KIT and/or KITLG was stably knocked down by expression of small hairpin RNAs from lentiviral vectors in DLD1, HT29, LS174T, and COLO320 DM colon cancer cell lines, and in UM-COLON#8 and POP77 xenografts; cells transduced with only vector were used as controls. He earned a B.A. RNA splicing programs define tissue compartments and cell types at single-cell resolution. Furthermore, we found that specifically inhibiting human DLL4 in the tumor, either alone or in combination with the chemotherapeutic agent irinotecan, reduced cancer stem cell frequency, as shown by flow cytometric and in vivo tumorigenicity studies. Rachel Ellehuus. Recently, there have been exciting developments in identifying high-risk patient cohorts, refinements in the understanding of systemic vs localized drug delivery to metastatic niches, liquid biomarker development, and dramatic advances in tumor immune therapy, all of which promise new and innovative approaches to tackling the problem ofdetecting and treating the metastatic spread of CRC to the liver. View details for DOI 10.1016/j.cell.2009.07.011, View details for Web of Science ID 000268771900022, View details for PubMedCentralID PMC2731699. Epigenetic regulation of normal and cancer stem cells, Neurobiology: At the root of brain cancer, Chronic myelogenous leukemia - Identifying the hydra's heads, Therapeutic implications of cancer stem cells. In approaching the bone marrow culture system, we recognize the critical role that hematopoietic growth factors (HGFs) play in hematopoiesis. View details for Web of Science ID 000083623000026. 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. Dr Ofer Fridman spoke on CNN about the nature of Russian hybrid warfare, discussed Israel's position in Russia and Ukraine border tensions in The Jerusalem Post and was in The i on whether Russia would attack the UK over the imposed sanctions. Many cancers overexpress a member of the bcl-2 family of inhibitors of apoptosis. View details for DOI 10.1016/j.stem.2016.11.007, View details for PubMedCentralID PMC5341693. Using these targeted reporter mice, we demonstrated that Bmi-1 is expressed in hematopoietic stem cells (HSCs) at its highest levels and downregulated upon commitment to differentiation. BMI1 has been demonstrated to play a role in self-renewal in other stem cell types and to be involved in tumorigenesis. As few as 100 cells with this phenotype were able to form tumors in mice, whereas tens of thousands of cells with alternate phenotypes failed to form tumors. Michael Clark. c-sis gene expression has been demonstrated in a variety of human tumors, although generally at levels much lower than those shown to transform cells in vitro. View details for DOI 10.1016/j.stemcr.2020.12.012. Here we implement single-cell PCR gene-expression analysis to dissect the cellular composition of primary human normal colon and colon cancer epithelia. This suggests that expression of DR antigens also can be modulated post-transcriptionally. (2010) dissect the gene expression signature of ES cells into three functional modules and find that the Myc module, including genes targeted by Myc-interacting proteins, accounts for most of the similarity between ES and cancer cells. View details for Web of Science ID A1995RY96700021. Like many epithelial tumors, head and neck squamous cell carcinoma (HNSCC) contains a heterogeneous population of cancer cells. Thus, bcl-2 protects cells from p53-dependent radiation-induced apoptotic cell death and attenuates p53-independent radiation-induced cell death. Director, Teaching & Learning. Using mammary epithelial-specific mouse models targeting Trp53 and Cdkn2a, the gene coding for p16INK4a and p19ARF, we demonstrate that p53, p16INK4a, and p19ARF do not play a significant role in the limitation of normal mammary epithelium self-renewal and proliferation, whereas in the presence of the inflammatory cytokine TNF-, Trp53-/-Cdkn2a-/- mammary basal cells exhibit amplified proliferation. Recently, his group described a molecular mechanism that confers resistance to radiation in breast cancer stem cells. Prior to that he was Professor of Defence Studies at King's College London, and Deputy Vice-Principal for Research Development. Han, J. S., Qian, D. L., Wicha, M. S., Clarke, M. F. Targeting cancer cell death with a bcl-x(s) adenovirus. 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. Although monoclonal in origin, most tumors appear to contain a heterogeneous population of cancer cells. 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. 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. Frequently, overexpression of a member of the Bcl-2 family results in a block in cell death and appears to nullify many built-in cellular defense mechanisms against cancer. Using in vivo lineage tracing and triple negative breast cancer (TNBC) patient derived xenografts we demonstrate that the repopulating capacity in normal mammary epithelial cells and tumorigenic capacity in TNBC is independent of expression of EMT-associated genes. Flow cytometry and microfluidics-based single-cell multiplex RT-PCR allowed dissection of IFN responses in single RV-infected and bystander intestinal epithelial cells (IECs). Furthermore, we propose a model in which transformation of stem cells, or early progenitor cells, results in carcinogenesis. A., Ozawa, M. G., Silva, O., Toland, A., Vemuri, V. N., Afik, S., Awayan, K., Bierman, R., Botvinnik, O. When isolated from mouse colon, cKit(+) cells promoted formation of organoids from Lgr5(+) stem cells, which expressed Kitl/stem cell factor, the ligand for cKit. By complementation of the E1a protein in trans, Ad5ERE2 allows restricted replication of a conventional E1a-deleted adenoviral vector. Pulse induction of p53 alone did not affect Shep-1 cell viability, while induction of p53, followed by IR, resulted in cell death and DNA fragmentation proportional to the dose of IR and the level of p53 expression. Ryan, J. J., Danish, R., Gottlieb, C. A., Clarke, M. F. C-MYB EFFECTS ON KINETIC EVENTS DURING MEL CELL-DIFFERENTIATION. Bcl-xs is a dominant negative repressor of Bcl-2 and Bcl-xL, both of which inhibit apoptosis. He is an adviser to two Parliamentary Committees and Associate Director of the Strategy and Security Institute at the University of Exeter. Mark Malloch Brown, Baron Malloch-Brown (* 1953), Politiker und stellvertretender Generalsekretr der Vereinten Nationen. The enhanced cytotoxicity was restricted to antibody-coated tumor cells. 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. Cai, S., Kalisky, T., Dalerba, P., Clarke, M., Stanford Univ. In this report we explore the role of Bcl-XL overexpression in protecting cancer cells from p53-mediated apoptosis. Michael Clarke is a UK academic and "terror expert". Following high-dose IR, cell fractionation demonstrated that p53 is induced and targeted to the nucleus. The ability to self-renew is essential for all kinds of stem cells regardless of tissue type. Taken together, these results indicate that wild-type p53 induces cell death in murine erythroleukemia cells and that this effect occurs predominantly in the G1 phase of actively cycling cells. Replication-defective retroviruses are frequently used as gene carriers for gene transfer into target cells. 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. Both fragments formed complexes with electrophoretic mobilities of nucleosomes containing the appropriate length of DNA. View details for Web of Science ID 000073794800011. View details for Web of Science ID A1995RC93600007. X-ray irradiated cells expressing wtp53 displayed microscopic and biochemical characteristics consistent with cell death due to apoptosis. Restricted neural progenitors from the gut and forebrain proliferate normally in the absence of Bmi-1. Patsialou, A., Bravo-Cordero, J., Wang, Y., Liu, H., Clarke, M. F., Condeells, J. S. Deregulation of stem cell self-renewal pathways in cancer, MicroRNA-30c inhibits human breast tumour chemotherapy resistance by regulating TWF1 and IL-11. These data represent a new resource for cell biology, reveal gene expression in poorly characterized cell populations and enable the direct and controlled comparison of gene expression in cell types that are shared between tissues, such as T lymphocytes and endothelial cells from different anatomical locations. Professor Michael Clarke was Director General of the Royal United Services Institute from 2007-2015, where he remains a Distinguished Fellow. 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. After 48 h in culture, DR antigen expression was substantially increased, but no significant changes were observed in methylation of the DR alpha locus or in the amount of DR mRNA which was present. Although an increasing number of interventions show promise for rejuvenation2, their effectiveness on disparate cell types across the body and the molecular pathways susceptible to rejuvenation remain largely unexplored. A central question in cancer biology is, which cells can be transformed to form tumors? View details for Web of Science ID 000079346200015. Several pathways, including Wnt signaling, MAP Kinase signaling, and Adherens Junction, are well known for their role in cancer development and stem cell biology. Programmed cell death (PCD) plays an important role in normal and malignant hematopoieis. 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. The safety and efficacy of targeting CD47 was further tested and validated in immune competent hosts using an orthotopic mouse breast cancer model. Previous studies have proposed that epithelial to mesenchymal transition (EMT) in breast cancer cells regulates metastasis, stem cell properties and chemo-resistance; most studies were based on in vitro culture of cell lines and mouse transgenic cancer models. However, multipotent progenitors lack the ability to self-renew, therefore their mitotic capacity and expansion potential are limited and they are destined to eventually stop proliferating after a finite number of cell divisions. Additionally, we suggest that constitutive expression of c-myb does not block early commitment events such as activation of histone Hl', subsequent chromatin condensation, and alteration of proliferation-related gene expression. 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. Michael was an assessor on Panel 35 in REF 2014 having been a specialist advisor for the 2008 RAE. A., Jones, R. C., Nicolis di Robilant, B. n., Nong, R. Y., Norton, J. Office Hours: Tuesday 12:00-1:00PM; Thursday 2:00-3:00PM; Friday 10:30-11:30AM. Here we show that in Ts65Dn mice, which are trisomic for 132 genes homologous to genes on human chromosome 21, triplication of Usp16 reduces the self-renewal of haematopoietic stem cells and the expansion of mammary epithelial cells, neural progenitors and fibroblasts. However, at later times X-ray irradiated parental DP16-1 cells also had decreased survival compared to the unirradiated control. In recent years solid tumors were studied utilizing similar techniques in mice. One of these, the goblet cells, contained a distinct cKit/CD117(+) crypt base subpopulation that expressed Dll1, Dll4, and epidermal growth factor, similar to Paneth cells, which were also marked by cKit. Using gene transfer technology, we can now deliver genes that accomplish this goal. Here, we report the results of using a bioreactor system to expand hematopoietic cells after a brief retrovirus infection using a high titer, replication defective virus encoding for murine CD18. In 2007, he became the Director of the Royal United Services Institute. Adjunct Professor Michael Whitehouse. Restoration of CTNNA1 expression in HL-60 cells resulted in reduced proliferation and apoptotic cell death. Sumantran, V. N., Ealovega, M. W., Nunez, G., Clarke, M. F., Wicha, M. S. In vitro expansion of hematopoietic cells for clinical application. 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. However, none of the NB cell lines expressed Bcl-xS. Zanini, F. n., Berghuis, B. 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. KIT signaling promotes growth of colon cancer cells and organoids in culture and xenograft tumors in mice via its ligand, KITLG, in an autocrine or paracrine manner. adequate tissue for cancer stem cell quantification. Therapeutic Implications of the Cancer Stem Cell Hypothesis, Dysregulated gene expression networks in human acute myelogenous leukemia stem cells. View details for DOI 10.1073/pnas.1212188109, View details for Web of Science ID 000312605600104, View details for PubMedCentralID PMC3528539. Professor Michael Clarke was Director-General of the Royal United Services Institute (RUSI) from 2007 to 2015 when he retired from that role. 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. 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