1,720,952 research outputs found
Development of imidazotetrazines for the treatment of glioblastoma & as synthetic precursors to diazo species
Get PDFGlioblastoma multiforme (GBM), a grade IV astrocytoma, is the most prevalent, aggressive, and deadly form of malignant brain tumor with only 10% of patients surviving five years. The current standard treatment for GBM patients is bulk surgical resection and radiotherapy with concomitant and adjuvant temozolomide (TMZ), a small molecule DNA alkylating agent. The antitumor effect of TMZ is ultimately mediated through methylation of the O6-position of guanine and subsequent mismatch repair (MMR)-dependent cell death. Although TMZ was first synthesized in 1984 and has been FDA approved for two decades, certain key derivatives have been inaccessible due to synthetic challenges, precluding a broad exploration of the link between imidazotetrazine structure and biological activity. Novel synthetic strategies provided access to several new classes of C8-substituted imidazotetrazines and an evaluation of their aqueous stabilities enabled the derivation of a predictive model for imidazotetrazine hydrolytic stability based on the Hammett constant of the C8 substituent. Promising compounds modified at the C8 position were identified and found to have appropriate hydrolytic stability, enhanced blood-brain barrier permeability, lower hematological toxicity profiles, and superior activity relative to TMZ in a mouse model of GBM.
Despite its widespread use, certain GBM patient populations do not respond to TMZ therapy. Expression of O6-methylguanine DNA methyltransferase (MGMT) and loss of MMR function are the primary clinical modes of resistance to TMZ. Imidazotetrazine analogs modified at the N3 position were designed to deliver alternative DNA adducts that were irremovable by MGMT. An analog bearing a propargyl group at N3 demonstrated MGMT-independent activity in GBM cells in culture. Tuning the stability with an electron-donating chloro substituent at the C8 position produced novel dual-substituted imidazotetrazine CPZ, which displayed anticancer activity irrespective of MGMT expression and MMR status.
Imidazotetrazines such as TMZ are precursors to alkyl diazoniums, used therapeutically to alkylate DNA and elicit an anticancer effect. Given their stability as prodrugs and the reactivity of the species released, imidazotetrazines were repurposed into synthetic surrogates for diazomethane and other diazoalkanes. TMZ was employed to conduct esterifications and metal-catalyzed cyclopropanations, with methyl ester formation from a wide variety of substrates proving efficient and operationally simple. As a commercially available solid that is non-explosive and non-toxic, TMZ should find broad utility as a synthetic replacement for diazomethane.Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2022-05-01The student, Riley Svec, accepted the attached license on 2020-04-14 at 17:59.The student, Riley Svec, submitted this Dissertation for approval on 2020-04-14 at 18:07.This Dissertation was approved for publication on 2020-04-16 at 13:46.DSpace SAF Submission Ingestion Package generated from Vireo submission #14980 on 2020-08-25 at 17:40:15Made available in DSpace on 2020-08-27T00:49:56Z (GMT). No. of bitstreams: 3
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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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