TLR2 Plays a Critical Role in HMGB1-Induced Glomeruli Cell Proliferation Through the FoxO1 Signaling Pathway in Lupus Nephritis.

The objective of this study was to examine the role and possible mechanisms of toll-like receptor 2 (TLR2) in high-mobility group box chromosomal protein 1 (HMGB1)-induced mouse mesangial cell (MMC) proliferation and glomeruli proliferation of MRL/Fas(lpr) mice. First, the expression of proliferating cell nuclear antigen (PCNA), TLR2 and Forkhead box protein O1 (FoxO1) messenger RNA (mRNA) and protein in the glomeruli of MRL/Fas(lpr) mice was quantified, and the correlation with cell proliferation of glomeruli was analyzed. Then, lipopolysaccharide (LPS), TLR2 neutralization antibody, and small hairpin TLR2 (shTLR2) were used to confirm the role of TLR2 in HMGB1-induced MMC proliferation. Furthermore, wild-type FoxO1 (WT-FoxO1) vector was used to investigate the effect of FoxO1 pathway on HMGB1-induced MMC proliferation. Finally, electroporation was used to knockdown TLR2 in the glomeruli of MRL/Fas(lpr) mice, and renal function, FoxO1, and PCNA expression were detected. The results showed that the TLR2 expression was upregulated and FoxO1 expression was decreased in the glomeruli of MRL/Fas(lpr) mice, and these effects were significantly correlated with cell proliferation of the glomeruli. In vitro, the TLR2 neutralization antibody and the WT-FoxO1 vector, both reduced the MMC proliferation levels induced by HMGB1. The TLR2 neutralization antibody also blocked the HMGB1-dependent activation of the FoxO1 pathway and cell proliferation. In addition, transfection with shTLR2 decreased the proliferation levels and PCNA expression induced by HMGB1. In vivo, treatment with shTLR2 significantly reduced the PCNA expression in the glomeruli of MRL/Fas(lpr) mice and improved renal function. In addition, treatment with shTLR2 or blocking of TLR2 also reduced the translocation of FoxO1. Thus, TLR2 plays a critical role in HMGB1-induced glomeruli cell proliferation through the FoxO1 signaling pathway in lupus nephritis.

Efficacy and safety of endostar® combined with chemotherapy in patients with advanced soft tissue sarcomas.

BACKGROUND: Soft tissue sarcomas (STS) are a heterogeneous group of tumors, and approximately 40-50% of patients with STS develop metastatic disease. The median overall survival of those patients was 12 months and their 5-year survival rate was 8%. Therefore, study on more effective treatment, especially the targeting therapies, is urgently needed. OBJECTIVE: To evaluate the efficacy and safety of Endostar® combined with chemotherapy in patients with advanced STS. METHODS: A retrospective case-series study was conducted in Cancer Institute of PLA, Xinqiao Hospital. A total of 71 patients suffering from advanced STS (IIB - IV) were included, of whom 49 cases treated with chemotherapy alone were defined as the control group and the rest 22 cases treated with the traditional chemotherapy combined with Endostar® were defined as the test group. The short-term therapeutic effects including objective response rate (ORR), disease control rate (DCR) and safety were evaluated in the two groups. In the follow-up, progression-free survival (PFS) and overall survival (OS) were also observed. RESULTS: In the test and control groups, the ORR was 18.2% and 12.2%, respectively (P = 0.767), and the DCR was 86.4% and 61.2%, respectively (P=0.034). The median time to progression in the test and control groups was 120 days and 70 days with significant difference (P = 0.017), while the median overall survival was 452 days and 286 days without significant difference (P = 0.503). The one-year survival rate in the test group and control group was 56.2% and 35.4%, respectively, while the two-year survival rate was 30.2% and 26.5%, respectively. No significant difference in the side effects was found between the two groups. CONCLUSIONS: Endostar® combined with chemotherapy resulted in a higher DCR and longer PFS in the patients with advanced STS, and the toxicity was tolerable.