Genetic Variants of the MDM2 Gene Are Predictive of Treatment-Related Toxicities and Overall Survival in Patients With Advanced NSCLC.

INTRODUCTION: Platinum agents can cause the formation of DNA adducts and induce apoptosis to eliminate tumor cells. The aim of the present study was to investigate the influence of genetic variants of MDM2 on chemotherapy-related toxicities and clinical outcomes in patients with advanced non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: We recruited 663 patients with advanced NSCLC who had been treated with first-line platinum-based chemotherapy. Five tagging single nucleotide polymorphisms (SNPs) in MDM2 were genotyped in these patients. The associations of these SNPs with clinical toxicities and outcomes were evaluated using logistic regression and Cox regression analyses. RESULTS: Two SNPs (rs1470383 and rs1690924) showed significant associations with chemotherapy-related toxicities (ie, overall, hematologic, and gastrointestinal toxicity). Compared with the wild genotype AA carriers, patients with the GG genotype of rs1470383 had an increased risk of overall toxicity (odds ratio [OR], 3.28; 95% confidence interval [CI], 1.34-8.02; P = .009) and hematologic toxicity (OR, 4.10; 95% CI, 1.73-9.71; P = .001). Likewise, patients with the AG genotype of rs1690924 showed more sensitivity to gastrointestinal toxicity than did those with the wild-type homozygote GG (OR, 2.32; 95% CI, 1.30-4.14; P = .004). Stratified survival analysis revealed significant associations between rs1470383 genotypes and overall survival in patients without overall or hematologic toxicity (P = .007 and P = .0009, respectively). CONCLUSION: The results of our study suggest that SNPs in MDM2 might be used to predict the toxicities of platinum-based chemotherapy and overall survival in patients with advanced NSCLC. Additional validations of the association are warranted.

Induction of anti-myelin antibodies in EAE and their possible role in demyelination.

Experimental allergic encephalomyelitis is characterized by invasion of lymphocytes and macrophages into the central nervous system resulting in inflammation, edema, and demyelination. Sera from Lewis rats from 7-95 days after immunization with purified guinea pig CNS myelin were examined with respect to their ability to opsonize myelin. This was correlated with the appearance of antibody components and the relative amounts of antibody to myelin basic protein (MBP) and proteolipid protein (PLP). Sera from rats 10-95 days after immunization preincubated with purified myelin induced phagocytosis of myelin by cultured macrophages with the resulting production of cholesterol ester. This opsonization activity as measured by the percentage of cholesterol esterified reached a peak at 26-27 days after immunization but remained significantly elevated up to 95 days post-immunization compared to the activity of serum from the Freund's adjuvant-injected controls. Immunoblots of the sera revealed a gradual increase in antibody activity against myelin components. ELISA assays for MBP and PLP antibody showed a similar pattern. Antibody to galactocerebroside (GC) was not detected by immunostains nor by the ELISA assay. Areas of demyelination were observed histologically by luxol-fast blue stained spinal cords up to 60 days post-immunization. These results indicate that antibodies to myelin protein when given access to myelin through or within the blood brain barrier could initiate or enhance the phagocytic response by peripheral or resident macrophages.

The impact of late career job loss on myocardial infarction and stroke: a 10 year follow up using the health and retirement survey.

BACKGROUND: Involuntary job loss is a major life event associated with social, economic, behavioural, and health outcomes, for which older workers are at elevated risk. OBJECTIVE: To assess the 10 year risk of myocardial infarction (MI) and stroke associated with involuntary job loss among workers over 50 years of age. METHODS: Analysing data from the nationally representative US Health and Retirement Survey (HRS), Cox proportional hazards analysis was used to estimate whether workers who suffered involuntary job loss were at higher risk for subsequent MI and stroke than individuals who continued to work. The sample included 4301 individuals who were employed at the 1992 study baseline. RESULTS: Over the 10 year study frame, 582 individuals (13.5% of the sample) experienced involuntary job loss. After controlling for established predictors of the outcomes, displaced workers had a more than twofold increase in the risk of subsequent MI (hazard ratio (HR) = 2.48; 95% confidence interval (CI) = 1.49 to 4.14) and stroke (HR = 2.43; 95% CI = 1.18 to 4.98) relative to working persons. CONCLUSION: Results suggest that the true costs of late career unemployment exceed financial deprivation, and include substantial health consequences. Physicians who treat individuals who lose jobs as they near retirement should consider the loss of employment a potential risk factor for adverse vascular health changes. Policy makers and programme planners should also be aware of the risks of job loss, so that programmatic interventions can be designed and implemented to ease the multiple burdens of joblessness.