Expression and prognostic roles of PRDXs gene family in hepatocellular carcinoma.

BACKGROUND: As the fourth leading cause of cancer-related death in the world, the therapeutic effect and 5-year overall survival of hepatocellular carcinoma (HCC) are not optimistic. Previous researches indicated that the disorder of PRDXs was related to the occurrence and development of cancers. METHODS: In this study, PRDXs were found in various tumor cell lines by CCLE database analysis. The analysis results of UALCAN, HCCDB and Human Protein Atlas databases showed the expression of PRDXs mRNA and protein in HCC tissues was dysregulated. Besides, UALCAN was used to assess the correlations between PRDXs mRNA as well as methylation levels and clinical characterization. RESULTS: High expression of PRDX1 or low expression of PRDX2/3 suggested poor prognosis for HCC patients which was demonstrated by Kaplan-Meier Plotter. The genetic alterations and biological interaction network of PRDXs in HCC samples were obtained from c-Bioportal. In addition, LinkedOmics was employed to analyze PRDXs related differentially expressed genes, and on this basis, enrichment of KEGG pathway and miRNAs targets of PRDXs were conducted. The results indicated that these genes were involved in several canonical pathways and certain amino acid metabolism, some of which may effect on the progression of HCC. CONCLUSIONS: In conclusion, the disordered expression of some PRDX family members was associated with the prognosis of HCC patients, suggesting that these PRDX family members may become new molecular targets for the treatment and prognosis prediction of HCC.

Bone marrow-derived mesenchymal stem cells utilize the notch signaling pathway to induce apoptosis of hepatic stellate cells via NF-κB sensor.

The present study aimed at evaluating the mechanism by which functionality of hepatic stellate cells (HSCs) is modulated by bone marrow stromal cells (BMSCs). Induction of apoptosis in HSCs was found to be caused by directly co-culturing HSCs with BMSCs, where the expression of α-smooth muscle actin (α-SMA) increased significantly in HSCs, along with an increase in their proliferation rate. Additionally, expression of Hes1 and Notch1 in HSCs co-cultured with BMSCs increased significantly at both protein and mRNA levels. Blocking of the notch signaling pathway (NSP) either by Notch1 siRNA or by DAPT treatment increased the proliferation rate while decreasing apoptosis and led to activation of the NF-κB signaling pathway in HSCs co-cultured with BMSCs. These effects were found to be reversed in HSCs overexpressing IκB S32/S36 mutants. The Notch signaling-mediated cell-cell contact was partially involved in the significant inhibition of proliferation of HSCs by BMSCs. Additionally, the NF-κB pathway was found to be responsible for NSP-mediated inhibition of growth of HSCs in the co-culture system. Thus, BMSCs might have a potential therapeutic significance in treating hepatic fibrosis.

Identification of CELSR2 as a novel prognostic biomarker for hepatocellular carcinoma.

BACKGROUND: CELSR2 is postulated to be a receptor involved in contact-mediated communication; however, the specific function of this particular member has not been determined in hepatocellular carcinoma (HCC). METHODS: Here, we explored the expression and function of CELSR2 in HCC patients through data mining and examined the results using clinical samples and in vitro experiments. RESULTS: It was found that CELSR2 mRNA and protein expression levels were significantly higher in cancerous tissue than in normal tissue. The increased mRNA expression of CELSR2 was significantly associated with overall survival (OS) in HCC patients. Moreover, the genetic alteration rate of CELSR2 gene in HCC can reach 8%, and these alterations would deeply influence its neighboring genes, then jointly affecting the occurrence and development of tumor through cell adhesion and numerous common carcinogenic pathways. Our in vitro results indicated that the depletion of CELSR2 inhibited liver cancer cell proliferation and invasion. Univariate and multivariate Cox regression analyses showed that CELSR2 could be viewed as an independent risk factor for HCC patients. CONCLUSIONS: This study demonstrated that data mining could efficiently reveal the roles of CELSR2 in HCC and its potential regulatory networks. The CELSR2 protein level may serve as a novel prognostic biomarker for HCC.

TRIM29 prevents hepatocellular carcinoma progression by inhibiting Wnt/ß-catenin signaling pathway.

TRIM29 plays an important role in many neoplasms. In this study, we aimed to elucidate its role in hepatocellular carcinoma (HCC) and explore the corresponding potential mechanism. The expression level of TRIM29 in HCC samples and hepatoma cell lines was detected. We found that TRIM29 was down-regulated in clinical HCC samples and cultured hepatoma cell lines by western blot analysis and quantitative polymerase chain reaction. In addition, we demonstrated that higher TRIM29 expression was associated with higher differentiation grade of HCC. To explore the effect of TRIM29 on hepatoma cells and its possible mechanisms, TRIM29-knockdown and overexpression cell models were constructed. The results showed that the depletion of TRIM29 promoted liver cancer cell proliferation, clone formation, migration and invasion in vitro probably through the Wnt/ß-catenin signaling pathway. This study revealed the inhibitory roles of TRIM29 in HCC and the possible mechanisms.

Antiviral therapy predicts the outcomes following resection of hepatocellular carcinoma in patients negative for HBV DNA: a propensity score matching analysis.

BACKGROUND: The effect of antiviral therapy (AVT) on clinical outcomes in patients with hepatocellular carcinoma (HCC) who are seronegative for hepatitis B virus (HBV), defined as HBV DNA < 100 IU/ml prior to surgical resection, is unknown. The main purpose of this study was to evaluate the possible value of AVT in this cohort of patients. METHODS: From January 2006 to January 2013, 161 HCC patients with positive serum tests for HBV surface antigen (HBsAg) but negative tests for HBV DNA who had undergone hepatectomy were included and analyzed. Propensity score matching (PSM) was used to balance the heterogeneity in baseline characteristics. RESULTS: All patients were divided into the following two groups: the AVT group (n = 73, 45.34%) and the non-AVT group (n = 88, 54.66%). HBV reactivation occurred in 20 patients in the non-AVT group (22.73%) but in only 2 patients in the AVT group (2.74%, p < 0.001). After PSM, the 1-, 2-, and 3-year recurrence-free survival (RFS) rates in the AVT group and the non-AVT group were 78.38%, 72.97%, and 62.16% and 81.08%, 72.97%, and 72.97%, respectively (p = 0.564); the 1-, 2-, and 3-year overall survival (OS) rates were 97.30%, 97.3%, and 91.89% and 94.59%, 94.59%, and 86.49% in the AVT group and non-AVT group, respectively (p = 0.447). CONCLUSIONS: Antiviral therapy can reduce HBV reactivation but is not correlated with a significant increase in postoperative RFS and OS in HCC patients with HBV DNA levels < 100 IU/ml.

Shp2 deletion in hepatocytes suppresses hepatocarcinogenesis driven by oncogenic ß-Catenin, PIK3CA and MET.

BACKGROUND & AIMS: Shp2 is an SH2-tyrosine phosphatase acting downstream of receptor tyrosine kinases (RTKs). Most recent data demonstrated a liver tumor-suppressing role for Shp2, as ablating Shp2 in hepatocytes aggravated hepatocellular carcinoma (HCC) induced by chemical carcinogens or Pten loss. We further investigated the effect of Shp2 deficiency on liver tumorigenesis driven by classical oncoproteins c-Met (receptor for HGF), ß-catenin and PIK3CA. METHODS: We performed hydrodynamic tail vein injection of two pairs of plasmids expressing c-Met and ΔN90-ß-catenin (MET/CAT), or c-Met and PIK3CAH1047R (MET/PIK), into WT and Shp2hep-/- mice. We compared liver tumor loads and investigated the pathogenesis and molecular mechanisms involved using multidisciplinary approaches. RESULTS: Despite the induction of oxidative and metabolic stresses, Shp2 deletion in hepatocytes suppressed hepatocarcinogenesis driven by overexpression of oncoproteins MET/CAT or MET/PIK. Shp2 loss inhibited proliferative signaling from c-Met, Wnt/ß-catenin, Ras/Erk and PI3K/Akt pathways, but triggered cell senescence following exogenous expression of the oncogenes. CONCLUSIONS: Shp2, acting downstream of RTKs, is positively required for hepatocyte-intrinsic tumorigenic signaling from these oncoproteins, even if Shp2 deficiency induces a tumor-promoting hepatic microenvironment. These data suggest a new and more effective therapeutic strategy for HCCs driven by oncogenic RTKs and other upstream molecules, by inhibiting Shp2 and also suppressing any tumor-enhancing stromal factors produced because of Shp2 inhibition. LAY SUMMARY: Primary liver cancer is a malignant disease with poor prognosis, largely because there are limited systemic therapies available. We show here that a cytoplasmic tyrosine phosphatase Shp2 is required for liver tumorigenesis. This tumorigenesis is driven by two oncoproteins that are implicated in human liver cancer. This, together with our previous studies, uncovers the complexity of liver tumorigenesis, by elucidating the pro- and anti-tumor effects of Shp2 in mouse models. This data can be used to guide new therapies.

Measurement of Serum and Hepatic Eicosanoids by Liquid Chromatography Tandem-Mass Spectrometry (LC-MS/MS) in a Mouse Model of Hepatocellular Carcinoma (HCC) with Delivery of c-Met and Activated ß-Catenin by Hepatocyte Hydrodynamic Injection.

BACKGROUND Most forms of cancer, including hepatocellular carcinoma (HCC), are associated with varying degrees of chronic inflammation. The association between the expression of eicosanoids, which are bioactive lipid mediators of inflammation, and HCC remains unknown. The aim of this study was to measure serum and hepatic eicosanoids in a mouse model of HCC with the delivery of c-Met and activated b-catenin by hepatocyte hydrodynamic injection. MATERIAL AND METHODS The HCC mouse model, and normal control mice, were used in this study with co-delivery of human c-Met combined with activated ß-catenin into hepatocytes through hydrodynamic injection. Liquid chromatography tandem-mass spectrometry (LC-MS/MS) analysis was used to measure serum and hepatic eicosanoid levels. RESULTS The combined activation of c-Met and ß-catenin was induced in the HCC mouse model. LC-MS/MS showed that a total of 13 eicosanoids in serum and 12 eicosanoids in liver tissue were significantly increased in the HCC mice, when compared with control mice. CONCLUSIONS In a mouse model of HCC, co-activation of the c-Met and ß-catenin signaling pathway resulted in increased levels of serum and hepatic eicosanoids.

Associating liver partition and portal vein ligation for staged hepatectomy versus conventional two-stage hepatectomy: a systematic review and meta-analysis.

BACKGROUND: It is generally accepted that an insufficient future liver remnant is a major limitation of large-scale hepatectomy for patients with primary hepatocellular carcinoma. Conventional two-stage hepatectomy (TSH) is commonly considered to accelerate future liver regeneration despite its low regeneration rate. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), which is characterized by a rapid regeneration, has brought new opportunities. METHODS: Relevant studies were identified by searching the selected databases up to September 2017. Then, a meta-analysis of regeneration efficiency, complication rate, R0 resection ratio, and short-term outcomes was performed. RESULTS: Ten studies, comprising 719 patients, were included. The overall analysis showed that ALPPS was associated with a larger hyperplastic volume and a shorter time interval (P < 0.00001) than TSH. ALPPS also exhibited a higher completion rate for second-stage operations (odds ratio, OR 9.50; P < 0.0001) and a slightly higher rate of R0 resection (OR 1.90; P = 0.11). Interestingly, there was no significant difference in 90-day mortality between the two treatments (OR 1.44; P = 0.35). CONCLUSIONS: These results indicate that compared with TSH, ALPPS possesses a stronger regenerative ability and better facilitates second-stage operations. However, the safety, patient outcomes, and patient selection for ALPPS require further study.

Laparoscopic RFA with splenectomy for hepatocellular carcinoma.

BACKGROUND: The treatment of hepatocellular carcinoma (HCC) is complicated and challenging because of the frequent presence of cirrhosis. Therefore, we propose a novel surgical approach to minimize the invasiveness and risk in patients with HCC, hypersplenism, and esophagogastric varices. METHODS: This was a retrospective study carried out in 25 patients with HCC and hypersplenism and who underwent simultaneous laparoscopic-guided radio-frequency ablation and laparoscopic splenectomy with endoscopic variceal ligation. Tumor size was restricted to a single nodule of <3 cm. Characteristics of the patients (cirrhosis etiology, liver function, tumor size, spleen size), surgery (complications, blood loss, time of stay), and follow-up (recurrence and survival) were examined. RESULTS: Mean operative time was 128 ± 18 min. Mean blood loss was 206 ± 57 mL. Length of stay was 7.0 ± 1.5 days. Mean total costs were 8064 USD. Cytopenia and thrombocytopenia recovered quickly after surgery. No procedure was converted to open surgery. Two patients showed worsening liver function after surgery, three patients showed worsening of ascites, and five patients suffered from portal vein thrombosis. The 1-year tumor-free survival was 78.8 %, and the 21-month tumor-free survival was 61.4 %. According to a literature review, these outcomes were comparable to those of simultaneous open hepatic resection and splenectomy. CONCLUSIONS: Laparoscopic-guided radio-frequency ablation with laparoscopic splenectomy and endoscopic variceal ligation could be an available technique for patients with HCC <3 cm, hypersplenism, and esophagogastric varices. This approach may help to minimize the surgical risks and results in a fast increase in platelet counts with an acceptable rate of complications.

Activated hepatic stellate cells promote angiogenesis via interleukin-8 in hepatocellular carcinoma.

BACKGROUND: Chemokines have been recognized as important modulators of angiogenesis, and they play critical roles in the development and metastasis of hepatocellular carcinoma (HCC), although their origins and latent molecular mechanisms remain elusive. The aim of this study was to investigate how activated hepatic stellate cells (a-HSCs) promote angiogenesis in HCC. METHODS: A total of 22 HCC patients were enrolled randomly. We used immunohistochemistry, western blotting, and enzyme-linked immunosorbent assay (ELISA) to analyse the production of interleukin-8 (IL-8) in a-HSCs derived from HCC tissues. The angiogenic effects of IL-8 in vitro and in vivo were assessed by ELISA, real-time quantitative polymerase chain reaction, capillary tube formation assay, and chick embryo chorioallantoic membrane assay. RESULTS: The present study showed that IL-8 was enriched predominantly in the tumour stroma of HCC tissues and was mainly derived from a-HSCs, rather than from hepatoma cells, in vivo and in vitro. Angiogenesis was most active at the invading edge, which was close to the a-HSCs. The angiogenic effect was dramatically attenuated by an IL-8 neutralizing antibody both in vitro and in vivo. Moreover, the IL-8 neutralizing antibody down-regulated Ser727-phosphorylated STAT3 levels in hepatoma cells treated with a-HSCs conditioned medium. CONCLUSIONS: These findings reveal that a-HSCs within the stroma of HCC contribute to tumour angiogenesis via IL-8.

Role of activated hepatic stellate cells in proliferation and metastasis of hepatocellular carcinoma.

AIM: Cancer is not only influenced by specific tumor cells but also by the stromal microenvironment. Upon liver damage, activated hepatic stellate cells (aHSC) become highly proliferative myofibroblast-like cells and are thought to secrete molecules that influence development of hepatocellular carcinoma (HCC). The aim of this study was to investigate the role of aHSC in the development of HCC. METHODS: To assess if aHSC secreted factor(s) that promote microvascular endothelial cell (MEC) tube formation, MEC were plated with aHSC-conditioned medium and tube formation analyzed by light microscopy. An established transendothelial migration assay with MEC was used to evaluate the role of aHSC in migration and metastasis. A novel in vitro and in vivo orthotopic mouse HCC tumor model was used to investigate angiogenic, proliferative and metastatic activity of aHSC. RESULTS: We found that aHSC promoted angiogenesis both in vitro and in vivo through vascular endothelial growth factor (VEGF). aHSC-conditioned medium increased the ability of MEC to form tubes which was dependent upon aHSC-secreted VEGF. In addition, HCC orthogenic tumors derived from co-injection of H22 cells plus aHSC into the hepatic lobes of mice had greater cell proliferation and vascularization, as evaluated by the presence of CD34 and VEGF expression, than tumors resulting from H22 injections alone. aHSC also migrated from the primary tumor to sites of metastasis. CONCLUSION: Our findings support aHSC playing multiple roles in HCC development and metastasis.

Reappraisal of evidence of microscopic portal vein involvement by hepatocellular carcinoma cells with stratification of tumor size.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death internationally, it is necessary to reappraise evidences of HCC cells involving the portal vein, especially considering tumor size. MATERIALS AND METHODS: Histopathological evidence and dynamic evidences of radiology and cytology from publication were collected and analyzed. RESULTS: Frequencies of microscopic portal vein involvement (MPVI) and microscopic intrahepatic metastasis (MIM) in resected specimens with single nodule HCC were lower than that of multi nodule HCC, although not significantly. Early HCC (≤1.5 cm) was with extremely low to 0 frequencies of MPVI and MIM. HCC >5 cm showed a tendency of flowing HCC cells into portal vein, which was coincident with significantly high frequency (64.1 %) of MPVI for HCC >5 cm. There were no significant difference of frequencies of MPVI and MIM between groups of tumor ≤2, ≤3, and ≤5 cm. CONCLUSIONS: Single nodule HCC >5 cm needs anatomic resection and the root of portal vein should be firstly ligated because of tendency of flowing HCC cells into portal vein. For single nodule HCC ≤2 cm, there was a risk of about 16.2 % of MPVI, and a risk of about 16.2-26.4 % of MPVI for those single nodule HCC ≤5 cm, however, there was a risk of extremely low to 0 of MPVI for early HCC (≤1.5 cm). Surgeons have to balance liver reserve and risk of MPVI for HCC ≤5 cm before deciding anatomic or nonanatomic resection.

Effect of transplantation route on stem cell migration to fibrotic liver of rats via cellular magnetic resonance imaging.

BACKGROUND AIMS: Assessing mesenchymal stromal cells (MSCs) after grafting is essential for understanding their migration and differentiation processes. The present study sought to evaluate via cellular magnetic resonance imaging (MRI) if transplantation route may have an effect on MSCs engrafting to fibrotic liver of rats. METHODS: Rat MSCs were prepared, labeled with superparamagnetic iron oxide and scanned with MRI. Labeled MSCs were transplanted via the portal vein or vena caudalis to rats with hepatic fibrosis. MRI was performed in vitro before and after transplantation. Histologic examination was performed. MRI scan and imaging parameter optimization in vitro and migration under in vivo conditions were demonstrated. RESULTS: Strong MRI susceptibility effects could be found on gradient echo-weighted, or T2∗-weighted, imaging sequences from 24 h after labeling to passage 4 of labeled MSCs in vitro. In vivo, MRI findings of the portal vein group indicated lower signal in liver on single shot fast spin echo-weighted, or T2-weighted, imaging and T2∗-weighted imaging sequences. The low liver MRI signal increased gradually from 0-3 h and decreased gradually from 3 h to 14 days post-transplantation. The distribution pattern of labeled MSCs in liver histologic sections was identical to that of MRI signal. It was difficult to find MSCs in tissues near the portal area on day 14 after transplantation; labeled MSCs appeared in fibrous tuberculum at the edge of the liver. No MRI signal change and a positive histologic examination were observed in the vena caudalis group. CONCLUSIONS: The portal vein route seemed to be more beneficial than the vena caudalis on MSC migration to fibrotic liver of rats via MRI.

Characteristics of submental muscles function and hyoid bone movement in patients with dysphagia after stroke.

BACKGROUND: Dysphagia is one of the common complications after stroke. Dysphagia significantly increases the probability of serious adverse consequences. The purpose of this study was to compare the characteristics of submental muscles electromyography and hyoid motion parameters between patients with dysphagia after stroke and healthy controls, and whether there is a synergistic effect between the function of the submental muscles and the movement of the hyoid. METHODS: Fifteen patients with post-stroke dysphagia and fifteen healthy adults simultaneously underwent the videofluoroscopic and surface electromyography of the submental muscles while swallowing 5 ml of concentrated liquid barium sulphate. The electromyographic signal of the submental muscles was analysed along with parameters of hyoid movement. FINDINGS: Stage transition duration and duration of surface electromyographic activity were extended significantly in post-stroke dysphagia patients(P < 0.05). Surface electromyography amplitude and hyoid movement were significantly reduced in patients (P < 0.05). There was a significant correlation between the maximum hyoid movement distance and the peak sEMG amplitude in healthy controls (r = 0.660, P = 0.014), but not in patients with dysphagia after stroke (r = 0.425, P = 0.148). INTERPRETATION: Submental muscles electromyographic signal changes in patients may be the result of uncoordinated muscle contractions and decreased muscle strength. Furthermore, the reduced hyoid movement distance may be due to impaired function of the submental muscles. In addition, the submental muscles and hyoid movement or other swallowing structures functions were impaired to varying degrees, resulting in the disappearance of the correlation between the maximum movement distance of the hyoid and the peak amplitude.

NP603, a novel and potent inhibitor of FGFR1 tyrosine kinase, inhibits hepatic stellate cell proliferation and ameliorates hepatic fibrosis in rats.

Fibroblast growth factor 2 (FGF-2) and its main receptor FGFR1 have been shown to promote hepatic stellate cell (HSC) activation and proliferation. However, scant information is available on the anti-fibrogenic activity of FGFR1 inhibitors. The aim of this study was to assess the impact of a selective FGFR1 tyrosine kinase inhibitor NP603 on HSC proliferation and hepatic fibrosis. We demonstrated that rat primary HSCs secreted significant amounts of FGF-2, and its tyrosine phosphorylation of FGFR1 was attenuated by NP603. NP603 inhibited HSC activaton by measuring the expression of α-smooth muscle actin (α-SMA) and the production of type I collagen using ELISA. Furthermore, NP603 (25 µM) in vitro strongly suppressed HSC growth induced by FGF-2 (10 ng/ml) and FCS. This effect correlated with the suppression of extracellular-regulated kinase (ERK) activity and its downstream targets cyclin D1 and p21. In addition, PO NP603 (20 mg·kg(-1)·day(-1)) administration significantly decreased hepatic collagen deposition and α-SMA expression in CCl(4)-treated rats. Collectively, these studies suggest that selective blocking of the FGFR1-mediated pathway could be a promising therapeutic approach for the treatment of hepatic fibrosis.

Surgical treatment of complicated hepatolithiasis using the ultrasound-guided fiberoptic choledochoscope.

BACKGROUND: The residual stones of postsurgical intrahepatic calculi have been among the most difficult problems in hepatobiliary surgery. Intraoperative ultrasound can clearly display the morphology of intrahepatic bile ducts and the distribution of calculi as well as the position of the choledochoscope and the calculus extraction instruments. Therefore, intraoperative ultrasound can guide the choledochoscope and its auxiliary equipment for calculus extraction. It is necessary to evaluate the effectiveness and safety of surgeries using an ultrasound-guided fiberoptic choledochoscope for the treatment of complicated hepatolithiasis. METHODS: The 56 cases in group A were selected from patients who had complicated hepatolithiasis treated with calculus extraction therapy using an ultrasound-guided fiberoptic choledochoscope in the authors' hospital between January 2006 and June 2009. The 63 cases of complicated hepatolithiasis in group B were chosen from patients treated with calculus extraction surgeries using a fiberoptic choledochoscope without the guidance of ultrasound from September 2001 through December 2005. Transabdominal ultrasound, T-tube cholangiography, and computed tomography (CT) examination were performed on day 15 after the surgery to compare the complete stone clearance rate, the residual stone rate, and the incidence rate of postoperative complications between groups A and B. RESULTS: The intrahepatic calculi were completely removed in 53 group A cases. The complete stone clearance rate was 94.6%, and the residual stone clearance rate was 5.4%. In group B, 51 cases had complete stone removal, for a stone clearance rate of 81% and a residual stone rate of 19%. The difference in the residual stone rates between the two groups is statistically significant (p=0.025). No hemobilia, biliary perforation, or other complications were observed in either group. CONCLUSION: Use of the intraoperative ultrasound-guided fiberoptic choledochoscope in the treatment of complicated hepatolithiasis can significantly reduce the residual stone rate of intrahepatic biliary calculi and significantly improve the treatment effect of hepatolithiasis.

The expression of PEDF and VEGF in the gastric wall of prehepatic portal hypertensive rats.

BACKGROUND/AIMS: Upper gastrointestinal bleeding of portal hypertension cases may result from gastric mucosal lesions due to portal hypertensive gastropathy. The pathological changes in the vessels of the gastric wall are very important in the pathogenesis of portal hypertensive gastropathy. However, the mechanisms of these pathological changes are not completely understood. In this study, we examined the expression levels of PEDF and VEGF in the gastric wall in rats with prehepatic portal hypertension. METHODOLOGY: Eighteen healthy Wistar rats were randomly divided into groups A and B. Group A was used to establish the prehepatic portal hypertensive model and group B to evaluate a sham surgery. The VEGF and PEDF expression in the rat gastric wall were detected by immunohistochemical staining and western blotting. RESULTS: VEGF and PEDF were mainly expressed in the basal layer of the mucosal glands. The expression levels of VEGF and PEDF in group A were higher than that in group B at 7, 10 and 14 days after surgery. The expression levels of VEFG and PEDF in group B did not show significant changes. CONCLUSIONS: The results from the present study showed a significantly elevated expression of both VEGF and PEDF in the gastric walls during the development of portal hypertension. The expression of these proteins was mainly located in the basal layer of the gastric mucosa.

Value of KPNA4 as a diagnostic and prognostic biomarker for hepatocellular carcinoma.

It is important to identify novel biomarkers to improve hepatocellular carcinoma (HCC) diagnosis and treatment. Herein, we reported the role of karyopherin α4 (KPNA4) in HCC patients through public data mining and examined the results using clinical samples in our center. Our results revealed that KPNA4 expression level was positively correlated with the infiltration of CD8+ T cells, B cells, dendritic cells, CD4+ T cells, neutrophils and macrophages. In addition, KPNA4 expression was significantly associated with T cell exhaustion. KPNA4 mRNA and protein expression levels were significantly higher in cancerous tissue than in normal tissue. Besides, the increased expression of KPNA4 indicated poor overall survival. Univariate and multivariate Cox regression analyses showed KPNA4 could be viewed as an independent risk factor for HCC patients. Moreover, our experimental results were consistent with those obtained from bioinformatic results. These findings revealed KPNA4 may serve as a novel prognostic biomarker and a potential therapeutic target for HCC.

A novel index for staging hepatitis B related liver cirrhosis in patients with hepatocellular carcinoma.

Information on the stage of liver cirrhosis is essential for prognostication and decisions on surgical planning for hepatocellular carcinoma (HCC) patients. But a non-invasive liver cirrhosis staging model is still lacking. The aim of our study was to develop a non-invasive model based on routine clinical parameters to evaluate the severity of cirrhosis in hepatitis B related HCC patients. A total of 226 HCC patients with chronic hepatitis B virus (HBV) infection who had liver resection were analyzed in this retrospective study. We found that platelets, prothrombin activity, maximum oblique diameter of right hepatic lobe and spleen length were the independent predictors of liver cirrhosis in HCC patients. By cumulating the weight of risk scores of independent variables, we constructed the PPMS (PLT/PTA/maximum oblique diameter of right hepatic lob/spleen length) index. The areas under the receiver operating characteristic curves (AUROC) of PPMS index were 0.820, 0.667, and 0.650 in predicting ≥cirrhosis 1 (C1), ≥cirrhosis 2 (C2), and ≥cirrhosis 3 (C3), respectively. The optimal cut-off value of the PPMS index for predicting ≥C1, ≥C2, and ≥C3 was 4.392, 4.471, and 4.784, respectively. And the corresponding sensitivity was 63.1%, 63.2%, and 64.7%, the corresponding specificity was 89.4%, 64.3%, and 62.5%, respectively. Our study constructed a non-invasive liver cirrhosis index (PPMS) could distinguish patients from different stages of liver cirrhosis, which might add more preoperative information for HCC patients.

Deficient proliferation of bone marrow-derived mesenchymal stem cells in patients with chronic hepatitis B viral infections and cirrhosis of the liver.

In this study, we determined whether the proliferation of bone marrow-derived mesenchymal stem cells (MSCs) is impaired in patients with chronic hepatitis B viral infection and cirrhosis of the liver. MSCs from 15 patients with chronic hepatitis B and cirrhosis of the liver (CIR-MSCs) and 11 normal donors (ND-MSCs) were collected and characterized in vitro. CIR-MSCs displayed an intact immunophenotype. The percentage of S-phase nuclei in CIR-MSCs (4.34%), however, was significantly lower than that in ND-MSCs (P < 0.001), indicating impaired proliferation of CIR-MSCs. Growth factor receptor expression (e.g., IGF1, PDGFalpha, and PDGFbeta) on the surface of CIR-MSCs decreased compared to that on ND-MSCs (P < 0.03). We found no evidence that CIR-MSCs were infected with the hepatitis B virus (HBV). Deficient proliferation of CIR-MSCs may result from the decreased expression of growth factor receptors and unbalanced production of cytokines in patients with HBV infection. Our results indicate that autologous MSCs of patients with chronic hepatitis B and cirrhosis of the liver may not be suitable for therapeutic purposes.