1,721,014 research outputs found
STUDY OF THE FUNCTION OF TBX3 TRANSCRIPTION FACTOR IN MAMMARY NORMAL AND CANCER STEM CELLS
No full textThe TBX3 gene, a member of the T-box family of transcription factors encodes for a protein involved in early embryonic cell fate decisions, including embryonic patterning, extra-embryonic structure regulation and organogenesis.
Mutations in human TBX3 cause the Ulnar-Mammary Syndrome (UMS, OMIM 181450), an autosomal dominant disorder that affects limb, apocrine-gland, hair, genital and dental development. In addition, TBX3 has a role in the posterior limb mesoderm and the dorsal/ventral axis of the forelimb specification.
TBX3 acts as a repressor or an activator of gene expression. The first TBX3 target to be identified was p19ARF, a gene that regulates senescence and apoptosis in mouse fibroblast and neural cells. In mammary epithelial cells, TBX3 also promotes cell proliferation by repressing p19ARF through a pathway alternative to Mdm2-p53 [12]. Recently, TBX3 over expression in melanoma cell lines was found to enhance cell invasiveness by repressing the expression of E-Cadherin [13].
As TBX3 was also found over expressed in a subset of breast cancer cell lines, this suggested that aberrant TBX3 expression may have a role in oncogenesis.
Our data suggest that TBX3 is a key gene in the regulation of mammary gland development due to its expression being necessary for the maintenance of the mammary stem cell pool. In agreement with our work in mouse embryonic stem cells (mESCs), TBX3 was described as a stem cell factor that is sufficient to maintain pluripotency in the absence of the leukaemia inhibitory factor (LIF) [87]. Other recent research suggests that embryonic stem cell associated genes and pathways are aberrantly regulated in mammary stem cell malignancy. To elucidate the role of TBX3 in mammary gland development and cancer initiation and progression, we initiated studies using rat (LA7) and human mammary cancer stem cells (CSCs) isolated from patients.
LA7 CSCs were isolated by Dr. Renato Dulbecco from a breast adenocarcinoma, and at the single cell level have multi-lineage differentiation, tubulo-alveolar-like structure and self-renewal capacity and the potential generate heterogenous tumors indefinitely [67, 68]. Quantitative Real PCR showed that TBX3 is expressed in LA7 and human CSCs and is down regulated during the onset of CSC differentiation, suggesting that TBX3 has a role in the CSC maintenance, while its down regulation induces CSC differentiation. It is likely that the role of TBX3 that we have uncovered is also valid in normal mammary SCs and other types of SCs.
Through optimization of the culture conditions that allowed for expansion and isolation of populations of cancer cells from human mammary gland of patients we identified in breast tumors a rare subpopulation of cells with stem-cell properties and designated these cells as human CSCs. Tumor samples were kindly provided by hospitals of Pavia and Crema, Italy. This rare subpopulation of cells had the potential to form mammospheres in non-adherent culture conditions and, when embedded in Matrigel, form tubular-like structures that recapitulate the branching structure of the mammary gland tree.
TBX3 down-regulation by TBX3-siRNA treatment resulted in the permanent loss of the capacity of LA7 and human CSCs to generate both mammospheres and tubular structures and the up regulation of mammary differentiation markers, demonstrating that TBX3 down regulation induced loss of CSC self-renewal and loss of multilineage differentiation.
Moreover, by screening candidate miRNAs from a microRNA gene chip array performed using LA7 cells cultured in non-differentiating and differentiating conditions, we identified a micro-RNA (miRNATBX3) that repressed TBX3 expression in mammary CSCs. We determined that TBX3 is the primary target of miRNATBX3 since down-regulation of TBX3 by itself was sufficient to induce CSC differentiation, and that inhibition of TBX3 down-regulation resulted in the repression of CSC differentiation and increased CSC proliferation. These results suggest that the normal role of TBX3 is to regulate the number of SCs in the normal mammary gland SC niche by modulating the rate of SC proliferation and repressing SC differentiation. In collaboration with Hans Schöler’s laboratory, we investigated the effects of TBX3 modulation in mESCs that were engineered to express the green fluorescent protein (GFP) under the control of OCT4 promoter, a gene essential for the maintenance of pluripotency. The down-regulation of TBX3 in undifferentiated mESCs lead to the differentiation of the mESCs that was readily observable since the colonies displayed morphologies typical of differentiated mESCs and had lost the GFP expression.
In order to obtain a deeper insight into the mechanisms by which TBX3 regulates mammary CSCs, we initiated studies to identify the target genes of TBX3. A set of candidate target genes such as GLI2 and GATA3, were confirmed to be TBX3 direct targets by chromatin immunoprecipitation (CHIP) analysis [118]. By global expression analysis with microarrays we determined that TBX3 is involved in a common pathway that regulates the inhibition of mESCs and mammary CSCs differentiation. A parallel circuit of LIF signalling in mES cells which maintains pluripotency involving TBX3 has recently been identified that leads to the activation of NANOG and SOX2 and the regulation of OCT3/4. By the silencing of TBX3 we observed down-regulation of both NANOG and SOX2 in LA7 and human CSCs. This preliminary result suggested that SOX2 could be a direct target of TBX3 and is supported by the overlap in the genes up or down -regulated both after TBX3 and SOX2 silencing. The gene overlap was identified by comparing microarray data generated from siRNA-TBX3 LA7CSC treated cells and mESCs in which SOX2 was down regulated.
Collectively, my thesis research suggests that TBX3 is an inhibitor of pluripotent ESC, mammary stem cell (SC) and cancer stem cell (CSC) differentiation and may represent a common master gene by which regulation of stem cell self-renewal is maintained in other types of stem cells. Our results reveal an unknown link between a regulatory network controlling self-renewal in mammary CSCs and pluripotency in mouse embryonic stem cell (mESC).
We hypothesize that the “normal” function of Tbx3 is maintain SCs in an equilibrium between a state of quiescence and a state that allows SCs to replenish themselves for the purpose of tissue expansion, regeneration and differentiation
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
Author Under Sail The Imagination of Jack London, 1893-1902
No full textIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Intro -- Title Page -- Copyright Page -- Dedication -- Contents -- Acknowledgments -- Introduction -- 1. Spirit Truth -- 2. From Absorption to Theatricality and Back Again -- 3. "I Will Build a New Present" -- 4. Sons as Authors -- 5. Fathers as Publishers -- 6. The Daughter as Author -- 7. Lovers as Authors -- 8. At Sea with the Family -- 9. Yellow News, Yellow Stories -- 10. The Return Home -- Notes -- Bibliography -- Index -- About Jay WilliamsIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Description based on publisher supplied metadata and other sources.Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, YYYY. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries
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