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Bianco, Anna Monica Rosaria. "Characterization of novel genes insolved in non syndromic cleft lip with or with out cleft palate (NSCLP)." Doctoral thesis, Università degli studi di Trieste, 2010. http://hdl.handle.net/10077/3735.
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2008/2009Non-syndromic cleft lip with or without cleft palate (NSCLP) is one of the most common birth defect. Genetic studies on human populations have identified numerous predisposing factors, as MYH9 and JARID2, whose role during palatogenesis remains obscure. In order to improve our knowledge on pathogenetic mechanisms, we carried out expression studies during mouse palate development using RNA in situ hybridization. As reference genes (Tgfb3, Irf6, Pvrl1, Foxe1 and Tp63) known to be required for correct palate formation, Jarid2 and Myh9 are expressed in the epithelial cells of the palatine processes before and at the time of contact. Then, this signal decreases and eventually disappears concomitantly with the degradation of the medial epithelial cells. Consistent with these observations, RT-PCR carried out on dissected palatal shelves detected products of Myh9 and Jarid2 from embryonic day E14.0 to E15.0 with a pick at E14.5, the stage when shelves appose in the midline. Taken together, these expression studies strongly support the association studies that designate these genes as predisposing factors for NSCLP. In multifactorial diseases as NSCLP once genetic studies demonstrate association, a major challenge is to identify mutations. In this regard, we started analyzing two in linkage disequilibrium SNPs (rs3752462 of MYH9 and rs2076056 of JARID2) that could be involved in defective splicing mechanisms, as hypothesized on the basis of their localization within splice sites. Using a hybrid minigene assay, however, we demonstrated that none of the allelic variants lead to any aberrant products at least in HeLa cells, the model used for this study. Moreover, we investigated whether alternative splicing events of the Myh9 gene detected in cochlea and brain (Li et al., 2008) could also be found in other tissues and palate. A small insertion of 12 bp between exon 4 and 5 (loop1) due to an alternative splicing was detected in all adult tissues analyzed. The same insertion was not detected in embryonic tissues, such as palatal samples at different stages of development, and brain. These results suggest that the genomic region of loop1 should be investigated in all risk haplotypes to search for pathogenetic variants. In conclusion, further investigations should be planned to explore the role of MYH9 and JARID2 in orofacial development in order to dissect signaling pathways during palate formation and identify the causative variants contributing to NSCLP.
XXII Ciclo
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Krüger, Marcus. "Molekulare und funktionale Charakterisierung der neuronalen bHLH Transkritptionsfaktoren NSCL-1 und NSCL-2." [S.l.] : [s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=969337183.
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Pegoraro, Ilan Emanuel Moreira. "NSCL in the ETSI M2M platform." Master's thesis, Universidade de Aveiro, 2014. http://hdl.handle.net/10773/14704.
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Mestrado em Engenharia de Computadores e TelemáticaThe evolution of every day gadgets into smart-devices able to react to their surrounding environment is enabling the development of novel applications aiming revolutionize the industry related to this technology. Currently much attention has been given to standardizing IoT and M2M in order to build an interoperable foundation that will enable the growth of the future Internet, where devices will communicate without, or at least minimizing, human intervention. In this dissertation is presented in first place issues such as: heterogeneity, scalability, addressing and the first approach taken by the ETSI M2M standard. Subsequently, is presented the ETSI M2M vision and high-level architecture together with current work in this area. Finally an implementation of the network middleware is going to be presented along with further testing.
A evolução dos dispositivos do dia a dia em dispositivos inteligentes capazes de reagir ao ambiente que os rodeia está a permitir a criação de novas aplicações que visam revolucionar a industria. Atualmente tem-se dado muita atenção a estandardização da Internet das Coisas e comunicações máquinaa- máquina, com o objetivo de construir uma fundação interoperável que permitirá o crescimento futuro da Internet, onde os dispositivos irão comunicar sem, ou com mínima, intervenção humana. Nesta dissertação é apresentado em primeiro lugar requisitos como heterogeneidade, escalabilidade, endereçamento e a primeira abordagem feita pelo standard M2M do ETSI. Consequentemente, é a apresentada a visão e a arquitetura e o trabalho realizado nesta área. Por fim é apresentada a implementação da componente de rede realizada nesta dissertação juntamente com os respetivos testes.
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Chater, Emily. "Novel therapeutic targets in NSCLC resistance to Erlotinib." Thesis, Imperial College London, 2017. http://hdl.handle.net/10044/1/50699.
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Approximately 10% of non-small cell lung cancers (NSCLCs) have an activating mutation within the kinase domain of epidermal growth factor receptor (EGFR). Competitive tyrosine kinase inhibitors (TKIs), such as Erlotinib and Gefitinib, have been developed to therapeutically exploit this. These compounds have shown excellent clinical responses in approximately 77% of patients with EGFR-mutant driven lung cancer. However, despite positive initial response, patients develop resistance, and this is often attributed (50% of cases) to the T790M secondary mutation in the ATP binding pocket of EGFR. This mutation increases the receptors affinity for ATP which competes out reversible first-generation inhibitors such as erlotinib and gefitinib. This thesis aims to better understand the underlying mechanisms involved in the resistance to this compound. Changes in metabolism have frequently been associated with tumour progression and drug resistance in many cancer types. Here, to identify novel resistance mechanisms, 1H-NMR metabolic profiling was performed on EGFR-driven NSCLC cells with and without, the additional T790M-EGFR resistance mutation. This study identified both glutathione (GSH) and phosphatidylcholine metabolism as two key pathways perturbed in erlotinib-resistant cells. Interestingly, 1H-NMR revealed lower levels of both oxidised and reduced forms of GSH in erlotinib-resistant cell lines and this was verified by colorimetric assays. This change correlated with reduced mRNA expression of GSH synthesizing enzymes in resistant cell lines. Increasing cellular GSH levels by siRNA-mediated targeting of GSH degrading enzymes sensitised erlotinib-resistant cells to erlotinib treatment. In addition, the use of GSH synthesizing enzyme inhibitors such as Buthionine Sulfoximine (BSO), which targets the gamma-glutamylcysteine synthetase (GCS, GSH synthesising enzyme) and degrading enzyme inhibitors such as Ethacrynic acid (EA) (inhibits glutathione S-transferase) increased and decreased resistance to erlotinib, respectively. EA also showed promising results in vivo as BALB/c nude mice, injected subcutaneously with PC9ER cells, showed increased sensitivity to erlotinib treatment when co-administered with EA. Furthermore, we demonstrated that mutant EGFR signalling can modulate the transcription of GSH enzymes likely via changes in the regulation of the transcription factor, Nuclear Factor (Erythroid-Derived 2)-Like 2 (NRF2). Targeting NRF2 using siRNAs decreased GSH abundance and increased erlotinib resistance. However, at present we do not understand how raised GSH levels might cause resistance to erlotinib in lung cancer cells expressing activated T790M-EGFR. To discover other differences between erlotinib-resistant and sensitive cells, we employed reverse phase protein array (RPPA) and, following DAVID bio-informatics analysis, 4 identified changes in both beta-oxidation and ataxia telangiectasia mutated kinase (ATM)/Ataxia Telangiectasia and Rad3-related kinase (ATR) cell cycle checkpoint proteins. Changes in these signalling molecules were confirmed by Western blotting. Yet, only targeting the ATR pathway affected the resistance to erlotinib in PC9ER cell lines. Indeed, inhibition of WEE1 with the compound MK1775 may hold promise as a treatment for patients with erlotinib-resistant NSCLC. In short, this work has identified GSH degrading enzymes and WEE1 as novel targets for reversing erlotinib resistance in EGFR-driven NSCLC. However, further investigation is needed to understand the mechanisms involved.
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Holgersson, Georg. "Prognostic Factors in Non-Small Cell Lung Cancer (NSCLC)." Doctoral thesis, Uppsala universitet, Experimentell och klinisk onkologi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-327925.
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Background: Non-small cell lung cancer (NSCLC) is the cancer disease with the highest mortality globally. About 75% of NSCLC patients are diagnosed in an advanced stage where surgical treatment is not possible. For patients with locally advanced disease without distant metastases, the treatment of choice is curatively intended radiotherapy. However, this treatment has considerable side effects and many patients relapse. To individualize the treatment strategy for these patients, it is essential to have as much prognostic information as possible. The aim of this thesis was to investigate the prognostic significance of histology and pre-treatment hematopoietic blood parameters. Material and Methods: Data were collected retrospectively for NSCLC patients treated between 1990 and 2000 with curatively intended radiotherapy. The data were obtained by manually searching patient records from all radiation oncology departments in Sweden. The prognostic significance of histology, and pre-treatment levels of hemoglobin (Hgb), white blood cells (WBC) and platelets (Plt) were analyzed in relation to overall survival using univariate and multivariate statistical methods. These prognostic factors were further analyzed in a chemoradiation patient cohort and in a cohort of patients with recurrent NSCLC treated with palliative docetaxel, or the insulin-like growth factor 1 receptor (IGF-1R) modulator AXL1717. Results: In the cohort of NSCLC patients treated between 1990 and 2000, squamous cell carcinoma (SCC) histology and pre-treatment anemia (Hgb <110 g/L), leukocytosis (WBC > 9.0 x109/L), and thrombocytosis (Plt >350 x109/L) were independent prognostic factors for shorter overall survival. However, in the chemoradiation cohort only thrombocytosis retained independent prognostic significance in a multivariate analysis. In the cohort of patients with recurrent disease treated with palliative systemic therapy, only leukocytosis was significantly associated with worse survival. Conclusions: Routine pre-treatment hematopoietic blood parameters—together with other prognostic factors such as disease stage and performance status—can provide decision-making support when individualizing treatment of NSCLC. The prognostic role of histology is unclear and further research is warranted to determine its significance.
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Stamatkin, Christopher W. "PHOSPHATIDYLINOSITOL 3-KINASE (PI3K) AS A THERAPEUTIC TARGET IN NSCLC." UKnowledge, 2014. http://uknowledge.uky.edu/pharmacy_etds/58.
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Deregulated activation of phosphatidylinositol 3-kinase (PI3K) pathway is central to many human malignancies. The functions of this pathway are critical for normal cell metabolism, proliferation, and survival. In lung cancers, the PI3K pathway activity is often aberrantly driven by multiple mutations, including EGFR, KRAS, and PIK3CA. Molecules targeting the PI3K pathway are intensely investigated as potential anti-cancer agents. Although inhibitors of the pathway are currently in clinical trials, rational and targeted use of these compounds, alone or in combination, requires an understanding of isoform-specific activity in context. We sought to identify class IA PI3K enzyme (p110a/PIK3CA, p110b/PIK3CB, p110d/PIK3CD) activities using isoform-specific inhibitors in a lung cancer model system. Treatment of non-small cell lung cancer (NSCLC) cell lines with PIK3CA, PIK3CB, PIK3CD or PIK3CB/D inhibitors resulted in pharmacokinetic and pharmacodynamic responses that frequently tracked with a specific mutation status. Activation of PIK3CA dictated response to the PIK3CA-specific inhibitor while deletion of PTEN phosphatase indicated response to the PIK3CB inhibitor. The PIK3CD isoform-specific inhibitors lacked efficacy in all NSCLC cell lines tested, however treatment at increased concentrations likely provide concurrent inhibition of both PIK3CB/D isoforms improving activity of either agent alone but did not track with a single biomarker. The observed pharmacodynamic and proliferation responses to isoform-specific inhibitors suggested that PI3K isoforms may functionally compensate for loss of another in certain genetic backgrounds. These studies demonstrate unanticipated cellular responses to PI3K isoform inhibition in NSCLC, suggesting that patient populations with specific mutations can benefit from certain isoform-selective inhibitors, or combinations, allowing for rational and targeted clinical use of these agents.
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Chatterjee, Saradiya. "Role of TLR7 in non-small cell lung carcinona (NSCLC)." Paris 6, 2013. http://www.theses.fr/2013PA066063.
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Le cancer du poumon cause de plus d’un million de décès par an, et le progonstique est très somber, avec un taux de survie à 5 ans de l’ordre de 8 à 12%. La stimulation des TLRs par des ligands agonistes naturels comme les PAMPs et les DAMPs résulte en l’activation d’une cascade de signalisation conduisant à l’expression de molecules proinflammatoires. Nous avons montré que la stimulation de lignées cellulaires de tumeur pulmonaire par des agonistes de TLR7 induit une survie cellulaire et une résistance à la mort induite par chimiothérapie in vitro. Nous avons étudié in vivo les effets d’injections d’agonistes de TLR7 sur la croissance tumorale et la résistance à la chimiothérapie dans des souris NOD/SCID et C57BL/6. L’injection de loxoribine, ou de CL264 a un effet pro-tumoral sur la croissance des cellules A549 et CL264, respectivement, et induit une chimioresistance dans des souris NOD/SCID. Le blocage de TLR7 réverse l’effet pro-tumoral de l’agoniste. Par ailleurs, l’injection de faible dose de CL264 a un effet anti-tumoral sur les cellules LL/2, alors que l’injection d’une forte concentration de l’agonsite a un effet pro-tumoral. Nous avons également démontré qu’une forte expression de TLR7 par les cellules tumorales de patients NSCLC est de mauvais pronostique sur la survie globale des patients. Ces résultats démontrent le rôle pro- tumoral de TLR7 et son implication potentielle dans le phénomène de chimiorésistance. Ainsi l’utilisation d’agonistes de TLR7 comme adjuvant de vaccination antitumorale devrait prendre en compte le niveau d’expression de TLR7 sur les cellules tumorales des patientsLung cancer accounts for over 1 million deaths per year with a 5-year survival of 8-12%. Stimulation of TLRs by the natural ligands like the PAMPs and DAMPs results in a proinflammatory signaling cascade. We have shown that stimulation of lung cancer cell lines with TLR7 agonist lead to tumor cell survival and chemoresistance in vitro. We studied the effect of TLR7 agonists on A549 and LL/2 cells injected in NOD/SCID and C57BL/6 mice either treated or not with cisplatin. Loxoribine has a pro-tumoral effect on A549 cells and induces chemoresistance in NOD/SCID mice. Blockade of TLR7 with IRS661 reversed the pro-tumoral effect of TLR7 agonist on A549 cells. CL264 was also found to have a pro-tumoral effect on LL/2 cells and induced chemoresistance in NOD/SCID mice. On the other hand CL264 at lower concentration induces an anti-tumoral effect on LL/2 cells while at a higher concentration demonstrated a pro-tumoral effect in C57BL/6 mice. We also demonstrated an overall bad prognostic value for higher expression of TLR7 by tumoral cells among NSCLC patients treated and not treated with neoadjuvant chemotherapy. These results suggest a pro- tumoral role and induction of chemoresistance by TLR7 in NSCLC patients. Use of TLR7 agonist as therapeutic option is recommended based on the TLR7 expression level for individual NSCLC patients. TLR7 antagonist holds promise for treatment of NSCLC in future
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Recondo, Gonzalo. "Resistance Mechanisms to ALK Tyrosine Kinase Inhibitors (TKIs) in NSCLC." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS248/document.
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Les analyses moléculaires et la classification des adénocarcinomes bronchiques ont conduit au développement de thérapies ciblées sélectives visant à améliorer le contrôle de la maladie et la survie des patients. ALK (anaplastic lymphoma kinase) est un récepteur tyrosine kinase de la famille des récepteurs de l'insuline. Des réarrangements chromosomiques impliquant le domaine kinase d’ALK sont présents dans environ 3 à 6% des patients atteints d'un adénocarcinome bronchique. La protéine de fusion provoque une activation du domaine kinase de manière constitutive et indépendante du ligand. Lorlatinib est un inhibiteur d’ALK de troisième génération avec une efficacité et une sélectivité optimale, ainsi qu’une pénétration élevée vers le système nerveux central. Lorlatinib peut vaincre la résistance induite par plus de 16 mutations secondaires dans le domaine kinase d’ALK acquises lors de la progression aux ALK TKI de première et deuxième générations. Le traitement par lorlatinib est donc efficace chez les patients préalablement traités par un ALK TKI de première ou deuxième génération, et est actuellement approuvé pour cette indication. Le spectre complet de mécanismes de résistance au lorlatinib chez les patients reste à élucider. Il a récemment été rapporté que l'acquisition séquentielle de deux mutations ou plus dans le domaine kinase, également appelées mutations composées, est responsable de la progression de la maladie chez environ 35% des patients traités par le lorlatinib, principalement en altérant sa liaison au domaine kinase d’ALK. Cependant, l’effet de ces mutations sur la sensibilité aux différents inhibiteurs d’ALK peut varier, et les autres mécanismes de résistance survenant chez la plupart des patients restent inconnus. Mon travail de thèse avait pour but d’explorer la résistance au lorlatinib chez des patients atteints d'un cancer du poumon ALK réarrangé par la mise en œuvre de biopsies spatiales et temporelles et le développement de modèles dérivés de patients. Dans le cadre de l’étude institutionnelle MATCH-R (NCT02517892), nous avons effectué un séquençage à haut débit de l’exome, de l’ARN et ciblé, ainsi qu’un séquençage des ctDNA afin d’identifier les mécanismes de résistance. Nous avons établi des lignées cellulaires dérivées de patients et caractérisé de nouveaux mécanismes de résistance et identifiés de nouvelles stratégies thérapeutiques in vitro et in vivo. Nous avons identifié trois mécanismes de résistance chez quatre patients avec des biopsies appariées. Nous avons étudié l'induction de la transition épithélio-mésenchymateuse (EMT) par l'activation de SRC dans une lignée cellulaire, dérivée d’un patient, exposée au lorlatinib. Les cellules mésenchymateuses étaient sensibles à l’inhibition combinée de SRC et d'ALK, montrant que même en présence d'un phénotype agressif, des stratégies de combinaison peuvent surmonter la résistance aux ALK TKI. Nous avons identifié deux nouvelles mutations composées du domaine kinase d’ALK, F1174L / G1202R, C1156Y / G1269A survenues chez deux patients traités par le lorlatinib. Nous avons développé des modèles de cellules Ba / F3 exprimant les mutations simples et composées pour étudier leur effet sur la résistance au lorlatinib. Enfin, nous avons caractérisé un nouveau mécanisme de résistance provoqué par la perte de fonction de NF2 au moment de la progression du lorlatinib par l’utilisation de PDX et de lignées cellulaires dérivées de patients, et par CRISPR / CAS9 knock-out de NF2. Nous avons constaté que l'activation de mTOR par la perte de fonction de NF2 provoquait la résistance au lorlatinib et qu'elle pouvait être surmontée par le traitement avec des inhibiteurs de mTOR.Cette étude montre que les mécanismes de résistance au lorlatinib sont plus divers et complexes que prévu. Nos résultats démontrent également comment les études longitudinales de la dynamique tumorale permettent de déchiffrer la résistance aux TKI et d'identifier des stratégies thérapeutiquesThe molecular study and classification of lung adenocarcinomas has led to the development of selective targeted therapies aiming to improve disease control and survival in patients. The anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor from the insulin tyrosine kinase receptor family, with a physiologic role in neural development. Gene rearrangements involving the ALK kinase domain occur in ~3-6% of patients with lung adenocarcinoma. The fusion protein dimerizes leading to transactivation of the ALK kinase domain in a ligand-independent and constitutive manner. Lorlatinib is a third generation ALK inhibitor with high potency and selectivity for this kinase in vitro and in vivo, and elevated penetrance in the central nervous system. Lorlatinib can overcome resistance mediated by over 16 secondary kinase domain mutations occurring in 13 residues upon progression to first - and second - generation ALK TKI. In addition, treatment with lorlatinib is effective for patients who have been previously treated with a first and a second generation or a second generation ALK TKI upfront and is currently approved for this indication. The full spectrum of biological mechanisms driving lorlatinib resistance in patients remains to be elucidated. It has been recently reported that the sequential acquisition of two or more mutations in the kinase domain, also referred as compound mutations, is responsible for disease progression in about 35% of patients treated with lorlatinib, mainly by impairing its binding to the ALK kinase domain. However, the effect of these compound mutations on the sensitivity to the repertoire of ALK inhibitors can vary, and other resistance mechanisms occurring in most patients are unknown. My PhD thesis aimed at exploring resistance to lorlatinib in patients with ALK-rearranged lung cancer through spatial and temporal tumor biopsies and development of patient-derived models. Within the institutional MATCH-R study (NCT02517892), we performed high-throughput whole exome, RNA and targeted next-generation sequencing, together with plasma sequencing to identify putative genomic and bypass mechanisms of resistance. We developed patient-derived cell lines and characterized novel mechanisms of resistance and personalized treatment strategies in vitro and in vivo. We characterized three mechanisms of resistance in four patients with paired biopsies. We studied the induction of epithelial-mesenchymal transition (EMT) by SRC activation in a patient-derived cell line exposed to lorlatinib. Mesenchymal cells were sensitive to combined SRC and ALK co-inhibition, showing that even in the presence of an aggressive and challenging phenotype, combination strategies can overcome ALK resistance. We identified two novel ALK kinase domain compound mutations, F1174L/G1202R, C1156Y/G1269A, occurring in two patients treated with lorlatinib. We developed Ba/F3 cell models harboring single and compound mutations to study the differential effect of these mutations on lorlatinib resistance. Finally, we characterized a novel mechanism of resistance caused by NF2 loss of function at the time of lorlatinib progression through the development of patients derived PDX and cell lines, and in vitro validation of NF2 knock-out with CRISPR/CAS9 gene editing. Downstream activation of mTOR was found to drive lorlatinib resistance by NF2 loss of function and was overcome by providing treatment with mTOR inhibitors.This study shows that mechanisms of resistance to lorlatinib are more diverse and complex than anticipated. Our findings also emphasize how longitudinal studies of tumor dynamics allow deciphering TKI resistance and identifying reversing strategies
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Baghai, Tabassom. "ATF3 as a Key Regulator of Cisplatin Cytotoxicity: Combining ATF3 Inducing Agents Enhances Cisplatin Activity in NSCLC." Thesis, Université d'Ottawa / University of Ottawa, 2018. http://hdl.handle.net/10393/37963.
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Lung cancer is the leading cause of cancer and cancer deaths worldwide, with non-small-cell lung carcinomas (NSCLC) representing 85% of all diagnosed lung cancers. Platinum-combination chemotherapy is the current standard treatment for NSCLC, however, associated toxicities and resistance limit its efficacy. Our laboratory previously identified activating transcription factor 3 (ATF3), a stress-inducible gene whose elevated and sustained expression can trigger apoptosis to a wide variety of stressors, as a key regulator of cisplatin cytotoxicity as well. Thus, enhanced and sustained induction of ATF3 by combining platins with other ATF3 inducers potentially represents an effective therapeutic strategy. A chemical library screen identified vorinostat and topotecan as ATF3 inducers that also enhance cisplatin cytotoxicity. ATF3 plays a significant role in cisplatin, vorinostat and topotecan and their combinations cytotoxicity. Importantly, vorinostat and topotecan induced synergistic cytotoxicity with cisplatin in NSCLC cell lines and their cisplatin resistance sub-lines with enhanced ATF3 expression observed. Our study suggests a potential novel therapeutic approach where ATF3 inducing agents in combination with platins represents a rational combination based therapeutic strategy.
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Daskalos, Alexandros. "Deregulation of DNA methylation aand retrotransposon reactivation in NSCL." Thesis, University of Liverpool, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.539561.
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Souza, Cristiano de Pádua. "Perfil de expressão de microRNAs e seus alvos moleculares em carcinoma pulmonar." Botucatu, 2016. http://hdl.handle.net/11449/140150.
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Orientador: Patrícia Pintor dos ReisResumo: Introdução: O câncer de pulmão é a principal causa de morte por câncer no mundo. Apesar dos avanços nas estratégias de diagnóstico e o desenvolvimento de novas terapias com alvos moleculares, pouco progresso tem sido observado quanto ao aumento de sobrevida dos pacientes. Portanto, a identificação de novos biomarcadores ainda é necessária para o desenvolvimento de novas terapêuticas para carcinomas pulmonares. Nesse contexto, os microRNAs (miRNAs) são moléculas promissoras, pois constituem uma classe de RNAs não-codantes reguladores da expressão gênica os quais têm sido evidenciados como biomarcadores diagnósticos, prognósticos e preditivos no câncer. Materiais e Métodos: Amostras de tecido pulmonar tumoral e normal de 38 pacientes com carcinoma de pulmão de células não pequenas (da sigla em inglês NSCLC), dos subtipos histológicos adenocarcinoma e carcinoma de células escamosas, foram avaliadas para a expressão global de miRNAs utilizando a plataforma TaqMan® Array Human MicroRNA card A v3.0 (Life Technologies). Os miRNAs com alterações na expressão (FC≥2,0) e p<0,05 foram considerados estatisticamente significativos. Os dados de expressão foram associados com a sobrevida global. Análises de bioinformática permitiram identificar genes-alvo regulados pelos miRNAs desregulados. A relação entre sobrevida global e a identificação de uma assinatura de expressão de miRNAs foi avaliada com objetivo de integrar nossos achados utilizando bancos de dados públicos. Resultados: Os resul... (Resumo completo, clicar acesso eletrônico abaixo)
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Campbell, Thomas. "The role of voltage-gated sodium channels in non-small cell lung cancer." Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/the-role-of-voltagegated-sodium-channels-in-nonsmall-cell-lung-cancer(a65f4c5e-b217-483b-91d3-bb669965eb03).html.
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Various ion channels are expressed in human cancers where they are intimately involved in proliferation, angiogenesis, migration and invasion. Expression of functional voltage-gated sodium (Nav) channels is implicated in the metastatic potential of breast, prostate, colon, cervical and lung cancer cells. However, the cellular mechanisms that regulate Nav channel expression in cancer remain largely unknown. Growth factors are attractive candidates; they not only play crucial roles in cancer progression but are also key regulators of ion channel expression and activity in non-cancerous cells. Here, the role of epidermal growth factor receptor (EGFR) signalling and Nav channels in non-small cell lung cancer (NSCLC) cell lines have been examined. It is shown that functional expression of Nav1.7 promotes invasion in strongly metastatic H460 NSCLC cells. However, in non-invasive A549 NSCLC cells, Nav1.7 is completely absent. Inhibition of Nav1.7 either pharmacologically by tetrodotoxin (TTX) or genetically by small interfering RNA (siRNA) reduces H460 cell invasion by up to 50%. Whilst EGFR signalling enhances proliferation, migration and invasion of H460 cells, EGFR-mediated upregulation of Nav1.7 specifically, is required to promote invasive behaviour in these cells. Examination of Nav1.7 expression at the mRNA, protein and functional levels further reveals that EGFR signalling via the ERK1/2 pathway controls transcriptional regulation of Nav1.7 expression to promote cellular invasion in NSCLC. The role of Nav channels in promoting cancer cell invasion is also unclear. Therefore, the effect of Nav channel activity on two likely downstream contributors to cellular invasion, intracellular calcium concentration, [Ca2+]i, and intracellular pH, pHi, have been examined. It is shown that functional expression of Nav1.7 likely drives H460 NSCLC cell invasion via H+ efflux from the cell in an uncharacterised mechanism potentially involving NHE1, resulting in extracellular acidification of the perimembrane space. However, much more work is needed to understand this Na+-dependent invasive mechanism. Immunohistochemistry (IHC) of patient biopsies confirms the clinical relevance of Nav1.7 expression in NSCLC. Thus, Nav1.7 has significant potential as a novel target for therapeutic intervention, possibly in conjunction with existing EGFR inhibitors, and/or as a diagnostic/prognostic marker in NSCLC.
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Schaal, Courtney. "Regulation of nAChRs and Stemness by Nicotine and E-cigarettes in NSCLC." Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6582.
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Lung cancer is the leading cause of cancer-related death in both men and women, nationally and internationally and kills more people each year than breast, prostate, and colon cancers combined. Non-small cell lung carcinoma (NSCLC) is the most common histological subtype of lung cancer, and accounts for 85% of all cases. Cigarette smoking is the single greatest risk factor for lung cancer, and is correlated with 80-90% of all lung cancer deaths. Nicotine, the addictive component of tobacco smoke, is not a carcinogen and cannot initiate tumors itself; however, it is known to act as a tumor promoter, by enhancing the proliferation, migration, and invasion of cells in vitro, thus accelerating tumor growth and metastasis in vivo. Nicotine exerts is tumor promoting effects primarily by binding to, and activation of, nicotinic acetylcholine receptors (nAChRs), specifically the α7 subunit of nAChRs. While α7 nAChR is expressed in a wide array of cells, how its expression is regulated is not fully understood. Here we sought to elucidate the transcriptional regulation of α7 nAChR in NSCLC cells. We report that α7 nAChR expression is induced by nicotine in an autoregulatory feedforward loop, and that the α7 gene promoter is differentially regulated by E2F1 and STAT1 transcription factors at an overlapping binding site suggesting a competitive interplay. Depletion of E2F1 resulted in a reduced ability of nicotine to induce α7 nAChR, while depletion of STAT1 resulted in enhanced induction, suggesting that nicotine might use these two transcription factors to modulate the expression of α7 nAChR in a very precise fashion. More recently, nicotine has been implicated in promoting self-renewal of stem-like side-population cells from lung cancers. Cancer stem-like cells have been implicated in tumor initiation as well as the maintenance, drug resistance, dormancy, recurrence, and metastasis of various tumor types. We had previously shown that the embryonic stem cell transcription factor, Sox2, is indispensable for self-renewal of stem-like cells from lung adenocarcinoma cell lines; hence we sought to determine whether nicotine enhances stemness of lung cancer stem-like cells through Sox2. We find that nicotine can induce the expression of Sox2 at the transcriptional level and this occurs through a nAChR-Src-Yap1-E2F1 signaling axis. Over recent years, electronic cigarettes (e-cigarettes) have emerged as healthy alternatives to traditional cigarette smoking as they do not contain tobacco; however, they do still contain nicotine. Our studies show that e-cigarette components can enhance tumor promoting properties of NSCLC cells similar to that observed with nicotine alone, and find that they can induce expression of Sox2 and mesenchymal markers as well as enhance migration and stemness of NSCLC cells. Taken together, these studies reveal novel molecular mechanisms by which exposure to nicotine, via cigarette smoke or e-cigarettes, could alter the oncogenic potential of NSCLC cells.
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Sarin, Navin [Verfasser]. "Cisplatin resistance is associated with altered signalling in NSCLC cells / Navin Sarin." Bonn : Universitäts- und Landesbibliothek Bonn, 2018. http://d-nb.info/1153467119/34.
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GIORDANO, FEDERICA. "Investigating the role of p65BTK as an emerging therapeutic target in NSCLC." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2019. http://hdl.handle.net/10281/241339.
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Il tumore al polmone è la principale causa di morte per tumore al mondo sia negli uomini che nelle donne. Il tumore polmonare non a piccole cellule (NSCLC) è il più frequente ed è relativamente insensibile a chemioterapia e radioterapia. Nonostante lo sviluppo di terapie molecolari personalizzate contro specifiche “mutazioni driver” e la combinazione di chemioterapia e terapie a bersaglio molecolare, la mortalità per tumore al polmone rimane molto alta a causa dello sviluppo di resistenza alle diverse terapie. Pertanto, rimane particolarmente urgente ricercare nuove terapie per NSCLC. Recentemente nel nostro laboratorio abbiamo scoperto p65BTK, una nuova isoforma della tirosina chinasi di bruton (BTK), la quale è risultata essere un nuovo oncogene a valle del pathway di RAS. Abbiamo dimostrato che la sua inibizione diminuisce la crescita e la sopravvivenza delle cellule di cancro del colon e ri-sensibilizza cellule tumorali resistenti ai trattamenti.
Gli obiettivi di questo progetto sono: studiare il ruolo di p65BTK nel NSCLC e verificare se p65BTK può essere un nuovo target teranostico nel NSCLC.
Studiando una coorte di 382 pazienti abbiamo dimostrato che p65BTK è espresso nel 50% dei tumori di pazienti con NSCLC e la sua espressione correla con l'istotipo, l’abitudine al fumo e lo stato mutazionale di EGFR. In particolare, abbiamo trovato una maggiore espressione di p65BTK in pazienti con adenocarcinoma, non fumatori e con EGFR non mutato. Generalmente questi pazienti non sono eleggibili per la terapia con inibitori di EGFR a causa della mancanza di EGFR mutato. Tramite western blot, abbiamo confermato l’over-espressione di p65BTK sia in linee cellulari umane di NSCLC mutate per RAS o per uno dei geni del pathway di RAS, che in cellule primarie derivate da tumori di topi Kras/Trp53 null, suggerendo una correlazione tra l’aumentata espressione di p65BTK e la iper-attivazione del pathway di RAS nel NSCLC.
In seguito, abbiamo dimostrato che l'inibizione di p65BTK tramite diversi inibitori di BTK (Ibrutinib, AVL-292, RN486) riduce efficacemente la proliferazione e la clonogenicità di linee di NSCLC con differenti background genetici. Per determinare se p65BTK può essere considerato un nuovo bersaglio terapeutico nel NSCLC, abbiamo trattato linee resistenti di NSCLC con chemioterapia (Cisplatino, Gemcitabina, Pemetrexed) o inibitori di EGFR (Gefitinib, Erlotinib) in singolo, o in combinazione con concentrazioni non tossiche degli inibitori di BTK, valutandone l’effetto sulla vitalità cellulare. Gli inibitori di BTK usati in combinazione con gli inibitori di EGFR o con la chemioterapia sono risultati più efficaci nel ri-sensibilizzare le linee di NSCLC scarsamente responsive ai trattamenti standard e le diverse combinazioni hanno mostrato diversi gradi di sinergia. In conclusione, abbiamo dimostrato che p65BTK è over-espressa nei tumori di pazienti con NSCLC e in linee cellulari umane e murine di NSCLC. Pertanto, i nostri dati indicano p65BTK come un emergente target nel NSCLC e suggeriscono che la combinazione di inibitori di BTK e chemioterapia o terapia a bersaglio molecolare potrebbe rappresentare un nuovo approccio per superare la resistenza alle terapie nel NSCLC. I prossimi passi saranno volti a validare gli effetti dell'inibizione di p65BTK in modelli ex vivo (sferoidi derivati da cellule di NSCLC) e in vivo in modelli murini di NSCLC.Lung cancer is the leading cause of cancer-related death worldwide both in men and women. In particular, Non-Small Cell Lung Cancer (NSCLC) is the most common subtype and is relatively insensitive to chemotherapy and radiation therapy. Despite the development of personalized molecular targeted therapies against specific driver mutations and the combination of chemotherapy with targeted therapy, lung cancer mortality remains very high because of intrinsic and acquired resistance. Thus, new strategies to overcome these limitations are needed. Recently, we discovered a new isoform of the Bruton Tyrosine Kinase (BTK), referred as p65BTK. We characterized p65BTK as a novel oncogene and a pivotal downstream effector of RAS. Moreover, we showed that its inhibition affected growth and survival of colon cancer cells and reverted resistance to chemotherapy. The aims of this project were: study the role of p65BTK in NSCLC cell biology and verify whether p65BTK may be a novel theranostic target in NSCLC. Studying a cohort of 382 patients, we observed that p65BTK was expressed in 50% of NSCLC patients’ tumors and its expression correlated with histotype, smoke habit and EGFR mutational status. In particular, we found p65BTK significantly more expressed in adenocarcinoma than in squamous carcinoma histotype and in non-smoker as compared to smoker patients. Moreover, its expression was significantly higher in non-smoker patients bearing wild type EGFR. Notably, these patients are not eligible for treatments with EGFR inhibitors due to a lack of EGFR mutation. By western blot analysis we confirmed p65BTK overexpression both in vitro, in NSCLC human cell lines with mutations in RAS or in one of the components of the RAS/MAPK pathway, and ex vivo, in tumor-derived primary cells from Kras/Trp53 null mice, suggesting that p65BTK overexpression correlate with a hyper-activated RAS/MAPK pathway also in NSCLC. Then, we showed that p65BTK inhibition by different BTK inhibitors (Ibrutinib, AVL-292, RN486) strongly impaired proliferation and clonogenicity of NSCLC cell lines with different genetic backgrounds. To determine if p65BTK could be a new theranostic target in NSCLC, representative resistant cell lines were treated with chemotherapy (Cisplatin, Gemcitabine, Pemetrexed) or EGFR-targeted therapy (Gefitinib, Erlotinib) alone or in combination with non-toxic concentrations of BTK inhibitors and then their viability was assessed. We found that BTK inhibitors were effective in re-sensitizing NSCLC cells scarcely responsive to the current treatments when used in combination with EGFR-targeted therapy or chemotherapy. However, the different BTK inhibitors’ combinations showed a better or worse synergy depending on which EGFR inhibitor or chemotherapeutic drug they were combined with. Thus, we demonstrate that p65BTK is overexpressed in NSCLC patients’ tumors and in human and murine NSCLC cells. Moreover, our data indicate p65BTK as an emerging actionable target in NSCLC and suggest that the combination of BTK inhibitors with chemotherapy or targeted therapy may represent a novel therapeutic approach to overcome drug resistance in NSCLC. As future perspectives, we will validate the effects of p65BTK inhibition in ex-vivo (spheroids derived from NSCLC cells) models and in in vivo mouse model of NSCLC.
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Petroff, Alev [Verfasser], and Christian [Akademischer Betreuer] Rübe. "Langzeitergebnisse radikal behandelter synchron vs. metachron oligometastasierter NSCLC / Alev Petroff ; Betreuer: Christian Rübe." Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2019. http://d-nb.info/1175950270/34.
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Parikh, Ravi B. "DEFINITIVE PRIMARY THERAPY IN PATIENTS PRESENTING WITH OLIGOMETASTATIC NON-SMALL CELL LUNG CANCER (NSCLC)." Thesis, Harvard University, 2014. http://etds.lib.harvard.edu/hms/admin/view/47.
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Background: Although palliative chemotherapy is the standard of care for patients diagnosed with stage IV NSCLC, patients with a small metastatic burden, “oligometastatic” disease, may benefit from definitive local therapy.
Methods: We identified 186 patients (26% of Stage IV patients) prospectively enrolled in our institutional database from 2002-2012 with oligometastatic disease, which we defined as five or fewer distant metastatic lesions at diagnosis. Univariable and multivariable Cox proportional hazards models were used to identify patient and disease factors associated with improved survival. Using propensity score methods, we investigated the effect of definitive local therapy to the primary site on overall survival.
Results: Median age at diagnosis was 61 years, 51% of patients were female, 12% had squamous histology, and 33% had N0-1 disease. On multivariable analysis, ECOG performance status ≥2 (hazard ratio [HR] 2.43), nodal status N2-3 (HR 2.16), squamous pathology, and metastases to multiple organs (HR 2.11) were associated with a greater hazard of death (all p<0.01). Number of metastatic lesions and size of primary were not significantly associated with overall survival. Definitive local therapy to the primary tumor was associated with prolonged survival (HR 0.65, p=0.043).
Conclusions: Definitive local therapy to the primary tumor appears to be associated with improved survival in patients with oligometastatic NSCLC. Select patient and tumor characteristics, including good performance status, non-squamous histology, and limited nodal disease, may predict for improved survival in these patients.
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Balko, Justin M. "THE PHARMACOGENOMICS OF EGFR-DEPENDENT NSCLC: PREDICTING AND ENHANCING RESPONSE TO TARGETED EGFR THERAPY." Lexington, Ky. : [University of Kentucky Libraries], 2009. http://hdl.handle.net/10225/1062.
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Thesis (Ph. D.)--University of Kentucky, 2009.Title from document title page (viewed on September 17, 2009). Document formatted into pages; contains: viii, 175 p : ill. (some col.). Includes abstract and vita. Includes bibliographical references (p. 103-123).
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Koch, Franziska [Verfasser]. "Humanes ex-vivo Lungentumormodell : Nutzung für Temperaturmessungen während der Thermoablation von NSCLC. / Franziska Koch." Greifswald : Universitätsbibliothek Greifswald, 2011. http://d-nb.info/1018242198/34.
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Carlson, Sarah Marie. "Student and Parent Perceptions of the Lunches Served Under the Revised Guidelines for the National School Lunch Program." Kent State University / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=kent1397165529.
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Ramos, Alexis. "Cancer Genome Characterization with SNP Array and Whole-Exome Sequencing Analysis." Thesis, Harvard University, 2011. http://dissertations.umi.com/gsas.harvard:10036.
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Cancer, the uncontrolled growth of morphologically and genetically abnormal cells in the body, is a major worldwide public health problem and there is a great need for novel insights into this disease. The majority of tumors arise from the acquisition of somatic alterations leading to changes in gene function and expression. The clinical success of targeted therapeutics in molecularly defined subsets of patients has highlighted the need for comprehensive characterization of the somatic alterations in individual cancer types. Copy number profiling using SNP arrays is a common approach for profiling the extent of copy number variation across the cancer genome. In addition, next-generation sequencing technologies now offer researchers the ability to also systematically catalog nucleotide substitutions and structural rearrangements in dramatically less time and expense. In this thesis, we describe the application of SNP arrays and whole-exome sequencing to characterize two separate cohorts of cancer samples, as well as describe the development of a software tool to aid in the annotation of mutational data. Specifically, we detailed focal amplifications of PDGFRA and KIT in a combined set of lung adenocarcinoma and squamous cell carcinomas. Furthermore, in a cohort of small bowel neuroendocrine tumors, we characterized the global genetic landscape to show that these tumors are molecularly distinct from other neuroendocrine tumors. Lastly, we report Oncotator, a novel web application and service for comprehensive annotation of point mutations and indels found in cancer. It is hoped that the knowledge gained from these studies will fuel improvements in cancer diagnosis, prognosis, and therapy.
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Usó, Marco Marta. "ANALYSIS OF IMMUNOREGULATORY BIOMARKERS IN NON-SMALL CELL LUNG CANCER." Doctoral thesis, Universitat Politècnica de València, 2015. http://hdl.handle.net/10251/51283.
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[EN] Lung cancer is the leading cause of cancer-related death worldwide, and is the third most common cancer type; it can be classified into two subgroups based on histology: non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). The 5-year survival still remains poor and despite the existence of several distinct tumour phenotypes, therapeutic decisions are mainly based on clinical features such as stage or performance status. This highlights the need for new diagnostic and prognostic biomarkers in different types of samples (such as blood, fresh-frozen tissue or formalin-fixed, paraffin-embedded samples).
The field of tumour immunology has changed in the last decade, and it is now accepted that the immune system plays a pivotal role in cancer. Although the immune cells that infiltrate the tumour microenvironment are potentially capable of eliminating tumour cells, they cannot prevent tumour development and progression. Tumours acquire mechanisms to regulate their immune microenvironment such as the release of a series of factors to subvert normal reaction mechanisms, the modulation of co-stimulatory pathways, also known as immune checkpoints, and the induction and attraction of suppressor cells (myeloid-derived suppressor cells, tumour-associated macrophages, and regulatory T cells). The potential effect of the patient's immune system on clinical outcome is important for the identification of prognostic markers as well as markers that predict treatment responses. The study of immune-related markers, especially those implicated in immunoregulatory processes, could provide valuable prognostic information that could help in many applications in future clinical practice.
Thus, the objective of this thesis is to characterise cancer immunoregulation biomarkers and to evaluate the possible correlation between these biomarkers and clinicopathological and prognostic variables in patients with NSCLC by the use of well-tested and accurate techniques such as quantitative PCR and immunohistochemistry. Furthermore, this study will provide information about the immunological features of the tumour microenvironment in NSCLCs.[ES] El cáncer de pulmón es una de las principales causas de muerte relacionada con cáncer en el mundo, siendo el tercer tipo de cáncer más común. El cáncer de pulmón no microcítico (CPNM) representa casi el 85% de todos los cánceres de pulmón y la supervivencia a los 5 años va desde el 50% en estadios IA hasta el 15% en estadios IIIA. Hasta el momento, no se han descubierto biomarcadores capaces de predecir la progresión de la enfermedad en pacientes tanto en estadios resecables como en estadios avanzados, por lo que existe una clara necesidad de realizar estudios centrados en la búsqueda de biomarcadores pronósticos y diagnósticos en los diferentes tipos de muestra disponibles, como por ejemplo sangre, tejido fresco y tejido parafinado. El campo de la inmunología tumoral ha cambiado en la última década y actualmente se sabe que el sistema inmune juega un papel clave en cáncer. Las células inmunes que infiltran el tumor son un componente más del microambiente tumoral. Pese a que son potencialmente capaces de eliminar los antígenos tumorales, estas células no pueden evitar la formación y progresión tumoral. Esto es debido a que el tumor adquiere diversos mecanismos de regulación del microambiente tumoral con el objetivo de escapar del ataque del sistema inmune, como por ejemplo liberación de factores que impiden el correcto funcionamiento de los mecanismos de reacción inmune, modulación de vías co-estimuladoras y reclutamiento y activación de células inmunoreguladoras como las células T reguladoras, las células mieloides supresoras y los macrófagos asociados a tumores. El estudio de marcadores relacionados con la respuesta inmune y concretamente con los procesos de inmunoregulación puede proporcionarnos información pronóstica y predictiva relevante sobre los pacientes con cáncer. Por todo ello, el principal objetivo de esta tesis doctoral es analizar la presencia de marcadores relacionados con la inmunoregulación y evaluar su posible correlación con las variables clínico-patológicas y pronósticas en pacientes con CPNM mediante el uso de técnicas fiables y aplicables en la práctica clínica como la PCR cuantitativa y la inmunohistoquímica. Así mismo, esto nos permitirá conocer en mayor profundidad las características inmunológicas del microambiente tumoral en pacientes con CPNM.
[CAT] El càncer de pulmó és una de les principals causes de mort relacionades amb càncer al món, sent a més a més el tercer tipus de càncer més comú. El càncer de pulmó no microcític (CPNM) representa el 85% de tots els casos de càncer de pulmó aproximadament i la supervivència als 5 anys continua sent molt baixa. Fins el moment, no s'han descobert biomarcadors capaços de predir la progressió de la malaltia tant en pacients en estadis inicials com en estadis avançats. Per aquest motiu, existeix una clara necessitat de realitzar estudis centrats en la recerca de biomarcadors pronòstics i predictius en els diferents tipus de mostres disponibles, com per exemple sang, teixit fresc i teixit parafinat. El camp de la immunologia tumoural ha canviat en l'última dècada i actualment se sap que el sistema immune exerceix un paper clau en el càncer. Les cèl¿lules immunològiques que infiltren el tumour són un component més del microambient tumoural. Malgrat que aquestes cèl¿lules són potencialment capaces d'eliminar el antígens tumourals, s'ha evidenciat que no poden previndre la formació i progressió tumoural. Una de les raons per les quals s'observa aquest fenomen és que el tumour adquireix diversos mecanismes de regulació del microambient tumoural. Aquests mecanismes es basen en l'alliberació de factors que impedeixen el correcte funcionament del sistema immune, la modulació de vies coestimuladores i el reclutament i activació de cèl¿lules immunoreguladores com poden ser les cèl¿lules T reguladores, les cèl¿lules mieloides supressores i els macròfags associats a tumour. L'estudi de marcadors relacionats amb la resposta immune i més concretament amb els processos d' immunoregulació pot proporcionar informació pronòstica i predictiva rellevant sobre els pacients amb càncer. Per tot això, el principal objectiu d'aquesta tesi doctoral és analitzar la presència de marcadors relacionats amb la immunoregulació i avaluar la seva possible correlació amb les variables clinicopatològiques i pronòstiques de pacients amb CPNM mitjançant l'ús de tècniques fiables i aplicables a la pràctica clínica com són la PCR quantitativa i la immunohistoquímica. Així mateix, aquestes anàlisis ens permetran conèixer amb major profunditat les característiques immunològiques del microambient tumoural de pacients amb CPNM.
Usó Marco, M. (2015). ANALYSIS OF IMMUNOREGULATORY BIOMARKERS IN NON-SMALL CELL LUNG CANCER [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/51283
TESIS
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Zhang, Kai. "Developing Novel Carriers to Deliver Targeted Immunotoxins for the Treatment of Primary and Metastatic Non-Small Cell Lung Cancer." Thesis, Griffith University, 2017. http://hdl.handle.net/10072/365662.
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Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer which is a leading cause of cancer death. Most patients (>80%) present with advanced NSCLC when curative surgery is no longer an option. Other conventional therapies, such as chemotherapy, radiotherapy and existing molecular targeted therapy have neither significantly extended the life span of most patients, nor improved their quality of life. This is not only because of the large tumor load in the advanced stage of NSCLC but its metastasis. This project devises a novel approach to shield the “magic bullet” and help it locate and kill targeted cancer cells.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medical Science
Griffith Health
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Schneeberger, Valentina. "Novel Roles of the Protein Tyrosine Phosphatase SHP2 in Non-small Cell Lung Cancer." Scholar Commons, 2014. https://scholarcommons.usf.edu/etd/5306.
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The gene PTPN11 was identified in the early 1990s, and encodes the non-transmembrane protein tyrosine phosphatase SHP2. SHP2 is expressed ubiquitously in cells, and plays an important role in cancer. Unlike most phosphatases, SHP2 positively regulates several signaling pathways including the Ras/MAPK and Src signaling pathways and acts as a proto-oncogene. SHP2 is also a cancer essential gene in certain types of carcinomas, and promotes growth, survival, and epithelial to mesenchymal transformation. Gain of function (GOF) SHP2 mutations are known leukemic oncogenes, and have been identified to a smaller extent in solid tumors as well. Currently, the roles of SHP2 in lung carcinoma are not fully understood. While GOF SHP2 mutations have been detected in lung cancer, their contributions to cellular transformation had not been established. In addition, SHP2 is known to promote EGF growth factor receptor (EGFR) signaling. Since GOF EGFR mutations induce transformation of lung epithelial cells, it is possible that SHP2 plays a role in promoting GOF EGFR mutant driven tumorigenesis. The objective of this dissertation is to determine whether SHP2 can act as an oncogene in lung epithelial cells and whether SHP2 inhibition can affect GOF EGFR mutant induced lung cancer. To achieve these aims, we generated two novel doxycycline (Dox) inducible transgenic mouse models which express either the GOF SHP2E76K leukemic oncogene or the dominant negative SHP2CSDA mutant under the control of the Clara cell secretory protein (CCSP) promoter to regulate transgene expression to type II pneumocytes.
To determine whether SHP2 plays a role in promoting GOF EGFR mutant signaling, we started by disrupting SHP2 function in vitro. Two non small lung cancer cell lines were used for this project: HCC827 carries the LREA deletion in exon 19, and H1975 co-expresses the EGFRL858R point mutation and the EGFRT790M gatekeeper mutation. After SHP2 PTP inhibition or knock-down by shRNA and siRNA, both cell lines exhibited decreased cell proliferation and reduced levels of pErk1/2 and c-Myc. Based on these results, we acquired a transgenic mouse line which expresses the EGFRL858R mutant under the control of the tet-O promoter and generated bitransgenic CCSP-rtTA/tetO-EGFRL858R and tritransgenic CCSP-rtTA/tetO-EGFRL858R/tetO-SHP2CSDA mice to study the effects of the dominant negative SHP2CDSA mutant on EGFRL858R mediated carcinogenesis in vivo. After 4, 6, and 8 weeks of Dox induction, pErk1/2 and pSrc levels were increased in the lungs of bitransgenic mice compared to wild type controls. Both kinases were suppressed by SHP2CSDA expression in tritransgenic mice. In addition, SHP2CSDA expression delayed tumor onset and prevented progression to a more aggressive phenotype. Tritransgenic mice also developed a smaller tumor burden compared to bitransgenic animals. These results suggest that SHP2 is critical for GOF EGFR mutant mediated lung tumorigenesis and describe a new role of SHP2 as a potential therapeutic target for the development of novel NSCLC drugs.
Once we generated our CCSP-rtTA/tetO-SHP2E76K transgenic mouse model, we administered Dox for one month and found that SHP2E76K expression upregulates pErk1/2, pSrc, pGab1, c-Myc and Mdm2 levels in the lungs of bitransgenic mice compared to controls. After six to nine months of Dox induction, SHP2E76K expression caused formation of lung adenomas and adenocarcinoma. We then took advantage of the reversible feature of our mouse model to test whether lung tumors are dependent on sustained SHP2E76K expression for survival. MRI analysis of lung adenocarcinomas showed full regression of the lung tumors after Dox withdrawal. Histological evaluation of lung tissues revealed residual hyperplastic lesions as well as evidence of necrosis, while biochemical analysis showed that pGab1, pErk1/2, pSrc and c-Myc returned to basal levels. These results demonstrate that sustained SHP2E76K expression is required for lung tumor maintenance. Moreover, this data describe a novel function of SHP2E76K as an oncogene in lung carcinoma.
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Reuter, Cécile [Verfasser]. "Mutationsabhängige Aktivität von niedermolekularen reversiblen und irreversiblen Inhibitoren der EGFR Signalkaskade in NSCLC / Cécile Reuter." Köln : Deutsche Zentralbibliothek für Medizin, 2012. http://d-nb.info/1026215080/34.
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Reinert, Christian Philipp [Verfasser]. "Einfluss von Lipoteichonsäuren von Staphylococcus aureus auf die Proliferation von NSCLC-Zelllinien / Christian Philipp Reinert." Gießen : Universitätsbibliothek, 2017. http://d-nb.info/1130119807/34.
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Tam, Yee-san Issan, and 譚薏珊. "Epidermal growth factor receptor (EGFR) mutations and phosphorylation pattern in non-small cell lung cancer (NSCLC)." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B40687673.
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Bertram, Veit [Verfasser], and Rainer M. [Akademischer Betreuer] Bohle. "Quantitative Expressionsanalyse von TTF-1 in NSCLC und pulmonalen Metastasen / Veit Bertram ; Betreuer: Rainer M. Bohle." Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2019. http://d-nb.info/1197612076/34.
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Lane, Keara M. "Negative feedback regulation as a means to constrain the oncogenic potential of mutant Egfr in NSCLC." Thesis, Massachusetts Institute of Technology, 2011. http://hdl.handle.net/1721.1/68427.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2011.Cataloged from PDF version of thesis. Vita.
Includes bibliographical references.
The discovery of EGFR kinase domain mutations in NSCLC patients who responded to tyrosine kinase inhibitors (TKIs) represented the first example of a targeted therapy for lung cancer. The dependence of these human tumors on sustained mutant receptor expression for survival, together with the discovery that ectopic expression of the receptor resulted in transformation, suggested that these mutations are causal events, and as such would be sufficient to induce tumor formation in the lung. To investigate this, and to further our understanding of how deregulated signaling through the mutant receptor could initiate tumor formation, we generated both a conditional and constitutive knock-in allele of one such mutation, L858R, at the endogenous murine Egfr locus. Expression of mutant Egfr failed to induce lung tumors in these mice; further analysis of the germline mutant mice revealed significant downregulation of the mutant receptor, and this was predominantly at the post-transcriptional level. These data suggest that normal cells can respond to an oncogenic lesion by upregulating negative feedback pathways to counteract the induction of aberrant signaling, and disabling these feedback mechanisms may be an essential component of the progression of EGFR mutant tumors. A multitude of positive and negative feedback loops converge on signaling pathways to ensure the appropriate output in response to a given stimulus. The role of oncogenes is typically thought of in terms of increasing the output of a signaling pathway, and while the contribution of the associated negative feedback loops is no doubt important, they have been afforded little attention. Recent studies have highlighted the existence of negative feedback mechanisms in established tumors and the integral role they play in shaping the signaling network, with a corresponding appreciation for how such feedback loops can profoundly influence therapeutic response. The capacity of negative regulators to modulate the oncogenic potential of a mutant protein in the context of tumor initiation has rarely been examined. Using a doxycyclineinducible system we recapitulate the aforementioned downregulation of mutant Egfr, initially observed in both tissues and MEFs derived from EgfrL858R mutant mice, in an ectopic cell culture expression system. We establish a role for ERK pathway signaling, and specifically DUSP6, in receptor degradation, and solidify the role of the E3 ligase, CULLIN5, in the downregulation of the mutant receptor. The existence of these negative feedback loops may explain the observation that mutation of EGFR is often coincident with gene amplification in NSCLC, and suggest that such amplification may primarily serve as a means to counteract the downregulation. The amplification of oncogenes is a recurring feature of many human tumors, but the contribution of gene amplification to particular stages of tumor development, or the molecular requirements for amplification to occur are unknown. EGFR is mutated and coincidentally amplified in NSCLC, but the relative contribution of mutation and amplification, both to tumor phenotype and therapeutic sensitivity, is not clear. The inability to model amplification in the mouse has contributed significantly to our limited mechanistic understanding of how gene amplification occurs in tumors. Using a yeast endonuclease, -Scel, and an allele that contains target sites for this enzyme engineered telomeric to mutant Egfr on chromosome 11, we attempted to initiate breakage-fusion-bridge (BFB) cycles in the lung, as these are thought to be a precursor to gene amplification. Our inability to elicit tumor formation using this strategy highlights the limitations in our understanding of how amplicons form in human tumors or the particular context required. While it would provide tremendous insight into mutant EGFR tumor development, a model of targeted gene amplification has thus far eluded us, and remains one of the significant challenges facing the mouse modeling community.
by Keara M. Lane.
Ph.D.
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Abdo, Mustafa [Verfasser]. "Prediction of patients’ response to immune checkpoint inhibitors in the treatment of advanced NSCLC / Mustafa Abdo." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2021. http://d-nb.info/1228623848/34.
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Storti, Camila Baldin. "Perfil de expressão de genes associados aos telômeros em carcinoma pulmonar de células não pequenas (NSCLC)." Botucatu, 2018. http://hdl.handle.net/11449/153294.
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Orientador: Maria Isabel Nogueira CanoResumo: O câncer de pulmão é o câncer que apresenta maior mortalidade no mundo: >1,6 milhões de óbitos por ano segundo a Organização Mundial de Saúde (OMS), sendo o câncer de pulmão de células não pequenas (NSCLC) o tipo mais frequente (~ 85%) de carcinoma pulmonar. O NSCLC apresenta dois subtipos histológicos principais: adenocarcinoma (LUAD) e carcinoma de células escamosas (LUSC). Pesquisas têm sido realizadas objetivando identificar biomarcadores moleculares úteis como alvo terapêuticos em NSCLC e os telômeros têm sido considerado alvos promissores para terapias antitumoral, devido ao seu papel crucial na integridade, estabilidade e manutenção genômica. Telômeros humanos consistem em DNA repetitivo rico em G associado a proteínas do complexo shelterin e mantido pela ação da telomerase. Estudos recentes mostraram que a expressão de TERT (subunidade catalítica da telomerase) e de alguns componentes do complexo shelterin estão alterados em câncer de pulmão. No entanto, a correlação entre alterações na função telomérica e o desenvolvimento e progressão de NSCLC não foi elucidada. Portanto, o objetivo do presente estudo foi verificar alterações na expressão de genes associados aos telômeros, incluindo os ncRNAs associados à regulação e manutenção dos telômeros em NSCLC, no intuito de identificar novos biomarcadores associados ao desenvolvimento e progressão do NSCLC. Para tanto, foram realizadas análises de expressão de 50 genes associados aos telômeros em amostras de tecido tumoral e... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: According to the World Health Organization, lung cancer has a high mortality rate associated with >1.6 million deaths per year, being Non-small cell lung cancer (NSCLC) the most frequent type (~ 85%) of lung carcinoma. Lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) are the two major histological subtypes of NSCLC. Research efforts have been made to identify molecular biomarkers useful as therapeutic targets in NSCLC and telomere have been considered very promising targets for anticancer therapies due to their crucial role in genome integrity maintenance and stability. Human telomeres consist of repetitive G-rich DNA associated with proteins of the shelterin complex, maintained by the action of telomerase. Recent studies showed that expression of TERT (telomerase reverse transcriptase component) and of some of the shelterin components are altered in lung cancer. However, the mechanisms of telomere deregulation associated with NSCLC development and progression have not been elucidated. Therefore, our aim was to study expression changes affecting telomere-associated genes and ncRNAs associated with telomere regulation and maintenance in NSCLC. Such alterations may represent novel biomarkers associated with NSCLC development and progression. For this purpose, expression analyzes of 50 telomere-associated genes were performed in samples of tumor tissue and normal lung tissue, adjacent to the tumor, from patients with NSCLC. The following techniques were used: 1... (Complete abstract click electronic access below)
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Wang, Yu-Chieh. "Exploitation and Mechanistic Validation of Drug-combination Strategies to Overcome EGFR-inhibitor resistance in NSCLC cells." The Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1226515990.
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Tam, Yee-san Issan. "Epidermal growth factor receptor (EGFR) mutations and phosphorylation pattern in non-small cell lung cancer (NSCLC)." Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/B40687673.
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Arthur, Muller [Verfasser], and Ursula [Akademischer Betreuer] Nestle. "Prospektive Evaluation des Verhaltens der Tumorgewebe bei NSCLC in der FDG-PET unter Strahlentherapie (Response PET/CT)." Freiburg : Universität, 2018. http://d-nb.info/1220225428/34.
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Linsel, Sören [Verfasser]. "Experimentelle Untersuchungen zum Proliferationsverhalten von NSCLC-Zelllinien unter Endotoxin-Stimulation : die Rolle des Cyclooxygenase-Metabolismus / Sören Linsel." Gießen : Universitätsbibliothek, 2016. http://d-nb.info/1102154792/34.
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Makowiecki, Christina Michaela [Verfasser]. "Potential der siRNA-Transfektion auf chemotherapieresistente NSCLC- und Pleuramesotheliomzellen - Auswirkungen auf Viabilität und Wachstumsverhalten / Christina Michaela Makowiecki." Tübingen : Universitätsbibliothek Tübingen, 2021. http://nbn-resolving.de/urn:nbn:de:bsz:21-dspace-1191334.
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Khaddam, Sinan M. D. "Difference in outcomes between central airway lesions requiring stents and lesions that donot in patients with NSCLC." University of Cincinnati / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1553513958608363.
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Schulze, Arik Bernard [Verfasser], and Rainer Gerhard [Akademischer Betreuer] Wiewrodt. "Das RhCE-Protein beeinflusst die Prognose von Patienten mit NSCLC / Arik Bernard Schulze ; Betreuer: Rainer Gerhard Wiewrodt." Münster : Universitäts- und Landesbibliothek Münster, 2016. http://d-nb.info/1140588087/34.
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Roesner, Anuschka Josphine [Verfasser], and Gian [Akademischer Betreuer] Kayser. "Einfluss der PD-L1-Expression sowie von tumorinfiltrierenden Lymphozyten auf das Ansprechen von Immuncheckpoint-Inhibitoren im NSCLC." Freiburg : Universität, 2019. http://d-nb.info/1212795601/34.
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GRISTINA, Valerio. "Circulating cell-free DNA (cfDNA) and extracellular vesicles (EVs) as prognostic and predictive biomarkers in patients with advanced Non-Small Cell Lung Cancer (NSCLC): the LEXOVE prospective study." Doctoral thesis, Università degli Studi di Palermo, 2022. https://hdl.handle.net/10447/571952.
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Müller, Benedikt Felix [Verfasser], and Ursula [Akademischer Betreuer] Klingmüller. "Interactions of EGFR/IGF-1R Signaling in NSCLC - A Systems Biology Approach / Benedikt Felix Müller ; Betreuer: Ursula Klingmüller." Heidelberg : Universitätsbibliothek Heidelberg, 2015. http://d-nb.info/1180501160/34.
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Seiz, Julia Raphaela [Verfasser]. "Rac1b-spezifische Effekte und Auswirkungen der 3D-Kultivierung auf Differenzierung und Signaltransduktion in NSCLC-Zelllinien / Julia Raphaela Seiz." Gießen : Universitätsbibliothek, 2019. http://d-nb.info/1199264474/34.
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Kurian, Stefanie [Verfasser]. "Effects of combination therapy of PDE5 inhibitor sildenafil and multikinase inhibitors sorafenib and sunitinib in NSCLC / Stefanie Kurian." Gießen : Universitätsbibliothek, 2015. http://d-nb.info/1076760546/34.
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Pamarthi, Pavan Kumar [Verfasser]. "Role of prostanoid receptor EP1 in the progression of non-small cell lung cancer (NSCLC) / Pavan Kumar Pamarthi." Gießen : Universitätsbibliothek, 2013. http://d-nb.info/106518395X/34.
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Müller, Benedikt [Verfasser], and Ursula [Akademischer Betreuer] Klingmüller. "Interactions of EGFR/IGF-1R Signaling in NSCLC - A Systems Biology Approach / Benedikt Felix Müller ; Betreuer: Ursula Klingmüller." Heidelberg : Universitätsbibliothek Heidelberg, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:16-heidok-191984.
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Jaber, Almahdi. "Oncogene driver mutations and copy number variation as markers for predicting drug resistance and disease outcome in NSCLC." Thesis, University of Leicester, 2017. http://hdl.handle.net/2381/39168.
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Introduction: Worldwide, lung cancer is the leading cause of death. Non-small cell lung cancer (NSCLC) patients with KRAS mutations have a poor prognosis and show drug resistance, with MCL-1 implicated in this mechanism via evasion of apoptosis. This study is aimed at evaluating the relationship between key oncogene driver mutations, MCL-1 regulation and MCL-1-induced drug resistance. Methods: We analysed 39 adenocarcinomas (ADCs), 38 squamous cell carcinomas (SCCs), two large cell lung carcinomas (LCCs) and cell lines. A PNA-LNA-based TaqMan qPCR approach was performed for eight KRAS, one BRAF, three PIK3CA and one EGFR mutations. MCL-1, PIK3CA and SOX2 were analysed for copy number variation (CNV). Immunohistochemistry (IHC) and in situ hybridization (ISH) was performed for protein and mRNA, respectively. Alamar blue assay was used to evaluate drug responses. Results: KRAS mutations were detected in 36% of ADCs and 0% of SCCs, whereas PIK3CA mutation was most common in SCC (15.7%) and found in 5% of ADCs. MCL-1, PIK3CA and SOX2 amplification were detected in 13%, 74% and 86.6% of SCCs respectively, and were detected in 2.5%, 25.9% and 13.3% of ADCs respectively. MCL-1-amplified tumours demonstrated high expression of MCL-1 mRNA compared to non-amplified (p < 0.05). Cases with high phospho-ERK and phospho-AKT also showed high expression of MCL-1 mRNA. No growth inhibition was detected in cell lines treated with 5 μM of SH-4-54 inhibitor; however, 10 μM caused 99.9% growth inhibition. Ex vivo experiments mimicking the in vivo tumour environment demonstrated that NSCLCs are sensitive to cisplatin, one of which was MCL-1amplified. Conclusion: We have shown that KRAS mutation is common in ADC, whereas PIK3CA is more common in SCC. Importantly, we have highlighted that CNV of MCL-1 may be an important driver in resistance to chemotherapy. The JAK/STAT pathway was the key regulator for MCL-1 transcription. Resistance to cisplatin was observed in the KRAS mutant cell, MCL-1-amplified cell, cells harbouring MCL-1 gain and Chr1 polysomy but not the SOX2-amplified cell.
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Besson, Florent. "Integrating PET-MR data for a multiparametric approach of tumour heterogeneity in non-small-cell lung cancer (NSCLC)." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASS081.
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L'hétérogénéité tumorale est un facteur important de progression et de résistance au traitement. L'imagerie multiparamétrique TEP-IRM offre des opportunités uniques de caractérisation biologique cellulaire, mais n’a jamais été évalué à l’échelle régionale intra-tumorale dans le cancer du poumon non à petites cellules (CBNPC), première cause de décès oncologique. Une approche multiparamétrique dynamique simultanée TEP-IRM au 18F-FDG a été développée en ce sens. Cette approche a nécessité l’implémentation « maison » de la méthode de référence de quantification TEP du métabolisme glucidique (modèle tri-compartimental de Sokoloff); le développement d’une méthode de correction inédite des distorsions géométriques en imagerie de diffusion, validée sur fantôme et testée cliniquement ; la validation sur fantôme de méthodes d’IRM quantitative (relaxométrie T1/T2), également testées cliniquement; et l’implémentation « maison » du modèle compartimental de Tofts (version étendue) pour l’évaluation de la vascularisation tumorale en IRM dynamique de perfusion. Les résultats de nos travaux expérimentaux effectués à l’échelle intra-tumorale régionale illustrent l’hétérogénéité des rapports entre métabolisme glucidique et vascularisation dans le CBNPC, deux caractéristiques biologiques fondamentales de progression tumorale, et montrent qu’un partitionnement tumoral non supervisé par modèle de mélange gaussien, intégrant l’ensemble des biomarqueurs TEP-IRM de ce projet, individualise 3 types de supervoxels, dont la signature biologique peut être prédite avec une exactitude de 97% par 4 biomarqueurs TEP-IRM dominants, révélés par méthodes métaheuristiques d'apprentissage machineTumor heterogeneity is an important factor of progression and resistance to treatment. Multiparametric PET-MRI imaging offers unique opportunities to characterize biological cellular processes, but has never been evaluated at the regional level in Non-Small Cell Lung Cancer (NSCLC), the leading cause of oncological death. A simultaneous dynamic multiparametric 18F-FDG PET-MRI approach has been developed to this end. This approach required the “in-house” implementation of the reference absolute PET quantitative method of glucose metabolism (Sokoloff's tri-compartmental model); the development of a method for correcting geometric distortions in diffusion weighted imaging, validated on phantom and clinically tested; the phantom validation of quantitative MRI methods (T1/T2 relaxometry), also clinically tested; and the "in-house" implementation of the Tofts compartmental model (extended version) for the evaluation of tumor vascularization by dynamic perfusion MRI. The results of our work, performed at the regional intra-tumor level, illustrate the heterogeneity of the regional interlinks between glucose metabolism and vascularization in NSCLC, two fundamental biological hallmarks of tumor progression, and show that an unsupervised tumor partitioning by Gaussian mixture model, integrating all the PET-MRI biomarkers of this project, individualizes 3 types of supervoxels, whose biological signature can be predicted with 97% accuracy by 4 dominant PET-MRI biomarkers, revealed by metaheuristic machine learning methods
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Seiz, Julia [Verfasser]. "Rac1b-spezifische Effekte und Auswirkungen der 3D-Kultivierung auf Differenzierung und Signaltransduktion in NSCLC-Zelllinien / Julia Raphaela Seiz." Gießen : Universitätsbibliothek, 2019. http://d-nb.info/1199264474/34.
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Samek, Melanie [Verfasser]. "Erlotinib beim fortgeschrittenen nichtkleinzelligen Lungenkarzinom (NSCLC) : klinische Evaluation im Rahmen einer Phase IV Studie (Tarceva EAP) / Melanie Samek." Lübeck : Zentrale Hochschulbibliothek Lübeck, 2010. http://d-nb.info/1004771843/34.
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Yang, Zheng. "Anti-cancer synergy of targeting pyruvate dehydrogenase kinase 1 (PDK1) in combination with EGFR-TKi in NSCLC therapy." Thesis, University of Macau, 2018. http://umaclib3.umac.mo/record=b3953612.
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