The lifetime risk of HBV carriers to develop cirrhosis, liver failure, or HCC may be as high as 15% to 40%.[1-3] The identification of risk factors for the development of advanced liver disease, including cirrhosis and HCC, in HBV carriers is important for implementing effective this website treatment. Recently, several qualitative and quantitative hepatitis B viral factors affecting the prognosis of HBV carriers have been identified.[3, 4] Among these viral factors, baseline serum HBV-DNA level is the main driving force for cirrhosis and HCC development in adult HBV

carriers.[5, 6] Recently, quantitative HBsAg (qHBsAg) has been increasingly recognized to be a promising biomarker to predict both favorable and adverse outcomes of HBV carriers. Based on the weight of each risk factor associated with HBV-related HCC and through a stratification process, it is possible to identify HBV carriers who are at an increased risk of disease progression and HCC development (Table 1). In this article, hepatitis B viral factors

leading to disease progression Buparlisib ic50 and the risk stratification for HBV-related HCC will be reviewed and discussed. Low serum level of HBV-DNA Low serum level of HBsAg HBV genotype C/D BCP A1762T/G1764A mutation Pre-S deletion High serum level of HBV-DNA High serum level of HBsAg According to the divergence in the entire HBV genomic sequences, at least 10 HBV genotypes (A to J) have been defined.[7-9] Several studies suggested that HBV genotype can influence the long-term outcomes of HBV infection. For

example, HBV genotype C and D patients, compared with genotype A and B patients, have late or absent HBeAg seroconversion after multiple hepatitis flares that accelerate the progression of chronic hepatitis.[10-12] Most case–control Olopatadine studies and community-based prospective cohort study indicated that patients with genotype C HBV infection have a higher risk of cirrhosis and HCC than those with genotype B infection.[13-17] In addition, several reports have also shown that HBV genotype B was associated with HCC development in young non-cirrhotic patients. Whereas genotype C was associated with HCC development in old cirrhotic patients.[13, 18, 19] Due to the spontaneous error of viral reverse transcription, HBV mutant strains occur during the natural course of infection as well as with antiviral therapy. Mutations in precore, core promoter, and deletion mutation in pre-S/S genes have been reported to be associated with the progression of liver disease, including cirrhosis and HCC. Previous studies revealed that dual mutations in basal core promoter (BCP) A1762T/G1764A were strongly associated with the risk of HCC development.

19 Moreover, the increase in Cx26 and Cx32 levels in hepsin−/− mice was correlated with an increase in hepatocyte size in vivo, and this phenomenon was reversed by the GJIC blocker, oleamide. In addition to forming gap junctions, Cx26 and Cx32 also form hemichannels, which, when opened in a reduced-calcium environment, can lead to an increase in cell size because they form a nonselective leak pathway to permit free ions into the cytoplasm,

Napabucasin order followed by water uptake to maintain isoosmotic conditions.18 Such changes in cell size do not occur in connexin-deficient cells and can also be inhibited by oleamide and other gap-junctional blockers.20 A similar phenomenon might have occurred in our hepsin−/− mice, with increased hepatocyte size induced by excessive GJIC/hemichannels derived

from overexpression of connexins on the cell surface. We propose that HGF/c-Met may regulate connexin expression in hepatocytes in vivo. The detailed mechanism(s), however, VX-809 chemical structure remains to be elucidated. Using isolated primary rat hepatocytes in vitro, Ikejima et al.23 showed that down-regulation of Cx32 protein amounts by HGF occurs very quickly, starting at 3 hours after exposure to HGF, most likely by post-transcriptional modifications. In our study, HGF and NK4 affected Cx26 and Cx32 protein levels in vivo as early as 1 hour after exposure

(Fig. 7), a result which further supports post-transcriptional mechanisms. Moreover, in rat hepatocytes, the reduction in connexins caused by HGF is prevented by genistein, an inhibitor of c-Met, which also indicates that c-Met signaling is likely to mediate this process.23 There are several modification pathways downstream of c-Met (i.e., the mitogen-activated protein kinase [MAPK], phosphoinositide 3-kinase, and signal transduction and activator of transcription 3 signaling pathways) that are coupled to HGF/c-Met.25 Although there is no direct evidence demonstrating which of these pathways is responsible for the decrease of Cx32 and Cx26, previous findings for connexin 43 (Cx43) may provide some clues. Turnover of Cx43 is regulated by endothelial growth factor (EGF) at multiple MycoClean Mycoplasma Removal Kit levels, including enhancing phosphorylation, ubiquitination, internalization, and degradation of this protein.26 Moreover, these EGF-induced modifications of Cx43 may be caused by the MAPK pathway.26 Because both Cx3227 and Cx2628 proteins turn over with a short half-life (1.5-5.0 hours), similar to that of Cx43,29 and because Cx32 and Cx43 have comparable responses to proteasome inhibitors,30 it is possible that similar signaling pathways or post-transcriptional modification mechanisms may be involved in the down-regulation of the levels of Cx32 and Cx26 by HGF/c-Met.

It is a highly fatal malignancy, accounting for nearly 500 000 deaths annually, the third leading cause of cancer mortality in the world and the most important in many East Asian and sub-Saharan African countries.1,2 Potentially curative treatments for hepatocellular carcinoma (HCC) include partial hepatectomy, liver transplantation, and local ablative therapy. Among these, partial hepatectomy is a standard treatment that offers a chance of cure for patients with preserved liver function. Following curative HCC resection, 50–90%

of postoperative deaths are caused by recurrent disease. Intrahepatic recurrence, frequently the only site learn more of recurrence, occurs in 68–96% of patients.3 The concept has long been held that prevention of HBV infection and elimination or suppression of HBV should prevent or reduce development of liver cirrhosis and its complications, including HCC. The advent of highly effective HBV vaccines and several anti-HBV therapeutic agents has made this goal achievable.1,2 Vaccination reduces IWR-1 price rates of HBV infection. One of the most successful examples is the Taiwanese national infant and childhood hepatitis B vaccination program, begun in 1984, which reduced the proportion of children who were carriers of

the hepatitis B surface antigen (HBsAg) from 9.8% to 0.7% in 15 years.6 More importantly, follow-up results from the Taiwan vaccination program showed that the incidence of HCC in children 6–14 years of age significantly decreased, from 0.7 per million children between 1981 and 1986 to 0.36 per million children between 1990 and 1994.7 A meta-analysis of 12 trials (1292 interferon [IFN]-treated and 1450 untreated patients) showed that the risk of HCC was reduced by 34% (relative risk [RR]: 0.66, 95% confidence interval [CI]: 0.48–0.89; P = 0.006) O-methylated flavonoid after IFN

treatment.8 Another meta-analysis involving 11 trials also showed that IFN therapy had a beneficial effect in reducing cirrhosis and HCC.9 Using a meta-analysis involving 1267 lamivudine (LAM)-treated patients (with or without adefovir [ADV]) and 1022 untreated patients, Sung et al.8 reported that HCC was reduced by 78% (RR: 0.22, 95% CI: 0.10–0.50; P = 0.0003) on maintained LAM +/− ADV therapy. More benefit was observed in cirrhotic patients (RR: 0.17 vs 0.21) and HBeAg-positive patients (RR: 0.21 vs 0.25). The REVEAL study has shown that higher HBV viral loads are associated with higher risk of developing HCC,10 but no previous reports explored the correlation between these viral factors and late recurrence of HCC. Recently, Wu et al.11 studied 193 HBV-related HCC patients who underwent tumor resection. During the follow up of 58 months, 134 patients had HCC recurrence.

Initial structural neuroimaging studies generated qualitative descriptions of brain morphology in migraineurs and healthy subjects, while subsequent non-conventional magnetic resonance (MR) imaging (MRI) techniques allowed for quantitative evaluation of brain structure.5 Early studies employed 133Xenon (133Xe) blood flow techniques, transcranial Doppler, positron emission tomography (PET), and single-photon emission tomography (SPECT) to investigate hemodynamic changes.6 Subsequent investigations used novel MR-based techniques (eg, whole-brain tractography, perfusion-weighted and diffusion-weighted

imaging) to enhance knowledge of the elusive “migraine generator” and to decipher the neural and vascular mechanisms of migraine initiation or progression. More and more,

these investigations bring an understanding of migraine as a complex sensory processing disturbance associated with widespread Sotrastaurin nmr central nervous system (CNS) dysfunction.7,8 This review discusses pivotal neuroimaging studies that shed light on the pathogenetic mechanisms of migraine by unveiling structural and functional brain abnormalities, some of them potentially linked to the duration and frequency of attacks. Structural and cerebrovascular changes will be addressed, followed by functional and selected metabolic alterations, as reported in 3 main categories of studies: (1) at the onset of migraine aura; (2) during migraine attack (ictal); and (3) between attacks (interictal). This review was initiated with a PubMed search of the US National Hydroxychloroquine in vitro Library of Medicine with the following key words: ([magnetic resonance] OR [MRI] OR [MRA] OR [functional MRI] OR [fMRI] OR [spectroscopy] OR [MRS] OR [diffusion tensor] OR [DTI] OR [voxel] OR [VBM] OR [positron] OR [PET] OR [SPECT] OR [susceptibility weighted] OR [SWI] OR [perfusion weighted] OR [PWI]) AND (migraine). A review of all titles was conducted to include only pertinent publications. A hand search of

imaging and headache journals was performed, and reference lists from relevant studies were searched. The last literature search was performed on May 20, 2012. Aura Imaging.— Migraine aura new represents a set of transient neurological symptoms with gradual onset that precedes headache in one fourth of migraineurs, lasts less than an hour, and includes visual disturbances (often a visual field distortion characterized by scintillating scotoma with an expanding zigzag border), sensory loss (eg, paresthesias of the face or an extremity), and/or dysphasia. The anatomical substrates of this phenomenon reside in the cerebral cortex and brainstem (see Table 1 for a summary of neuroimaging findings in migraine aura). Reverse retinotopic mapping of aura symptoms reveals a constant propagation speed of about 3 mm/minute on the cortical surface.

A good HRQL measure would investigate environmental and personal aspects that influence function. Finally, HRQL should be measured from a subjective point of view (i.e., from the patient’s perspective), take into account the individual patient’s values, desires, expectations and autonomy of choice

(i.e., measure function against what the patient wants to achieve, rather than what the questionnaire developers expect or feel to be normal) [39,40,42]. Health status and HRQL measures are sometimes divided into generic and disease-specific. Generic measures have the advantage of being applicable across the whole spectrum of diseases, and therefore allow standardization and comparison between persons with haemophilia and patients with other diseases. However, find protocol the effects of interventions directed specifically towards haemophilia

(e.g. factor prophylaxis to reduce bleeding frequency) may not be measurable with generic measures (that may not, for example, have specific questions about bleeding). Several generic HRQL measures have been used in haemophilia studies, namely the Short Form 36 (SF-36), SF-12, Sickness Impact Profile (SIP) and the Quality of Well-Being Index (QWB) [43]. Bullinger, et al., representing the International Prophylaxis Study Group (IPSG) have reviewed the haemophilia-specific HRQL questionnaires [43]. For adults, these are selleck chemical the Haemo-Qol-A [44], Haem-A-Qol [45], the Hemofilia-QoL [46], Hemolatin-QoL [47] and QUAL-HEMO. For children, these are the Haemo-QoL [48], CHO-KLAT [49] and a proxy measure for very young patients [50]. Most of these tools were studied and shown to have good to excellent reliability and construct validity; i.e., most of these tools have demonstrated measurement properties that make them suitable for use in studies

and in the clinic. Furthermore, in general, these tools address five domains of health – physical, emotional/social, functional, mental and treatment-related Selleck 5FU – and can therefore be thought of as addressing some of the main areas defined by the ICF model. There are some ways, though, in which these measures fall short of the ideal detailed above. Although persons with haemophilia (or in some cases their parents) answer these questions from their own experience – the questions asked, the scoring options listed and the values attached to those scores reflect the values and expectations of the questionnaire developers,1 rather than the values and expectations of the individual patient answering the questionnaire. That is, these measures are not fully subjective, and do not take into account individual autonomy of choice. They are missing key elements important for the assessment of QoL. A better name for these tools, then, might be ‘self-reported measures of health status’.

1 In this article, we report that TNFα sensitizes primary mouse hepatocytes to FasL-induced apoptosis in a Bid-dependent and Bim-dependent manner. We further show that this crosstalk involves JNK activation and most likely Bim phosphorylation, cleavage of Bid, and, consequently, activation of

the type II mitochondrial pathway and results in cytochrome c release and effector caspase-3/caspase-7 activation. Controversial results have so far been reported concerning the crosstalk of TNFα and FasL in apoptosis induction. On the one hand, TNFα has been shown to confer resistance to Fas-induced cell death in eosinophilic acute myeloid leukemia cells because of its NF-κB–mediated antiapoptotic functions.25

In this respect, we analyzed some typical antiapoptotic NF-κB target genes such as cellular inhibitor of apoptosis BGB324 2 (cIAP2), c-FLIP, and XIAP, but we found that they were only moderately up-regulated (if ever) in response to TNFα (see Supporting Fig. 16). cIAP1 protein was not at all detected in hepatocytes (see also Walter et al.12; data not shown). On the other hand, several studies have indicated that TNFα positively Erlotinib mouse regulates Fas-mediated apoptosis. In one case, TNFα could even overcome the Fas resistance of human lung fibroblasts26 by allowing more FADD adaptor to bind to Fas and therefore increase DISC formation and FasL-mediated apoptotic signaling. In contrast to human lung fibroblasts, primary mouse hepatocytes do not seem to have impaired DISC formation because they are quite sensitive to FasL-induced apoptosis.

To obtain evidence for the physiological relevance of TNFα/FasL crosstalk, Costelli et al.27 used gene targeting to show that a loss of TNFR1 and TNFR2 protects mice from anti-Fas antibody–induced liver injury. Our results confirm these findings and demonstrate that TNFα is necessary for efficient FasL-mediated hepatocyte apoptosis. However, the exact mechanism of the interplay PLEK2 of the two pathways was not unraveled in the previous study. It was shown that liver tissue levels of Fas and FasL as well as Fas expression on the hepatocyte surface were unchanged, but Bcl2 was up-regulated upon TNFR1 and TNFR2 depletion; this indicates that TNFα may regulate Bcl2 family members.27 This again is consistent with our finding that neither Fas up-regulation nor endogenous FasL is critical for the TNFα sensitizing effect, and changes in members of the Bcl2 protein family could be the underlying mechanisms for the involvement of the type II mitochondrial pathway in the sensitization process. On the other hand, it is widely accepted that TNFα fails to induce apoptosis in hepatocytes under normal conditions because of activation of the NF-κB survival pathway. Inhibition of this pathway restores apoptosis, and one mechanism involves the inducement of sustained activation of JNK.

“
“Purpose: The purpose of this study was to test the hypothesis that all-ceramic crown core-veneer

system reliability is improved by modifying the core design and as a result is comparable in reliability to metal-ceramic retainers (MCR). Finite element NVP-LDE225 solubility dmso analysis (FEA) was performed to verify maximum principal stress distribution in the systems. Materials and Methods: A first lower molar full crown preparation was modeled by reducing the height of proximal walls by 1.5 mm and occlusal surface by 2.0 mm. The CAD-based preparation was replicated and positioned in a dental articulator for specimen fabrication. Conventional (0.5 mm uniform thickness) and modified (2.5 mm height, 1 mm thickness at the lingual extending to proximals) selleck zirconia (Y-TZP) core designs were produced with 1.5 mm veneer porcelain. MCR controls were fabricated following conventional design. All crowns were resin cemented to 30-day aged

composite dies, aged 14 days in water and either single-loaded to failure or step-stress fatigue tested. The loads were positioned either on the mesiobuccal or mesiolingual cusp (n = 21 for each ceramic system and cusp). Probability Weibull and use level probability curves were calculated. Crack evolution was followed, and postmortem specimens were analyzed and compared to clinical failures. Results: Compared to conventional and MCRs, increased levels of stress were observed in the core region for the modified Y-TZP core design. The reliability was higher in the Y-TZP-lingual-modified group at 100,000 cycles and 200 N, but not significantly different from the MCR-mesiolingual group. The MCR-distobuccal group showed the highest Protirelin reliability. Fracture modes for Y-TZP groups were veneer chipping not exposing the core for the conventional design groups, and exposing the veneer-core interface for the modified group. MCR fractures were mostly chipping combined with metal coping exposure. Conclusions: FEA showed higher levels of stress for both Y-TZP core designs and veneer layers compared to MCR. Core design modification resulted in fatigue reliability response of Y-TZP comparable to MCR at 100,000 cycles and 200 N. Fracture modes

observed matched with clinical scenarios. “
“Purpose: The aim of this study was to evaluate the effect of mechanical cycling and different misfit levels on Vicker’s microhardness of retention screws for single implant-supported prostheses. Materials and Methods: Premachined UCLA abutments were cast with cobalt-chromium alloy to obtain 48 crowns divided into four groups (n = 12). The crowns presented no misfit in group A (control group) and unilateral misfits of 50 μm, 100 μm, and 200 μm in groups B, C, and D, respectively. The crowns were screwed to external hexagon implants with titanium retention screws (torque of 30 N/cm), and the sets were submitted to three different periods of mechanical cycling: 2×104, 5×104, and 1×106 cycles.

40 With the exception of VDR and LXR, other NR expression levels are rather low in activated Protein Tyrosine Kinase inhibitor mouse and human HSCs.39 These findings should place VDR into the center of interest for future antifibrotic strategies. The liver plays a central role in lipid homeostasis and NRs control several aspects of hepatic lipid and lipoprotein metabolism which may be relevant for the pathogenesis and treatment of metabolic syndrome, hepatic insulin resistance, dyslipidemia, atherosclerosis, and nonalcoholic fatty liver disease (NAFLD). Several endogenous and

exogenous lipids such as cholesterol or fatty acids act as physiological NR ligands and NRs may be viewed as “lipostats” as their activation frequently promotes metabolism/catabolism of respective ligands and/or provides a negative-feedback for self termination of their synthesis

(Supporting Table 4). More specifically, PPARα/γ/δ and hepatocyte nuclear factor 4α (HNF4α) are activated by various fatty acids,41,42 oxidation products ABT-263 purchase of cholesterol such as 24(S)-hydroxycholesterol act as ligands for LXR,43,44 and cholesterol metabolites like bile acids act as FXR ligands (Supporting Table 4).45-47 Modulation of the activity of these NRs by already available synthetic compounds represents an attractive therapeutic strategy for these metabolic disturbances (Supporting Table 4). NRs regulate both hepatic production and clearance of triglycerides from plasma which is mediated by a lipoprotein lipase (LPL). LPL activity is modulated by apolipoproteins that act either as cofactors

or inhibitors which again are controlled by NRs. PPARα activation by fibrates lowers serum triglyceride levels by way of multiple mechanisms including (1) induction of LPL activity by way of inhibition of apoCIII (LPL inhibitor) expression48 and activation of apolipoprotein AV (apoAV) (LPL cofactor)48; (2) lowering hepatic very low density lipoprotein (VLDL) production; and (3) increasing fatty acid oxidation49 (Fig. 2). LXR activation increases triglyceride levels in mice by way of up-regulation of the lipogenic master regulator sterol regulatory element-binding protein 1c (SREBP1c) that in turn induces the expression of enzymes involved in de novo lipogenesis43,50 (Fig. 2). Recently, OSBPL9 specific LXR ligands with potent antiatherosclerotic effects but without negative effects such as hepatic steatosis have been identified.51 Besides their well-established roles in dietary lipid absorption and cholesterol homeostasis, bile acids also have systemic endocrine functions that are mediated by FXR and the G-protein-coupled receptor TGR5.52 Bile acids may serve as nutrient signaling molecules during the feed/fast cycle where the flux of reabsorbed bile acids by way of the enterohepatic circulation, arriving in the liver with the coabsorbed nutrients (e.g.

Disclosures: The

following people have nothing to disclose: Guohua Lou, Yanning Liu, Zhi Chen BACKGROUND: ALR is a sulfhydryl oxidase enzyme present (1) in all mammalian tissues. We reported its anti-apoptotic and anti-oxidative activity both, in vivo, (2) and, in vitro (3), in neo-plastic glioma cells treated with specific ALR siRNA. In both experimental models, we demonstrated that ALR is a key factor for the maintenance of cell survival (apoptosis) cellular nor-moxic state control and for mitochondrial membrane integrity. AIM: To evaluate the biological effects of ALR on hepatocyte apoptosis and proliferation by reducing ALR expression Decitabine order in hepatic tissue of PH rats. MATERIALS AND METHODS: Seventy

percent PH rats were administered, just after the surgery, with adenovirus-carrying ALR shRNA (AD-shRNA) and followed for 48 hours. At the time of the sacrifice (12, 24, 48 hours after PH), polyamine levels, ALR expression (Western Blot analysis), cell proliferation (BrdU+ and mitotic index) and apoptosis (Bcl-2, Bax and activated caspase 3) and liver mass recovery were evaluated on hepatic tissue. Liver cell toxicity was determined by ALT serum levels and by histology. PH rats injected with adeno-LacZ were used as control. RESULTS: The AD-shRNA treatment did not show any cell toxicity. A statistically significant reduction of ALR expression was demonstrated at 12 and 24 hours after PH with a parallel decrease of hepatocyte proliferation and polyamine

synthesis. In liver tissue of AD-shRNA treated rats, a decrease of anti-apoptotic factors (Bcl-2) and an increase of pro-apoptotic factors RAD001 (activated caspase 3 and Bax) was observed. At 24 hr after partial hepatectomy, there were major expression differences in ALR protein and mitotic index, comparing rats treated and not treated with AD-shRNA: AD-shRNA treated: ALR:actin 4.7 mitotic index 0.003 % Controls: ALR:actin 10.7 mitotic index 0.8% CONCLUSION: Our data confirm that abolishing ALR expression in vivo in 70% PH rats there is a complete change in the physiological state of hepatocytes only with prevalence of apoptosis, increase of reactive oxygen species induced by surgery, decrease of polyamine synthesis, all parameters necessary for a correct liver mass regeneration after 70% PH confirming the physiological importance of ALR in the first phase of liver regeneration. References: (1) Francavilla A. et al. Hepatology 1 994 (2) Polimeno L. et al. Free Rad. Res. 201 1 (3) Polimeno L. etal. Cell Death Dis. 2012 Disclosures: The following people have nothing to disclose: Antonio Francavilla, Barbara Pesetti, Angela Tafaro, Giusy Bianco, Francesco Russo, Michele Linsalata, Lorenzo Polimeno Introduction: Recombinant adenoviruses (rAd) are the most common vectors used in clinical trials for gene therapy. Systemic administration of rAd show prominent tropism for liver.

To determine its suppressive effect in cancer,

we performed supplementary R788 order experiments in HCC by in vitro and in vivo studies. However, the molecular mechanisms underlying the role of PTPRO as a tumor suppressor remain unclear. Regarding the potential function of PTP, we hypothesized that PTPRO was able to counterbalance oncogenic tyrosine kinase signaling. In this study, we aimed to investigate the tumor-suppression ability of PTPRO with regard to STAT3 activation. AP-1, activator protein 1; Bcl-2, B-cell lymphoma 2; bp, base pairs; BrdU, bromodeoxyuridine; DEN, diethylnitrosamine; E2, 17β-estradiol; EGF, epidermal growth factor; ERs, estrogen receptors; ERα, estrogen receptor alpha; ERβ, estrogen receptor beta; EREs, estrogen-responsive elements; ERK, extracellular signal-regulated kinase; FGF, fibroblast growth factor; HBV, hepatitis B virus; HCV, hepatitis C virus; HCC, hepatocellular carcinoma; HGF, hepatocyte growth factor; IFN-γ, interferon-gamma; IHC, immunohistochemistry; IL-6, interleukin-6; IOD, integrated optical density; JAK2, Janus kinase 2; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; mRNA,

messenger RNA; mTOR, mammalian target of rapamycin; MTT, ACP-196 supplier tetrazolium; PCR, polymerase chain reaction; PI, propidium iodide; PI3K, phosphoinositide 3-kinase; p-JAK2, phosphorylated JAK2; p-STAT3, phosphorylated STAT3; PTEN, phosphatase and tensin homolog; PTP, phosphotyrosine phosphatase; Liothyronine Sodium PTPRO, protein tyrosine phosphatase receptor type O; S727, serine 727; SHP, SHATTERPROOF; STAT3, signal transducer and activator of transcription 3; WT, wild type; Y705, tyrosine 705. HCC and adjacent tissues were obtained from 120 male and 60 female patients at the time of surgical resection at the First Affiliated Hospital of Nanjing Medical University (Nanjing, China) between January 2008 and August 2010. Informed consent for gene-expression analysis of tissue was obtained from each patient before surgery, and the study was approved by our institutional ethics

committee. HCC staging was performed according to the tumor node metastasis staging system. Adjacent tissue was located within 1 cm of the tumor margin and was confirmed to be nontumor tissue by pathological examination. Detailed patient information is listed in Supporting Table 1. Detailed information regarding animal model, lentivirus production and transduction, quantitative real-time polymerase chain reaction (PCR), western blotting, immunohistochemistry (IHC), cloning of ptpro promoter and mutagenesis, luciferase reporter assay, cell culture, cell-proliferation assay, cell-apoptosis assay, and statistical analysis is provided in the Supporting Materials. We investigated 180 pairs of HCC and adjacent patient tissue specimens using real-time PCR and IHC; both HCC and adjacent tissues were grouped by gender.