Effect of entecavir in the treatment of patients with hepatitis B virus-related compensated and decompensated cirrhosis.

Chronic hepatitis B virus (CHB) infection is a burden on global healthcare and is associated with a higher risk of serious sequelae, including cirrhosis and hepatocellular carcinoma. The clinical application of entecavir as a treatment for CHB has produced positive outcomes, and so is an attractive form of pharmacological therapy. However, little data exists comparing the safety and efficacy of entecavir for the treatment of hepatitis B virus (HBV)-related compensated, and decompensated cirrhosis, respectively. The aim of the present study was to evaluate entecavir therapy as a treatment for patients with HBV-related compensated and decompensated cirrhosis. A retrospective analysis of 46 compensated patients (compensated group) and 51 decompensated cirrhotic patients (decompensated group) treated with entecavir was conducted. Baseline demographics, clinical outcomes, and adverse events during the treatment were compared. Treatment with entecavir for 96 weeks resulted in significant improvements in serum levels of HBV DNA (P=0.002), albumin (P=0.014), cholinesterase (CHE; P=0.001), HBV DNA negativity rate (P=0.004), Child-Turcotte-Pugh score (P=0.030), alanine aminotransferase normalized rate (P=0.039), and the degree of esophageal varices liver stiffness (P=0.002) in the two groups. However, statistical analysis revealed that the improvements were significantly higher in the compensated group compared with the decompensated group (P<0.05). The complement component (C)3 and C4 levels were also significantly increased in the compensated group compared with the decompensated group at weeks 24, 48 and 96 (P<0.05). In addition, the incidences of hepatocellular carcinoma, upper digestive tract hemorrhage and ascites were significantly higher in the decompensated group compared with the compensated group (P<0.05). In conclusion, treatment with 96-week entecavir therapy produced similar clinical outcomes in compensated and decompensated cirrhotic patients via inhibiting HBV-DNA viral load and recovering complement C3 and C4; however, entecavir exerts a better effect on patients with compensated cirrhosis, and so this therapy may improve the prognosis of such patients.

B7-H1 and B7-H4 expression in colorectal carcinoma: correlation with tumor FOXP3(+) regulatory T-cell infiltration.

B7-H1 and B7-H4 are newly discovered members of the B7-CD28 family. They can inhibit T cell activation and proliferation and regulate T cell immune response negatively. Both B7-H1 and B7-H4 are expressed in many tumors and are classified as co-inhibitors of cell-mediated immunity. FOXP3(+) regulatory T cells (Tregs) play an important role in the maintenance of tumor immunity tolerance. However, the implication of B7-H1 and B7-H4 expression and their interaction with Tregs infiltration in colorectal cancer are unknown. The present study aimed to determine the expression of B7-H1 and B7-H4 as well as Tregs infiltration in colorectal cancer and to explore the clinical and pathological implication of suppressor immune cells and molecules. Frozen sections and immunohistochemical assay were undertaken to assess B7-H1, B7-H4 expression and Tregs infiltration in fresh specimens collected from 56 patients with colorectal carcinoma. The results showed that expression of B7-H1 and B7-H4 in colorectal carcinoma tissues was significantly higher than in adjacent normal mucosa (P<0.001). B7-H1 expression was positively correlated to the infiltration depth, lymph node metastasis and advanced Duke's stage (P<0.05, P<0.05 and P<0.05, respectively), whereas B7-H4 expression was positively related to the infiltration depth and lymph node metastasis (P<0.01 and P<0.05, respectively). Furthermore, Tregs infiltration was more frequent in tumor tissue than in adjacent normal mucosa and was associated with poor differentiation and positive lymph node metastasis (P<0.01, and P<0.01, respectively). The statistical analysis indicated a significant correlation between Tregs infiltration and B7-H1 or B7-H4 expression respectively. These results suggest that over-expression of B7-H1 and B7-H4 has stronger prognostic significance and promote tumor tolerance, and they might contribute to Tregs development in the colorectal carcinoma tolerogenic milieu.

Sorbitol induces apoptosis of human colorectal cancer cells via p38 MAPK signal transduction.

Sorbitol has been reported to have anticancer effects in several tumor models, however its effects on colorectal cancer remain elusive. In the present study, the effects of sorbitol on growth inhibition and apoptosis in the colorectal cancer HCT116 cell line were evaluated and its mechanism of action was examined. An MTT assay was utilized to determine the effect of sorbitol on HCT116 cell proliferation at different time points and variable doses. Western blot analysis was used to examine the effect of sorbitol on apoptosis-related protein expression and the p38 MAPK signaling pathway. The results revealed that sorbitol may inhibit the growth of HCT116 cells in a time- and dose-dependent manner. Following treatment with sorbitol for 3 h, western blotting demonstrated cleavage of the caspase-3 zymogen protein and a cleavage product of poly (ADP-ribose) polymerase (PARP), a known substrate of caspase-3, was also evident. During sorbitol-induced apoptosis, the mitochondrial pathway was activated by a dose-dependent increase in Bax expression and cytochrome c release, while the expression of anti-apoptotic protein Bcl-2 was significantly decreased in a dose-dependent manner. The investigation for the downstream signal pathway revealed that sorbitol-induced apoptosis was mediated by an increase in phosphorylated p38 MAPK expression. Overall, the observations from the present study imply that sorbitol causes increased levels of Bax in response to p38 MAPK signaling, which results in the initiation of the mitochondrial death cascade. Therefore, sorbitol is a promising candidate as a potential chemotherapeutic agent for the treatment of colorectal cancer HCT116 cells.

Effect of low intensity pulsed ultrasound on repairing the periodontal bone of Beagle canines.

OBJECTIVE: To investigate the repairing effect of low intensity pulsed ultrasound (LIPUS) on the Beagle canines periodontal bone defect. METHODS: A total of 12 Beagle dogs with periodontal bone defect model were randomly divided into control group, LIPUS group, guided tissue regeneration (GTR) group and LIPUS+GTR group, with three in each. After completion of the models, no other proceeding was performed in control group; LIPUS group adopt direct exposure to radiation line LIPUS processing 1 week after modeling; GTR group adopted treatment with GTR, following the CTR standard operation reference; LIPUS+GTR group was treated with LIPUS joint GTR. Temperature change before treatment and histopathological change of periodontal tissue after repair was observed. RESULTS: There was no significant difference in temperature changes of periodontal tissue between groups (P>0.05). The amount and maturity of LIPUS+GTR group were superior to other groups; new cementum, dental periodontal bones of GTR group were superior to the control group but less than LIPUS group; new collagen and maturity of the control group is not high relatively. CONCLUSIONS: LIPUS can accelerate the calcium salt deposition and new bone maturation, thus it can serve as promoting periodontal tissue repair, and shortening the periodontal tissue repair time.

Potential role of plasmacytoid dendritic cells for FOXP3+ regulatory T cell development in human colorectal cancer and tumor draining lymph node.

FOXP3(+) regulatory T cells (Tregs) play an important role in the maintenance of tumor immunity tolerance. Compared with conventional myeloid dentritic cells (mDCs), plasmacytoid dendritic cells (pDCs) exhibit poor immunostimulatory ability, and their interaction with T cells often promotes the development of Tregs. The aim of this study was to determine FOXP3(+) Tregs and CD123(+)pDCs infiltration in colorectal cancer and tumor draining lymph node (TDLN), and to evaluate the clinical significance and relationship between pDCs infiltration and Tregs development in the CRC tolerogenic milieu. An immunohistochemical assay was conducted to assess FOXP3(+)Tregs and CD123(+)pDCs infiltration in tumor tissue and in metastatic-free TDLN (mfTDLN) and metastatic TDLN (mTDLN). The results showed that FOXP3(+) Tregs infiltration was more frequent in tumor tissue than in adjacent normal mucosa (P<0.001). FOXP3(+)Tregs infiltration was associated with advanced TNM stage and lymph node metastasis (P<0.01 and P<0.01 for TNM stage and lymph node metastasis, respectively). Different from FOXP3(+)Tregs, CD123(+)pDCs frequencies were lower in most CRC tumor tissues, whereas the positive rate of CD123 expression in CRC was significantly higher than in adjacent normal mucosa tissue (P<0.01). Compared to mfTDLN, mTDLN was significantly enriched in FOXP3(+) Tregs (P<0.01) and increased in pDC/mDC ratio (P<0.01). The statistical analysis demonstrated a significant correlation in both Tregs and pDC/mDC ratio in mTDLN. These results suggest that there are more FOXP3(+) Tregs with a stronger prognostic significance which might promote tumor tolerance, and that CD123(+)pDCs might contribute to Tregs development in the CRC tolerogenic milieu.

FOXP3 and TLR4 protein expression are correlated in non-small cell lung cancer: implications for tumor progression and escape.

NSCLC (non-small cell lung cancer) is the most common type of lung cancer and usually has poor prognosis. FOXP3 in regulatory T cells (Tregs) and toll-like receptor 4 (TLR4) on some tumor cells are known to be important for tumor escape and clinical tumor formation. Since FOXP3 was found recently in some tumor cells, we speculated if lung tumor cells express FOXP3 and then mimic Tregs to promote tumor escape. As TLR4 induces activation of Tregs, we also hypothesized that FOXP3 and TLR4 may have a correlation in NSCLC progression. The expression levels of FOXP3 and TLR4 protein were detected using immunohistochemistry in 53 postoperative specimens of NSCLC patients and in 15 normal lung tissues from excisions of benign lesion. The relationship between protein expression levels and clinical pathology parameters, as well as the relationship between the expression of FOXP3 and TLR4, were analyzed. FOXP3 and TLR4 expression in NSCLC were significantly elevated as compared to normal lung tissue. FOXP3 expression was closely related with lymph node metastasis and TNM staging, whereas TLR4 expression was closely related with tumor differentiation. The Spearman correlation coefficient indicated a significant positive correlation between FOXP3 and TLR4 expression. These results indicate that FOXP3 and TLR4 may coordinate to play a role in tumor escape and subsequent tumor progression.

In situ analysis of FOXP3+ regulatory T cells and myeloid dendritic cells in human colorectal cancer tissue and tumor-draining lymph node.

Forkhead box protein 3 (FOXP3) regulatory T cells (Tregs) are important in the maintenance of tumor immunity tolerance. Myeloid dendritic cells (mDCs) are antigen-presenting cells (APCs) specialized to initiate and regulate immunity. Tregs and mDCs are suspected of influencing the interaction between the tumor and immune system, and thus the course of tumors. However, the implication and interaction of their concurrent infitration in colorectal cancer (CRC) remain unknown. The aim of this study was to determine FOXP3+ Tregs and CD11c+ mDCs infiltration in CRC and tumor-draining lymph node (TDLN) and to explore the clinical and pathological implication of suppressor and effector immune cell subsets. Immunohistochemical assay was conducted to assess FOXP3+ Tregs and CD11c+ mDCs infiltration in tumor tissue and in metastasis-free TDLN (mfTDLN) and metastatic TDLN (mTDLN). The results showed that FOXP3+ Tregs and CD11c+ mDCs infiltration was higher in tumor tissue compared to adjacent normal mucosa (P<0.001). FOXP3+ Tregs infiltration was associated with advanced tumor-node-metastasis (TNM) stage and lymph node metastasis (P<0.001 and P<0.001, for TNM stage and lymph node metastasis, respectively), whereas less CD11c+ mDCs infiltration of tumor in situ was associated with deeper tumor invasion, advanced TNM stages and lymph node metastasis (P<0.05, P<0.001 and P<0.001, for tumor invasion depth, TNM stages and lymph node metastasis, respectively). Compared to mfTDLN, mTDLN was significantly enriched in FOXP3+ Tregs (P<0.001) and reduced in CD11c+ mDCs (P<0.001). The statistical analysis demonstrated no significant correlations in Tregs and mDCs infiltration. These results suggest that more FOXP3+ Tregs and less CD11c+ mDCs infiltration have stronger prognostic significance in CRC. The presence of tumor cells in mTDLN may contribute to a tolerogenic milieu and facilitate the survival of metastatic tumor cells.

[Expressions of survivin and GRIM-19 in prostate cancer].

OBJECTIVE: To investigate the expressions of survivin and GRIM-19 in prostatic cancer tissue and their clinical implications. METHODS: We detected the expressions of survivin and GRIM-19 in the tissues of normal prostate (NP), benign prostate hyperplasia (BPH) and prostate cancer (PCa) using immunohistochemical staining, RT-PCR and Western blot, and processed the data by SPSS12. RESULTS: The positive rates of survivin expression were 6.25% , 18.18% and 90.62% in NP, BPH and PCa (P < 0.01), while those of GRIM-19 were 87.50%, 81.82% and 9.37% , respectively (P < 0.01). Semiquantitative RT-PCR and immunohistochemical staining showed that both survivin mRNA and survivin expressions were highly positive in PCa but negative in NP and BPH. Western blot exhibited that the survivin protein was expressed strongly in PCa but weakly in NP and BPH, while the GRIM-19 protein was expressed just contrariwise (P < 0.01). CONCLUSION: The expressions of survivin and GRIM-19 may be closely correlated with the pathogenesis of prostate cancer.

[Comparison of curative effect of low flow rate plasma exchange combined with hemofiltration for treatment of liver failure].

OBJECTIVE: To investigate the effect of plasma exchange (PE) combined with hemofiltration (HF) on liver failure. METHODS: Seventy-seven inpatients with liver failure admitted during January 2006 to August 2007 were randomly assigned to receive PE combined with HF (PE+HF group, 38 cases), or PE alone (PE group, 39 cases). Forty-one inpatients with liver failure who had not received artificial liver support treatment were assigned to serve as control group. The survival rates and biochemical parameters of three groups were compared. RESULTS: There was no significant difference in biochemical parameters before treatment among three groups. Compared with pre-treatment values, albumin (Alb), cholinesterase (ChE) and prothrombin activity (PTA) of both PE group and PE+HF group were significantly increased after treatment, and total bilirubin (TBIL), alanine transaminase (ALT), aspartate transaminase (AST) of both PE group and PE+HF group were significantly decreased after treatment (P<0.05 or P<0.01). The survival rate of PE group, PE+HF group and control group was 48.7% (19/39), 68.4% (26/38), and 29.3% (12/41) respectively. The survival rate of PE+HF group was significantly higher than that of control group (chi(2)=12.11, P<0.01). The rate of recovery of consciousness of patients with hepatic encephalopathy in PE+HF group was higher than that of PE group (42.8% vs. 0, P<0.05). Compared with PE alone, the result was better when it was combined with HF in correction of electrolyte disturbance and acid-base imbalance (19/23 vs. 0/21, P<0.05). CONCLUSION: Treatment of liver failure by PE combined with HF is safe and effective, and its efficacy is higher than PE alone.

[Reversal of multidrug resistance of human hepatocellular carcinoma cells by wild-type p53 gene and related mechanisms].

BACKGROUND & OBJECTIVE: The mechanism of cell apoptosis plays an important role in tumor multidrug resistance (MDR). Wild-type p53 (wt-p53) gene is an activator of cell apoptosis, and is closely related to tumor MDR. This study was to explore the effect of p53 gene on the reversal of MDR of human hepatocellular carcinoma (HCC) and related mechanisms. METHODS: The eukaryotic expression plasmid pCR 3.1-p53 was constructed and transfected into human HCC cell line Bel-7402. Proliferation and chemosensitivity of Bel-7402 cells to vincristine (VCR) were measured by MTT assay. The morphology of transfected Bel-7402 cells was observed. The expression of P-glycoprotein (P-gp) was detected by immunochemistry. The expression of multidrug resistance gene 1 (mdr1), multidrug resistance related protein (MRP), glutathione S-transferase pi (GST pi), and topoisomerase II alpha (Topo II alpha) were detected by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: The growth of wt-p53-transfected Bel-7402 cells was obviously slower than that of untransfected cells. After transfection with wt-p53, the chemosensivity of Bel-7402 cells to VCR was enhanced at the concentration of 0.01, 0.1, 1.0, 10, and 25 microg/ml. The optimal concentration was 1.0 microg/ml. After wt-p53 transfection and VCR treatment, the number of Bel-7402 cells was decreased; the cells were swollen severely with irregular projections; pyknosis, karyorrhexis and karyolysis were observed. After wt-p53 transfection, the expression of mdr1 and P-gp in Bel-7402 cells was down-regulated remarkably, and the expression of Topo II alpha was up-regulated. CONCLUSION: Wild-type p53 gene raises chemosensitivity of Bel-7402 cells to VCR, which may be partly related to the down-regulation of mdr1 and up-regulation of Topo II alpha.