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Cancer cells require oxygen and nutrients for growth, making angiogenesis one of the essential components of tumor growth. Gangliosides, constituting membrane lipid rafts, regulate intracellular signal transduction and are involved in the malignancy of cancer cells. While endothelial cells, as well as cancer cells, express vast amounts of gangliosides, the precise function of endothelial gangliosides in angiogenesis remains unclear. In this study, we focused on gangliosides of vascular endothelial cells and analyzed their functions on tumor angiogenesis. In human breast cancer, GM3 synthase was highly expressed in vascular endothelial cells as well as immune cells. Angiogenesis increased in GM3S-KO mice. In BAEC, RNA interference of GM3S showed increased cellular invasion and oxidative stress tolerance through activation of ERK. In the breast cancer model, GM3-KO mice showed an increase in tumor growth and angiogenesis. These results suggest that the endothelial ganglioside GM3 regulates tumor angiogenesis by suppressing cellular invasion and oxidative stress tolerance in endothelial cells.

Introduction The pharmacokinetics, pharmacodynamics, and safety and tolerability profile of etelcalcetide (ONO-5163/AMG 416), a novel, i.v., long-acting calcium-sensing receptor agonist, were studied in Japanese hemodialysis patients with secondary hyperparathyroidism. Methods This multicenter, randomized, double-blind, placebo-controlled, parallel-group study consisted of a single dose part and a multiple dose (3 times weekly for 4 weeks) part. Major inclusion criteria were hemodialysis for at least 90 days, serum intact parathyroid hormone (iPTH) ≥ 300 pg/ml, and serum albumin-corrected Ca (cCa) ≥ 9.0 mg/dl. There were 3 single-dose cohorts (n = 6 each) randomized 2:1 to 5, 10, or 20 mg etelcalcetide or placebo, and 2 multiple-dose cohorts (n = 11 each) randomized 8:3 to 2.5 or 5 mg etelcalcetide or placebo. Results Etelcalcetide plasma concentration decreased rapidly after i.v. administration, generally remained stable from 24 hours postdose to the next dialysis, and then decreased by dialysis. Etelcalcetide exposure increased dose proportionally. Etelcalcetide plasma predialysis concentration reached almost steady state at week 4. A single dose of etelcalcetide dose-dependently reduced serum iPTH in 30 minutes, and the reduction reached a plateau at 1 hour that lasted until 8 hours. The percent change from baseline serum iPTH thereafter showed a trend to gradually decrease; it was still −30% or greater on day 3. Similar results were obtained at the last injection (days 27–29) of the multiple dose. The effect of the multiple dose was sustained during the interdialytic period. Etelcalcetide decreased serum cCa in a more gradual but dose-dependent and sustained manner. Discussion Etelcalcetide dose-dependently reduced serum iPTH and serum cCa. Moreover, the effect was sustained in the interdialytic period.

Pranlukast is a cysteinyl leukotriene receptor antagonist that has been used to treat bronchial asthma and allergic rhinitis. In vitro data suggest that pranlukast is a substrate of CYP3A4. Thus, the effect of clarithromycin, a potent CYP3A4 inhibitor, on the pharmacokinetics of pranlukast was examined in an open-label, randomized, two-way crossover study in 16 healthy male volunteers. In treatment A, volunteers received a single, 225 mg dose of pranlukast. In treatment B, 200 mg of clarithromycin was administered twice daily for 7 days and a single, 225 mg dose of pranlukast was coadministered on day 7. Blood samples were collected up to 24 hours after treatment, and pranlukast concentrations in the plasma were measured. The geometric mean ratios [GMR] (90% confidence intervals [CIs]) for pranlukast AUC(0-infinity) and C(max) (with/without clarithromycin) were 1.06 (0.91, 1.24) and 1.17 (0.95, 1.45), respectively. In conclusion, clarithromycin and pranlukast could be coadministered without dose adjustment because clarithromycin minimally affected the pharmacokinetics of pranlukast.

To characterize Japanese encephalitis virus (JEV) strains recently prevalent in Japan, JEV surveillance was performed in pigs from 2002 to 2004. Eleven new JEV isolates were obtained and compared with previous isolates from Japan and other Asian countries. All of the isolates were classified into genotype 1 by nucleotide sequence analysis of the E gene. Two new isolates with different levels of neurovirulence and neuroinvasiveness, but with only one nucleotide difference in the E gene, Sw/Mie/34/2004 and Sw/Mie/40/2004, were isolated at the same farm on the same day. Sw/Mie/40/2004 displayed higher neurovirulence and neuroinvasiveness in mice than the other four new isolates. Another new isolate, Sw/Hiroshima/25/2002, was neutralized by antiserum to Beijing-1 at a level similar to the homologous Beijing-1 strain, whilst seven other new isolates were neutralized at 10-fold-lower titres. However, there were no amino acid differences in the E protein among these eight isolates. The present study indicated that the 11 new JEV isolates were genetically similar, but biologically and serologically heterogeneous.

Vibrio parahaemolyticus isolated from the feces of patients with food poisoning contains in most cases either thermostable direct hemolysin (TDH) and/or TDHrelated hemolysin (TRH), both important pathogenic factors carried by this microorganism [1–3]. However, most organisms from brackish water, estuary mud or fish that cause food poisoning have neither the TDH production gene (tdh) nor the TRH production gene (trh) [1]. This seems to be because TDH-producing V. parahaemolyticus occurs in only small amounts in nature or foods compared to other Vibrio spp. In addition, it is difficult to grow in artificial media, since TDH-producing V. parahaemolyticus is in the viable but nonculturable (VNC) state due to nutrient limitation, low temperature, etc. [4, 5]. Therefore, TDH-producing V parahaemolyticus is rarely isolated from foods assumed to cause food poisoning that have a high probability of containing TDH-producing V. parahaemolyticus Accordingly, it is very difficult to quantitate TDH-producing V. parahaemolyticus by culture. In order to estimate the content of TDH-producing V. parahaemolyticus in suspect foods, we have developed a LightCycler assay to quantitate tdh.