Evaluation for effect of hypothermia on the disposition of 4-nitrophenol in rats by in-vitro metabolism study and rat liver perfusion system

Objectives The aim of this study was to evaluate the effect of hypothermia on the in-vivo pharmacokinetics of 4-nitrophenol (4NP) using rat liver homogenate and rat liver perfusion system. Methods Rat liver homogenate was incubated with 4NP, which is mainly metabolized by cytochrome P450 2E1, at 37, 34, 32 or 28°C. The Michaelis constant (Km) and maximum elimination velocity (Vmax) of 4NP were calculated by a Hanes-Woolf plot. The hepatic extraction ratio (Eh) of 4NP was evaluated in a rat liver perfusion study at 37, 34, 32 or 28°C. Moreover, the plasma concentration profiles of 4NP after its intravenous (i.v.) administration to rats were analysed by the moment theory and were compared with in-vitro parameters. Key findings While the Km of 4NP was not changed, the Vmax and Eh were reduced at low temperatures. The plasma concentrations of 4NP after its i.v. administration to rats were significantly increased at 28°C. Conclusion Changes in the pharmacokinetics of 4NP under hypothermic conditions were caused by alterations in Vmax and E h. We may be able to predict the disposition of a drug by in-vitro studies

Variations of tropospheric methane over Japan during 1988–2010

We present observations of CH4 concentrations from the lower to upper troposphere (LT and UT) over Japan during 1988–2010 based on aircraft measurements from the Tohoku University (TU). The analysis is aided by simulation results using an atmospheric chemistry transport model (i.e. ACTM). Tropospheric CH4 over Japan shows interannual and seasonal variations that are dependent on altitudes, primarily reflecting differences in air mass origins at different altitudes. The long-term trend and interannual variation of CH4 in the LT are consistent with previous reports of measurements at surface baseline stations in the northern hemisphere. However, those in the UT show slightly different features from those in the LT. In the UT, CH4 concentrations show a seasonal maximum in August due to efficient transport of air masses influenced by continental CH4 sources, while LT CH4 reaches its seasonal minimum during summer due to enhanced chemical loss. Vertical profiles of the CH4 concentrations also vary with season, reflecting the seasonal cycles at the respective altitudes. In summer, transport of CH4-rich air from Asian regions elevates UT CH4 levels, forming a uniform vertical profile above the mid-troposphere. On the other hand, CH4 decreases nearly monotonically with altitude in winter–spring. The ACTM simulations with different emission scenarios reproduce general features of the tropospheric CH4 variations over Japan. Tagged tracer simulations using the ACTM indicate substantial contributions of CH4 sources in South Asia and East Asia to the summertime high CH4 values observed in the UT. This suggests that our observations over Japan are highly sensitive to CH4 emission signals particularly from Asia

Gernet-sillimanite gneisses from the Lutzow-Holm Bay region East Antarctica

This paper presents the regional distribution and petrographical features of garnet-sillimanite gneisses in the Lutzow-Holm Bay region, East Antarctica. In addition to sillimanite, such aluminous silicate and oxide minerals as kyanite, staurolite, sapphirine and spinel occur in the gneisses. Among them, sapphirine is the first report in a pelitic rock from the region. From their microscopic textures, it is inferred that the rocks in the region suffered the prograde metamorphism of kyanite-sillimanite type as those in the Prince Olav Coast did. Thus, it is clarified that the rocks in the present region and the Prince Olav Coast have the same metamorphic history and possibly belong to the same geological unit. The metamorphic grade is expected to increase progressively towards the southern part of the Lutzow-Holm Bay region

Humoral immune responses to EGFR-derived peptides predict progression-free and overall survival of non-small cell lung cancer patients receiving gefitinib.

Somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with clinical response to EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib, in patients with non-small cell lung cancer (NSCLC). However, humoral immune responses to EGFR in NSCLC patients have not been well studied. In this study, we investigated the clinical significance of immunoglobulin G (IgG) responses to EGFR-derived peptides in NSCLC patients receiving gefitinib. Plasma IgG titers to each of 60 different EGFR-derived 20-mer peptides were measured by the Luminex system in 42 NSCLC patients receiving gefitinib therapy. The relationships between the peptide-specific IgG titers and presence of EGFR mutations or patient survival were evaluated statistically. IgG titers against the egfr_481-500, egfr_721-740, and egfr_741-760 peptides were significantly higher in patients with exon 21 mutation than in those without it. On the other hand, IgG titers against the egfr_841-860 and egfr_1001-1020 peptides were significantly lower and higher, respectively, in patients with deletion in exon 19. Multivariate Cox regression analysis showed that IgG responses to egfr_41_ 60, egfr_61_80 and egfr_481_500 were significantly prognostic for progression-free survival independent of other clinicopathological characteristics, whereas those to the egfr_41_60 and egfr_481_500 peptides were significantly prognostic for overall survival. Detection of IgG responses to EGFR-derived peptides may be a promising method for prognostication of NSCLC patients receiving gefitinib. Our results may provide new insight for better understanding of humoral responses to EGFR in NSCLC patients