GWAS Identifies Novel Susceptibility Loci on 6p21.32 and 21q21.3 for Hepatocellular Carcinoma in Chronic Hepatitis B Virus Carriers

Genome-wide association studies (GWAS) have recently identified KIF1B as susceptibility locus for hepatitis B virus (HBV)–related hepatocellular carcinoma (HCC). To further identify novel susceptibility loci associated with HBV–related HCC and replicate the previously reported association, we performed a large three-stage GWAS in the Han Chinese population. 523,663 autosomal SNPs in 1,538 HBV–positive HCC patients and 1,465 chronic HBV carriers were genotyped for the discovery stage. Top candidate SNPs were genotyped in the initial validation samples of 2,112 HBV–positive HCC cases and 2,208 HBV carriers and then in the second validation samples of 1,021 cases and 1,491 HBV carriers. We discovered two novel associations at rs9272105 (HLA-DQA1/DRB1) on 6p21.32 (OR = 1.30, P = 1.13×$10^{−19}$) and rs455804 (GRIK1) on 21q21.3 (OR = 0.84, P = 1.86×$10^{−8}$), which were further replicated in the fourth independent sample of 1,298 cases and 1,026 controls (rs9272105: OR = 1.25, P = 1.71×$10^{−4}$; rs455804: OR = 0.84, P = 6.92×$10^{−3}$). We also revealed the associations of HLA-DRB1*0405 and 0901*0602, which could partially account for the association at rs9272105. The association at rs455804 implicates GRIK1 as a novel susceptibility gene for HBV–related HCC, suggesting the involvement of glutamate signaling in the development of HBV–related HCC

Improvement of biological total phosphorus release and uptake by low electrical current application in lab-scale bio-electrochemical reactors

The overall process enhancement by different electrical current application on the biological phosphorus release and uptake have been investigated. Five reactors were constructed for three experiments and activated sludge was used as inoculums. In Exp.1 by comparing the control and the bio-electrochemical reactors, it was found that the overall phosphorus removal efficiency could be enhanced at lower electrical current applications of 5. mA and 10. mA, but were restrained at higher than 20. mA, although 20. mA could be a sensitive turning point. Moreover, the electrochemical effects of the cathodic and the anodic reactions on the phosphorus release and uptake, respectively, have been further evaluated separately under an electrical current application of 10. mA in Exp.2 and Exp.3, respectively. As observed, both of the biological release and uptake were improved by the cathodic reactions in the cathode reactor, but not by the anodic reactions in the anode reactor, and thus indicated that the cathodic reactions play an important role in the improvement of the biological phosphorus release and uptake. © 2012 Elsevier B.V.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Effect of the chemical oxidation demand to sulfide ratio on sulfide oxidation in microbial fuel cells treating sulfide-rich wastewater

This work focused on studying the effect of the chemical oxidation demand to sulfide ratio (COD/S) on power generation and sulfide oxidation in microbial fuel cells treating sulfide-rich wastewater containing organic contaminants. The maximum power density achieved was 20±1 W m -3 V Anode and the Coulombic yield was 20±2%. The COD/S of influent played an important role in elemental sulfur and sulfate production because of competition between acetate oxidation and element sulfur oxidation to sulfate in the anode. When the COD/S was 12.50/1, more than 74.0% of sulfide was converted into elemental sulfur after 24 hours of operation. The effect of the COD/S on power generation was negligible when the COD/S ranged between 4.85/1 and 18.53/1. After 24 hours, the COD removals were 110±6, 213±9, 375±8 and 410±10 mg l -1 when the COD/S was 4.85/1, 8.9/1, 12.5/1 and 18.53/1, respectively. The COD removal increased with the increasing COD of the influent, which fitted to the model of first-order reaction kinetics. © 2013 Copyright Taylor and Francis Group, LLC.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Meta-analysis: preoperative transcatheter arterial chemoembolization does not improve prognosis of patients with resectable hepatocellular carcinoma

Background: Long-term outcomes of partial liver resection of hepatocellular carcinoma (HCC) remain satisfactory due to high incidences of recurrence. This study was intended to see whether preoperative transcatheter arterial chemoembolization (TACE) reduces postoperative tumor recurrences and prolongs survival of patients with resectable HCC. Methods: A computerized literature search was performed to identify relevant articles. The quality of nonrandomized comparative studies (NRCTs) was assessed using the methodological index for nonrandomized studies (MINORS). Data synthesis was performed using Review Manager 5.0 software. Results: Twenty-one studies (4 randomized controlled trials and 17 NRCTs) with a total of 3,210 participants were suitable for analysis. There was no significant difference in disease-free and overall survival at 5-year (32.1% vs. 30.0% and 40.2% vs. 45.2%), and intra-and extra-hepatic recurrence (51.2% vs. 53.6% and 12.9% vs. 10.3%) between patients with and without preoperative TACE. Postoperative morbidity (28.9% vs. 26.8%) and in-hospital mortality (4.1% vs. 3.1%) were also similar between the two groups. Conclusions: Preoperative TACE does not seem to improve prognosis and therefore it is prudent to recommend it as a preoperative routine procedure for resectable HCC

Intratumoral Hepatic Stellate Cells as a Poor Prognostic Marker and a New Treatment Target for Hepatocellular Carcinoma

<div><p>Hepatic stellate cells (HSCs), a specialized stromal cytotype in the liver, have been demonstrated to actively contribute to hepatocellular carcinoma (HCC) development. However, the previous studies were performed using HSC cell lines, and the prognostic value of intratumoral HSCs (tHSCs) was unclear. Here we isolated tHSCs from fresh human HCC tissues, and analyzed the abilities of tHSCs to promote HCC progression by using in vitro assays for cell viability, migration and invasion as well as epithelial-mesenchymal transition (EMT) phenotype. 252 HCC patients who underwent hepatectomy were enrolled for analysis of tHSCs and E-cadherin expression in tumor tissues, and 55 HCC patients for analysis of tHSCs in tumor tissues and circulating tumor cells (CTCs) in blood. Prognostic factors were then identified. The results showed that coculture of tHSCs with HCC cells had a stronger effect on HCC cell viability, migration and invasion, accompanied with the acquisition of epithelial-mesenchymal transition (EMT) phenotype. In vivo cotransplantation of HCC cells with tHSCs into nude mice more efficiently promoted tumor formation and growth. Icaritin, a known apoptosis inducer of HSCs, was demonstrated to effectively inhibit tHSC proliferation in vitro and tHSC-induced HCC-promoting effects in vivo. Clinical evidence indicated that tHSCs were rich in 45% of the HCC specimens, tHSC-rich subtypes were negatively correlated either with E-cadherin expression in tumor tissues (r = -0.256, p < 0.001) or with preoperative CTCs in blood (r = -0.287, p = 0.033), and were significantly correlated with tumor size (p = 0.027), TNM staging (p = 0.018), and vascular invasion (p = 0.008). Overall and recurrence-free survival rates of tHSC-rich patients were significantly worse than those for tHSC-poor patients. Multivariate analysis revealed tHSC-rich as an independent factor for overall and recurrence-free survival. In conclusion, tHSCs provide a promising prognostic biomarker and a new treatment target for HCC.</p> </div

tHSCs are associated with E-cadherin expression, HCC cell invasion in human HCC specimens, and poor survival outcome.

<p>(A) Representative immunostaining of HSCs in normal liver tissues and HCC tissues with α-SMA and desmin antibodies. (B) Representative samples of the tHSC density determined by α-SMA immunostaining (magnification, ×200). Typical grades 0, 1, 2, and 3 are shown in a, b, c, and d, respectively. (C) Representative pictures of α-SMA and E-cadherin expressions in human HCC tissues detected by immunostaining (magnification, ×400). tHSC-rich is accompanied by deccreased E-cadherin expression in case 1 (upper panel), and tHSC-poor is accompanied by increase E-cadherin expression in case 2 (lower panel). (D) Immunofluorescence staining separately with Hep Par 1 and E-cadherin antibody on serial sections of one HCC sample (magnification, ×400). The white arrows indicated the tumor cells with both Hep Par 1-positive and E-cadherin-negative staining that have infiltrated from their nests into the surrounding stroma. (E) The impact of tHSCs on the survival of HCC patients. (a) tHSC-associated overall survival rate. (b) tHSC-associated recurrence-free survival rate.</p

tHSC-CM promoted proliferation, migration and invasion of PLC/PRF/5 cells.

<p>(A and B) tHSC-CM significantly promoted HCC cell growth with time- and concentration-dependent manner. (C) Representative images of wound migration assays (left panel). Results are expressed as the percentage of the wounded area (right panel). (D) Representative images of invasion assays performed by transwell chamber (left panel). Results are expressed as the number of cells per field (right panel). *p < 0.05; **p < 0.01. </p

tHSCs promote HCC growth, and icaritin effectively inhibits tHSC-induced HCC-promoting effects in vivo.

<p>(A) The tumor volumes were monitored every 4 days up to 23 days after cell implantation. (B) The tumor weights at the end of experiments (*p < 0.05). (C) Representative immunohistochemical staining of α-SMA, E-cadherin, Ki-67, and CD34 expressions in different xenografts. (D) Representative images of TUNEL assay in different xenografts (magnification, ×200). PLC: PLC/PRF/5.</p

tHSC-CM induces EMT-like phenotype in HCC cells.

<p>(A) The morphology changes in PLC/PRF/5 cells (magnification, ×200). (B) Western blot analysis of E-cadherin and vimentin expressions in PLC/PRF/5 cells (left panel). Results are expressed as the fold value of protein levels compared with GAPDH (right panel). *p < 0.05. (C and D) Representative images of E-cadherin and vimentin expressions in PLC/PRF/5 cells by immunoflurescence staining (magnification, ×400). </p