Toshio Fukusato

Teikyo University, Edo, Tōkyō, Japan

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Publications (113)252.7 Total impact

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    ABSTRACT: Hepatocellular nodules caused by congenital extrahepatic portosystemic shunts (CEPS) occur as a result of abnormal portal blood flow, and are mostly cases of benign focal nodular hyperplasia (FNH). However, hepatocellular adenomas (HCA) and hepatocellular carcinomas have been documented in the CEPS patients. HCA can now be immunohistochemically diagnosed; therefore, the concept of hepatocellular nodules resulting from CEPS should be revisited. In this study, we performed a retrospective immunohistochemical investigation of hepatocellular nodules from livers isolated from the CEPS patients undergoing living donor liver transplantation (LDLT). Hepatocellular nodules from livers of five patients with CEPS who underwent LDLT between June 2004 and October 2012 at our institution were immunohistochemically investigated. HCA were classified into four subtypes (HNF1α-inactivated HCA, H-HCA; inflammatory HCA, I-HCA; β-catenin-activated HCA, b-HCA; unclassified HCA, u-HCA). Sixteen hepatocellular nodules were collected from livers of five patients with CEPS who underwent LDLT. Ten hepatocellular nodules were categorized as FNH (62.5%), five were categorized as b-HCA (31.3%), and one was categorized as H-HCA (6.2%). Some of the hepatocellular nodules resulting from CEPS were indicative of HCAs, especially the b-HCA subtype which has a potential of malignant transformation. Surgical or interventional treatments might have to be performed when hepatocellular nodules appear in the CEPS patients. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Hepato-Biliary-Pancreatic Sciences 07/2015; DOI:10.1002/jhbp.277 · 2.31 Impact Factor
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    ABSTRACT: Purpose To use inductively coupled plasma mass spectroscopy (ICP-MS) to evaluate gadolinium accumulation in brain tissues, including the dentate nucleus (DN) and globus pallidus (GP), in subjects who received a gadolinium-based contrast agent (GBCA). Materials and Methods Institutional review board approval was obtained for this study. Written informed consent for postmortem investigation was obtained either from the subject prior to his or her death or afterward from the subject's relatives. Brain tissues obtained at autopsy in five subjects who received a linear GBCA (GBCA group) and five subjects with no history of GBCA administration (non-GBCA group) were examined with ICP-MS. Formalin-fixed DN tissue, the inner segment of the GP, cerebellar white matter, the frontal lobe cortex, and frontal lobe white matter were obtained, and their gadolinium concentrations were measured. None of the subjects had received a diagnosis of severely compromised renal function (estimated glomerular filtration rate <45 mL/min/1.73 m(2)) or acute renal failure. Fisher permutation test was used to compare gadolinium concentrations between the two groups and among brain regions. Results Gadolinium was detected in all specimens in the GBCA agent group (mean, 0.25 µg per gram of brain tissue ± 0.44 [standard deviation]), with significantly higher concentrations in each region (P = .004 vs the non-GBCA group for all regions). In the GBCA group, the DN and GP showed significantly higher gadolinium concentrations (mean, 0.44 µg/g ± 0.63) than other regions (0.12 µg/g ± 0.16) (P = .029). Conclusion Even in subjects without severe renal dysfunction, GBCA administration causes gadolinium accumulation in the brain, especially in the DN and GP. (©) RSNA, 2015.
    Radiology 05/2015; DOI:10.1148/radiol.2015142690 · 6.21 Impact Factor
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    ABSTRACT: Nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) is considered to be a hepatic manifestation of metabolic syndrome, and its incidence is rapidly increasing worldwide. It is currently the most common chronic liver disease. NASH can progress to liver cirrhosis and hepatocellular carcinoma, and may result in liver-related death. Currently, the principal treatment for NAFLD/NASH is lifestyle modification by diet and exercise. However, pharmacological therapy is indispensable because obese patients with NAFLD often have difficulty maintaining improved lifestyles. The pathogenesis of NAFLD/NASH has not been completely elucidated. However, insulin resistance, inflammatory cytokines, and oxidative stress are thought to be important in the development and/or progression of the disease. Currently, insulin sensitizers (thiazolidinediones) and antioxidants (vitamin E) seem to be the most promising therapeutic agents for NAFLD/NASH, and lipid-lowering drugs, pentoxifylline, angiotensin receptor blockers, and n-3 polyunsaturated fatty acids also have promise. However, there is a lack of consensus regarding the most effective and appropriate pharmacotherapy for NAFLD/NASH. Animal experiments suggest that herbal medicines and natural products may be promising therapeutic agents for NAFLD/NASH, but their efficacy and safety are yet to be investigated in human studies. In this paper, we review the existing and potential pharmacological therapies for NAFLD/NASH.
    04/2015; 21(13):3777-85. DOI:10.3748/wjg.v21.i13.3777
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    ABSTRACT: Some follow-up studies of large regenerative nodules (LRNs) and dysplastic nodules (DNs) were reported previously. However, the pre-malignant potentiality of LRNs has remained controversial up to now. No LRNs showed malignant transformation in our previous study. We aimed to evaluate the pre-malignant potentiality of LRNs and DNs with a greater number of cases and longer follow-up periods. From 1982 to 2005, 1,500 consecutive nodular lesions up to 2 cm in diameter were subjected to US guided thin-needle biopsy in cirrhotic patients at Chiba University Hospital. Of these lesions, 68 LRNs in 60 cases and 20 DNs in 22 cases were followed up for more than 6 months without any anti-cancer therapy. The last US examination was in 2010. The total study period was 28 years. We analyzed the histological findings and the clinical data of all cases retrospectively. The outcome of the lesions was examined. The mean follow-up period was 38.9 (16-119) months in LRNs and 31.9 (6-101 months) in DNs. Rate of nodule enlargement was higher in DNs (8/24 nodules, 33 %) than LRNs (11/68 nodules, 16 %), (p = 0.0743, not significant). Rate of malignant transformation was also higher in DNs (10/24 nodules, 42 %) than LRNs (9/68 nodules, 13 %), (p = 0.0040, significant). The rate of disappearance in images was similar between LRNs and DNs. We should recognize LRN as low risk pre-malignant lesions whereas DNs as high risk lesions.
    Hepatology International 03/2015; 9(2). DOI:10.1007/s12072-015-9620-6 · 2.47 Impact Factor
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    ABSTRACT: Hepatocellular adenoma (HCA) is a rare primary benign tumor of the liver, which occurs predominantly in young and middle-aged women. Recently, the subclassification of HCA was proposed by the Bordeaux group. Subsequently, characteristic radiological and clinical features have been revealed in each HCA subtype. According to the previous literature, diffuse intratumoral fat deposition is a very common finding in hepatocyte nuclear factor 1α-negative HCA, but this finding has been reported in β-catenin-positive HCA in the literature for only one case. In this case report, we report the second case of β-catenin-positive HCA with MR imaging sign of diffuse intratumoral fat deposition, confirmed immunohistologically on the basis of a surgical specimen. In addition, our case showed hypovascularity and isointensity on the hepatobiliary phase which have been reported as characteristic findings in β-catenin-positive HCA. Diffuse intratumoral fat deposition can be observed in β-catenin-positive HCA, which has a greater probability of malignant transformation than other types of HCA.
    Abdominal Imaging 01/2015; DOI:10.1007/s00261-014-0342-3 · 1.73 Impact Factor
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    ABSTRACT: Nonalcoholic steatohepatitis (NASH) is a liver disease associated with metabolic syndrome. The aim of this work was to examine whether eucalyptus (Eucalyptus globulus) leaf extract (ELE) and banaba (Lagerstroemia speciosa L.) leaf extract (BLE) inhibited NASH induced by excessive ingestion of fructose in rats. Wistar rats were divided into four groups according to four distinct diets: starch diet (ST), high-fructose/high-glucose diet (FG), FG diet supplemented with ELE, or FG diet supplemented with BLE. All rats were killed after 5 weeks of treatment. Serum alanine aminotransferase and total cholesterol levels were significantly lower in the BLE group than in the FG group. Liver histopathology, including steatosis, lipogranulomas, and perisinusoidal fibrosis, was significantly attenuated in the ELE and BLE groups compared with the FG group. Levels of 2-thiobarbituric acid reactive substances (TBARS), which reflect oxidative injury to the liver, were significantly suppressed by ELE and BLE. Western blotting analysis indicated that interleukin-6 expression levels were significantly lower in the ELE and BLE groups than in the FG group. These results suggest that ELE and BLE reduced lipogenesis, oxidative stress, and inflammatory cytokine expression and thus inhibited NASH induced by excessive ingestion of fructose in rats.
    01/2015; 2015:1-9. DOI:10.1155/2015/296207
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    ABSTRACT: To investigate the significance of downregulation of liver fatty acid-binding protein (L-FABP) expression in hepatocellular carcinoma (HCC). Tissue microarrays of 146 cases of HCC were used to perform immunohistochemical staining for L-FABP. For each L-FABP-negative HCC, further immunohistochemical staining was performed using a representative whole-tissue section to confirm the downregulation of L-FABP expression and to assess the intratumoral heterogeneity of the staining pattern. Clinical data were retrieved from the clinical files, and histological slides were reviewed. Immunohistochemical staining for cytokeratin (CK) 7, CK 19, β-catenin, glutamine synthetase (GS), and serum amyloid A were also performed on the tissue microarrays. Clinicopathological features of the L-FABP-negative and L-FABP-positive HCC cases were compared. Furthermore, L-FABP and GS gene expression in HCC and cholangiocarcinoma cell lines were analyzed using real-time reverse transcription polymerase chain reaction. Mutation analysis of HNF1A [encoding hepatocyte nuclear factor 1 (HNF1)α] was performed for L-FABP-negative HCC cases. Sixteen (10.9%) of the 146 cases of HCC stained negative for L-FABP. When we examined the correlation between the downregulation pattern of L-FABP and tumor size, most cases of smaller HCC (≤ 2 cm in diameter) exhibited focal downregulation, while most cases of larger HCC (> 2 cm in diameter) exhibited diffuse downregulation. The correlation was statistically significant (P = 0.036). When the HCC was smaller, the L-FABP-negative area often corresponded to a "nodule-in-nodule" appearance. Among the small HCC cases, tumor differentiation was significantly lower, and the frequency of intratumoral inflammation was significantly lower in L-FABP-negative cases than in L-FABP-positive cases (P = 0.032 and P = 0.009, respectively). The frequency of positivity for β-catenin and GS staining was significantly higher in L-FABP-negative cases of small HCC than in L-FABP-positive cases of small HCC (P = 0.009 and P = 0.000, respectively). Among six HCC cell lines examined, four showed higher expression of L-FABP, and the remaining two cell lines showed lower or no expression of L-FABP. Two of the 16 L-FABP-negative HCC cases possessed a mutation in exon 4 of HNF1A. In smaller HCC, L-FABP downregulation probably occurs because of phenotypic changes during tumor progression. Moreover, this downregulation correlated with tumor differentiation and intratumoral inflammation.
    World Journal of Gastroenterology 12/2014; 20(46):17541-51. DOI:10.3748/wjg.v20.i46.17541 · 2.43 Impact Factor
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    ABSTRACT: Recent studies have indicated that hepatocellular adenoma (HCA) is a heterogenous group of benign tumors with various genetic and clinicopathological characteristics. We delineated the clinicopathological characteristics of HCA subtypes and evaluated the expression of transporter protein OATP1B3 in HCAs. HCAs in 34 Japanese patients were investigated immunohistochemically and classified into four subtypes (HNF1α-inactivated type, H-HCA; β-catenin-activated type, b-HCA; inflammatory type, I-HCA; unclassified type, u-HCA). Immunostaining of OATP1B3 protein in HCA tissue sections was performed to determine the association between OATP1B3 expression and HCA subtypes. HCA was categorized into the following four subtypes and two combined subtypes: 10 H-HCAs (29%), 10 I-HCAs (29%), 7 b-HCAs (21%), 2 b-HCA/H-HCA (6%), 2 b-HCA/I-HCA (6%), and 3 u-HCAs (9%). The male-to-female ratio was 18:16. Oral contraceptive use was rare but 7 HCAs were found in patients with glycogen storage disease, congenital absence of the portal vein, and idiopathic portal hypertension. OATP1B3 expression was decreased in 24 HCAs but was preserved or increased in 10 HCAs. All nine HCAs with nuclear staining for β-catenin showed preserved or enhanced OATP1B3 expression, indicating a significant association between nuclear β-catenin accumulation and OATP1B3 expression in HCAs. HCA subtype classification was validated in 91% of our Japanese subjects although their clinical backgrounds including rare contraceptive use were different from European subjects. A close association between preserved or enhanced OATP1B3 expression and b-HCA subtype indicated important modalities for clinical decisions in the treatment and follow-up of patients with HCAs. This article is protected by copyright. All rights reserved.
    Hepatology Research 11/2014; DOI:10.1111/hepr.12453 · 2.22 Impact Factor
  • Yoshihisa Takahashi, Toshio Fukusato
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    ABSTRACT: Nonalcoholic fatty liver disease (NAFLD), a hepatic manifestation of metabolic syndrome, is the most common chronic liver disease, and the prevalence is rapidly increasing worldwide. Nonalcoholic steatohepatitis (NASH), the severe form of NAFLD, can progress to liver cirrhosis and hepatocellular carcinoma (HCC). Although noninvasive clinical scores and image-based diagnosis for NAFLD have improved, histopathological evaluation of biopsy specimens remains the gold standard for diagnosing NAFLD/NASH. Steatosis, lobular inflammation, and hepatocellular ballooning are all necessary components for the diagnosis of NASH; fibrosis is also typically observed. Other histopathological abnormalities commonly observed in NASH include hepatocellular glycogenated nuclei, lipogranulomas, and acidophil bodies. The characteristics of pediatric NAFLD/NASH differ from adult NAFLD/NASH. Specifically, steatosis and portal inflammation are more severe in pediatric NAFLD, while intralobular inflammation and perisinusoidal fibrosis are milder. Although interobserver agreement for evaluating the extent of steatosis and fibrosis is high, agreement is low for intralobular and portal inflammation. A recently reported histological variant of HCC, steatohepatitic HCC (SH-HCC), shows features that resemble non-neoplastic steatohepatitis, and is thought to be strongly associated with underlying NASH. In this report, we review the histopathological features of NAFLD/NASH.
    World Journal of Gastroenterology 11/2014; 20(42):15539-15548. DOI:10.3748/wjg.v20.i42.15539 · 2.43 Impact Factor
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    ABSTRACT: AimsWe characterized serum amyloid A (SAA)-positive hepatocellular neoplasm/nodules arising in alcoholic cirrhosis, which is detected as a hypervascular hepatocellular nodules resembling hepatocellular carcinoma on imaging.Methods and ResultsFifty-three hepatocellular nodules were examined using immunostaining for SAA, glutamine synthetase and glypican-3 in 23 patients (4 women and 19 men) with alcoholic cirrhosis. Sixteen nodules were examined on the magnetic resonance imaging with EOB enhancement (EOB-MRI). Somatic mutations on IL6ST, GNAS and STAT3 were examined in 19 nodules. Thirty-six nodules in 18 patients were diagnosed as SAA-positive hepatocellular neoplasm/nodules and the remaining seventeen nodules in 8 patients were SAA-negative focal nodular hyperplasia (FNH)-like nodules. SAA-positive hepatocellular neoplasms/nodules showed significantly more extensive sinusoidal dilatation, inflammatory reaction, abnormal thick arteries and cellular atypia than FNH-like nodules (p<0.05). Eight SAA-positive hepatocellular neoplasms/nodules (67%) showed slight hypointensity in the hepatobiliary phase on the EOB-MRI, whereas all 4 FNH-like nodules showed iso-intensity (p<0.05). STAT3 mutations were detected in 2 of 17 SAA-positive hepatocellular neoplasms/nodules.Conclusions This study disclosed that about two thirds of hypervascular hepatocellular nodules arising in alcoholic cirrhosis were SAA-positive hepatocellular neoplasms/nodules which show different finings on the EOB-MRI. STAT3 mutations were detected in 11.8% of SAA-positive hepatocellular neoplasms/nodules, supporting neoplastic nature.This article is protected by copyright. All rights reserved.
    Histopathology 10/2014; DOI:10.1111/his.12588 · 3.30 Impact Factor
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    ABSTRACT: Few studies have investigated the effects of Japanese herbal medicines on nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). To the best of our knowledge, only one study has examined whether high-fat (HF) diet-fed db/db mice are appropriate animal models of NASH. We investigated the effects of four types of Japanese herbal medicines (shosaikoto (TJ-9), inchinkoto (TJ-135), juzentaihoto (TJ-48), and keishibukuryogan (TJ-25)) on hepatic lesions of HF diet-fed db/db mice. Db/db mice were divided into six groups: control diet (control); HF diet (HF); and HF diet supplemented with TJ-9, TJ-135, TJ-48, or TJ-25 (TJ-9, TJ-135, TJ-48, and TJ-25, respectively). Mice were killed after 6 weeks of treatment, and biochemical and pathological analyses were performed. Mice in the HF group consistently developed histopathological features consistent with definite NASH, and marked necroinflammation occurred. Serum alanine aminotransferase levels in the TJ-9, TJ-135, and TJ-48 groups were significantly improved compared with those in the HF group. With regard to liver histology, TJ-9 and TJ-48 significantly improved lobular inflammation, and TJ-135 significantly improved ballooning degeneration. We have shown that HF diet-fed db/db mice are animal models that correctly recapitulate the histopathology of human NASH and that TJ-9, TJ-135, and TJ-48 inhibit necroinflammatory activity in this model.
    Pathology International 10/2014; 64(10). DOI:10.1111/pin.12199 · 1.59 Impact Factor
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    ABSTRACT: Background Gastric cancer (GC) is a common cancer globally. miRNA-21 (miR-21) appears to be important in the tumourigenesis of almost all types of human cancer. However its precise localization in GC has not yet to be clarified. We thus examined miR-21 localization in GC and revealed its clinicopathological importance.Methods Tissue arrays of 469 GCs from 454 patients were examined for miR-21 using in situ hybridization (ISH). The positivity was evaluated separately in tumour cells and stromal cells. Conventional sections of 10 GCs were also stained. Eight cases were examined by quantitative RT-PCR (qRT-PCR).ResultsmiR-21 was highly expressed in tumour cells of 44% of cases and in cancer stroma of 51% of cases. miR-21 of tumour cells was not related to clinicopathological factors, whereas stromal miR-21 was related to many factors including tumour stage, size, and nodal metastasis. Stromal miR-21 gradually increased during tumour progression. ISH of whole sections showed stronger stromal positivity in invasive areas with desmoplastic reaction. Cancer stroma also showed higher miR-21 expression than tumour and non-tumourous tissue in the qRT-PCR study.Conclusion Stromal miR-21 is closely related to tumour progression in GC. Stromal miR-21 of tumours might be a target of treatment.This article is protected by copyright. All rights reserved.
    Histopathology 07/2014; DOI:10.1111/his.12491 · 3.30 Impact Factor
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    ABSTRACT: The aim of this study was to evaluate integrin expression and immunolocalization of the extracellular matrix proteins in cholangiolocellular carcinoma (CoCC). Tissue specimens of 23 CoCCs, 28 cholangiocarcinomas (CCCs), 42 hepatocellular carcinomas (HCCs), and 11 classical type combined hepatocellular-cholangiocarcinomas (CHCs) were immunostained for β6, β4 and α3 integrins, fibronectin and laminin. ITGB6, B4 and A3 mRNA levels in six HCC cell lines, five CCC cell lines and two CHC cell lines were quantified by quantitative reverse transcription-polymerase chain reaction. Little or no positivity for β6, β4 and α3 integrins was shown in 91%, 91% and 52% of CoCCs and 100%, 98% and 81% of HCCs, respectively, according to immunostaining, whereas intense positive staining for these integrins was demonstrated in 64%, 96% and 75% of CCCs, respectively. There was a close correlation between β4 and α3 integrin expression and intracytoplasmic laminin in CoCC, CCC and HCC, but not between β6 expression and its ligand, fibronectin. Integrin mRNA levels were increased in four of five CCC cell lines, but nearly undetectable in five of six HCC cell lines and one CHC cell line. Tubular differentiation of a CHC cell line cultured in collagen-gel matrix induced up-regulation of these integrins. Our results first indicated down-regulation of αvβ6, α6β4 and α3β1 integrins in CoCC, in contrast to its high expression in CCC, suggesting a diagnostic value of integrins in the differential diagnosis of CoCC and CCC, as well as a useful inducible marker of the intermediate features of CoCC.
    Hepatology Research 02/2014; DOI:10.1111/hepr.12312 · 2.22 Impact Factor
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    ABSTRACT: Although Japanese herbal medicines (JHMs) are widely used in Japan, only a few studies have investigated their effects on nonalcoholic steatohepatitis (NASH). In the present study, we examined the effect of 4 kinds of JHMs [sho-saiko-to (TJ-9), inchin-ko-to (TJ-135), juzen-taiho-to (TJ-48), and keishi-bukuryo-gan (TJ-25)] on a mouse model of NASH. Db/db mice were divided into 6 groups: control diet (control), methionine- and choline-deficient diet (MCD), and MCD diet supplemented with TJ-9, TJ-135, TJ-48, and TJ-25 (TJ-9, TJ-135, TJ-48, and TJ-25, respectively). All mice were sacrificed after 4 weeks of treatment, and biochemical, pathological, and molecular analyses were performed. Serum alanine aminotransferase levels and liver histology, including necroinflammation and fibrosis, were significantly alleviated in the TJ-9 and TJ-48 groups compared with the MCD group. The expression level of transforming growth factor (TGF)-β1 mRNA in the liver was significantly suppressed by TJ-48. Although the differences were not statistically significant, the expression levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 were lower, and those of peroxisome proliferators-activated receptor (PPAR)γ were higher in the TJ-9 and/or TJ-48 groups than in the MCD group. Similarly, even though the results were not statistically significant, malondialdehyde levels in liver tissues were lower in the TJ-9 and TJ-48 groups than in the MCD group. We showed that JHMs, especially TJ-9 and TJ-48, inhibited the necroinflammation and fibrosis in the liver of a mouse model of NASH, even though the mechanisms were not fully elucidated. Further studies are needed in the future to investigate the possibility of clinical application of these medicines in the treatment for NASH.
    PLoS ONE 01/2014; 9(1):e87279. DOI:10.1371/journal.pone.0087279 · 3.53 Impact Factor
  • Fukuo Kondo, Toshio Fukusato, Masatoshi Kudo
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    ABSTRACT: There are various types of benign hepatocellular nodular lesions, and their diagnostic criteria were formulated in detail. However, in 2010, the new World Health Organization (WHO) classification introduced immunohistochemical diagnostic criteria for hepatocellular adenoma (HCA) reflecting molecular pathological properties, and HCA was classified into 4 subtypes. These criteria were useful for its differential diagnosis from focal nodular hyperplasia (FNH). They were also useful for the diagnosis of HCA, its subtyping, and differentiation from FNH in Japan. However, the new WHO classification is based on principles that differ from those of conventional definitions of disease concepts and methods for the differential diagnosis. Therefore, it has caused disagreements in the diagnosis in some cases. Based on this background, we present a new perspective on the diagnosis of benign hepatocellular nodular lesions. © 2014 S. Karger AG, Basel.
    Oncology 01/2014; 87 Suppl 1(12):37-49. DOI:10.1159/000368144 · 2.61 Impact Factor
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    ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is a condition characterized by excessive fat accumulation in the liver of a patient without a history of alcohol abuse. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, may progress to liver cirrhosis and hepatocellular carcinoma. NAFLD/NASH is considered a hepatic manifestation of metabolic syndrome and is increasing globally with the increased prevalence of obesity. Animal models of NAFLD/NASH yield important information for elucidating the pathogenesis of NAFLD/NASH and for developing new treatments for the disease. An ideal animal model of NAFLD/NASH should correctly reflect both the histopathology and pathophysiology of human NAFLD/NASH. Animal models of NAFLD/NASH are classified into genetic models, nutritional models, and combination models of genetic and nutritional factors. In this chapter, we review representative animal models of NAFLD/NASH, referring to their advantages and disadvantages.
    Integrative Weight Management, 01/2014: pages 61-69; , ISBN: 978-1-4939-0547-8
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    ABSTRACT: Flat epithelial lesions of the biliary tract cannot be detected by the image analysis, and the diagnosis entirely depends on pathological examination. The biliary tract is often affected by inflammatory conditions, and the resultant changes of the biliary epithelium make it difficult to differentiate them from neoplasia. Thus, the pathological diagnosis of biliary flat epithelial lesions can be challenging. In the biliary tract, there are several forms of intraepithelial neoplasia of the flat type, and biliary intraepithelial neoplasia (BilIN) is known as one of such lesions that represent the multistep cholangiocarcinogenesis. In this article, the diagnostic criteria and the differential diagnosis of biliary flat epithelial lesions, particularly focusing on BilIN, were presented and discussed to provide help to advance clinical and research applications of the BilIN system.
    Journal of Gastroenterology 01/2014; DOI:10.1007/s00535-013-0810-5 · 4.02 Impact Factor
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    ABSTRACT: Great progress has been made in the diagnosis of focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA) in the last few years due to the use of molecular criteria. This has allowed us to identify a new type of hepatic nodule. In this case report, we present a male patient with a hepatic nodule associated with idiopathic portal hypertension (IPH) pathologically exhibiting not only the morphological features of FNH, such as ductular reactions, dilated sinusoids, major vascular abnormalities and an immunohistochemical "map-like" pattern of glutamine synthetase (GS), but also the immunohistological features of focal HCA, such as strong expression of serum amyloid A and C-reactive protein and weak expression of GS. As the final diagnosis, the nodule was identified as an FNH-like lesion with focal inflammatory hepatocellular adenoma.
    Hepatology Research 11/2013; 44(10). DOI:10.1111/hepr.12273 · 2.22 Impact Factor
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    ABSTRACT: The estrogen receptor (ER) is a key molecule for growth of breast cancers. It has been a successful target for treatment of breast cancers. Elucidation of ER expression mechanism is of importance for designing therapeutics for ER-positive breast cancers. However, the detailed mechanism of ER stability is still unclear. Here we report that histone acetyltransferase Hbo1 promotes destabilization of estrogen receptor α (ERα) in breast cancers through lysine 48-linked ubiquitination. The acetyltransferase activity of Hbo1 is linked to its activity for ERα ubiquitination. Depletion of Hbo1 and anti-estrogen treatment displayed a potent growth suppression of breast cancer cell line. Hbo1 modulated transcription by ERα. Mutually exclusive expression of Hbo1 and ERα was observed in roughly half of human breast tumors. Modulation of ER stability by Hbo1 in breast cancers may provide a novel therapeutic possibility. This article is protected by copyright. All rights reserved.
    Cancer Science 10/2013; DOI:10.1111/cas.12303 · 3.53 Impact Factor

Publication Stats

938 Citations
252.70 Total Impact Points

Institutions

  • 2007–2015
    • Teikyo University
      Edo, Tōkyō, Japan
  • 2004–2014
    • Teikyo University Hospital
      Edo, Tōkyō, Japan
  • 2011
    • The University of Tokyo
      • Department of Pathology
      Edo, Tōkyō, Japan
  • 1998–2003
    • Gunma University
      • • Department of Surgery
      • • Department of Pathology
      Maebashi, Gunma Prefecture, Japan