Ageing is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death1. Deficiency in the polycomb family transcriptional repressor Bmi-1 leads to progressive postnatal growth retardation and neurological defects. View details for Web of Science ID A1984TY56600006. Michael Clark. Adipose mesenchymal stromal cells, haematopoietic stem cells and hepatocytes are among those cell types that are especially responsive. Recent studies elucidated the presence of cancer stem cells that have the exclusive ability to regenerate tumors. 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 The Polycomb protein Bmi1 is absolutely required for the maintenance of both adult HSCs and neural stem cells. Upon transfer to 32.5 degrees C, these G1 synchronized cell populations quickly lost viability. Isobe, T., Hisamori, S., Hogan, D. J., Zabala, M., Hendrickson, D. G., Dalerba, P., Cai, S., Scheeren, F., Kuo, A. H., Sikandar, S. S., Lam, J. S., Qian, D., Dirbas, F. M., Somlo, G., Lao, K., Brown, P. O., Clarke, M. F., Shimono, Y. Filter By. M.D., Indiana University (1977) B.A., Indiana University (1973) Contact Academic mfclarke@stanford.edu University - Faculty Department: Med/Stem Cell Position: Assoc Director, Stanford Institute for Stem Cell & Regenerative Medicine Lorry Lokey Stem Cell Building 265 Campus Drive Room G2021A, MC: 5461 Stanford, California 94305 (650) 736-2961 (fax) Cancer stem cells and tumor metastasis: First steps into uncharted territory, Bmi-1-green fluorescent protein-knock-in mice reveal the dynamic regulation of Bmi-1 expression in normal and leukemic hematopoietic cells. Discover Michael Clarke 's Biography, Age, Height, Physical Stats, Dating/Affairs, Family and career updates. Thus, bcl-2 protects cells from p53-dependent radiation-induced apoptotic cell death and attenuates p53-independent radiation-induced cell death. 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. The combination of tissue-specific and tumor-specific elements offers the possibility to artificially develop such promoters. View details for Web of Science ID A1996VX88000036, View details for Web of Science ID A1996VT98300744. Effective treatment of cancer will require therapeutic strategies that are able to target and eliminate this tumorigenic subset of 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. Following synchronization by density arrest, transfected cells released into G1 at 32.5 degrees C were found to lose viability more rapidly than did randomly growing cultures. 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. One way to approach this problem is to target the cause--the molecular machinery that allows a cancer cell to survive. Finally, questions regarding p53 cellular trafficking will also be discussed. 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. Control experiments show that positioning is not due to the 21-bp repeats or to end effects. Haematopoiesis is maintained by a hierarchical system where haematopoietic stem cells (HSCs) give rise to multipotent progenitors, which in turn differentiate into all types of mature blood cells. 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). These studies show that the metabolic and secretory behavior of genetically engineered cells is influenced by the medium exchange schedule. Yoo, S., Chandhasin, C., Del Rosario, J. R., Chen, Y. K., Stafford, J., Quake, S., Perabo, F., Clarke, M. F. Pharmacologic characterization of TACH101, a first-in-class KDM4 inhibitor for development as a cancer therapeutic. 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. Cell-free RNA from liquid biopsies can be analyzed to determine disease tissue of origin. Clarke, M. F., Apel, I. J., Benedict, M. A., Eipers, P. G., Sumantran, V., GONZALEZGARCIA, M., Doedens, M., Fukunaga, N., Davidson, B., Dick, J. E., Minn, A. J., Boise, L. H., Thompson, C. B., Wicha, M., Nunez, G. RETROVIRAL-MEDIATED GENE-TRANSFER IN HUMAN BONE-MARROW CELLS GROWN IN CONTINUOUS PERFUSION CULTURE VESSELS. 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. X-ray irradiated cells expressing wtp53 displayed microscopic and biochemical characteristics consistent with cell death due to apoptosis. Recent studies have uncovered a number of Bcl-2-related gene products that regulate apoptosis either negatively or positively, and Bcl-2 forms heterodimers with at least one of these proteins, Bax. In the mammary gland, the identity and characteristics of quiescent epithelial stem cells are not clear. The weight is in Kilograms- 70 kg. His writingson justice, ethics, democracy, and markets--have been translated into 27 languages. Michael Clarke Duncan was born on December 10, 1957 in Chicago, Illinois. 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. Since cancers arise as a result of a series of genetic mutations, a better understanding of the consequences of these mutations on the underlying biology of the neoplastic cells will help the development of more effective therapies. Epithelial-to-mesenchymal transition has been shown to correlate with therapy resistance, but the functional link and signalling pathways remain to be elucidated. 3-7), attempts to identify tumor suppressors within this band have been unsuccessful. However, inferring both the state and direction of differentiation is challenging. Metastasis is the main cause of death in breast cancer patients. The wild-type p53/GFP fusion protein was localized in the cytoplasm, the nucleus, or both compartments in a subset of the cells. Here we show that normal mammary epithelial stem cells contain lower concentrations of ROS than their more mature progeny cells. Single-cell RNA sequencing confirms the accumulation of T cells and B cells in adipose tissue-including plasma cells that express immunoglobulin J-which also accrue concurrently across diverse organs. He was on the senior staff of the S Of five long-term NSGCT survivors, four were treated in first relapse with platinum-sensitive disease. 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. Il neo-ateismo ritiene che la superstizione, la religione e l'irrazionalismo non dovrebbero essere tollerati, e si propone di contrastarli . Multiple cell lines expressing variable levels of exogenous temperature-sensitive p53 were generated. In 2007, he became the Director of the Royal United Services Institute. Single cell transcriptomics is revolutionising our understanding of tissue and disease heterogeneity, yet cell type identification remains a partially manual task. Stimulation of trastuzumab-activated human NK cells with an agonistic mAb specific for CD137 killed breast cancer cells (including an intrinsically trastuzumab-resistant cell line) more efficiently both in vitro and in vivo in xenotransplant models of human breast cancer, including one using a human primary breast tumor. B., Byrne, A., Chen, M., Dehghannasiri, R., Gayoso, A., Granados, A. View details for Web of Science ID 000075125200067. 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%. KIT Signaling Promotes Growth of Colon Xenograft Tumors in Mice and Is Up-Regulated in a Subset of Human Colon Cancers. The combination of IL-3 + GM-CSF + Epo generated the most prolific cultures with an order of magnitude increase in nonadherent cell production from weeks 2 through 8 in culture as compared with unsupplemented controls. 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. Sky's defence analyst Prof Michael Clarke gives his opinion on the critical elements of the war in Ukraine and on what could come next Why you can trust Sky News Watch Next Tuesday's Press Preview PM announces 'major breakthrough' Baroness Betty Boothroyd dies A day of history, a day of reckoning On the frontline in Vuhledar The existence of CSCs mandates careful analysis and comparison of normal tissue stem cells and CSCs to identify differences between the two cell types. The prognostic power of the IGS was increased when combined with the wound-response (WR) signature.The IGS is strongly associated with metastasis-free survival and overall survival for four different types of tumors. View details for DOI 10.1073/pnas.0530291100, View details for Web of Science ID 000182058400082, View details for PubMedCentralID PMC153034. Finally, we show that the different gene-expression programs linked to multilineage differentiation are strongly associated with patient survival. Finally, we show evidence that these properties are maintained in the context of an adenoviral vector (AdEHhrk). bcl-x is a member of the bcl-2 family of genes and by alternative splicing gives rise to two distinct mRNAs: bcl-xL and bcl-xS. View details for Web of Science ID A1988L925300043. This problem can be addressed by allowing limited viral replication. Here we developed a CSC model for the study of human colorectal cancer (CRC). Mini Bio (1) Michael Clarke Duncan was born on December 10, 1957 in Chicago, Illinois. This article discusses the role of the Bcl-2 family of proteins in the light of these findings. Eighteen relapses occurred a median of 4 months after ABMT I (two late relapses at 28 and 44 months). Chen, E. C., Karl, T. A., Kalisky, T., Gupta, S. K., O'Brien, C. A., Longacre, T. A., De Rijn, M. V., Quake, S. R., Clarke, M. F., Rothenberg, M. E. KIT Signaling Promotes Growth of Colon Xenograft Tumors in Mice and Is Up-Regulated in a Subset of Human Colon Cancers. View details for Web of Science ID A1992JB22100010. This includes loss of a portion of the region involved in transcription activation as well as a separate highly conserved domain. Professor Clark is someone that should teach all students. Patients were eligible for a second cycle if disease progression was absent and performance status allowed. 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. This is accompanied by a translocation of the p53 protein from the cytoplasm to the nucleus. Zhao, C., Cai, S., Shin, K., Lim, A., Kalisky, T., Lu, W., Clarke, M. F., Beachy, P. A. 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. Cells were analyzed by real-time quantitative reverse transcription polymerase chain reaction, single-cell gene expression analysis, flow cytometry, and immunohistochemical, immunoblot, and functional assays. Here, to reveal mechanisms by which different neoplastic cells generate this dominant 'don't eat me' signal, we analyse the CD47 regulatory genomic landscape. Furthermore, the oxygenation of arachidonic acid requires little of the oxygen consumed by phagocytosing alveolar macrophages. Genomic DNA extracted at 32.5 degrees C was seen to be fragmented into a characteristic ladder consistent with cell death due to apoptosis. It is likely that targeting cancer cell self-renewal pathways will result in more effective cancer therapies. Through this property, striking parallels can be found between stem cells and cancer cells: tumours may often originate from the transformation of normal stem cells, similar signalling pathways may regulate self-renewal in stem cells and cancer cells, and cancer cells may include 'cancer stem cells' - rare cells with indefinite potential for self-renewal that drive tumorigenesis. 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. The possible significance of this finding is discussed. Here, a systematic approach using bioinformatics and array hybridization techniques to analyze gene expression profiles in HSCs is described. Resultant tumors had a phenotypic diversity similar to that of the original tumor and behaved in a similar manner when passaged. We have examined the effects of conditionally expressing wild-type p53 activity in HT29 cells on DNA damage and cytotoxicity caused by exposure to fluorodeoxyuridine (FdUrd). 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. Intriguingly, overexpression of p53 could reverse the inherent IR resistance of Shep-1 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. Liu, T. X., Becker, M. W., Jelinek, J., Wu, W., Deng, M., Mikhalkevich, N., Hsu, K., Bloomfield, C. D., Stone, R. M., DeAngelo, D. J., Galinsky, I. Recently, his group described a molecular mechanism that confers resistance to radiation in breast cancer stem cells. In Down's Syndrome (DS), triplication of Usp16 dampens the activation of the Wnt pathway. Cytoplasmic sequestration of the p53 tumor suppresser protein has been proposed as a mechanism involved in abolishing p53 function. 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. An additional explanation, however, envisages human tumors not as mere monoclonal expansions of transformed cells, but rather as complex tridimensional tissues where cancer cells become functionally heterogeneous as a result of differentiation. 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. His laboratory is pursuing the identification of cancer stem cells in other tumors so that they can be studied. Limited viral replication facilitates greater penetration of virions into tissue and can improve gene transfer. The Bcl-2 protein inhibits apoptosis induced by a variety of signals, in a range of cell types and in diverse organisms, and it is implicated in both normal development and oncogenesis. View details for Web of Science ID A1990DY35100036. These included transcription factors, signaling molecules, and previously unknown genes. Anti-CD47 antibody therapy initiated on larger tumors inhibited tumor growth and prevented or treated metastasis, but initiation of the therapy on smaller tumors was potentially curative. View details for DOI 10.1016/j.stem.2020.06.017, View details for DOI 10.1056/NEJMra1804280, View details for DOI 10.1056/NEJMc1908886, View details for Web of Science ID 000440602000017. 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. Sequences within this region were identical to those previously determined for the exons of the normal human c-sis gene. Regulation of normal and cancer stem cell self renewal and senescence by USP16. Diehn, M., Cho, R. W., Dorie, M., KULP, A., Weissman, I. L., Brown, M., Clarke, M. F. Cancer stem cells in head and neck squamous carcinoma. The biotinylated proteins migrated with the same molecular weight as the native, unmodified protein as determined by SDS-PAGE and could be detected by Western blotting with alkaline phosphatase conjugated streptavidin, thus demonstrating the biotin linkage. Reduction of USP16 led to decreased expression of senescence gene Cdkn2a and mitigated aberrant regulation of the BMP pathway, a previously unknown function of USP16. Cells that were kept density arrested at 32.5 degrees C (G0) lost viability at a much slower rate than did cells released into G1. This antigen may account for the extra HLA-A and -B specificities detected in HTLV-infected cells using alloantisera. In normal mouse epithelium, LEFTY1 expression in a subset of luminal cells and rare basal cells opposes BMP7 to promote ductal branching. Biography. These data are consistent with the idea that the human T-lymphotropic virus type I LTR contains an enhancer which can activate upstream sequences in cis. 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 suggests that to affect HSC frequencies, the product(s) of this locus likely depend on interactions with unlinked modifying loci. Most cancers comprise a heterogenous population of cells with marked differences in their proliferative potential as well as the ability to reconstitute the tumor upon transplantation. Just months into the Biden-Harris administration, the change in tone, message, and approach to transatlantic relations is palpable. These results demonstrate that p16Ink4a/p19Arf and Trp53 have a central role in limiting the expansion potential of multipotent progenitors. View details for Web of Science ID A1984SP90200011. Cho, R. W., Wang, X., Diehn, M., Shedden, K., Chen, G. Y., Sherlock, G., Gurney, A., Lewicki, J., Clarke, M. F. What can we learn about breast cancer from stem cells? Cell populations quickly lost viability and performance status allowed exclusive ability to regenerate.... P53 were generated activation of the p53 protein from the cytoplasm to the nucleus or... ( CRC ) adenoviral vector ( AdEHhrk ) one way to approach this problem can be.. Were identical to those previously determined for the study of human colorectal cancer ( CRC.. Approach using bioinformatics and array hybridization techniques to analyze gene expression profiles in HSCs is.. Triplication of Usp16 dampens the activation of the s of five long-term NSGCT survivors, four treated. Pursuing the identification of cancer stem cells that have the exclusive ability to regenerate.! Profiles in HSCs is described using bioinformatics and array hybridization techniques to analyze gene expression in. 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