Zhongxia Wang

Systematic review and meta-analysis of triclosan-coated sutures for the prevention of surgical-site infection.

Surgical‐site infections (SSIs) increase morbidity and mortality in surgical patients and represent an economic burden to healthcare systems. Experiments have shown that triclosan‐coated sutures (TCS) are beneficial in the prevention of SSI, although the results from individual randomized controlled trials (RCTs) are inconclusive. A meta‐analysis of available RCTs was performed to evaluate the efficacy of TCS in the prevention of SSI.

The Role of Hypoxia Inducible Factor-1 in Hepatocellular Carcinoma

Hypoxia is a common feature of many solid tumors, including hepatocellular carcinoma (HCC). Hypoxia can promote tumor progression and induce radiation and chemotherapy resistance. As one of the major mediators of hypoxic response, hypoxia inducible factor-1 (HIF-1) has been shown to activate hypoxia-responsive genes, which are involved in multiple aspects of tumorigenesis and cancer progression, including proliferation, metabolism, angiogenesis, invasion, metastasis and therapy resistance. It has been demonstrated that a high level of HIF-1 in the HCC microenvironment leads to enhanced proliferation and survival of HCC cells. Accordingly, overexpression, of HIF-1 is associated with poor prognosis in HCC. In this review, we described the mechanism by which HIF-1 is regulated and how HIF-1 mediates the biological effects of hypoxia in tissues. We also summarized the latest findings concerning the role of HIF-1 in the development of HCC, which could shed light on new therapeutic approaches for the treatment of HCC.

Lack of Association of Two Common Polymorphisms rs2910164 and rs11614913 with Susceptibility to Hepatocellular Carcinoma: A Meta-Analysis

Background Single nucleotide polymorphisms (SNPs) in microRNA-coding genes may participate in the process of carcinogenesis by altering the expression of tumor-related microRNAs. It has been suggested that two common SNPs rs2910164 in miR-146a and rs11614913 in miR-196a2 are associated with susceptibility to hepatocellular carcinoma (HCC). However, published results are inconsistent and inconclusive. In the present study, we performed a meta-analysis to systematically summarize the possible association between the two SNPs and the risk for HCC. Methodology/Principal Findings We conducted a search of case-control studies on the associations of SNPs rs2910164 and/or rs11614913 with susceptibility to HCC in PubMed, EMBASE, ISI Web of Science, Cochrane Central Register of Controlled Trials, ScienceDirect, Wiley Online Library and Chinese National Knowledge Infrastructure databases. Data from eligible studies were extracted for meta-analysis. HCC risk associated with the two polymorphisms was estimated by pooled odds ratios (ORs) and 95% confidence intervals (95% CIs). 5 studies on rs2910164 and 4 studies on rs11614913 were included in our meta-analysis. Our results showed that neither allele frequency nor genotype distribution of the two polymorphisms was associated with risk for HCC in all genetic models. Similarly, subgroup analysis in Chinese population showed no association between the two SNPs and the susceptibility to HCC. Conclusions/Significance This meta-analysis suggests that two common SNPs rs2910164 and rs11614913 are not associated with the risk of HCC. Well-designed studies with larger sample size and more ethnic groups are required to further validate the results.

PP2A-Mediated Anticancer Therapy

PP2A is a family of mammalian serine/threonine phosphatases that is involved in the control of many cellular functions including protein synthesis, cellular signaling, cell cycle determination, apoptosis, metabolism, and stress responses through the negative regulation of signaling pathways initiated by protein kinases. Rapid progress is being made in the understanding of PP2A complex and its functions. Emerging studies have correlated changes in PP2A with human diseases, especially cancer. PP2A is comprised of 3 subunits: a catalytic subunit, a scaffolding subunit, and a regulatory subunit. The alternations of the subunits have been shown to be in association with many human malignancies. Therapeutic agents targeting PP2A inhibitors or activating PP2A directly have shed light on the therapy of cancers. This review focuses on PP2A structure, cancer-associated mutations, and the targeting of PP2A-related molecules to restore or reactivate PP2A in anticancer therapy, especially in digestive system cancer therapy.

Expression of Potential Cancer Stem Cell Marker ABCG2 is Associated with Malignant Behaviors of Hepatocellular Carcinoma

Background. Despite improvement in treatment, the prognosis of hepatocellular carcinoma (HCC) remains disastrous. Cancer stem cells (CSCs) may be responsible for cancer malignant behaviors. ATP-binding cassette, subfamily G, member 2 (ABCG2) is widely expressed in both normal and cancer stem cells and may play an important role in cancer malignant behaviors. Methods. The expression of ABCG2 in HCC tissues and SMMC-7721 cells was examined, and the relevance of ABCG2 expression with clinical characteristics was analyzed. ABCG2+ and ABCG2− cells were sorted, and the potential of tumorigenicity was determined. Expression level of ABCG2 was manipulated by RNA interference and overexpression. Malignant behaviors including proliferation, drug resistance, migration, and invasion were studied in vitro. Results. Expression of ABCG2 was found in a minor group of cells in HCC tissues and cell lines. ABCG2 expression showed tendencies of association with unfavorable prognosis factors. ABCG2 positive cells showed a superior tumorigenicity. Upregulation of ABCG2 enhanced the capacity of proliferation, doxorubicin resistance, migration, and invasion potential, while downregulation of ABCG2 significantly decreased these malignant behaviors. Conclusion. Our results indicate that ABCG2 is a potential CSC marker for HCC. Its expression level has a close relationship with tumorigenicity, proliferation, drug resistance, and metastasis ability.

Baicalein Induces Apoptosis and Autophagy via Endoplasmic Reticulum Stress in Hepatocellular Carcinoma Cells

Background. Hepatocellular carcinoma (HCC) remains a disastrous disease and the treatment for HCC is rather limited. Separation and identification of active compounds from traditionally used herbs in HCC treatment may shed light on novel therapeutic drugs for HCC. Methods. Cell viability and colony forming assay were conducted to determine anti-HCC activity. Morphology of cells and activity of caspases were analyzed. Antiapoptotic Bcl-2 family proteins and JNK were also examined. Levels of unfolded protein response (UPR) markers were determined and intracellular calcium was assayed. Small interfering RNAs (siRNAs) were used to investigate the role of UPR and autophagy in baicalein-induced cell death. Results. Among four studied flavonoids, only baicalein exhibited satisfactory inhibition of viability and colony formation of HCC cells within water-soluble concentration. Baicalein induced apoptosis via endoplasmic reticulum (ER) stress, possibly by downregulating prosurvival Bcl-2 family, increasing intracellular calcium, and activating JNK. CHOP was the executor of cell death during baicalein-induced ER stress while eIF2α and IRE1α played protective roles. Protective autophagy was also triggered by baicalein in HCC cells. Conclusion. Baicalein exhibits prominent anti-HCC activity. This flavonoid induces apoptosis and protective autophagy via ER stress. Combination of baicalein and autophagy inhibitors may represent a promising therapy against HCC.

Hepatic stellate cell coculture enables sorafenib resistance in Huh7 cells through HGF/c-Met/Akt and Jak2/Stat3 pathways.

Purpose. Tumor microenvironment confers drug resistance to kinase inhibitors by increasing RKT ligand levels that result in the activation of cell-survival signaling including PI3K and MAPK signals. We assessed whether HSC-LX2 coculture conferred sorafenib resistance in Huh7 and revealed the mechanism underlying the drug resistance. Experimental Design. The effect of LX2 on sorafenib resistance was determined by coculture system with Huh7 cells. The rescue function of LX2 supernatants was assessed by MTT assay and fluorescence microscopy. The underlying mechanism was tested by administration of pathway inhibitors and manifested by Western blotting. Results. LX2 coculture significantly induced sorafenib resistance in Huh7 by activating p-Akt that led to reactivation of p-ERK. LX2 secreted HGF into the culture medium that triggered drug resistance, and exogenous HGF could also induce sorafenib resistance. The inhibition of p-Akt blocked sorafenib resistance caused by LX2 coculture. Increased phosphorylation of Jak2 and Stat3 was also detected in LX2 cocultured Huh7 cells. The Jak inhibitor tofacitinib reversed sorafenib resistance by blocking Jak2 and Stat3 activation. The combined administration of sorafenib and p-Stat3 inhibitor S3I-201 augmented induced apoptosis even in the presence of sorafenib resistance. Conclusions. HSC-LX2 coculture induced sorafenib resistance in Huh7 through multiple pathways: HGF/c-Met/Akt pathway and Jak2/Stat3 pathway. A combined administration of sorafenib and S3I-201 was able to augment sorafenib-induced apoptosis even in the presence of LX2 coculture.

Associations of miR-499 and miR-34b/c Polymorphisms with Susceptibility to Hepatocellular Carcinoma: An Evidence-Based Evaluation

Background. Hepatocellular carcinoma (HCC) represents the sixth common cancer in the world. Single nucleotide polymorphisms (SNPs) in microRNA genes may be associated with susceptibility to HCC. Recently, several studies have reported possible associations of SNPs miR-499 T>C rs3746444 and miR-34b/c T>C rs4938723 with the risk of HCC. However the results are inconsistent and inconclusive. In this present study, we conducted a meta-analysis to comprehensively evaluate potential associations between the two SNPs and HCC susceptibility. Methods. Through a systematic literature search, 8-case-control studies involving 5464 subjects were identified and included in this meta-analysis. The association between the two common SNPs and HCC risk was estimated by pooled odds ratios (ORs) and 95% confidence intervals (95% CIs). Our results showed no significant association between rs3746444 and susceptibility to HCC, whereas variant genotypes of rs4938723 were associated with increased HCC risk in allele frequency model and heterozygous model (C versus T, OR = 1.11, 95% CI: 1.01–1.23, P = 0.04; TC versus TT, OR = 1.19, 95% CI: 1.03–1.37, P = 0.02). Conclusions. The current evidence did not support association between rs3746444 and HCC risk. SNP rs4938723 may be associated with susceptibility to HCC. Further well-designed studies are required to clarify the relationships between the two SNPs and HCC risk.

Preoperative serum liver enzyme markers for predicting early recurrence after curative resection of hepatocellular carcinoma.

BACKGROUND Early recurrence of hepatocellular carcinoma (HCC) is associated with worse prognosis after liver resection. This study aimed to investigate the prognostic value of common liver enzyme markers in HCC early recurrence after curative hepatectomy and to establish a simple predictive model for HCC early recurrence. METHODS A total of 200 patients who had undergone curative resection for HCC were retrospectively analyzed. The patients were divided into early recurrence (within 2 years) and non-early recurrence groups. Demographical characteristics, preoperative liver function parameters, surgical factors and tumor related factors of the patients were assessed by univariate analysis to identify potential significant predictors for early recurrence after resection of HCC. Parameters with statistical significance were entered into a Cox proportional hazard model to find independent risk factors. Receiver operating characteristic analysis was done to determine optimal cut-off values and the number of combined factors in multi-factor predictive model. RESULTS Of 13 potential risk factors for early recurrence identified by univariate analysis, high lactate dehydrogenase (LDH>206 U/L, HR=1.711, P=0.006), high aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio (AST/ALT>0.96, HR=1.769, P=0.006), elevated alpha-fetoprotein (AFP<8.6 ng/mL, HR=2.079, P=0.007), small resection margin (≤1 cm, HR=2.354, P<0.001) and advanced TNM stage (TNM III-IV, HR=2.164, P<0.001) were independent risk factors for early recurrence of HCC shown by multivariate analysis. Patients with three or more concurrent independent risk factors had significantly higher risk for early recurrence than those with low risk factors. The sensitivity and specificity of this predictive model are 53.6% and 80.7%, respectively (area under curve=0.741, 95% CI 0.674-0.800, P<0.0001). CONCLUSIONS Preoperative common liver enzyme markers, LDH and AST/ALT ratio, were independently associated with early recurrence of HCC. The combination of serum liver enzyme markers with AFP, resection margin and TNM stage better predicted early recurrence of HCC after curative resection in a simple multi-factor model.

Preoperative inflammation-based markers predict early and late recurrence of hepatocellular carcinoma after curative hepatectomy.

BACKGROUND Recurrence of hepatocellular carcinoma (HCC) after curative resection remains a major cause of treatment failure and tumor-related death. Patterns of HCC recurrence can be categorized into early recurrence and late recurrence which have different underlying mechanisms. In this study, we investigated if simple inflammation-based clinical markers can distinguish patterns of recurrence after curative resection of HCC. METHODS A retrospective analysis of 223 patients who underwent curative hepatectomy for HCC was performed. Preoperative inflammation-based factors including neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio, gamma-glutamyl transferase/alanine aminotransferase ratio, aspartate aminotransferase/platelet ratio index (APRI) and prognostic nutritional index together with other clinicopathologic parameters were evaluated by univariate analysis and multivariate analysis to identify independent prognostic factors. By combining risk factors, predictive models were established to distinguish populations at high risk of early or late recurrence. RESULTS Age ≤50 years, resection margin ≤1 cm, TNM stage III-IV, NLR>2.75, APRI>0.23 and positive alpha-fetoprotein were independent adverse prognostic factors for early recurrence. Patients with three or more risk factors were at significant higher risk of early recurrence. APRI>0.23 and positive hepatitis B e antigen (HBeAg) were independent risk factors of late recurrence, the coexistence of high APRI and positive HBeAg increased the risk of late recurrence. CONCLUSIONS Preoperative inflammation-based prognostic factors predict early and late recurrence of HCC after curative resection. Different prognostic factor combinations distinguish high-risk populations of early or late HCC recurrence.