1,721,021 research outputs found
THE ROLE OF NOTCH PATHWAY IN MULTIPLE MYELOMA-ASSOCIATED DRUG RESISTANCE
Full text linkBACKGROUND: Multiple myeloma (MM) is an incurable hematological malignancy characterized by drug resistance, intrinsic or induced by bone marrow stromal cells (BMSCs). In MM cells, Notch pathway may be aberrantly activated due to the hyperexpression of Notch1, Notch2 or Jagged1 and 2 ligands. This effect may be attributed to genetic mutation only in part (i.e. translocations involving the MAF transcription factors may increase the transcriptional activity on their target gene Notch2). MM cells settle in the bone marrow (BM) and the BM microenvironment may be another player contributing to Notch signaling activation by triggering Notch receptors through BMSC-derived ligands or other stimuli including hypoxia. Indeed, recent evidences indicate that both hypoxic stimuli and Notch signaling activation are involved in cancer stem cell maintenance and self-renewal, thereby contributing to drug resistance due to the resilience of this cancer subpopulation. MM stem cells (MM-SCs) have been characterized as a CD138- subpopulation.
AIM: The aim of this study was to investigate the outcome of Notch signaling hyper-activation in intrinsic and BMSC-mediated drug resistance in MM cells and MM-SCs.
METHODS: I assessed the effect of Jagged ligands by an inhibitory approach on MM cells. This was carried out by silencing Jagged1 and 2 through specific siRNAs or lentivirally expressed shRNAs. The study got advantage of OPM2 and U266 cell lines and MM primary cells from 10 patients. MM cells were cultured alone, to assess the effect of Jagged silencing on intrinsic drug resistance, or co-cultured with BMSCs, to investigate the effect of Jagged inhibition on BMSC-mediated drug resistance. The BMSC models used were: i) the human HS5GFP+ cell line that, when cultured with MM cell lines, enabled a flow cytometric analysis of variations in drug resistance and anti-apoptotic proteins expressed by MM cells, along with changes in BMSC-production of pro-tumor cytokines (i.e. IL-6 and SDF-1); ii) the murine fibroblasts NIH3T3. These cell lines mimic BMSCs and, when cultured with MM cell lines, enabled to confirm changes in key proteins by gene expression analysis through RT-PCR using species-specific primers to distinguish the contribution of MM cells (human) or NIH3T3 cells (murine); iii) experiments on primary CD138- MM cells were carried out using primary BMSCs stained with PKH26 as feeder cells. Intrinsic and BMSC-induced drug resistance was analyzed by challenging MM cells cultured alone or in co-culture systems with standard-of care drugs, i.e. Bortezomib. Apoptosis was assessed by detection of the percentage of AnnexinV+ cells through flow cytometry. Hypoxic BM microenvironment was mimicked by using cobalt chloride (CoCl2), while Notch pathway activation was inhibited using DAPT (a γ-secretase inhibitor). MM-SCs were analyzed in H929 cell line by flow cytometric analysis of the CD138- subpopulation. The effect of hypoxia on protein expression changes of Notch pathway members (i.e. Notch2 and Jagged1) was assessed by Western blot assay, while changes of Notch transactivation activity were assessed by dual luciferase Notch reporter assay in OPM2 cells and HEK293 cells. The high transfectability level of HEK293 cell line also enabled its transfection with multiple plasmids to assess the specific effect of CoCl2 treatment on the transcriptional activity of Notch1 and Notch2.
RESULTS: The results of this work demonstrate that Jagged1 and 2 increased expression levels affect MM cell biology maintaining high levels of intrinsic drug resistance through the expression of anti-apoptotic genes, i.e. BCL2, Survivin and ABCC1, BCLXL, SDF-1α, CXCR4, with the consequent increase of MM cell sensitivity to standard-of-care drugs. Concerning the interaction of MM cells and BMSCs, MM cells stimulate the protective behavior of BMSCs, by inducing Notch activation through tumor-derived Jagged1 and 2, with a consequent increase of drug resistance due to: i) release of pro-tumor soluble factors by BMSCs, i.e. SDF-1α and VEGF; ii) the induction of an elevated anti-apoptotic background in MM cells due to an increased expression of anti-apoptotic genes such as BCL2, Survivin and ABCC1. In vitro results were confirmed by co-cultures of primary MM cells. Finally, I verified that an hypoxic stimulus, mimicked by CoCl2, may be a cause of Notch activation in MM cells by increasing the transcriptional activity of Notch1 and Notch2, supposedly through interaction with HIF-1α that prevents ICN proteosomal degradation. Notch signaling activated by CoCl2 positively regulates the MM-SC population. The resilience that characterizes MM-SCs suggests that hypoxia-mediated activation of Notch signaling may be a further mechanism by which the BM microenvironment may induce the acquisition of drug resistance in MM.
CONCLUSION: The evidences that Jagged1 and 2 silencing affects the intrinsic and acquired drug resistance in MM cells support the rationale for a Notch-tailored approach to overcome MM patients relapse
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe 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
Full text link“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
Full text linkWe 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
Full text linkWe 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
- …
