Publications by authors named "Ryota Masuzaki"

69 Publications

Knockdown of Mitogen-Activated Protein Kinase Kinase 3 Negatively Regulates Hepatitis A Virus Replication.

Int J Mol Sci 2021 Jul 10;22(14). Epub 2021 Jul 10.

Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan.

Zinc chloride is known to be effective in combatting hepatitis A virus (HAV) infection, and zinc ions seem to be especially involved in Toll-like receptor (TLR) signaling pathways. In the present study, we examined this involvement in human hepatoma cell lines using a human TLR signaling target RT-PCR array. We also observed that zinc chloride inhibited mitogen-activated protein kinase kinase 3 (MAP2K3) expression, which could downregulate HAV replication in human hepatocytes. It is possible that zinc chloride may inhibit HAV replication in association with its inhibition of MAP2K3. In that regard, this study set out to determine whether MAP2K3 could be considered a modulating factor in the development of the HAV pathogen-associated molecular pattern (PAMP) and its triggering of interferon-β production. Because MAP2K3 seems to play a role in antiviral immunity against HAV infection, it is a promising target for drug development. The inhibition of MAP2K3 may also prevent HAV patients from developing a severe hepatitis A infection.
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http://dx.doi.org/10.3390/ijms22147420DOI Listing
July 2021

Ultrasonographic grayscale findings related to fibrosis in patients with non-alcoholic fatty liver disease: comparison with transient elastography and Fib-4 index.

J Med Ultrason (2001) 2021 Jul 16;48(3):323-333. Epub 2021 Jun 16.

Department of Pathology, Nihon University School of Medicine, 30-1 Oyaguchi Kamimachi, Itabashi-ku, Tokyo, 173-8610, Japan.

Purpose: Fibrosis is a predictor of mortality in patients with non-alcoholic fatty liver disease (NAFLD). In our institution, abdominal ultrasonography has been performed based on a unified method consisting of 25 images. We investigated ultrasonographic grayscale findings related to fibrosis in patients with NAFLD.

Methods: This retrospective study comprised 41 cases of pathologically proven fatty liver between January 2015 and September 2020. A total of 26 ultrasonographic findings were subjectively evaluated. These findings, transient elastography (TE) with M probe, and FIB-4 index were compared with fibrosis stage.

Results: The frequency of roughness of the dorsal side of the surface (p < 0.001), heterogenicity of the parenchyma (p = 0.003), narrowing of the hepatic vein (p = 0.004), and splenomegaly (p < 0.001) were strongly correlated with the fibrosis stage. Logistic regression analysis for stage ≥ 3 showed narrowing of the hepatic vein (odds ratio [OR] 5.860, p = 0.031) and splenomegaly (OR 6.290, p = 0.028). Logistic regression analysis for stage 4 showed roughness of the ventral side of the surface (OR 42.0, p = 0.019). The AUROC for stage 3 and stage 4 with the number of positive ultrasonographic findings was 0.856, and 0.940, respectively. The AUROC for F3 and F4 with TE was 0.831 and 0.861, respectively. The AUROC for stage 3 and stage 4 with FIB-4 index was 0.815 and 0.806, respectively.

Conclusions: Narrowing of the hepatic vein, roughness of the dorsal side of the surface, heterogenicity of the parenchyma, and splenomegaly and their combination could predict fibrosis in patients with NAFLD.
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http://dx.doi.org/10.1007/s10396-021-01107-0DOI Listing
July 2021

Occurrence of hepatitis in an elderly woman during the treatment of pembrolizumab for right advanced renal pelvis, ureteral cancer, and bladder cancer.

JGH Open 2021 Jun 6;5(6):722-724. Epub 2021 May 6.

Division of Gastroenterology and Hepatology, Department of Medicine Nihon University School of Medicine Tokyo Japan.

Recently, the use of immune checkpoint inhibitors (ICIs) with or without chemotherapeutic agents has been increasing in the treatment for advanced cancer. Here, we report the occurrence of liver failure after the use of pembrolizumab in an 82-year-old woman with metastatic liver disease derived from right advanced renal pelvis, ureteral cancer, and bladder cancer. She was successfully treated with 0.6 mg/kg daily prednisolone. In patients treated with ICIs, ICI-induced hepatitis is occasionally observed. Even if patients are older, it appears important to diagnose and treat ICI-induced hepatitis earlier by multidisciplinary therapies including steroid treatment. This is a first report of pembrolizumab-induced liver failure in elder patient with age over 80 years. Even if patients are older, it appears important to diagnose and treat ICI-induced hepatitis earlier by multidisciplinary therapies including steroid treatment.
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http://dx.doi.org/10.1002/jgh3.12554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171158PMC
June 2021

Male-Dominant Hepatitis A Outbreak Observed among Non-HIV-Infected Persons in the Northern Part of Tokyo, Japan.

Viruses 2021 01 29;13(2). Epub 2021 Jan 29.

Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi, Tokyo 173-8610, Japan.

Recently, we experienced an outbreak of acute hepatitis A virus (HAV) infection between 2018 and 2020. Herein, we describe this male-dominant HAV infection outbreak observed among non-human immunodeficiency virus (HIV)-infected persons in the northern part of Tokyo, Japan. Clinical information was collected from patient interviews and from medical record descriptions. In the present study, 21 patients were retrospectively analyzed. A total of 90.4 and 33.3% of patients were males, and men who have sex with men (MSM), respectively. The total bilirubin levels and platelet counts tended to be lower in the MSM group than in the non-MSM group. C-reactive protein (CRP) levels tended to be higher in acute liver failure (ALF) patients than in non-ALF patients. Prolonged cholestasis was observed in one patient (4.8%). We also found that 18 HAV isolates belonged to HAV subgenotype IA/subgroup 13 (S13), which clustered with the HAV isolate (KX151459) that was derived from an outbreak of HAV infection among MSM in Taiwan in 2015. Our results suggest that the application of antivirals against HAV, as well as HAV vaccines, would be useful for the treatment and prevention of severe HAV infection.
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http://dx.doi.org/10.3390/v13020207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910831PMC
January 2021

Japanese Man with HCV Genotype 4 Infection and Cirrhosis Who Was Successfully Treated by the Combination of Glecaprevir and Pibrentasvir.

Intern Med 2021 Jul 1;60(13):2061-2066. Epub 2021 Feb 1.

Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Japan.

A 74-year-old man with a history of transfusion at 35 years old in Egypt was referred to our hospital. He was infected with hepatitis C virus (HCV) genotype 4 (GT4), which is a rare HCV GT in Japan, and was also diagnosed with hepatic compensated cirrhosis. We safely treated the patient for 12 weeks with the combination of glecaprevir and pibrentasvir, and a sustained virologic response (SVR) was achieved. This is the first report of HCV GT4 infection in a treatment-naïve Japanese patient with cirrhosis in whom SVR was achieved with the combination treatment of glecaprevir and pibrentasvir.
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http://dx.doi.org/10.2169/internalmedicine.6728-20DOI Listing
July 2021

Integrin β1 Establishes Liver Microstructure and Modulates Transforming Growth Factor β during Liver Development and Regeneration.

Am J Pathol 2021 02 4;191(2):309-319. Epub 2020 Nov 4.

Section of Surgical Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee. Electronic address:

A unique and complex microstructure underlies the diverse functions of the liver. Breakdown of this organization, as occurs in fibrosis and cirrhosis, impairs liver function and leads to disease. The role of integrin β1 was examined both in establishing liver microstructure and recreating it after injury. Embryonic deletion of integrin β1 in the liver disrupts the normal development of hepatocyte polarity, specification of cell-cell junctions, and canalicular formation. This in turn leads to the expression of transforming growth factor β (TGF-β) and widespread fibrosis. Targeted deletion of integrin β1 in adult hepatocytes prevents recreation of normal hepatocyte architecture after liver injury, with resultant fibrosis. In vitro, integrin β1 is essential for canalicular formation and is needed to prevent stellate cell activation by modulating TGF-β. Taken together, these findings identify integrin β1 as a key determinant of liver architecture with a critical role as a regulator of TGF-β secretion. These results suggest that disrupting the hepatocyte-extracellular matrix interaction is sufficient to drive fibrosis.
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http://dx.doi.org/10.1016/j.ajpath.2020.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888191PMC
February 2021

Additive Effects of Zinc Chloride on the Suppression of Hepatitis A Virus Replication by Interferon in Human Hepatoma Huh7 Cells.

In Vivo 2020 Nov-Dec;34(6):3301-3308

Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.

Background/aim: Hepatitis A virus (HAV) infection is still one of the serious health problems worldwide, despite the existence of effective vaccines for HAV. Zinc compounds have antiviral activities against various DNA and RNA viruses. Therefore, we investigated the effects of zinc compounds on the antiviral activity of interferon against HAV.

Materials And Methods: The effects of zinc compounds with or without interferon on HAV genotype IIIA HA11-1299 replication were examined in human hepatoma Huh7 cells. Cell viability was examined by the MTS assay. Inflammasome associated gene expression was examined by real-time reverse transcription-polymerase chain reaction.

Results: Both zinc sulfate and zinc chloride had an inhibitory effect on HAV replication. Zinc sulfate tended to enhance while zinc chloride significantly enhanced the anti-HAV effect induced by interferon-alpha-2a. Zinc chloride significantly up-regulated mitogen-activated protein kinase 12 (MAPK12) and down-regulated 6 related genes [baculoviral IAP repeat containing 3 (BIRC3), interleukin 1 beta (IL1B), proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1), prostaglandin-endoperoxide synthase 2 (PTGS2), PYD and CARD domain containing (PYCARD), and tumor necrosis factor (TNF)].

Conclusion: Zinc chloride inhibits HAV replication and has additive effects on the anti-HAV activities of interferon.
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http://dx.doi.org/10.21873/invivo.12168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811611PMC
June 2021

Co-Occurrence of Hepatitis A Infection and Chronic Liver Disease.

Int J Mol Sci 2020 Sep 2;21(17). Epub 2020 Sep 2.

Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan.

Hepatitis A virus (HAV) infection occasionally leads to a critical condition in patients with or without chronic liver diseases. Acute-on-chronic liver disease includes acute-on-chronic liver failure (ACLF) and non-ACLF. In this review, we searched the literature concerning the association between HAV infection and chronic liver diseases in PubMed. Chronic liver diseases, such as metabolic associated fatty liver disease and alcoholic liver disease, coinfection with other viruses, and host genetic factors may be associated with severe hepatitis A. It is important to understand these conditions and mechanisms. There may be no etiological correlation between liver failure and HAV infection, but there is an association between the level of chronic liver damage and the severity of acute-on-chronic liver disease. While the application of an HAV vaccination is important for preventing HAV infection, the development of antivirals against HAV may be important for preventing the development of ACLF with HAV infection as an acute insult. The latter is all the more urgent given that the lives of patients with HAV infection and a chronic liver disease of another etiology may be at immediate risk.
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http://dx.doi.org/10.3390/ijms21176384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504211PMC
September 2020

Quantitative Ultrasound Image Analysis Helps in the Differentiation of Hepatocellular Carcinoma (HCC) From Borderline Lesions and Predicting the Histologic Grade of HCC and Microvascular Invasion.

J Ultrasound Med 2021 Apr 25;40(4):689-698. Epub 2020 Aug 25.

Department of Pathology, Nihon University School of Medicine, Tokyo, Japan.

Objectives: Quantitative image analysis is one of the methods to overcome the lack of objectivity of ultrasound (US). The aim of this study was to clarify the correlation between the features from a US image analysis and the histologic grade and microvascular invasion (MVI) of hepatocellular carcinoma (HCC) and differentiation of HCC smaller than 2 cm from borderline lesions.

Methods: We retrospectively analyzed grayscale US images with histopathologic evidence of HCC or a precancerous lesion using ImageJ version 1.47 software (National Institutes of Health, Bethesda, MD).

Results: A total of 148 nodules were included (borderline lesion, n = 31; early HCC [eHCC], n = 3; well-differentiated HCC [wHCC], n = 16; moderately differentiated HCC [mHCC], n = 79; and poorly differentiated HCC [pHCC], n = 19). A multivariate analysis selected lower minimum gray values (odds ratio [OR], 0.431; P = .003) and a higher standard deviation (OR, 1.880; P = .019) as predictors of HCC smaller than 2 cm. Median (range) minimum gray values of borderline lesions, eHCC, wHCC, mHCC, and pHCC were 29 (0-103), 7 (0-47), 6 (0-60), 10 (0-53), and 2 (0-38), respectively, and gradually decreased from borderline lesions to pHCC (P < 0.001). The multivariate analysis showed a higher aspect ratio (OR, 2.170; P = .001) and lower minimum gray value (OR, 0.475; P = .043) as predictors of MVI. An anechoic area diagnosed by a subjective evaluation was correlated with the minimum gray value (P < .0001). The proportion of the anechoic area gradually increased from eHCC to pHCC (P = .031).

Conclusions: In a US image analysis, HCC smaller than 2 cm had features of greater heterogeneity and a lower minimum gray value than borderline lesions. Moderately differentiated HCC was smoother than borderline lesions, and the anechoic area correlated with histologic grading. Microvascular invasion was correlated with a slender shape and a lower minimum gray value.
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http://dx.doi.org/10.1002/jum.15439DOI Listing
April 2021

Involvement of the Interferon Signaling Pathways in Pancreatic Cancer Cells.

Anticancer Res 2020 Aug;40(8):4445-4455

Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.

Background/aim: To examine interferon (IFN) signaling pathways in human pancreatic cancer cells and their therapeutic application for pancreatic ductal adenocarcinoma (PDAC).

Materials And Methods: We examined the effects of IFNα on cytotoxicity, migration, as well as on the levels of toll-like receptor (TLR) signaling pathway-associated genes expression in pancreatic cancer cells. We also examined the additive effects of IFNα and poly(I-C) on tyrosine kinase inhibitor (TKI)-induced cytotoxicity. We performed transcriptome analysis (RNA-Seq) of clinical samples and compared the profile between pancreatic intraepithelial neoplasias (PanINs) and PDACs.

Results: IFNα suppressed cell viability and cell migration, and affected TLR signaling pathways, in pancreatic cancer cells. TLR3 is one of the potential genes involved in IFN-treated pancreatic cancer cells. Furthermore, similar to IFN, extracellular addition of poly(I-C) enhanced TKI-induced cytotoxicity in pancreatic cancer cells. RNA-Seq analysis demonstrated that IFN signaling is one of the potential pathways involved in the progression of PanIN to PDAC.

Conclusion: IFN signaling may be involved in the development of PDAC. Treatments that target the IFN and TLR3 signaling pathways may be therapeutic options against PDAC.
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http://dx.doi.org/10.21873/anticanres.14449DOI Listing
August 2020

Noninvasive Assessment of Liver Fibrosis: Current and Future Clinical and Molecular Perspectives.

Int J Mol Sci 2020 Jul 11;21(14). Epub 2020 Jul 11.

Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-Ku, Tokyo 173-8610, Japan.

Liver fibrosis is one of the risk factors for hepatocellular carcinoma (HCC) development. The staging of liver fibrosis can be evaluated only via a liver biopsy, which is an invasive procedure. Noninvasive methods for the diagnosis of liver fibrosis can be divided into morphological tests such as elastography and serum biochemical tests. Transient elastography is reported to have excellent performance in the diagnosis of liver fibrosis and has been accepted as a useful tool for the prediction of HCC development and other clinical outcomes. Two-dimensional shear wave elastography is a new technique and provides a real-time stiffness image. Serum fibrosis markers have been studied based on the mechanism of fibrogenesis and fibrolysis. In the healthy liver, homeostasis of the extracellular matrix is maintained directly by enzymes called matrix metalloproteinases (MMPs) and their specific inhibitors, tissue inhibitors of metalloproteinases (TIMPs). MMPs and TIMPs could be useful serum biomarkers for liver fibrosis and promising candidates for the treatment of liver fibrosis. Further studies are required to establish liver fibrosis-specific markers based on further clinical and molecular research. In this review, we summarize noninvasive fibrosis tests and molecular mechanism of liver fibrosis in current daily clinical practice.
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http://dx.doi.org/10.3390/ijms21144906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402287PMC
July 2020

Cell Culture Systems and Drug Targets for Hepatitis A Virus Infection.

Viruses 2020 05 12;12(5). Epub 2020 May 12.

Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan.

Hepatitis A virus (HAV) infection is one of the major causes of acute hepatitis, and this infection occasionally causes acute liver failure. HAV infection is associated with HAV-contaminated food and water as well as sexual transmission among men who have sex with men. Although an HAV vaccine has been developed, outbreaks of hepatitis A and life-threatening severe HAV infections are still observed worldwide. Therefore, an improved HAV vaccine and anti-HAV drugs for severe hepatitis A should be developed. Here, we reviewed cell culture systems for HAV infection, and other issues. This review may help with improving the HAV vaccine and developing anti-HAV drugs.
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http://dx.doi.org/10.3390/v12050533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291253PMC
May 2020

Different Mechanisms of Action of Regorafenib and Lenvatinib on Toll-Like Receptor-Signaling Pathways in Human Hepatoma Cell Lines.

Int J Mol Sci 2020 May 9;21(9). Epub 2020 May 9.

Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan.

Multiple kinase inhibitors are available for patients with advanced hepatocellular carcinoma (HCC). It is largely unknown whether regorafenib or lenvatinib modulates innate immunity including Toll-like receptor (TLR)-signaling pathways in HCC. We performed real-time RT-PCR to investigate 84 TLR-associated gene expression levels and compared these gene expression levels in each hepatoma cells treated with or without regorafenib or lenvatinib. In response to regorafenib, nine and 10 genes were upregulated in Huh7 and HepG2 cells, respectively, and only C-X-C motif chemokine ligand 10 was upregulated in both cell lines. A total of 14 and 12 genes were downregulated in Huh7 and HepG2 cells, respectively, and two genes (Fos proto-oncogene, AP-1 transcription factor subunit, and ubiquitin conjugating enzyme E2 N) were downregulated in both cell lines. In response to lenvatinib, four and 16 genes were upregulated in Huh7 and HepG2 cells, respectively, and two genes (interleukin 1 alpha and TLR4) were upregulated in both cells. Six and one genes were downregulated in Huh7 and HepG2, respectively, and no genes were downregulated in both cell lines. In summary, regorafenib and lenvatinib affect TLR signaling pathways in human hepatoma cell lines. Modulation of TLR signaling pathway may improve the treatment of HCC patients with refractory disease.
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http://dx.doi.org/10.3390/ijms21093349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246870PMC
May 2020

Molecular Mechanisms: Connections between Nonalcoholic Fatty Liver Disease, Steatohepatitis and Hepatocellular Carcinoma.

Int J Mol Sci 2020 Feb 23;21(4). Epub 2020 Feb 23.

Genome Analysis Center, Yamanashi Central Hospital, Yamanashi 400-8506, Japan.

Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), causes hepatic fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The patatin-like phospholipase-3 (PNPLA3) I148M sequence variant is one of the strongest genetic determinants of NAFLD/NASH. PNPLA3 is an independent risk factor for HCC among patients with NASH. The obesity epidemic is closely associated with the rising prevalence and severity of NAFLD/NASH. Furthermore, metabolic syndrome exacerbates the course of NAFLD/NASH. These factors are able to induce apoptosis and activate immune and inflammatory pathways, resulting in the development of hepatic fibrosis and NASH, leading to progression toward HCC. Small intestinal bacterial overgrowth (SIBO), destruction of the intestinal mucosa barrier function and a high-fat diet all seem to exacerbate the development of hepatic fibrosis and NASH, leading to HCC in patients with NAFLD/NASH. Thus, the intestinal microbiota may play a role in the development of NAFLD/NASH. In this review, we describe recent advances in our knowledge of the molecular mechanisms contributing to the development of hepatic fibrosis and HCC in patients with NAFLD/NASH.
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http://dx.doi.org/10.3390/ijms21041525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073210PMC
February 2020

Liver stiffness measurements in chronic hepatitis C: Treatment evaluation and risk assessment.

J Gastroenterol Hepatol 2019 May 7;34(5):921-928. Epub 2018 Dec 7.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background And Aim: Liver stiffness (LS), measured by transient elastography, has been validated as a non-invasive surrogate for liver fibrosis.

Methods: We investigated the long-term predictive ability of LS for hepatocellular carcinoma (HCC) development and overall survival in 1146 patients with chronic hepatitis C by using LS value at enrollment. We also investigated chronological changes in LS based on antiviral therapy and its outcome in 752 patients.

Results: During the mean follow-up period of 6.6 years, 190 patients developed HCC. Cumulative HCC incidence rates at 5 years were clearly stratified as 1.7% in the ≤ 5 kPa, 3.3% in 5.1-10 kPa, 16.7% in 10.1-15 kPa, 24.4% in 15.1-20 kPa, 36.3% in 20.1-25 kPa, and 43.7% in > 25 kPa subgroups (P < 0.001). Overall survival was also stratified: 10-year survival rates were 99.3% in the ≤ 5 kPa, 95.4% in 5.1-10 kPa, 81.4% in 10.1-15 kPa, 79.5% in 15.1-20 kPa, 66.1% in 20.1-25 kPa, and 49.1% in > 25 kPa subgroups (P < 0.001). LS decreased at a rate of 8.1% per year in those who achieved sustained virological responses, but increased at 0.1% per year in those who could not achieve sustained virological response instead of antiviral therapy, and increased at 3.7% per year in those who did not undergo antiviral therapy.

Conclusions: Liver stiffness measurements can be useful in the prediction of HCC development and overall survival and in the evaluation of chronological changes in liver fibrosis grade during and after antiviral therapy.
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http://dx.doi.org/10.1111/jgh.14530DOI Listing
May 2019

RASAL1 is a potent regulator of hepatic stellate cell activity and liver fibrosis.

Oncotarget 2017 Sep 4;8(39):64840-64852. Epub 2017 May 4.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Liver fibrosis, leading to cirrhosis and liver failure, can occur after chronic liver injury. The transition of hepatic stellate cells (HSCs) from quiescent cells into proliferative and fibrogenic cells is a central event in liver fibrosis. Here, we show that RAS protein activator like-1 (RASAL1), a RAS-GTPase-activating protein, which switches off RAS activity, is significantly decreased during HSC activation, and that HSC activation can be antagonized by forced expression of the RASAL1 protein. We demonstrate that RASAL1 suppresses HSC proliferation by regulating the Ras-MAPK pathway, and that RASAL1 suppresses HSC fibrogenic activity by regulating the PKA-LKB1-AMPK-SRF pathway by interacting with angiotensin II receptor, type 1. We also show that RASAL1-deficient mice are more susceptible to liver fibrosis. These data demonstrate that deregulated RASAL1 expression levels and the affected downstream intracellular signaling are central mediators of perpetuated HSC activation and fibrogenesis in the liver.
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http://dx.doi.org/10.18632/oncotarget.17609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630295PMC
September 2017

Dicer-dependent production of microRNA221 in hepatocytes inhibits p27 and is required for liver regeneration in mice.

Am J Physiol Gastrointest Liver Physiol 2017 May 23;312(5):G464-G473. Epub 2017 Feb 23.

Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee; and

Dicer processes microRNAs (miRs) into active forms in a wide variety of tissues, including the liver. To determine the role of Dicer in liver regeneration, we performed a series of in vivo and in vitro studies in a murine 2/3 hepatectomy model. Dicer was downregulated after 2/3 hepatectomy, and loss of Dicer inhibited liver regeneration associated with decreased cyclin A2 and miR-221, as well as increased levels of the cell cycle inhibitor p27. In vitro, miR-221 inhibited p27 production in primary hepatocytes and increased hepatocyte proliferation. Specific reconstitution of miR-221 in hepatocyte-specific Dicer-null mice inhibited p27 and restored liver regeneration. In wild type mice, targeted inhibition of miR-221 using a cholesterol-conjugated miR-221 inhibited hepatocyte proliferation after 2/3 hepatectomy. These results identify Dicer production of miR-221 as an essential component of a miRNA-dependent mechanism for suppression of p27 that controls the rate of hepatocyte proliferation after partial hepatectomy. Our findings demonstrate a direct role for microRNAs in controlling the rate of liver regeneration after injury. By deleting Dicer, an enzyme responsible for processing microRNAs into mature forms, we determined miR-221 is a critical microRNA in the physiological process of restoration of liver mass after injury. miR-221 suppresses p27, releasing its inhibitory effects on hepatocyte proliferation. Pharmaceuticals based on miR-221 may be useful to modulate hepatocyte proliferation in the setting of liver injury.
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http://dx.doi.org/10.1152/ajpgi.00383.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451560PMC
May 2017

NAFLD as a risk factor for HCC: new rules of engagement?

Hepatol Int 2016 Jul 5;10(4):533-4. Epub 2016 May 5.

Department of Gastroenterology, Yamanashi Prefectural Central Hospital, Kofu, Yamanashi, Japan.

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http://dx.doi.org/10.1007/s12072-016-9731-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4939149PMC
July 2016

SOCS2 Balances Metabolic and Restorative Requirements during Liver Regeneration.

J Biol Chem 2016 Feb 23;291(7):3346-58. Epub 2015 Dec 23.

From the Transplant Center, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232,

After significant injury, the liver must maintain homeostasis during the regenerative process. We hypothesized the existence of mechanisms to limit hepatocyte proliferation after injury to maintain metabolic and synthetic function. A screen for candidates revealed suppressor of cytokine signaling 2 (SOCS2), an inhibitor of growth hormone (GH) signaling, was strongly induced after partial hepatectomy. Using genetic deletion and administration of various factors we investigated the role of SOCS2 during liver regeneration. SOCS2 preserves liver function by restraining the first round of hepatocyte proliferation after partial hepatectomy by preventing increases in growth hormone receptor (GHR) via ubiquitination, suppressing GH pathway activity. At later times, SOCS2 enhances hepatocyte proliferation by modulating a decrease in serum insulin-like growth factor 1 (IGF-1) that allows GH release from the pituitary. SOCS2, therefore, plays a dual role in modulating the rate of hepatocyte proliferation. In particular, this is the first demonstration of an endogenous mechanism to limit hepatocyte proliferation after injury.
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http://dx.doi.org/10.1074/jbc.M115.703264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4751379PMC
February 2016

Cytometry-based single-cell analysis of intact epithelial signaling reveals MAPK activation divergent from TNF-α-induced apoptosis in vivo.

Mol Syst Biol 2015 Oct 30;11(10):835. Epub 2015 Oct 30.

Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA Department of Chemical and Physical Biology, Vanderbilt University Medical Center, Nashville, TN, USA

Understanding heterogeneous cellular behaviors in a complex tissue requires the evaluation of signaling networks at single-cell resolution. However, probing signaling in epithelial tissues using cytometry-based single-cell analysis has been confounded by the necessity of single-cell dissociation, where disrupting cell-to-cell connections inherently perturbs native cell signaling states. Here, we demonstrate a novel strategy (Disaggregation for Intracellular Signaling in Single Epithelial Cells from Tissue-DISSECT) that preserves native signaling for Cytometry Time-of-Flight (CyTOF) and fluorescent flow cytometry applications. A 21-plex CyTOF analysis encompassing core signaling and cell-identity markers was performed on the small intestinal epithelium after systemic tumor necrosis factor-alpha (TNF-α) stimulation. Unsupervised and supervised analyses robustly selected signaling features that identify a unique subset of epithelial cells that are sensitized to TNF-α-induced apoptosis in the seemingly homogeneous enterocyte population. Specifically, p-ERK and apoptosis are divergently regulated in neighboring enterocytes within the epithelium, suggesting a mechanism of contact-dependent survival. Our novel single-cell approach can broadly be applied, using both CyTOF and multi-parameter flow cytometry, for investigating normal and diseased cell states in a wide range of epithelial tissues.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631206PMC
http://dx.doi.org/10.15252/msb.20156282DOI Listing
October 2015

Functional Implications of Biochemical and Molecular Characteristics of Donation After Circulatory Death Livers.

Transplant Direct 2015 Jun 15;1(5):e18. Epub 2015 Jun 15.

The Transplant Center, Department of Surgery, Vanderbilt University Medical Center, Nashville, TN.

Unlabelled: In aggregate, livers donated after circulatory death (DCD) provide lower rates of graft and patient survival compared to brain dead donors (DBD). A method to identify DCD livers likely to perform well would lead to better decision-making regarding which livers to use and which to discard and is an important unmet clinical need. We hypothesized that the ischemic time between extubation and cold perfusion in the donor leads to immediate and unique biochemical and molecular changes that could be used to predict subsequent function.

Methods: Biopsies from normal perfused liver, immediately after cold perfusion during DCD or DBD liver procurement, and during subsequent cold storage were analyzed and compared. Biochemical analysis included adenosine triphosphate (ATP), adenosine diphosphate, adenosine monophosphate, hypoxanthine, xanthine, inosine, nicotinamide adenine dinucleotide, and flavin adenine dinucleotide. Levels of these metabolites were compared to peak posttransplant aspartate aminotransferase as a marker of ischemic injury. Molecular analysis was performed by transcriptional profiling using high throughput sequencing.

Results: Immediately after cold perfusion in the donor, biochemical analysis revealed lower levels of ATP and adenosine diphosphate in DCD versus DBD liver samples (P < 0.01 in both cases). The ATP levels showed high negative correlation with peak aspartate aminotransferase levels in recipients (P = 0.029). Four hundred seventy genes showed differential expression in DCD but not DBD samples immediately after cold perfusion compared with normal liver samples. Upregulated genes function in inflammation and immunity, whereas downregulated genes function in translation. During cold storage, samples were transcriptionally inactive with no consistent changes in messenger RNA expression.

Conclusion: The ATP content of liver samples taken immediately postperfusion correlates with ischemic injury. Transcriptional profiling identifies biological process that may be relevant for enhancing function in DCD liver transplantation. Transcriptional inactivity of cold stored samples suggests messenger RNA levels over time are unlikely to provide prognostic data.
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http://dx.doi.org/10.1097/TXD.0000000000000527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4946467PMC
June 2015

Specific activin receptor-like kinase 3 inhibitors enhance liver regeneration.

J Pharmacol Exp Ther 2014 Dec 30;351(3):549-58. Epub 2014 Sep 30.

The Transplant Center and Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (D.T., Y.O., R.M., K.R., S.J.K.); Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee (D.W.E., C.W.L., C.R.H.); Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts (M.D., N.D.); Department of Surgery, Kobe University, Kobe, Japan (K.K.); Department of Surgery (K.H.), and Division of Cardiology, Department of Medicine (P.B.Y.), Brigham and Women's Hospital, Boston, Massachusetts; Anesthesia Center for Critical Care Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts (K.D.B.); Department of Chemistry, Vanderbilt University, Nashville, Tennessee (C.W.L.); and Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee (A.F., C.C.H.)

Pharmacologic agents to enhance liver regeneration after injury would have wide therapeutic application. Based on previous work suggesting inhibition of bone morphogenetic protein (BMP) signaling stimulates liver regeneration, we tested known and novel BMP inhibitors for their ability to accelerate regeneration in a partial hepatectomy (PH) model. Compounds were produced based on the 3,6-disubstituted pyrazolo[1,5-a] pyrimidine core of the BMP antagonist dorsomorphin and evaluated for their ability to inhibit BMP signaling and enhance liver regeneration. Antagonists of the BMP receptor activin receptor-like kinase 3 (ALK3), including LDN-193189 (LDN; 4-[6-[4-(1-piperazinyl)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]-quinoline), DMH2 (4-(2-(4-(3-(quinolin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)phenoxy)ethyl)morpholine; VU0364849), and the novel compound VU0465350 (7-(4-isopropoxyphenyl)-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine; VU5350), blocked SMAD phosphorylation in vitro and in vivo, and enhanced liver regeneration after PH. In contrast, an antagonist of the BMP receptor ALK2, VU0469381 (5-(6-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl)quinolone; 1LWY), did not affect liver regeneration. LDN did not affect liver synthetic or metabolic function. Mechanistically, LDN increased serum interleukin-6 levels and signal transducer and activator of transcription 3 phosphorylation in the liver, and modulated other factors known to be important for liver regeneration, including suppressor of cytokine signaling 3 and p53. These findings suggest that inhibition of ALK3 may be part of a therapeutic strategy for treating human liver disease.
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http://dx.doi.org/10.1124/jpet.114.216903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4244585PMC
December 2014

Cause-specific mortality associated with aging in patients with hepatocellular carcinoma undergoing percutaneous radiofrequency ablation.

Eur J Gastroenterol Hepatol 2014 Sep;26(9):1039-46

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Objective: The number of elderly patients diagnosed with hepatocellular carcinoma (HCC) is expected to increase. The aim of this study is to evaluate the efficacy of radiofrequency ablation (RFA) in elderly patients with HCC and to investigate cause-specific excess deaths associated with increasing number of elderly patients.

Materials And Methods: We enrolled 1401 naive patients with HCC who were treated initially by RFA from 1999 to 2011. Patients below 75 years of age were categorized as 'younger' and those at least 75 as 'elderly'. Differences in the demographic and laboratory data of these patients were assessed, along with Kaplan-Meier analysis of survival using the log-rank test. In addition, we assessed the causes of death, defined as liver related and liver unrelated, by competing risk analysis and risk factors for respective causes of death by a proportional subdistribution model.

Results: Overall, 353 patients were categorized as elderly. Elderly patients were more likely to be women, infected with hepatitis C virus, and score better in the Child-Pugh classification. The mortality at 5 years was lower in the elderly than in the younger patients (47.3 vs. 37.1%; P<0.001). Competing risk analysis showed a significant difference in liver-unrelated death (P<0.001) between the two groups, whereas there were no significant differences in liver-related death (P=0.64). By the proportional subdistribution model, age was a significant risk factor only for liver-unrelated death.

Conclusion: RFA provided satisfactory 5-year survival rates in elderly patients with HCC. The elderly tended to die from liver-unrelated causes.
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http://dx.doi.org/10.1097/MEG.0000000000000161DOI Listing
September 2014

Tumor markers are more useful in patients undergoing surveillance for hepatocellular carcinoma with unreliable results by ultrasonography.

Hepatol Res 2015 Apr 19;45(4):415-22. Epub 2014 Jun 19.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Aim: The objectives of this study was to evaluate the utility of tumor markers in hepatocellular carcinoma (HCC) surveillance based on the reliability of ultrasonography.

Methods: We analyzed 313 patients with HCC detected through a surveillance program using ultrasonography combined with three tumor markers from February 2000 to December 2010. The patients were categorized into two groups based on the triggering event: the US group (n = 281) in which a tumor was first detected using ultrasonography and the TM group (n = 32) in which elevated tumor markers led to the diagnosis of a tumor that was undetected using ultrasonography. The reliability of ultrasonography was scored on a 4-point scale based on three items (coarseness of liver parenchyma, patient obesity and liver atrophy). Additionally, patient survival was assessed using the Kaplan-Meier method and log-rank test.

Results: The median tumor size was 20 mm (interquartile range, 15-24). The reliability of ultrasonography was evaluated as good in 208 (66.5%), satisfactory in 80 (8.0%), poor in 21 (6.7%) and unsatisfactory in four (1.2%) patients. The proportion of patients in the TM group increased significantly according to the score, from 7.2% to 25.0% (P = 0.01). The survival rates of patients at 3 and 5 years were 83.7% and 57.2% in the US group, and 79.3% and 59.4% in the TM group, respectively (P = 0.98).

Conclusion: Tumor markers may play a diagnostic role in patients with unreliable ultrasonography results. The survival of patients diagnosed by elevated tumor markers was not significantly different from those diagnosed by ultrasonography.
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http://dx.doi.org/10.1111/hepr.12365DOI Listing
April 2015

Sublethal heat treatment promotes epithelial-mesenchymal transition and enhances the malignant potential of hepatocellular carcinoma.

Hepatology 2013 Nov 19;58(5):1667-80. Epub 2013 Sep 19.

Division of Gastroenterology and Liver Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.

Unlabelled: Radiofrequency ablation (RFA) is a potentially curative therapy for hepatocellular carcinoma (HCC). However, incomplete RFA can induce accelerated invasive growth at the periphery. The mechanisms underlying the RFA-induced tumor promotion remain largely unexplored. Three human HCC cell lines were exposed to 45°C-55°C for 10 minutes, simulating the marginal zone of RFA treatment. At 5-12 days post-treatment cell proliferation, parameters of epithelial-mesenchymal transition (EMT), and activation of mitogen-activated protein kinases were analyzed. Livers from patients with viral hepatitis without and with HCC (n = 114) were examined to confirm the relevance of altered kinase patterns. In vivo tumorigenic potential of heat-treated versus untreated HCC cells was studied in nude mice. Heating to 55°C killed all HCC cells, whereas 65%-85% of cells survived 48°C-50°C, developing spindle-like morphology and expressing CD133, cytokeratin (CK)7, CK19, procollagen-α1(I), and Snail at day 5 after heat exposure, which returned to baseline at day 12. Heat-exposed HCC cells showed enhanced proliferation and prominent activation of p46-Shc (Src homology and collagen) and downstream extracellular signal-related kinase (Erk)1/2. In patients, Shc expression correlated with malignant potential and overall survival. Blocking Erk1/2 reduced proliferation and EMT-like changes of heat-treated HCC cells. Implantation of heat-exposed HEPG2 cells into nude mice induced significantly larger, more aggressive tumors than untreated cells.

Conclusions: Sublethal heat treatment skews HCC cells toward EMT and transforms them to a progenitor-like, highly proliferative cellular phenotype in vitro and in vivo, which is driven significantly by p46Shc-Erk1/2. Suboptimal RFA accelerates HCC growth and spread by transiently inducing an EMT-like, more aggressive cellular phenotype.
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http://dx.doi.org/10.1002/hep.26526DOI Listing
November 2013

Frequency, risk factors and survival associated with an intrasubsegmental recurrence after radiofrequency ablation for hepatocellular carcinoma.

PLoS One 2013 12;8(4):e59040. Epub 2013 Apr 12.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background: In the treatment of hepatocellular carcinoma (HCC), hepatic resection has the advantage over radiofrequency ablation (RFA) in terms of systematic removal of a hepatic segment.

Methods: We enrolled 303 consecutive patients of a single naïve HCC that had been treated by RFA at The University of Tokyo Hospital from 1999 to 2004. Recurrence was categorized as either intra- or extra-subsegmental as according to the Couinaud's segment of the original nodule. To assess the relationship between the subsegments of the original and recurrent nodules, we calculated the kappa coefficient. We assessed the risk factors for intra- and extra-subsegmental recurrence independently using univariate and multivariate Cox proportional hazard regression. We also assessed the impact of the mode of recurrence on the survival outcome.

Results: During the follow-up period, 201 patients in our cohort showed tumor recurrence distributed in a total of 340 subsegments. Recurrence was categorized as exclusively intra-subsegmental, exclusively extra-subsegmental, and simultaneously intra- and extra-subsegmental in 40 (20%), 110 (55%), and 51 (25%) patients, respectively. The kappa coefficient was measured at 0.135 (95% CI, 0.079-0.190; P<0.001). Multivariate analysis revealed that of the tumor size, AFP value and platelet count were all risk factors for both intra- and extra-subsegmental recurrence. Of the patients in whom recurrent HCC was found to be exclusively intra-subsegmental, extra-subsegmental, and simultaneously intra- and extra-subsegmental, 37 (92.5%), 99 (90.8%) and 42 (82.3%), respectively, were treated using RFA. The survival outcomes after recurrence were similar between patients with an exclusively intra- or extra-subsegmental recurrence.

Conclusions: The effectiveness of systematic subsegmentectomy may be limited in the patients with both HCC and chronic liver disease who frequently undergo multi-focal tumor recurrence.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0059040PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3625228PMC
October 2013

Perihepatic lymph node enlargement is a negative predictor for sustained responses to pegylated interferon-α and ribavirin therapy for Japanese patients infected with hepatitis C virus genotype 1.

Hepatol Res 2013 Oct 29;43(10):1005-12. Epub 2013 Jan 29.

Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan.

Aim: Although perihepatic lymph node enlargement (PLNE) is reportedly associated with the negative outcome of interferon therapy for chronic hepatitis C, there were limitations in that the results were obtained in patients with various genotypes, viral loads and treatment regimens. We aimed to precisely clarify the significance of PLNE in interferon therapy for chronic hepatitis C.

Methods: Between December 2004 and June 2005, 112 patients with hepatitis C virus (HCV) genotype 1 and HCV RNA of more than 100 KIU/mL were enrolled, who underwent pegylated interferon-α plus ribavirin therapy thereafter. PLNE was defined as a perihepatic lymph node of more than 1 cm in the longest axis by ultrasonography.

Results: The sustained virological response (SVR) rate was lower in patients with PLNE (4/22, 18.2%) than in those without (37/90, 41.1%; P = 0.045) and viral load decline was smaller in patients with PLNE than in those without (P = 0.028). The proportion of PLNE positive patients was the smallest in the SVR group (P = 0.033) among the patient groups divided by the treatment outcome. PLNE was retained as a negative predictor for SVR by multivariate logistic regression analysis (P = 0.012). Furthermore, PLNE was not significantly associated with the mutations at HCV core protein and at interferon sensitivity-determining region, or interleukin-28B polymorphism in 45 patients with HCV genotype 1, enrolled between December 2011 and March 2012.

Conclusion: PLNE is a negative predictor for SVR in patients with HCV genotype 1 and HCV RNA of more than 100 KIU/mL treated with pegylated interferon-α plus ribavirin, independent of other known predictors for SVR.
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http://dx.doi.org/10.1111/hepr.12061DOI Listing
October 2013

Scar formation and lack of regeneration in adult and neonatal liver after stromal injury.

Wound Repair Regen 2013 Jan-Feb;21(1):122-30. Epub 2012 Dec 10.

Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232-4761, USA.

Known as a uniquely regenerative tissue, the liver shows a remarkable capacity to heal without scarring after many types of acute injury. In contrast, during chronic liver disease, the liver responds with fibrosis, which can progress to cirrhosis and ultimately liver failure. The cause of this shift from a nonfibrotic to a fibrotic response is unknown. We hypothesized that stromal injury is a key event that prevents restoration of normal liver architecture. To test this, we developed a model of stromal injury using a surgical incision through the normal liver in adult and neonatal mice. This injury produces minimal cell death but locally complete stromal (extracellular matrix) disruption. The adult liver responds with inflammation and stellate cell activation, culminating in fibrosis characterized by collagen deposition. This sequence of events is remarkably similar to the fibrotic response leading to cirrhosis. Studies in neonates reveal a similar fibrotic response to a stromal injury. These findings suggest that extracellular matrix disruption leads not to regeneration but rather to scar, similar to other mammalian organs. These findings may shed light on the pathogenesis of chronic liver disease, and suggest therapeutic strategies.
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http://dx.doi.org/10.1111/j.1524-475X.2012.00868.xDOI Listing
July 2013

New serum markers of hepatocellular carcinoma.

Semin Oncol 2012 Aug;39(4):434-9

Department of Surgery, Division of Liver Transplantation, Vanderbilt University, Nashville, TN, USA.

Hepatocellular carcinoma (HCC), one of the most common cancers worldwide, usually develops in a liver already suffering from chronic damages, often cirrhosis. There has been marked progress in the treatment of HCC. However, effective treatments are limited to patients with less advanced HCC. The detection of HCC at an early stage is still a prerequisite for improved prognosis. To address this problem, a variety of screening modalities are used, including measurement of alpha-fetoprotein (AFP) and ultrasonography (US) at regular intervals in high-risk populations. Unfortunately, poor sensitivity and specificity of AFP and the operator-dependency of US limit the value of either test to diagnose early-stage lesions. Other tests, including Lens culinaris agglutinin-reactive AFP and des-gamma carboxyprothrombin (DCP), are currently being evaluated and may be superior to current tests. Recent developments in gene-expressing microarrays and proteomics promise even more potential diagnostic options. The strict application of the Early Detection Research Network methodology will aid in the assessment of their diagnostic utility, and provide an objective basis for the assessment of their clinical utility.
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http://dx.doi.org/10.1053/j.seminoncol.2012.05.009DOI Listing
August 2012
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