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. Our results indicate that Bmi-1 is essential for the generation of self-renewing adult HSCs. Liu, H., Bockhorn, J., Dalton, R., Olopade, O. F., Clarke, M. F., Greene, G. L. MicroRNAs regulating breast cancer stem cells and metastasis. These cancer stem cells share many characteristics with normal stem cells, including self-renewal and differentiation. Northstar is a useful tool to assign known and novel cell type and states in the age of cell atlases. 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. Bcl11b maintains the long-term mammary stem cell and is crucial for drug resistance in breast cancer. 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. It is most highly expressed in bone marrow followed by fetal liver, spleen, and then lung. While the majority of the cancer cells have a limited ability to divide, a population of cancer stem cells that has the exclusive ability to extensively proliferate and form new tumors can be identified based on marker expression. Recently, we have found that a recombinant adenovirus vector that contains a bcl-x, minigene (a dominant negative inhibitor of the bcl-2 family), called the bcl-x(s) adenovirus, is lethal to cancer cells derived from epithelial tissues, but not to normal human hematopoietic cells. 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. Both VIM and TWF1 have been shown to regulate epithelial-to-mesenchymal transition. Taken together, these results show that c-myb acts very late in the process of differentiation. Patsialou, A., Bravo-Cordero, J., Wang, Y., Liu, H., Clarke, M. F., Condeells, J. S. Deregulation of stem cell self-renewal pathways in cancer, MicroRNA-30c inhibits human breast tumour chemotherapy resistance by regulating TWF1 and IL-11. Professor Clarke was presented by Professor Len Scott from the Department of International Politics. Cytoplasmic sequestration of the p53 tumor suppresser protein has been proposed as a mechanism involved in abolishing p53 function. This decrease in survival began 48 h following radiation. This cell line contains a wild-type p53 gene and is an ideal model for studying the mechanism of IR resistance in this disease. View details for Web of Science ID A1984SP90200011. The molecular mechanisms that limit the proliferation capacity of multipotent progenitors and other more mature progenitors are not fully understood. 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. Oncolytic adenoviruses with restricted replication can be produced if the expression of crucial transcription units of the virus is controlled by tissue- or tumor-specific promoters. These findings have important implications for the development and evaluation of oncologic therapies and present opportunities for potential gains in patient outcome. For more information, please contact Ruth Lira, 650-723-1367. Other pathways have not been previously implicated in the regulation of cancer stem cell functions, including Ribosome and T Cell Receptor Signaling pathway. Josephs, S. F., Ratner, L., Clarke, M. F., Westin, E. H., Reitz, M. S., WONGSTAAL, F. DIFFERENTIAL METHYLATION OF CLASS-I HISTOCOMPATIBILITY ANTIGEN GENES IN T-CELL LINES DERIVED FROM TWO DIFFERENT TYPES OF T-CELL MALIGNANCIES, TRANSFORMATION OF NIH 3T3-CELLS BY A HUMAN C-SIS CDNA CLONE. . There was no detectable self-renewal of adult HSCs, indicating a cell autonomous defect in Bmi-1-/- mice. Furthermore, the tumorigenic CD44(+) cells differentially express the BMI1 gene, at both the RNA and protein levels. Patients with KIT-expressing colon tumors can benefit from KIT RTK inhibitors. 444 Hutchison (585) 275-3432 [email protected]. 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. Multiple cell lines expressing variable levels of exogenous temperature-sensitive p53 were generated. Established HTLV-infected cell lines constitutively express viral RNA. Alterations in the phenotype of the clones that expressed c-sis ranged from increased growth in soft agar to malignant tumor formation in nude and syngeneic mice. 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. 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. Parashurama, N., Lobo, N. A., Ito, K., Mosley, A. R., Habte, F. G., Zabala, M., Smith, B. R., Lam, J., Weissman, I. L., Clarke, M. F., Gambhir, S. S. Effect of stimulation of natural killer cells with an anti-CD137 mAb on the efficacy of trastuzumab, cetuximab, and rituximab. Because of the unusual findings of apparently inappropriate HLA antigens in HTLV infected cells, we had previously looked for rearrangement of class I-related genes in HTLV infected cells but failed to find any. Cells that were kept density arrested at 32.5 degrees C (G0) lost viability at a much slower rate than did cells released into G1. 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. In both breast cancers and central nervous system tumors, cancer cells differ in their ability to form tumors. 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. Adjunct Professor Michael Whitehouse. Amine-derivatized analogues of 1.2 and 3.8 mol of biotin/mol of protein (N1-bGM-CSF and N4-bGM-CSF) and a carboxyl-modified analogue of 4.6 mol of biotin/mol of protein (C5-bGM-CSF) were synthesized. Akala, O. O., Park, I., Qian, D., Pihalja, M., Becker, M. W., Clarke, M. F. A gene signature in breast cancer - Reply. However, the bone marrow of such patients is often contaminated with tumor cells. identify miR-22 as both a repressor of TET proteins and a powerful oncogene in the mammary epithelium and hematopoietic system. 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. 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 DOI 10.1158/1538-7445.TIM2013-PR5, View details for Web of Science ID 000209496400262, View details for DOI 10.1158/1538-7445.TIM2013-IA20, View details for Web of Science ID 000209496400253. 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. It has been viewed by tens of millions of people around the world, including in China, where Sandel was named the "most . To examine the role of breast cancer stem cells (BCSCs) in metastasis, we generated human-in-mouse breast cancer orthotopic models using patient tumor specimens, labeled with optical reporter fusion genes. Here, we report that genetic or pharmacologic Hedgehog pathway inhibition intensifies colon inflammation (colitis) in mice. Subsequently, the majority of tumors adapt to the withdrawal of KrasG12D expression and return. Usp16 regulation of the Wnt pathway in mouse and human tissues is at least in part mediated by activation of Cdkn2a, a regulator of senescence. M.D., Indiana University (1977) B.A., Indiana University (1973) Contact Academic [email protected] University - Faculty Department: Med/Stem Cell Position: Assoc Director, Stanford Institute for Stem Cell & Regenerative Medicine Lorry Lokey Stem Cell Building 265 Campus Drive Room G2021A, MC: 5461 Stanford, California 94305 (650) 736-2961 (fax) Here, a systematic approach using bioinformatics and array hybridization techniques to analyze gene expression profiles in HSCs is described. We confirm that CSC drive tumorigenesis, suggesting a link between CSC and remodeling. Mark Malloch Brown, Baron Malloch-Brown (* 1953), Politiker und stellvertretender Generalsekretr der Vereinten Nationen. Cells that expressed kappa- or lambda-light chains were separated by cell sorting from kappa- or lambda-negative cells and replaced in culture. View details for Web of Science ID A1991GV58400008. Two clones which initially expressed low levels of human c-myb transcripts and which differentiated normally were subsequently inhibited in their ability to differentiate when grown in successively higher concentrations of methotrexate, due to amplification and enhanced expression of plasmid sequences. Using gene transfer technology, we can now deliver genes that accomplish this goal. 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. Within the colon, the Hedgehog protein signal does not act directly on the epithelium itself, but on underlying stromal cells to induce expression of IL-10, an immune-modulatory cytokine long known to suppress inflammatory intestinal damage. We propose the use of this promoter for transcriptional targeting of breast cancer. Intriguingly, overexpression of p53 could reverse the inherent IR resistance of Shep-1 cells. In culture, codelivery of virus and pE1 resulted in a large increase in infected cells when compared with control cells exposed to virus and pUC19. Sky's defence analyst Prof Michael Clarke gives his opinion on the critical elements of the war in Ukraine and on what could come next Why you can trust Sky News Watch Next Tuesday's Press Preview PM announces 'major breakthrough' Baroness Betty Boothroyd dies A day of history, a day of reckoning On the frontline in Vuhledar Join Facebook to connect with Michael Clarke and others you may know. A., Spallino, E., Aaron, K. A., Concepcion, W., Gardner, J. M., Kelly, B., Neidlinger, N., Wang, Z., Crasta, S., Kolluru, S., Morri, M., Tan, S. Y., Travaglini, K. J., Xu, C., Alcantara-Hernandez, M., Almanzar, N., Antony, J., Beyersdorf, B., Burhan, D., Calcuttawala, K., Carter, M. M., Chan, C. K., Chang, C. A., Chang, S., Colville, A., Culver, R. N., Cvijovic, I., D'Amato, G., Ezran, C., Galdos, F. X., Gillich, A., Goodyer, W. R., Hang, Y., Hayashi, A., Houshdaran, S., Huang, X., Irwin, J. C., Jang, S., Juanico, J. V., Kershner, A. M., Kim, S., Kiss, B., Kong, W., Kumar, M. E., Kuo, A. H., Leylek, R., Li, B., Loeb, G. B., Lu, W., Mantri, S., Markovic, M., McAlpine, P. L., de Morree, A., Mrouj, K., Mukherjee, S., Muser, T., Neuhofer, P., Nguyen, T. D., Perez, K., Phansalkar, R., Puluca, N., Qi, Z., Rao, P., Raquer-McKay, H., Schaum, N., Scott, B., Seddighzadeh, B., Segal, J., Sen, S., Sikandar, S., Spencer, S. P., Steffes, L., Subramaniam, V. R., Swarup, A., Swift, M., Van Treuren, W., Trimm, E., Veizades, S., Vijayakumar, S., Vo, K. C., Vorperian, S. K., Wang, W., Weinstein, H. N., Winkler, J., Wu, T. T., Xie, J., Yung, A. R., Zhang, Y., Detweiler, A. M., Mekonen, H., Neff, N. F., Sit, R. V., Tan, M., Yan, J., Bean, G. R., Charu, V., Forgo, E., Martin, B. Clarke, M. F., Gelmann, E. P., Reitz, M. S. RELATION OF RESPIRATORY BURST AND ARACHIDONATE METABOLISM DURING PHAGOCYTOSIS BY GUINEA-PIG ALVEOLAR MACROPHAGES. Identification of pancreatic cancer stem cells and further elucidation of the signaling pathways that regulate their growth and survival may provide novel therapeutic approaches to treat pancreatic cancer, which is notoriously resistant to standard chemotherapy and radiation. 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. However, no indomethacin or ETYA inhibition of oxygen utilization was detected in the presence of 1 mM KCN, suggesting that the inhibitable portion of the respiratory burst observed with indomethacin or ETYA was dependent on mitochondrial respiration. 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. Professor Michael Clarke, Director of the Royal United Services Institute and a graduate of the Department of International Politics, was honoured as Fellow of Aberystwyth University on Tuesday 10 July. Furthermore, the oxygenation of arachidonic acid requires little of the oxygen consumed by phagocytosing alveolar macrophages. The productivity of cultures exposed to conCM for 4 weeks dropped significantly when unsupplemented medium was used for the latter 4 weeks of culture. View details for Web of Science ID 000173193700014. Weber, B. L., Westin, E. H., Clarke, M. F. ALTERNATIVE SPLICING OF THE HUMAN C-MYB GENE. Mutagenesis analysis demonstrated that a single amino acid mutation of Lys-305 (mt p53) caused cytoplasmic sequestration of the p53 protein in the MCF-7 and RKO cells, whereas the fusion protein was distributed in both the cytoplasm and the nucleus of SAOS-2 cells. Dr Michael Clarke is an internationally recognised expert on the history and politics of the Xinjiang Uyghur Autonomous Region, People's Republic of China (PRC), Chinese foreign policy in Central Asia, Central Asian geopolitics, nuclear proliferation and non-proliferation and American grand strategy and foreign policy. View details for DOI 10.1016/j.stem.2016.11.007, View details for PubMedCentralID PMC5341693. To explore the possible role of c-sis expression in HTLV-induced disease, we have obtained cDNA clones of c-sis from HUT-102 cells. In this report we explore the role of Bcl-XL overexpression in protecting cancer cells from p53-mediated apoptosis. The combination of IL-3 + GM-CSF + Epo generated the most prolific cultures with an order of magnitude increase in nonadherent cell production from weeks 2 through 8 in culture as compared with unsupplemented controls. 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. van Weele, L. J., Djomehri, S. I., Cai, S., Antony, J., Sikandar, S. S., Qian, D., Ho, W. H., West, R., Scheeren, F. A., Clarke, M. F. Publisher Correction: Cell types of origin of the cell-free transcriptome. Replication-deficient viral vectors are currently being used in gene transfer strategies to treat cancer cells. Lower ROS levels in CSCs are associated with increased expression of free radical scavenging systems. A basic domain, Lys(305)-Arg(306), is required for p53 nuclear import, and a carboxyl-terminal domain, namely the cytoplasmic sequestration domain (CSD) from residues 326-355, could block the nuclear import of Lys(305) or Arg(306) mutated p53. These results demonstrate that p16Ink4a/p19Arf and Trp53 have a central role in limiting the expansion potential of multipotent progenitors. 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. Frequently, overexpression of a member of the Bcl-2 family results in a block in cell death and appears to nullify many built-in cellular defense mechanisms against cancer. Furthermore, we identify unique, CSC-specific, remodeling events. 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. Liu, H., Bockhorn, J., Dalton, R., Chang, Y., Qian, D., Zitzow, L. A., Clarke, M. F., Greene, G. L. Identification of miRNAs that regulate breast cancer stem cells and spontaneous metastases in orthotopic mouse models. A., Sim, S., Okamoto, J., Johnston, D. M., Qian, D., Zabala, M., Bueno, J., Neff, N. F., Wang, J., Shelton, A. Taken together, these data demonstrate that cells within the CD44(+) population of human HNSCC possess the unique properties of cancer stem cells in functional assays for cancer stem cell self-renewal and differentiation and form unique histological microdomains that may aid in cancer diagnosis. To solve this problem, a new generation of tumor-specific, conditionally replicative adenoviruses is being developed. We define cell type signature scores, which allow the inference of cell types that contribute to cell-free RNA for a variety of diseases. DP16-1 cells which were untransfected or co-transfected with wtp53 and bcl-2 displayed characteristics of cells undergoing necrosis. Furthermore, the LTBMCs produced nonadherent colony-forming unit-GM (CFU-GM) for more than 20 weeks. van Weele, L. J., Scheeren, F. A., Cai, S. n., Kuo, A. H., Qian, D. n., Ho, W. H., Clarke, M. F. Single-cell transcriptional diversity is a hallmark of developmental potential. Using model cell lines (NIH-3T3 and CV-1), it was shown that gene transfer rates can be increased by more than an order of magnitude using the same concentration infection medium. Ryan, J. J., Danish, R., Gottlieb, C. A., Clarke, M. F. C-MYB EFFECTS ON KINETIC EVENTS DURING MEL CELL-DIFFERENTIATION. Both fragments formed complexes with electrophoretic mobilities of nucleosomes containing the appropriate length of DNA. Together, these data lay the groundwork for a systemic understanding of the interplay between blood-borne factors and cellular integrity. One such cDNA clone, KT1, was isolated and its nucleotide sequence was determined. This study thus establishes a key RNA-based feature of developmental potential and a platform for delineation of cellular hierarchies. We will discuss the important implications of this mammary tumour stem-cell model. Diehn, M., Cho, R. W., Ailles, L., Lam, J. S., Kaplan, M. J., Somlo, G., Weissman, I. L., Clarke, M. F. Implications of Cancer Stem Cells for Tumor Metastasis. View details for DOI 10.1016/j.cell.2009.07.011, View details for Web of Science ID 000268771900022, View details for PubMedCentralID PMC2731699. View details for Web of Science ID 000255592400041, View details for Web of Science ID 000246136200023.
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