1,720,975 research outputs found
Caractérisation du micro-environnement des carcinomes rénaux à cellules claires et détermination des marqueurs de réponse aux inhibiteurs de checkpoints immunologiques
No full textLe cancer du rein à cellules claires (ccRCC) a bénéficié ces dernières années d'avancées thérapeutiques majeures. Le nivolumab, inhibiteur du point de contrôle immunitaire Programmed Cell Death-1 (PD-1), permettant de restaurer l'immunité adaptative anti-tumorale via l'activation des lymphocytes T (LT) CD8, est devenu depuis 2017 un standard de traitement en situation métastatique après échec d'un TKI anti-VEGFR. Cependant, seuls un quart des patients répondent au traitement et nous ne disposons pas à l'heure actuel de biomarqueur robuste prédictif d'efficacité. L'arrivée imminente de la combinaison nivolumab-ipilimumab en 1ère ligne de RCC métastatique suivi de la combinaison TKI anti-VEGFR plus anti-PD-1 pose d'autant plus la question du biomarqueur de sélection, sachant les toxicités potentiellement graves et le cout financier pour la société. La composition du microenvironnement tumoral et les interactions cellules immunitaires - cellules tumorales sont les pistes explorées les plus solides pour prédire la réponse aux immunothérapies. Mon travail de thèse s'inscrit dans la continuité des travaux menés par mon équipe d'accueil sur la caractérisation du microenvironnement immunitaire des ccRCC. A l'aide plusieurs cohortes distinctes de patients avec un ccRCC, nous avons rapporté dans 3 études publiées que : 1) une forte densité de LT CD8+ (immunohistochimie (IHC)) était associée à un mauvais pronostic à l'inverse de la plupart des autres tumeurs solides. Nous avons montré que ces CD8 avaient un phénotype « épuisé » potentiellement du fait de l'absence de coordination de la réponse immunitaire par des cellules dendritiques (DC) majoritairement immatures, situées en dehors des structures lymphoïdes tertiaires (TLS) ; 2) par l'analyse des lymphocytes infiltrant les tumeurs (TIL), nous identifions 3 groupes aux profil immunitaires distincts, « immuno-activé », « immuno-silencieux » et « immuno-régulé ». Ce dernier groupe caractérisé par une population lymphocytaire polyclonale, faiblement cytotoxique CD8+PD-1+Tim-3+Lag-3+ ainsi qu'une population de T régulateurs (Treg) ICOS+ avait un risque de récidive significativement plus important que les deux autres dans l'année suivant la néphrectomie. L'analyse du phénotype des LT circulants identifiait 2 groupes dont le groupe immuno-régulé ; 3) la voie classique du complément jouait un rôle pro-inflammatoire clé dans la progression tumorale, via la coopération entre les cellules tumorales et les macrophages associés à la tumeur (TAM). Les résultats préliminaires d'un 4ème travail en cours montrent des proportions/phénotypes de populations de LT, DC et de Treg différentes dans le sang circulant entre 24 patients avec une tumeur localisé et 17 patients métastatiques débutant du nivolumab. Nous identifions également des phénotypes immunitaires associés à la réponse au nivolumab. Enfin, ces travaux se concluent par la conduite de l'essai clinique de phase II académique BIONIKK (NCT NCT02960906, promoteur ARTIC) dans lequel les patients avec un ccRCC métastatique sont traités soit par TKI anti-VEGFR, soit par nivolumab soit par nivolumab-ipilimumab en fonction de leur groupe moléculaire (de 1 à 4), déterminé à l'inclusion sur tissu tumoral congelé à partir d'une signature d'expression de 35 gènes co-développé par mon équipe d'accueil. L'objectif principal est d'étudier la réponse au traitement en fonction du groupe moléculaire. De nombreuses analyses ancillaires sont associées à cette étude incluant analyses transcriptomiques, quantification des infiltrats immunitaires et de leur phénotype (PD-1, PD-L1, Tim-3...) par IHC, analyse des populations immunitaires circulantes etc. Au 1er juillet 2019, l'ensemble des patients prévus ont été randomisés (N=200) et des premiers résultats de l'analyse intermédiaire seront présentés lors de la soutenance (confidentiel).Clear cell renal cell carcinomas (ccRCC) has benefited from major therapeutic advance in recent years. Since 2017, nivolumab, an immune checkpoint inhibitor targeting the Programmed Cell Death-1 (PD-1) allowing to restore the adaptive anti-tumour immunity via the CD8 T cell activation, has become a standard treatment for metastatic patients with ccRCC after failure of an anti-VEGFR TKI. However, only a quarter of patients respond to treatment and we do not currently have a robust biomarker that predicts efficacy. The imminent arrival of the nivolumab-ipilimumab combination in the first line of metastatic ccRCC followed by the arrival of anti-VEGFR TKI and anti-PD-1 combination further raises the question of a selection biomarker, given the potentially severe toxicities and the financial cost for the society. The composition of the tumour microenvironment and immune cell-tumour cell interactions are the most promising issues explored to predict the response to immunotherapies. My thesis work is in line with the work carried out by my host team on the characterization of the ccRCC immune microenvironment. Using several separate cohorts of patients with ccRCCs, we reported in 3 published studies that: 1) high CD8+ T-cell (LT) density (immunohistochemistry (IHC)) was associated with a poor prognosis unlike most other solid tumours. We showed that these CD8 had an "exhausted" phenotype potentially due to a lack of immune response coordination by immature dendritic cells (DC) located outside the tertiary lymphoid structures (TLS); 2) by the analysis of tumour infiltrating lymphocytes (TIL), we identified 3 groups with distinct immune profiles, "immune-activated", "immune-silent" and "immune-regulated". The latter group, characterized by a polyclonal, low cytotoxic CD8+PD-1+Tim-3+Tim-3+Lag-3+ population as well as an ICOS+ T regulators (Treg) one, had a significantly higher risk of recurrence than the two other groups in the year following nephrectomy. Analysis of the phenotype of circulating LT identified 2 groups including the immune-regulated group; 3) the classical complement pathway played a key pro-inflammatory role in tumour progression, via cooperation between tumour cells and tumour associated macrophages (TAM). Preliminary results of our 4th ongoing study show different LT, DC and Treg population proportions and/or phenotypes in circulating blood between 24 patients with localized tumour and 17 metastatic patients starting nivolumab. We also identify immune phenotypes associated with response to nivolumab. Finally, this work is concluded with the conduct of the BIONIKK academic Phase II clinical trial (NCT02960906, sponsor: ARTIC) in which patients with metastatic ccRCC are treated either with anti-VEGFR TKI, or nivolumab alone or nivolumab-ipilimumab depending on their molecular group (from 1 to 4), determined at inclusion on frozen tumour tissue from a 35-gene expression signature previously co-developed by my host team. The main objective is the response to treatment according to the molecular group. Many ancillary analyses are associated including transcriptomic analyses, quantification of immune infiltrates and their phenotype (PD-1, PD-L1, Tim-3...) by IHC, analysis of circulating immune populations etc. As of July 1st 2019, all planned patients have been randomized (N=200) and initial results of the interim analysis will be presented during the thesis defense (confidential)
Valeur pronostique de la réponse précoce dans les cancers broncho-pulmonaires non à petites cellules localement avancés, traité par radiochimiothérapie
No full textNICE-BU Médecine Odontologie (060882102) / SudocSudocFranceF
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
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