Here, we show that LEFTY1, a secreted inhibitor of NODAL/SMAD2 signaling, is produced by mammary progenitor cells and, concomitantly, suppresses SMAD2 and SMAD5 signaling to promote long-term proliferation of normal and malignant mammary epithelial cells. 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. We have introduced this construct into Friend erythroleukemia (F-MEL) cells and have isolated a number of clones which contain intact and transcriptionally active human c-myb sequences. In addition, Usp16 is associated with decreased ubiquitination of Cdkn2a and accelerated senescence in Ts65Dn fibroblasts. In this report we explore the role of Bcl-XL overexpression in protecting cancer cells from p53-mediated apoptosis. Cai, S., Kalisky, T., Dalerba, P., Clarke, M., Stanford Univ. Furthermore, in human tissues overexpression of USP16 reduces the expansion of normal fibroblasts and postnatal neural progenitors, whereas downregulation of USP16 partially rescues the proliferation defects of Down's syndrome fibroblasts. Perhaps the most important and useful property of stem cells is that of self-renewal. The tumors in these tissues consist of heterogeneous populations of cancer cells that differ markedly in their ability to proliferate and form new tumors. View details for Web of Science ID 000186360800006. Eighteen relapses occurred a median of 4 months after ABMT I (two late relapses at 28 and 44 months). Furthermore, these approaches are not feasible for primary tumor cells that cannot survive tissue culture conditions or that may change phenotype in rats. We have previously shown that two human T-cell lines (HSB and 8402) derived from patients with childhood T-cell ALL (T-ALL) do not synthesize detectable mRNA for HLA-DR alpha. These advances in BCSC imaging revealed that CD44(+) cells from both primary tumors and lung metastases are highly enriched for tumor-initiating cells. Dalerba, P., Kalisky, T., Sahoo, D., Rajendran, P. S., Rothenberg, M. E., Leyrat, A. 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. ANGELOTTI, T. P., Clarke, M. F., Longino, M. A., Emerson, S. G. THE CONSTRUCTION OF HIGH-EFFICIENCY HUMAN BONE-MARROW TISSUE EXVIVO. Lower ROS levels in CSCs are associated with increased expression of free radical scavenging systems. 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. In some cancer cells, the process of self-renewal is de-regulated resulting in expansion of these cells and tumors. One of the best candidate genes involved in conferring self-renewal capacity is Bmi-1, which has been proven to be essential for the maintenance of both normal adult hematopoietic and leukemia stem cells, as well as adult neural stem cells. It is unusual among haemopoietic cell lines in that one of these is c-sis, the gene from which the oncogene v-sis of the simian sarcoma virus was derived, and perhaps the gene for platelet-derived growth factor (PDGF). View details for Web of Science ID A1992KX78000004. Taken together, these results indicate that wild-type p53 induces cell death in murine erythroleukemia cells and that this effect occurs predominantly in the G1 phase of actively cycling cells. This suggests that agents that target the defective self-renewal pathways in cancer cells might lead to improved outcomes in the treatment of these diseases. He was Director of the Royal United Services Institute from 2007 to 2015. The regulation of hematopoietic stem cell (HSC) homeostasis is not well understood. A., Beachy, P. A., Berdnik, D., Bilen, B., Brownfield, D., Cain, C., Chan, C. K., Chen, M. B., Clarke, M. F., Conley, S. D., Demers, A., Demir, K., de Morree, A., Divita, T., du Bois, H., Ebadi, H., Espinoza, F. H., Fish, M., Gan, Q., George, B. M., Gillich, A., Gomez-Sjoberg, R., Green, F., Genetiano, G., Gu, X., Gulati, G. S., Hahn, O., Haney, M. S., Hang, Y., Harris, L., He, M., Hosseinzadeh, S., Huang, A., Huang, K. C., Iram, T., Isobe, T., Ives, F., Jones, R. C., Kao, K. S., Karnam, G., Kershner, A. M., Khoury, N., Kim, S. K., Kiss, B. M., Kong, W., Krasnow, M. A., Kumar, M. E., Kuo, C. S., Lam, J., Lee, D. P., Lee, S. E., Lehallier, B., Leventhal, O., Li, G., Li, Q., Liu, L., Lo, A., Lu, W., Lugo-Fagundo, M. F., Manjunath, A., May, A. P., Maynard, A., McKay, M., McNerney, M. W., Merrill, B., Metzger, R. J., Mignardi, M., Min, D., Nabhan, A. N., Ng, K. M., Nguyen, P. K., Noh, J., Nusse, R., Patkar, R., Peng, W. C., Penland, L., Pollard, K., Puccinelli, R., Qi, Z., Rando, T. A., Rulifson, E. J., Segal, J. M., Sikandar, S. S., Sinha, R., Sit, R. V., Sonnenburg, J., Staehli, D., Szade, K., Tan, M., Tato, C., Tellez, K., Torrez Dulgeroff, L. B., Travaglini, K. J., Tropini, C., Tsui, M., Waldburger, L., Wang, B. M., van Weele, L. J., Weinberg, K., Weissman, I. L., Wosczyna, M. N., Wu, S. M., Xiang, J., Xue, S., Yamauchi, K. A., Yang, A. C., Yerra, L. P., Youngyunpipatkul, J., Yu, B., Zanini, F., Zardeneta, M. E., Zee, A., Zhao, C., Zhang, F., Zhang, H., Zhang, M. J., Zhou, L., Zou, J. The weight is in Kilograms- 70 kg. The reasons for the limited longevity are unknown. Michael Clarke, defence analyst: Yes, the Black Sea is international and a UK warship went in there to Ukraine when the QE carrier was on its world tour last year. CHUCK, A. S., Clarke, M. F., Palsson, B. O. bcl-x(s) gene therapy induces apoptosis of human mammary tumors in nude mice. Mcl1, Tel/Etv6, Gfi1, Pten and Stat5) have been identified. Kim et al. Stanford is currently not accepting patients for this trial. Patients were eligible for a second cycle if disease progression was absent and performance status allowed. View details for Web of Science ID 000168861600008. Morrison, S., Park, I., Qian, D. L., Jerabek, L., Weissman, I., Clarke, M. F. Retroviral infection is limited by Brownian motion. 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. Five thousand cDNA clones with very low hybridization signals were selected for sequencing and further analysis using microarrays on glass slides. A group of 87 of 2115 tumor samples (4.1%) lacked CDX2 expression. 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. Isobe, T., Hisamori, S., Hogan, D. J., Zabala, M., Hendrickson, D. G., Dalerba, P., Cai, S., Scheeren, F., Kuo, A. H., Sikandar, S. S., Lam, J. S., Qian, D., Dirbas, F. M., Somlo, G., Lao, K., Brown, P. O., Clarke, M. F., Shimono, Y. These included transcription factors, signaling molecules, and previously unknown genes. Professor Michael Clarke, a prominent military analyst, told Express.co.uk that Ukraine could use Britain's Challenger 2 tanks to split the combat frontline and "isolate Crimea". These results demonstrate the feasibility of using continuous perfusion bioreactors as a method of efficiently modifying human hematopoietic stem cells. 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 Michael Clarke Duncan was born on December 10, 1957 in Chicago, Illinois. A central question in cancer biology is, which cells can be transformed to form tumors? However, the mechanisms regulating p53 subcellular localization remain unclear. Pharmacological depletion of ROS scavengers in CSCs markedly decreases their clonogenicity and results in radiosensitization. The rapid medium exchange combined with the addition of human hematopoietic CSFs significantly enhances the proliferation and differentiation of LTBMCs. 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. Michael Clarke is a UK academic and "terror expert". FUKUNAGAJOHNSON, N., Ryan, J. J., Wicha, M., Nunez, G., Clarke, M. F. OVEREXPRESSION OF BCL-X(S), SENSITIZES MCF-7 CELLS TO CHEMOTHERAPY-INDUCED APOPTOSIS. These data demonstrate that the transcomplementation of replication-deficient adenovirus with exogenous E1 DNA leads to limited replication, and this controlled replication enhances gene transfer efficiency of adenovirus in vivo. 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. Recently, his group described a molecular mechanism that confers resistance to radiation in breast cancer stem cells. Human breast tumors contain a breast cancer stem cell (BCSC) population with properties reminiscent of normal stem cells. The metabolic and secretory characteristics of NIH-3T3 fibroblasts transfected with a cDNA encoding human granulocyte-macrophage colony stimulating factor (GM-CSF) were examined as a function of the culture medium exchange schedule. He is so driven about his work and is so charismatic to his students. 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. This makes it virtually impossible to infect the majority of tumor cells in vivo and results in inadequate gene transfer. View details for Web of Science ID A1994PC47400008. Hosen, N., Yamane, T., Muijtjens, M., Pham, K., Clarke, M. F., Weissman, I. L. Phenotypic characterization of human colorectal cancer stem cells. 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. We used Bcl-XS, a dominant negative inhibitor of Bcl-2 and Bcl-XL, to demonstrate the role of these genes in modulating chemotherapy-induced apoptosis. Prior to coming to UK, Dr. Clark was the Chief Economist for the Kentucky Legislative Research . View details for Web of Science ID 000243488100004. 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. MicroRNAs (miRNAs) are important regulators of stem and progenitor cell functions. 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. View details for Web of Science ID 000073794800011. We review the biological basis and the therapeutic implications of the stem cell model of cancer. He was Director General of the Royal United Services Institute from 2017-2015 and is now a Distinguished Fellow at RUSI. The GM-CSF production by the transfected 3T3 cells was stable but exhibited substantial transient increases during periods of cell proliferation, demonstrating that the secretion of transfected gene products can be highly modulated even when the cDNA is driven from a constitutive promoter. The productivity of cultures exposed to conCM for 4 weeks dropped significantly when unsupplemented medium was used for the latter 4 weeks of culture. Two distinct technical approaches were used for most organs: one approach, microfluidic droplet-based 3'-end counting, enabled the survey of thousands of cells at relatively low coverage, whereas the other, full-length transcript analysis based on fluorescence-activated cell sorting, enabled the characterization of cell types with high sensitivity and coverage. Surface markers that displayed intratumor heterogeneous expression among epithelial cancer cells were selected for cell sorting and tumorigenicity experiments. View details for DOI 10.1634/stemcells.2006-0229, View details for Web of Science ID 000247722100006. Adjunct Senior Lecturer Dr Jan Warnken. Cytoplasmic sequestration of the p53 tumor suppresser protein has been proposed as a mechanism involved in abolishing p53 function. School of Civil Engineering +61 7 336 56464. william.clarke@uq.edu.au. He is the Karel and Avice Beekhuis Professor in Cancer Biology and Associate Director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine. We developed a new technique that replaces immunoprecipitation with a simplified chromatin fragmentation and proximity ligation step that eliminates bead purification and washing steps. identify miR-22 as both a repressor of TET proteins and a powerful oncogene in the mammary epithelium and hematopoietic system. The results indicate that locally produced GM-CSF and IL-3 do augment hematopoiesis for several weeks in culture. The subpopulation of human colorectal tumor cells with an ESA(+)CD44(+) phenotype are uniquely responsible for tumorigenesis and have the capacity to generate heterogeneous tumors in a xenograft setting (i.e. This system allows one round of viral replication. This effect is the same as that of Lys-305 mutation. Ayash, L. J., Clarke, M., Adams, P., Ferrara, J., Ratanatharathorn, V., Reynolds, C., Roessler, B., Silver, S., Strawderman, M., Uberti, J., Wicha, M. Double dose-intensive chemotherapy with autologous stem cell support for relapsed and refractory testicular cancer: the University of Michigan experience and literature review. The main focus of this review is the role of mammary stem cells in normal breast development and carcinogenesis. Using terminal transferase-mediated dUTP-digoxigenin nick end labeling, we observed apoptotic cells at sites of bcl-xs adenoviral injection. View details for Web of Science ID A1984SJ97500057. In back-to-back articles in Cell and Cell Stem Cell, Song etal. Dr. Michael F. Clarke is the Karel and Avice Beekhuis Professor in Cancer Biology and Associate Director of the Stanford Institute for Stem Cell and Regenerative Medicine. Reply. Two cDNA clones of the human c-myb gene have been isolated from a CCRF-CEM leukemia cell cDNA library and sequenced in their entirety. Cell-free RNA from liquid biopsies can be analyzed to determine disease tissue of origin. We show that human colon cancer tissues contain distinct cell populations whose transcriptional identities mirror those of the different cellular lineages of normal colon. We present a simple single tube proximity ligation technique, targeted chromatin ligation, that captures histone modification patterns with only 200 cells. View details for Web of Science ID A1982NS41700015, American Association of Physicians, - (-), American Society of Clinical Investigation, - (-), Rackham Award, University of Michigan (-), Please see Dr. Michael Clarke's bio on the following School of Medicine website(s). These results suggest all human solid tumor cells require CD47 expression to suppress phagocytic innate immune surveillance and elimination. However, the consequences of the underlying gene-dosage imbalance on adult tissues remain poorly understood. Clarke M, Mitchell KW, Goodship J, McDonnell S, Barker MD, Griffiths ID, McKie N. Clinical features of a novel TIMP-3 mutation causing Sorsby's fundus dystrophy: implications for disease mechanism. C-myb, the normal cellular homolog of the retroviral transforming gene v-myb, encodes a nuclear, transcriptional regulatory protein (p75c-myb). Park, I. K., Morrison, S. J., Clarke, M. F. Applying the principles of stem-cell biology to cancer. Cells that expressed kappa- or lambda-light chains were separated by cell sorting from kappa- or lambda-negative cells and replaced in culture. When isolated from mouse colon, cKit(+) cells promoted formation of organoids from Lgr5(+) stem cells, which expressed Kitl/stem cell factor, the ligand for cKit. Upon inactivation of KrasG12D , tumors initially regress and enter remission. Usp16 contributes to somatic stem-cell defects in Down's syndrome. Two populations of cells, HSCs and MPP cells, were compared for differential gene expression using microarray analysis. To understand the regulation of p53 cellular trafficking, we have previously identified two p53 domains involved in its localization. View details for Web of Science ID A1995RC93600007. The molecular mechanisms that limit the proliferation capacity of multipotent progenitors and other more mature progenitors are not fully understood. We therefore propose to initiate a phase I clinical trial to test the safety of this virus in women with breast cancer undergoing high does chemotherapy and autologous BMT. 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. 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. 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. View details for DOI 10.1172/JCI200420800, View details for Web of Science ID 000188195600005, View details for Web of Science ID 000187068700011. Eight (28%) patients are continuously progression-free a median 60 months (range, 31-93) from first ABMT. Here we developed a CSC model for the study of human colorectal cancer (CRC). The efficiency of gene therapy strategies against cancer is limited by the poor distribution of the vectors in the malignant tissues. To achieve long-lasting responses in the clinic to RAS-fueled cancer, treatment will need to focus in parallel on obstructing tumors from adapting to oncogene inhibition. SMAD pathways govern epithelial proliferation, and transforming growth factor beta (TGF-beta and BMP signaling through SMAD members has distinct effects on mammary development and homeostasis. These models recapitulate human cancer features not captured with previous models, including spontaneous metastasis in particular, and provide a useful platform for studies of breast tumor initiation and progression. Effect of ASXL1 on the stemness of colorectal cancer initiating cells. George Malcolm (1917-1997), Pianist, Cembalist, Dirigent und Komponist. Down's syndrome results from full or partial trisomy of chromosome 21. These findings have implications for the development of effective therapeutic agents targeting tumor-initiating cells. The ability to slow or reverse biological ageing would have major implications for mitigating disease risk and maintaining vitality1. 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. View details for Web of Science ID A1991EY27300001. 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