1,720,960 research outputs found
Pharmacogénomique de la voie de glucuronidation : mécanismes moléculaires et impact clinique
No full textLa voie de glucuronidation catalyse l’inactivation de nombreux métabolites endogènes, tels que la bilirubine ou les hormones stéroïdiennes, ainsi que des substances exogènes incluant notamment des médicaments et des carcinogènes. Ce processus enzymatique opéré par les enzymes UDP-glucuronosyltransférases (UGT) entraîne généralement l’abolition de l’activité biologique ou pharmacologique des composés et en augmente la solubilité afin de favoriser leur élimination de l’organisme. Une importante variabilité dans l’expression et l’activité de la voie de glucuronidation est observée entre les individus, pouvant affecter l’exposition aux substrats de cette voie enzymatique. Dans le cadre de ma thèse, je me suis intéressé à l’influence des polymorphismes génétiques et de l’épissage alternatif sur la variabilité de la voie de glucuronidation et la réponse au traitement. La relation entre les variations génétiques et la réponse au traitement de chimiothérapie de première intention à base d’irinotécan a d’abord été étudiée chez des patients atteints du cancer colorectal métastatique (CCRm). De nouveaux marqueurs germinaux ont été associés à la survie des patients de deux cohortes indépendantes, notamment dans les gènes UGT1, CES1 (carboxylestérase 1), ABCC1 (multidrug resistance-associated protein 1), RPL28 (protéine ribosomique L28) et du facteur de transcription HNF1A (hepatocyte nuclear factor 1-alpha). D’autre part, nos travaux révèlent que les variants d’épissage d’UGT2B10 représentent plus de la moitié du transcriptome dérivé de ce gène dans le tissu hépatique. Les protéines alternatives codées par ces nouveaux transcrits affectent la capacité de glucuronidation d’agents pharmacologiques pris en charge par l’enzyme. L’exposition des cellules hépatiques à certains composés exogènes semble remodeler l’épissage du gène UGT2B10 au détriment de l’expression de l’enzyme. Les travaux présentés dans cette thèse supportent que la génétique du patient ainsi que les processus d’épissage alternatif au niveau tissulaire aient le potentiel d’affecter la capacité de glucuronidation et la réponse au traitement. Puisque ces deux mécanismes contribuent à la variabilité de la voie des UGT, ils pourraient constituer de nouveaux biomarqueurs de réponse aux composés pris en charge par ces enzymes.The UDP-glucuronosyltransferases enzymes (UGTs) are responsible for the conjugation of their co-substrate UDP-glucuronic acid to numerous endogenous and exogenous substrates, including many drugs. This metabolic reaction, called glucuronidation, generally results in substrate inactivation and leads to increased solubility, leading to its elimination through bile and urine. Along with other enzymatic conversions and transport pathways, glucuronidation is a determinant of drug response. However, an important interindividual variability in its expression and activity is observed in patients and may lead to variable bioavailability and response to drugs. During my thesis, my interests were to investigate the role of germline genetic variations and alternative splicing events as mechanisms involved in the interindividual variability of the UGT pathway. First, we investigated genetic polymorphisms of irinotecan-related pathways including UGTs, in relation to outcomes in 417 metastatic colorectal cancer patients treated with first-line irinotecan-based chemotherapy. We identified several markers of survival, namely polymorphisms in UGT1, CES1 (carboxylesterase 1), ABCC1 (multidrug resistance-associated protein 1), RPL28 (ribosomal protein L28) genes as well as in HNF1A (hepatocyte nuclear factor 1-alpha) transcription factor gene. Then, we demonstrated that alternative transcripts represent half of the UGT2B10 hepatic transcriptome. Alternative proteins arising from UGT2B10 splicing events alter enzymatic activity for UGT2B10 substrates. We also showed that pharmacological compounds may affect splicing events at the UGT2B10 locus. These studies support an impact of common genetic variations and post-transcriptional mechanisms on glucuronidation, drug exposure and possibly drug response. Germline variations and alternative splicing seem to significantly contribute to the high interindividual variability of the UGT pathway. They may be potential biomarkers of the response to drugs metabolized by this pathway
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
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