The metabolism of oxygen, although central to life, produces reactive oxygen species (ROS) that have been implicated in processes as diverse as cancer, cardiovascular disease and ageing. In order to better understand HSC self-renewal, we need to understand how these pathways are coordinated. 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. View details for DOI 10.1007/s10549-012-2346-4, View details for Web of Science ID 000313201100005, View details for PubMedCentralID PMC3583223. Current page 1; Page 2; Down's syndrome results from full or partial trisomy of chromosome 21. Furthermore, we identify unique, CSC-specific, remodeling events. In this study we describe the effect on murine erythroleukemia cells, transfected with a temperature-sensitive mutant p53, of exposure to the differentiating agent dimethylsulfoxide (DMSO). Lobo, N., Zabala, M., Qian, D., Clarke, M. F. The DLK1-DIO3 imprinted region regulates long-term proliferation in normal and malignant breast epithelium. This system allows one round of viral replication. 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. Stem cells in many tissues sustain themselves by entering a quiescent state to avoid genomic insults and to prevent exhaustion caused by excessive proliferation. 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. Also, HTLV can be transmitted in vitro to cord blood T-lymphocytes. - Associate Professor: Business Management Akala, O. O., Park, I., Qian, D., Pihalja, M., Becker, M. W., Clarke, M. F. A gene signature in breast cancer - Reply. Stimulation of trastuzumab-activated human NK cells with an agonistic mAb specific for CD137 killed breast cancer cells (including an intrinsically trastuzumab-resistant cell line) more efficiently both in vitro and in vivo in xenotransplant models of human breast cancer, including one using a human primary breast tumor. The reasons for the limited longevity are unknown. Here we describe a method for the rapid incorporation of exogenous promoters into the E1A and E4 regions of the human adenovirus type 5 genome. Adams, S., Upadhyaya, G., Clarke, M. F., Emerson, S. G. CONSTITUTIVE EXPRESSION OF A C-MYB CDNA BLOCKS FRIEND MURINE ERYTHROLEUKEMIA CELL-DIFFERENTIATION. Resistance to apoptosis plays an important role in tumors that are refractory to chemotherapy. Restricted neural progenitors from the gut and forebrain proliferate normally in the absence of Bmi-1. Here we show that bone marrow cells from mice deficient in three genes genetically downstream of Bmi1--p16Ink4a, p19Arf and Trp53 (triple mutant mice; p16Ink4a and p19Arf are alternative reading frames of the same gene (also called Cdkn2a) that encode different proteins)--have an approximately 10-fold increase in cells able to reconstitute the blood long term. Synchronized cells allowed to pass out of G1 prior to being placed at 32.5 degrees C continued to cycle until subsequently arrested in G1; loss of viability occurred following G1 arrest. Alzheimer's disease (AD) is a progressive neurodegenerative disease observed with aging that represents the most common form of dementia. To solve this problem, a new generation of tumor-specific, conditionally replicative adenoviruses is being developed. Some mice were given the RTK inhibitor imatinib after injection of cancer cells; tumor growth was measured based on bioluminescence. Treatment-related mortality was 10%. The reduced self-renewal of Bmi-1-deficient neural stem cells leads to their postnatal depletion. CD47, a "don't eat me" signal for phagocytic cells, is expressed on the surface of all human solid tumor cells. Hoey, T., Yen, W., Axelrod, F., Basi, J., Donigian, L., Dylla, S., Fitch-Bruhns, M., Lazetic, S., Park, I., Sato, A., Satyal, S., Wang, X., Clarke, M. F., Lewicki, J., Gurney, A. Published algorithms for automatic cell annotation are limited to known cell types and fail to capture novel populations, especially cancer cells. The p53-independent pathway does not appear to involve apoptosis and occurs at a later time, starting 48 h after X-ray exposure. View details for DOI 10.1073/pnas.1006732107, View details for Web of Science ID 000283184800050, View details for PubMedCentralID PMC2964232. We used Bcl-XS, a dominant negative inhibitor of Bcl-2 and Bcl-XL, to demonstrate the role of these genes in modulating chemotherapy-induced apoptosis. 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. identify miR-22 as both a repressor of TET proteins and a powerful oncogene in the mammary epithelium and hematopoietic system. B., Byrne, A., Chen, M., Dehghannasiri, R., Gayoso, A., Granados, A. In this issue of Cancer Cell, Inoue et al. 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%. 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. While cell lines expressing p53 alone rapidly died, those cells co-expressing Bcl-XL survived. Deletion of MYD88 or TLR2 in the intestinal epithelium markedly reduces DSS-induced colitis regeneration and spontaneous tumour development in mice. The miR-30c-VIM/TWF1 signaling cascade is also associated with clinical outcome in breast cancer patients. Cell migration is an essential component of almost every step of the metastatic cascade, especially the early step of invasion inside the primary tumor. 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. Liu, H., Bockhorn, J., Dalton, R., Chang, Y., Qian, D., Zitzow, L. A., Clarke, M. F., Greene, G. L. Identification of miRNAs that regulate breast cancer stem cells and spontaneous metastases in orthotopic mouse models. Gain- and loss-of-function studies show that Bcl11b induces cells to enter the G0 phase of the cell cycle and become quiescent. Analysis of patient tumor and matched adjacent normal (nontumor) tissue revealed that CD47 is overexpressed on cancer cells. The successful ex vivo reconstruction of human bone marrow is an extraordinarily important basic scientific and clinical goal. We present a simple single tube proximity ligation technique, targeted chromatin ligation, that captures histone modification patterns with only 200 cells. This cell line contains a wild-type p53 gene and is an ideal model for studying the mechanism of IR resistance in this disease. PHD Student in Computer Science. 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. 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 tumorigenic cell population could be identified prospectively and consistently had definable and identical phenotype. 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. Oncolytic adenoviruses with restricted replication can be produced if the expression of crucial transcription units of the virus is controlled by tissue- or tumor-specific promoters. This raises the issue of whether there is a conserved mechanism to effect self-renewing divisions. Mandel, Michael - Associate Professor: Computer and Information Science Manlow, Veronica B. His laboratory is pursuing the identification of cancer stem cells in other tumors so that they can be studied. One of the best candidate genes involved in conferring self-renewal capacity is Bmi-1, which has been proven to be essential for the maintenance of both normal adult hematopoietic and leukemia stem cells, as well as adult neural stem cells. As we continue to advance clinically and technologically in the field of colorectal tumor biology, ourgoal should be continuedrefinement of predictive and prognostic studiesto decrease recurrence after curative resection and minimize treatment toxicity to patients through a tailoredmultidisciplinary approach to cancer care. Liu, T. X., Becker, M. W., Jelinek, J., Wu, W., Deng, M., Mikhalkevich, N., Hsu, K., Bloomfield, C. D., Stone, R. M., DeAngelo, D. J., Galinsky, I. My research is located in three overlapping fields: (a) linguistic and cultural transfer from Mediterranean Antiquity to the medieval European vernaculars; (b) comparative study of epic and heroic narrative traditions, especially in Greek, Latin, and Babylonian, and of their Celtic and Germanic successors and analogues; (c) semantic Paneth cells contribute to the small intestinal niche of Lgr5(+) stem cells. Taken together, these results show that c-myb acts very late in the process of differentiation. These cancer stem cells share many characteristics with normal stem cells, including self-renewal and differentiation. In recent years solid tumors were studied utilizing similar techniques in mice. 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. 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. In contrast, at least some of these sites were not methylated in DNA from the B-cells expressing high levels of DR alpha mRNA. 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. 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. Amy Smith Berylson Professor of Materials Science and Professor of Chemistry & Chemical Biology. He was, from 1990 to 2001, the founding Director of the Centre for Defence Studies (CDS) at King's. He was appointed as Professor of Defence Studies in 1995. 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. View details for Web of Science ID 000168861600008. MMTV-Wnt-1 breast tumors were harvested, dissociated into single-cell suspensions, and sorted by flow cytometry on Thy1, CD24, and CD45. List A-Z. Here, we report the results of using a bioreactor system to expand hematopoietic cells after a brief retrovirus infection using a high titer, replication defective virus encoding for murine CD18. Majetl, R., Becker, M. W., Tian, Q., Lee, T. M., Yan, X., Liu, R., Chiang, J., Hood, L., Clarke, M. F., Weissman, I. L. Identification of Conserved Gene Expression Programs in Epithelial Cancer Stem Cells. Treatment with anti-human DLL4 inhibited the expression of Notch target genes and reduced proliferation of tumor cells. RADIATION THERAPY ONCOLOGY GROUP TRANSLATIONAL RESEARCH PROGRAM STEM CELL SYMPOSIUM: INCORPORATING STEM CELL HYPOTHESES INTO CLINICAL TRIALS. Professor Michael Clarke was Director-General of the Royal United Services Institute (RUSI) from 2007 to 2015 when he retired from that role. Box 270211 Rochester, NY 14627. Metastasis remains a significant challenge in treating cancer. The results indicate that locally produced GM-CSF and IL-3 do augment hematopoiesis for several weeks in culture. This apparent paradox is the focus of our interest. To see if a limited sampling of tumor tissue from human subjects is a feasible way to gather Major conclusions of the symposium were that the flow cytometry of multiple markers in fresh tissue would remain the standard technique of evaluating cancer-initiating cells and that surrogates need to be developed for both experimental and clinical use. Cell surface GM-CSF receptor binding was characterized by the binding of the analogues to human neutrophils, with detection by fluorescein-conjugated avidin and fluorescence-activated cell sorting. 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. The rapid medium exchange combined with the addition of human hematopoietic CSFs significantly enhances the proliferation and differentiation of LTBMCs. In some cancer cells, the process of self-renewal is de-regulated resulting in expansion of these cells and tumors. Modulation of p53 function is of interest, therefore, both in understanding the control of apoptosis and as a potential therapeutic intervention. View details for DOI 10.1056/NEJMc1602584, View details for PubMedCentralID PMC4955394. A gene expression analysis revealed that the expression of stem cell associated genes, cell survival genes, transcription factors, and genes modulating proliferation including p16Ink4a and p19Arf was altered in bone marrow cells of the Bmi-1-/- mice. The results of in vitro GTPase single-turnover assays using Galpha(i) indicated that RGS18 accelerates the intrinsic GTPase activity of Galpha(i). We have previously investigated the expression of Bcl-x in neuroblastoma (NB) cell lines and have shown that Bcl-xL is expressed and functions to inhibit chemotherapy-induced apoptosis. Associate Professor of Instruction; PhD. Increased levels of Bcl-XL were found in a subset of primary human breast carcinomas, as well as in the breast cancer line, T47D. 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. Here we performed single-cell RNA sequencing on 20 organs to reveal cell-type-specific responses to young and aged blood in heterochronic parabiosis. 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. Adjunct Senior Lecturer Dr Michael Williams. 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, to reveal mechanisms by which different neoplastic cells generate this dominant 'don't eat me' signal, we analyse the CD47 regulatory genomic landscape. The effect of these changes on protein function is currently unknown. Both KrasG12D -dependent and KrasG12D -independent tumors display a high level of genomic instability, and KrasG12D -independent tumors harbor numerous amplified genes that can activate the MAPK/ERK signaling pathway. 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. It has recently been shown that central nervous system stem cells and haematopoietic stem cells and early progenitors contain lower levels of ROS than their more mature progeny, and that these differences are critical for maintaining stem cell function. View details for Web of Science ID 000072317400002. To investigate the possible role of Bmi-1 in other cell types that also self-renew, we generated Bmi-1-green fluorescent protein (GFP)-knock-in mice, in which GFP was expressed under the endogenous transcriptional regulatory elements of the Bmi-1 gene. This effect is the same as that of Lys-305 mutation. DP16-1 cells which were untransfected or co-transfected with wtp53 and bcl-2 displayed characteristics of cells undergoing necrosis. INGRAHAM, L. M., Weening, R. S., Clarke, M. F., Boxer, L. A., Baehner, R. L. Freeman Spogli Institute for International Studies, Institute for Computational and Mathematical Engineering (ICME), Institute for Human-Centered Artificial Intelligence (HAI), Institute for Stem Cell Biology and Regenerative Medicine, Stanford Institute for Economic Policy Research (SIEPR), Stanford Woods Institute for the Environment, Office of VP for University Human Resources, Office of Vice President for Business Affairs and Chief Financial Officer, Directed Reading in Stem Cell Biology and Regenerative Medicine, Stem Cell Biology and Regenerative Medicine (Phd Program), DOI 10.1146/annurev.cellbio.22.010305.104154. He is so driven about his work and is so charismatic to his students. View details for DOI 10.1158/0008-5472.CAN-06-2030, View details for Web of Science ID 000244137300026. These cancerous cells then grow clonally into tumors and eventually have the potential to metastasize. A., Jones, R. C., Nicolis di Robilant, B. n., Nong, R. Y., Norton, J. Cancer stem cells and tumor metastasis: First steps into uncharted territory, Bmi-1-green fluorescent protein-knock-in mice reveal the dynamic regulation of Bmi-1 expression in normal and leukemic hematopoietic cells. This will allow the characterization of crucial signaling pathways involved in processes such as self-renewal that are critical for tumor formation by the cancer cells within de novo tumors. Hematopoietic stem cells (HSCs) have self-renewal capacity and multilineage developmental potentials. Bcl-2 displayed characteristics of cells undergoing necrosis to enter the G0 phase of the cell cycle and quiescent... R., Gayoso, A., Granados, a or co-transfected with wtp53 and Bcl-2 displayed of... For several weeks in culture DOI 10.1158/0008-5472.CAN-06-2030, View details for PubMedCentralID PMC3583223 Bcl-2 and Bcl-XL, to the. Genomic insults and to prevent exhaustion caused by excessive proliferation some mice were given RTK... 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