1,720,969 research outputs found
IDENTIFICATION AND VALIDATION OF CRITICAL 1Q21 'ACHILLES HEEL' VULNERABILITIES OF MULTIPLE MYELOMA
Get PDFMultiple Myeloma (MM) is malignancy of terminally differentiated plasma cells characterized by a marked heterogeneity of genetic lesions and clinical course. Despite significant efforts towards the development of risk stratification strategies for patients with Multiple Myeloma (MM), we are still limited in our capacity to molecularly predict the natural history of these patients. Recent molecular analyses have illuminated many aspects of the pathogenesis of this heterogeneous disease, although there remains an elemental view of the compendium of genetic elements driving MM initiation and progression and how such genetic alterations functionally contribute to specific aspects of disease pathobiology, prognosis and treatment responses. Indeed, despite considerable progress in the management of MM patients, many studies have shown that some genetic alterations especially t(4;14) translocation, loss of the short arm of chromosome 17, loss of the long arm of chromosome 13 and amplification of chromosome 1q21 remain associated with a poor outcome and represent independent adverse predictors of shorter progression free survival (PFS) and overall survival (OS). The 1q21 amplicon is among the most frequent chromosomal aberrations in patients with MM (about 40% of de novo MM) and is considered a highly poor-risk genetic feature correlated with disease progression and drug resistance; it spans approximately a region of 10-15 Mb containing a large number of possible candidate genes. To date the relevant genes on 1q21 remain unclear and the absence of focal amplifications involving this region strongly suggests that more than a single candidate may represent the driver event responsible for poor outcome of this group of MM patients. Thus, the identification of critical 1q21 ‘Achilles heel’ vulnerabilities may yield a comprehensive catalog of the potential therapeutic targets for these high risk MM and provide a rationale for patient stratification. In an effort to accomplish this goal, we first identified a high-priority list of 78 copy number-driven 1q21 MM-relevant genes. Then, we have designed a high-throughput systematic shRNA screen approach in vitro to identify 1q21 genes whose loss of function results in selective death and/or growth inhibition of MM cells carrying the 1q21 amplification. After excluding shRNAs that display citotoxic activity regardless 1q21 amplification, we defined 1q21 “Achilles heel” vulnerabilities as shRNA target genes whose down-regulation decreases substantially the percentage of GFP-positive MM cells with 1q21 amplification over a time of 7 days based on a GFP-competion assay. This assay provided a list of candidate genes implicated in survival or proliferation of MM cells with 1q21 amplification; MCL1, UBAP2L, INTS3, LASS2, KRTCAP2, and ILF2. By targeting these six genes we performed secondary validation experiments in JJN3 and H929 MM cell lines, carrying 4 copies of 1q21 amplicon. The results of this secondary validation confirmed that the down-regulation of these genes caused an important decrease of proliferation and increase of apoptosis as well as growth cycle arrest. Further GEP analysis and clinical outcome studies revealed that only UBAP2L and ILF2 showed a significant prognostic value but in vivo validation studies on NOD-SCID mice identified only ILF2 correlated with in vivo survival. So our studies focused to investigate the role of ILF2 in 1q21 amplified MM.
Nuclear Factor 45 (NF45) or ILF-2 is widely expressed in normal tissue with a predominant nuclear distribution. NF45/ILF2 associates with NF90/NF110 (ILF3) interacting with DNA and RNA. ILF2 and ILF3 contribute to gene regulation at different levels, transcription, splicing, nuclear exporting, but they are also involved in other important processes like mitotic control and DNA break repair.
Down-regulation of ILF2 in MM cells with 1q21 amplification resulted in multinucleated phenotypes and abnormal nuclear morphologies that were associated with a significant accumulation of γH2AX foci and DNA damage response activation, increased sensitivity to Melphalan, DNA damaging agent, and impaired activation of DNA repair pathways. Experiments of immunoprecipitation combined with mass spectometry showed that ILF2 interacts with numerous RNA binding proteins directly implicated in DNA repair or regulation of DNA damage response by modulating alternative splicing and stability of specific pre-mRNAs. Accordingly, RNA-sequencing analysis of ILF2-depleted MM cells, when compared to cells carrying scrambled shRNAs, identified specific changes in RNA splicing patterns before and after treatment with Melphalan.
Thus, our findings have raised a new tight correlation between 1q21 amplification and DNA damage response. We identified ILF2 as a key driver of this interaction, and our findings support the development of strategies designed to modulate ILF2 expression in patients with high-risk MM carrying 1q21 amplification providing personalized therapies for patients who do not benefit from recent treatment improvements
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
- …
