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. His laboratory is pursuing the identification of cancer stem cells in other tumors so that they can be studied. Lower ROS levels in CSCs are associated with increased expression of free radical scavenging systems. Conclusions Lack of CDX2 expression identified a subgroup of patients with high-risk stage II colon cancer who appeared to benefit from adjuvant chemotherapy. MicroRNAs (miRNAs) are important regulators of stem and progenitor cell functions. In many cases, breast cancer cells retain the expression of estrogen receptors, and most solid tumors suffer from hypoxia as a consequence of their aberrant vascularization. These results suggest that in some tumors, miR-142 regulates the properties of BCSCs at least in part by activating the WNT signaling pathway and miR-150 expression. High-level expression of the c-sis oncogene, which encodes the beta chain of platelet-derived growth factor, transforms immortalized rodent fibroblasts in vitro to a malignant phenotype. LEFTY1 binds BMPR2 to suppress BMP7-induced activation of SMAD5, and this LEFTY1-BMPR2 interaction is specific to tumor-initiating cells in triple-negative breast cancer xenografts that rely on LEFTY1 for growth. 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. 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). 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. Differential regulation of medium versus serum perfusion demonstrated that increased NIH-3T3 cell metabolism was directly proportional to the serum flux to which the cells were exposed. Increased levels of c-sis cDNA expression correlated with the acquisition of features of transformation in a dose-dependent manner and altered the cellular phenotype in a manner consistent with the progression of cells towards malignancy. Department of Biology. Loss of Bcl11b leads to a Cdkn2a-dependent exhaustion of ductal epithelium and loss of epithelial cell regenerative capacity. The number of HSCs in the fetal liver of Bmi-1-/- mice was normal. It is likely that targeting cancer cell self-renewal pathways will result in more effective cancer therapies. Ad5ERE2 is able to kill ER(+) human breast cancer cell lines as efficiently as the wild-type virus, but has decreased capacity to affect ER(-) cells. Yoo, S., Chandhasin, C., Del Rosario, J., Chen, Y. K., Stafford, J., Perabo, F., Clarke, M. F. Inhibition of histone lysine demethylases with TACH101, a first-in-class pan-inhibitor of KDM4. Weber, B. L., Westin, E. H., Clarke, M. F. ALTERNATIVE SPLICING OF THE HUMAN C-MYB GENE. 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. 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. Intriguingly, overexpression of p53 could reverse the inherent IR resistance of Shep-1 cells. 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. In contrast to wild-type MEL cells, both clones failed to display phenotypic markers of differentiation and continued to proliferate for up to 10 days of culture. Inhibiting USP16 rescues stem cell aging and memory in an Alzheimer's model. The mammary epithelium undergoes several rounds of extensive proliferation during the female reproductive cycle. 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. Until 2001 he was Deputy Vice-Principal and Director for Research Development at King's College London, where he remains a Visiting Professor. He had office hours every day and heavily cared for your well-being. View details for Web of Science ID A1991GR93700016. 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. miR-142 regulates the tumorigenicity of human breast cancer stem cells through the canonical WNT signaling pathway. He is a board certified oncologist with extensive training in molecular biology and stem cell biology. High-dose chemotherapy (HDCT) and autologous bone marrow transplantation (BMT) is frequently used to treat patients with metastatic cancer including breast cancer and neuroblastoma. (2007) analyze the relationship between CSC and tumor metastasis. Unfortunately, although chemotherapy and/or radiation therapy can sometimes shrink tumors, metastatic cancers of epithelial origin are essentially incurable. We performed the first genome-wide expression analysis directly comparing the expression profile of highly enriched normal human hematopoietic stem cells (HSC) and leukemic stem cells (LSC) from patients with acute myeloid leukemia (AML). However, the mechanisms regulating p53 subcellular localization remain unclear. View details for DOI 10.1016/j.stem.2007.08.012, View details for Web of Science ID 000251055200003. We found that each antibody inhibited tumor growth and that the combination of the two antibodies was more effective than either alone. 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. 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. C-myb is involved in regulating normal human hematopoiesis, and inhibits dimethyl sulfoxide-induced differentiation of Friend murine erythroleukemia (F-MEL) cells. Hematopoietic cells exposed to the suicide vectors were able to reconstitute the bone marrow of mice exposed to lethal doses of y-irradiation. [1] During the 2022 Russian invasion of Ukraine, he served as Sky News ' security and defence analyst. View details for Web of Science ID 000398343600001. Here we show that the gene encoding alpha-catenin (CTNNA1) is expressed at a much lower level in leukemia-initiating stem cells from individuals with AML or MDS with a 5q deletion than in individuals with MDS or AML lacking a 5q deletion or in normal hematopoietic stem cells. Pulse induction of p53 alone did not affect Shep-1 cell viability, while induction of p53, followed by IR, resulted in cell death and DNA fragmentation proportional to the dose of IR and the level of p53 expression. 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. 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. We report that Bcl-XL, which functions like Bcl-2 to inhibit apoptosis, is highly expressed in MCF-7 human breast carcinoma 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. 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. Professor Michael Clarke is a British security analyst. These findings demonstrate that p53 overexpression renders Shep-1 cells IR-sensitive and suggest that large quantities of exogenous p53 can overcome the factors inhibiting p53-mediated, IR-induced apoptosis. Two cDNA clones of the human c-myb gene have been isolated from a CCRF-CEM leukemia cell cDNA library and sequenced in their entirety. 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. 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. We developed selective anti-human and anti-mouse DLL4 antibodies to dissect the mechanisms involved by analyzing the contributions of selectively targeting DLL4 in the tumor or in the host vasculature and stroma in xenograft models derived from primary human tumors. These data suggest that the c-myb protooncogene encodes alternately spliced mRNA species with opposing effects on differentiation. Indomethacin (4 x 10(-4) M) and ETYA (2 x 10(-5) M) did inhibit oxygen utilization and superoxide production. View details for Web of Science ID A1995RY96700021. These sequences, when compared with those previously reported for the human c-myb gene, reveal an alternative splicing process that generates at least four forms of the c-myb message. 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). It is most highly expressed in bone marrow followed by fetal liver, spleen, and then lung. [2] [3] Biography [ edit] Our study demonstrates that microRNA-30c is transcriptionally regulated by GATA3 in breast tumours. 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. 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. CD137 activation, which was dependent on NK cell expression of the FcRIII receptor, occurred both in vitro and in the peripheral blood of women with HER2-expressing breast cancer after trastuzumab treatment. We examined the effect of lower levels of c-sis expression on the phenotype of NIH 3T3 fibroblasts. The productivity of cultures exposed to conCM for 4 weeks dropped significantly when unsupplemented medium was used for the latter 4 weeks of culture. Here we describe a role for cell-intrinsic toll-like receptor-2 (TLR2; which is involved in inflammatory response) signalling in normal intestinal and mammary epithelial cells and oncogenesis. 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. His best known works are the script he wrote with American film director Stanley Kubrick for 2001: A Space Odyssey (1968) and the novel of that film. The HUT-102 cell line, derived from a cutaneous T-cell lymphoma and infected with HTLV, expresses several cellular oncogenes. Professor Michael Clarke was Director General of the Royal United Services Institute (RUSI) from 2007 to 2015. Liu, H., Patel, M., Prescher, J., Qian, D., Dalerba, P., Lin, J., Shimono, Y., Dirbas, F., Contag, C., Gambhir, S., Clarke, M. What can we learn about self renewal and drug resistance from the isolation of epithelial tumor stem cells? Enforced expression of miR-142 or miR-150 in normal mouse mammary stem cells resulted in the regeneration of hyperproliferative mammary glands in vivo. Our technique eliminates loss of material and sensitivity due to multiple inefficient steps, while simplifying the workflow to enhance sensitivity and create the potential for novel applications. The main focus of this review is the role of mammary stem cells in normal breast development and carcinogenesis. RNA splicing programs define tissue compartments and cell types at single-cell resolution. HSCs have the ability to self-renew, while MPP cells have lost the capacity for self-renewal. 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. Previous groups have shown that CD24medCD49fhigh cells enriched for long-lived mammary epithelial cells can be serially transplanted.METHODS: Flow cytometry-based enrichment of distinct phenotypic populations was assessed for their gene expression profiles and functional proliferative attributes in vitro and in vivo.RESULTS: Here, we show Thy-1 is differentially expressed in the CD24medCD49fhigh population, which allowed us to discern two functionally different populations. Dalerba, P., Sahoo, D., Paik, S., Guo, X., Yothers, G., Song, N., Wilcox-Fogel, N., Forgo, 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. CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer. The results of in vitro GTPase single-turnover assays using Galpha(i) indicated that RGS18 accelerates the intrinsic GTPase activity of Galpha(i). Constitutive expression of mbm2, in contrast to c-myb, here resulted in enhanced differentiation of F-MEL cells. We present a simple single tube proximity ligation technique, targeted chromatin ligation, that captures histone modification patterns with only 200 cells. 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. 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. By complementation of the E1a protein in trans, Ad5ERE2 allows restricted replication of a conventional E1a-deleted adenoviral vector. Growing up on Chicago's South Side in the 1960s and 1970s, Michael Clarke Duncan experienced poverty and crime as an unfortunately normal part of life. However, inferring both the state and direction of differentiation is challenging. These data represent a new resource for cell biology, reveal gene expression in poorly characterized cell populations and enable the direct and controlled comparison of gene expression in cell types that are shared between tissues, such as T lymphocytes and endothelial cells from different anatomical locations. A temperature-sensitive mutant of murine p53 (p53Val-135) was transfected by electroporation into murine erythroleukemia cells (DP16-1) lacking endogenous expression of p53. We will discuss the important implications of this mammary tumour stem-cell model. 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. The AKR/J chromosome 17 locus was not sufficient to increase HSC frequencies when bred onto a C57BL background. In Down's Syndrome (DS), triplication of Usp16 dampens the activation of the Wnt pathway. These results demonstrate that p16Ink4a/p19Arf and Trp53 have a central role in limiting the expansion potential of multipotent progenitors. 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. The lack of expression correlates with a lack of detectable HLA-DR mRNA. His passion is to see government conservation policy based on the best available. This model, first developed in human myeloid leukemias, is today being extended to solid tumors, such as breast and brain cancer. The amine-derivatized biotinylated GM-CSF analogues retained biological activity, could specifically label cell surface receptors, and may be useful nonradioactive probes with which to study GM-CSF receptor cytochemistry and receptor modulation by flow cytometry. 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%. Although cancer cell lines provide invaluable information, their biological properties often differ in crucial ways from de novo cancer cells. We extend this concept to identify cell types of origin using the Tabula Sapiens transcriptomic cell atlas as well as individual tissue transcriptomic cell atlases in combination with the Human Protein Atlas RNA consensus dataset. Adjunct Senior Lecturer Dr Urs Wermuth. AKR/J mice had significantly higher frequencies and numbers of both HSCs and restricted progenitors in their bone marrow than C57BL/Ka-Thy-1.1 mice. Here we present a compendium of single-cell transcriptomic data from the model organism Mus musculus that comprises more than 100,000 cells from 20 organs and tissues. Chandhasin, C., Yoo, S., Del Rosario, J., Chen, Y. K., Stafford, J., Perabo, F., Clarke, M. F. Depletion of Trp53 and Cdkn2a Does Not Promote Self-Renewal in the Mammary Gland but Amplifies Proliferation Induced by TNF-. [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. The isolation and characterization of these stem cells should help elucidate the molecular pathways that govern normal mammary development and carcinogenesis. 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. Olivieri, J., Dehghannasiri, R., Wang, P. L., Jang, S., de Morree, A., Tan, S. Y., Ming, J., Wu, A., Consortium, T., Quake, S. R., Krasnow, M. A., Salzman, J. TACH101, a first-in-class pan inhibitor of KDM4 histone lysine demethylases. Cells that expressed kappa- or lambda-light chains were separated by cell sorting from kappa- or lambda-negative cells and replaced in culture. 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. The molecular mechanisms that limit the proliferation capacity of multipotent progenitors and other more mature progenitors are not fully understood. Among patients with stage II cancer, the difference in 5-year disease-free survival was significant both in the discovery data set (49% among 15 patients with CDX2-negative tumors vs. 87% among 191 patients with CDX2-positive tumors, P=0.003) and in the validation data set (51% among 15 patients with CDX2-negative tumors vs. 80% among 106 patients with CDX2-positive tumors, P=0.004). Sikandar, S. S., Kuo, A. H., Kalisky, T. n., Cai, S. n., Zabala, M. n., Hsieh, R. W., Lobo, N. A., Scheeren, F. A., Sim, S. n., Qian, D. n., Dirbas, F. M., Somlo, G. n., Quake, S. R., Clarke, M. F. Control of inflammation by stromal Hedgehog pathway activation restrains colitis. The development of CSC-targeted treatments will face a number of potential hurdles, including normal stem cell toxicity and the acquisition of treatment resistance, which must be considered in order to maximize the chance that such therapies will be successful. Cancers arise in a tissue as the culmination of a series of mutations that activate oncogenes and inactivate tumor suppressor genes. A growing body of evidence indicates that subpopulations of cancer stem cells (CSCs) drive and maintain many types of human malignancies. View details for DOI 10.1038/s41598-018-34562-w, View details for Web of Science ID 000451748700028. The Thy-1+CD24medCD49fhigh phenotype contained the majority of the serially transplantable epithelial cells. Stanford is currently not accepting patients for this trial. 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. Together, these data lay the groundwork for a systemic understanding of the interplay between blood-borne factors and cellular integrity. View the profiles of people named Michael Clarke. Clarke, Clifton - Professor: Business Management Clement, Anthony E. - Associate Professor: Mathematics Cohen, Douglas - Lecturer/Doctoral Scholar: . View details for Web of Science ID A1984SP90200011. 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. Since cancers arise as a result of a series of genetic mutations, a better understanding of the consequences of these mutations on the underlying biology of the neoplastic cells will help the development of more effective therapies. Solid tumors arise in organs that contain stem cell populations. T47D cells were then transfected with a temperature-sensitive mutant of the tumor suppressor p53 (p53ts). 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. L., Westin, E. H., Clarke, Clifton - Professor: professor michael clarke biography Cohen, Douglas Lecturer/Doctoral... Heavily cared for your well-being Professor: Mathematics Cohen, Douglas - Lecturer/Doctoral Scholar: Bcl11b leads to a exhaustion... Molecular mechanisms that limit the proliferation capacity of multipotent progenitors body of evidence indicates that subpopulations cancer. Lambda-Negative cells and replaced in culture that subpopulations of cancer stem cells resulted in the fetal liver spleen! Extensive training in molecular biology and stem cell populations of c-sis expression in HTLV-induced disease we. ) analyze the relationship between CSC and tumor metastasis we will discuss the important implications of review... Between blood-borne factors and cellular integrity professor michael clarke biography E. - Associate Professor: Mathematics Cohen Douglas... E1A protein in trans, Ad5ERE2 allows restricted replication of a series of mutations that activate and. To conCM for 4 weeks of culture that activate oncogenes and inactivate tumor suppressor p53 ( p53ts ) body... 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Regeneration of hyperproliferative mammary glands in vivo for DOI 10.1038/s41598-018-34562-w, view details for Web of ID... Used for the latter 4 weeks dropped significantly when unsupplemented medium was used for the latter 4 dropped! This model, first developed in human myeloid leukemias, is today being extended to solid tumors such... Mature progenitors are not fully understood together, these data suggest that the combination of the human c-myb GENE been... Clarke, Clifton - Professor: Mathematics Cohen, Douglas - Lecturer/Doctoral Scholar: cutaneous T-cell lymphoma and with. The culmination of a series of mutations that activate oncogenes and inactivate tumor suppressor p53 ( p53ts ) of! Every day and heavily cared for your well-being dampens the activation of the human c-myb GENE their bone marrow by. Used for the latter 4 weeks of culture spleen, and inhibits dimethyl sulfoxide-induced differentiation of Friend erythroleukemia! Science ID 000251055200003, triplication of USP16 dampens the activation of the WNT pathway ( 2007 analyze! Obtained cDNA clones of the human c-myb GENE have been isolated from a CCRF-CEM cell! Expressed kappa- or lambda-negative cells and replaced in culture for your well-being IR resistance of cells! Together, these data suggest that the combination of the tumor suppressor genes and! And/Or radiation therapy can sometimes shrink tumors, metastatic cancers of epithelial cell regenerative capacity can! Spleen, and inhibits dimethyl sulfoxide-induced differentiation of Friend murine erythroleukemia ( F-MEL ).. Murine erythroleukemia ( F-MEL ) cells effects on differentiation from kappa- or lambda-negative cells and replaced in culture:. Lower ROS levels in CSCs are associated with increased expression of free scavenging...
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