Hulin Chang

Protective role of hydrogen-rich water on aspirin-induced gastric mucosal damage in rats

AIM To investigate the role of the hydrogen-rich water (HRW) in the prevention of aspirin-induced gastric mucosal injury in rats. METHODS Forty male rats were allocated into four groups: normal control group, HRW group, aspirin group, and HRW plus aspirin group. The protective efficacy was tested by determining the gastric mucosal damage score. Malondialdehyde (MDA), superoxide dismutase (SOD), myeloperoxidase (MPO), interleukin (IL)-06 and tumor necrosis factor (TNF)-α in gastric tissues were evaluated. The serum levels of IL-1β and TNF-α were also detected. Histopathology of gastric tissues and localization of Cyclooxygenase 2 (COX-2) were detected using hematoxylin and eosin staining and immunohistochemistry, respectively. RESULTS Pretreatment with HRW obviously reduced aspirin-induced gastric damage scores (4.04 ± 0.492 vs 2.10 ± 0.437, P < 0.05). The oxidative stress levels of MDA and MPO in the gastric tissues increased significantly in the aspirin-treated group compared with the HRW group (2.43 ± 0.145 vs 1.79 ± 0.116 nmol/mg prot, P < 0.05 and 2.53 ± 0.238 vs 1.40 ± 0.208 U/g tissue, P < 0.05, respectively). HRW could obviously elevated the SOD levels in the gastric tissues (37.94 ± 8.44 vs 59.55 ± 9.02 nmol/mg prot, P < 0.05). Pretreatment with HRW significantly reduced IL-06 and TNF-α in the gastric tissues (46.65 ± 5.50 vs 32.15 ± 4.83 pg/mg, P < 0.05 and 1305.08 ± 101.23 vs 855.96 ± 93.22 pg/mg, P < 0.05), and IL-1β and TNF-α in the serum (505.38 ± 32.97 vs 343.37 ± 25.09 pg/mL, P < 0.05 and 264.53 ± 28.63 vs 114.96 ± 21.79 pg/mL, P < 0.05) compared to treatment with aspirin alone. HRW could significantly decrease the COX-2 expression in the gastric tissues (staining score: 8.4 ± 2.1 vs 2.9 ± 1.5, P < 0.05). CONCLUSION HRW pretreatment alleviated the aspirin-induced gastric lesions by inhibiting the oxidative stress, inflammatory reaction and reducing the COX-2 in the gastric tissues.

Reactive oxygen species generation is essential for cisplatininduced accelerated senescence in hepatocellular carcinoma

Accelerated senescence is important because this process is involved in tumor suppression and has been induced by many chemotherapeutic agents. The platinum-based chemotherapeutic agent cisplatin displays a wide range of antitumor activities. However, the molecular mechanism of cisplatin-induced accelerated senescence in hepatocellular carcinoma (HCC) remains unclear. In the present study, the growth inhibitory effect of cisplatin on HepG2 and SMMC-7721 cells was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cellular senescence was then assessed by β-galactosidase assay. Senescence-related factors, including p53, p21, and p16, were evaluated by quantitative reverse transcription-polymerase chain reaction. Reactive oxygen species (ROS) was analyzed by flow cytometry. Our results revealed that cisplatin reduced the proliferation of HepG2 and SMMC-7721 cells in a dose- and time-dependent manner. Senescent phenotype observed in cisplatintreated hepatoma cells was dependent on p53 and p21 activation but not on p16 activation. Furthermore, cisplatininduced accelerated senescence depended on intracellular ROS generation. The ROS scavenger N-acetyl-L-cysteine also significantly suppressed the cisplatin-induced senescence of HepG2 and SMMC-7721 cells. In conclusion, our results revealed a functional link between intracellular ROS generation and cisplatin-induced accelerated senescence, and this link may be used as a potential target of HCC.

New Insight into the Anti-liver Fibrosis Effect of Multitargeted Tyrosine Kinase Inhibitors: From Molecular Target to Clinical Trials

Tyrosine kinases (TKs) is a family of tyrosine protein kinases with important functions in the regulation of a broad variety of physiological cell processes. Overactivity of TK disturbs cellular homeostasis and has been linked to the development of certain diseases, including various fibrotic diseases. In regard to liver fibrosis, several TKs, such as vascular endothelial growth factor receptor, platelet-derived growth factor receptor, fibroblast growth factor receptor, and epidermal growth factor receptor kinases, have been identified as central mediators in collagen production and potential targets for anti-liver fibrosis therapies. Given the essential role of TKs during liver fibrogenesis, multitargeted inhibitors of aberrant TK activity, including sorafenib, erlotinib, imatinib, sunitinib, nilotinib, brivanib and vatalanib, have been shown to have potential for treating liver fibrosis. Beneficial effects are observed by researchers of this field using these multitargeted TK inhibitors in preclinical animal models and in patients with liver fibrosis. The present review will briefly summarize the anti-liver fibrosis effects of multitargeted TK inhibitors and molecular mechanisms.

Distinctions between clinicopathological factors and prognosis of alpha-fetoprotein negative and positive hepatocelluar carcinoma patients.

Serum alpha-fetoprotein (AFP) is a significant marker for clinical diagnosis and prognosis evaluation in hepatocellular carcinoma (HCC) patients. However, some proportion of liver cancer patients are AFP-negative (AFP ≤20 ng/ml). In order to study the differences between clinicopathological factors and prognosis of alpha-fetoprotein negative and positive patients, a total of 114 cases (41 AFP-negative and 73 AFP-positive) were selected for our research. By systematically statistical analysis, the results demonstrated that compared with AFP-negative patients, AFP-positive examples were more likely to feature cirrhosis nodules, non-complete neoplasm capsules, and a poor Edmondson-steiner grade. Furthermore, AFP-negative patients demonstrated a favorable long-term prognosis. By univariate analysis and multivariate analysis with Coxs proportional hazards model, multiple tumors were found to be independent risk factors for worse survival of AFP negative patients; however, less tumor-free margins, multiple tumors and Edmondson-steiner grades III/IV, proved to be independent risk factors leading to a poor prognosis of AFP positive cases. Finally, we can infer that high levels of AFP signify a highly malignant tumor and unfavorable prognosis.

Circulating miRNA-21-5p as a diagnostic biomarker for pancreatic cancer: evidence from comprehensive miRNA expression profiling analysis and clinical validation

Pancreatic cancer (PC) is a highly fatal disease worldwide and is often misdiagnosed in its early stages. The exploration of novel non-invasive biomarkers will definitely benefit PC patients. Recently, circulating miRNAs in body fluids are emerging as non-invasive biomarkers for PC diagnosis. In this study, we first conducted comprehensive robust rank aggregation (RRA) analysis based on 21 published miRome profiling studies. We statistically identified and clinically validated a miRNA expression pattern in PC patients. These miRNAs consisted of four up-regulated (hsa-miR-21-5p, hsa-miR-31-5p, hsa-miR-210-3p and hsa-miR-155-5p) and three down-regulated miRNAs (hsa-miR-217, hsa-miR-148a-3p and hsa-miR-375). Among them, hsa-miR-21-5p was one of the most highly expressed miRNAs in the serum of PC patients. Our validation test further suggested a relatively high accuracy of serum hsa-miR-21-5p levels in the diagnosis of PC, with a sensitivity of 0.77 and a specificity of 0.80. Finally, a diagnostic meta-analysis based on 9 studies also revealed favorable sensitivity and specificity of circulating hsa-miR-21-5p for the diagnosis of PC (pooled sensitivity and specificity were 0.76 and 0.74, respectively), which was consistent with our findings. Taken together, as one of the most aberrantly expressed miRNAs in PC, circulating hsa-miR-21-5p might be a promising serum biomarker in patients with PC.

Prognosis and Management for Gallbladder Cancer with Hepatic Invasion: Long-term Results of 139 Patients from a Single Center in China

OBJECTIVE To improve the diagnosis of primary gallbladder carcinoma (GBC) with/without hepatic metastases by analyzing our experience of different GBC treatment in our patients. METHODS A retrospective study was carried out to analyze the clinical data of the 139 patients with GBC who underwent hepatic resection in our unit from January 2003 to December 2007. Patients were divided into two groups according to whether they demonstrated hepatic invasion. Tumor presentation, surgical modes, and prognosis of each patient were retrospectively reviewed. Kaplan-Meier curves and log-rank tests were employed to compare the survival rates of those patients undergoing different surgical procedures. RESULTS Of the 139 patients, 46 were men and 93 were women with the male to female ratio of 1:2.0. Their ages were ranged from 35 to 86 years with a mean age of 62.8±10.4 years. There were 73 patients complicated with hepatic invasion (group A), and no hepatic invasion occurred in the other 66 patients (group B). Compared with the group B, the patients with hepatic invasion suffered lower differentiation of tumor (p=0.000), more advanced Nevin staging (p=0.008) and poorer prognosis (p=0.013). Radical resection were more frequently performed in group B (75.76%) than in group A (45.20%) with better outcomes (p=0.000). CONCLUSION GBC patients complicated with hepatic invasion had poorer prognosis than those without invasion in long-term follow-ups. Radical resection might result in a satisfied prognosis in patients without hepatic invasion, but appears less favorable than palliative resection in those who were complicated with hepatic invasion.

Upregulation of Glycoprotein Nonmetastatic B by Colony-Stimulating Factor-1 and Epithelial Cell Adhesion Molecule in Hepatocellular Carcinoma Cells

Considerable effort has been made in elucidating the appropriate biomarkers and the mechanism and functional significance of these biomarkers in hepatocellular carcinoma (HCC). Glycoprotein nonmetastatic B (GPNMB) overexpression occurs in cutaneous melanomas and breast cancer, and it is an attractive candidate for cancer therapy. However, little is known about the expression and regulation of GPNMB in HCC. In this study, we investigated the expression of GPNMB in HCC histochemically and tested the regulation effects of the epithelial cell adhesion molecule (EpCAM) and colony-stimulating factor (CSF-1) on the expression of GPNMB in HCC cells. Our results demonstrated that GPNMB levels were significantly enhanced in HCC compared with adjacent normal liver tissues. In HCC cells, GPNMB expression was regulated by EpCAM and CSF-1 partly through their common downstream product c-myc. Taken together, these results suggest that GPNMB, the expression of which was regulated in HCC cells by the highly coordinated function of various proteins, may be a potential target for HCC therapy.

Gallbladder cancer: a subtype of biliary tract cancer which is a current challenge in China.

Biliary tract cancers, broadly described as malignancies that arise from the biliary tract epithelia, are usually divided into two major clinical phenotypes: cholangiocarcinoma and gallbladder cancer, differing in etiopathogenesis, risk factors, and perhaps molecular and genetic signatures. Atypical symptoms and lack of tumor biomarkers make it difficult to diagnose in early stages. At the time of presentation, few patients are candidates for potentially curative surgical resection. We here assessed and compared features of a total of 150 cases divided into extra- and intrahepatic cholangiocarcinomas and gallbladder cancers (GBC). Although there were no significant differences in serum tumour marker levels, GBC patients had the poorest prognosis. Furthermore, gallbladder cancer respond poorly to chemotherapy or radiation therapy and approximately half of untreated patients died within 10 months. Therefore, treatment for patients with gallbladder cancer is still in challenge. Outcomes and survival of these patients had improved little over the past three decades - a period in which new successful treatments have greatly contributed to the prolonged patient survival for many other cancers.

Polymorphisms of glutathione S-transferase genes and survival of resected hepatocellular carcinoma patients.

AIM To investigate the effects of single nucleotide polymorphisms (SNPs) in glutathione S-transferase (GST) genes on survival of hepatocellular carcinoma (HCC) patients. METHODS Twelve tagging SNPs in GST genes (including GSTA1, GSTA4, GSTM2, GSTM3, GSTO1, GSTO2 and GSTP1) were genotyped using Sequenom MassARRAY iPLEX genotyping method in a cohort of 214 Chinese patients with resected HCC. The Cox proportional hazards model and log-rank test were performed to determine the SNPs related to outcome. Additionally, stratified analysis was performed at each level of the demographic and clinical variables. An SNP-gene expression association model was further established to investigate the correlation between SNP and gene expression. RESULTS Two SNPs (GSTO2: rs7085725 and GSTP1: rs4147581) were significantly associated with overall survival in HCC patients (P = 0.035 and 0.042, respectively). In stratified analysis, they were more significantly associated with overall survival in patients with younger age, male gender and cirrhosis. We further investigated cumulative effects of these two SNPs on overall survival in HCC patients. Compared with the patients carrying no unfavorable genotypes, those carrying 2 unfavorable genotypes had a 1.70-fold increased risk of death (P < 0.001). The cumulative effects were more significant in those patients with younger age, male gender and cirrhosis (HR = 2.00, 1.94 and 1.97, respectively; all P < 0.001). Additionally, we found that heavy smoking resulted in a significantly worse overall survival in those patients carrying variant alleles of rs7085725 (HR = 2.07, 95%CI: 1.13-3.76, P = 0.018). The distributions of GSTO2: rs7085725 and GSTP1: rs4147581 genotypes were associated with altered gene expression and contributed to influences on overall survival. CONCLUSION Our study provides the first evidence that GSTO2 and GSTP1 gene polymorphisms may serve as independent prognostic markers for HCC patients.

Highlights for α-fetoprotein in determining prognosis and treatment monitoring for hepatocellular carcinoma.

AIM To explore the prognostic value in the monitoring of treatment efficacy of serial α-fetoprotein (AFP) in hepatocellular carcinoma (HCC) patients. METHODS We searched MEDLINE, EMBASE and COCHRANE LIBRARY through April 21, 2012, to find qualifying articles. Our overall search strategy included terms for HCC, AFP, treatment response, and prognosis. Literature was limited to English-language, human studies. Studies reporting cumulative survival rates were summarized qualitatively. For the prognostic meta-analysis, we undertook a series of meta-analyses that summarised the Cox proportional hazard ratios (HRs) by assuming a random effects model. With regards to the correlation of AFP change with radiologic response, the categorical dichotomous variables were assessed using Poisson relative risks (RRs), which were incorporated into the random effects model meta-analysis of accuracy prediction. Between-study heterogeneity was estimated by use of the I² statistic. Publication bias was evaluated using the Begg funnel plot and Egger plot. Sensitivity analyses were conducted first by separating systemic treatment estimates from locoregional therapy estimates, evaluating different AFP response cut-off point effects, and exploring the impact of different study sizes. RESULTS Of 142 titles identified in our original search, 11 articles (12 clinical studies) met our criteria. Six studies investigated outcome in a total of 464 cases who underwent systemic treatment, and six studies investigated outcome in a total of 510 patients who received locoregional therapy. A random-effects model meta-analysis showed that AFP response was associated with an mortality HR of 0.55 (95%CI, 0.47-0.65) across HCC in overall survival (OS) and 0.50 (95%CI, 0.38-0.65) in progression-free survival. Restricting analysis to the six eligible analyses of systemic treatment, the pooled HRs were 0.64 (95%CI, 0.53-0.77) for OS. Limiting analysis to the six analyses of locoregional therapy, the pooled HRs for OS was 0.39 (95%CI, 0.29-0.53). We showed a larger pooled HR in the 50% definition studies (HR, 0.67, 95%CI, 0.55-0.83) compared with that from the 20% definition studies (HR, 0.41, 95%CI, 0.32-0.53). Restricting analysis to the four studies including over 100 patients individually, the pooled HR was 0.65 (95%CI, 0.54-0.79), with a pooled HR for OS of 0.35 (95%CI, 0.23-0.46) in the studies of less than 100 patients. As to radiological imaging, 43.1% (155/360) of the patients in the AFP response group presented with a radiological overall response, while the response rate decreased to 11.5% (36/313) in the patients from the AFP nonresponse group. The RR of having no overall response was significantly lower in the AFP response group than the AFP nonresponse group (RR, 0.67; 95%CI, 0.61-0.75). In terms of disease control rate, 86.9% (287/330) in the AFP response group and 51.0% (153/300) in the AFP nonresponse group showed successful disease control, respectively. The RR of disease control failure, similarly, was significantly lower in the AFP response group (RR, 0.37; 95%CI, 0.23-0.58). But these findings could be overestimates because of publication and reporting bias. CONCLUSION HCC patients presenting with an AFP response are at decreased risk of mortality. In addition, patients with an AFP response also present with a higher overall response rate and disease control rate.