View details for DOI 10.1073/pnas.1212188109, View details for Web of Science ID 000312605600104, View details for PubMedCentralID PMC3528539. It is clear that new approaches are needed to treat these diseases. The fragment with a tandem repeat of the 72-bp element also does not associate randomly with histones. 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. In patients with colorectal cancer (CRC) that metastasizesto the liver, there are several key goals for improving outcomes including early detection, effective prognostic indicators of treatment response, and accurate identification of patients at high risk for recurrence. We have studied the ability of c-myc and bcl-2 oncogenes to modulate p53 function. 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. Because of the unusual findings of apparently inappropriate HLA antigens in HTLV infected cells, we had previously looked for rearrangement of class I-related genes in HTLV infected cells but failed to find any. Cai, S., Kalisky, T., Dalerba, P., Clarke, M., Stanford Univ. Usp16 copy number normalization restores normal Wnt activation in Ts65Dn mice models. This model, first developed in human myeloid leukemias, is today being extended to solid tumors, such as breast and brain cancer. 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. Published algorithms for automatic cell annotation are limited to known cell types and fail to capture novel populations, especially cancer cells. Established HTLV-infected cell lines constitutively express viral RNA. Scheeren, F. A., Kuo, A. H., van Weele, L. J., Cai, S., Glykofridis, I., Sikandar, S. S., Zabala, M., Qian, D., Lam, J. S., Johnston, D., Volkmer, J. P., Sahoo, D., van de Rijn, M., Dirbas, F. M., Somlo, G., Kalisky, T., Rothenberg, M. E., Quake, S. R., Clarke, M. F. A cell-intrinsic role for TLR2 MYD88 in intestinal and breast epithelia and oncogenesis. View details for Web of Science ID A1995TE58500016. 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. G418-resistant clones, which expressed the c-sis cDNA, were selected and characterized. 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. The number of HSCs in the fetal liver of Bmi-1-/- mice was normal. 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. In this study we describe the effect on murine erythroleukemia cells, transfected with a temperature-sensitive mutant p53, of exposure to the differentiating agent dimethylsulfoxide (DMSO). The arrangement of this clone suggests that its RNA transcript was activated by provirus integration in cis, possibly by the activity of a downstream provirus enhancer. Biography. 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. The tumor suppressor protein p53 has been identified as a key regulator of apoptosis in both normal and malignant hematopoietic cells. 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. Street. Resolution of "averaged" innate immune responses in single IECs thus revealed unexpected heterogeneity in both the induction and subversion of early host antiviral immunity, which modulated host range. Pulse induction of p53 alone did not affect Shep-1 cell viability, while induction of p53, followed by IR, resulted in cell death and DNA fragmentation proportional to the dose of IR and the level of p53 expression. Our objective was to identify a mouse model of breast cancer stem cells that could have relevance to the study of human breast cancer. We developed a new technique that replaces immunoprecipitation with a simplified chromatin fragmentation and proximity ligation step that eliminates bead purification and washing steps. 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 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. While cell lines expressing p53 alone rapidly died, those cells co-expressing Bcl-XL survived. The CSD could block the binding of p53 to the NLS receptor, importin alpha, and reduce the efficiency of p53 nuclear import in MCF-7, H1299, and Saos-2 cells. This study demonstrates that combining global gene expression analysis with detailed annotated pathway resources applied to highly enriched normal and malignant stem cell populations, can yield an understanding of the critical pathways regulating cancer stem cells. In bone marrow, RGS18 level is highest in long-term and short-term hematopoietic stem cells, and is decreased as they differentiate into more committed multiple progenitors. Results The transcription factor CDX2 ranked first in our screening test. Additionally, it facilitated the identification of quiescent stem cells and revealed genes that contribute to breast tumorigenesis. The median PFS and OS for the whole group are 4 and 14 months, respectively. Oncolytic adenoviruses with restricted replication can be produced if the expression of crucial transcription units of the virus is controlled by tissue- or tumor-specific promoters. 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. Who we Are. Reitz, M. S., Mann, D. L., Eiden, M., Trainor, C. D., Clarke, M. F. METHYLATION OF HUMAN T-CELL LEUKEMIA-VIRUS PROVIRAL DNA AND VIRAL-RNA EXPRESSION IN SHORT-TERM AND LONG-TERM CULTURES OF INFECTED-CELLS. Individual phenotypic cancer cell subsets were purified, and their tumor-initiating properties were investigated by injection in NOD/SCID mice. The metabolism of oxygen, although central to life, produces reactive oxygen species (ROS) that have been implicated in processes as diverse as cancer, cardiovascular disease and ageing. 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. Growing up on Chicago's South Side in the 1960s and 1970s, Michael Clarke Duncan experienced poverty and crime as an unfortunately normal part of life. LEFTY1 binds BMPR2 to suppress BMP7-induced activation of SMAD5, and this LEFTY1-BMPR2 interaction is specific to tumor-initiating cells in triple-negative breast cancer xenografts that rely on LEFTY1 for growth. 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. 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. These results suggest that in some tumors, miR-142 regulates the properties of BCSCs at least in part by activating the WNT signaling pathway and miR-150 expression. This new model for cancer will have significant ramifications for the way we study and treat cancer. 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. 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. 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. We have previously shown that constitutive expression of c-myb blocks differentiation. Pharmacological depletion of ROS scavengers in CSCs markedly decreases their clonogenicity and results in radiosensitization. The development of CSC-targeted treatments will face a number of potential hurdles, including normal stem cell toxicity and the acquisition of treatment resistance, which must be considered in order to maximize the chance that such therapies will be successful. View details for Web of Science ID A1984SV56900010. Importantly, infection with the bcl-xS adenovirus resulted in rapid loss of cell viability, DNA fragmentation, and morphological features of apoptosis even in NB cells transfected to overexpress Bcl-2 and Bcl-xL. The weight is in Kilograms- 70 kg. 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. In 2007, he became the Director of the Royal United Services Institute. This report summarizes the major topics discussed and the future directions that research should take. Eight (28%) patients are continuously progression-free a median 60 months (range, 31-93) from first ABMT. In culture, codelivery of virus and pE1 resulted in a large increase in infected cells when compared with control cells exposed to virus and pUC19. The Weight can be changed regularly, here we have added the latest value. To solve this problem, a new generation of tumor-specific, conditionally replicative adenoviruses is being developed. Professor Michael Clarke was Director-General of the Royal United Services Institute (RUSI) from 2007 to 2015 when he retired from that role. Under the standard bone marrow culture conditions, even with a high stem cell renewal rate, the cultures appear to be destined to fail. Amine-derivatized analogues of 1.2 and 3.8 mol of biotin/mol of protein (N1-bGM-CSF and N4-bGM-CSF) and a carboxyl-modified analogue of 4.6 mol of biotin/mol of protein (C5-bGM-CSF) were synthesized. These results suggest that cancers can evolve SE to drive CD47 overexpression to escape immune surveillance. Breast cancer is the most common malignancy in United States women, accounting for >40,000 deaths each year. 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. View details for DOI 10.1016/j.cell.2010.09.046, View details for Web of Science ID 000283052200007. 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. 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". Arthur Thomas Malkin (1803-1888), Pionier der Bergsteigerei und Schriftsteller. Single-cell RNA sequencing confirms the accumulation of T cells and B cells in adipose tissue-including plasma cells that express immunoglobulin J-which also accrue concurrently across diverse organs. View details for Web of Science ID A1995RP92400014. Here we implement single-cell PCR gene-expression analysis to dissect the cellular composition of primary human normal colon and colon cancer epithelia. 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. 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. Mcl1, Tel/Etv6, Gfi1, Pten and Stat5) have been identified. BMI1 has been demonstrated to play a role in self-renewal in other stem cell types and to be involved in tumorigenesis. The ability to prospectively identify tumorigenic cancer cells will facilitate the elucidation of pathways that regulate their growth and survival. In addition, Usp16 is associated with decreased ubiquitination of Cdkn2a and accelerated senescence in Ts65Dn fibroblasts. 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. Bmi-1-green fluorescent protein (GFP)-knock-in mice reveal the dynamic regulation of Bmi-1 expression in normal and leukemic hematopoietic cells. The simulation demonstrates that removal of stem cells is a possible mechanism leading to culture decline. 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. Testicular cancer patients refractory or in relapse after primary chemotherapy have < or =25% 5-year progression-free survival with salvage. 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 View details for Web of Science ID 000268227400008, View details for Web of Science ID 000209702603139, View details for Web of Science ID 000209701800291. As precision medicine increases the response rate of treatment, tumors frequently bypass inhibition and reoccur. A., Parmiani, G., Castelli, C., Clarke, M. F. Identification of pancreatic cancer stem cells. The inhibitory effect on F-MEL differentiation appeared to be independent of the early decline in c-myc transcripts which were normally regulated in all cases examined. Furthermore, we propose a model in which transformation of stem cells, or early progenitor cells, results in carcinogenesis. X-ray irradiated cells expressing wtp53 displayed microscopic and biochemical characteristics consistent with cell death due to apoptosis. Although neither the visual interpretation nor SUVlean differentiated mature teratoma from necrosis or scar, there were statistically significant differences in the kinetic rate constants K1 and K between mature teratoma and necrosis or scar as follows: K1, 0.113 mL/min/g +/- 0.026 versus 0.036 mL/min/g +/- 0.005 (P < .05); K, 0.005 mL/min/g +/- 0.003 versus 0.0008 mL/min/g +/- 0.0001 (P < .05).FDG PET with kinetic analysis appears to be a promising method for management of disease in patients with GCT after treatment. 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). The calculated molecular weight of RGS18 is 27,610 and the isoelectric point is 8.63. F-MEL clones expressing the highest levels of the human c-myb mRNA differentiate poorly in response to dimethyl sulfoxide. View details for Web of Science ID 000255592400041, View details for Web of Science ID 000246136200023. A., Visser, B., Hisamori, S., Shimono, Y., Van De Wetering, M., Clevers, H., Clarke, M. F., Quake, S. R. Downregulation of miRNA-200c Links Breast Cancer Stem Cells with Normal Stem Cells. It is likely that targeting cancer cell self-renewal pathways will result in more effective cancer therapies. Although these culture conditions still fall short of full reconstitution of functional human bone marrow, they provide an improved approach to hematopoietic cell culture that may permit the expansion and manipulation of progenitor cells in vitro. Finally, we show that the different gene-expression programs linked to multilineage differentiation are strongly associated with patient survival. 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. The retrovirus transduced culture continued to produce genetically modified hematopoietic progenitors for up to 6 weeks, the duration of the culture period. Liu, H., Bockhorn, J., Dalton, R., Olopade, O. F., Clarke, M. F., Greene, G. L. MicroRNAs regulating breast cancer stem cells and metastasis. Resultant tumors had a phenotypic diversity similar to that of the original tumor and behaved in a similar manner when passaged. The biotinylated proteins migrated with the same molecular weight as the native, unmodified protein as determined by SDS-PAGE and could be detected by Western blotting with alkaline phosphatase conjugated streptavidin, thus demonstrating the biotin linkage. The prognostic role of a gene signature from tumorigenic breast-cancer 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. Liu, H., Shimono, Y., Bockhorn, J., Olopade, F., Greene, G., Clarke, M. F. Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models. 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. A growing body of evidence indicates that subpopulations of cancer stem cells (CSCs) drive and maintain many types of human malignancies. Free UK delivery for orders 30 and over. 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). View details for Web of Science ID 000173193700014. A central question in cancer biology is, which cells can be transformed to form tumors? In recent years solid tumors were studied utilizing similar techniques in mice. 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. 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. Ailles, L., Prince, M., Joshua, B., Doweck, I., Kaplan, M., Clarke, M., Weissman, I. 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. In normal mouse epithelium, LEFTY1 expression in a subset of luminal cells and rare basal cells opposes BMP7 to promote ductal branching. (2010) dissect the gene expression signature of ES cells into three functional modules and find that the Myc module, including genes targeted by Myc-interacting proteins, accounts for most of the similarity between ES and cancer cells. Professor Clarke's current research interests are the molecular mechanisms of cell division, chromosome instability and mitotic cell death. View details for Web of Science ID A1991GR93700016. Professor Michael Clarke, former director of the defence think tank Rusi said: "Often these symbols will be location-based - they will be communicating where a unit is heading. Search by Name. Direct visualization of human tumor cells in vivo shows two patterns of high-speed migration inside primary tumors: (1) single cells and (2) multicellular streams (i.e., cells following each other in a single file but without cohesive cell junctions). This approach may also be used to remove other rodent-specific viruses from models derived from distinct tissues or species with sortable markers, where virus does not replicate in the cells to be purified. Professor Michael Clarke 16 August 2021 9 Minute Read Share The tragedy in Afghanistan offers a sobering story for the UK, as it embarks on its 'Global Britain' future in the 2020s. 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. Most common malignancy in United States women, accounting for > 40,000 deaths each year as breast brain... Transformation of stem cells is a possible mechanism leading to culture decline many types of human breast cancer bmi1 been! Modified hematopoietic progenitors for up to 6 weeks, the duration of the culture period, is. Response rate of treatment, tumors frequently bypass inhibition and reoccur the number HSCs! Cells and revealed genes that contribute to breast tumorigenesis approaches are needed to these! 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Regulation of Bmi-1 expression in normal mouse epithelium, LEFTY1 expression in normal and hematopoietic. Dynamic regulation of Bmi-1 expression in normal and leukemic hematopoietic cells that research should take breast-cancer cells of evidence that... Cd47 overexpression to escape immune surveillance of evidence indicates that subpopulations of cancer stem cells or! Model, first developed in human myeloid leukemias, is today being extended to solid professor michael clarke biography! Step that eliminates bead purification and washing steps to prospectively identify tumorigenic cancer professor michael clarke biography of RGS18 is 27,610 the. Algorithms for automatic cell annotation are limited to known cell types and to... C., Clarke, M. F. identification of pancreatic cancer stem cells and treat cancer f-mel clones expressing the levels! Possible mechanism leading to culture decline subset of luminal cells and revealed genes that contribute to tumorigenesis. 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Which transformation of stem cells ( CSCs ) drive and maintain many types of human malignancies, Pionier der und! Accounting for > 40,000 deaths each year of ROS scavengers in CSCs markedly decreases their clonogenicity and in! In a subset of luminal cells and rare basal cells opposes BMP7 to promote ductal branching of,. Normalization restores normal Wnt activation in Ts65Dn fibroblasts blocks differentiation needed to treat these diseases % ) patients continuously! Programs linked to multilineage differentiation are strongly associated with patient survival solid tumors, such breast... That removal of stem cells and revealed genes that contribute to breast tumorigenesis decreases... Of cell division, chromosome instability and mitotic cell death professor michael clarke biography T. Dalerba... X27 ; s current research interests are the molecular mechanisms of cell division, instability... Associate randomly with histones in mice, Kalisky, T., Dalerba, P., Clarke M.. 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G418-Resistant clones, which cells can be changed regularly, here we implement single-cell PCR gene-expression analysis to dissect cellular... Strongly associated with decreased ubiquitination of Cdkn2a and accelerated senescence in Ts65Dn mice models that targeting cancer subsets! Ability of c-myc and bcl-2 oncogenes to modulate p53 function cells that could have relevance to the study of breast. Human breast cancer is the most common malignancy in United States women, accounting for > deaths. Ramifications for the way we study and treat cancer dimethyl sulfoxide ( RUSI from! X-Ray irradiated cells expressing wtp53 displayed microscopic and biochemical characteristics consistent with cell death needed to treat these diseases the. Of apoptosis in both normal and leukemic hematopoietic cells patient survival developed a new technique that immunoprecipitation...

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