We assessed tumorigenicity using limiting dilution analysis.KIT and KITLG were expressed heterogeneously by a subset of human colon tumors. Clarke, M. F., Dick, J. E., Dirks, P. B., Eaves, C. J., Jamieson, C. H., Jones, D. L., Visvader, J., Weissman, I. L., Wahl, G. M. A self-renewal assay for cancer stem cells. This suggests RGS18 can act on G(q)-mediated signaling pathways in vivo. HSCs maintain themselves for the lifetime of the organism because of their ability to self-renew. BMI1 has been demonstrated to play a role in self-renewal in other stem cell types and to be involved in tumorigenesis. Rachel Ellehuus. A panel of NB cell lines (CHP-382, GOTO, SHEP-1, SHSY-5Y, and GI-CA-N) were infected with either a bcl-xS adenovirus (pAdRSV-bcl-xS) or a control virus (pAdRSV-lac-z). Multiple cell lines expressing variable levels of exogenous temperature-sensitive p53 were generated. Sufficient new cells have to be produced to maintain the integrity of a tissue, but excessive proliferation resulting in tumorigenesis needs to be prevented. patients) at transplant: primary refractory disease (six), first relapse (10), second relapse (eight), third relapse (five). Overall, we demonstrate a novel approach for imaging physiologic and pathological remodeling. Intravital multiphoton imaging reveals multicellular streaming as a crucial component of in vivo cell migration in human breast tumors. By complementation of the E1a protein in trans, Ad5ERE2 allows restricted replication of a conventional E1a-deleted adenoviral vector. 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. View details for DOI 10.1056/NEJMc1602584, View details for PubMedCentralID PMC4955394. While cell lines expressing p53 alone rapidly died, those cells co-expressing Bcl-XL survived. Our study demonstrates that microRNA-30c is transcriptionally regulated by GATA3 in breast tumours. Specifically, in the presence of CSC, we identified an increased number of branches, branch points, ducts which have greater than 40 branches (5/33 for CSC and 0/39 for non-CSC), and histological evidence of increased branching. Reinitz, F., Chen, E. Y., Nicolis di Robilant, B., Chuluun, B., Antony, J., Jones, R. C., Gubbi, N., Lee, K., Ho, W. H., Kolluru, S. S., Qian, D., Adorno, M., Piltti, K., Anderson, A., Monje, M., Heller, H. C., Quake, S. R., Clarke, M. F. LEFTY1 Is a Dual-SMAD Inhibitor that Promotes Mammary Progenitor Growth and Tumorigenesis. Direct visualization of human tumor cells in vivo shows two patterns of high-speed migration inside primary tumors: (1) single cells and (2) multicellular streams (i.e., cells following each other in a single file but without cohesive cell junctions). High transduction rates could be obtained even in the absence of polycations, such as Polybrene, which heretofore have been required to achieve reasonable transduction rates. View details for Web of Science ID 000072317400002. Il termine stato coniato dal giornalista statunitense Gary Wolf nel 2006. 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). Dr. Jim Clarke is an Adjunct Professor of Civil and Environmental Engineering and an Adjunct Professor of Earth and Environmental Sciences at Vanderbilt University. The prognostic power of the IGS was increased when combined with the wound-response (WR) signature.The IGS is strongly associated with metastasis-free survival and overall survival for four different types of tumors. 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? More. The data are consistent with formation of a core particle on one or the other of the repeated enhancer sequences. View details for DOI 10.1016/j.patbio.2006.01.004, View details for Web of Science ID 000236287600008. 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 . Following high-dose IR, cell fractionation demonstrated that p53 is induced and targeted to the nucleus. The complexity and inefficiency of chromatin immunoprecipitation strategies restrict their sensitivity and application when examining rare cell populations. Thus, Bmi-1 dependence distinguishes stem cell self-renewal from restricted progenitor proliferation in these tissues. Parsels, L. A., Zellars, R. C., Loney, T. L., Parsels, J. D., Clarke, M. F., MERCHANT, A. K., Lawrence, T. S., Maybaum, J. Bcl-x(s) enhances adenoviral vector-induced apoptosis in neuroblastoma 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. A., Stelzer, Y., Luong, A. V., Isobe, T., Zarnegar, M. A., Watanabe, N., Antonana, S., Lam, J., Qian, D., Sikandar, S. S., Kuo, A. H., Heitink, L. S., Shimono, Y., Scheeren, F. A., Cai, S., Hisamori, S., Sahoo, D., Dirbas, F. M., Somlo, G., Jaenisch, R., Christina, C., Clarke, M. F. Characterizing the role of the nuclear coactivator AIB1 in triple-negative breast cancer. 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. Herrema I, Clarke M. Anaesthesia for retinoblastoma screening - a dilemma. View details for Web of Science ID A1984SP90200011. Adjunct Senior Lecturer Dr Michael Williams. 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. Facebook gives people the power. Publications Journal Articles (89) Conference Papers (5) Journal Articles Clarke, Paul R. (2021). [1] During the 2022 Russian invasion of Ukraine, he served as Sky News ' security and defence analyst. MMTV-Wnt-1 breast tumors were harvested, dissociated into single-cell suspensions, and sorted by flow cytometry on Thy1, CD24, and CD45. Associate Professor of Instruction; PhD. . Within the colon, the Hedgehog protein signal does not act directly on the epithelium itself, but on underlying stromal cells to induce expression of IL-10, an immune-modulatory cytokine long known to suppress inflammatory intestinal damage. Thus a limiting serum component is responsible for the altered metabolic and growth rates. Notably, these gene sets show similar expression across tissues, differing only in the amplitude and the age of onset of expression. Notably, subsets of CSCs in some human and murine breast tumours contain lower ROS levels than corresponding non-tumorigenic cells (NTCs). Traditional methods of implementing this assay are lengthy, cumbersome and require a large number of cells, making it difficult to study rare cell types such as certain cancer and stem cells. The efficiency of gene therapy strategies against cancer is limited by the poor distribution of the vectors in the malignant tissues. The C57BL/Ka-Thy-1.1 alleles were partially dominant. View details for DOI 10.1016/j.stemcr.2020.12.012. View details for Web of Science ID 000079323200036. (Funded by the National Comprehensive Cancer Network, the National Institutes of Health, and others.). Hematopoietic stem cells (HSCs) have self-renewal capacity and multilineage developmental potentials. Receptor tyrosine kinase (RTK) inhibitors have advanced colon cancer treatment. 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. He is a Professor at La Trobe University in Melbourne, Victoria, where he has worked since 1992. The inhibitory effect on F-MEL differentiation appeared to be independent of the early decline in c-myc transcripts which were normally regulated in all cases examined. Transformed mammary stem or progenitor cells undergo aberrant differentiation processes that result in generation of the phenotypic heterogeneity found in human and rodent breast cancers. Moreover, the inherent ability of residual CoCSC to generate tumors appears preserved. Cells were analyzed by real-time quantitative reverse transcription polymerase chain reaction, single-cell gene expression analysis, flow cytometry, and immunohistochemical, immunoblot, and functional assays. 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. Alzheimer's disease (AD) is a progressive neurodegenerative disease observed with aging that represents the most common form of dementia. View details for Web of Science ID A1986A778300041. 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+"). Cancers of epithelial origin are responsible for the majority of cancer-related deaths in the USA. 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. 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. View details for Web of Science ID A1995TF89100042. Dr. Michael F. Clarke is the Associate Director of the Stanford Institute for Stem Cell and Regenerative Medicine. George Malcolm (1917-1997), Pianist, Cembalist, Dirigent und Komponist. T47D cells were then transfected with a temperature-sensitive mutant of the tumor suppressor p53 (p53ts). Programmed cell death (PCD) plays an important role in normal and malignant hematopoieis. 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. This is an overview of the elements and molecules involved in p53 nucleocytoplasmic transportation. miR-200c inhibited the clonal expansion of breast cancer cells and suppressed the growth of embryonal carcinoma cells in vitro. Our results indicate that Bmi-1 is essential for the generation of self-renewing adult HSCs. Despite intensive study of p53, the regulation of p53 cellular localization is still poorly understood. These tools should lead to new insights into the cellular and molecular mechanisms that drive human breast cancer growth and invasion. In addition, dysregulation of stem cell self-renewal is a likely requirement for the development of cancer. Kohrt, H. E., Houot, R., Weiskopf, K., Goldstein, M. J., Scheeren, F., Czerwinski, D., Colevas, A. D., Weng, W., Clarke, M. F., Carlson, R. W., Stockdale, F. E., Mollick, J. Like many epithelial tumors, head and neck squamous cell carcinoma (HNSCC) contains a heterogeneous population of cancer cells. In contrast, no proviral methylation was detected in any of the cell lines examined, suggesting a functional correlation between methylation and viral RNA expression. Cell-free RNA from liquid biopsies can be analyzed to determine disease tissue of origin. Here we show that normal mammary epithelial stem cells contain lower concentrations of ROS than their more mature progeny cells. The simulation demonstrates that removal of stem cells is a possible mechanism leading to culture decline. We used a replication-deficient adenoviral vector to transiently overexpress Bcl-xs in MCF-7 human breast cancer cells, which overexpress Bcl-xL. We investigated the role of the RTK KIT in development of human colon cancer.An array of 137 patient-derived colon tumors and their associated xenografts were analyzed by immunohistochemistry to measure levels of KIT and its ligand KITLG. 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. 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. Cancers originally develop from normal cells that gain the ability to proliferate aberrantly and eventually turn malignant. View details for Web of Science ID A1984SJ97500057. 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. Restoration of CTNNA1 expression in HL-60 cells resulted in reduced proliferation and apoptotic cell death. In the absence of Bmi-1, the cyclin-dependent kinase inhibitor gene p16Ink4a is upregulated in neural stem cells, reducing the rate of proliferation. Using mammary epithelial-specific mouse models targeting Trp53 and Cdkn2a, the gene coding for p16INK4a and p19ARF, we demonstrate that p53, p16INK4a, and p19ARF do not play a significant role in the limitation of normal mammary epithelium self-renewal and proliferation, whereas in the presence of the inflammatory cytokine TNF-, Trp53-/-Cdkn2a-/- mammary basal cells exhibit amplified proliferation. Tumor kinetic rate constants (K1, k2, k3) and net rate of FDG phosphorylation (K = [K1.k3]/[k2 + k3]) in tumors were calculated from the dynamic data by means of a three-compartment model, assuming k4 = 0.Viable tumors (n = 10) showed intense FDG uptake and could easily be differentiated visually from mature teratoma (n = 6) and necrosis or scar (n = 10). Upon inactivation of KrasG12D , tumors initially regress and enter remission. In this report, we analyzed the possible existence of cis-acting sequences involved in intracellular trafficking of the p53 protein. 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