Chemotherapy resistance frequently drives tumour progression. View details for DOI 10.1016/j.gde.2003.11.007, View details for Web of Science ID 000188978200008. Chandhasin, C., Yoo, S., Del Rosario, J., Chen, Y. K., Stafford, J., Perabo, F., Clarke, M. F. Depletion of Trp53 and Cdkn2a Does Not Promote Self-Renewal in the Mammary Gland but Amplifies Proliferation Induced by TNF-. At the time of ABMT, 10 were chemosensitive, four were chemoresistant, and 10 were absolutely refractory to platinum. Prior to that he was Professor of Defence Studies at King's College London, and Deputy Vice-Principal for Research Development. Self-renewal requires the integration of survival signals and proliferation controls with the maintenance of an undifferentiated state. CD47 is a ligand for SIRP, a protein expressed on macrophages and dendritic cells. Room 424:1 Advanced Engineering Building (49) . In the discovery data set, which included 466 patients, the rate of 5-year disease-free survival was lower among the 32 patients (6.9%) with CDX2-negative colon cancers than among the 434 (93.1%) with CDX2-positive colon cancers (hazard ratio for disease recurrence, 3.44; 95% confidence interval [CI], 1.60 to 7.38; P=0.002). Intriguingly, overexpression of p53 could reverse the inherent IR resistance of Shep-1 cells. Unequivocal proof that stem cells exist in the haematopoietic system has given way to the prospective isolation of several tissue-specific stem and progenitor cells, the initial delineation of their properties and expressed genetic programmes, and the beginnings of their utility in regenerative medicine. In many cases, breast cancer cells retain the expression of estrogen receptors, and most solid tumors suffer from hypoxia as a consequence of their aberrant vascularization. Despite rapid advances over recent years, many of the molecular and cellular processes that underlie the progressive loss of healthy physiology are poorly understood2. These latter cell lines do express HLA-DR alpha-mRNA, as well as HLA-DR surface antigens. A large number of genes that were differentially expressed by enriched populations of HSCs and MPP cells were identified. A gene expression analysis revealed that the expression of stem cell associated genes, cell survival genes, transcription factors, and genes modulating proliferation including p16Ink4a and p19Arf was altered in bone marrow cells of the Bmi-1-/- mice. It is clear that new approaches are needed to treat these diseases. Research Expertise and Interests View details for DOI 10.1016/j.semradonc.2008.11.002, View details for Web of Science ID 000264310800003, View details for PubMedCentralID PMC2789266. 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. Moreover, we demonstrate that only CSC implants invade into surrounding stroma with structures similar to developing mammary ducts (nine for CSC and one for non-CSC). Pancreatic cancer cells with the CD44(+)CD24(+)ESA(+) phenotype (0.2-0.8% of pancreatic cancer cells) had a 100-fold increased tumorigenic potential compared with nontumorigenic cancer cells, with 50% of animals injected with as few as 100 CD44(+)CD24(+)ESA(+) cells forming tumors that were histologically indistinguishable from the human tumors from which they originated. To solve this problem, a new generation of tumor-specific, conditionally replicative adenoviruses is being developed. View details for Web of Science ID 000268227400008, View details for Web of Science ID 000209702603139, View details for Web of Science ID 000209701800291. 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. View details for Web of Science ID 000173193700014. Eipers, P. G., Krauss, J. C., Palsson, B. O., Emerson, S. G., Todd, R. F., Clarke, M. F. BCL-X(L) PROTECTS CANCER-CELLS FROM P53-MEDIATED APOPTOSIS. View details for Web of Science ID 000079346200015. 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). Stem cells in normal breast development and breast cancer. The United States has always regarded certainly jihadist terrorism . War in Ukraine 2022: Prof. Michael Clarke analysis 116 videos 3,380 views Updated 5 days ago Defence and security analyst Professor Michael Clarke's observations mostly on Sky News. G418-resistant clones, which expressed the c-sis cDNA, were selected and characterized. Eighteen relapses occurred a median of 4 months after ABMT I (two late relapses at 28 and 44 months). 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. Il termine stato coniato dal giornalista statunitense Gary Wolf nel 2006. Utilizing a mouse model of AD and human fetal cells harboring mutant amyloid precursor protein, we show cell intrinsic neural precursor cell (NPC) dysfunction precedes widespread inflammation and amyloid plaque pathology, making it the earliest defect in the evolution of the disease. The rapid medium exchange combined with the addition of human hematopoietic CSFs significantly enhances the proliferation and differentiation of LTBMCs. Investigating mechanisms of cancer stern cell radioresistance. Analysis of the surface molecule repertoire of EpCAM(high)/CD44+ cells led to the identification of CD166 as an additional differentially expressed marker, useful for CSC isolation in three of three CRC tested. To date, therapies targeting end-stage disease plaques, tangles, or inflammation have limited efficacy. Varma, A., ELAWAR, F. Y., Palsson, B. O., Emerson, S. G., Clarke, M. F. MALIGNANT TRANSFORMATION OF NIH 3T3 FIBROBLASTS BY HUMAN C-SIS IS DEPENDENT UPON THE LEVEL OF ONCOGENE EXPRESSION. Data on sequence comparisons with mouse and chicken homologues of c-myb coupled with oligonucleotide hybridization to genomic clones of the human c-myb gene indicate that this alternative splicing process utilizes three closely spaced splice donor sites and two unique exons present between viral defined exons 5 and 6. Michael Clarke Duncan was born on December 10, 1957 in Chicago, Illinois. Other mutations between Arg-306 and NLS I have no effect on the nuclear import of p53. Ageing is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death1. By examining the pathways upstream and downstream of Bmi1, hence the molecular pathways that regulate self-renewal, his laboratory found that USP16, a protein that dampens Bmi1 signals, causes a stem cell defect in various stem cells in Downs syndrome, including neural stem cells. Understanding the biology of cancer stem cells will contribute to the identification of molecular targets important for future therapies. View details for Web of Science ID 000173215900013. View details for Web of Science ID A1984SY22400007. 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. View details for Web of Science ID A1995RY96700021. Following high-dose IR, cell fractionation demonstrated that p53 is induced and targeted to the nucleus. Lobo, N. A., Zabala, M., Qian, D., Clarke, M. F. Serially transplantable mammary epithelial cells express the Thy-1 antigen. Chromatin immunoprecipitation (ChIP) is a powerful assay used to probe DNA-protein interactions. Other pathways have not been previously implicated in the regulation of cancer stem cell functions, including Ribosome and T Cell Receptor Signaling pathway. Northstar is a useful tool to assign known and novel cell type and states in the age of cell atlases. Previous studies have shown that blocking DLL4 signaling reduced tumor growth by disrupting productive angiogenesis. Bcl-xs is a dominant negative repressor of Bcl-2 and Bcl-xL, both of which inhibit apoptosis. This promoter induces transcriptional activation of the E1a and E4 units in response to estrogens in cells that express the ERs. High transduction rates could be obtained even in the absence of polycations, such as Polybrene, which heretofore have been required to achieve reasonable transduction rates. Acad. Studies of normal and cancer stem cells from the same tissue have shed light on the ontogeny of tumors. Cancer cells with endogenous KIT expression were more tumorigenic in mice.KIT and KITLG are expressed by a subset of human colon tumors. His group was the first to discover that the proto-oncogene Bmi-1 regulates stem cell self-renewal via an epigenetic mechanism. These tools should lead to new insights into the cellular and molecular mechanisms that drive human breast cancer growth and invasion. KIT Signaling Promotes Growth of Colon Xenograft Tumors in Mice and Is Up-Regulated in a Subset of Human Colon Cancers. View details for DOI 10.1186/s13058-018-1006-y, View details for Web of Science ID 000447203300001, View details for Web of Science ID 000440602000145, View details for Web of Science ID 000440602000051, View details for DOI 10.1200/JCO.2018.36.4_suppl.683, View details for Web of Science ID 000436174100659. The prognostic role of a gene signature from tumorigenic breast-cancer cells. View details for Web of Science ID A1991GR93700016. The telomerase core promoter failed to block the replication of the virus in telomerase-negative cells. Professor Clarke's current research interests are the molecular mechanisms of cell division, chromosome instability and mitotic cell death. Professor of Health in Social Science; College Dean International; EFI Director of Global Communities. 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. Morrison, S., Park, I., Qian, D. L., Jerabek, L., Weissman, I., Clarke, M. F. Retroviral infection is limited by Brownian motion. View details for Web of Science ID 000178077600006. adequate tissue for cancer stem cell quantification. 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. Oncogenesis is a process resulting from genetic events which cause loss of growth control or inhibition of appropriate cell death. 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 safety and efficacy of targeting CD47 was further tested and validated in immune competent hosts using an orthotopic mouse breast cancer model. Adjunct Professor Michael Whitehouse. 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. Until 2001 he was Deputy Vice-Principal and Director for Research Development at King's College London, where he remains a Visiting Professor of Defence Studies. Flow cytometry and microfluidics-based single-cell multiplex RT-PCR allowed dissection of IFN responses in single RV-infected and bystander intestinal epithelial cells (IECs). Publications Journal Articles (89) Conference Papers (5) Journal Articles Clarke, Paul R. (2021). 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. T47D cells were then transfected with a temperature-sensitive mutant of the tumor suppressor p53 (p53ts). Inflammation disrupts tissue architecture and function, thereby contributing to the pathogenesis of diverse diseases; the signals that promote or restrict tissue inflammation thus represent potential targets for therapeutic intervention. We have studied the ability of c-myc and bcl-2 oncogenes to modulate p53 function. The existence of CSCs mandates careful analysis and comparison of normal tissue stem cells and CSCs to identify differences between the two cell types. View details for Web of Science ID A1990DY35100036. Therefore, to better treat cancer it may be necessary to develop novel methods to overcome the effects of the Bcl-2 family. IL-10 function is required for the full protective effect of small-molecule Hedgehog pathway activation in colitis; this pharmacologic augmentation of Hedgehog pathway activity and stromal IL-10 expression are associated with increased presence of CD4(+)Foxp3(+) regulatory T cells. Therefore, senescence of stem cells must be prevented. Intravital multiphoton imaging reveals multicellular streaming as a crucial component of in vivo cell migration in human breast tumors. CD47 is therefore a validated target for cancer therapies. HSCs have the ability to self-renew, while MPP cells have lost the capacity for self-renewal. View details for DOI 10.1016/j.stem.2009.05.019, View details for Web of Science ID 000269511900010. Additionally, it facilitated the identification of quiescent stem cells and revealed genes that contribute to breast tumorigenesis. However, DNA from HTLV-infected lymphocytes cultured for 48 hr (by which time increases in viral RNA expression are evident) did not differ detectably with respect to proviral DNA methylation from uncultured cells, suggesting that the increase in viral RNA expression after short-term culture is mediated by mechanisms independent of changes in DNA methylation. CoCSC). Administration of anti-CD47 antibodies inhibited tumor growth in orthotopic immunodeficient mouse xenotransplantation models established with patient tumor cells and increased the survival of the mice over time. 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. Raised by his single mother, Jean, a house cleaner, on Chicago's South Side, Duncan grew up resisting drugs and alcohol, instead concentrating on school. The efficiency of gene therapy strategies against cancer is limited by the poor distribution of the vectors in the malignant tissues. With the growing evidence that cancer stem cells exist in a wide array of tumors, it is becoming increasingly important to understand the molecular mechanisms that regulate self-renewal and differentiation because corruption of genes involved in these pathways likely participates in tumor growth. Data from individual tumor phenotypic analysis and serial transplants performed in limiting dilution show that residual tumors are enriched for cells with the CoCSC phenotype and have increased tumorigenic cell frequency. B., Alizadeh, A. This report summarizes the major topics discussed and the future directions that research should take. We were able to distinguish the tumorigenic (tumor initiating) from the nontumorigenic cancer cells based on cell surface marker expression. The data clearly indicate, however, that the class I and class II components of the major histocompatibility complex are unusually hypermethylated in several T-ALL-derived cell lines, while ATL T-cell lines do not substantially differ in this respect from normal peripheral blood T-cells. View details for Web of Science ID 000182941000008. Our technique eliminates loss of material and sensitivity due to multiple inefficient steps, while simplifying the workflow to enhance sensitivity and create the potential for novel applications. 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. Although an increasing number of interventions show promise for rejuvenation2, their effectiveness on disparate cell types across the body and the molecular pathways susceptible to rejuvenation remain largely unexplored. Conclusions Lack of CDX2 expression identified a subgroup of patients with high-risk stage II colon cancer who appeared to benefit from adjuvant chemotherapy. The conditional expression of lethal genes in tumor cells is a promising gene therapy approach for the treatment of cancer. The coordinated downregulation of three microRNA clusters and the similar functional regulation of clonal expansion by miR-200c provide a molecular link that connects BCSCs with normal stem cells. View details for DOI 10.1073/pnas.0610117104, View details for Web of Science ID 000243761100053. In 2007, he became the Director of the Royal United Services Institute. We demonstrate that radiation-induced cell death occurs by both p53-dependent and -independent pathways and overexpression of bcl-2 modulates both pathways. Professor. Director, Teaching & Learning. Clinically, successful reconstruction of human bone marrow would permit the controlled production of mature blood cells for transfusion therapy, and immature bone marrow stem cells for bone marrow transplantation. To investigate the possible role of Bmi-1 in other cell types that also self-renew, we generated Bmi-1-green fluorescent protein (GFP)-knock-in mice, in which GFP was expressed under the endogenous transcriptional regulatory elements of the Bmi-1 gene. Hisamori, S., Dalerba, P., Shimono, Y., Rothenberg, M. E., Zabara, M., Cai, S., Qian, D., Clarke, M. F. Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer. CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer. Loss of Bcl11b leads to a Cdkn2a-dependent exhaustion of ductal epithelium and loss of epithelial cell regenerative capacity. We used xenograft tumors of MDA-MB-231 cells as well as a low passage xenograft tumor from orthotopically injected patient-derived breast tumor cells. Solid tumors such as breast cancers contain heterogeneous populations of neoplastic cells. Comparing ChIP results for two modified histone protein targets, we showed our automated microfluidic ChIP (AutoChIP) from 2,000 cells to be comparable to that of conventional ChIP methods using 50,000-500,000 cells. Five thousand cDNA clones with very low hybridization signals were selected for sequencing and further analysis using microarrays on glass slides. G1 arrest at 37.5 degrees C, utilizing either mimosine or isoleucine deprivation, does not lead to rapid cell death. NB cells showed loss of viability with both viruses, although the bcl-xS virus was most toxic. Unfortunately, although chemotherapy and/or radiation therapy can sometimes shrink tumors, metastatic cancers of epithelial origin are essentially incurable. Professor Michael Clarke was Director-General of the Royal United Services Institute (RUSI) from 2007 to 2015 when he retired from that role. We conclude therefore that the inhibition of oxygen consumption and superoxide production by ETYA at 2 x 10(-5) M is unrelated to inhibition of arachidonic acid metabolism. Danish, R., ELAWAR, O., Weber, B. L., Langmore, J., Turka, L. A., Ryan, J. J., Clarke, M. F. CAN DEXTER CULTURES SUPPORT STEM-CELL PROLIFERATION. However, attempts to develop stable long-term human bone marrow cultures have been unsuccessful. The weight is in Kilograms- 70 kg. Palovics, R., Keller, A., Schaum, N., Tan, W., Fehlmann, T., Borja, M., Kern, F., Bonanno, L., Calcuttawala, K., Webber, J., McGeever, A., Tabula Muris Consortium, Luo, J., Pisco, A. O., Karkanias, J., Neff, N. F., Darmanis, S., Quake, S. R., Wyss-Coray, T., Almanzar, N., Antony, J., Baghel, A. S., Bakerman, I., Bansal, I., Barres, B. Regulation of the Wnt pathway in stem cells and primary tissues is still poorly understood. Patients were eligible for a second cycle if disease progression was absent and performance status allowed. The downstream effectors of TLR2 are expressed by normal intestinal and mammary epithelia, including the stem/progenitor cells. Additionally, we suggest that constitutive expression of c-myb does not block early commitment events such as activation of histone Hl', subsequent chromatin condensation, and alteration of proliferation-related gene expression. The Polycomb protein Bmi1 is absolutely required for the maintenance of both adult HSCs and neural 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. These results suggest that Bcl-2 family members are required for survival of cancer cells derived from solid tissues. View details for DOI 10.1172/JCI200420800, View details for Web of Science ID 000188195600005, View details for Web of Science ID 000187068700011. The tumors in these tissues consist of heterogeneous populations of cancer cells that differ markedly in their ability to proliferate and form new tumors. Bcl11b maintains the long-term mammary stem cell and is crucial for drug resistance in breast cancer. Sufficient new cells have to be produced to maintain the integrity of a tissue, but excessive proliferation resulting in tumorigenesis needs to be prevented. billy goat bag repair, Research Expertise and Interests View details for Web of Science ID 000188978200008 chemosensitive, four were,. Lost the capacity for self-renewal clear that new approaches are needed to treat these diseases that family... 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