[Effects of both folic acid, p16 protein expression and their interaction on progression of cervical cancerization].

Objective: To explore the effects of both folic acid, p16 protein expression and their interaction on progression of cervical cancerization. Methods: Participants were pathologically diagnosed new cases, including 80 women with normal cervical (NC), 55 patients with low-grade cervical intraepithelial neoplasia (CINⅠ), 55 patients with high-grade cervical intraepithelial neoplasia (CINⅡ/Ⅲ) and 64 patients with cervical squamous cell carcinoma (SCC). Serum folate levels were detected by microbiological assay method while p16 protein expression levels were measured by Western-blot. In vitro, cervical cancer cell lines C33A (HPV negative) and Caski (HPV16 positive) were treated with different concentrations of folate. Proliferation and apoptosis of cells and the levels of p16 protein expression were measured in groups with different folic acid concentrations. Results: Results showed that the levels of serum folate were (5.96±3.93) ng/ml, (5.08±3.43) ng/ml, (3.92±2.59) ng/ml and (3.18±2.71) ng/ml, and the levels of p16 protein were 0.80±0.32, 1.33±0.52, 1.91±0.77, and 2.09±0.72 in the group of NC, CINⅠ, CINⅡ/Ⅲ and SCC, respectively. However, the levels of serum folate decreased (trend χ2=32.71, P<0.001) and p16 protein expression increased (trend χ2=56.06, P<0.001) gradually along with the severity of cervix lesions. An additive interaction was seen between serum folate deficiency and high expression of p16 protein in the CINⅠ, CINⅡ/Ⅲ and SCC group. Results in vitro showed that, with the increase of folate concentration, the inhibition rate of cell proliferation (C33A: r=0.928, P=0.003; Caski: r=0.962, P=0.001) and the rate on cell apoptosis (C33A: r=0.984, P<0.001; Caski: r=0.986, P<0.001) all increased but the levels of p16 protein expression (C33A: r=-0.817, P=0.025; Caski: r=-0.871, P=0.011) reduced. The proliferation inhibition rate (C33A: r=-0.935, P=0.002; Caski: r=-0.963, P=0.001) and apoptosis rate of cells (C33A: r=-0.844, P=0.017; Caski: r=-0.898, P=0.006) were negatively correlated with the levels of p16 protein expression. Conclusions: Our findings indicated that both serum folate deficiency and high expression of p16 protein could increase the risk of cervical cancer and cervix precancerous lesion, and there was an additive interaction between them. Our findings suggested that folic acid supplementation could reverse the abnormal expression of p16 protein, and effectively promote apoptosis and inhibit proliferation in cervical carcinoma cells.

Effects of silymarin on the resolution of liver fibrosis induced by carbon tetrachloride in rats.

Silymarin, a standardized extract of the milk thistle (Silybum marianum), has a long tradition as a herbal remedy, and was introduced as a hepatoprotective agent a few years ago. However, the therapeutic effects of silymarin remain undefined. Carbon tetrachloride (CCl4) is a xenobiotic used extensively to induce oxidative stress and is one of the most widely used hepatic toxins for experimental induction of liver fibrosis in the laboratory. In this study, we investigated the restoration of the CCl4-induced hepatic fibrosis by high dose of silymarin in rats. After treatment with oil (as normal group; n = 6) or CCl4 [as model (n = 7) and therapeutic (n = 7) groups] by intragastric delivery for 8 weeks for the induction of liver fibrosis, the rats in the normal and model group were administered orally normal saline four times a week for 3 weeks whilst the therapeutic group received silymarin (200 mg/kg). The histopathological changes were observed with Masson staining. The results showed that the restoration of the CCl4-induced damage of liver fibrosis in the therapeutic group was significantly increased as compared to that in the model group. Moreover, silymarin significantly decreased the elevation of aspartate aminotransferase (AST), alanine aminotransferase, and alkaline phosphatase in serum, and also reversed the altered expressions of alpha-smooth muscle actin in liver tissue. Therefore, these findings indicated that silymarin may have the potential to increase the resolution of the CCl4-induced liver fibrosis in rats.

Molecular predictors of survival after adjuvant chemotherapy for colon cancer.

BACKGROUND: Adjuvant chemotherapy improves survival among patients with stage III colon cancer, but no reliable molecular predictors of outcome have been identified. METHODS: We evaluated loss of chromosomal material (also called loss of heterozygosity or allelic loss) from chromosomes 18q, 17p, and 8p; cellular levels of p53 and p21(WAF1/CIP1) proteins; and microsatellite instability as molecular markers. We analyzed tumor tissue from 460 patients with stage III and high-risk stage II colon cancer who had been treated with various combinations of adjuvant fluorouracil, leucovorin, and levamisole to determine the ability of these markers to predict survival. RESULTS: Loss of heterozygosity at 18q was present in 155 of 319 cancers (49 percent). High levels of microsatellite instability were found in 62 of 298 tumors (21 percent), and 38 of these 62 tumors (61 percent) had a mutation of the gene for the type II receptor for transforming growth factor beta1 (TGF-beta1). Among patients with microsatellite-stable stage III cancer, five-year overall survival after fluorouracil-based chemotherapy was 74 percent in those whose cancer retained 18q alleles and 50 percent in those with loss of 18q alleles (relative risk of death with loss at 18q, 2.75; 95 percent confidence interval, 1.34 to 5.65; P=0.006). The five-year survival rate among patients whose cancer had high levels of microsatellite instability was 74 percent in the presence of a mutated gene for the type II receptor for TGF-beta1 and 46 percent if the tumor did not have this mutation (relative risk of death, 2.90; 95 percent confidence interval, 1.14 to 7.35; P=0.03). CONCLUSIONS: Retention of 18q alleles in microsatellite-stable cancers and mutation of the gene for the type II receptor for TGF-beta1 in cancers with high levels of microsatellite instability point to a favorable outcome after adjuvant chemotherapy with fluorouracil-based regimens for stage III colon cancer.

Phase II evaluation of preoperative chemoradiation and postoperative adjuvant chemotherapy for squamous cell and adenocarcinoma of the esophagus.

PURPOSE: This phase II trial evaluated continuous-infusion cisplatin and fluorouracil (5-FU) with radiotherapy followed by esophagectomy. The objectives of this trial were to determine the complete pathologic response rate, survival rate, toxicity, pattern of failure, and feasibility of administering adjuvant chemotherapy in patients with resectable cancer of the esophagus treated with preoperative chemoradiation. PATIENTS AND METHODS: Patients were staged using computed tomography, endoscopic ultrasound, and laparoscopy. The preoperative treatment plan consisted of continuous intravenous infusion of cisplatin and 5-FU and a total dose of 44 Gy of radiation. Esophagogastrectomy was planned for approximately 4 weeks after the completion of chemoradiotherapy. Paclitaxel and cisplatin were administered as postoperative adjuvant therapy. RESULTS: Forty-two patients were enrolled onto the trial. Of the 39 patients who proceeded to surgery, 29 responded to preoperative treatment: 11 achieved pathologic complete response (CR) and 18 achieved a lower posttreatment stage. Five patients had no change in stage, whereas eight had progressive disease (four with distant metastases and four with increases in the T and N stages). At a median follow-up of 30.2 months, the median survival time has not been reached and the 2-year survival rate is 62%. The median survival of pathologic complete responders has not been reached, whereas the 2-year survival rate of this group is 91% compared with 51% in patients with complete tumor resection with residual tumor (P =.03). CONCLUSION: An excellent survival rate, comparable to that of our prior preoperative trial, was achieved with lower doses of preoperative cisplatin and 5-FU concurrent with radiotherapy.