Anti-EDN1 monoclonal antibody, clone US.FU.48.6

Purpose: We aimed to investigate the prognostic role of endothelin-1 (EDN1) and endothelin A receptor (EDNRA) gene polymorphisms in patients with locoregionally advanced nasopharyngeal carcinoma (NPC). Experimental Design: Two hundred three consecutive patients with locoregionally advanced NPC were enrolled. Seven potentially functional polymorphisms in the EDN1 and EDNRA genes were determined by ligase detection reaction-PCR method from prospectively collected blood samples. The influence of the genetic polymorphisms on patient overall survival (OS) was analyzed using Cox proportional hazards model, Kaplan-Meier method, and the log-rank test. Results: The 5-year OS in patients with EDNRA/H323H TT, TC, and CC genotypes were 81.3%, 62.1%, and 75.0%, respectively (P = 0.004). Patients carrying the heterozygous (TC) or homozygous variant (CC) genotype in EDNRA/H323H were combined for analysis, which revealed that the 5-year OS in patients with TC/CC genotypes was significantly lower than those with the wild-type TT genotype (63.2% vs. 81.3%; P = 0.002). Multivariate analysis showed that EDNRA/H323H polymorphism (HR: 1.95; 95% CI: 1.18-3.23; P = 0.009) and N classification (HR: 1.35; 95% CI: 1.03-1.79; P = 0.03) were independent significant prognostic factors for OS in patients with locoregionally advanced NPC. In contrast, the EDN1 polymorphisms revealed no prognostic value. Conclusions: The EDNRA/H323H polymorphism was a novel and independent prognostic marker for patients with locoregionally advanced NPC. The analysis of EDNRA/H323H polymorphism may help identify patient subgroups at high risk for poor disease outcome. Clin Cancer Res; 17(8); 2451-8. (C) 2011 AACR.

Mechanistic target of rapamycin complex 1 (mTORC1) signaling is active in inflammation, but its involvement in septic acute kidney injury (AKI) has not been shown. mTORC1 activation (p-S6) in renal fibroblasts was increased in a mouse AKI model induced by 1.5 mg/kg lipopolysaccharide (LPS). Deletion of tuberous sclerosis complex 1 (TSC1), an mTORC1 negative regulator, in fibroblasts (Fibro-TSC1(-/-)) inhibited the elevation of serum creatinine and blood urea nitrogen in AKI compared with that in TSC1(fl/fl) control mice. Endothelin-1 (EDN1) and phospho-Jun-amino-terminal kinase (p-JNK) were up-regulated in Fibro-TSC1(-/-) renal fibroblasts after LPS challenge. Rapamycin, an mTORC1 inhibitor, and bosentan, an EDN1 antagonist, eliminated the difference in renal function between TSC1(fl/fl) and Fibro-TSC1(-/-) mice after LPS injection. Rapamycin restored LPS-induced up-regulation of EDN1, endothelia converting enzyme-1 (ECE1), and p-JNK in TSC1-knockdown mouse embryonic fibroblasts (MEFs). SP600125, a Jun-amino-terminal kinase (JNK) inhibitor, attenuated LPS-induced enhancement of EDN1 and ECE1 in TSC1-knockdown MEFs without a change in phospho-S6 ribosomal protein (p-S6) level. The results indicate that mTORC1-JNK-dependent up-regulation of ECE1 elevated EDN1 in TSC1-knockout renal fibroblasts and contributed to improvement of renal function in Fibro-TSC1(-/-) mice with LPS-induced AKI. Renal fibroblast mTORC1 plays an important role in septic AKI.