Academic literature on the topic 'Profil mutationnel'
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Journal articles on the topic "Profil mutationnel"
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Rached, H. A., E. Desmedt, C. Templier, P. Lepesant, and L. Mortier. "Variabilité intra-individuelle du profil mutationnel d’un mélanome métastatique." Annales de Dermatologie et de Vénéréologie 143, no. 12 (December 2016): S374—S375. http://dx.doi.org/10.1016/j.annder.2016.09.599.
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Szablewski, V., F. Poizat, R. Garrel, J. Solassol, and V. Costes-Martineau. "Profil mutationnel de KRAS et KRAS dans les ITAC : une relation clinicopathologique ?" Annales de Pathologie 32, no. 5 (November 2012): S117—S118. http://dx.doi.org/10.1016/j.annpat.2012.09.113.
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Wylomanski, S., M. Denis, S. Theoleyre, A. C. Knol, R. Bouquin, L. Peuvrel, M. Saint-Jean, B. Dréno, and G. Quereux. "Profil mutationnel de mélanomes de la sphère génitale féminine : résultats d’une cohorte monocentrique." Annales de Dermatologie et de Vénéréologie 144, no. 12 (December 2017): S312—S313. http://dx.doi.org/10.1016/j.annder.2017.09.526.
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Fallet, V., and M. Wislez. "Profil mutationnel des carcinomes sarcomatoïdes pulmonaires par une technique de génotypage à haut débit." Revue des Maladies Respiratoires 31 (January 2014): A197. http://dx.doi.org/10.1016/j.rmr.2013.10.137.
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Fallet, V., and M. Wislez. "Profil mutationnel des carcinomes sarcomatoïdes pulmonaires primitifs par une technique de génotypage à haut débit." Revue des Maladies Respiratoires 31, no. 9 (November 2014): 879–80. http://dx.doi.org/10.1016/j.rmr.2014.06.011.
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Boussemart, L., C. Mateus, N. Kamsu-Kom, E. Routier, M. Thomas, G. Tomasic, L. Lacroix, S. Vagner, and C. Robert. "Comparaison du profil mutationnel somatique de métastases de mélanome avant traitement et après résistance au vémurafénib." Annales de Dermatologie et de Vénéréologie 141, no. 12 (December 2014): S283. http://dx.doi.org/10.1016/j.annder.2014.09.132.
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Veronese, Lauren, Florence Nguyen Khac, Hedi Bensaber, Tournilhac Olivier, Bruno Pereira, Louis Thomas Dannus, Romain Guieze, and Andrei Tchirkov. "Étude GFCH/FILO du profil mutationnel des leucémies lymphoïdes chroniques et autres syndromes lymphoprolifératifs B avec translocation IG::BCL3." Morphologie 107, no. 359 (December 2023): 100638. http://dx.doi.org/10.1016/j.morpho.2023.100638.
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Schneider, P., R. Porcher, C. Pagès, I. Sidina, L. da Meda, M. Battistella, M. Viguier, et al. "Étude de l’incidence du profil mutationnel des mélanomes sur la survie globale chez des patients avec un mélanome stade IV." Annales de Dermatologie et de Vénéréologie 139, no. 12 (December 2012): B115. http://dx.doi.org/10.1016/j.annder.2012.10.145.
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Passet, M., C. Lepelletier, M. D. Vignon-Pennamen, P. Hirsch, M. Battistella, P. Duriez, M. Bagot, F. Chasset, E. Clappier, and J. D. Bouaziz. "L’infiltrat neutrophilique cutané des syndromes de Sweet associés aux hémopathies myéloïdes a le même profil mutationnel que la cellule myéloïde tumorale." Annales de Dermatologie et de Vénéréologie 146, no. 12 (December 2019): A75. http://dx.doi.org/10.1016/j.annder.2019.09.061.
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König, Anna-Katharina, Stefan Fritz, Michael Volkmar, Atanasios Tampakis, Ji Youm, Matthias Gaida, Jens Werner, et al. "Mutational profile in IPMN subtypes." Pancreatology 17, no. 3 (July 2017): S25. http://dx.doi.org/10.1016/j.pan.2017.05.079.
Full textDissertations / Theses on the topic "Profil mutationnel"
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Abbar, Baptiste. "Cancers associés au VIH : immunogénomique, immunogénicité et immunothérapie." Electronic Thesis or Diss., Sorbonne université, 2024. https://accesdistant.sorbonne-universite.fr/login?url=https://theses-intra.sorbonne-universite.fr/2024SORUS441.pdf.
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Les cancers, notamment les cancers bronchiques non à petites cellules (CBNPC), sont particulièrement fréquents chez les personnes vivant avec le VIH (PVVIH). Cependant, malgré cette association, les profils moléculaires et immunologiques des CBNPC chez les PVVIH restent encore mal connus. L'avènement des immunothérapies antitumorales, en particulier des inhibiteurs de points de contrôle immunitaires (ICI), a révolutionné la prise en charge de nombreux cancers, dont certains touchent fréquemment les PVVIH. Cependant, les PVVIH ont été systématiquement exclus des essais cliniques évaluant l'utilisation des ICI en oncologie. Par conséquent, les données disponibles sur le profil de toxicité de ces traitements et leur impact immunovirologique sur l'infection par le VIH restent limitées. Dans la première partie de ce travail, nous avons comparé prospectivement les caractéristiques immunogénomiques de 27 CBNPC provenant de 15 PVVIH et de 12 patients immunocompétents (IC). Les charges mutationnelles tumorales, les profils moléculaires, le nombre de néoépitopes prédits, ainsi que leur restriction prédite par les molécules du complexe majeur d'histocompatibilité (CMH) de classe I/II étaient similaires dans les deux groupes. Cependant, les réponses T aux néoépitopes, détectées chez 4/11 PVVIH et 5/11 IC, étaient exclusivement dirigées contre des néoépitopes restreints au CMH de classe II chez les PVVIH, tandis que chez les patients IC, la moitié des réponses ciblaient des néoépitopes restreints au CMH de classe I. De plus, un faible nadir de CD4 était associé à l'absence de réponses spécifiques aux néoépitopes chez les PVVIH. Enfin, les microenvironnements tumoraux des CBNPC chez les PVVIH présentaient des proportions plus faibles de neutrophiles et une diminution des marqueurs de la fonction des cellules T. Ainsi, malgré des profils moléculaires similaires, l'infection par le VIH altère gravement les réponses immunitaires antitumorales chez les patients atteints de CBNPC, en particulier celles dirigées contre les néoépitopes restreints au CMH de classe I, ce qui plaide en faveur de l'utilisation d'immunothérapies basées sur les néoépitopes restreints au CMH de classe I dans cette population. Dans la deuxième partie de ce travail, nous avons étudié, à travers une revue systématique de la littérature, et des études dédiées, le profil de toxicité, l'impact immunovirologique (charge virale et taux de CD4), ainsi que l'effet des ICI sur le réservoir et l'immunité anti-VIH chez les PVVIH, dans le cadre d'une stratégie de « shock and kill » visant à éradiquer le VIH. Nos recherches ont montré que le profil de toxicité des ICI chez les PVVIH est comparable à celui observé dans la population générale. De plus, nous avons démontré que les ICI n'ont pas d'effet négatif sur les marqueurs de l'infection par le VIH, comme la charge virale et le taux de CD4. Enfin, notre étude portant sur 32 PVVIH traités par anti-PD1 en monothérapie, a révélé une diminution précoce, modérée et transitoire du réservoir VIH, sans augmentation significative de l'immunité anti-VIH. L'augmentation précoce sous ICI d'autres points de contrôle immunitaires, tels que CTLA4 et TIM3, pourrait expliquer cet impact limité in vivo sur le réservoir VIH et l'immunité antivirale des anti-PD1. Ainsi, l'utilisation des anti-PD1 en monothérapie ne semble pas constituer une stratégie prometteuse de « shock and kill » pour éradiquer le VIH. Au total, nous avons démontré que le VIH altère fortement la réponse immunitaire antitumorale chez les patients atteints de CBNPC, malgré des profils tumoraux moléculaires similaires. Toutefois, l'utilisation des ICI chez les PVVIH n'est pas associée à un risque accru de toxicité et montre une efficacité comparable à celle des patients immunocompétents. Nos résultats soutiennent le développement de vaccins personnalisés ciblant les néoépitopes restreints au CMH de classe I, en combinaison avec les ICI, pour les PVVIH atteints de CBNPCCancers, particularly non-small cell lung cancers (NSCLC), are notably more frequent among people living with HIV (PLWHIV). However, despite this association, the molecular and immunological profiles of NSCLC in PLWHIV remain poorly explored. Characterizing these immunogenomics features in malignant tumors has become critical for understanding the mechanisms of oncogenesis and developing more effective antitumor therapies. The advent of immunotherapies, especially immune checkpoint inhibitors (ICIs), has revolutionized cancer treatment, including cancers that frequently affect PLWHIV. However, PLWHIV have been systematically excluded from clinical trials evaluating ICIs in oncology. As a result, data on the safety profile of these treatments and their immunovirological impact on HIV infection remain limited.In the first part of this work, we prospectively compared the immunogenomics features of 27 NSCLC from 15 PLWHIV and 12 immunocompetent patients (IC). Tumor mutational burdens, molecular profiles, number of predicted neoepitopes, and their MHC-class I/II predicted restriction were similar in both groups. However, monofunctional T cell responses to neoepitopes, detectable in 4/11 PLWHIV and 5/11 IC, were exclusively directed against MHC-class-II-restricted neoepitopes in PLWHIV while half were directed against MHC-class-I-restricted in IC. A low CD4 nadir was associated with the lack of neoepitope-specific responses in PLWHIV. Furthermore, PLWHIV tumor microenvironments displayed lower neutrophils proportions and decreased T cell function markers. Thus, despite similar molecular profiles, HIV-infection severely impairs antitumor immune responses in patients with NSCLC, particularly to MHC-class-I-restricted neoepitopes, supporting the use of MHC-class-I-restricted neoepitope-based immunotherapy in this population. In the second part of this work, we conducted a systematic review of the literature, dedicated clinical studies, and biological sub-studies to assess the toxicity profile, immunovirological impact (viral load and CD4 count), as well as the effects of ICIs on the HIV reservoir and anti-HIV immunity in PLWHIV, as part of a “shock and kill” strategy for an HIV cure. Our research demonstrated that the toxicity profile of ICIs in PLWHIV is similar to that observed in the general population. We also identified specific risk factors in this population associated with the occurrence of severe immune-related adverse events, such as long-term HIV infection, low CD4 count, positive cytomegalovirus serology, and a history of oncological surgery. Additionally, we showed that ICIs do not have a negative impact on HIV infection markers, such as viral load and CD4 count. Finally, our study of 32 PLWHIV treated with anti-PD1 monotherapy, with monitoring of plasma viral load, anti-HIV immunity, and the viral reservoir, revealed an early, moderate, and transient reduction in the HIV reservoir, without a significant increase in anti-HIV immunity. The early upregulation of other immune checkpoints, such as CTLA4 and TIM3, under ICI treatment may explain the limited in vivo effect on the HIV reservoir and antiviral immunity of anti-PD1 therapy. Thus, the use of anti-PD1 monotherapy does not appear to be a promising “shock and kill” strategy for eradicating HIV. Overall, we demonstrated that HIV significantly impairs the antitumor immune response in patients with NSCLC, despite similar molecular tumor profiles. However, the use of ICI in PLWHIV is not associated with an increased risk of toxicity and shows efficacy comparable to that observed in IC patients. Our results support the approach of personalized vaccines targeting MHC class I-restricted neoepitopes, combined with ICIs, for PLWHIV with NSCLC
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Saaidi, Afaf. "Multi-dimensional probing for RNA secondary structure(s) prediction." Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLX067/document.
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En bioinformatique structurale, la prédiction de la (des) structure(s) secondaire(s) des acides ribonucléiques (ARNs) constitue une direction de recherche majeure pour comprendre les mécanismes cellulaires. Une approche classique pour la prédiction de la structure postule qu'à l'équilibre thermodynamique, l'ARN adopte plusieurs conformations, caractérisées par leur énergie libre, dans l’ensemble de Boltzmann. Les approches modernes privilégient donc une considération des conformations dominantes. Ces approches voient leur précision limitées par l'imprécision des modèles d'énergie et les restrictions topologiques pesant sur les espaces de conformations.Les données expérimentales peuvent être utilisées pour pallier aux lacunes des méthodes de prédiction. Différents protocoles permettent ainsi la révélation d'informations structurales partielles via une exposition à un réactif chimique/enzymatique, dont l'effet dépend, et est donc révélateur, de la (les) structure(s) adoptée(s). Les données de sondage mono-réactif sont utilisées pour valider et complémenter les modèles d’énergie libre, permettant ainsi d’améliorer la précision des prédictions. En pratique, cependant, les praticiens basent leur modélisation sur des données de sondage produites dans diverses conditions expérimentales, utilisant différents réactifs ou associées à une collection de séquences mutées. Une telle approche intégrative est répandue mais reste manuelle, onéreuse et subjective. Au cours de cette thèse, nous avons développé des méthodes in silico pour une modélisation automatisée de la structure à partir de plusieurs sources de données de sondage.En premier lieu, nous avons établi des pipelines d’analyse automatisés pour l'acquisition de profils de réactivité à partir de données brutes produites à travers une série de protocoles. Nous avons ensuite conçu et implémenté une nouvelle méthode qui permet l'intégration simultanée de plusieurs profils de sondage. Basée sur une combinaison d'échantillonnage de l'ensemble de Boltzmann et de clustering structurel, notre méthode produit des conformations dominantes, stables et compatible avec les données de sondage. En favorisant les structures récurrentes, notre méthode permet d’exploiter la complémentarité entre plusieurs données de sondage. Ses performances dans le cas mono-sondage sont comparables ou meilleures que celles des méthodes prédictives de pointe.Cette méthode a permis de proposer des modèles pour les régions structurées des virus. En collaboration avec des expérimentalistes, nous avons suggéré une structure raffinée de l'IRES du VIH-1 Gag, compatible avec les données de sondage chimiques et enzymatiques, qui nous a permis d’identifier des sites d'interactions putatifs avec le ribosome. Nous avons également modélisé la structure des régions non traduites d'Ebola. Cohérents avec les données de sondage SHAPE et les données de covariation, nos modèles montrent l’existence d'une tige-boucle conservée et stable à l'extrémité 5', une structure typiquement présente dans les génomes viraux pour protéger l'ARN de la dégradation par les nucléases.L’extension de notre méthode pour l’analyse simultanée de variants, appliquée dans un premier temps sur des mutants produits par le protocole Mutate-and-Map et sondés par le DMS, a permis d'enregistrer une amélioration en précision de prédiction. Pour éviter la production systématique de mutants ponctuels et exploiter le protocole récent SHAPEMap, nous avons conçu un protocole expérimental basé sur une mutagenèse non dirigé et le séquençage, où plusieurs ARN mutés sont produits et simultanément sondés. Nous avons traité l’affectation des reads aux mutants de références à l'aide d'une instance de l'algorithme "Expectation-Maximization" dont les résultats préliminaires, sur un échantillon de reads réduit/simulé, ont montré un faible taux d’erreurs d'assignation par rapport à une affectation classique des reads aux séquences d'ARN de référenceIn structural bioinformatics, predicting the secondary structure(s) of ribonucleic acids (RNAs) represents a major direction of research to understand cellular mechanisms. A classic approach for structure postulates that, at the thermodynamic equilibrium, RNA adopts its various conformations according to a Boltzmann distribution based on its free energy. Modern approaches, therefore, favor the consideration of the dominant conformations. Such approaches are limited in accuracy due to the imprecision of the energy model and the structure topology restrictions.Experimental data can be used to circumvent the shortcomings of predictive computational methods. RNA probing encompasses a wide array of experimental protocols dedicated to revealing partial structural information through exposure to a chemical or enzymatic reagent, whose effect depends on, and thus reveals, features of its adopted structure(s). Accordingly, single-reagent probing data is used to supplement free-energy models within computational methods, leading to significant gains in prediction accuracy. In practice, however, structural biologists integrate probing data produced in various experimental conditions, using different reagents or over a collection of mutated sequences, to model RNA structure(s). This integrative approach remains manual, time-consuming and arguably subjective in its modeling principles. In this Ph.D., we contributed in silico methods for an automated modeling of RNA structure(s) from multiple sources of probing data.We have first established automated pipelines for the acquisition of reactivity profiles from primary data produced through a variety of protocols (SHAPE, DMS using Capillary Electrophoresis, SHAPE-Map/Ion Torrent). We have designed and implemented a new, versatile, method that simultaneously integrates multiple probing profiles. Based on a combination of Boltzmann sampling and structural clustering, it produces alternative stable conformations jointly supported by a set of probing experiments. As it favors recurrent structures, our method allows exploiting the complementarity of several probing assays. The quality of predictions produced using our method compared favorably against state-of-the-art computational predictive methods on single-probing assays.Our method was used to identify models for structured regions in RNA viruses. In collaboration with experimental partners, we suggested a refined structure of the HIV-1 Gag IRES, showing a good compatibility with chemical and enzymatic probing data. The predicted structure allowed us to build hypotheses on binding sites that are functionally relevant to the translation. We also proposed conserved structures in Ebola Untranslated regions, showing a high consistency with both SHAPE probing and evolutionary data. Our modeling allows us to detect conserved and stable stem-loop at the 5’end of each UTR, a typical structure found in viral genomes to protect the RNA from being degraded by nucleases.Our method was extended to the analysis of sequence variants. We analyzed a collection of DMS probed mutants, produced by the Mutate-and-Map protocol, leading to better structural models for the GIR1 lariat-capping ribozyme than from the sole wild-type sequence. To avoid systematic production of point-wise mutants, and exploit the recent SHAPEMap protocol, we designed an experimental protocol based on undirected mutagenesis and sequencing, where several mutated RNAs are produced and simultaneously probed. Produced reads must then be re-assigned to mutants to establish their reactivity profiles used later for structure modeling. The assignment problem was modeled as a likelihood maximization joint inference of mutational profiles and assignments, and solved using an instance of the "Expectation-Maximization" algorithm. Preliminary results on a reduced/simulated sample of reads showed a remarkable decrease of the reads assignment errors compared to a classic algorithm
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Berquet, Laure. "Etude des profils d'expression des petits ARN nucléolaires (snoARN) dans la leucémie lymphoïde chronique." Thesis, Toulouse 3, 2015. http://www.theses.fr/2015TOU30070/document.
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Les petits ARN nucléolaires (snoARN) sont d'abondants petits ARN non codants impliqués dans la modification post-transcriptionnelle des ARN ribosomiques. Plus récemment, ils ont été associés à de nouvelles fonctions et des dérégulations dans les cancers. La leucémie lymphoïde chronique (LLC) est l'hémopathie maligne la plus courante dans les pays occidentaux. Cette pathologie, bien qu'indolente, est toujours incurable et est très hétérogène en termes d'évolution et de réponse au traitement. Il est ainsi nécessaire de découvrir de nouveaux marqueurs permettant de stratifier le risque d'évolution de la LLC afin d'améliorer la prise en charge thérapeutique des patients. Le but de mon projet a été d'étudier les profils d'expression des snoARN dans la LLC et de les corréler aux données cliniques et biologiques. Par des expériences de PCR quantitative à grande échelle (Fluidigm), j'ai mis en évidence la dérégulation des snoARN dans la LLC. De plus, j'ai pu montrer qu'une signature spécifique était capable de définir un nouveau sous-groupe de mauvais pronostic au sein des patients IGHV-mutés, initialement classés dans un groupe de bon pronostic. La surexpression de la signature est corrélée à un temps de survie sans traitement plus court et semble être principalement activée par les signaux de prolifération. Ainsi, cette étude démontre l'intérêt d'étudier la valeur pronostique des snoARN dans la LLC et plus largement dans les hémopathies malignesSmall nucleolar RNAs (snoRNAs) are an abundant class of small non-coding RNAs responsible for the post-transcriptional modifications of ribosomal RNAs. They have been recently associated with new functions and described as deregulated in many cancers. Chronic lymphocytic leukemia (CLL) is the most frequent leukemia in the western world. This disease has a slow progression rate but is still incurable and is also very heterogeneous in terms of clinical course and response to therapy. Thus, it is essential to find new molecular markers allowing improvement of patient therapeutic care. This study aimed at establishing the expression profiles of snoRNAs in a CLL cohort and to correlate them to the clinico-biological parameters. By means of high-throughput quantitative PCR, I showed that snoRNAs were deregulated in CLL. Moreover, a specific signature was able to define a new adverse prognostic subgroup among IGHV-mutated patients, initially classified as good prognosis cases. The overexpression of the signature is correlated to a shorter treatment-free survival and seems to be mainly activated by proliferation signals. All in all, this study demonstrates the prognostic value of snoRNAs in CLL and prompts us to further explore their deregulation in hematological malignancies
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OMARINI, Claudia. "PROFILO MUTAZIONALE DI TUMORI MAMMARI HER2 POSITIVI TRATTATI CON CHEMIOTERAPIA NEOADIUVANTE." Doctoral thesis, Università degli studi di Modena e Reggio Emilia, 2020. http://hdl.handle.net/11380/1201013.
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Background
I tumori mammari con amplificazione o overespressione del gene Human Epidermal growth factor Receptor 2 (HER2) costituiscono circa il 20% delle diagnosi di tumori mammari. Tali tumori sono caratterizzati da una biologia particolarmente aggressiva e da prognosi infausta. Nelle pazienti con tumore mammario HER2 positivo, diagnosticato in stadio precoce, la chemioterapia neoadiuvante rimane una ottima opzione di trattamento, in quanto la risposta alla terapia correla significativamente con la sopravvivenza. In particolare, l’ottenimento della risposta patologica completa (pCR) è indicativo di una migliore sopravvivenza e di un minor rischio di recidiva nel tempo. Le evidenze scientifiche derivanti da studi su pazienti trattati con chemioterapia neoadiuvante suggeriscono che i tumori mammari HER2+ comprendono un gruppo eterogeneo di neoplasie con differente chemio-sensibilità e prognosi. Attualmente, l’obiettivo primario rimane l’identificazione di profili mutazionali in grado di predire la sensibilità del tumore al trattamento.
Obiettivi
Il principale obiettivo dello studio è di individuare i possibili meccanismi di resistenza ai trattamenti antineoplastici nelle pazienti con tumore mammario HER2+ sottoposte a chemioterapia neoadiuvante. A tal fine abbiamo comparato il profilo mutazionale di tumori mammario HER2+ che hanno ottenuto la risposta patologica completa con tumori mammari con residuo di malattia al termine del trattamento neoadiuvante. Inoltre abbiamo identificato le mutazioni geniche indotte dal trattamento neoadiuvante nelle pazienti che presentavano tumore residuo alla chirurgia.
Metodi
Utilizzando la metodologia di Next-generation sequencing (NGS), abbiamo analizzato lo stato mutazionale di 22 geni sia sul tessuto proveniente dalla biopsia mammaria diagnostica che sul residuo tumorale operatorio per le pazienti che non avevano raggiunto la pCR. NGS è una tecnica innovative capace di valutare contemporaneamente: profili di espressione genica, conteggiare dei cromosomi, identificare le modifiche epigenetiche ed effettuare analisi molecolari. In particolare noi abbiamo analizzato lo stato mutazionale dei seguenti geni, noti per essere coinvolti nei processi di cancerogenesi mammaria: EGFR, ALK, ERBB2, ERBB4, FGFR1, FGFR2, FGFR3, MET, DDR2, KRAS, PIK3CA, BRAF, AKT1, PTEN, NRAS, MAP2K1, STK11, NOTCH1,CTNNB1, SMAD4, FBXW7, TP53. Inoltre abbiamo effettuato una analisi esplorativa comparando lo stato mutazionale con la risposta al trattamento e con gli outcomes di sopravvivenza.
Resultati
Complessivamente abbiamo identificato 571 pazienti trattate con chemioterapia neoadiuvante presso l’Azienda Ospedaliero Universitaria di Modena. 196 pazienti avevano un tumore mammario HER2 positivo stadio I-II. Le caratteristiche cliniche delle pazienti, le informazioni riguardanti i trattamenti effettuati così come la caratteristiche biologiche del tumore mammario, sono state raccolte in un database. I parametri biologici quali Ki67, grado nucleare, stato ormonale ed espressione di HER2 sono stati correlati con la risposta al trattamento e con gli outcomes di sopravvivenza. Complessivamente la pCR è stata raggiunta in 66 pazienti (33%), principalmente in quelli con tumore mammario a recettori ormonali negativi. Per l’analisi mutazionale abbiamo selezionato un campione di 64 pazienti: 32 che avevano ottenuto la pCR e 32 con residuo di malattia. L’elaborazione complessiva dei dati è attualmente in corso, ad oggi PI3KCA è il gene trovato maggiormente mutato.
Conclusioni
L’analisi dell’espressione genica ha identificato un profilo di espressione genica potenzialmente correlato con la resistenza al trattamento neoadiuvante. Le analisi definitive sono attualmente in corso.Background Breast cancer (BC) with amplification and/or overexpression of Human Epidermal growth factor Receptor 2 (HER2+) oncogene are about 15% of the BC diagnosis. Poor prognostic clinical features and aggressive behavior characterize HER2+ tumors. Neoadjuvant systemic therapy (NST) is a treatment option in patients with early-stage HER2+ BC. Tumor response to NST well correlates with survival. In particular, pathological complete response (pCR) significantly predicts long-term outcomes. Results from neoadjuvant trials suggest that HER2+ BC subtype is a heterogeneous group including tumors with different treatment sensitivity and prognosis. To date, the main challenge remains the identification of mutational profile able to predict treatment sensitivity prior any intervention. Objectives The aim of the study is to investigate the mechanisms of treatment resistance/sensitivity in a sample of HER2+ BC patients treated with NST. We compare the mutational profile of HER2+ BCs that achieved pCR to those with residual disease after NST. Moreover, we want to identify treatment-induced mutation on the surgical specimens of patients with residual tumor after primary systemic treatments. Methods Next-generation sequencing (NGS) methodology is used to analyze genetic status of 22 cancer-related genes on tumor tissue from both primary BC biopsy and surgical specimens in women with residual disease after NST. NGS is a high-throughput methodology able to performed gene expression profiling, chromosome counting, detection of epigenetic changes and molecular analysis. In particular, we analyze the status of the following genes: EGFR, ALK, ERBB2, ERBB4, FGFR1, FGFR2, FGFR3, MET, DDR2, KRAS, PIK3CA, BRAF, AKT1, PTEN, NRAS, MAP2K1, STK11, NOTCH1,CTNNB1, SMAD4, FBXW7, TP53. An exploratory analysis in terms of treatment outcome, survival outcomes and single gene mutation will be carry out. Results Overall, we identified 571 patients treated with neoadjuvant systemic chemotherapy who underwent surgery at Modena Cancer Center. 196 of them had HER2 positive stage I-III BC. Patient and tumour characteristics and treatment information were collected. Standard biological parameters (Ki67, nuclear grade, hormone receptors and HER2 status) were correlated to pCR. Globally, pCR was achieved in 66 patients (33%), mainly in hormone receptor negative HER2+ BC. We select a sample size of 64 patients suitable for genes analysis: 32 with pCR and 32 with residual BC disease. To date, PI3KCA was found to be the gene with main mutations. The evaluation of mutational gene profile on all the samples is ongoing as well as the correlation between gene mutations, survival outcomes and treatment sensibility. Conclusions Gene expression analysis, performed until now, identify some gene mutations potentially predictive of treatment resistance. Further analysis are ongoing.
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Filho, TarcÃsio Paulo de Almeida. "Expression and mutational profile of BCR-ABL gene in patients with chronic mieloid leukemia treated with tyrosine kinase inhibitors." Universidade Federal do CearÃ, 2017. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=19145.
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Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgicoMost patients with chronic myeloid leukemia (CML) express the transcripts b2a2, b3a2 or both of the BCR-ABL gene. The role of these transcripts in the prognosis of patients undergoing treatment with tyrosine kinase inhibitors (ITKs) has been poorly investigated and remains unclear to date. In this study, we evaluated the prognostic value of the main transcripts in patients with CML, by evaluating the expression and mutational profile of the BCR-ABL gene in patients treated with ITKs. Sixty patients with CML were evaluated transversally. Demographic, hematological, and clinical data and mutation profile of CML patients treated with ITKs were obtained from medical records. Molecular analyzes for the determination of transcripts and mutations (T315, E255V and Y253H) were performed by the qPCR technique. Statistical analyzes were performed using the Kruskal-Wallis or one-way ANOVA tests, depending on the normality of the data. The level of significance was 0.05 and p values of less than 0.05 were considered significant. Of the sixty patients, 12 (20%) expressed the b2a2 transcript, 18 (30%) the b3a2 transcript, 10 (16.7%) both b2a2/b3a2 transcripts and 20 (33.3%) had undetectable levels. Twenty-eight patients (46.7%) were female and 32 (53.3%) were males, with a mean age of 46.5 Â 15.7 years (ranging from 19-82). The comparative analysis of hematological data with transcripts showed a significant difference in the number of leukocytes in patients expressing the b2a2 and b3a2 transcripts (p <0.05), with patients with the b2a2 transcript associated with lower amounts. The other data, hematological and clinical, did not show statistically significant differences in relation to transcripts (p>0.05). Regarding mutations of the kinase domain, the presence of the T315, E255V and Y253H mutations in the study patients was not evidenced. These are the first results found in this population, being necessary more studies with a greater number of individuals and evaluation of the cytogenetic and molecular responses to the treatment. If confirmed as a prognostic factor capable of providing better outcomes and response to treatment, the transcripts could be used in the elaboration of new mathematical models for patient risk stratification and in the selection of the best therapy with ITKs for patients with CML.
A maioria dos pacientes com leucemia mieloide crÃnica (LMC) expressam os transcritos b2a2, b3a2 ou ambos do gene BCR-ABL. O papel desses transcritos no prognÃstico dos pacientes em tratamento com inibidores de tirosina quinase (ITKs) tem sido pouco investigado e atà o momento permanece incerto. Neste estudo, foi avaliado o valor prognÃstico dos principais transcritos nos pacientes com LMC, atravÃs da avaliaÃÃo da expressÃo e perfil mutacional do gene BCR-ABL em pacientes tratados com ITKs. Sessenta pacientes com LMC foram avaliados transversalmente. Os dados demogrÃficos, hematolÃgicos, clÃnicos e o perfil de mutaÃÃes dos pacientes com LMC tratados com ITKs foram obtidos atravÃs dos prontuÃrios. As anÃlises moleculares para a determinaÃÃo dos transcritos e das mutaÃÃes (T315, E255V e Y253H) foram realizadas pela tÃcnica de qPCR. As anÃlises estatÃsticas foram realizadas atravÃs dos testes Kruskal-Wallis ou one-way ANOVA dependendo da normalidade dos dados. O nÃvel de significÃncia foi de 0,05 e valores de p inferiores a 0,05 foram considerados significativos. Dos sessenta pacientes, 12 (20%) expressavam o transcrito b2a2, 18 (30%) o transcrito b3a2, 10 (16,7%) ambos os transcritos b2a2/b3a2 e 20 (33,3%) apresentaram nÃveis indetectÃveis. Vinte e oito pacientes (46,7%) eram do sexo feminino e 32 (53,3%) do sexo masculino, com mÃdia de idade 46,5  15,7 anos (variando de 19-82). A anÃlise comparativa dos dados hematolÃgicos com transcritos mostrou diferenÃa significante na quantidade de leucÃcitos nos pacientes que expressavam os transcritos b2a2 e b3a2 (p<0,05), sendo os pacientes com o transcrito b2a2 associados a quantidades inferiores. Os demais dados, hematolÃgicos e clÃnicos, nÃo mostraram diferenÃa estatisticamente significantes com relaÃÃo aos transcritos (p>0.05). Quanto Ãs mutaÃÃes do domÃnio quinase, nÃo foi evidenciada a presenÃa das mutaÃÃes T315, E255V e Y253H nos pacientes em estudo. Estes sÃo os primeiros resultados encontrados nesta populaÃÃo, sendo necessÃrio mais estudos com um nÃmero maior de indivÃduos e avaliaÃÃo das respostas citogenÃticas e moleculares ao tratamento. Se confirmado como fator de prognÃstico capaz de proporcionar melhores desfechos e resposta ao tratamento, os transcritos poderÃo ser empregados na elaboraÃÃo de novos modelos matemÃticos para estratificaÃÃo de risco dos pacientes e na seleÃÃo da melhor terapia com ITKs para pacientes com LMC.
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Conci, Simone. "Multigene mutational profiling of biliary tract cancer is related with pattern of recurrence in surgical resected patients." Doctoral thesis, 2019. http://hdl.handle.net/11562/995070.
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Background and Aims: Biliary tract cancer (BTC) is a heterogeneous group of malignancies with poor prognosis arising from the epithelial cells of biliary tree. Recently it has been reported that specific molecular mutations are associated with different types of biliary tree carcinomas, supporting their pathologic and molecular heterogeneity. However, the pathogenic pathways involved in carcinogenesis of BTC are still to be fully defined, and data regarding the relationship between molecular alterations and pattern or timing of recurrence is lacking. The aim of the present study was to investigate the relationship between the mutational gene profile and the pattern of recurrence in BTCs. Patients and Methods: From September 1990 to December 2012, a total of 103 specimens of patients with BTC (56 PCC, 35 ICC, and 12 GBC), who underwent curative surgery in a single tertiary HPB surgery referral center, were assessed for mutational status in 56 cancer-related genes. Results: Considering the different types of BTC, the 5-years RFS rate was 16.7%. (median RFS, 7 months) in GBC, 42.9%. (median RFS, 26.4 months) in ICC, 19.7% (median RFS, 16.5 months) in PCC, p=0.166 (figure 3). The presence of mutations in ARID1A, BRAF, ERBB2, FGFR3, PIK3CA and TP53 genes was significantly associated with poor RFS compared with wild type tumors (median RFS of 11.5 months vs. 19.2 months, p=0.039; 3.0 months vs. 17.0 months, p= 0.002; 5.0 months vs 16.5 months, p=0.017; 5.1 months vs. 16.5 months, p=0.024; 11.1 months vs 18.5 months , p= 0.032 and 8.6 months vs 21.9 months , p = 0.003 respectively). At the multivariate analysis including clinical, pathological and molecular characteristics, the factors independently related with survival were: Radicality of surgery (OR 2.050, C.I. 1.104-3.807, p=0.023), LN status (OR 1.835, C.I. 1.006-3.348, p=0.048), mutational status of ARID1A (OR 2.566, C.I. 1.174-5.608, p=0.018) and TP53 (OR 2.805, C.I. 4.432-5.496, p=0.003). Considering the pattern of recurrence, local recurrence occurred in 47 patients (73.4%) , while systemic recurrence occurred in 17 patients (26.4%) . Regarding the prognostic genes identified at the univariate analysis: ARID1A mutation was associated with a local and systemic recurrence in the 43% and 29% of cases, respectively; BRAF mutation was associated with a local and systemic recurrence in the 33% and 33% of cases, respectively; ERBB2 and FGFR3 mutation were always associated with a local recurrence; PIK3CA mutation was related with a local and systemic recurrence in the 72% and 14% of cases, respectively; and TP53 mutation was associated with a local and systemic recurrence in the 29% and 41% of cases. Regarding other genes with relatively high rate of mutation: BAP1 mutation was associated with a local and systemic recurrence in the 57% and 29% of cases, respectively; KRAS mutation was related with a local and systemic recurrence in the 42% and 10% of cases, respectively; PBRM1 mutation was associated in the 64% of cases with a local recurrence. Conclusion: Our study reported specific prognostic genes for GBC, PCC and ICC that can identify patients with poor prognosis after curative surgery . Moreover, we analyzed the relationship between the mutational gene profile and the recurrence of BTCs. Disease-specific genes identified can be explored for new molecular therapies in clinical trial.
Books on the topic "Profil mutationnel"
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Geberhiwot, Tarekegn, and Carla E. M. Hollak. Niemann-Pick Disease Type B. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199972135.003.0048.
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Niemann-Pick disease type B (NPDB) is caused by deficient activity of sphingomyelin phosphodiesterase leading to the accumulation of sphingomyelin and other lipids, primarily within macrophages. The disease is characterised by hepatosplenomegaly, a bleeding tendency, interstitial lung disease and an atherogenic lipid profile. The diagnosis of NPDB is usually made in childhood after organomegaly is noted, and patients often survive into adulthood. The diagnostic work up includes enzymatic determination of sphingomyelinase activity, mutational analysis and screening and/or quantification for target organ involvement. NPDB has a variable clinical expression and may be a life-limiting disorder with significant morbidity and mortality. There is no disease specific therapy yet and hence management is symptomatic with particular attention to treating the long term complications of the disease.
Book chapters on the topic "Profil mutationnel"
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Lee, Christopher Seungkyu. "Mutational Profile of Ocular Lymphoma." In Ocular and Adnexal Lymphoma, 23–29. Cham: Springer International Publishing, 2023. http://dx.doi.org/10.1007/978-3-031-24595-4_4.
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Li, Hua, and Jennifer R. Grandis. "Mutational Profile of HPV-Positive HNSCC." In Human Papillomavirus (HPV)-Associated Oropharyngeal Cancer, 171–94. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-21100-8_8.
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Jenifer Michael Raj, Minu, Fenwick Antony Edwin Rodrigues, and Sivasamy Ramasamy. "Mutational Profile of Human Papilloma Virus (HPV) Induced and Non-HPV Induced Head and Neck Squamous Cell Carcinoma." In Squamous Cell Carcinoma [Working Title]. IntechOpen, 2022. http://dx.doi.org/10.5772/intechopen.103737.
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Head and Neck cancer accounts for approximately 900,000 cases and over 400,000 deaths annually worldwide. The primary risk factors associated with Head and Neck cancer include usage of tobacco, alcohol consumption, Human Papillomavirus (HPV) infection and Epstein-Barr virus (EBV) infection. Few subsites of Head and Neck Squamous Cell Carcinoma (HNSCC) are associated with Human Papilloma Virus (HPV) while others remain non-associated. The anatomical, physiological, genetic, protein profile and epigenetic changes that occur in both HPV-positive and HPV-negative HNSCC has been discussed in this chapter. The mutational profile plays a crucial role in the treatment of the HNSCC patients as the HPV-positive HNSCC patients have a better prognosis compared to the HPV-negative HNSCC patients. This chapter mainly focusses on the mutational profile of both HPV-associated and non-HPV associated HNSCC tumours.
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Anto, Nikhil Ponnoor, Amitha Muraleedharan, and Rashmi Mittal. "Molecular Sub-Typing and Exploration of Key Signalling Pathways Involved in Complicating the Disease." In Therapeutic Drug Targets and Phytomedicine For Triple Negative Breast Cancer, 47–72. BENTHAM SCIENCE PUBLISHERS, 2023. http://dx.doi.org/10.2174/9789815079784123010006.
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Triple-negative breast cancer is characterized by distinct molecular profiles, unique metastatic patterns, aggressive behavior, lacks the targeted therapeutic approach, and caused significant mortality worldwide. The molecular complexity of angiogenesis, autophagy, apoptosis, and metastasis process in TNBC has fostered research efforts to unleash the molecular, pathological, and genetic drivers of their lethal cascade. This complex disease entity involves PI3k/Akt/mTOR, NF-kB, ERRs, and miRNA trafficking which has further worsened the clinical outcome. Due to their heterogeneous nature, none of the drugs were able to completely target the TNBC tumor spectrum. This chapter highlights the classification of TNBC on the basis of aberrated copy number, histology, proteomic, and mutational profiles to understand the aetiology of the disease. The identification of therapeutic vulnerabilities was also carried out by gaining insights into the above-mentioned signalling pathways and their role in further complicating the disease.
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Divan, Aysha, and Janice A. Royds. "Cancer Fundamentals." In Cancer Biology and Treatment. Oxford University Press, 2020. http://dx.doi.org/10.1093/hesc/9780198813477.003.0001.
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This chapter provides an overview of the fundamentals of cancer. Normal cells evolve to become cancer cells by acquiring successive mutations in primarily two classes of genes: the proto-oncogenes and the tumour suppressor genes. Mutations that specifically drive cancer development and disease progression are called driver mutations; the rest are termed passenger mutations and their role in carcinogenesis is less clear. Large-scale cancer genome studies have provided deep insight into the mutational profile of the cancer genome, and are presently informing not only basic research but also the clinical management of cancer patients. The chapter then looks at cancer stem cells, which have the capacity to self-renew and differentiate into cell types that recreate the cellular heterogeneity of the tumour from which they derive. Viruses are also associated with the development of some cancers as are certain bacteria.
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Mukherjee, Riya, Anjali Priyadarshini, Ramendra Pati Pandey, and Vethakkani Samuel Raj. "Antimicrobial Resistance in Staphylococcus aureus." In Staphylococcus aureus [Working Title]. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.96888.
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Staphylococcus aureus is a Gram-Positive bacteria that are responsible to cause skin infections and also shows toxic shock syndrome. Several antibiotics were given against the S. aureus infections but eventually, the prevalence of multidrug resistance of Staphylococcus aureus started emerging. Since then Methicillin-resistant Staphylococcus aureus strains (MRSA)were very common which causes nosocomial infections. Microorganisms for the need of the survival undergoes mutational changes either in their chromosomal DNA/RNA which confers the resistance. One of the famous examples is the resistance against methicillin in Staphylococcus aureus. The evolution of S. aureus is successful in developing multiple resistant strains. Plasmids are capable of carrying the resistant genes and also several toxic genes. In a recent study, it has been observed that drug resistance genes are located in the R plasmids and they are also responsible in conferring multi drug resistance and induce less utilization of multiple antimicrobial therapy. MRSA was not only resistant to methicillin, studies proved MRSA strains were resistant to macrolides, tetracyclines, chloramphenicol. Resistance to vancomycin was very evidently observed, and its transfer among the population and rising of resistant strains was becoming a major threat globally. The resistance of all these antimicrobial agents against the pathogenic microorganisms are taking a rise in some patients due to prolong use of the antimicrobial agents by these patients. The multi drug resistance has enhanced the mortality and morbidity rate which referred to the infecting agents as the “Super Bugs”. Survival of the microorganisms has increased due to the gradual development of extensive resistance against varied antimicrobial drugs. Possible treatments with combinations are found to be the only hope for infections against S. aureus. Few drugs are in development such as Dalbavancin, Oritavancin, Tigecycline. These are the possible treatments upon which the work is going on to reduce the resistance against the invasive MRSA. This chapter highlights the profiles of Staphylococcus aureus and the resistance patterns along with transmission and the role of the plasmid in transmitting the resistance.
Conference papers on the topic "Profil mutationnel"
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Bittencourt, Yuri Cardoso Rodrigues Beckedorff, Lucas Soares Almada, Tatiana Strava Corrêa, Daniele Xavier Assad, Marina Sahade Gonçalves, Andrea Kazumi Shimada, Artur Katz, and Romualdo Barroso-Sousa. "SOMATIC MUTATIONAL LANDSCAPE CHARACTERIZATION OF METASTATIC BREAST CANCER IN BRAZIL." In Brazilian Breast Cancer Symposium 2022. Mastology, 2022. http://dx.doi.org/10.29289/259453942022v32s2025.
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Objective: Breast cancer (BC) is the most common malignancy among Brazilian women after non-melanoma skin cancer. The mutational landscape of BC in Brazil is unknown. This study describes the mutational profile of a cohort of patients with metastatic breast cancer (MBC) who had undergone next-generation sequencing (NGS) using a comprehensive somatic tumor panel. Methods: We retrospectively reviewed medical records from MBC patients. The mutational profile, clinical, and demographic characteristics were abstracted. Furthermore, the patterns of ordering the panel and its usefulness for a clinical decision were evaluated. Results: We found 54 female patients who fulfilled the above criteria. The median age was 58 years (32–86). Most tumors tested were hormone receptor-positive (74%), followed by triple-negative (20.3%), hormone receptor-positive/HER2-positive (3.7%), and HER-2 positive (1.85%). The median time between the diagnosis of metastatic disease and the NGS execution was 40 months (0–112), and only three patients (5.5%) had not received systemic treatment prior to the test recommendation. Somatic mutations were identified in 94.4% (n=51) of the patients, mainly in PIK3CA (48.1%), TP53 (42.5%), and ESR1 (18.5%) genes. Tumor burden mutation (TMB) was informed in 61.1% (n=33) somatic panels, and 15.1% (n=5) had tumors with TMB ≥10 mutations/megabase. Approved genome-driven cancer therapy was found in 54.9% (n=28), and eight patients (28.5%) received it. Conclusion: This study showed a high proportion of actionable somatic genomic alterations, and it reinforces the growing usefulness of a comprehensive NGS tumor somatic panel in managing patients with MBC.
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Kaur, Pali, Victoria Sachs, Amanda L. Christie, David M. Weinstock, and James G. Keck. "Abstract 700: Characterization of new AML PDX models: Engraftment kinetics and mutational profile." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-700.
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Taff, J., J. Suh, B. Singh, C. Denkert, AB Troxel, JS Ross, and S. Adams. "Abstract P3-05-03: Metaplastic breast cancers: Genomic profile, mutational burden and TILs." In Abstracts: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, Texas. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.sabcs17-p3-05-03.
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Jagdhari, Yash, Ajay Kumar Verma, Surya Kant, Richa Mishra, Kanchan Srivastava, and Jyoti Bajpai. "Clinical and mutational profile of extensively drug resistant tuberculosis cases in northern India." In ERS International Congress 2021 abstracts. European Respiratory Society, 2021. http://dx.doi.org/10.1183/13993003.congress-2021.pa3334.
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Van Laere, S., P. Finetti, C. Rypens, C. Billet, D. Birnbaum, P. Vermeulen, P. Viens, L. Dirix, and F. Bertucci. "Abstract P4-04-04: The mutational profile of inflammatory breast cancer reveals a higher mutational burden leading to MAPK activation and chromatin remodeling." In Abstracts: 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, Texas. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-p4-04-04.
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Dooper, Marten. "Deep learning models predict the risk of relapse and the mutational profile in GIST." In ESMO Congress 2022, edited by Stefan Rauh. Baarn, the Netherlands: Medicom Medical Publishers, 2022. http://dx.doi.org/10.55788/1a4aa886.
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Canto, Luisa Matos do, Simon J. Larsen, Bruna E. Catin Kupper, Maria D. Ferreira de Souza Begnami, Cristovam Scapulatempo Neto, Jan Baumbach, Annabeth Høgh Petersen, Mads Malik Aagaard Jørgensen, Samuel Aguiar, and Silvia R. Rogatto. "Abstract 5360: Mutational profile and genomic instability according to response to therapy in rectal carcinomas." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-5360.
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Lindsay, Colin R., Pantelis Nicola, Mariam Jamal-Hanjani, Andrew Wallace, Gareth Wilson, George Burghel, Helene Schlecht, et al. "Abstract B49: “Triple wild-type” co-mutational profile in early-stage KRAS-mutant lung cancer." In Abstracts: AACR Special Conference on Targeting RAS-Driven Cancers; December 9-12, 2018; San Diego, CA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1557-3125.ras18-b49.
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Vaide, I., V. Aabrams, C. E. Ursu, and E. Laane. "Prevention of haemostatic complications Myeloproliferative Neoplasms: retrospective mutational and haemostatic profile study in Western Estonia." In GTH Congress 2024 – 68th Annual Meeting of the Society of Thrombosis and Haemostasis Research – Building Bridges in Coagulation. Georg Thieme Verlag, 2024. http://dx.doi.org/10.1055/s-0044-1779199.
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Krumbach, Rebekka, Jagatheswari Virajah, Thomas Metcalfe, Heiner Fiebig, and Vincent Vuaroqueaux. "Abstract B178: A functional mutational profile of a compendium of 350 patient-derived tumor xenografts (PDXs)." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Oct 19-23, 2013; Boston, MA. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1535-7163.targ-13-b178.
Full textReports on the topic "Profil mutationnel"
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Splitter, Gary, and Menachem Banai. Microarray Analysis of Brucella melitensis Pathogenesis. United States Department of Agriculture, 2006. http://dx.doi.org/10.32747/2006.7709884.bard.
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Original Objectives 1. To determine the Brucella genes that lead to chronic macrophage infection. 2. To identify Brucella genes that contribute to infection. 3. To confirm the importance of Brucella genes in macrophages and placental cells by mutational analysis. Background Brucella spp. is a Gram-negative facultative intracellular bacterium that infects ruminants causing abortion or birth of severely debilitated animals. Brucellosis continues in Israel, caused by B. melitensis despite an intensive eradication campaign. Problems with the Rev1 vaccine emphasize the need for a greater understanding of Brucella pathogenesis that could improve vaccine designs. Virulent Brucella has developed a successful strategy for survival in its host and transmission to other hosts. To invade the host, virulent Brucella establishes an intracellular niche within macrophages avoiding macrophage killing, ensuring its long-term survival. Then, to exit the host, Brucella uses placenta where it replicates to high numbers resulting in abortion. Also, Brucella traffics to the mammary gland where it is secreted in milk. Missing from our understanding of brucellosis is the surprisingly lillie basic information detailing the mechanisms that permit bacterial persistence in infected macrophages (chronic infection) and dissemination to other animals from infected placental cells and milk (acute infection). Microarray analysis is a powerful approach to determine global gene expression in bacteria. The close genomic similarities of Brucella species and our recent comparative genomic studies of Brucella species using our B. melitensis microarray, suqqests that the data obtained from studying B. melitensis 16M would enable understanding the pathogenicity of other Brucella organisms, particularly the diverse B. melitensis variants that confound Brucella eradication in Israel. Conclusions Results from our BARD studies have identified previously unknown mechanisms of Brucella melitensis pathogenesis- i.e., response to blue light, quorum sensing, second messenger signaling by cyclic di-GMP, the importance of genomic island 2 for lipopolysaccharide in the outer bacterial membrane, and the role of a TIR domain containing protein that mimics a host intracellular signaling molecule. Each one of these pathogenic mechanisms offers major steps in our understanding of Brucella pathogenesis. Strikingly, our molecular results have correlated well to the pathognomonic profile of the disease. We have shown that infected cattle do not elicit antibodies to the organisms at the onset of infection, in correlation to the stealth pathogenesis shown by a molecular approach. Moreover, our field studies have shown that Brucella exploit this time frame to transmit in nature by synchronizing their life cycle to the gestation cycle of their host succumbing to abortion in the last trimester of pregnancy that spreads massive numbers of organisms in the environment. Knowing the bacterial mechanisms that contribute to the virulence of Brucella in its host has initiated the agricultural opportunities for developing new vaccines and diagnostic assays as well as improving control and eradication campaigns based on herd management and linking diagnosis to the pregnancy status of the animals. Scientific and Agricultural Implications Our BARD funded studies have revealed important Brucella virulence mechanisms of pathogenesis. Our publication in Science has identified a highly novel concept where Brucella utilizes blue light to increase its virulence similar to some plant bacterial pathogens. Further, our studies have revealed bacterial second messengers that regulate virulence, quorum sensing mechanisms permitting bacteria to evaluate their environment, and a genomic island that controls synthesis of its lipopolysaccharide surface. Discussions are ongoing with a vaccine company for application of this genomic island knowledge in a Brucella vaccine by the U.S. lab. Also, our new technology of bioengineering bioluminescent Brucella has resulted in a spin-off application for diagnosis of Brucella infected animals by the Israeli lab by prioritizing bacterial diagnosis over serological diagnosis.