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. View details for Web of Science ID A1995RP92400014. 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. Here we show that the gene encoding alpha-catenin (CTNNA1) is expressed at a much lower level in leukemia-initiating stem cells from individuals with AML or MDS with a 5q deletion than in individuals with MDS or AML lacking a 5q deletion or in normal hematopoietic stem cells. Using this system, we have generated AdEHT2 and AdEHE2F, two conditionally replicative adenoviruses for the treatment of breast cancer. In contrast to our previous experience, where all such lines expressed T cell markers, these two cell lines expressed B cell antigens and Ig light chains (kappa on CF-2, lambda on HS). 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. The molecular mechanisms that control the self-renewal of HSCs are still largely unknown. Sen, A., Rothenberg, M. E., Mukherjee, G., Feng, N., Kalisky, T., Nair, N., Johnstone, I. M., Clarke, M. F., Greenberg, H. B. Remodeling of Endogenous Mammary Epithelium by Breast Cancer Stem Cells. Michael was an assessor on Panel 35 in REF 2014 having been a specialist advisor for the 2008 RAE. Liu, H., Patel, M. R., Prescher, J. Many of these mutations affect cell proliferation and survival. In combination with geometric and dynamic approaches to reconstructing physiological bone marrow microenvironments, we believe that this approach has promise for reconstructing human bone marrow ex vivo, thereby permitting its application to a variety of basic and clinical problems. A., Clarke, M. F., Weissman, I. L. MicroRNAs regulate breast cancer stem cells and spontaneous metastases in orthotopic xenograft models. Lobo, N. A., Zabala, M., Qian, D., Clarke, M. F. Serially transplantable mammary epithelial cells express the Thy-1 antigen. View details for DOI 10.1002/1878-0261.13220, View details for DOI 10.1038/s41587-022-01293-3. 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. KIT Signaling Promotes Growth of Colon Xenograft Tumors in Mice and Is Up-Regulated in a Subset of Human Colon Cancers. 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. The telomerase core promoter failed to block the replication of the virus in telomerase-negative cells. Cells that expressed kappa- or lambda-light chains were separated by cell sorting from kappa- or lambda-negative cells and replaced in culture. This decrease in survival began 48 h following radiation. View details for DOI 10.1016/j.semradonc.2008.11.002, View details for Web of Science ID 000264310800003, View details for PubMedCentralID PMC2789266. Within 24-48 hr, viral RNA expression increased at least four- to eightfold. 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. His interest is in Stem Cell Biology. Programmed cell death, or apoptosis, may play an important role in the regulation of hematopoiesis. We review the biological basis and the therapeutic implications of the stem cell model of cancer. A., Clarke, M. F., Quake, S. R. A single-cell transcriptomic atlas characterizes ageing tissues in the mouse. 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. Professor Michael Clarke was Director-General of the Royal United Services Institute (RUSI) from 2007 to 2015 when he retired from that role. He had office hours every day and heavily cared for your well-being. Transformation is a complex cellular process that requires several genetic abnormalities. By focusing on the biology of CoCSC, major resistance mechanisms to specific chemotherapeutic agents can be attributed to specific genes, thereby suggesting avenues for improving cancer therapy. Published Oct. 2, 2020 Updated Oct. 5, 2020. The hair color is Light brown and the eye color is Blue. Vorperian, S. K., Moufarrej, M. N., Tabula Sapiens Consortium, Quake, S. R., Jones, R. C., Karkanias, J., Krasnow, M., Pisco, A. O., Quake, S. R., Salzman, J., Yosef, N., Bulthaup, B., Brown, P., Harper, W., Hemenez, M., Ponnusamy, R., Salehi, A., Sanagavarapu, B. 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. X-ray irradiated cells expressing wtp53 displayed microscopic and biochemical characteristics consistent with cell death due to apoptosis. 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. 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. View details for DOI 10.1016/j.cell.2010.09.046, View details for Web of Science ID 000283052200007. It has been reported that Lysine-305 is needed for the nuclear import of the p53 protein (Liang et al., 1998). In both breast cancers and central nervous system tumors, cancer cells differ in their ability to form tumors. The GM-CSF production by the transfected 3T3 cells was stable but exhibited substantial transient increases during periods of cell proliferation, demonstrating that the secretion of transfected gene products can be highly modulated even when the cDNA is driven from a constitutive promoter. The Weight can be changed regularly, here we have added the latest value. They discuss the increasing threat of China, the post-Brexit identity of "Global Britain" and how the . Data on sequence comparisons with mouse and chicken homologues of c-myb coupled with oligonucleotide hybridization to genomic clones of the human c-myb gene indicate that this alternative splicing process utilizes three closely spaced splice donor sites and two unique exons present between viral defined exons 5 and 6. Professor Michael Clarke write a piece in The Sun saying time was running out for Putin. Strategies that enhance the activity of ADCC effectors, including NK cells, may improve the efficacy of trastuzumab. Here we describe two such clones and report that one of them transforms NIH-3T3 cells. Michael Clarke (academic) is a British academic who specialises in defence studies. 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. In vitro, blockade of CD47 signaling using targeted monoclonal antibodies enabled macrophage phagocytosis of tumor cells that were otherwise protected. and Ph.D. in economics from the University of Kentucky. 2010). However, the underlying molecular mechanisms are poorly characterized. 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. The results indicate that locally produced GM-CSF and IL-3 do augment hematopoiesis for several weeks in culture. These findings demonstrate that p53 overexpression renders Shep-1 cells IR-sensitive and suggest that large quantities of exogenous p53 can overcome the factors inhibiting p53-mediated, IR-induced apoptosis. Regulation of normal and cancer stem cell self renewal and senescence by USP16. We previously reported that miR-142 and miR-150 are upregulated in human breast cancer stem cells (BCSCs) as compared to the non-tumorigenic breast cancer cells. To assess CSC-specific remodeling events, we isolated CSC from MMTV-Wnt1 (mouse mammary tumor virus long-term repeat enhancer driving Wnt1 oncogene) breast tumors, a well studied model in which tissue remodeling affects tumorigenesis. However, the identity and function of cells expressing EMT-associated genes in normal murine mammary gland homeostasis and human breast cancer still remains under debate. Understanding the biology of cancer stem cells will contribute to the identification of molecular targets important for future therapies. CD47, a "don't eat me" signal for phagocytic cells, is expressed on the surface of all human solid tumor cells. Michael Clarke is a British academic who specialises in defence studies. 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 cells. This development may play an important role in realizing human gene therapy. In the discovery data set, which included 466 patients, the rate of 5-year disease-free survival was lower among the 32 patients (6.9%) with CDX2-negative colon cancers than among the 434 (93.1%) with CDX2-positive colon cancers (hazard ratio for disease recurrence, 3.44; 95% confidence interval [CI], 1.60 to 7.38; P=0.002). View details for Web of Science ID 000076744000010. 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. Herein, we present a discussion around the issues facing treatment of patients with CRCliver metastases, including the relationship of discretegene signatures with prognosis. We found 37 microRNAs that were differentially expressed between human BCSCs and nontumorigenic cancer cells. Several pathways, including Wnt signaling, MAP Kinase signaling, and Adherens Junction, are well known for their role in cancer development and stem cell biology. Orhan Eren Akgun. Adorno, M., di Robilant, B. N., Sikandar, S. S., Acosta, V. H., Antony, J., Heller, C. H., Clarke, M. F. Usp16 modulates Wnt signaling in primary tissues through Cdkn2a regulation. The metabolic and secretory characteristics of NIH-3T3 fibroblasts transfected with a cDNA encoding human granulocyte-macrophage colony stimulating factor (GM-CSF) were examined as a function of the culture medium exchange schedule. These results validate the stem cell working model in human CRC and provide a highly robust surface marker profile for CRC stem cell isolation. Here we show that Bmi-1 is required for the self-renewal of stem cells in the peripheral and central nervous systems but not for their survival or differentiation. 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. 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. 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. Regulation of the Wnt pathway in stem cells and primary tissues is still poorly understood. This makes it virtually impossible to infect the majority of tumor cells in vivo and results in inadequate gene transfer. 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. Microarray analysis comparing Thy1+CD24+ tumor cells to not-Thy1+CD24+ cells identified a list of differentially expressed genes. Leukemic peripheral blood lymphocytes from individuals infected with the human T-cell leukemia/lymphoma virus (HTLV) were found to express little or no viral RNA before being put into tissue culture. 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. Hosen, N., Yamane, T., Muijtjens, M., Pham, K., Clarke, M. F., Weissman, I. L. Phenotypic characterization of human colorectal cancer stem cells. To evaluate the feasibility of positron emission tomography (PET) with 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG) in patients with germ cell tumor (GCT) to monitor treatment and differentiate residual masses after chemotherapy.Twenty-six FDG PET studies were performed in 21 patients with GCT, FDG uptake of tumors was interpreted visually, and the lean standardized uptake value (SUVlean) was determined. By immunohistochemical analysis, the CD44(+) cells in the tumor express high levels of nuclear BMI1, and are arrayed in characteristic tumor microdomains. Here, we have shown that upon encountering trastuzumab-coated, HER2-overexpressing breast cancer cells, human NK cells become activated and express the costimulatory receptor CD137. 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. 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 That signaling pathways such as Bmi1 and Wnt have similar effects in normal and cancer stem cell self-renewal suggests that common molecular pathways regulate both populations. We have studied the ability of c-myc and bcl-2 oncogenes to modulate p53 function. 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. However, deletions of more than two amino acids between this region abolished the transport of p53 into the nucleus. The weight is in Kilograms- 70 kg. Filter By. Our laboratory has developed a novel mouse model that reliably permits individual cancer cells isolated directly from patients' tumors to be assayed. It is clear that new approaches are needed to treat these diseases. Professor Michael Clarke was Director General of the Royal United Services Institute (RUSI) from 2007 to 2015. View details for Web of Science ID 000169201800006. Treatment-related mortality was 10%. Interest in single-cell whole-transcriptome analysis is growing rapidly, especially for profiling rare or heterogeneous populations of cells. His group was the first to discover that the proto-oncogene Bmi-1 regulates stem cell self-renewal via an epigenetic mechanism. View details for Web of Science ID 000079346200015. The wild-type p53/GFP fusion protein was localized in the cytoplasm, the nucleus, or both compartments in a subset of the cells. 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. To see if a limited sampling of tumor tissue from human subjects is a feasible way to gather The HUT-102 cell line, derived from a cutaneous T-cell lymphoma and infected with HTLV, expresses several cellular oncogenes. Akala, O. O., Park, I., Qian, D., Pihalja, M., Becker, M. W., Clarke, M. F. A gene signature in breast cancer - Reply. Profiles. 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. 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 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. Established HTLV-infected cell lines constitutively express viral RNA. Adjunct Associate Professor David Welsh. Gene expression analysis of single CD44(+) cells indicated that KIT can promote growth via KITLG autocrine and/or paracrine signaling. He is a Professor at La Trobe University in Melbourne, Victoria, where he has worked since 1992. Join Facebook to connect with Michael Clarke and others you may know. KrasG12D -independent tumor cells show a strong mesenchymal profile with active RAS-RAF-MEK-ERK (MAPK/ERK) signaling. 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. We have developed a new in vitro culture system that permits, for the first time, the propagation of mammary stem and progenitor cells in an undifferentiated state, which should facilitate the elucidation of pathways that regulate normal mammary stem-cell self-renewal and differentiation. 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. Liu, H., Qian, D., Lin, J., Lobo, N., Zhang, H., Dalerba, P., Shimono, Y., Diehn, M., Jeffrey, S., Clarke, M. Isolation and molecular characterization of cancer stem cells in MMTV-Wnt-1 murine breast tumors. Location University of Rochester 402 Hutchison Hall P.O. The Polycomb protein Bmi1 is absolutely required for the maintenance of both adult HSCs and neural stem cells. The main objectives of his laboratory are to pursue how perturbations in the self-renewal machinery contribute to human diseases and to use the findings to aid the development of more effective treatment therapies.His laboratory has a long history of innovative findings which include: the first to demonstrate that inappropriate expression of a normal gene could cause a tumor; the first to identify a dominant-negative splice variant of an oncogene; the first to identify a molecular regulator of stem cell self-renewal; the first to identify a solid tumor stem cell (in breast cancer) and the first to demonstrate a molecular linkage of a self-renewal program used by normal mammary stem cells and breast cancer cells. In this report, we have used intravital multiphoton microscopy to visualize the different migration patterns of human breast tumor cells in live primary tumors. Control experiments show that positioning is not due to the 21-bp repeats or to end effects. High-level expression of the c-sis oncogene, which encodes the beta chain of platelet-derived growth factor, transforms immortalized rodent fibroblasts in vitro to a malignant phenotype. Many cancers overexpress a member of the bcl-2 family of inhibitors of apoptosis. View details for Web of Science ID 000243488100004. Human tumors where evidence of cancer stem cells has been published include tumors of the breast, brain, pancreas, head and neck, and colon. 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. Two clones which initially expressed low levels of human c-myb transcripts and which differentiated normally were subsequently inhibited in their ability to differentiate when grown in successively higher concentrations of methotrexate, due to amplification and enhanced expression of plasmid sequences. This suggests RGS18 can act on G(q)-mediated signaling pathways in vivo. Alzheimer's disease (AD) is a progressive neurodegenerative disease observed with aging that represents the most common form of dementia. This suggests that expression of DR antigens also can be modulated post-transcriptionally. 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 addition, wild-type p53 expression also prevented FdUrd-induced DNA double-strand breaks and, unexpectedly, single-strand breaks in parental (mature) DNA. 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). Michael W. Clark is the Director of the Center for Business and Economic Research and an Associate Professor of Economics at the University of Kentucky's Gatton College of Business and Economics. 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. 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