Comparison of IRF3 and NF-B induction in STAT1(-/-) mice revealed that murine but not simian RRV mediated accumulation of IkB- protein and decreased transcription of NF-B-dependent genes. Of five long-term NSGCT survivors, four were treated in first relapse with platinum-sensitive disease. Paneth cells contribute to the small intestinal niche of Lgr5(+) stem cells. Clarke was interested . Expression of p16Ink4a and p19Arf in normal HSCs resulted in proliferative arrest and p53-dependent cell death, respectively. We found that each antibody inhibited tumor growth and that the combination of the two antibodies was more effective than either alone. 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. Program Affiliations. Professor Michael Clarke write a piece in The Sun saying time was running out for Putin. 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. By immunohistochemical analysis, the CD44(+) cells in the tumor express high levels of nuclear BMI1, and are arrayed in characteristic tumor microdomains. 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. We prospectively identified and isolated the tumorigenic cells as CD44(+)CD24(-/low)Lineage(-) in eight of nine patients. Il termine stato coniato dal giornalista statunitense Gary Wolf nel 2006. 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. 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. Dalerba, P., Sahoo, D., Paik, S., Guo, X., Yothers, G., Song, N., Wilcox-Fogel, N., Forgo, 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. CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer. Thomas Jeffrey Hanks ( Concord, California; 9 de julio de 1956) es un actor y director de cine estadounidense. Clarke, M. F., Apel, I. J., Benedict, M. A., Eipers, P. G., Sumantran, V., GONZALEZGARCIA, M., Doedens, M., Fukunaga, N., Davidson, B., Dick, J. E., Minn, A. J., Boise, L. H., Thompson, C. B., Wicha, M., Nunez, G. RETROVIRAL-MEDIATED GENE-TRANSFER IN HUMAN BONE-MARROW CELLS GROWN IN CONTINUOUS PERFUSION CULTURE VESSELS. 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. . In human breast cancers, a phenotypically distinct minority population of tumorigenic (TG) cancer cells (sometimes referred to as cancer stem cells) drives tumor growth when transplanted into immunodeficient mice. PHD Student in Computer Science. Using single-cell transcriptomic data, we assessed cell-type-specific manifestations of different hallmarks of ageing-such as senescence3, genomic instability4 and changes in the immune system2. Conclusions Lack of CDX2 expression identified a subgroup of patients with high-risk stage II colon cancer who appeared to benefit from adjuvant chemotherapy. Investigating mechanisms of cancer stern cell radioresistance. CD47 is a ligand for SIRP, a protein expressed on macrophages and dendritic cells. HSCs maintain themselves for the lifetime of the organism because of their ability to self-renew. Under the standard bone marrow culture conditions, even with a high stem cell renewal rate, the cultures appear to be destined to fail. Available culture systems all have finite and relatively short lifetimes. This concept was first demonstrated in the study of leukemia where only cells with specific surface antigen profiles were able to cause leukemia when engrafted into immunodeficient mice. We hypothesized that if non-tumorigenic cells are more susceptible to chemotherapeutic agents, then residual tumors might be expected to contain a higher frequency of CoCSC.Xenogeneic tumors initiated with CoCSC were allowed to reach approximately 400 mm(3), at which point mice were randomized and chemotherapeutic regimens involving cyclophosphamide or Irinotecan were initiated. Patsialou, A., Bravo-Cordero, J., Wang, Y., Liu, H., Clarke, M. F., Condeells, J. S. Deregulation of stem cell self-renewal pathways in cancer, MicroRNA-30c inhibits human breast tumour chemotherapy resistance by regulating TWF1 and IL-11. Chemotherapy resistance frequently drives tumour progression. 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. View details for Web of Science ID A1986A778300041. 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. These data indicate that the simultaneous regulation of E1A and E4 viral transcription units by the appropriate combination of promoters can increase the tumor selectivity of oncolytic adenoviruses. Here, we demonstrate a simple, yet robust, determinant of developmental potential-the number of expressed genes per cell-and leverage this measure of transcriptional diversity to develop a computational framework (CytoTRACE) for predicting differentiation states from scRNA-seq data. 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. [2] Dr. Jim Clarke is an Adjunct Professor of Civil and Environmental Engineering and an Adjunct Professor of Earth and Environmental Sciences at Vanderbilt University. These cancerous cells then grow clonally into tumors and eventually have the potential to metastasize. adequate tissue for cancer stem cell quantification. The induced p53 is functional as p53-responsive genes (Waf-1 and MDM-2) are appropriately induced following IR. In order to better understand HSC self-renewal, we need to understand how these pathways are coordinated. We developed selective anti-human and anti-mouse DLL4 antibodies to dissect the mechanisms involved by analyzing the contributions of selectively targeting DLL4 in the tumor or in the host vasculature and stroma in xenograft models derived from primary human tumors. The pattern of triple mutant multipotent progenitor response to growth factors resembles that of wild-type multipotent progenitors but not wild-type HSCs. Cytoplasmic sequestration of the mt p53 was dependent upon the C-terminal region (residues 326-355) of the protein. View details for Web of Science ID A1993KD78500072. Disruption of the regulation of self-renewal results in cancer. View details for DOI 10.1146/annurev.med.58.062105.204854, View details for Web of Science ID 000244461500018, View details for Web of Science ID 000242973400002, View details for Web of Science ID 000242440001597. It has been postulated that there is a link between inflammation and cancer. CD47 is a cell surface molecule that inhibits phagocytosis of cells that express it by binding to its receptor, SIRP, on macrophages and other immune cells. Although data have been provided to support this theory in human blood, brain, and breast cancers, the identity of pancreatic cancer stem cells has not been determined. They discuss the increasing threat of China, the post-Brexit identity of "Global Britain" and how the . By complementation of the E1a protein in trans, Ad5ERE2 allows restricted replication of a conventional E1a-deleted adenoviral vector. Following high-dose IR, cell fractionation demonstrated that p53 is induced and targeted to the nucleus. 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. Bcl11b(high) cells are enriched for cells that can regenerate mammary glands in secondary transplants. Individual phenotypic cancer cell subsets were purified, and their tumor-initiating properties were investigated by injection in NOD/SCID mice. A subpopulation of tumor cells, termed cancer stem cells (CSC), appears uniquely able to fuel the growth of phenotypically and histologically diverse tumors. The C57BL/Ka-Thy-1.1 alleles were partially dominant. In many tissues, a cellular hierarchy exists in which a small population of stem cells is responsible for the production of the mature cells of the organ. The results demonstrate that cell sorting is effective, much faster and less likely to alter tumor cell phenotype than traditional methods for removing LDV from xenograft models. Orhan Eren Akgun. According to a story Tom Hanks told at. 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. 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. Professor Michael Clarke was Director General of the Royal United Services Institute from 2007-2015, where he remains a Distinguished Fellow. 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. The possible significance of this finding is discussed. Their scholarship is deepening our understanding of learning while changing policy and practice. Cancers of epithelial origin are responsible for the majority of cancer-related deaths in the USA. On the basis of the wild-type adenovirus type 5, we have constructed a conditionally replicative adenovirus (Ad5ERE2) in which the E1a and E4 promoters have been replaced by a portion of the pS2 promoter containing two estrogen-responsive elements (EREs). Three seminoma patients remain progression-free. Mann, D. L., Clark, J., Clarke, M., Reitz, M., Popovic, M., Franchini, G., Trainor, C. D., STRONG, D. M., Blattner, W. A., Gallo, R. C. Presence of HTLV in a subset of T cells from an infected patient: some immunochemical properties of the infected cells. 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. Clinical and Therapeutic Implications of Cancer Stem Cells. CD137 activation, which was dependent on NK cell expression of the FcRIII receptor, occurred both in vitro and in the peripheral blood of women with HER2-expressing breast cancer after trastuzumab treatment. These studies show that the metabolic and secretory behavior of genetically engineered cells is influenced by the medium exchange schedule. Understanding and reproducing the molecular interactions between bone marrow stromal cells and stem cells in tissue culture models is therefore the critical step in successful bone marrow tissue culture. The simulation demonstrates that removal of stem cells is a possible mechanism leading to culture decline. Fundamentally, the system is the paradigm of a complex interactive tissue, in which the proliferation and regulated differentiation of one parenchymal cell type (the hematopoietic stem cell) is governed by the surrounding stromal cells. The retrovirus transduced culture continued to produce genetically modified hematopoietic progenitors for up to 6 weeks, the duration of the culture period. Cytoplasmic sequestration of the p53 tumor suppresser protein has been proposed as a mechanism involved in abolishing p53 function. Shimono, Y., Zabala, M., Cho, R. W., Lobo, N., Dalerba, P., Qian, D., Diehn, M., Liu, H., Panula, S. P., Chiao, E., Dirbas, F. M., Somlo, G., Pera, R. A., Lao, K., Clarke, M. F. Association of reactive oxygen species levels and radioresistance in cancer stem cells. School of Civil Engineering +61 7 336 56464. william.clarke@uq.edu.au. To further characterize the role of the TWF1 pathway in breast cancer, we found that IL-11 is an important target of TWF1 that regulates breast cancer cell invasion and STAT3 phosphorylation. Clarke, M. F., Trainor, C. D., Mann, D. L., Gallo, R. C., Reitz, M. S. TRANSFORMING POTENTIAL OF HUMAN C-SIS NUCLEOTIDE-SEQUENCES ENCODING PLATELET-DERIVED GROWTH-FACTOR. Zhao, C., Cai, S., Shin, K., Lim, A., Kalisky, T., Lu, W., Clarke, M. F., Beachy, P. A. We found 37 microRNAs that were differentially expressed between human BCSCs and nontumorigenic cancer cells. View details for Web of Science ID 000255592400041, View details for Web of Science ID 000246136200023. Alzheimer's disease (AD) is a progressive neurodegenerative disease observed with aging that represents the most common form of dementia. Schott, A. F., Apel, I. J., Nunez, G., Clarke, M. F. BCL-2 PROTECTS MURINE ERYTHROLEUKEMIA-CELLS FROM P53-DEPENDENT AND -INDEPENDENT RADIATION-INDUCED CELL-DEATH. Search by Name. 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. 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. Pagination. We have studied the ability of c-myc and bcl-2 oncogenes to modulate p53 function. Here we report that Usp16, a negative regulator of Bmi1/PRC1 function, modulates the Wnt pathway in mammary epithelia, primary human fibroblasts and MEFs, affecting their expansion and self-renewal potential. These findings have implications for the development of effective therapeutic agents targeting tumor-initiating cells. Director, Teaching & Learning. We show that human colon cancer tissues contain distinct cell populations whose transcriptional identities mirror those of the different cellular lineages of normal colon. Parsels, L. A., Zellars, R. C., Loney, T. L., Parsels, J. D., Clarke, M. F., MERCHANT, A. K., Lawrence, T. S., Maybaum, J. Bcl-x(s) enhances adenoviral vector-induced apoptosis in neuroblastoma cells. Downregulation of Usp16, either by mutation of a single normal Usp16 allele or by short interfering RNAs, largely rescues all of these defects. 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. To enrich mRNAs predominantly expressed in uncommitted cell lineages, 54 000 cDNA clones generated from a highly enriched population of HSCs and a mixed population of stem and early multipotent progenitor (MPP) cells were arrayed on nylon membranes (macroarray or high-density array), and subtracted with cDNA probes derived from mature lineage cells including spleen, thymus, and bone marrow. Among patients with stage II cancer, the difference in 5-year disease-free survival was significant both in the discovery data set (49% among 15 patients with CDX2-negative tumors vs. 87% among 191 patients with CDX2-positive tumors, P=0.003) and in the validation data set (51% among 15 patients with CDX2-negative tumors vs. 80% among 106 patients with CDX2-positive tumors, P=0.004). Adorno, M., Sikandar, S., Mitra, S. S., Kuo, A., Nicolis Di Robilant, B., Haro-Acosta, V., Ouadah, Y., Quarta, M., Rodriguez, J., Qian, D., Reddy, V. M., Cheshier, S., Garner, C. C., Clarke, M. F. Identification of a cKit(+) Colonic Crypt Base Secretory Cell That Supports Lgr5(+) Stem Cells in Mice. Loss of Bcl11b leads to a Cdkn2a-dependent exhaustion of ductal epithelium and loss of epithelial cell regenerative capacity. LONDON Dancer, choreographer, ex-heroin addict, prodigal son, perfectionist, art-world darling, club-world star: Michael Clark was for a long time . These results indicate that a basic domain other than the well defined NLS is required for the nuclear import of p53. Liu, H., Patel, M. R., Prescher, J. We have designed a microfluidic device to perform sensitive ChIP analysis on low cell numbers in a rapid, automated fashion while preserving the specificity of the assay. Southern blots of DNA from HTLV-infected cells digested with the methylation-sensitive restriction enzyme HpaII showed that the proviral DNA was methylated in all of the uncultured peripheral blood cells tested. Our results indicate that Bmi-1 is essential for the generation of self-renewing adult HSCs. This new paradigm of oncogenesis has been validated in a growing list of tumors. Unfortunately, although chemotherapy and/or radiation therapy can sometimes shrink tumors, metastatic cancers of epithelial origin are essentially incurable. We found cell-specific changes occurring across multiple cell types and organs, as well as age-related changes in the cellular composition of different organs. Michael Clarke Duncan was born on December 10, 1957 in Chicago, Illinois. 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. Understanding the biology of cancer stem cells will contribute to the identification of molecular targets important for future therapies. Clarke, M. F., Gelmann, E. P., Reitz, M. S. RELATION OF RESPIRATORY BURST AND ARACHIDONATE METABOLISM DURING PHAGOCYTOSIS BY GUINEA-PIG ALVEOLAR MACROPHAGES. The nucleotide sequence of a transforming human c-sis complementary DNA shows an open reading frame 723 base pairs in length located downstream from an in-phase terminator thymine-guanine-adenine codon. While the majority of the cancer cells have a limited ability to divide, a population of cancer stem cells that has the exclusive ability to extensively proliferate and form new tumors can be identified based on marker expression. This new model for cancer will have significant ramifications for the way we study and treat cancer. We developed an immunodeficient mouse model to test the tumorigenic potential of different populations of cancer cells derived from primary, unmanipulated human HNSCC samples. We review the biological basis and the therapeutic implications of the stem cell model of cancer. No activating mutations in KIT were detected in DLD1, POP77, or UM-COLON#8 cells. Recent studies have begun to elucidate the mechanisms controlling hematopoietic stem cell (HSC) self-renewal. These results indicate that, similar to normal tissue stem cells, subsets of CSCs in some tumours contain lower ROS levels and enhanced ROS defences compared to their non-tumorigenic progeny, which may contribute to tumour radioresistance. Deficiency in the polycomb family transcriptional repressor Bmi-1 leads to progressive postnatal growth retardation and neurological defects. Herrema I, Clarke M. Anaesthesia for retinoblastoma screening - a dilemma. 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. Other mutations between Arg-306 and NLS I have no effect on the nuclear import of p53. We used immunostaining and fluorescence-activated cell sorting analyses with in vivo administration of a Notch inhibitor and in vitro organoid cultures to characterize different cell types.Multicolor fluorescence-activated cell sorting could isolate distinct regions of colonic crypts. Biography. For more information, please contact Ruth Lira, 650-723-1367. View details for Web of Science ID A1996WD32200005. (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. Okamoto, T., Reitz, M. S., Clarke, M. F., JAGODZINSKI, L. J., WONGSTAAL, F. Sequence-specific interaction of histones with the simian virus 40 enhancer region in vitro. The presence of the concentrated conditioned medium (conCM) enhanced the production of nonadherent cells three-fold compared with control over an eight week culture period. The productivity of cultures exposed to conCM for 4 weeks dropped significantly when unsupplemented medium was used for the latter 4 weeks of culture. Knockdown of endogenous miR-142 effectively suppressed organoid formation by BCSCs and slowed tumor growth initiated by human BCSCs in vivo. In this report, we analyzed the possible existence of cis-acting sequences involved in intracellular trafficking of the p53 protein. Hosen, N., Yamane, T., Muijtjens, M., Pham, K., Clarke, M. F., Weissman, I. L. Phenotypic characterization of human colorectal cancer stem cells. Eighteen relapses occurred a median of 4 months after ABMT I (two late relapses at 28 and 44 months). This tumorigenic cell population could be identified prospectively and consistently had definable and identical phenotype. 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. Taken together, these data demonstrate that cells within the CD44(+) population of human HNSCC possess the unique properties of cancer stem cells in functional assays for cancer stem cell self-renewal and differentiation and form unique histological microdomains that may aid in cancer diagnosis. 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. Cai, S., Kalisky, T., Sahoo, D., Dalerba, P., Feng, W., Lin, Y., Qian, D., Kong, A., Yu, J., Wang, F., Chen, E. Y., Scheeren, F. A., Kuo, A. H., Sikandar, S. S., Hisamori, S., van Weele, L. J., Heiser, D., Sim, S., Lam, J., Quake, S., Clarke, M. F. Targeted chromatin ligation, a robust epigenetic profiling technique for small cell numbers. View details for DOI 10.1016/j.gde.2008.01.017, View details for Web of Science ID 000256954100008, View details for Web of Science ID 000253701800002, View details for Web of Science ID 000258805300065, View details for Web of Science ID 000251969000893. Critically, we found that only streaming and not random migration of single cells was significantly correlated with proximity to vessels, with intravasation and with numbers of elevated circulating tumor cells in the bloodstream. Thus, we reveal USP16 as a novel target in an AD model that can both ameliorate the NPC defect and rescue memory and learning through its regulation of both Cdkn2a and BMP signaling.'. A., Chen, L., Levy, R. Removal of lactate dehydrogenase-elevating virus from human-in-mouse breast tumor xenografts by cell-sorting. 3-7), attempts to identify tumor suppressors within this band have been unsuccessful. Notably, these gene sets show similar expression across tissues, differing only in the amplitude and the age of onset of expression. As few as 100 cells with this phenotype were able to form tumors in mice, whereas tens of thousands of cells with alternate phenotypes failed to form tumors. View details for Web of Science ID 000079323200036. Effect of ASXL1 on the stemness of colorectal cancer initiating cells. We performed the first genome-wide expression analysis directly comparing the expression profile of highly enriched normal human hematopoietic stem cells (HSC) and leukemic stem cells (LSC) from patients with acute myeloid leukemia (AML). Three of these forms co-migrate on Northern blots and are co-expressed in several human hematopoietic cell types. View details for DOI 10.1056/NEJMoa1506597, View details for Web of Science ID 000368404800006, View details for PubMedCentralID PMC4784450. 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