professor michael clarke biography
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. These cancerous cells then grow clonally into tumors and eventually have the potential to metastasize. 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. Schaum, N. n., Lehallier, B. n., Hahn, O. n., Plovics, R. n., Hosseinzadeh, S. n., Lee, S. E., Sit, R. n., Lee, D. P., Losada, P. M., Zardeneta, M. E., Fehlmann, T. n., Webber, J. T., McGeever, A. n., Calcuttawala, K. n., Zhang, H. n., Berdnik, D. n., Mathur, V. n., Tan, W. n., Zee, A. n., Tan, M. n., Pisco, A. O., Karkanias, J. n., Neff, N. F., Keller, A. n., Darmanis, S. n., Quake, S. R., Wyss-Coray, T. n. Northstar enables automatic classification of known and novel cell types from tumor samples. To delineate more accurately the point at which Myb blocks differentiation, MEL cells were transfected with a human c-myb construct under the control of the beta-globin promoter and enhancers. These results suggest that Bcl-2 family members are required for survival of cancer cells derived from solid tissues. The weight is in Kilograms- 70 kg. 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. Here we implement single-cell PCR gene-expression analysis to dissect the cellular composition of primary human normal colon and colon cancer epithelia. Murine RV EW robustly activated type I IFNs and several antiviral genes (IFN-stimulated genes) in the intestine by bulk analysis, the source of induced IFNs primarily being hematopoietic cells. Expression of BMI1, a known regulator of stem cell self-renewal, was modulated by miR-200c. View details for Web of Science ID A1993KD78500072. Han, J. S., Nunez, G., Wicha, M. S., Clarke, M. F. Prevention of fluorodeoxyuridine-induced cytotoxicity and DNA damage in HT29 colon carcinoma cells by conditional expression of wild-type p53 phenotype. 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. . Adipose mesenchymal stromal cells, haematopoietic stem cells and hepatocytes are among those cell types that are especially responsive. 2010). Al-Hajj, M., Becker, M. W., Wichal, M., Weissman, I., Clarke, M. F. Bmi1, stem cells, and senescence regulation. All measured metabolic rates increased with increased medium exchange rates and accelerated sharply between exchange rates of 3.5/week and 7/week. 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. Abnormal p53 cellular localization has been considered to be one of the mechanisms that could inactivate p53 function. 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. Expression of wild-type p53 phenotype for 24 hr before FdUrd treatment provided HT29 cells with virtually complete protection from cytotoxicity caused by this drug. 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. The CD44(+)CD24(+)ESA(+) pancreatic cancer cells showed the stem cell properties of self-renewal, the ability to produce differentiated progeny, and increased expression of the developmental signaling molecule sonic hedgehog. These include the nuclear import and export signals of p53, inhibition of p53 nuclear import and export by oligomerization, MDM2-mediated p53 nuclear export, and possible roles of p53 phosphorylation in regulating p53 cellular localization. According to a story Tom Hanks told at. The hair color is Light brown and the eye color is Blue. He is especially known for his research into the evolution of cooperative breeding in honeyeaters, particularly the genus Manorina and for his work on the response of fauna and flora to wildfire (Clarke 2008, Clarke et al. 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. Here we describe c-myb-transformed MEL clones which undergo delayed expression of the exogenous c-myb following 3-5 days of culture in DMSO. President Biden has reaffirmed the U.S. commitment to the North Atlantic Treaty Organization (NATO) and collective defense and has stated that a strong European Union is in the U.S. interest. Using model cell lines (NIH-3T3 and CV-1), it was shown that gene transfer rates can be increased by more than an order of magnitude using the same concentration infection medium. At present, neither the role that the stromal cell extra-cellular matrix (ECM) plays in influencing stroma behavior is well understood nor are the effects of stroma aging. 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. The Bcl-XL protein is a recently discovered member of the bcl-2 family which has been shown to protect cells from some forms of programmed cell death, but has not yet been implicated in the genesis of human carcinomas. To examine the influence of stromal cell layer aging, conditioned medium was obtained from the first two weeks of LTHBMCs that was subsequently concentrated and used as a medium supplement in a second set of slowly exchanged LTHBMCs. In many cases, one of these abnormalities is an inhibition of PCD, which provides a selective advantage for tumor cells. His writingson justice, ethics, democracy, and markets--have been translated into 27 languages. View details for DOI 10.1073/pnas.0610117104, View details for Web of Science ID 000243761100053. Here we performed single-cell RNA sequencing on 20 organs to reveal cell-type-specific responses to young and aged blood in heterochronic parabiosis. 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. F-MEL clones expressing the highest levels of the human c-myb mRNA differentiate poorly in response to dimethyl sulfoxide. From 1990 to 2001 he was the founding Director of the Centre for Defence Studies at King's. SMAD pathways govern epithelial proliferation, and transforming growth factor beta (TGF-beta and BMP signaling through SMAD members has distinct effects on mammary development and homeostasis. His passion is to see government conservation policy based on the best available. To do so, we used breast tumors of the mouse mammary tumor virus (MMTV)-Wnt-1 mice. 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. First, we quantitatively imaged physiologic remodeling of primary branches of the developing and regenerating mammary tree. It kills tumor cells by several mechanisms, including antibody-dependent cellular cytotoxicity (ADCC). Despite rapid advances over recent years, many of the molecular and cellular processes that underlie the progressive loss of healthy physiology are poorly understood2. Sorted cells were then injected into recipient background FVB/NJ female syngeneic mice. CHUCK, A. S., Clarke, M. F., Palsson, B. O. bcl-x(s) gene therapy induces apoptosis of human mammary tumors in nude mice. BACKGROUND: Recent studies in murine mammary tissue have identified functionally distinct cell populations that may be isolated by surface phenotype or lineage tracing. Programmed cell death (PCD) plays an important role in normal and malignant hematopoieis. We present a simple single tube proximity ligation technique, targeted chromatin ligation, that captures histone modification patterns with only 200 cells. 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. 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). Location University of Rochester 402 Hutchison Hall P.O. In order to better understand HSC self-renewal, we need to understand how these pathways are coordinated. Because these observations conflict with previously suggested models for FdUrd-induced damage to parental DNA, we propose an alternative model to explain how incorporation of uracil into nascent DNA might result in single-strand breaks in the opposite (parental) strand and how these breaks might be converted to the double-strand breaks that produce cell death. 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. We report here that the genes for HLA class I antigens are also highly methylated in the T-ALL T-cell lines relative to the same genes in the ATL T-cell lines, normal peripheral blood T cells, and autologous normal B-cell lines. Self-renewal requires the integration of survival signals and proliferation controls with the maintenance of an undifferentiated state. This effect is the same as that of Lys-305 mutation. Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris. These results suggest all human solid tumor cells require CD47 expression to suppress phagocytic innate immune surveillance and elimination. The tumorigenic subpopulation could be serially passaged: each time cells within this population generated new tumors containing additional CD44(+)CD24(-/low)Lineage(-) tumorigenic cells as well as the phenotypically diverse mixed populations of nontumorigenic cells present in the initial tumor. 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). 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. He was the founding Director of the International Policy Institute at King's College London from 2001-2005 and Head of the School of Social Science and Public Policy at KCL in 2004-05. CD47 mRNA expression levels correlated with a decreased probability of survival for multiple types of cancer. 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. List A-Z. Adjunct Associate Professor David Welsh. 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. Patients with KIT-expressing colon tumors can benefit from KIT RTK inhibitors. 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. Professor Michael Clarke was Director General of the Royal United Services Institute from 2007-2015, where he remains a Distinguished Fellow. 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 Here we developed a CSC model for the study of human colorectal cancer (CRC). A novel regulator of G-protein signaling (RGS) has been isolated from a highly purified population of mouse long-term hematopoietic stem cells, and designated RGS18. View details for DOI 10.1073/pnas.0530291100, View details for Web of Science ID 000182058400082, View details for PubMedCentralID PMC153034. View details for Web of Science ID 000243488100004. U.S.A. 1995;92:11024-11028) is used in combination with Ad5ERE2, the ability of both viruses to induce cell death is dramatically increased, and the effect can be modulated by addition of the antiestrogen tamoxifen. Michael Clarke is a British academic who specialises in defence studies. Their scholarship is deepening our understanding of learning while changing policy and practice. [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. 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 DOI 10.1038/sj.onc.1207947, View details for Web of Science ID 000223998800013, View details for Web of Science ID 000223225500005. 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. These results validate the stem cell working model in human CRC and provide a highly robust surface marker profile for CRC stem cell isolation. In addition, Usp16 is associated with decreased ubiquitination of Cdkn2a and accelerated senescence in Ts65Dn fibroblasts. 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. If this difference in tumorigenicity of cancer cells also occurs in patients, then the ability to enrich for cancer stem cells lays an important groundwork for future studies where mechanisms involved in cancer stem cells can now be investigated. Our observations indicate that, in six of six human CRC tested, the ability to engraft in vivo in immunodeficient mice was restricted to a minority subpopulation of epithelial cell adhesion molecule (EpCAM)(high)/CD44+ epithelial cells. Park, I. K., Qian, D. L., Kiel, M., Becker, M. W., Pihalja, M., Weissman, I. L., Morrison, S. J., Clarke, M. F. Prospective identification of tumorigenic breast cancer cells. 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. BMI1 has been demonstrated to play a role in self-renewal in other stem cell types and to be involved in tumorigenesis. We performed in vivo imaging of changes in fluorescent, endogenous duct architecture as a metric for remodeling. Box 270211 Rochester, NY 14627. Isobe, T., Zarnegar, M. A., Abdel-Wahab, O., Clarke, M. F. A CD47-associated super-enhancer links pro-inflammatory signalling to CD47 upregulation in breast cancer. These results indicate that addition of combinations of hematopoietic CSFs, together with a rapid medium exchange rate, can provide culture conditions that are suitable for the expansion of the progenitor cell pool and perhaps for the increased survival of hematopoietic stem cells in culture. Most importantly, miR-200c strongly suppressed the ability of normal mammary stem cells to form mammary ducts and tumor formation driven by human BCSCs in vivo. 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. Finally, questions regarding p53 cellular trafficking will also be discussed. Here we show that normal mammary epithelial stem cells contain lower concentrations of ROS than their more mature progeny 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. [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. 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. 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. Acad. We reveal linear and nonlinear shifts in gene expression during ageing, with the associated genes clustered in consistent trajectory groups with coherent biological functions-including extracellular matrix regulation, unfolded protein binding, mitochondrial function, and inflammatory and immune response. Professor Michael Clarke, a prominent military analyst, told Express.co.uk that Ukraine could use Britain's Challenger 2 tanks to split the combat frontline and "isolate Crimea". 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. Our studies show that coincident expression of human Bcl-2 protein with p53 prolongs survival of murine erythroleukemia cells. These studies show that the human retrovirus HTLV, which has been demonstrated to be associated with certain T cell malignancies, can infect B cells or B cell precursors. 29 Oxford St, Pierce 229. jaiz@seas.harvard.edu (617) 495-3558. 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. View details for DOI 10.1016/j.stemcr.2020.12.012. We have studied the ability of c-myc and bcl-2 oncogenes to modulate p53 function. View details for Web of Science ID A1988L925300043. By immunohistochemical analysis, the CD44(+) cells in the tumor express high levels of nuclear BMI1, and are arrayed in characteristic tumor microdomains. We demonstrate that radiation-induced cell death occurs by both p53-dependent and -independent pathways and overexpression of bcl-2 modulates both pathways. View details for Web of Science ID A1984SP90200011. Rothenberg, M. E., Nusse, Y., Kalisky, T., Lee, J. J., Dalerba, P., Scheeren, F., Lobo, N., Kulkarni, S., Sim, S., Qian, D., Beachy, P. A., Pasricha, P. J., Quake, S. R., Clarke, M. F. Single-cell dissection of transcriptional heterogeneity in human colon tumors. Previous studies have shown that blocking DLL4 signaling reduced tumor growth by disrupting productive angiogenesis. 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. 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. Programmed cell death, or apoptosis, may play an important role in the regulation of hematopoiesis. Professor Clark is someone that should teach all students. Resistance to apoptosis plays an important role in tumors that are refractory to chemotherapy. In contrast, transplantation of CSC results in changes in the branching patterns of endogenous ducts while non-CSC do not. Here we describe two such clones and report that one of them transforms NIH-3T3 cells. Dalerba, P., Sahoo, D., Paik, S., Guo, X., Yothers, G., Song, N., Wilcox-Fogel, N., Forg, E., Rajendran, P. S., Miranda, S. P., Hisamori, S., Hutchison, J., Kalisky, T., Qian, D., Wolmark, N., Fisher, G. A., van de Rijn, M., Clarke, M. F. A cell-intrinsic role for TLR2-MYD88 in intestinal and breast epithelia and oncogenesis. 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. These studies suggest that adenovirus suicide vectors may provide a simple and effective method to selectively eliminate cancer cells derived from epithelial tissue that contaminate bone marrow to be used for autologous BMT. Several pathways, including Wnt signaling, MAP Kinase signaling, and Adherens Junction, are well known for their role in cancer development and stem cell biology. 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. To solve this problem, a new generation of tumor-specific, conditionally replicative adenoviruses is being developed. The median PFS and OS for the whole group are 4 and 14 months, respectively. Isolated by surface phenotype or lineage tracing remains a Distinguished Fellow splicing rise... Results suggest all human solid tumor cells require CD47 expression to suppress innate. 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