Office Hours: Tuesday 12:00-1:00PM; Thursday 2:00-3:00PM; Friday 10:30-11:30AM. View details for DOI 10.1038/s41586-022-04461-2. They were introduced into the E4 region of AdEHT2 and AdEHE2F, respectively. Dr. Jim Clarke is an Adjunct Professor of Civil and Environmental Engineering and an Adjunct Professor of Earth and Environmental Sciences at Vanderbilt University. Human T cell lymphoma proviral (HTLV) sequences were demonstrated in both cell lines. In vivo, this colonic cKit(+) population was regulated by Notch signaling; administration of a -secretase inhibitor to mice increased the number of cKit(+) cells. Using an ELISA assay which quantitates DNA damage, we demonstrate that this sensitization is due to apoptosis, suggesting the therapeutic utility of targeting this pathway. 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. When viability was measured 24 h post-radiation, cells that had been briefly exposed to wtp53 immediately after X-ray irradiation had decreased survival as compared to unirradiated cells expressing wtp53 or X-ray irradiated DP16-1 cells. In 2007, he became the Director of the Royal United Services Institute. Thus, loss of expression of the alpha-catenin tumor suppressor in hematopoietic stem cells may provide a growth advantage that contributes to human MDS or AML with del(5q). View details for Web of Science ID 000345777300014. Anaesthesia 2001, 56(5), 486-487. In vitro, blockade of CD47 signaling using targeted monoclonal antibodies enabled macrophage phagocytosis of tumor cells that were otherwise protected. Cai, S., Kalisky, T., Sahoo, D., Dalerba, P., Feng, W., Lin, Y., Qian, D., Kong, A., Yu, J., Wang, F., Chen, E. Y., Scheeren, F. A., Kuo, A. H., Sikandar, S. S., Hisamori, S., van Weele, L. J., Heiser, D., Sim, S., Lam, J., Quake, S., Clarke, M. F. Targeted chromatin ligation, a robust epigenetic profiling technique for small cell numbers. Emerson, S. G., Palsson, B. O., Clarke, M. F. INFLUENCE OF MEDIUM EXCHANGE SCHEDULES ON METABOLIC, GROWTH, AND GM-CSF SECRETION RATES OF GENETICALLY ENGINEERED NIH-3T3 CELLS. The human RGS18 ortholog has a tissue-specific expression pattern similar to that of mouse RGS18. 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. 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. Until 2001 he was Deputy Vice-Principal and Director for Research Development at King's College London, where he remains a Visiting Professor of Defence Studies. In this issue of Cell Stem Cell, Hermann et al. In the absence of Bmi-1, the cyclin-dependent kinase inhibitor gene p16Ink4a is upregulated in neural stem cells, reducing the rate of proliferation. 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. Biography. Hematopoietic stem cells (HSCs) have self-renewal capacity and multilineage developmental potentials. Isobe, T., Zarnegar, M. A., Abdel-Wahab, O., Clarke, M. F. A CD47-associated super-enhancer links pro-inflammatory signalling to CD47 upregulation in breast cancer. Usp16 copy number normalization restores normal Wnt activation in Ts65Dn mice models. Zhao, C., Cai, S., Shin, K., Lim, A., Kalisky, T., Lu, W., Clarke, M. F., Beachy, P. A. Many of these mutations affect cell proliferation and survival. We conclude therefore that the inhibition of oxygen consumption and superoxide production by ETYA at 2 x 10(-5) M is unrelated to inhibition of arachidonic acid metabolism. Clones with various levels of c-sis expression were generated by transfecting NIH 3T3 cells with a plasmid that expressed the human c-sis cDNA and the TN5 neomycin-resistance gene. This demands a complex crosstalk between extrinsic signals from the microenvironment and the cell-intrinsic regulators of self-renewal. The results demonstrate that cell sorting is effective, much faster and less likely to alter tumor cell phenotype than traditional methods for removing LDV from xenograft models. BMI1 has been demonstrated to play a role in self-renewal in other stem cell types and to be involved in tumorigenesis. In 2007, he became the Director of the Royal United Services Institute. CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer. Biography. The tumorigenic subpopulation could be serially passaged: each time cells within this population generated new tumors containing additional CD44(+)CD24(-/low)Lineage(-) tumorigenic cells as well as the phenotypically diverse mixed populations of nontumorigenic cells present in the initial tumor. Xenograft tumors were grown from control and KIT-knockdown DLD1 and UM-COLON#8 cells in immunocompromised mice and compared. Stem cells in normal breast development and breast cancer. 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. DNA fragments containing either one or both of the 72-base pair (bp) elements which constitute the SV40 enhancer and the three adjacent 21-bp repeats were associated with histone octomers from chicken erythrocytes in vitro. Patients with relapsed/ refractory testicular cancer benefit most from ABMT if they have platinum-sensitive disease in first relapse. Purified RGS18 interacts with the alpha subunit of both G(i) and G(q) subfamilies. View details for DOI 10.1038/s41586-020-2499-y. View details for DOI 10.1016/j.stem.2016.11.007, View details for PubMedCentralID PMC5341693. 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. In six of seven tumors examined, Thy1+CD24+ cancer cells, which constituted approximately 1%-4% of tumor cells, were highly enriched for cells capable of regenerating new tumors compared with cells of the tumor that did not fit this profile ("not-Thy1+CD24+"). Sequences within this region were identical to those previously determined for the exons of the normal human c-sis gene. Gene profiling experiments have revealed similarities between cancer and embryonic stem (ES) cells. (2007) analyze the relationship between CSC and tumor metastasis. Ryan, J. J., Prochownik, E., Gottlieb, C. A., Apel, I. J., Merino, R., Nunez, G., Clarke, M. F. CELL-CYCLE ANALYSIS OF P53-INDUCED CELL-DEATH IN MURINE ERYTHROLEUKEMIA-CELLS. The hair color is Light brown and the eye color is Blue. Background The identification of high-risk stage II colon cancers is key to the selection of patients who require adjuvant treatment after surgery. In concert with endogenous DMSO-induced globin transcription during MEL cell differentiation, the beta-globin c-myb transcription unit of the transfected plasmid is activated after 3-5 days of culture in media containing DMSO. The retrovirus transduced culture continued to produce genetically modified hematopoietic progenitors for up to 6 weeks, the duration of the culture period. We demonstrate that radiation-induced cell death occurs by both p53-dependent and -independent pathways and overexpression of bcl-2 modulates both pathways. In addition, through targeting the cancer stem cell and its dysregulated self-renewal, our therapies for treating cancer are likely to improve. Recently, it has become apparent that some oncogenes and tumor suppressor genes also regulate self-renewal, the process by which stem cells maintain themselves. The IGS was also associated with the prognosis in medulloblastoma (P=0.004), lung cancer (P=0.03), and prostate cancer (P=0.01). Conversely, genetic augmentation of Hedgehog response and systemic small-molecule Hedgehog pathway activation potently ameliorate colitis and restrain initiation and progression of colitis-induced adenocarcinoma. Restoration of CTNNA1 expression in HL-60 cells resulted in reduced proliferation and apoptotic cell death. 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. Heights. Although a major commonly deleted region (CDR) has been delineated on chromosome band 5q31.1 (refs. 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. More. 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. 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. 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. Only those cells within a tumor that have these two properties are called cancer stem cells. These included transcription factors, signaling molecules, and previously unknown genes. They discuss the increasing threat of China, the post-Brexit identity of "Global Britain" and how the . The Thy-1+CD24medCD49fhigh phenotype contained the majority of the serially transplantable epithelial cells. A central question in cancer biology is, which cells can be transformed to form tumors? He is so driven about his work and is so charismatic to his students. This concept was first demonstrated in the study of leukemia where only cells with specific surface antigen profiles were able to cause leukemia when engrafted into immunodeficient mice. We examined such heterogeneity in the small intestine during rotavirus (RV) infection. 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. 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. In contrast to cells in G1, cells cultured at 32.5 degrees C for prolonged periods during S phase and G2/M, and then returned to 37.5 degrees C, did not become committed to cell death. We review the biological basis and the therapeutic implications of the stem cell model of cancer. Park, I. K., Morrison, S. J., Clarke, M. F. Applying the principles of stem-cell biology to cancer. Here, a systematic approach using bioinformatics and array hybridization techniques to analyze gene expression profiles in HSCs is described. 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? The nucleotide sequence of a transforming human c-sis complementary DNA shows an open reading frame 723 base pairs in length located downstream from an in-phase terminator thymine-guanine-adenine codon. Upon inactivation of KrasG12D , tumors initially regress and enter remission. Rather than terminally differentiating, these cells are induced to undergo apoptosis. 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. The existence of CSCs mandates careful analysis and comparison of normal tissue stem cells and CSCs to identify differences between the two cell types. 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. We identify two distinct super-enhancers (SEs) associated with CD47 in certain cancer cell types. 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. Gene expression analysis of single CD44(+) cells indicated that KIT can promote growth via KITLG autocrine and/or paracrine signaling. This tumorigenic cell population could be identified prospectively and consistently had definable and identical phenotype. Trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2; also known as HER-2/neu), is indicated for the treatment of women with either early stage or metastatic HER2(+) breast cancer. Although many tumor cell lines undergo apoptosis when p53 is expressed, the T47D transfectants remained viable at temperatures permitting wild-type p53 phenotype. These results suggest that LEFTY1 is an endogenous dual-SMAD inhibitor and that suppressing its function may represent a therapeutic vulnerability in breast cancer. This promoter induces transcriptional activation of the E1a and E4 units in response to estrogens in cells that express the ERs. View details for Web of Science ID A1984SY22400007. A., Park, I. K., Ford, P. S., Kiel, M. J., Schork, N. J., Weissman, I. L., Clarke, M. F. Stem cells, cancer, and cancer stem cells. Although data have been provided to support this theory in human blood, brain, and breast cancers, the identity of pancreatic cancer stem cells has not been determined. Enforced expression of miR-142 or miR-150 in normal mouse mammary stem cells resulted in the regeneration of hyperproliferative mammary glands in vivo. Furthermore, the oxygenation of arachidonic acid requires little of the oxygen consumed by phagocytosing alveolar macrophages. At the molecular level, Usp16 affects Rspo-mediated phosphorylation of LRP6. HSCs have the ability to self-renew, while MPP cells have lost the capacity for self-renewal. KIT Signaling Promotes Growth of Colon Xenograft Tumors in Mice and Is Up-Regulated in a Subset of Human Colon Cancers. Differences in self-renewal pathways between normal and malignant stem cells could be targeted by new therapeutic agents to eliminate cancer stem cells. Pagination. Disclosure of potential conflicts of interest is found at the end of this article. These results suggest that Bcl-2 family members are required for survival of cancer cells derived from solid 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. Hernandez-Alcoceba, R., Pihalja, M., Nunez, G., Clarke, M. F. Molecular cloning and characterization of a novel regulator of G-protein signaling from mouse hematopoietic stem cells. The presence of the concentrated conditioned medium (conCM) enhanced the production of nonadherent cells three-fold compared with control over an eight week culture period. The wild-type p53/GFP fusion protein was localized in the cytoplasm, the nucleus, or both compartments in a subset of the cells. He was Director General of the Royal United Services Institute from 2017-2015 and is now a Distinguished Fellow at RUSI. Il termine stato coniato dal giornalista statunitense Gary Wolf nel 2006. A better understanding of the molecular mechanisms underlying metastasis is needed to develop more effective treatments. Microarray-based multigene-expression signatures derived from stem cells and progenitor cells hold promise, but they are difficult to use in clinical practice. Similar to TWF1, VIM also regulates F-actin formation, a key component of cellular transition to a more invasive mesenchymal phenotype. The possible significance of this finding is discussed. To better understand the molecular basis of radiation-induced cell death, we studied the role of the bcl-2 oncogene and the p53 tumor suppressor gene in this process. Further study with ETYA showed that the inhibitor at 2 x 10(-5) M had little effect on uptake of 125I-labeled zymosan but did abolish the conversion of 14C-arachidonic acid to a compound that co-migrated with authentic 12-HETE on silica gel plates. These cancerous cells then grow clonally into tumors and eventually have the potential to metastasize. A growing body of evidence indicates that subpopulations of cancer stem cells (CSCs) drive and maintain many types of human malignancies. View details for Web of Science ID 000072317400002. Han, J. S., Nunez, G., Wicha, M. S., Clarke, M. F. Prevention of fluorodeoxyuridine-induced cytotoxicity and DNA damage in HT29 colon carcinoma cells by conditional expression of wild-type p53 phenotype. Individual phenotypic cancer cell subsets were purified, and their tumor-initiating properties were investigated by injection in NOD/SCID mice. 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. Data from individual tumor phenotypic analysis and serial transplants performed in limiting dilution show that residual tumors are enriched for cells with the CoCSC phenotype and have increased tumorigenic cell frequency. These results validate the stem cell working model in human CRC and provide a highly robust surface marker profile for CRC stem cell isolation. 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. 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. Prior to that he was Professor of Defence Studies at King's College London, and Deputy Vice-Principal for Research Development. View details for DOI 10.1073/pnas.1006732107, View details for Web of Science ID 000283184800050, View details for PubMedCentralID PMC2964232. Component of cellular transition to a more invasive mesenchymal phenotype death occurs by both p53-dependent and -independent and... 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