Results The transcription factor CDX2 ranked first in our screening test. Using 2 independent analyses, we identified multiple pathways that are aberrantly regulated in leukemic stem cells compared with normal HSC. In the validation data set, which included 314 patients, the rate of 5-year disease-free survival was lower among the 38 patients (12.1%) with CDX2 protein-negative colon cancers than among the 276 (87.9%) with CDX2 protein-positive colon cancers (hazard ratio, 2.42; 95% CI, 1.36 to 4.29; P=0.003). 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. LDV infects specifically mouse macrophages and alters immune system and tumor phenotype. Transformed mammary stem or progenitor cells undergo aberrant differentiation processes that result in generation of the phenotypic heterogeneity found in human and rodent breast cancers. Through collaboration, his group pioneered and organized a team to use single cell genomics to understand complex tissue hierarchy in normal and malignant cells present in human breast, colon and head and neck cancer tumors. Professor Clark is someone that should teach all students. 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. Transient overexpression of RGS18 attenuated inositol phosphates production via angiotensin receptor and transcriptional activation through cAMP-responsive element via M1 muscarinic receptor. Pharmacological depletion of ROS scavengers in CSCs markedly decreases their clonogenicity and results in radiosensitization. View details for Web of Science ID A1984SP90200011. Downregulation of Usp16, either by mutation of a single normal Usp16 allele or by short interfering RNAs, largely rescues all of these defects. Programmed cell death (PCD) plays an important role in normal and malignant hematopoieis. View details for Web of Science ID 000075125200067. Our objective was to identify a mouse model of breast cancer stem cells that could have relevance to the study of human breast cancer. 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. Stem cells in normal breast development and breast cancer. 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. Hematopoietic stem cell gene therapy holds the promise of being able to treat a variety of inherited and acquired diseases of the hematopoietic stem cell. Both VIM and TWF1 have been shown to regulate epithelial-to-mesenchymal transition. Scheeren, F. A., Kuo, A. H., van Weele, L. J., Cai, S., Glykofridis, I., Sikandar, S. S., Zabala, M., Qian, D., Lam, J. S., Johnston, D., Volkmer, J. P., Sahoo, D., van de Rijn, M., Dirbas, F. M., Somlo, G., Kalisky, T., Rothenberg, M. E., Quake, S. R., Clarke, M. F. A cell-intrinsic role for TLR2 MYD88 in intestinal and breast epithelia and oncogenesis. Treatment with anti-human DLL4 inhibited the expression of Notch target genes and reduced proliferation of tumor cells. Nuovo ateismo o neo-ateismo, anche nella grafia neoateismo (in inglese New Atheism), una corrente di pensiero che raccoglie le posizioni promosse da alcuni atei del XXI secolo. Free UK delivery for orders 30 and over. 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. Perhaps the most important and useful property of stem cells is that of self-renewal. Han, J. S., Qian, D. L., Wicha, M. S., Clarke, M. F. Targeting cancer cell death with a bcl-x(s) adenovirus. Although major categories of ageing damage have been identified-such as altered intercellular communication, loss of proteostasis and eroded mitochondrial function1-these deleterious processes interact with extraordinary complexity within and between organs, and a comprehensive, whole-organism analysis of ageing dynamics has been lacking. Infection with this vector induced apoptosis in vitro. We hypothesized that if non-tumorigenic cells are more susceptible to chemotherapeutic agents, then residual tumors might be expected to contain a higher frequency of CoCSC.Xenogeneic tumors initiated with CoCSC were allowed to reach approximately 400 mm(3), at which point mice were randomized and chemotherapeutic regimens involving cyclophosphamide or Irinotecan were initiated. While the class is nonetheless challenging, Professor Clark does his best to help all students pass. Control cultures that were exposed to conCM after 4 weeks in culture significantly improved their cell productivity during the latter 4 weeks of culture compared with control. Profiles. Here we describe a method for the rapid incorporation of exogenous promoters into the E1A and E4 regions of the human adenovirus type 5 genome. 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. Park, I. K., He, Y. Q., Lin, F. M., Laerum, O. D., Tian, Q., Bumgarner, R., Klug, C. A., Li, K. J., Kuhr, C., Doyle, M. J., Xie, T., Schummer, M., Sun, Y., GOLDSMITH, A., Clarke, M. F., Weissman, I. L., Hood, L., Li, L. H. A genetic determinant that specifically regulates the frequency of hematopoietic stem cells. 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. The height of Michael Clarke is in centimeters- 165 cm in meters- 1.65 m in Feet Inches- 5' 5". The fragment with a tandem repeat of the 72-bp element also does not associate randomly with histones. He has also acted as a reviewer for the EPSRC and for funding councils in Austria, Finland, France and Germany. 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. 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. Understanding the pathways that regulate proliferation, self-renewal, survival, and differentiation of malignant and normal stem cells may shed light on mechanisms that lead to cancer and suggest better modes of treatment. 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. We have developed an in vitro cultivation system that allows for propagation of human mammary epithelial cells (HMECs) in an undifferentiated state, based on their ability to proliferate in suspension, as nonadherent mammospheres. Zarour, L. R., Anand, S., Billingsley, K. G., Bisson, W. H., Cercek, A., Clarke, M. F., Coussens, L. M., Gast, C. E., Geltzeiler, C. B., Hansen, L., Kelley, K. A., Lopez, C. D., Rana, S. R., Ruhl, R., Tsikitis, V. L., Vaccaro, G. M., Wong, M. H., Mayo, S. C. Role of epithelial to mesenchymal transition associated genes in mammary gland regeneration and breast tumorigenesis. He is so driven about his work and is so charismatic to his students. Only those cells within a tumor that have these two properties are called cancer stem cells. 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. Oncogenesis is a process resulting from genetic events which cause loss of growth control or inhibition of appropriate cell death. Although a major commonly deleted region (CDR) has been delineated on chromosome band 5q31.1 (refs. Usp16 copy number normalization restores normal Wnt activation in Ts65Dn mice models. Here we performed single-cell RNA sequencing on 20 organs to reveal cell-type-specific responses to young and aged blood in heterochronic parabiosis. These findings have important implications for the development and evaluation of oncologic therapies and present opportunities for potential gains in patient outcome. Thus understanding the mechanisms that regulate stem cell generation has implications for normal development and disease. Murine CD18 can be expressed on the cell surface of up to 20% of the mature cells generated by the culture system, suggesting that clinically significant levels of gene transfer may be occurring. On the pathway level, young blood invokes new gene sets in addition to reversing established ageing patterns, with the global rescue of genes encoding electron transport chain subunits pinpointing a prominent role of mitochondrial function in parabiosis-mediated rejuvenation. Furthermore, we identify unique, CSC-specific, remodeling events. 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. This is accompanied by a translocation of the p53 protein from the cytoplasm to the nucleus. Upon inactivation of KrasG12D , tumors initially regress and enter remission. Taken together, these results suggest that USP16 has an important role in antagonizing the self-renewal and/or senescence pathways in Down's syndrome and could serve as an attractive target to ameliorate some of the associated pathologies. These studies suggest that adenovirus suicide vectors may provide a simple and effective method to selectively eliminate cancer cells derived from epithelial tissue that contaminate bone marrow to be used for autologous BMT. The regulation of hematopoietic stem cell (HSC) homeostasis is not well understood. George Malcolm (1917-1997), Pianist, Cembalist, Dirigent und Komponist. We have previously shown that constitutive expression of c-myb blocks differentiation. Here we investigate the roles of these three proteins in the regulation of self-renewal and proliferation of mammary epithelial cells. It has been reported that Lysine-305 is needed for the nuclear import of the p53 protein (Liang et al., 1998). Epigenetic regulation of normal and cancer stem cells, Neurobiology: At the root of brain cancer, Chronic myelogenous leukemia - Identifying the hydra's heads, Therapeutic implications of cancer stem cells. Lower ROS levels in CSCs are associated with increased expression of free radical scavenging systems. Here we describe c-myb-transformed MEL clones which undergo delayed expression of the exogenous c-myb following 3-5 days of culture in DMSO. Analysis of HUT102 DNA shows that one allele of the KT1 UCR is rearranged. Faculty. We discuss possible functional consequences of such nucleosome positioning. This new paradigm of oncogenesis has been validated in a growing list of tumors. Differentially expressed genes were used to generate a 186-gene "invasiveness" gene signature (IGS), which was evaluated for its association with overall survival and metastasis-free survival in patients with breast cancer or other types of cancer.There was a significant association between the IGS and both overall and metastasis-free survival (P<0.001, for both) in patients with breast cancer, which was independent of established clinical and pathological variables. 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. Michael Clarke is a British academic who specialises in defence studies. Available culture systems all have finite and relatively short lifetimes. Disease status (no. Hernandez-Alcoceba, R., Pihalja, M., Qian, D. L., Clarke, M. F. Differential gene expression profiling of adult murine hematopoietic stem cells. The downstream effectors of TLR2 are expressed by normal intestinal and mammary epithelia, including the stem/progenitor cells. 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. View details for Web of Science ID A1992GX27300015. He is a Professor at La Trobe University in Melbourne, Victoria, where he has worked since 1992. From 1990 to 2001 he was the founding Director of the Centre for Defence Studies at King's. The conditional expression of lethal genes in tumor cells is a promising gene therapy approach for the treatment of cancer. 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. Orhan Eren Akgun. Finally, the laboratory is actively pursuing how cancer stem cells self-renew to maintain themselves and escape the genetic constraints on unlimited self-renewal that regulate normal stem cell numbers. 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. These data suggest that the c-myb protooncogene encodes alternately spliced mRNA species with opposing effects on differentiation. These breast tumors are comprised of phenotypically diverse populations of breast cancer cells. The tumorigenic cells displayed stem cell-like properties in that they were capable of generating new tumors containing additional stem cells as well as regenerating the phenotypically mixed populations of non-tumorigenic cells present in the original tumor. 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. In contrast, transplantation of CSC results in changes in the branching patterns of endogenous ducts while non-CSC do not. CD47 mRNA expression levels correlated with a decreased probability of survival for multiple types of cancer. Restoration of CTNNA1 expression in HL-60 cells resulted in reduced proliferation and apoptotic cell death. In one clone, the alternative splicing would generate a predicted myb protein with a three amino acid deletion in the region involved in transcription activation. Herein, we present a discussion around the issues facing treatment of patients with CRCliver metastases, including the relationship of discretegene signatures with prognosis. Temporary expression of wild-type p53 activity in the absence of drug treatment caused some loss of clonogenicity, although the magnitude of this cytotoxic effect was small compared with the level of cell kill obtained by treatment with cytotoxic drugs for similar periods of time, indicating that HT29 cells are not highly sensitive to induction of programmed cell death by wild-type p53. However, to date, genetic modification of the human hematopoietic stem cell has been relatively inefficient. View details for Web of Science ID A1986A778300041. We examined the effect of this limited adenovirus replication in vitro and in vivo. Although new therapeutic regimens developed over the past decade haveincreased survival, there is substantial room for improvement in selecting targeted treatment regimens forthe patients who will derive the most benefit. Recently, various new players that regulate HSC maintenance (e.g. 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. Comparing the expression signature of normal HSC to that of LSC, we identified 3,005 differentially expressed genes. Our data are the first direct visualization and assessment of in vivo migration within a live patient-derived breast xenograft tumor. 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. RADIATION THERAPY ONCOLOGY GROUP TRANSLATIONAL RESEARCH PROGRAM STEM CELL SYMPOSIUM: INCORPORATING STEM CELL HYPOTHESES INTO CLINICAL TRIALS. Pardal, R., Clarke, M. F., Morrison, S. J. Michael Clarke Duncan was born on December 10, 1957 in Chicago, Illinois. Tel: +44 (0)131 650 4327. 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. 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. Here we show that bone marrow cells from mice deficient in three genes genetically downstream of Bmi1--p16Ink4a, p19Arf and Trp53 (triple mutant mice; p16Ink4a and p19Arf are alternative reading frames of the same gene (also called Cdkn2a) that encode different proteins)--have an approximately 10-fold increase in cells able to reconstitute the blood long term. 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