Chronic Ingestion of Ethanol Induces Hepatocellular Carcinoma in Mice Without Additional Hepatic Insult

Abstract Background Chronic intake of alcohol increases the risk of gastrointestinal and hepatic carcinogenesis. The present study was focused to investigate the incidence and mechanism of pathogenesis of hepatocellular carcinoma (HCC) during chronic ingestion of alcohol without any additional hepatic injury. Methods Ethanol was administered to Institute for Cancer Research male mice through drinking water for 70 weeks at concentrations of 5 % (first week), 10 % (next 8 weeks), and 15 % thereafter. The animals were killed at 60 and 70 weeks, the livers were examined for hepatic tumors, and evaluated for foci of cellular alteration (FCA). Immunohistochemical staining was performed in the liver sections for cytochrome P4502E1 (CYP2E1), 4-hydroxy-nonenal (4-HNE), and proto-oncogene, c-Myc. Results At the 60th week, 40 % of the mice in the ethanol group had visible white nodules (5-10 mm) in the liver, but not in the control mice. At the 70th week, several larger nodules (5-22 mm) were present in the livers of 50 % mice in the ethanol group. In the control group, one mouse developed a single nodule. All nodules were histologically trabecular HCC composed of eosinophilic and vacuolated cells. In the livers of both control and ethanol group, several foci with cellular alteration were present, which were significantly higher in ethanol group. Staining for CYP2E1, 4-HNE and c-Myc depicted marked upregulation of all these molecules in the FCA. Conclusions Our data demonstrated that upregulation of CYP2E1 and subsequent production of reactive oxygen species along with the persistent expression of c-Myc play a significant role in the pathogenesis of HCC during chronic ingestion of ethanol

A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details

IgG4-related disease (IgG4RD) is a novel clinical disease entity characterized by elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4-positive plasma cells. IgG4RD may be present in a certain proportion of patients with a wide variety of diseases, including Mikulicz’s disease, autoimmune pancreatitis, hypophysitis, Riedel thyroiditis, interstitial pneumonitis, interstitial nephritis, prostatitis, lymphadenopathy, retroperitoneal fibrosis, inflammatory aortic aneurysm, and inflammatory pseudotumor. Although IgG4RD forms a distinct, clinically independent disease category and is attracting strong attention as a new clinical entity, many questions and problems still remain to be elucidated, including its pathogenesis, the establishment of diagnostic criteria, and the role of IgG4. Here we describe the concept of IgG4RD and up-to-date information on this emerging disease entity

Observation of Live Ticks (Haemaphysalis flava) by Scanning Electron Microscopy under High Vacuum Pressure

Scanning electron microscopes (SEM), which image sample surfaces by scanning with an electron beam, are widely used for steric observations of resting samples in basic and applied biology. Various conventional methods exist for SEM sample preparation. However, conventional SEM is not a good tool to observe living organisms because of the associated exposure to high vacuum pressure and electron beam radiation. Here we attempted SEM observations of live ticks. During 1.5×10−3 Pa vacuum pressure and electron beam irradiation with accelerated voltages (2–5 kV), many ticks remained alive and moved their legs. After 30-min observation, we removed the ticks from the SEM stage; they could walk actively under atmospheric pressure. When we tested 20 ticks (8 female adults and 12 nymphs), they survived for two days after SEM observation. These results indicate the resistance of ticks against SEM observation. Our second survival test showed that the electron beam, not vacuum conditions, results in tick death. Moreover, we describe the reaction of their legs to electron beam exposure. These findings open the new possibility of SEM observation of living organisms and showed the resistance of living ticks to vacuum condition in SEM. These data also indicate, for the first time, the usefulness of tick as a model system for biology under extreme condition

Hepatitis C Virus NS3 Protein Can Activate the Notch-Signaling Pathway through Binding to a Transcription Factor, SRCAP

Persistent infections of hepatitis C virus (HCV) are known to be a major risk factor for causing hepatocellular carcinomas. Nonstructural protein 3 (NS3) of HCV has serine protease and RNA helicase domains, and is essential for the viral replication. Further, NS3 is also considered to be involved in the development of HCV-induced hepatocellular carcinomas. In this report, we focus on the function of NS3 protein, and propose a novel possible molecular mechanism which is thought to be related to the tumorigenesis caused by the persistent infection of HCV. We identified SRCAP (Snf2-related CBP activator protein) as a NS3 binding protein using yeast two-hybrid screening, and a co-immunoprecipitation assay demonstrated that NS3 can bind to SRCAP in mammalian cells. The results of a reporter gene assay using Hes-1 promoter which is known to be a target gene activated by Notch, indicate that NS3 and SRCAP cooperatively activate the Hes-1 promoter in Hep3B cells. In addition, we show in this report that also p400, which is known as a protein closely resembling SRCAP, would be targeted by NS3. NS3 exhibited binding activity also to the 1449-1808 region of p400 by a co-immunoprecipitation assay, and further the activation of the Notch-mediated transcription of Hes-1 promoter by NS3 decreased significantly by the combined silencing of SRCAP and p400 mRNA using short hairpin RNA. These results suggest that the HCV NS3 protein is involved in the activation of the Notch-signaling pathway through the targeting to both SRCAP and p400

Design Method of Acoustic Metamaterials for Negative Refractive Index Acoustic Lenses Based on the Transmission-Line Theory

The design theory for electromagnetic metamaterials with negative refractive indices by using a distributed transmission-line model is introduced to the design of acoustic metamaterials, and a negative refractive index (NRI) acoustic lens is designed theoretically. Adjustments to the negative refractive indices of metamaterials have been carried out by calculations with numerical simulators in conventional design methods. As the results show, many calculations are needed to determine the shape of the unit structures and there are issues in that it is difficult to design those rigorously, meaning that limitations regarding the degree of freedom in the designs are many. On the other hand, the transmission-line model can rigorously design the unit cell structures of both the negative refractive index metamaterials and the background media with the positive refractive indices by calculations with the design formulas and modifying the error from the theory with a small calculation. In this paper, a meander acoustic waveguide unit cell structure is proposed in order to realize a structure with characteristics equivalent to the model, and the waveguide width and length for realizing an NRI acoustic lens are determined from the design formula of the model. The frequency dispersion characteristics of the proposed structure are also computed by eigenvalue analysis and the error in the waveguide length from the theoretical value is modified by a minor adjustment of the waveguide length. In addition, the NRI acoustic lens is constituted by periodically arranging the proposed unit cell structure with the calculated parameters, and the full-wave simulations are carried out to show the validity of the design theory. The results show that the designed lens operates at 2.5 kHz

Design Method of Acoustic Metamaterials for Negative Refractive Index Acoustic Lenses Based on the Transmission-Line Theory

The design theory for electromagnetic metamaterials with negative refractive indices by using a distributed transmission-line model is introduced to the design of acoustic metamaterials, and a negative refractive index (NRI) acoustic lens is designed theoretically. Adjustments to the negative refractive indices of metamaterials have been carried out by calculations with numerical simulators in conventional design methods. As the results show, many calculations are needed to determine the shape of the unit structures and there are issues in that it is difficult to design those rigorously, meaning that limitations regarding the degree of freedom in the designs are many. On the other hand, the transmission-line model can rigorously design the unit cell structures of both the negative refractive index metamaterials and the background media with the positive refractive indices by calculations with the design formulas and modifying the error from the theory with a small calculation. In this paper, a meander acoustic waveguide unit cell structure is proposed in order to realize a structure with characteristics equivalent to the model, and the waveguide width and length for realizing an NRI acoustic lens are determined from the design formula of the model. The frequency dispersion characteristics of the proposed structure are also computed by eigenvalue analysis and the error in the waveguide length from the theoretical value is modified by a minor adjustment of the waveguide length. In addition, the NRI acoustic lens is constituted by periodically arranging the proposed unit cell structure with the calculated parameters, and the full-wave simulations are carried out to show the validity of the design theory. The results show that the designed lens operates at 2.5 kHz