1,720,979 research outputs found
In vitro and in vivo antitumor activity of new choline kinase inhibitor: a pharmacological strategy for breast cancer and leukemia treatment.
Full text linkAberrant choline metabolism is a feature shared by many tumors. It is predominantly caused by elevated expression and activation of choline kinase alpha (ChoKα), which catalyzes the phosphorylation of choline to phosphocholine in the Kennedy’s pathway for membrane lipids synthesis. In this PhD thesis, the most promising symmetrical ChoKα inhibitor has been identified from the novel series of choline kinase inhibitors, designed and synthesized by Prof. Lopez-Cara’s group, University of Granada, Spain. The therapeutic potential of the selected lead compound was compared to previously reported symmetrical ChoKα inhibitors and evaluated in two different tumoral contexts. Furthermore, the new ChoKα inhibitor was used to investigate for the first time choline metabolism deregulation in hematological tumors.
The ChoKα inhibitor EB-3D (also known as compound 10a) was selected as lead compound. The crystal structure of ChoKα1 in complex with compound EB-3D (PDB ID: 5FTG) reveals that the compound effectively binds to the choline-binding site and inhibits ChoKα1 with IC50 of 1.00 ± 0.01 μM. EB-3D strongly inhibits cell growth in a panel of cancer cell lines with GI50 ranging from 27 to 110 nM for solid tumors and from 0.9 to 479 nM for hematological tumors. EB-3D inhibits also the formation of phosphocholine and reduces the content of choline-containg metabolites in treated cells.
In triple-negative MDA-MB-231 breast cancer cells, EB-3D arrests cells in the G0/G1 phase of the cell cycle triggering irreversible cellular senescence. Moreover, EB-3D potentiates the antitumoral effect of cisplatin and impairs migration and invasiveness of the higly metastatic MDA-MB-231 cell line. Lastly, treatment of syngeneic orthotopic EO771- C57BL/6 mouse model with 1mg/kg of EB-3D i.p. resulted in strong tumour growth inhibition and reduction of metastasis formation. Alltogether, these data reveal the antitumorigenic and antimetastatic potential of EB-3D in triple-negative breast cancer (TNBC).
T acute lymphoblastic leukemia (T-ALL) cell lines exhibit increased levels of ChoKα compared to healthy lymphocytes and higher ChoKα/β ratio. EB-3D induces G0/G1 cell cycle arrest in T-ALL and, in contrast to breast cancer cells, induces cell death by apoptosis. The effect is rapidly triggered and cannot be rescued by compound withdrawal. EB-3D modulates the AMPK-mTOR pathway leading to the inactivation of final effectors required for protein synthesis and cell cycle progression. On the contrary, the effect appears attenuated in normal lymphocytes where other signaling pathways are involved.
Finally, EB-3D strongly synergizes with L-asparaginase lowering the GI50 and increasing cell death. Taken together, these data validate ChoKα as a novel attractive therapeutic target in T-ALL and justify the further development of EB-3D inhibitor.L’enzima colina chinasi α (ChoKα) catalizza la fosforilazione della colina in fosfocolina nel primo step del Kennedy pathway che porta alla biosintesi dei fosfolipidi di membrana. Negli ultimi anni l’overespressione e/o iperattivazione dell’enzima ChoKα sono state descritte in diverse neoplasie, dove correlano con una peggior prognosi oltre che ad un’aumentata invasività e resistenza alle comuni terapie oncologiche. Dunque, per la sua rilevanza in campo oncologico, quest’enzima è recentemente diventato oggetto di interesse per lo sviluppo di inibitori selettivi.
In questa tesi di Dottorato viene identificato l’inibitore simmetrico di ChoKα più promettente all’interno di una serie di nuovi composti disegnati e sintetizzati dal gruppo della Prof.ssa Lopez-Cara dell’Università di Granada, Spagna. Il potenziale terapeutico del composto selezionato è stato comparato con i due inibitori simmetrici di ChoKα di riferimento descritti in letteratura e valutato in due diversi contesti tumorali. Inoltre, il nuovo inibitore di ChoKα è stato usato per descrivere per la prima volta l’alterato metabolismo della colina nei tumori ematologici.
Il composto EB-3D (riportato anche con il nome di composto 10a) è stato selezionato come migliore inibitore simmetrico di ChoKα. La struttura cristallografica di EB-3D in complesso con l’isoforma ChoKα1 (PDB ID: 5FTG) rivela che il composto si colloca nella tasca contenente il sito di legame della colina inibendo così ChoKα1 con IC50 di 1.00 ± 0.01 μM. EB-3D riduce drasticamente la proliferazione cellulare in un pannello di linee tumorali con GI50 che variano da 27 a 110 nM per i tumori solidi e da 0.9 a 479 nM per i tumori ematologici. EB-3D inoltre inibisce la formazione di fosfocolina e, in generale, riduce la quantità dei composti contenenti colina nelle cellule trattate.
Nella linea cellulare di tumore mammario triplo negativo MDA-MB-231, EB-3D induce un blocco del ciclo cellulare nella fase G0/G1 innescando il processo della senescenza cellulare. EB-3D inoltre potenzia l’effetto antitumorale del cisplatino e interferisce sia sulla migrazione che sull’invasione di questa linea cellulare altamente metastatica. Infine, la somministrazione per via intraperitoneale di EB-3D nel modello murino singenico ortotopico EO771-C57BL/6 ha portato ad una significativa riduzione della massa tumorale e alla riduzione della formazione di metastasi polmonari. Complessivamente, questi dati rivelano il potenziale antitumorale e antimetastastico del nuovo inibitore di ChoKα EB-3D nella forma più aggressive di tumore al seno.
Parallelamente, in questa tesi viene descritto per la prima volta che diverse linee cellulari di leucemia linfoblastica acuta di tipo T (T-ALL) esibiscono elevati livelli di ChoKα rispetto ai linfociti sani. EB-3D induce anche in questo caso l’arresto del ciclo cellulare in fase G0/G1 e, contrariamente a quanto osservato nelle cellule di tumore mammario, innesca l’apoptosi in modo rapido e irreversibile. EB-3D modula inoltre il pathway di AMPK-mTOR portando all’inattivazione degli effettori finali coinvolti nella sintesi proteica e nella progressione del ciclo cellulare. Infine, EB-3D sinergizza con L-asparaginasi, con incremento dell’apoptosi cellulare. Concludendo, questi risultati dimostrano che ChoKα può essere considerato un nuovo target terapeutico per le leucemie acute linfoblastiche e giustificano l’ulteriore sviluppo dell’inibitore EB-3D
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
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