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. To gain a better insight into these processes, here we generate a single-cell transcriptomic atlas across the lifespan of Mus musculus that includes data from 23 tissues and organs. Free UK delivery for orders 30 and over. Available culture systems all have finite and relatively short lifetimes. To date, therapies targeting end-stage disease plaques, tangles, or inflammation have limited efficacy. Here, we report that genetic or pharmacologic Hedgehog pathway inhibition intensifies colon inflammation (colitis) in mice. 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. Together, these data demonstrate a similar yet asynchronous inter- and intra-organ progression of ageing, providing a foundation from which to track systemic sources of declining health at old age. He has also acted as a reviewer for the EPSRC and for funding councils in Austria, Finland, France and Germany. Prior to that he was Professor of Defence Studies at King's College London, and Deputy Vice-Principal for Research Development. The results indicate that locally produced GM-CSF and IL-3 do augment hematopoiesis for several weeks in culture. View details for DOI 10.1146/annurev.med.58.062105.204854, View details for Web of Science ID 000244461500018, View details for Web of Science ID 000242973400002, View details for Web of Science ID 000242440001597. View details for Web of Science ID 000173215900013. Interstitial loss of all or part of the long arm of chromosome 5, or del(5q), is a frequent clonal chromosomal abnormality in human myelodysplastic syndrome (MDS, a preleukemic disorder) and acute myeloid leukemia (AML), and is thought to contribute to the pathogenesis of these diseases by deleting one or more tumor-suppressor genes. Effect of ASXL1 on the stemness of colorectal cancer initiating cells. 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. 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. With noninvasive imaging approaches, as few as 10 cells of stably labeled BCSCs could be tracked in vivo, enabling studies of early tumor growth and spontaneous metastasis. View details for DOI 10.1073/pnas.1212188109, View details for Web of Science ID 000312605600104, View details for PubMedCentralID PMC3528539. In 2007, he became the Director of the Royal United Services Institute. These findings have important implications for the development and evaluation of oncologic therapies and present opportunities for potential gains in patient outcome. View details for DOI 10.1146/annurev.cellbio.22.010305.104154, View details for Web of Science ID 000250896200025. New treatment modalities are needed for the latter group. The miR-30c-VIM/TWF1 signaling cascade is also associated with clinical outcome in breast cancer patients. Morrison, S. J., Qian, D., Jerabek, L., Thiel, B. The p53-independent pathway does not appear to involve apoptosis and occurs at a later time, starting 48 h after X-ray exposure. These breast tumors are comprised of phenotypically diverse populations of breast cancer cells. We performed in vivo imaging of changes in fluorescent, endogenous duct architecture as a metric for remodeling. That signaling pathways such as Bmi1 and Wnt have similar effects in normal and cancer stem cell self-renewal suggests that common molecular pathways regulate both populations. View details for Web of Science ID A1995RC93600007. According to a story Tom Hanks told at. The blocking effect of the CSD is not due to the enhancement of nuclear export or oligomerization of the p53. We have studied the ability of c-myc and bcl-2 oncogenes to modulate p53 function. View details for Web of Science ID 000075125200067. To test this hypothesis, murine erythroleukemia cells were transfected with bcl-XL and p53ts. The ability to prospectively identify tumorigenic cancer cells will facilitate the elucidation of pathways that regulate their growth and survival. HSCs maintain themselves for the lifetime of the organism because of their ability to self-renew. Although a major commonly deleted region (CDR) has been delineated on chromosome band 5q31.1 (refs. - Associate Professor: Business Management These results suggest that LEFTY1 is an endogenous dual-SMAD inhibitor and that suppressing its function may represent a therapeutic vulnerability in breast cancer. A full-length human c-myb cDNA clone has been isolated from a CCRF-CEM leukemia cell cDNA library. 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. Michael Clarke is a British academic who specialises in defence studies. 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. In contrast, C5-bGM-CSF binding above background fluorescence could not be detected using this system, suggesting that this derivative could bind to and activate the receptor, but not simultaneously bind fluorescein-conjugated avidin. Surface markers that displayed intratumor heterogeneous expression among epithelial cancer cells were selected for cell sorting and tumorigenicity experiments. Human breast tumors contain a breast cancer stem cell (BCSC) population with properties reminiscent of normal stem cells. 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. We show that a set of active constituent enhancers, located within the two CD47 SEs, regulate CD47 expression in different cancer cell types and that disruption of CD47 SEs reduces CD47 gene expression. Regulation of the Wnt pathway in stem cells and primary tissues is still poorly understood. Russian forces are. These results demonstrate the feasibility of using continuous perfusion bioreactors as a method of efficiently modifying human hematopoietic stem cells. Gene expression analysis of cells isolated from nonadherent mammospheres revealed overlapping genetic programs with other stem and progenitor cells and identified new markers that may be useful in the identification of mammary stem cells. This apparent paradox is the focus of our interest. To evaluate the feasibility of positron emission tomography (PET) with 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG) in patients with germ cell tumor (GCT) to monitor treatment and differentiate residual masses after chemotherapy.Twenty-six FDG PET studies were performed in 21 patients with GCT, FDG uptake of tumors was interpreted visually, and the lean standardized uptake value (SUVlean) was determined. The ability to self-renew is essential for all kinds of stem cells regardless of tissue type. Orhan Eren Akgun. View details for DOI 10.1073/pnas.1006732107, View details for Web of Science ID 000283184800050, View details for PubMedCentralID PMC2964232. We propose the use of this promoter for transcriptional targeting of breast cancer. Mandel, Michael - Associate Professor: Computer and Information Science Manlow, Veronica B. Sumantran, V. N., Ealovega, M. W., Nunez, G., Clarke, M. F., Wicha, M. S. In vitro expansion of hematopoietic cells for clinical application. Estrogen response elements and hypoxia-responsive elements were combined to activate transcription in cells that present at least one of these characteristics. 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. Lobo, N. A., Zabala, M., Qian, D., Clarke, M. F. Serially transplantable mammary epithelial cells express the Thy-1 antigen. Of five long-term NSGCT survivors, four were treated in first relapse with platinum-sensitive disease. A., Parmiani, G., Castelli, C., Clarke, M. F. Identification of pancreatic cancer stem cells. Disruption of the regulation of self-renewal results in cancer. However, deletions of more than two amino acids between this region abolished the transport of p53 into the nucleus. In approaching the bone marrow culture system, we recognize the critical role that hematopoietic growth factors (HGFs) play in hematopoiesis. 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. Michael W. Clark is the Director of the Center for Business and Economic Research and an Associate Professor of Economics at the University of Kentucky's Gatton College of Business and Economics. This makes it virtually impossible to infect the majority of tumor cells in vivo and results in inadequate gene transfer. Three of these forms co-migrate on Northern blots and are co-expressed in several human hematopoietic cell types. The tumor suppressor protein p53 has been identified as a key regulator of apoptosis in both normal and malignant hematopoietic cells. Schwartz, R. M., Emerson, S. G., Clarke, M. F., Palsson, B. O. BIOTINYLATED GRANULOCYTE MACROPHAGE COLONY-STIMULATING FACTOR ANALOGS - EFFECT OF LINKAGE CHEMISTRY ON ACTIVITY AND BINDING. T-cell lines established from human T-cell leukemia-lymphoma virus associated T-cell neoplasias, in contrast to the T-cell acute lymphocytic leukemia cell lines, expressed both DR antigens and DR alpha mRNA; the HpaII sites within the BglII fragment of DR alpha DNA of these human T-cell leukemia-lymphoma virus-positive T-cell lines were in all cases at least partially unmethylated. He is especially known for his research into the evolution of cooperative breeding in honeyeaters, particularly the genus Manorina and for his work on the response of fauna and flora to wildfire (Clarke 2008, Clarke et al. [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. Michael Clarke was the original drummer of the Byrds, appearing on their first five albums before leaving around the end of 1967.Clarke was the least talented of the five members that were on the Byrds' 1965-1967 recordings, as unlike the others as could be, since he did almost no songwriting. Analysis of patient tumor and matched adjacent normal (nontumor) tissue revealed that CD47 is overexpressed on cancer cells. Ageing is the single greatest cause of disease and death worldwide, and understanding the associated processes could vastly improve quality of life. View details for Web of Science ID A1988L925300043. 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. There was no detectable self-renewal of adult HSCs, indicating a cell autonomous defect in Bmi-1-/- mice. These data suggest that the late fall in c-myb levels may be required in order for differentiation to occur. Rachel Ellehuus. Chemotherapy resistance frequently drives tumour progression. Individually and in combinations, IL-3, GM-CSF, and Epo were added to the culture medium of LTBMCs that were maintained with 50% medium volume exchange per day. We present a simple single tube proximity ligation technique, targeted chromatin ligation, that captures histone modification patterns with only 200 cells. 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. Their scholarship is deepening our understanding of learning while changing policy and practice. 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. Under these conditions, the cultures produced as many cells as were inoculated every 2 weeks and led to a greater than 2.5-fold expansion in terms of the number of nonadherent cells produced over a 6- to 8-week period. Enforced expression of miR-142 or miR-150 in normal mouse mammary stem cells resulted in the regeneration of hyperproliferative mammary glands in vivo. Herein, we present a discussion around the issues facing treatment of patients with CRCliver metastases, including the relationship of discretegene signatures with prognosis. Gene expression analysis of single CD44(+) cells indicated that KIT can promote growth via KITLG autocrine and/or paracrine signaling. Therefore, infection with this virus preferentially kills estrogen receptor-positive breast cancer cells, or cells growing under hypoxic conditions. 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. Together, these data lay the groundwork for a systemic understanding of the interplay between blood-borne factors and cellular integrity. 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. The main focus of this review is the role of mammary stem cells in normal breast development and carcinogenesis. Adjunct Senior Lecturer Dr Michael Williams. This includes loss of a portion of the region involved in transcription activation as well as a separate highly conserved domain. Infection with this vector induced apoptosis in vitro. It has 234 amino acids consisting of a central RGS box and short divergent NH(2) and COOH termini. Isobe, T., Zarneger, M. A., Matsubara, J., Abdel-Wahab, O., Clarke, M. F. Usp16 modulates Wnt signaling in primary tissues through Cdkn2a regulation. Furthermore, the tumorigenic CD44(+) cells differentially express the BMI1 gene, at both the RNA and protein levels. His passion is to see government conservation policy based on the best available. Furthermore, the LTBMCs produced nonadherent colony-forming unit-GM (CFU-GM) for more than 20 weeks. Ryan, J. J., Danish, R., Gottlieb, C. A., Clarke, M. F. C-MYB EFFECTS ON KINETIC EVENTS DURING MEL CELL-DIFFERENTIATION. Wu, A. R., Neff, N. F., Kalisky, T., Dalerba, P., Treutlein, B., Rothenberg, M. E., Mburu, F. M., Mantalas, G. L., Sim, S., Clarke, M. F., Quake, S. R. Oncogenic miRNAs and the perils of losing control of a stem cell's epigenetic identity. Like many epithelial tumors, head and neck squamous cell carcinoma (HNSCC) contains a heterogeneous population of cancer cells. He is member of the Board of Parks Victoria. However, DNA from HTLV-infected lymphocytes cultured for 48 hr (by which time increases in viral RNA expression are evident) did not differ detectably with respect to proviral DNA methylation from uncultured cells, suggesting that the increase in viral RNA expression after short-term culture is mediated by mechanisms independent of changes in DNA methylation. Sci. Using single-cell transcriptomic data, we assessed cell-type-specific manifestations of different hallmarks of ageing-such as senescence3, genomic instability4 and changes in the immune system2. Woodward, W. A., Bristow, R. G., Clarke, M. F., Coppes, R. P., Cristofanilli, M., Duda, D. G., Fike, J. R., Hambardzumyan, D., Hill, R. P., Jordan, C. T., Milas, L., Pajonk, F., Curran, W. J., Dicker, A. P., Chen, Y. 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. Inhibiting USP16 rescues stem cell aging and memory in an Alzheimer's model. He is a Professor at La Trobe University in Melbourne, Victoria, where he has worked since 1992. RRV replication was significantly rescued in IFN types I and II, as well as STAT1 (IFN types I, II, and III) deficient mice in contrast to EW, which was only modestly sensitive to IFNs I and II. Unfortunately, although chemotherapy and/or radiation therapy can sometimes shrink tumors, metastatic cancers of epithelial origin are essentially incurable. The DR alpha genes in both cell lines are hypermethylated relative to the same genes in T-cell lines infected with human T-cell leukemia virus (HTLV) and derived from patients with adult T-cell leukemia/lymphoma (ATL). . Analysis of HUT102 DNA shows that one allele of the KT1 UCR is rearranged. Thus, the predicted transforming product, a protein of 27,281 daltons, may be the actual precursor for normal human platelet-derived growth factor chain A. 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 . Ukraine War: Prof Michael Clarke answers your questions Sky News 6.14M subscribers 1.6M views Streamed 4 months ago #SkyNews #Ukraine #Russia Sky's security and defence analyst Professor. erenakgun@g.harvard.edu. In Down's Syndrome (DS), triplication of Usp16 dampens the activation of the Wnt pathway. 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. This is an overview of the elements and molecules involved in p53 nucleocytoplasmic transportation. View details for Web of Science ID 000178717500001. These cancer stem cells share many characteristics with normal stem cells, including self-renewal and differentiation. 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. 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. Other mutations between Arg-306 and NLS I have no effect on the nuclear import of p53. Programmed cell death (PCD) plays an important role in normal and malignant hematopoieis. Molofsky, A. V., Pardal, R., Iwashita, T., Park, I. K., Clarke, M. F., Morrison, S. J. Bmi-1 is required for maintenance of adult self-renewing hematopoietic stem cells. Self-renewal requires the integration of survival signals and proliferation controls with the maintenance of an undifferentiated state. The efficiency of gene therapy strategies against cancer is limited by the poor distribution of the vectors in the malignant tissues. 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. Cells that expressed kappa- or lambda-light chains were separated by cell sorting from kappa- or lambda-negative cells and replaced in culture. 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. Diehn, M., Cho, R. W., Lobo, N. A., Kalisky, T., Dorie, M. J., Kulp, A. N., Qian, D., Lam, J. S., Ailles, L. E., Wong, M., Joshua, B., Kaplan, M. J., Wapnir, I., Dirbas, F. M., Somlo, G., Garberoglio, C., Paz, B., Shen, J., Lau, S. K., Quake, S. R., Brown, J. M., Weissman, I. L., Clarke, M. F. Long-term haematopoietic reconstitution by Trp53(-/-)p16(Ink4a-/-)p19(Arf-/-) multipotent progenitors. Investigating mechanisms of cancer stern cell radioresistance. The rates of glucose and glutamine consumption and of lactate and ammonia production were measured over exchange schedules ranging from complete medium replacement weekly (1/week) to complete medium replacement daily (7/week). B-cell lines established from two individuals with T-cell acute lymphocytic leukemia (T-ALL) express HLA-DR antigens, whereas the isogenic T-cells do not. This effect was associated with a loss of the G1 specificity of p53-mediated cell cycle arrest. The height of Michael Clarke is in centimeters- 165 cm in meters- 1.65 m in Feet Inches- 5' 5". Furthermore, these approaches are not feasible for primary tumor cells that cannot survive tissue culture conditions or that may change phenotype in rats. Professor Clarke has over 45 years of professional experience with approximately 250 publications and presentations. He was the founding Director of the International Policy Institute at King's College London from 2001-2005 and Head of the School of Social Science and Public Policy at KCL in 2004-05. Most cancers comprise a heterogenous population of cells with marked differences in their proliferative potential as well as the ability to reconstitute the tumor upon transplantation. We screened for genetic polymorphisms that were linked to differences between mouse strains in the numbers of long-term reconstituting HSCs or restricted progenitors in the bone marrow. 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. Overall, we demonstrate a novel approach for imaging physiologic and pathological remodeling. We then determined the effects of intratumoral injection of bcl-xs adenovirus on solid MCF-7 tumors in nude mice. Finally, we show evidence that these properties are maintained in the context of an adenoviral vector (AdEHhrk). Rothenberg, M. E., Nusse, Y., Kalisky, T., Lee, J. J., Dalerba, P., Scheeren, F., Lobo, N., Kulkarni, S., Sim, S., Qian, D., Beachy, P. A., Pasricha, P. J., Quake, S. R., Clarke, M. F. Single-cell dissection of transcriptional heterogeneity in human colon tumors. Expression of BMI1, a known regulator of stem cell self-renewal, was modulated by miR-200c. In contrast, AdEHE2F was attenuated in nontransformed quiescent cells growing under normoxic conditions, suggesting that an intact pRB pathway with low levels of E2F transcription factors acts as a negative modulator for the virus. He is an adviser to two Parliamentary Committees and Associate Director of the Strategy and Security Institute at the University of Exeter. View details for Web of Science ID 000169201800006. Our data suggest that CSC interact with the microenvironment differently than non-CSC, and that this could eventually be a therapeutic approach for targeting CSC. Microarray analysis comparing Thy1+CD24+ tumor cells to not-Thy1+CD24+ cells identified a list of differentially expressed genes. View details for DOI 10.1016/j.stem.2013.06.012. These analogues were compared to determine the effect of biotinylation on biological activity and GM-CSF receptor binding characteristics. His course "Justice" is the first Harvard course to be made freely available online and on television. View details for DOI 10.1038/s41586-018-0590-4, View details for DOI 10.1126/science.aal3485, View details for Web of Science ID 000399540100053. Stem cells generate the differentiated cell types within many organs throughout the lifespan of an organism and are thus ultimately responsible for the longevity of multicellular organisms. View details for Web of Science ID A1991GR93700016. Receptor tyrosine kinase (RTK) inhibitors have advanced colon cancer treatment. Effective treatment of cancer will require therapeutic strategies that are able to target and eliminate this tumorigenic subset of cells. Differences in self-renewal pathways between normal and malignant stem cells could be targeted by new therapeutic agents to eliminate cancer stem cells. Biological activity and GM-CSF receptor binding characteristics in both normal and malignant hematopoieis for. 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