The efficiency of gene therapy strategies against cancer is limited by the poor distribution of the vectors in the malignant tissues. View details for DOI 10.1016/j.gde.2006.08.011, View details for Web of Science ID 000241320300009, View details for Web of Science ID 000238326700034. Here, we report a mouse model that, in the absence of p53 and the presence of oncogenic KrasG12D , develops breast tumors. Bockhorn, J., Yee, K., Chang, Y., Prat, A., Huo, D., Nwachukwu, C., Dalton, R., Huang, S., Swanson, K. E., Perou, C. M., Olopade, O. I., Clarke, M. F., Greene, G. L., Liu, H. Innate immune response to homologous rotavirus infection in the small intestinal villous epithelium at single-cell resolution. This apparent paradox is the focus of our interest. BACKGROUND: Recent studies in murine mammary tissue have identified functionally distinct cell populations that may be isolated by surface phenotype or lineage tracing. Although initial adhesion of hematopoietic cells was improved by the presence of both ECMs, the overall progenitor and nonadherent cell productivity was not improved nor did the stroma grow to confluency faster. In the absence of Bmi-1, the cyclin-dependent kinase inhibitor gene p16Ink4a is upregulated in neural stem cells, reducing the rate of proliferation. 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. We demonstrate that radiation-induced cell death occurs by both p53-dependent and -independent pathways and overexpression of bcl-2 modulates both pathways. He is a board certified oncologist with extensive training in molecular biology and stem cell biology. In order for treatment to be effective long term, the mechanisms enabling treatment adaptation need to be understood. 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. Emerson, S. G., Palsson, B. O., Clarke, M. F., Silver, S. M., Adams, P. T., Koller, M. R., Van Zant, G., Rummel, S., Armstrong, R. D., MALUTA, J. We examined the effect of lower levels of c-sis expression on the phenotype of NIH 3T3 fibroblasts. Thus understanding the mechanisms that regulate stem cell generation has implications for normal development and disease. 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. 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. In some cancer cells, the process of self-renewal is de-regulated resulting in expansion of these cells and tumors. All three analogues retained full agonist activity relative to the native protein (EC50 = 10-15 pM) when assayed for the stimulation of human bone marrow progenitor cell growth. Professor Clarke has over 45 years of professional experience with approximately 250 publications and presentations. 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. We confirm that CSC drive tumorigenesis, suggesting a link between CSC and remodeling. A., Stelzer, Y., Luong, A. V., Isobe, T., Zarnegar, M. A., Watanabe, N., Antonana, S., Lam, J., Qian, D., Sikandar, S. S., Kuo, A. H., Heitink, L. S., Shimono, Y., Scheeren, F. A., Cai, S., Hisamori, S., Sahoo, D., Dirbas, F. M., Somlo, G., Jaenisch, R., Christina, C., Clarke, M. F. Characterizing the role of the nuclear coactivator AIB1 in triple-negative breast cancer. 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. Adjunct Professor Michael Whitehouse. He earned a B.A. The simulation demonstrates that removal of stem cells is a possible mechanism leading to culture decline. View details for PubMedCentralID PMC3816928. Sugawara, Y., Zasadny, K. R., Grossman, H. B., Francis, I. R., Clarke, M. F., Wahl, R. L. The nuclear import of p53 is determined by the presence of a basic domain and its relative position to the nuclear localization signal, Role of p53 in the regulation of irradiation-induced apoptosis in neuroblastoma cells. This decrease in survival began 48 h following radiation. 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. Pardal, R., Clarke, M. F., Morrison, S. J. Hematopoietic stem cells (HSCs) have self-renewal capacity and multilineage developmental potentials. Free UK delivery for orders 30 and over. A shift-up in medium perfusion rates from 3.5/week to 7/week resulted in increased metabolic rates that resembled those observed in the cultures that were exchanged at the 7/week rate throughout, showing that the metabolic rates could be directly controlled by the perfusion rate. Professor Michael Clarke said that sending soldiers to take Kyiv was 'massively foolish' and could become a 'peak Putin' moment that leads eventually to his downfall. Cytoplasmic sequestration of the p53 tumor suppresser protein has been proposed as a mechanism involved in abolishing p53 function. Cancer stem cells and tumor metastasis: First steps into uncharted territory, Bmi-1-green fluorescent protein-knock-in mice reveal the dynamic regulation of Bmi-1 expression in normal and leukemic hematopoietic cells. The calculated molecular weight of RGS18 is 27,610 and the isoelectric point is 8.63. This new model for cancer will have significant ramifications for the way we study and treat cancer. View details for DOI 10.1038/sj.onc.1207947, View details for Web of Science ID 000223998800013, View details for Web of Science ID 000223225500005. The tumors in these tissues consist of heterogeneous populations of cancer cells that differ markedly in their ability to proliferate and form new tumors. In addition to his clinical duties in the division of Oncology, Dr. Clarke maintains a laboratory focused on two areas of research: i) the control of self-renewal of normal stem cells and their malignant counterparts; and ii) the identification and characterization of cancer stem cells. An interleukin-6 family member, interleukin-11 is identified as a secondary target of twinfilin 1 in the microRNA-30c signalling pathway. adequate tissue for cancer stem cell quantification. Deletion of MYD88 or TLR2 in the intestinal epithelium markedly reduces DSS-induced colitis regeneration and spontaneous tumour development in mice. To test this hypothesis, murine erythroleukemia cells were transfected with bcl-XL and p53ts. Despite intensive study of p53, the regulation of p53 cellular localization is still poorly understood. Perhaps the most important and useful property of stem cells is that of self-renewal. Moreover, the inherent ability of residual CoCSC to generate tumors appears preserved. 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. 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. Professor Michael Clarke is a Fellow of King's College London. 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.'. 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]. Lobo, N., Zabala, M., Qian, D., Clarke, M. F. The DLK1-DIO3 imprinted region regulates long-term proliferation in normal and malignant breast epithelium. Although cancer cell lines provide invaluable information, their biological properties often differ in crucial ways from de novo cancer cells. The blocking effect of the CSD is not due to the enhancement of nuclear export or oligomerization of the p53. View details for DOI 10.1146/annurev.cellbio.22.010305.104154, View details for Web of Science ID 000250896200025. Our study demonstrates that microRNA-30c is transcriptionally regulated by GATA3 in breast tumours. These results suggest that LEFTY1 is an endogenous dual-SMAD inhibitor and that suppressing its function may represent a therapeutic vulnerability in breast cancer. 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. Epithelial-to-mesenchymal transition has been shown to correlate with therapy resistance, but the functional link and signalling pathways remain to be elucidated. A temperature-sensitive mutant of murine p53 (p53Val-135) was transfected by electroporation into murine erythroleukemia cells (DP16-1) lacking endogenous expression of p53. Genomic DNA extracted at 32.5 degrees C was seen to be fragmented into a characteristic ladder consistent with cell death due to apoptosis. Following synchronization by density arrest, transfected cells released into G1 at 32.5 degrees C were found to lose viability more rapidly than did randomly growing cultures. View details for Web of Science ID A1991EY27300001. Li, C., Heidt, D. G., Dalerba, P., Burant, C. F., Zhang, L., Adsay, V., Wicha, M., Clarke, M. F., Simeone, D. M. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. 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 A1990DX36100002, View details for Web of Science ID A1989T821800013. 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. Westin, E. H., Gorse, K. M., Clarke, M. F. THE PROLIFERATION OF AML-193 IS REGULATED BY MULTIPLE HEMATOPOIETIC GROWTH-FACTORS AND CYTOKINES. The fragment with a tandem repeat of the 72-bp element also does not associate randomly with histones. From August 1990 to June 1998, 29 males (25 NSGCT) were treated. 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. [1] Clarke is a former Deputy Vice-Principal and Director of Research Development at King's College London, where he remains a Visiting Professor of Defence Studies. Zabala, M., Lobo, N. A., Seoane, J. Trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2; also known as HER-2/neu), is indicated for the treatment of women with either early stage or metastatic HER2(+) breast cancer. This effect was associated with a loss of the G1 specificity of p53-mediated cell cycle arrest. 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. Most importantly, miR-200c strongly suppressed the ability of normal mammary stem cells to form mammary ducts and tumor formation driven by human BCSCs in vivo. We identify two distinct super-enhancers (SEs) associated with CD47 in certain cancer cell types. Vorperian, S. K., Moufarrej, M. N., Tabula Sapiens Consortium, Quake, S. R., Jones, R. C., Karkanias, J., Krasnow, M., Pisco, A. O., Quake, S. R., Salzman, J., Yosef, N., Bulthaup, B., Brown, P., Harper, W., Hemenez, M., Ponnusamy, R., Salehi, A., Sanagavarapu, B. 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). Kim et al. 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. Dr. Michael F. Clarke is the Associate Director of the Stanford Institute for Stem Cell and Regenerative Medicine. View details for Web of Science ID A1994NT46100030. Anaesthesia 2001, 56(5), 486-487. Established HTLV-infected cell lines constitutively express viral RNA. We present a simple single tube proximity ligation technique, targeted chromatin ligation, that captures histone modification patterns with only 200 cells. Dr Michael Clarke is Associate Professor at the National Security College, Crawford School of Public Policy, Australian National University, and Director of the ANU-Indiana University Pan-Asia Institute. Bmi-1-green fluorescent protein (GFP)-knock-in mice reveal the dynamic regulation of Bmi-1 expression in normal and leukemic hematopoietic cells. 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. PROF. MICHAEL CLARKE (Director, Royal United Services Institute): I think the United States has been behind us in this respect. These data, taken together with similar findings with other human neoplasms, show that CD47 is a commonly expressed molecule on all cancers, its function to block phagocytosis is known, and blockade of its function leads to tumor cell phagocytosis and elimination. An in vivo reconstitution assay revealed that the frequency of HSCs was 1/16 in Bmi-1high c-kit+ lin -Sca-1+ bone marrow (BM) cells and 1/49 in Bmi-1 high lin- BM cells, suggesting that Bmi-1 may serve as a marker for normal HSCs. Our multidisciplinary group held a state-of-the-science symposium this past year to review advancesin this rapidly evolving field. 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. 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. 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. When applied to diverse tissue types and organisms, CytoTRACE outperformed previous methods and nearly 19,000 annotated gene sets for resolving 52 experimentally determined developmental trajectories. In 2007, he became the Director of the Royal United Services Institute. These results suggest that cancers can evolve SE to drive CD47 overexpression to escape immune surveillance. All together, these findings link important stem cell regulators like Bmi1/Usp16 and Cdkn2a to Wnt signaling, and have implications for designing therapies for conditions, like DS, aging or degenerative diseases, where the Wnt pathway is hampered. The main focus of this review is the role of mammary stem cells in normal breast development and carcinogenesis. This article discusses the role of the Bcl-2 family of proteins in the light of these findings. It has been reported that Lysine-305 is needed for the nuclear import of the p53 protein (Liang et al., 1998). First, we quantitatively imaged physiologic remodeling of primary branches of the developing and regenerating mammary tree. However, the underlying molecular mechanisms are poorly characterized. Since cancers arise as a result of a series of genetic mutations, a better understanding of the consequences of these mutations on the underlying biology of the neoplastic cells will help the development of more effective therapies. Discover Michael Clarke 's Biography, Age, Height, Physical Stats, Dating/Affairs, Family and career updates. Cancer is often viewed as a caricature of normal developmental processes, but the extent to which its cellular heterogeneity truly recapitulates multilineage differentiation processes of normal tissues remains unknown. Through this property, striking parallels can be found between stem cells and cancer cells: tumours may often originate from the transformation of normal stem cells, similar signalling pathways may regulate self-renewal in stem cells and cancer cells, and cancer cells may include 'cancer stem cells' - rare cells with indefinite potential for self-renewal that drive tumorigenesis. First, we report a mouse model that, in the malignant tissues the Royal United Services.! To drive CD47 overexpression to escape immune surveillance technique, targeted chromatin ligation, that captures histone modification with... 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