TEK is a novel prognostic marker for clear cell renal cell carcinoma.

OBJECTIVE: Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer. However, effective therapeutics for ccRCC are lacking. Novel biomarkers could provide critical information when determining prognoses for patients with ccRCC. In this study, we sought to determine if the expression of receptor tyrosine kinase (TEK) could be a potential novel prognostic biomarker for ccRCC. TEK, originally identified as an endothelial cell-specific receptor, plays an important role in the modulation of vasculogenesis and remodeling. Altered TEK expression has been observed in tumor tissues (e.g., oral squamous cell carcinomas, leukemia) and breast, gastric and thyroid cancers. However, the role of TEK in ccRCC remains unknown. PATIENTS AND METHODS: Differential TEK expression between non-metastatic (stage M0) and metastatic (stage M1) ccRCC patient cohorts was determined from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC). Furthermore, TEK expression was assessed as a prognostic factor using the time-dependent area under the curve (AUC) of Uno's C-index, the AUC value of the receiver operating characteristics (ROC) at 5 years, Kaplan-Meier survival curves and multivariate analyses. RESULTS: A Kaplan-Meier curve analysis revealed that the downregulation of TEK expression was associated with a poor prognosis for patients with ccRCC with good discrimination (p<0.0001 and p=0.0044 for the TGCA and ICGC cohorts, respectively). Analyses of C-indices and receiver operating characteristic AUC values further support this discriminative ability. Moreover, multivariate analyses showed the prognostic significance of TEK expression levels (p<0.001). CONCLUSIONS: Although additional clinical investigations will be needed, our results suggest that TEK is a potential biomarker for ccRCC.

Nitric oxide synthase inhibitors enhance 5-HT2 receptor-mediated behavior, the head-twitch response in mice.

The purpose of this study was to characterize behavioral interactions between nitric oxide synthase (NOS) inhibitors and serotonergic 5-HT2 receptors. In the present study, NOS inhibitors, N(G)-nitro-L-arginine, N(G)-nitro-L-arginine methylester, N(G)-monomethyl-L-arginine, 7-nitroindazole, trifluoperazine and NO scavenger, methylene blue markedly enhanced 5-hydroxytryptamine (5-HT)-induced selective serotonergic behavior, the head twitch response (HTR), in mice. However NO generators, sodium nitroprusside, 3-morpholinosydnonimine and S-nitroso-N-acetylpenicillamine as well as NO precursor, L-arginine markedly inhibited 5-HT induced HTR in mice. In the previous study, it was demonstrated that the N-methyl-D-aspartate (NMDA) receptor antagonists markedly enhanced 5-HT-induced selective serotonergic behavior, HTR, whereas NMDA itself inhibited 5-HT-induced HTR in mice. In the present study, it was demonstrated that the inhibition by a NMDA receptor agonist, NMDA of 5-HT-induced HTR was reversed by the treatment with NOS inhibitors, N(G)-nitro-L-arginine and N(G)-nitro-L-arginine methylester. The suppressive action by a NO generator, S-nitroso-N-acetylpenicillamine of 5-HT-induced HTR was also reversed by the treatment with NMDA receptor antagonists, MK-801 and dextromethorphan. These results have shown that the NO system is located down stream of NMDA receptors involved in modulation of 5-HT2-mediated HTR. Therefore, the enhanced effects of NOS inhibitors on 5-HT-induced HTR support experimental evidence for the NO/5-HT2 as well as NMDA/5-HT2 receptor interactions indicating that NO plays an important role in the glutamatergic modulation of the serotonergic function at the 5-HT2 receptor.