1,721,226 research outputs found
Metabolic liver disease and hepatocellular carcinoma : prediction from carcinogenesis to treatment response through proteomic profiling
No full textLa stéatohépatite liée à une dysfonction métabolique (MASH) représente jusqu’à 35% des carcinomes hépatocellulaires (CHC) dans le monde et constitue la première cause de transplantation pour CHC aux États-Unis. Contrairement à d'autres étiologies, un tiers des CHC liés à la MASH se développent sur un foie non cirrhotique, échappant ainsi aux recommandations de dépistage réservées aux patients cirrhotiques, et conduisant à un diagnostic tardif et un pronostic défavorable. Le dépistage systématique est irréalisable en raison du nombre élevé de patients et il n'existe aucun marqueur prédictif de transformation tumorale. De plus, en cas de CHC avancé, les seules options disponibles sont les thérapies systémiques palliatives. Après des années de monothérapie par sorafénib, l'association atezolizumab/bevacizumab, combinant immunothérapie et antiangiogénique, est désormais recommandée en première ligne. Cependant, le taux de réponse reste limité à 30%, peu de patients accèdent à une deuxième ligne de traitement et il n'existe à ce jour aucun facteur prédictif de réponse. Le profilage protéomique tissulaire par spectrométrie de masse est une approche globale et sans a priori adaptée à ces problématiques complexes. Elle a permis à notre équipe d’identifier une signature prédictive de la non réponse à l’atezolizumab/bevacizumab associée à un shift métabolique.Au cours de ma thèse, mon premier but était d’identifier une signature protéomique prédictive du CHC sur foie MASH et d’étudier les voies de carcinogenèse mises en évidence. Le second but était de valider dans un modèle cellulaire 3D l’implication de la diminution du métabolisme oxydatif dans la résistance à l’atezolizumab/bevacizumab.Premièrement, nous avons mené une étude rétrospective sur biopsies hépatiques de 20 patients atteints de MASH : 11 patients ayant développé un CHC dans les 15 ans suivant leur biopsie initiale (groupe 1, avec une médiane entre la biopsie et le CHC de 7,70 ans) et 9 patients contrôles (groupe 2). Les patients étaient comparables sur les plans clinique et histologique. Nous avons obtenu une signature protéomique de prédiction du CHC de 330 protéines significativement dérégulées et permettant de séparer les deux groupes. Une cohorte de 13 nouveaux patients a permis de valider cette signature protéomique. Parmi ces 330 protéines, la prothymosine alpha (PTMA) était significativement surexprimée dans le groupe 1 avec le plus fort ratio entre les deux groupes. PTMA est surexprimée dans de nombreux cancers dont le CHC et impliquée dans des voies de prolifération cellulaire et de résistance à l’apoptose, ce qui en fait un candidat pertinent. La validation fonctionnelle de PTMA est en cours dans un modèle cellulaire de MASH.Deuxièmement, nous avons mis au point un modèle d’infiltration immunitaire au sein d’un sphéroïde de CHC puis mimé le shift métabolique des patients non répondeurs de façon pharmacologique par un inhibiteur de la chaine respiratoire mitochondriale. Nous avons montré une diminution de l’infiltrat immunitaire dans les sphéroïdes traités, ce qui peut participer à une moindre efficacité de l’immunothérapie chez ces patients.Notre signature protéomique apporte des résultats prometteurs sur la prédiction du CHC sur foie MASH, soulignant une possible implication précoce de la protéine PTMA. L’exploration du rôle de PTMA et des autres cibles identifiées pourra ouvrir des pistes de prévention du développement tumoral. Une validation externe de cette signature sur une plus large cohorte sera nécessaire avant un transfert à la clinique, dans le but d’optimiser le dépistage du CHC chez les patients atteints de MASH. La deuxième partie de cette thèse identifie un mécanisme de résistance du CHC à l’atezolizumab/bevacizumab. Cette approche pourra être étendue à l’ensemble des traitements de première ligne du CHC ouvrant ainsi la voie à une médecine personnalisée et à des pistes de recherche visant à améliorer l’efficacité des traitements.Metabolic dysfunction-associated steatohepatitis (MASH) is responsible for up to 35% of hepatocellular carcinomas (HCC) worldwide and is the leading cause of liver transplantation for HCC in the United States. Unlike other etiologies, a third of MASH-driven HCC develop in non-cirrhotic livers, thereby escaping screening recommendations restricted to cirrhotic patients, and leading to late diagnosis and poor prognosis. Systematic screening is not feasible due to the high number of patients, and there is currently no predictive marker for HCC development. Moreover, in case of advanced HCC, the only available treatments are palliative systemic therapies. After years of monotherapy with sorafenib, the combination of atezolizumab and bevacizumab, which includes immunotherapy and anti-angiogenic treatment, is now recommended as first-line treatment. However, the response rate remains restricted to 30%, few patients have access to second-line treatment, and there are no predictive factors of response. Tissue proteomic profiling by mass spectrometry is a comprehensive and unbiased approach adapted to these complex issues. It enabled our team to identify a predictive signature of non-response to atezolizumab/bevacizumab associated with a metabolic shift.During my PhD, my first aim was to identify a proteomic signature of prediction of MASH-driven HCC and to study pathways involved in carcinogenesis. The second aim was to validate in a 3D cellular model the implication of decreased oxidative metabolism in resistance to atezolizumab/bevacizumab.Firstly, we conducted a retrospective study on liver biopsies from 20 MASH patients: 11 patients who developed HCC within 15 years following their initial biopsy (group 1, with a median time from biopsy to HCC of 7.70 years) and 9 control patients (group 2). The patients were similar in clinical and histological terms. We obtained a proteomic signature of HCC prediction consisting in 330 significantly deregulated proteins, which allowed differentiation between the two groups. This proteomic signature was validated in a cohort of 13 new patients. Among these 330 proteins, prothymosin alpha (PTMA) was significantly overexpressed in group 1, with the highest ratio between the two groups. PTMA is overexpressed in many cancers including HCC and is involved in cell proliferation and apoptosis resistance pathways, making it a relevant candidate. Functional validation of PTMA is ongoing in a cellular model of MASH.Secondly, we developed a model of immune infiltration within an HCC spheroid and mimicked the metabolic shift of non-responder patients with a pharmacological inhibitor of mitochondrial respiratory chain. We demonstrated a decrease in immune infiltration in treated spheroids, which may contribute to the reduced efficacy of immunotherapy in these patients.Our proteomic signature yields promising results for predicting MASH-driven HCC, highlighting a potential early involvement of PTMA. Investigating the role of PTMA and other identified targets could open research avenues for preventing tumor development. External validation of this signature in a larger cohort will be necessary before clinical application, in order to optimize HCC screening in MASH patients. The second part of this thesis identifies a mechanism of HCC resistance to atezolizumab/bevacizumab. This approach could be extended to all first-line treatments of HCC, paving the way for personalized medicine and future research to enhance treatment efficacy
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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