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‣ Arginine vasopressin controls p27(KiP1) protein expression by PKC activation and irreversibly inhibits the proliferation of K-Ras-dependent mouse Y1 adrenocortical malignant cells

FORTI, Fabio L.; ARMELIN, Hugo A.
Fonte: ELSEVIER SCIENCE BV Publicador: ELSEVIER SCIENCE BV
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
67.44076%
The neurohypophyseal hormone arginine vasopressin (AVP) is a classic mitogen in many cells. In K-Ras-dependent mouse Y1 adrenocortical malignant cells, AVP elicits antagonistic responses such as the activation of the PKC and the ERK1/2 mitogenic pathways to down-regulate cyclin D1 gene expression, which induces senescence-associated beta-galactosidase (SA-beta Gal) and leads to cell cycle arrest. Here, we report that in the metabolic background of Y1 cells, PKC activation either by AVP or by PMA inhibits the PI3K/Akt pathway and stabilises the p27(Kip1) protein even in the presence of the mitogen fibroblast growth factor 2 (FGF2). These results suggest that p27(Kip1) is a critical signalling node in the mechanisms underlying the survival of the Y1 cells. In Y1 cells that transiently express wild-type p27(Kip1), AVP caused a severe reduction in cell survival, as shown by clonogenic assays. However, AVP promoted the survival of Y1 cells transiently expressing mutant p27-S10A or mutant p27-T187A, which cannot be phosphorylated at Ser10 and Thr187, respectively. In addition, PKC activation by PMA mimics the toxic effect caused by AVP in Y1 cells, and inhibition of PKC completely abolishes the effects caused by both PMA and AVP in clonogenic assays. The vulnerability of Y1 cells during PKC activation is a phenotype conditioned upon K-ras oncogene amplification because K-Ras down-regulation with an inducible form of the dominant-negative mutant H-RasN17 has resulted in Y1 cells that are resistant to AVP`s deleterious effects. These data show that the survival destabilisation of K-Ras-dependent Y1 malignant cells by AVP requires large quantities of the p27(Kip1) protein as well as phosphorylation of the p27(Kip1) protein at both Ser10 and Thr187. (C) 2011 Elsevier B.V. All rights reserved.; Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP); Sao Paulo Research Foundation...

‣ Detection of codon 12 mutation in the k-ras oncogene in pancreatic tumors

Kubrusly,Márcia Saldanha; Matheucci Junior,Euclides; Leite,Kátia Ramos Moreira; Coelho,Ana Maria de Mendonça; Monte,Osmar; Machado,Marcel Cerqueira Cesar; Pinotti,Henrique Walter
Fonte: Faculdade de Medicina / Universidade de São Paulo - FM/USP Publicador: Faculdade de Medicina / Universidade de São Paulo - FM/USP
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/02/1999 Português
Relevância na Pesquisa
67.46%
Mutations at codons 12, 13, or 61 of the H-ras, K-ras, and N-ras have been detected in human neoplasias by a variety of techniques. Some of these techniques are very sensitive and can detect K-ras mutation in 90% of the cases of pancreatic adenocarcinomas. We analyzed 11 samples of pancreatic adenocarcinoma, three samples of pancreatic mucinous cystadenoma, and two samples without tumors in formalin-fixed paraffin embedded tissue sections. K-ras mutations at codon 12 were detected by a two-step PCR-enriched technique in all the samples of pancreatic adenocarcinoma, but not in cystadenoma or control samples. This technique may be useful for early detection of pancreatic cancer.

‣ Incidência de mutação no códon 12 do protoncogene K-ras em carcinoma de próstata humana em uma amostra da população brasileira

Gajardo,José Raul Cisternas; Tobias-Machado,Marcos; Simardi,Lucila Heloisa; Corrêa,Thiago Domingos; Wroclawski,Eric Roger
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 01/06/2004 Português
Relevância na Pesquisa
67.44076%
Com o intuito de estudar a participação do gene ras ativado na tumorigênese humana, pesquisamos a freqüência de mutação pontual no códon 12 do gene K-ras em espécimes cirúrgicos de pacientes portadores de câncer de próstata. Foi utilizado um grupo controle de pacientes com hiperplasia prostática benigna (HPB). Os cortes destinados ao estudo foram submetidos a extração do DNA pelo método da proteinase K. A amplificação do fragmento isolado foi obtida pela reação em cadeia de polimerase seguida por clivagem, utilizando-se a enzima de restrição Mval. A eletroforese em gel de agarose permitiu a verificação da presença de mutações. Constatamos a presença de mutação no códon 12 do gene K-ras em dois dos 15 carcinomas de próstata estudados (13,3%), sendo que nenhuma em pacientes com HPB. A ocorrência de mutação de 13,3% na amostra da população brasileira analisada caracteriza uma incidência intermediária entre as populações japonesa e americana. É pouco provável que a mutação isolada do K-ras seja um evento significativo na carcinogênese prostática nesta população.

‣ K-ras mutations in the bile of patients with primary sclerosing cholangitis

Kubicka, S; Kuhnel, F; Flemming, P; Hain, B; Kezmic, N; Rudolph, K; Manns, M; Meier, P
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /03/2001 Português
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BACKGROUND AND AIMS—The development of cholangiocarcinoma (CCC) is a complication of primary sclerosing cholangitis (PSC). To date, no reliable factors have been described which can define those PSC patients at high risk for the development of CCC and the clinical diagnosis of CCC in PSC patients is difficult. Therefore, molecular markers of cholangiocarcinogenesis, such as K-ras mutations, may improve the early diagnosis of CCC or the timing of liver transplantation.
METHODS—K-ras mutations were analysed by enriched polymerase chain reaction/restriction fragment length polymorphism in the bile fluid of 56 PSC patients and 20 patients with other cholestatic diseases. To assess the value of K-ras mutations as a risk factor for cholangiocarcinogenesis, patients were prospectively investigated over a mean period of 31.5 months.
RESULTS—In contrast with the control group, 17 (30%) patients with PSC revealed K-ras mutations in bile fluid. The mean Mayo score was not significantly different between PSC patients with (mean score 0.70) and without (mean score 0.13; p=0.2) K-ras mutations. In contrast with the group of PSC patients without K-ras mutations, four CCCs and two dysplasia were diagnosed in the group of patients with K-ras mutations during the follow up investigation (p<0.001).
CONCLUSIONS—Our results indicate that K-ras mutations in bile fluid of PSC patients represent frequent early events during cholangiocarcinogenesis. However...

‣ Oncogenic K-Ras Signals through Epidermal Growth Factor Receptor and Wild-Type H-Ras to Promote Radiation Survival in Pancreatic and Colorectal Carcinoma Cells1

Cengel, Keith A.; Voong, K. Rahn; Chandrasekaran, Sanjay; Maggiorella, Laurence; Brunner, Thomas B.; Stanbridge, Eric; Kao, Gary D.; McKenna, W. Gillies; Bernhard, Eric J.
Fonte: Neoplasia Press Inc. Publicador: Neoplasia Press Inc.
Tipo: Artigo de Revista Científica
Publicado em /04/2007 Português
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Pancreatic and colorectal carcinomas frequently express oncogenic/mutant K-Ras that contributes to both tumorigenesis and clinically observed resistance to radiation treatment. We have previously shown that farnesyltransferase inhibitors (FTI) radiosensitize many pancreatic and colorectal cancer cell lines that express oncogenic K-ras at doses that inhibit the prenylation and activation of H-Ras but not K-Ras. In the present study, we have examined the mechanism of FTI-mediated radiosensitization in cell lines that express oncogenic K-Ras and found that wild-type H-Ras is a contributor to radiation survival in tumor cells that express oncogenic K-Ras. In these experiments, inhibiting the expression of oncogenic K-Ras, wild-type H-Ras, or epidermal growth factor receptor (EGFR) led to similar levels of radiosensitization as treatment with the FTI tipifarnib. Treatment with the EGFR inhibitor gefitinib led to similar levels of radiosensitization, and the combinations of tipifarnib or gefitinib plus inhibition of K-Ras, H-Ras, or EGFR expression did not provide additional radiosensitization compared with tipifarnib or gefitinib alone. Finally, supplementing culture medium with the EGFR ligand transforming growth factor α was able to reverse the radiosensitizing effect of inhibiting K-ras expression. Taken together...

‣ Relationship of the K-ras/c-mos expression patterns with angiogenesis in non-small cell lung carcinomas.

Zacharatos, P.; Kotsinas, A.; Tsantoulis, P.; Evangelou, K.; Kletsas, D.; Asimacopoulos, P. J.; Doussis-Anagnostopoulou, I.; Pezzella, F.; Gatter, K.; Papavassiliou, A. G.; Kittas, C.; Gorgoulis, V. G.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /09/2001 Português
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BACKGROUND: Neo-angiogenesis is an acquired capability vital for a tumor to grow and metastasize. Evidence has shown that the mitogen-activated protein (MAP) kinase pathway is involved in this process. Alterations of K-ras and c-mos, two pivotal components of this pathway, have been implicated in non-small cell lung carcinogenesis. In the present report, we examine, in a series of non-small cell lung carcinomas (NSCLCs), the status of K-ras and c-mos oncoproteins in correlation with the tumor neo-angiogenesis state and the major angiogenic factor, vascular endothelial growth factor (VEGF). MATERIALS AND METHODS: c-mos and p-ERK1/2 status was evaluated immunohistochemically in a total of 65 NSCLCs, whereas the presence of K-ras mutations was examined by reverse transcriptase-polymerase chain reaction (RT-PCR) restriction fragment length polymorphism (RFLP) in available matched normal tumor material from 56 cases. Microvessel density (MVD) was estimated by immunodetection of CD3, endothelial marker, and VEGF expression was assessed by immunohistochemistry. All possible associations were examined by a series of statistical methods. RESULTS: Expression of oncogenic activated K-ras and c-mos overexpression was observed in 12 of 49 (25%) and in 16 of 61 (26%) informative cases...

‣ Systemic activation of K-ras rapidly induces gastric hyperplasia and metaplasia in mice

Matkar, Smita S; Durham, Amy; Brice, Angela; Wang, Timothy C; Rustgi, Anil K; Hua, Xianxin
Fonte: e-Century Publishing Corporation Publicador: e-Century Publishing Corporation
Tipo: Artigo de Revista Científica
Publicado em 16/02/2010 Português
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Mouse models with conditional activation of K-ras (K-rasG12D) are used widely to investigate the role of oncogenic K-ras in a tissue-specific manner. However, the effect of ubiquitous activation of K-ras in adult mice has not been well studied. Herein, we report that systemic activation of K-ras in mice leads to rapid changes in gastric cellular homeostasis. Conditional activation of K-ras results in activation of the MAPK pathway and hyperproliferation of squamous epithelium in the forestomach and metaplasia in the glandular stomach. Parietal cells almost completely disappear from the upper part of the stomach adjacent to forestomach of K-ras activated mice. CDX2, a caudal-related homeobox transcription factor normally expressed in the intestine, is upregulated in parts of the stomach, following activation of K-ras in mice. Cyclooxygenase 2 (COX-2), a mediator of inflammation, is also upregulated in parts of the stomach of the K-ras activated mice with concomitant infiltration of hematopoietic cells in the hyperplastic tissue. Moreover, in K-ras activated mice, the expression of putative progenitor cell marker Dcamkl1 is upregulated in the glandular stomach. Expression of CD44, a candidate stomach cancer stem cell marker, is also increased in forestomach and the glandular stomach. These results suggest that cells of the stomach...

‣ Caveolin-1 is a novel regulator of K-RAS-dependent migration in colon carcinogenesis

Basu Roy, Upal K.; Henkhaus, Rebecca S.; Loupakis, Fotios; Cremolini, Chiara; Gerner, Eugene W.; Ignatenko, Natalia A.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
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Caveolin-1 is an essential component of membrane caveolae. It is an important regulator of cellular processes such as signal transduction and endocytosis. We report here, for the first time, that caveolin-1 is a target of the K-RAS oncogene in colon carcinogenesis. Caveolin-1 is induced in colon cancer cells and in human colon tumor samples, in response to K-RAS activating mutations. An activated K-RAS oncogene transcriptionally induces caveolin-1 expression in human colon cancer cells and this effect is not restricted to the type of activating K-RAS mutation. Inhibition of the P-I3 Kinase-AKT pathway, but not the ERK MAPK pathway, both important K-RAS effectors, leads to a decrease in caveolin-1 expression indicating that the AKT pathway is involved in caveolin-1 expression in response to an activated K-RAS. Increased AKT signaling induces caveolin-1 expression by increasing the activity of the transcription factor, Sp1. Interestingly; caveolin-1 depletion alters K-RAS-dependent signaling by decreasing Grb2-SOS activity. Consistent with these finding, caveolin-1-depleted cells shows decreased migration in vitro. However, caveolin-1 over-expression by itself does not increase migration whereas an activated Src can increase migration in a caveolin-1-dependent manner. This increased migration is highly dependent on the RhoA GTPase...

‣ Wild-type K-ras has a tumour suppressor effect on carcinogen-induced murine colorectal adenoma formation

Luo, Feijun; Poulogiannis, George; Ye, Hongtao; Hamoudi, Rifat; Dong, Gehong; Zhang, Wenyan; Ibrahim, Ashraf E K; Arends, Mark J
Fonte: Blackwell publishing Ltd Publicador: Blackwell publishing Ltd
Tipo: Artigo de Revista Científica
Português
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K-ras mutations are found in ∼40% of human colorectal adenomas and carcinomas and contribute to colorectal tumour formation at an early stage. Wild-type K-ras has been reported to be deleted in some tumours, but the consequences of changes in wild-type K-ras copy number for experimental colorectal carcinogenesis have not been investigated. To characterize the effects of K-ras copy number changes on formation of carcinogen-induced colorectal neoplasms in mice, wild-type (K-ras+/+) and heterozygous K-ras exon 1 knockout (K-ras+/−) mice were given 10 weekly treatments of 1, 2-dimethylhydrazine (DMH) to induce colorectal tumours. Colorectal expression levels of K-ras 4A and 4B transcripts in K-ras+/− mice were ∼50% decreased compared with K-ras+/+ mice. One year after DMH treatment, survival of K-ras+/− mice decreased from 88 to 82% compared with wild-type mice. Colorectal adenomas significantly increased from 0.52 ± 0.15 in K-ras+/+ mice to 0.87 ± 0.14 in K-ras+/− mice (mean ± SEM per mouse, P < 0.01); total tumour volume increased 2.13-fold (P < 0.05). Comparing K-ras+/+ with K-ras+/− murine adenomas, Ki-67-positive proliferating tumour cells significantly increased from 7.77 ± 0.64% to 9.15 ± 0.92% and cleaved caspase-3-positive apoptotic tumour cells decreased from 1.40 ± 0.37% to 0.80 ± 0.22% (mean ± SEM...

‣ Translation-Dependent Mechanisms Lead to PML Upregulation and Mediate Oncogenic K-RAS-Induced Cellular Senescence

Scaglioni, Pier Paolo; Rabellino, Andrea; Bernardi, Rosa; Choi, Sooyeon; Konstantinidou, Georgia; Nardella, Caterina; Cheng, Ke; Pandolfi, Pier Paolo; Yung, Thomas M.
Fonte: Wiley Publicador: Wiley
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
67.482944%
Expression of oncogenic K-RAS in primary cells elicits oncogene-induced cellular senescence (OIS), a form of growth arrest that potently opposes tumourigenesis. This effect has been largely attributed to transcriptional mechanisms that depend on the p53 tumour suppressor protein. The PML tumour suppressor was initially identified as a component of the (PML-RARalpha) oncoprotein of acute promyelocytic leukaemia (APL). PML, a critical OIS mediator, is upregulated by oncogenic K-RAS in vivo and in vitro. We demonstrate here that oncogenic K-RAS induces PML protein upregulation by activating the RAS/MEK1/mTOR/eIF4E pathway even in the absence of p53. Under these circumstances, PML mRNA is selectively associated to polysomes. Importantly, we find that the PML 5′ untranslated mRNA region plays a key role in mediating PML protein upregulation and that its presence is essential for an efficient OIS response. These findings demonstrate that upregulation of PML translation plays a central role in oncogenic K-RAS-induced OIS. Thus, selective translation initiation plays a critical role in tumour suppression with important therapeutic implications for the treatment of solid tumours and APL.

‣ Rôles de K-RAS et de ERCC1 dans le traitement des carcinomes épidermoïdes avancés de la tête et du cou traités par chimioradiothérapie concomitante

Abboud, Olivier-Michel
Fonte: Université de Montréal Publicador: Université de Montréal
Tipo: Thèse ou Mémoire numérique / Electronic Thesis or Dissertation
Português
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67.68747%
Introduction: Les mutations du gène RAS sont présentes dans plusieurs types de cancers et ont une influence sur la réponse à la chimiothérapie. Excision repair cross- complementation group 1 (ERCC1) est un gène impliqué dans la réparation de l’acide désoxyribonucléique (ADN), et son polymorphisme au codon 118 est également associé à la réponse au traitement. Le peu d’études pronostiques portant sur ces deux gènes dans les cancers oto-rhino-laryngologiques (ORL) ne permet de tirer des conclusions claires. Objectifs: Déterminer l’influence des mutations de K-RAS codons 12 et 13 et du polymorphisme de ERCC1 codon 118 dans le traitement des cancers épidermoïdes avancés tête et cou traités par chimioradiothérapie concomitante à base de sels de platine. Méthode: Extraction de l’ADN provenant de spécimens de biopsie de patients traités par chimioradiothérapie concomitante pour des cancers avancés tête et cou, et ayant un suivi prospectif d’au moins deux ans. Identification des mutations de K-RAS codons 12 et 13 et du polymorphisme de ERCC1 au codon 118 dans les spécimens et corrélation de ces marqueurs avec la réponse au traitement. Résultats: Les mutations de K-RAS codon 12 sont associées à un moins bon contrôle loco-régional par rapport aux tumeurs ne démontrant pas la mutation (32% vs 83% p=0.03)...

‣ K-ras mutations and benefit from cetuximab in advanced colorectal cancer

Karapetis, C.; Khambata-Ford, S.; Jonker, D.; O'Callaghan, C.; Tu, D.; Tebbutt, N.; Simes, R.; Chalchal, H.; Shapiro, J.; Robitaille, S.; Price, T.; Shepherd, L.; Au, H.J.; Langer, C.; Moore, M.; Zalcberg, J.
Fonte: Massachusetts Medical Soc Publicador: Massachusetts Medical Soc
Tipo: Artigo de Revista Científica
Publicado em //2008 Português
Relevância na Pesquisa
57.692935%
Background: Treatment with cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor, improves overall and progression-free survival and preserves the quality of life in patients with colorectal cancer that has not responded to chemotherapy. The mutation status of the K-ras gene in the tumor may affect the response to cetuximab and have treatment-independent prognostic value. Methods: We analyzed tumor samples, obtained from 394 of 572 patients (68.9%) with colorectal cancer who were randomly assigned to receive cetuximab plus best supportive care or best supportive care alone, to look for activating mutations in exon 2 of the K-ras gene. We assessed whether the mutation status of the K-ras gene was associated with survival in the cetuximab and supportive-care groups. Results: Of the tumors evaluated for K-ras mutations, 42.3% had at least one mutation in exon 2 of the gene. The effectiveness of cetuximab was significantly associated with K-ras mutation status (P=0.01 and P<0.001 for the interaction of K-ras mutation status with overall survival and progression-free survival, respectively). In patients with wild-type K-ras tumors, treatment with cetuximab as compared with supportive care alone significantly improved overall survival (median...

‣ Il ripristino della via di segnale del TGF-b si associa ad una riduzione del potenziale metastatico delle cellule di tiroide trasformate dall’oncogene K-ras

NICOLUSSI, ARIANNA
Fonte: La Sapienza Universidade de Roma Publicador: La Sapienza Universidade de Roma
Tipo: Tese de Doutorado
Português
Relevância na Pesquisa
67.44076%
Il Trasforming Growth Factor-beta1 (TGF-b1) è una citochina multifunzionale in grado di controllare, attraverso il legame ai suoi recettori, numerosi processi cellulari come la proliferazione, la differenziazione, la plasticità, lo sviluppo, l’embriogenesi, l’adesività, la motilità e l’apoptosi. Abbiamo precedentemente dimostrato che le cellule di tiroide di ratto trasformate dall’oncogene K-ras, K10, sono resistenti all’azione inibitoria della crescita del TGF-b1, visto che mostrano una diminuita espressione del recettore di tipo II (TbRII) e che i cloni ottenuti transfettando il TbRII, revertono parzialmente il loro fenotipo maligno riducendo in maniera statisticamente significativa la crescita ancoraggio-dipendente e indipendente e la loro tumorigenicità (numero di metastasi artificiali e spontanee) rispetto alle cellule parentali altamente maligne, quando trapiantate in topi nudi atimici. Lo scopo di questo lavoro è di chiarire gli eventi molecolari coinvolti in questa modulazione del potenziale tumorigenico delle cellule di tiroide di ratto trasformate dall’oncogene K-ras over-esprimenti il TbRII. Il nostro lavoro dimostra che il TbRII iperespresso nelle cellule di tiroide di ratto trasformate da K-ras è un recettore funzionale...

‣ Influències clíniques i ambientals en la prevalença de mutacions en l'oncogèn K-ras en pacients amb adenocarcinoma ductal de pàncrees

Crous Bou, Marta
Fonte: Bellaterra : Universitat Autònoma de Barcelona, Publicador: Bellaterra : Universitat Autònoma de Barcelona,
Tipo: Tesis i dissertacions electròniques; info:eu-repo/semantics/doctoralThesis Formato: application/pdf
Publicado em //2009 Português
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Descripció del recurs: 27 gener 2010; Antecedents La prevenció primària de l'adenocarcinoma ductal de pàncrees (ADP) està limitada per la falta de coneixement sobre la seva etiologia. El factor de risc més ben establert és el consum de tabac, però explica només una petita proporció de casos. Es discuteix el paper d'altres factors etiològics com els antecedents patològics de diabetis i pancreatitis, la dieta, determinades exposicions ambientals o laborals, i els factors hereditaris. Mutacions puntuals en l'oncogèn K-ras, i la seva conseqüent activació, són presents en més del 80% dels casos d'ADP; és un dels esdeveniments genètics fonamentals perquè el càncer tingui lloc. L'activació d'aquest oncogèn dóna lloc a gran varietat de respostes, des de l'augment de la proliferació cel·lular fins a la inhibició de l'apoptosi, en funció del context cel·lular. Els gens Ras són dianes crítiques per als carcinògens químics; els càncers de pàncrees amb i sense mutacions en l'oncogèn K-ras probablement es desenvolupen a partir de diferents interaccions gen-ambient. Tot i això, els estils de vida i les exposicions ambientals que poden influir en la presència de mutacions en el gen K-ras són pràcticament desconeguts. L'objectiu general d'aquesta tesi és estudiar la relació entre la prevalença de mutacions en el codó 12 de l'oncogèn K-ras i diferents factors ambientals (consum de tabac i alcohol)...

‣ Significació pronòstica de l'estatus mutacional del gen K-RAS en càncer de còlon. Estudi retrospectiu.

Surrallés Calonge, M.Lluïsa; Surrallés Calonge, Jordi
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
Relevância na Pesquisa
57.828047%
El càncer colorectal és el tipus de neoplàsia més comuna en els països desenvolupats i representa la segona causa de mort per càncer. Per tant, el coneixement de les bases moleculars implicades en la carcinogènesi poden facilitar el diagnòstic i el tractament del càncer. Un dels gens implicats en les bases moleculars del càncer de còlon és el proto-oncogèn K-RAS. El gen K-RAS es localitza en el cromosoma 12 i codifica per la proteïna K-RAS. El proto-oncogèn K-RAS s'activa específicament per mutacions puntuals en el codó12 (aproximadament el 82% de totes les mutacions) i el codó13 (aproximadament el 17%) de l'exó 2 del gen K-RAS. S'han descrit altres mutacions en el codó 61 i 146, representant aproximadament entre 1-4 %. En el càncer colorectal aquestes alteracions es presenten en aproximadament el 40% dels casos. Aquestes mutacions provoquen canvis en l'activitat GTPasa i ocasionen acumulació de la proteïna RAS en el seu estat actiu (unida a GTP). La proteïna mutada altera les vies de trasducció de senyals mitogèniques produint-se l'estimulació del creixement cel·lular i l'expansió clonal. L'estadiatge del càncer colorectal es basa en una sèrie de criteris clinicopatològics que es tenen en compte per l'elecció del tractament al qual es sotmetrà el pacient. Pels tractaments actuals es necessita conèixer les bases biològiques i moleculars dels tumors per poder oferir el tractament més correcte...

‣ Fenotips tumorals induïts per mutació puntual al codó 12 o 13 del gen k-ras humà

Guerrero Caballero, Sílvia
Fonte: Bellaterra : Universitat Autònoma de Barcelona, Publicador: Bellaterra : Universitat Autònoma de Barcelona,
Tipo: Tesis i dissertacions electròniques; info:eu-repo/semantics/doctoralThesis Formato: application/pdf
Publicado em //2003 Português
Relevância na Pesquisa
57.810127%
Consultable des del TDX; Títol obtingut de la portada digitalitzada; El gen K-ras, és molt important clínicament ja que es troba mutat en un 40% dels casos de carcinomes colorectals i en un 90% dels casos de carcinomes de pàncreas, que constitueixen la segona i quarta causa de mort per càncer en països desenvolupats i juga un paper important en el desenvolupament dels sarcomes. Degut a la importància clínica del gen K-ras, un model que millori el seu coneixement en l'àmbit molecular, ajudarà a predir el comportament biològic del tumor abans de decidir el tractament més adequat per un pacient concret. Aquests coneixements, poden portar a una millora substancial des del punt de vista terapèutic. Les mutacions activants de l'oncogen K-ras, s'han localitzat al codó 12 o 13 del mateix. Prèviament, s'ha associat la presència de mutacions al codó 13 amb un fenotip tumoral menys agressiu que quan aquestes es localitzen al codó 12. Concretament, la mutació al codó 13 s'associa amb menor capacitat invasiva local i metastàsica. L'objectiu d'aquesta tesi es trobar una explicació molecular al diferent comportament clínic descrit amb anterioritat en tumors humans segons si la mutació activant es troba al codó 12 o al codó 13 del gen K-ras. També es preten trobar una explicació molecular a la transformació produïda pel gen normal sobrexpressat...

‣ Mutación del gen K-ras en el cáncer de la vesícula biliar

Roa S,Juan Carlos; Roa E,Iván; Aretxabala U,Xabier de; Melo A,Angélica; Faría O,Gaspar; Tapia E,Oscar
Fonte: Sociedad Médica de Santiago Publicador: Sociedad Médica de Santiago
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/08/2004 Português
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Background: Different K-ras mutation frequencies in gallbladder cancer have been reported. Aim: To study the frequency of K-ras gene mutations in advanced gallbladder carcinoma not associated to anomalous junction of pancreatic-biliary duct (AJPBD). Material and methods: 33 formalin fixed paraffin embedded samples of gallbladder carcinoma (30 women, age range 32-86 years) were selected. Pancreatic cancer tissue with K-ras mutations was used as control. DNA was extracted from the histological section by mean of microdissection and K-ras mutations in codon 12 were detected by polymerase chain reaction and restriction fragment length polymorphism (RFLP), using previously reported technique. Results: Most cases were poorly differentiated adenocarcinomas. K-ras mutation was detected in 10 cases (30%) samples. No differences in K-ras mutation frequency between subserous and serous tumors were detected and no relation between histological features and the mutation was observed. Conclusions: K-ras mutation in codon 12 is present in 30% in our advanced gallbladder carcinomas. The study of K-ras mutation in preneoplastic lesions and early carcinomas will be important to determine the role of this gene in the gallbladder carcinogenesis in Chile (Rev Méd Chile 2004; 132: 955-60)

‣ Antisense gene therapy using anti-k-ras and antitelomerase oligonucleotides in colorectal cancer

Lledó,S.; Alfonso,R.; Aliño,S. F.
Fonte: Revista Española de Enfermedades Digestivas Publicador: Revista Española de Enfermedades Digestivas
Tipo: info:eu-repo/semantics/article; journal article; info:eu-repo/semantics/publishedVersion Formato: text/html; application/pdf
Publicado em 01/07/2005 Português
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Aim: to test the efficacy of anti-k-ras and antitelomerase oligonucleotides for disabling colorectal cancer cell growth. Material and methods: an established human colorectal cancer cell line (SW 480, ATTC®) was used. Oligodeoxiribonucleotides (ODNs) have a phosphorotioate modification to ensure intracellular intake. We used an antitelomerase ODN (Telp5) and two anti-k-ras ODNs (AS-KRAS and ISIS). AS-KRAS is designed to join the k-ras oncogene's exon 1. ISIS links to the terminal transcription unit 5' of k-ras. Telp5 joins the template region of the hTR telomerase subunit. ODNs have been tested in different concentrations (1, 5, 10, 20 micromolar). Cell viability has been tested at 48 and 72 hours. Statistical analysis and graphic design were made with the statistical package "Analyzing Data with GraphPad Prism-1999", GraphPad Sofware Inc., San Diego CA©. We used the Student's t test for statistical analysis. Results: the lowest dose (1 µM) was not effective. Using the highest dose (20 mM for 48 hours) of combined AS-KRAS and Telp5 cell viability decreased to 99.67%. The rest of results varied depending on ODN type, dose, and exposure time. Conclusions: tested antisense ODNs stop colorectal cancer cell growth, and a combination of anti-telomerase and anti-k-ras is the most useful treatment. Efficacy is best with a higher dose and longer treatment period.

‣ Evaluación de las mutaciones del oncogen K-ras 12 en pacientes venezolanos infectados con Helicobacter pylori

Mastromatteo,Patrizzia; Correnti,María; Cavazza,María Eugenia; Perrone,Marianella; Tombazzi,Claudio; Lecuna,Víctor
Fonte: Universidad del Zulia Publicador: Universidad del Zulia
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/12/2005 Português
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En el presente trabajo se evaluó la presencia de mutaciones del gen K-ras 12 en pacientes infectados con H. pylori y su asociación con distintas patologías de las vías gastroduodenales superiores. Se estudiaron 62 pacientes a quienes se les practicó endoscopia digestiva superior, tomando 3 biopsias utilizadas para el estudio histológico, pruebas de biología molecular y la determinación de mutaciones puntuales del gen K-ras 12. Los resultados mostraron una alta incidencia de la infección por H. pylori en pacientes con gastritis crónica activa (GCAc) (90%), gastritis crónica atrófica (GCAt) (70%), metaplasia intestinal (MI) (67%), cambios displásicos (CD) (83%), disminuyendo en cáncer gástrico (CG) (33%). En la evaluación de las mutaciones del oncogen K-ras 12 se observó que 68% de los pacientes presentaron mutaciones en los diferentes aminoácidos analizados. En el codon 12 del gen K-ras, se detectaron mutaciones puntuales simples y combinadas en la misma muestra proveniente de diferentes patologías gástricas, registrándose en los casos de gastritis crónica activa (GCAc) el mayor número de mutaciones, disminuyendo a medida que progresan las etapas de diferenciación histológica hacia cáncer gástrico. Los resultados indicarían que existen mutaciones específicas que pudieran emplearse como marcadores moleculares de malignidad y el eventual desarrollo de cáncer gástrico

‣ Frecuencia y asociación clínicopatológico de las mutaciones del oncogen K-ras en pacientes venezolanos con cáncer colorectal

Estrada,Pedro; Rojas-Atencio,Alicia; Zabala,William; Borjas,Lisbeth; Soca,Lazaro; Urdaneta,Karelis; Alvarez-Nava,Francisco; Cañizales,Jenny; Rojas,Janeth; Soto,Marisol
Fonte: Universidad del Zulia Publicador: Universidad del Zulia
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/03/2009 Português
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Las mutaciones en el oncogén K-ras son comunes en cáncer colo-rectal, afectan el comportamiento biológico y podrían influir en la susceptibilidad terapéutica en estos tumores. El objetivo de este trabajo fue identificar los tipos de mutación K-ras observados en pacientes referidos con cáncer colo-rectal y relacionarlos con el grado de diferenciación histológica y con el estadio clínico. Se obtuvo ADN genómico tanto de tejido tumoral incluido en parafina, como de tejido fresco. Se amplificó el gen K-ras a través de la reacción en cadena de la polimerasa (RCP) y se digirieron los fragmentos amplificados con enzimas de restricción, por último se obtuvieron datos clínicos e histopatológicos de las historias clínicas. Se encontraron mutaciones en los codones 12 y 13 del oncogén K-ras en el 23,33% de los pacientes. De estos 28,57% en el codón 12, en el codón 13 se encontró un 57,14% y 14,29% para ambos codones. Fueron más frecuentes en el hemicolon izquierdo con 78,57% y según la clasificación histológica en los adenocarcinomas bien diferenciados (58,70%) y en los mucinosos (28,57%). Las mutaciones identificadas fueron mas frecuentes en estadios avanzados C2 de la clasificación de Dukes`. El análisis molecular del oncogén K-ras permitió evidenciar mutaciones que sirven como parámetro diagnóstico y pronóstico en los tumores colo-rectales. La frecuencia de mutaciones encontradas en este trabajo es similar a algunas de las reportadas a nivel mundial...