pinecone/core-2020-05-10-deduplication huggingface dataset:
Re-evaluation of thediagnostic criteria for Wilson disease in children with mild liver disease.

The diagnosis of Wilson disease (WD) is challenging, especially in children. Early detection is desirable in order to avoid dramatic disease progression. The aim of our study was to re-evaluate in WD children with mild liver disease the conventional diagnostic criteria and the WD scoring system proposed by an international consensus in 2001. Forty children with WD (26 boys and 14 girls, age range = 1.1-20.9 years) and 58 age-matched and sex-matched patients with a liver disease other than WD were evaluated. Both groups were symptom-free and had elevated aminotransferases as predominant signs of liver disease. In all WD patients, the diagnosis was supported by molecular analysis, the liver copper content, or both. A receiver operating characteristic (ROC) analysis of ceruloplasmin at the cutoff value of 20 mg/dL showed a sensitivity of 95% [95% confidence interval (CI) = 83%-99.4%] and a specificity of 84.5% (95% CI = 72.6%-92.6%). The optimal basal urinary copper diagnostic cutoff value was found to be 40 μg/24 hours (sensitivity = 78.9%, 95% CI = 62.7%-90.4%; specificity = 87.9%, 95% CI = 76.7%-95%). Urinary copper values after penicillamine challenge did not significantly differ between WD patients and control subjects, and the ROC analysis showed a sensitivity of only 12%. The WD scoring system was proved to have positive and negative predictive values of 93% and 91.6%, respectively. Conclusion: Urinary copper excretion greater than 40 μg/24 hours is suggestive of WD in asymptomatic children, whereas the penicillamine challenge test does not have a diagnostic role in this subset of patients. The WD scoring system provides good diagnostic accuracy
Effect of immune pressure on hepatitis C virus evolution: insights from a single-source outbreak.

The host's immune response to hepatitis C virus (HCV) can result in the selection of characteristic mutations (adaptations) that enable the virus to escape this response. The ability of the virus to mutate at these sites is dependent on the incoming virus, the fitness cost incurred by the mutation, and the benefit to the virus in escaping the response. Studies examining viral adaptation in chronic HCV infection have shown that these characteristic immune escape mutations can be observed at the population level as human leukocyte antigen (HLA)-specific viral polymorphisms. We examined 63 individuals with chronic HCV infection who were infected from a single HCV genotype 1b source. Our aim was to determine the extent to which the host's immune pressure affects HCV diversity and the ways in which the sequence of the incoming virus, including preexisting escape mutations, can influence subsequent mutations in recipients and infection outcomes. Conclusion: HCV sequences from these individuals revealed 29 significant associations between specific HLA types within the new hosts and variations within their viruses, which likely represent new viral adaptations. These associations did not overlap with previously reported adaptations for genotypes 1a and 3a and possibly reflected a combination of constraint due to the incoming virus and genetic distance between the strains. However, these sites accounted for only a portion of the sites in which viral diversity was observed in the new hosts. Furthermore, preexisting viral adaptations in the incoming (source) virus likely influenced the outcomes in the new hosts
Estimating the net contribution of interleukin-28B variation to spontaneous hepatitis C virus clearance.

The identification of associations between interleukin-28B (IL-28B) variants and the spontaneous clearance of hepatitis C virus (HCV) raises the issues of causality and the net contribution of host genetics to the trait. To estimate more precisely the net effect of IL-28B genetic variation on HCV clearance, we optimized genotyping and compared the host contributions in multiple- and single-source cohorts to control for viral and demographic effects. The analysis included individuals with chronic or spontaneously cleared HCV infections from a multiple-source cohort (n = 389) and a single-source cohort (n = 71). We performed detailed genotyping in the coding region of IL-28B and searched for copy number variations to identify the genetic variant or haplotype carrying the strongest association with viral clearance. This analysis was used to compare the effects of IL-28B variation in the two cohorts. Haplotypes characterized by carriage of the major alleles at IL-28B single-nucleotide polymorphisms (SNPs) were highly overrepresented in individuals with spontaneous clearance versus those with chronic HCV infections (66.1% versus 38.6%, P = 6 × 10(-9) ). The odds ratios for clearance were 2.1 [95% confidence interval (CI) = 1.6-3.0] and 3.9 (95% CI = 1.5-10.2) in the multiple- and single-source cohorts, respectively. Protective haplotypes were in perfect linkage (r(2) = 1.0) with a nonsynonymous coding variant (rs8103142). Copy number variants were not detected.
We identified IL-28B haplotypes highly predictive of spontaneous HCV clearance. The high linkage disequilibrium between IL-28B SNPs indicates that association studies need to be complemented by functional experiments to identify single causal variants. The point estimate for the genetic effect was higher in the single-source cohort, which was used to effectively control for viral diversity, sex, and coinfections and, therefore, offered a precise estimate of the net host genetic contribution
The stable repression of mesenchymal program is required for hepatocyte identity: A novel role for hepatocyte nuclear factor 4Î±

The concept that cellular terminal differentiation is stably maintained once development is complete has been questioned by numerous observations showing that differentiated epithelium may undergo an epithelial-to-mesenchymal transition (EMT) program. EMT and the reverse process, mesenchymal-to-epithelial transition (MET), are typical events of development, tissue repair, and tumor progression. In this study, we aimed to clarify the molecular mechanisms underlying these phenotypic conversions in hepatocytes. Hepatocyte nuclear factor 4Î± (HNF4Î±) was overexpressed in different hepatocyte cell lines and the resulting gene expression profile was determined by real-time quantitative polymerase chain reaction. HNF4Î± recruitment on promoters of both mesenchymal and EMT regulator genes was determined by way of electrophoretic mobility shift assay and chromatin immunoprecipitation. The effect of HNF4Î± depletion was assessed in silenced cells and in the context of the whole liver of HNF4 knockout animals. Our results identified key EMT regulators and mesenchymal genes as new targets of HNF4Î±. HNF4Î±, in cooperation with its target HNF1Î±, directly inhibits transcription of the EMT master regulatory genes Snail, Slug, and HMGA2 and of several mesenchymal markers. HNF4Î±-mediated repression of EMT genes induces MET in hepatomas, and its silencing triggers the mesenchymal program in differentiated hepatocytes both in cell culture and in the whole liver. Conclusion: The pivotal role of HNF4Î± in the induction and maintenance of hepatocyte differentiation should also be ascribed to its capacity to continuously repress the mesenchymal program; thus, both HNF4Î± activator and repressor functions are necessary for the identity of hepatocytes. Copyright Â© 2011 American Association for the Study of Liver Diseases
RN181 suppresses hepatocellular carcinoma growth by inhibition of the ERK/MAPK pathway.

UNLABELLED: The activation of oncogenes and the inactivation of tumor suppressor genes by mutations or chronic hepatitis virus infections play key roles in the pathogenesis of hepatocellular carcinoma (HCC). Here we report that RN181, a really interesting new gene finger domain-containing protein, was down-regulated in highly malignant cell lines and in tumor cells of 139 HCC clinical samples in comparison with adjacent normal liver tissues. The expression of RN181 was strongly associated with the pathological grade of HCC. Alterations of the expression of RN181 by retrovirus-transduced up-regulation and short hairpin RNA-mediated down-regulation demonstrated the function of RN181 as a tumor suppressor because it decreased the proliferation and colony formation of HCC cells in vitro and inhibited tumor growth in vivo by suppressing cell proliferation and enhancing cell apoptosis in xenografted tumors. Proteomic analyses showed that RN181 regulates the expression of many proteins that are important in many cellular processes. Statistical analyses identified 33 proteins with consistent changes (≥2-fold) in RN181-transformed cells. Ten of these proteins were up-regulated by RN181, and 23 were down-regulated. Representative proteins were validated by western blotting. Interaction network investigations revealed that 20 RN181-regulated proteins could integrate several key biological processes such as survival, metabolism, and mitogen-activated protein kinase (MAPK) pathways. Remarkably, 11 of the 33 proteins are associated with MAPK signaling in one or more ways. RN181 suppressed the tyrosine phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in cell lines and in tumor cells of xenografts and HCC clinical samples, and removing the suppression increased tumor growth. CONCLUSION: We have shown that RN181 suppresses the tumorigenesis of HCC through the inhibition of ERK/MAPK signaling in the liver. Our results provide new insights into the pathogenesis of HCC and may help with the development of novel therapeutic strategies
Serum and Liver Iron Differently Regulate the Bone Morphogenetic Protein 6 (BMP6)-SMAD Signaling Pathway in Mice

The bone morphogenetic protein 6 (BMP6)-SMAD signaling pathway is a central regulator of hepcidin expression and systemic iron balance. However, the molecular mechanisms by which iron is sensed to regulate BMP6-SMAD signaling and hepcidin expression are unknown. Here we examined the effects of circulating and tissue iron on Bmp6-Smad pathway activation and hepcidin expression in vivo after acute and chronic enteral iron administration in mice. We demonstrated that both transferrin saturation and liver iron content independently influence hepcidin expression. Although liver iron content is independently positively correlated with hepatic Bmp6 messenger RNA (mRNA) expression and overall activation of the Smad1/5/8 signaling pathway, transferrin saturation activates the downstream Smad1/5/8 signaling cascade, but does not induce Bmp6 mRNA expression in the liver. Hepatic inhibitory Smad7 mRNA expression is increased by both acute and chronic iron administration and mirrors overall activation of the Smad1/5/8 signaling cascade. In contrast to the Smad pathway, the extracellular signal-regulated kinase 1 and 2 (Erk1/2) mitogen-activated protein kinase (Mapk) signaling pathway in the liver is not activated by acute or chronic iron administration in mice. Conclusion: Our data demonstrate that the hepatic Bmp6-Smad signaling pathway is differentially activated by circulating and tissue iron to induce hepcidin expression, whereas the hepatic Erk1/2 signaling pathway is not activated by iron in vivo
Predicting clinical outcomes using baseline and follow‐up laboratory data from the hepatitis C long‐term treatment against cirrhosis trial

Predicting clinical outcomes in patients with chronic hepatitis C is challenging. We used the hepatitis C long‐term treatment against cirrhosis (HALT‐C) trial database to develop two models, using baseline values of routinely available laboratory tests together with changes in these values during follow‐up to predict clinical decompensation and liver‐related death/liver transplant in patients with advanced hepatitis C. Patients randomized to no treatment and who had ≥2‐year follow‐up without a clinical outcome were included in the analysis. Four variables (platelet count, aspartate aminotransferase [AST]/alanine aminotransferase [ALT] ratio, total bilirubin, and albumin) with three categories of change (stable, mild, or severe) over 2 years were analyzed. Cumulative incidence of clinical outcome was determined by Kaplan‐Meier analysis and Cox regression was used to evaluate predictors of clinical outcome. In all, 470 patients with 60 events were used to develop models to predict clinical decompensation. Baseline values of all four variables were predictive of decompensation. There was a general trend of increasing outcomes with more marked worsening of laboratory values over 2 years, particularly for patients with abnormal baseline values. A model that included baseline platelet count, AST/ALT ratio, bilirubin, and severe worsening of platelet count, bilirubin, and albumin was the best predictor of clinical decompensation. A total of 483 patients with 79 events were used to evaluate predictors of liver‐related death or liver transplant. A model that included baseline platelet count and albumin as well as severe worsening of AST/ALT ratio and albumin was the best predictor of liver‐related outcomes.  Conclusion:  Both the baseline value and the rapidity in change of the value of routine laboratory variables were shown to be important in predicting clinical outcomes in patients with advanced chronic hepatitis C. (H EPATOLOGY  2011;
Expression of paramyxovirus V proteins promotes replication and spread of hepatitis C virus in cultures of primary human fetal liver cells

Here we demonstrate that primary cultures of human fetal liver cells (HFLC) reliably support infection with laboratory strains of hepatitis C virus (HCV), although levels of virus replication vary significantly between different donor cell preparations and frequently decline in a manner suggestive of active viral clearance. To investigate possible contributions of the interferon (IFN) system to control HCV infection in HFLC, we exploited the well-characterized ability of paramyxovirus (PMV) V proteins to counteract both IFN induction and antiviral signaling. The V proteins of measles virus (MV) and parainfluenza virus 5 (PIV5) were introduced into HFLC using lentiviral vectors encoding a fluorescent reporter for visualization of HCV-infected cells. V protein-transduced HFLC supported enhanced (10 to 100-fold) levels of HCV infection relative to untransduced or control vector-transduced HFLC. Infection was assessed by measurement of virus-driven luciferase, by assays for infectious HCV and viral RNA, and by direct visualization of HCV-infected hepatocytes. Live cell imaging between 48 and 119 hours postinfection demonstrated little or no spread of infection in the absence of PMV V protein expression. In contrast, V protein-transduced HFLC showed numerous HCV infection events. V protein expression efficiently antagonized the HCV-inhibitory effects of added IFNs in HFLC. In addition, induction of the type III IFN, IL29, following acute HCV infection was inhibited in V protein-transduced cultures. Conclusion: These studies suggest that the cellular IFN response plays a significant role in limiting the spread of HCV infection in primary hepatocyte cultures. Strategies aimed at dampening this response may be key to further development of robust HCV culture systems, enabling studies of virus pathogenicity and the mechanisms by which HCV spreads in its natural host cell population.National Institutes of Health (U.S.) (NIH Roadmap for Medical Research Grant 1 R01 DK085713-01)Greenberg Institute for Medical ResearchStarr Foundatio
End‐stage liver disease candidates at the highest model for end‐stage liver disease scores have higher wait‐list mortality than status‐1A candidates

Candidates with fulminant hepatic failure (Status‐1A) receive the highest priority for liver transplantation (LT) in the United States. However, no studies have compared wait‐list mortality risk among end‐stage liver disease (ESLD) candidates with high Model for End‐Stage Liver Disease (MELD) scores to those listed as Status‐1A. We aimed to determine if there are MELD scores for ESLD candidates at which their wait‐list mortality risk is higher than that of Status‐1A, and to identify the factors predicting wait‐list mortality among those who are Status‐1A. Data were obtained from the Scientific Registry of Transplant Recipients for adult LT candidates (n = 52,459) listed between September 1, 2001, and December 31, 2007. Candidates listed for repeat LT as Status‐1 A were excluded. Starting from the date of wait listing, candidates were followed for 14 days or until the earliest occurrence of death, transplant, or granting of an exception MELD score. ESLD candidates were categorized by MELD score, with a separate category for those with calculated MELD > 40. We compared wait‐list mortality between each MELD category and Status‐1A (reference) using time‐dependent Cox regression. ESLD candidates with MELD > 40 had almost twice the wait‐list mortality risk of Status‐1A candidates, with a covariate‐adjusted hazard ratio of HR = 1.96 ( P  = 0.004). There was no difference in wait‐list mortality risk for candidates with MELD 36‐40 and Status‐1A, whereas candidates with MELD < 36 had significantly lower mortality risk than Status‐1A candidates. MELD score did not significantly predict wait‐list mortality among Status‐1A candidates ( P  = 0.18). Among Status‐1A candidates with acetaminophen toxicity, MELD was a significant predictor of wait‐list mortality ( P  < 0.0009). Posttransplant survival was similar for Status‐1A and ESLD candidates with MELD > 20 ( P  = 0.6).  Conclusion : Candidates with MELD > 40 have significantly higher wait‐list mortality and similar posttransplant survival as candidates who are Status‐1A, and therefore, should be assigned higher priority than Status‐1A for allocation. Because ESLD candidates with MELD 36‐40 and Status‐1A have similar wait‐list mortality risk and posttransplant survival, these candidates should be assigned similar rather than sequential priority for deceased donor LT. (H epatology  2012
Identification of osteopontin as a novel marker for early hepatocellular carcinoma

The aim of this study was to identify a biomarker that could improve alpha‐fetoprotein (AFP) performance in hepatocellular carcinoma (HCC) surveillance among patients with cirrhosis. We performed proteomic profiling of plasma from patients with cirrhosis or HCC and validated selected candidate HCC biomarkers in two geographically distinct cohorts to include HCC of different etiologies. Mass spectrometry profiling of highly fractionated plasma from 18 cirrhosis and 17 HCC patients identified osteopontin (OPN) as significantly up‐regulated in HCC cases, compared to cirrhosis controls. OPN levels were subsequently measured in 312 plasma samples collected from 131 HCC patients, 76 cirrhosis patients, 52 chronic hepatitis C (CHC) and B (CHB) patients, and 53 healthy controls in two independent cohorts. OPN plasma levels were significantly elevated in HCC patients, compared to cirrhosis, CHC, CHB, or healthy controls, in both cohorts. OPN alone or in combination with AFP had significantly better area under the receiver operating characteristic curve, compared to AFP, in comparing cirrhosis and HCC in both cohorts. OPN overall performance remained higher than AFP in comparing cirrhosis and the following HCC groups: HCV‐related HCC, HBV‐associated HCC, and early HCC. OPN also had a good sensitivity in AFP‐negative HCC. In a pilot prospective study including 22 patients who developed HCC during follow‐up, OPN was already elevated 1 year before diagnosis.  Conclusion : OPN was more sensitive than AFP for the diagnosis of HCC in all studied HCC groups. In addition, OPN performance remained intact in samples collected 1 year before diagnosis. (H EPATOLOGY  2012
Human leukocyte antigen class II molecules confer both susceptibility and progression in Japanese patients with primary biliary cirrhosis

Along with twin and family studies, recent genome-wide association studies suggest that genetic factors contribute to the susceptibility and severity of primary biliary cirrhosis (PBC). Although several reports have demonstrated that the human leukocyte antigen (HLA) DRB1*08:03 allele is associated with disease susceptibility in Japan, the precise analysis of HLA haplotypes and the role of amino acid alignment have not been fully clarified. We investigated HLA class I A, B, and C and HLA class II DRB1 and DQB1 alleles and haplotypes in 229 Japanese patients with PBC and compared them with the published data of 523 healthy subjects. Significant associations were found with PBC susceptibility for the DRB1*08:03-DQB1*06:01 (13% versus 6%; P = 0.000025; odds ratio [OR] = 2.22) and DRB1*04:05-DQB1*04:01 haplotypes (17% versus 13%; P = 0.044; OR = 1.38). Conversely, there were significant protective associations with the DRB1*13:02-DQB1*06:04 (2% versus 5%; P = 0.00093; OR = 0.27) and DRB1*11:01-DQB1*03:01 haplotypes (1% versus 4%; P = 0.03; OR = 0.37). The frequency of the DRB1*09:01-DQB1*03:03 haplotype was significantly higher in patients who had received orthotopic liver transplantation (33% versus 11%; P = 0.0012; OR = 3.96). Furthermore, the frequency of serine at position 57 (P = 0.0000015; OR = 1.83) of the DR beta chain differed the most in patients with PBC, compared with healthy subjects. Conclusion: This study established the role of HLA haplotypes in determining PBC susceptibility and progression in the Japanese population. Further resequencing of the HLA region is required to more precisely identify the genetic components of PBC. (HEPATOLOGY 2012
Two distinct subtypes of hepatitis B virus–related acute liver failure are separable by quantitative serum immunoglobulin M anti‐hepatitis B core antibody and hepatitis B virus DNA levels

Hepatitis B virus (HBV)‐related acute liver failure (HBV‐ALF) may occur after acute HBV infection (AHBV‐ALF) or during an exacerbation of chronic HBV infection (CHBV‐ALF). Clinical differentiation of the two is often difficult if a previous history of HBV is not available. Quantitative measurements of immunoglobulin M (IgM) anti–hepatitis B core antibody (anti‐HBc) titers and of HBV viral loads (VLs) might allow the separation of AHBV‐ALF from CHBV‐ALF. Of 1,602 patients with ALF, 60 met clinical criteria for AHBV‐ALF and 27 for CHBV‐ALF. Sera were available on 47 and 23 patients, respectively. A quantitative immunoassay was used to determine IgM anti‐HBc levels, and real‐time polymerase chain reaction (rtPCR) was used to determine HBV VLs. AHBV‐ALFs had much higher IgM anti‐HBc titers than CHBV‐ALFs (signal‐to‐noise [S/N] ratio median: 88.5; range, 0‐1,120 versus 1.3, 0‐750;  P  < 0.001); a cut point for a S/N ratio of 5.0 correctly identified 44 of 46 (96%) AHBV‐ALFs and 16 of 23 (70%) CHBV‐ALFs; the area under the receiver operator characteristic curve was 0.86 ( P  < 0.001). AHBV‐ALF median admission VL was 3.9 (0‐8.1) log10 IU/mL versus 5.2 (2.0‐8.7) log10 IU/mL for CHBV‐ALF ( P  < 0.025). Twenty percent (12 of 60) of the AHBV‐ALF group had no hepatitis B surface antigen (HBsAg) detectable on admission to study, wheras no CHBV‐ALF patients experienced HBsAg clearance. Rates of transplant‐free survival were 33% (20 of 60) for AHBV‐ALF versus 11% (3 of 27) for CHBV‐ALF ( P  = 0.030).  Conclusions:  AHBV‐ALF and CHBV‐ALF differ markedly in IgM anti‐HBc titers, in HBV VLs, and in prognosis, suggesting that the two forms are, indeed, different entities that might each have a unique pathogenesis. (H EPATOLOGY  2011