Epidermal growth factor receptor tyrosine kinase defines critical prognostic genes of stage I lung adenocarcinoma.

PURPOSE: To identify stage I lung adenocarcinoma patients with a poor prognosis who will benefit from adjuvant therapy. PATIENTS AND METHODS: Whole gene expression profiles were obtained at 19 time points over a 48-hour time course from human primary lung epithelial cells that were stimulated with epidermal growth factor (EGF) in the presence or absence of a clinically used EGF receptor tyrosine kinase (RTK)-specific inhibitor, gefitinib. The data were subjected to a mathematical simulation using the State Space Model (SSM). "Gefitinib-sensitive" genes, the expressional dynamics of which were altered by addition of gefitinib, were identified. A risk scoring model was constructed to classify high- or low-risk patients based on expression signatures of 139 gefitinib-sensitive genes in lung cancer using a training data set of 253 lung adenocarcinomas of North American cohort. The predictive ability of the risk scoring model was examined in independent cohorts of surgical specimens of lung cancer. RESULTS: The risk scoring model enabled the identification of high-risk stage IA and IB cases in another North American cohort for overall survival (OS) with a hazard ratio (HR) of 7.16 (P = 0.029) and 3.26 (P = 0.0072), respectively. It also enabled the identification of high-risk stage I cases without bronchioalveolar carcinoma (BAC) histology in a Japanese cohort for OS and recurrence-free survival (RFS) with HRs of 8.79 (P = 0.001) and 3.72 (P = 0.0049), respectively. CONCLUSION: The set of 139 gefitinib-sensitive genes includes many genes known to be involved in biological aspects of cancer phenotypes, but not known to be involved in EGF signaling. The present result strongly re-emphasizes that EGF signaling status in cancer cells underlies an aggressive phenotype of cancer cells, which is useful for the selection of early-stage lung adenocarcinoma patients with a poor prognosis. TRIAL REGISTRATION: The Gene Expression Omnibus (GEO) GSE31210.

A comparative study of the effects of erabu sea snake (Laticauda semifasciata) lipids, green tea extract and conjugated linoleic acid on the swimming endurance of mice.

The aim of this study was to assess the interaction between physical and biochemical parameters in mice fed 1 % sea snake lipids (SSL) and compare these with animals fed diets containing 0.2 % green tea extract (GTE) or 0.5 % conjugated linoleic acid (CLA). The swimming times of the SSL group were significantly increased at Weeks 12 and 16 (p<0.001), and those of the GTE group, at Week 12 (p<0.005), but not those of the control or CLA group, compared with those at Week 0. The increase tended to be significant in the SSL group compared with the control group at Week 12 (p=0.09). Both the SSL and GTE groups had significantly longer swimming times than the CLA group at Weeks 12 and 16 (p<0.001). After 5 minutes of swimming exercise, the SSL group exhibited significantly lower levels of plasma and muscle lactates (p<0.01), and plasma non-esterified fatty acid (NEFA) (p<0.001) than the control group. There were no significant differences in any of plasma glucose, muscle and liver glycogens, muscle lactate dehydrogenase (LDH), carnitine palmitoyltransferase (CPT), or monocarboxylate transporter 1 (MCT1) between SSL and control groups. The results suggest that the intake of 1 % SSL improved endurance more than the intake of 0.2 % GTE or 0.5 % CLA in mice. This action may involve the promotion of lactate oxidation for utilization.

Effects of yogurt supplemented with fish oil on plasma lipid and glucose concentrations, and liver lipid contents in mice.

The aim of this study is to clarify the effects of yogurt supplemented with fish oil on plasma lipid and glucose concentrations, and hepatic lipid contents in mice. Male Crlj:CD-1 (ICR) mice were fed five experimental diets for 12 weeks. The experimental diets were as follows: without yogurt and fish oil (control diet); 10% (w/w) yogurt without fish oil [10% FO(-)]; 10% yogurt with fish oil [10% FO(+)]; 30% yogurt without fish oil [30% FO(-)]; 30% yogurt with fish oil [30% FO(+)]. Plasma triacylglycerol concentrations in the 10% FO(+) and 30% FO(-) groups were significantly lower than that in the control diet group (p < 0.05 and p < 0.05, respectively). Plasma total cholesterol and phospholipid concentrations were significantly lower in the 30% FO(+) group than in the control diet group (p < 0.005). Concentrations tended to be lower with supplementation with fish oil. Plasma glucose concentrations in the 10% FO(+) and 30% FO(+) groups were significantly lower than those in the control diet group (p < 0.005 and p < 0.01, respectively). Hepatic triacylglycerol and total cholesterol contents in the 30% FO(+) group were significantly lower than those in the control diet group (p < 0.05 and p < 0.005, respectively). These results suggest that plasma triacylglycerol and glucose concentrations are effectively decreased by supplementation of yogurt with fish oil.

Levels of plasma insulin, leptin and adiponectin, and activities of key enzymes in carbohydrate metabolism in skeletal muscle and liver in fasted ICR mice fed dietary n-3 polyunsaturated fatty acids.

The aim of this study was to clarify the mechanisms related to plasma glucose concentration in mice fed a diet rich in n-3 polyunsaturated fatty acids (n-3 PUFAs). Male Crlj:CD-1 (ICR) mice were fed experimental diets containing 6% lard (LD), 6% fish oil (FO) or 4.1% lard plus 1.5% docosahexaenoic acid ethyl ester and 0.4% eicosapentaenoic acid ethyl ester (DE) for 12 weeks. There were no marked differences in plasma glucose and insulin concentration changes on glucose tolerance test between the three dietary groups. At the end of the feeding trial, plasma glucose concentration was significantly lower in fasted mice in the FO group than in those in the LD group (P<.005). Plasma adiponectin concentration was significantly higher in the FO group than in the LD group (P<.05). Hexokinase, phosphofructokinase, glucose-6-phosphate dehydrogenase and glycerophosphate dehydrogenase activities in skeletal muscle tended to be lower in the FO group than in the LD group, while there were no differences in glucokinase and phosphofructokinase activities in liver between the three dietary groups. However, hepatic glycerophosphate dehydrogenase activity was 53-fold and 4.2-fold higher in the FO group than in the LD and DE groups, respectively (P<.0005 and P<.05, respectively). These results suggest that the reduction in plasma glucose concentration in mice fed n-3 PUFAs is mainly caused by acceleration of glucose uptake and glycerol synthesis in the liver rather than in the skeletal muscle.

Effect of lipids extracted from a salted herring roe food product on maze-behavior in mice.

Male mice (11 mo old) were fed 5% lard, fish oil, or Kazunoko (salted fish roe product) lipids for 4 mo to investigate their effects on maze behavior. The time required and distance traveled to reach the maze exit, and number of times that a mouse strayed into blind alleys in the maze, and the fatty acid compositions of brain lipids after the maze-behavior experiment were measured. The Kazunoko lipid group showed a significant improvement in all three parameters compared with the lard diet group, but the fish oil group showed only a significant decrease in the number of times that a mouse strayed into blind alleys compared with the lard diet group. The mice in the fish oil and Kazunoko lipid groups had significantly lower levels of arachidonic acid and higher percentages of docosahexaenoic acid in brain lipids compared with animals in the lard group. The mice in the Kazunoko lipid group had significantly lower levels of arachidonic acid in brain lipids than those in the fish oil group but the percentages of docosahexaenoic acid were not significantly different between these two diet groups. Our results suggest that an intake of Kazunoko lipids may suppress the percentage of n-6 fatty acids in brain lipids and this diet can be even more effective than fish oil as a supplement to improve learning capacity in mice.