In bone marrow, RGS18 level is highest in long-term and short-term hematopoietic stem cells, and is decreased as they differentiate into more committed multiple progenitors. To date, therapies targeting end-stage disease plaques, tangles, or inflammation have limited efficacy. Rachel Ellehuus. This demonstrates that there are distinct genetic determinants of the frequencies of HSCs and restricted progenitors in vivo. Research Expertise and Interests 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. 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. To determine the role of these proteins in maintaining cancer cell viability, an adenovirus vector that expresses bcl-xs, a functional inhibitor of these proteins, was constructed. This is an overview of the elements and molecules involved in p53 nucleocytoplasmic transportation. Limiting dilution transplantations of breast epithelial cells devoid of TLR2 or MYD88 revealed a significant decrease in mammary repopulating unit frequency compared with the control. Schott, A. F., Apel, I. J., Nunez, G., Clarke, M. F. BCL-2 PROTECTS MURINE ERYTHROLEUKEMIA-CELLS FROM P53-DEPENDENT AND -INDEPENDENT RADIATION-INDUCED CELL-DEATH. View details for DOI 10.1158/0008-5472.CAN-06-2030, View details for Web of Science ID 000244137300026. The cumulative data provide the foundation for an atlas of transcriptomic cell biology. To direct the replication of the virus to breast cancer, we have considered one characteristic present in a great proportion of these cancers, which is the expression of estrogen receptors (ERs). 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. This new model for cancer will have significant ramifications for the way we study and treat cancer. In both breast cancers and central nervous system tumors, cancer cells differ in their ability to form tumors. The molecular mechanisms that control the self-renewal of HSCs are still largely unknown. Here, we show that human breast tumor biomarker miR-30c regulates invasion by targeting the cytoskeleton network genes encoding twinfilin 1 (TWF1) and vimentin (VIM). An interleukin-6 family member, interleukin-11 is identified as a secondary target of twinfilin 1 in the microRNA-30c signalling pathway. The tumors that arose from purified CD44(+) cells reproduced the original tumor heterogeneity and could be serially passaged, thus demonstrating the two defining properties of stem cells: ability to self-renew and to differentiate. Morrison, S. J., Qian, D., Jerabek, L., Thiel, B. Transplanted fetal liver and bone marrow cells obtained from Bmi-1-/- mice were able to contribute only transiently to haematopoiesis. Therefore, senescence of stem cells must be prevented. Clarke, M. F., Westin, E., Schmidt, D., Josephs, S. F., Ratner, L., WONGSTAAL, F., Gallo, R. C., Reitz, M. S. IDENTIFICATION OF THE HUMAN T-CELL LYMPHOMA VIRUS IN B-CELL LINES ESTABLISHED FROM PATIENTS WITH ADULT T-CELL LEUKEMIA. 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. Office Hours: Tuesday 12:00-1:00PM; Thursday 2:00-3:00PM; Friday 10:30-11:30AM. Professor Michael Clarke is a Fellow of King's College London. A subpopulation of tumor cells, termed cancer stem cells (CSC), appears uniquely able to fuel the growth of phenotypically and histologically diverse tumors. Although wild-type p53 is expressed in virtually all neuroblastoma tumors, treatment failures secondary to inadequate local control with radiotherapy are a problem in patients with advanced stage disease. In many cases, one of these abnormalities is an inhibition of PCD, which provides a selective advantage for tumor cells. Human tumors where evidence of cancer stem cells has been published include tumors of the breast, brain, pancreas, head and neck, and colon. A., Li, Q., Mahmoudabadi, G., McGeever, A., Olivieri, J. E., Park, M., Ravikumar, N., Stanley, G., Tan, W., Tarashansky, A. J., Vanheusden, R., Wang, P., Wang, S., Xing, G., Xu, C., Yosef, N., Culver, R., Dethlefsen, L., Ho, P., Liu, S., Maltzman, J. S., Metzger, R. J., Sasagawa, K., Sinha, R., Song, H., Wang, B., Artandi, S. E., Beachy, P. A., Clarke, M. F., Giudice, L. C., Huang, F. W., Huang, K. C., Idoyaga, J., Kim, S. K., Kuo, C. S., Nguyen, P., Rando, T. A., Red-Horse, K., Reiter, J., Relman, D. A., Sonnenburg, J. L., Wu, A., Wu, S. M., Wyss-Coray, T. Molecular hallmarks of heterochronic parabiosis at single-cell resolution. Like many epithelial tumors, head and neck squamous cell carcinoma (HNSCC) contains a heterogeneous population of cancer cells. Comparison of IRF3 and NF-B induction in STAT1(-/-) mice revealed that murine but not simian RRV mediated accumulation of IkB- protein and decreased transcription of NF-B-dependent genes. We investigated the existence of colonic Paneth-like cells that have a distinct transcriptional signature and support Lgr5(+) stem cells.We used multicolor fluorescence-activated cell sorting to isolate different subregions of colon crypts, based on known markers, from dissociated colonic epithelium of mice. Identification of a novel microRNA-mediated pathway that regulates chemoresistance in breast cancer will facilitate the development of novel therapeutic strategies. This tumorigenic cell population could be identified prospectively and consistently had definable and identical phenotype. 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. IL-10 function is required for the full protective effect of small-molecule Hedgehog pathway activation in colitis; this pharmacologic augmentation of Hedgehog pathway activity and stromal IL-10 expression are associated with increased presence of CD4(+)Foxp3(+) regulatory T cells. In addition, through targeting the cancer stem cell and its dysregulated self-renewal, our therapies for treating cancer are likely to improve. When purified from Matrigel contaminated LDV(+) tumors, sorted human breast tumor cells, as well as tumors grown from sorted cells, were shown to be LDV-free, as tested by PCR. 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. 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. Mini Bio (1) Michael Clarke Duncan was born on December 10, 1957 in Chicago, Illinois. These studies show that the human retrovirus HTLV, which has been demonstrated to be associated with certain T cell malignancies, can infect B cells or B cell precursors. 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. He wanted to play football in high school, but his mother wouldn't let him, afraid that he would get hurt. We confirm that CSC drive tumorigenesis, suggesting a link between CSC and remodeling. identify miR-22 as both a repressor of TET proteins and a powerful oncogene in the mammary epithelium and hematopoietic system. View details for DOI 10.1016/j.stem.2007.08.012, View details for Web of Science ID 000251055200003. We propose the use of this promoter for transcriptional targeting of breast cancer. These data suggest that the c-myb protooncogene encodes alternately spliced mRNA species with opposing effects on differentiation. 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). RNA splicing programs define tissue compartments and cell types at single-cell resolution. c-sis gene expression has been demonstrated in a variety of human tumors, although generally at levels much lower than those shown to transform cells in vitro. To delineate more accurately the point at which Myb blocks differentiation, MEL cells were transfected with a human c-myb construct under the control of the beta-globin promoter and enhancers. 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. We focused our analysis of gene expression on RNA from primitive leukemia-initiating cells, which harbor 5q deletions, and analyzed 12 genes within the CDR that are expressed by normal hematopoietic 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. Although the existence of mammary stem cells has been suggested by serial transplantation studies in mice, their identification has been hindered by the lack of specific surface markers, and by the absence of suitable in vitro assays for testing stem cell properties: self-renewal and ability to generate differentiated progeny. 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. View details for DOI 10.1073/pnas.1006732107, View details for Web of Science ID 000283184800050, View details for PubMedCentralID PMC2964232. Lower concentrations of ETYA (5 x 10(-6) M), which had no effect on the respiratory burst of phagocytosing alveolar macrophages, also inhibited arachidonic acid metabolism. This sequential antibody strategy, combining a tumor-targeting antibody with a second antibody that activates the host innate immune system, may improve the therapeutic effects of antibodies against breast cancer and other HER2-expressing tumors. 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. Thus, we reveal USP16 as a novel target in an AD model that can both ameliorate the NPC defect and rescue memory and learning through its regulation of both Cdkn2a and BMP signaling.'. View details for Web of Science ID 000089592300005. This suggests RGS18 can act on G(q)-mediated signaling pathways in vivo. View details for DOI 10.1038/s41586-022-04461-2. View details for Web of Science ID A1995RP92400014. It has been viewed by tens of millions of people around the world, including in China, where Sandel was named the "most . Poorly regulated tissue remodeling results in increased breast cancer risk, yet how breast cancer stem cells (CSC) participate in remodeling is unknown. The regulation of hematopoietic stem cell (HSC) homeostasis is not well understood. The Thy-1-CD24medCD49fhigh phenotype contains a rare progenitor population that is able to form primary mammary outgrowths with significantly decreased serial in vivo transplantation potential.CONCLUSIONS: Therefore, Thy-1 expression in the immature cell compartment is a useful tool to study the functional heterogeneity that drives mammary gland development and has implications for disease etiology. Professor Michael Clarke is a British security analyst. bcl-x is a member of the bcl-2 family of genes and by alternative splicing gives rise to two distinct mRNAs: bcl-xL and bcl-xS. View details for Web of Science ID A1984TC73000037. A better understanding of the molecular mechanisms underlying metastasis is needed to develop more effective treatments. View details for DOI 10.1056/NEJMoa1506597, View details for Web of Science ID 000368404800006, View details for PubMedCentralID PMC4784450. Therefore, functional inhibition of Bcl-2 family members is lethal to many cancer cells. Published Oct. 2, 2020 Updated Oct. 5, 2020. This genetic signature of tumorigenic breast-cancer cells was even more strongly associated with clinical outcomes when combined with the WR signature in breast cancer. 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. Professor Michael Clarke said that sending soldiers to take Kyiv was 'massively foolish' and could become a 'peak Putin' moment that leads eventually to his downfall. Using 2 independent analyses, we identified multiple pathways that are aberrantly regulated in leukemic stem cells compared with normal HSC. http://med.stanford.edu/profiles/, Position:Assoc Director, Stanford Institute for Stem Cell & Regenerative Medicine, Biopsy of Human Tumors for Cancer Stem Cell Characterization: a Feasibility Study. 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. Park, I. K., Qian, D. L., Kiel, M., Becker, M. W., Pihalja, M., Weissman, I. L., Morrison, S. J., Clarke, M. F. Prospective identification of tumorigenic breast cancer cells. To determine the mechanism, by which this virus spares normal hematopoietic cells, we isolated normal mouse hematopoietic stem cells and infected them with an adenovirus that contains a beta-galactosidase minigene. Tumors injected four times with the bcl-xs adenovirus showed a 50% reduction in size. View details for Web of Science ID A1991FC72500007. Okamoto, T., Reitz, M. S., Clarke, M. F., JAGODZINSKI, L. J., WONGSTAAL, F. Sequence-specific interaction of histones with the simian virus 40 enhancer region in vitro. Furthermore, we found that the c-myc and bcl-2 genes cooperate to inhibit p53 functions. ANGELOTTI, T. P., Clarke, M. F., Longino, M. A., Emerson, S. G. THE CONSTRUCTION OF HIGH-EFFICIENCY HUMAN BONE-MARROW TISSUE EXVIVO. In spite of substantial differences in the extent of methylation of class I-related genes, no obvious differences exist among these cell types in their levels of expression of HLA-A and -B antigens. The tight regulation of E1A expression correlated with the ability of these viruses to replicate and kill human cancer cells that express estrogen receptors, or are maintained under hypoxic conditions. School of Civil Engineering +61 7 336 56464. william.clarke@uq.edu.au. According to this second scenario, tumors act as caricatures of their corresponding normal tissues and are sustained in their growth by a pathological counterpart of normal adult stem cells, cancer stem cells. In this report we explore the role of Bcl-XL overexpression in protecting cancer cells from p53-mediated apoptosis. This phenotypic diversity is driven by a small subset of mammary tumour stem cells. 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. View details for Web of Science ID 000182853100046. This study demonstrates that combining global gene expression analysis with detailed annotated pathway resources applied to highly enriched normal and malignant stem cell populations, can yield an understanding of the critical pathways regulating cancer stem cells. View details for Web of Science ID 000169201800006. In order to better understand HSC self-renewal, we need to understand how these pathways are coordinated. The height of Michael Clarke is in centimeters- 165 cm in meters- 1.65 m in Feet Inches- 5' 5". These pathways are commonly repressed in cancer, suggesting a mechanism by which early progenitor cells could gain the ability to self-renew and become malignant with further oncogenic mutations. 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. Filter By. We found that each antibody inhibited tumor growth and that the combination of the two antibodies was more effective than either alone. The reasons for the limited longevity are unknown. T47D cells were then transfected with a temperature-sensitive mutant of the tumor suppressor p53 (p53ts). Interestingly, exposure to DMSO leads to an alteration of the protein conformation of the p53 mutant to one recognized by a wild-type specific monoclonal antibody. His laboratory is pursuing the identification of cancer stem cells in other tumors so that they can be studied. This technology may provide a solution to the need for a high sensitivity, rapid, and automated ChIP assay, and in doing so facilitate the use of ChIP for many interesting and valuable applications. In breast cancer, while a subset of cells with epithelial and mesenchymal phenotypes have stem cell activity, in many cells that have lost epithelial characteristics with increased expression of mesenchymal genes, have decreased tumor-initiating capacity and plasticity. 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. View details for DOI 10.1038/s41586-020-2496-1, View details for Web of Science ID 000485326200019, View details for DOI 10.1158/1538-7445.SABCS18-SY17-02, View details for Web of Science ID 000488129901140, View details for Web of Science ID 000453773601250. . Alzheimer's disease (AD) is a progressive neurodegenerative disease observed with aging that represents the most common form of dementia. 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. These findings have important implications for the development and evaluation of oncologic therapies and present opportunities for potential gains in patient outcome. His course "Justice" is the first Harvard course to be made freely available online and on television. He also carries out research into the cellular responses to anti-cancer drugs. 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. Here we performed bulk RNA sequencing of 17 organs and plasma proteomics at 10 ages across the lifespan of Mus musculus, and integrated these findings with data from the accompanying Tabula Muris Senis2-or 'Mouse Ageing Cell Atlas'-which follows on from the original Tabula Muris3. Here we show that the short half-lives of retroviruses limit the distance that they can effectively travel in solution by Brownian motion, and thus the possibility of successful gene transfer. 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). War in Ukraine 2022: Prof. Michael Clarke analysis 116 videos 3,380 views Updated 5 days ago Defence and security analyst Professor Michael Clarke's observations mostly on Sky News. When combined with the prognostic criteria of the National Institutes of Health, the IGS was used to stratify patients with high-risk early breast cancer into prognostic categories (good or poor); among patients with a good prognosis, the 10-year rate of metastasis-free survival was 81%, and among those with a poor prognosis, it was 57%. 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 We have developed a new in vitro culture system that permits, for the first time, the propagation of mammary stem and progenitor cells in an undifferentiated state, which should facilitate the elucidation of pathways that regulate normal mammary stem-cell self-renewal and differentiation. 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