Liver Research Center

Trieste, Italy

Liver Research Center

Trieste, Italy
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Gazzin S.,Liver Research Center | Masutti F.,Liver Research Center | Masutti F.,Center for Liver Diseases | Vitek L.,Charles University | Tiribelli C.,Liver Research Center
Liver International | Year: 2017

Increased serum bilirubin level is a widely used diagnostic marker for hepatic illnesses. Nevertheless, mild elevation of unconjugated serum bilirubin (such as in Gilbert syndrome) has been recently demonstrated to correlate with low risk of chronic inflammatory and/or oxidative stress-mediated diseases. In accord, a low serum bilirubin level has emerged as an important predisposing factor or a biomarker of these pathologic conditions including cardiovascular, tumour, and possibly neurodegenerative diseases. Bilirubin possesses multiple biological actions with interaction in a complex network of enzymatic and signalling pathways. The fact that the liver is the main organ controlling the bioavailability of bilirubin emphasizes the central role of this organ in human health. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd


Yeh C.-T.,Liver Research Center | Yeh C.-T.,Chang Gung University | So M.,New York University | Ng J.,New York University | And 7 more authors.
Hepatology | Year: 2010

Hepatitis B virus (HBV) is a major etiological factor of hepatocellular carcinoma (HCC). However, the postoperative prognostic value of the virological factors assayed directly from liver tissue has never been investigated. To address this issue, 185 liver samples obtained from the noncancerous part of surgically removed HBV-associated HCC tissues were subjected to virological analysis. Assayed factors included the amount of HBV-DNA in the liver tissues; genotype; and the presence of the HBV precore stop codon G1896A mutation, basal core promoter A1762T/G1764A mutation, and pre-S deletions/stop codon mutation. All virological factors and clinicopathological factors were subjected to Cox proportional hazard model analysis to estimate postoperative survival. It was found that an HBV-DNA level >3.0 × 107 copies/g of liver tissue and the presence of the basal core promoter mutation independently predicted disease-free (adjusted hazard ratio 1.641 [95% confidence interval (CI) 1.010-2.667] and 2.075 [95% CI 1.203-3.579], respectively) and overall (adjusted hazard ratio 2.807 [95% CI 1.000-7.880] and 5.697 [95% CI 1.678-19.342], respectively) survival. Kaplan-Meier survival analysis indicated that in-frame, short stretch (<100 bp) pre-S deletions, but not large fragment (>100 bp) pre-S deletions, were significantly associated with poorer disease-free (P = 0.005) and overall (P = 0.020) survival. A hot deletion region located between codons 107 and 141 of the pre-S sequence was identified for the short stretch pre-S deletion mutants. Conclusion: The amount of HBV-DNA in liver tissue and the presence of the basal core promoter mutation were two independent predictors for postoperative survival in HCC. A short stretch pre-S deletion located between codons 107 and 141 was strongly associated with a poorer postoperative prognosis. Copyright © 2010 American Association for the Study of Liver Diseases.


Weng L.-C.,Chang Gung University | Chen H.C.,Liver Research Center | Huang H.L.,Chang Gung University | Wang Y.-W.,Chang Gung University | Lee W.-C.,Chang Gung Memorial Hospital
Transplantation Proceedings | Year: 2012

Background: Returning to work has been recognized as an indicator of functional recovery. Few studies have aimed to explore whether one's type of work changes after transplantation. Purpose: This study aims to describe the change in types of work in liver transplant patients. Methods: A retrospective and descriptive study was conducted at a medical center in northern Taiwan. The data were collected by a self-report questionnaire between July and September 2010. Descriptive statistics an correlational analysis were used to analyze the data. Results: A convenience sample of 111 adult liver transplant patients was included in this study. Of the sample, 20 patients remained unemployed, 44 had a change in status by becoming unemployed (n = 42) or employed (n = 2), and 47 patients remained employed after transplantation. At the time of data collection, 49 (44.1%) liver transplant patients were gainfully employed, a rate that was lower than that of the pretransplantation stage (n = 89, 80.2%). The number of workers engaged in manual labor decreased from 40 to 18 between pre- and posttransplantation. Of the 47 still-employed patients, 6 (12.8%) changed their occupation after transplantation. Conclusion: The rate of gainful employment after liver transplantation was low, and those patients who had done manual labor pretransplantation were no longer able to do this type of work and were unemployed. The still-employed patients who worked in management or were professionals did not change their type of work after transplantation; however, service and labor workers did change their type of work. © 2012 by Elsevier Inc. All rights reserved.


PubMed | Semmelweis University, University of Verona, Medical University of Graz, University of Turin and 23 more.
Type: | Journal: Oral diseases | Year: 2016

Osteonecrosis of the jaw (ONJ) is a potentially severe adverse effect of bisphosphonates (BP). Although the risk of ONJ increases with increasing duration of BP treatment, there are currently no reliable estimates of the ONJ time to onset (TTO). The objective of this study was to estimate the TTO and associated risk factors in BP-treated patients.Retrospective analysis of data from 22 secondary care centres in 7 countries relevant to 349 patients who developed BP-related ONJ between 2004 and 2012.The median (95%CI) TTO was 6.0 years in patients treated with alendronate (n = 88) and 2.2 years in those treated with zoledronate (n = 218). Multivariable Cox regression showed that dentoalveolar surgery was inversely associated, and the use of antiangiogenics directly associated, with the TTO in cancer patients treated with zoledronate.The incidence of ONJ increases with the duration of BP therapy, with notable differences observed with respect to BP type and potency, route of administration and underlying disease. When data are stratified by BP type, a time of 6.0 and 2.2 years of oral alendronate of intravenous zoledronate therapy, respectively, is required for 50% of patients to develop ONJ. After stratification by disease, a time of 5.3 and 2.2 years of BP therapy is required for 50% of patients with osteoporosis and cancer, respectively, to develop ONJ. These findings have significant implications for the design of future clinical studies and the development of risk reduction strategies aimed at either assessing or modulating the risk of ONJ associated with BP. This article is protected by copyright. All rights reserved.


PubMed | University of Rhode Island, Midwestern University and Liver Research Center
Type: Journal Article | Journal: Heliyon | Year: 2016

Despite therapeutic advances, survival with glioblastoma multiforme (GBM) remains below 15 months from diagnosis due to GBMs highly infiltrative nature which precludes complete surgical resection. Patient outcomes could potentially be improved by targeting genes and pathways that drive neoplastic cell motility and invasiveness, including hypoxia-inducible factor-1 (HIF-1), NOTCH, and aspartate--hydroxylase (ASPH).Human astrocytoma biopsy specimens (n = 37), WHO Grades II-IV, were analyzed for levels and distributions of ASPH and HIF-1 immunoreactivity by immunohistochemical staining, and ASPH, Notch, JAG, HES1, HEY1 and HIF1 mRNA expression by quantigene multiplex analysis. The effects of small molecule inhibitors on ASPHs catalytic activity, cell viability and directional motility were examined in vitro in established GBM cell lines and primary tumor cells from an invasive mouse model of GBM.The highest grade astrocytoma, i.e. GBM was associated with the highest levels of ASPH and HIF1, and both proteins were more abundantly distributed in hypoxic compared with normoxic regions of tumor. Furthermore, mining of the TCGA database revealed higher levels of ASPH expression in the mesenchymal subtype of GBM, which is associated with more aggressive and invasive behavior. In contrast, lower grade astrocytomas had low expression levels of ASPH and HIF1. In vitro experiments demonstrated that small molecule inhibitors targeting ASPHs catalytic activity significantly reduced GBM viability and directional motility. Similar effects occurred in GBM cells that were transduced with a lentiviral sh-ASPH construct.This study demonstrates that increased ASPH expression could serve as a prognostic biomarker of gliomas and may assist in assigning tumor grade when biopsy specimens are scant. In addition, the findings suggest that GBM treatment strategies could be made more effective by including small molecule inhibitors of ASPH.


Scaglioni F.,Liver Center | Ciccia S.,Liver Center | Marino M.,Liver Center | Bedogni G.,Liver Research Center | And 2 more authors.
Digestive Diseases | Year: 2011

Non-alcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH) have a similar pathogenesis and histopathology but a different etiology and epidemiology. NASH and ASH are advanced stages of non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD). NAFLD is characterized by excessive fat accumulation in the liver (steatosis), without any other evident causes of chronic liver diseases (viral, autoimmune, genetic, etc.), and with an alcohol consumption ≤20-30 g/day. On the contrary, AFLD is defined as the presence of steatosis and alcohol consumption >20-30 g/day. The most common phenotypic manifestations of primary NAFLD/NASH are overweight/obesity, visceral adiposity, type 2 diabetes, hypertriglyceridemia and hypertension. The prevalence of NAFLD in the general population in Western countries is estimated to be 25-30%. The prevalence and incidence of NASH and ASH are not known because of the impossibility of performing liver biopsy in the general population. Up to 90% of alcoholics have fatty liver, and 5-15% of these subjects will develop cirrhosis over 20 years. The risk of cirrhosis increases to 30-40% in those who continue to drink alcohol. About 10-35% of alcoholics exhibit changes on liver biopsy consistent with alcoholic hepatitis. Natural histories of NASH and ASH are not completely defined, even if patients with NASH have a reduced life expectancy due to liver-related death and cardiovascular diseases. The best treatment of AFLD/ASH is to stop drinking, and the most effective first-line therapeutic option for NAFLD/NASH is non-pharmacologic lifestyle interventions through a multidisciplinary approach including weight loss, dietary changes, physical exercise, and cognitive-behavior therapy. Copyright © 2011 S. Karger AG, Basel.


Bedogni G.,Liver Research Center | Bedogni G.,University of Milan | Grugni G.,Instituto Auxologico Italiano | Nobili V.,Bambino Gesu Childrens Hospital | And 3 more authors.
Obesity Facts | Year: 2014

Objective: Patients with Prader-Willi syndrome (PWS) have been hypothesized to be at lower risk of non-alcoholic fatty liver disease (NAFLD) because of higher insulin sensitivity. However, PWS patients have a peculiar body composition, i.e. higher fat mass and lower fat-free mass, which may confound such associations. We evaluated whether NAFLD is less frequent in PWS than in non-PWS women matched on percent body fat (PBF). Methods: PBF was measured by dual-energy X-ray absorptiometry. Liver fat was assessed by ultrasonography. Insulin sensitivity and beta-cell function were evaluated by oral glucose tolerance testing. Coarsened exact matching (CEM) was used to match PWS and non-PWS women on PBF. General and generalized linear models taking CEM into account were used to perform comparisons between PWS and non-PWS women. Results: 20 women with PWS were matched to 27 women without PWS on the basis of PBF (mean 53 vs. 54%, p = 0.6). Insulin sensitivity and beta-cell function were similar in the two groups. However, the prevalence of NAFLD was 25% in PWS versus 59% in non-PWS women (p = 0.04). Conclusion: NAFLD is less frequent in PWS than in non-PWS women but this finding is not associated with higher insulin sensitivity. © 2014 S. Karger GmbH, Freiburg.


Zabetta C.D.C.,Liver Research Center | Iskander I.F.,Cairo University | Greco C.,Liver Research Center | Bellarosa C.,Liver Research Center | And 4 more authors.
Neonatology | Year: 2013

Background: Severe neonatal hyperbilirubinemia, with consequent encephalopathy, remains a common cause of morbidity and death in many regions of the world. Poor access to clinical laboratory resources and screening programs to measure plasma bilirubin levels is a major contributor to delayed treatment in developing countries, and the cost of existing point-of-care screening instruments precludes their dissemination. Objectives: We are evaluating the accuracy of a low-cost, minimally invasive point-of-care system (Bilistick) requiring a 25-μl blood sample that could be used in low-resource environments to evaluate patients with neonatal jaundice. Methods: We compared plasma bilirubin levels in divided blood samples by clinical laboratories and by Bilistick at two medical centers serving term and near-term newborns from ethnically different populations. Results: 118 neonates with bilirubin levels ranging from 24.8 to 501.0 μmol/l were analyzed. The mean bilirubin concentration (±SD) was 215.6 ± 85.5 μmol/l for Bilistick and 226.1 ± 86.4 μmol/l by laboratory determination. Pearson's correlation coefficient between all paired results was 0.961, and the Bland-Altman analysis showed a mean difference of 10.3 μmol/l with a 95% interval of agreement of -38.0 to 58.7 μmol/l. Conclusion: Bilistick is a minimally invasive method for measuring total bilirubin concentration over a wide range of values and should provide an affordable and accurate system for pre-discharge and follow-up screening of jaundiced infants, particularly in low-resource environments. Copyright © 2012 S. Karger AG, Basel.


De La Monte S.M.,Rhode Island Hospital | De La Monte S.M.,Liver Research Center | De La Monte S.M.,Brown University | Tong M.,Liver Research Center | And 3 more authors.
Molecular Brain | Year: 2011

Background: In experimental models of fetal alcohol spectrum disorder (FASD), cerebellar hypoplasia and hypofoliation are associated with insulin and insulin-like growth factor (IGF) resistance with impaired signaling through pathways that mediate growth, survival, plasticity, metabolism, and neurotransmitter function. To more directly assess the roles of impaired insulin and IGF signaling during brain development, we administered intracerebroventricular (ICV) injections of si-RNA targeting the insulin receptor, (InR), IGF-1 receptor (IGF-1R), or IGF-2R into postnatal day 2 (P2) Long Evans rat pups and examined the sustained effects on cerebellar function, structure, and neurotransmitter-related gene expression (P20). Results: Rotarod tests on P20 demonstrated significant impairments in motor function, and histological studies revealed pronounced cerebellar hypotrophy, hypoplasia, and hypofoliation in si-InR, si-IGF-1R, and si-IGF-2R treated rats. Quantitative RT-PCR analysis showed that si-InR, and to a lesser extent si-IGF-2R, broadly inhibited expression of insulin and IGF-2 polypeptides, and insulin, IGF-1, and IGF-2 receptors in the brain. ELISA studies showed that si-InR increased cerebellar levels of tau, phospho-tau and β-actin, and inhibited GAPDH. In addition, si-InR, si-IGF-1R, and si-IGF-2R inhibited expression of choline acetyltransferase, which mediates motor function. Although the ICV si-RNA treatments generally spared the neurotrophin and neurotrophin receptor expression, si-InR and si-IGF-1R inhibited NT3, while si-IGF-1R suppressed BDNF. Conclusions: early postnatal inhibition of brain InR expression, and to lesser extents, IGF-R, causes structural and functional abnormalities that resemble effects of FASD. The findings suggest that major abnormalities in brains with FASD are mediated by impairments in insulin/IGF signaling. Potential therapeutic strategies to reduce the long-term impact of prenatal alcohol exposure may include treatment with agents that restore brain insulin and IGF responsiveness. © 2011 de la Monte et al; licensee BioMed Central Ltd.


Nambotin S.B.,French Institute of Health and Medical Research | Lefrancois L.,French Institute of Health and Medical Research | Sainsily X.,French Institute of Health and Medical Research | Berthillon P.,French Institute of Health and Medical Research | And 8 more authors.
Journal of Hepatology | Year: 2011

Background & Aims: We previously reported the frequent overexpression of the FZD7 membrane receptor in hepatocellular carcinoma (HCC) and its role for controlling cancer phenotype. Herein, this study aimed at assessing the anticancer properties of compounds inhibiting FZD7 activity by disrupting its binding with the cytosolic Dishevelled (DVL) adaptator. Methods: We have designed small interfering peptides (RHPDs) that are able to enter within cells and to competitively antagonize the binding of FZD7 to the PDZ domain of DVL. Their anti-neoplastic properties were assessed in vitro on a panel of human HCC cell lines and in vivo on the SV40-TAg transgenic mouse model of HCC. Results: We have shown that RHPDs decrease cell viability via apoptosis depending on their affinity for PDZ, with a therapeutic index between cancerous and non-cancerous cells. RHPD properties were linked to β-catenin degradation and PKCδ activation. In transgenic mice, intra-tumor injection of RHPDs inhibited HCC progression. Conclusions: We have completed a proof-of-concept showing that in vitro and in vivo the pharmacological inhibition of FZD7 displays anti-cancerous properties against HCC. The mechanisms can involve β-catenin and PKCδ modulations. Further studies are warranted to design protocols showing the compatibility with systemic in vivo applications. © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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