Michiie Sakamoto

Keio University, Edo, Tōkyō, Japan

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Publications (351)1418.5 Total impact

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    ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is a highly aggressive and often lethal malignant tumor. Several studies have shown that epithelial-mesenchymal transition (EMT) is frequently observed in clinical samples of PDA and is related to high metastatic rates and poor outcomes. To identify candidate molecules regulating EMT in PDA, we previously used cDNA microarray analysis and identified integrin β4 (ITGB4) as one of the genes upregulated in high-EMT xenografts derived from PDA patients. The aim of the current study was to clarify the clinicopathological and functional significance of ITGB4 overexpression in PDA. ITGB4 upregulation in high-EMT xenografts was confirmed by immunohistochemistry. Immunohistochemical analyses of 134 surgically resected PDA cases revealed intratumoral heterogeneity with respect to ITGB4 expression and showed that cancer cells undergoing EMT often display strong diffuse ITGB4 expression. High levels of ITGB4 expression were significantly correlated with the hallmarks of EMT (solitary cell infiltration, reduced E-cadherin expression, and increased vimentin expression), with high tumor grade, and with the presence of lymph node metastasis, and showed an independent prognostic effect. Immunocytochemical analyses of PDA cell lines revealed that localization of ITGB4 changed from regions of cell-cell contact to diffuse cytoplasm and cell edges with occasional localization in filopodia during EMT. Knockdown of ITGB4 reduced the migratory and invasive ability of PDA cells. Overexpression of ITGB4 promoted cell scattering and cell motility in combination with downregulation of E-cadherin and upregulation of vimentin expression. In conclusion, we elucidated the prognostic and clinicopathological significance of ITGB4 overexpression in PDA and also the potential role for ITGB4 in the regulation of cancer invasion and EMT.Laboratory Investigation advance online publication, 19 January 2015; doi:10.1038/labinvest.2014.166.
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    ABSTRACT: High-mobility group box 1 (HMGB1) has recently been identified as an important mediator of various kinds of acute and chronic inflammation. The protein encoded by the box-A domain of the HMGB1 gene is known to act as a competitive inhibitor of HMGB1. In this study, we investigated whether box-A gene transfer results in box-A protein production in rats and assessed therapeutic efficacy in vivo using an acute liver failure (ALF) model. Three types of adenovirus vectors were constructed-a wild type and two mutants-and a mutant vector was then selected based on the secretion from HeLa cells. The secreted protein was subjected to a tumor necrosis factor (TNF) production inhibition test in vitro. The vector was injected via the portal vein in healthy Wistar rats to confirm box-A protein production in the liver. The vector was then injected via the portal vein in rats with ALF. Western blot analysis showed enhanced expression of box-A protein in HeLa cells transfected with one of the mutant vectors. The culture supernatant from HeLa cells transfected with the vector inhibited TNF-α production from macrophages. Expression of box-A protein was confirmed in the transfected liver at 72 h after transfection. Transfected rats showed decreased hepatic enzymes, plasma HMGB1, and hepatic TNF-α messenger RNA levels, and histologic findings and survival were significantly improved. HMGB1 box-A gene transfer results in box-A protein production in the liver and appears to have a beneficial effect on ALF in rats. Copyright © 2014 Elsevier Inc. All rights reserved.
    Journal of Surgical Research 11/2014; · 2.12 Impact Factor
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    ABSTRACT: Background & Aims In the current era of emerging molecular targeted drugs, it is necessary to identify before treatment the specific subclass to which a tumour belongs. Gadoxetic acid is a liver-specific contrast agent that is preferentially taken up by hepatocytes. Therefore, gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) should provide precise molecular information about hepatocellular carcinomas (HCCs). The aim of this study was to investigate the transporters of gadoxetic acid in HCC comprehensively and to analyse the molecular regulatory mechanism of such transporters. Methods Expression levels of transporters, transcriptional factors and Wnt target genes in clinical samples were examined by quantitative real-time reverse transcription polymerase chain reaction and immunohistochemistry. LiCl treatment of the HCC cell line KYN-2 was conducted in vitro to assess the effects of Wnt signalling activity. Results Comprehensive analyses of transporter mRNAs and protein expressions revealed that the organic anion transporting polypeptide 1B3 (OATP1B3) had the strongest correlation with tumour enhancement in hepatobiliary-phase images of EOB-MRI. Association analysis with OATP1B3 expression revealed significant correlation with the expression of Wnt/β-catenin target genes. Further, LiCl treatment induced OATP1B3 mRNA expression in KYN-2 cells, indicating a strong association between OATP1B3 expression and Wnt/β-catenin signalling. The sensitivity and specificity to predict Wnt/β-catenin-activated HCC using tumour enhancement in EOB-MRI were 78.9% and 81.7%, respectively. Conclusions OATP1B3 was confirmed as the most important transporter mediating HCC enhancement in EOB-MRI. OATP1B3 expression showed a strong association with the expression of Wnt/β-catenin target genes, therefore, OATP1B3-upregulated HCC likely represents a specific subclass of Wnt/β-catenin-activated HCC.
    Journal of Hepatology. 11/2014; 61(5):1080–1087.
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    ABSTRACT: We have been developing a prototype system for the automatic detection of hepatocellular carcinoma (HCC) from whole slide images (WSIs) of liver biopsy based on image analysis techniques. In this paper, we present two color-related topics of this system: color correction and the calculation of color-related features of cytoplasm. A WSI-basis color correction method was implemented for the prototype system. We tested the color correction using more than 300 WISs, and it was confirmed that the color correction works well and stably. In addition, it was found that the success rate of nuclei detection significantly increaseed due to color correction. As for color-related features, we propose a method to calculate the representative color of cytoplasm and the clearness of cytoplasm. It was found that there was slight difference between the distributions of the representative colors of HCC and non-cancer tissues. In addition, there was slight correlation between the clearness of cytoplasm and nuclei density, which implies a promising role of the clearness index in a nuclei-based HCC detection.
    Color and Imaging Conference. 11/2014;
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    ABSTRACT: Accurately evaluating liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD) is important for identifying those who may develop complications. The aims of this study were (1) to measure serum Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA(+)-M2BP) using the glycan sugar chain-based immunoassay and (2) to compare the results with clinical assessments of fibrosis.
    Journal of Gastroenterology 10/2014; · 4.02 Impact Factor
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    ABSTRACT: We recently established a high-speed, label-free, spectral imaging method based on stimulated Raman scattering (SRS). This method enables examination of cellular features within relatively short periods, thus enabling new imaging applications in pathology. Previously, we reported on label-free visualization of mouse tissue using SRS spectral microscopy combined with multivariate image analysis, but the feasibility of applying this approach to diseased tissues with diverse morphology and irregular chemical species has not been examined. We, therefore, assessed acetaminophen-induced liver injury to evaluate the potential use of Raman spectral microscopy for visualizing histopathologic specimens. Acetaminophen-overdosed mouse liver was prepared and the pathologic changes including centrilobular necrosis were confirmed. Multi-colored images were reconstructed through principal component analysis (PCA) of a multi-band SRS dataset, which provided rich information compared with a monochrome single-band SRS dataset. A wide view of the multi-colored principal component (PC) images showed the distribution of cellular constituents, which was similar to that observed by fat staining. In addition, different types of cells in liver parenchyma were also demonstrated. In conclusion, the combination of SRS spectral microscopy and PCA has the potential to reveal both the morphological and chemical features of specimens and therefore has potential utility in diagnostic pathology.
    Pathology International 10/2014; · 1.59 Impact Factor
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    ABSTRACT: To compare the prognostic factors and outcomes after hepatic resection among patients with hepatitis B virus (HBV)-positive, hepatitis C virus (HCV)-positive, and negative for hepatitis B surface antigen and hepatitis C antibody, so-called "NBNC"-hepatocellular carcinoma (HCC) using the data from a nationwide survey.
    Annals of Surgery 07/2014; · 7.19 Impact Factor
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    ABSTRACT: In the current era of emerging molecular targeted drugs, it is necessary to identify before treatment the specific subclass to which a tumor belongs. Gadoxetic acid is a liver-specific contrast agent that is preferentially taken up by hepatocytes. Therefore, gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) should provide precise molecular information about hepatocellular carcinomas (HCCs). The aim of this study was to investigate the transporters of gadoxetic acid in HCC comprehensively and to analyze the molecular regulatory mechanism of such transporters.
    Journal of Hepatology 06/2014; · 10.40 Impact Factor
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    ABSTRACT: Background & Aims Although liver fibrosis is an important predictor of outcomes for biliary atresia (BA), postsurgical native liver histology has not been well reported. Here, we retrospectively evaluated postsurgical native liver histology, and developed and assessed a novel scoring system—the BA liver fibrosis (BALF) score for noninvasively predicting liver fibrosis grades. Methods We identified 259 native liver specimens from 91 BA patients. Of these, 180 specimens, obtained from 62 patients aged ⩾1 year at examination, were used to develop the BALF scoring system. The BALF score equation was determined according to the prediction of histological fibrosis grades by multivariate ordered logistic regression analysis. The diagnostic powers of the BALF score and several noninvasive markers were assessed by area under the receiver operating characteristic curve (AUROC) analyses. Results Natural logarithms of the serum total bilirubin, γ-glutamyltransferase, and albumin levels, and age were selected as significant independent variables for the BALF score equation. The BALF score had a good diagnostic power (AUROCs = 0.86–0.94, P < 0.001) and good diagnostic accuracy (79.4–93.3%) for each fibrosis grade. The BALF score revealed a strong correlation with fibrosis grade (r = 0.77, P < 0.001), and was the preferable noninvasive marker for diagnosing fibrosis grades ⩾F2. In a serial liver histology subgroup analysis, 7/15 patients exhibited liver fibrosis improvement with BALF scores being equivalent to histological fibrosis grades of F0–1. Conclusion In postsurgical BA patients aged ⩾1 year, the BALF score is a potential noninvasive marker of native liver fibrosis.
    Journal of Hepatology 06/2014; · 9.86 Impact Factor
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    ABSTRACT: Bone remodeling is maintained by the delicate balance between osteoblasts (OBs) and osteoclasts (OCs). However, the role of CD26 in regulating bone remodeling has not yet been characterized. We herein show that CD26 is preferentially expressed on normal human OCs and is intensely expressed on activated human OCs in osteolytic bone alterations. Macrophage-colony stimulating factor (M-CSF) and soluble receptor activator of NF-κB ligand (sRANKL) induced human OC differentiation, in association with CD26 expression on monocyte-macrophage lineage cells. CD26 expression was accompanied by increased phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), which is crucial for early human OC differentiation. The humanized anti-CD26 monoclonal antibody, huCD26mAb, impaired the formation and function of tartrate-resistant acid phosphatase (TRAP)/CD26 positive multi-nucleated (nuclei > 3) OCs with maturation in the manner of dose-dependency. It was revealed that huCD26mAb inhibits early OC differentiation via the inactivation of MKK3/6, p38 MAPK and subsequent dephosphorylation of microphthalmia-associated transcription factor (mi/Mitf). These inhibitions occur immediately after RANKL binds to RANK on the human OC precursor cells, and were demonstrated using the OC functional assays. huCD26mAb subsequently impaired OC maturation and bone resorption by suppressing the expression of TRAP and OC fusion proteins. In addition, p38 MAPK inhibitor also strongly inhibited OC formation and function. Our results suggest that the blockade of CD26 signaling impairs the development of human functional OCs by inhibiting p38 MAPK-mi/Mitf phosphorylation pathway and that targeting human OCs with huCD26mAb may have therapeutic potential for the treatment of osteolytic lesions following metastasis to alleviate bone destruction and reduce total skeletal-related events (SREs). © 2014 American Society for Bone and Mineral Research.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 05/2014; · 6.04 Impact Factor
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    ABSTRACT: In pancreatic ductal adenocarcinoma (PDAC), features of epithelial-mesenchymal transition (EMT) are often seen in tumor tissue, and such features correlate with poor prognosis. Solitary infiltration of tumor cells represents a morphological phenotype of EMT, and we previously reported that a high degree of solitary cell infiltration correlates with EMT-like features, including reduced E-cadherin and elevated vimentin levels. Using solitary cell infiltration to evaluate the degree of EMT, gene-expression profiling of 12 PDAC xenografts was performed, and SMAD3 was identified as an EMT-related gene. Immunohistochemistry using clinical specimens (n=113) showed that SMAD3 accumulated in the nuclei of tumor cells, but was not detected in most epithelial cells in the pancreatic duct. Moreover, SMAD3 upregulation correlated with malignant characteristics, such as higher tumor grade and lymph node metastasis, as well as with EMT-like features. SMAD4, which plays a key role in transforming growth factor-β (TGF-β) signaling, is inactivated in approximately half of PDAC cases. In this study, the nuclear accumulation of SMAD3 was immunohistochemically detected even in SMAD4-negative cases. SMAD3 knockdown resulted in upregulated E-cadherin, downregulated vimentin, and reduced cell motility in pancreatic cancer cells regardless of SMAD4 status. In addition, TGF-β-treatment resulted in EMT induction in cells carrying wild-type SMAD4, and EMT was suppressed by SMAD3 knockdown. Patients with upregulated SMAD3 and a high degree of solitary cell infiltration had shorter times to recurrence and shorter survival times after surgery, and multivariate analysis showed that both factors were independent prognostic factors linked to unfavorable outcomes. These findings suggest that SMAD3 in PDAC is involved in the promotion of malignant potential through EMT induction in tumor cells regardless of SMAD4 status and serves as a potential biomarker of poor prognosis.Laboratory Investigation advance online publication, 7 April 2014; doi:10.1038/labinvest.2014.53.
    Laboratory Investigation 04/2014; · 3.96 Impact Factor
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    ABSTRACT: Although liver biopsy is the gold standard for viral liver disease management, it is invasive and the sampling error rate is problematic. Real-time tissue elastography (RTE), a recently developed method of ultrasound elastography, can be used to assess liver fibrosis noninvasively but the overlap between fibrosis stages limits its ability to assess liver fibrosis adequately when used alone. A multicenter collaborative study involving 542 patients with chronic viral hepatitis and cirrhosis who were scheduled to undergo liver biopsy compared the image features obtained from RTE image analysis, the liver fibrosis index (LFI), and pathological diagnosis. RTE and a blood test were performed on the same day as the liver biopsy. Data mining was also performed to construct a decision tree, and its diagnostic performance for assessing liver fibrosis was evaluated. The LFI was higher in patients with chronic hepatitis C (CHC) than in those with chronic hepatitis B (CHB). When a decision tree was constructed by data mining of RTE and serological findings, the diagnostic accuracy was very high for all fibrosis stages, with respective rates at F1, F2, F3, and F4 of 94.4, 54.1, 38.7, and 81.3% for patients with CHC and of 97.1, 50.0, 43.8, and 80.6% for patients with CHB. The variation in LFI values between the different etiologies appears to reflect the difference in the development style of liver fibrosis. The decision tree for assessing liver fibrosis constructed by data mining of both RTE and serological findings had a high diagnostic performance in assessing liver fibrosis and shows promising clinical utility. © 2014 S. Karger AG, Basel.
    Oncology 01/2014; 87 Suppl 1:63-72. · 2.61 Impact Factor
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    ABSTRACT: Clinical staging is very important for optimal therapeutic strategy and prognostic prediction in patients with hepatocellular carcinoma (HCC). The Barcelona Clinic Liver Cancer (BCLC) staging system is the most widely used and best-validated method for HCC. Similarly, the conventional Japan Integrated Staging (c-JIS) score and the biomarker-combined JIS (bm-JIS) score have also been reported to effectively stratify HCC patients. The aim of this study was to evaluate the performance of these three staging systems for prognostic prediction.
    Digestive Diseases 01/2014; 32(6):717-24. · 2.73 Impact Factor
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    ABSTRACT: As the utility of liver-specific magnetic resonance imaging (MRI) increases, it is pertinent to optimize and expand protocols to improve accuracy and foster evolution of techniques; in turn, positive impacts should be seen in patient management. This article reports on the latest expert thinking and current evidence in the field of liver-specific MRI, as discussed at the 6(th) International Forum for Liver MRI, which was held in Vancouver, Canada in September 2012. Topics discussed at this forum described the use of gadoxetic acid-enhanced MRI for the assessment of liver function at the segmental level; to increase accuracy in the diagnosis of liver metastases; to overcome current challenges in patients with cirrhosis, including management of arterial hypo-/isovascular, hepatobiliary phase hypointense nodules; and the data which would be required in order to recommend the use of this modality in hepatocellular carcinoma management guidelines. Growing evidence suggests that gadoxetic acid-enhanced MRI can help to improve the management of patients with a number of different liver disorders; however, more data are needed in some areas, and there may be a case for developing an interpretation guideline for gadoxetic acid-enhanced MRI findings to aid standardization. J. Magn. Reson. Imaging 2013;. © 2013 Wiley Periodicals, Inc.
    Journal of Magnetic Resonance Imaging 11/2013; · 2.57 Impact Factor
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    ABSTRACT: Purpose: Hypovascular nodules that exhibit hypointensity in hepatocyte-phase images of gadoxetic acid-enhanced magnetic resonance (MR) imaging are frequently encountered in clinical practice. We investigated risk factors for the development of these nodules into hypervascular hepatocellular carcinoma (HCC). Methods: We retrospectively reviewed our institutional database and identified 302 patients who underwent gadoxetic acid-enhanced MR imaging for suspected or confirmed HCC from February 1, 2008 to January 30, 2011. We excluded patients who were examined for metastasis of other malignancies or for other hepatic tumors, such as focal nodular hyperplasia. We identified hypovascular nodules that were hypointense in hepatocyte-phase images, recorded their characteristics, and calculated the cumulative hypervascularization rate for nodules that were followed up. Results: Of the 302 patients, 82 had hypovascular nodules (178 nodules; mean size, 9.3 mm). Sixty nodules were followed up for over 6 months, and eight progressed to hypervascular HCC. Hypervascularization occurred more frequently in nodules with fat than those without (P<0.01). The cumulative hypervascularization rate was 5.1% over a year. Conclusion: The presence of intralesional fat was found to be a risk factor for hypervascularization of hypovascular nodules that exhibited hypointensity in the hepatocyte-phase images of gadoxetic acid-enhanced MR imaging.
    Magnetic Resonance in Medical Sciences 10/2013; · 1.04 Impact Factor
  • Human pathology 10/2013; · 2.81 Impact Factor
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    ABSTRACT: Background:The efficacy of hepatic arterial infusion chemotherapy for the treatment of advanced hepatocellular carcinoma (HCC) remains unclear.Methods:The outcome of 476 patients with HCC who underwent hepatic arterial infusion chemotherapy with 5-fluorouracil and cisplatin (HAIC) were compared with 1466 patients who did not receive active therapy.Results:A survival benefit of the therapy after adjusting for known risk factors was observed (hazard ratio, 0.48; 95% CI, 0.41-0.56; P<0.0001). In propensity score-matched analysis (n=682), median survival time was longer for patients who underwent chemotherapy (14.0 months) than for patients who did not receive active treatment (5.2 months, P<0.0001).Conclusion:For advanced HCC, HAIC is considered to be an effective treatment.British Journal of Cancer advance online publication, 5 September 2013; doi:10.1038/bjc.2013.542 www.bjcancer.com.
    British Journal of Cancer 09/2013; · 5.08 Impact Factor

Publication Stats

10k Citations
1,418.50 Total Impact Points


  • 1992–2014
    • Keio University
      • • Department of Pathology
      • • Department of Surgery
      Edo, Tōkyō, Japan
  • 2002–2013
    • Tokyo Medical and Dental University
      • • Department of Hepato-Biliary-Pancreatic Surgery
      • • Department of Pathology
      Edo, Tōkyō, Japan
  • 2012
    • Higashiosaka City General Hospital
      Ōsaka, Ōsaka, Japan
    • Tokyo Institute of Technology
      • Department of Computational Intelligence and Systems Science
      Tokyo, Tokyo-to, Japan
  • 2011
    • Kawasaki Municipal Hospital
      Kawasaki Si, Kanagawa, Japan
  • 2000–2011
    • Nara Medical University
      • Department of Radiology
      Nara-shi, Nara, Japan
  • 1989–2011
    • National Cancer Center, Japan
      • • Department of Diagnostic Radiology
      • • Center for Cancer Control and Information Services
      • • Endoscopy Division
      Edo, Tōkyō, Japan
  • 2010
    • Tokyo Dental College
      Tiba, Chiba, Japan
    • Kinki University
      • Department of Gastroenterology and Hepatology
      Ōsaka, Ōsaka, Japan
  • 2004–2005
    • National Research Institute for Child Health and Development, Tokyo
      Edo, Tōkyō, Japan
  • 2003
    • Hokkaido University
      Sapporo, Hokkaidō, Japan
  • 1998–2001
    • The University of Tokyo
      • Department of Surgical Sciences
      Tokyo, Tokyo-to, Japan
  • 1992–1998
    • National Hospital Organization Kyushu Cancer Center
      Hukuoka, Fukuoka, Japan
  • 1995
    • Chiba Cancer Center
      Tiba, Chiba, Japan