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‣ Association of EGFR c.2073A > T polymorphism with decreased risk of diffusely infiltrating astrocytoma in a Brazilian case-control study

BARBOSA, K. C.; OBA-SHINJO, S. M.; UNO, M.; CARVALHO, Po.; ROSEMBERG, S.; AGUIAR, Ph. P.; CARLOTTI, C. G.; MALHEIROS, S. M. F.; TOLEDOS, S.; LOTUFO, P.; MARIE, S. K. N.
Fonte: WICHTIG EDITORE Publicador: WICHTIG EDITORE
Tipo: Artigo de Revista Científica
Português
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Epidermal growth factor receptor (EGFR) gene overexpression has been implicated in the development of many types of tumors, including glioblastomas, the most frequent diffusely infiltrating astrocytomas. However, little is known about the influence of the polymorphisms of EGFR on EGFR production and/or activity, possibly modulating the susceptibility to astrocytomas. This study aimed to examine the association of two EGFR promoter polymorphisms (c.-191C > A and c.-216G > T) and the c.2073A > T polymorphism located in exon 16 with susceptibility to astrocytomas, EGFR gene expression and survival in a case-control study of 193 astrocytoma patients and 200 cancer-free controls. We found that the variant TT genotype of the EGFR c.2073A > T polymorphism was associated with a significantly decreased risk of astrocytoma when compared with the AA genotype [sex- and age-adjusted odds ratio 0.51, 95% confidence interval 0.26-0.98]. No association of the two promoter EGFR polymorphisms (or combinations of these polymorphisms) and risk of astrocytomas, EGFR expression or survival was found. Our findings suggest that modulation of the EGFR c.2073A > T polymorphism could play a role in future therapeutic approaches to astrocytoma. (Int J Biol Markers 2008; 23: 140-6); FAPESP[04/12133-6]; Ludwig Institute for Cancer Research...

‣ Early weaning accelerates the differentiation of mucous neck cells in rat gastric mucosa: Possible role of TGF alpha/EGFR

OSAKI, Luciana H.; CURI, Marco A. F.; ALVARES, Eliana P.; GAMA, Patricia
Fonte: ELSEVIER SCI LTD Publicador: ELSEVIER SCI LTD
Tipo: Artigo de Revista Científica
Português
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The development of the gastric mucosa is controlled by hormones, growth factors and feeding behavior. Early weaning (EW), which means the abrupt interruption of suckling, increases proliferation and differentiation in the rat gastric epithelium. Transforming growth factor alpha(TGF alpha) is secreted in the stomach, binds to the epidermal growth factor receptor( EGFR) and may control cell proliferation, differentiation and migration. Here, we investigated the influence of suckling-weaning transition on the differentiation of mucous neck cells in the stomach and its association to the expression of TGF alpha and EGFR. Fifteen-day-old Wistar rats were divided into two groups: suckling( control), in which pups were kept with the dam, and early weaning( EW), in which rats were separated from their mother and fed with hydrated powdered chow. TGF alpha and EGFR levels were increased at 18 days in EW animals compared to control ones (p<0.05). Histochemical reactions with Periodic Acid-Schiff reagent+Alcian Blue or Bandeiraea simplicifolia II lectin were used to stain the mucous neck cells and showed an increase in this cell population throughout EW, which was more pronounced at 17 days when compared to suckling pups (p<0.05). These morphological results were confirmed by RT-PCR for mucin 6. The levels of mucin 6 mRNA were higher in EW animals from the 16th to the 18th day(1-3 days post-weaning) when compared to the respective control group. Inhibition of EGFR through AG1478 administration to EW animals prevented the expansion of mucous neck cell population induced by EW (p<0.05). Therefore...

‣ Expressão do EGFr como fator prognóstico da recidiva do carcinoma hepatocelular pós-transplante

Kiss, Guilhermo
Fonte: Universidade Federal do Rio Grande do Sul Publicador: Universidade Federal do Rio Grande do Sul
Tipo: Dissertação Formato: application/pdf
Português
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Justificativa: A recidiva do Carcinoma Hepatocelular (CHC) é um fator limitante da sobrevida nos indivíduos submetidos a transplante hepático (TxH). Além do número e tamanho do tumor, invasão vascular e grau de diferenciação, compreender a biologia tumoral e os biomarcadores relacionados é um passo importante para prever a recidiva e estabelecer estratégias terapêuticas. Objetivos: Analisar a expressão e valor prognóstico do receptor do Fator de Crescimento Epidérmico (EGFr) e sua relação com outros fatores implicados na recidiva no CHC. Pacientes e métodos: Foram analisados retrospectivamente os dados de 59 pacientes cirróticos submetidos a TxH no nosso centro com diagnóstico histopatológico confirmado de CHC no período de 2001 a 2006. Resultados: Foi registrada uma sobrevida global e em 1, 3 e 5 anos de 89,3%, 74,9% e 72,4% respectivamente e uma sobrevida livre de doença em 1, 3 e 5 anos de 84,8%, 69,6% e 69,6% respectivamente. A taxa de recidiva foi de 22,03%. O EGFr foi expresso em 93,2% dos tumores, mas não apresentou relação estatisticamente significatica com risco de recidiva (p=0,147) ou outros fatores de risco. Somente a invasão vascular (p=0,046) e o tamanho > 5 cm (p=0,046) foram capazes de predizer o risco de recidiva. Conclusão: O tamanho tumoral e a invasão vascular foram os principais fatores de risco relacionados à recidiva tumoral...

‣ Analysis of EGFR Overexpression, EGFR gene amplification and the EGFRvIII Mutation in portuguese high-grade gliomas

Viana, Marta Pereira; Lopes, José M.; Little, Suzie; Milanezi, Fernanda; Basto, Diana; Pardal, Fernando; Jones, C.; Reis, R. M.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /03/2008 Português
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Background: Patients with malignant gliomas do not respond to any current therapy. Epidermal growth factor receptor (EGFR) controls several oncogenic processes, being frequently up-regulated in gliomas due to overexpression, gene amplification and gene mutation. EGFR inhibitors are being tried in gliomas, yet the molecular determinants of therapeutic response are unclear. Materials and Methods: EGFR overexpression, EGFRvIII mutation and EGFR amplification were determined by immunohistochemistry and chromogenic in situ hybridization (CISH) in 27 primary glioblastomas (GBM), 24 anaplastic oligodendrogliomas (AO) and four anaplastic oligoastrocytomas (AOA). Results: EGFR overexpression was associated with EGFR amplification, being found in 48% and 53% GBM, 33% and 40% AO and 75% and 67% AOA, respectively. EGFRvIII was found in 22% GBM, 8% AO and was absent in AOA. No association was observed between EGFR alterations and patient survival. Conclusion: We characterized, for the first time, EGFR molecular alterations in Portuguese patients with malignant glioma and identified a subpopulation of patients presenting putative biomarkers for EGFR-based therapies.

‣ Molecular study of therapeutic targets of tyrosine kinase inhibitors in endometrial stromal tumors: molecular and protein expression of kit, PDGFRA and EGFR

Sardinha, Ruth Andreia Henriques
Fonte: Universidade de Évora Publicador: Universidade de Évora
Tipo: Tese de Doutorado
Português
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Estudo molecular dos alvos terapêuticos dos inibidores tirosina cinase em Tumores do Estroma Endometrial: Expressão Molecular e Proteica de KIT, PDGFRA e EGFR Os tumores do estroma endometrial (EST) representam 15% dos sarcomas uterinos, e são caraterizados por recorrências tardias e metástases à distância. O tratamento sistémico destas neoplasias não está totalmente estabelecido e alguns estudos descrevem respostas objetivas ao inibidor tirosina cinase (TKI) imatinib, o que sugere uma nova estratégia terapêutica para estes tumores. Nesse sentido, o presente trabalho teve como objetivo efetuar uma análise retrospetiva dos possíveis alvos moleculares dos TKI em EST: KIT, PDGFRA e EGFR. Numa extensa série de EST que incluiu sarcomas do estroma endometrial de baixo grau (n=52) e sarcomas endometriais indiferenciados (n=13) foi efetuada a análise mutacional dos exões 9, 11, 13, e 17 do gene KIT, exões 12 e 18 do gene PDGFRA e exões 18, 19, 20 e 21 do gene EGFR. A expressão proteica de cada recetor foi avaliada por imunohistoquímica, e a técnica de hibridação in situ por fluorescência foi utilizada para avaliar o status do gene EGFR. A sobreexpressão proteica de KIT...

‣ Estudo de gliomas cerebrais no cão, padrões imagiológicos, estudo das mutações de p53, expressão dos receptores do factor de crescimento epidérmico (EGFR), e marcadores imunohistoquímicos

Jesus, Sandra de Oliveira Tavares de Sousa
Fonte: Universidade Técnica de Lisboa. Faculdade de Medicina Veterinária Publicador: Universidade Técnica de Lisboa. Faculdade de Medicina Veterinária
Tipo: Tese de Doutorado
Publicado em 15/06/2011 Português
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Tese de Doutoramento em Ciências Veterinárias. Especialidade de Clínica; O objectivo deste trabalho foi estudar os padrões imagiológicos em TAC dos tumores cerebrais do cão, com particular interesse nos gliomas, assim como tentar determinar o estatuto dos genes p53 e EGFR nestes tumores, realizando estudos moleculares e de imunohistoquímica. Foram realizadas TACs crânio-encefálicas em 105 cães, tendo-se confirmado em todos a presença de lesão intracraniana. O Boxer foi a raça mais representada com 51,4%, a média de idades foi de 9,44 anos e o sintoma mais frequente foi epilepsia (62,7%). 43,8% dos gliomas eram hipodensos, 62,5% captaram contraste, destes 60% captaram contraste em anel, e 80% revelaram desvio da foice do cérebro. Dos 26 tumores classificados por histopatologia, 61,5% foram gliomas e 26,9% meningiomas. O estudo das mutações do gene p53 foi realizado em 19 casos, incluindo 12 gliomas e 6 meningiomas, não tendo sido detectada qualquer mutação. A expressão relativa do gene EGFR, avaliada por PCR em tempo-real, revelou ser significativa em meningiomas, oligodendrogliomas e astrocitomas (p<0,05) e em gliomas (p<0,01). O estudo imunohistoquímico foi realizado em 24 casos, incluindo 16 gliomas e 8 meningiomas...

‣ Epidermal growth factor receptor (EGFR) mutations in lung cancer: preclinical and clinical data

Jorge,S.E.D.C.; Kobayashi,S.S.; Costa,D.B.
Fonte: Associação Brasileira de Divulgação Científica Publicador: Associação Brasileira de Divulgação Científica
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/11/2014 Português
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Lung cancer leads cancer-related mortality worldwide. Non-small-cell lung cancer (NSCLC), the most prevalent subtype of this recalcitrant cancer, is usually diagnosed at advanced stages, and available systemic therapies are mostly palliative. The probing of the NSCLC kinome has identified numerous nonoverlapping driver genomic events, including epidermal growth factor receptor (EGFR) gene mutations. This review provides a synopsis of preclinical and clinical data on EGFR mutated NSCLC and EGFR tyrosine kinase inhibitors (TKIs). Classic somatic EGFR kinase domain mutations (such as L858R and exon 19 deletions) make tumors addicted to their signaling cascades and generate a therapeutic window for the use of ATP-mimetic EGFR TKIs. The latter inhibit these kinases and their downstream effectors, and induce apoptosis in preclinical models. The aforementioned EGFR mutations are stout predictors of response and augmentation of progression-free survival when gefitinib, erlotinib, and afatinib are used for patients with advanced NSCLC. The benefits associated with these EGFR TKIs are limited by the mechanisms of tumor resistance, such as the gatekeeper EGFR-T790M mutation, and bypass activation of signaling cascades. Ongoing preclinical efforts for treating resistance have started to translate into patient care (including clinical trials of the covalent EGFR-T790M TKIs AZD9291 and CO-1686) and hold promise to further boost the median survival of patients with EGFR mutated NSCLC.

‣ Análise da expressão imuno-histoquímica de c-erbB-2 e EGFR em carcinoma epidermóide de esôfago

Sato,Yukie; Nascimento,Carlos Ferreira; Ferreira,Severino da Silva; Fregnani,José Humberto T. G.; Soares,Fernando Augusto
Fonte: Sociedade Brasileira de Patologia Clínica; Sociedade Brasileira de Patologia; Sociedade Brasileira de Citopatologia Publicador: Sociedade Brasileira de Patologia Clínica; Sociedade Brasileira de Patologia; Sociedade Brasileira de Citopatologia
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/08/2007 Português
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INTRODUÇÃO: O carcinoma epidermóide de esôfago (CEE) possui alta incidência em nosso país, com altas taxas de mortalidade. A família dos receptores do fator epitelial de crescimento (EGFR) é composta por quatro membros, e muitos estudos têm sido direcionados para a expressão de EGFR e c-erbB-2, com implicações terapêuticas. OBJETIVO: Investigar as expressões imuno-histoquímicas de EGFR e c-erbB-2 e correlacioná-las a aspectos clinicopatológicos em casos de CEE. MATERIAL E MÉTODOS: Para esse estudo, dados clinicopatológicos de 613 CEE foram revistos. A imunoistoquímica foi feita utilizando anticorpo policlonal para c-erbB-2 e monoclonal para EGFR em 597 e 585 casos, respectivamente. Os casos representados por peças cirúrgicas foram distribuídos em três blocos de parafina de tissue microarray (TMA), inseridos em duplicata; aqueles com biópsias foram analisados em corte convencional. Todos foram classificados de acordo com intensidade e padrão de marcação de membrana das células tumorais. RESULTADOS: As expressões de c-erbB-2 e EGFR foram observadas em 42,4% e 77,6% dos casos, respectivamente. Observou-se correlação estatisticamente significativa entre as expressões de c-erbB-2 (p = 0,04) e EGFR (p = 0...

‣ Acquired MET Expression Confers Resistance to EGFR Inhibition In a Mouse Model of Glioblastoma Multiforme

Jun, Hyun Jung; Acquaviva, Jaime; Chi, Dorcas; Lessard, Julie; Zhu, Haihao; Woolfenden, Steve; Bronson, Roderick T.; Pfannl, Rolf; White, Forest; Housman, David E.; Iyer, Lakshmanan; Whittaker, Charles A.; Boskovitz, Abraham; Raval, Ami; Charest, Alain
Fonte: Harvard University Publicador: Harvard University
Tipo: Artigo de Revista Científica
Português
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Glioblastoma Multiforme (GBM) is an aggressive brain tumor for which there is no cure. Overexpression of wild-type EGFR and loss of the tumor suppressor genes Ink4a/Arf and PTEN are salient features of this deadly cancer. Surprisingly, targeted inhibition of EGFR has been clinically disappointing, demonstrating an innate ability for GBM to develop resistance. Efforts at modeling GBM in mice using wild-type EGFR have proven unsuccessful to date, hampering endeavors at understanding molecular mechanisms of therapeutic resistance. Here, we describe a unique genetically engineered mouse model of EGFR-driven gliomagenesis that uses a somatic conditional overexpression and chronic activation of wild-type EGFR in cooperation with deletions in the Ink4a/Arf and PTEN genes in adult brains. Using this model, we establish that chronic activation of wild-type EGFR with a ligand is necessary for generating tumors with histopathological and molecular characteristics of GBMs. We show that these GBMs are resistant to EGFR kinase inhibition and we define this resistance molecularly. Inhibition of EGFR kinase activity using tyrosine kinase inhibitors in GBM tumor cells generates a cytostatic response characterized by a cell cycle arrest, which is accompanied by a substantial change in global gene expression levels. We demonstrate that a key component of this pattern is the transcriptional activation of the MET receptor tyrosine kinase and that pharmacological inhibition of MET overcomes the resistance to EGFR inhibition in these cells. These findings provide important new insights into mechanisms of resistance to EGFR inhibition and suggest that inhibition of multiple targets will be necessary to provide therapeutic benefit for GBM patients.

‣ An EGFR Targeted PET Imaging Probe for the Detection of Colonic Adenocarcinomas in the Setting of Colitis

Turker, N. Selcan; Heidari, Pedram; Kucherlapati, Raju; Kucherlapati, Melanie; Mahmood, Umar
Fonte: Ivyspring International Publisher Publicador: Ivyspring International Publisher
Tipo: Artigo de Revista Científica
Português
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Colorectal cancer is a serious complication associated with inflammatory bowel disease, often indistinguishable by screening with conventional FDG PET probes. We have developed an alternative EGFR-targeted PET imaging probe that may be used to overcome this difficulty, and successfully assessed its utility for neoplastic lesion detection in preclinical models. Cetuximab F(ab′)2 fragments were enzymatically generated, purified, and DOTA-conjugated. Radiolabeling was performed with 67Ga for cell based studies and 64Cu for in vivo imaging. Competitive binding studies were performed on CT26 cells to assess affinity (KD) and receptors per cell (Bmax). In vivo imaging using the EGFR targeted PET probe and 18F FDG was performed on CT26 tumor bearing mice in both control and dextran sodium sulfate (DSS) induced colitis settings. Spontaneous adenomas in genetically engineered mouse (GEM) models of colon cancer were additionally imaged. The EGFR imaging agent was generated with high purity (> 98%), with a labeling efficiency of 60 ± 5% and ≥99% radiochemical purity. The KD was 6.6 ± 0.7 nM and the Bmax for CT26 cells was 3.3 ± 0.1 × 106 receptors/cell. Target to background ratios (TBR) for CT26 tumors compared to colonic uptake demonstrated high values for both 18F-FDG (3.95 ± 0.13) and the developed 64Cu-DOTA-cetuximab-F(ab′)2 probe (4.42 ± 0.11) in control mice. The TBR for the EGFR targeted probe remained high (3.78 ± 0.06) in the setting of colitis...

‣ Epidermal growth factor receptor (EGFR) mutations in lung cancer: preclinical and clinical data

Jorge, S.E.D.C.; Kobayashi, S.S.; Costa, D.B.
Fonte: Associação Brasileira de Divulgação Científica Publicador: Associação Brasileira de Divulgação Científica
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
37.021982%
Lung cancer leads cancer-related mortality worldwide. Non-small-cell lung cancer (NSCLC), the most prevalent subtype of this recalcitrant cancer, is usually diagnosed at advanced stages, and available systemic therapies are mostly palliative. The probing of the NSCLC kinome has identified numerous nonoverlapping driver genomic events, including epidermal growth factor receptor (EGFR) gene mutations. This review provides a synopsis of preclinical and clinical data on EGFR mutated NSCLC and EGFR tyrosine kinase inhibitors (TKIs). Classic somatic EGFR kinase domain mutations (such as L858R and exon 19 deletions) make tumors addicted to their signaling cascades and generate a therapeutic window for the use of ATP-mimetic EGFR TKIs. The latter inhibit these kinases and their downstream effectors, and induce apoptosis in preclinical models. The aforementioned EGFR mutations are stout predictors of response and augmentation of progression-free survival when gefitinib, erlotinib, and afatinib are used for patients with advanced NSCLC. The benefits associated with these EGFR TKIs are limited by the mechanisms of tumor resistance, such as the gatekeeper EGFR-T790M mutation, and bypass activation of signaling cascades. Ongoing preclinical efforts for treating resistance have started to translate into patient care (including clinical trials of the covalent EGFR-T790M TKIs AZD9291 and CO-1686) and hold promise to further boost the median survival of patients with EGFR mutated NSCLC.

‣ Imunoexpressão do EGFR e da podoplanina em cistos radiculares e dentígeros

Maia, Viviane Alves de Oliveira
Fonte: Universidade Federal do Rio Grande do Norte; BR; UFRN; Programa de Pós-Graduação em Patologia Oral; Odontologia Publicador: Universidade Federal do Rio Grande do Norte; BR; UFRN; Programa de Pós-Graduação em Patologia Oral; Odontologia
Tipo: Dissertação Formato: application/pdf
Português
Relevância na Pesquisa
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The radicular cysts (RCs) and dentigerous (DCs), despite having different etiologies, form a pathological cavity lined by epithelium, which grows due to the buildup of fluid inside, as the surrounding bone is reabsorbed and the epithelium will being induced to proliferate. The epithelial proliferation, which has been identified as one of the key processes in the growth of odontogenic cystic lesions, is influenced by growth factors such as EGFR (epidermal growth receptor factor) and podoplanin (PDPN), many of which may have its production stimulated mainly during inflammatory processes. The objective of this research was to evaluate and compare the immunohistochemical expression of EGFR and PDPN in 30 cases of RCs and 30 cases of DCs, semiquantitatively, in light microscopy, associating it with the degree of inflammation, cellular localization of immunostaining and with the immunostained epithelial layers. Data were statistically analyzed by Chi-square test and Fisher exact test, considering a significance level of 5 %. The results showed high immunoreactivity of both proteins in the lesions studied, only statistically significant difference was observed in immunostaining of PDPN (p=0.033), which proved higher in RCs. The other analyzed parameters showed no relevant significant differences. We conclude that...

‣ Treatment of triple-negative breast cancer using anti-EGFR-directed radioimmunotherapy combined with radiosensitizing chemotherapy and PARP inhibitor

Al-ejeh, F.; Shi, W.; Miranda, M.; Simpson, P.; Vargas, A.; Song, S.; Wiegmans, A.; Swarbrick, A.; Welm, A.; Brown, M.; Chenevix-Trench, G.; Lakhani, S.; Khanna, K.
Fonte: Soc Nuclear Medicine Inc Publicador: Soc Nuclear Medicine Inc
Tipo: Artigo de Revista Científica
Publicado em //2013 Português
Relevância na Pesquisa
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UNLABELLED: Triple-negative breast cancer (TNBC) is associated with poor survival. Chemotherapy is the only standard treatment for TNBC. The prevalence of BRCA1 inactivation in TNBC has rationalized clinical trials of poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors. Similarly, the overexpression of epidermal growth factor receptor (EGFR) rationalized anti-EGFR therapies in this disease. However, clinical trials using these 2 strategies have not reached their promise. In this study, we used EGFR as a target for radioimmunotherapy and hypothesized that EGFR-directed radioimmunotherapy can deliver a continuous lethal radiation dose to residual tumors that are radiosensitized by PARP inhibitors and chemotherapy. METHODS: We analyzed EGFR messenger RNA in published gene expression array studies and investigated EGFR protein expression by immunohistochemistry in a cohort of breast cancer patients to confirm EGFR as a target in TNBC. Preclinically, using orthotopic and metastatic xenograft models of EGFR-positive TNBC, we investigated the effect of the novel combination of (177)Lu-labeled anti-EGFR monoclonal antibody, chemotherapy, and PARP inhibitors on cell death and the survival of breast cancer stem cells. RESULTS: In this first preclinical study of anti-EGFR radioimmunotherapy in breast cancer...

‣ Mechanism and role of EGFR Tyrosine Kinase Inhibition in radiation response of human tumor and normal cells; Mechanismus und Rolle der EGFR-Tyrosinekinase-Inhibition während der Strahlenantwort von Tumor- und Normalzellen; Mechanismus und Rolle der EGFR-Tyrosinekinase-Inhibition während der Strahlenantwort von Tumor- und Normalzellen

Toulany, Mahmoud
Fonte: Universidade de Tubinga Publicador: Universidade de Tubinga
Tipo: Dissertação
Português
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Cancer is a public health problem worldwide and the main cause of mortality. Surgery, radiotherapy and chemotherapy are the three major cancer treatment modalities. Applying advanced technical developments in radiation oncology has improved the quality of cancer treatment by radiotherapy alone as well as in combination with chemotherapy. Nevertheless, further progress in clinical efficiency of radiotherapy can only be expected when in addition to technological advances biological parameters of the radiation response profile of tumors are taken into account for the development of treatment strategies. Therefore clarifying the underlying molecular mechanisms of radiation responses and identifying molecular targets for intervention will create the potential to develop specific therapeutic strategies in radiation oncology based on individual biological parameters of the tumors to be treated. Accelerated repopulation of tumors during fractionated radiotherapy is one of the phenomenons that limits the success and effectiveness of radiation treatment. One proposed mechanism for tumor repopulation is the potential of ionizing radiation to activate the epidermal growth factor receptor (EGFR) which is linked to several components of mitogenic and survival signaling pathways mediating resistance to ionizing radiation and failure in tumor treatment. Based on the prominent role of EGFR in accelerated repopulation as well as cellular radioresistance...

‣ Charakterisierung prädiktiver molekularer Biomarker für die Aktivität von therapeutischen anti-EGFR Antikörpern; Characterization of predictive molecular biomarkers for the activity of therapeutic anti-EGFR antibodies

Bergmann, Katharina
Fonte: Universidade de Tubinga Publicador: Universidade de Tubinga
Tipo: Dissertação
Português
Relevância na Pesquisa
37.176384%
Der epidermale Wachstumsfaktorrezeptor (EGFR) ist eine Rezeptor-Tyrosinkinase, die sowohl in Wachstum und Differenzierung von Zellen als auch in der Tumorprogression eine Rolle spielt. Derzeit sind sieben EGFR-Liganden bekannt, darunter der epidermale Wachstumsfaktor (EGF), der transformierende Wachstumsfaktor (TGFA), Amphiregulin (AREG) und Epiregulin (EREG), die mit unterschiedlicher Affinität den EGFR binden und aktivieren. Die Ligandenbindung und somit die Aktivierung des EGFR kann durch anti-EGFR monoklonale Antikörper (mAb) blockiert werden. Dabei ist das Ansprechen auf mAb nicht nur von der Expression des EGFR abhängig sondern auch von Mutations- und Expressionsstatus weiterer Biomarker, die in der EGFR-Signaltransduktion eine Rolle spielen. In dieser Arbeit wurde daher der Einfluss folgender potentieller Biomarker auf die Sensitivität von Zellen gegen die therapeutischen anti-EGFR mAb Cetuximab, Matuzumab, Panitumumab und Nimotuzumab in vitro untersucht: (1) der EGFR-Polymorphismus R521K, (2) die EGFR-Liganden EGF, TGFA, AREG und EREG, (3) ErbB3 und (4) KRAS. Zur Untersuchung des EGFR-Polymorphismus R521K wurden stabil transfizierte Modellzelllinien (NIH3T3) generiert, die entweder humanen EGFR 521K oder humanen EGFR 521R exprimierten. In Proliferationsassays konnte beobachtet werden...

‣ Co-Inhibition von epidermal growth factor receptor (EGFR) und insulin-like growth factor-I receptor (IGF-IR): Ein neuer Ansatz für die Reduktion der Zelltodresistenz humaner maligner Gliomzellen; Co-inhibition of epidermal growth factor receptor and type 1 insulin-like growth factor receptor: a new approach in reducing of restistance to apoptosis of human malignant glioma cells

Eisenmann, Christine
Fonte: Universität Tübingen Publicador: Universität Tübingen
Tipo: Dissertation; info:eu-repo/semantics/doctoralThesis
Português
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In der vorliegenden Arbeit wurde zunächst der Effekt der Wachstumsfaktoren EGF, IGF-I, FGF-I und PDGF auf Wachstum und Überleben von zwölf humanen malignen Glioblastomzellinien bei Serumentzug untersucht. Dabei wurden bei den einzelnen Zelllinien unterschiedliche Abhängigkeit von individuellen Wachstumsfaktoren beobachtet, die als eine Art 'molekulare Signatur' Hinweise auf die Relevanz der zugehörigen Rezeptortyrosinkinase gelten können. Die Charakterisierung der Effekte einer Co-Inhibition von EGFR und IGF-IR auf den CD95L-induzierten Zelltod war der zentrale Bestandteil dieser Arbeit. Dabei konnte zunächst eine synergistische Sensitivierung gegenüber CD95 durch die Co-Inhibition bei den p53-Wildtyp-Zelllinien LNT-229 und U87MG nachgewiesen werden, nicht jedoch bei den p53-mutanten Zelllinien LN-18 und T98G. Experimente mit dem temperatursensitiven p53val135A zeigten jedoch, dass der sensitivierende Effekt der Co-Inhibition nicht p53-abhängig ist. Der Typ des durch die Co-Inhibition fazilitierten Zelltods war apoptotisch und begleitet von einer crmA-sensitiven Aktivierung von Caspase 8, den Effektorcaspasen 3 und 7, und dem Caspasesubstrat PARP. Da ein Effekt der Co-Inhibition auf das Expressionsniveau von CD95 ausgeschlossen wurde...

‣ Early Detection of Progressive Chronic Kidney Disease by Monitoring Change in eGFR in CKD Stages 1, 2 & 3

Collier, CHRISTINE
Fonte: Quens University Publicador: Quens University
Tipo: Tese de Doutorado
Português
Relevância na Pesquisa
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RATIONALE: Early detection and effective treatment of chronic kidney disease (CKD) is reported to halt or slow progression (pCKD) to end-stage renal disease (ESRD) in many patients. Current guidelines recommend an eGFR upper reporting limit of > 60 mL/min/1.73m2. However, this severely limits the detection of pCKD as the first time a patient is diagnosed with CKD, they are already in Stage 3. OBJECTIVE: To determine if the rate of change in eGFR during early stages of CKD (i.e. 1 - 3) is different in those who progress to ESRD compared to those who are currently not anticipated to progress. METHODS: This retrospective case-control (1:2) study used 5 years of hospital laboratory data (2008 – 2013). All subjects had a maximum eGFR-EPI > 90 mL/min/1.73m2. Cases had a minimum eGFR-EPI < 15 mL/min/1.73m2, while age- and sex-matched controls (± 5 years) had a minimum eGFR-EPI > 45 mL/min/1.73m2. JOINPOINT (JP) regression software was used to identify and estimate the declining “linear” slope for eGFR most reflective of early pCKD. Multi-level modelling (MLM) was used for statistical analysis. RESULTS: There were 30 cases (13 women, 17 men), and 60 controls (26 women, 34 men), for a total of 3,217 observations in 90 subjects. The mean eGFR-EPI slope by MLM was -2.9 mL/min/1.73m2/year (95%CI: -3.3 to -2.4) for controls...

‣ Implementação da técnica Silver In Situ Hibridization para avaliação do status do gene EGFR em doentes com CPNPC

Reis, Sandra; Scigliano, Horácio; Teixeira, Paulo; Silva, Regina
Fonte: Instituto Politécnico do Porto. Escola Superior de Tecnologia da Saúde do Porto - Politema Publicador: Instituto Politécnico do Porto. Escola Superior de Tecnologia da Saúde do Porto - Politema
Tipo: Conferência ou Objeto de Conferência
Publicado em //2010 Português
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Avaliação do estado do gene Epidermal Growth Factor Receptor (EGFR), por Silver In Situ Hibridization (SISH), tem-se destacado como biomarcador preditivo na resposta à terapêutica. O principal objectivo foi optimizar a etapa de recuperação por calor da metodologia automatizada SISH Dual-Colour, em carcinomas pulmonares fixados em formol durante 24 e 72 horas. A optimização levou a um aumento da preservação do contorno nuclear e da intensidade e contraste dos sinais para os dois tempos de fixação, permitindo avaliar o estado do EGFR em 83,3% dos casos em estudo. A SISH Dual-Colour é uma alternativa para avaliar o estado do EGFR.; Assessment of the status of the gene Epidermal Growth Factor Receptor (EGFR), by Silver in Situ Hibridization (SISH) has been highlighted as a predictive biomarker in the response to therapy. The main objective was to optimize the recovery stage of heat-automated methodology SISH Dual-Colour in lung carcinoma with 24 and 72 hours of formaldehyde fixation. The optimization led to an increase in the preservation of the nuclear contour, intensity and contrast of the signals for both fixation times, allowing evaluation of EGFR state in 83.3% of studied cases. The SISH Dual-Colour is an alternative to assess the status of EGFR.

‣ Estudi de les mutacions del gen EGFR en pacients d'estadis avançats per CPCNP

Queralt Herrero, Cristina
Fonte: [Barcelona] : Universitat Autònoma de Barcelona, Publicador: [Barcelona] : Universitat Autònoma de Barcelona,
Tipo: Tesis i dissertacions electròniques; info:eu-repo/semantics/doctoralThesis; info:eu-repo/semantics/publishedVersion Formato: application/pdf
Publicado em //2014 Português
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37.021982%
El carcinoma de pulmó de cèl·lula no petita (CPCNP) és un dels tumors més freqüents en la població caucàsica en què la histologia més comuna és l'adenocarcinoma. En diversos estudis clínics es va observar que un subgrup de pacients amb CPCNP avançat, amb unes característiques molt concretes (sexe femení, d'histologia adenocarcinoma i no fumador), es beneficiaven del tractament amb uns inhibidors de l'activitat tirosina quinasa (ITQ) d'EGFR (Epidermal Growth Factor Receptor). Les mutacions en aquest domini del gen EGFR, descobertes l'any 2004, van ser descrites com les responsables de les respostes als ITQ. El 90% d'aquestes mutacions són delecions en l'exó 19 i una mutació puntual en la posició L858R de l'exó 21. Tot i així, més de la meitat dels pacients amb les mutacions de sensibilitat tractats amb ITQ recauen. Una de causes més comunes és l'aparició de la mutació de resistència T790M en l'exó 20. El mètode estàndard per estudiar alteracions genètiques és la seqüenciació Sanger. Com que la seva sensibilitat de detecció es situa al voltant del 20%, en aquest treball s'han optimitzat altres tècniques més sensibles, com l'anàlisi de fragments per detectar les delecions de l'exó 19 (GeneScan) i la discriminació al·lèlica per TaqMan per a les mutacions L858R i T790M en mostres de teixit tumoral inclòs en parafina i per a mostres amb poca cel·lularitat tumoral. A continuació...

‣ Polysomy and amplification of chromosome 7 defined for EGFR gene in squamous cell carcinoma of the lung together with exons 19 and 21 wild type

Couceiro,Patrícia; Sousa,Vítor; Alarcão,Ana; Silva,Maria; Carvalho,Lina
Fonte: Sociedade Portuguesa de Pneumologia Publicador: Sociedade Portuguesa de Pneumologia
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/06/2010 Português
Relevância na Pesquisa
37.054536%
Purpose: The epidermal growth factor receptor (EGFR) is overexpressed in the majority of nonsmall-cell lung cancers (NSCLC) and is a major target specific EGFR tyrosine kinase inhibitors (TKIs) developed and used for the treatment of advanced NSCLC. A number of biological factors are also associated with EGFR-TKIs responsiveness. This study was focused on EGFR somatic mutations and amplifications in squamous cell lung cancer. Material and methods: Representative sections of squamous cell carcinoma were selected from 54 surgical specimens from formalin-fixed paraffin-embedded tissues and submitted to TMA construction. Determination of EGFR protein expression was done by immunohistochemistry( IHC) (Zymed, Laboratories). Fluorescence in situ hybridization (FISH) was performed with LSI EGFR/CEP 7 (Vysis; Abbott Molecular, USA). Genomic DNA was extracted from 48 cases and exon 19 was amplified by polymerase chain reaction (PCR) for search deletions and point mutations for exon 21. All cases expressed high weigh cytokeratin and were observed negativity for CK7, CD56 and chromogranin. Results: EGFR protein overexpression was identified in 49 cases, by the application of Hirsh’s scoring system. The chromosome 7 and EGFR gene were analyzed by FISH and scored according to Cappuzzo’s method that showed high polysomy in 31 cases and amplification in 7 cases. Deletion in exon 19 of EGFR was detected in 3 cases of 48 samples; the exon 21 of EGFR was expressed in its wild type by RFLP in all cases. Conclusions: Detection of common EGFR deletion and mutation showed to be a rare event in Squamous cell carcinoma of the lung. While EGFR mutation is the most effective molecular predictor or sensitivity in patients with advanced NSCLC submitted to EGFR-TKIs treatment...