JAK2 tyrosine kinase inhibitor AG490 suppresses cell growth and invasion of gallbladder cancer cells via inhibition of JAK2/STAT3 signaling.

The Janus kinase-signal transducers and activators of transcription signaling pathway (JAK/STAT pathway) have displayed a critical role in tumor development and progression in multiple malignancies. Previous studies showed that inhibition of JAK/STAT signaling blocked cell growth and metastasis in cancer cells, however, the antitumor effects of JAK inhibitor AG490 on gallbladder cancer (GBC) have not been reported. Our present study aimed to investigate the effects and associated mechanisms of JAK inhibitor AG490 on cell growth, invasive potential and apoptosis in GBC cells (GBC-SD and SGC-996) indicated by MTT, cell colony formation, Transwell and flow cytometry. As a consequence, we found that JAK2 inhibitor AG490 inhibited cell growth and invasion, and induced cell apoptosis and cycle arrest in GBC-SD and SGC-996 cells. Furthermore, the expression levels of p-JAK2, p-STAT3, VEGFC-/-D and cyclinD1 were downregulated, while p53 expression was upregulated in AG490-treated GBC cells indicated by Western blot assay. Therefore, our findings demonstrate that JAK inhibitor AG490 inhibits growth and invasion of GBC cells via blockade of JAK2/STAT3 signaling and provides the potential therapeutic strategy for the treatment of GBC patients.

Particle image velocimetry measurements of three proximal anastomosis models under a pulsatile flow condition.

This study was designed to examine the effects of the anastomotic angle on the flow and haemodynamic parameter distribution patterns of the proximal anastomoses, with emphasis on identifying site-specific haemodynamic features that could reasonably be expected to trigger the initiation and further development of anastomotic intimal hyperplasia. Particle image velocimetry measurements were carried out with three simplified glass proximal models under a physiological flow condition. The results revealed that the disturbed flow and the induced shear stress patterns including low recirculation flow, stagnation point, high wall shear stress, high temporal wall shear stress gradient, low time-averaged wall shear stress (TAWSS), and high oscillating shear index (OSI) occurred around the anastomotic joints and the flow field at proximal anastomosis was strongly affected by the anastomotic angle. Among the three models investigated, the 45 degrees backward anastomosis is found to have a smaller low-recirculation-flow region along the graft inner wall, non-stationary stagnation, and separation points, a higher TAWSS and smaller high-OSI low-TAWSS and low-OSI high-TAWSS regions.

The structure basis of the poor fibrin specificity of urokinase (II)--The inhibition of urokinase A chain 149-157 on the fibrin stimulated activation of plasminogen by tissue type plasminogen activator.

In view of the similarity of the charge distribution between fibrin A alpha 148-161 and A chain 149-157 of urokinase, the latter might compete with fibrin A alpha 148-161 when single chain pro-urokinase is converted to double chain urokinase. To test this, the stretch of urokinase A chain 135-157 was separated from the low molecular weight urokinase, a competitive binding between this stretch and fibrin to tPA kringle-2 was shown by radio-binding assay. The inhibition of the stretch on the fibrin stimulated activation of plasminogen was demonstrated in the caseinolytic system. The synthesized novapeptide urokinase A chain 149-157 (R-peptide) showed a significant inhibition on the activation of plasminogen in the presence of fibrin. By contrasting finely with R-peptide, a synthesized novapeptide in which Arg154 and Arg156 were replaced by Asp (D-peptide) did not show any inhibition effect on the fibrin stimulated activation of plasminogen by tPA. These results suggest that the positively charged residues in the stretch 149-157 of urokinase are crucial for the inhibition of fibrin binding with the kringle domain of urokinase.