Enhanced sensitivity of celecoxib in human glioblastoma cells: Induction of DNA damage leading to p53-dependent G1 cell cycle arrest and autophagy

<p>Abstract</p> <p>Background</p> <p>Selective cyclooxygenase (COX)-2 inhibitors elicit anti-proliferative responses in various tumours, however the underlying anti-tumour mechanisms are unclear. Mutational inactivation of the tumour suppressor p53 gene is frequent in malignant gliomas. The role of p53 mutation in the anti-tumour responses of the selective COX-2 inhibitor celecoxib in human glioblastoma cells is unknown. In this study, we used human glioblastoma cells with various p53 status; U87MG (with high and low p53 functional levels), LN229 (functional p53) and U373MG (mutant p53) cells. Inhibition of p53 was achieved in U87MG cells transfected with E6 oncoprotein (U87MG-E6) and treated with pifithrin-α, a reversible inhibitor of p53 (U87MG-PFT). We investigated whether the anti-glioblastoma responses of celecoxib were p53-dependent, and whether celecoxib induced DNA damage leading to p53-dependent G₁cell cycle arrest, followed by autophagy or apoptosis.</p> <p>Results</p> <p>Our findings demonstrated that celecoxib concentration-dependently reduced glioblastoma cell viability, following 24 and 72 hours of treatment. Inhibition of functional p53 in glioblastoma cells significantly reduced the anti-proliferative effect of celecoxib. In U87MG cells, celecoxib (8 and 30 μM) significantly induced DNA damage and inhibited DNA synthesis, corresponding with p53 activation. Celecoxib induced G₁-phase cell cycle arrest, accompanied with p21 activation in U87MG cells. Cell cycle progression of U87MG-E6 and U87MG-PFT cells was not affected by celecoxib. In parallel, celecoxib induced G₁cell cycle arrest in LN229 cells, but not in U373MG cells. Autophagy was induced by celecoxib in U87MG and LN229 cells, as shown by the significantly greater population of acridine orange-stained cells and increased levels of LC3-II protein (in comparison with non-treated controls). Celecoxib did not induce significant autophagy in U87MG-PFT, U87MG-E6 and U373MG cells, which lack functional p53. Regardless of p53 status, celecoxib caused no significant difference in apoptosis level of U87MG, U87MG-PFT, U87MG-E6 and U373MG cells.</p> <p>Conclusion</p> <p>Our findings reveal that p53 increases human glioblastoma sensitivity to celecoxib. Celecoxib inhibits glioblastoma cell viability by induction of DNA damage, leading to p53-dependent G₁cell cycle arrest and p53-dependent autophagy, but not apoptosis.</p

Colorectal cancer screening: Barriers to the faecal occult blood test (FOBT) and colonoscopy in Singapore

Introduction: This study aims to identify the barriers to adopting faecal occult blood test (FOBT) and colonoscopy as colorectal cancer (CRC) screening methods among the eligible target population of Singapore. Materials and methods: This study was previously part of a randomised controlled trial reported elsewhere. Data was collected from Singapore residents aged 50 and above, via a household sample survey. The study recruited subjects who were aware of CRC screening methods, and interviewed them about the barriers to screening that they faced. Collected results on barriers to each screening method were analysed separately. Results: Out of the 343 subjects, 85 (24.8%) recruited knew about FOBT and/or colonoscopy. Most of the respondents (48.9%) cited not having symptoms as the reason for not using the FOBT. This is followed by inconvenience (31.1%), not having any family history of colon cancer (28.9%), lack of time (28.9%) and lack of reminders/recommendation (28.9%). Of the respondents who indicated not choosing colonoscopy as a screening method, more than one-half (54.8%) identified not having any symptoms as the main barrier for them, followed by not having any family history (38.7%) and having a healthy/low-risk lifestyle (29.0%). There was no difference between the reported barriers to each of the screening methods and the respondents\u27 dwelling types. Conclusions: Lack of knowledge, particularly the misconceptions of not having symptoms and being healthy, were identified as the main barriers to FOBT and colonoscopy as screening methods. Interventions to increase the uptake of CRC screening in this population should be tailored to address this misconception

Colorectal cancer screening: Barriers to the faecal occult blood test (FOBT) and colonoscopy in Singapore

Introduction: This study aims to identify the barriers to adopting faecal occult blood test (FOBT) and colonoscopy as colorectal cancer (CRC) screening methods among the eligible target population of Singapore. Materials and methods: This study was previously part of a randomised controlled trial reported elsewhere. Data was collected from Singapore residents aged 50 and above, via a household sample survey. The study recruited subjects who were aware of CRC screening methods, and interviewed them about the barriers to screening that they faced. Collected results on barriers to each screening method were analysed separately. Results: Out of the 343 subjects, 85 (24.8%) recruited knew about FOBT and/or colonoscopy. Most of the respondents (48.9%) cited not having symptoms as the reason for not using the FOBT. This is followed by inconvenience (31.1%), not having any family history of colon cancer (28.9%), lack of time (28.9%) and lack of reminders/recommendation (28.9%). Of the respondents who indicated not choosing colonoscopy as a screening method, more than one-half (54.8%) identified not having any symptoms as the main barrier for them, followed by not having any family history (38.7%) and having a healthy/low-risk lifestyle (29.0%). There was no difference between the reported barriers to each of the screening methods and the respondents\u27 dwelling types. Conclusions: Lack of knowledge, particularly the misconceptions of not having symptoms and being healthy, were identified as the main barriers to FOBT and colonoscopy as screening methods. Interventions to increase the uptake of CRC screening in this population should be tailored to address this misconception

Metode Nonlinear Least Square (NLS) Untuk Estimasi Parameter Model Wavelet Radial Basis Neural Network (WRBNN)

The use of wavelet radial basis model for forecasting nonlinear time series is introduced in this paper. The model is generated by artificial neural network approximation under restriction that the activation function on the hidden layers is radial basis. The current model is developed from the multiresolution autoregressives (MAR) model, with addition of radial basis function in the hidden layers. The power of model is compared to the other nonlinear model existed before, such as MAR model and Generalized Autoregressives Conditional Heteroscedastic (GARCH) model. The simulation data which be generated from GARCH process is applied to support the aim of research. The sufficiency of model is measured by sum squared of error (SSE). The computation results show that the proposed model has a power as good as GARCH model to carry on the heteroscedastic process

Associations of lifestyle and diet with the risk of nasopharyngeal carcinoma in Singapore: A case-control study

The Author(s) 2017. Background: Nasopharyngeal carcinoma (NPC) is a commonly diagnosed cancer in Southeast Asia. Many studies have examined the risk factors for NPC, yet the roles of some risk factors remain inconclusive. The purpose of this study was to examine associations between modifiable lifestyle factors and the risk of NPC in the Singaporean population. Methods: We conducted a case-control study in Singapore with 300 patients and 310 controls who were recruited between 2008 and 2012. Each control was selected and individually matched to each patient based on sex, ethnicity, and age (±5 years). A total of 290 pairs of cases and controls were matched successfully. We examined lifestyle factors such as tobacco smoking, alcohol drinking, various salted and preserved food consumption, and weaning practices. Results: After adjusting for covariates, multivariate analysis showed that those participants who were current smokers and had ever smoked tobacco had a higher risk of NPC than participants who had never smoked, with odds ratios (ORs) of 4.50 (95% confidence interval [CI] 2.58-7.86; P \u3c 0.001) and 2.52 (95% CI 1.54-4.12; P \u3c 0.001), respectively. Those who consumed salted vegetables at least once a week also showed a significantly increased risk of NPC than those who never or rarely consumed salted vegetables, with an OR of 4.18 (95% CI 1.69-10.38; P = 0.002). Conclusion: Smoking (currently and ever-smoked) and consuming salted vegetables once a week or more were lifestyle risk factors for NPC, and changes of these factors for the better may reduce the risk of NPC

Cardiac Malformations Are Associated with Altered Expression of Vascular Endothelial Growth Factor and Endothelial Nitric Oxide Synthase Genes in Embryos of Diabetic Mice

EXPERIMENTAL BIOLOGY AND MEDICINE233111421-1432United State