JNK regulates Fas receptor mediated apoptosis in prostate cancer cell lines

Prostate Cancer is a disease that primarily affects elderly men. The incidence of prostate cancer has been progressively increasing in the western world over the last two decades. Life expectancy and diet are believed to be the main factors contributing to this increase in prevalence. Prostate cancer is a slowly progressing disorder and patients often live for over 10 years after initially being diagnosed with prostate cancer. However, patients with hormone refractory prostate cancer have a poor prognosis and generally do not survive for longer than 2 or 3 years. Hormone refractory prostate cancer is responsible for over 200,000 deaths each year and current chemotherapeutic regimens are only useful as palliative agents. The long-term survival rate is poor and chemotherapy does not significantly increase this. Cell lines derived from hormone refractory tumours usually display elevated resistance to many cytotoxic drugs. The Fas receptor is a membrane bound protein capable of binding to a ligand called Fas ligand. Engagement of Fas receptor with Fas ligand results in clustering of Fas receptor on the plasma membrane of cells. A number of proteins responsible for initiating apoptosis are recruited to the plasma membrane and are activated in response to elevated local concentrations. This series of events initiates a proteolysis cascade and that culminates in the degradation of structural and enzymatic processes and the repackaging of cellular constituents within membrane bound vesicles that can be endocytosed and recycled by surrounding phagocytic cells. The Fas receptor is believed to be a key mechanism by which immune cells can destroy damaged cells. Consequently, resistance to Fas receptor mediated apoptosis often correlates with tumour progression. It has been reported that prostate cancer cell lines display elevated resistance to Fas receptor mediated apoptosis and this correlates with the stage of tumour from which the cell lines were isolated. JNK, a stress-activated protein kinase, has been implicated both with increased survival and increased apoptosis in prostate cancer. Elevated endogenous JNK activity has been demonstrated to correlate with prostate cancer progression. It has been shown that endogenous JNK activity increases the expression of anti-apoptotic proteins and can increase the resistance of prostate cancer cell lines to chemotherapy. In addition, elevated endogenous JNK activity is required for improved proliferation and transformation of a number of epithelial tumours. However, prolonged JNK activation in response to cytotoxic stimuli can increase the sensitivity of cells to apoptosis. Prolonged JNK activity appears to induce the expression of a separate set of genes responsible for promoting apoptosis. Our group has recently shown that activation of JNK by chemotherapeutic drugs can sensitise DU 145 prostate carcinoma cells to Fas receptor mediated apoptosis. In order toidentify novel targets for treating hormone refractory prostate cancer we have investigated the role of JNK in Fas receptor mediated apoptosis. We have demonstrated that prolonged JNK activation is defective in DU 145 cells in response to Fas receptor activation alone. Co-administering anisomycin, a JNK agonist, greatly enhances the ability of DU 145 cells to undergo apoptosis by increasing the rate of Caspase 8 cleavage. We also investigated the role of endogenous JNK activity in Fas receptor mediated.

Socioeconomic inequalities of cardiovascular risk factors among manufacturing employees in the Republic of Ireland: a cross-sectional study

Objectives: To explore socioeconomic differences in four cardiovascular disease risk factors (overweight/obesity, smoking, hypertension, height) among manufacturing employees in the Republic of Ireland (ROI). Methods: Cross-sectional analysis of 850 manufacturing employees aged 18–64 years. Education and job position served as socioeconomic indicators. Group-specific differences in prevalence were assessed with the Chi-squared test. Multivariate regression models were explored if education and job position were independent predictors of the CVD risk factors. Cochran–Armitage test for trend was used to assess the presence of a social gradient. Results: A social gradient was found across educational levels for smoking and height. Employees with the highest education were less likely to smoke compared to the least educated employees (OR 0.2, [95% CI 0.1–0.4]; p b 0.001). Lower educational attainment was associated with a reduction in mean height. Non-linear differences were found in both educational level and job position for obesity/overweight. Managers were more than twice as likely to be overweight or obese relative to those employees in the lowest job position (OR 2.4 [95% CI 1.3–4.6]; p = 0.008). Conclusion: Socioeconomic inequalities in height, smoking and overweight/obesity were highlighted within a sub-section of the working population in ROI.

Perceived risk of death in older primary care patients

There is a large gap between life expectancy and healthy life years at age 65. To reduce this gap, it is necessary that people with medical concerns perceived at higher risk of adverse outcomes are readily identified and treated. The same goes for the need to implement prevention plans. The main objectives of this study are to, in a first step, (a) estimate the percentage of medical concerns, (b) identify factors associated with this concern; in a second step, (c) estimate the perceived risk of death, and (d) evaluate the ability of medical concerns to predict this risk. Results show that the existence and severity of medical concerns are crucial in the prediction of perceived risk of death. Early identification of severity of medical concerns and the availability and adequacy of informal caregiving should allow healthcare professionals to promptly initiate an appropriate assessment and treatment of older patients.