Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 178
Filter
1.
Article in English | WPRIM | ID: wpr-928605

ABSTRACT

OBJECTIVES@#To investigate the mutation rate of the RAS gene and its clinical significance in children with acute lymphoblastic leukemia.@*METHODS@#A retrospective analysis was performed on the medical data of 120 children with newly diagnosed acute lymphoblastic leukemia, who were admitted to the Third Affiliated Hospital of Zhengzhou University from January 2015 to January 2020 and underwent next-generation sequencing. The clinical and molecular features were analyzed. The impact of RAS gene mutation on the overall survival rate was evaluated in these children.@*RESULTS@#Among the 120 children, 35 (29.2%) had RAS gene mutation, 30 (25.0%) had KRAS gene mutation, and 5 (4.2%) had both NRAS and KRAS gene mutations. All NRAS mutations and 71% (25/35) of KRAS mutations were located at the 12th and 13th codons. RAS gene mutation was detected in 35 (33.3%) out of 105 children with B-lineage acute lymphoblastic leukemia, but it was not detected in those with acute T lymphocyte leukemia. Of all the children, 11 (9.2%) were lost to follow-up, and among the 109 children followed up, 16 (14.7%) died. The children with RAS gene mutation had a significantly lower 2-year overall survival rate than those without RAS gene mutation (P<0.05). The prognosis of children with RAS gene mutation combined with WT1 overexpression and WBC>50×109/L at diagnosis was worse (P<0.05).@*CONCLUSIONS@#RAS gene mutation is commonly observed in children with B-lineage acute lymphoblastic leukemia and may have an adverse effect on prognosis.


Subject(s)
Child , Genes, ras , Humans , Mutation , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Prognosis , Retrospective Studies
2.
Article in English | WPRIM | ID: wpr-879949

ABSTRACT

The gene is frequently mutated and abnormally activated in many cancers,and plays an important role in cancer development. Metabolic reprogramming occurs in malignant tumors,which can be one of the key targets for anti-tumor therapy. gene can regulate lipid metabolism through AKT-mTORC1 single axis or multiple pathways,such as lipid synthesis pathways and degradation pathways. Similarly,lipid metabolism can also modify and activate RAS protein and its downstream signaling pathways. This article overviews the current research progress on the interaction between lipid metabolism and ,to provide insight in therapeutic strategies of lipid metabolism for -driven tumors.


Subject(s)
Genes, ras , Humans , Lipid Metabolism/genetics , Neoplasms/genetics , Signal Transduction , ras Proteins/metabolism
3.
Article in Chinese | WPRIM | ID: wpr-879489

ABSTRACT

RASopathies are a group of disorders caused by germline variants of genes involved in RAS/MAPK pathway with overlapping features which may complicate their diagnosis. Since almost all RASopathies are autosomal dominant inherited disorders, the affected families may give birth to multiple children with the disease. Owning to the advance in sequencing technology, the genotype-phenotype correlation of RASopathies has become clearer in recent years, and genetic testing is now available in many places, which make prenatal diagnosis for couples with increased risk possible. For de novo variants of RASopathies, prenatal diagnosis is still difficult as the findings in routine ultrasonography are not specific enough. Nevertheless, certain findings may still be used as clues for prenatal diagnosis. This article overviews the common disorders of RASopathies, with an emphasis on the features that can be used as clues for the prenatal diagnosis of RASopathies.


Subject(s)
Female , Genes, ras , Humans , MAP Kinase Signaling System/genetics , Pregnancy , Prenatal Diagnosis
4.
Article in English | WPRIM | ID: wpr-786127

ABSTRACT

BACKGROUND: In the present multi-institutional study, the prevalence and clinicopathologic characteristics of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) were evaluated among Korean patients who underwent thyroidectomy for papillary thyroid carcinoma (PTC).METHODS: Data from 18,819 patients with PTC from eight university hospitals between January 2012 and February 2018 were retrospectively evaluated. Pathology reports of all PTCs and slides of potential NIFTP cases were reviewed. The strict criterion of no papillae was applied for the diagnosis of NIFTP. Due to assumptions regarding misclassification of NIFTP as non-PTC tumors, the lower boundary of NIFTP prevalence among PTCs was estimated. Mutational analysis for BRAF and three RAS isoforms was performed in 27 randomly selected NIFTP cases.RESULTS: The prevalence of NIFTP was 1.3% (238/18,819) of all PTCs when the same histologic criteria were applied for NIFTP regardless of the tumor size but decreased to 0.8% (152/18,819) when tumors ≥1 cm in size were included. The mean follow-up was 37.7 months and no patient with NIFTP had evidence of lymph node metastasis, distant metastasis, or disease recurrence during the follow-up period. A difference in prevalence of NIFTP before and after NIFTP introduction was not observed. BRAF(V600E) mutation was not found in NIFTP. The mutation rate for the three RAS genes was 55.6% (15/27).CONCLUSIONS: The low prevalence and indolent clinical outcome of NIFTP in Korea was confirmed using the largest number of cases to date. The introduction of NIFTP may have a small overall impact in Korean practice.


Subject(s)
Carcinoma, Papillary , Diagnosis , Follow-Up Studies , Genes, ras , Hospitals, University , Humans , Korea , Lymph Nodes , Mutation Rate , Neoplasm Metastasis , Pathology , Prevalence , Protein Isoforms , Recurrence , Retrospective Studies , Thyroid Gland , Thyroid Neoplasms , Thyroidectomy
5.
São Paulo; s.n; s.n; 2018. 133 p. graf, tab.
Thesis in Portuguese | LILACS | ID: biblio-999085

ABSTRACT

As alterações genéticas mais frequentes em câncer de pulmão são mutações pontuais que ativam o oncogene KRAS. Embora estas mutações estejam causalmente relacionadas à oncogênese, até hoje diferentes abordagens para inibir as proteínas RAS diretamente não obtiveram sucesso. Portanto, para que melhores alvos terapêuticos para o câncer de pulmão se tornem disponíveis é necessário identificar os mecanismos moleculares ativados por KRAS que estão diretamente envolvidos com a aquisição de propriedades malignas importantes, como o desenvolvimento e a manutenção de um fenótipo tronco-tumoral pelas células iniciadoras de tumor (CITs). CITs, também conhecidas como células tronco-tumorais, são definidas como uma subpopulação de células tumorais capazes de se autorrenovar, iniciar a formação de tumores e sustentar o crescimento tumoral. O desenvolvimento de estratégias terapêuticas dirigidas a estas células é imprescindível para melhorar a eficácia da terapia antitumoral. Uma vez que KRAS está associada a manutenção de um fenótipo tronco-tumoral e ativa o fator de transcrição NF-kB através da quinase IKKß para promover a tumorigênese pulmonar, nós hipotetizamos que a quinase IKKß contribui para o fenótipo tronco-tumoral induzido por KRAS em câncer de pulmão. Nós utilizamos ensaios de formação de tumoresferas para enriquecer e avaliar a função de CITs das linhagens pulmonares positivas para KRAS A549 e H358. As células A549 e H358 formaram tumoresferas em cultura de baixa aderência e, quando comparadas às células derivadas da cultura aderente, as células oriundas da cultura de tumoresferas apresentaram maior crescimento clonogênico, maior expressão de genes associados ao fenótipo tronco por qPCR e maior atividade da quinase IKKß. A inibição da atividade de IKKß através de um inibidor farmacológico altamente específico (Composto A) diminuiu levemente a proliferação de células A549 e H358, sem resultar em morte celular significativa. Entretanto, a inibição da atividade ou da expressão de IKKß por interferência de RNA reduziu a expressão de genes associados ao fenótipo tronco e diminuiu a formação de tumoresferas. A inibição da expressão de IKKß em células A549 reduziu também a capacidade de autorrenovação de CITs. Estes resultados sugerem que IKKß desempenha um papel importante na manutenção do fenótipo tronco-tumoral de CITs pulmonares induzidas por KRAS. Em seguida, nós demonstramos que a inibição da atividade de IKKß afetou preferencialmente a proliferação celular e o crescimento clonogênico de células oriundas da cultura de tumoresfera, sugerindo que IKKß desempenha um papel mais importante em CITs do que em células derivadas da cultura aderente. A análise por citometria de fluxo identificou que células derivadas da cultura de tumoresfera apresentam um enriquecimento para células CD24+ na linhagem A549 e células CD44+ na linhagem H358, sugerindo que estes possam ser marcadores promissores para purificação de CITs nestas linhagens. Adicionalmente, demonstramos, por ensaios de wound-healing de células A549 e H358, que a inibição da atividade de IKKß reduziu a migração celular, uma outra uma propriedade aumentada em CITs. Além disso, mostramos que a atividade da quinase IKKß em células A549 e H358 não depende das vias da MAPK ou PI3K/Akt. Interessantemente, a inibição combinada de IKK (um efetor downstream de KRAS) e de EGFR/ERRB2 (reguladores upstream de KRAS que ativam as vias MAPK e PI3K/Akt) reduziu de forma aditiva a formação de tumoresferas, proliferação e migração celular. Quando avaliados em conjunto, nossos resultados sugerem que a quinase IKKß desempenha um papel importante na biologia de CITs pulmonares portadoras de KRAS oncogênica e que a inibição desta quinase sozinha ou em combinação com a inibição de outras vias pode representar uma estratégia terapêutica promissora a ser explorada para reduzir a recidiva e metástase no câncer de pulmão induzido por KRAS


The most frequent genetic alterations in lung cancer are point mutations that activate the KRAS oncogene. Although these mutations are causally related to oncogenesis, different approaches to inhibit RAS proteins directly have not been successful to date. Therefore, for better therapeutic targets for lung cancer to become available, it is necessary to identify the molecular mechanisms activated by KRAS that are directly involved with important malignant features, such as the development and maintenance of a cancer stem-like phenotype by the tumour-initiating cells (TICs). TICs, also known as cancer stem cells, are defined as a subpopulation of tumour cells able to self-renew, promote tumour initiation, and sustain tumour growth. The development of therapeutic strategies to target these cells is imperative to improve the efficacy of antitumor therapy. Since KRAS is associated with the maintenance of a cancer stem-like phenotype and activates the transcription factor NF-kB through the IKKß kinase to promote lung tumourigenesis, we hypothesised that IKKß kinase contributes to the cancer stem-like phenotype induced by KRAS in lung cancer. We used tumoursphere formation assays to enrich and evaluate the function of TICs of KRAS-mutant cell lines A549 and H358. A549 and H358 cells formed tumourspheres in low adhesion culture and, when compared to cells grown in adherent culture, sphere-derived cells displayed increased clonogenic growth, higher expression of stemness genes by qPCR, and increased IKKß kinase activity . Inhibition of IKKß activity through a highly specific pharmacological inhibitor (Compound A) slightly decreased proliferation of A549 and H358 cells without inducing significant cell death. On the other hand, inhibition of IKKß activity or expression by RNA interference reduced the expression of stemness genes and decreased tumoursphere formation. Inhibition of IKKß expression in A549 cells also reduced TICs self-renewal . These results suggest that IKKß plays an important role in maintaining the cancer stem-like phenotype of KRAS-driven lung TICs. Next, we demonstrated that IKKß inhibition preferentially reduced cell proliferation and clonogenic growth of sphere-derived cells, suggesting that IKKß plays a more important role in TICs than in adherent culture-derived cells. Flow cytometry analysis identified that sphere-derived cells display an enrichment for the surface marker CD24 in A549 cells and CD44 in H358 cells, indicating that these could be promising markers for the purification of TICs in these cell lines. Furthermore, we have shown by wound-healing assays of A549 and H358 cells that IKKß inhibition reduced cell migration , another feature increased in TICs. In addition, we have shown that IKKß activity in A549 and H358 cells does not depend on the MAPK or PI3K/Akt pathways. Interestingly, combined inhibition of IKKß (a downstream effector of KRAS) and EGFR/ERBB2 (upstream regulators of KRAS that activate the MAPK and PI3K/Akt pathways) additively reduced tumoursphere formation, cell proliferation and migration. Taken together, our results suggest that IKKß kinase plays an important role in the biology of KRAS-driven lung TICs, and that inhibition of this kinase alone or in combination with inhibition of other signalling pathways may represent a promising therapeutic strategy to be explored in order to reduce tumour recurrence and metastasis in KRAS-driven lung cancer


Subject(s)
Genes, ras , I-kappa B Kinase/analysis , Lung Neoplasms/diagnosis , Lung Neoplasms/drug therapy
6.
São Paulo; s.n; s.n; 2018. 165 p. ilus, tab, graf.
Thesis in Portuguese | LILACS | ID: biblio-911612

ABSTRACT

O FGF2 (Fibroblast Growth Factor 2) é um clássico fator peptídico de crescimento que ativa vias intracelulares de sinalização molecular promovendo a transição G0 → G1 e o comprometimento com o ciclo celular. Não surpreendentemente, seus papéis pró-tumoral e angiogênico estão bem caracterizados e estabelecidos na literatura. No entanto, um crescente corpo de evidências tem indicado que o FGF2 também pode exercer efeitos anti-tumorais in vitro e in vivo, em modelos murinos e também humanos. Neste contexto, nosso grupo publicou em 2008 que o FGF2 exerce um efeito antiproliferativo seletivo em células murinas malignas dependentes de alta atividade de K-Ras e H-Ras. Os genes ras compõem a família de oncogenes mais frequentemente mutada em tumores malignos humanos, alcançando aproximadamente 30% de todos os casos. O desenvolvimento de terapias contra tumores dependentes de Ras fracassou, apesar dos intensos esforços e investimentos desde a descoberta em 1982 de suas mutações ativadoras em múltiplos cânceres. O objetivo deste trabalho foi desvendar os mecanismos moleculares pelo quais o FGF2 inibe irreversivelmente a proliferação de células malignas dependentes da atividade de Ras, empregando como modelos experimentais a linhagem murina Y1 de células adrenocorticais, e 4 linhagens humanas derivadas de sarcomas de Ewing. Identificamos que o efeito citotóxico do FGF2 não se processa por um mecanismo novo e independente das viasproliferativas classicamente ativadas por fatores peptídicos de crescimento. Ao contrário, seu efeito tóxico é resultado de sinalização mitogênica exagerada decorrente de estimulação sustentada por FGF2. A ativação da via de MAPK, principal sinalização mitogênica intracelular, a níveis elevados e sustentados provoca estresse mitogênico, que se propaga para a fase S na forma de estresse replicativo. Nesta situação, a célula passa a depender exageradamente da sinalização protetora de ATR, de modo que a combinação de estimulação com FGF2 e inibição de ATR foi altamente letal para as células malignas dependentes de Ras empregadas neste trabalho. Também analisamos as bases moleculares de resistência a FGF2 exibida por células Y1 anteriormente selecionadas para resistir ao efeito tóxico do FGF2 (Y1FRs). Descobrimos que a pressão seletiva do FGF2 não teve efeito na expressão de seus receptores, mas provocou a eliminação de um dos dois cromossomos que portam a amplificação gênica de ras nesta linhagem, enquanto o segundo cromossomo foi mantido por ser a única fonte de genes ribossomais ativos. Suas cópias de ras, no entanto, mostraram-se transcricionalmente silenciadas. Além disso, as sublinhagens Y1FRs não expressam o principal RasGEF, GRP4, encontrado nas células parentais Y1, o que pode ter influenciado o surgimento do fenótipo resistente ao FGF2. As linhagens resistentes mostraram grande redução no número de cromossomos e aumento da frequência de fusões entre cromossomos não homólogos em relação às células parentais


FGF2 (Fibroblast Growth Factor 2) is a classic peptide growth factor that activates intracellular molecular signaling pathways promoting the G0 → G1 transition and cell cycle commitment. Not surprisingly, its pro-tumor and angiogenic roles are well characterized and established in the literature. However, a growing body of evidence has indicated that FGF2 may also exert anti-tumor effects in vitro and in vivo in murine and human models. In this context, our group reported in 2008 that FGF2 exerts a selective antiproliferative effect in murine cells dependent on high activity of K-Ras and H-Ras. Ras genes make up the most frequently mutated oncogene family in human malignant tumors, reaching approximately 30% of all cases. The development of therapies against Ras-dependent tumors has failed despite intense efforts and investments since the discovery in 1982 of its activating mutations in multiple cancers. The objective of this work was to uncover the molecular mechanisms by which FGF2 irreversibly inhibits the proliferation of malignant cells dependent on Ras activity, using as experimental models the Y1 murine lineage of adrenocortical malignant cells and 4 human lineages derived from Ewing sarcomas. We showed that the cytotoxic effect of FGF2 did not involve novel cell cycle regulatory pathways; instead, this cytotoxic effect is a result of sustainedhyper mitogenic stimulation by FGF2. Activation of the KRas/MAPK pathway, the major intracellular mitogenic signaling, at high and sustained levels provokes mitogenic stress, which is propagated to S phase as replicative stress. In this situation, the cell dependence on the ATR protective signaling is enhanced, so that the combination of stimulation with FGF2 and inhibition of ATR was highly lethal for the Ras dependent malignant cells employed in this work. We also analyzed the molecular basis of FGF2 resistance exhibited by Y1 cells previously selected for resistance to FGF2. We found that the selective pressure of FGF2 had no effect on the expression of its receptors but promoted the elimination of one of the two marker chromosomes that carry the K-ras amplified copies, while the second chromosome was maintained because it is the only source of active ribosomal genes; however, its K-ras amplified copies were transcriptionally silenced. In addition, the Y1FRs sublines did not express the main RasGEF, GRP4, found in the parental Y1 cells, which might have played a role in the emergence of the FGF2-resistant phenotype. The resistant Y1FRs sublines showed a large reduction in chromosome numbers and increased frequency of fusions between non-homologous chromosomes in relation to parental cells


Subject(s)
Fibroblast Growth Factor 2/analysis , Fibroblast Growth Factor 2/adverse effects , Genes, ras/genetics , Adrenocortical Carcinoma/classification , Molecular Mechanisms of Pharmacological Action , Synthetic Lethal Mutations
7.
Acta cir. bras ; 32(3): 243-250, Mar. 2017. tab, graf
Article in English | LILACS | ID: biblio-837691

ABSTRACT

Abstract Purpose: To evaluate the expression of EGFR, KRAS genes, microRNAs-21 and 203 in colon and rectal cancer samples, correlated with their age at diagnosis, histological subtype, value of pretreatment CEA, TNM staging and clinical outcome. Methods: Expression of genes and microRNAs by real time PCR in tumor and non-tumor samples obtained from surgical treatment of 50 patients. Results: An increased expression of microRNAs-21 and 203 in tumor samples in relation to non-tumor samples was found. There was no statistically significant difference between the expression of these genes and microRNAs when compared to age at diagnosis and histological subtype. The EGFR gene showed higher expression in relation to the value of CEA diagnosis. The expression of microRNA-203 was progressively lower in relation to the TNM staging and was higher in the patient group in clinical remission. Conclusions: The therapy of colon and rectum tumors based on microRNAs remains under investigation reserving huge potential for future applications and clinical interventions in conjunction with existing therapies. We expect, based on the exposed data, to stimulate the development of new therapeutic possibilities, making the treatment of these tumors more effective.


Subject(s)
Humans , Male , Female , Middle Aged , Aged , Aged, 80 and over , Colorectal Neoplasms/genetics , Adenocarcinoma/genetics , Gene Expression , Proto-Oncogene Proteins p21(ras)/analysis , Genes, ras , Genes, erbB-1 , MicroRNAs/analysis , Colorectal Neoplasms/pathology , Colorectal Neoplasms/drug therapy , Adenocarcinoma/pathology , Adenocarcinoma/drug therapy , Carcinoembryonic Antigen/analysis , Biomarkers, Tumor/analysis , Prospective Studies , Age Factors , Treatment Outcome , Real-Time Polymerase Chain Reaction , Neoplasm Staging
8.
Article in English | WPRIM | ID: wpr-6996

ABSTRACT

PURPOSE: Cetuximab demonstrates improved efficacy outcomes in patients with metastatic colorectal cancer (mCRC) harboring wild-type KRAS exon 2. Resistance to cetuximab is mediated by activating less frequent mutations in the RAS genes beyond KRAS exon 2. We performed extended RAS Mutational analysis using a high-throughput genotyping platform (OncoMap) and evaluated extended RAS analysis for predicting cetuximab efficacy in patients harboring wild-type KRAS exon 2 tumors following Sanger sequencing. MATERIALS AND METHODS: Extended RAS analysis was performed on 227 wild-type KRAS exon 2 mCRC patients who received cetuximab as salvage treatment using OncoMap ver. 4.0. Targeted genes included exon 2, exon 3, and exon 4, both in KRAS and NRAS, and included BRAF exon 15. We assessed efficacy by the new RAS mutation status. RESULTS: The OncoMap detected 57 additional mutations (25.1%): 25 (11%) in KRAS exon 2 and 32 (14.1%) beyond KRAS exon 2. Survival differences were observed after dividing patients into the wild-type RAS group (n=170) and mutant RAS group (n=57) using OncoMap. Progression-free survival was 4.8 months versus 1.8 months (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.32 to 0.61), and overall survival was 11.9 months versus 8.4 months (HR, 0.65; 95% CI, 0.47 to 0.88). CONCLUSION: Sanger sequencing is not sufficient for selecting candidates for cetuximab treatment. High-throughput extended RAS genotyping is a feasible approach for this purpose and identifies patients who might benefit from cetuximab treatment.


Subject(s)
Cetuximab , Colorectal Neoplasms , Disease-Free Survival , Exons , Genes, ras , High-Throughput Nucleotide Sequencing , Humans , Salvage Therapy
9.
Article in Chinese | WPRIM | ID: wpr-323510

ABSTRACT

Serrated polyposis syndrome (SPS) is closely associated with the initiation and development of colorectal cancer (CRC), however, there is few research on SPS in China. Serrated polyps can be divided into hyperplastic polyps, sessile serrated polyps and traditional serrated polyps. The diagnosis standard of SPS is as following: (1) There are at least 5 serrated lesions in proximal colon, and diameter of more than 2 lesions is >10 mm; (2) The patient has one serrated polyp with family history of SPS; (3) More than 20 serrated polyps can be found in the entire large bowel. The risk of SPS is relatively high in the development of colorectal cancer and 25%-70% of the SPS patients is diagnosed with synchronous or metachronous colorectal cancer during following-up. The clinical characteristics of SPS include that patients are relatively old; no significant racial difference exists in the morbidity; patients have family history of colorectal cancer. The mutation of BRAF or KRAS gene, which induces colorectal cancer through the RAS-RAF-MAPK signaling pathway, is often found in SPS as well as CpG island methylation phenotype (CIMP) and microsatellite instability (MSI). The difference between SPS and traditional familial adenomatous polyposis (FAP) should be noted because of the different pathology mechanism, clinical characteristics and the risk of malignancy. Nowadays, the common technologies of detecting serrated polyps are auto-fluorescence imaging (AFI) and narrow-band imaging (NBI), whose detective rate is around 55%. The SPS patients are advised to undergo the resection of all the serrated polyps with diameter larger than 3-5 mm and receive the colonoscopy examination every 1 or 2 year. Not only the research about SPS is on the initiation step and the molecular mechanism is still unknown, but also the scholars do not come to achieve agreement about the risk of SPS in the malignancy of colorectal cancer, which is essential for further research therefore.


Subject(s)
Adenoma , Genetics , Pathology , Therapeutics , Adenomatous Polyposis Coli , Genetics , Pathology , Therapeutics , Colonic Polyps , Colonoscopy , Colorectal Neoplasms , Genetics , Pathology , Therapeutics , DNA Methylation , Genes, ras , Humans , Microsatellite Instability , Mutation , Phenotype , Proto-Oncogene Proteins B-raf , Syndrome
10.
Med. lab ; 22(9-10): 479-486, 2016. ilus
Article in Spanish | LILACS | ID: biblio-907821

ABSTRACT

Resumen: el síndrome cardio-facio-cutáneo es una entidad clínica y genéticamente heterogénea, perteneciente a un grupo de síndromes conocidos como RASopatías.Este trastorno es de baja prevalencia, con alrededor de 200 a 300 casos en el mundo, e incluye entre sus manifestaciones clínicas rasgos faciales dismórficos, defectos cardíacos y alteraciones cutáneas. Los hallazgos fenotípicos del síndrome cardio-facio-cutáneo que se comparten con otros síndromes y la ausencia de criteriosdiagnósticos o signos patognomónicos lo convierten en un reto diagnóstico. En este manuscrito se presenta un caso confirmado de síndrome cardio-facio-cutáneo por estudios de genética molecular en una paciente de siete años de edad, mediante el cual se exponen las principales características de esta condición.


Abstract: The cardio-facio-cutaneous syndrome is a clinically and genetically heterogeneous disorder, belonging to a group of syndromes known as RASopathies. This condition has a low prevalence, with around of 200 to 300 cases in the world, and includes dysmorphic facial features, heart defects, and skin abnormalities among its clinical manifestations. The phenotypic findings of cardio-facio-cutane1ous syndrome that are shares with other syndromes and the absence of diagnostic criteria or pathognomonic signs make it a diagnostic challenge. Here its present a confirmed case of cardio-facio-cutaneous syndrome by molecular genetic studies in one seven years old patient, through which are exposed the main characteristics of this condition.


Subject(s)
Humans , Cardiovascular Abnormalities , Genes, ras , ras Proteins , Syndrome
11.
Brasília; CONITEC; 2015. graf, ilus, tab.
Non-conventional in Portuguese | LILACS, BRISA | ID: biblio-875626

ABSTRACT

CONTEXTO: O câncer colorretal refere-se ao câncer que acomete o intestino grosso (cólon e reto). O Instituto Nacional de Câncer (INCA) estimou para 2014 a ocorrência de 32.600 novos casos de câncer colorretal (15.070 casos entre homens e 17.530 casos entre mulheres). O câncer colorretal é uma doença tratável e frequentemente curável quando localizada no intestino (sem extensão para outros órgãos) por ocasião do diagnóstico. A recorrência após o tratamento cirúrgico é um relevante evento clínico no curso da doença, constituindo-se na maioria destes casos, na causa primária de morte. O tratamento padrão para o câncer de cólon localizado envolve a ressecção cirúrgica por via aberta do tumor primário e linfonodos regionais. O tratamento cirúrgico do câncer de cólon pode ainda ser indicado com intenção curativa para casos selecionados de doentes com metástase hepática ou pulmonar ressecável, ou com finalidade paliativa, sempre na dependência das condições do doente e da reserva funcional do órgão acometido. TRATAMENTO: O tratamento padrão para o câncer do reto é a ressecção cirúrgica do tumor primário. Mesmo após cirurgia ótima, a taxa de recorrência local do câncer retal justifica a realização de tratamento multidisciplinar para os doentes com doença no estágio II e III. A quimiorradioterapia pode ser administrada antes da cirurgia (prévia ou neoadjuvante) para doentes com a doença classificada como em T3/T4 ou N1, ou após o procedimento cirúrgico (adjuvante) para doentes com doença em estágio II ou III. A quimioterapia paliativa está indicada para doentes com câncer colorretal recidivado inoperável ou com doença no estágio IV ao diagnóstico. Para qualquer das finalidades, empregam-se esquemas quimioterápicos baseados em fluoropirimidina, associada ou não a outros quimioterápicos. A TECNOLOGIA: Cetuximabe - O receptor do fator de crescimento epidérmico (EGFR - EpidermalGrowthFactor Receptor -, em inglês) faz parte da via de sinalização envolvida no controle de sobrevivência da célula, progressão do ciclo celular, angiogênese, migração celular e invasão celular/metástase. O cetuximabe é um anticorpo monoclonal quimérico que age como um antagonista competitivo ligando-se ao domínio extracelular do receptor do fator de crescimento epidérmico (Epitelial GrowthFactor Receptor - EGFR), bloqueando desta forma a regulação do crescimento e da proliferação celular. Ele se liga ao EGFR com uma afinidade que é aproximadamente 5 a 10 vezes maior do que o ligante endógeno e bloqueia a ligação de ligantes endógenos do EGFR, resultando em uma inibição da função do receptor. Induz a internalização do EGFR, o que pode levar a uma redução da regulação do EGFR. Também envia células imunoefetoras citotóxicas na direção de células tumorais que expressam EGFR (mecanismo conhecido como Toxicidade Celular Dependente de Anticorpos [ADCC]). O cetuximabe mostrou atividade quando usado como agente único e em combinação com a quimioterapia citotóxica no tratamento do câncer colorretal metastático. EVIDÊNCIAS CIENTÍFICAS: Os ensaios clínicos radomizados presentes mostram que o uso associado do cetuximabe a quimioterapia pode aumentar a taxa de resposta e aumenta a sobrevida livre de progressão, mas a sobrevida global não apresentou aumento significativo, mesmo nos subgrupos geneticamente identificados como do tipo KRAS selvagem. O estudo FIRE-3, estudo de 2014 que comparou a eficácia e segurança de se adicionar cetuximabe ou bevacizumabe ao esquema de quimioterapia habitual foi o fato novo que motivou a empresa demandante a realizar nova proposta de análise na CONITEC. Por esse motivo o estudo foi considerado, quando comumente seria excluído da análise das evidências visto que o comparador não é o tratamento usual no SUS. CONSIDERAÇÕES FINAIS: A evidência atualmente disponível sobre a eficácia e segurança do cetuximabe para o tratamento de primeira linha do câncer colorretal mestatático é baseada em ensaios clínicos randomizados (ECR). Os resultados de eficácia apresentados pelos estudos mostram que o cetuximabe diminuiu a probabilidade da progressão da doença, no entanto o efeito é de pequena magnitude. Pois, no desfecho sobrevida global, não houve aumento de forma estatisticamente significante. A avaliação econômica apresentou a razão de custo-efetividade de um modelo que utilizou como fonte de dados de eficácia a análise de subgrupo realizado após a conclusão do estudo (análise post hoc), sem poder estatístico, portanto para embasar a assertiva de superioridade. Assim, sem a comprovação de ganhos em sobrevida, o estudo de custo-efetividade ficou prejudicado. O impacto orçamentário seguiu as diretrizes. O estudo FIRE-3, estudo de 2014 que comparou a eficácia e segurança de se adicionar cetuximabe ou bevacizumabe ao esquema de quimioterapia habitual foi o fato novo que motivou a empresa demandante a realizar nova proposta de análise na CONITEC. Por esse motivo o estudo foi considerado, quando o padrão seria excluí-lo da análise das evidências visto que o comparador não é o tratamento usual no SUS. DELIBERAÇÃO FINAL: Na reunião do plenário do dia 03/09/2015 foi deliberado, por unanimidade recomendar a não incorporação do cetuximabe para o tratamento em primeira linha de pacientes com câncer colorretal metastático com expressão de EGFR, sem mutação do gene RAS. DECISÃO: PORTARIA Nº 64, de 28 de outubro de 2015 - Torna pública a decisão de não incorporar o cetuximabe para o tratamento em primeira linha de pacientes com câncer colorretal metastático com expressão de EGFR, sem mutação do gene RAS no âmbito do Sistema Único de Saúde - SUS.


Subject(s)
Humans , Colorectal Neoplasms/drug therapy , Genes, ras , Genes, erbB-1 , Cetuximab , Unified Health System , Brazil , Cost-Benefit Analysis/economics
12.
Chinese Medical Journal ; (24): 1887-1892, 2015.
Article in English | WPRIM | ID: wpr-335690

ABSTRACT

<p><b>BACKGROUND</b>In qualitative diagnosis of bile duct stenosis, single diagnostic measure is difficult to make a correct diagnosis, to combine several diagnostic techniques may be helpful to make an accurate diagnosis. The aim of this study was to evaluate the value of intraductal ultrasonography (IDUS), endoscopic brush cytology and K-ras, P53 gene mutation in the early diagnosis of malignant biliary stricture.</p><p><b>METHODS</b>From February 2012 to February 2013, 84 patients with suspected malignant biliary stricture were performed IDUS firstly, then endoscopic brush cytology and finally K-ras, P53 gene mutation detection, the sensitivity, specificity, positive predictive value, negative predictive value and accuracy of all above ways were evaluated and compared.</p><p><b>RESULTS</b>Of 84 patients, 52 cases were ultimately diagnosed malignant biliary stenosis; of which, 9 cases had no recurrence or metastasis to other organs after radical operation during the follow-up period. IDUS combined with brush cytology and K-ras + P53 gene mutation detection had obvious advantage in the sensitivity, accuracy and negative predictive value than any other joint detection and single detection (the advantage was more significant compared with IDUS + brush cytology or any single detection P < 0.01). There were obvious statistical significance in the sensitivity and accuracy between IDUS + brush cytology + P53 or IDUS + brush cytology + K-ras and IDUS + brush cytology or IDUS (P < 0.05). There was no statistical significance in the sensitivity, specificity, positive predictive value, negative predictive value and accuracy between IDUS + brush cytology + P53 and IDUS + brush cytology + K-ras (P > 0.05).</p><p><b>CONCLUSIONS</b>IDUS combined with brush cytology and K-ras, P53 gene mutation detection is better than the separate detection and contribute to the early diagnosis of malignant biliary stricture. Its more widespread use is recommended.</p>


Subject(s)
Aged , Aged, 80 and over , Bile Duct Diseases , Diagnosis , Genetics , Bile Duct Neoplasms , Diagnosis , Genetics , Bile Ducts , Pathology , Constriction, Pathologic , Diagnosis , Genetics , Female , Genes, p53 , Genetics , Genes, ras , Genetics , Humans , Male , Middle Aged , Mutation
13.
Chinese Journal of Cancer ; (12): 166-176, 2015.
Article in English | WPRIM | ID: wpr-349605

ABSTRACT

<p><b>INTRODUCTION</b>Oncogenic activation of the K-ras gene occurs in >90% of pancreatic ductal carcinoma and plays a critical role in the pathogenesis of this malignancy. Increase of reactive oxygen species (ROS) has also been observed in a wide spectrum of cancers. This study aimed to investigate the mechanistic association between K-ras-induced transformation and increased ROS stress and its therapeutic implications in pancreatic cancer.</p><p><b>METHODS</b>ROS level, NADPH oxidase (NOX) activity and expression, and cell invasion were examined in human pancreatic duct epithelial E6E7 cells transfected with K-ras (G12V) compared with parental E6E7 cells. The cytotoxic effect and antitumor effect of capsaicin, a NOX inhibitor, were also tested in vitro and in vivo.</p><p><b>RESULTS</b>K-ras transfection caused activation of the membrane-associated redox enzyme NOX and elevated ROS generation through the phosphatidylinositol 3'-kinase (PI3K) pathway. Importantly, capsaicin preferentially inhibited the enzyme activity of NOX and induced severe ROS accumulation in K-ras-transformed cells compared with parental E6E7 cells. Furthermore, capsaicin effectively inhibited cell proliferation, prevented invasiveness of K-ras-transformed pancreatic cancer cells, and caused minimum toxicity to parental E6E7 cells. In vivo, capsaicin exhibited antitumor activity against pancreatic cancer and showed oxidative damage to the xenograft tumor cells.</p><p><b>CONCLUSIONS</b>K-ras oncogenic signaling causes increased ROS stress through NOX, and abnormal ROS stress can selectively kill tumor cells by using NOX inhibitors. Our study provides a basis for developing a novel therapeutic strategy to effectively kill K-ras-transformed cells through a redox-mediated mechanism.</p>


Subject(s)
Capsaicin , Carcinoma, Pancreatic Ductal , Cell Proliferation , Cell Transformation, Neoplastic , Epithelial Cells , Genes, ras , Humans , NADPH Oxidases , Pancreatic Neoplasms , Phosphatidylinositol 3-Kinases , Reactive Oxygen Species , Signal Transduction , Transfection
14.
Article in Chinese | WPRIM | ID: wpr-289481

ABSTRACT

<p><b>OBJECTIVE</b>To study gene mutations and clinical features in children with juvenile myelomonocytic leukemia (JMML).</p><p><b>METHODS</b>The clinical data of 14 children who were diagnosed with JMML and were examined for the detection of common gene mutations were retrospectively analyzed.</p><p><b>RESULTS</b>Eleven (79%) out of 14 cases were male, and 3 (21%) were female. The median age at diagnosis was 2.0 years (age range: 0.6-6.0 years). Among 14 cases, there were 4 cases (29%) with PTPN11 mutation, 3 cases (21%) with N-RAS mutation, 1 case (7%) with PTPN11 mutation and K-RAS mutation, and 6 cases (43%) without any mutation. All four cases in the PTPN11 mutation group were male, and their median age was 2.5 years; interval from onset to diagnosis was 1.0 month; the white blood cell (WBC) count and absolute monocytes in peripheral blood were significantly higher, while the platelet (PLT) count was lower, as compared with the other three groups; they were followed up, and 3 cases died and 1 case had a progressive disease. In the N-RAS mutation group, there were two male cases and one female case, and their median age was 2.0 years; interval from onset to diagnosis was 13.7 months; after follow-up, 2 cases died and 1 case did not have an obviously progressive disease.</p><p><b>CONCLUSIONS</b>PTPN11 mutation is the most common mutation in JMML. The cases with PTPN11 mutation often have higher WBC count and absolute monocytes in peripheral blood, a lower PLT count, and a rapid disease progression, and their clinical outcomes are poor. The cases with N-RAS mutation have a slow disease progression. The clinical characteristics of the patients with compound mutations are not sure because of the small number of cases, and further clinical observation is indispensable.</p>


Subject(s)
Child , Child, Preschool , Female , Genes, ras , Humans , Infant , Leukemia, Myelomonocytic, Juvenile , Blood , Genetics , Male , Mutation , Protein Tyrosine Phosphatase, Non-Receptor Type 11 , Genetics , Retrospective Studies
15.
Chinese Journal of Pathology ; (12): 254-257, 2015.
Article in Chinese | WPRIM | ID: wpr-298124

ABSTRACT

<p><b>OBJECTIVE</b>To investigate mutations frequencies of KRAS,NRAS and BRAF genes in colorectal carcinoma.</p><p><b>METHODS</b>Tissue specimens from 200 colorectal cancer patients at diagnosis were collected and subject to KRAS,NRAS and BRAF mutation analyses by PCR-based direct DNA sequencing targeting exons 2, 3 and 4 of KRAS gene, exons 2, 3 and 4 of NRAS gene and exon 15 of BRAF gene.</p><p><b>RESULTS</b>Activating mutations were detected in KRAS (44%, 88/200), NRAS (2%, 4/200) and BRAF (5%, 10/200) in this study cohort.Among KRAS mutations, 64.8% (57/88) occurred in codon 12 and 12.5% (11/88) occurred in codon 13. KRAS gene mutation in exon 3 mainly involved codons 59 and 61. KRAS gene mutation in exon 4 mainly involved codons 117 and 146.</p><p><b>CONCLUSIONS</b>Mutations at exon 2 of KRAS gene have the highest frequency in colorectal carcinoma. Expanding the detection sites of KRAS gene combined with NRAS and BRAF genes may help to identify patients who will most likely benefit from targeted therapies.</p>


Subject(s)
Base Sequence , Codon , Colorectal Neoplasms , Genetics , DNA Mutational Analysis , Exons , Female , Genes, ras , Humans , Mutation , Proto-Oncogene Proteins , Proto-Oncogene Proteins B-raf , Genetics , Sequence Analysis, DNA
16.
Article in English | WPRIM | ID: wpr-257627

ABSTRACT

A variety of molecules are involved in tumorigenesis,during which the RAS pathway-related molecules play key roles. RAS gene mutations exist in about 30% of human tumors;in some tumors(e.g. pancreatic adenocarcinomas),the mutation rates may rise to 75%-95%. Even in tumors without RAS mutations,the RAS pathway-related molecules can also be highly activated. RAS-GTPase-activating proteins(RASGAPs)are a group of tumor suppressors. They normally turn off RAS pathway by catalyzing the hydrolysis of RAS-GTP. However,the mutation or hypermethylation of their promoters will inactivate their roles and thus provide an alternative mechanism of activating Ras. This article reviews the research advances in the role of RASGAPs in the development of tumors.


Subject(s)
Cell Transformation, Neoplastic , DNA Methylation , Genes, ras , Humans , Mutation , Neoplasms , ras GTPase-Activating Proteins
17.
Article in Korean | WPRIM | ID: wpr-103842

ABSTRACT

An accurate diagnosis of cancer or benign disease is important for the effective clinical management of the patients. Thyroid fine needle aspiration cytology (FNAC) is a safe and cost effective technic for evaluating thyroid nodules. However, 20-30% of thyroid FNAC specimens are indeterminate and fall into one of the following categories; AUS/FLUS (atypical ceils of undetermined significance/follicular cells of undetermined significance), FN/SFN (follicular neoplasm/suspicious for follicular neoplasm), and SMC (suspicious for malignant cells). The AUS/FLUS, FN/SFN, and SMC diagnostic category is associated with a 5-15%, 15-30%, and 60-75% risk of malignancy, respectively. Of the indeterminate thyroid nodules that are surgically resected, 10-40% were confirmed to be malignant. A significant progress has been made in the development of molecular tests for cancer diagnosis in thyroid nodules. Most common molecular alteration in thyroid cancer is the activation of mitogen-activated protein kinase (MAPK) pathway. Activation of this pathway in thyroid cells results from point mutation of BRAF and RAS genes and rearrangement of RET/PTC and NTRK genes and these genetic alterations are mutually exclusive. Preoperative molecular diagnostic techniques could be applied in FNAC specimen when optimum dissection techniques are provided to collect sufficient numbers of target cells without contamination of blood cells, inflammatory cells including histiocytes, and stromal cells. The optimum number of cells for PCR is about 100 although as few 50 cells has been successful. To obtain a good DNA yield from a very limited number of target cells, avoid DNA loss as much as possible.


Subject(s)
Biopsy, Fine-Needle , Blood Cells , Diagnosis , DNA , Genes, ras , Histiocytes , Humans , Molecular Diagnostic Techniques , Point Mutation , Polymerase Chain Reaction , Protein Kinases , Stromal Cells , Thyroid Gland , Thyroid Neoplasms , Thyroid Nodule
18.
Hist. ciênc. saúde-Manguinhos ; 21(4): 1179-1196, Oct-Dec/2014.
Article in Portuguese | LILACS | ID: lil-732513

ABSTRACT

O artigo analisa o livro Boys in white: student culture in medical school, de Howard S. Becker, Blanche Geer, Everett C. Hughes e Anselm Strauss, considerado um dos modelos de pesquisa qualitativa em sociologia. A análise aborda as trajetórias dos autores, do livro, da pesquisa qualitativa e dos estudantes de medicina, enfatizando sua importância nas origens da sociologia médica e da sociologia da educação médica. Na trajetória dos autores são apresentados aspectos biobibliográficos; na da pesquisa qualitativa, o modo como essa metodologia de investigação atravessa a construção do trabalho de campo; e na dos estudantes, sua forma de atravessar os primeiros anos da escola médica e construir sua própria “cultura do estudante”.


This article analyzes Boys in white: student culture in medical schoolby Howard S. Becker, Blanche Geer, Everett C. Hughes and Anselm Strauss, considered a model of qualitative research in sociology. The analysis investigates the trajectories of the authors, the book, qualitative analysis, and the medical students, emphasizing their importance in the origins of medical sociology and the sociology of medical education. In the trajectory of the authors, bibliographical information is given. The trajectory of qualitative research focuses on how this methodology influences the construction of the field. The investigation of the students’ trajectory shows how they progress through their first years at medical school to build their own student culture.


Subject(s)
Animals , Female , Mice , Adenocarcinoma/drug therapy , Antimetabolites, Antineoplastic/pharmacology , Antineoplastic Agents, Hormonal/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Apoptosis/drug effects , Breast Neoplasms/drug therapy , Estrogens , Estrogen Antagonists/pharmacology , Growth Inhibitors/pharmacology , Neoplasms, Hormone-Dependent/drug therapy , Phenylacetates/pharmacology , /biosynthesis , Tamoxifen/pharmacology , Adenocarcinoma/pathology , Antimetabolites, Antineoplastic/administration & dosage , Antineoplastic Agents, Hormonal/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Breast Neoplasms/pathology , Cell Differentiation/drug effects , Cell Division/drug effects , Drug Synergism , Genes, ras , Mice, Nude , Neoplasm Transplantation , Neoplasms, Hormone-Dependent/pathology , /physiology , Phenylacetates/administration & dosage , /genetics , Transfection , Tamoxifen/administration & dosage , Tumor Cells, Cultured/drug effects
19.
Braz. dent. j ; 25(5): 447-450, Sep-Oct/2014. graf
Article in English | LILACS | ID: lil-731048

ABSTRACT

The radicular cyst is an inflammatory odontogenic cyst of endodontic origin. Radiographically, the lesion appears as a periapical radiolucent image. This report describes a very rare case of a mixed periapical radiographic image diagnosed as a radicular cyst. A 37-year-old female patient presented a mixed, well-circumscribed image located in the periapical region of the left maxillary central incisor, which presented unsatisfactory endodontic treatment. Microscopic examination revealed a cavity lined by non-keratinized squamous epithelium and extensive calcifications in the cystic lumen and lining epithelium. Diagnosis of radicular cyst with extensive calcifications was established. Endodontic retreatment was performed and no radiographic signs of recurrence were observed 18 months after treatment. Although very rare, a radicular cyst should be considered in the differential diagnosis of a mixed periapical image associated to teeth with pulp necrosis.


O cisto radicular é um cisto odontogênico inflamatório de origem endodôntica. Radiograficamente, a lesão se apresenta como uma imagem radiolúcida periapical. Este relato descreve um caso muito raro de uma imagem radiográfica periapical mista diagnosticada como cisto radicular. Uma paciente de 37 anos de idade, do gênero feminino, apresentava uma imagem mista, bem circunscrita, localizada na região periapical do incisivo central superior esquerdo, que apresentava tratamento endodôntico insatisfatório. Avaliação microscópica revelou uma cavidade revestida por epitélio escamoso não-queratinizado e calcificações extensas na cavidade cística e revestimento epitelial. O diagnóstico de cisto radicular com extensas calcificações foi estabelecido. Retratamento endodôntico foi realizado e não foram observados sinais radiográficos de recorrência da lesão após 18 meses de tratamento. Embora muito raro, um cisto radicular deve ser considerado no diagnóstico diferencial de uma imagem periapical mista associada a dentes com necrose pulpar.


Subject(s)
Animals , Mice , Cellular Senescence/physiology , Genes, ras/genetics , MAP Kinase Signaling System/physiology , Nuclear Proteins , /metabolism , Cell Fractionation , Cells, Cultured , Colony-Forming Units Assay , Cell Cycle/physiology , Enzyme Activation , Embryo, Mammalian/physiology , Fibroblasts/cytology , Fibroblasts/metabolism , MAP Kinase Kinase 1 , Mice, Knockout , Microscopy, Fluorescence , Mitogen-Activated Protein Kinase Kinases/metabolism , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , Temperature , /metabolism , ras Proteins/metabolism
20.
Braz. j. med. biol. res ; 47(1): 35-41, 01/2014. tab, graf
Article in English | LILACS | ID: lil-697670

ABSTRACT

The incidence of colorectal cancer (CRC) is increasing daily worldwide. Although different aspects of CRC have been studied in other parts of the world, relatively little or almost no information is available in Pakistan about different aspects of this disease at the molecular level. The present study was aimed at determining the frequency and prevalence of K ras gene mutations in Pakistani CRC patients. Tissue and blood samples of 150 CRC patients (64% male and 36% female) were used for PCR amplification of K ras and detection of mutations by denaturing gradient gel electrophoresis, restriction fragment length polymorphism analysis, and nucleotide sequencing. The K ras mutation frequency was found to be 13%, and the most prevalent mutations were found at codons 12 and 13. A novel mutation was also found at codon 31. The dominant mutation observed was a G to A transition. Female patients were more susceptible to K ras mutations, and these mutations were predominant in patients with a nonmetastatic stage of CRC. No significant differences in the prevalence of K ras mutations were observed for patient age, gender, or tumor type. It can be inferred from this study that Pakistani CRC patients have a lower frequency of K ras mutations compared to those observed in other parts of the world, and that K ras mutations seemed to be significantly associated with female patients.


Subject(s)
Adult , Female , Humans , Male , Colorectal Neoplasms/genetics , Genes, ras/genetics , Mutation/genetics , Genotype , Genetic Predisposition to Disease/genetics , Neoplasm Staging , Pakistan , Polymorphism, Genetic , Polymorphism, Restriction Fragment Length
SELECTION OF CITATIONS
SEARCH DETAIL