Liu, H., Bockhorn, J., Dalton, R., Olopade, O. F., Clarke, M. F., Greene, G. L. MicroRNAs regulating breast cancer stem cells and metastasis. A spacer between this basic domain and NLS I is necessary for the entrance of p53 into the cell nucleus. 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. 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. His laboratory is pursuing the identification of cancer stem cells in other tumors so that they can be studied. James H. Clarke, Michael P. Vandenbergh . Here, we report that genetic or pharmacologic Hedgehog pathway inhibition intensifies colon inflammation (colitis) in mice. Stromal Gli2 activity coordinates a niche signaling program for mammary epithelial stem cells. Adorno, M., di Robilant, B. N., Sikandar, S. S., Acosta, V. H., Antony, J., Heller, C. H., Clarke, M. F. Usp16 modulates Wnt signaling in primary tissues through Cdkn2a regulation. At the time of ABMT, 10 were chemosensitive, four were chemoresistant, and 10 were absolutely refractory to platinum. View details for Web of Science ID A1984TC73000037. Using a model in which human breast cancer cells were grown in immunocompromised mice, we found that only a minority of breast cancer cells had the ability to form new tumors. He was on the senior staff of the S View details for DOI 10.1073/pnas.1121623109, View details for DOI 10.1158/1538-7445.AM2012-3331, View details for Web of Science ID 000209701505088, View details for DOI 10.1158/1538-7445.AM2012-1012, View details for Web of Science ID 000209701505194. Treatment-related mortality was 10%. George Malcolm (1917-1997), Pianist, Cembalist, Dirigent und Komponist. View details for DOI 10.1016/j.stem.2020.06.017, View details for DOI 10.1056/NEJMra1804280, View details for DOI 10.1056/NEJMc1908886, View details for Web of Science ID 000440602000017. View details for Web of Science ID A1995RP92400014. These data are consistent with the idea that the human T-lymphotropic virus type I LTR contains an enhancer which can activate upstream sequences in cis. An in vivo reconstitution assay revealed that the frequency of HSCs was 1/16 in Bmi-1high c-kit+ lin -Sca-1+ bone marrow (BM) cells and 1/49 in Bmi-1 high lin- BM cells, suggesting that Bmi-1 may serve as a marker for normal HSCs. View details for Web of Science ID 000178717500001. View details for Web of Science ID A1984SY22400007. View details for Web of Science ID A1994PC47400008. 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. Biotinylated granulocyte/macrophage colony-stimulating factor (GM-CSF) analogues with different linkage chemistries and levels of conjugated biotin were synthesized by reacting recombinant human GM-CSF with sulfosuccinimidyl 6-biotinamidohexanoate or biotin hydrazide/1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide. He wanted to play football in high school, but his mother wouldn't let him, afraid that he would get hurt. 2 Conocido por ser uno de los intrpretes ms reconocidos de Hollywood, y muchas de sus pelculas, ya sean dramas o comedias, han recibido reconocimiento internacional. Surface markers that displayed intratumor heterogeneous expression among epithelial cancer cells were selected for cell sorting and tumorigenicity experiments. His interest is in Stem Cell Biology. Analysis of HUT102 DNA shows that one allele of the KT1 UCR is rearranged. Facebook gives people the power. Most cancers comprise a heterogenous population of cells with marked differences in their proliferative potential as well as the ability to reconstitute the tumor upon transplantation. As well as addressing the patient's medical needs, these highly trained professionals . The fragment with a tandem repeat of the 72-bp element also does not associate randomly with histones. Strategies that enhance the activity of ADCC effectors, including NK cells, may improve the efficacy of trastuzumab. U.S.A. 1995;92:11024-11028) is used in combination with Ad5ERE2, the ability of both viruses to induce cell death is dramatically increased, and the effect can be modulated by addition of the antiestrogen tamoxifen. Dalerba, P., Kalisky, T., Sahoo, D., Rajendran, P. S., Rothenberg, M. E., Leyrat, A. 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. Fifteen (52%) received both transplants. Finally, the laboratory is actively pursuing how cancer stem cells self-renew to maintain themselves and escape the genetic constraints on unlimited self-renewal that regulate normal stem cell numbers. To examine the influence of stromal cell layer aging, conditioned medium was obtained from the first two weeks of LTHBMCs that was subsequently concentrated and used as a medium supplement in a second set of slowly exchanged LTHBMCs. B., Alizadeh, A. Clarke was interested . Best response after ABMT included: two CR, one CR surgically NED, five PR, three PR surgically NED, seven SD, and eight PD. ANGELOTTI, T. P., Clarke, M. F., Longino, M. A., Emerson, S. G. THE CONSTRUCTION OF HIGH-EFFICIENCY HUMAN BONE-MARROW TISSUE EXVIVO. Professor William Clarke. View details for Web of Science ID A1990DY35100036. 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. Enforced expression of miR-142 or miR-150 in normal mouse mammary stem cells resulted in the regeneration of hyperproliferative mammary glands in vivo. On the pathway level, young blood invokes new gene sets in addition to reversing established ageing patterns, with the global rescue of genes encoding electron transport chain subunits pinpointing a prominent role of mitochondrial function in parabiosis-mediated rejuvenation. Upon inactivation of KrasG12D , tumors initially regress and enter remission. Gene expression analysis of cells isolated from nonadherent mammospheres revealed overlapping genetic programs with other stem and progenitor cells and identified new markers that may be useful in the identification of mammary stem cells. According to a story Tom Hanks told at. 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. (Funded by the National Comprehensive Cancer Network, the National Institutes of Health, and others.). For more information, please contact Ruth Lira, 650-723-1367. This is accompanied by a translocation of the p53 protein from the cytoplasm to the nucleus. 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. However, deletions of more than two amino acids between this region abolished the transport of p53 into the nucleus. In contrast, no proviral methylation was detected in any of the cell lines examined, suggesting a functional correlation between methylation and viral RNA expression. The possible significance of this finding is discussed. We were able to distinguish the tumorigenic (tumor initiating) from the nontumorigenic cancer cells based on cell surface marker expression. Bmi-1-green fluorescent protein (GFP)-knock-in mice reveal the dynamic regulation of Bmi-1 expression in normal and leukemic hematopoietic cells. To delineate more accurately the point at which Myb blocks differentiation, MEL cells were transfected with a human c-myb construct under the control of the beta-globin promoter and enhancers. Ageing is the single greatest cause of disease and death worldwide, and understanding the associated processes could vastly improve quality of life. View details for DOI 10.1038/s41586-020-2499-y. This suggests RGS18 can act on G(q)-mediated signaling pathways in vivo. Other mutations between Arg-306 and NLS I have no effect on the nuclear import of p53. These breast tumors are comprised of phenotypically diverse populations of breast cancer cells. adequate tissue for cancer stem cell quantification. Here we describe c-myb-transformed MEL clones which undergo delayed expression of the exogenous c-myb following 3-5 days of culture in DMSO. The conditional expression of lethal genes in tumor cells is a promising gene therapy approach for the treatment of cancer. Wu, A. R., Neff, N. F., Kalisky, T., Dalerba, P., Treutlein, B., Rothenberg, M. E., Mburu, F. M., Mantalas, G. L., Sim, S., Clarke, M. F., Quake, S. R. Oncogenic miRNAs and the perils of losing control of a stem cell's epigenetic identity. This phenotypic diversity is driven by a small subset of mammary tumour stem cells. In human breast cancers, a phenotypically distinct minority population of tumorigenic (TG) cancer cells (sometimes referred to as cancer stem cells) drives tumor growth when transplanted into immunodeficient mice. 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. However, the consequences of the underlying gene-dosage imbalance on adult tissues remain poorly understood. Kim et al. View details for Web of Science ID A1997YA26800007. In experiments on nude mice bearing HeLa ascites tumors, intraperitoneal injection of AdRSVlaclys/pE1 resulted in a significantly higher percentage of infected HeLa cells as compared with the PBS controls (p < 0.05) or the AdRSVlaclys/pUC19 controls (p < 0.01). Recently, his group described a molecular mechanism that confers resistance to radiation in breast cancer stem cells. We performed in vivo imaging of changes in fluorescent, endogenous duct architecture as a metric for remodeling. Within 24-48 hr, viral RNA expression increased at least four- to eightfold. Intriguingly, overexpression of p53 could reverse the inherent IR resistance of Shep-1 cells. Microarray-based multigene-expression signatures derived from stem cells and progenitor cells hold promise, but they are difficult to use in clinical practice. Dr Michael Clarke is an internationally recognised expert on the history and politics of the Xinjiang Uyghur Autonomous Region, People's Republic of China (PRC), Chinese foreign policy in Central Asia, Central Asian geopolitics, nuclear proliferation and non-proliferation and American grand strategy and foreign policy. Liu, H., Shimono, Y., Bockhorn, J., Olopade, F., Greene, G., Clarke, M. F. Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models. These tools should lead to new insights into the cellular and molecular mechanisms that drive human breast cancer growth and invasion. Our metastatic cancer models, combined with noninvasive imaging techniques, constitute an integrated approach that could be applied to dissect the molecular mechanisms underlying the dissemination of metastatic CSCs (MCSCs) and to explore therapeutic strategies targeting MCSCs in general or to evaluate individual patient tumor cells and predict response to therapy. Michael Clarke, MD is a Professor of Medicine at Stanford University. Metastasis remains a significant challenge in treating cancer. Following his specialty training in medical oncology at Royal Prince Alfred and Westmead Hospitals, Professor Boyer was a Research Fellow and Clinical Fellow at the Ontario Cancer Institute and Princess Margaret Hospital in Toronto, Canada, where he completed his PhD on cell biology. The lactate/glucose and ammonia/glutamine yield coefficients, however, remained invariant at about 1.9 and 1.0 mol/mol, respectively, under all medium perfusion conditions. In many tissues, a cellular hierarchy exists in which a small population of stem cells is responsible for the production of the mature cells of the organ. The productivity of cultures exposed to conCM for 4 weeks dropped significantly when unsupplemented medium was used for the latter 4 weeks of culture. Arthur C. Clarke, in full Sir Arthur Charles Clarke, (born December 16, 1917, Minehead, Somerset, Englanddied March 19, 2008, Colombo, Sri Lanka), English writer, notable for both his science fiction and his nonfiction. Only a small minority of cancer cells had the capacity to form new tumors in a xenograft model. We tested northstar on data from glioblastoma, melanoma, and seven different healthy tissues and obtained high accuracy and robustness. It has 234 amino acids consisting of a central RGS box and short divergent NH(2) and COOH termini. Mouse RGS18 is expressed from a single gene and shows tissue specific distribution. Kohrt, H. E., Houot, R., Weiskopf, K., Goldstein, M., Lund, P., Scheeren, F., Czerwinski, D., Colevas, A. D., Weng, W., Clarke, M. F., Carlson, R. W., Sunwoo, J., Tedder, T., Chen, L., Levy, R. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. While cell lines expressing p53 alone rapidly died, those cells co-expressing Bcl-XL survived. 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. Clarke, M. F., Gelmann, E. P., Reitz, M. S. RELATION OF RESPIRATORY BURST AND ARACHIDONATE METABOLISM DURING PHAGOCYTOSIS BY GUINEA-PIG ALVEOLAR MACROPHAGES. Human T cell lymphoma proviral (HTLV) sequences were demonstrated in both cell lines. Professor Michael Clarke is a Fellow of King's College London. Even in the absence of an exogenous apoptotic signal such as x-irradiation, this virus specifically and efficiently kills carcinoma cells arising from multiple organs including breast, colon, stomach, and neuroblasts. View details for Web of Science ID 000083623000026. 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. 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. We observed an almost universal loss of gene expression with age that is largely mimicked by parabiosis: aged blood reduces global gene expression, and young blood restores it in select cell types. Recently, it has become apparent that some oncogenes and tumor suppressor genes also regulate self-renewal, the process by which stem cells maintain themselves. View details for DOI 10.1016/j.stem.2009.05.019, View details for Web of Science ID 000269511900010. Here we show that normal mammary epithelial stem cells contain lower concentrations of ROS than their more mature progeny cells. Replication-defective retroviruses are frequently used as gene carriers for gene transfer into target cells. He served as the Head of the School of Life Sciences from 2011-2019. Usp16 can remove ubiquitin from histone H2A on lysine 119, a critical mark for the maintenance of multiple somatic tissues. 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). To date, therapies targeting end-stage disease plaques, tangles, or inflammation have limited efficacy. One way to approach this problem is to target the cause--the molecular machinery that allows a cancer cell to survive. Lactate dehydrogenase-elevating virus (LDV) can infect transplantable mouse tumors or xenograft tumors in mice through LDV-contaminated mouse biological materials, such as Matrigel, or through mice infected with LDV. Four major epithelial subtypes or transcriptional states were revealed by gene expression analysis of selected populations of single cells. Mandel, Michael - Associate Professor: Computer and Information Science Manlow, Veronica B. View details for Web of Science ID A1984SP90200011. The miR-30c-VIM/TWF1 signaling cascade is also associated with clinical outcome in breast cancer patients. 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. Raised by his single mother, Jean, a house cleaner, on Chicago's South Side, Duncan grew up resisting drugs and alcohol, instead concentrating on school. Here, we identify a quiescent mammary epithelial cell population expressing high levels of Bcl11b and located at the interface between luminal and basal cells. Disclosure of potential conflicts of interest is found at the end of this article. 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. Patients were eligible for a second cycle if disease progression was absent and performance status allowed. Research Expertise and Interests Differences in self-renewal pathways between normal and malignant stem cells could be targeted by new therapeutic agents to eliminate cancer stem cells. Therefore, we set out to identify a potential earlier targetable phenotype. Schott, A. F., Apel, I. J., Nunez, G., Clarke, M. F. BCL-2 PROTECTS MURINE ERYTHROLEUKEMIA-CELLS FROM P53-DEPENDENT AND -INDEPENDENT RADIATION-INDUCED CELL-DEATH. View details for DOI 10.1038/s41598-020-71805-1. Pardal, R., Clarke, M. F., Morrison, S. J. Our objective was to identify a mouse model of breast cancer stem cells that could have relevance to the study of human breast cancer. A temperature-sensitive mutant of murine p53 (p53Val-135) and/or bcl-2 was transfected into murine erythroleukemia cells (MEL, DP16-1, which are null in p53). The retrovirus transduced culture continued to produce genetically modified hematopoietic progenitors for up to 6 weeks, the duration of the culture period. Unfortunately, viruses are limited in their ability to diffuse through tissue. Established HTLV-infected cell lines constitutively express viral RNA. 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. All measured metabolic rates increased with increased medium exchange rates and accelerated sharply between exchange rates of 3.5/week and 7/week. View details for Web of Science ID 000243488100004. A cDNA library was constructed from the HUT102 cell line established from a patient with adult T-cell leukemia/lymphoma and screened for cDNA clones that contain (i) cellular sequences abundantly expressed in HUT102 cells and not in the virus-negative T-cell line HUT78, and (ii) viral long terminal repeat (LTR) sequences either in the 5' end or in the 3' end. 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. View details for Web of Science ID A1986A778300041. It kills tumor cells by several mechanisms, including antibody-dependent cellular cytotoxicity (ADCC). 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. Dole, M. G., Clarke, M. F., Holman, P., Benedict, M., Lu, J. Y., Jasty, R., EIPERS, P., Thompson, C. B., Rode, C., Bloch, C., Nunez, G., Castle, V. P. Strategy for identifying genes responsible for hemotopoietic stem cell homeostasis. 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. This has been recently shown in an in vivo model, where overexpression of Bcl-XL, is a crucial step in the progression from hyperplasia to neoplasia and is accompanied by a significant decrease in tumor apoptosis [56]. We have developed a new in vitro culture system that permits, for the first time, the propagation of mammary stem and progenitor cells in an undifferentiated state, which should facilitate the elucidation of pathways that regulate normal mammary stem-cell self-renewal and differentiation. Clarke, M. F., Trainor, C. D., Mann, D. L., Gallo, R. C., Reitz, M. S. TRANSFORMING POTENTIAL OF HUMAN C-SIS NUCLEOTIDE-SEQUENCES ENCODING PLATELET-DERIVED GROWTH-FACTOR. View details for Web of Science ID A1994NT46100030. CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer. Utilizing a mouse model of AD and human fetal cells harboring mutant amyloid precursor protein, we show cell intrinsic neural precursor cell (NPC) dysfunction precedes widespread inflammation and amyloid plaque pathology, making it the earliest defect in the evolution of the disease. Thus, these mice allow for the isolation of viable Bmi-1-expressing cells and have the potential to become a useful tool for understanding the role of Bmi-1 in normal and cancer stem cells in multiple tissue types. Here we report that microRNA-30c, a human breast tumour prognostic marker, has a pivotal role in chemoresistance by a direct targeting of the actin-binding protein twinfilin 1, which promotes epithelial-to-mesenchymal transition. 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