Effects of TACE and preventive antiviral therapy on HBV reactivation and subsequent hepatitis in hepatocellular carcinoma: a meta-analysis.

BACKGROUND AND AIM: The impact of transarterial chemoembolization (TACE) and preventive antiviral therapy on the occurrence of hepatitis B virus (HBV) reactivation and subsequent hepatitis remains controversial. This meta-analysis aimed to evaluate the effect of TACE and preventive antiviral therapy on the risk of HBV reactivation and subsequent hepatitis. Meanwhile, we explored the role of HBeAg status in HBV reactivation after TACE. METHODS: We performed this meta-analysis with 11 included studies to assess the effect of TACE and preventive antiviral therapy on predicting clinical outcomes in HBV-related hepatocellular carcinoma (HCC). The pooled odds ratios (OR) were calculated using a random or fixed effects model. PUBMED, MEDLINE, EMBASE and the Cochrane Central Register of Controlled were searched for the included articles (from 2000 to December 2017). RESULTS: Our results showed that TACE significantly increased the risk of HBV reactivation (OR: 3.70; 95% CI 1.45-9.42; P < 0.01) and subsequent hepatitis (OR: 4.30; 95% CI 2.28-8.13; P < 0.01) in HCC patients. There was no significant difference in HBV reactivation after TACE between HBeAg positive and negative patients (OR: 1.28; 95% CI 0.31-5.34; P = 0.73). Preventive antiviral therapy could statistically reduce the rate of HBV reactivation (OR: 0.08; 95% CI 0.02-0.32; P < 0.01) and hepatitis (OR: 0.22; 95% CI 0.06-0.80; P = 0.02) in those with TACE treatment. CONCLUSIONS: The present study suggested that TACE was associated with a higher possibility of HBV reactivation and subsequent hepatitis. Preventive antiviral therapy is significantly in favor of a protective effect.

Correlation between S100A11 and the TGF-ß1/SMAD4 pathway and its effects on the proliferation and apoptosis of pancreatic cancer cell line PANC-1.

S100A11 as a S100 protein family member has been documented to play dual-direction regulation over cancer cell proliferation. We explored the role of S100A11 in the proliferation and apoptosis of pancreatic cancer cell line PANC-1 and the potential mechanisms involving the TGF-ß1/SMAD4/p21 pathway. S100A11 and TGF-ß1 protein expressions in 30 paraffin-embedded specimens were evaluated by immunohistochemistry. S100A11 and TGF-ß1 expression in PANC-1 cell line was suppressed using small interfering RNA (siRNA), respectively. Subsequently, pancreatic cancer cell apoptosis was measured by Cell Counting Kit-8 and flow cytometry, and S100A11 and TGF-ß1/SMAD4/p21 pathway proteins and genes were detected with Western blotting and quantitative polymerase chain reaction (qPCR). S100A11 cytoplasmic/nuclear protein translocation was examined using NE-PER® cytoplasm/nuclear protein extraction in cells interfered with TGF-ß1 siRNA. Our results showed that S100A11 expression was positively correlated with TGF-ß1 expression in pancreatic cancerous tissue. Silencing TGF-ß1 down-regulated intracellular P21WAF1 expression by 90%, blocked S100A11 from cytoplasm entering nucleus, and enhanced cell proliferation. Silencing S100A11 down-regulated intracellular P21 expression and promoted cell apoptosis without significantly changing TGF-ß1 and SMAD4 expression. Our findings revealed that S100A11 and TGF-ß1/SMAD4 signaling pathway were related but mutually independent in regulating PANC-1 cells proliferation and apoptosis. Other independent mechanisms might be involved in S100A11's regulation of pancreatic cell growth. S100A11 could be a potential gene therapy target for pancreatic cancer.

Actin related protein 3 (ARP3) promotes apoptosis of intestinal epithelial cells in ulcerative colitis.

Apoptosis in intestinal epithelial cells (IECs) promotes the development of ulcerative colitis (UC), a type of inflammatory bowel disease (IBD). Efficient clearance of apoptotic cells is essential for tissue homeostasis in metazoans. Actin related protein 3 (ARP3) promotes endothelial dysfunction. The expression and function of ARP3 in UC remains unclear. In this study, the expression of apoptotic markers as p53, Bax, Cleaved-Caspease9 and Cleaved-Caspease3 were proved to be increased in the intestinal epithelial cells (IECs) of UC patients and in a mouse disuccinimidyl suberate(DSS)-induced colitis model; meanwhile, ARP3 expression was elevated. ARP3 expression levels and the severity of symptoms in patients with UC were positively correlated. By knocking down ARP3 in a TNF-α-treated NCM-460 cell colitis model, the apoptotic markers described above were all decreased. In conclusion, our data indicates that ARP3 might promote the apoptosis of IECs in UC, revealing a potential molecular target for treating UC.

ß2-AR regulates the expression of AKR1B1 in human pancreatic cancer cells and promotes their proliferation via the ERK1/2 pathway.

Psychological stress has been recognized as a well-documented risk factor associated with ß2-adrenergic receptor (ß2-AR) in the development of pancreatic cancer. Aldo-keto reductase 1 member B1 (AKR1B1) is a potential interacting partner of ß2-AR, but the effect of their interaction on pancreatic cancer cells is not known at present. We found a positive correlation between AKR1B1 and ß2-AR expression in pancreatic cancer tissue samples, and co-localization of these proteins in the human pancreatic cancer BXPC-3 cell line. Compared to the controls, the CFPAC-1 and PANC-1 pancreatic cancer cells overexpressing ß2-AR and AKR1B1 respectively showed significantly higher proliferation rates, which is attributed to higher proportion of cells in the S phase and decreased percentage of early apoptotic cells. Furthermore, overexpression of ß2-AR led to a significant increase in the expression of AKR1B1 and phosphorylated extracellular signal-regulated kinase (p-ERK1/2). Overexpression of AKR1B1 significantly decreased ß2-AR levels and increased that of p-ERK1/2. Taken together, ß2-AR directly interacted with and up-regulated AKR1B1 in pancreatic cancer cells, and promoted their proliferation and inhibited apoptosis via the ERK1/2 pathway. Our findings also highlight the ß2-AR-AKR1B1 axis as a potential therapeutic target for pancreatic cancer.

A Comparison of Traditional and Novel Methods for the Separation of Exosomes from Human Samples.

Exosomes are discrete populations of small (40-200 nm in diameter) membranous vesicles that are released into the extracellular space by most cell types, eventually accumulating in the circulation. As molecular messengers, exosomes exert a broad array of vital physiologic functions by transporting information between different cell types. Because of these functional properties, they may have potential as biomarker sources for prognostic and diagnostic disease. Recent research has found that exosomes have potential to be utilized as drug delivery agents for therapeutic targets. However, basic researches on exosomes and researches on their therapeutic potential both require the existence of effective and rapid methods for their separation from human samples. In the current absence of a standardized method, there are several methods available for the separation of exosomes, but very few studies have previously compared the efficiency and suitability of these different methods. This review summarized and compared the available traditional and novel methods for the extraction of exosomes from human samples and considered their advantages and disadvantages for use in clinical laboratories and point-of-care settings.

Sex comb on midleg like-2 is a novel specific marker for the diagnosis of gastroenteropancreatic neuroendocrine tumors.

Sex comb on midleg like-2 (SCML2) is a polycomb-group protein that encodes transcriptional repressors essential for appropriate development in the fly and in mammals. On the basis of previous findings, the present study aimed to explore the possibility of developing SCML2 into a new diagnostic marker for gastroenteropancreatic neuroendocrine tumors (GEP-NETs). A total of 64 paired GEP-NET tissues and adjacent non-tumorous tissues were obtained from patients who had undergone surgical resection between January 2009 and January 2014, and the expression of SCML2 and two neuroendocrine markers, namely synaptophysin (Syn) and chromogranin A (CgA), in the tissues was assessed by immunohistochemistry. Strong SCML2 staining was observed predominantly in the cell nuclei of GEP-NET tissues, and the overall expression rate and staining intensity of SCML2 were higher than those of Syn or CgA, respectively. Spearman rank correlation analysis demonstrated that SCML2 was not correlated with either Syn or CgA, while the combined detection of SCML2 with Syn or with CgA increased the diagnostic sensitivity to 100%. SCML2 expression in GEP-NETs was associated with several clinicopathological parameters, such as histological type, tumor grade, depth of invasion and clinical stage. Kaplan-Meier survival curves revealed that patients with higher SCML2 expression had lower survival rates than those with lower expression levels, while Cox proportional hazards regression analysis revealed that SCML2 was not an independent prognostic factor for GEP-NET patients. Therefore, SCML2 may have potential as a specific marker for joint use with other markers to improve the diagnostic efficiency of GEP-NETs.

Far upstream element-binding protein 1 (FUBP1) is a potential c-Myc regulator in esophageal squamous cell carcinoma (ESCC) and its expression promotes ESCC progression.

The human far upstream element (FUSE) binding protein 1 (FUBP1) belongs to an ancient family which is required for proper regulation of the c-Myc proto-oncogene. Although c-Myc plays an important role in development of various carcinomas, the relevance of FUBP1 and their contribution to esophageal squamous cell carcinoma (ESCC) development remain unclear. In this study, we aimed to investigate the relationship between FUBP1 and c-Myc as well as their contribution to ESCC development. Western blot and immunohistochemical analyses were performed to evaluate FUBP1 expression. Coimmunoprecipitation analysis was performed to explore the correlation between FUBP1 and c-Myc in ESCC. In addition, the role of FUBP1 in ESCC proliferation was studied in ESCC cells through knocking FUBP1 down. The regulation of FUBP1 on proliferation was confirmed by Cell Counting Kit-8 (CCK-8) assay, flow cytometric assays, and clone formation assays. The expressions of FUBP1 and c-Myc were both upregulated in ESCC tissues. In addition to correlation between expression of FUBP1 and tumor grade, we also confirmed the correlation of FUBP1, c-Myc, and Ki-67 expression by twos. Moreover, upregulation of FUBP1 and c-Myc in ESCC was associated with poor survival. FUBP1 was confirmed to activate c-Myc in ESCC tissues and cells. FUBP1 was demonstrated to promote proliferation of ESCC cells. Moreover, downregulation of both FUBP1 and c-Myc was confirmed to inhibit proliferation of ESCC cells. Our results indicated that FUBP1 may potentially stimulate c-Myc expression in ESCC and its expression may promote ESCC progression.

Transplantation of mouse embryonic stem cell-derived oligodendrocytes in the murine model of globoid cell leukodystrophy.

INTRODUCTION: Globoid cell leukodystrophy (GLD) is a severe disorder of the central and peripheral nervous system caused by the absence of galactocerebrosidase (GALC) activity. Cell-based therapies are highly promising strategies for GLD. In this study, G-Olig2 mouse embryonic stem cells (ESCs) were induced into oligodendrocyte progenitor cells (OPCs) and were implanted into the brains of twitcher mice, an animal model of GLD, to explore the therapeutic potential of the cells. METHODS: The G-Olig2 ESCs were induced into OPCs by using cytokines and a multi-step differentiation procedure. Oligodendrocyte markers were detected by reverse transcription-polymerase chain reaction (RT-PCR) and immunocytochemistry. The toxicity of psychosine to OPCs was determined by a cell proliferation assay kit. The GALC level of OPCs was also examined. OPCs were labeled with Dir and transplanted into the brains of twitcher mice. The transplanted cells were detected by in-Vivo Multispectral Imaging System and real-time PCR. The physiological effects of twitcher mice were assessed. RESULTS: Oligodendrocyte markers were expressed in OPCs, and 76%±5.76% of the OPCs were enhanced green fluorescent protein (eGFP)-positive, eGFP was driven by the Olig2 promoter. The effect of psychosine on cell viability indicated that OPCs were more resistant to psychosine toxicity. The GALC level of OPCs was 10.0±1.23 nmol/hour per mg protein, which was significantly higher than other cells. Dir-labeled OPCs were injected into the forebrain of post-natal day 10 twitcher mice. The transplanted OPCs were myelin basic protein (MBP)-positive and remained along the injection tract as observed by fluorescent microscopy. The level of the Dir fluorescent signal and eGFP mRNA significantly decreased at days 10 and 20 after injection, as indicated by in-Vivo Multispectral Imaging System and real-time PCR. Because of poor cell survival and limited migration ability, there was no significant improvement in brain GALC activity, MBP level, life span, body weight, and behavioral deficits of twitcher mice. CONCLUSIONS: ESC-derived OPC transplantation was not sufficient to reverse the clinical course of GLD in twitcher mice.

High expression of peroxiredoxin 4 affects the survival time of colorectal cancer patients, but is not an independent unfavorable prognostic factor.

Peroxiredoxin 4 (Prx4) has a number of important biological functions, such as efficient antioxidant capacity and promotion of cell proliferation and differentiation. The purpose of this study was to investigate the expression and significance of Prx4 in human colorectal cancer (CRC). Quantitative polymerase chain reaction (qPCR) was performed to detect Prx4 in 8 freshly frozen specimens of CRC and their adjacent normal tissues. In addition, immunohistochemical analysis was performed to detect Prx4 in 59 specimens of CRC and 26 of adjacent normal tissues. The immunohistochemical and qPCR results demonstrated that the expressions of the Prx4 gene and protein were higher in CRC compared to those in the adjacent normal tissues. The expression intensity of the Prx4 protein was correlated with depth of invasion (P=0.001), lymph node metastasis (P=0.006) and Dukes' classification (P=0.004) in CRC. The Kaplan-Meier survival curves revealed that high Prx4 expression was correlated with short survival time. However, the Cox proportional hazards regression analysis did not identify Prx4 as an independent prognostic marker for CRC (P>0.05). These results suggested that Prx4 may be associated with carcinogenesis and the development of CRC and it may be a prognostic marker for postoperative CRC patients.

S100 family signaling network and related proteins in pancreatic cancer (Review).

The occurrence and development of pancreatic cancer is a complex process convoluted by multi-pathogenies, multi-stages and multi-factors. S100 proteins are members of the S100 family that regulate multiple cellular pathways related to pancreatic cancer progression and metastasis. S100 proteins have a broad range of intracellular and extracellular functions, including the regulation of protein phosphorylation and enzyme activity, calcium homeostasis and the regulation of cytoskeletal components and transcriptional factors. S100 proteins interact with receptor for advanced glycation end-products (RAGE), p53 and p21, which play a role in the degradation of the extracellular matrix (ECM) and metastasis, and also interact with cytoskeletal proteins and the plasma membrane in pancreatic cancer progression and metastasis. S100A11 and S100P are significant tumor markers for pancreatic cancer and unfavorable predictors for the prognosis of patients who have undergone surgical resection. Recently, S100A2 has been suggested to be a negative prognostic biomarker in pancreatic cancer, and the expression of S100A6 may be an independent prognostic impact factor. The expression of S100A4 and S100P is associated with drug resistance, differentiation, metastasis and clinical outcome. This review summarizes the role and significance of the S100 family signaling network and related proteins in pancreatic cancer.

Chronic pouchitis is associated with pouch polyp formation in patients with underlying ulcerative colitis.

BACKGROUND: Polypoid lesions can develop in ileal pouches. The risk factors associated with the development of pouch polyps have not been studied. AIM: To characterize clinical features, risk factors, and disease course of pouch polyp in a cohort of patients with underlying inflammatory bowel disease (IBD) from a subspecialty clinic. METHOD: A total of 1094 patients with restorative proctocolectomy and IPAA for IBD presenting to our Pouchitis Clinic from 2002 to 2010 were included. Demographic, clinical, and endoscopic variables were analyzed. RESULTS: The median durations from UC diagnosis to colectomy and from pouch creation to the last follow-up for the whole cohort were 6 (interquartile range [IQR]: 3-13) and 9years (IQR: 5-14), respectively. A total of 2472 surveillance and/or diagnostic pouchoscopies were performed for the cohort with a median follow-up of 5 (IQR: 2-6) years in the Pouchitis Clinic. The median number of pouchoscopies per patient was 2 (IQR: 1-3). Of the 1094 patients, 96 (8.8%) were found to have pouch polyps. The median size of the polyps was 1.2 (IQR: 1.0-2.0) cm. On histology, 93 patients (96.9%) had inflammatory-type polyps and 3 (3.1%) had polyps with low-grade dysplasia or indefinite for dysplasia. Multivariate logistic regression analysis demonstrated that chronic pouch inflammatory change was a risk factor for the development of pouch polyp with an odds ratio of 2.26 (95% confidence interval: 1.35-3.79; P=0.002). CONCLUSION: The majority of pouch polyps in patients with underlying UC were benign. Patients with concomitant chronic pouch inflammatory changes had an increased risk for developing pouch polyps.

Effect of combined mutations in the enhancer II and basal core promoter of hepatitis B virus on development of hepatocellular carcinoma in Qidong, China.

AIM: To investigate the roles of mutations in enhancer II (Enh II), basal core promoter (BCP) and precore (PC) regions of hepatitis B virus (HBV) in the progression of hepatocellular carcinoma (HCC) in Qidong, China. METHODS: We conducted a case-control study within a cohort of 2387 male HBV carriers who were recruited between August and September 1996. The HBV DNA sequence was determined in 152 HCC and 131 chronic hepatitis patients. Mutation exchanges during follow up in 115 cases were compared with 108 controls with serum samples taken during a similar length of follow up. In addition, a longitudinal study was conducted in 22 cases in which serial serum samples were available before HCC. RESULTS: After adjustment for age, history of cigarette smoking and alcohol consumption, hepatitis B e-antigen positivity, T1653, V1753 and T1762/A1764 double mutations were associated with risk of HCC. Multivariate analysis showed that T1653, V1753 and T1762/A1764 double mutations were independent risk factors of HCC. Moreover, a significant biological gradient of HCC risk by number of mutations in Enh II/BCP regions was observed. Paired samples analysis indicated that the increased HCC risk for at-risk sequence mutations were attributable to the persistence of these mutations, but not a single time point mutation. The longitudinal observation demonstrated a gradual combination of mutations in Enh II/BCP regions accumulated during the development of HCC. CONCLUSION: T1653, V1753 and T1762/A1764 double mutations were independent risk factors of HCC. The effect of combined mutations in Enh II/BCP regions increased the risk and persistence of at-risk sequence mutations and was critical for HCC development.

Serum GP73 is complementary to AFP and GGT-II for the diagnosis of hepatocellular carcinoma.

Golgi protein 73 (GP73) is a resident Golgi type II transmembrane protein that has been reported to markedly increase in chronic liver disease, particularly in hepatocellular carcinoma (HCC). However, it remains unclear as to whether serum GP73 represents a reliable serum marker for the diagnosis of HCC. The aim of the present study was to evaluate the diagnostic value of serum GP73 in patients with HCC and to determine the diagnostic accuracy of measuring serum GP73 in combination with α-fetoprotein (AFP) and γ-glutamyl transferase isoenzyme II (GGT-II) in HCC. Serum GP73 was detected using a time-resolved fluorescence immunological assay (TRFIA) and enzyme-linked immunosorbent assay (ELISA) in 79 HCC cases, including 16 liver cirrhosis, 30 chronic hepatitis and 28 healthy individuals. The correlation between serum GP73 and tumor size and HCC grading was analyzed and the complementary diagnostic value of serum GP73, AFP and GGT-II was evaluated. TRFIA was established for the detection of serum GP73 and was sensitive and reproducible. The expression levels of serum GP73 were markedly higher in the patients with HCC when compared with those of the individuals with liver cirrhosis and chronic hepatitis or the healthy individuals. According to the receiver operating characteristic (ROC) curve, diagnostic sensitivity and specificity for HCC with a cut-off value of 78.1 ng/l were 73.4 and 79.0%, respectively. However, no correlation was identified among serum GP73 and tumor size or grading, and no correlations were identified among serum GP73, AFP and GGT-II. The diagnostic sensitivities for HCC, as detected by TRFIA of GP73, AFP and GGT-II, were 73.4, 55.6 and 68.4%, respectively, and the specificities were 80.0, 86.7 and 97.1%, respectively. The combined determination of these markers increased the diagnostic sensitivity to 96.3% for HCC. TRFIA functions as a sensitive and replicable assay for the detection of serum GP73. The levels of serum GP73 were significantly higher in the HCC group when compared with the individuals with benign liver diseases. Serum GP73 may serve as a potential independent diagnostic candidate for HCC and the combined determination of serum GP73, AFP and GGT-II may increase the diagnostic efficiency of HCC.

Expression of FOXJ1 in hepatocellular carcinoma: correlation with patients' prognosis and tumor cell proliferation.

FOXJ1 is a member of the forkhead box (FOX) family of transcription factors. Recent studies suggested that FOXJ1 may function as a tumor suppressor gene in breast cancer. To investigate the potential roles of FOXJ1 in hepatocellular carcinoma (HCC), expression of FOXJ1 was first examined in eight paired frozen HCC and adjacent noncancerous liver tissues by Western blot, and we found that FOXJ1 was upregulated in HCC specimens. In addition, immunohistochemistry was performed to confirm our results in 108 HCC samples. Moreover, we also evaluated its relation with clinicopathological variables and the prognostic significance. The data showed that high expression of FOXJ1 was associated with histological grade (P < 0.001), and FOXJ1 was positively correlated with proliferation marker Ki-67 (P < 0.01). Univariate analysis suggested that FOXJ1 expression was associated with poor prognosis (P < 0.001). Multivariate analysis indicated that tumor grade (P < 0.0001), metastasis (P = 0.0451), tumor size (P = 0.0459), FOXJ1 (P = 0.0011), and Ki-67 (P = 0.0006) were independent prognostic markers for HCC. Furthermore, we noted that there existed the change of the level of FOXJ1 subcellular localization during cell-cycle transition in HepG2 cells by immunofluorescence and cell fractionation. Besides, we employed FOXJ1 overexpression/knockdown approaches to investigate the effects of FOXJ1 on HCC cell proliferation and cell-cycle distribution and found that overexpression of FOXJ1 can promote tumor cell proliferation and cell-cycle transition. Our results suggested that FOXJ1 was overexpressed in HCCs and associated with histological grade and poor prognosis. Overexpression of FOXJ1 was also involved in tumor cell proliferation and cell-cycle progression in HCC cell lines.

Effects of hepatitis B e-antigen on recurrence of hepatitis B-related hepatocellular carcinoma after curative resection: A meta-analysis.

AIM: The impact of hepatitis B e-antigen (HBeAg) on recurrence of hepatocellular carcinoma (HCC) after curative resection remains controversial. This meta-analysis aimed to determine whether the presence of HBeAg influenced the recurrence of HCC after curative resection. METHODS: We performed a meta-analysis including six studies (a total of 865 patients) to assess the effect of HBeAg on recurrence of HCC after curative resection. The pooled odds ratios (OR) were calculated using a random or fixed effects model. PUBMED, MEDLINE, EMBASE and the Cochrane Database were searched for articles published from 1990 to March 2012. Sensitivity analysis and publication bias estimate were also performed to evaluate the potential risk bias in the overall results of pooled analysis. RESULTS: Our results showed that the presence of HBeAg significantly increased the overall HCC recurrence risk after curative resection (OR = 1.63, 95% confidence interval (CI) = 1.11-2.40; P = 0.01). Pooled data from three studies on the risk of early recurrence among HBeAg positive patients compared with HBeAg negative patients showed an increased risk of early recurrence (OR = 1.50, 95% CI = 1.02-2.19; P = 0.04). However, there was no significant difference in late HCC recurrence between HBeAg positive and negative patients (OR = 1.17, 95% CI = 0.62-2.19; P = 0.62). CONCLUSION: The present study suggested that HBeAg positive patients had a significantly higher risk of early recurrence after curative resection of HCC.

Combined analysis of serum γ-glutamyl transferase isoenzyme II, α-L-fucosidase and α-fetoprotein detected using a commercial kit in the diagnosis of hepatocellular carcinoma.

γ-glutamyl transferase isoenzyme II (GGT-II) is a sensitive biomarker of hepatocellular carcinoma (HCC). However, numerous disadvantages of the traditional manual method affected its application. The commercial kit provided a convenient and fast method for the determination of GGT-II levels. The purposes of the present study were to compare the reproducibility and sensitivity between the manual and commercial kit methods and to evaluate the diagnostic efficiency for HCC with the combined analysis of GGT-II, α-L-fucosidase (AFU) and α-fetoprotein (AFP). In patients with various liver diseases (HCC, liver cirrhosis and chronic hepatitis) and normal subjects, GGT-II was detected by manual and commercial polyacrylamide gel electrophoresis (PAGE). The levels of AFU and AFP were assayed by colorimetry and a chemiluminescence immunoassay, respectively. The commercial PAGE had equal diagnostic efficiency with traditional manual PAGE and no significant differences were observed in intra- and average-gel reproducibility and GGT-II sensitivities between the manual and commercial PAGE (P>0.05). The incidence of GGT-II detected by commercial PAGE in HCC patients was 84.1% and <8% in benign liver disease. The levels of AFU and AFP in the benign liver diseases and normal subjects were lower than those in HCC. According to the cut-off value obtained by receiver operating characteristic curves, a total of 56.6 and 59.3% of HCC patients (64 out of 113 and 67 out of 113) had AFU >636.5 µmol/l h and AFP >44.0 µg/l, respectively. There were no significant correlations between GGT-II and AFU or AFP. Combined detection of GGT-II with AFU or AFP increased the diagnostic sensitivity to 92.9 and 93.8%, respectively. These results suggest that commercial PAGE provides a simple and reproducible method for GGT-II detection. Combined determination of GGT-II with AFU or AFP exhibited superior sensitivity and specificity for the diagnosis of HCC.

The expressions and clinical significances of tissue and serum galectin-3 in pancreatic carcinoma.

PURPOSE: Galectin-3, a member of the beta-galactoside-binding protein family, is involved in many biological processes, including cell proliferation, regulating cell cycle, angiogenesis, tumorigenesis, metastasis, etc. The aim of this study is to elucidate the relationship between galectin-3 and clinicopathological variables and to evaluate the clinical significance of serum galectin-3 in the diagnosis of pancreas carcinoma. METHODS: Galectin-3 expression in 78 pairs of pancreatic carcinoma tissues and the adjacent nontumorous tissues was tested by immunohistochemistry. The relationship between galectin-3 expression and clinical variables was analyzed. A sensitive method of time-resolved fluorescence immunological assay (TRFIA) for the detection of galectin-3 was established, and serum galectin-3 in cases with different pancreatic diseases was measured by TRFIA and ELISA. Further we compared the sensitivity and specificity of determining galectin-3, carcinoembryonic antigen (CEA) and carbohydrate antigen199 (CA199) for diagnosis of pancreatic carcinoma and assessed the complementary diagnostic value of galectin-3, CEA and CA199 for pancreatic carcinoma. RESULTS: Immunohistochemistry showed that galectin-3 expression was significantly higher in the human pancreatic carcinoma tissues than in the adjacent nontumorous tissues. The expression levels were correlated with the differentiation degree with the higher expression in poor differentiation tissues. Serum galectin-3 detected by both TRFIA and ELISA was much higher in patients with pancreatic carcinoma than in other groups. Serum galectin-3 was not correlated with CEA and CA199. Combined determination of these three markers has the complementary diagnostic value for human pancreatic carcinoma and may increase the diagnostic sensitivity to 97.5%. CONCLUSIONS: Galectin-3 is overexpressed in pancreatic carcinoma tissues, and it is correlated with the tumor differentiation. Serum galectin-3 is higher in cases with pancreatic carcinoma than in benign pancreatic diseases and healthy persons. Combined determination of serum galectin-3, CEA and CA199 may improve the diagnostic power for pancreatic carcinoma.

Ectopic expression of guanylyl cyclase C and endogenous ligand guanylin correlates significantly with Helicobacter pylori infection in gastric carcinogenesis.

The molecular mechanisms leading to gastric carcinogenesis still remain unclear. Recently, several studies demonstrated that over-expression of guanylyl cyclase C (GCC) has been detected in intestinal-type gastric cancer (GC) and precursor lesions. Our objective was to explore the expression levels of GCC and endogenous ligands guanylin (GN) and uroguanylin (UGN) and the correlation between Helicobacter pylori (H. pylori) and GCC, GN, and UGN expressions in patients at different stages from normal mucosa to superficial gastritis, atrophic gastritis, intestinal metaplasia (IM), dysplasia, and finally adenocarcinoma. The expression of GCC and GN was absent in the distal normal gastric tissues and superficial gastritis in all cases, whereas they were measured in IM, dysplasia, and GC. The expression of GCC and GN was closely related to intestinal-type GC. From superficial gastritis to gastric carcinomas, the H. pylori positive rate was 19.7, 33.3, 69.6, 80.0, and 82.1%, respectively. The positive correlation was found between GCC and GN in IM, dysplasia, and GC. Also, the positive correlation was found between GCC, GN, and H. pylori infection in them. These results demonstrate that the detection of GCC and GN will be beneficial to diagnosis human gastric carcinoma and precancerous lesions. Ectopic expression of GCC and GN in human gastric mucosa and H. pylori infection may play an important role in the carcinogenesis of the intestinal-type GC.

High expression of S100A11 in pancreatic adenocarcinoma is an unfavorable prognostic marker.

S100A11 is a member of S100 protein family, and our previous study showed that S100A11 is one of the up-regulated proteins that have not been reported to be associated with pancreatic carcinoma. The purpose of this study was to investigate the relation between S100A11 expression and the clinicopathological variables and clinical outcome in patients with pancreatic adenocarcinoma. Immunohistochemistry analysis was performed for S100A11 in 78 pairs of specimens of human pancreatic adenocarcinoma tissues and adjacent nontumorous tissues. The univariate and multivariate survival analyses were also performed to determine its prognostic significance. S100A11 expression in pancreatic adenocarcinoma (62/78) was significantly higher than that in the adjacent nontumorous tissues (19/78) (P = 0.000). High expression of S100A11 was associated with the lymph node metastasis and histological differentiation (P = 0.003 and 0.004, respectively). Univariate analysis showed that S100A11 expression was associated with poor prognosis (P = 0.0000). Multivariate analysis using the Cox regression model indicated that age ≥ 65 years, CA19-9 ≥ 1,000 U/ml and positive S100A11 were independent prognostic indicators of pancreatic adenocarcinoma (P = 0.002, 0.004 and 0.001, respectively). These results suggested that S100A11 might be a significant tumor marker for pancreatic adenocarcinoma and an unfavorable predictor for prognosis of patients who have undergone surgical resection.

Clinical significance of indefinite for dysplasia on pouch biopsy in patients with underlying inflammatory bowel disease.

BACKGROUND: "Indefinite for dysplasia" (IND) on pouch mucosal biopsy is occasionally reported during routine histopathological evaluation. The natural history and implication of this histologic entity in ileal pouch-anal anastomosis (IPAA) has not been studied. AIM: The aim of this study is to characterize cumulative probability, natural history, and clinical outcome of pouch IND in a cohort of patients with inflammatory bowel disease (IBD). METHODS: All 932 patients with restorative proctocolectomy and IPAA for IBD were included. Patients with or without IND were classified into the study and control groups. Demographic, clinical, endoscopic, and histologic variables were analyzed. RESULTS: The mean duration from IBD diagnosis to colectomy and from pouch construction to data entry was 8.4 ± 8.5 and 9.7 ± 6.2 years, respectively. A total of 2,250 surveillance or diagnostic pouchoscopies with biopsies were performed for the cohort. Twenty-one patients (2.3%) were diagnosed with anal transitional zone and/or pouch IND, for whom subsequent pouchoscopies were performed with the mean procedure number being 3.4 ± 2.2 per patient during a mean of follow-up of 19.3 ± 16.1 months. One patient with IND developed low-grade dysplasia and one had high-grade dysplasia in a separate endoscopy. Cox model showed the presence of primary sclerosing cholangitis was an independent risk factor for pouch IND [hazard ratio = 6.76 (95% CI 2.56-17.88)]. Interobserver agreement (kappa score) for diagnosing pouch IND between GI pathologists ranged from 0.67 to 0.76. CONCLUSIONS: Subsequent dysplasia was uncommon in pouch patients with IND. Natural history of pouch IND warrants further long-term investigation.