Who we Are. Ryan, J. J., Danish, R., Gottlieb, C. A., Clarke, M. F. C-MYB EFFECTS ON KINETIC EVENTS DURING MEL CELL-DIFFERENTIATION. Guinea pig alveolar macrophages were stimulated with opsonized zymosan in the presence of inhibitors of arachidonic acid metabolism: ASA, indomethacin, and ETYA, ASA, at concentrations as high as 60 micrograms/ml, had no effect on either oxygen consumption or superoxide ion formation. Until 2001 he was Deputy Vice-Principal and Director for Research Development at King's College London, where he remains a Visiting Professor. He is an adviser to two Parliamentary Committees and Associate Director of the Strategy and Security Institute at the University of Exeter. View details for Web of Science ID A1984SP90200011. The rates of glucose and glutamine consumption and of lactate and ammonia production were measured over exchange schedules ranging from complete medium replacement weekly (1/week) to complete medium replacement daily (7/week). A., Clarke, M. F., Weissman, I. L. MicroRNAs regulate breast cancer stem cells and spontaneous metastases in orthotopic xenograft models. In this episode, Eliot Wilson talks to Professor Michael Clarke, former head of the Royal United Services Institute, about the UK's Integrated Review and how far it represents a break from traditional thinking on our place in the world. Resultant tumors had a phenotypic diversity similar to that of the original tumor and behaved in a similar manner when passaged. (2007) analyze the relationship between CSC and tumor metastasis. Clarke, M. F., Westin, E., Schmidt, D., Josephs, S. F., Ratner, L., WONGSTAAL, F., Gallo, R. C., Reitz, M. S. IDENTIFICATION OF THE HUMAN T-CELL LYMPHOMA VIRUS IN B-CELL LINES ESTABLISHED FROM PATIENTS WITH ADULT T-CELL LEUKEMIA. However, inferring both the state and direction of differentiation is challenging. Breast cancers contain a minority population of cancer cells characterized by CD44 expression but low or undetectable levels of CD24 (CD44+CD24-/low) that have higher tumorigenic capacity than other subtypes of cancer cells.We compared the gene-expression profile of CD44+CD24-/low tumorigenic breast-cancer cells with that of normal breast epithelium. No activating mutations in KIT were detected in DLD1, POP77, or UM-COLON#8 cells. However, at later times X-ray irradiated parental DP16-1 cells also had decreased survival compared to the unirradiated control. Liu, H., Patel, M., Prescher, J., Qian, D., Dalerba, P., Lin, J., Shimono, Y., Dirbas, F., Contag, C., Gambhir, S., Clarke, M. What can we learn about self renewal and drug resistance from the isolation of epithelial tumor stem cells? In experiments on nude mice bearing HeLa ascites tumors, intraperitoneal injection of AdRSVlaclys/pE1 resulted in a significantly higher percentage of infected HeLa cells as compared with the PBS controls (p < 0.05) or the AdRSVlaclys/pUC19 controls (p < 0.01). The stromal cell layer is believed to play an important role in long-term human bone marrow cultures (LTHBMCs). Stanford is currently not accepting patients for this trial. Upon transfer to 32.5 degrees C, these G1 synchronized cell populations quickly lost viability. Gain- and loss-of-function studies show that Bcl11b induces cells to enter the G0 phase of the cell cycle and become quiescent. Intriguingly, overexpression of p53 could reverse the inherent IR resistance of Shep-1 cells. View details for Web of Science ID 000089592300005. Cancer stem cells are a minor population of tumor cells that possess the stem cell property of self-renewal. View details for Web of Science ID 000243301800039. Understanding the pathways that regulate proliferation, self-renewal, survival, and differentiation of malignant and normal stem cells may shed light on mechanisms that lead to cancer and suggest better modes of treatment. 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. Under the standard bone marrow culture conditions, even with a high stem cell renewal rate, the cultures appear to be destined to fail. All three analogues retained full agonist activity relative to the native protein (EC50 = 10-15 pM) when assayed for the stimulation of human bone marrow progenitor cell growth. Taken together, these results indicate that wild-type p53 induces cell death in murine erythroleukemia cells and that this effect occurs predominantly in the G1 phase of actively cycling cells. In order to better understand HSC self-renewal, we need to understand how these pathways are coordinated. 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. He was, from 1990 to 2001, the founding Director of the Centre for Defence Studies (CDS) at King's. He was appointed as Professor of Defence Studies in 1995. 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. Liu, H., Patel, M. R., Prescher, J. The results indicate that locally produced GM-CSF and IL-3 do augment hematopoiesis for several weeks in culture. View details for DOI 10.1016/j.ijrobp.2009.03.047, View details for Web of Science ID 000268346100041. 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). 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 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. 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. CLARKE Michael Function : Distinguished Fellow, Royal United Services Institute (RUSI) Political Committee, Saturday 12 October Biography Professor Michael Clarke was Director General of the Royal United Services Institute from 2007-2015, where he remains a Distinguished Fellow. MACARTHUR, L. H., Clarke, M. F., Westin, E. H. THE INFLUENCE OF EXTRACELLULAR-MATRIX AND STROMA REMODELING ON THE PRODUCTIVITY OF LONG-TERM HUMAN BONE-MARROW CULTURES. View details for Web of Science ID 000182853100046. This observation is traditionally explained by postulating variations in tumor microenvironment and coexistence of multiple genetic subclones, created by progressive and divergent accumulation of independent somatic mutations. The tight regulation of E1A expression correlated with the ability of these viruses to replicate and kill human cancer cells that express estrogen receptors, or are maintained under hypoxic conditions. Stem cells in many tissues sustain themselves by entering a quiescent state to avoid genomic insults and to prevent exhaustion caused by excessive proliferation. Raised by his single mother, Jean, a house cleaner, on Chicago's South Side, Duncan grew up resisting drugs and alcohol, instead concentrating on school. Bcl11b(high) cells are enriched for cells that can regenerate mammary glands in secondary transplants. Single-cell RNA sequencing (scRNA-seq) is a powerful approach for reconstructing cellular differentiation trajectories. 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. Hematopoietic stem cell gene therapy holds the promise of being able to treat a variety of inherited and acquired diseases of the hematopoietic stem cell. Park, I. K., He, Y. Q., Lin, F. M., Laerum, O. D., Tian, Q., Bumgarner, R., Klug, C. A., Li, K. J., Kuhr, C., Doyle, M. J., Xie, T., Schummer, M., Sun, Y., GOLDSMITH, A., Clarke, M. F., Weissman, I. L., Hood, L., Li, L. H. A genetic determinant that specifically regulates the frequency of hematopoietic stem cells. Furthermore, the oxygenation of arachidonic acid requires little of the oxygen consumed by phagocytosing alveolar macrophages. The plasmid vector contains simian virus 40-derived promotor, splice, and polyadenylation sequences as well as a transcription unit for a dihydrofolate reductase cDNA. 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. 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. 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. In recent years solid tumors were studied utilizing similar techniques in mice. Finally, we show evidence that these properties are maintained in the context of an adenoviral vector (AdEHhrk). Furthermore, in human tissues overexpression of USP16 reduces the expansion of normal fibroblasts and postnatal neural progenitors, whereas downregulation of USP16 partially rescues the proliferation defects of Down's syndrome fibroblasts. Office Hours: Tuesday 12:00-1:00PM; Thursday 2:00-3:00PM; Friday 10:30-11:30AM. These advances in BCSC imaging revealed that CD44(+) cells from both primary tumors and lung metastases are highly enriched for tumor-initiating cells. We found that adult and fetal mouse and adult human HSCs express the proto-oncogene Bmi-1. We examined such heterogeneity in the small intestine during rotavirus (RV) infection. Lobo, N. A., Zabala, M., Qian, D., Clarke, M. F. Serially transplantable mammary epithelial cells express the Thy-1 antigen. 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. 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. Tumors originated from EpCAM(high)/CD44+ cells maintained a differentiated phenotype and reproduced the full morphologic and phenotypic heterogeneity of their parental lesions. View details for Web of Science ID A1994NT46100030. A., Spallino, E., Aaron, K. A., Concepcion, W., Gardner, J. M., Kelly, B., Neidlinger, N., Wang, Z., Crasta, S., Kolluru, S., Morri, M., Tan, S. Y., Travaglini, K. J., Xu, C., Alcantara-Hernandez, M., Almanzar, N., Antony, J., Beyersdorf, B., Burhan, D., Calcuttawala, K., Carter, M. M., Chan, C. K., Chang, C. A., Chang, S., Colville, A., Culver, R. N., Cvijovic, I., D'Amato, G., Ezran, C., Galdos, F. X., Gillich, A., Goodyer, W. R., Hang, Y., Hayashi, A., Houshdaran, S., Huang, X., Irwin, J. C., Jang, S., Juanico, J. V., Kershner, A. M., Kim, S., Kiss, B., Kong, W., Kumar, M. E., Kuo, A. H., Leylek, R., Li, B., Loeb, G. B., Lu, W., Mantri, S., Markovic, M., McAlpine, P. L., de Morree, A., Mrouj, K., Mukherjee, S., Muser, T., Neuhofer, P., Nguyen, T. D., Perez, K., Phansalkar, R., Puluca, N., Qi, Z., Rao, P., Raquer-McKay, H., Schaum, N., Scott, B., Seddighzadeh, B., Segal, J., Sen, S., Sikandar, S., Spencer, S. P., Steffes, L., Subramaniam, V. R., Swarup, A., Swift, M., Van Treuren, W., Trimm, E., Veizades, S., Vijayakumar, S., Vo, K. C., Vorperian, S. K., Wang, W., Weinstein, H. N., Winkler, J., Wu, T. T., Xie, J., Yung, A. R., Zhang, Y., Detweiler, A. M., Mekonen, H., Neff, N. F., Sit, R. V., Tan, M., Yan, J., Bean, G. R., Charu, V., Forgo, E., Martin, B. We show that single-cell RNA-seq can be used to perform accurate quantitative transcriptome measurement in individual cells with a relatively small number of sequencing reads and that sequencing large numbers of single cells can recapitulate bulk transcriptome complexity. The results of in vitro GTPase single-turnover assays using Galpha(i) indicated that RGS18 accelerates the intrinsic GTPase activity of Galpha(i). Eighteen relapses occurred a median of 4 months after ABMT I (two late relapses at 28 and 44 months). In some cancer cells, the process of self-renewal is de-regulated resulting in expansion of these cells and tumors. A., Chen, L., Levy, R. Removal of lactate dehydrogenase-elevating virus from human-in-mouse breast tumor xenografts by cell-sorting. Bcl-xs is a dominant negative repressor of Bcl-2 and Bcl-xL, both of which inhibit apoptosis. 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. G418-resistant clones, which expressed the c-sis cDNA, were selected and characterized. High transduction rates could be obtained even in the absence of polycations, such as Polybrene, which heretofore have been required to achieve reasonable transduction rates. View details for DOI 10.1053/j.gastro.2012.02.006, View details for Web of Science ID 000303113600038, View details for PubMedCentralID PMC3911891. Major conclusions of the symposium were that the flow cytometry of multiple markers in fresh tissue would remain the standard technique of evaluating cancer-initiating cells and that surrogates need to be developed for both experimental and clinical use. 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. This promoter induces transcriptional activation of the E1a and E4 units in response to estrogens in cells that express the ERs. This effect is the same as that of Lys-305 mutation. Notably, subsets of CSCs in some human and murine breast tumours contain lower ROS levels than corresponding non-tumorigenic cells (NTCs). In 2007, he became the Director of the Royal United Services Institute. 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. Sci. Automated microfluidic chromatin immunoprecipitation from 2,000 cells. However, none of the NB cell lines expressed Bcl-xS. The Thy-1+CD24medCD49fhigh phenotype contained the majority of the serially transplantable epithelial cells. Park, I. K., Morrison, S. J., Clarke, M. F. Applying the principles of stem-cell biology to cancer. (Funded by the National Comprehensive Cancer Network, the National Institutes of Health, and others.). 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. Hoey, T., Yen, W., Axelrod, F., Basi, J., Donigian, L., Dylla, S., Fitch-Bruhns, M., Lazetic, S., Park, I., Sato, A., Satyal, S., Wang, X., Clarke, M. F., Lewicki, J., Gurney, A. The Thy-1-CD24medCD49fhigh phenotype contains a rare progenitor population that is able to form primary mammary outgrowths with significantly decreased serial in vivo transplantation potential.CONCLUSIONS: Therefore, Thy-1 expression in the immature cell compartment is a useful tool to study the functional heterogeneity that drives mammary gland development and has implications for disease etiology. Finally, the laboratory is actively pursuing how cancer stem cells self-renew to maintain themselves and escape the genetic constraints on unlimited self-renewal that regulate normal stem cell numbers. At the time of ABMT, 10 were chemosensitive, four were chemoresistant, and 10 were absolutely refractory to platinum. Cell-free RNA from liquid biopsies can be analyzed to determine disease tissue of origin. A panel of NB cell lines (CHP-382, GOTO, SHEP-1, SHSY-5Y, and GI-CA-N) were infected with either a bcl-xS adenovirus (pAdRSV-bcl-xS) or a control virus (pAdRSV-lac-z). Its expansion is a tightly regulated process, fueled by the mammary stem cells and these cells' unique property of self-renewal. Three clusters, miR-200c-141, miR-200b-200a-429, and miR-183-96-182 were downregulated in human BCSCs, normal human and murine mammary stem/progenitor cells, and embryonal carcinoma cells. Temporary expression of wild-type p53 activity in the absence of drug treatment caused some loss of clonogenicity, although the magnitude of this cytotoxic effect was small compared with the level of cell kill obtained by treatment with cytotoxic drugs for similar periods of time, indicating that HT29 cells are not highly sensitive to induction of programmed cell death by wild-type p53. Similarly, tumors contain a minority population of cancer stem cells that maintain the tumor.
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