1,721,036 research outputs found
Impact of the MET dysregulation on the phenotype of EGFR mutated non-small cell lung cancers during EGFR tyrosine kinase inhibitors resistance
No full textIntroduction : Le traitement des cancers bronchiques non à petites cellules (CBNPC) EGFR mutés repose sur les inhibiteurs de tyrosine kinase (ITK) du récepteur de l’Epidermal Growth Factor (EGFR). Cependant tous les patients traités par ITK EGFR finissent par présenter une progression tumorale, du fait de mécanismes de résistance comme l’amplification du gène codant pour le récepteur tyrosine kinase MET. Il n’existe actuellement aucune donnée sur les modifications phénotypiques induites par l’activation de MET dans ce contexte. L’objectif de cette thèse est de déterminer si l’amplification de MET, lors de la résistance aux ITK EGFR dans les CBNPC EGFR mutés, confère aux cellules tumorales un phénotype plus agressif et modifie l’histoire naturelle de la maladie.Méthodes : Les capacités de prolifération, de croissance sans ancrage, de formation de sphéroïdes, de résistance à l’anoïkis et de migration ont été étudiées in vitro dans la lignée HCC827, dérivée d’un CBNPC EGFR muté, et dans sa lignée fille HCC827-GR6 (GR6) devenue résistante aux ITK EGFR via une amplification du gène MET. L’expression de la vimentine, de ZEB1, et de la E-cadherine a également été étudiée dans les deux lignées cellulaires afin d’évaluer l’impact de l’amplification de MET sur la transition épithélio-mésenchymateuse (TEM). In vivo la croissance tumorale et le potentiel métastatique ont respectivement été analysés dans des modèles murins de xénogreffe ectopique et d’injection intracardiaque. Enfin les données cliniques de patients issus de 15 centres avec un CBNPC EGFR muté métastatique, présentant une forte surexpression de MET en immunohistochimie (score 3+) ou une amplification de MET en FISH sur une re-biopsie réalisée après la progression sous ITK EGFR ont été analysées rétrospectivement. Résultats : In vitro, l’amplification de MET induisait une augmentation significative de la prolifération, de la croissance sans ancrage, de la formation de sphéroïdes, de la résistance à l’anoïkis et de la migration. En présence d’un inhibiteur de MET, le PHA-665752, ces différentes propriétés biologiques étaient réduites de façon significative dans les cellules GR6 porteuses de l’amplification de MET. Il était également mis en évidence dans les cellules GR6 une augmentation de l’expression de la vimentine et de ZEB1. In vivo, l’amplification de MET augmentait significativement la croissance tumorale et le potentiel métastatique. Un traitement par crizotinib, ITK ciblant MET, diminuait de façon significative le potentiel métastatique des cellules porteuses de l’amplification de MET. Enfin les patients atteints d’un CBNPC EGFR muté, porteur d’une amplification de MET à la résistance à l’ITK EGFR, présentaient une durée jusqu’à apparition de nouvelles métastases plus courte après progression sous ITK EGFR que les patients avec une forte surexpression de MET sans amplification génique. Conclusion L’amplification de MET dans un contexte de résistance aux ITK EGFR est associée à un phénotype tumoral plus agressif. Ces résultats plaident en faveur d’une utilisation précoce d’inhibiteurs de MET en association avec les ITK EGFR afin d’éviter l’émergence d’un clone tumoral résistant plus agressif.Introduction: Treatment of Epidermal Growth Factor Receptor (EGFR) mutated non-small cell lung cancers (NSCLC) relies on EGFR tyrosine kinase inhibitors (TKI). However, all patients treated with EGFR TKI eventually present tumor progression, due to mechanisms of resistance such as the MET amplification. There is currently no data on phenotypic changes induced by MET activation in this context. The objective of this thesis is to determine whether the MET amplification during EGFR TKI resistance in the EGFR mutated NSCLC induces a more aggressive phenotype in tumor cells and alters the natural history of the disease.Methods: Proliferation, anchorage independent growth, spheroid formation, anoïkis resistance and migration were studied in vitro in the HCC827 cell line, derived from an EGFR mutated NSCLC, and in its daughter cell line HCC827-GR6 (GR6) which became resistant to EGFR TKI through MET amplification. The expression of vimentin, ZEB1, and E-cadherin was evaluated in these cellular models in order to investigate an epithelial to mesenchymal transition (EMT) process induced by the MET amplification. In vivo, the tumor growth and the metastatic potential were analyzed by subcutaneous xenograft and intracardiac injection in mouse models. Finally, the clinical data of patients from 15 centers with a metastatic EGFR mutated NSCLC, exhibiting high MET overexpression in immunohistochemistry (score 3+) or MET amplification assessed by FISH on a re-biopsy performed after TKI EGFR progression were analyzed retrospectively.Results: In vitro, the MET amplification induced a significant increase in proliferation, anchorage independent growth, spheroid formation, anoïkis resistance and migration. Treatment with PHA-665752, a MET TKI, significantly reduced these biological properties in the GR6 cells harboring the MET amplification. An increase in the expression of vimentin and ZEB1 was also observed in the GR6 cells. In vivo, the MET amplification significantly increased the tumor growth and the metastatic potential. Treatment with crizotinib, another MET TKI, significantly decreased the metastatic potential of cells carrying MET amplification. Finally, patients with an EGFR mutated NSCLC, displayed a time to new metastases after TKI EGFR progression shorter than patients with high MET overexpression without MET amplification.Conclusion: The MET amplification during EGFR TKI resistance is associated in EGFR muted NSCLC with a more aggressive tumor phenotype. These results argue for the early use of MET inhibitors in combination with EGFR TKIs to avoid the emergence of a more aggressive resistant tumor clone
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
PD-1/PD-L1 inhibitor activity in patients with gene-rearrangement positive non-small cell lung cancer—an IMMUNOTARGET case series
Full text linkBACKGROUND: Prior IMMUNOTARGET registry data had suggested that responses to immune [anti PD(L)1] monotherapy in gene-arranged non-small cell lung cancer (NSCLC) were rare or absent, depending on the specific oncogene. METHODS: IMMUNOTARGET sites reporting prior registry data or new individual cases of gene rearranged NSCLC seeming to benefit from immune monotherapy were explored in detail looking to both validate their diagnosis of a functional gene rearrangement and to look for features potentially differentiating them from other such cases associated with low response rates. RESULTS: Five cases of NSCLC with a gene rearrangement with reported responses or prolonged stabilization from immune monotherapy were identified in total. All had little or no prior smoking history and had programmed death-ligand 1 (PD-L1) values ranging from zero to 100%. A confirmed rearrangement partner was reported in only 2 of the cases (CD74-ROS1 and KIF5B-RET), however in one of the other three cases [analplastic lymophoma kinase (ALK)], significant benefit from a relevant prior targeted therapy was noted, also consistent with the rearrangement status being correctly assigned. CONCLUSIONS: Not all driver oncogene subtypes of NSCLC are equally responsive to immune monotherapy, however even among patients with well-validated gene rearranged NSCLC which has traditionally been considered immune hyporesponsive, objective responses can occur. Additional explorations of the features associated with and underlying the immune hypo-responsiveness of most, but not all, cases of gene-rearranged NSCLC are required
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
Cancer with oncogenic addiction , detection of new targets and research of mechanisms of resistance
No full textIntroductionLa détection d’altérations moléculaires susceptibles de répondre à des thérapies ciblées ainsi que l’identification des mécanismes de résistance à ces thérapies représentent deux aspects majeurs de la médecine de précision qui ont été étudiés dans mes travaux de thèse.ArticlesMes travaux de thèses se sont d’abord focalisés sur l’étude des altérations de la voie PI3K-AKT dans la résistance aux inhibiteurs tyrosines kinase MET (ITK MET) dans les cancers bronchiques non à petites cellules porteurs d’un saut de l’exon 14 de MET (CBNPC-METex14) (article n°1). En constituant une cohorte de 65 patients, nous avons mis en évidence que des altérations de la voie PI3K (i.e mutation PIK3CA et perte de PTEN) étaient communes dans les CBNPC METex14. Nous avons observé que le taux de réponse à un ITK MET des patients porteurs d’une co-altération MET/PI3K était plus faible que dans les CBNPC-METex14 sans altération PI3K. In vitro, l’étude de lignées cellulaires mutées METex14 avec une altération de la voie PI3K a permis de confirmer la résistance aux ITK MET, surmonter par l’ajout d’un inhibiteur PI3K.Par la suite, nous nous sommes intéressés à la recherche de nouveaux biomarqueurs prédictifs de réponse aux ITK MET. Nous avons identifié un patient porteur d’un cholangiocarcinome avec une fusion CAPZA-2-MET. Ce patient, initialement réfractaire à la chimiothérapie, a reçu un ITK MET (capmatinib) permettant l’obtention d’une réponse objective. Après plusieurs mois de traitement, une progression tumorale nous a conduit à mettre en évidence l’émergence d’une mutation du domaine kinase de MET (article n°2).Enfin, nous nous sommes intéressés à la faisabilité de la recherche des mutations de résistance à d’autres thérapies ciblées, les ITK ALK, chez les patients porteurs d’un CBNPC ALK+ (article n°3). Nous avons établi une cohorte de 23 patients porteurs d’un CBNPC ALK+ traité par un ITK ALK pour lesquels une biopsie à progression était disponible. Un mécanisme de résistance a été identifié chez 9 patients (39%). Tous les patients ayant reçu un ITK ALK présumé actif sur le mécanisme de résistance détecté ont présenté une réponse de leur maladie. Ces résultats confirment l’utilité de rechercher les mécanismes de résistance afin d’orienter les choix thérapeutiquesConclusionCes travaux illustrent la pertinence d’identifier des cibles thérapeutiques nouvelles, comme les mutations METex14 ou les fusions de MET. Ils illustrent aussi les limites de cette approche avec la survenue de mécanismes de résistance primaire ou acquise, et la nécessité de les identifier pour pouvoir mieux les surmonter.IntroductionThe identification of mechanisms of resistance to targeted therapies and the detection of new predictive biomarkers of response are crucial to improving patient management. My PhD thesis work focuses on these two aspects of precision medicine.ArticlesMy thesis work explores the study of alterations in the PI3K-AKT pathway as a mechanism of resistance to MET tyrosine kinase inhibitors (MET TKI) in non-small cell lung cancers (NSCLC) with MET exon 14 skipping mutation (NSCLC-METex14) (Article #1). We reviewed clinical data from 65 patients with METex14 NSCLC, assessing PI3K pathway alterations. We observed that PI3K pathway alterations (i.e., PIK3CA mutation and loss of PTEN expression) are common in METex14 NSCLC. We discovered that the clinical activity of MET TKI is lower in patients with METex14 NSCLC and PI3K alteration. In vitro studies of METex14 mutated cell lines with alterations in the PI3K pathway confirmed resistance to METTKI, which can be overcome by the addition of a PI3K inhibitor.Subsequently, we focused on research for new predictive biomarkers of response to MET TKI. We examined a cholangiocarcinoma patient with a CAPZA-2-MET fusion and observed that MET fusion is associated with a response to the MET TKI capmatinib. We also found the emergence of a MET kinase mutation (D1228N) as a potential resistance mechanism to first generation MET TKI (Article #2).Finally, we investigated the feasibility and relevance of detection of mechanisms of resistance to ALK inhibitors in ALK-rearranged NSCLC. We reviewed clinical data from 23 patients with advanced ALK-rearranged NSCLC who had undergone at least one repeat biopsy at progression during an ALK TKI treatment. A resistance mechanism was identified in 9 of the 23 patients (39%). All patients who received a TKI presumed to act on the detected ALK mutant achieved disease control. These results confirm that the detection of mechanism of resistance is suitable for routine practice and can help select the best treatment for patients.ConclusionsThis work illustrates the relevance of identifying new therapeutic targets, such as METex14 mutations or MET fusions. It also illustrates the limitations of this strategy with the emergence of primary or acquired mechanisms of resistance, and the necessity to identify them in order to overcome them
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