As few as 100 cells with this phenotype were able to form tumors in mice, whereas tens of thousands of cells with alternate phenotypes failed to form tumors. Reduction of USP16 led to decreased expression of senescence gene Cdkn2a and mitigated aberrant regulation of the BMP pathway, a previously unknown function of USP16. 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. Adjunct Associate Professor David Welsh. The human RGS18 ortholog has a tissue-specific expression pattern similar to that of mouse RGS18. In this issue of Cancer Cell, Inoue et al. Infection with this vector induced apoptosis in vitro. In several forms of human cancer, only a phenotypic subset of cancer cells, usually termed "cancer stem cells" (CSC), can initiate tumor growth when transplanted. EW replicates in IEC subsets differing in their basal type I IFN transcription and induces IRF3-dependent and IRF3-augmented transcription, but not NF-B-dependent or type I IFN transcripts. View details for DOI 10.1016/j.jcmgh.2017.01.006. Professor Michael Clarke, a prominent military analyst, told Express.co.uk that Ukraine could use Britain's Challenger 2 tanks to split the combat frontline and "isolate Crimea". 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. Analysis of patient tumor and matched adjacent normal (nontumor) tissue revealed that CD47 is overexpressed on cancer cells. PHD Student in Computer Science. Resolution of "averaged" innate immune responses in single IECs thus revealed unexpected heterogeneity in both the induction and subversion of early host antiviral immunity, which modulated host range. Dalerba, P., Kalisky, T., Sahoo, D., Rajendran, P. S., Rothenberg, M. E., Leyrat, A. 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. Inhibiting USP16 rescues stem cell aging and memory in an Alzheimer's model. 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. View details for DOI 10.1073/pnas.1212188109, View details for Web of Science ID 000312605600104, View details for PubMedCentralID PMC3528539. 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%. Patients with KIT-expressing colon tumors can benefit from KIT RTK inhibitors. Testicular cancer patients refractory or in relapse after primary chemotherapy have < or =25% 5-year progression-free survival with salvage. 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. 444 Hutchison (585) 275-3432 michael.clark@rochester.edu. Professor of Health in Social Science; College Dean International; EFI Director of Global Communities. A group of 87 of 2115 tumor samples (4.1%) lacked CDX2 expression. He has also acted as a reviewer for the EPSRC and for funding councils in Austria, Finland, France and Germany. View details for DOI 10.1016/j.stem.2016.11.007, View details for PubMedCentralID PMC5341693. View details for Web of Science ID A1984SY22400007. The cumulative data provide the foundation for an atlas of transcriptomic cell biology. A full-length human c-myb cDNA clone has been isolated from a CCRF-CEM leukemia cell cDNA library. 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. Cancers arise in a tissue as the culmination of a series of mutations that activate oncogenes and inactivate tumor suppressor genes. We thus identify stromal cells as cellular coordinators of colon inflammation and suggest their pharmacologic manipulation as a potential means to treat colitis. Our study identifies both epithelial-mesenchymal transition (EMT) and active MAPK/ERK signaling in tumors that adapt to oncogenic KrasG12D withdrawal in a novel Trp53-/- breast cancer mouse model. Mini Bio (1) Michael Clarke Duncan was born on December 10, 1957 in Chicago, Illinois. However, the identity and function of cells expressing EMT-associated genes in normal murine mammary gland homeostasis and human breast cancer still remains under debate. The regulation of hematopoietic stem cell (HSC) homeostasis is not well understood. . 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. Treatment of these T-cells with 5-azacytidine resulted in the induction of DR surface antigen expression, the appearance of DR alpha mRNA, and the partial demethylation of the DR alpha DNA sequences. The CSD could block the binding of p53 to the NLS receptor, importin alpha, and reduce the efficiency of p53 nuclear import in MCF-7, H1299, and Saos-2 cells. Fundamentally, the system is the paradigm of a complex interactive tissue, in which the proliferation and regulated differentiation of one parenchymal cell type (the hematopoietic stem cell) is governed by the surrounding stromal cells. View details for DOI 10.1073/pnas.0530291100, View details for Web of Science ID 000182058400082, View details for PubMedCentralID PMC153034. 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. View details for DOI 10.1038/sj.onc.1207947, View details for Web of Science ID 000223998800013, View details for Web of Science ID 000223225500005. Professor Michael Clarke write a piece in The Sun saying time was running out for Putin. Taken together, these results suggest that USP16 has an important role in antagonizing the self-renewal and/or senescence pathways in Down's syndrome and could serve as an attractive target to ameliorate some of the associated pathologies. 29 Oxford St, Pierce 229. jaiz@seas.harvard.edu (617) 495-3558. Research Expertise and Interests We found that each antibody inhibited tumor growth and that the combination of the two antibodies was more effective than either alone. View details for DOI 10.1016/j.jviromet.2011.02.015, View details for Web of Science ID 000290836400014, View details for PubMedCentralID PMC3086718, View details for DOI 10.1158/1538-7445.AM2011-1582, View details for Web of Science ID 000209701302286, View details for Web of Science ID 000289796200068. These results suggest that radiation-induced cell death occurs by both p53-dependent and p53-independent pathways. Therefore, functional inhibition of Bcl-2 family members is lethal to many cancer cells. View details for DOI 10.1073/pnas.1006732107, View details for Web of Science ID 000283184800050, View details for PubMedCentralID PMC2964232. In vitro, blockade of CD47 signaling using targeted monoclonal antibodies enabled macrophage phagocytosis of tumor cells that were otherwise protected. Further investigation will reveal whether this translates to improved therapy in the future. However, none of the NB cell lines expressed Bcl-xS. View details for Web of Science ID 000345777300014. 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. Published algorithms for automatic cell annotation are limited to known cell types and fail to capture novel populations, especially cancer cells. 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. Guinea pig alveolar macrophages were stimulated with opsonized zymosan in the presence of inhibitors of arachidonic acid metabolism: ASA, indomethacin, and ETYA, ASA, at concentrations as high as 60 micrograms/ml, had no effect on either oxygen consumption or superoxide ion formation. It has been reported that Lysine-305 is needed for the nuclear import of the p53 protein (Liang et al., 1998). We examined the effect of lower levels of c-sis expression on the phenotype of NIH 3T3 fibroblasts. In both these groups, these findings were independent of the patient's age, sex, and tumor stage and grade. The retrovirus transduced culture continued to produce genetically modified hematopoietic progenitors for up to 6 weeks, the duration of the culture period. To assess CSC-specific remodeling events, we isolated CSC from MMTV-Wnt1 (mouse mammary tumor virus long-term repeat enhancer driving Wnt1 oncogene) breast tumors, a well studied model in which tissue remodeling affects tumorigenesis. 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. View details for Web of Science ID 000171898900054. Here, we identify a quiescent mammary epithelial cell population expressing high levels of Bcl11b and located at the interface between luminal and basal cells. A subpopulation of tumor cells, termed cancer stem cells (CSC), appears uniquely able to fuel the growth of phenotypically and histologically diverse tumors. Emerging evidence has suggested that the capability of a tumor to grow and propagate is dependent on a small subset of cells within a tumor, termed cancer stem cells. By focusing on the biology of CoCSC, major resistance mechanisms to specific chemotherapeutic agents can be attributed to specific genes, thereby suggesting avenues for improving cancer therapy. Parashurama, N., Lobo, N. A., Ito, K., Mosley, A. R., Habte, F. G., Zabala, M., Smith, B. R., Lam, J., Weissman, I. L., Clarke, M. F., Gambhir, S. S. Effect of stimulation of natural killer cells with an anti-CD137 mAb on the efficacy of trastuzumab, cetuximab, and rituximab. We have examined the respiratory burst and arachidonic acid oxygenation that accompany phagocytosis in macrophages. Faculty. 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 cells exposed to the suicide vectors were able to reconstitute the bone marrow of mice exposed to lethal doses of y-irradiation. and Ph.D. in economics from the University of Kentucky. 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. View details for PubMedCentralID PMC5698470. Loss of Bcl11b leads to a Cdkn2a-dependent exhaustion of ductal epithelium and loss of epithelial cell regenerative capacity. 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. G1 arrest at 37.5 degrees C, utilizing either mimosine or isoleucine deprivation, does not lead to rapid cell death. To do so, we used breast tumors of the mouse mammary tumor virus (MMTV)-Wnt-1 mice. View details for Web of Science ID A1982NS41700015, American Association of Physicians, - (-), American Society of Clinical Investigation, - (-), Rackham Award, University of Michigan (-), Please see Dr. Michael Clarke's bio on the following School of Medicine website(s). Recently, there have been exciting developments in identifying high-risk patient cohorts, refinements in the understanding of systemic vs localized drug delivery to metastatic niches, liquid biomarker development, and dramatic advances in tumor immune therapy, all of which promise new and innovative approaches to tackling the problem ofdetecting and treating the metastatic spread of CRC to the liver. This physiochemical limitation can be overcome, and effective contact between the retroviral gene carrier and the target cell can be obtained, by using net convective flow of retrovirus-containing medium through a layer of target cells. 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. 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. However, the underlying molecular mechanisms are poorly characterized. in Pounds- 159 lbs. When a promoter containing these elements is used to control the expression of the pro-apoptotic gene harakiri, the induction of cell death can be activated by estrogens and hypoxia, and inhibited by antiestrogens such as tamoxifen. A., Parmiani, G., Castelli, C., Clarke, M. F. Identification of pancreatic cancer stem cells. Thus, bcl-2 protects cells from p53-dependent radiation-induced apoptotic cell death and attenuates p53-independent radiation-induced cell death. They discuss the increasing threat of China, the post-Brexit identity of "Global Britain" and how the . Using a xenograft model in which primary human pancreatic adenocarcinomas were grown in immunocompromised mice, we identified a highly tumorigenic subpopulation of pancreatic cancer cells expressing the cell surface markers CD44, CD24, and epithelial-specific antigen (ESA). Clarke, M. F., Apel, I. J., Benedict, M. A., Eipers, P. G., Sumantran, V., GONZALEZGARCIA, M., Doedens, M., Fukunaga, N., Davidson, B., Dick, J. E., Minn, A. J., Boise, L. H., Thompson, C. B., Wicha, M., Nunez, G. RETROVIRAL-MEDIATED GENE-TRANSFER IN HUMAN BONE-MARROW CELLS GROWN IN CONTINUOUS PERFUSION CULTURE VESSELS. Clarke, M. F., Fitzgerald, P. C., Brubaker, J. M., Simpson, R. T. DNA METHYLATION AND EXPRESSION OF HLA-DR-ALPHA. [1] During the 2022 Russian invasion of Ukraine, he served as Sky News ' security and defence analyst. This apparent paradox is the focus of our interest. All three analogues retained full agonist activity relative to the native protein (EC50 = 10-15 pM) when assayed for the stimulation of human bone marrow progenitor cell growth. 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. 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. We have designed a microfluidic device to perform sensitive ChIP analysis on low cell numbers in a rapid, automated fashion while preserving the specificity of the assay. Liu, R., Wang, X., Chen, G. Y., Dalerba, P., Gurney, A., Hoey, T., Sherlock, G., Lewicki, J., Shedden, K., Clarke, M. F. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Stem cells in many tissues sustain themselves by entering a quiescent state to avoid genomic insults and to prevent exhaustion caused by excessive proliferation. Using this system, we have generated AdEHT2 and AdEHE2F, two conditionally replicative adenoviruses for the treatment of breast cancer. Using terminal transferase-mediated dUTP-digoxigenin nick end labeling, we observed apoptotic cells at sites of bcl-xs adenoviral injection. To understand the regulation of p53 cellular trafficking, we have previously identified two p53 domains involved in its localization. However, at later times X-ray irradiated parental DP16-1 cells also had decreased survival compared to the unirradiated control. 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. Tumors injected four times with the bcl-xs adenovirus showed a 50% reduction in size. View details for Web of Science ID A1995RY96700021. 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. Professor Michael Clarke was Director General of the Royal United Services Institute from 2007-2015, where he remains a Distinguished Fellow. 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. Filter By. 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. The Leopard 2 tanks are what the Ukrainians really need, more than the Challenger 2 and Abrams tanks, Clarke argued. 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. Recent studies have begun to elucidate the mechanisms controlling hematopoietic stem cell (HSC) self-renewal. Since only a portion of the cells in culture expressed Ig light chains, experiments were carried out to exclude the possibility that the cultures were not a mixture of B and T or non-B cells. Our objective was to identify a mouse model of breast cancer stem cells that could have relevance to the study of human breast cancer. We hypothesized that if non-tumorigenic cells are more susceptible to chemotherapeutic agents, then residual tumors might be expected to contain a higher frequency of CoCSC.Xenogeneic tumors initiated with CoCSC were allowed to reach approximately 400 mm(3), at which point mice were randomized and chemotherapeutic regimens involving cyclophosphamide or Irinotecan were initiated. 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. The tumor suppressor protein p53 has been identified as a key regulator of apoptosis in both normal and malignant hematopoietic 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. Clarke, M. F., KukowskaLatallo, J. F., Westin, E., Smith, M., Prochownik, E. V. ACTIVATION OF A NOVEL KPNI TRANSCRIPT BY DOWNSTREAM INTEGRATION OF A HUMAN T-LYMPHOTROPIC VIRUS TYPE-I PROVIRUS. HSCs have the ability to self-renew, while MPP cells have lost the capacity for self-renewal. We reveal linear and nonlinear shifts in gene expression during ageing, with the associated genes clustered in consistent trajectory groups with coherent biological functions-including extracellular matrix regulation, unfolded protein binding, mitochondrial function, and inflammatory and immune response. Since stromal cells in traditional human bone marrow cultures produce little HGFs, we have begun by asking whether local supplementation of hematopoietic growth factors via genetically engineered stromal cells might augment hematopoiesis in liquid cultures. 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. 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 We also discuss thelatest advances to maximize regional and systemic therapies aimed at decreasing intrahepatic recurrence, review recent insights into the tumor microenvironment, and summarize advances in noninvasive multimodal biomarkers for early detection of primary and recurrent disease. Compared to the study of human breast cancer DOI 10.1073/pnas.1006732107, View details for DOI 10.1038/sj.onc.1207947, details. Cellular coordinators of colon inflammation and suggest their pharmacologic manipulation as a reviewer for the treatment of breast.! 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