The Ubiquitin-proteasome system has recently been shown to be involved in the regulation of cytokine expression. We tested the hypothesis of whether the in vivo administration of proteasome inhibitor MG-132 can modulate cytokine response and mortality in sepsis. Sepsis was induced in mice by caecal ligation and puncture (CLP). Animals were divided into four groups: control, CLP, CLP and 1 microg MG-132/g of b.w. intraperitoneally, and CLP and 10 microg MG-132/g of b.w. Plasma levels of interleukin (IL)-1, tumour necrosis factor-alpha (TNF-alpha, IL-6 and IL-10 were determined by ELISA 6 h after the induction of sepsis. CLP induced significant increase in plasma levels of all measured cytokines. MG-132 treatment resulted in lower increase in IL-1, TNF-alpha and IL-10 levels. IL-6 was not significantly affected. A mortality study revealed prolonged survival in MG-132 treated mice. We conclude that MG-132 treatment decreases inflammatory response and prolongs survival in the CLP model of sepsis.
The efficacy of postoperative adjuvant chemotherapy using oral fluoropyrimidines such as UFT and 5'-DFUR may not be as great for patients with a tumor positive for MMP-9 having a greater risk to postoperative recurrence.
Abstract. The aim of this study was to determine any correlation between the efficacy of post-operative adjuvant chemotherapy using oral fluoropyrimidines and the vascular endothelial growth factor (VEGF) expression in primary colorectal cancer tissues. The data were reviewed retrospectively on 342 patients with colorectal cancer at stage II or III, who underwent potentially curative resection between 1988 and 1998. Of these, 225 received post-operative administration of oral fluoropyrimidines such as UFT and 5'-DFUR, while the other 117 patients underwent surgery alone. Immunostaining for VEGF was performed using colorectal tumours. Overall, VEGF was positively expressed in primary tumour cells in 48% of patients. The disease-free survival rate and the overall survival rate in the chemotherapy group were higher than those in the surgery-alone group, although not significantly. However, the disease-free survival rate and the overall survival rate were similar between the two groups in patients with a tumour positive for VEGF. Multivariate analysis revealed that the VEGF expression was an independent factor for post-operative recurrence, and the VEGF expression and post-operative adjuvant chemotherapy were an independent factor for overall survival, in addition to the lymph node metastasis and the venous invasion. In conclusion, the efficacy of post-operative adjuvant chemotherapy using oral fluoropyrimidines may not be as great for patients with a tumour positive for VEGF having a greater risk of post-operative recurrence. The results support further investigation on efficacy of molecular targeting therapy for VEGF in combination with oral fluoropyrimidines as post-operative adjuvant therapy in colorectal cancer positive for VEGF.
Leukocytapheresis therapy could be a new therapeutic strategy for patients with pouchitis after ileal pouch-anal anastomosis for ulcerative colitis. These encouraging results lead us to propose a randomized controlled trial.
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