineated on chromosome band 5q31.1 (refs. We show that single-cell RNA-seq can be used to perform accurate quantitative transcriptome measurement in individual cells with a relatively small number of sequencing reads and that sequencing large numbers of single cells can recapitulate bulk transcriptome complexity. 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. We develop two-gene classifier systems (KRT20 versus CA1, MS4A12, CD177, SLC26A3) that predict clinical outcomes with hazard ratios superior to those of pathological grade and comparable to those of microarray-derived multigene expression signatures. Here we investigate the roles of these three proteins in the regulation of self-renewal and proliferation of mammary epithelial cells. Bystander cells did not display enhanced type I IFN transcription but had elevated levels of certain IFN-stimulated genes, presumably in response to exogenous IFNs secreted from immune cells. We investigated the role of the RTK KIT in development of human colon cancer.An array of 137 patient-derived colon tumors and their associated xenografts were analyzed by immunohistochemistry to measure levels of KIT and its ligand KITLG. Bcl11b(high) cells are enriched for cells that can regenerate mammary glands in secondary transplants. [2] 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. Some factors that regulate this process of self-renewal are conserved from fruit fly to humans. and Ph.D. in economics from the University of Kentucky. Professor Clarke was presented by Professor Len Scott from the Department of International Politics. 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. Mcl1, Tel/Etv6, Gfi1, Pten and Stat5) have been identified. 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. We examined the effect of lower levels of c-sis expression on the phenotype of NIH 3T3 fibroblasts. Previous groups have shown that CD24medCD49fhigh cells enriched for long-lived mammary epithelial cells can be serially transplanted.METHODS: Flow cytometry-based enrichment of distinct phenotypic populations was assessed for their gene expression profiles and functional proliferative attributes in vitro and in vivo.RESULTS: Here, we show Thy-1 is differentially expressed in the CD24medCD49fhigh population, which allowed us to discern two functionally different populations. Such cells do not express beta-galactosidase, indicating that hematopoietic stem cells do not express transgene encoded by adenovirus vectors based upon the RSV-AD5 vector system. Similarly, tumors contain a minority population of cancer stem cells that maintain the tumor. Herein, we present a discussion around the issues facing treatment of patients with CRCliver metastases, including the relationship of discretegene signatures with prognosis. A., Ozawa, M. G., Silva, O., Toland, A., Vemuri, V. N., Afik, S., Awayan, K., Bierman, R., Botvinnik, O. Bcl-xs is a dominant negative repressor of Bcl-2 and Bcl-xL, both of which inhibit apoptosis. Disease status (no. View details for DOI 10.1038/s41586-020-2496-1, View details for Web of Science ID 000485326200019, View details for DOI 10.1158/1538-7445.SABCS18-SY17-02, View details for Web of Science ID 000488129901140, View details for Web of Science ID 000453773601250. 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. A temperature-sensitive mutant of murine p53 (p53Val-135) was transfected by electroporation into murine erythroleukemia cells (DP16-1) lacking endogenous expression of p53. Cell surface GM-CSF receptor binding was characterized by the binding of the analogues to human neutrophils, with detection by fluorescein-conjugated avidin and fluorescence-activated cell sorting. 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. Facebook gives people the power. The C57BL/Ka-Thy-1.1 alleles were partially dominant. Michael Clarke is a British academic who specialises in defence studies. View details for DOI 10.1186/s13058-018-1006-y, View details for Web of Science ID 000447203300001, View details for Web of Science ID 000440602000145, View details for Web of Science ID 000440602000051, View details for DOI 10.1200/JCO.2018.36.4_suppl.683, View details for Web of Science ID 000436174100659. Mark Malloch Brown, Baron Malloch-Brown (* 1953), Politiker und stellvertretender Generalsekretr der Vereinten Nationen. Shimono, Y., Zabala, M., Cho, R. W., Lobo, N., Dalerba, P., Qian, D., Diehn, M., Liu, H., Panula, S. P., Chiao, E., Dirbas, F. M., Somlo, G., Pera, R. A., Lao, K., Clarke, M. F. Association of reactive oxygen species levels and radioresistance in cancer stem cells. 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. Up to one-third of the long-term culture initiating cell (LTC-IC) are genetically modified by the culture conditions. View details for Web of Science ID 000186360800006. Michael Clarke 30.99 Hardback Inspiring Impressionism: Michael Clarke 24.95 Paperback Add to Basket The Xinjiang Emergency: Michael Clarke 20.00 Paperback Add to Basket Understanding Foreign Policy: Michael Clarke 28.95 Paperback Add to Basket The Story of Troy (Hardback) Michael Clarke 42.90 Hardback Add to Basket Regulation of the Wnt pathway in stem cells and primary tissues is still poorly understood. View details for Web of Science ID A1986A778300041. In contrast to wild-type MEL cells, both clones failed to display phenotypic markers of differentiation and continued to proliferate for up to 10 days of culture. Westin, E. H., Gorse, K. M., Clarke, M. F. THE PROLIFERATION OF AML-193 IS REGULATED BY MULTIPLE HEMATOPOIETIC GROWTH-FACTORS AND CYTOKINES. 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. 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 These results suggest that inhibitors of the TLR2 pathway merit investigation as possible therapeutic and chemoprevention agents. As well as addressing the patient's medical needs, these highly trained professionals . 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). Expression of BMI1, a known regulator of stem cell self-renewal, was modulated by miR-200c. Recently, we have found that a recombinant adenovirus vector that contains a bcl-x, minigene (a dominant negative inhibitor of the bcl-2 family), called the bcl-x(s) adenovirus, is lethal to cancer cells derived from epithelial tissues, but not to normal human hematopoietic cells. Similar to TWF1, VIM also regulates F-actin formation, a key component of cellular transition to a more invasive mesenchymal phenotype. The IGS was also associated with the prognosis in medulloblastoma (P=0.004), lung cancer (P=0.03), and prostate cancer (P=0.01). This promoter induces transcriptional activation of the E1a and E4 units in response to estrogens in cells that express the ERs. Professor of Health in Social Science; College Dean International; EFI Director of Global Communities. Mutagenesis analysis demonstrated that a single amino acid mutation of Lys-305 (mt p53) caused cytoplasmic sequestration of the p53 protein in the MCF-7 and RKO cells, whereas the fusion protein was distributed in both the cytoplasm and the nucleus of SAOS-2 cells. Email: charlotte.clarke@ed.ac.uk. 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-. This increase is associated with the acquisition of long-term reconstitution capacity by cells of the phenotype c-kit+Sca-1+Flt3+CD150-CD48-Lin-, which defines multipotent progenitors in wild-type mice. The expression of the E1A gene in both viruses is controlled by a minimal dual-specificity promoter that responds to estrogens and hypoxia. He was Director of the Royal United Services Institute from 2007 to 2015. Science-Fiction, auch Sciencefiction geschrieben ([sans fkn]; englisch science: Naturwissenschaft, fiction: Fiktion), ist ein Genre in Literatur (Prosa, Comic), Film, Hrspiel, Videospiel und Kunst.Charakteristisch sind wissenschaftlich-technische Spekulationen, Raumfahrtthemen, ferne Zukunft, fremde Zivilisationen und meist zuknftige Entwicklungen. CoCSC). . View details for DOI 10.1016/j.jcmgh.2017.01.006. Parks, I. K., Klug, C. A., Li, K. J., Jerabek, L., Li, L. H., Nanamori, M., Neubig, R. R., Hood, L., Weissman, I. L., Clarke, M. F. A novel, conditionally replicative adenovirus for the treatment of breast cancer that allows controlled replication of E1a-deleted adenoviral vectors. In recent years solid tumors were studied utilizing similar techniques in mice. In contrast, BMP7, a NODAL antagonist with context-dependent functions, is produced by basal cells and restrains progenitor cell proliferation. In addition to his clinical duties in the division of Oncology, Dr. Clarke maintains a laboratory focused on two areas of research: i) the control of self-renewal of normal stem cells and their malignant counterparts; and ii) the identification and characterization of cancer stem . Effective treatment of cancer will require therapeutic strategies that are able to target and eliminate this tumorigenic subset of cells. His course "Justice" is the first Harvard course to be made freely available online and on television. Our results indicate that constitutive expression of a nontruncated human c-myb cDNA can exert profound effects on erythroid differentiation and argue for a causal role of c-myb in the F-MEL differentiation process. These results demonstrate that p16Ink4a/p19Arf and Trp53 have a central role in limiting the expansion potential of multipotent progenitors. Receptor tyrosine kinase (RTK) inhibitors have advanced colon cancer treatment. These results validate the stem cell working model in human CRC and provide a highly robust surface marker profile for CRC stem cell isolation.
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