Propofol improved hypoxia-impaired integrity of blood-brain barrier via modulating the expression and phosphorylation of zonula occludens-1.

AIMS: Hypoxia may damage blood-brain barrier (BBB). The neuroprotective effect of propofol has been reported. We aimed to identify whether and how propofol improved hypoxia-induced impairment of BBB integrity. METHODS: Mouse brain microvascular endothelial cells (MBMECs) and astrocytes were cocultured to establish in vitro BBB model. The effects of hypoxia and propofol on BBB integrity were examined. Further, zonula occludens-1 (ZO-1) expression and phosphorylation, hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression, intracellular calcium concentration and Ca2+ /calmodulin-dependent protein kinase II (CAMKII) activation were measured. RESULTS: Hypoxia-impaired BBB integrity, which was protected by propofol. Hypoxia-reduced ZO-1 expression, while induced ZO-1 phosphorylation. These effects were attenuated by propofol. The expression of HIF-1α and VEGF was increased by hypoxia and was alleviated by propofol. The hypoxia-mediated suppression of ZO-1 and impaired BBB integrity was reversed by HIF-α inhibitor and VEGF inhibitor. In addition, hypoxia increased the intracellular calcium concentration and induced the phosphorylation of CAMKII, which were mitigated by propofol. The hypoxia-induced phosphorylation of ZO-1 and impaired BBB integrity was ameliorated by calcium chelator and CAMKII inhibitor. CONCLUSION: Propofol could protect against hypoxia-mediated impairment of BBB integrity. The underlying mechanisms may involve the expression and phosphorylation of ZO-1.

A prospective study of fertility-sparing treatment with megestrol acetate following hysteroscopic curettage for well-differentiated endometrioid carcinoma and atypical hyperplasia in young women.

PURPOSE: To investigate the feasibility and efficacy of curettage with hysteroscopy followed by megestrol acetate (MA) for well-differentiated endometrioid carcinoma (EC) confined to the endometrium and for atypical hyperplasia (AH) in young women. PATIENTS AND METHODS: Fourteen patients with EC and 12 patients with AH were prospectively enrolled in this study. All of the patients received at least 12 weeks of oral MA (160 mg/day) following thorough curettage with hysteroscopy. The response was assessed histologically every 12 weeks. The primary endpoint was the complete response rate. Adverse events, pregnancy rates and recurrence rates were secondary end points. RESULTS: Twenty-one (80.8 %) patients responded to treatment. The median time to response was 12 weeks. After a median follow-up of 32 months, 6 patients had recurrences. Significantly, more patients with infertility or PCOS experienced recurrence (P = 0.040, P = 0.015). Eight patients attempted to conceive after complete response; two spontaneous conceptions and one normal delivery were achieved. No disease-related or treatment-related deaths were observed. CONCLUSIONS: Fertility-sparing treatment with MA following entirely hysteroscopic curettage is effective, demonstrating the least toxicity for rigorously selected young women with well-differentiated EC confined to the endometrium or with AH; however, close follow-up is required for the potential consequences of improper patient selection and a substantial rate of recurrence.

[Nerve-sparing radical hysterectomy and radical hysterectomy: a retrospective study].

OBJECTIVE: To compare Piver radical hysterectomy (RH) with nerve-sparing radical hysterectomy (NSRH) for cervical cancer patients in terms of postoperative physiology of pelvic autonomic nerve and perioperative complications. METHODS: Ninety-three consecutive patients with invasive cervical cancer underwent RH (69 cases) or NSRH (24 cases) from March 2005 to March 2006 at Fudan University Cancer Hospital. The postoperative function of bladder, bowel and sexual function and perioperative morbidity were assessed. RESULTS: Compared with patients received RH, patients underwent NSRH presented a significantly prompter recovery of bladder function (8.7 vs. 14.8 days, P < 0.01) and bowel function (2.9 vs. 3.2 days, P < 0.01). However, there were not significant difference in terms of operative time (146.7 vs. 143.3 minutes, P > 0.05), estimated blood loss (441.7 vs. 565.9 ml, P > 0.05) and hospital stay (10.21 vs. 10.19 days, P > 0.05). No positive surgical margin was found in both groups. No surgery complication was found in NSRH group, while there were 1 case presented the infection of lymphocyst and 1 case presented intestinal obstruction in RH group. After following up postoperative 6 months, the patients received NSRH had a higher rate of satisfaction at sex activity than those received RH (29% vs. 9%, P = 0.042). CONCLUSION: NSRH is safe and feasible surgical management for cervical cancer patients, which would improved the physiology of pelvic autonomic nerve postoperatively.

EMMPRIN expression as a prognostic factor in radiotherapy of cervical cancer.

PURPOSE: Overexpression of extracellular matrix metalloproteinase inducer (EMMPRIN), a member of the immunoglobulin family and a glycoprotein enriched on the surface of many types of tumor cells, has been reported to be linked to invasion, metastasis, growth, and survival of malignant cells. Cervical cancer, the second most prevalent cancer in women worldwide and the fifth leading cause of cancer deaths, responds to radiotherapy variably, with 30% of cases recurring after therapy. The purpose of this study was to determine whether expression of EMMPRIN affects the response of cervical cancer to radiation therapy, and whether this membrane protein can be used as a prognostic marker for cervical cancer. EXPERIMENTAL DESIGN: The retrospective cohort study included 82 patients with invasive cervical cancer referred to the Department of Gynecologic Oncology at The Cancer Hospital of Fudan University (Shanghai) between 1991 and 2000. These patients were treated with brachytherapy at a dose of 15 Gy at point A before radical hysterectomy. Expression of EMMPRIN in cervical tumor specimens was examined by immunohistochemistry staining before and after brachytherapy and scored for both staining intensity and percentage of tumor cells stained. EMMPRIN immunoreactivity and clinicopathologic data were analyzed with respect to survival end points using univariate and multivariate approaches. RESULTS: The frequency of EMMPRIN overexpression was 52.4% in primary cervical cancer. After brachytherapy, EMMPRIN overexpression was significantly reduced (13.4%) compared with corresponding tumor before brachytherapy (P = 0.032). EMMPRIN expression was associated with pelvic lymph node metastasis (P = 0.026) and reduction in primary tumor volume following brachytherapy (P = 0.008). Although EMMPRIN expression before or after brachytherapy did not correlate with tumor-specific survival, but increased expression of EMMPRIN following brachytherapy tended to predict poor outcomes by univariate survival analysis (P = 0.0008). In addition, lymph vascular space invasion, deep stromal invasion, and lymph node metastasis were significantly associated with poor prognosis. In multivariate analysis, the independent prognostic factors for tumor-specific survival included the decreased expression of EMMPRIN after brachytherapy (P = 0.002; hazard ratio, 0.339; 95% confidence interval, 0.172-0.672) as well as lymph node metastasis (P = 0.044; hazard ratio, 2.053; 95% confidence interval, 1.020-4.133). CONCLUSION: Expression of EMMPRIN was associated with a decrease in the reduction of cervical tumor following brachytherapy, and increased EMMPRIN expression after brachytherapy seemed to be an important predictor of poor survival in this patient cohort. Our study suggests that expression of EMMPRIN confers resistance to radiotherapy. Therefore, EMMPRIN expression in cervical cancer may be regarded both as a prognostic factor and a therapeutic target.