Induction of senescence markers after neo-adjuvant chemotherapy of malignant pleural mesothelioma and association with clinical outcome: an exploratory analysis.

The aim of this study was to assess the induction of senescence markers versus apoptosis pathways in malignant pleural mesothelioma (MPM) tumour samples before and after neo-adjuvant platinum-based chemotherapy and to investigate their relationship with clinical outcome. Specific senescence pathways were assessed by quantifying the expression of p21 and plasminogen activator inhibitor-1 (PAI-1) for the p21-p53 pathway, IGFBP7 for the IGF pathway and ALDH1A3 for the IFN pathway. p21 and PAI-1 expression were also assessed by immunohistochemistry. In addition, beta-galactosidase activity staining at pH 6.0 was performed. Apoptosis was determined by TUNEL assay. Clinical outcome was assessed by modified RECIST criteria, progression-free and overall survival. In a training set (n=9 patients) paired comparison demonstrated a significant increase in p21 (p<0.05), PAI-1 (p<0.01) and apoptosis (p<0.01) after neo-adjuvant chemotherapy. The patients with the highest increase in PAI-1 had stable disease, whilst patients with little change in senescence markers accompanied by a high increase in apoptosis had an objective response after chemotherapy. The hypothesis that stable disease might be associated with an increase in senescence markers was confirmed in a tissue microarray (n=26 patients) using p21 and PAI-1 immunohistochemistry as readouts. For patients where survival and time to progression data were available, increased PAI-1 levels were significantly associated with a worst outcome. Our results demonstrate induction of senescence markers by neo-adjuvant chemotherapy in a proportion of patients with MPM and its potential association with a poor outcome.

Relation of clinical benefit of raising high-density lipoprotein cholesterol to serum levels of low-density lipoprotein cholesterol in patients with coronary heart disease (from the Bezafibrate Infarction Prevention Trial).

Low high-density lipoprotein (HDL) cholesterol is a strong independent predictor of cardiovascular risk. The present study was designed to assess the relation between the clinical response to HDL cholesterol modification and serum levels of low-density lipoprotein (LDL) cholesterol in patients with coronary artery disease (CAD). The risk for a major cardiac event (defined as nonfatal myocardial infarction or cardiac death) during a median 7.9-year follow-up period in 3,020 patients with CAD enrolled in the Bezafibrate Infarction Prevention (BIP) trial was related to changes in lipid levels during the study. Baseline LDL cholesterol levels were categorized according to National Cholesterol Education Program Adult Treatment Panel III criteria. Multivariate analysis demonstrated that the benefit of HDL cholesterol increase was most pronounced in patients with low baseline LDL cholesterol (or=160 mg/dl; hazard ratio 0.94, 95% confidence interval 0.75 to 1.17, p = 0.14). A similar relation was shown for risk reduction-associated triglyceride decrements, whereas the benefit of LDL cholesterol reduction was more pronounced in patients with baseline LDL cholesterol >or=130 mg/dl. In conclusion, these data suggest that the clinical response to HDL cholesterol and triglyceride modification is inversely related to baseline LDL cholesterol levels. Thus, combined assessment of baseline and follow-up lipid levels to direct therapeutic goals in patients with CAD may provide incremental prognostic information to secondary prevention that is based solely on LDL cholesterol modification.

Clinical manifestations in Israeli cystinuria patients and molecular assessment of carrier rates in Libyan Jewish controls.

BACKGROUND: Cystinuria is an autosomal recessive disease that is manifested by the development of kidney stones. Mutations in SLC3A1 cause type I disease, while mutations in SLC7A9 are associated with non-type I disease. In Israel, cystinuria is especially common among Libyan Jews who suffer from non-type I disease. OBJECTIVES: To compare clinical manifestations of patients with mutations in SLC3A1 to those with mutations in SLC7A9, and to assess the carrier rate among unaffected Libyan Jewish controls. METHODS: Clinical manifestations were evaluated in patients with mutations in SLC3A1 and in patients with mutations in SLC7A9. Carrier rates for two SLC7A9 mutations were assessed in 287 unaffected Libyan Jewish controls. RESULTS: Twelve patients with mutations in SLC3A1 were compared to 15 patients with mutations in SLC7A9. No differences were detected between the patients with mutations in SLC3A1 and those with mutations in SLC7A9 in relation to the age of disease onset, the estimated number of stones, the number of invasive procedures, the number of patients receiving drug therapy, or the patients' urinary pH. Eleven of the unaffected Libyan Jewish controls were found to be heterozygotes for the V170M mutation, establishing a carrier rate of 1:25. The 1584 + 3 del AAGT mutation was not found in any of the Libyan Jewish controls. CONCLUSION: Mutations in SLC3A1 and SLC7A9 cystinuria patients result in indistinguishable disease manifestations. The high carrier rate among Libyan Jews is a result of a single missense mutation, V170M.

Megalencephalic leukoencephalopathy with subcortical cysts; a founder effect in Israeli patients and a higher than expected carrier rate among Libyan Jews.

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a progressive inherited neurological disorder characterized by macrocephaly, deterioration in motor functions and cerebellar ataxia. In Israel the disease is found in an increased frequency among Libyan Jews. The disease is caused by mutations in the MLC1 gene, which encodes a putative CNS membrane transporter. We describe three novel mutations (p.G59E, p.P92S, and 134_136insC) in seven MLC families. One of these mutations, p.G59E, was found in the vast majority of MLC patients in Israel. Screening of 200 normal Libyan Jewish individuals for the p.G59E mutation, revealed a carrier rate of 1/40 compared with an expected carrier rate of 1/81. Several explanations could account for this difference the most likely one is an admixture of the Libyan Jewish population.