In addition, wild-type p53 expression also prevented FdUrd-induced DNA double-strand breaks and, unexpectedly, single-strand breaks in parental (mature) DNA. 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. The IGS was also associated with the prognosis in medulloblastoma (P=0.004), lung cancer (P=0.03), and prostate cancer (P=0.01). Prof Mike Clarke is Professor of Zoology at La Trobe University. View details for DOI 10.1053/j.gastro.2012.02.006, View details for Web of Science ID 000303113600038, View details for PubMedCentralID PMC3911891. 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. View details for Web of Science ID A1984SV56900010. Orthologs of these differentially expressed genes predicted survival of human breast cancer patients from two different study groups. Dr. Michael F. Clarke is the Associate Director of the Stanford Institute for Stem Cell and Regenerative Medicine. Interest in single-cell whole-transcriptome analysis is growing rapidly, especially for profiling rare or heterogeneous populations of cells. Although the existence of mammary stem cells has been suggested by serial transplantation studies in mice, their identification has been hindered by the lack of specific surface markers, and by the absence of suitable in vitro assays for testing stem cell properties: self-renewal and ability to generate differentiated progeny. We were able to distinguish the tumorigenic (tumor initiating) from the nontumorigenic cancer cells based on cell surface marker expression. These data, taken together with similar findings with other human neoplasms, show that CD47 is a commonly expressed molecule on all cancers, its function to block phagocytosis is known, and blockade of its function leads to tumor cell phagocytosis and elimination. View details for DOI 10.1073/pnas.0900089106, View details for Web of Science ID 000270573602118, View details for DOI 10.1007/978-1-60327-087-8_38, View details for Web of Science ID 000267947100039, View details for Web of Science ID 000311099200058. CD47 is a cell surface molecule that inhibits phagocytosis of cells that express it by binding to its receptor, SIRP, on macrophages and other immune cells. When viability was measured 24 h post-radiation, cells that had been briefly exposed to wtp53 immediately after X-ray irradiation had decreased survival as compared to unirradiated cells expressing wtp53 or X-ray irradiated DP16-1 cells. In 2007, he became the Director of the Royal United Services Institute. Michael was an assessor on Panel 35 in REF 2014 having been a specialist advisor for the 2008 RAE. Purified RGS18 interacts with the alpha subunit of both G(i) and G(q) subfamilies. View details for Web of Science ID A1992KX78000004. Search by Name. 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. Consistent with ROS being critical mediators of ionizing-radiation-induced cell killing, CSCs in these tumours develop less DNA damage and are preferentially spared after irradiation compared to NTCs. "Bulk" measurements of antiviral innate immune responses from pooled cells yield averaged signals and do not reveal underlying signaling heterogeneity in infected and bystander single cells. Thus, loss of expression of the alpha-catenin tumor suppressor in hematopoietic stem cells may provide a growth advantage that contributes to human MDS or AML with del(5q). The reasons for the limited longevity are unknown. in Pounds- 159 lbs. This finding suggests a mechanism by which normal hematopoietic progenitors can survive and proliferate despite p53 expression and by which the inappropriate expression of bcl-2 and c-myc can cooperate in transformation. We have examined the respiratory burst and arachidonic acid oxygenation that accompany phagocytosis in macrophages. The results demonstrate that cell sorting is effective, much faster and less likely to alter tumor cell phenotype than traditional methods for removing LDV from xenograft models. Here we implement single-cell PCR gene-expression analysis to dissect the cellular composition of primary human normal colon and colon cancer epithelia. View details for Web of Science ID 000398343600001. It has been postulated that there is a link between inflammation and cancer. While cell lines expressing p53 alone rapidly died, those cells co-expressing Bcl-XL survived. At the time of ABMT, 10 were chemosensitive, four were chemoresistant, and 10 were absolutely refractory to platinum. Zabala, M., Lobo, N. A., Seoane, J. The induced p53 is functional as p53-responsive genes (Waf-1 and MDM-2) are appropriately induced following IR. Interstitial loss of all or part of the long arm of chromosome 5, or del(5q), is a frequent clonal chromosomal abnormality in human myelodysplastic syndrome (MDS, a preleukemic disorder) and acute myeloid leukemia (AML), and is thought to contribute to the pathogenesis of these diseases by deleting one or more tumor-suppressor genes. The molecular mechanisms that control the self-renewal of HSCs are still largely unknown. Microarray analysis comparing Thy1+CD24+ tumor cells to not-Thy1+CD24+ cells identified a list of differentially expressed genes. 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%. 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. [2] Such a block presents a problem because radiation and chemotherapy, standard cancer treatments, ultimately exert their effect by induction of apoptosis and would also be made less effective. View details for Web of Science ID A1991EY27300001. View details for DOI 10.1146/annurev.med.58.062105.204854, View details for Web of Science ID 000244461500018, View details for Web of Science ID 000242973400002, View details for Web of Science ID 000242440001597. View details for Web of Science ID A1995RP92400014. View details for DOI 10.1196/annals.1349.012, View details for Web of Science ID 000230894100011, View details for Web of Science ID 000225161400025. Dontu, G., Al-Hajj, M., Abdallah, W. A., Clarke, M. F., Wicha, M. S. In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Administration of anti-CD47 antibodies inhibited tumor growth in orthotopic immunodeficient mouse xenotransplantation models established with patient tumor cells and increased the survival of the mice over time. EW replicates in IEC subsets differing in their basal type I IFN transcription and induces IRF3-dependent and IRF3-augmented transcription, but not NF-B-dependent or type I IFN transcripts. Methods We used a new bioinformatics approach to search for biomarkers of colon epithelial differentiation across gene-expression arrays and then ranked candidate genes according to the availability of clinical-grade diagnostic assays. Cytoplasmic sequestration of the p53 tumor suppresser protein has been proposed as a mechanism involved in abolishing p53 function. We focused our analysis of gene expression on RNA from primitive leukemia-initiating cells, which harbor 5q deletions, and analyzed 12 genes within the CDR that are expressed by normal hematopoietic stem cells. This new model for cancer will have significant ramifications for the way we study and treat cancer. DNA fragments containing either one or both of the 72-base pair (bp) elements which constitute the SV40 enhancer and the three adjacent 21-bp repeats were associated with histone octomers from chicken erythrocytes in vitro. 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. Advances in our understanding of apoptosis has identified the Bcl-2 family as a mediator of most apoptosis pathways, including those initiated by oncogenes, tumor suppressor genes, growth factor withdrawal, and external damaging signals. Some mice were given the RTK inhibitor imatinib after injection of cancer cells; tumor growth was measured based on bioluminescence. This functional subset of cancer cells is operationally defined as the "cancer stem cell" (CSC) subset. A spacer between this basic domain and NLS I is necessary for the entrance of p53 into the cell nucleus. Herein, we present a discussion around the issues facing treatment of patients with CRCliver metastases, including the relationship of discretegene signatures with prognosis. A., Jones, R. C., Nicolis di Robilant, B. n., Nong, R. Y., Norton, J. Inhibiting USP16 rescues stem cell aging and memory in an Alzheimer's model. 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. 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. Even in the absence of an exogenous apoptotic signal such as x-irradiation, this virus specifically and efficiently kills carcinoma cells arising from multiple organs including breast, colon, stomach, and neuroblasts. Zarnegar, M. A., Reinitz, F. n., Newman, A. M., Clarke, M. F. CDX2 as a Prognostic Biomarker in Colon Cancer. We describe the construction and characterization of a hybrid promoter for transcriptional targeting of breast cancer. Oncogenesis is a process resulting from genetic events which cause loss of growth control or inhibition of appropriate cell death. 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. View details for DOI 10.1016/j.stem.2009.05.019, View details for Web of Science ID 000269511900010. The tumor suppressor protein p53 has been identified as a key regulator of apoptosis in both normal and malignant hematopoietic cells. In postnatal Bmi-1-/- mice, the number of HSCs was markedly reduced. Identification of a novel microRNA-mediated pathway that regulates chemoresistance in breast cancer will facilitate the development of novel therapeutic strategies. Professor Michael Clarke is a Fellow of King's College London. Cytoplasmic sequestration of the mt p53 was dependent upon the C-terminal region (residues 326-355) of the protein. From 1990 to 2001 he was the founding Director of the Centre for Defence Studies at King's. The productivity of cultures exposed to conCM for 4 weeks dropped significantly when unsupplemented medium was used for the latter 4 weeks of culture. Both fragments formed complexes with electrophoretic mobilities of nucleosomes containing the appropriate length of DNA. 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. Michael Clarke is a British academic who specialises in defence studies. The number of HSCs in the fetal liver of Bmi-1-/- mice was normal. 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. CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer. View details for DOI 10.1634/stemcells.2006-0229, View details for Web of Science ID 000247722100006. We found 37 microRNAs that were differentially expressed between human BCSCs and nontumorigenic cancer cells. A full-length human c-myb cDNA clone has been isolated from a CCRF-CEM leukemia cell cDNA library. Discover Michael Clarke 's Biography, Age, Height, Physical Stats, Dating/Affairs, Family and career updates. In many cases, breast cancer cells retain the expression of estrogen receptors, and most solid tumors suffer from hypoxia as a consequence of their aberrant vascularization. Michael Clarke Duncan was born on December 10, 1957 in Chicago, Illinois. Furthermore, the oxygenation of arachidonic acid requires little of the oxygen consumed by phagocytosing alveolar macrophages. Effect of ASXL1 on the stemness of colorectal cancer initiating cells. B-cell lines established from two individuals with T-cell acute lymphocytic leukemia (T-ALL) express HLA-DR antigens, whereas the isogenic T-cells do not. Zarour, L. R., Anand, S., Billingsley, K. G., Bisson, W. H., Cercek, A., Clarke, M. F., Coussens, L. M., Gast, C. E., Geltzeiler, C. B., Hansen, L., Kelley, K. A., Lopez, C. D., Rana, S. R., Ruhl, R., Tsikitis, V. L., Vaccaro, G. M., Wong, M. H., Mayo, S. C. Role of epithelial to mesenchymal transition associated genes in mammary gland regeneration and breast tumorigenesis. Solid tumors such as breast cancers contain heterogeneous populations of neoplastic cells. The main battle tanks have a maximum speed of around 43.5mph and a range of . Programmed cell death (PCD) plays an important role in normal and malignant hematopoieis. Control experiments show that positioning is not due to the 21-bp repeats or to end effects. 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. 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). 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. IL-10 function is required for the full protective effect of small-molecule Hedgehog pathway activation in colitis; this pharmacologic augmentation of Hedgehog pathway activity and stromal IL-10 expression are associated with increased presence of CD4(+)Foxp3(+) regulatory T cells. Here we show that bone marrow cells from mice deficient in three genes genetically downstream of Bmi1--p16Ink4a, p19Arf and Trp53 (triple mutant mice; p16Ink4a and p19Arf are alternative reading frames of the same gene (also called Cdkn2a) that encode different proteins)--have an approximately 10-fold increase in cells able to reconstitute the blood long term. Hosen, N., Clarke, M. F., Weissman, I. L. Cancer stem cells--perspectives on current status and future directions: AACR Workshop on cancer stem cells. adequate tissue for cancer stem cell quantification. Adjunct Senior Lecturer Dr Jan Warnken. Human T-cell leukaemia virus (HTLV), first isolated in the United States from a patient with cutaneous T-cell lymphoma, is a unique horizontally transmitted retrovirus which is highly associated with certain adult T-cell malignancies. View details for Web of Science ID A1992GX27300015. He has also acted as a reviewer for the EPSRC and for funding councils in Austria, Finland, France and Germany. A locus on chromosome 17, including the H-2 complex, was significantly linked to the frequency of long-term self-renewing HSCs but showed no evidence of linkage to the frequency of restricted progenitors. There will be a great deal of national soul-searching as the tragedy in Afghanistan unfolds before us. A better understanding of the molecular mechanisms underlying metastasis is needed to develop more effective treatments. This suggests that expression of DR antigens also can be modulated post-transcriptionally. Also, HTLV can be transmitted in vitro to cord blood T-lymphocytes. 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. Thus, the development of proper sampling techniques or improved stem cell retention may be critical to obtain successful long-term cultures. Mandel, Michael - Associate Professor: Computer and Information Science Manlow, Veronica B. 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. After 5-azacytidine treatment of the cell lines, all cells expressed Ig light chains. Adjunct Professor Michael Whitehouse. Danish, R., ELAWAR, O., Weber, B. L., Langmore, J., Turka, L. A., Ryan, J. J., Clarke, M. F. CAN DEXTER CULTURES SUPPORT STEM-CELL PROLIFERATION. These chemically reactive forms of biotin produced derivatives biotinylated at amine or carboxyl groups, respectively. Biotinylated granulocyte/macrophage colony-stimulating factor (GM-CSF) analogues with different linkage chemistries and levels of conjugated biotin were synthesized by reacting recombinant human GM-CSF with sulfosuccinimidyl 6-biotinamidohexanoate or biotin hydrazide/1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide. These findings suggest that deregulated expression of Bcl-xS using an adenovirus may provide a novel mechanism for initiating cell death in tumors that express Bcl-2 or Bcl-xL. Kohrt, H. E., Houot, R., Weiskopf, K., Goldstein, M., Lund, P., Scheeren, F., Czerwinski, D., Colevas, A. D., Weng, W., Clarke, M. F., Carlson, R. W., Sunwoo, J., Tedder, T., Chen, L., Levy, R. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Other pathways have not been previously implicated in the regulation of cancer stem cell functions, including Ribosome and T Cell Receptor Signaling pathway. He is a board certified oncologist with extensive training in molecular biology and stem cell biology. These included transcription factors, signaling molecules, and previously unknown genes. G418-resistant clones, which expressed the c-sis cDNA, were selected and characterized. 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. Michael Clarke, defence analyst: Yes, the Black Sea is international and a UK warship went in there to Ukraine when the QE carrier was on its world tour last year. In contrast, at least some of these sites were not methylated in DNA from the B-cells expressing high levels of DR alpha mRNA. Genomic DNA extracted at 32.5 degrees C was seen to be fragmented into a characteristic ladder consistent with cell death due to apoptosis. Resistance to apoptosis plays an important role in tumors that are refractory to chemotherapy. The height of Michael Clarke is in centimeters- 165 cm in meters- 1.65 m in Feet Inches- 5' 5". His course "Justice" is the first Harvard course to be made freely available online and on television. The wild-type p53/GFP fusion protein was localized in the cytoplasm, the nucleus, or both compartments in a subset of the cells. Emerging evidence has suggested that the capability of a tumor to grow and propagate is dependent on a small subset of cells within a tumor, termed cancer stem cells. 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. In recent years solid tumors were studied utilizing similar techniques in mice. Strategies that enhance the activity of ADCC effectors, including NK cells, may improve the efficacy of trastuzumab. To characterize further the function of these two domains, we demonstrate in this report that the previously described major nuclear localization signal works together with Lys(305)-Arg(306) to form a bipartite and functional nuclear localization sequence (NLS) for p53 nuclear import. 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. 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. Reinitz, F., Chen, E. Y., Nicolis di Robilant, B., Chuluun, B., Antony, J., Jones, R. C., Gubbi, N., Lee, K., Ho, W. H., Kolluru, S. S., Qian, D., Adorno, M., Piltti, K., Anderson, A., Monje, M., Heller, H. C., Quake, S. R., Clarke, M. F. LEFTY1 Is a Dual-SMAD Inhibitor that Promotes Mammary Progenitor Growth and Tumorigenesis. View details for DOI 10.1016/j.cell.2006.03.011, View details for Web of Science ID 000237241400007. View details for DOI 10.1016/j.ijrobp.2009.03.047, View details for Web of Science ID 000268346100041. Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris. Although monoclonal in origin, most tumors appear to contain a heterogeneous population of cancer cells. These results suggest that the activity of some mutant p53 proteins can be functionally modified by exogenous compounds. 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. Faculty. 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. As precision medicine increases the response rate of treatment, tumors frequently bypass inhibition and reoccur. Cancers of epithelial origin are responsible for the majority of cancer-related deaths in the USA. Taken together, these results suggest that Bcl11b acts as acentral intrinsic regulator of mammary epithelial stem cell quiescence and exhaustion and is necessary for long-term maintenance of the mammary gland. In normal mouse epithelium, LEFTY1 expression in a subset of luminal cells and rare basal cells opposes BMP7 to promote ductal branching. Cancers arise in a tissue as the culmination of a series of mutations that activate oncogenes and inactivate tumor suppressor genes. Following high-dose IR, cell fractionation demonstrated that p53 is induced and targeted to the nucleus. Michael Clarke is a British academic who specialises in defence studies. 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. We collected eleven pancreatic tumors and identified three shared and five private neoplastic cell populations, offering insight into the origins of neuroendocrine and exocrine tumors. Adorno, M., di Robilant, B., Sikandar, S., Acosta, V., Antony, J., Heller, C. H., Clarke, M. F. Serially transplantable mammary epithelial cells express the Thy-1 antigen. 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. Widespread activation of immune cells is especially pronounced, and is first detectable in white adipose depots during middle age. In the other clone, incorporation of a new exon leads to introduction of a translation stop codon leading to loss of the entire carboxy terminus of the protein. 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 . 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