1,721,032 research outputs found
Molecular characterization of acute myeloid leukemia with myelodysplasia related changes
No full textLes leucémies aiguës myéloïdes (LAM) avec dysplasie, identifiées par la classification OMS 2008 sous le nom de LAM-MRC (« AML with myelodysplasia-related changes »), sont actuellement définies par la présence de critères cliniques, cytologiques et cytogénétiques. Elles forment un groupe hétérogène tant sur le plan biologique que pronostique. Nous avons fait l'hypothèse que la caractérisation moléculaire des LAM-MRC pourrait permettre d'identifier des marqueurs spécifiques associés à ces pathologies et d'en distinguer différents sous-groupes. Nous avons mis en évidence que les LAM-MRC de risque cytogénétique intermédiaire présentent un profil mutationnel spécifique caractérisé par un taux élevé de mutation d'ASXL1 et une faible proportion de mutations de DNMT3A, NPM1 et FLT3. Les LAM-MRC de risque cytogénétique défavorable, essentiellement complexes et/ou monosomales, sont quant à elle associées aux mutations de TP53. Alors que les critères actuels des LAM-MRC ne permettent pas d'en stratifier le pronostic, nous avons montré que les mutations d'ASXL1 ou de TP53 sont des facteurs pronostics péjoratifs majeurs. Ainsi, une reclassification basée sur la présence de ces altérations moléculaires exclusives entre elles permettrait d'affiner le diagnostic et la stratification pronostique de ces maladies. Enfin, dans une stratégie de médecine personnalisée combinant le séquençage à haut débit à des tests de sensibilité thérapeutique in vitro, l'identification de tels marqueurs moléculaires permettraient de prédire la réponse aux traitements, de guider les choix thérapeutiques et d'orienter le développement de nouvelles drogues.Acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) as reported in the WHO 2008 classification are defined by the presence of clinical, morphological and cytogenetic criteria. AML-MRCs are heterogeneous diseases with prognostic heterogeneity. We hypothesized that molecular characterization of AML-MRC could identify specific molecular markers and disease subgroups. We showed that AML-MRCs with intermediate cytogenetic risk harbor a specific mutational profile characterized by a high frequency of ASXL1 mutations and a low incidence of DNMT3A, NPM1 and FLT3 mutations. Unfavorable cytogenetic risk AML-MRCs, especially due to complex and/or monosomal karyotypes, are associated with TP53 mutations. While WHO criteria do not stratify the prognosis of AML-MRC patients, we showed that the mutations of ASXL1 or TP53 are major poor prognostic factors. The criteria defining AML-MRC do not identify distinct clinical and biological subgroups and do not predict outcome of patients with AML-MRC. In contrast, ASXL1 and TP53-mutated AML identify two distinct biological subgroups of AML-MRC with very poor outcome. This molecular characterization could be useful to redefine AML-MRC in a future classification aiming at merging biological characterization and specific prognostic value. Finally, we showed that a personalized treatment approach combining next generation sequencing and in vitro drug screening could be useful to predict therapeutic response and to guide both treatment choices and new targeted drug developments
NK and gamma delta T lymphocytes expansions as a post-allograft therapeutic tool in Acute Myeloid Leukemia
No full textLa Leucémie Aigüe Myéloïde est une hémopathie maligne sévère touchant près de 3500 personnes en France, en particulier les sujets âgés. Malgré l’amélioration de la prise en charge, la survie à 5 ans reste en 2023 inférieure à 25%, ce qui en fait l’un des cancers au pronostic le plus sombre.À ce jour, l’allogreffe de cellules souches hématopoïétiques (Allo-CSH) demeure l'un des seuls traitements curatifs. A travers l’effet « Graft Versus Leukemia » (GVL) médié par le système immunitaire du donneur. Dirigé contre les blastes leucémiques, cet effet cytotoxique provoque une lyse des cellules tumorales restantes. Les lymphocytes T jouent un rôle majeur dans l’effet GVL. Cependant, par un mécanisme similaire, les lymphocytes T allogéniques peuvent lyser les tissus sains du receveur, dans le cadre d’un syndrome d’alloréactivité : la maladie du greffon contre l’hôte (« Graft Versus Host Disease », GVHD). Aussi, alors que la mortalité liée à la procédure de greffe a diminué ces dernières décennies, la rechute de LAM après allogreffe touche encore près de 50% des patients devenant ainsi la principale cause d’échec de l’allogreffe.Plus récemment, il a été rapporté que d’autres effecteurs immuns pouvaient médier un effet GVL sans déclencher de GVHD. En particulier, les cellules NK et les lymphocytes Tγδ (LTγδ) par leur mécanisme d'activation non restreint à la présentation antigénique par le complexe majeur d'histocompatibilité (CMH-1) et leur potentiel cytotoxique élevé semblent particulièrement intéressants. Aussi, leurs schémas d'activation légèrement différents suggèrent des capacités complémentaires voire synergiques lorsqu’utilisés conjointement.Afin de démontrer la faisabilité et l’efficacité d’un produit cellulaire composé de NK et de LTγδ, nous développons et validons un processus d'expansion combiné de ces deux sous-types, spécifique et efficace à partir de sang périphérique en utilisant des cellules supportrices irradiées.L'objectif de ma thèse est donc la mise au point d’une méthode d’expansion combinée de NK et LTγδ, sa validation et l’utilisation d’outils d’éditions génétiques pour proposer une plateforme cytotoxique modulable. Pour cela, nous avons tout d’abord évalué une méthode d’expansion in vitro, ses performances (taux d’expansion, pureté), nous avons étudié les caractéristiques phénotypiques du produit ainsi obtenu par cytométrie de masse.Nous avons obtenu, à partir de sang périphérique de volontaires sain et en utilisant des cellules supportrices irradiées, un produit cellulaire compatible en qualité et quantité avec une translation vers la clinique.Une étude fonctionnelle nous a permis de valider l’intérêt de l’approche combinée sur le plan des capacités cytotoxiques, que nous avons par la suite confirmé dans un modèle de transfert adoptif in vivo. Enfin, nous avons entrepris l’édition génétique du produit de thérapie cellulaire ainsi obtenu. Des outils innovants ont permis de lever les verrous technologiques existant et nos premiers résultats montrent qu’il est possible de rediriger les NK et de LTγδ expandus de manière combinée, vers une cible de manière précise et efficace.En somme, mes travaux de thèse montrent la faisabilité d’une plateforme d’expansion combinée NK et LTγδ. L’étude fonctionnelle confirme le potentiel cytotoxique envisagé par la caractérisation phénotypique. Le transfert adoptif in vivo prouve l’intérêt en terme de contrôle de la prolifération de blastes leucémiques et ouvre la porte à un développement vers la clinique. La possibilité d’éditer de manière performante les cellules suggère un modèle de plateforme cytotoxique modulable et utilisable en conditions allogénique, potentiellement dans de nombreuses pathologies.Acute myeloid leukemia is a severe hematological malignancy affecting nearly 3,500 patients in France, particularly elderly patients. Despite improvements in disease management, 5-year survival in 2023 was still less than 25%, making it one of the darkest cancers in terms of prognosis.To date, allogeneic hematopoietic stem cell transplantation (Allo-HSCT) remains one of the only curative treatments through the "Graft Versus Leukemia" (GVL) effect mediated by the donor's immune system. Directed against leukemic blasts, this cytotoxic effect causes lysis of the remaining tumor cells. T lymphocytes play a major role in the GVL effect. However, by a similar mechanism, allogeneic T lymphocytes can lyse the recipient's healthy tissues, as part of an alloreactivity syndrome: Graft Versus Host Disease (GVHD). And while graft-related mortality has declined in recent decades, relapse of AML after Allo-HSCT still affects almost 50% of patients, making it the main cause of failure.More recently, it has been reported that other immune effectors can mediate a GVL effect without triggering GVHD. In particular, NK cells and Tγδ lymphocytes (LTγδ), with their activation mechanism unrestricted by the antigenic presentation of the major histocompatibility complex (MHC-1) and their high cytotoxic potential, seem of particular interest. Also, their slightly different activation patterns suggest complementary or even synergistic capabilities when used in combination.To demonstrate the feasibility and efficacy of a cellular product composed of NK and LTγδ, we developed and validated a process for the combined, specific and efficient expansion of these two subtypes from peripheral blood using irradiated carrier cells.The aim of my thesis was thus to develop a combined NK and LTγδ expansion method, validate it and employ genetic editing tools to offer a modular cytotoxic platform. To this end, we first evaluated an in vitro expansion method and its performance (expansion rate, purity), and assessed the phenotypic characteristics of the resulting product by mass cytometry.Using peripheral blood from healthy volunteers and irradiated feeder cells, we obtained a cell product compatible in quality and quantity with translation to the clinic.A functional study enabled us to assess the cytotoxic potential of the combined approach, which we subsequently confirmed in an in vivo adoptive transfer model.Finally, we undertook the genetic editing of the resulting cell therapy product. Innovative tools have enabled us to overcome existing technological hurdles, and our initial results show that it is possible to redirect expanded NK and LTγδ cells in a combined manner, towards a target in a precise and effective manner.In all, my thesis work demonstrates the feasibility of a combined NK and LTγδ expansion platform. The functional study confirms the cytotoxic properties foreseen by the phenotypic characterization. In vivo adoptive transfer reveals the potential for leukemic blasts proliferation inhibition and thus paves the way for further clinical developments. The possibility of high-performance cell editing suggests a modular cytotoxic platform model that can be used under allogeneic conditions, potentially in a wide range of malignancies
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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