bluuebunny/crossref_metadata_2025_split huggingface dataset:
Accelerated orthotopic hepatocellular carcinomas growth is linked to increased expression of pro‐angiogenic and prometastatic factors in murine liver fibrosis
Authors: Kornek Miroslaw , Raskopf Esther , Tolba Rene , Becker Ursula , Klöckner Maren , Sauerbruch Tilman , Schmitz Volker 
Published: August 2010

AbstractBackground: Most experimental therapy studies are performed in mice that bear subcutaneous or orthotopic hepatoma but are otherwise healthy. We questioned whether a pre‐existing fibrosis affects tumour development of implanted syngenic hepatoma cells. To further investigate a selected panel of factors involved in tumour growth, tumour organ samples were characterized for gene expression of vascular endothelial growth factor (VEGF)‐A/‐C, VEGF receptors Flt1, Flk‐1, Flt‐4 and for VEGF‐A protein levels.Results: The presented data show that tumour sizes were 3.7‐fold increased and fibrotic livers had numerous satellites. Increased tumour sizes were associated with elevated intratumoral VEGF‐A protein amounts and intratumoral increased VEGF receptor gene expression levels in tumour tissue from fibrotic livers as compared with non‐fibrotic livers. Additionally, intratumoral gene expression levels of matrix metalloproteinase‐2 (MMP‐2) and MMP‐9 were elevated in fibrotic mice.Conclusion: Our results indicate that liver fibrosis stimulates tumour development of implanted syngenic hepatoma cells. Accelerated tumour growth was going along with elevated intratumoral VEGF‐A and VEGF‐A receptor status, which most probably mediated pro‐angiogenic and prometastatic effects in this model. Furthermore, advanced tumour spread was associated with increased MMP‐2/‐9 expression. These data suggest that the intratumoral VEGF‐A proteins levels and VEGF receptor status contribute to accelerated hepatocellular carcinoma development in fibrotic mice and that elevated MMP‐2, MMP‐9 and VEGF‐C levels could promote tumour metastasis in this model.
Trafficking of recirculating lymphocytes in the rat liver: rapid transmigration into the portal area and then to the hepatic lymph
Authors: Xu Xue‐Dong , Ueta Hisashi , Zhou Shu , Shi Changde , Koga Daisuke , Ushiki Tatsuo , Matsuno Kenjiro 
Published: August 2010

AbstractBackground: We have investigated how recirculating lymphocytes patrol the liver in a normal steady state.Methods: Thoracic duct lymphocytes of congeneic rats were intravenously transferred to host rats and donor cell trafficking in the liver and hepatic lymph was examined. Host hepatic lymph nodes (HLNs) were selectively removed, which allowed liver‐derived donor cells to collect in the thoracic duct without transit in the intervening HLNs.Results: The number of donor cells in the thoracic duct lymph significantly increased over the baseline 3, 5 and 11 h after transfer in the HLN‐removed, non‐pretreated, and HLN‐ligated (in which a lymph efflux was blocked) groups, respectively. Histologically, donor cells appeared in the portal area from 0.5 h after transfer and frequently attached to the basal lamina of portal vein both externally and internally. Three hours after transfer, a few donor cells appeared in the subcapsular sinus of HLNs.Conclusion: The minimal transit time of rat recirculating lymphocytes is 3–4 h in the liver and 5–8 h in the hepatic LNs, in a normal steady state. Recirculating lymphocytes might transmigrate through the portal vein as well as the sinusoid in the periportal zone. This rapid transit might enable an efficient surveillance of the liver portal area by the recirculating lymphocytes.
A decision analysis study of the value of a liver biopsy in nonalcoholic steatohepatitis
Authors: Gaidos Jill K. J. , Hillner Bruce E. , Sanyal Arun J. 
Published: August 2010

AbstractObjectives: Nonalcoholic fatty liver disease (NAFLD) is an increasingly prevalent clinical syndrome reflecting a mixture of pathological liver histology with the potential to progress to cryptogenic cirrhosis. Liver biopsy (LB) is the only way to determine the severity of disease. However, LB is invasive, has complications and financial costs. The aim of this study is to determine the benefits of early LB for diagnosis and early treatment.Methods: A decision tree model tracked the potential outcomes of NAFLD between an LB‐directed approach vs. no initial LB. Each specific biopsy category determined subsequent care actions. The baseline probabilities were determined by literature review and expert opinion.Results: An initial LB strategy was projected to have a lower mortality compared with the no initial LB group and fewer transplant eligible patients after 5 years. If the prevalence of NAFLD is increased, the mortality increases in both the study groups. With improved efficacy of medical and/or surgical intervention, the mortality rate was decreased.Conclusion: This decision tree model provides a context for balancing the risk and benefit of LB in NAFLD. With early biopsy, and early intervention, the relative return of preventing advanced liver disease per LB was high.
Hepatic granulomas: histological and molecular pathological approach to differential diagnosis–a study of 442 cases
Authors: Drebber Uta , Kasper Hans‐Udo , Ratering Judith , Wedemeyer Inga , Schirmacher Peter , Dienes Hans‐Peter , Odenthal Margarete 
Published: August 2010

AbstractBackground/Aims: The incidence of hepatic granulomas is reported in 2–15% of liver biopsies. This study was carried out to evaluate the incidence and aetiology of hepatic granulomas in a German Institute of Pathology with specialization in liver diseases.Methods: A retrospective case review was performed on 12 161 liver biopsies of the Institute of Pathology (University of Cologne) between 1996 and 2004. Aetiology was determined according to histomorphological changes, clinicopathological data and liver tissue polymerase chain reaction (PCR) for detection of diverse putative pathogens in the liver tissue.Results: Four hundred and forty‐two liver biopsies revealed granulomatous lesions (3.63%). Two hundred and fifteen cases (1.77% of all biopsies and 48.64% of granulomatous lesions) were diagnosed as primary biliary cirrhosis. In 37 cases (0.3% of all biopsies and 8.37% of granulomatous lesions), the diagnosis of sarcoidosis was established. A positive PCR result for an infectious pathogen was obtained in 15 samples (3.39%) [Bartonella henselae (n=2), Listeria (n=3), Mycobacterium tuberculosis (n=3), Yersinia pseudotuberculosis (n=1), cytomegalovirus (n=2), Epstein–Barr virus (n=4)]. In six cases, a putative diagnosis was established according to the report of clinical conditions. In 11 cases (2.48%), drugs were the putative causative agent. In 158 cases (36%) a definite diagnosis could not be established.Conclusions: Hepatic granulomas have a broad range of underlying aetiologies. With a combined histological, clinical, serological, and molecular approach, we were able to clarify the cause in 64% of the cases. Owing to the diverse prognosis and therapeutic implications, a detailed interdisciplinary workup of all liver biopsies with granulomatous lesions is mandatory.
Comparing the safety, tolerability and quality of life in patients with chronic hepatitis B vs chronic hepatitis C treated with peginterferon alpha‐2a
Authors: Marcellin Patrick , Lau George K. K. , Zeuzem Stefan , Heathcote E. Jenny , Pockros Paul J. , Reddy K. Rajender , Piratvisuth Teerha , Farci Patrizia , Chow Wan‐Cheng , Jia Ji‐Dong , Paik Woon , Wintfeld Neil , Pluck Nigel 
Published: August 2010

Abstract Background/Aims: Hepatitis B and C viruses (HBV and HCV) are two clinically distinct but related diseases. Pooled data from five studies of peginterferon alpha‐2a in patients with chronic HCV infection (CHC) were compared with two studies of the drug in patients with chronic HBV infection (CHB). Method: The HBV studies included both hepatitis B e antigen (HBeAg)‐positive (n=271) and HBeAg‐negative (n=177) patients; 791 patients took part in the HCV trials. In all studies, patients were treated with 180 μg peginterferon alpha‐2a monotherapy once weekly for 48 weeks. The number of adverse events (AEs), discontinuations and dose modifications were documented. Health‐related quality of life (HRQL) was assessed using the Short‐Form 36 questionnaire. Safety was assessed throughout the treatment period. A 24‐week treatment‐free follow‐up period was also included. Results: Differences (HBV vs HCV) were observed in the incidence of AEs (88–89 vs 96–100%), serious AEs (4–5 vs 7–16%) and treatment withdrawals (6–8 vs 17–33%). The frequency of depression‐related events was lower in CHB patients (4 vs 22%, P<0.001), as was the impact of treatment on HRQL. Conclusions: The safety and tolerability of peginterferon alpha‐2a in patients with CHB compares favourably with that observed in CHC patients, with a lower incidence of common interferon‐related AEs and a significantly lower incidence of depression.
Role of nitric oxide synthesized by nitric oxide synthase 2 in liver regeneration
Authors: Kumamoto Takafumi , Togo Shinji , Ishibe Atsushi , Morioka Daisuke , Watanabe Kazuteru , Takahashi Takuji , Shimizu Tetsuya , Matsuo Ken‐ichi , Kubota Toru , Tanaka Kuniya , Nagashima Yoji , Kawai Jun , Hayashizaki Yoshihide , Shimada Hiroshi 
Published: August 2010

AbstractBackground/Aims: Nitric oxide synthase 2 (NOS2) is expressed during liver regeneration after a partial hepatectomy (PHx); NOS2 subsequently synthesizes nitric oxide (NO). However, the role of NOS2‐synthesized NO in post‐PHx liver regeneration remains unclear. We investigated the role of NOS2‐synthesized NO in liver regeneration.Methods: NOS2 knockout (NOS2‐KO) mice and control mice were subjected to PHx. Liver mass recovery and serum alanine aminotransferase (ALT) levels were then evaluated. The expressions of Ki‐67 and single‐strand DNA were also evaluated in remnant liver specimens. Differences in the gene expression profiles of the two groups of remnant liver specimens were analysed using a microarray and were validated using a reverse transcription‐polymerase chain reaction (RT‐PCR).Results: In NOS2‐KO mice, liver regeneration was delayed and apoptosis and serum ALT levels were higher than the levels in the control mice. A microarray study and RT‐PCR revealed that heat shock protein 70 family (HSP70 family), haeme oxygenase 1 (Hmox1), neuropilin 1 (Nrp1) and epidermal growth factor receptor (EGFR) were downregulated in NOS2‐KO mice.Conclusions: NOS2‐synthesized NO may improve hepatocyte viability through the induction of the HSP70 family and Hmox1 and may sensitize the remnant liver to growth factors through the induction of Nrp1 and EGFR post‐PHx.
Sialoadenectomy enhances hepatic injury induced by lipopolysaccharide/galactosamine in mice
Authors: Sánchez Olga , Almagro Albert , Viladrich Meritxell , Ramírez Ignasi , Soley Maria 
Published: August 2010

AbstractBackground: Submandibular salivary glands (SMGs) synthesize, accumulate and secrete a large amount of epidermal growth factor (EGF) in mice. It is known that surgical removal of SMG (sialoadenectomy) alters cell turnover in the liver and exacerbates liver injury induced by lipopolysaccharide/galactosamine (LPS/GalN).Results: Here we show that such increased hepatotoxicity is not the consequence of the lack of EGF production from SMG. On the contrary, it appears to be the consequence of an inadequate cytokine production by the liver of sialoadenectomized mice. Thus, we found that the increase of plasma tumour necrosis factor‐α and interleukin‐6 was slower in sialoadenectomized than in sham‐operated mice. This is because of a decreased rate of production of both cytokines by the liver. We found that the increase of plasma corticosterone (CS) concentration is lower in sialoadenectomized than that in sham‐operated mice. Adrenalectomy exacerbated liver injury induced by LPS/GalN. In these animals, sialoadenectomy did not further increase the effect of LPS/GalN.Conclusions: Our results suggest that the effect of sialoadenectomy on LPS/GalN‐induced liver toxicity may be the consequence of an altered cytokine production by the liver and a reduced CS release from adrenal glands.
Potential and limitations of lamivudine monotherapy in chronic hepatitis B: evidence from genotyping
Authors: Kennedy Patrick TF. , Phillips Natalie , Chandrasekhar Jaya , Jacobs Ruth , Jacobs Michael , Dusheiko Geoffrey 
Published: August 2010

AbstractBackground: Current oral therapy for hepatitis B virus (HBV) is limited by the presence of resistance leading to resumption of higher levels of HBV replication. Therefore, there is a need for a better definition of the potential role and limitations of lamivudine or similar therapies, used alone.Aims: To examine the viability of lamivudine and similar monotherapies as a treatment strategy in chronic HBV in the face of the worldwide burden of disease.Methods: We have reviewed the role of lamivudine monotherapy in the treatment of chronic HBV in a single tertiary referral liver centre over a 9‐year period. We analysed the outcome in 90 patients where lamivudine has apparently conferred long‐term viral suppression and investigated the development of genotypic resistance in the absence of ostensible phenotypic resistance. Patients were subdivided into hepatitis B e antigen (HBeAg)‐positive and anti‐HBe‐positive groups.Results: Virtually all HBeAg‐positive patients who failed to seroconvert have progressed to combination antiviral therapy. Only 19%(7/36) of HBeAg‐negative patients have continued suppression without detectable genotypic change after 4 years of therapy.Conclusions: These data demonstrate that despite a relatively low level of viraemia in HBeAg‐negative patients, we could detect resistance mutations by direct sequencing in all patients with amplifiable HBV DNA. Our results suggest that for patients with ongoing replication at ‘amplifiable’ levels of HBV DNA, but <105 copies/ml, genotypic selection is readily detectable. Lamivudine monotherapy has not sufficed for the overwhelming majority of patients.
Intracrine signalling of activin A in hepatocytes upregulates connective tissue growth factor (CTGF/CCN2) expression
Authors: Gressner Olav A. , Lahme Birgit , Siluschek Monika , Rehbein Katharina , Weiskirchen Ralf , Gressner Axel M. 
Published: August 2010

AbstractBackground/Aims: Up to now, the effect of activin A on the expression of the important transforming growth factor (TGF)‐β downstream modulator connective tissue growth factor (CTGF) is not known, but might be of relevance for the functional effects of this cytokine on several liver cell types.Methods: In this study, activin A‐dependent CTGF expression in hepatocytes (PC) primed by exogenous activin A and in PC maintained under complete activin‐free culture conditions was analysed by Western blots, metabolic labelling, gene silencing, reverse transcriptase‐polymerase chain reaction (RT‐PCR) and CTGF reporter gene assays. This study was supplemented by immunocytochemical staining of activin A and CTGF in PC of injured liver.Results: Using alkaline phosphatase α‐alkaline phosphatase staining, it is demonstrated that activin A becomes increasingly detectable during the course of CCl4‐liver damage. Addition of activin A to cultured PC induced CTGF protein expression via phosphorylation of Smad2 and Smad3. This induction can be inhibited by the antagonist follistatin and α‐activin A antibody respectively. When PC were cultured under serum(i.e. activin A)‐free culture conditions, a time‐dependent increase of activin expression during the course of the culture was proven by RT‐PCR. Silencing of inhibin βA gene expression under serum‐free conditions by small interfering RNAs greatly suppressed CTGF synthesis and the phosphorylations of Smad2 and Smad3. However, both the extracellularly acting follistatin and the α‐activin A antibody could not inhibit spontaneous CTGF expression, which, however, was achieved by the cell‐permeable TGF‐β Alk4/Alk5 receptor‐kinase‐inhibitor SB431542.Conclusions: In conclusion, the results point to activin A as an inducer of CTGF synthesis in PC. Intracellular activin A contributes to spontaneous CTGF expression in PC independent of exogenous activin A, which is proposed to occur via Alk4/Alk5‐receptors. The findings might be important for many actions of activin A on the liver.
Is serum alanine transaminase level a reliable marker of histological disease in chronic hepatitis C infection?
Authors: Sanai Faisal M. , Benmousa Ali , Al‐Hussaini Hussa , Ashraf Suhail , Alhafi Osama , Abdo Ayman A. , Alameri Hatem F. , Akbar Hisham O. , Bzeizi Khalid I. 
Published: August 2010

AbstractBackground: Approximately 20–30% of patients chronically infected with hepatitis C virus (HCV) have persistently normal alanine transaminase (PNALT) levels. These patients are described to have a mild degree of histological liver damage. We aimed to assess the histological liver changes in HCV patients with PNALT.Patients and methods: Sixty‐five patients with HCV and PNALT (group A) underwent a liver biopsy. PNALT was defined as three or more determinations identified to be within the normal range over 6 months or longer. The demographical features and histological changes were compared with 66 consecutive patients with chronic HCV infection and elevated ALT (group B). All patients had a detectable HCV RNA. Histological disease was scored according to the METAVIR system.Results: Females were more likely to have normal ALT levels (65%). The mean ALT level in Group A and B was 30 and 105 IU/L respectively. No patient in either group had normal histology. The mean necro‐inflammatory scores in groups A and B (2.0±0.68 vs 2.09±0.67) and the mean fibrosis scores (2.11±0.87 vs 2.24±1.04) were not significantly different. Bridging fibrosis in groups A and B was seen in 24.6 and 37.9% patients, respectively, while cirrhosis was seen in 6.2 and 7.6% patients respectively. Hepatic steatosis in groups A and B (0.94±0.86 vs 1.0±1.02 respectively) was also not significantly different and did not show any association with the fibrosis scores across the two groups. In group A, the necro‐inflammatory and fibrosis scores of patients with and without steatosis were not statistically significant. Age was the only predictor of normal ALT levels. However, increasing age did not show a significant increase in histological activity in either group beyond a certain age.Conclusion: This study demonstrates that ALT is a poor surrogate marker for inflammation and fibrosis in HCV patients. Given the presence of significant necro‐inflammation in PNALT patients, the risk/benefit ratio justifies treatment without the need for a liver biopsy.
Induction of innate immune response and absence of subsequent tolerance to dsRNA in biliary epithelial cells relate to the pathogenesis of biliary atresia
Authors: Harada Kenichi , Sato Yasunori , Isse Kumiko , Ikeda Hiroko , Nakanuma Yasuni 
Published: August 2010

AbstractBackground/Aims: Biliary epithelial cells (BECs) possess negative regulatory mechanisms of Toll‐like receptor (TLR)‐based tolerance to bacteria (e.g. endotoxin tolerance). Viral infections of the Reoviridae genus with a dsRNA genome are suspected to be part of the aetiology of biliary atresia (BA), but the negative biliary mechanisms remain unexplored.Methods: Cultured human intrahepatic BECs (HIBECs) pretreated with polyinosinic–polycytidylic acid [poly(I:C)] (a synthetic analogue of viral dsRNA) for 24 h were exposed to poly(I:C) in fresh medium. The activation of nuclear factor‐κB (NF‐κB) and the expression of myxovirus resistance protein A (MxA) and tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL) mRNAs were evaluated. Moreover, after the pretreatment, the transition of these molecules was examined in poly(I:C)‐free conditions.Results: Treatment with poly(I:C) significantly upregulated NF‐κB activity in fresh HIBECs, and pretreatment failed to show tolerance to poly(I:C). The production of MxA and TRAIL was also preserved. Moreover, upregulation in the pretreated HIBECs was well preserved in poly(I:C)‐free medium for at least 72 h.Conclusions: BECs fail to show tolerance to poly(I:C), and once innate immunity is activated it is sustained in poly(I:C)‐free conditions, suggesting that the initiation of the immune response to dsRNA in HIBECs and its presence after the clearance of virus are closely associated with the progression of BA.
Effect of adrenomedullin on hepatic damage in hepatic ischaemia/reperfusion injury in rats
Authors: Kerem Mustafa , Bedirli Abdulkadir , Pasaoglu Hatice , Ofluoğlu Ebru , Yilmazer Demet , Salman Bulent , Yilmaz Tonguc Utku 
Published: August 2010

AbstractAims: Adrenomedullin (AM) is a multifunctional peptide with a putative beneficial role after an ischaemic insult. The aim of this study was to evaluate the effect of AM on partial hepatic ischaemia reperfusion (I/R) injury.Methods: Rats were subjected to 1 h of 70% hepatic ischaemia, followed by reperfusion or sham. At the end of ischaemia, vehicle (phosphate‐buffered saline solution), N‐nitro‐l‐arginine methyl ester (l‐NAME) and AM with or without l‐NAME were infused via the portal vein. Analysis was performed at pre‐ischaemia, ischaemia onset and 1, 2 and 4 h after reperfusion. Hepatic tissue blood flow (HTBF) was evaluated by laser Doppler.Results: Plasma AM levels in the I/R groups were significantly lower than the levels in the sham group. AM treatment significantly reduced levels of aspartate transaminase and tissue arginase (P<0.05). Significant decreases of tumour necrosis factor‐α, interleukin‐1β and endothelin‐1 levels were also found in the serum. Endothelin‐1, malondialdehyde and necrosis were observed more frequently in liver tissue in the AM group than the control (P<0.05). Tissue nitric oxide, energy charge and HTBF were significantly increased in AM treatment experiments (P<0.05).Conclusion: The improved HTBF, energy charge and nitric oxide and the reduction of hepatic necrosis, oxidative stress, liver enzymes, endotelin‐1 and pro‐inflammatory cytokines demonstrate that treatment with AM attenuates liver I/R injury.
All‐trans‐retinoic acid ameliorates carbon tetrachloride‐induced liver fibrosis in mice through modulating cytokine production
Authors: Hisamori Shigeo , Tabata Chiharu , Kadokawa Yoshio , Okoshi Kae , Tabata Rie , Mori Akira , Nagayama Satoshi , Watanabe Go , Kubo Hajime , Sakai Yoshiharu 
Published: August 2010

AbstractBackground/Aims: Liver fibrosis with any aetiology, induced by the transdifferentiation and proliferation of hepatic stellate cells (HSCs) to produce collagen, is characterized by progressive worsening in liver function, leading to a high incidence of death. We have recently reported that all‐trans‐retinoic acid (ATRA) suppresses the transdifferentiation and proliferation of lung fibroblasts and prevents radiation‐ or bleomycin‐induced lung fibrosis.Methods: We examined the impact of ATRA on carbon tetrachloride (CCl4)‐induced liver fibrosis. We performed histological examinations and quantitative measurements of transforming growth factor (TGF)‐β1 and interleukin (IL)‐6 in CCl4‐treated mouse liver tissues with or without the administration of ATRA, and investigated the effect of ATRA on the production of the cytokines in quiescent and activated HSCs.Results: CCl4‐induced liver fibrosis was attenuated in histology by intraperitoneal administration of ATRA, and the overall survival rate at 12 weeks was 26.5% without ATRA (n=25), whereas it was 75.0% (n=24) in the treatment group (P=0.0187). In vitro studies disclosed that the administration of ATRA reduced (i) the production of TGF‐β1, IL‐6 and collagen from HSCs, (ii) TGF‐β‐dependent transdifferentiation of the cells and IL‐6‐dependent cell proliferation and (iii) the activities of nuclear factor‐κB p65 and p38mitogen‐activated protein kinase, which stimulate the production of TGF‐β1 and IL‐6, which could be the mechanism underlying the preventive effect of ATRA on liver fibrosis.Conclusions: Our findings indicate that ATRA ameliorates liver fibrosis. As the oral administration of the drug results in good compliance, ATRA could be a novel approach in the treatment of liver fibrosis.