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Cizkova, Magdalena. "Pronostic and Predictive Markers in Breast Cancer - PI3K Signaling Pathway." Thesis, Paris 11, 2013. http://www.theses.fr/2013PA11T021.
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Les résultats des projets actuels apportent une information, sur différents aspects des rôles de la voie PI3K, dans le développement du cancer du sein, et la réponse au traitement. Les projets particuliers couvrent des sujets liés à la voie aux niveaux concernant les récepteurs de la famille HER, activant la voie PI3K, ainsi que PI3K et les effecteurs en découlant. Les effets pronostic et prédictif de la dérégulation de PI3K sont les sujets centraux de la recherche décrite ici. Une baisse d’expression de PI3KR1 est associée à une survie réduite dans notre cohorte de patients. Une attention particulière a été portée aux mutations de PIK3CA communes dans le cancer du sein. Tandis que les mutations de PIK3CA agissent comme des marqueurs de bon pronostic chez les patients anti-HER2-naïfs, ces mutations agissent au contraire comme prédicteurs négatifs de la réponse au traitement par trastuzumab. Les résultats décrits mènent un peu plus vers l’implication de plusieurs voies moléculaires altérées, en particulier la voie de signalisation Wnt, dans la tumorigénèse des cancers du sein PIK3CA mutés. De plus, nous avons testé les taux de lapatinib plasmatique montrant une augmentation pertinente dans les périodes d’état d’équilibre du traitement. Par ailleurs, nous avons démontré des incohérences dans l’évaluation de l’EGFR et proposé des approches pour l’interprétation des comptages d’immunohistochimie et de FISH. Tous ces sujets sont connectés par la 170 voie PI3K, et le besoin d’approfondir les connaissances actuelles, et d’apporter de nouvelles informations utiles applicables dans le futur dans les pratiques cliniquesResults of the presented research projects bring information about several aspects of the PI3K signaling pathway roles in breast cancer development and treatment response. The particular projects covered the subjects connected with the signaling pathway, ranging from the HER family receptors activating the pathway, and PI3K to the downstream levels of signalisation. The prognostic and predictive effect of PI3K deregulation was the central subject of the described research. The decreased expression of PIK3R1 associated with reduced survival of our patients. A special focus was put on the PIK3CA mutations which are common in breast cancer. Whereas the PIK3CA mutations act as a good prognostic marker in patients non-treated with the HER2 inhibitors, these mutations predict a negative response to trastuzumab treatment. The described results, furthermore, draw attention to the role of several altered molecular signaling pathways in breast cancer development, especially to the Wnt signaling pathway. The lapatinib plasma levels showing the relevant increase in comparison with the already described efficient steady-state levels were also described in one of the projects. Moreover, various modifications to EGFR status assessment were compared and showed that EGFR FISH and IHC count interpretation depended significantly on method and thresholds used. All these subjects are connected by the PI3K pathway, the need to deepen current knowledge and bring new useful information applicable in future clinical practice
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Tomlinson, Patsy Roseanne. "Mechanistic investigation of genotype-phenotype correlations in PIK3R1-related diseases." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/271188.
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The PIK3R1 gene encodes three proteins - p85$\alpha$, p50$\alpha$ and p55$\alpha$ - that are regulatory subunits of Class IA phosphoinositide 3-kinases (PI3Ks). These regulatory subunits heterodimerise with one of three catalytic subunit isoforms, namely p110$\alpha$, p110$\beta$, or p110$\delta$. Class IA PI3Ks are critical enzymes involved in fundamental metabolic and mitogenic signalling pathways. This thesis describes the delineation of biochemical and molecular mechanisms whereby PIK3R1 mutations cause diverse disease phenotypes observed in SHORT syndrome (defined by Short stature, Hyperextensibility, Ocular depression, Rieger anomaly and Teething delay), the primary immunodeficiency Activated PI3K-$\delta$ Syndrome 2 (APDS2), and cancer. Initial studies of purified wildtype or mutant PI3K complexes, utilising a modified PI3K fluorescence polarisation lipid kinase assay, established that SHORT syndrome-associated p85$\alpha$ mutations impaired phosphotyrosine peptide-stimulated PI3K activity when heterodimerised with either of the Class IA catalytic subunit isoforms. Two cancer-associated mutations assessed using the same assay demonstrated differential effects on PI3K function, causing either basal activation or impaired phosphotyrosine peptide-stimulated PI3K activity. To examine the effect of SHORT syndrome-associated p85$\alpha$ mutations in insulin-responsive cell types, 3T3-L1 preadipocyte models with conditional overexpression of p85$\alpha$ Y657X or p85$\alpha$ R649W were generated. Doxycycline-induced overexpression of mutant p85$\alpha$ attenuated insulin-stimulated Akt phosphorylation due to reduced insulin-stimulated association of p85$\alpha$/p110$\alpha$ heterodimers with either IRS1 or IRS2. This in turn resulted in impaired downstream signalling as indicated by low adipogenic efficiency. Cells and tissues isolated from Pik3r1$^{WT/Y657X}$ knock-in mice also demonstrated decreased insulin-stimulated Akt phosphorylation. Observations from a system with endogenous expression of mutant p85$\alpha$ Y657X supported the results obtained in the 3T3-L1 p85$\alpha$ overexpression models. The final part of this thesis focussed on a PIK3R1 exon skipping mutant (p85$\alpha$ $\Delta$Ex11) that confers PI3K activation in lymphocytes and causes APDS2. APDS2 patients have an immune-restricted phenotype, even though the mutation occurs within the ubiquitously expressed PIK3R1. To investigate this phenomenon, the doxycycline-inducible system was used to model overexpression of p85$\alpha$ $\Delta$Ex11, as well as an activating p110$\alpha$ H1047R mutation associated with cancer, in 3T3-L1 preadipocytes. Surprisingly, given that APDS2 is not normally associated with metabolic or growth problems, high overexpression of p85$\alpha$ $\Delta$Ex11 severely attenuated insulin-stimulated Akt phosphorylation and adipocyte differentiation. There was also reduced insulin-stimulated recruitment of p110$\alpha$ to either IRS1 or IRS2, and impaired heterodimerisation of p85$\alpha$ $\Delta$Ex11 with p110$\alpha$. Collectively, the data presented in this thesis contributes to the developing knowledge of PIK3R1-related diseases. In particular, these studies provided novel insights into the biochemical and molecular mechanisms of SHORT syndrome-associated p85$\alpha$ mutations. Additionally, these data delivered further understanding of potential mechanisms underlying the immune-specific phenotype of APDS2 caused by PIK3R1 mutations.
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Clayton, Zachary. "The Role of Pik3r1 in the Regulation of Adipose Tissue Insulin Sensitivity." Thesis, University of Oregon, 2018. http://hdl.handle.net/1794/23757.
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Obesity is a burgeoning health crisis in the United States. Obesity is associated with an earlier and greater risk for developing metabolic diseases. Insulin resistance is a central and defining feature of the metabolic diseases associated with obesity.
Class 1a Phosphatidylinositol 3-kinase (PI3K) is integral in canonical insulin signaling. PI3K contains regulatory (p85/, p55/, p50) and catalytic (p110//) subunits. The regulatory subunits are encoded by Pik3r1. Increased Pik3r1 abundance has been observed in obese white adipose tissue (WAT). Furthermore, obese mice with heterozygous (HZ) knockout of Pik3r1 remain insulin sensitive, despite marked obesity.
Taken together, it is crucial to understand the role of WAT Pik3r1 in regulating insulin sensitivity. Recently, literature has demonstrated that standard vivarium temperature (~22C) is a thermal stress for mice, as their thermoneutral zone is ~30C. Considering mice are a preclinical model for studying metabolic disease, it is critical to understand cellular and systemic responses to high fat diet (HFD) at 22C and 30C.
To determine the role of AT Pik3r1 in regulating insulin sensitivity, mice with constitutive and inducible adipocyte specific hetero/homozygous knockout of Pik3r1 were studied following acute (three days) and chronic (12 week) HFD, respectively. Furthermore, insulin sensitivity was assessed in mice with adipocyte specific overexpression (OX) of p55. To determine the influence of short-term (8 and 12 days) thermoneutral housing on insulin sensitivity, mice were studied following one and five days of HFD at 22C and 30C (one week acclimation at 30C prior to starting HFD).
Visceral WAT p85 abundance was increased (2-fold) following acute HFD in wild-type mice, with a parallel increase in systemic insulin resistance. HZ knockout of adipocyte Pik3r1 prevented acute HFD induced systemic insulin resistance. Furthermore, HZ knockout of adipocyte Pik3r1 reversed obesity induced glucose intolerance and enhanced systemic insulin sensitivity and adipocyte insulin signaling. Moreover, OX of adipocyte p55 enhanced (40%) glucose tolerance, energy expenditure (30%: light cycle; 45%: dark cycle) and markers of AT thermogenesis in brown AT. Lastly, housing temperature had a significant impact on the cellular pathways that regulate glucose metabolism in response to HFD exposure. This dissertation includes previously published co-authored material.
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Behrmann, Christoph [Verfasser], Hubert [Gutachter] Kübler, and Ralf C. [Gutachter] Bargou. "MicroRNA-221 sensitiviert Prostatakarzinomzellen gegenüber TRAIL durch Inhibition von SOCS-3 und PIK3R1 / Christoph Behrmann ; Gutachter: Hubert Kübler, Ralf C. Bargou." Würzburg : Universität Würzburg, 2020. http://d-nb.info/1204006334/34.
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Behrmann, Christoph Verfasser], Hubert [Gutachter] Kübler, and Ralf C. [Gutachter] [Bargou. "MicroRNA-221 sensitiviert Prostatakarzinomzellen gegenüber TRAIL durch Inhibition von SOCS-3 und PIK3R1 / Christoph Behrmann ; Gutachter: Hubert Kübler, Ralf C. Bargou." Würzburg : Universität Würzburg, 2020. http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-199205.
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Nilsson, Ardnor Sofie. "Genetic studies of stroke in Northern Sweden." Doctoral thesis, Umeå : Umeå University, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-887.
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Reinhardt, Kristin [Verfasser]. "Prävalenz von PIK3CA-Genmutationen beim Mammakarzinom / Kristin Reinhardt." Halle, 2018. http://d-nb.info/1160514526/34.
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Gebauer, Mirjam. "Wendekrisen der Pikaro im deutschen Roman der 1990er Jahre." Trier Wiss. Verl. Trier, 2003. http://deposit.ddb.de/cgi-bin/dokserv?id=2826307&prov=M&dok_var=1&dok_ext=htm.
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Gebauer, Mirjam. "Wendekrisen der Pikaro im deutschen Roman der 1990er Jahre /." Trier : WVT, Wissenschaftlicher Verlag Trier, 2006. http://catalog.hathitrust.org/api/volumes/oclc/70840926.html.
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Schacht, Hannes Verfasser], and Guido [Akademischer Betreuer] [Sauter. "PIK3CA-Amplifikationen in humanen Lungenkarzinomen / Hannes Schacht. Betreuer: Guido Sauter." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2011. http://d-nb.info/1020465387/34.
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Toh, Hirotaka. "Group A Streptococcus modulates RAB1- and PIK3C3 complex-dependent autophagy." Doctoral thesis, Kyoto University, 2021. http://hdl.handle.net/2433/263524.
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Madsen, Ralitsa Radostinova. "Investigation of genetic PIK3CA activation in genome-edited human pluripotent stem cells." Thesis, University of Cambridge, 2019. https://www.repository.cam.ac.uk/handle/1810/289436.
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Mosaic, activating mutations in PIK3CA, the gene encoding the catalytic p110α subunit of class IA phosphatidylinositol 3-kinase (PI3K), are the cause of rare, developmental growth disorders collectively known as PIK3CA-Related Overgrowth Spectrum (PROS). Given the pressing need for targeted therapy and evidence for tissue- and cell lineage-specific distribution of PIK3CA mutations in PROS, developmental models of this disease will be a key asset for preclinical drug testing and for a better understanding of PIK3CA activation in development. This PhD project addressed the lack of human, developmental PROS models by establishing isogenic series of human induced pluripotent stem cells (iPSCs) with endogenously expressed, activating PIK3CA mutations. This involved the optimisation of a CRISPR/Cas9 protocol for efficient knockin of different PIK3CA variants into human iPSCs. An isogenic iPSC series was established with cells expressing either wild-type PIK3CA or PIK3CA-H1047R, knocked into either one or both endogenous alleles. In parallel, mosaic patient- derived fibroblast cultures were reprogrammed to obtain isogenic wild-type and heterozygous iPSCs expressing PIK3CA-E418K. The models were used in comprehensive signalling studies, providing new insights into PI3K signalling in human iPSCs and how it is perturbed by genetic p110α activation. PIK3CA-E418K, a rare variant in both PROS and cancer, caused minimal pathway activation, in contrast to the highly recurrent variant PIK3CA-H1047R which induced strong PI3K signalling in both heterozygous and homozygous iPSCs according to a graded pattern. Studies of clinically relevant PI3K pathway inhibitors provided proof-of-concept that stem cell-based PROS models can be used for preclinical drug testing, and demonstrated that p110α is likely to be the main catalytic isoform mediating canonical PI3K signalling in human iPSCs. Differentiation assays revealed allele dose-dependent effects of PIK3CA-H1047R on stemness, with homozygous iPSCs exhibiting widespread transcriptome remodelling affect- ing genes implicated in cancer and development. Accordingly, these cells showed increased expression of pluripotency genes such as NANOG and NODAL, resulting in self-sustained "stemness" in embryoid body and teratoma assays. In comparison, heterozygous mutants behaved similar to wild-type controls under all differentiation paradigms. Furthermore, evidence was obtained that strong activation of PI3K signalling is fully compatible with definitive endoderm formation, arguing against cell-autonomous differentiation defects as the cause of endoderm sparing in PROS. In summary, these studies demonstrate the utility of human stem cell-based models of PROS for preclinical drug testing and for improved understanding of class IA PI3K signalling in human development. They are also likely to be useful in efforts to obtain a better understanding of PIK3CA-H1047R in human cancer.
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Pikora, Kolja [Verfasser]. "Automatische Mehrzielverfolgung als Grundlage für Kontaktfusion und Parameterschätzung in einem Aktivsonarsystem / Kolja Pikora." Aachen : Shaker, 2017. http://d-nb.info/1138177377/34.
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Yahiaoui-Bentounsi, Ouardia Imene. "Analyse de l'activation de la voie PI3K/AKT dans le lymphome folliculaire." Thesis, Aix-Marseille, 2014. http://www.theses.fr/2014AIXM5060.
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La voie PI3K/AKT est impliquée dans la progression de divers cancers humains, et semble jouer un rôle majeur dans le développement de tumeurs lymphoïdes. Elle pourrait être impliquée dans la pathogénie du lymphome folliculaire (LF) par certains mécanismes non identifiés. Les travaux de thèse portent sur l'étude des anomalies de la voie PI3K/AKT dans le LF, dans le but d'apporter une nouvelle cible thérapeutique. 38 biopsies tissulaires de LF humain ont été étudiées pour une analyse mutationnelle du gène PIK3CA dans les exons 9 et 20 par séquençage. Les mêmes échantillons ont été analysés par western blot et immunohistochimie pour détecter l'expression des protéines AKT, AKT phosphorylée (pAKT), et PTEN. Deux cas de lymphadénite ont été utilisés comme témoins.Les résultats obtenus montrent que l'expression d'AKT était présente dans tous les cas de LF et lymphadénite, et 14/38 (37%) échantillons de LF et 2/2 cas de lymphadénite exprimaient pAKT. 9/38 (24%) échantillons de LF ont montré un niveau élevé d'expression de pAKT, alors que 5/38 (13%) cas de LF, et 2/2 échantillons de lymphadénite montraient un faible niveau d'expression de pAKT. L'expression de PTEN a été observée dans 30/38 (79%) cas de LF et 2/2 cas de lymphadénite, tandis que 8/38 (21%) cas ont montré une perte d'expression de PTEN. En outre, 3 cas qui expriment pAKT montrent une perte d'expression de PTEN. Aucune mutation du gène PIK3CA n'a été détectée dans les échantillons étudiés. Ces données suggèrent que la voie PI3K/AKT peut être activée dans certains cas de LF, soit en raison de la phosphorylation d'AKT, soit en raison d'une perte d'expression de PTEN, en absence de mutations de PIK3CAThe phosphoinositide 3- kinase (PI3K) pathway is involved in the growth of various human cancers, including lymphoid malignancies. However its role in the pathogenesis of follicular lymphoma (FL) has not been yet described.The PhD work focuses on the study of alterations in the PI3K/AKT pathway in follicular lymphoma, in order to provide a new therapeutic target.To clarify this point, biopsy tissue samples from 38 human FL cases were investigated for PIK3CA somatic mutations in exons 9 and 20 using Sanger sequencing. The same samples were analyzed using western blotting and immunohistochemistry to detect expression of AKT, phosphorylated AKT (pAKT), and PTEN proteins. Two cases of benign lymphadenitis were used as controls. AKT expression was present in all FL and lymphadenitis cases. 14/38 (37%) FL and 2/2 lymphadenitis cases expressed pAKT. 9/38 (24%) FL samples showed high level of pAKT, whereas 5/38 (13%) FL cases and 2/2 benign lymphadenitis samples expressed pAKT at low level. PTEN expression was observed in 30/38 (79%) FL and 2/2 benign lymphadenitis cases, whereas 8/38 (21%) of FL cases showed loss of PTEN expression. In addition, 3 cases with positive pAKT did not express PTEN. PIK3CA mutations were not detected in any sample. These data suggest that the PI3K/AKT signaling pathway could be activated in a subset of FL cases, due to either AKT phosphorylation or PTEN downregulation, in the absence of PIK3CA mutations
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Li, Shao Ying. "Study of the role of DNA methylation and PIK3CA mutations in human breast cancer." University of Western Australia. School of Surgery and Pathology, 2006. http://theses.library.uwa.edu.au/adt-WU2006.0031.
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[Truncated abstract] Introduction: Breast cancer is a heterogeneous disease, resulting in very different outcomes for women with apparently similar tumour characteristics. In order for patients to have optimal treatment, a better understanding of the molecular nature of their disease is required. Aims: The aims of this thesis were: 1) To determine whether methylation of RARβ2, ER, CDH1, BRCA1, CCND2, p16 and TWIST genes are associated with phenotypic features of breast cancer and the prognostic significance of methylation of these genes. 2) To investigate for possible associations between the frequency of methylation at RARβ2, CDH1, ER, BRCA1, CCND2, p16 and TWIST genes and the presence of germ-line variants in the TS, MTHFR, MS, CBS, MTHFD1 and DNMT3B genes, as well as for possible correlations between these polymorphisms and clincopathological features of breast cancer including patient outcome. 3) To determine whether PIK3CA mutations determined clinical phenotype and the prognostic significance of PIK3CA mutations in a large and well characterized cohort of breast cancer patients. Methods: A large and well characterized series of primary breast tumours were selected for methylation of RARβ2, ER, CDH1, BRCA1, CCND2, p16 and TWIST genes using MSP, and for polymorphisms in TS, MTHFR, MS, CBS, MTHFD1 and DNMT3B genes using PCR, PCR-RFLP and PCR-SSCP. Mutations to PIK3CA were detected using F-SSCP. Results and Conclusions: Methylation frequencies ranged from 11% for CCND2 to 84% for ER. More frequent hypermethylation was observed in tumours with poor histological differentiation compared to those with well/moderate differentiation, as well as trends for association with larger tumour size and mutant TP53. Tumours with ER and CDH1 methylation were associated with significantly lower hormone receptor levels, younger age at diagnosis and the presence of mutant p53. TWIST methylation is firstly reported to be associated with significantly older patient age at diagnosis and larger tumour size. Our data suggests that gene methylation may be linked to various pathological features of breast cancer. However, there appears to be little support for a distinctive CpG island methylator phenotype in breast cancer.
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Li, Shao Ying. "Study of the role of DNA methylation and PIK3CA mutations in human breast cancer /." Connect to this title, 2005. http://theses.library.uwa.edu.au/adt-WU2006.0031.
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Blankenstein, Thomas. "Mutationsanalyse von TP53, KRAS und PIK3CA bei einzelnen disseminierten Tumorzellen aus dem Knochenmark von Karzinompatienten." Diss., Ludwig-Maximilians-Universität München, 2013. http://nbn-resolving.de/urn:nbn:de:bvb:19-156444.
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Varghese, Robin. "Novel Prognostic Markers and Therapeutic Targets for Glioblastoma." Diss., Virginia Tech, 2016. http://hdl.handle.net/10919/71420.
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Glioblastoma is the most common and lethal malignant brain tumor with a survival rate of 14.6 months and a tumor recurrence rate of ninety percent. Two key causes for glioblastomas grim outcome derive from the lack of applicable prognostic markers and effective therapeutic targets. By employing a loss of function RNAi screen in glioblastoma cells we found a list of 20 kinases that can be considered glioblastoma survival kinases. These survival kinases which we term as survival kinase genes, (SKGs) were investigated to find prognostic markers as well as therapeutic targets for glioblastoma. Analyzing these survival kinases in The Cancer Genome Atlas patient database, we found that CDCP1, CDKL5, CSNK1𝜀, IRAK3, LATS2, PRKAA1, STK3, TBRG4, and ULK4 genes could be used as prognostic markers for glioblastoma with or without temozolomide chemotherapeutic treatment as a covariate. For the first time, we found that patients with increased levels of NEK9 and PIK3CB mRNA expression had a higher probability of recurrent tumors. We also discovered that expression of CDCP1, IGF2R, IRAK3, LATS2, PIK3CB, ULK4, or VRK1 in primary glioblastoma tumors was associated with tumor recurrence prognosis. To note, of these recurrent prognostic candidates, PIK3CB expression in recurrent tumor tissue had much higher expression compared to primary tissue. Further investigation in the PI3K pathway showed a strong correlation with recurrence rate, days to recurrence and survival emphasizing the role of PIK3CB in tumor recurrence in glioblastoma. In efforts to find effective therapeutic targets for glioblastoma we used SKGs as potential candidates. We chose the serine/threonine kinase, Casein Kinase 1 Epsilon (CSNK1𝜀) as a target for glioblastoma because multiple shRNAs targeted this gene in our loss of function screen and multiple commercially available inhibitors of this gene are available. Casein kinase 1 epsilon protein and mRNA expression were investigated using computational tools. It was revealed that CSNK1𝜀 expression has higher expression in glioblastoma than normal tissue. To further examine this gene we knocked down (KD) or inhibited CSNK1𝜀 in glioblastoma cells lines and noticed a significant increase in cell death without any significant effect on normal cell lines. KD and inhibition of CSNK1𝜀 in cancer stem cells, a culprit of tumor recurrence, also revealed limited self-renewal and proliferation in cancer stem cells and a significant decrease in cell survival without affecting normal stem cells. Further analysis of downstream effects of CSNK1𝜀 knockdown and inhibition indicate a significant increase in the protein expression of β-catenin (CTNNB1). We found that CSNK1𝜀 KD activated β-catenin, which increased GBM cell death, but can be rescued using CTNNB1 shRNA. Our survival kinase screen, computational analyses, patient database analyses and experimental methods contributed to the discovery of novel prognostic markers and therapeutic targets for glioblastoma.Ph. D.
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Werner, Eva Maria. "Genomischer Zugewinn der PIK3CA und gesteigerte p110alpha-Proteinexpression in Dysplasien und invasiven Plattenepithelkarzinomen des oberen Aerodigestivtraktes." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=972172114.
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Englisch, Julianna [Verfasser]. "Prävalenz und Heterogenität von KRAS-, BRAF- und PIK3CA-Mutationen in Magenkarzinomen und ihren Metastasen / Julianna Englisch." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2016. http://d-nb.info/1118687795/34.
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Jonasson, Jennifer. "Analysis of PIK3CA mutations in tumours from patients with non-small cell lung cancer using pyrosequencing." Thesis, Uppsala universitet, Institutionen för kvinnors och barns hälsa, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-227762.
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A subgroup of non-small cell lung cancer (NSCLC) cases harbour mutations in classical oncogenes, which can affect therapy response and prognosis. By therapeutically targeting the corresponding proteins with inhibitory drugs, the clinical outcome for these lung cancer patients may be improved. One of these oncogenes is the phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) which encodes the catalytic subunit of the phosphatidylinositol 3 kinase (PI3K). PIK3CA is a central regulator in the PI3K/Akt/mTOR pathway, which controls cell growth and apoptosis. Mutations in the PIK3CA gene are considered to up-regulate the kinase activity in tumour cells and through that dysregulate fundamental cellular processes. PI3K inhibitors are currently tested in clinical trials and present a promising therapy option in lung cancer patients. In this study, a pyrosequencing assay for detection of PIK3CA mutations in tumours from patients with NSCLC was established. The three "hot-spot" codons 542, 545 and 1047 of the PIK3CA gene were analysed. The sensitivity of this assay was determined to the presence of 5 % of mutant alleles. In agreement with previous reports, three of the 60 lung cancer cases revealed PIK3CA mutations (5 %). All mutations occurred in exon 9 codon 542 or 545. In line with previous reports, two of the three samples harboured concurrent mutation in the EGFR or KRAS gene. The established pyrosequencing analysis for PI3KCA mutations provides a reliable and cost-effective assay for clinical diagnostics. The determination of the PI3KCA mutation status may help to distinguish patients for treatment targeting the PI3K pathway.
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Hartleb, Dinah [Verfasser]. "Prävalenz und Heterogenität von KRAS, BRAF und PIK3CA Mutationen in kolorektalen Adenokarzinomen und ihren korrespondierenden Metastasen / Dinah Hartleb." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2016. http://d-nb.info/1099593468/34.
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Lion, Maëva. "Biomarqueurs prédictifs de la réponse aux traitements par thérapies ciblées dans le cancer du sein." Thesis, Université de Lorraine, 2015. http://www.theses.fr/2015LORR0287.
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Le cancer du sein est le cancer le plus fréquemment diagnostiqué chez la femme et constitue un véritable problème de santé publique. Les progrès de la biologie moléculaire ont permis la caractérisation des principales voies de signalisation et ont mis en évidence l'implication majeure de la signalisation cellulaire dans les processus de cancérogenèse. Des cibles moléculaires ont ainsi été identifiées et ont permis le développement de thérapeutiques dites ciblées, telles que les anticorps monoclonaux ou encore les inhibiteurs de kinase. Malgré ces avancées considérables qui ont permis l'amélioration de la prise en charge des patientes, on constate l'apparition de résistances aux traitements. Ce travail avait pour objectifs d'identifier de nouveaux biomarqueurs et de déterminer leur signification clinique, leur intérêt théranostique ainsi que leur impact sur la réponse aux traitements. Dans un premier temps nous avons étudié les mutations activatrices du gène PIK3CA. Ces mutations sont retrouvées dans 25% des cancers du sein et sont impliquées dans la résistance au trastuzumab, aux anti-œstrogènes et aux inhibiteurs de mTOR. 149 échantillons de tumeurs de sein infiltrantes ont été analysés par une technique de PCR-HRM (High Resolution Melting) et 118 échantillons par une technique de PCR-ARMS (Amplification Refractory Mutation System). Les résultats des 2 techniques étaient concordants (k=0,845 ; p<0,001) et une relation entre mutations du gène PIK3CA et grade SBR a été mise en évidence, les tumeurs de grade SBR III étant moins fréquemment mutées que les autres (p=0.025 en HRM et p=0.009 en ARMS). Dans un second temps, notre travail a consisté en l'exploration fonctionnelle des voies de signalisation PI3K/AKT/mTOR, RAS/RAF/MAPKinases et P38MAPKinase. Pour cela nous avons analysé le niveau d'expression des phosphoprotéines p-AKT, p-GSK3ß, p-S6 kinase, p-MEK1, p-ERK1/2, p-P90RSK, p-IGF1R ainsi que p-P38MAPK par immuno-analyse multiplexe. Cette partie a comporté 3 études. Une première étude rétrospective sur 45 échantillons de tumeurs mammaires invasives congelées a mis en évidence des niveaux d'expression de P38 et de p-P38 plus élevés dans les tumeurs RE+. La deuxième étude était une étude prospective visant à déterminer des biomarqueurs de réponse à l'association trastuzumab-évérolimus chez des patientes présentant un cancer du sein précoce traitées en préopératoire. Cette étude a révélé une augmentation statistiquement significative du niveau d'expression de p-MEK1 (p=0.012), p-ERK1/2 (p=0.003) et p-P38MAPK (p<0.001) dans le bras de traitement associant l'évérolimus au trastuzumab qui pourrait s'expliquer par la suppression par l'évérolimus d’une boucle de rétrocontrôle négatif contrôlant l'activation de la voie RAS/RAF/MAPKinases. Dans le bras de traitement évaluant le trastuzumab seul, aucune variation du niveau d'expression des phosphoprotéines n'a été mise en évidence, y compris en aval du récepteur HER2, ce qui soulève l'hypothèse d'un mécanisme d'action prédominant immunologique du trastuzumab. La troisième étude qui comparait l'impact du trastuzumab in vitro et en situation clinique confirme la différence des mécanismes d'action mis en jeu en fonction des conditions cellulaires et cliniques. Dans son ensemble, ce travail a mis en évidence que la détermination du statut mutationnel du gène PIK3CA et du niveau d’expression des phosphoprotéines pourrait être utile à une meilleure caractérisation moléculaire des cancers du sein et à l’optimisation de la personnalisation des prescriptions de thérapies cibléesBreast cancer is the most frequently diagnosed cancer in women and is a real public health problem.Advances in molecular biology have allowed the characterization of the major signaling pathways and revealed their major implication in carcinogenesis processes. Molecular targets have been identified and have enabled the development of targeted therapies, such as monoclonal antibodies, or kinase inhibitors. Despite these considerable advances that have improved the care of patients, emerging of resistance to treatments has been observed. The aim of this work was to identify new tumor biomarkers and determine their clinical significance, their theranostic interest and their impact on the response to targeted therapies. Initially, we studied the activating mutations of the PIK3CA gene. These mutations are found in 25% of breast cancers and are involved in resistance to trastuzumab, antiestrogens and mTOR inhibitors. We analyzed 149 invasive breast tumor samples for PIK3CA gene mutations by PCR-HRM (High Resolution Melting) and 118 by PCR-ARMS (Amplification Refractory Mutation System). The results achieved with the 2 techniques were consistent (k = 0.845; p <0.001) and a relationship between PIK3CA mutations and grade SBR was highlighted with a lower occurrence of mutations in SBR grade III tumors (p=0.025 in HRM and p=0.009 in ARMS). Secondly, we investigated the functional alteration of PI3K/AKT/mTOR, RAS/RAF/MAPKinases and P38MAPKinase signaling pathways. We have analyzed the expression level of phosphoproteins p-AKT, p-GSK3ß, p-S6 kinase, p-MEK1, p-ERK1 / 2, p-P90RSK, p-IGF1R and p-p38MAPK by multiplex immunoanalysis. This part includes 3 studies. The first study was a retrospective study of 45 frozen samples of invasive breast tumors in which we observed that the level of expression of P38 and p-P38 was higher in the ER + tumors. The second study was a prospective study to identify biomarkers of response to trastuzumab-everolimus association in patients with early breast cancer treated preoperatively. This study showed a statistically significant increase of the expression level of p-MEK1 (p = 0.012), p-ERK1/2 (p = 0.003) and p-p38MAPK (p<0.001) in arm treated by trastuzumab associated with everolimus. It could be explained by the repression of a negative feedback loop involving S6K, PI3K and RAS by everolimus, leading to the activation of RAS/RAF/MAPKinases signaling pathway. In the control arm investigating trastuzumab alone, no significant variations of the level of expression of phosphoproteins was demonstrated, raising the hypothesis of the implementation of a predominant immunological mechanism of action for Trastuzumab. The third study that compared effect of trastuzumab in vitro and in clinical setting confirms that trastuzumab has different modes of action when evaluated in cells and in clinical conditions. As a whole, this work showed that determining the mutation status of PIK3CA and the expression level of phosphoproteins could be useful to refine the molecular characterization of breast cancers and optimize the criteria used to personalize the prescription of targeted therapies
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Sanfeliu, Torres Esther. "Estudi mutacional d'EGFR i PIK3CA i d'hipermetilació del promotor del gen BRCA1 en càncer de mama, tipus "triple negatiu"." Doctoral thesis, Universitat Autònoma de Barcelona, 2015. http://hdl.handle.net/10803/392725.
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El càncer de mama és una malaltia molt heterogènia a nivell clínic, morfològic i biològic, que es classifica en diferents subgrups amb perfils immunohistoquímics i evolució clínica-pronòstica diferents. Entre ells, mencionar que el tipus “triple negatiu” (TNBC) representa entre el 10-20% de tots els càncers de mama i es caracteritza per l’absència d’expressió de receptors hormonals d’estrògens i progesterona, així com d’Her2. Es tracta d’un subgrup amb freqüent expressió de marcadors basals, que afecta a dones joves, són tumors d’alt grau, amb mal pronòstic i freqüent progressió en els primers anys després del diagnòstic, i sense una teràpia dirigida, només amb resposta parcial a la quimioteràpia sistèmica. Es per això, que s’ha intentat subdividir de diferents maneres però cap d’elles està totalment acceptable, plantegen així l’estudi d’algunes alteracions moleculars, que encara que estiguin present en un petit percentatge no són despreciables i podrien suggerir una teràpia específica.
Es tracta d’un estudi retrospectiu de 60 casos de càncer de mama diagnosticats de “triple negatiu” en el Consorci Sanitari Parc Taulí, Hospital Universitari, en les quals s’estudia la presència de tres possibles alteracions moleculars (mutació d’EGFR i PIK3CA i hipermetilació del promotor del gen BRCA1) a través de la piroseqüenciació.
En la nostra cohort de TNBC només un 28,33% s’ha diagnosticat en pacient menors o iguals a 50 anys; la majoria són carcinomes ductals infiltrants de tipus no específic, seguits de carcinomes medul·lars; la majoria són d’alt grau histològic. Només 16,67% dels casos han progressat i tots, menys un han mort, en un interval d’entre 1 i 5 anys des del diagnòstic, sent la forma de disseminació més freqüent la via hematògena amb metàstasis viscerals. En només 5 dels 16 casos estudiats s’ha trobat mutació patogènica de BRCA.
A nivell immunohistoquímica la majoria són tumors amb alt índex proliferatiu de Ki67 i un 73,33% són “basal-like” per expressió de CK5/6 i/o EGFR.
A nivell molecular no s’han observat mutacions activadores d’EGFR malgrat que el 53,33% mostren sobrexpressió immunohistoquímica d’EGFR. Mentre que la mutació de PIK3CA s’ha observat en un 10% dels casos, amb predomini de del domini cinasa de l’exó 20 en 66,67% versus el domini hèlix de l’exó 9; i tres d’aquests casos mostren coexpressió de Receptors d’Andrògens, entre els 7 casos de la cohort que n’expressen. S’ha trobat hipermetilació del promotor del gen BRCA1 en un 25% dels casos i només coexistint en un d’ells la presència d’hipermetilació de l’estroma no tumoral.
En general els resultats observats són similars als descrits en la literatura. Fent èmfasi que la discordança observada en l’estudi d’EGFR també es present en les sèries europees, caucàsiques i japoneses, però no d’àsia de l’est, probablement degut a alguna influència ambiental. Malgrat el percentatge de mutacions PIK3CA és discretament menor al descrit, si que s’observa que casi la meitat dels casos expressen receptors d’andrògens positius. El percentatge d’hipermetilació de BRCA1 en el TNBC oscil·la entre 10-35% en funció de les diferents sèries.Breast cancer is a clinical, morphological and biological heterogeneity disease. It is classified in distinct subtypes which have different immunohistochemical patterns and clinical evolution. Triple negative breast cancer (TNBC) represent approximately 10-20% of all breast cancers and it is defined by lacking expression of oestrogen receptor, progesterone receptor and Her2 amplification. TNBC is a subtype of breast cancer with frequent expression of basal markers, and preferentially affecting young women. They are high grade carcinomas and, despite overall poor prognostic and the absent of specific therapy, some TNBC respond partially to neoadjuvant chemotherapy. Several intends of classifying TNBC have been reported, but no one of them are totally accepted. Although the low frequency of some molecular alterations, their presence in breast cancer suggests a possible targeted therapy. We present a retrospective study of a series of 60 patients from the “Corporació Sanitària Parc Taulí, Hospital Universitari” with triple negative breast cancer diagnosis. We studied three molecular alterations (EGFR and PIK3CA mutation and BRCA1 promoter hypermethylation) by pyrosequencing. Our results show that 28,33% of patients are diagnosed before or equal to 50 years. The majority of TNBC are high histological grade and no specific invasive ductal carcinoma type, followed by medullar carcinoma. Only 16,67% of patients had clinical progression and all of them, excepted one, died from breast cancer during the first 5 years after diagnosis. The most frequent recurrence is haematological dissemination with visceral metastasis. BRCA mutation has been studied in 16 patients and only 5 of these patients present a pathogenic known mutation. Immunohistochemical study shows a high proliferative Ki67 index. 73,33% of carcinomas are basal-like for CK5/6 and/or EGFR expression. Although we did not find any EGFR-activating mutation, the EGFR overexpression is present in 53,33% of patients. PIK3CA mutation are identified in 10% of patients, being the localization of this mutation more frequently (66,67%) in cinasa domain of exon 20 than helical domain of exon 9. Three of these patients with mutations show androgen receptor expression. BRCA1 promoter hypermethylation was observed in 25% of the patients, and only one of these patients exhibited stromal BRCA1 hypermethylation. Our results are, globally, similar to those from the literature. The differences observed in the EGFR study are described in some European, Caucasians and Japanese publications, but not in East Asian publications, suggesting a possible environmental influence. Although the percentage of PIK3CA mutations are lower than those from the literature, half of cases express androgen receptors. BRCA1 promoter hypermethylation in TNBC is described from 10 to 35%, depending on the series.
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Adimonye, Anthiny. "The genetic status of the PIK3CA oncogene and activity of the PI3K-AKTmTOR pathway in penile squamous cell carcinoma." Thesis, Queen Mary, University of London, 2017. http://qmro.qmul.ac.uk/xmlui/handle/123456789/24528.
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Penile squamous cell carcinoma (PSCC) is rare; hence little is known about its aetiology and pathogenesis. Two challenges exist in the clinical management of PSCC patients. Firstly, finding a non-invasive method to aid the detection of occult lymph node metastasis to improve patient selection for inguinal lymphadenectomy. Secondly, the development of novel treatment strategies for those with advanced PSCC, as current treatment options are limited. A high prevalence of copy number gain in the chromosome 3q arm has been identified and linked to poor cancer-specific and disease-free survival in PSCC. Within this region lies the PIK3CA oncogene, which is mutated/amplified/gained and results in the activation of the PI3K-AKT-mTOR pathway. PIK3CA copy number gain has not been fully investigated in PSCC and it has the potential to be a driver gene in penile carcinogenesis and the PI3K-AKT-mTOR pathway presents an opportunity for targeted therapeutics in PSCC. I demonstrated an increasing frequency of PIK3CA copy number gain with evolving PSCC disease state (penile intraepithelial neoplasia (10/58; 17%), primary PSCC (83/199; 42%), advanced primary PSCC (20/26; 77%); p < 0.0001) with few PIK3CA mutations in PSCC (3/51; 6%). PIK3CA copy number gain correlated with more aggressive PSCC subtypes (p=0.0028), higher tumour grade (p < 0.0001) and stage (p=0.0043) and thus could be used as a marker of high-risk disease. However, it shows no significant association with lymph node metastasis or prognostic value for cancer-specific survival in PSCC. Overall, I confirmed that the PI3K-AKT-mTOR pathway activity is primarily involved in early penile carcinogenesis and based on these findings the therapeutic targeting of this pathway in those with advanced PSCC disease is unlikely to produce significant clinical benefit. Future studies will need to focus on the identification of new clinically relevant candidate genes and signalling pathways, which offer prognostic value and the potential for targeted therapeutics in this rare cancer.
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Blankenstein, Thomas [Verfasser], and Christoph [Akademischer Betreuer] Klein. "Mutationsanalyse von TP53, KRAS und PIK3CA bei einzelnen disseminierten Tumorzellen aus dem Knochenmark von Karzinompatienten / Thomas Blankenstein. Betreuer: Christoph Klein." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2013. http://d-nb.info/103447488X/34.
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Gasser, Jessica Ann. "Serum and Glucocorticoid-Regulated Kinase Signaling in Breast Cancer." Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:11296.
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Oncogenic activating mutations in PIK3CA, the gene encoding the catalytic subunit of phosphoinositide 3-kinase (PI 3-K), are highly prevalent in breast cancer. The protein kinase Akt is considered to be the primary effector of PIK3CA, though the mechanisms by which PI 3-K mediates tumorigenic signals in an Akt-independent manner remain obscure. My studies show that the serum and glucocorticoid-regulated kinases (SGKs) can function as effectors of PI 3-kinase and transduce signals to phenotypes associated with malignancy. We show that SGK3 is amplified in breast cancer and identify the mechanism by which SGK3 is activated downstream of PIK3CA, specifically through the catalytic activity of the phosphoinositide phosphatase INPP4B. Expression of INPP4B promotes SGK3 activation and in turn inhibits Akt phosphorylation. In breast cancer cell lines with elevated levels of INPP4B, SGK3 is required for proliferation in 3D and also for invasive migration. SGK3 phenotypes are in part mediated by phosphorylation of the substrate protein N-myc downstream regulated 1 (NDRG1), an established metastasis suppressor. The phosphorylation of NDRG1 leads to recruitment by F-box and WD repeat domain-containing 7 (FBW7), the substrate recognition domain of the Skp, Cullin, F-box containing (SCF) complex. Binding of Fbw7 to NDRG1 promotes its polyubiquitination and subsequent degradation by the 26S proteasome. By contrast, our studies also show that the related SGK1 isoform is polyubiquitinated by the functional E3 ubiquitin ligase Rictor-Cullin-1 complex, leading to SGK1 degradation. Proteasomal degradation of SGK1 by Rictor-Cullin-1is the first identified mTORC2-independent function of the Rictor protein. Moreover, the deregulation of SGK1 ubiquitination highlights a mechanism of SGK1 overexpression in breast cancers.
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Sewing, Marie Verfasser], and Guido [Akademischer Betreuer] [Sauter. "Der Einfluss von p53 mediierter genetischer Instabilität auf die Entstehung von PIK3CA-Amplifikationen in malignen Ovarialtumoren / Marie Sewing. Betreuer: Guido Sauter." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2011. http://d-nb.info/1020419059/34.
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Gebauer, Leonie [Verfasser], and Andreas [Akademischer Betreuer] Neubauer. "10-Jahres-Überlebensrate von Patienten mit kolorektalem Karzinom in Abhängigkeit vom PIK3CA- und KRAS- Mutations- und Acetylsalicylsäureeinnahmestatus / Leonie Gebauer ; Betreuer: Andreas Neubauer." Marburg : Philipps-Universität Marburg, 2020. http://d-nb.info/1221270591/34.
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Filho, Júlio Cezar Marques Ricarte. "Envolvimento dos oncogenes BRAF, PIK3CA e AKT1 e do microRNA supressor de tumor let-7 na transformação maligna e progressão tumoral tiroidiana." Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/42/42134/tde-06102009-094118/.
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Neste estudo, geramos ensaios de espectrometria de massa para detecção de 111 mutações nos genes RET, BRAF, NRAS, HRAS, KRAS, PIK3CA e AKT1 e avaliamos inúmeras linhagens celulares e tumores tiroidianos. Mostramos que as mutações dos genes BRAF e RAS refletem prognósticos distintos e que as mutações BRAF são altamente prevalentes em câncer metastático. Mutações dos genes PIK3CA e AKT1, esta última sendo reportada pela primeira vez no câncer de tiróide, são relativamente frequentes neste câncer. Avaliamos ainda a função do microRNA let-7 neste câncer. Mostramos que a ativação do rearranjo RET/PTC3 em células de tiróide PCCl3 reduz a expressão de let-7. Além disso, a transfecção deste microRNA em células TPC-1, que apresentam o rearranjo RET/PTC1, inibe a fosforilação de ERK, o crescimento celular e modula a expressão de genes do ciclo celular e diferenciação. Estes dados contribuem na aplicação de terapias dirigidas a efetores das vias PI3K e MAPK no câncer de tiróide, além de salientar o envolvimento do miRNA let-7 como um gene supressor tumoral nesta doença.In this study, we designed an assay panel for genotyping 111 mutations by mass spectrometry in RET, BRAF, NRAS, HRAS, KRAS, PIK3CA, AKT1 and other related genes in many thyroid cancer cell lines and tumors. We show that patients with BRAF and RAS mutations have distinct prognosis and that BRAF mutations are highly prevalent in metastatic thyroid cancers. Mutations of PIK3CA and AKT1, the latter not previously described in this disease, are comparatively frequent in thyroid cancers. In addition, we evaluated the role of let-7 microRNA in this cancer. We show that RET/PTC3 activation in PCCl3 thyroid cells reduces let-7 expression. Moreover, transfection of let-7 in TPC-1 cells, which harbor RET/PTC1 rearrangement, inhibits MAPK activation, reduces cell growth and modulates the expression of cell cycle and differentiation genes. These findings may contribute to the design of therapies directed at MAPK and PI3K effectors and to highlight the function of let-7 as tumor suppressor gene in thyroid cancer.
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Velasco, Sánchez Ana. "Oncogenes y genes supresores de tumores en carcinoma de endometrio." Doctoral thesis, Universitat de Lleida, 2012. http://hdl.handle.net/10803/110545.
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El objetivo principal de este trabajo ha sido la identificación de alteraciones moleculares que participen de manera significativa en el desarrollo y la progresión del cáncer de endometrio, con el propósito de añadir mas claves para el descubrimiento de nuevas dianas de diagnosis y terapias individuales contra esta patología. El trabajo ha sido centrado en el estudio de modificaciones en el ADN de las células que forman el tejido tumoral en una serie de pacientes con carcinoma endometrial, en concreto, en el análisis mutacional de los genes PIK3CA y FGFR2 y el análisis de hipermetilación del promotor de los genes RASSF2A y SPRY2, elementos que forman parte de importantes vías de transducción de señales implicadas principalmente en procesos de crecimiento y diferenciación celular. Por un lado, hemos advertido cierto grado de variabilidad en el patrón de expresión de los genes estudiados en los tejidos tumoral y no tumoral y esas diferencias de expresión son, en parte, debidas a la existencia de hipermetilación en las regiones promotoras de los genes implicados. Así mismo, la presencia de mutaciones en regiones génicas que codifican partes de la proteína claves para su función en la célula es también un factor que modifica el patrón de expresión entre tejidos. En concreto, tras el análisis de la expresión inmunohistoquímica de RASSF1A y la presencia o ausencia de metilación en la zona promotora del gen RASSF1A se detectaron tumores con niveles de expresión reducidos y presencia de hipermetilación en el promotor, ambos fenómenos asociados de manera estadísticamente significativa. Lo mismo ocurre, aunque en un grado distinto, con la expresión de SPRY2 en algunos tumores en asociación con la presencia de hipermetilación en el promotor del gen. A través de este análisis hemos descubierto que la expresión de SPRY2 presenta variabilidad en las glándulas endometriales de los tejidos no tumorales a lo largo del ciclo menstrual. Por otro lado hemos visto como el gen PIK3CA se encuentra frecuentemente mutado en las células que forman los tumores de carcinoma de endometrio y que, además, es un suceso que coincide con la presencia de mutaciones en el gen PTEN. Sin embargo, la frecuencia de mutaciones en el gen FGFR2 se ha mostrado baja aunque su expresión a nivel inmunohistoquímico refleja diferencias entre carcinoma de tipo endometrioide y no endometrioide. Por ultimo, añadir una revisión de uno de los fenómenos que ocurren de manera mas frecuente durante la formación y el progreso de los tumores en carcinoma de endometrio: el concepto de “pérdida de heterocigosidad”. En este trabajo hemos considerado primordial incluir un obra en la que se realiza una incursión a los mecanismos moleculares a través de los cuales se produce la pérdida de heterocigosidad, asi como los métodos que se utilizan para su detección y el significado de algunos patrones de pérdida de heterocigosidad en determinadas regiones cromosómicas en carcinoma de endometrio.L'objectiu principal d'aquest treball ha estat la identificació d'alteracions moleculars que participin de manera significativa al desenvolupament i la progressió del càncer d'endometri, amb el propòsit d'afegir més claus pel descobriment de noves dianes de diagnosi i teràpies individuals contra aquesta patologia. El treball ha estat centrat en l’estudi de modificacions en l’ADN de les cèl-lules que formen el teixit tumoral en una sèrie de pacients amb carcinoma endometrial, en concret, en l’anàlisi mutacional del gens PIK3CA i FGFR2 i l’anàlisi de hipermetilació del promotor dels gens RASSF1A i SPRY2, elements que formen part d’importants vies de transducció de senyals implicades principalment en processos de creixement i diferenciació cel-lular. En primer lloc hem advertit cert grau de variabilitat en el patró d'expressió dels gens estudiats entre els teixits tumoral i no tumoral i aquestes diferències d'expressió són, en part, degudes a l'existència de hipermetilació en les regions promotores dels gens implicats. Així mateix, la presencia de mutacions en regions gèniques que codifiquen parts de la proteïna claus per la seva funció a la cèl-lula, és també un factor que modifica el patró d'expressió entre entre els teixits tumoral i no tumoral. En concret, després de l’anàlisi immunohistoquímic de l’expressió de RASSF1A i la presència o absència de metilació a la zona promotora del gen RASSF1A, es van detectar tumors amb nivells d’expressió reduïts i presència de hipermetilació en el promotor, ambdós fenòmens associats de manera estadísticament significativa. El mateix passa, encara que amb diferent grau, amb l’expressió de SPRY2 en alguns tumors en associació amb la presència de ipermetilació en el promotor del gen. A través d’aquest anàlisi hem descobert que l’expressió de SPRY2 presenta variabilitat en les glàndules endometrials dels teixits no tumorals al llarg del cicle menstrual. D'altra banda hem vist com el gen PIK3CA es troba freqüentment mutat en les cèl-lules que formen els tumors de carcinoma d'endometri i coincideix amb la presència de mutacions en el gen PTEN. No obstant això, la freqüència de mutacions en el gen FGFR2 s'ha mostrat baixa encara que la seva expressió a nivell inmunohistoquímic reflecteix diferencies entre carcinoma de tipus endometrioide y no endometrioide. Finalment, afegir una revisió d'un dels fenòmens més freqüent en la formació i el progrés dels tumors en carcinoma d'endometri: el concepte de "pèrdua de heterozigositat". En aquest treball hem considerat primordial incloure una obra en que es realitza una incursió als mecanismes moleculars a través dels quals es produeix la pèrdua de heterozigositat, aixi com els mètodes que s'utilitzen en la seva detecció i el significant d'alguns patrons de pèrdua de heterozigositat en determinades regions cromosòmiques en carcinoma d'endometri.
The main point of this study was the identification of molecular alterations that participate in the development and progression of endometrial cancer, in order to add more keys to the discovery of new targets for diagnosis and therapies against this disease. The work has been focused on the study of molecular alterations of DNA from tumour tissues in a series of endometrial carcinoma patients, above all, mutational analysis of PIK3CA and FGFR2 genes and analysis of promoter hyper methylation of SPRY2 and RASSF2A genes, together forming part of signal transduction pathways that are involved in processes of growth and cell differentiation. To begin with, we noticed some variability in the gene expression pattern examined between tumour and normal tissue, and these differences are partly due to hyper methylation in promoter regions at the involved genes. Likewise, mutations in gene regions encoding key protein domains in the cell are also a factor that modifies the gene expression pattern between tumour and normal tissue. In particular, after analysing the immunohistochemical expression of RASSF1A and the presence or absence of methylation in the RASSF1A gene promoter we detected tumours with low expression levels and promoter hyper methylation. The same applies, albeit in a different degree, with SPRY2 expression in some tumours in association with the presence of gene promoter hyper methylation. Through this analysis we found some SPRY2 expression variability in endometrial glands from non-tumour tissues throughout the menstrual cycle. On the other hand we have seen that the PIK3CA gene is frequently mutated in tumour cells from endometrial carcinoma, and this is also a PTEN gene mutation coincident event. However, FGFR2 gene mutation ratio has shown to be low although immunohistochemical expression reflects differences between endometrioid endometrial carcinoma and no-endometrioid type. Finally, we wanted to add a review of one of the phenomena, which occurs more frequently during the formation and progress of tumours in endometrial carcinoma: LOH "loss of heterozygosity". We have considered essential include a review work about the molecular mechanisms through which loss of heterozygosity is produced, the methods used in their detection and significance of some patterns of loss of heterozygosity in specific chromosomal regions in endometrial carcinoma.
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Choy, Kit-chi, and 蔡潔芝. "Epidermal growth factor receptor (EGFR) and phosphoinositide-3-kinase catalytic alpha (PIK3CA) mutations in non-small cell lung cancer(NSCLC) and response to tyrosine kinase inhibitor therapy." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B46632426.
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Pikart, Philip [Verfasser], Christoph Pascal [Akademischer Betreuer] Hugenschmidt, and Peter [Akademischer Betreuer] Müller-Buschbaum. "Advances in Coincident Doppler Broadening Spectroscopy: Element Selective Studies on Metallic Nanolayers with Monoenergetic Positrons / Philip Pikart. Gutachter: Peter Müller-Buschbaum ; Christoph Pascal Hugenschmidt. Betreuer: Christoph Pascal Hugenschmidt." München : Universitätsbibliothek der TU München, 2012. http://d-nb.info/1024567427/34.
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Chen, Shuhui. "Étude des mutations des gènes KRAS, NRAS, BRAF, PIK3CA, MET et de l’expression des protéines P53 et PTEN et leurs implications cliniques dans le carcinome ovarien de haut grade." Thesis, Université de Lorraine, 2016. http://www.theses.fr/2016LORR0093/document.
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Objectifs: Malgré leur grande hétérogénéité histologique et moléculaire, la prise en charge clinique des carcinomes ovariens de haut-grade (COHG) reste peu variable. Le pronostic sombre de cette pathologie implique un réel besoin des nouvelles thérapies. Au-delà des marqueurs pronostiques histologiques classiques et des enquêtes oncogénétiques, l’objectif de cette étude a consisté à rechercher des cibles moléculaires pharmacologiquement recrutables afin de pouvoir proposer aux patientes un accès à la thérapie innovante et personnalisée. Méthodes: Cette étude a été réalisée chez 53 patientes (pts) (âge moyen 58,9 ans, intervalle 25-87) de COHG histologiquement prouvés dont 45 pts de sous-type séreux. 19 pts ont fait l’objet d’une consultation et d’un test oncogénétique sur la base d’antécédents familiaux / personnel de cancer de sein/ovaire. chez. L’expression de P53 et de PTEN a été évaluée sur des tissus fixés au formol et inclus en paraffine par immunohistochimie. Les mutations somatiques de KRAS, NRAS, BRAF, PIK3CA et MET ont été recherchées par PCR-HRM (Polymerase Chain Reaction High Resolution Melting) puis vérifiées par NGS (Next Generation Sequencing) sur des extraits d'ADN préparés à partir d'échantillons de tumeurs congelés, prélevés au moment du diagnostic. Résultats: Des mutations germinales de BRCA1 / 2 ont été identifiées chez 7 pts, toutes atteintes des carcinomes séreux. Une mutation du gène KRAS (exon 2), 2 mutations du gène NRAS (exon 3), 6 mutations du gène PIK3CA (exon 5, 10 et 21) et 5 mutations du gène MET (exon 14 et 18) ont été identifiées chez les 53 tumeurs par NGS, dont deux mutations du gène NRAS et 2 mutations du gène PIK3CA détectées précédemment par PCR-HRM. Aucun profil mutationnel multiple n’a été retrouvé. La surexpression de P53 et la perte d’expression de PTEN ont été constatées chez 32 sur 53 (60%) et 19 sur 46 (41%) des tumeurs. L’analyse statistique n’a été réalisée que chez le sous-groupe de pts atteintes des carcinomes séreux à cause de l’effectif de l’étude. Avec un suivi médian de 38 mois (intervalle de 6-93), 35 pts ont eu une rechute de la maladie et 25 pts sont décédées. La survie sans progression à 2 ans est 28%, et la survie globale à 5 ans est 37%. La surexpression de P53 a été trouvée associée à une meilleure chimiosensibilité, une meilleure survie sans progression et une meilleure survie globale. Conclusion: Pour des COHG, au-delà des altérations de P53 et PTEN, des anomalies génétiques somatiques concernant les voies de signalisation PI3K et MAPK ne sont pas rares et peuvent être détectées par NGS. L’identification de ces anomalies somatiques pourrait offrir une possibilité des thérapies ciblées innovantes pour les patientes sur la base d’éléments diagnostics moléculairesObjectives: Despite the great histological and molecular heterogeneity, the clinical management of high-grade ovarian carcinoma remains univo-cal. As a major subgroup of ovarian carcinoma, high-grade ovarian carci-nomas (HGOC) need novel therapy. Additionally to conventional histolog-ical prognostic markers and oncogenetic investigations, molecular diag-nostic was performed using PCR-HRM (Polymerase Chain Reaction High Resolution Melting) and NGS (Next Generation Sequencing) to identify "druggable" targets that could provide access to innovative personalized therapy. Methods: This study was performed in 53 patients (pts) (mean age 58.9 years, range 25-87) with histologically proven HGOC of which 45 pts with serous carcinoma. BRCA1/2 germline mutations had been screened in 19 pts with familial/personal history of breast/ovarian cancer justifying on-cogenetic investigations. P53 and PTEN expression was assessed on for-malin fixed paraffin-embedded tissues using immunohistochemistry. So-matic mutations of KRAS, NRAS, BRAF, PIK3CA and MET were screened using PCR-HRM and then confirmed using NGS on DNA extracts from frozen tumor specimens taken at diagnosis. Results: Seven pts had BRCA1 / 2 germline mutations, all had serous carcinomas. One mutation of KRAS (exon 2), 2 mutations of NRAS (exon 3), 6 mutations of PIK3CA (exon 5, 10 and 21) and 5 mutations of MET (exon 14 and 18) were identified using NGS, of which 2 mutations of NRAS and 2 mutations de PIK3CA detected previously by PCR-HRM, no multiple mutation was detected. P53 overexpression and PTEN loss of expression was detected respectively in 32 of 53 (60%) and 19 of 46 (41%) of all the tumors. Because of the efffective of the study, statistical analyses were restricted to pts with serous carcinoma. With a median follow-up of 38 months (range 6-93), 35 pts had disease progression and 25 pts died during the follow-up. The 2-year progression-free survival (PFS) rate was 28% and 5-year overall survival (OS) rate was 37%. Overexpression of mutant P53 was found to be associated with chemosensitivity and longer PFS and OS. Conclusion: In HGOC, beside P53 and PTEN alterations, somatic genetic abnormalities of PI3K and MAPK signaling pathways can be detected us-ing NGS and provide molecular rationale for targeted therapies, potential-ly offering new therapeutic opportunities to the patients
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Mujalli, Abdulrahman. "Phosphoinositides in blood platelet : mapping of molecular species and evidence for a new localization and role of PI3P." Thesis, Toulouse 3, 2018. http://www.theses.fr/2018TOU30110.
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Les phosphoinositides (PIs) sont des phospholipides membranaires qui jouent un rôle crucial dans le contrôle de l'organisation spatio-temporelle de nombreuses voies de signalisation intracellulaire, du réarrangement du cytosquelette d'actine et du trafic de vésicules. Dans la plaquette, le métabolisme des PIs est particulièrement actif et génère, par le jeu de kinases, phosphatases et phospholipases spécifiques, des seconds messagers indispensables à l'activation plaquettaire, notamment le phosphatidylinositol 3,4,5-trisphosphate (PIP3). La première partie de la thèse concerne l'étude des différentes espèces moléculaires (composition en acides gras) des 4 grandes classes de PIs (PI, PIP, PIP2 et PIP3) dans les plaquettes humaines et de souris au repos ou lors de leur activation. Cette analyse, jamais réalisée précédemment, a été possible grâce à une technique de spectrométrie de masse (LC-MS), basée sur la méthylation avec le TMS-diazomethane des groupements phosphates des PIs. Cette étude montre une augmentation rapide et transitoire de 2 espèces moléculaires majoritaires de PIP3 lors d'une stimulation plaquettaire avec une réactivité différente des plaquettes humaines et de souris en réponse aux agonistes plaquettaires (thrombine et CRP). En utilisant des modèles murins présentant une inactivation des PI3-kinases (PI3K) dans la lignée mégacaryocytaire et des inhibiteurs spécifiques de PI3K, j'ai montré que l'isoforme PI3Kß (p110ß) de classe I est très majoritairement responsable de la production des diverses espèces moléculaires de PI(3,4,5)P3 en réponse à la thrombine ou au CRP alors que la PI3Ka (p110a) est faiblement impliquée. Les résultats montrent également une grande variété d'espèces moléculaires de PI et seulement 2 espèces moléculaires prédominantes pour les PIP, PIP2 et PIP3, aussi bien chez l'homme que chez la souris malgré des régimes alimentaires très différents. Nous montrons des différences importantes dans le métabolisme des espèces moléculaires de PI, PIP et PIP2 dans les plaquettes humaines et de souris lors de la stimulation. Dans cette étude, nous avons identifié pour la première fois des espèces moléculaires minoritaire de PIP2 mais qui augmentent de façon importante lors de la stimulation plaquettaire. Ce travail permet de dresser la première cartographie des différentes espèces moléculaires de PIs présents dans les plaquettes humaines et de souris et les modifications induites par leur activation. La deuxième partie de la thèse montre pour la première fois une localisation atypique du phosphatidylinositol 3- monophosphate (PI3P), dans le feuillet externe de la membrane plasmique plaquettaire. Je démontre que ce lipide minoritaire (environ 10% de PIP), connu pour être intracellulaire et impliqué dans le trafic vésiculaire, est également présent à la surface des plaquettes au repos. Aucun autre PI n'a pu être détecté dans le feuillet externe de la membrane plasmique plaquettaire. Ce résultat a été obtenu en utilisant différentes sondes fluorescentes se liant spécifiquement au PI3P et leurs contrôles mutées. Nous montrons que le traitement des plaquettes avec des enzymes métabolisant spécifiquement le PI3P (MTM1 et ABH) réduit significativement ce pool de PI3P. Les plaquettes de souris déficientes en PI3K de classe II et III présentent une diminution du PI3P de surface. De manière intéressante, ce pool externe de PI3P permet l'endocytose des protéines circulantes liant le PI3P, in vitro, ex vivo et in vivo. Les sondes PI3P spécifiques internalisées dans la plaquette sont stockées dans les granules a puis sécrétées lors de l'activation plaquettaire. Cette étude montre que le PI3P se comporte comme un récepteur permettant l'endocytose de protéines plasmatiques spécifiquesPhosphoinositides (PIs) are membrane phospholipids that play a crucial role in controlling the spatiotemporal organization of many intracellular signaling pathways, actin cytoskeleton rearrangement, and vesicle trafficking. In platelet, the metabolism of PIs is highly active and generates, by the interplay of specific kinases, phosphatases and phospholipases, second messengers essential for platelet activation, in particular phosphatidylinositol 3,4,5-trisphosphate (PIP3). The first part of the thesis concerns the study of the different molecular species (fatty-acyl composition) of 4 PIs classes (PI, PIP, PIP2 and PIP3) in resting and stimulated human and mouse platelets. This analysis, never realized previously, was possible thanks to a mass spectrometry (LC-MS) technique, based on methylation of PIs phosphates groups with TMS- diazomethane. This study shows a rapid and transient increase in the 2 major molecular species of PIP3 during platelet stimulation with a different reactivity of human and mice platelets according to the used agonists (thrombin and CRP). Using mice models with selective deletion of PI3-kinases (PI3K) in the megakaryocyte lineage and specific PI3K inhibitor, I showed that the class I PI3Kß (p110ß) is the major isoform responsible for the production of the various molecular species of PIP3 in response to thrombin or CRP whereas class I PI3Ka (p110a) is weakly involved. The results also show a large variety of molecular species of PI while only 2 predominant molecular species for PIP, PIP2 and PIP3, both in humans and mice platelets despite very different diet. We show a significant difference in terms of PI, PIP and PIP2 molecular species metabolism in human and mice platelets during stimulation. In this study, we identified for the first time the presence of low-abundance molecular species of PIP2 but which increase significantly during platelet stimulation. This work constitutes the first comprehensive analysis of PIs molecular species and the changes in their actual mass during platelet stimulation. The second part of the thesis shows for the first time an atypical localization of phosphatidylinositol 3-monophosphate (PI3P), in the outer leaflet of the platelet plasma membrane. I demonstrate that this minor lipid (about 10% of PIP), known to be intracellular and involved in vesicular trafficking, is also present at the surface of resting platelet. No other PIs could be detected in the outer leaflet of the platelet plasma membrane. This result was obtained using fluorescent probes binding specifically to PI3P and their mutated controls. Treatment of platelets with PI3P specific metabolizing enzymes (MTM1 and ABH) significantly reduced this particular pool of PI3P. Class II and III PI3K deficient mouse platelets showed a decrease in surface PI3P. Interestingly, this external pool of PI3P was able to mediate endocytosis of circulating PI3P- binding proteins, in vitro, ex vivo and in vivo. Internalized specific PI3P probes were stored into platelets a-granules and could then be secreted during platelets activation. This study shows that PI3P acts as a receptor allowing endocytosis of specific plasma proteins
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Andersson, Patiyan. "Molecular Genetic Studies on Prostate and Penile Cancer." Doctoral thesis, Linköping : Univ, 2008. http://www.bibl.liu.se/liupubl/disp/disp2007/med1041s.pdf.
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Zenthoefer, Marion [Verfasser], Holger [Akademischer Betreuer] Kalthoff, Levent [Akademischer Betreuer] Piker, Roland [Gutachter] Lauster, Holger [Gutachter] Kalthoff, and Juri [Gutachter] Rappsilber. "Neue Wirkstoffe gegen Pankreaskrebs aus der Ostsee-Braunalge Fucus vesiculosus: Etablierung eines Aufreinigungsschemas nach dem Prinzip der Aktivitäts-geleiteten Fraktionierung / Marion Zenthoefer ; Gutachter: Roland Lauster, Holger Kalthoff, Juri Rappsilber ; Holger Kalthoff, Levent Piker." Berlin : Technische Universität Berlin, 2021. http://d-nb.info/1238141447/34.
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Brenny, Glaucia Maria. "Implicações da Lei n. 12.690 de 2012 para as cooperativas de catadores de materiais recicláveis." Universidade do Estado do Rio de Janeiro, 2014. http://www.bdtd.uerj.br/tde_busca/arquivo.php?codArquivo=8022.
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Este trabalho visa analisar as implicações da Lei n. 12.690 de 2012 para as
cooperativas de trabalho em relação à situação organizacional, socioeconômica e às
condições gerais de trabalho, em particular, no caso das cooperativas de catadores
de material recicláveis. A pesquisa tem caráter exploratório e qualitativo. Como
procedimento, adotou-se a revisão da literatura, complementada com entrevistas
dirigidas às lideranças de cooperativas de catadores localizadas no Estado do Rio
de Janeiro. É inegável que esta lei é um marco para os trabalhadores de
cooperativas. Dentre outros, ela visa regulamentar os aspectos socioeconômicos da
organização e propiciar garantias mínimas nas relações de trabalho, tais como:
número mínimo de sete trabalhadores para abrir uma cooperativa; retirada de um
salário mínimo mensal; remuneração do trabalho noturno superior à do
diurno; duração do trabalho não superior a oito horas diárias e 44 horas semanais;
repouso semanal remunerado; além de estabelecer em assembleia, os fundos para
possibilitar outros direitos dos sócios, dentre eles a saúde e segurança no trabalho.
O estudo concluiu que considerável parte dos entrevistados desconhece a referida
lei e que o fator econômico é um dos aspectos de maior impacto na sua aplicação.
Contudo, eles poderão ser superados com a efetividade das políticas públicas a fim
de compensar os custos adicionais que terão as cooperativas com a aplicação desta
lei. Recomenda-se a implantação de programas municipais de coleta seletiva de
resíduos com a participação ativa dos catadores, como determina a Política Nacional
de Resíduos Sólidos, sendo fundamental o envolvimento de todos os setores da
sociedade. Além disso, que a nova lei das cooperativas de trabalho seja mais
divulgada e debatida com os setores interessados. Deve-se aperfeiçoar os
programas dirigidos às cooperativas de catadores, com maior incentivo à reciclagem,
através da redução ou isenção dos impostos para as atividades de reciclagem e dos
materiais reciclados, por exemplo. Nas áreas de saúde e segurança do trabalho, é
importante a criação de normas específicas para esta categoria de trabalhadores em
conformidade com a sua realidade. Espera-se que a pesquisa contribua para a
melhor aplicação prática da lei analisada nas cooperativas. Como proposta de
estudos futuros, sugere-se a criação de indicadores para o monitoramento da
aplicação da Lei n. 12.690 de 2012 após a sua regulamentação, os quais poderão
ser utilizados com a finalidade de garantir a melhoria contínua e fortalecer as
cooperativas de trabalho, em particular, as de catadores de materiais recicláveis.The purpose of this research is to answer if the Brazilian federal law 12,690 from 2012, that supports the activities of labor cooperatives, presents benefits or obstacles in the particular case of waste pickers cooperatives. In addition, it will be also identified its positive or negative points and the difficulty of its implementation, that can be bureaucratic, technical or economic. The overall goal is to analyze the implications of this law, with respect to the organization, socioeconomic status and general labor conditions. This research can be considered exploratory, because there are few discussions or papers about actual legislation on labor cooperatives that support this study. This is considered a qualitative research, that compares the new legislation (law no. 12,690 from 2012) with the previous legislation (law no. 5,764 from 1971) and investigates the possible implications for cooperatives and cooperative workers. It was verified that the law has not essentially a "formal worker" character, as verified in a comparative analysis between the three laws, the present law, the Federal Brazilian Constitution and the Brazilian Consolidation of Labor Laws. It is noted that the law n 12,690 from 2012 only emphasized social rights of the Brazilian Federal Constitution, which apply to all working relationship to ensure human dignity. The study shows that the greatest impact of this law will be in the economic sector of waste pickers cooperatives, because the implementation and impact of these rules to labor relations may increase the final selling material price. The recyclable materials more expensive, some companies cannot purchase them and the cooperatives cannot be able to self-sustaining and eventually should close their businesses. Therefore, considering an adequate public policies to balance the socioeconomic factor, the Law 12,690 from 2012 would meet the expectations of the category of recyclable materials and guarantee the dignity in their work activities. To establish the balance between public policies and the Law 12,690 from 2012, it is recommended to implement municipal programs of selective waste collection. The society must be stimulated to segregate the domestic and industrial waste. Moreover the existing social programs shall be reinforced, and the cooperatives of recyclable materials needs to become more popular in the market and the recycling activity must be encouraged, in which reduction of taxes on recycled materials should occur. It is also recommended to create specific legal rules for the recyclable materials pikers category, especially on health and safety, in accordance with their reality. It is due to the fact that they are different from other companies that envisage the profit and transmit the costs to the final consumers.
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Mordant, Pierre. "Cancer bronchique primitif, voies de signalisation intra-cellulaires et modèles précliniques." Phd thesis, Université Paris Sud - Paris XI, 2012. http://tel.archives-ouvertes.fr/tel-00809668.
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Contexte. Le cancer bronchopulmonaire (CBP) demeure la première cause de mortalité par cancer dans le monde. Malgré l'espoir suscité par le développement des thérapies ciblées, son pronostic demeure sombre, particulièrement dans les cas de CBP à petites cellules (CBP-PC) et de CBP non à petites cellules (CBP-NPC) présentant une activation de l'oncogène KRAS. Matériel et Méthodes. Nous avons mené 3 études successives, visant à (i) radiosensibiliser des modèles de CBP-PC par l'ajout d'un inhibiteur de BCL2, (ii) cibler des modèles de CBP-NPC mutés KRAS par l'association d'un inhibiteur de mTOR et d'un inhibiteur de RAF, et (iii) créer un modèle préclinique orthotopique murin de CBP reproduisant la progression tumorale observée en clinique. Résultats. Dans la première étude, l'inhibiteur de BCL2 oblimersen a présenté un effet radiosensibilisant sur des modèles de CBP-PC, in vitro et in vivo. Dans la seconde étude, l'association de l'inhibiteur de mTOR everolimus et de l'inhibiteur de RAF/VEGFR RAF265 a présenté un effet synergique sur des lignées cellulaires de cancers présentant la double mutation de KRAS et de PIK3CA, in vitro et in vivo. Dans la troisième étude, l'injection orthotopique d'une lignée bioluminescente de CBP-NPC chez des souris nude a permis d'établir des tumeurs intra pulmonaires évoluant vers une extension métastatique ganglionnaire et hématogène, et de détecter la présence de cellules tumorales circulantes. Conclusion. L'association d'un inhibiteur de BCL2 à la radiothérapie est une stratégie intéressante dans le CBP-PC, l'association d'un inhibiteur de mTOR et d'un inhibiteur de RAF/VEGFR est une stratégie intéressante dans le CBP-NPC présentant une double mutation KRAS-PIK3CA, mais ces données doivent être confirmées sur des modèles orthotopiques afin de gagner en pertinence avant d'envisager un transfert en clinique.
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Souza, José Raimundo de. "Possibilidades e limites da associação na estruturação de unidades locais de reciclagem: o caso da Associação Nora: Novo Osasco reciclando atitudes dos trabalhadores com materiais recicláveis." Universidade do Vale do Rio do Sinos, 2005. http://www.repositorio.jesuita.org.br/handle/UNISINOS/2116.
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Previous issue date: 19Programa Internacional de Bolsas de Pós-Graduação da Fundação Ford
Esta pesquisa aborda ações que agregam catadores de papel e que, embora se mantenham na informalidade ou se legalizem como associações, são geralmente identificadas como “cooperativas de reciclagem”. Para os catadores de papel, no entanto, o formato da associação permite a existência de vínculos socioeconômicos, culturais e fluxos de trabalho e de recursos, que se dão entre a economia em estruturação no empreendimento e as economias dos indivíduos e das famílias que o integram. A hipótese é a de que o modelo da associação representa uma forma de organização que permite o surgimento do empreendimento como uma extensão das unidades domésticas dos indivíduos que o compõem, possibilitando a legalização da ação sem, no entanto, obrigá-los a optarem entre sua família ou o trabalho. Este, ao invés de exigir dedicação exclusiva, antes possibilita a união entre a reprodução e a produção (meios de subsistência), regidas por uma mesma lógica: a da reprodução ampliada da vida
The approach of this research is the actions that gather picker-garbages and, even in informality or legalized as associations, they are generally called as “recycling cooperatives”. But, for these picker-garbages, an association format gives a strong socioeconomic and cultural link, and also a flux of work and resources that happen between the structure of the economy in the enterprise and the personal and family economy. The hypothesis is that the association model represents a kind of organization that allows the beginning of the enterprise as an extension of each individual´s domestic unities, giving the possibility of legalization without forcing them to make a choice between their family and their work. This, instead of demanding an exclusive dedication, makes possible the joining between reproduction and production (subsistence ways), defined by a unique logic: of life’s broader reproduction
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Lupieri, Adrien. "Fonctions catalytique et non-catalytique de la PI3Ky dans la réponse artérielle aux stress." Thesis, Toulouse 3, 2017. http://www.theses.fr/2017TOU30095.
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La physiopathologie artérielle comprend différentes pathologies telles que l'hypertension, l'athérosclérose, l'hyperplasie intimale qui sont caractérisées par un remodelage artériel en réponse à différents stress environnementaux. Mon travail de thèse s'est intéressé à décrire les mécanismes cellulaires et moléculaires mis en jeu en réponse à un stress artériel dans des modèles murins et de proposer de nouvelles approches thérapeutiques dans la prévention des dommages artériels. Ainsi, nous nous sommes intéressés au rôle d'une isoforme particulière de la famille des phosphoinositide 3-kinase, la PI3Ky. Cette protéine est largement exprimée dans le compartiment hématopoïétique, où son activité catalytique intervient dans l'inflammation de la paroi artérielle, mais elle est également présente à de plus faible niveau dans les CML et les CE. Associée à son rôle catalytique largement impliqué dans la migration et la libération de facteurs inflammatoires, la PI3Ky a été décrite comme ayant des fonctions non-catalytiques, dite " d'ancrage ", activant des phosphodiestérases (PDE). Ainsi, en utilisant deux modèles murins génétiquement modifiés pour la PI3Ky, l'un délété pour la PI3Ky (PI3KyKO pour knockout) et l'autre exprimant une forme inactive de la PI3Ky (PI3KyKD pour kinase dead) nous avons pu évaluer le rôle des 2 fonctions dans des modèles murins de lésions artérielle. Dans un premier temps, nous nous sommes intéressés au rôle non-catalytique de la PI3Ky dans les CML. A partir d'un modèle murin de remodelage artériel induit par un stress hypertenseur nous avons observé que l'hyperplasie médiale des CML est dépendante de la PI3Ky, mais indépendante de son activité catalytique. In vitro à partir de cultures primaires de CML de souris nous avons démontré que la PI3Ky régule l'activité des PDE indépendamment de son activité, limitant les taux intracellulaires d'AMPc qui est un puissant frein de la prolifération des CML. Ces modèles nous ont aussi permis de tester une stratégie thérapeutique originale utilisant un peptide perméant inhibant l'interaction PI3Ky/PDE. Ce peptide est capable de prévenir à la fois la prolifération des CML in vitro mais aussi l'hyperplasie médiale in vivo. Dans un deuxième temps, nous avons étudié comment l'activité PI3Ky inflammatoire, inhibe la cicatrisation endothéliale suite à une lésion endovasculaire. A l'aide de différents modèles in vivo et ex vivo de réendothélialisation chez la souris, nous avons pu observer que suite à une lésion vasculaire l'activité de PI3Ky des lymphocytes T induit la sécrétion d'IFNy, entrainant une production locale de CXCL10 par les CML. Cette chimiokine va directement inhiber la cicatrisation endothéliale, indépendamment du compartiment immun. Ces travaux ont permis d'une part de démontrer que l'inhibition de la PI3Ky représentait une stratégie thérapeutique envisageable dans les complications de l'angioplastie mais ont également permis de montrer les mécanismes d'interactions cellulaires complexes mis en jeu lors d'une agression artérielle. Ils ont notamment permis de démontrer un rôle central de la CML agissant comme un relai entre l'inflammation adventitielle et l'endothélium. L'ensemble de ces données a pu mettre en avant une double fonction de la PI3Ky dans les processus de réponse à un stress inflammatoire ou hémodynamique. D'une part, son rôle pro-inflammatoire contrôlé par son activité catalytique, responsable d'une inhibition de la cicatrisation endothéliale via l'activation des CML. D'autre part, son rôle non-catalytique dans les CML, modulant leur prolifération via la signalisation de l'AMPc. Ces travaux permettent d'envisager de nouvelles stratégies thérapeutiques visant d'une part à inhiber son activité en utilisant des inhibiteurs hautement spécifiques pour cette isoforme et d'autre part des peptides capables de bloquer le rôle non catalytique de la PI3KyCardiovascular diseases represent the first cause of death worldwide and a large part of them concerns different arterial disorders as hypertension, atherosclerosis, intimal hyperplasia and aneurism. All of these diseases are characterized by arterial remodeling resulting in a complex collaboration between environment and arterial physiology participants: Blood flow, endothelial cells (EC), smooth muscle cells (SMC) and arterial inflammation. In this context, this thesis project is interested in y-isoform of phosphoinositide 3-kinase (PI3Ky). PI3Ky is largely expressed in hematopoietic compartment where its catalytic activity drives arterial wall inflammation, but it is also lower expressed in cardiovascular system such as SMC and EC. Moreover, in addition to catalytic function implicated in chemoattraction and release of inflammatory mediators, PI3Ky has been described to activate phosphodiesterases (PDE) activity, through a non-catalytic "docking" function. At first, this work studied studied non-catalytic docking function of PI3Ky in SMC. Using hypertension-induced arterial remodeling in mice showed that SMC hyperplasia was dependent of PI3Ky protein expression but independent of its activity. Further, in vitro exploration with primary-SMC from mice aorta highlighted that PI3Ky activates PDE independently of its catalytic function, which promotes SMC proliferation by hydrolysis of an anti-mitotic second messenger: the cyclic-AMP. In the same approach, we tested original therapeutic strategy using a permeant-peptide which inhibits PI3Ky/PDE interaction. This permeant-peptide showed good efficiency to prevent both in vitro SMC proliferation and in vivo arterial SMC hyperplasia. The second part of this work how PI3Ky activity in inflammatory cells modulates endothelial healing following endovascular injury. Using in vivo and ex vivo models of arterial de-endothelialization in mouse, we observed a cellular cross talk in arterial wall between T-cells, SMC and EC. PI3Ky activity in T-cells promotes IFNy secretion following arterial injury which indirectly decreases re-endothelialization through a local secretion of CXCL10 by SMC. Indeed, CXCL10 directly inhibits endothelial healing independently of immune compartment. Our findings provide a new promising target to promote endothelial repair and therefore prevent cardiovascular events following endovascular intervention.Altogether, these works unravel an interesting dual function of PI3Ky in arterial stress response. In one hand, catalytic function of PI3Ky drives inflammatory-induced inhibition of endothelial healing, and in other hand, non-catalytic function controls SMC proliferation via inhibition of cyclic-AMP pathway
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Winter, Sarah. "Identification and characterization of new genetic defects involved in Epstein-Barr virus immune response and T-cell proliferation Loss of RASGRP1 in humans impairs T-cell expansion leading to Epstein-Barr virus susceptibility RASGRP1 is a negative factor of EOMES expression in T cells in association with an exhausted phenotype IL-27RA deficiency in humans, a new cause of susceptibility to Epstein-Barr virus infection Association of bi-allelic loss-of-function mutations in PIK3CD and TNFRSF9 causes fatal chronic active Epstein-Barr virus infection with T-cell lymphoproliferation." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCB180.
Full textAbstract:
L'infection par le virus d'Epstein-Barr (EBV) touche plus de 90% de la population mondiale et est dans la majorité des cas asymptomatique dans l'enfance. Certains individus, souvent à l'adolescence, développent une primo-infection symptomatique appelée mononucléose infectieuse. L'EBV peut également entraîner chez des individus immunodéprimés des désordres lymphoprolifératifs, des lymphomes ou syndromes d'activation lymphohistiocytaire. Depuis une trentaine d'années plusieurs déficits immunitaires primitifs entraînant une susceptibilité particulière à l'infection par l'EBV ont été identifiés ; parmi ceux-ci figurent les déficits en SAP, XIAP, ITK, MAGT1, CTPS1, CD27 ou CD70. Leur caractérisation a permis de mettre en évidence de nouveaux mécanismes immunitaires impliqués dans la réponse anti-EBV. L'objectif de ce travail a donc été d'identifier de nouveaux défauts génétiques entraînant une susceptibilité particulière à l'infection par l'EBV. Au sein de deux familles consanguines, trois patients ont développé des lymphomes B liés à l'EBV ainsi que des épisodes de lymphoproliférations également liées à ce virus. Deux mutations homozygotes dans RASGRP1 entraînant un stop prématuré, A638GfsStoXp16 et S314X ont été respectivement identifiées par séquençage d'exome (WES) chez ces deux familles. Sur le plan immunologique ces patients sont caractérisés par une lymphopénie CD4+, un défaut de cellules T naïves, une accumulation de cellules T effectrices mémoires et une absence de cellules MAIT et iNKT. RASGRP1 est une protéine de la famille des facteurs d'échange nucléotidiques fortement exprimée dans les lymphocytes T et NK. Elle active la petite protéine G Ras qui elle-même va activer la cascade des kinases Raf-MEK-ERK (ou cascade des MAP kinases). L'analyse des cellules du patient ou de cellules de contrôles sains dans lesquelles l'expression de RASGRP1 a été inhibée par RNA interférents a permis de mettre en évidence le rôle fondamental de RASGRP1 dans la prolifération lymphocytaire T et l'expression de gènes impliqués dans cette prolifération tels que CTPS1, PCNA ou RECQL4. A l'inverse, RASGRP1 semble être un régulateur négatif du facteur de transcription EOMES impliqué dans la différenciation des lymphocytes T. EOMES est retrouvé surexprimé dans les lymphocytes T en l'absence de RASGRP1, pouvant expliquer le phénotype effecteur mémoire et sénescent des lymphocytes des patients déficients en RASGRP1. Au sein d'une autre famille consanguine, chez deux patients ayant développé une primo-infection à l'EBV symptomatique, dont l'un a nécessité un traitement par anti-CD20 et corticoïdes, a été identifiée une mutation homozygote non-sens dans IL27RA entraînant un codon stop précoce (G96X) et une absence d'expression protéique dans les cellules T des patients. IL-27RA code pour la sous-unité alpha du récepteur à l'IL-27 impliqué dans la prolifération des lymphocytes T et le développement Th1 des lymphocytes CD4+ via la cascade des JAKs/STATs. Dans les lymphocytes T des patients, l'activation de la voie JAK/STAT par l'IL-27 est complètement abolie et l'IL-27 n'augmente pas leur prolifération en réponse à une stimulation anti-CD3 (au contraire des cellules contrôles issues de donneurs sains). De plus, un défaut fonctionnel de la voie Th1 est retrouvé chez un des deux patients. Ces résultats démontrent que la voie dépendante de l'IL-27RA est déficiente chez ces deux patients et que ce défaut génétique rend vraisemblablement compte de leur immunodéficience. La description de ces deux nouveaux déficits immunitaires caractérisés par une susceptibilité à l'EBV a permis de confirmer le rôle fondamental dans l'étape de prolifération et d'expansion des lymphocytes T au cours de la réponse immune anti-EBV, mais également de mettre en évidence de nouveaux mécanismes et facteurs impliqués dans cette étapeEpstein-Barr virus (EBV) is a gamma-herpes virus that infects 90% of humans without any symptoms in most cases. Some individuals, mostly adolescents, can develop infectious mononucleosis. In immunocompromised individuals, EBV can lead to lymphoproliferative disorders, lymphomas or virus-associated hemophagocytic syndrome. In the past 30 years, several primary immunodeficiencies associated with a high risk to develop EBV-associated disorders have been identified, including SAP, XIAP, ITK, MAGT1, CTPS1, CD27 or CD70 deficiencies. Their characterization has highlighted specific pathways required for efficient immunity to EBV. The objective of this work was to identify new genetic defects associated to a peculiar susceptibility to EBV infection. In two consanguineous families 3 patients developed EBV-associated B cell lymphomas and other EBV-associated lymphoproliferative disorders. By while exome sequencing (WES) we identified two homozygous mutations in RASGRP1 leading to a premature stop codon (A638GfsX16 and S314X). Immunologically these patients presented with CD4+ lymphopenia, low number of naïve T cells and absence of MAIT and iNKT cells. RASGRP1 codes for a diacylglycerol-regulated exchange factor preferentially expressed in T and NK cells, which acts as an activator of the small G protein RAS and the downstream RAF-MEK-ERK kinases cascade (or MAP kinases pathway). Analysis of patients' T cells or control T cells in which RASGRP1 expression was downregulated by short-hairpin RNA technique has highlighted the crucial role of RASGRP1 in T cell proliferation and in the expression of genes known to be involved in cell proliferation or replication such as CTPS1, PCNA or RECQL4. Furthermore, RASGRP1 seems to be a negative regulator of the transcription factor EOMES involved in T cell differentiation. EOMES was found overexpressed in T cells in the absence of RASGRP1. This might explain the skewed effector-memory and exhausted phenotype observed in RASGRP1-deficient patients. In another large consanguineous family two patients developed symptomatic EBV primary infection requiring for one or them anti-CD20 and corticosteroids treatment. Homozygous nonsense mutation leading to a premature stop codon in IL-27RA (G96X) was identified by exome sequencing. No protein expression could be detected in patients' cells. IL-27RA codes for the subunit of IL-27 receptor involved T cell proliferation and Th1 CD4+ development through JAKs/STATs pathway. Stimulation of patients' T cells with IL-27 led to absent JAK/STAT activation pathway and did not enhance their proliferation after anti-CD3 stimulation (contrary to healthy control T cells). Furthermore, Th1 functional defect was found in one patient. These results demonstrate that IL-27RA pathway is deficient is these two patients and that this genetic defect causes their immunodeficiency. Characterization of these two new primary immunodeficiencies associated with a high susceptibility to EBV infection has confirmed the crucial role of T cell proliferation and activation in EBV immune response but has also highlighted new pathways involved in T cell expansion
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Coussy, Florence. "Identification de nouvelles thérapeutiques ciblées dans le cancer du sein à l’aide d’un large panel de tumeurs humaines xénogreffées." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS560.
Full textAbstract:
Le cancer du sein triple négatif (CSTN) représente 10-15% des cancers du sein. Son pronostic est sombre en particulier face à la rareté des thérapies ciblées adaptées à ce sous type. Sa complexité de prise en charge est directement liée à sa grande hétérogénéité tant au niveau moléculaire que morphologique.Dans ce contexte, nous avons développés des modèles de Patient Derived Xenograft (PDX) issus de CSTN. Ce modèle, robuste, a la particularité de retenir les caractéristiques (histologiques, génotypiques mais aussi phénotypiques) des tumeurs observées chez les patients.Dans notre cohorte de 61 PDX de CSTN, nous avons confirmé l’hétérogénéité anatomopathologique et génomique de ce sous type. Les différentes anomalies moléculaires mises en évidence sont de faible fréquence (<10%) mais 88% de nos modèles ont une altération potentiellement ciblables et plus de la moitié ont au moins 2 altérations ciblables. Nous nous sommes particulièrement intéressés à 2 sous types de CSTN : (i) le sous -type LAR (Luminal Androgen Receptor) dont nous avons décrit les premiers modèles de PDX : ces modèles présentent des altérations fréquentes de la voie PI3K ainsi que des réponses majeures aux inhibiteurs de cette voie ; (ii) le sous type métaplasique, dont 4 de nos 9 modèles présentent une double altération genomique dans les voies PI3K et RTK-MAPK ainsi que des réponses complètes et durables à la combinaison d’inhibiteurs de PI3K et de MAPK.Dans les autres sous-types de CSTN, nous avons également mis en évidence des taux de réponse importants aux inhibiteurs de la voie PI3K et MAPK. Les biomarqueurs de réponse à ces différentes thérapies ciblées testées sont en cours d’étude en particulier par intégration des données génomique et protéique de nos modèlesTriple negative breast cancer (TNBC) accounts for 10-15% of breast cancers. Its prognosis is worse, particularly due to the rarity of targeted therapies adapted to this subtype. Its complexity of management is directly related to its high heterogeneity, both at the morphological and genomical levels.In this context, we developed Patient Derived Xenograft (PDX) models from TNBC. This robust model has the specificity of retaining the characteristics (histological, genotypic but also phenotypic) of the tumors observed in patients.In our cohort of 61 PDXs of TNBC, we confirmed the anatomopathological and genomical heterogeneity of this subtype. Majority of targeted alterations are of low frequency (<10%) but 88% of our models harbour a potential targetable alteration and more than half have at least 2 targetable alterations. We were particularly interested in 2 subtypes of TNBC: (i) the LAR subtype for which we have described the first PDX models: these models present frequent alterations of the PI3K pathway as well as major responses to PI3K inhibitors; (ii) the metaplastic subtype, of which 4 of our 9 models show double alterations in the PI3K and RTK-MAPK pathways and complete and durable responses to the combination of PI3K-MAPK inhibitors.In the other CSTN subtypes, we have also demonstrated significant response rates to PI3K and MAPK inhibitors. Biomarkers of response to these various targeted therapies tested are being studied, in particular by integrating the genomic and protein data from a higher number of PDX models
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Behrmann, Christoph. "MicroRNA-221 sensitiviert Prostatakarzinomzellen gegenüber TRAIL durch Inhibition von SOCS-3 und PIK3R1." Doctoral thesis, 2020. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-199205.
Full textAbstract:
MicroRNA-221 (miR-221) führt in Prostatakarzinomzellen zu einer Induktion einer TRAIL-supprotiven Signatur als Folge einer Interferonaktivierung mit Heraufregulation von STAT-1 und den TRAIL-relevanten, interferonsensitiven Genen TNFSF-10 und XAF-1. Ferner führt die Inhibierung des bekannten Zielgenes SOCS-3 sowie die Inhibierung des neu beschriebenen Zielgenens PIK3R1 zu einer TRAIL-Sensitivierung in den untersuchten ProstatakarzinomzellenMicroRNA-221 (miR-221) mediates TRAIL-sensitivation of prostate cancer cells via inducing an TRAIL-supportive signature. This was shown by upregulation of STAT-1 and the TRAIL inducing the interferone sensitive genes XAF-1 and TNFSF-10. Furthermore the inhibition of two miR-221 targets mediates TRAIL sensitivation. The inhibition of the known target SOCS-3 and the new target PIK3R1 both led to TRAIL sensitivation of prostate cancer cells
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Tomás, Ana Catarina Serra. "Targeted inhibition of PIK3CA mutations in glioma cell models." Master's thesis, 2020. http://hdl.handle.net/10362/114348.
Full textAbstract:
Gliomas are the most common and lethal brain tumors in adults, with efficient therapies
non-existent. PIK3CA mutations are potential therapeutic targets, described as early constitutive events
in glioblastomas (GBM).
The goal of this project was to assess the impact of PIK3CA mutations on glioma aggressiveness
and evaluate the inhibition of PI3Kα in glioma cell models harboring PIK3CA mutations. Additionally,
we intended to characterize the IPOLFG cohort with IDH2 mutational analysis, previously classified
according to IDH1 and PIK3CA mutational status and 1p19q co-deletion.
Thus, IDH2 mutations were evaluated by Sanger sequencing, and immune cell infiltrates were
estimated using the TIMER platform. Functional studies were performed using a GBM cell line –
U87MG, transfected to contain E545K and H1047R mutations. The effects of temozolomide and
alpelisib treatment on cell viability, death, and PI3K/AKT pathway activation were assessed.
Only one out of 279 sequenced samples harbored an IDH2 mutation. PIK3CA mutation frequencies
remained unaltered in glioma molecular subgroups.
Using TIMER analysis, we observed increased CD8+ T cell infiltration in PIK3CA mutant low-grade
gliomas, whilst PIK3CA and STAT5B expressions were positively correlated.
Regarding PIK3CA mutations on glioma aggressiveness, no differences were observed in U87MG
colony formation, migration, or invasion, regardless of PIK3CA mutational status. Moreover, PIK3CA
mutations did not change U87MG cells’ sensitivity to either alpelisib or temozolomide, with alpelisib
potentiating PI3K/AKT signaling.
Here, we achieved a more refined characterization of the IPOLFG glioma cohort and uncovered a
possible, novel link between tumor microenvironment and the prevalence of PIK3CA mutations during
glioma progression. Our data shows that PIK3CA mutations neither significantly impact GBM cell
aggressiveness nor confer added sensitivity to PI3Kα targeted inhibition. Nevertheless, we found that
GBM cells seem to trigger complex, not yet described compensatory mechanisms, which could pave
the way for future studies relating pan-PI3K inhibitors and the targeting of other pathways.
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Brito, Cheila Martins. "Clinical implications of PIK3CA mutations in gliomas molecular subgroups." Master's thesis, 2018. http://hdl.handle.net/10362/58097.
Full textAbstract:
Gliomas are the most common and lethal malignant tumors of central nervous system. In 2016, World Health Organization (WHO) classification included IDH mutations and 1p/19q codeletion as a diagnostic criteria to define gliomas. However new biomarkers of diagnosis, prognosis and response to therapy are needed. In this context, PIK3CA mutations have been described as constitutive mutations seeming to be a good therapeutic target.
Our objective was to clarify the clinical importance of PIK3CA mutations according to the 2016 WHO classification, as well as the impact of several biomarkers on diagnosis, prognosis and response to therapy in 437 glioma samples.
According to the multivariate analysis performed, gliomas molecular subgroups have higher prognostic value than histological subgroups (P<0.001). PTEN deletions were considered prognostic factors of poor outcomes in astrocytomas IDH wildtype, while in GBM IDH wildtype were associated with better prognosis. On opposite, EGFR amplification and TERT mutations had no impact in the overall survival of patients. We verified that EGFR amplification had a predictive value of response to radiotherapy (P=0.007).
PIK3CA mutations were most common in IDH mutant + 1p/19q codeletion (oligodendrogliomas) (10%). H1047R and E542K were the most frequent mutations identified in the remaining gliomas molecular subgroups. Importantly, we found 3 unreported pathogenic variants in exon 20 of PIK3CA (c.3112T>C, c.2988T>C, c.3040C>T) and one polymorphic variant (c.3210A>G). For the first time, it was identified the rs45455192 polymorphism (16% - 24%) in the different gliomas molecular subgroups, although this polymorphism did not showed prognostic value. The recurrences analysis demonstrated that PIK3CA mutations constitute early events maintained during tumor progression.
Overall, this study showed molecular classification is a more accurate method to predict clinical outcome and despite PIK3CA mutations being present at low frequency in gliomas, they seem to be important for tumor progression.
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Ross, R. L., H. R. McPherson, L. Kettlewell, Steven D. Shnyder, C. D. Hurst, O. Alder, and M. A. Knowles. "PIK3CA dependence and sensitivity to therapeutic targeting in urothelial carcinoma." 2016. http://hdl.handle.net/10454/8800.
Full textAbstract:
YesBackground: Many urothelial carcinomas (UC) contain activating PIK3CA mutations. In telomerase-immortalized normal urothelial cells (TERT-NHUC), ectopic expression of mutant PIK3CA induces PI3K pathway activation, cell proliferation and cell migration. However, it is not clear whether advanced UC tumors are PIK3CA-dependent and whether PI3K pathway inhibition is a good therapeutic option in such cases. Methods: We used retrovirus-mediated delivery of shRNA to knock down mutant PIK3CA in UC cell lines and assessed effects on pathway activation, cell proliferation, migration and tumorigenicity. The effect of the class I PI3K inhibitor GDC-0941 was assessed in a panel of UC cell lines with a range of known molecular alterations in the PI3K pathway. Results: Specific knockdown of PIK3CA inhibited proliferation, migration, anchorage-independent growth and in vivo tumor growth of cells with PIK3CA mutations. Sensitivity to GDC-0941 was dependent on hotspot PIK3CA mutation status. Cells with rare PIK3CA mutations and co-occurring TSC1 or PTEN mutations were less sensitive. Furthermore, downstream PI3K pathway alterations in TSC1 or PTEN or co-occurring AKT1 and RAS gene mutations were associated with GDC-0941 resistance. Conclusions: Mutant PIK3CA is a potent oncogenic driver in many UC cell lines and may represent a valuable therapeutic target in advanced bladder cancer.
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Adams, Jessica. "Defining the Roles of Oncogenic Pik3ca Mutations and Genetic Cooperation in Mouse Models of Breast Cancer." Thesis, 2012. http://hdl.handle.net/1807/43368.
Full textAbstract:
Most human breast tumors have mutations in the growth factor/phosphatidylinositol 3’ kinase (PI3K) pathway. These can occur in genes coding for receptors, adaptor proteins, catalytic and regulatory subunits of PI3K, downstream kinases, or antagonistic tumor suppressors. While each genetic change results in elevated PI3K signaling, and all major breast cancer subtypes show pathway activation, the specific mutations involved in any one tumor may play an important role in defining tumor subtype, prognosis and sensitivity to therapy. Here, I describe mouse models of PI3K-induced breast cancer.
First I generated mice that express Pik3ca cDNA under control of the ROSA26 promoter, in a Cre-dependent and therefore tissue specific way. I have generated four strains of knock-in mice: R26-Pik3cawt, R26-Pik3caE545K, R26-Pik3caH1047R, and R26-Pik3caE545K-H1047R, which can be induced to express wild type, helical domain, kinase domain and double mutant forms of mouse p110α, respectively. Mice expressing mutant Pi3kca develop mammary tumors, but the phenotypic spectrum for each mutation is unique. Indeed, many E545K mammary tumors are
ii
vascularized, whereas H1047R tumors are not. Using these models, I have compared downstream signaling properties of E545K and H1047R.
The potential for improved breast cancer treatment lies in combination therapies that target more than one oncogenic pathway. To develop such treatments, we need good mouse models, and an understanding of the oncogenic network. To this end, my Pik3caH1047R model was mated to p53 and PTEN knockout mice, and to mice with active Notch1 signaling. In each case, genetic cooperation was observed and characterized. Oncogenic PI3K cooperated with p53-loss and active Notch1 to decrease survival and alter tumor phenotype in distinct ways. Loss of PTEN cooperated with oncogenic PI3K to alter tumor type, decrease average age at end point, and increase the number of tumors per mouse. Overall, I have shown that Pik3caE545K and Pik3caH1047R are sufficient to induce mammary tumors, and that tumor characteristics differ with these mutations, and with cooperating genetic changes.
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Droßbach, Christiane [Verfasser]. "Mutationsanalyse der Gene FANCE, Kiss1 und PIK3CA bei sporadischem Brustkrebs / vorgelegt von Christiane Droßbach." 2009. http://d-nb.info/1000930300/34.
Full text
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Yang, Shu-Ting, and 楊舒婷. "Prediction of TP53/PIK3CA Mutation on Magnetic Resonance Images Using Deep Convolutional Neural Networks." Thesis, 2019. http://ndltd.ncl.edu.tw/handle/y98q5r.
Full textAbstract:
碩士國立臺灣大學
資訊網路與多媒體研究所
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Breast cancer is one of the most common malignancies in females, while an early-stage detection can reduce the mortality. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is commonly used for breast cancer examination. Once breast cancer is diagnosed, it is more beneficial to recognize related biomarkers for customizing a treatment plan. Radiogenomics research has emerged recently, which focuses on the associations between imaging features and genomic patterns. It provides non-invasive and overall quantification to identify the biomarkers. In recent years, deep learning with convolutional neural networks (CNNs) has been broadly adopted and achieved remarkable performance on various tasks, including medical image analysis. In this study, we propose a method that exploits deep learning to automatically extract image features to differentiate the TP53 and PIK3CA mutations on 3-D breast MRI with 107 cases. The proposed method achieves the accuracies of 87.97% and 82.24%, and the sensitivities of 82.50% and 74.29%, for identifying TP53 and PIK3CA mutations, respectively. The result shows the high potential of this method to recognize these two gene mutations.