Deficiency in the polycomb family transcriptional repressor Bmi-1 leads to progressive postnatal growth retardation and neurological defects. View details for Web of Science ID 000173193700014. 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. 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. Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J., Clarke, M. F. Mesenchymal tumor cells drive adaptive resistance of Trp53-/- breast tumor cells to inactivated mutant Kras. 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. He wanted to play football in high school, but his mother wouldn't let him, afraid that he would get hurt. CHUCK, A. S., Clarke, M. F., Palsson, B. O. bcl-x(s) gene therapy induces apoptosis of human mammary tumors in nude mice. CD47 is therefore a validated target for cancer therapies. Here we performed single-cell RNA sequencing on 20 organs to reveal cell-type-specific responses to young and aged blood in heterochronic parabiosis. Moreover, the inherent ability of residual CoCSC to generate tumors appears preserved. However, the underlying molecular mechanisms are poorly characterized. This demands a complex crosstalk between extrinsic signals from the microenvironment and the cell-intrinsic regulators of self-renewal. This is the first example of transformation of NIH-3T3 cells by a human onc gene other than c-ras or Blym, as well as the first demonstration of transformation by a human cDNA clone. View details for Web of Science ID 000182853100046. The enhanced cytotoxicity was restricted to antibody-coated tumor cells. B., Alizadeh, A. Discover Michael Clarke 's Biography, Age, Height, Physical Stats, Dating/Affairs, Family and career updates. 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. We examined the effect of this limited adenovirus replication in vitro and in vivo. Here we report that microRNA-30c, a human breast tumour prognostic marker, has a pivotal role in chemoresistance by a direct targeting of the actin-binding protein twinfilin 1, which promotes epithelial-to-mesenchymal transition. Finally, we show how gene expression shifts in distinct tissues are highly correlated with corresponding protein levels in plasma, thus potentially contributing to the ageing of the systemic circulation. In contrast, at least some of these sites were not methylated in DNA from the B-cells expressing high levels of DR alpha mRNA. 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. In approaching the bone marrow culture system, we recognize the critical role that hematopoietic growth factors (HGFs) play in hematopoiesis. First, we quantitatively imaged physiologic remodeling of primary branches of the developing and regenerating mammary tree. Mandel, Michael - Associate Professor: Computer and Information Science Manlow, Veronica B. The molecular mechanisms that limit the proliferation capacity of multipotent progenitors and other more mature progenitors are not fully understood. Dontu, G., Al-Hajj, M., Abdallah, W. A., Clarke, M. F., Wicha, M. S. In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. President Biden has reaffirmed the U.S. commitment to the North Atlantic Treaty Organization (NATO) and collective defense and has stated that a strong European Union is in the U.S. interest. The Bcl-2 protein inhibits apoptosis induced by a variety of signals, in a range of cell types and in diverse organisms, and it is implicated in both normal development and oncogenesis. The United States has always regarded certainly jihadist terrorism . One of these, the goblet cells, contained a distinct cKit/CD117(+) crypt base subpopulation that expressed Dll1, Dll4, and epidermal growth factor, similar to Paneth cells, which were also marked by cKit. All measured metabolic rates increased with increased medium exchange rates and accelerated sharply between exchange rates of 3.5/week and 7/week. View details for Web of Science ID A1995RY96700021. Orhan Eren Akgun. Here, we identify a quiescent mammary epithelial cell population expressing high levels of Bcl11b and located at the interface between luminal and basal cells. We have developed a strategy of limited viral replication using AdRSVlaclys, a chemically modified E1-deleted adenovirus, to codeliver an exogenous plasmid encoding the adenovirus E1 region. The isolation and characterization of these stem cells should help elucidate the molecular pathways that govern normal mammary development and carcinogenesis. Furthermore, we found that the c-myc and bcl-2 genes cooperate to inhibit p53 functions. At the molecular level, Usp16 affects Rspo-mediated phosphorylation of LRP6. Consistent with ROS being critical mediators of ionizing-radiation-induced cell killing, CSCs in these tumours develop less DNA damage and are preferentially spared after irradiation compared to NTCs. We demonstrate that radiation-induced cell death occurs by both p53-dependent and -independent pathways and overexpression of bcl-2 modulates both pathways. View details for Web of Science ID 000345638500001, View details for DOI 10.1158/1538-7445.AM2014-SY12-04, View details for Web of Science ID 000349910205454, View details for Web of Science ID 000351670400001. View details for DOI 10.1016/j.cell.2010.09.046, View details for Web of Science ID 000283052200007. These studies suggest that there is a cancer stem cell compartment in the MMTV-Wnt-1 murine breast tumor and that there is a clinical utility of this model for the study of cancer stem cells. View details for DOI 10.1053/j.gastro.2012.02.006, View details for Web of Science ID 000303113600038, View details for PubMedCentralID PMC3911891. Ailles, L., Prince, M., Joshua, B., Doweck, I., Kaplan, M., Clarke, M., Weissman, I. The N-bGM-CSFs demonstrated GM-CSF receptor specific binding that was displaceable by excess underivatized protein, with the detected fluorescence signal decreasing with increasing biotin to protein molar ratio. Analysis of DNase I cutting of uniquely end-labeled complexes suggests that the fragment containing a single 72-bp element forms a positioned core particle. Russian forces are. Bmi1 is required for the maintenance of adult stem cells in some tissues partly because it represses genes that induce cellular senescence and cell death. View details for DOI 10.1073/pnas.0900089106, View details for Web of Science ID 000270573602118, View details for DOI 10.1007/978-1-60327-087-8_38, View details for Web of Science ID 000267947100039, View details for Web of Science ID 000311099200058. Taken together, these results suggest that Bcl11b acts as acentral intrinsic regulator of mammary epithelial stem cell quiescence and exhaustion and is necessary for long-term maintenance of the mammary gland. HSCs maintain themselves for the lifetime of the organism because of their ability to self-renew. A., Issa, J., Clarke, M. F., Look, A. T. Lobo, N. A., Shimono, Y., Qian, D., Clarke, M. F. Cancer stem cells and radiotherapy: New insights into tumor radioresistance. T47D cells were then transfected with a temperature-sensitive mutant of the tumor suppressor p53 (p53ts). 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. The height of Michael Clarke is in centimeters- 165 cm in meters- 1.65 m in Feet Inches- 5' 5". He has also acted as a reviewer for the EPSRC and for funding councils in Austria, Finland, France and Germany. Here, a systematic approach using bioinformatics and array hybridization techniques to analyze gene expression profiles in HSCs is described. In this episode, Eliot Wilson talks to Professor Michael Clarke, former head of the Royal United Services Institute, about the UK's Integrated Review and how far it represents a break from traditional thinking on our place in the world. Immunohistochemistry revealed that the CD44(+) cancer cells have a primitive cellular morphology and costain with the basal cell marker Cytokeratin 5/14, whereas the CD44(-) cancer cells resemble differentiated squamous epithelium and express the differentiation marker Involucrin. He is member of the Board of Parks Victoria. Hisamori, S., Dalerba, P., Shimono, Y., Rothenberg, M. E., Zabara, M., Cai, S., Qian, D., Clarke, M. F. Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer. Specifically, in the presence of CSC, we identified an increased number of branches, branch points, ducts which have greater than 40 branches (5/33 for CSC and 0/39 for non-CSC), and histological evidence of increased branching. Infection with this vector induced apoptosis in vitro. Analysis of HL-60 cells, a myeloid leukemia line with deletion of the 5q31 region, showed that the CTNNA1 promoter of the retained allele is suppressed by both methylation and histone deacetylation. Patsialou, A., Bravo-Cordero, J. J., Wang, Y., Entenberg, D., Liu, H., Clarke, M., Condeelis, J. S. Intravital multiphoton imaging reveals multicellular streaming as a crucial component of in vivo cell migration in human breast tumors. To see if a limited sampling of tumor tissue from human subjects is a feasible way to gather They were introduced into the E4 region of AdEHT2 and AdEHE2F, respectively. Lee, J. J., Rothenberg, M. E., Seeley, E. S., Zimdahl, B., Kawano, S., Lu, W., Shin, K., Sakata-Kato, T., Chen, J. K., Diehn, M., Clarke, M. F., Beachy, P. A. Pancreatic cancer cells with the CD44(+)CD24(+)ESA(+) phenotype (0.2-0.8% of pancreatic cancer cells) had a 100-fold increased tumorigenic potential compared with nontumorigenic cancer cells, with 50% of animals injected with as few as 100 CD44(+)CD24(+)ESA(+) cells forming tumors that were histologically indistinguishable from the human tumors from which they originated. C-myb, the normal cellular homolog of the retroviral transforming gene v-myb, encodes a nuclear, transcriptional regulatory protein (p75c-myb). At a meeting of the Translation Research Program of the Radiation Therapy Oncology Group held in early 2008, attendees focused on updating the current state of knowledge in cancer stem cell research and discussing ways in which this knowledge can be translated into clinical use across all disease sites. We assessed tumorigenicity using limiting dilution analysis.KIT and KITLG were expressed heterogeneously by a subset of human colon tumors. The calculated molecular weight of RGS18 is 27,610 and the isoelectric point is 8.63. Background The identification of high-risk stage II colon cancers is key to the selection of patients who require adjuvant treatment after surgery. To characterize further the function of these two domains, we demonstrate in this report that the previously described major nuclear localization signal works together with Lys(305)-Arg(306) to form a bipartite and functional nuclear localization sequence (NLS) for p53 nuclear import. Eight (28%) patients are continuously progression-free a median 60 months (range, 31-93) from first ABMT. Tel: +44 (0)131 650 4327. We performed multiplexed single-cell gene expression analysis with quantitative reverse transcriptase polymerase chain reaction followed by hierarchical clustering analysis to characterize distinct cell types. To improve prognosis, patients entered a phase I/II tandem dose-escalation trial of carboplatin (1500-2100 mg/m(2)) and etoposide (1200-2250 mg/m(2)) with ABMT. 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. Kohrt, H. E., Houot, R., Weiskopf, K., Goldstein, M., Lund, P., Scheeren, F., Czerwinski, D., Colevas, A. D., Weng, W., Clarke, M. F., Carlson, R. W., Sunwoo, J., Tedder, T., Chen, L., Levy, R. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Prof Mike Clarke is Professor of Zoology at La Trobe University. Effective treatment of cancer will require therapeutic strategies that are able to target and eliminate this tumorigenic subset of cells. Chen, E. C., Karl, T. A., Kalisky, T., Gupta, S. K., O'Brien, C. A., Longacre, T. A., van de Rijn, M., Quake, S. R., Clarke, M. F., Rothenberg, M. E. miR-142 regulates the tumorigenicity of human breast cancer stem cells through the canonical WNT signaling pathway. Using this system, we have generated AdEHT2 and AdEHE2F, two conditionally replicative adenoviruses for the treatment of breast cancer. Studies of normal and cancer stem cells from the same tissue have shed light on the ontogeny of tumors. Professor William Clarke. A key event in this process is the deregulation of normal self-renewal in these cells. View details for DOI 10.1073/pnas.1212188109, View details for Web of Science ID 000312605600104, View details for PubMedCentralID PMC3528539. Cancers originally develop from normal cells that gain the ability to proliferate aberrantly and eventually turn malignant. A., Patsialou, A., Qian, D., Lin, J., Wen, S., Chang, Y., Bachmann, M. H., Shimono, Y., Dalerba, P., Adorno, M., Lobo, N., Bueno, J., Dirbas, F. M., Goswami, S., Somlo, G., Condeelis, J., Contag, C. H., Gambhir, S. S., Clarke, M. F. Rothenberg, M. E., Clarke, M. F., Diehn, M. DLL4 Blockade Inhibits Tumor Growth and Reduces Tumor-Initiating Cell Frequency. Al-Hajj, M., Becker, M. W., Wichal, M., Weissman, I., Clarke, M. F. Bmi1, stem cells, and senescence regulation. 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. 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. To date, therapies targeting end-stage disease plaques, tangles, or inflammation have limited efficacy. View details for DOI 10.1186/s13058-018-1006-y, View details for Web of Science ID 000447203300001, View details for Web of Science ID 000440602000145, View details for Web of Science ID 000440602000051, View details for DOI 10.1200/JCO.2018.36.4_suppl.683, View details for Web of Science ID 000436174100659. 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. In the accompanying paper it was shown that all T cells producing HTLV, whether cultured from infected persons or infected in vitro, bind a monoclonal antibody (4D12) which recognizes an epitope shared by certain cross-reactive class I major histocompatibility antigens. 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. 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). Patients who do poorly despite ABMT have a mediastinal primary site, true cisplatin-refractory disease, disease progression prior to ABMT, and/or markedly elevated betaHCG at ABMT. View details for Web of Science ID A1991EY27300001. Therefore, infection with this virus preferentially kills estrogen receptor-positive breast cancer cells, or cells growing under hypoxic conditions. We examined such heterogeneity in the small intestine during rotavirus (RV) infection. In contrast to our previous experience, where all such lines expressed T cell markers, these two cell lines expressed B cell antigens and Ig light chains (kappa on CF-2, lambda on HS). Ealovega, M. W., McGinnis, P. K., Sumantran, V. N., Clarke, M. F., Wicha, M. S. A RECOMBINANT BCL-X(S) ADENOVIRUS SELECTIVELY INDUCES APOPTOSIS IN CANCER-CELLS BUT NOT IN NORMAL BONE-MARROW CELLS. Therapeutic Implications of the Cancer Stem Cell Hypothesis, Dysregulated gene expression networks in human acute myelogenous leukemia stem cells. We show that single-cell RNA-seq can be used to perform accurate quantitative transcriptome measurement in individual cells with a relatively small number of sequencing reads and that sequencing large numbers of single cells can recapitulate bulk transcriptome complexity. 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. In addition, wild-type p53 expression also prevented FdUrd-induced DNA double-strand breaks and, unexpectedly, single-strand breaks in parental (mature) DNA. The miR-30c-VIM/TWF1 signaling cascade is also associated with clinical outcome in breast cancer patients. The Department of Adolescent and Young Adult Medicine's multidisciplinary team includes adolescent physicians, clinical nurse consultant, social worker, clinical psychologist, occupational therapist, dietitian and experienced ward nurses. His passion is to see government conservation policy based on the best available. The expression of the KT1 UCR is unique to HUT102. This transcriptomic atlas-which we denote Tabula Muris Senis, or 'Mouse Ageing Cell Atlas'-provides molecular information about how the most important hallmarks of ageing are reflected in a broad range of tissues and cell types. Treatment-related mortality was 10%. The bcl-xs adenovirus vector may prove useful in killing cancer cells contaminating the bone marrow of patients undergoing autologous bone marrow transplantation. Maintain themselves for the treatment of cancer will require therapeutic strategies that are able to target and eliminate this subset... The underlying molecular mechanisms are poorly characterized performed single-cell RNA sequencing on 20 organs reveal! Growth retardation and neurological defects and characterization of these sites were not methylated in from! Clarke is Professor of Zoology at La Trobe University with clinical outcome in breast cancer patients is to see conservation! 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