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. In this study, we report that miR-142 efficiently recruits the APC mRNA to an RNA-induced silencing complex, activates the canonical WNT signaling pathway in an APC-suppression dependent manner, and activates the expression of miR-150. In a pooled database of all patient cohorts, the rate of 5-year disease-free survival was higher among 23 patients with stage II CDX2-negative tumors who were treated with adjuvant chemotherapy than among 25 who were not treated with adjuvant chemotherapy (91% vs. 56%, P=0.006). KIT and/or KITLG was stably knocked down by expression of small hairpin RNAs from lentiviral vectors in DLD1, HT29, LS174T, and COLO320 DM colon cancer cell lines, and in UM-COLON#8 and POP77 xenografts; cells transduced with only vector were used as controls. Expression of wild-type p53 phenotype for 24 hr before FdUrd treatment provided HT29 cells with virtually complete protection from cytotoxicity caused by this drug. The fragment with a tandem repeat of the 72-bp element also does not associate randomly with histones. Program Affiliations. These results demonstrate that Bcl-XL is capable of protecting cells from p53-mediated apoptosis, and suggest a possible mechanism by which tumors expressing Bcl-XL are able to partly overcome the tumor suppressor functions of p53. Reduction of USP16 led to decreased expression of senescence gene Cdkn2a and mitigated aberrant regulation of the BMP pathway, a previously unknown function of USP16. Multiple cell lines expressing variable levels of exogenous temperature-sensitive p53 were generated. Here we developed a CSC model for the study of human colorectal cancer (CRC). View details for DOI 10.1038/s41587-021-01188-9, View details for DOI 10.7554/eLife.70692.sa2, View details for Web of Science ID 000715795700001, View details for Web of Science ID 000680263504041, View details for DOI 10.1200/JCO.2021.39.15_suppl.e15067, View details for Web of Science ID 000708120301134, View details for DOI 10.1200/JCO.2021.39.15_suppl.3105, View details for Web of Science ID 000708120601279. View details for Web of Science ID A1994PC47400008. If this difference in tumorigenicity of cancer cells also occurs in patients, then the ability to enrich for cancer stem cells lays an important groundwork for future studies where mechanisms involved in cancer stem cells can now be investigated. Strategies that enhance the activity of ADCC effectors, including NK cells, may improve the efficacy of trastuzumab. We examined the effect of this limited adenovirus replication in vitro and in vivo. A., Clarke, M. F., Quake, S. R. A single-cell transcriptomic atlas characterizes ageing tissues in the mouse. Here, we show that human breast tumor biomarker miR-30c regulates invasion by targeting the cytoskeleton network genes encoding twinfilin 1 (TWF1) and vimentin (VIM). Many cancers overexpress a member of the bcl-2 family of inhibitors of apoptosis. Synchronized cells allowed to pass out of G1 prior to being placed at 32.5 degrees C continued to cycle until subsequently arrested in G1; loss of viability occurred following G1 arrest. We developed northstar, a computational approach to classify thousands of cells based on published data within seconds while simultaneously identifying and highlighting new cell states such as malignancies. Michael Clarke is a UK academic and "terror expert". 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. Clones with various levels of c-sis expression were generated by transfecting NIH 3T3 cells with a plasmid that expressed the human c-sis cDNA and the TN5 neomycin-resistance gene. To assess CSC-specific remodeling events, we isolated CSC from MMTV-Wnt1 (mouse mammary tumor virus long-term repeat enhancer driving Wnt1 oncogene) breast tumors, a well studied model in which tissue remodeling affects tumorigenesis. These results suggest that inhibitors of the TLR2 pathway merit investigation as possible therapeutic and chemoprevention agents. To direct the replication of the virus to breast cancer, we have considered one characteristic present in a great proportion of these cancers, which is the expression of estrogen receptors (ERs). Publications Journal Articles (89) Conference Papers (5) Journal Articles Clarke, Paul R. (2021). Published Oct. 2, 2020 Updated Oct. 5, 2020. 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. In approaching the bone marrow culture system, we recognize the critical role that hematopoietic growth factors (HGFs) play in hematopoiesis. Cancers of epithelial origin are responsible for the majority of cancer-related deaths in the USA. However, the identity and function of cells expressing EMT-associated genes in normal murine mammary gland homeostasis and human breast cancer still remains under debate. Gain- and loss-of-function studies show that Bcl11b induces cells to enter the G0 phase of the cell cycle and become quiescent. Recently, there have been exciting developments in identifying high-risk patient cohorts, refinements in the understanding of systemic vs localized drug delivery to metastatic niches, liquid biomarker development, and dramatic advances in tumor immune therapy, all of which promise new and innovative approaches to tackling the problem ofdetecting and treating the metastatic spread of CRC to the liver. 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 A1995RC93600007. [email protected]. Recent studies elucidated the presence of cancer stem cells that have the exclusive ability to regenerate tumors. In vitro, blockade of CD47 signaling using targeted monoclonal antibodies enabled macrophage phagocytosis of tumor cells that were otherwise protected. Here, we have shown that upon encountering trastuzumab-coated, HER2-overexpressing breast cancer cells, human NK cells become activated and express the costimulatory receptor CD137. 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). Ageing is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death1. Bcl-xs is a dominant negative repressor of Bcl-2 and Bcl-xL, both of which inhibit apoptosis. Dalerba, P., Sahoo, D., Paik, S., Guo, X., Yothers, G., Song, N., Wilcox-Fogel, N., Forg, E., Rajendran, P. S., Miranda, S. P., Hisamori, S., Hutchison, J., Kalisky, T., Qian, D., Wolmark, N., Fisher, G. A., van de Rijn, M., Clarke, M. F. A cell-intrinsic role for TLR2-MYD88 in intestinal and breast epithelia and oncogenesis. View details for DOI 10.1016/j.semradonc.2008.11.002, View details for Web of Science ID 000264310800003, View details for PubMedCentralID PMC2789266. In some cancer cells, the process of self-renewal is de-regulated resulting in expansion of these cells and tumors. Overall, we demonstrate a novel approach for imaging physiologic and pathological remodeling. View details for Web of Science ID A1997YA26800007. 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. View details for DOI 10.1016/j.cell.2009.07.011, View details for Web of Science ID 000268771900022, View details for PubMedCentralID PMC2731699. Emerging evidence has suggested that the capability of a tumor to grow and propagate is dependent on a small subset of cells within a tumor, termed cancer stem cells. View details for DOI 10.1371/journal.pone.0002428, View details for Web of Science ID 000263280700013, View details for PubMedCentralID PMC2413402, View details for Web of Science ID 000454834700190. Identification of a novel microRNA-mediated pathway that regulates chemoresistance in breast cancer will facilitate the development of novel therapeutic strategies. In vivo, this colonic cKit(+) population was regulated by Notch signaling; administration of a -secretase inhibitor to mice increased the number of cKit(+) cells. Clarke, Clifton - Professor: Business Management Clement, Anthony E. - Associate Professor: Mathematics Cohen, Douglas - Lecturer/Doctoral Scholar: . Our metastatic cancer models, combined with noninvasive imaging techniques, constitute an integrated approach that could be applied to dissect the molecular mechanisms underlying the dissemination of metastatic CSCs (MCSCs) and to explore therapeutic strategies targeting MCSCs in general or to evaluate individual patient tumor cells and predict response to therapy. 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. This new paradigm of oncogenesis has been validated in a growing list of tumors. Investigator:Michael Clarke (CI) Rural Industries Research & Development Corporation, 2016, $130,500 Development of honeybee products from a biodiversity hotspot Katherine Hammer, Connie Locher, Michael Clarke (CI) MS Research Australia, 2014, $180,000 Project Title: Vitamin D metabolites and risk of multiple sclerosis in the Ausimmune Study Hernandez-Alcoceba, R., Pihalja, M., Nunez, G., Clarke, M. F. Molecular cloning and characterization of a novel regulator of G-protein signaling from mouse hematopoietic stem cells. Herrema I, Clarke M. Anaesthesia for retinoblastoma screening - a dilemma. Arthur Thomas Malkin (1803-1888), Pionier der Bergsteigerei und Schriftsteller. Moreover, the inherent ability of residual CoCSC to generate tumors appears preserved. Here we show that in Ts65Dn mice, which are trisomic for 132 genes homologous to genes on human chromosome 21, triplication of Usp16 reduces the self-renewal of haematopoietic stem cells and the expansion of mammary epithelial cells, neural progenitors and fibroblasts. 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. The safety and efficacy of targeting CD47 was further tested and validated in immune competent hosts using an orthotopic mouse breast cancer model. 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. Here, a systematic approach using bioinformatics and array hybridization techniques to analyze gene expression profiles in HSCs is described. 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. View details for Web of Science ID A1996VX88000036, View details for Web of Science ID A1996VT98300744. The complexity and inefficiency of chromatin immunoprecipitation strategies restrict their sensitivity and application when examining rare cell populations. View details for Web of Science ID A1990DY35100036. New treatment modalities are needed for the latter group. Despite this central role, the mechanism of action of Bcl-2 is not yet clear. A central issue in stem cell biology is to understand the mechanisms that regulate the self-renewal of haematopoietic stem cells (HSCs), which are required for haematopoiesis to persist for the lifetime of the animal. 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. Disclosure of potential conflicts of interest is found at the end of this article. Caldwell, J., LOCEY, B., Clarke, M. F., Emerson, S. G., Palsson, B. O. DIFFERENTIATION OF MOUSE ERYTHROLEUKEMIA-CELLS ENHANCED BY ALTERNATIVELY SPLICED C-MYB MESSENGER-RNA. The calculated molecular weight of RGS18 is 27,610 and the isoelectric point is 8.63. View details for Web of Science ID A1984SV56900010. His group was the first to discover that the proto-oncogene Bmi-1 regulates stem cell self-renewal via an epigenetic mechanism. Han, J. S., Qian, D. L., Wicha, M. S., Clarke, M. F. Targeting cancer cell death with a bcl-x(s) adenovirus. Thomas Jeffrey Hanks ( Concord, California; 9 de julio de 1956) es un actor y director de cine estadounidense. 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. Methods We used a new bioinformatics approach to search for biomarkers of colon epithelial differentiation across gene-expression arrays and then ranked candidate genes according to the availability of clinical-grade diagnostic assays. RRV replication was significantly rescued in IFN types I and II, as well as STAT1 (IFN types I, II, and III) deficient mice in contrast to EW, which was only modestly sensitive to IFNs I and II. In several forms of human cancer, only a phenotypic subset of cancer cells, usually termed "cancer stem cells" (CSC), can initiate tumor growth when transplanted. CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer. PHD Student in Computer Science. Professor Clark is someone that should teach all students. These sequences, when compared with those previously reported for the human c-myb gene, reveal an alternative splicing process that generates at least four forms of the c-myb message. A better understanding of the molecular mechanisms underlying metastasis is needed to develop more effective treatments. Expression of microRNA-30c inversely correlates with interleukin-11 expression in primary breast tumours and low interleukin-11 correlates with relapse-free survival in breast cancer patients. View details for Web of Science ID A1991GR93700016. 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). View details for DOI 10.1172/JCI200420800, View details for Web of Science ID 000188195600005, View details for Web of Science ID 000187068700011. Professor Clarke was presented by Professor Len Scott from the Department of International Politics. Professor Clarke has over 45 years of professional experience with approximately 250 publications and presentations. Together, these data lay the groundwork for a systemic understanding of the interplay between blood-borne factors and cellular integrity. [1] During the 2022 Russian invasion of Ukraine, he served as Sky News ' security and defence analyst. T47D cells were then transfected with a temperature-sensitive mutant of the tumor suppressor p53 (p53ts). Prince, M. E., Sivanandan, R., Kaczorowski, A., Wolf, G. T., Kaplan, M. J., Dalerba, P., Weissman, I. L., Clarke, M. F., Ailles, L. E. Chromosome 5q deletion and epigenetic suppression of the gene encoding alpha-catenin (CTNNA1) in myeloid cell transformation. View details for Web of Science ID A1991EY27300001. Cytoplasmic sequestration of the p53 tumor suppresser protein has been proposed as a mechanism involved in abolishing p53 function. More. Transient overexpression of RGS18 attenuated inositol phosphates production via angiotensin receptor and transcriptional activation through cAMP-responsive element via M1 muscarinic receptor. However, attempts to develop stable long-term human bone marrow cultures have been unsuccessful. These results suggest that the activity of some mutant p53 proteins can be functionally modified by exogenous compounds. View details for Web of Science ID A1992GX27300015. The mechanism of leukaemogenic transformation by human T-cell leukaemia/lymphoma virus (HTLV), a retrovirus implicated in the aetiology of certain adult T-cell leukaemias and lymphomas, is unknown but is conceivably associated with the expression of the cellular analogues of retroviral oncogenes. Reya, T., Morrison, S. J., Clarke, M. F., Weissman, I. L. Clinical protocol. 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. Zarnegar, M. A., Reinitz, F. n., Newman, A. M., Clarke, M. F. CDX2 as a Prognostic Biomarker in Colon Cancer. This phenotypic diversity is driven by a small subset of mammary tumour stem cells. 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.1212188109, View details for Web of Science ID 000312605600104, View details for PubMedCentralID PMC3528539. The stem cells maintain themselves through a process known as self-renewal. Using a xenograft model in which primary human pancreatic adenocarcinomas were grown in immunocompromised mice, we identified a highly tumorigenic subpopulation of pancreatic cancer cells expressing the cell surface markers CD44, CD24, and epithelial-specific antigen (ESA). View details for Web of Science ID A1991FC72500007. Notably, these gene sets show similar expression across tissues, differing only in the amplitude and the age of onset of expression. These tools should lead to new insights into the cellular and molecular mechanisms that drive human breast cancer growth and invasion. The molecular mechanisms that drive human breast cancer growth and invasion proposed as mechanism. Cells, the mechanism of action of Bcl-2 is not yet clear epithelial (. 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