1,721,156 research outputs found
Activity and mechanism of action of histone deacetylase inhibitors in synovial sarcoma
No full textSynovial sarcoma is a rare but aggressive paediatric soft tissue sarcoma that is driven by the genomic rearrangement t(X;18)(p11.2;q11.2). The resulting fusion protein, SS18- SSX, exhibits oncogenic properties through protein-protein interactions that alter gene transcriptions and chromatin remodelling. Synovial sarcomas respond poorly to the conventional chemotherapies. Hence, it is necessary to develop novel therapeutic targets to improve the outcome of the treatment in synovial sarcoma. Considering that the expression of the fusion protein SS18-SSX is specific and essential for synovial sarcoma development and survival, targeting this chimeric oncoprotein or its functional protein network is a potential therapeutic strategy. To date there are no known compounds that directly target SS18-SSX, the driving fusion protein of synovial sarcoma.SS18 is a transcriptional activator, member of the SWI/SNF complex that is ubiquitously expressed in normal cells. In the SS18-SSX fusion protein, the last nine amino acids of SS18 are replaced by 78 C-terminal amino acids of SSX. The resultant fusion protein therefore inherits oncogenic activities that are independent of the wild type SS18 and SSX. It recruits proteins that are involved in epigenetic gene regulation such as histone deacetylases and polycomb group proteins to form a fusion protein complex that regulates gene transcription and subsequently drives malignant transformation.The work in this thesis explores the role of two class III histone deacetylases, SIRT1 and SIRT2, in the proliferation and survival of synovial sarcoma. We found that SIRT1 is overexpressed in primary synovial sarcomas. Both siRNA mediated and pharmacological knock down of SIRT1 and SIRT2 in synovial sarcomas and rhabdomyosarcomas impairs cell proliferation and autophagy flux. The overexpression of SIRT1 in synovial sarcomas was not associated with the clinical outcome of patients. However, in experimental in vitro cell assays, we observed that nutrient deprivation enhanced the sensitivity of synovial sarcoma and rhabdomyosarcoma cells to sirtuin inhibition. These results suggest a role of SIRT1 and SIRT2 in tumor cell survival under conditions of nutrient deficiency.Mechanistically, we found that SIRT1 and SIRT2 form a complex with SS18-SSX and their histone substrate H4K16ac in a synovial sarcoma cell line and a patient-derived synovial sarcoma. This complex is disrupted shortly after exposure to the sirtuin inhibitors tenovin-6 and AGK2. These findings indicate that the interactions between SIRT1/SIRT2 and SS18-SSX may contribute to the malignant phenotype of synovial sarcoma by modifying acetylation of the SIRT1 and SIRT2 substrate, H4K16. The acetylation of H4K16 is associated with autophagy. Future studies should address whether autophagy genes are targets of the SS18-SSX/SIRT1/SIRT2 complex.We set up a proximity ligation assay (PLA) as a screening method to search for small compounds that disrupt the SS18-SSX fusion protein complex. We first validated the method and showed that the association of SS18-SSX with TLE1 is specific for synovial sarcoma and can be visualised by PLA. We then screened a library of 16000 molecules and identified class I HDAC inhibitors and a novel compound, SXT1596, as agents that are able to dissociate the SS18-SSX/TLE1 complex and induce apoptosis in synovial sarcomas. We further showed that the disruption of the SS18-SSX/TLE1 complex by SXT1596 in synovial sarcoma released repression of EGR1 and rescued normal signaling.The studies in this thesis provide direct evidences that SS18-SSX interacts with proteins that regulate transcription by epigenetic modification of targets, such as class I histone deacetylases and sirtuins. The disruption of the SS18-SSX protein complex with small molecular HDAC inhibitors induces rapid death of synovial sarcoma cells proving that targeting the driving complex of synovial sarcoma may give an opportunity to develop effective therapies for synovial sarcoma patients. Furthermore, PLA based drug screening is shown to be a reliable and valuable technique to identify lead compounds that disrupt protein-protein interactions and could be applied in other cancer types that are driven by fusion transcription factors.List of scientific papersI. SIRT1 and SIRT2 inhibition impairs paediatric soft tissue sarcoma growth. Limin Ma, Maruwge W, Strambi A, D'Arcy P, Pellegrini P, Kis L, de Milito A, Lain S, Brodin B. Cell Death and Disease (2014) 5, e1483. https://doi.org/10.1038/cddis.2014.385 II. Identification of cytotoxic agents disrupting synovial sarcoma oncoprotein interactions by proximity ligation assay. Aimée N Laporte, Jennifer X Ji, Limin Ma, Torsten O Nielsen and Bertha Brodin. Oncotarget, 2016 Apr 21. https://doi.org/10.18632/oncotarget.8882 III. Studies on the clinical relevance and mechanism of activity of sirtuin inhibitors in synovial sarcoma. Limin Ma, Lingjing Chen and Bertha Brodin. [Manuscript]</p
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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