The role of PKC-delta was evaluated using a PKC activator (PMA, 1

The role of PKC-delta was evaluated using a PKC activator (PMA, 100 nM), PKC inhibitors KU 57788 (5 uM chelethryine, 100 uM H-7 or 0.5 uM calphostin), siRNA to PKC delta, and wild type (WT) or constitutively active (CA) PKC delta plasmid constructs. Activation of PKC

delta was monitored by immunoblotting for Thr 505 phosphorylation (HUH7Ntcp) or for total PKC delta in the mitochondria (rat hepatocytes). Phosphorylation of JNK and Akt and the amount of total BIM were determined by immunoblotting. RESULTS: GCDC treatment increased total PKC delta expression in rat hepatocyte mitochondria by 1.70 +/- 0.22 fold and induced a 5.71 +/-1.2 fold increase in the phosphorylation of PKC delta in HUH7-Ntcp cells. Within 2 hrs GCDC induced apoptosis in 16% +/- 4.5 % of rat hepatocytes and 10.5% +/- 2.3% of HUH7-Ntcp cells and resulted XL184 price in cleavage of caspase 3.Treatment of hepatocytes or HUH7-Ntcp cells with PMA decreased GCDC apoptosis by 71% +/-3.4% and 92% +/1 6.7%, respectively. In rat hepatocytes, PKC inhibitors increased GCDC induced apoptosis from 24% to 92%. Knock down of PKC delta increased GCDC apoptosis by 2.7 +/-0.98

fold, while WT- and CA-PKC-delta decreased apoptosis by 35% +/2.5% and 54% +/- 5.6%, respectively. Knock down of PKC delta increased pro-apoptotic JNK phosphorylation and total BIM levels by 2.4 and 2.3 times, respectively and decreased anti-apoptotic Akt phosphorylation by 52% +/-6.7%. GCDC apoptosis was accompanied by mitochondrial translocation of BIM and knock down

of BIM decreased GCDC induced apoptosis in HUH7-Ntcp cells by 51% +/- Exoribonuclease 3.6%. CONCLUSION: Taken together, these results suggest that activation of PKC-delta by GCDC induces a cytoprotective pathway that results in inhibition of JNK activation, activation of Akt and down-regulation of BIM. Disclosures: The following people have nothing to disclose: Cynthia R. Webster, Mohammed S. Anwer “
“Background and Aim:  Gallstone formation is characterized by the abnormal regulation of cholesterol trafficking and solubilization. The prevalence of gallstone disease (GSD) differs between ethnic groups sharing the common environment. These differences can be explained by a genetic predisposition to gallstone formation. Studies have identified single nucleotide polymorphisms (SNP) D19H and T400K in the cholesterol transporter gene ATP-binding cassette, subfamily G, member 8 (ABCG8) in patients with cholesterol gallstones. The aim of this study was to analyze the relationship between D19H and T400K polymorphisms in the ABCG8 gene and GSD in an Indian population, and the effects of these polymorphisms on cholesterol levels in sera and bile. Methods:  A total of 226 patients with GSD were analyzed for their lipid profile in plasma and bile.

For this reason, it should be recommended to perform endoscopic r

For this reason, it should be recommended to perform endoscopic resection for high-grade dysplasia (early mucosal gastric cancer according to the Japanese criteria). To reconcile these discrepant diagnostic criteria between Japan and the West, the term “noninvasive high-grade neoplasia” was adopted in the Vienna classification. Unfortunately, however, this term has not been widely used in either side. Moreover, the term, “intraepithelial neoplasia”

was introduced in the recent World Health Organization classification. In the future, we definitely need a global consensus how to deal with such “neoplastic” lesions, for which recent BMS-354825 nmr technological advancement would be instrumental in promoting mutual understanding. This review article is the results of intensive clinical and research efforts of colleagues in Jichi Medical University. Special thanks to Dr Hiroyuki

Mutoh who contributed to the molecular mechanisms of IM and to Dr Kiichi Satoh for the histological analysis. I also thank Dr Yoshikazu Hayashi in our department and Dr Shunji Hayashi in the department of microbiology, Jichi Medical University who contributed to gastric microbiology. Endoscopic images were kindly provided by Dr Hiroyuki Osawa Carfilzomib cell line in our department. “
“We read with interest the article by Ghouri et al.,1 who reviewed the evidence regarding the link between nonalcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD). The authors concluded that the connection between NAFLD and CVD is not well supported by existing data because of the presence of confounders such as age and established cardiovascular risk factors. We agree that the main limitation of these studies is that their results make it difficult to distinguish the contribution of liver fat per se to the risk of CVD. However, we should consider that the liver is the main regulator of insulin sensitivity

and finely tunes insulin-regulated metabolic Ibrutinib pathways such as glucose and lipid homeostasis that are involved in endothelial dysfunction and atherogenesis. Studies in null mice have clearly substantiated this issue. In particular, the disruption of insulin signaling in the liver is more relevant to whole body glucose homeostasis than its disruption in adipose tissue and muscle.2 In addition, hepatic insulin signaling regulates the secretion of very low density lipoprotein and thus lipotoxicity and atherogenesis.3 Therefore, it is impossible to identify the intrahepatic triglyceride level, which precisely reflects liver insulin resistance, as an isolated variable in the generation of CVD risk.

5 ug/kg/week for 24 weeks along with continuation of nucleoside t

5 ug/kg/week for 24 weeks along with continuation of nucleoside till end of therapy) for 52 weeks. Monitoring included Hepatitis B profile (HbsAg, HbeAg, Anti-Hbe, HBV DNA levels) and safety assessment (hematology, thyroid profile and growth assessment). Results: A total of 33 chronic hepatitis b patients (20 in immunotolerant and 13 in immunoclearance phase) were enrolled in the study. 10 immunotolerant and 5 immunoclearance children agreed to participate in the study

and were given the sequential therapy. Mean age of the children was 10.16 + 4.58 years. Of 11 patients with available genotype data, 8 belonged to genotype D with 2 patients of genotype A and 1 Dabrafenib mouse of genotype B. In Immunoclearance group (3 in lamivudine and 2 in tenofovir RO4929097 purchase group), all 5 patients (100 %) cleared HbeAg after completion of therapy

and 2 out of 5 (in lamivudine group) cleared HbsAg with appearance of anti-Hbs suggestive of cure. In the immunotolerant phase, none out of the 10 patients had HbeAg clearance after 52 weeks of therapy. Side effects included mild cytopenias (4 patients), transient flu-like illness (all patients) and interferon dose reduction in 2 patients. Conclusion: In immunoclearance phase, sequential therapy allows HbeAg seroconversion in all cases and around half of the cases may be amenable

to apparent cure with HbsAg loss. Six months of Pegylated Interferon therapy preceded by nucleoside therapy is not sufficient enough to allow response in immunotolerant phase which may be due to predominance of Genotype D in our population. Overall, therapy was well tolerated by all children Disclosures: The following people have nothing to disclose: Vikrant Sood, Sanjeev K. Verma, Seema Alam, Rajeev Khanna, Dinesh Rawat Data on long-term outcomes after interferon (IFN) based therapy in chronic hepatitis B (CHB) are limited. mRNA expression of PRKD3 interferon-stimulated genes (ISG) in pre-treatment liver biopsy in immunotolerant CHB patients prior to IFN therapy showed that lower mRNA CXCL10 expression in the liver was associated with therapy response, but there was wide variability in mRNA ISG expression results in therapy non-responders. We aimed to assess whether different viral (genotype, precore) factors at baseline and long-term post-therapy responses might contribute to variability in ISG expression and can predict long- term CHB outcome. Patients: 23 patients (8 males, median age 10.2 years) with infancy-acquired CHB, treated for 52 weeks [lead-in LAM (3mg/kg/d) for 9 weeks; add-on IFN-α (5MU/ m2TIW) from week 9] were followed-up 13 years post-stopping therapy.

The suppressed translocation of Parkin to the mitochondria inhibi

The suppressed translocation of Parkin to the mitochondria inhibited mitochondrial ubiquitination’decreased the number of mitochondria sequestered in isolation

membranes (mitophagosomes), and reduced autophagic degradation activity, which clearly indicated the suppression of mitophagy. However, OR6 cells promoted autophagy under non-selective autophagyinducible conditions (amino acid starvation), as indicated by the increased expression Dorsomorphin in vivo of the microtubule-associated protein light chain 3 (LC3)-II. CONCLUSIONS: Through a direct interaction with Parkin, the HCV core protein suppressed mitophagy by inhibiting the translocation of Parkin to the mitochondria. These results have implications for the amplification and sustainability of mitochondria-induced oxidative stress observed in patients with HCV-related chronic liver disease and an increased risk of hepatocarcinogenesis. Disclosures: Kazuaki Chayama – Consulting:

Abbvie; Grant/Research Support: Dainippon Sumitomo, Chugai, Mitsubishi Tanabe, DAIICHI SANKYO, Toray, BMS, MSD; Speaking and Teaching: Chugai, Mitsubishi Tanabe, Histone Methyltransferase inhibitor DAIICHI SANKYO, KYORIN, Nihon Medi-Physics, BMS, Dainippon Sumitomo, MSD, ASKA, Astellas, AstraZeneca, Eisai, Olympus, GlaxoSmithKline, ZERIA, Bayer, Minophagen, JANSSEN, JIMTO, TSUMUTA, Otsuka, Taiho, Nippon Kayaku, Nippon Shinyaku, Takeda, AJINOMOTO, Meiji Seika, Toray The following people have nothing to disclose: Yuichi Hara, Sohji Nishina, Izumi Yanatori, Masanori Ikeda, Emi Kiyokage, Yasuyuki Tomiyama, Kazunori Toida, Fumio Kishi, Nobuyuki Kato, Michio Imamura, Keisuke Hino Aims: To investigate the role of the flavonoid quercetin (Q) on modulation of lipid droplets (LDs) size and morphology

and HCV core protein localization and (3) HCV life cycle focusing on Fossariinae entry and replication. Methods: The morphology of LDs and core localisation were studied by immunofluorescence using confocal microscopy on Huh-7 cells transduced with lentivectors encoding the core protein of HCV genotype3a and treated with quercetin for 48h at different concentrations (50μM-100μM). LDs analysis was done using MetaMorph Microscopy-Software. To study the effects of quercetin on viral replication (iRNA), Huh7 cells were infected with Jc1 ccHCV particles (1Moi) and subsequently treated with quercetin for 48 and 72h. NS3 and core protein levels were evaluated by immunoblot. HCV entry was assessed using HCV pseudoparticies(HCVpp), which are lentivectors harboring HCV entry proteins and containing luciferase as reporter gene. Results: LDs morphology(area, radium, and volume) and distribution were modified by quercetin in Huh7. Quercetin treatment could impede the core 3a- induced increase of LD size in cells transduced with lentivirus expressing the Core genotype 3a protein [LD area (μm2): 3a:109.8±33.72; 3aQ50μM: 79.90±36(p<0.001); 3aQ100μM: 72, 6±35.4(p<0, 0003); radium(μm): 3a: 5.85±0.88; 3aQ50μM: 4.91 ±1.15(p<0.001) 3aQ100μM: 4.65±1.22 (p<0.0002), voiumen (μm3) 3a: 894.7±418.5; 3aQ50μM: 577.03±379.

16, 17 Protein extracts from human liver tumors and from healthy

16, 17 Protein extracts from human liver tumors and from healthy patients were obtained from OriGene (Rockville, MD). Liver tumors were induced in wild-type (WT) and Little mice via diethylnitrosoamine (DEN) tumor liver

induction as described.5 For FXR agonist treatment experiment, 8-week-old mice were injected with FXR agonist GW4064 intraperitoneally (30 mg/kg body weight). Alvelestat mouse Control mice were injected with vehicle (corn oil). Nuclear and cytoplasmic extract isolation and western blot analysis were performed as described our previous publications.18, 19 A typical picture of the quality of the separation of cytoplasmic and nuclear proteins is shown in Supporting Fig. 2. Total RNA from liver tissues or Hep3B2 cells was extracted with an RNeasy Mini Kit (Qiagen,

Germantown, MD) according to the manufacturer’s instructions. Complementary DNA was synthesized using SuperScript III First-strand (Invitrogen) and random primer hexamers. The primer sequences used in the studies are presented in the Supporting Information. Chromatin immunoprecipitation assay (ChIP) was performed as described5, 18 using the ChIP-IT kit (Active Motif, Carlsbad, CA). Electrophoretic mobility shift assay was performed as described.19 Antibodies to FXR (C20 and H130), gankyrin, C/EBPβ (C19), C/EBPα (A144), cdk4, cdc2, cyclin D3, Rb, p53, and HDAC1 (H-51) were obtained from Santa Cruz Biotechnology (Santa Cruz, CA). Antibodies to acetyl-histone H3 (Lys9) and histone H3 trimethyl Lys9 were obtained from Abcam (Cambridge, MA). Monoclonal anti–β-actin antibody was from Sigma (St. Louis, MO). The bromodeoxyuridine NVP-AUY922 (BrdU) uptake

assay kit was obtained from Invitrogen (Carlsbad, CA). Co-immunoprecipitation studies were performed using TrueBlot reagents as described.5, 19 Hepa 1-6 cells were transduced with the shRNA-expressing lentivirus (Sigma-Aldrich, St. Louis, MO), and stable cell lines were generated by selection with puromycin for 2 weeks. For in vivo silencing experiments, 3-month-old mice were injected via the tail vein with C/EBPβ siRNA or nontarget siRNA (50 Ixazomib price μg of siRNA from Dharmcon complexed with in vivo-jet PEI, N/P ratio of 6 per mouse). FXR/SHP KO mice have hepatobiliary dysfunctions, including increased liver proliferation16 and development of liver cancer at age of 12 months (Anakk et al., submitted for publication). Because gankyrin-mediated elimination of C/EBPα is one of the key events in the development of liver cancer,5 we examined whether this pathway is activated in the livers of FXR/SHP KO mice. Figure 1A shows a typical liver of a 17-month-old FXR/SHP KO mouse with advanced cancer. BrdU uptake confirmed that liver proliferation was increased in these animals (Fig. 1B). Because C/EBPα needs to be phosphorylated at S193 by cdc2 and cdk4 to be degraded by gankyrin,5 we examined the expression of C/EBPα, gankyrin, cdc2, and cdk4 in livers of FXR/SHP KO mice. Figure 1C shows that gankyrin was elevated in the livers of FXR/SHP KO mice.

[17, 21, 22] Insulin and insulin-like growth factor (IGF) can pro

[17, 21, 22] Insulin and insulin-like growth factor (IGF) can promote the growth of HCC.[40] Kawaguchi et al. reported that BCAA granules suppress liver carcinogenesis through amelioration of insulin resistance via: (i) BCAA activation of the insulin signaling cascade through upregulation of phosphatidylinositol 3-kinase with reduction of serum insulin levels; and (ii) inhibition of the IGF/IGF-1 receptor axis by suppressing the expressions of IGF-1, IGF-2 and IGF-1 receptor mRNA.[17, 41] They also reported that the improvement of insulin resistance by BCAA granules may

be related to the migration of Selleck Compound Library HCC, suppression of angiogenesis and epithelial–mesenchymal transition of hepatocytes, and that BCAA granules may inhibit liver carcinogenesis (at least in part) by reduction of oxidative stress and strengthening of immune functions.[17] There are several reports of the usefulness of BCAA supplementation on the QoL of patients with liver cirrhosis.[42, 43] Kawamura et al. demonstrated that, in 453 patients with chronic liver disease, QoL decreased significantly according to the progression of disease as assessed by the scores from Short Form 36 (P < 0.05) and that the QoL of patients with chronic liver diseases was improved in the BCAA granules administration LEE011 solubility dmso group (n = 13)

compared with the control group (n = 12) after 6 months.[42] Hepatic encephalopathy (HE) is a major complication in patients with liver cirrhosis that is related to a poor prognosis and poor QoL.[44] Sleep disturbance may be associated with minimal HE.[45] Les et al. conducted a randomized study involving 116 patients who had experienced an episode of HE (58 patients in the BCAA group

and 58 patients in the maltodextrin group) to examine the effect of BCAA: they reported that supplementation with BCAA improves minimal HE and muscle mass.[43] Tryptophan, which is a precursor of the neurotransmitter 5-hydroxytryptamine Adenosine triphosphate (which is related to sleep disturbance), may be regulated by BCAA supplementation.[46] With the wide range of pharmacological actions, such as increasing the serum albumin level,[16-19] inhibiting cirrhosis complications/angiogenesis/hepatic carcinogenesis,[17-20, 22, 27-29] improving insulin resistance[17, 21, 22] and fatty-acid metabolism,[17, 24] reducing oxidative stress,[17, 23] and increasing stimulation of the immune system,[17, 25, 26] therapy using BCAA granules may be an indispensable treatment for cirrhosis. Along with liver transplantation, hepatectomy is a curative treatment approach for HCC.[6, 8, 9, 47-49] According to guidelines set by the European Association for the Study of the Liver (EASL), hepatectomy is indicated in patients with a single tumor of 2 cm or less in diameter, performance status (PS) 0, Child–Pugh class A and no portal hypertension.

8) Both NALP3 and NALP1 are highly expressed in primary immune c

8). Both NALP3 and NALP1 are highly expressed in primary immune cells and in other cell types, including epithelial cells, neurons, and gonadal cells.24 Here we report that hepatocytes express NALPs. We have found that hepatocytes express the adaptor molecule ASC and the entire functional inflammasome machine and are capable of

IL-1β production. The elucidation of the triggering factors responsible for increased inflammasome expression and function in NASH is of emerging importance. FFAs can be recognized as endogenous danger molecules and induce inflammatory find more signaling and activation of nuclear factor kappa B and c-Jun N-terminal kinase–activator protein 1 pathways leading to cytokine and chemokine production.25, 26 Although TLRs detect ligands either on the cell surface or in the lumen

of the endoplasmatic reticulum,27 NLRs are intracellular cytoplasmic (NALP3) or nuclear (NALP1) sensors.24 We have found that saturated FAs induce up-regulation of pro–IL-1β and NALP3 in hepatocytes. Increased FFA levels have been reported in mice with MCD diet–induced,28 HFD-induced,29 or leptin deficiency–induced steatohepatitis30 and in human NAFLD patients with either steatosis or steatohepatitis.4, 5 Although several reports have evaluated the FA profile and the ratio selleck products of saturated and unsaturated FAs in animal models28-30 and in human plasma in the setting of NASH,4, 5 it is yet to be determined whether changes in the FA composition in the liver or serum correlate with steatosis or steatohepatitis. We speculate that saturated FAs in NASH may favor inflammasome activation, whereas a different composition of FFAs in simple steatosis may not trigger such events. These differences could be further amplified by the presence of additional signals such as LPS or danger signals from damaged hepatocytes.

Accumulating evidence shows that innate immune pathways are activated in metabolic syndrome and play a crucial role in the pathogenesis of NASH.31 Increased plasma levels of the TLR4 ligand LPS and enhanced Forskolin purchase susceptibility to LPS-induced liver damage have been observed.7-9 We found increased serum endotoxin levels in mice with steatohepatitis, which suggested the presence of an exogenous TLR ligand. We and others have shown that a TLR4 deficiency can prevent experimental NASH.9, 32 The exogenous administration of LPS further increased IL-1β levels and inflammasome expression in livers with steatohepatitis; this suggests that the fatty liver is primed for LPS-induced inflammasome activation. This novel observation complements previous reports demonstrating that the fatty liver is sensitized to LPS-induced TNF-α production and LPS-induced liver damage.

The last group was defined as the migraine control group, that is

The last group was defined as the migraine control group, that is, a control group consisting of women with migraine who had not reported any triptan use during pregnancy. These subsets were created using

answers to questions regarding both triptan use and migraine in both GS-1101 research buy questionnaires 1 and 2 as long as the name of the triptan and the timing of either triptan use or migraine was specified. The pregnancy outcome of the exposed subgroups was compared with women who did not report any use of triptans at all. This group of women was defined as the nonmigraine control group. Drug therapy was classified and grouped according to the Anatomical Therapeutic Chemical Classification System developed by the World Health Organization.25 Outcome Variables.— The outcome variables were retrieved from the Medical Birth Registry of Norway and included primary outcome variables consisting of congenital malformations (yes/no) and other adverse pregnancy outcome variables consisting of survival (live birth, miscarriage/stillbirth, perinatal death, death during the first 12 months of life) (yes/no), birth weight <2500 g (yes/no), gestational age Protease Inhibitor Library <37 weeks (yes/no), Apgar scores <7 at 1 and 5 minutes (yes/no), atonic uterus (yes/no), prolonged labor (yes/no), and perinatal and/or postpartum blood loss >500 mL (yes/no). Possible Confounding Factors.— Possible confounding factors including

maternal sociodemographic and medical characteristics are categorized as shown in Tables 2 and 3, and those including maternal health and pregnancy complications are categorized as shown in Table 4. Statistical Analysis.— Individual logistic regression analyses were used to identify significant associations between triptan therapy, possible confounding factors and pregnancy outcomes. Different potential confounding GNA12 factors were chosen for each pregnancy outcome depending on clinical plausibility,

statistical significance, and the size of the outcome event rates. Confounding factors which were to be controlled for in the logistic regression analyses were chosen on the basis of theoretical clinical significance and initial Pearson’s χ2 analyses where the P value was <.25. During preliminary logistic regression analyses, potential confounding variables with a P value of >.5 were removed one by one excluding those instances where the coefficient change of the exposure variable was greater than 20%. The final logistic regression models for pregnancy outcomes were restricted to include statistically significant variables and clinically plausible interactions. The threshold for retaining these variables in the final logistic regression model was P < .05. Possible multicollinearity among the independent variables was identified using multiple regression analysis. The tolerance values for multicollinearity were set at >.5. Hosmer and Lemeshow goodness-of-fit tests >.

The PNPLA3 and APOC3 genes are by no means the only genetic playe

The PNPLA3 and APOC3 genes are by no means the only genetic players in the causation of NAFLD. A recent meta-analysis of several genome-wide association studies of hepatic steatosis revealed loci in or near the NCAN

(neurocan), GCKR (glucokinase regulatory protein), LYPLAL1 (lysophospholipase-like protein 1), and PPP1R3B (protein phosphatase 1, regulatory subunit 3B) genes, that associate with glycemic traits, serum lipid levels, Dabrafenib purchase hepatic steatosis, hepatic inflammation/fibrosis, or a combination of these.19 Future studies on these loci would add to our knowledge on heritability of NAFLD. What do we do with the available information? With a strong evidence base supporting it, the relationship of PNPLA3 variant with NAFLD is ripe for moving from the bench to the bedside. We need to now generate data to find out whether the determination of PNPLA3 genotype in an individual with suspected or confirmed NAFLD can add to the diagnostic algorithm,

say by predicting disease severity. This may be particularly helpful in children since the effect of genotype may be additive over time and early institution of preventive measures may be important. Similarly, understanding the biology of PNPLA3 in relation to NAFLD may help in the design of novel treatment strategies. Emerging data on the effect of PNPLA3 variants on other diseases with hepatic steatosis, such as alcoholic liver disease and chronic hepatitis C, may mean that such interventions OSI-906 cell line may play a role beyond NAFLD.20,21 “
“Fibrosis prediction is an essential part of the assessment

and management of patients with chronic liver disease. Blood-based biomarkers offer a number of advantages over the traditional standard of fibrosis assessment of liver biopsy, including safety, cost-savings and wide spread accessibility. Current biomarker algorithms include indirect surrogate measures of fibrosis, Nintedanib (BIBF 1120) including aminotransaminases and platelet count, or direct measures of fibrinogenesis or fibrinolysis such as hyaluronic acid and tissue inhibitor of metalloproteinase-1. A number of algorithms have now been validated across a range of chronic liver disease including chronic viral hepatitis, alcoholic and non-alcoholic fatty liver disease. Furthermore, several models have been demonstrated to be dynamic to changes in fibrosis over time and are predictive of liver-related survival and overall survival to a greater degree than liver biopsy. Current limitations of biomarker models include a significant indeterminate range, and a predictive ability that is limited to only a few stages of fibrosis. Utilization of these biomarker models requires knowledge of patient co-morbidities which may produce false positive or negative results in a small proportion of individuals.

For ETV treatment effect, we estimated the hazard ratio of HCC de

For ETV treatment effect, we estimated the hazard ratio of HCC development, adjusting for multiple baseline variables (age, gender, alcohol consumption, smoking, preexisting cirrhosis, HBeAg, HBV DNA, ALT, albumin, γ-GTP, total bilirubin, and platelet count) in the propensity matched cohort. Proteases inhibitor Progression of cirrhosis within 5 years was used as a time-dependent covariate in the proportional hazard regression but it did

not show a statistically significant hazard to HCC development. PS matching of the LAM-treated patients without rescue therapy (n = 492) with ETV-treated patients resulted in a matched cohort of 182 patients (Supporting Table 3). The rate of nonrescued LAM-treated group having undetectable HBV DNA at 1 year after treatment was lower when compared with the ETV-treated group.

The LAM-treated group also had a higher drug-resistant mutation rate. Comparisons of HCC incidence among the ETV-treated group, nonrescued LAM-treated group, and control showed that the HCC suppression effect was greater in ETV-treated (P < 0.001) than nonrescued LAM-treated (P = 0.019) when compared with the control group (Fig. 3). The difference of effect between ETV and LAM was also significant (P = 0.043). The treatment effect was seen in cirrhosis patients but not in noncirrhosis patients. The result showed ETV's superiority to LAM in suppressing HCC. To further examine the ETV treatment effect, we compared the ETV and Talazoparib nmr the control groups by preexisting cirrhosis and published risk scores. Viral response rates (HBV DNA < 400 copies/mL) of 1-year post-ETV treatment was 87% in the noncirrhosis patients and 91% in the cirrhosis patients (LC). Adenosine ALT normalization was 94% and 90% in the chronic hepatitis and cirrhosis patients, respectively. The treatment effect was not inferior by cirrhosis status. Among those who developed HCC, 97 out of 144 patients in the control group and 9 out of 12 patients in the ETV group had cirrhosis. Interactions between preexisting cirrhosis

and ETV treatment were not observed (P = 0.177). Cumulative HCC incidence rates by risk scores are compared between the two cohorts in Fig. 4A-G. Figure 4A,B shows the risk scores developed by Yang et al.10 Figure 4C,D shows the risk scores developed by Yuen et al.11 Figure 4E-G shows the risk scores developed by Wong et al.12 All three risk score scales showed that ETV significantly reduced HCC incidence in patients with a higher risk (risk score ≥12, P = 0.006; risk score ≥82, P = 0.002; medium risk, P = 0.062; high risk, P < 0.001). Interactions between risk scores and ETV treatment were not observed (Yang et al.: P = 0.713, Yuen et al.: P = 0.267, Wong et al.: P = 0.265). Our study suggests that long-term ETV therapy would significantly suppress the development of HCC in HBV-infected patients when compared with HBV-infected patients in the control group. The treatment effect was more prominent among patients at high risk of HCC than those at low risk.