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STUDIO DELLE VIE DI SEGNALAZIONE PROTEICA COINVOLTE NELLA RESISTENZA AI GLUCOCORTICOIDI NEI PAZIENTI PEDIATRICI AFFETTI DA LEUCEMIA LINFOBLASTICA ACUTA A CELLULE T (T-ALL) E DA LINFOMA LINFOBLASTICO T (T-LBL)
No full textLa leucemia linfoblastica acuta a cellule T (T-ALL) e il linfoma linfoblastico T (T-LBL) sono tumori pediatrici con caratteristiche morfologiche, immunofenotipiche e un approccio terapeutico simili. Ad oggi non è ancora chiaro se queste due neoplasie rappresentino due manifestazioni distinte della stessa malattia o due patologie completamente diverse. Inoltre, finora la diagnosi differenziale dei casi T-ALL e T-LBL è basata sulla percentuale di blasti nel midollo osseo (MO), che è inferiore al 25% per i pazienti con T-LBL. Pertanto, la diagnosi è particolarmente critica per i casi di IV stadio T-LBL con un'infiltrazione del MO prossima al 25%. Ad oggi, non sono disponibili dati sul profilo fosfoproteomico dei pazienti con T-ALL e T-LBL che potrebbero contribuire a questa discriminazione e portare all'identificazione di potenziali nuovi biomarcatori utili per distinguere i pazienti T-ALL e IV stadio T-LBL. I glucocorticoidi (GC) sono ampiamente utilizzati per il trattamento sia dei pazienti pediatrici T-ALL che T-LBL. Nonostante la resistenza ai GC sia frequente e abbia un impatto negativo sulla prognosi di questi pazienti, i meccanismi responsabili dell'insorgenza della resistenza ai GC non sono ancora del tutto delineati. Pertanto, gli obiettivi principali di questo studio sono stati: i) caratterizzare il profilo fosfoproteomico dei pazienti pediatrici T-ALL e T-LBL alla diagnosi, per contribuire a capire se queste due entità rappresentino o meno la stessa malattia e rivelare potenziali nuovi biomarcatori utili alla discriminazione dei pazienti IV stadio T-LBL e T-ALL, ii) identificare nuovi potenziali bersagli terapeutici coinvolti nella resistenza ai GC nei pazienti pediatrici T-LBL e T-ALL. In questo studio, abbiamo osservato che i pazienti pediatrici T-ALL e T-LBL sono caratterizzati da un profilo fosfoproteomico unico, suggerendo che queste neoplasie rappresentino due diverse malattie ematologiche. In aggiunta, abbiamo osservato che l’espressione/attivazione complessiva di ERK1/2 T202/Y204, AKT S473/tot, mTOR S2448/tot, FAK Y397, P21 e BAX, può distinguere i pazienti T-ALL dai T-LBL stadio IV, proponendo così un nuovo potenziale biomarcatore utile alla diagnosi delle due patologie. In aggiunta, abbiamo dimostrato che l’inibitore specifico di JAK1-2 ruxolitinib, può sensibilizzare all’azione dei GC i pazienti T-LBL con progressione della malattia e/o recidiva caratterizzati dall’iperattivazione di JAK2. Per quanto riguarda i pazienti T-ALL, abbiamo osservato che NFATc1 e c2 sono più espressi nel sottogruppo resistente ai GC, e che la via di segnalazione Calcineurina/NFAT modula la risposta ai GC nelle cellule T-ALL. In particolare, abbiamo dimostrato che il silenziamento genico di NFATc1 e NFATc2, in modo mutuamente esclusivo, può ridurre la resistenza ai GC nelle cellule T-ALL ripristinando la capacità del recettore dei glucocorticoidi di trascrivere geni pro-apoptotici. Inoltre, abbiamo dimostrato che NFATc1 modula la risposta ai GC controllando la biosintesi del colesterolo, che a sua volta può influenzare l'abbondanza delle zattere lipidiche nella membrana plasmatica e di conseguenza l’attivazione della via LCK/PLCγ, a valle del TCR. Al contrario, NFATc2 può probabilmente influenzare la risposta ai GC regolando la staminalità delle cellule T. Infine, mediante l’utilizzo in vitro, della simvastatina, abbiamo dimostrato come l’inibizione della biosintesi del colesterolo possa rappresentare una nuova opzione terapeutica per sensibilizzare ai GC i pazienti pediatrici T-ALL in cui NFATc1 guida la resistenza. Concludendo, abbiamo dimostrato che i pazienti pediatrici T-ALL e T-LBL, nonostante condividano origini e caratteristiche comuni, sono caratterizzati da un diverso profilo fosfoproteomico, che a sua volta si riflette nella capacità delle cellule di leucemia e linfoma di sfruttare vie di segnalazione e processi biologici differenti per sfuggire all'attività pro-apoptotica dei GC.T-cell acute lymphoblastic leukemia (T-ALL) and T-lymphomas lymphoma (T-LBL) represent pediatric hematological malignancies, arising from T-cell precursors transformation, with common morphological and immunophenotypic features, and similar therapeutic strategies. Nowadays, there is still an ongoing discussion in the scientific community on whether the two malignancies represent two different disease entities or two distinct clinical manifestations of the same disease. Moreover, the clinical discrimination between T-ALL and T-LBL is still arbitrarily based on the blasts percentage in the Bone Marrow (BM) that is less than 25% for T-LBL patients. However, this cut-off value is particularly critical for the diagnosis of stage IV T-LBL patients since they are characterized by a BM infiltration near to 25%. Notably, so far there is no available data on T-ALL and T-LBL patients phosphoproteomic profile that could contribute to this discrimination, paving the way for the identification of potential new biomarkers useful to distinguish T-ALL from stage IV T-LBL patients. Importantly, glucocorticoids (GCs) are widely used to treat both T-ALL and T-LBL pediatric patients. Although GC resistance is rather frequent and has a negative impact on patients’ prognosis, the mechanisms responsible for GC resistance in T-ALL and T-LBL are not fully defined. Thus, the identification of novel GC resistance mechanisms could allow identifying possible new therapeutic targets for pediatric T-ALL and T-LBL patients. Therefore, the major aims of this study had been: i) to characterize T-ALL and T-LBL pediatric patients phosphoproteomic profile at diagnosis, to contribute in understanding whether these two entities represent or not the same disease and to disclose potential new biomarker(s) that could contribute discriminating between stage IV T-LBL and T-ALL patients, ii) to unveil and deeply characterize new potentially targetable pathways involved in GC resistance in T-ALL and T-LBL pediatric patients. Interestingly, we uncovered that T-ALL and T-LBL patients are characterized by a unique phosphoproteomic profile suggesting that these malignancies are likely to represent two different diseases. Moreover, we identified a proteomic signature of 6 proteins, namely ERK1/2 T202/Y204, AKT S473/tot, mTOR S2448/tot, FAK Y397, P21 and BAX, whose expression/activation can discriminate stage IV T-LBL from T-ALL. Furthermore, we demonstrated that the FDA-approved specific JAK1-2 inhibitor ruxolitinib can revert GC resistance in T-LBL patients with disease progression and/or relapsed, characterized by JAK2 hyperactivation. Regarding T-ALL patients, we observed that NFATc1 and c2 are more expressed in patients that display resistance to GC at diagnosis and that Calcineurin/NFAT pathway regulates GC response in T-ALL cells. Specifically, we demonstrated that both NFATc1 and NFATc2 gene silencing, in a mutually exclusive manner, can impair GC resistance in T-ALL cells by restoring the glucocorticoid receptor ability to transcribe pro-apoptotic genes. Moreover, we observed that NFATc1 regulates GC response by controlling cholesterol biosynthesis, that in turn can affect plasma membrane lipid rafts abundance and as consequence the LCK/PLCγ TCR downstream pathway activation. Conversely, NFATc2 by regulating T cell stemness can likely influence GC response. Finally, by in vitro experiments, we demonstrated that the cholesterol biosynthesis inhibitor simvastatin can represent a new therapeutic option to overcome GC resistance in T-ALL pediatric patients in whom NFATc1 drives the resistance. In conclusion, we demonstrated that T-ALL and T-LBL pediatric patients, despite sharing common origins and features, are characterized by a different phosphoproteomic profile, which in turns is reflected by the evidence that leukemia and lymphoma cells exploit different signaling protein pathways and biological processes to escape GC pro-apoptotic activity
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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