The aim of this study was to evaluate the association between thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR) and reduced folate carrier (SLC19A1) gene polymorphisms and the treatment efficacy of pemetrexed-based chemotherapy in advanced non-small cell lung cancer (NSCLC). Advanced NSCLC patients received pemetrexed and cisplatin every three weeks. Polymorphisms in the TS, MTHFR and SLC19A1 genes were detected in peripheral blood samples using DNA sequencing and Taqman PCR. An analysis of gene polymorphisms was performed with respect to the progression-free survival (PFS), response rate (RR) and overall survival (OS) of patients treated with pemetrexed. The median PFS times for patients with the TS 2R/2R, 2R/3C or 3C/3C genotypes were significantly longer than those of patients with the 2R/3G, 3C/3G or 3G/3G genotypes (P=0.036). Patients with the SLC19A1 CC genotype had a significantly longer median OS compared with individuals with the homozygous and heterozygous genotypes (12.2 vs. 8.9 and 7.3 months, respectively; P=0.022). The PFS and OS did not differ for the three genotypes of MTHFR assessed. The RR was higher in patients with the TS 2R/2R, 2R/3C or 3C/3C genotypes than in the other groups (P=0.044). The polymorphisms of the 5′-UTR of the TS gene and exon 6 (2522) C/T of the SLC19A1 gene predict the survival of advanced NSCLC patients treated with pemetrexed. However, a large scale clinical trial is required to validate these findings.

Hickory milk and reconstituted milk (about 12 g/100 g total solid) were mixed in the proportion of 3:7 by volume to prepare hickory milk yogurt. Cow milk yogurt was used as control. The acidity and total count of lactic acid bacteria of hickory milk yogurt were not significantly different from cow milk yogurt (p > 0.05). Compared with cow milk yogurt, hickory milk yogurt had higher total solids, fat, crude protein, and amino acids, but lower ash and not-fat solids. Sensory evaluation showed that the appearance and flavor scores of hickory milk yogurt had no significant difference from cow milk yogurt (p > 0.05), but the texture score was significantly higher (p < 0.05). IC 50 values in relation to 1,1-diphenyl-2-picrylhydrazyl scavenging activity and inhibition of lipid peroxidation (46.88 and 26.70 g/L) of hickory milk yogurt were significantly lower than those of cow milk yogurt which suggested that the antioxidant activity of hickory milk yogurt was significantly higher than cow milk yogurt (p < 0.05). There were 30 and 28 kinds of volatile compounds identified in hickory milk yogurt and cow milk yogurt, respectively. Compared with cow milk yogurt, the concentration of acetaldehyde, hexanal, nonanal, 2-nonanone, caproic acid, heptylic acid, and nonanoic acid in hickory milk yogurt increased significantly, and the concentration of benzaldehyde, 2,3-pentanedione, 2,3-butanedione, 3-hydroxy-2-butanone, acetic acid, butyric acid, and benzoic acid decreased significantly (p < 0.05). ARTICLE HISTORY

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There are three difficulties in topology optimization of continuum structures. 1) The topology under multiple load case is more difficult to be optimized than under single load case, because the former becomes a multiple objective based on compliance objective functions. 2) With local constraints, such as an elemental stress limit, the topology is more difficult to be solved than with global constraints, such as the displacement or frequency limits, because the sensitivity analysis of the former has very expensive computation. 3) With the phenomenon of load illness, which is similar with stiffness illness in the structural analysis, it is not easy to get the reasonable final topological structure, because it is difficult to consider different influences between the loads with small forces and big forces, and some topology paths of transferring small forces may disappear during the iteration process. To overcome difficulties above, four measures are adopted. 1) Topology optimization model is established by independent continuous mapping (ICM) method. 2) Based on the von Mises strength theory, all elements' stress constraints are transformed into a structural energy constraint. 3) The phenomenon of load illness is divided to classify into three cases. 4) A strategy based on strain energy is proposed to adopt ICM method with stress globalization, and the problems of the above mentioned three cases of load illness are solved in terms of different complementary approaches. Several numerical examples show that the topology path of transferring forces can be obtained more easily by substituting global strain energy constraints for local stresses constraints, and the problem of load illness can be solved well by the weighting method that takes the structural energy as a weighting coefficient.