To do so, we used breast tumors of the mouse mammary tumor virus (MMTV)-Wnt-1 mice. View details for Web of Science ID A1984SP90200011. Stem cells persist throughout life by self-renewing in numerous tissues including the central and peripheral nervous systems. Zarnegar, M. A., Reinitz, F. n., Newman, A. M., Clarke, M. F. CDX2 as a Prognostic Biomarker in Colon Cancer. In concert with endogenous DMSO-induced globin transcription during MEL cell differentiation, the beta-globin c-myb transcription unit of the transfected plasmid is activated after 3-5 days of culture in media containing DMSO. Northstar is a useful tool to assign known and novel cell type and states in the age of cell atlases. To date, therapies targeting end-stage disease plaques, tangles, or inflammation have limited efficacy. Our studies show that coincident expression of human Bcl-2 protein with p53 prolongs survival of murine erythroleukemia cells. The DR alpha genes in both cell lines are hypermethylated relative to the same genes in T-cell lines infected with human T-cell leukemia virus (HTLV) and derived from patients with adult T-cell leukemia/lymphoma (ATL). In the accompanying paper it was shown that all T cells producing HTLV, whether cultured from infected persons or infected in vitro, bind a monoclonal antibody (4D12) which recognizes an epitope shared by certain cross-reactive class I major histocompatibility antigens. Acad. Discover Michael Clarke 's Biography, Age, Height, Physical Stats, Dating/Affairs, Family and career updates. T-cell lines established from human T-cell leukemia-lymphoma virus associated T-cell neoplasias, in contrast to the T-cell acute lymphocytic leukemia cell lines, expressed both DR antigens and DR alpha mRNA; the HpaII sites within the BglII fragment of DR alpha DNA of these human T-cell leukemia-lymphoma virus-positive T-cell lines were in all cases at least partially unmethylated. This model, first developed in human myeloid leukemias, is today being extended to solid tumors, such as breast and brain cancer. Il termine stato coniato dal giornalista statunitense Gary Wolf nel 2006. This is the first example of transformation of NIH-3T3 cells by a human onc gene other than c-ras or Blym, as well as the first demonstration of transformation by a human cDNA clone. In murine leukemia models induced by P210BCR/ABL or TEL/PDGFbetaR + AML1/ETO, Bmi-1 was not overexpressed in leukemic HSCs, despite the increase in the HSC numbers. Thus a limiting serum component is responsible for the altered metabolic and growth rates. Loss of Bcl11b leads to a Cdkn2a-dependent exhaustion of ductal epithelium and loss of epithelial cell regenerative capacity. Some factors that regulate this process of self-renewal are conserved from fruit fly to humans. 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. The plasmid vector contains simian virus 40-derived promotor, splice, and polyadenylation sequences as well as a transcription unit for a dihydrofolate reductase cDNA. The fragment with a tandem repeat of the 72-bp element also does not associate randomly with histones. Liu, H., Bockhorn, J., Dalton, R., Olopade, O. F., Clarke, M. F., Greene, G. L. MicroRNAs regulating breast cancer stem cells and metastasis. Liu, R., Wang, X., Chen, G. Y., Dalerba, P., Gurney, A., Hoey, T., Sherlock, G., Lewicki, J., Shedden, K., Clarke, M. F. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. ANGELOTTI, T. P., Clarke, M. F., Longino, M. A., Emerson, S. G. THE CONSTRUCTION OF HIGH-EFFICIENCY HUMAN BONE-MARROW TISSUE EXVIVO. A., Issa, J., Clarke, M. F., Look, A. T. Lobo, N. A., Shimono, Y., Qian, D., Clarke, M. F. Cancer stem cells and radiotherapy: New insights into tumor radioresistance. As we continue to advance clinically and technologically in the field of colorectal tumor biology, ourgoal should be continuedrefinement of predictive and prognostic studiesto decrease recurrence after curative resection and minimize treatment toxicity to patients through a tailoredmultidisciplinary approach to cancer care. Further study with ETYA showed that the inhibitor at 2 x 10(-5) M had little effect on uptake of 125I-labeled zymosan but did abolish the conversion of 14C-arachidonic acid to a compound that co-migrated with authentic 12-HETE on silica gel plates. In recent years solid tumors were studied utilizing similar techniques in mice. 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. We then determined the effects of intratumoral injection of bcl-xs adenovirus on solid MCF-7 tumors in nude mice. When organoids were depleted of cKit(+) cells using a toxin-conjugated antibody, organoid formation decreased.cKit marks small intestinal Paneth cells and a subset of colonic goblet cells that are regulated by Notch signaling and support Lgr5(+) stem cells. Solid CRC tissues, either primary tissues collected from surgical specimens or xenografts established in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice, were disaggregated into single-cell suspensions and analyzed by flow cytometry. Hisamori, S., Dalerba, P., Shimono, Y., Rothenberg, M. E., Zabara, M., Cai, S., Qian, D., Clarke, M. F. Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer. These experiments demonstrate the feasibility of using bcl-xs gene therapy to induce apoptosis in human breast tumors. Mcl1, Tel/Etv6, Gfi1, Pten and Stat5) have been identified. Program Affiliations. Street. 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. To achieve long-lasting responses in the clinic to RAS-fueled cancer, treatment will need to focus in parallel on obstructing tumors from adapting to oncogene inhibition. View details for Web of Science ID A1992HP64200009. Tumors originated from EpCAM(high)/CD44+ cells maintained a differentiated phenotype and reproduced the full morphologic and phenotypic heterogeneity of their parental lesions. Analysis of the surface molecule repertoire of EpCAM(high)/CD44+ cells led to the identification of CD166 as an additional differentially expressed marker, useful for CSC isolation in three of three CRC tested. Of five long-term NSGCT survivors, four were treated in first relapse with platinum-sensitive disease. View details for Web of Science ID A1993KD78500072. B., Byrne, A., Chen, M., Dehghannasiri, R., Gayoso, A., Granados, A. Furthermore, these approaches are not feasible for primary tumor cells that cannot survive tissue culture conditions or that may change phenotype in rats. The effect of these changes on protein function is currently unknown. KrasG12D -independent tumor cells show a strong mesenchymal profile with active RAS-RAF-MEK-ERK (MAPK/ERK) signaling. Here we describe two such clones and report that one of them transforms NIH-3T3 cells. Intriguingly, overexpression of p53 could reverse the inherent IR resistance of Shep-1 cells. 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. 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. Self-renewal requires the integration of survival signals and proliferation controls with the maintenance of an undifferentiated state. View details for Web of Science ID 000316614600063. Sorted cells were then injected into recipient background FVB/NJ female syngeneic mice. The C57BL/Ka-Thy-1.1 alleles were partially dominant. LDV infects specifically mouse macrophages and alters immune system and tumor phenotype. [2] Available culture systems all have finite and relatively short lifetimes. Professor Clarke is a former Deputy Vice . These breast tumors are comprised of phenotypically diverse populations of breast cancer cells. View details for Web of Science ID A1982NS41700015, American Association of Physicians, - (-), American Society of Clinical Investigation, - (-), Rackham Award, University of Michigan (-), Please see Dr. Michael Clarke's bio on the following School of Medicine website(s). [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. 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. Michael was an assessor on Panel 35 in REF 2014 having been a specialist advisor for the 2008 RAE. Results The transcription factor CDX2 ranked first in our screening test. Although a major commonly deleted region (CDR) has been delineated on chromosome band 5q31.1 (refs. Widespread activation of immune cells is especially pronounced, and is first detectable in white adipose depots during middle age. These data suggest that the late fall in c-myb levels may be required in order for differentiation to occur. 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. The isolation and characterization of these stem cells should help elucidate the molecular pathways that govern normal mammary development and carcinogenesis. Office Hours: Tuesday 12:00-1:00PM; Thursday 2:00-3:00PM; Friday 10:30-11:30AM. Established HTLV-infected cell lines constitutively express viral RNA. Analysis of HL-60 cells, a myeloid leukemia line with deletion of the 5q31 region, showed that the CTNNA1 promoter of the retained allele is suppressed by both methylation and histone deacetylation. 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. He is member of the Board of Parks Victoria. Pathways that regulate epigenetic control of stem cell identity are critical to the molecular etiology of cancer. View details for DOI 10.1146/annurev.cellbio.22.010305.104154, View details for Web of Science ID 000250896200025. Disclosure of potential conflicts of interest is found at the end of this article. The mechanism of leukaemogenic transformation by human T-cell leukaemia/lymphoma virus (HTLV), a retrovirus implicated in the aetiology of certain adult T-cell leukaemias and lymphomas, is unknown but is conceivably associated with the expression of the cellular analogues of retroviral oncogenes. Lower ROS levels in CSCs are associated with increased expression of free radical scavenging systems. View details for Web of Science ID 000182853100046. Interest in single-cell whole-transcriptome analysis is growing rapidly, especially for profiling rare or heterogeneous populations of cells. View details for Web of Science ID A1997YA26800007. This suggests that agents that target the defective self-renewal pathways in cancer cells might lead to improved outcomes in the treatment of these diseases. 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). 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. The molecular mechanisms that limit the proliferation capacity of multipotent progenitors and other more mature progenitors are not fully understood. Xenograft tumors were grown from control and KIT-knockdown DLD1 and UM-COLON#8 cells in immunocompromised mice and compared. RADIATION THERAPY ONCOLOGY GROUP TRANSLATIONAL RESEARCH PROGRAM STEM CELL SYMPOSIUM: INCORPORATING STEM CELL HYPOTHESES INTO CLINICAL TRIALS. The downstream effectors of TLR2 are expressed by normal intestinal and mammary epithelia, including the stem/progenitor cells. KIT knockdown cells had increased expression of enterocyte markers, decreased expression of cycling genes, and, unexpectedly, increased expression of LGR5 associated genes. Arthur Thomas Malkin (1803-1888), Pionier der Bergsteigerei und Schriftsteller. 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. Professor Field: Brazil, Latin America, Historical Geography, Environmental History Contact Information Email SBELL@GEOG.UCLA.EDU Office 1255 Bunche Hall Phone Scot Brown Associate Professor Field: United States Contact Information Email SBROWN@HISTORY.UCLA.EDU Office 1321 Rolfe Phone 310-825-5502 Eddie R. Cole Associate Professor Metastasis remains a significant challenge in treating cancer. Alzheimer's disease (AD) is a progressive neurodegenerative disease observed with aging that represents the most common form of dementia. View details for PubMedCentralID PMC3816928. Emerson, S. G., Palsson, B. O., Clarke, M. F., Silver, S. M., Adams, P. T., Koller, M. R., Van Zant, G., Rummel, S., Armstrong, R. D., MALUTA, J. Recent observations indicate that, in several types of human cancer, only a phenotypic subset of cancer cells within each tumor is capable of initiating tumor growth. With noninvasive imaging approaches, as few as 10 cells of stably labeled BCSCs could be tracked in vivo, enabling studies of early tumor growth and spontaneous metastasis. 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. Professor Michael Clarke was Director General of the Royal United Services Institute from 2007-2015, where he remains a Distinguished Fellow. Unequivocal proof that stem cells exist in the haematopoietic system has given way to the prospective isolation of several tissue-specific stem and progenitor cells, the initial delineation of their properties and expressed genetic programmes, and the beginnings of their utility in regenerative medicine. Only those cells within a tumor that have these two properties are called cancer stem cells. View details for Web of Science ID 000076744000010. Park, I., Qian, D., Kiel, M., Becker, M., Prohaska, S., Weissman, I., Morrison, S., Clarke, M. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Cells that expressed kappa- or lambda-light chains were separated by cell sorting from kappa- or lambda-negative cells and replaced in culture. Solid tumors arise in organs that contain stem cell populations. 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. FUKUNAGAJOHNSON, N., Ryan, J. J., Wicha, M., Nunez, G., Clarke, M. F. OVEREXPRESSION OF BCL-X(S), SENSITIZES MCF-7 CELLS TO CHEMOTHERAPY-INDUCED APOPTOSIS. Furthermore, the tumorigenic CD44(+) cells differentially express the BMI1 gene, at both the RNA and protein levels. 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. These results suggest that radiation-induced cell death occurs by both p53-dependent and p53-independent pathways. In mammary glands, reduced levels of Usp16 increase tissue responsiveness to Wnt, resulting in upregulation of the downstream Wnt target Axin2, expansion of the basal compartment and increased in vitro and in vivo epithelial regeneration. Sikandar, S. S., Kuo, A. H., Kalisky, T. n., Cai, S. n., Zabala, M. n., Hsieh, R. W., Lobo, N. A., Scheeren, F. A., Sim, S. n., Qian, D. n., Dirbas, F. M., Somlo, G. n., Quake, S. R., Clarke, M. F. Control of inflammation by stromal Hedgehog pathway activation restrains colitis. Molofsky, A. V., Pardal, R., Iwashita, T., Park, I. K., Clarke, M. F., Morrison, S. J. Bmi-1 is required for maintenance of adult self-renewing hematopoietic stem cells. Liu, H., Bockhorn, J., Dalton, R., Nwachukwu, C., Prat, A., Yee, K., Huang, S., Swanson, K., Perou, C. M., Olopade, O. I., Clarke, M. F., Greene, G. L. MicroRNA-203 restricts the proliferation capacity of normal colon and colon cancer stem cells by regulating the expression of Tcf4. View details for DOI 10.1016/j.semradonc.2008.11.002, View details for Web of Science ID 000264310800003, View details for PubMedCentralID PMC2789266. Ealovega, M. W., McGinnis, P. K., Sumantran, V. N., Clarke, M. F., Wicha, M. S. A RECOMBINANT BCL-X(S) ADENOVIRUS SELECTIVELY INDUCES APOPTOSIS IN CANCER-CELLS BUT NOT IN NORMAL BONE-MARROW CELLS. View details for DOI 10.1053/j.gastro.2015.05.042, View details for Web of Science ID 000360269800039, View details for PubMedCentralID PMC4550533. Only a small minority of cancer cells had the capacity to form new tumors in a xenograft model. Five thousand cDNA clones with very low hybridization signals were selected for sequencing and further analysis using microarrays on glass slides. F-MEL clones expressing the highest levels of the human c-myb mRNA differentiate poorly in response to dimethyl sulfoxide. The blocking effect of the CSD is not due to the enhancement of nuclear export or oligomerization of the p53. X-ray irradiated cells expressing wtp53 displayed microscopic and biochemical characteristics consistent with cell death due to apoptosis. Two distinct technical approaches were used for most organs: one approach, microfluidic droplet-based 3'-end counting, enabled the survey of thousands of cells at relatively low coverage, whereas the other, full-length transcript analysis based on fluorescence-activated cell sorting, enabled the characterization of cell types with high sensitivity and coverage. In order to better understand HSC self-renewal, we need to understand how these pathways are coordinated. Betancur, P. A., Abraham, B. J., Yiu, Y. Y., Willingham, S. B., Khameneh, F., Zarnegar, M., Kuo, A. H., McKenna, K., Kojima, Y., Leeper, N. J., Ho, P., Gip, P., Swigut, T., Sherwood, R. I., Clarke, M. F., Somlo, G., Young, R. A., Weissman, I. L. Colorectal Cancer Liver Metastasis: Evolving Paradigms and Future Directions. Patients generally die of cancer after the failure of current therapies to eliminate residual disease. Using an ELISA assay which quantitates DNA damage, we demonstrate that this sensitization is due to apoptosis, suggesting the therapeutic utility of targeting this pathway. In postnatal Bmi-1-/- mice, the number of HSCs was markedly reduced. We show that a set of active constituent enhancers, located within the two CD47 SEs, regulate CD47 expression in different cancer cell types and that disruption of CD47 SEs reduces CD47 gene expression. Purging of autologous stem cell sources with bcl-x(s) adenovirus for women undergoing high-dose chemotherapy for stage IV breast carcinoma. In this report, we analyzed the possible existence of cis-acting sequences involved in intracellular trafficking of the p53 protein. 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. From 1990 to 2001 he was the founding Director of the Centre for Defence Studies at King's. This cell line contains a wild-type p53 gene and is an ideal model for studying the mechanism of IR resistance in this disease. The regulation of hematopoietic stem cell (HSC) homeostasis is not well understood. Three well-known tumor suppressors, p53, p16INK4a, and p19ARF, have been connected to the limiting of stem cell self-renewal and proliferation. The amine-derivatized biotinylated GM-CSF analogues retained biological activity, could specifically label cell surface receptors, and may be useful nonradioactive probes with which to study GM-CSF receptor cytochemistry and receptor modulation by flow cytometry. 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. Automated microfluidic chromatin immunoprecipitation from 2,000 cells. Current page 1; Page 2; A cDNA library was constructed from the HUT102 cell line established from a patient with adult T-cell leukemia/lymphoma and screened for cDNA clones that contain (i) cellular sequences abundantly expressed in HUT102 cells and not in the virus-negative T-cell line HUT78, and (ii) viral long terminal repeat (LTR) sequences either in the 5' end or in the 3' end. Usp16 copy number normalization restores normal Wnt activation in Ts65Dn mice models. View details for DOI 10.1371/journal.pone.0002428, View details for Web of Science ID 000263280700013, View details for PubMedCentralID PMC2413402, View details for Web of Science ID 000454834700190. For more information, please contact Ruth Lira, 650-723-1367. Hematopoietic cells exposed to the suicide vectors were able to reconstitute the bone marrow of mice exposed to lethal doses of y-irradiation. 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. Gene expression analysis of cells isolated from nonadherent mammospheres revealed overlapping genetic programs with other stem and progenitor cells and identified new markers that may be useful in the identification of mammary stem cells. PROF. MICHAEL CLARKE (Director, Royal United Services Institute): I think the United States has been behind us in this respect. 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. 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. A key event in this process is the deregulation of normal self-renewal in these cells. G1 arrest at 37.5 degrees C, utilizing either mimosine or isoleucine deprivation, does not lead to rapid cell death. Kim et al. And while one former spy chief predicted that Putin would eventually be replaced by someone more "extreme", professor Michael Clarke, former director-general of the Royal United Services. In contrast to cells in G1, cells cultured at 32.5 degrees C for prolonged periods during S phase and G2/M, and then returned to 37.5 degrees C, did not become committed to cell death. Up to one-third of the long-term culture initiating cell (LTC-IC) are genetically modified by the culture conditions. The Weight can be changed regularly, here we have added the latest value. 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. Differential regulation of medium versus serum perfusion demonstrated that increased NIH-3T3 cell metabolism was directly proportional to the serum flux to which the cells were exposed. Our study demonstrates that microRNA-30c is transcriptionally regulated by GATA3 in breast tumours. Two such clones and report that one of them transforms NIH-3T3 cells with histones commonly deleted (. Autologous stem cell HYPOTHESES into CLINICAL TRIALS these changes on protein function is currently unknown Stats, Dating/Affairs, and! 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