RESUMEN
Silencing of tumour-suppressor genes through promoter methylation is frequently observed in carcinogenesis. In this study, we determined the methylation status of RASSF1A, MGMT, APC, AXIN2 and DACT1 genes in 73 cases of non-small cell lung cancer. Methylation-sensitive high-resolution melting analysis (MS-HRM) was used to analyse the promoter methylation, which was further validated with Bisulfite pyrosequencing or Sanger sequencing. Promoter methylation of RASSF1A and APC was frequently found (56% and 49% of cases, respectively), while methylation of MGMT, AXIN2, DACT1 was observed in 30%, 19% and 16%, respectively. Concurrent gene methylation of at least two genes was observed in 55% of the examined cases, with a total of 89% of samples displaying methylation in one or more of the investigated genes. Further analysis of concurrent methylation revealed a positive correlation between AXIN2-DACT1 and an inverse correlation of APC-MGMT. Associations of methylated genes and clinicopathological features were emerged. In more detail, APC promoter methylation was correlated with smoking status (p= 0.020) and non-metastatic cases (p= 0.003). Moreover, MGMT methylation was preferentially found in TTF1-negative cases (p= 0.049). Interestingly, correlation occurred between AXIN2/DACT1 methylation and smoking status (p= 0.009) as well as tumour grade (p= 0.013), as none of these genes was methylated in the majority of smokers and one of the genes was methylated in high-grade tumours. We conclude that aberrant promoter methylation was observed in our cohort while concurrent methylation patterns were also determined. APC, MGMT and AXIN2/DACT1 methylation are potentially of clinical importance regarding prognosis and histological subtyping of NSCLC.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Proteínas Adaptadoras Transductoras de Señales/genética , Proteína Axina/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Metilación de ADN/genética , Metilasas de Modificación del ADN/genética , Metilasas de Modificación del ADN/metabolismo , Enzimas Reparadoras del ADN/genética , Enzimas Reparadoras del ADN/metabolismo , Humanos , Neoplasias Pulmonares/genética , Proteínas Nucleares/genética , Regiones Promotoras Genéticas/genética , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Non-small cell lung cancer (NSCLC) targeted therapies are mostly based on activating mutations and rearrangements which are rare events in Lung Squamous Cell Carcinomas (LUSC). Recently advances in immunotherapy have improved the therapeutic repository for LUSC, but there is still an urgent need for novel targets and biomarkers. We examined 73 cases of LUSC for relative copy number amplification of DCUN1D1, BCL9, FGFR1 and ERBB2 genes and searched for correlations with molecular alterations and clinicopathological characteristics. In our cohort BCL9 gene was amplified in 57.5 % of the cases, followed by DCUN1D1 in 37 %, FGFR1 in 19 % whereas none of the cases were amplified in ERBB2 gene. The majority of the samples exhibited amplification in at least one gene while half of them displayed concurrent amplification of two/three genes. Interestingly, 93 % of the FGFR1 amplified cases were also found co amplified with DCUN1D1 and/or BCL9 genes. Linear correlations were found between BCL9 and DCUN1D1 as well as BCL9 and FGFR1 gene amplification. BCL9 and DCUN1D1 genes' amplification was correlated with poorly differentiated tumors (p = 0.035 and p = 0.056 respectively), implying their possible role in tumor aggressiveness. This is the first study, to the best of our knowledge that examines the correlation of DCUN1D1 and BCL9 genes relative copy number amplification with molecular alterations and clinicopathologic characteristics of squamous cell lung cancer tissue samples. Our findings show concurrent amplification of genes in different chromosomes, with possible involvement in tumor aggressiveness. These results support the complexity of LUSC tumorigenesis and imply the necessity of multiple biomarkers / targets for a more effective therapeutic result in LUSC.
Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/patología , Péptidos y Proteínas de Señalización Intracelular/genética , Neoplasias Pulmonares/patología , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Factores de Transcripción/genética , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/genética , Femenino , Amplificación de Genes/genética , Dosificación de Gen/genética , Humanos , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
BACKGROUND: A possible association between dry eye disease (DED) and irritable bowel syndrome (IBS) has been hypothesized based on the fact that they both share an inflammatory pathogenesis. METHODS: Ninety-five patients with IBS and 276 healthy controls were enrolled in the study. All patients answered a questionnaire regarding DED symptoms and had a complete ophthalmic examination. DED signs were evaluated using Schirmer's 1 and tear break-up time (tBUT) tests in both groups. RESULTS: Female IBS participants presented significantly lower Schirmer's test and tBUT (P=0.002 and P<0.001 respectively) than controls. Both diagnostic tests in male IBS patients were also significantly lower than in controls (P<0.001). 72% of IBS patients gave at least 3 positive answers to the questionnaire compared with 42% of the control group (P<0.01). CONCLUSION: Our results suggest a correlation between IBS and DED. DED symptoms can cause further complications in patients with IBS, and should be considered in their management. However, further research is needed to establish a possible pathophysiologic association.
RESUMEN
During the past few decades, the development and use of individually ventilated cages (IVC), which are now commercially available for housing laboratory mice and rats, have increased. Because limited information is available regarding the influence of caging systems on the growth of rats, the present study assessed body weight and food and water consumption in growing male rats that were housed in IVC and open-top cages (OTC). We allocated 21-d-old male Wistar outbred rats (HsdOla:WI; n = 24) into 2 groups, which then were housed in pairs in IVC (n = 12) and OTC (n = 12). After an 8-d acclimatization period, body weight and food and water consumption were assessed every 3 d until the rats were 94 d old. There were no significant differences between the body weights of rats housed in IVC compared with OTC over the 65-d observation period. Food and water consumption were greater in rats housed in OTC compared with IVC, becoming significantly different when the rats were 50 and 53 d old, respectively. In conclusion, IVC and OTC housing conditions influenced food and water intakes but not body weight in growing male rats. Further research is needed to clarify the exact basis for these changes in food and water consumption.