Dontu, G., Al-Hajj, M., Abdallah, W. A., Clarke, M. F., Wicha, M. S. In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. We demonstrate that radiation-induced cell death occurs by both p53-dependent and -independent pathways and overexpression of bcl-2 modulates both pathways. This finding suggests a mechanism by which normal hematopoietic progenitors can survive and proliferate despite p53 expression and by which the inappropriate expression of bcl-2 and c-myc can cooperate in transformation. Upon transfer to 32.5 degrees C, these G1 synchronized cell populations quickly lost viability. 2010). Limiting dilution transplantations of breast epithelial cells devoid of TLR2 or MYD88 revealed a significant decrease in mammary repopulating unit frequency compared with the control. 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 describe c-myb-transformed MEL clones which undergo delayed expression of the exogenous c-myb following 3-5 days of culture in DMSO. 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. Automated microfluidic chromatin immunoprecipitation from 2,000 cells. Yoo, S., Chandhasin, C., Del Rosario, J. R., Chen, Y. K., Stafford, J., Quake, S., Perabo, F., Clarke, M. F. Pharmacologic characterization of TACH101, a first-in-class KDM4 inhibitor for development as a cancer therapeutic. Michael Clarke (academic) is a British academic who specialises in defence studies. View details for Web of Science ID 000345638500001, View details for DOI 10.1158/1538-7445.AM2014-SY12-04, View details for Web of Science ID 000349910205454, View details for Web of Science ID 000351670400001. No activating mutations in KIT were detected in DLD1, POP77, or UM-COLON#8 cells. Although new therapeutic regimens developed over the past decade haveincreased survival, there is substantial room for improvement in selecting targeted treatment regimens forthe patients who will derive the most benefit. Clarke, M. F., Dick, J. E., Dirks, P. B., Eaves, C. J., Jamieson, C. H., Jones, D. L., Visvader, J., Weissman, I. L., Wahl, G. M. A self-renewal assay for cancer stem cells. We demonstrate that reversing impaired NPC self-renewal via genetic reduction of USP16, a histone modifier and critical physiological antagonist of the Polycomb Repressor Complex 1, can prevent downstream cognitive defects and decrease astrogliosis in vivo. 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. It contains three regions: a KpnI repeat, a unique cellular region (UCR), and the U3 + R sequence of the human T-lymphotropic virus type I LTR. EW replicates in IEC subsets differing in their basal type I IFN transcription and induces IRF3-dependent and IRF3-augmented transcription, but not NF-B-dependent or type I IFN transcripts. Il neo-ateismo ritiene che la superstizione, la religione e l'irrazionalismo non dovrebbero essere tollerati, e si propone di contrastarli . Thus, Bmi-1 dependence distinguishes stem cell self-renewal from restricted progenitor proliferation in these tissues. 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). In addition, Usp16 is associated with decreased ubiquitination of Cdkn2a and accelerated senescence in Ts65Dn fibroblasts. (2007) analyze the relationship between CSC and tumor metastasis. A., Li, Q., Mahmoudabadi, G., McGeever, A., Olivieri, J. E., Park, M., Ravikumar, N., Stanley, G., Tan, W., Tarashansky, A. J., Vanheusden, R., Wang, P., Wang, S., Xing, G., Xu, C., Yosef, N., Culver, R., Dethlefsen, L., Ho, P., Liu, S., Maltzman, J. S., Metzger, R. J., Sasagawa, K., Sinha, R., Song, H., Wang, B., Artandi, S. E., Beachy, P. A., Clarke, M. F., Giudice, L. C., Huang, F. W., Huang, K. C., Idoyaga, J., Kim, S. K., Kuo, C. S., Nguyen, P., Rando, T. A., Red-Horse, K., Reiter, J., Relman, D. A., Sonnenburg, J. L., Wu, A., Wu, S. M., Wyss-Coray, T. Molecular hallmarks of heterochronic parabiosis at single-cell resolution. 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. Thus, these mice allow for the isolation of viable Bmi-1-expressing cells and have the potential to become a useful tool for understanding the role of Bmi-1 in normal and cancer stem cells in multiple tissue types. Uncultured peripheral blood T-cells from human T-cell leukemia-lymphoma virus-infected individuals expressed DR antigens at a low level, and the DR alpha locus was partially unmethylated. This has been recently shown in an in vivo model, where overexpression of Bcl-XL, is a crucial step in the progression from hyperplasia to neoplasia and is accompanied by a significant decrease in tumor apoptosis [56]. View details for Web of Science ID A1991GV58400008. The human RGS18 ortholog has a tissue-specific expression pattern similar to that of mouse RGS18. Intriguingly, overexpression of p53 could reverse the inherent IR resistance of Shep-1 cells. 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. These latter cell lines do express HLA-DR alpha-mRNA, as well as HLA-DR surface antigens. Bcl-2 prevented radiation-induced cell death in DP16-1 cells expressing wtp53 and delayed radiation-induced cell death in DP16-1 cells without wtp53. Herein, we present a discussion around the issues facing treatment of patients with CRCliver metastases, including the relationship of discretegene signatures with prognosis. Recently, various new players that regulate HSC maintenance (e.g. 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. Orthologs of these differentially expressed genes predicted survival of human breast cancer patients from two different study groups. 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. Using an ELISA assay which quantitates DNA damage, we demonstrate that this sensitization is due to apoptosis, suggesting the therapeutic utility of targeting this pathway. Northstar is a useful tool to assign known and novel cell type and states in the age of cell atlases. View details for Web of Science ID 000083623000026. Eighteen relapses occurred a median of 4 months after ABMT I (two late relapses at 28 and 44 months). Perhaps the most important and useful property of stem cells is that of self-renewal. Only a small minority of cancer cells had the capacity to form new tumors in a xenograft model. Following his specialty training in medical oncology at Royal Prince Alfred and Westmead Hospitals, Professor Boyer was a Research Fellow and Clinical Fellow at the Ontario Cancer Institute and Princess Margaret Hospital in Toronto, Canada, where he completed his PhD on cell biology. 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. Three of these forms co-migrate on Northern blots and are co-expressed in several human hematopoietic cell types. These results suggest that LEFTY1 is an endogenous dual-SMAD inhibitor and that suppressing its function may represent a therapeutic vulnerability in breast cancer. erenakgun@g.harvard.edu. View details for Web of Science ID 000169201800006. These data suggest that the c-myb protooncogene encodes alternately spliced mRNA species with opposing effects on differentiation. Moreover, the inherent ability of residual CoCSC to generate tumors appears preserved. Limited viral replication facilitates greater penetration of virions into tissue and can improve gene transfer. We studied the effect of the combination of rapid culture medium exchange with the addition of the human hematopoietic growth factors interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and erythropoietin (Epo) on the proliferation and differentiation of human long-term bone marrow cultures (LTBMCs). Disclosure of potential conflicts of interest is found at the end of this article. Patients with KIT-expressing colon tumors can benefit from KIT RTK inhibitors. View details for Web of Science ID A1991GR93700016. 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. The main focus of this review is the role of mammary stem cells in normal breast development and carcinogenesis. We examined such heterogeneity in the small intestine during rotavirus (RV) infection. This includes loss of a portion of the region involved in transcription activation as well as a separate highly conserved domain. In spite of substantial differences in the extent of methylation of class I-related genes, no obvious differences exist among these cell types in their levels of expression of HLA-A and -B antigens. View details for Web of Science ID 000345777300014. Anti-CD47 antibody therapy initiated on larger tumors inhibited tumor growth and prevented or treated metastasis, but initiation of the therapy on smaller tumors was potentially curative. Increased levels of c-sis cDNA expression correlated with the acquisition of features of transformation in a dose-dependent manner and altered the cellular phenotype in a manner consistent with the progression of cells towards malignancy. George Malcolm (1917-1997), Pianist, Cembalist, Dirigent und Komponist. View the profiles of people named Michael Clarke. Adjunct Associate Professor Jon Womersley. We develop two-gene classifier systems (KRT20 versus CA1, MS4A12, CD177, SLC26A3) that predict clinical outcomes with hazard ratios superior to those of pathological grade and comparable to those of microarray-derived multigene expression signatures. Stromal Gli2 activity coordinates a niche signaling program for mammary epithelial stem cells. It has been reported that Lysine-305 is needed for the nuclear import of the p53 protein (Liang et al., 1998). This decrease in survival began 48 h following radiation. These breast tumors are comprised of phenotypically diverse populations of breast cancer cells. View details for DOI 10.1038/s41586-020-2499-y. The pattern of triple mutant multipotent progenitor response to growth factors resembles that of wild-type multipotent progenitors but not wild-type HSCs. However, the consequences of the underlying gene-dosage imbalance on adult tissues remain poorly understood. To better understand the molecular basis of radiation-induced cell death, we studied the role of the bcl-2 oncogene and the p53 tumor suppressor gene in this process. He is an adviser to two Parliamentary Committees and Associate Director of the Strategy and Security Institute at the University of Exeter. The p53-independent pathway does not appear to involve apoptosis and occurs at a later time, starting 48 h after X-ray exposure. Adams, S., Upadhyaya, G., Clarke, M. F., Emerson, S. G. CONSTITUTIVE EXPRESSION OF A C-MYB CDNA BLOCKS FRIEND MURINE ERYTHROLEUKEMIA CELL-DIFFERENTIATION. A large number of genes that were differentially expressed by enriched populations of HSCs and MPP cells were identified. View details for DOI 10.1073/pnas.1006732107, View details for Web of Science ID 000283184800050, View details for PubMedCentralID PMC2964232. Strategies that enhance the activity of ADCC effectors, including NK cells, may improve the efficacy of trastuzumab. This cell line contains a wild-type p53 gene and is an ideal model for studying the mechanism of IR resistance in this disease. We focused our analysis of gene expression on RNA from primitive leukemia-initiating cells, which harbor 5q deletions, and analyzed 12 genes within the CDR that are expressed by normal hematopoietic stem cells. He is a board certified oncologist with extensive training in molecular biology and stem cell biology. - Associate Professor: Business Management In contrast, BMP7, a NODAL antagonist with context-dependent functions, is produced by basal cells and restrains progenitor cell proliferation. It has been proposed, therefore, that failure to effectively treat cancer may in part be due to preferential resistance of these CSC to chemotherapeutic agents. Wild-type p53 plays a crucial role in the control of apoptosis following ionizing radiation (IR); conversely, mutant p53 is associated with IR resistance. Knockdown of KIT decreased proliferation of colon cancer cell lines and growth of xenograft tumors in mice compared with control cells. PROF. MICHAEL CLARKE (Director, Royal United Services Institute): I think the United States has been behind us in this respect. Gene expression analysis of single CD44(+) cells indicated that KIT can promote growth via KITLG autocrine and/or paracrine signaling. Most cancers comprise a heterogenous population of cells with marked differences in their proliferative potential as well as the ability to reconstitute the tumor upon transplantation. This is accompanied by a translocation of the p53 protein from the cytoplasm to the nucleus. Cell migration is an essential component of almost every step of the metastatic cascade, especially the early step of invasion inside the primary tumor. Some factors that regulate this process of self-renewal are conserved from fruit fly to humans. This new model for cancer will have significant ramifications for the way we study and treat cancer. Free UK delivery for orders 30 and over. AKR/J mice had significantly higher frequencies and numbers of both HSCs and restricted progenitors in their bone marrow than C57BL/Ka-Thy-1.1 mice. Here we report that microRNA-30c, a human breast tumour prognostic marker, has a pivotal role in chemoresistance by a direct targeting of the actin-binding protein twinfilin 1, which promotes epithelial-to-mesenchymal transition. In some cancer cells, the process of self-renewal is de-regulated resulting in expansion of these cells and tumors. View details for Web of Science ID 000079323200036. Further study with ETYA showed that the inhibitor at 2 x 10(-5) M had little effect on uptake of 125I-labeled zymosan but did abolish the conversion of 14C-arachidonic acid to a compound that co-migrated with authentic 12-HETE on silica gel plates. In concert with endogenous DMSO-induced globin transcription during MEL cell differentiation, the beta-globin c-myb transcription unit of the transfected plasmid is activated after 3-5 days of culture in media containing DMSO. View details for Web of Science ID A1984SP90200011. Professor Clarke is a former Deputy Vice . Our results indicate that Bmi-1 is essential for the generation of self-renewing adult HSCs. 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. Tumors injected four times with the bcl-xs adenovirus showed a 50% reduction in size. LDV infects specifically mouse macrophages and alters immune system and tumor phenotype. and Ph.D. in economics from the University of Kentucky. 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. This report summarizes the major topics discussed and the future directions that research should take. Genetic upregulation of the Wnt pathway in Ts65Dn mice rescues the proliferation defect observed in mammary epithelial cells. Clinical and Therapeutic Implications of Cancer Stem Cells. Thus, the predicted transforming product, a protein of 27,281 daltons, may be the actual precursor for normal human platelet-derived growth factor chain A. 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. This suggested that endogenous Bcl-XL could protect cancer cells from p53-mediated apoptosis. The main objectives of his laboratory are to pursue how perturbations in the self-renewal machinery contribute to human diseases and to use the findings to aid the development of more effective treatment therapies.His laboratory has a long history of innovative findings which include: the first to demonstrate that inappropriate expression of a normal gene could cause a tumor; the first to identify a dominant-negative splice variant of an oncogene; the first to identify a molecular regulator of stem cell self-renewal; the first to identify a solid tumor stem cell (in breast cancer) and the first to demonstrate a molecular linkage of a self-renewal program used by normal mammary stem cells and breast cancer cells. View details for Web of Science ID 000073794800011. 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. BIO-IMEB - Biofilms in Industry, Medicine & Environmental Biot, Galway, Ireland, 9-14 August 2003. With the use of subgroup analysis involving independent and retrospective cohorts of patients with stage II or stage III colon cancer, the top candidate gene was tested for its association with disease-free survival and a benefit from adjuvant chemotherapy. Differentially expressed genes were used to generate a 186-gene "invasiveness" gene signature (IGS), which was evaluated for its association with overall survival and metastasis-free survival in patients with breast cancer or other types of cancer.There was a significant association between the IGS and both overall and metastasis-free survival (P<0.001, for both) in patients with breast cancer, which was independent of established clinical and pathological variables.