pinecone/core-2020-05-10-deduplication huggingface dataset:
Extrahepatic cancers are the leading cause of death in patients achieving hepatitis B virus control or hepatitis C virus eradication.

Data on extrahepatic cancers (EHCs) in compensated viral cirrhosis are limited. The objective of the prospective multicenter Agence Nationale de Recherche sur le SIDA et les Hépatites virales CO12 CirVir cohort was to assess the occurrence of all clinical events in patients with compensated viral cirrhosis, including all types of cancer. Patients with the following inclusion criteria were enrolled in 35 French centers: (1) biopsy-proven hepatitis B virus (HBV) or hepatitis C virus (HCV) cirrhosis, (2) Child-Pugh A, or (3) absence of previous liver complications including primary liver cancer (PLC). Patients were followed up prospectively every 6 months. The standardized mortality ratio (SMR) was calculated according to age and gender using 5-year periods. The impact of sustained viral response (SVR) in HCV patients and maintained viral suppression in HBV patients were assessed using time-dependent analysis. A total of 1,671 patients were enrolled between 2006 and 2012 (median age, 54.9 years; men, 67.3%; HCV, 1,323; HBV, 317; HCV-HBV, 31). Metabolic features and excessive alcohol and tobacco consumption were recorded in 15.2%, 36.4%, and 56.4% of cases, respectively. After a median follow-up of 59.7 months, 227 PLCs were diagnosed (5-year cumulative incidence [CumI] 13.4%) and 93 patients developed EHC (14 patients with lymphoid or related tissue cancer and 79 with solid tissue cancer; 5-year EHC CumI, 5.9%). Compared to the general French population, patients were younger at cancer diagnosis, with significantly higher risk of EHC in HCV patients (SMR, 1.31; 95 confidence interval [CI], 1.04-1.64; P = 0.017) and after SVR (SMR = 1.57; 95% CI, 1.08-2.22; P = 0.013). EHC was the fourth leading cause of death in the whole cohort and the first in patients with viral control/eradication.
CONCLUSION: Compared to the general French population, HCV cirrhosis is associated with a higher risk of EHC and the first cause of death in patients with viral cirrhosis who achieve virological control/eradication. (Hepatology 2018)
Bacterial lipopolysaccharide antagonizes transforming growth factor β1–induced apoptosis in primary cultures of hepatocytes

8 pages, 6 figures, 1 table.Incubation of primary cultures of fetal hepatocytes with lipopolysaccharide (LPS) elicited the expression of nitric oxide (NO) synthetase as well as antagonized the apoptotic cell death evoked by treating the cells with transforming growth factor 1 (TGF-1). In addition to LPS, exposure of the cells to chemical NO donors also protected against apoptotic cell death when assayed at concentrations in the low micromolar range. Treatment of hepatocytes with large concentrations of NO donors promoted both apoptotic and necrotic cell death. These results suggest that NO synthesis by hepatocytes might be involved in the protection against apoptotic death.Supported by grant PB92/070 from the Comisión Interministerial de Ciencia\ud
y Tecnología and grant 92/0267 from the Fondo de Investigaciones Sanitarias de la Seguridad Social, respectively.Peer reviewe
Differential expression pattern of S-adenosylmethionine synthetase isoenzymes during rat liver development

6 pages, 5 figures.-- Published Online: 30 Dec. 2003.The pattern of expression of liver-specific and extrahepatic S-adenosylmethionine (SAM) synthetase in developing rat liver was established by determining steady-state levels of the respective messenger RNAs (mRNAs) and protein content. Levels of liver-specific SAM synthetase mRNA increased progressively from day 20 of gestation, increased 10-fold immediately after birth, and reached a peak at 10 days of age, decreasing slightly by adulthood. Conversely, mRNA levels of extrahepatic isoenzyme decreased toward birth, increased threefold in the newborn, and decreased further in the postnatal life, reaching a minimum in the adult. Similar expression profiles were observed in isolated hepatocytes, indicating that both mRNAs are differentially regulated in the same cell type. Western blot analysis showed that levels of immunoreactive liver-specific isoenzyme followed a trend similar to the mRNA, indicating that developmental regulation of this enzyme is mediated at the mRNA level. Developmental patterns of expression of albumin and -fetoprotein (AFP) mRNAs were closely related to those for liver-specific and extrahepatic isoenzymes, respectively. Therefore, it is suggested that liver-specific SAM synthetase may be a marker for hepatocyte differentiation. Incubation of primary cultures of hepatocytes from 21-day-old fetuses with permeant cyclic adenosine monophosphate (cAMP) analogues elicited an up-regulation of the mRNA for the liver-specific isoenzyme with a concomitant down-regulation of the extrahepatic message, suggesting a physiological role for the increased postnatal glucagonemia in the control of this isoenzyme switching. In contrast with the isoenzyme expression profiles, the levels of SAM, the product of SAM synthetase reaction, were determined to be greater during gestation than in immediate postnatal periods. These results indicate that synthesis and utilization of SAM may be regulated differentially in fetal and adult hepatocytes.Supported by grants 94/0231 and 95/0966 from the Fondo de Investigaciones Sanitarias, grant PB 94/0087 from the Dirección General de Investigaciones Científicas, and grant\ud
SCI*-CT92-0780 from the Science program of the European Community and by Europharma. Drs. Casado and Gil are fellows of the Ministerio de Educación y Ciencia.Peer reviewe
Indocyanine green elimination test in orthotopic liver recipients.

OBJECTIVE: To determine its predictive capability on graft quality and resultant clinical outcome, the indocyanine green (ICG) elimination test was performed by a spectrophotometric method and a noninvasive finger-piece method with 50 orthotopic liver transplantations. BACKGROUND: Early detection of poor-functioning hepatic grafts is one of the most important issues in liver transplantation, but no reliable methods exist. METHODS: The ICG test was performed after 50 orthotopic liver transplantations on postoperative days 1, 3, and 7. Indocyanine green elimination constants (K(ICG)) were measured by both a standard spectrophotometric analysis (K(ICG)-B) and by a finger-piece method (K(ICG)-F). The patients were followed for a minimum of 3 months after transplantation. Results of ICG tests were correlated with various clinical determinations. RESULTS: Twelve of the 50 grafts were lost within three months, of which 7 were related to graft failure. Multivariate analysis using the Cox proportional hazard model revealed that K(ICG) on postoperative day 1 was a better predictor of liver-related graft outcome than any of the conventional liver function tests. Furthermore, K(ICG) values showed significant correlation with the severity of preservation injury, longer intensive care unit (ICU) and hospital stay, prolonged liver dysfunction, and septic complications. Correlation of K(ICG) values by the spectrophotometric method with those by the finger-piece method was highly satisfactory in the grafts that had K(ICG)-B <0.15 min-1 (y = 0.868x -0.011, r = .955). CONCLUSION: The ICG elimination test, conducted spectrophotometrically or optically on the day after liver transplantation, is a reliable indicator of graft quality and subsequent graft outcome early after liver transplantation
Induction of cytotoxic T-cell response against hepatitis C virus structural antigens using a defective recombinant adenovirus

A replication-defective recombinant adenovirus (RAd), RAdCMV-CE1, containing core and E1 genes of hepatitis C virus (HCV) was constructed. RAdCMV-CE1 was able to express core and E1 proteins both in mice and human cells. Immunization of BALB/c mice with RAdCMV-CE1 induced a specific cytotoxic T-cell response against the two HCV proteins. This response was characterized using a panel of 60 synthetic 14- or 15-mer overlapping peptides (10 amino-acid overlap) spanning the entire sequence of these proteins. Five main epitopes were found in the core protein, four of which had been previously described either in mice or humans. One single novel epitope was found in E1. Fine mapping of this E1 determinant, showed that octamer GHRMAWDM is the minimal epitope recognized by cytotoxic T lymphocytes (CTL). The cytotoxic T-cell response was H-2d restricted, lasted for at least 100 days, and was mediated by T cells with the classic CD4-CD8+ phenotype. This work demonstrates that replication-defective recombinant adenoviruses can efficiently express HCV proteins and are able to induce an in vivo cytotoxic T-cell response against a diversity of epitopes from HCV antigens. These vectors should be taken into consideration in the design of vaccines and also as a means to stimulate specific T-cell responses in chronic HCV carriers
A prognostic model for the outcome of liver transplantation in patients with cholestatic liver disease

We studied the outcome of 436 patients with primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC) who underwent orthotopic liver transplant (OLT) at three major liver transplant centers. Univariate predictors of outcome included age, Karnofsky score, Child's class, Mayo risk score, United Network for Organ Sharing (UNOS) status, nutritional status, serum albumin, serum bilirubin, international normalized ratio, and the presence of ascites, encephalopathy, renal failure (serum creatinine > 2 mg/dL), and edema refractory to diuretics. Using these predictors, we developed a four variable mathematical prognostic model to help the liver transplant physician predict the following: 1) the amount of intraoperative blood loss; 2) the number of days in the intensive care unit (ICU); and 3) severe complications after surgery. The model uses age, renal failure, Child's class, and United Network for Organ Sharing status. This study is the first to model the outcome of liver transplant in patients with a specific etiology of chronic liver disease (PBC or PSC). The model may be used to help select patients for OLT and to plan the timing of their transplantation
S-adenosyl-L-methionine protects the liver against the cholestatic, cytotoxic, and vasoactive effects of leukotriene D4: a study with isolated and perfused rat liver

Cysteinyl-leukotrienes can cause cholestasis and liver damage when administered at nanomolar concentrations. Using the isolated and perfused rat liver we analyzed whether S-adenosyl-L-methionine (SAMe) may protect this organ against the noxious effects of leukotriene-D4 (LTD4). We observed that a 2 nmol bolus of this compound decreased bile flow (-12.6% +/- 1.6%, P < .02), and bile salt excretion (-23.5% +/- 2.2%, P < .02; both compared with baseline values), caused the release of glutamic-oxaloacetic transaminase (GOT) and lactic dehydrogenase (LDH) to the hepatic effluent, and increased significantly the perfusion pressure as compared with a control group not receiving LTD4 (6.0 +/- 1.1 vs. 0.2 +/- 0.02 mm hg, respectively; P < .001). The cholestatic effect of LTD4 was attenuated by infusion of SAMe which, at rates of 67 and 100 microg/min, totally prevented the decrease in bile salt excretion. Likewise, in SAMe infused livers, the release to the effluent of GOT and LDH was lower than in the group receiving LTD4 only, and was even lower than in the control group. We also found that the increase in perfusion pressure induced by LTD4 was prevented by SAMe in a dose-dependent manner. Of interest, SAMe increased the biliary excretion of the eicosanoid in a dose-related fashion. We conclude that SAMe reverts the cholestatic, cytotoxic, and hemodynamic effects of LTD4 on the liver, and that these protective effects might be partly because of a stimulation of the biliary excretion of the leukotriene
Treatment of fibrolamellar hepatoma with subtotal hepatectomy or transplantation

Fibrolamellar hepatoma (FL-HCC) is an uncommon variant of hepatocellular carcinoma (HCC), distinguished by histopathological features suggesting greater differentiation than conventional HCC. However, the optimal treatment and the prognosis of FL-HCC have been controversial. Follow-up studies are available from 1 year to 27 years, after 41 patients with FL-HCC were treated with partial hepatectomy (PHx) (28 patients) or liver transplantation (13 patients). In this retrospective study, the effect on outcome was determined for the pTNM stage and other prognostic factors routinely recorded at the time of surgery. Cumulative survival at 1, 3, 5, and 10 years was 97.6%, 72.3%, 66.2%, and 47.4%. Tumor-free survival at these times was 80.3%, 49.4%, 33%, and 29.3%. The TNM stage was significantly associated with tumor-free survival. Patients with positive nodes had a shorter tumor-free survival than those with negative nodes (P < .015). Patient survival was most adversely affected by the presence of vascular invasion (P < .05). FL-HCC is an indolently growing tumor of the liver, which usually was diagnosed in our patients at a stage too advanced for effective surgical treatment of most conventional HCC. Nevertheless, long-term survival frequently was achieved with aggressive surgical treatment. When a subtotal hepatectomy could not be performed, total hepatectomy (THx) with liver transplantation was a valuable option
Cellular immunity to hepatitis C virus core protein and the response to interferon in patients with chronic hepatitis C

To investigate the involvement of T-cell response against hepatitis C virus (HCV) antigens in viral clearance after interferon therapy, we measured interleukin-2 (IL-2) production by peripheral mononuclear cells in response to HCV core in patients with chronic hepatitis C. In a cohort of 43 patients, we investigated the frequency of circulating core-specific T-helper (Th) cell precursors by the limiting-dilution assay, and in a second cohort of 60 patients, we analyzed the response to specific core epitopes using 52 synthetic 15-mer overlapping peptides. We observed that the frequency of core-specific Th cell precursors was significantly higher in patients with sustained biochemical and virological response (SR) after interferon (IFN) therapy (median, 1/55,736) than in untreated patients (1/274,023) or that in patients who remained viremic after completion of the treatment-nonresponders (NR) plus transient responders (TR) (1/1,909,972). Patients who failed to respond to IFN (NR) and those who relapsed after IFN discontinuation (TR) had a similarly low number of precursors. The number of core peptides recognized by SR, TR, NR, UT, and healthy controls was 8.2 +/- 1.5, 6.5 +/- 1.2, 2.0 +/- 0.5, 2.7 +/- 0.9, and 0.3 +/- 0.2, respectively. In SR, the intensity of the proliferative response to core peptides as estimated by the summation of stimulation indexes (sigmaSI) was significantly higher than in NR and than in UT, but not different from that of TR. Our results indicate that both expansion of HCV-specific Th cell precursors and Th cell recognition of multiple core epitopes seem to be important in the elimination of HCV after IFN therapy
Nitric oxide inactivates rat hepatic methionine adenosyltransferase In vivo by S-nitrosylation

We investigated the mechanism of nitric oxide (NO) action on hepatic methionine adenosyltransferase (MAT) activity using S-nitrosoglutathione (GSNO) as NO donor. Hepatic MAT plays an essential role in the metabolism of methionine, converting this amino acid into S-adenosylmethionine. Hepatic MAT exists in two oligomeric states: as a tetramer (MAT I) and as a dimer (MAT III) of the same subunit. This subunit contains 10 cysteine residues. In MAT I, S-nitrosylation of 1 thiol residue per subunit was associated with a marked inactivation of the enzyme (about 70%) that was reversed by glutathione (GSH). In MAT III, S-nitrosylation of 3 thiol residues per subunit led to a similar inactivation of the enzyme, which was also reversed by GSH. Incubation of isolated rat hepatocytes with S-nitrosoglutathione monoethyl ester (EGSNO), a NO donor permeable through the cellular membrane, induced a dose-dependent inactivation of MAT that was reversed by removing the NO donor from the cell suspension. MAT, purified from isolated rat hepatocytes, contained S-nitrosothiol groups and the addition of increasing concentrations of EGSNO to the hepatocyte suspension led to a progressive S-nitrosylation of the enzyme. Removal of the NO donor from the incubation media resulted in loss of most NO groups associated to the enzyme. Finally, induction in rats of the production of NO, by the administration of bacterial lipopolysaccharide (LPS), induced a fivefold increase in the S-nitrosylation of hepatic MAT, which led to a marked inactivation of the enzyme. Thus, the activity of liver MAT appears to be regulated in vivo by S-nitrosylation
A fresh look at augmenter of liver regeneration in rats.

Augmenter of liver regeneration (ALR) is a hepatotrophic protein originally identified by bioassay in regenerating rat and canine livers following partial hepatectomy and in the hyperplastic livers of weanling rats, but not in resting adult livers. The ALR gene and gene product were subsequently described, but little is known about the cellular/subcellular sites of ALR synthesis in the liver, or about the release and dissemination of the peptide. To obtain this information in rats, we raised antibodies in rabbits against rat ALR for development of an enzyme-linked immunosorbent assay (ELISA). ALR concentrations were then determined in intact livers of unaltered weanling and adult rats; in regenerating residual liver after partial hepatectomy; in cultured hepatocytes and nonparenchymal cells (NPCs); and in culture medium and serum. ALR in the various liver cells was localized with immunohistochemistry. In addition, hepatic ALR and ALR mRNA were assayed with Western blotting and reverse-transcriptase polymerase chain reaction (RT-PCR), respectively. The hepatocyte was the predominant liver cell in which ALR was synthesized and stored; the cultured hepatocytes secreted ALR into the medium in a time-dependent fashion. Contrary to previous belief, the ALR peptide and ALR mRNA were present in comparable concentrations in the hepatocytes of both weanling and resting adult livers, as well as in cultured hepatocytes. A further unexpected finding was that hepatic ALR levels decreased for 12 hours after 70% hepatectomy in adult rats and then rose with no corresponding change in mRNA transcripts. In the meantime, circulating (serum) ALR levels increased up to 12 hours and declined thereafter. Thus, ALR appears to be constitutively expressed in hepatocytes in an inactive form, and released from the cells in an active form by unknown means in response to partial hepatectomy and under other circumstances of liver maturation (as in weanling rats) or regeneration
Three cases of severe subfulminant hepatitis in heart-transplanted patients after nosocomial transmission of a mutant hepatitis B virus

Fulminant and severe viral hepatitis are frequently associated with mutant hepatitis B virus (HBV) strains. In this study, the genetic background of a viral strain causing severe subfulminant outcome in heart-transplanted patients was studied and compared with viral hepatitis B strains that were not linked to severe liver disease in the same setting. A total of 46 patients infected nosocomially with HBV genotype A were studied. Five different viral strains were detected, infecting 3, 9, 5, 24, and 5 patients, respectively. Only one viral strain was found to be associated with the subfulminant outcome and 3 patient deaths as a consequence of severe liver disease. The remaining 43 patients with posttransplantation HBV infection did not show this fatal outcome. Instead, symptoms of hepatitis were generally mild or clinically undiagnosed. Comparison of this virus genome with the four other strains showed an accumulation of mutations in the basic core promoter, a region that influences viral replication, but also in hepatitis B X protein (HBX) (7 mutant motifs), core (10 mutant motifs), the preS1 region (5 mutant motifs), and the HBpolymerase open reading frame (17 motifs). Some of these variations, such as those in the core region, were located on the tip of the protruding spike of the viral capsid (codons 60 to 90), also known in part as an important HLA class II-restricted epitope region. These mutations might therefore influence the immune-mediated response. The viral strain causing subfulminant hepatitis was, in addition, the only strain with a preCore stop codon mutation and, thus, hepatitis B e antigen (HBeAg) expression was never observed. The combination of these specific viral factors is thought to be responsible for the fatal outcome in these immune-suppressed heart-transplant recipients
Interferon alfa subtypes and levels of type I interferons in the liver and peripheral mononuclear cells in patients with chronic hepatitis C and controls

Viral infections stimulate the transcription of interferon type I, which includes IFN-alfa (IFN-alpha) (13 subtypes) and IFN-beta (a single substance). Hepatitis C virus (HCV) infection is remarkable by its ability to evade host antiviral defenses; however, there is little information as to whether endogenous IFN is activated or not in this disease. Additionally, despite the fact that the various IFN-alpha subtypes may differ in biological activity, there are no data concerning the IFN-alpha subtypes specifically expressed in normal and diseased liver tissue. Thus, we have analyzed the IFN-alpha subtypes and the mRNA levels of type I IFNs in samples of normal liver tissue and in liver from patients with chronic hepatitis C. Similar studies were performed in peripheral blood mononuclear cells (PBMC) from patients and controls. After amplification and cloning of IFN-alpha cDNA, we observed that 98 of the 100 clones from normal liver tissue corresponded to the IFN-alpha5 subtype. However, in livers with chronic hepatitis C and in PBMC from controls and patients, a variety of subtypes, in addition to IFN-alpha5, were detected, suggesting a participation of infiltrating leukocytes in the production of IFN-alpha in livers with chronic hepatitis C. As compared with controls, patients with chronic hepatitis C showed a significant increase in IFN-beta mRNA in both the liver and PBMC, while IFN-alpha mRNA was significantly increased in PBMC but markedly reduced in liver tissue. In conclusion, IFN-alpha5 is the sole IFN-alpha subtype expressed in normal liver tissue. The hepatic levels of IFN-alpha are reduced in chronic hepatitis C, an event that may favor viral persistence