1,720,966 research outputs found
HSP70/HSF1 axis has a role in the pathogenesis of Chronic Lymphocytic Leukemia and is a druggable target
Get PDFChronic Lymphocytic Leukemia (CLL) is a neoplastic disorder, characterized by the accumulation of clonal B lymphocytes due to an increased proliferation and the inability to reach programmed cell death. CLL is a heterogeneous disease with some patients asymptomatic, while others experience a more aggressive disorder, treatment failure and a poor overall survival. As a consequence, novel biological and cytogenetic features are crucial to predict patient’s prognosis, and the search for key molecules involved in the pathogenesis of the disease is still ongoing.
We previously performed a Reverse Phase Protein Array (RPPA) analysis for the identification of new proteins, which might contribute to the apoptosis resistance and the increased survival of CLL cells. We found the Heat Shock Protein of 70kDa (HSP70) significantly overexpressed in CLL cells with respect to normal controls. HSP70 is a molecular chaperone induced in response to several physiological and environmental insults, thus allowing cells to survive to otherwise lethal conditions. The main responsible of HSP70 transcription is the Heat Shock Factor 1 (HSF1), able to bind to DNA and to activate Heat Shock gene transcription in response to stress.
During this three-year PhD project, we were aimed at characterizing HSP70 and its major regulator, HSF1, in CLL cells.
We found HSP70 and HSF1 both overexpressed (138 CLL patients, 1.24±0.85 vs 32 healthy controls, 0.77±0.57; p<0.01; 85 CLL patients 0.81±0.77 vs 19 healthy controls, 0.30±0.36; p<0.01, respectively), correlated to poor prognosis and abnormally localized in the nucleus of CLL cells. We showed that the two protein levels were decreased, and positively correlated to each other (e.g. p<0.05; r=0.94), in patients responding to in vivo therapeutic regimens.
To better understand HSP70 and HSF1 role in CLL, we performed in vitro inhibition of these proteins using specific drugs (VER-155008, KRIBB11, zafirlukast, fisetin), which led to a dose-dependent apoptosis of leukemic cells from CLL patients (e.g. cell viability at 24h: CLL cells alone 63±14%, vs CLL cells + 15µM fisetin 35±19%, p<0.0001). Moreover, we demonstrated that fisetin was able to bypass the microenvironmental protection when neoplastic B cells were co-cultured with 15µM fisetin and MSCs (e.g. 30±17%, 25±19%, 26±15% without MSCs, and 32±14%, 35±23%, 33±22% with MSCs at 24, 48, 72h, respectively).
HSF1 is regulated by its interactions with molecular chaperones, and also by a fine balance of activatory and inhibitory phosphorylations. Since most of HSF1-phosphorylating molecules belong to two RAS-signalling pathways (PI3K/AKT/mTOR and RAF/MEK/ERK), taking advantage from our previous RPPA analysis, we correlated HSP70 to different proteins related to these signals. By a cluster analysis, we divided our patients in HSP70high and HSP70low, on the basis of HSP70 protein levels, demonstrating that the RAS pathway proteins are differently regulated in the two groups. For HSP70high patients, we developed a model based on high AKT-Ser473 levels, in which AKT-Ser473 inhibits GSK3a/b that, in turn, is unable to inhibit HSF1. On the other hand, HSP70low patients present high MEK1/2-Ser217/221 and ERK-Thr202/Tyr204, that negatively regulate HSF1. As a result, the activation of the PI3K/AKT/mTOR pathway leads to a higher expression of HSP70, while an activation of the RAF/MEK/ERK pathway results in HSP70 downregulation.
By RAS pathway inhibition, we validated our model for the aberrant regulation of HSP70/HSF1 axis in CLL. To this purpose, we used resveratrol, a natural polyphenol, able to inhibit AKT and to activate ERK. After 24h treatment with 40µM resveratrol, we observed a reduction in cell viability (61±18% of untreated cells vs 54±20%; p<0.01) with a decreased protein expression both for HSF1 and HSP70: 1.15±0.69 to 0.50±0.64, and from 1.13±0.69 to 0.54±0.35, respectively; p<0.01).
In conclusion, the HSP70 and HSF1 overexpression and correlation with resistance to therapy in CLL, together with the ability of fisetin to induce apoptosis in leukemic B cells bypassing the pro-survival stimuli of tumor microenvironment, represent a starting point for the development of new therapeutic strategies. Moreover, the study of resveratrol effects on leukemic B cells provides new insights on the cross-talk between HSP70/HSF1 axis and RAS signalling in CLL
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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