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BACKGROUND: Activin A receptor type 2A (ACVR2A) is one of the most frequently mutated genes in microsatellite instability-high (MSI-H) gastric cancer. However, the clinical relevance of the ACVR2A mutation in MSI-H gastric cancer patients remains unclear. The aims of this study were to explore the effect of ACVR2A mutation on the tumor behavior and to identify the clinicopathological characteristics of gastric cancer patients with ACVR2A mutations. METHODS: An in vitro study was performed to investigate the biological role of ACVR2A via CRISPR/Cas9-mediated ACVR2A knockout MKN74 human gastric cancer cells. One hundred twenty-four patients with gastric cancer were retrospectively analyzed, and relations between MSI status, ACVR2A mutations, and clinicopathological factors were evaluated. RESULTS: ACVR2A knockout cells showed less aggressive tumor biology than mock-transfected cells, displaying reduced proliferation, migration, and invasion (P < 0.05). MSI mutations were found in 10% (13/124) of gastric cancer patients, and ACVR2A mutations were found in 8.1% (10/124) of patients. All ACVR2A mutations were accompanied by MSI. The 5-year overall survival rates of ACVR2A wild-type patients and ACVR2A-mutated patients were 57% and 90%, respectively (P = 0.048). Multivariate analysis revealed that older age (P = 0.015), distant metastasis (P < 0.001), and ACVR2A wild-type status (P = 0.040) were independent prognostic factors for overall survival. CONCLUSIONS: Our study demonstrated that gastric cancer patients with ACVR2A mutation have a significantly better prognosis than those without. Dysfunction of ACVR2A in MKN74 human gastric cancer cells caused less aggressive tumor biology, indicating the importance of ACVR2A in the progression of MSI-H tumors.

DOI： 10.1007/s11605-020-04889-9

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PURPOSE: To investigate the possibility that the antioxidant stress protein Heme oxygenase-1 (HO-1) is involved in the acquisition of chemoresistance in cisplatin and pirarubicin (CITA) therapy. METHODS: Human hepatoblastoma-derived cell line (HepG2) was used to generate a knockdown cell line of HO-1 by small interfering RNA (siRNA). Expression of HO-1, epidermal growth factor receptor (EGFR), Akt, and extracellular signal-regulated kinase1/2 (ERK1/2) was examined by Western blot. The cytotoxic effect of cisplatin, pirarubicin, and EGFR inhibitor was examined by trypan blue staining. In human hepatoblastoma specimens (n = 5), changes of HO-1 expression were examined immunohistochemically before and after CITA therapy. RESULTS: HO-1 expression in HepG2 cells was increased by the treatment of cisplatin (CDDP) and pirarubicin (THP) dose-dependently. In HO-1 knockdown HepG2 cells, the HO-1 was not expressed and the percentage of trypan blue-positive cells (dead cells) was significantly increased after treatment of CDDP and THP. The EGFR inhibitor decreased the levels of HO-1, phospho-Akt and phospho-ERK1/2 in HepG2 cells. Combination treatment of EGFR inhibitor with CDDP and THP increased the cytotoxic effect in HepG2 cells. In human hepatoblastoma specimens, 4 of the 5 patients (80%) showed HO-1 expression changed much stronger in the viable tumor cells after CITA therapy. CONCLUSION: The cytotoxic effects of CDDP and THP were both enhanced under HO-1 knockdown conditions as well as under conditions that inhibit the activation pathway of HO-1 by EGFR inhibitors. EGFR/HO-1 axis may be involved in acquiring chemoresistance in HepG2 cell lines as well as in human hepatoblastoma.

DOI： 10.1007/s00383-019-04563-5

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Cell motility plays an important role in intrahepatic metastasis of hepatocellular carcinoma (HCC), and predicts poor prognosis in patients. The present study investigated the role of a disintegrin and metalloproteinases (ADAMs) in HCC, since these proteins are known to be associated with cell motility. We confirmed the expression of 12 ADAMs with putative metalloproteinase activity in HCC cells, and established a KYN-2 HCC cell line stably expressing short interfering RNA against ADAM21 to investigate the effect of ADAM21 deficiency on HCC cell motility and metastasis in vitro and in vivo. We also examined ADAM21 expression in a cohort of 119 HCC patients by immunohistochemistry. ADAM21 was overexpressed in KYN-2 cells, and its knockdown reduced invasion, migration, proliferation, and metastasis relative to controls. In clinical specimens, ADAM21 positivity was associated with vascular invasion, large tumor size, high histological grade, and lower overall and recurrence-free survival as compared to cases that were negative for ADAM21 expression. A multivariate analysis revealed that ADAM21 positivity was an independent risk factor for overall (P = 0.003) and recurrence-free (P = 0.001) survival. These results suggest that ADAM21 plays a role in HCC metastasis and can serve as a prognostic marker for disease progression.

DOI： 10.1038/s41598-017-15800-z

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NAD(P)H: quinone oxidoreductase-1 (NQO1) protects cells against redox cycling and oxidative stress; however, in cancer cells, NQO1 confers resistance against anticancer agents. The aim of this study was to evaluate the association between NQO1 expression and prognosis in patients with advanced (locally advanced or metastatic/recurrent) colorectal cancer (CRC). A retrospective analysis of 47 patients [28 male and 19 female; median age: 62 years (range, 17-78)] with advanced CRC was conducted. Immunohistochemical examination of tumor tissue specimens was performed using monoclonal anti-NQO1 antibody. The association of NQO1 expression with patient characteristics, chemotherapeutic response, and clinical prognosis was assessed. Therapeutic efficacy (complete response, partial response, stable disease, and progressive disease) was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. We compared the therapeutic efficacy in KRAS wild and mutant CRC because epidermal growth factor receptor (EGFR)-signaling pathway plays a pivotal role in CRC. Of the 47 patients, 31 (66.0%) had KRAS wild CRC and 16 (34.0%) had KRAS mutant CRC. Moreover, 37 (78.7%) had NQO1-positive tumors and 10 (21.3%) had NQO1-negative tumors. Among the patients with KRAS wild CRC, NQO1-negative patients showed significantly better disease control rate (complete response + partial response + stable disease) than NQO1-positive patients (P = 0.028). Moreover, NQO1-negative patients had longer progression-free survival and overall survival than NQO1-positive patients (P = 0.041 and P = 0.043, respectively). NQO1 expression in the tumor may be a predictor of therapeutic efficacy and prognosis in patients with KRAS wild advanced CRC.

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Patients with unresectable hepatocellular carcinoma (HCC) cannot generally be cured by systemic chemotherapy or radiotherapy due to their poor response to conventional therapeutic agents. The development of novel and efficient targeted therapies to increase their treatment options depends on the elucidation of the molecular mechanisms that underlie the pathogenesis of HCC. The DNA damage response (DDR) is a network of cell-signaling events that are triggered by DNA damage. Its dysregulation is thought to be one of the key mechanisms underlying the generation of HCC. Sphingosine-1-phosphate (S1P), a lipid mediator, has emerged as an important signaling molecule that has been found to be involved in many cellular functions. In the liver, the alteration of S1P signaling potentially affects the DDR pathways. In this review, we explore the role of the DDR in hepatocarcinogenesis of various etiologies, including hepatitis B and C infection and non-alcoholic steatohepatitis. Furthermore, we discuss the metabolism and functions of S1P that may affect the hepatic DDR. The elucidation of the pathogenic role of S1P may create new avenues of research into therapeutic strategies for patients with HCC.

DOI： 10.1007/s00595-015-1270-8

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This study aimed to compare the utility of the number of positive lymph nodes with the lymph node ratio (LNR) in predicting survival after resection of extrahepatic cholangiocarcinoma.
A retrospective analysis of 142 consecutive patients who underwent radical resection of extrahepatic cholangiocarcinoma was performed. A total of 3066 regional lymph nodes were resected. The median number of nodes per patient was 21. The optimal cutoff values for the number of positive nodes and the LNR were determined using the Chi square scores calculated by the Cox proportional hazards regression model.
Nodal disease was found in 59 patients (42 %). In the subsequent analysis of the impact that nodal status has on survival, 18 patients with R1/2 resection and 6 patients with paraaortic nodal disease who did not survive for more than 5 years after resection were excluded. The optimal cutoff value for the number of positive nodes was 1, and the optimal cutoff value for the LNR was 5 %. Univariate analysis identified both the number of positive nodes (0, 1, or a parts per thousand yen2; P = 0.005) and the LNR (0, 0-5, or &gt; 5 %; P = 0.007) as significant prognostic factors. Multivariate analysis identified the number of positive nodes but not the LNR as an independent prognostic factor (P = 0.012). The 5-year survival rates were 64 % for the patients with no positive nodes, 46 % for the patients with one positive node, and 28 % for the patients with two or more positive nodes.
The number of positive lymph nodes predicts survival better than the LNR after resection of extrahepatic cholangiocarcinoma, provided that nodal evaluation is sufficient.

DOI： 10.1245/s10434-015-4609-x

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MED12 is a transcriptional mediator complex subunit, which negatively regulates the transforming growth factor beta (TGF-beta) pathway. The TGF-beta pathway plays a major role in the induction of epithelial-mesenchymal transition 9EMT). MED12 loss induces activation of the TGF-beta pathway, resulting in EMT and drug resistance to epidermal growth factor receptor (EGFR)-targeted therapy. We aimed to investigate the clinical significance of MED12 loss detected by immunohistochemistry in patients with colorectal cancer (CRC). A total of 100 patients diagnosed with stage I-IV CRC were enrolled in this retrospective study. MED12 expression was evaluated immunohistochemically, and classified as either positive (&gt;= 20%) or negative (&lt;20%) with regard to the percentage of immunoreactive cells. The relationships between MED12 loss and clinicopathological characteristics and RAS mutation status were analyzed. Overall, 79 and 21 patients were classified as MED12 positive and MED12 negative, respectively. MED12 negativity was significantly associated with tumor budding (P = 0.034), N category (P = 0.010), and M category (P = 0.031). Among stage IV CRC patients, 18 of 31 patients had the RAS wild-type gene; 6 of these patients were MED12 negative, and were considered to have the potential for resistance to EGFR-targeted therapy despite the presence of the wild-type gene. In conclusion, MED12 loss is associated with tumor budding, nodal metastasis, and distant metastasis in patients with CRC, suggesting that MED12 loss induces activation of the TGF-beta pathway resulting in EMT. Future treatment strategies focusing on patients MED12 loss may improve the prognosis of patients with CRC.

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NAD(P) H:quinone oxidoreductase-1 (NQO1) confers resistance to anticancer agents, particularly to oxidative stress inducers such as cisplatin or 5-fluorouracil in malignant tumors. Here we evaluated the association between NQO1 expression in esophageal squamous cell carcinoma (ESCC) cells and the patients' responses to preoperative chemotherapy with cisplatin and 5-fluorouracil (CF), and we elucidated the prognostic significance of NQO1 expression in ESCC patients. We retrospectively analyzed the cases of 40 patients who underwent preoperative CF therapy followed by curative esophagectomy with lymphadenectomy. Immunohistochemistry of the surgically resected specimens was conducted using the primary monoclonal antibody against NQO1. Eighteen of the 40 patients (45%) had tumors that showed high NQO1 expression (NQO1-high group). The poorer histological response to preoperative CF therapy was dominant in the NQO1-high group compared to the NQO1-low group (72% and 45%, respectively) but the difference was not significant (P=0.09). The 3-year recurrence-free survival rate after esophagectomy in the NQO1-high group was significantly lower compared to the NQO1-low group (39% vs. 76%; P&lt;0.01). A Cox proportional hazards model revealed that high NQO1 expression was an independent unfavorable prognostic factor (HR=3.53; P=0.02) as was pN3 (HR=14.7; P&lt;0.01). The immunohistochemical evaluation of NQO1 expression has potential to predict the treatment response and prognosis in patients who undergo preoperative CF therapy followed by esophagectomy for ESCC.

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A well-known tumor suppressor, p21, acts paradoxically by promoting tumor growth in some cellular conditions. These conflicting functions have been demonstrated in association with the HBx gene and in hepatocarcinogenesis. The molecular behavior of p21 depends on its subcellular localization. Nuclear p21 may inhibit cell proliferation and be proapoptotic, while cytoplasmic p21 may have oncogenic and anti-apoptotic functions. Because most typical tumor suppressive proteins also have different effects according to subcellular localization, elucidating the regulatory mechanisms underlying nucleo-cytoplasmic transport of these proteins would be significant and may lead to a new strategy for anti-hepatocellular carcinoma (HCC) therapy. Chromosome region maintenance 1 (CRM1) is a major nuclear export receptor involved in transport of tumor suppressors from nucleus to cytoplasm. Expression of CRM1 is enhanced in a variety of malignancies and in vitro studies have shown the efficacy of specific inhibition of CRM1 against cancer cell lines. Interestingly, interferon may keep p21 in the nucleus; this is one of the mechanisms of its anti-hepatocarcinogenic function. Here we review the oncogenic property of p21, which depends on its subcellular localization, and discuss the rationale underlying a new strategy for HCC treatment and prevention.

DOI： 10.3748/wjg.v21.i42.12150

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AimIncreased serum -fetoprotein (AFP) has been associated with a good prognosis following acute liver failure (ALF), but the levels of the fucosylated fraction of AFP (Lens culinaris agglutinin-reactive fraction of AFP [AFP-L3]) following acute liver injury remain unknown. The aim of the present study was to investigate the clinical significance of AFP and AFP-L3 in patients with acute liver injury.
MethodsWe investigated the serum levels of AFP and highly sensitive AFP-L3% in 27 patients with acute-onset autoimmune hepatitis (AIH), 28 patients with acute hepatitis (AH) and 22 patients with ALF at the onset using a highly sensitive immunoassay (micro-total analysis system).
ResultsThe serum AFP levels were increased in patients with AIH, AH and ALF, but the levels did not significantly differ among them. However, the mean AFP-L3% level was significantly higher in patients with AIH than in patients with AH (P=0.0039). Moreover, significantly more patients with AIH demonstrated AFP-L3 positivity (10%) when compared with patients with AH (P=0.014). Although the percentage of AFP-L3 positivity increased with AFP levels, at low serum AFP levels (&lt;10ng/mL), significantly more patients with AIH demonstrated AFP-L3 positivity than did patients with AH (P=0.024) or ALF (P=0.038).
ConclusionWe demonstrated for the first time that highly sensitive AFP-L3% levels were increased at the onset of AIH. The mechanism underlying the increase in AFP-L3 remains to be elucidated, but this finding may reflect an alteration of the glycosylation such as hyperfucosylation, which can influence the modifications of self-antigens in hepatocytes.

DOI： 10.1111/hepr.12318

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Progressive liver fibrosis remains a major problem for patients with recurrent chronic hepatitis C (CHC) after liver transplantation (LT). However, the involvement of natural killer (NK) and natural killer T (NKT) cells, which predominate in the liver, in recurrent CHC after LT remains unclear. In the present study, we investigated the status of NK and NKT cells in the liver and peripheral blood obtained from 10 patients with recurrent CHC after LT (LT-C), 15 patients with CHC, and 7 normal donors for living donor LT. CD56(+) NK cells were separated into two subsets: CD56(+bright) subset, which is identified as major NK cytokine producer, and CD56(+dim) subset, which has greater spontaneous cytotoxicity. We found a significant decrease in the CD56(+bright) subset in the liver of patients with LT-C compared to patients with CHC (P &lt; 0.01) and normal donors (P = 0.03). The expression of inhibitory NK cell receptor NKG2A was significantly increased on intrahepatic CD56(+bright) subset in LT-C patients, and activated CD69(+)CD56(+dim) NK cell subset was significantly increased. in the liver of LT-C patients. Our results suggest that a significant imbalance between CD56(+bright) and CD56(+dim) NK cell subsets in the liver may contribute to the progression of recurrent CHC after LT.

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Sorafenib is a multi-kinase inhibitor approved for hepatocellular carcinoma, but rarely causes tumor regression in patients with chronic liver diseases. To investigate whether growth factor-mediated signaling is involved in sorafenib resistance, HepG2 and PLC/PRF/5 hepatoma cells were exposed to epidermal growth factor (EGF), hepatocyte growth factor (HGF) or transforming growth factor-beta (TGF-beta) prior to treatment with sorafenib. Furthermore, to identify an effective combination treatment with sorafenib, growth factor-sensitized cells were treated with sorafenib alone or in combination with celecoxib, lovastatin or valproic acid (VPA). Trypan blue staining and Annexin V assays showed that the cytotoxic effect of sorafenib was inhibited by 15-54% in cells sensitized to TGF-beta (P&lt;0.05). Western blotting analysis showed that TGF-beta significantly activated extracellular signal-regulated kinase (ERK)-mediated AKT signaling, and sorafenib failed to suppress both ERK and AKT in TGF-beta-sensitized cells. The decreased anti-tumor effect of sorafenib was rescued by chemical inhibition of ERK and AKT. When TGF-beta-sensitized cells were treated with sorafenib plus VPA, the levels of phosphorylated ERK and AKT were considerably suppressed and the numbers of dead cells were increased by 3.7-5.7-fold compared with those exposed to sorafenib alone (P&lt;0.05). Moreover, low dose sorafenib-induced cell migration was effectively suppressed by combination treatment with sorafenib and VPA. Collectively, TGF-beta/ERK/AKT signaling might play a critical role in sorafenib resistance in hepatoma cells, and combination treatment with VPA may be effective against this drug resistance.

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Hepatitis B virus X (HBX) protein plays a crucial role in carcinogenesis, but its mechanism is unclear. The involvement of ataxia telangiectasia mutated (ATM) kinase in the enhanced redox system was investigated by examining the phosphorylation level of ATM in HBX gene-transfected cells and in transgenic mice following redox system manipulation by treatment with hydrogen peroxide (H2O2) or antioxidant. Western blotting and immunostaining showed that phospho-ATM was significantly increased by HBX both in vitro (3.2-fold; p&lt;0.05) and in vivo (4-fold; p&lt;0.05), and this effect was abrogated by antioxidant treatment. The level of PKC-delta in HBX-expressing cells was increased 3.5-fold compared to controls. Nuclear localized NF-E2-related factor 2 (Nrf2) was increased in HBX-expressing cells exposed to H2O2, but remained at lower levels after the treatment with rottlerin, KU55933, or caffeine. The levels of anti-oxidant molecules were increased in HBX expressing cells and in transgenic mice, indicating that HBX stimulates the Nrf2-mediated redox system. The levels of intracellular reactive oxygen species (ROS) were significantly increased in HBX-expressing cells treated with hydrogen peroxide in the presence of ATM inhibitor KU55933 or caffeine. Treatment of HBX-expressing cells with KU55933 or caffeine before the exposure to H2O2 increased the ratio of cell apoptosis to 33 +/- 4% (p&lt;0.05) and 22 +/- 4% (p&lt;0.05), respectively. Collectively, HBX stimulates the ATM-mediated PKC-delta/Nrf2 pathway, and maintains the enhanced activity of the redox system. Therefore, manipulating ATM kinase activity might be a useful strategy for treating HBX-induced carcinogenesis.

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Sphingosine-1-phosphate (S1P) is a pleiotropic lipid mediator that regulates cell survival, migration, the recruitment of immune cells, angiogenesis, and lymphangiogenesis, all of which are involved in cancer progression. S1P is generated inside cancer cells by sphingosine kinases then exported outside of the cell into the tumor microenvironment where it binds to any of five G protein coupled receptors and proceeds to regulate a variety of functions. We have recently reported on the mechanisms underlying the "inside-out" signaling of S1P, its export through the plasma membrane, and its interaction with cell surface receptors. Membrane lipids, including S1P, do not spontaneously exchange through lipid bilayers since the polar head groups do not readily go through the hydrophobic interior of the plasma membrane. Instead, specific transporter proteins exist on the membrane to exchange these lipids. This review summarizes what is known regarding S1P transport through the cell membrane via ATP-binding cassette transporters and the spinster 2 transporter and discusses the roles for these transporters in cancer and in the tumor microenvironment. Based on our research and the emerging understanding of the role of S1P signaling in cancer and in the tumor microenvironment, S1P transporters and S1P signaling hold promise as new therapeutic targets for cancer drug development.

DOI： 10.1155/2014/651727

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We herein report three cases of alcoholic cirrhosis complicated by deep bleeding. In two of the three cases, intramuscular or retroperitoneal hematomas developed spontaneously. In contrast, in the remaining case, an intramuscular hematoma developed after trauma. In the former two patients, the intramuscular hematomas recurred at other sites during hospitalization. All three patients received conservative therapy, and one patient with a retroperitoneal hematoma underwent transcatheter arterial embolization. All of the patients eventually died of liver failure. The occurrence of severe alcoholic liver disease with deep bleeding has recently been reported with increasing frequency, and clinicians should bear this condition in mind as a life-threatening complication of alcoholic liver disease.

DOI： 10.2169/internalmedicine.53.2123

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Introduction: In experiments involving tracheal wall defects in rabbits, metallic coil stents inevitably induce granulation formation in the defects. We examined the involvement of the mammalian target of rapamycin (mTOR) signaling pathway in granulation formation and examined the effects of rapamycin. Methods: The anterior half of the tracheal wall was removed for a longitudinal length of six tracheal rings. Metallic coils were placed into the tracheal lumen through a wall defect. The rabbits were sacrificed two months after undergoing an endoscopic examination, and the granulation tissue in the tracheal defects was removed for a Western blot analysis and immunohistochemical analysis. Rapamycin (0.5 mg kg- 1 day- 1) was administered three times per week intramuscularly. The data were expressed as the relative expression versus the expression of actin. Results: The level of mTOR phosphorylation in the resected trachea was 0.72 ± 0.45, and it significantly increased in the granulation tissue to 11.6 ± 5.2, with concomitant increases in the phosphorylation levels of p70S6K and S6RP in all five rabbits. Although the systemic administration of rapamycin significantly decreased the levels of phosphorylated mTOR to 4.0 ± 2.4 in the five treated rabbits, the clinical outcomes were unsatisfactory. Three of the five treated rabbits exhibited signs of wound complications, and wet granulation tissue that caused respiratory symptoms was found inside and outside of the coils in four rabbits. Conclusions: Although rapamycin effectively reduced the mTOR activity in the granulation tissue, the granulation formation process seemed to be disturbed, most likely owing to the immunosuppressive effects of rapamycin. © 2013 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.jpedsurg.2013.08.013

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It is well accepted that cell cycle regulators are strongly implicated in the progression of cancer development. p16 and p27 are potent cyclin-dependent kinase (CDK) inhibitors involved in G1 phase progression, and are regarded as adverse prognostic biomarkers for various types of cancers. It has been reported that the main mechanism for p16 inactivation is aberrant DNA methylation, while p27 is exclusively inactivated by proteasome-mediated protein degradation. We have found that p27 is decreased in around half of hepatocellular carcinomas (HCCs), and in some cases p27 is inactivated by inappropriate interaction with cyclin D1/CDK4 complexes. In such cases, p16 is concomitantly inactivated through DNA methylation. Taking into consideration the complex interaction between p16 and p27, a comprehensive analysis including p16 and p27 would be useful for predicting the prognosis of HCC patients. © 2013 The Japanese Society for Clinical Molecular Morphology.

DOI： 10.1007/s00795-013-0047-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Non-alcoholic steatohepatitis (NASH) is a recently identified chronic liver disease, which progresses to liver cirrhosis and hepatocellular carcinoma (HCC). As the number of patients studied to date has been limited, clinically useful prognostic biomarkers of NASH-related HCC have not been available. In this study, we investigated the status of a cell-cycle regulator, p27, in NASH-related HCC. p27 has been regarded as a prognostic factor in various types of cancer patients. A total of 22 cases with NASH-related HCC were analyzed for p27 protein expression, and phosphorylation at threonine 157 (T157) and serine 10 (S10) by immunohistochemical analysis. The correlation of p27 with tumor characteristics, disease-free survival (DFS), and overall survival was analyzed. p27 expression was decreased in 13 HCCs (59%), and was significantly correlated with enlarged tumor size (p = 0.01) and increased cell proliferation (p &lt; 0.01). Phospho-p27 at T157 and S10 was detected in four (18%) and seven (32%) cases, respectively, and patients positive for phospho-p27 (S10) showed reduced DFS (hazard ratio 7.623, p = 0.016) by univariate analysis. Further studies with more patients are required to verify the usefulness of p27 as a biomarker for predicting tumor recurrence in NASH patients.

DOI： 10.3390/ijms141223499

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Background: Hepatitis B virus X protein (HBx) has been shown to induce hepatocarcinogenesis by disrupting the functions of intracellular molecules. Cyclin-dependent kinase inhibitor p21 (Cip1/WAF1), known as a tumour-suppressor gene, has been reported to have paradoxical function, that is, acting as an oncogene, particularly when expressed in the cytoplasm. The effects of HBx on the expression and function of p21 also remain controversial. Aims: We attempted to investigate the role of HBx in the hepatocarcinogenic process, focusing on the association with this paradoxical function of p21. The results obtained were further verified with experiments using the antihepatocarcinogenic action of interferon (IFN)-β. Methods: HBx transgenic mice (Xg) and HBx-transfected hepatoma cell lines were used. Intracellular localization of p21 was determined by Western blot analysis and immunofluorescence. Results: Xg and HBx-transfected cells exhibited increased expression of p21. Up-regulation of p21 was positively correlated with the expression of cyclin D1 and inactive phosphorylation of retinoblastoma protein (pRb). These HBx-induced cell proliferative responses were cancelled by knockdown of p21, which resulted in growth reduction in HBx-expressing cells, suggesting the oncogenic properties of HBx-induced p21. HBx induced accumulation of p21 in the cytoplasm, and activation of PKCα was involved. Finally, IFN-β-treated Xg liver, as well as hepatoma cells, showed a shift of cytoplasmic p21 to the nucleus, accompanied by the abrogation of HBx-induced oncogenic modulation. Conclusions: Our results suggest that HBx induces hepatocarcinogenesis via PKCα-mediated overexpression of cytoplasmic p21 and IFN-β suppressed these molecular events by shifting p21 to the nucleus. © 2013 John Wiley &amp
Sons A/S. Published by John Wiley &amp
Sons Ltd.

DOI： 10.1111/liv.12176

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Hepatocellular carcinoma (HCC) is a common malignant disease with poor prognosis. To improve the clinical outcome, early diagnosis of HCC arising from nonviral agents and hepatitis virus is important. Among several etiological factors, mycotoxins defined as carcinogens by the International Agency for Research in Cancer (IARC) might be one of the critical risk factors for nonviral HCC. Afatoxin B1 is the most well-known carcinogenic mycotoxin for HCC, but the role of the other types of mycotoxin remains unclear. Several studies have reported that a chromatographic separation technique based on high-performance liquid chromatography can successfully detect the concentration of mycotoxins in plasma. Recently, serum level of ochra-toxin A (OTA), a widely distributed mycotoxin classified as Group 2B by IARC, was evaluated in HCC patients in Egypt. The results suggested that serum OTA levels might be a good biomarker for HCC. In this article, we review recent studies of OTA, and discuss its possible significance as a biomarker of HCC. © 2013 Baishideng. All rights reserved.

DOI： 10.3748/wjg.v19.i17.2587

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DOI： 10.1007/s00795-012-0003-y

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Background and Aim The aim of this study was to elucidate the risk of subsequent biliary malignancy in patients undergoing cyst excision for congenital choledochal cysts. Methods A retrospective analysis of 94 patients who had undergone cyst excision for congenital choledochal cysts was conducted. The median age at the time of cyst excision and median follow-up time after cyst excision were 7 years and 181 months, respectively. Results Biliary tract cancer developed in four patients at 13, 15, 23, and 32 years after cyst excision. The cumulative incidences of biliary tract cancer at 15, 20, and 25 years after cyst excision were 1.6%, 3.9%, and 11.3%, respectively. The sites of biliary tract cancer were the intrahepatic (n?=?2), hilar (n?=?1), and intrapancreatic (n?=?1) bile ducts. Of the four patients with biliary tract cancer after cyst excision, three patients underwent surgical resection and one patient received chemo-radiotherapy. The overall cumulative survival rates after treatment in the four patients with biliary tract cancer were 50% at 2 years and 25% at 3 years, with a median survival time of 15 months. Conclusions The risk of subsequent biliary malignancy in patients undergoing cyst excision for congenital choledochal cysts seems to be relatively high in the long-term. The risk of biliary malignancy in the remnant bile duct increases more than 15 years after cyst excision. Despite an aggressive treatment approach for this condition, subsequent biliary malignancy following cyst excision for congenital choledochal cysts shows an unfavorable outcome.

DOI： 10.1111/j.1440-1746.2012.07260.x

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Background and Aim: The aim of this study was to elucidate the risk of subsequent biliary malignancy in patients undergoing cyst excision for congenital choledochal cysts. Methods: A retrospective analysis of 94 patients who had undergone cyst excision for congenital choledochal cysts was conducted. The median age at the time of cyst excision and median follow-up time after cyst excision were 7 years and 181 months, respectively. Results: Biliary tract cancer developed in four patients at 13, 15, 23, and 32 years after cyst excision. The cumulative incidences of biliary tract cancer at 15, 20, and 25 years after cyst excision were 1.6%, 3.9%, and 11.3%, respectively. The sites of biliary tract cancer were the intrahepatic (n=2), hilar (n=1), and intrapancreatic (n=1) bile ducts. Of the four patients with biliary tract cancer after cyst excision, three patients underwent surgical resection and one patient received chemo-radiotherapy. The overall cumulative survival rates after treatment in the four patients with biliary tract cancer were 50% at 2 years and 25% at 3 years, with a median survival time of 15 months. Conclusions: The risk of subsequent biliary malignancy in patients undergoing cyst excision for congenital choledochal cysts seems to be relatively high in the long-term. The risk of biliary malignancy in the remnant bile duct increases more than 15 years after cyst excision. Despite an aggressive treatment approach for this condition, subsequent biliary malignancy following cyst excision for congenital choledochal cysts shows an unfavorable outcome. © 2012 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

DOI： 10.1111/j.1440-1746.2012.07260.x

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Cadherins constitute a superfamily of Ca2+-dependent cell adhesion molecules that play critical roles in the maintenance of tissue structure and morphogenesis. Their dysregulation is commonly observed in a variety of cancers. Liver-intestine cadherin (LI-cadherin), which was so named in view of its sole expression in the liver and intestine of the rat, is a structurally unique member of the cadherin superfamily, possessing seven cadherin repeats within the extracellular cadherin domain and only 25 amino acids in the cytoplasmic domain. Its adhesive property does not require any interaction with cytoplasmic components such as catenins, and it responds to small changes in extracellular Ca2+ below the physiological plasma concentration. In humans, the distribution of LI-cadherin is limited to the duodenum, jejunum, ileum, colon, and part of the pancreatic duct. Data accumulated from studies of the biological characteristics of LI-cadherin have shown that it plays an important role in the pathophysiology of human cancers. Here, we review recent information about LI-cadherin and its implications for cancer progression. © 2012 The Japanese Society for Clinical Molecular Morphology.

DOI： 10.1007/s00795-012-0003-y

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Background and Aim: Transforming growth factor-β (TGF-β) has been shown to play a central role in the promotion of cell motility, but its functional mechanism has remained unclear. With the aim of investigating the diagnostic and treatment modalities for patients with hepatocellular carcinoma (HCC), the signaling pathway that may contribute to TGF-β-mediated cell invasion in hepatoma cells was evaluated. Methods: Three hepatoma cell lines, HepG2, PLC/PRF/5, and HLF, were treated with TGF-β, and the involvement of the non-canonical TGF-β pathway was analyzed by cell migration assays. HepG2 cells were treated with a p21-activated kinase-2 (PAK2)-targeting small interfering RNA and analyzed for their cell motility. The relationships between the PAK2 status and the clinicopathological characteristics of 62 HCC patients were also analyzed. Results: The cell migration assays showed that Akt is a critical regulator of TGF-β-mediated cell migration. Western blotting analyses showed that TGF-β stimulated Akt and PAK2 in all three hepatoma cell lines, and phosphorylated PAK2 was blocked by Akt inhibitor. Suppression of PAK2 expression by small interfering RNA resulted in increased focal adhesions with significantly repressed cell migration in the presence of TGF-β. Clinicopathological analyses showed that the phosphorylation level of PAK2 was closely associated with tumor progression, metastasis, and early recurrence of HCC. Conclusions: PAK2 may be a critical mediator of TGF-β-mediated hepatoma cell migration, and may represent a potential target for the treatment of HCC. © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

DOI： 10.1111/jgh.12150

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Background. Phosphorylated histone H2AX (γ-H2AX) is a potential regulator of DNA repair and is a useful tool for detecting DNA damage. To evaluate the clinical usefulness of γ-H2AX in hepatocellular carcinoma (HCC), we measured the level of γ-H2AX in HCC, dysplastic nodule, and nontumorous liver diseases. Methods. The level of γ-H2AX was measured by immunohistochemistry in fifty-eight HCC, 18 chronic hepatitis, 22 liver cirrhosis, and 19 dysplastic nodules. Appropriate cases were also examined by fluorescence analysis and western blotting. Results. All cases with chronic liver disease showed increased levels of γ-H2AX expression. In 40 (69.9%) of 58 cases with HCC, the labeling index (LI) of γ-H2AX was above 50% and was inversely correlated with the histological grade. Mean γ-H2AX LI was the highest in dysplastic nodule (74.1 ± 22.1 %), which was significantly higher than HCC (P &lt
0.005). Moreover, γ-H2AX was significantly increased in nontumorous tissues of HCC as compared with liver cirrhosis without HCC (62.5 ± 24.7 %, from 5.1 to 96.0%, P &lt
0.005). Conclusions. γ-H2AX was increased in the preneoplastic lesions of HCC and might be a useful biomarker for predicting the risk of HCC. © 2013 Yasunobu Matsuda et al.

DOI： 10.1155/2013/597095

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Sorafenib is a multi-kinase inhibitor applicable to hepatocellular carcinoma (HCC), but its limited therapeutic effects are a major problem to be solved. Here, we show that blockade of ataxia telangiectasia mutated (ATM) improves the antitumor effects of sorafenib. When hepatoma cell lines HepG2 and PLC/PRF/5 were treated with sorafenib plus ATM small inhibitory RNAs, ATM inhibitor KU55933 or caffeine, Akt signaling was suppressed and the cytotoxic effects were significantly potentiated. Moreover, ATM inhibition effectively suppressed the sorafenib-induced cell migration. Taken together, manipulation of ATM activity might be a useful strategy for improving sorafenib treatment of HCC. © 2012 Elsevier Ireland Ltd.

DOI： 10.1016/j.canlet.2011.12.043

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There has been increased interest in the role of B cells in the pathogenesis of primary biliary cirrhosis (PBC). Although the vast majority of patients with this disease have anti-mitochondrial antibodies, there is no correlation of anti-mitochondrial antibody titer and/or presence with disease severity. Furthermore, in murine models of PBC, it has been suggested that depletion of B cells may exacerbate biliary pathology. To address this issue, we focused on a detailed phenotypic characterization of mononuclear cell infiltrates surrounding the intrahepatic bile ducts of patients with PBC, primary sclerosing cholangitis, autoimmune hepatitis, chronic hepatitis C, and graft-versus-host disease, including CD3, CD4, CD8, CD20, CD38, and immunoglobulin classes, as well as double immunohistochemical staining for CD38 and IgM. Interestingly, CD20 B lymphocytes, which are a precursor of plasma cells, were found in scattered locations or occasionally forming follicle-like aggregations but were not noted at the proximal location of chronic nonsuppurative destructive cholangitis. In contrast, there was a unique and distinct coronal arrangement of CD38 cells around the intrahepatic ducts in PBC but not controls
the majority of such cells were considered plasma cells based on their expression of intracellular immunoglobulins, including IgM and IgG, but not IgA. Patients with PBC who manifest this unique coronal arrangement were those with significantly higher titers of anti-mitochondrial antibodies. Conclusion: These data collectively suggest a role for plasma cells in the specific destruction of intrahepatic bile ducts in PBC and confirm the increasing interest in plasma cells and autoimmunity. (HEPATOLOGY 2012) © 2011 American Association for the Study of Liver Diseases.

DOI： 10.1002/hep.24757

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BACKGROUND &amp; AIMS: The activating receptor natural killer group 2, member D (NKG2D) and its ligands play a crucial role in immune response to tumors. NKG2D ligand expression in tumors has been shown to be associated with tumor eradication and superior patient survival, but the involvement of NKG2D ligands in the immune response against hepatocellular carcinoma (HCC) still remains to be elucidated. METHODS: We investigated the expression of NKG2D ligands in HCC tissues collected from 54 patients and HCC cell lines. We also examined the proteasome expression and the effect of inhibition of proteasome activity on NKG2D ligand expression in HCC tissues and cell lines. RESULTS: In dysplastic nodules (DN), well-differentiated (well-HCC), and moderately-differentiated HCCs (mod-HCC), UL16-binding protein (ULBP) 1 was expressed predominantly in tumor cells, but not in poorly-differentiated HCCs (poor-HCC). Remarkably, recurrence-free survival of patients with ULBP1-negative HCC was significantly shorter than that of patients with ULBP1-positive HCC (p=0.006). Cox regression analysis revealed that loss of ULBP1 expression was an independent predictor of early recurrence (p=0.008). We c

DOI： 10.1016/j.jhep.2011.06.017

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Background 82 Aims: The activating receptor natural killer group 2, member D (NKG2D) and its ligands play a crucial role in immune response to tumors. NKG2D ligand expression in tumors has been shown to be associated with tumor eradication and superior patient survival, but the involvement of NKG2D ligands in the immune response against hepatocellular carcinoma (HCC) still remains to be elucidated.
Methods: We investigated the expression of NKG2D ligands in HCC tissues collected from 54 patients and HCC cell lines. We also examined the proteasome expression and the effect of inhibition of proteasome activity on NKG2D ligand expression in HCC tissues and cell lines.
Results: In dysplastic nodules (DN), well-differentiated (well-HCC), and moderately-differentiated HCCs (mod-HCC), UL16-binding protein (ULBP) 1 was expressed predominantly in tumor cells, but not in poorly-differentiated HCCs (poor-HCC). Remarkably, recurrence-free survival of patients with ULBP1-negative HCC was significantly shorter than that of patients with ULBP1-positive HCC (p = 0.006). Cox regression analysis revealed that loss of ULBP1 expression was an independent predictor of early recurrence (p = 0.008). We confirmed that ULBP1 was expressed in the well- and mod-HCC cell lines, but not in the poor-HCC cell line KYN-2. However, inhibition of proteasome activity resulted in significant up-regulation of ULBP1 expression in KYN-2. Moreover, we found that 20S proteasome expression was more abundant in KYN-2 than that in the well- and mod-HCC cell lines.
Conclusions: ULBP1 is prevalently expressed in DN to mod-HCC, but loss of its expression correlates with tumor progression and early recurrence. (C) 2011 European Association for the Study of the Liver. Published by Elsevier By. All rights reserved.

DOI： 10.1016/j.jhep.2011.07.008

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Hepatocellular carcinoma (HCC) is the most common primary cancer worldwide. The only current drug available for clinical treatment of HCC is sorafenib, which inhibits multiple signaling kinases including Raf family members, platelet-derived growth factor receptor, vascular endothelial growth factor receptors 1 and 2, c-Kit, and Fms-like tyrosine kinase 3. Many studies have revealed that the mechanism underlying the antitumor effect of sorafenib is complex. Because sorafenib inhibits C-Raf more potently than B-Raf, the therapeutic efficacy of sorafenib is strongly influenced by the relative expression and activity of B-Raf and C-Raf and the complex interactions between these factors. Moreover, Rafindependent signaling mechanisms have recently emerged as important pathways of sorafenib-induced cell death. Basic research studies have suggested that using sorafenib as part of a combination therapy may improve its effect, although this has yet to be confirmed by clinical evidence. Further studies of the functional mechanism of sorafenib are required to advance the development of targeted therapy for HCC. To aid future work on sorafenib, we here review the current literature pertaining to sorafenib signaling and its clinical efficacy in both monotherapy and combination therapy. © The Japanese Society for Clinical Molecular Morphology 2011.

DOI： 10.1007/s00795-011-0558-z

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Background/Aims: Ribonucleotide reductase M1 (RRM1) is a key molecule for gemcitabine resistance. This study evaluated the immunohistochemical expression of RRM1 in resected specimens of intrahepatic cholangiocarcinoma (ICC) and investigated the efficacy of gemcitabine-based neoadjuvant chemotherapy in relation to RRM1 expression in tumors.
Methodology: A retrospective analysis was conducted on 34 consecutive Japanese patients who underwent resection of ICC. Of the 34 patients, 2 were treated with neoadjuvant chemotherapy consisting of gemcitabine 800mg/m(2) every 2 weeks to address extrahepatic tumor extension. Expression of RRM1 in tumor specimens was assessed using immunohistochemistry and was classified as either positive or negative.
Results: RRM1-positive expression was detected in 19/34 (56%) tumor specimens. Two patients were treated with gemcitabine-based neoadjuvant chemotherapy; one had a tumor specimen showing RRM1-positive expression and showed a 14% tumor reduction rate (stable disease); another patient had a tumor showing RRM1-negative expression and showed a 68% tumor reduction rate (partial response). Surgical procedures planned before administration of neoadjuvant chemotherapy were performed in both patients.
Conclusions: Neoadjuvant chemotherapy with gemcitabine for locally advanced ICC was well tolerated and did not impair planned surgical resections. Tumor expression of RRM1 may determine the efficacy of gemcitabine-based chemotherapy for patients with ICC.

DOI： 10.5754/hge11175

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Hepatocellular carcinoma (HCC) has an aggressive clinical course with frequent recurrence and metastasis. Orthotopic liver transplantation has been the only curative tool for unresectable HCC
therefore, recent advances in molecular targeted therapy may improve the prognosis of HCC. The multiple kinase inhibitor sorafenib and the macrolide antibiotic rapamycin are currently the most promising agents for treating unresectable HCC. A large population-based clinical trial revealed that sorafenib significantly prolonged the overall survival of HCC patients. However, subsequent clinical studies showed that sorafenib rarely reduced tumor volume and inadequately prolonged survival of patients with severe liver damage. To improve its therapeutic effect, the development of a predictive biomarker and a sorafenib-based combination is awaited. Another molecular targeting agent, rapamycin, has now been considered as a putative agent for preventing tumor recurrence in post-liver transplantation HCC patients, because it not only has immunosuppressive activity but also exerts an anti-tumor effect. In the near future, a combination of molecular targeting agents, such as sorafenib and rapamycin, may become a standard protocol for treating unresectable HCC. For specifying cases with more effective and less harmful modalities, further investigation in clinical and basic research to identify unexpected effects are needed. © The Japanese Society for Clinical Molecular Morphology 2011.

DOI： 10.1007/s00795-011-0547-2

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Background/Aims: To clarify clinical parameters predicting sustained viral response (SVR) during 48 weeks pegylated-interferon (peg-IFN)alpha-2b plus ribavirin therapy for Japanese patients with chronic hepatitis C [CH(C)] genotype 1b and high viral titers.
Methodology: One hundred and fifty-one (151) patients receiving peg-IFN alpha-2b plus ribavirin therapy for 48 weeks were enrolled. SVR and clinical parameters were evaluated. The relationship between virological parameters (substitutions in the core and NS5A) and the degree of early viral decrease was also studied.
Results: Seventy (46.4%) patients achieved SVR (per protocol analysis). Negative predictive value (NPV) of &lt;2-log(10), decrease after 4 weeks of therapy for SVR was 78.0%; similar to that for failing to achieve early viral response (EVR) at 12 weeks (82.2%).
Conclusions: Failure to achieve 2-log(10)) decrease in the first 4 weeks may be an important predictor of non-SVR during 48 weeks of peg-IFN alpha-2b plus ribavirin therapy; thus, therapeutic plans should be reassessed at that point.

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P53-binding protein 1 (53BP1) is an early DNA damage response-protein that is rapidly recruited to sites of DNA double-strand breaks. The presence of 53BP1 nuclear foci can be considered as a cytologic marker for endogenous double-strand breaks reflecting genomic instability. This study aimed to clarify the early DNA damage response mediated by 53BP1 in tumor specimens of ductal resection margins and to elucidate its predictive value for clinically evident local recurrence at ductal stumps in 110 patients undergoing resection for extrahepatic cholangiocarcinoma. The ductal resection margin status was classified as negative (85 patients), positive with carcinoma in situ (14 patients), or positive with invasive carcinoma (11 patients). The nuclear staining pattern of 53BP1 was evaluated by immunofluorescence. TUNEL analysis was used to calculate apoptotic index. Ductal margin status was the only independent risk factor for local recurrence (P=0.001). The cumulative probability of local recurrence at 5 years was 10%, 40% and 100% in patients with negative ductal margins, positive with carcinoma in situ and positive with invasive carcinoma, respectively (P<0.001). Of the 14 tumor specimens of carcinoma in situ, 10 showed diffuse localization of 53BP1 in nuclei (53BP1 inactivation) and 4 showed discrete nuclear foci of 53BP1 (53BP1 activation). All 11 tumor specimens of invasive carcinoma showed 53BP1 inactivation. Apoptotic index was markedly decreased in tumor specimens with 53BP1 inactivation compared to those with 53BP1 activation (median index, 0% vs. 22%; P<0.001). Among 14 patients with residual carcinoma in situ, the cumulative probability of local recurrence was significantly higher in patients with 53BP1 inactivation than in patients with 53BP1 activation (60% vs. 0% at 5 years; P=0.020). In conclusion, after resection for extrahepatic cholangiocarcinoma, clinically evident local recurrence at ductal stumps is closely associated with 53BP1 inactivation and decreased apoptosis.

DOI： 10.3892/ijo.2011.959

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We report a case of chronic hepatitis C in whom liver cirrhosis was later diagnosed following abnormality of ALT levels during pegylated interferon α2a and ribavirin treatment. A 62-year-old woman with chronic hepatitis C was treated with pegylated interferon α2a plus ribavirin for 72 weeks. Her HCV RNA became negative 16 weeks after the start of treatment and continued to be negative for most of the treatment duration. Her AST/ALT, ALP/γ-GTP levels became elevated soon after the initiation of treatment and thereafter remained unchanged. However, most of these levels normalized after the end of treatment. Posttreatment liver biopsy showed liver cirrhosis, probably due to the interferon treatment itself. This unusual therapeutic outcome should be considered if the levels of hepatic dysfunction during interferon treatment are severe.

DOI： 10.11405/nisshoshi.108.267

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Aim:
Elevation of alanine aminotransferase (ALT) levels during pegylated-interferon (peg-IFN) plus ribavirin therapy in patients with chronic hepatitis C [CHC] is a problem that cannot be disregarded. The aim of this study is to assess the frequency and to characterize clinical parameters of this phenomenon.
Methods:
Two hundred and thirty-five (235) CHC patients with genotype 1b receiving peg-IFN alpha-2b plus ribavirin therapy were analyzed. Clinical parameters that may be associated with abnormal ALT values during treatment and therapy outcomes were evaluated statistically. One hundred and sixteen (116) patients treated with peg-IFN alpha-2a plus ribavirin were also included for partial analysis.
Results:
Abnormal ALT values during treatment were observed in 23.0% of patients. It was observed in 14.5% of those with sustained virological response (SVR) and 17.8% of those with relapse, in whom viral clearance was observed during therapy. Multivariate logistic regression analysis revealed that pretreatment ALT values, therapy outcome, and body mass index (BMI) were significant factors related to abnormal ALT values during treatment. Abnormal ALT values during treatment became normal in SVR patients at 6 months after the completion of treatment, but not in NR (non-response) patients. Mean ALT values were significantly higher at some time points during treatment in patients treated with alpha-2a when compared to those treated with alpha-2b.
Conclusion:
Abnormal ALT values during peg-IFN plus ribavirin treatment are observed relatively frequently, even in patients without detectable HCV RNA. Direct or indirect involvement of drugs is considered as one possible cause.

DOI： 10.1111/j.1872-034X.2010.00749.x

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This study aimed to evaluate the association between the immunohistochemical expression of NAD(P) H: quinone oxidoreductase-1 (NQO1) and nuclear factor erythroid 2-related factor 2 (Nrf2) in resected specimens of intrahepatic cholangiocarcinoma (ICC) and to elucidate the prognostic value of NQO1 and Nrf2 expression. A retrospective analysis was conducted of 34 consecutive patients who underwent surgical resection for ICC. Immunohistochemistry of the resected specimens was conducted using each of the following primary monoclonal antibodies against NQO1 and Nrf2. Of the 34 patients, 23 were classified as having tumors with NQO1-positive expression and 11 had tumors with loss of NQO1 expression, whereas 22 patients had tumors with Nrf2-positive expression and 12 had tumors with loss of Nrf2 expression. NQO1 expression showed a positive association with Nrf2 expression (p=0.005). Loss of NQO1 expression was more frequent in tumor specimens that were moderately or poorly differentiated (11/26; 42%) than in well-differentiated tumors (0/8; 0%; p=0.034). Post-resection survival was significantly worse in patients with tumors with loss of NQO1 expression than in patients with NQO1-positive tumors (cumulative 5 -year survival rate of 0% and 51%, respectively; p=0.005). Nrf2 expression was not associated with survival after resection (p=0.287). The Cox proportional hazards regression analysis revealed that lymph node involvement (p&lt;0.001) and loss of NQO1 expression (p&lt;0.001) had an independent adverse effect on survival. Loss of NQO1 expression reflects dedifferentiation and thus indicates a poor prognosis for patients undergoing resection for ICC.

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Aim: To reveal the manner of hepatocellular carcinoma (HCC) development in patients with nonalcoholic steatohepatitis (NASH) focusing on multicentric occurrence (MO) of HCC. Methods: We compared clinicopathological characteristics between patients with and without MO of HCC arising from NASH background. The clinical features were implicated with reference to the literature available. Results: MO of HCC was identified with histological proof in 4 out of 12 patients with NASH-related HCC (2 males and 2 females). One patient had synchronous MO
an advanced HCC, two well-differentiated HCCs and a dysplastic nodule, followed by the development of metachronous MO of HCC. The other three patients had multiple advanced HCCs accompanied by a well-differentiated HCC or a dysplastic nodule. Of these three patients, one had synchronous MO, one had metachronous MO and the other had both synchronous and metachronous MO. There were no obvious differences between the patients with or without MO in terms of liver function tests, tumor markers and anatomical extent of HCC. On the other hand, all four patients with MO of HCC were older than 70 years old and had the comorbidities of obesity, type 2 diabetes mellitus (T2DM), hypertension and cirrhosis. Although these conditions were not limited to MO of HCC, all the conditions were met in only one of eight patients without MO of HCC. Thus, concurrence of these conditions may be a predisposing situation to synchronous MO of HCC. In particular, old age, T2DM and cirrhosis were suggested to be prerequisite for MO because these factors were depicted in common among two other cases with MO of HCC under NASH in the literature. Conclusion: The putative predisposing factors and necessary preconditions for synchronous MO of HCC in NASH were suggested in this study. Further investigations are required to clarify the accurate prevalence and predictors of MO to establish better strategies for treatment and prevention leading to the prognostic improvement in NASH. © 2011 Baishideng.

DOI： 10.4254/wjh.v3.i1.15

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We hypothesized that expression of multidrug resistance-associated protein 2 (MRP2), a major cisplatin transporter, may determine the efficacy of cisplatin as a treatment for patients with hepatocellular carcinoma (HCC). A prospective analysis was conducted of 49 consecutive patients who underwent resection for HCC (16 patients treated with cisplatin-based neoadjuvant chemotherapy and 33 patients treated without neoadjuvant chemotherapy). Expression of MRP2 in resected specimens was assessed by immunohistochemical and Western blot analyses. The extent of tumor necrosis was assessed histologically in the greatest dimension of the tumor specimen from each patient. The median percentage of tumor necrosis was 81% (range: 0-100%) and complete tumor necrosis was found in 3 patients. Over-expression of MRP2 was detected in 24/46 (52%) tumor specimens. In 16 patients treated with cisplatin, tumor size and dose of cisplatin did not correlate with tumor necrosis of the resected specimens (P=0.706 and P=0.555, respectively). Of 13 tumor specimens containing vivid tumor from 16 patients treated with cisplatin, 8 had overexpression of MRP2. Tumor specimens with overexpression of MRP2 showed a lower percentage of tumor necrosis than those with non-overexpression (median percentage of tumor necrosis, 19% vs. 99%, P=0.003). In conclusion, overexpression of MRP2 correlates with a lower percentage of tumor necrosis in patients treated with cisplatin-based neoadjuvant chemotherapy for HCC, whereas either tumor size or dose of cisplatin does not. Expression of MRP2 determines the efficacy of cisplatinbased chemotherapy in patients with HCC.

DOI： 10.3892/or-00000721

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Mast cells play a key role in the pathophysiology of inflammatory bowel disease (IBD). Tranilast, a mast cell stabilizer, has been empirically used for IBD in Japan, but its precise role in the treatment of IBD is largely unknown. To investigate the role of tranilast for the treatment of IBD, tranilast was administered intrarectally to mice with dextran sulfate sodium (DSS)-induced colitis. Tranilast ameliorated DSS colitis clinically and pathologically, as demonstrated by decreased number and degranulation of mast cells in the colon. mRNA expression was increased for tumor necrosis factor-α, interferon-γ and interleukin (IL)-6, and decreased for IL-10 in the colon of DSS colitis mice. In contrast, tranilast markedly decreased expression of mRNAs for the pro-inflammatory cytokines, and increased that of the anti-inflammatory cytokines. Moreover, tranilast increased heme oxygenase (HO)-1 expression on colonic epithelial cells as well as on colon-infiltrating cells of DSS colitis. In conclusion, tranilast ameliorated DSS colitis by regulating mast cell degranulation, decreasing inflammatory cytokines and increasing anti-inflammatory cytokines. Tranilast might exert these effects partly through enhanced HO-1 expression in the colon, suggesting a potential adjunctive therapy for IBD. © 2009 Japanese Society of Pathology.

DOI： 10.1111/j.1440-1827.2009.02490.x

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Liver-intestine cadherin (LI-cadherin) represents a novel type of cadherin within the cadherin superfamily that comprises seven cadherin repeats and a short cytoplasmic domain. In this study, we first examined LI-cadherin expression immunohistochemically in 34 specimens of human intrahepatic cholangiocarcinoma (ICC). LI-cadherin expression was positive (defined as positivity in ≥10% of cells) in 18 of the ICCs (52.9%). LI-cadherin negativity was significantly correlated with tumor dedifferentiation (P=0.026) and vascular invasion (P=0.015). The cumulative survival rate of patients with LI-cadherin-negative ICC was significantly shorter than that of patients with LI-cadherinpositive ICC (P=0.021). Multivariate analysis identified the extent of LI-cadherin staining as an independent prognostic factor for ICC survival (P=0.027). Next, to elucidate the mechanism of loss of LI-cadherin-mediated aggressiveness in ICC, we knocked down LI-cadherin expression in an ICC cell line using small interfering RNA (siRNA) technology, and screened for genes that were expressed differentially between these cells and ICC cells transfected with scrambled siRNA using microarray analysis with real-time polymerase chain reaction confirmation. Among 21 identified genes, we focused on metal-responsive transcription factor-1 (MTF-1), whose target genes might contribute to tumor aggressiveness. Expression of placental growth factor (PlGF), one of the MTF-1 target genes, was up-regulated in the ICC cells transfected with LI-cadherin siRNA. Likewise, PlGF expression was up-regulated in LI-cadherin-negative ICC specimens. There was a significant inverse relationship between these expressions (P=0.033). Furthermore, the microvessel density of LI-cadherin-negative ICC specimens was higher than that of LI-cadherin-positive specimens. These findings suggest that loss of LI-cadherin in ICC is associated with tumor dedifferentiation and vascular invasion, and thus poor prognosis. Loss of LI-cadherin results in up-regulation of MTF-1 and PlGF, thereby regulating angiogenesis in ICC.

DOI： 10.3892/ijo-00000495

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Despite the recent progress in interferon (IFN) therapies for chronic hepatitis C, liver cirrhosis remains refractory. One of the major obstacles to successful IFN therapy is low platelet count. Currently, splenic interventions, such as partial splenic embolization (PSE) or surgical splenectomy, have been applied effectively and make standard IFN therapy possible. However, there may be a group of patients with low platelet counts who can be treated without splenic intervention. We here report two patients with advanced type C liver cirrhosis who were successfully treated using very-low-dose pegylated interferon α2a plus ribavirin. One patient had a very low platelet count (2.5 × 104/μl) due to splenomegaly before treatment. However, pretreatment serum HCV titers were low in both patients and early viral responses were obtained in both. Because PSE or splenectomy may still have some safety concerns, this attenuated IFN treatment protocol can be an alternative therapeutic option for patients with advanced type C liver disease, but good virological factors for sustained virological response. © 2010 S. Karger AG, Basel.

DOI： 10.1159/000318742

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Aim:
Hepatic stem cells are capable of dramatically changing and differentiating to form mature hepatocytes in acute and chronically damaged livers; however, the clinicopathological characteristics of these heterogeneous cell populations have not been sufficiently analyzed.
Methods:
In this study, cells in tissue sections from 12 cases of acute damaged livers and 31 cases of hepatocellular carcinomas (HCC), and the surrounding chronically damaged liver tissues, were analyzed by immunohistochemistry using the previously reported hepatic stem/progenitor cell marker CD133 (AC133) and the neural cell adhesion molecule (NCAM) marker.
Results:
In both the acute and chronically damaged livers, CD133+ cells and NCAM+ cells were present in ductular reactions (DR), which include hepatic stem/progenitor cells, and became more apparent in proportion to the degree of fibrosis or histological damage. Analysis of their distribution and morphological similarities revealed that the NCAM+ cell population included cells that were closer to, and morphologically more similar to, hepatocytes than were CD133+ cells. Analysis of HCC using these markers revealed that 9.7% of HCC expressed NCAM (two cases had abundant NCAM+ cells), while CD133+ HCC were not detected.
Conclusion:
These results suggest that CD133 and NCAM can be employed to enrich for hepatic stem/progenitor cells and that DR can be distinguished in greater detail using these markers. NCAM+ HCC were detected, but their function remains unresolved. Expression of CD133, a potent stem cell marker, may be extremely rare in the common human HCC examined.

DOI： 10.1111/j.1872-034X.2009.00559.x

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Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers worldwide. The main HCC-associated diseases are chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV), and HBV-associated HCC is still prevalent in Asia. Many studies have suggested that HBV X protein (HBX), which is the most common ORF integrated into the host genome, plays a crucial role in hepatocarcinogenesis. However, the accumulated evidence regarding HBX-mediated signaling pathways is not concordant, and it is difficult to understand the mechanistic nature of HBX-associated hepatocarcinogenesis. For example, HBX was reported to inactivate the early responses to DNA damage via p53-dependent and -independent pathways by interacting with several DNA damage-binding proteins and was also reported to sensitize cells to p53-mediated apoptosis via ataxia-telangiectasia and Rad3-related (ATR)-dependent signaling. HBX also interferes with the centrosome replication process, resulting in rearrangement of chromosomes with micronuclei. Moreover, HBX was found to sensitize protein kinases such as Ras/Raf/mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), stress-activated protein kinase/NH2-terminal-Jun kinase (SAPK/JNK), protein kinase B (PKB/Akt), and Janus kinase/STAT (JAK/STAT), indicating that a variety of signaling pathways may be activated by HBX. In this review, we focus on the roles of HBX in DNA damage repair during HCC development, with a view to achieving a better understanding of the significance of HBX in the early steps of hepatocarcinogenesis. © 2009 The Japanese Society for Clinical Molecular Morphology.

DOI： 10.1007/s00795-009-0457-8

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PURPOSE: Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a member of the carcinoembryonic antigen family of immunoglobulin-like adhesion molecules. The aim of this study was to test the hypothesis that loss of CEACAM1 expression in hepatoblastoma cells may promote hematogeneous metastasis and function as an adverse prognostic factor. METHODS: Immunohistochemical expression of CEACAM1 in surgically resected specimens from 19 patients with hepatoblastoma was examined retrospectively. The CEACAM1 expression in the epithelial area of the tumor was classified into 2 categories as follows: diffuse expression, characterized by positive staining throughout the tumor specimen, or loss of expression, in which there were distinct areas of negative staining within the tumor specimen. RESULTS: Of the 19 patients, 12 were classified as having tumors with diffuse expression, and 7 had loss-of-expression tumors. Survival after treatment was significantly worse in patients with tumors with loss of CEACAM1 expression (cumulative 5-year survival rate, 29%) than in patients with diffuse CEACAM1 expression (cumulative 5-year survival rate, 92%; P = .0062). Loss of CEACAM1 expr

DOI： 10.1016/j.jpedsurg.2008.12.035

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The aim of this study was to determine to what extent hypermethylation of the p16(INK4A) (p16) gene promoter is increased in nontumorous liver tissues compared with in normal liver, using two quantitative methylation-specific polymerase chain reaction (MS-PCR) methods and a bisulfite sequencing method. Methylation of the p16 gene was detected more frequently in nontumorous liver than in normal liver using the TaqMan PCR method. Methylation indices also were significantly higher in nontumorous than in normal liver. However, the bisulfite sequencing method did not detect significantly more methylation of the p16 gene in nontumorous than normal liver, nor was there a significant difference in the level of p16 mRNA. There may be a greater proportion of cells which contain methylated p16 in nontumorous than in normal liver. However, the difference was so small that the functional relevance to hepatocarcinogenesis remains elusive.

DOI： 10.1007/s10620-008-0611-5

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Paraneoplastic syndromes of hepatocellular carcinoma (HCC) are not uncommon. However, the prognosis is poor and follow-up and improvement of paraneoplastic syndromes with treatment have been reported rarely. We report a successful case in an aged man of a massive HCC with paraneoplastic syndrome, treated by combined intraarterial chemotherapy and hepatic resection. Paraneoplastic syndrome (erythrocytosis and hyperlipidemia) was monitored throughout the treatment and erythropoietin (EPO) mRNA also was analyzed in the resected liver. The hemoglobin level and serum levels of EPO and total cholesterol (T-cho) decreased dramatically with treatment, along with a decrease in serum levels of alpha-fetoprotein and protein induced by vitamin vitamin K absence II (PIVKA-II). Semiquantitative reverse transcription polymerase chain reaction (RT-PCR) revealed that the residual cancer expressed EPO RNA but the nontumor tissue did not. This was a rare case of paraneoplastic syndrome of HCC that was treated successfully. This case indicates that paraneoplastic syndrome reflected tumor progression and that serum levels of both EPO and T-cho might be used as tumor markers.

DOI： 10.1159/000213480,

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Language：Japanese   Publishing type：Research paper (scientific journal)  

A 73-year-old man with chronic hepatitis C was Successfully treated for hepatocellular carcinoma (HCC) by localized treatment During the follow-up period, abdominal computed tomography (CT) revealed no HCC recurrence in the liver. However, 9 months after the treatment, abdominal lymph nodes appeared enlarged on CT. Laparoscopic biopsy of the lymph nodes showed that the lesion was HCC, and TS-1/cisplatin chemotherapy was performed. However, extra-hepatic lymph nodes rapidly grew, leading to obstructive jaundice and finally death 10 months after of HCC metastasis. Although abdominal lymph node metastasis of HCC has been widely considered to be rare, the confirmation of effective therapy is awaited because histological studies have suggested that this pathologic lesion may occur more often than expected.

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This study retrospectively evaluated the immunohistochemical expression of 3 cell adhesion molecules (CAMs), E-cadherin, beta-catenin, and osteopontin, according to tumor grade in 125 surgically resected specimens of hepatocellular carcinoma (HCC). The aims of this study were to identify factors associated with vascular invasion and to elucidate the prognostic value of CAMs. The median follow-up time was 110 months. The levels of E-cadherin, beta-catenin, and osteopontin immunoreactivity were significantly associated with Edmondson-Steiner grade but not with tumor size. There was increased loss of E-cadherin, nonnuclear overexpression of beta-catenin, and overexpression of osteopontin in tumors of higher histologic grade. Vascular invasion was found in 44 (35%) of 125 resected specimens. Logistic regression analysis identified 3 tumor-related factors that were independently associated with vascular invasion-tumor size more than 3 cm, Edmondson-Steiner grades III to IV, and overexpression of osteopontin. Among the tested CAMs, osteopontin (P = .0110) and E-cadherin (P = .0287) were significant prognostic factors by univariate analysis. The Cox proportional hazard regression analy

DOI： 10.1016/j.humpath.2008.05.006

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Purpose To study the changes in serum ferritin levels in lamivudine (LAM)-treated patients with chronic hepatitis and liver cirrhosis type B and determine whether successful treatment with LAM results in a reduction of serum ferritin levels.
Methods Thirty patients with chronic hepatitis B virus (HBV) infection were followed prospectively during their treatment with LAM for 12 months. Serum HBV DNA, ferritin levels, and emergence of YMDD mutants were monitored. A case of severe liver cirrhosis with hepatic hemosiderosis that was treated successfully with LAM also is shown as a representative case.
Results Serum alanine aminotransferase and ferritin levels decreased significantly more in the patients treated with LAM without YMDD mutants (n = 23) than those with mutants (n = 7). Hepatic hemosiderosis along with serum iron markers improved greatly in the representative patient.
Conclusion Successful treatment with LAM may reduce serum ferritin levels and improve hepatic siderosis in a subset of patients with chronic HBV infection.

DOI： 10.1007/s12072-008-9084-z

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Aim: Previous studies have revealed that functional impairment of innate immune cells, including natural killer (NK) and natural killer T (NKT) cells, might be associated with the persistence of hepatitis C virus (HCV) infection. However, the involvement of innate immune cells, which predominate in the liver, in therapeutic HCV clearance is still unclear.
Methods: To clarify the role of intrahepatic innate immune cells in the clinical outcome of patients with chronic hepatitis C (CHC) treated with interferon-alpha plus ribavirin (IFN/RBV), we prospectively investigated the status of NK and NKT cells in paired liver biopsy and peripheral blood (PB) samples obtained from 21 CHC patients before and immediately after IFN/RBV treatment by flow cytometry. Normal liver and PB samples were obtained from 10 healthy donors for living donor liver transplantation.
Results: Before treatment, intrahepatic NK and NKT cells constituted a significantly lower proportion in CHC patients than in healthy individuals (P &lt; 0.05). After IFN/RBV treatment, the proportions and absolute numbers of CD3(-)CD161(+) NK and CD3(+)CD56(+) NKT cells in the liver, but not in PB, were significantly increased in sustained responders (SR) as compared with poor responders (P &lt; 0.05). The proportion of CD3(+)CD161(+) NKT cells was also increased in the liver of SR after the treatment. Moreover, there was a striking increase of activated CD152(+) cells among CD3(+)CD56(+) NKT cells in the liver of SR (P = 0.041).
Conclusion: These findings demonstrate that sustained response to IFN/RBV treatment for patients with CHC is closely associated with increased dynamism of NK and NKT cells in the liver.

DOI： 10.1111/j.1872-034X.2008.00317.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W J G PRESS  

Hepatocellular carcinoma (HCC) is one of the most common human cancers, and its incidence is still increasing in many countries. The prognosis of HCC patients remains poor, and identification of useful molecular prognostic markers is required. Many recent studies have shown that functional alterations of cell-cycle regulators can be observed in HCC. Among the various types of cell-cycle regulators, p16 and p27 are frequently inactivated in HCC and are considered to be potent tumor suppressors. p16, a G1-specific cell-cycle inhibitor that prevents the association of cyclindependent kinase (CDK) 4 and CDK6 with cyclin D1, is frequently inactivated in HCC via CpG methylation of its promoter region. p16 may be involved in the early steps of hepatocarcinogenesis, since p16 gene methylation has been detected in subsets of pre-neoplastic liver cirrhosis patients. p27, a negative regulator of the G1-S phase transition through inhibition of the kinase activities of Cdk2/cyclin A and Cdk2/cyclin E complexes, is now considered to be an adverse prognostic factor in HCC. In some cases of HCC with increased cell proliferation, p27 is overexpressed but inactivated by sequestration into cyclin D1-CDK4-containing complexes. Since loss of p16 is closely related to functional inactivation of p27 in HCC, investigating both p16 and p27 may be useful for precise prognostic predictions in individuals with HCC. (c) 2008 WJG. All rights reserved.

DOI： 10.3748/wjg.14.1734

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Background/Aims: The preventive effect of interferon (IFN) against hepatocellular carcinoma (HCC) has been confirmed clinically. We sought to determine whether the temporal administration of IFN-beta prevents hepatocarcinogenesis in a mouse model where HCC develops without necroinflammation.
Methods: Hepatocarcinogenic mice that are transgenic for the hepatitis B virus X gene (HBx-Tg) were treated with IFN-beta or saline (control) for three months, from 3 to 6 months of age, and the incidence of HCC was determined at 18 months of age. The effects of IFN-beta on DNA synthesis and apoptosis were tested.
Results: The incidence of HCC was significantly lower in the IFN-beta-treated mice than the controls (0 vs. 50%, P &lt; 0.01). Inhibition of DNA synthesis in hepatocytes by IFN-beta was observed in the livers of HBx-Tg, without any significant induction of apoptosis. Although the treatment of IFN-beta was temporal, the number of hepatocytes with DNA synthesis remained lower 3 and 12 months later in life.
Conclusions: Temporal administration of IFN-beta has a significant preventive effect on the occurrence of HCC in a mouse model where HCC develops without inflammation. The mechanisms are the inhibition of DNA synthesis and cell cycle progression of hepatocytes. (c) 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jhep.2007.09.012

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DOI： 10.1016/j.bbrc.2007.10.150

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Backgrounds/Aims: Toll-like receptors (TLRs) have emerged as a key component of the innate immune system that triggers antimicrobial responses. Altered monocyte responses to ligands for TLRs have been reported in patients with primary biliary cirrhosis (PBC), yet the precise mechanism remains unknown.
Methods: We investigated in vitro responses to a TLR4 ligand, lipopolysaccharide (LPS), using peripheral blood mononuclear cells and monocytes from 25patients with PBC, 10 patients with chronic viral hepatitis(CVH), and 20 healthy individuals.
Results: After stimulation with LPS, we found significantly higher amounts of IL-I beta, IL-6, and IL-8 production in PBC patients. Through the TLR4 signaling pathway, activation of NF-kappa B and expression of MyD88 mRNA were significantly increased in PBC patients, and the level of TLR4 expression was significantly increased on PBC monocytes as compared with CVH patients and controls. Of significance, the surface expression of RP105, which has recently been shown to be involved in negative regulation of TLR4 signaling, on PBC monocytes was significantly decreased in comparison with CVH patients (P = 0.016) and controls (P &lt; 0.001).
Conclusions: These results suggest that expression of RP105 and TLR4 is altered on PBC monocytes, which appear to be hypersensitive to LPS, resulting in increased secretion of pro-inflammatory cytokines. (C). 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jhep.2007.03.012

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), an adhesion molecule of the immunoglobulin superfamily, has been characterized as a putative tumor suppressor because it is frequently down-regulated in aggressive types of cancer cells. Recently, however, several studies have shown that CEACAM 1 actively contributes to malignant progression or migration in some types of tumor cells, suggesting that the role of CEACAM 1 might be diverse among different types of cancer cells. To investigate the functional consequences of CEACAM 1 expression in hepatocellular carcinoma, we analyzed the status of CEACAM 1 in hepatoma cell lines HLF, PLC/PRF/5, HepG2 and KYN-2. We found that CEACAM1 was only expressed in HepG2 cells, which show a unique property for enhanced anchorage-independent growth. When HepG2 cells were treated with small interfering RNA targeted against CEACAM1, the growth rate in monolayer culture was increased. In contrast, when HepG2 cells were cultured in suspension, inhibition of CEACAM1 expression significantly decreased the growth rate, and the speed of cell-cell attachment was repressed. Hyaluronidase treatment attenuated the growth rate of HepG2 cells in suspension culture, indicating that cell-cell attachment is a requisite for anchorage-independent growth. Our data may reveal the dual role of CEACAM1 on hepatocarcinogenesis, by showing that CEACAM1 acts as a tumor suppressor in HepG2 cells in anchorage-dependent growth conditions, while in anchorage-independent growth conditions, it augments cell proliferation by potentiating the cell-cell attachment. (c) 2007 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.lfs.2007.06.002

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A patient with chronic hepatitis B and C undergoing treatment with interferon and ribavirin showed an upsurge in hepatitis B virus surface antibody (anti-HBs) titer, accompanied by a decrease in hepatitis B virus surface antigen (HBsAg) during the early treatment phase. Simultaneously, elevation of alanine aminotransferase (ALT) was observed. Subsequently, the hepatitis B virus (HBV) DNA titer decreased and HBV e antigen (HBeAg) to anti-HBe seroconversion occurred. The anti-HBs titer gradually returned to the pretreatment level after cessation of ribavirin treatment and HBV-DNA became undetectable. We found no nucleotide mutations in HBV-DNA that could explain the sudden elevation in anti-HBs titer. The appearance of anti-HBs was considered to be a break in immune tolerance against some epitopes in HBsAg, possibly the r epitope, stimulated by interferon/ribavirin treatment. The immunomodulatory effect of ribavirin might have caused this unexpected early immune response to HBsAg that preceded seroconversion to anti-HBe.

DOI： 10.1111/j.1872-034X.2004.00059.x

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Fulminant hepatic failure (FHF) is a dramatic clinical syndrome characterized by massive hepatocyte apoptosis and very high mortality. The c-Jun-N-terminal kinase (JNK) pathway is an important stress-responsive kinase activated by several forms of liver injury. The aim of this study is to assess the role of JNK during D-galactosamine (GalN)/lipopolysaccharide (LPS)-induced liver injury, an experimental model of FHF, using SP600125. a small molecule JNK-specific inhibitor. Mice were given an intraperitoneal dose of GalN (800 mu g/g body weight)/LPS (100 ng/g body weight) with and without subcutaneous SP600125 (50 mg/kg body weight) treatment (at 6 and 2 h before and 2 h after GalN/LPS administration). GalN/LPS treatment induced sustained INK activation. Administration of SP600125 diminished INK activity, suppressed lethality and the elevation of both serum alanine aminotransferase and aspartate aminotransferase, but had no effect on serum tumor necrosis factor-alpha. and reduced hepatocyte apoptosis after GalN/LPS administration. In support of the role of JNK in promoting the mitochondria-mediated apoptosis pathway, SP600125 prevented cytochrome c release, caspase-9 and caspase-3 activity. Moreover, SP600125 downregulated the mRNA and protein expression of Bad in the early periods following GalN/LPS injection and prevented Bid cleavage in the late periods. These results confirm the role of JNK as a critical apoptotic mediator in GalN/LPS-induced FHF. SP600125 has the potential to protect FTF by downregulating Bad and inhibiting Bid cleavage. (c) 2007 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.lfs.2006.12.034

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ALPHAMED PRESS  

Few studies on the long-term culture of postnatal mouse hepatic stem/progenitor cells have been reported. We successfully adapted a serum-free culture system that we employed previously to expand fetal mouse hepatic stem/progenitor cells and maintained them in culture over long periods. The expanded postnatal cells contained immature alpha-fetoprotein-positive cells along with hepatocytic and cholangiocytic lineage-committed cells. These cells expressed CD49f but not CD45, CD34, Thy-1, c-kit, CD31, or flk-1, and oncostatin M induced their differentiation. This heterogeneous population contained side population (SP) cells, which express the ATP-binding cassette transporter ABCG2, and sca-1+ cells. As mice aged, the frequency of SP and sca-1+ cells decreased along with the ability of cultured cells to expand. Approximately 20%-40% of the SP cells expressed sca-1, but only a few sca-1+ cells were also SP cells. Analysis of colonies derived from single SP or sca-1+ cells revealed that, although both cells had dual differentiation potential and self-renewal ability, SP cells formed colonies more efficiently and gave rise to SP and sca-1+ cells, whereas sca-1+ cells generated only sca-1+ progeny. Thus, SP cells are more characteristic of stem cells than are sca-1+ cells. In regenerating livers, ABCG2+ cells and sca-1+ cells were detected around or in the portal area (the putative hepatic stem cell niche). The expanded cells share many features of fetal hepatic stem/progenitor cells or oval cells and may be useful in determining the mechanisms whereby hepatic stem cells self-renew and differentiate.

DOI： 10.1634/stemcells.2006-0558

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The molecular mechanism of the cell-cycle machinery in hepatocellular carcinoma (HCC) has not yet been fully elucidated. Among the various types of cell-cycle regulators, p16 and p27 are now considered to be potent tumor suppressors. p16 is a G1-specific cell-cycle inhibitor that prevents the association of cyclin-dependent kinase (CDK) 4 and CDK6 with cyclin D, Many studies have reported that p16 is inactivated not only in aggressive types of HCC but also in preneoplastic liver cirrhosis. In many cases of HCC, p16 is mainly inactivated by extensive CpG methylation, suggesting that epigenetic changes in the p16 gene may be important events during hepatocarcinogenesis. p27, an inhibitor of CDK2, is presently regarded as a potent adverse prognostic factor in many aggressive cancers. It should be noted that some cases of HCC show increased cell proliferation despite the expression of considerable amounts of p27. In these cases, p27 is inactivated by sequestration kinto cyclin D-1-CDK4-containing complexes. Al, though the reason for the compositional changes in the p27-containing complexes is unclear, our experimental results indicate that loss of p16 following DNA methylation is closely related to the functional inactivation of p27 in HCC. We suggest that assessment of the p16 status may be useful for a precise prognostic prediction for individuals with HCCs expressing high levels of p27.

DOI： 10.1007/s00795-006-0339-2

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Background/Aims: The immune response to tumor-specific antigens is typically unable to control the growth and spread of malignant cells. Accumulating evidence indicates that the suppressive effects of CD4(+) CD25(+) regulatory T-cells are at least partially responsible for the failure of immune-mediated elimination of tumor cells.
Methods: We have studied 25 patients with hepatocellular carcinoma (HCC). The liver tissues with HCC were separated into the marginal region of tumor (peri-tumor region) and the non-tumor region distant from the tumor. CD4(+) CD25(+) T-cells were quantified in the blood and the liver by flow cytometry and immunohistochemistry, and their effect on T-cell proliferation and activation was determined.
Results: We found a significant increase in both the proportion and absolute numbers of CD4(+) CD25(+) T-cells in the peri-tumor regions, but not in unaffected areas (9.5 4.5 vs. 4.6 2.8%, P = 0.011). C134(+) CD25(+) T-cells isolated from peri-tumor regions displayed phenotype markers characteristic of regulatory T-cells, and expressed Foxp3 mRNA. CD8(+) T-cells in peri-tumor regions were inversely proportional to CD4(+) CD25(+) T-cells in the same region (P &lt; 0.001). Moreover, isolated C134(+) CD25(+) T-cells inhibited autologous C138(+) T-cell proliferation.
Conclusions: Our results suggest that CD4(+) CD25(+) T-cells in the marginal region of HCC may play a critical role in controlling CD8(+) cytotoxic T-cell activity and, thereby, contribute to the progression of HCC. (c) 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jhep.2006.01.036

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The human hepatocellular carcinoma (HCC)-derived cell line KYN-2 is thought to provide a good model for studying the molecular basis of invasion and metastasis of human HCC, because it often shows cell scattering in vitro and intrahepatic metastasis in vivo. We previously found that integrin-mediated extracellular signals inactivated E-cadherin in KYN-2, and caused loss of cell-cell contact with gain of cell motility, which is considered to be a critical step in the process of cancer cell invasion and metastasis. To further understand molecular mechanisms involved in biological aggressiveness of HCC, we investigated intracellular signaling involved in integrin-mediated scattering of KYN-2 cells. Cultured KYN-2 cells formed trabecular aggregates in suspension, but when adhering to integrin-stimulating substrata, they scattered according to phosphorylation of extracellular signal-regulated kinase (ERK). Upon treatment with ERK kinase (MEK) inhibitor PD98059, adhered KYN-2 cell scattering was inhibited, tight cell-to-cell contact was recovered, and both E-cadherin and actin filaments accumulated in the area of intercellular contact zone. In contrast, constitutively active MEK1-transfected KYN-2 cells showed reduced E-cadherin and actin filaments in the intercellular contact zone, showing a flattened phenotype with broad lamellipodia. Enforced signaling of MEK-ERK pathway in KYN-2 cells suppressed cadherin-mediated homotypic adhesion and increased the potential of cell motility. An antibody-based protein microarray analysis revealed that the cytoplasmic protein c-Cbl was significantly downregulated in MEK1-transfected KYN-2 cells, suggesting that c-Cbl might be a candidate downstream mediator of integrin/MEK/ERK-mediated cell scattering. In conclusion, cell scattering of the highly metastatic cell line KYN-2 is regulated through the integrin-MEK-ERK signaling cascade, suggesting that this molecular pathway may be critical in intrahepatic metastasis of human HCC.

DOI： 10.1038/labinvest.3700427

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A 48-year-old man was admitted to our hospital because of repeated episodes of epigastralgia. Endoscopy showed multiple whitish granules extending from the 2nd to 3rd portion of the duodenum. Biopsy specimens showed well circumscribed follicles with a monotonous population of predominantly small cleaved cells that were positive for CD20, CD10 and BCL-2, but negative for CD5. A full staging study showed no abnormalities. The tumor was finally diagnosed according to the WHO classification as a stage I follicular lymphoma (FL), grade 1, of the duodenum and subsequently received irradiation to the involved area. After 3 years of follow-up, he is still in complete remission. Because FL arising in the duodenum has recently reported with increasing frequency, patients with multiple granules in the duodenum should be examined carefully. © 2006 The Japanese Society of Internal Medicine.

DOI： 10.2169/internalmedicine.45.1464

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AIM: To determine which treatment modality hepatectomy or percutaneous ablation - is more beneficial for patients with small hepatocellular carcinoma (HCC) (&lt;= 4 cm) in terms of long-term outcomes.
METHODS: A retrospective analysis of 149 patients with HCC &lt;= 4 cm was conducted. Eighty-five patients underwent partial hepatectomy (anatomic in 47 and non-anatomic in 38) and 64 underwent percutaneous ablation (percutaneous ethanol injection in 37, radiofrequency ablation in 21, and microwave coagulation in 6). The median follow-up period was 69 mo.
RESULTS: Hepatectomy was associated with larger tumor size (P&lt;0.001), whereas percutaneous ablation was significantly associated with impaired hepatic functional reserve. Local recurrence was less frequent following hepatectomy (P&lt;0.0001). Survival was better following hepatectomy (median survival time: 122 mo) than following percutaneous ablation (median survival time: 66 mo; P = 0.0123). When tumor size was divided into &lt;= 2 cm vs &gt; 2 cm, the favorable effects of hepatectomy on long-term survival was seen only in patients with tumors &gt;2 cm (P=0.0001). The Cox proportional hazards regression model revealed that hepatectomy (P=0.006) and tumors &lt;= 2 cm (P=0.017) were independently associated with better survival.
CONCLUSION: Hepatectomy provides both better local control and better long-term survival for patients with HCC &lt;= 4 cm compared with percutaneous ablation. Of the patients with HCC &lt;= 4 cm, those with tumors &gt; 2 cm are good candidates for hepatectomy, provided that the hepatic functional reserve of the patient permits resection. (C) 2006 The WJG Press. All rights reserved.

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BACKGROUND. Inhibitor of differentiation/ DNA binding protein 1 (Id-1) plays a pivotal role in the regulation of cell proliferation and carcinogenesis via inhibiting basic helix-loop -helix (HLH) transcription factors. Recently, Id-1 was found to repress p16 in tumorous tissue specimens including hepatocellular carcinoma (HCC), but its relevance in precancerous liver tissues is unknown.
METHODS. Id-1 expression in the liver tissue specimens of 112 patients with cirrhosis without HCC was studied by immunohistochemical analysis. Correlations were investigated between Id-1 expression and clinicopathologic features, the status of p16, and the risk of HCC occurrence.
RESULTS. A high expression of Id-1 was observed in 42 patients (38%). The level of Id-1 expression was not associated with clinical standard parameters or the status of p16 in cirrhotic tissue specimens. The cumulative incidence of HCC development was significantly higher in a group of patients with high Id-1 expression (P 0.0008). Multivariate analysis revealed that increased Id-1 expression is an independent significant factor for the risk of HCC development in patients with cirrhosis (relative risk = 2.75, P = 0.003).
CONCLUSIONS. The results of the current study suggested that increased expression of Id-1 may play an important role in the early step of hepatocarcinogenesis, and might serve as a useful marker for determining patients with cirrhosis with a high risk of HCC occurrence.

DOI： 10.1002/cncr.21259

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Background &amp
Aims: The liver has high regenerative potential. We attempted to establish a novel culture system for extensive expansion of fetal mouse hepatic stem/progenitor cells and to characterize cultured cells. Methods: Hepatic spheroids collected from 6-day floating cultures were cultured on collagen-coated dishes in serum-free conditions in medium containing growth factors. Cultured cells were mainly characterized by immunocytochemistry and flow cytometry or transplanted into adult mice. Results: Approximately 400 expanding hepatic spheroids were generated from every 1 × 106 fetal liver cells. Subsequently, highly replicative colonies were subcultured with maintaining colony formation on collagen-coated dishes. These colonies consisted of small immature α-fetoprotein-positive cells and hepatocytic and cholangiocytic lineage-committed cells. The immature α-fetoprotein- positive cells could be expanded in a reproducible manner at least 5 × 105-fold (which involved at least 30 passages over &gt
6 months) without losing differentiation potential. Flow cytometric analysis showed that all cultured cells expressed CD49f, but not CD34, Thy-1, c-kit, or CD45. Nearly 15% of the cells expressed Sca-1, and approximately 5%-20% of the cells were side population cells. Both sorted side population cells and Sca-1-positive cells (especially side population cells) produced a large number of α-fetoprotein-positive cells and lineage-committed cells. Expanded cells had bidirectional differentiation potential and improved serum albumin levels in mice with severe liver damage. Conclusions: Long-term extensive expansion of transplantable hepatic stem/progenitor cells was reproducibly achieved in a novel serum-free culture system. Moreover, this culture system yielded side population and Sca-1-positive cell populations that included hepatic stem/progenitor cells with differentiation and proliferation properties. © 2005 by the American Gastroenterological Association.

DOI： 10.1053/j.gastro.2005.03.030

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A case of the complete shrinkage of pulmonary metastases from multiple hepatocellular carcinomas (HCC) after administration of docetaxel, cisplatin and enteric-coated tegafur/uracil is reported. A 54-year-old Japanese man was diagnosed with recurrent multiple HCC associated with pulmonary metastases and compensated liver cirrhosis. Docetaxel, cisplatin and enteric-coated tegafur/uracil were given to this patient. After 2 months of treatment, there was a decrease in tumor markers and a shrinkage of the pulmonary metastases. Image analyses such as chest X-rays and chest computed tomography scans showed a disappearance of the pulmonary metastases, although the multiple HCC did not disappear completely. This was evaluated as a complete remission of metastatic lesions or a partial remission of primary lesions according to the World Health Organization criteria. No recurrence of pulmonary metastasis was seen for 10 months. This combination therapy was well-tolerated for lung cancer and could represent an effective treatment for pulmonary metastases from HCC. (C) 2004 Blackwell Publishing Asia Pty Ltd.

DOI： 10.1111/j.1400-1746.2004.03737.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL MUNKSGAARD  

Background: Dysregulation of cell proliferation is one of the most important features of human cancers including hepatocellular carcinoma (HCC). However, the molecular basis underlying the proliferation of HCC has not been fully clarified. Because a previous study reported that overexpression of extracellular signal-regulated protein kinase (ERK), which transduces extracellular growth stimuli to the nuclei, was frequently observed in several human cancers, this study was performed to analyze the expression of ERK in human HCC and its correlation with HCC proliferation. Methods: Twenty-four paired samples of primary HCCs and corresponding noncancerous liver tissues, and six samples of histologically normal liver tissue were obtained from surgically resected materials. The expression of ERK was examined by immunoblotting and immunohistochemical analysis. Proliferative activity of each HCC was examined by immunohistochemical demonstration of proliferative cell nuclear antigen (PCNA). Results: The ERK1 and ERK2 expression in HCCs was significantly higher than that in noncancerous liver tissues, and the ERK1 expression in noncancerous liver tissues from patients with HCC was higher than that in tissue from normal liver. Immunohistochemical examination revealed enhanced accumulation of ERK1 in the nuclei of HCC cells. Regression analysis revealed a significant correlation between ERK expression and PCNA labeling index in HCC. Conclusions: Our findings suggest that ERK overexpression contributes to the proliferation of HCC.

DOI： 10.1111/j.1478-3231.2004.0940.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI IRELAND LTD  

Liver-intestine cadherin (LI-cadherin) is a recently identified member of the cadherin superfamily. We examined LI-cadherin expression in four human colorectal carcinoma cell lines and 45 human primary colorectal carcinomas using a monoclonal antibody against LI-cadherin. We also investigated the correlation between LI-cadherin expression and clinicopathologic parameters. Among the cell lines, LI-cadherin expression was detected in a differentiated phenotype, but not in dedifferentiated phenotypes. Among the 45 tumor samples, LI-cadherin expression was preserved in 28 (62%) and reduced in 17 (38%). Reduced LI-cadherin expression was significantly associated with a high tumor grade (P = 0.015), lymphatic invasion (P = 0.033), lymph node metastasis (P = 0.015), and an advanced pTNM stage (P 0.033). These results suggest that analysis of LI-cadherin expression may help to indicate the biological aggressiveness of this malignancy. (C) 2004 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.canlet.2004.03.016

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

We report a 54-year-old Japanese woman who developed liver tumors 102 months after hepatic resection for hepatocellular carcinoma (HCC) and percutaneous transluminal angioplasty (PTA) for membranous obstruction of the inferior vena cava (MOVC), which is one form of Budd-Chiari syndrome. In the present admission workup showed no evidence of co-infection with hepatitis B and C viruses. Dynamic computed tomography (CT) and magnetic resonance imaging showed an enhanced lesion, 1.5 cm in diameter, in segment 3 of the liver, and no obstruction of the inferior vena cava after PTA. CT during both arterial portography and hepatic arteriography revealed another lesion, showing different hemodynamics, in segment 2. The patient therefore underwent hepatic resection, and the tumors were diagnosed histologically as HCC. The two tumors differed in their morphological features, one containing abundant fibrous stroma, whereas the other did not. The nontumorous liver tissue showed central zonal fibrosis, i.e., reversed lobulation, and partial expansion of nodule-like formations, indicating lack of progression since the situation seen at the initial hepatectomy. The presence of nontumorous liver tissue showing the above features suggests that, even after successful treatment for relief of congestion, patients who have had MOVC should be followed closely for as long as possible because of the risk of HCC recurrence. This is the first reported case of HCC recurrence after successful treatment of MOVC.

DOI： 10.1007/s535-004-1365-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Purpose: p27(Kipl) (p27) might act as an adverse prognostic marker for various types of cancers. However, its clinical usefulness remains uncertain, because it is sometimes overexpressed in aggressive types.
Experimental Design: To precisely evaluate the practical significance of p27 in hepatocellular carcinoma (HCC), we immunohistochemically compared the level of p27 expression with Ki-67 labeling in 74 HCCs and focused on tumors in which cell proliferation increased despite a high level of p27 expression. We then analyzed the status of p27 and related cell-cycle regulators using kinase and immuno-precipitation assays, Western blotting, and methylation-specific PCR to understand the rationale for the functional inactivation of p27 in HCC. We also evaluated relationships between the key biological characteristics of HCC and survival.
Results: Immunohistochemical studies showed that 40 (54%) of 74 HCCs expressed high levels of p27 (&gt;50% of the tumor cells). Of these, the Ki-67 labeling index was low (&lt;20%) in 26 (65%) and high (&gt;20%) in 14 (35%). Increased proliferative activities were closely correlated with elevated kinase activities, sequestration of p27 protein, and p16 gene methylation. The association between a loss of p16 and poor prognosis was significant when p27 expression was high (P &lt; 0.01).
Conclusions: The loss of p16 appears to be closely related to the functional inactivation of p27, and assessment of p16 status may be useful for a precise prognostic prediction of individuals with HCC expressing high levels of p27.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BRITISH MED JOURNAL PUBL GROUP  

Background and aims: The genetic contribution to inflammatory bowel disease (IBD) is under investigation. Recent evidence indicates a significant linkage between a locus on chromosome 19p13 and IBD. We investigated the association between an intercellular adhesion molecule 1 gene (ICAM-1) polymorphism located on chromosome 19p13 and IBD in a Japanese population.
Methods: We compared 207 Japanese patients who had IBD (79 with Crohn's disease (CD); 128 with ulcerative colitis (UC)) with 103 unrelated Japanese controls. We determined R241G and K469E polymorphisms of the ICAM-1 gene using polymerase chain reaction (PCR) techniques.
Results: Both frequency and carriage rate of the K469 allele were significantly higher in IBD patients than in controls (allelic frequency, p(c)=0.0026; carriage rate, p(c)=0.0034; odds ratio 2.59; 95% confidence interval 1.42-4.68). Furthermore, the frequency of the K469 allele was significantly increased in both CD and UC. Subgroup analysis demonstrated that both K469 allelic frequency and K469 carriage rate were significantly higher in patients with the small bowel and colon type of CD and entire colitis compared with healthy controls.
Conclusions: We identified an overall association between IBD and ICAM-1 K469 in a Japanese population. Further studies of this chromosome region are required to elucidate the gene responsible for IBD.

DOI： 10.1136/gut.52.1.75

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI IRELAND LTD  

Thrombocytopenia is one of the major complications of liver cirrhosis. Except for hypersplenism associated with portal hypertension, it is not known which abnormalities of thrombopoiesis cause thrombocytopenia. To evaluate thrombopoiesis in liver cirrhosis, we analyzed thrombopoietin (TPO) and its receptor c-Mpl levels in cirrhotic patients. Expression of c-Mpl on platelets and the serum level of TPO were investigated from 38 patients with various stages of liver cirrhosis by flow-cytometric analysis and enzyme-immuno assay. Samples obtained from 22 individuals without evidence of liver disease were used as controls. Neither platelet counts nor TPO levels correlated with disease progression defined by the Child-Pugh classification. c-Mpl was constitutively expressed on the platelets of cirrhotic patients, and its expression level was reduced with disease progression defined by the Child-Pugh classification. In this study, serum TPO did not fluctuate according to the grade of cirrhosis. However, its receptor c-Mpl, which is expressed on platelets, was decreased significantly in severely cirrhotic patients with thrombocytopenia. Thus, a correlation between reduced c-Mpl expression and the progression of liver cirrhosis was demonstrated. We conclude that, in addition to hypersplenism, the reduced expression of c-Mpl may play a significant role in the thrombocytopenia observed in severe liver cirrhosis. (C) 2002 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S1386-6346(01)00170-X

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE ASIA  

Background and Aims: The main causes of thrombocytopenia in cirrhosis are thought to be platelet destruction and the reduction of thrombopoietin (TPO) expression in the liver. The mechanisms by which levels of TPO mRNA are regulated in cirrhosis have not been elucidated. In this study, we investigated some possible mechanisms.
Methods: We used three experimental models: bone marrow suppression, acute liver injury and primary cultured hepatocytes. We used northern blots to assess the kinetics of TPO mRNA expression in the livers of irradiated rats (with and without cirrhosis) in acute liver injury and in primary cultured hepatocytes treated with hepatotoxin or cytokines.
Results: Although the bone marrow was hypocellular, there was no apparent enhancement of TPO mRNA expression in the irradiated rats with cirrhotic livers compared with the unirradiated rats with cirrhotic livers. There were no conspicuous changes in hepatic TPO mRNA expression between the livers of the control rats and the three models of acute liver injury. There were no conspicuous changes in the levels of TPO mRNA between control hepatocytes and hepatocytes treated with hepatotoxin or cytokines.
Conclusions: Our results suggest that bone marrow is not a regulator of hepatic TPO production in cirrhosis. The reduced TPO mRNA expression found in cirrhotic rats may not result merely from serious cellular damage; it may be associated with cirrhosis-specific regulatory mechanisms for the expression of the TPO gene. Further studies are needed to search for other factors that may induce reduced TPO expression. (C) 2000 Blackwell Science Asia Pty Ltd.

DOI： 10.1046/j.1440-1746.2000.02087.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CHURCHILL LIVINGSTONE  

Post-translational stabilization of beta-catenin through mutation of the adenomatous polyposis coli (APC) gene has been proposed as an early step in colorectal carcinogenesis. Beta-catenin may translocate from the cytoplasm to the nucleus, where it might serve as a transcriptional factor to stimulate tumour formation. We investigated intracellular localization of beta-catenin in sporadic colorectal adenomas and cancers as well as familial adenomatous polyposis (FAP). Nuclear over-expression of beta-catenin was observed in 35% (7/20) of intramucosal cancers and 42% (23/55) of invasive cancers but was not seen in any adenomas from sporadic or FAP cases. Cytoplasmic beta-catenin in adenomas was significantly higher than that of normal mucosa in both sporadic and FAP cases. The cytoplasmic intensity index of cancers was significantly higher than that of sporadic adenomas, but the index was not correlated with nuclear expression in cancers. These findings suggest that nuclear translocation of beta-catenin is involved in development of intramucosal cancer rather than adenoma, independent of APC mutations. Cytoplasmic accumulation of beta-catenin may occur in adenomas, but it remains to be determined whether this is a cause or a consequence of colorectal cancer. (C) 2000 Cancer Research Campaign.

DOI： 10.1054/bjoc.1999.1112

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE ASIA  

Background: A significant increase in serum hyaluronan (HA) levels has been reported in patients with liver cirrhosis. This mechanism is not yet clear, and receptors for HA have not been characterized. In this study, we examined the expression of both HA and its receptors, CD44 and intercellular adhesion molecule-1 (ICAM-1), in dimethylnitrosamine-induced liver cirrhosis.
Methods and Results: Using biotinylated HA binding protein, HA was detected in the area of periportal fibrosis and around the sinusoidal wall where hepatic fibrosis was developing. Electron microscopy revealed that HA was localized on Ito cells and sinusoidal endothelial cells (SEC). Conversely, CD44, which was only expressed weakly in normal liver, was present in large amounts in cirrhotic liver. The distribution pattern of CD44 was similar to that of HA, however, CD44 was mainly localized on the infiltrating lymphocytes and Kupffer cells. Moreover, CD44 was detected on part of factor VIII-positive SEC. intercellular adhesion molecule-1, another receptor for HA, was detected on the surface of hepatocytes and around the sinusoidal wall in cirrhotic liver, but its distribution was not accompanied by expression of HA. With respect to CD44 isoforms, the standard form m-RNA predominated in both normal and cirrhotic liver. Variant pMeta-1 mRNA was detected at low levels.
Conclusions: An interaction between HA and CD44 may play a role in the recruitment of numerous infiltrating cells and HA accumulation in hepatic sinusoids. Together with phenotypic changes in the SEC, these results may lead to a disturbance in the elimination of HA during the progression of liver cirrhosis. (C) 2000 Blackwell Science Asia Pty Ltd.

DOI： 10.1046/j.1440-1746.2000.02164.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO  

Background & Aims: The molecular status of the p16(INK4) tumor-suppressor gene has not been fully elucidated in hepatocellular carcinoma. The aim of this study was to clarify the mechanism that gives rise to inactivation of p16(INK4) in hepatocellular carcinoma. Methods: The status of p16(INK4) was evaluated in 60 hepatocellular carcinomas by immunohistochemical staining, differential polymerase chain reaction, single-strand conformational polymorphism, methylation-specific polymerase chain reaction, and methylation-sensitive single nucleotide primer extension. Results: Immunohistochemical staining showed that 29 of the 60 tumors exhibited complete toss of p16(INK4) expression. High levels of DNA methylation were detected in 24 of 29 cases of hepatocellular carcinoma with negative p16(INK4) expression, with methylation of 60%-85% of the CpG islands. In contrast, the level of methylation was &lt;25% in tumors with faint p16(INK4) staining and no methylation was detected in tumors with positive immunostaining. Intragenic alteration of p16(INK4) was detected in 4 cases. Conclusions: A strong correlation was found between the extent of methylation and the degree of expression of p16(INK4) in tumor tissues, indicating that epigenetic change due to extensive CpG methylation is the main cause of inactivation of p16(INK4) in hepatocellular carcinoma.

DOI： 10.1016/S0016-5085(99)70137-X

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MUNKSGAARD INT PUBL LTD  

Aims/Background: Thick hepatic plates have been considered one of the morphological characteristics of hepatocyte regeneration in cirrhotic nodules. They can be recognized by the sinusoidal surface predominance of their nuclei. We have investigated the prevalence of this in HBV and HCV infections. Methods and Results: This feature was more frequently present in type C chronic hepatitis with low activity of inflammation and low grade of fibrosis, than with type B chronic hepatitis. Additionally, this area of sinusoidal surface hepatocyte nuclear predominance (ASSHNP) was seen in zone II, rather than in periportal zones, in type C chronic hepatitis. Clinical data were analyzed statistically. Immunohistochemical reactivity of type IV collagen, laminin, Ulex europaeus agglutinin 1 lectin (UEA-1), and factor VIII-related antigen were increased in ASSHNP. Immunohistochemical staining of Ki-67 antigen was performed in order to assess the regenerative capacity of this area and showed a low level of regeneration. Ultrastructure of this area in type C chronic hepatitis showed a decrease in the number of mitochondria and an increase of nuclear pleomorphism together with basement membrane formation in the space of Disse. Conclusion. Although the cause of these abnormalities was not clarified in this study, it is suggested that they are related to chronic hepatitis C virus (HCV) infection per se, rather than regeneration or inflammatory activity. These changes may be significant in HCV-associated hepatocarcinogenesis.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE  

It is widely accepted that thrombocytopenia associated with liver cirrhosis is caused by increased platelet destruction in the enlarged spleen, but this issue has not yet been analysed sufficiently in terms of platelet production. Thrombopoietin is produced mainly in the liver and strongly promotes platelet production. We studied serum thrombopoietin and the levels of its mRNA in liver tissue of cirrhotic patients and also in a rat model of liver cirrhosis. Furthermore, to clarify the influence of the spleen, we investigated thrombopoietin mRNA in splenectomized rats. The serum thrombopoietin level in humans with liver cirrhosis was not significantly reduced instead of thrombocytopenia. The expression of thrombopoietin mRNA in liver tissue decreased with the progression of liver cirrhosis in both patients and the rat model and no compensatory expression was observed in other organs or nonparenchymal cells. The level of thrombopoietin mRNA did not differ significantly in splenectomized cirrhotic rats before or after administration of dimethylnitrosamine, but was lower than that in splenectomized rats without cirrhosis. We conclude that thrombocytopenia in liver cirrhosis is caused not only by platelet destruction but also by decreased platelet production, perhaps due to reduction of thrombopoietin mRNA in the liver.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE  

It has been reported that the presence of anti-nuclear antibody against a 210 kDa glycoprotein of nuclear pore complex (anti-gp210) is highly specific for primary biliary cirrhosis (PBC). The aim of the present study was to investigate the significance of anti-gp210, especially as a prognostic marker. The presence of anti-gp210 was ascertained in 113 patients with PBC and 162 controls by indirect immunofluorescence assay using HepG2. cells and immunoblotting analysis using nuclear extracts from HeLa cells. Anti-gp210 was detected in 25 of the 113 (22.1%) patients. None of the 162 controls was positive for anti-gp210. The appearance and titre of anti-gp210 in the patients with PBC did not vary from the time of diagnosis and through their clinical course. Anti-mitochondrial antibodies (AMA), including antibodies against pyruvate dehydrogenase complex, branched chain a-ketoacid dehydrogenase complex and or-ketoglutarate dehydrogenase complex, were not detected by enzyme-linked immunosorbent assay in five of the 113 (4.4%) patients with PBC. However, anti-gp210 alone was positive in one of these five patients. The difference in prognosis was statistically significant; patients with PBC positive for anti-gp210 died from hepatic failure more frequently than those who were negative (P &lt; 0.01), although there were no statistically significant differences in the frequency of jaundice and the histological stage at the time of diagnosis between the two groups. We suggest that the presence of anti-gp210 is one of the independent prognostic markers able to predict, at the time of diagnosis, a poor outcome in patients with PBC.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO  

Background & Aims: Activin A, a member of the transforming growth factor (TGF)-beta superfamily, recently has been reported to suppress DNA synthesis and to induce apoptosis of hepatocytes. These biological functions are similar to those of TGF-beta 1, which is overexpressed in liver cirrhosis. The aim of this study was to examine whether activin A is involved in liver cirrhosis and fibrosis. Methods: Liver cirrhosis or fibrosis was induced by intraperitoneal injections of dimethylnitrosamine or porcine serum into rats. The kinetics of activin A messenger RNA (mRNA) expression in cirrhotic and fibrotic livers and primary cultured rat hepatocytes were assessed by Northern blotting, and the localization of activin A was determined immunohistochemically. Modulation of type 1 collagen mRNA expression by activin A in rat cultured Ito/fat-storing cells and fibroblasts was also examined. Results: Northern blotting showed that activin A mRNA expression was enhanced in fibrotic livers. The numbers of hepatocytes expressing immunoreactive activin A were significantly greater, especially around the fibrotic areas. Activin A mRNA expression in cultured hepatocytes was increased significantly by TGF-beta 1 and by activin A itself. Furthermore, type 1 collagen mRNA expression in cultured cells was enhanced by activin A and TGF-beta 1 in a synergistic manner. Conclusions: Activin A is overexpressed in rat cirrhotic and fibrotic livers and may contribute to hepatic fibrogenesis.

DOI： 10.1016/S0016-5085(98)70539-6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE  

Administration of dextran sulphate sodium to animals induces acute colitis characterized by infiltration of large numbers of neutrophils into the colonic mucosa, which histologically resembles human active ulcerative colitis. It has been reported that neutrophils and the reactive oxygen metabolites produced by them are involved in the progress of ulcerative colitis. This study was intended to clarify their roles by using this animal model. First, possible sources and species of reactive oxygen metabolites were determined using luminol-dependent chemiluminescence with addition of enzyme inhibitors and reactive oxygen metabolite scavengers. Next, to examine whether neutrophils and hypochlorous acid derived from them contribute to tissue injury, we administered RP-3, a monoclonal antibody capable of selectively depleting neutrophils, and taurine, a hypochlorous acid scavenger, to rats treated with dextran sulphate sodium. Addition of azide, taurine, catalase, superoxide dismutase and dimethyl sulphoxide into colonic mucosal scrapings significantly inhibited chemiluminescence production, but allopurinol and indomethacin had no effects. These results suggest that excessive hypochlorous acid, hydrogen peroxide, superoxide anion and hydroxyl radical are generated by the inflamed colonic mucosa. Intraperitoneal injections of RP-3 significantly suppressed bleeding, tissue myeloperoxidase activity, chemiluminescence production and erosion formation. On the other hand, administration of taurine tended to inhibit bleeding and erosion formation to some extent, although it could not significantly suppress them. These data suggest that neutrophils play an important role in the development of this colitis and that hypochlorous acid might be one of the causes of tissue injury induced by neutrophils.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL MUNKSGAARD  

Metallothionein is the carrier protein of heavy metal ions, such as copper (Cu) and zinc (Zn). In this study, the relationships among immunohistochemical expression of metallothionein, concentrations of Cu and Zn, histological differentiation and proliferative activity of hepatocellular carcinoma were investigated in 51 cases. The concentrations of Cu and Zn in both tumor and non-tumor tissues were determined using electron probe microanalysis. Immunohistochemical expression of metallothionein in tumor tissues decreased with the degree of differentiation, whereas the number of hepatocytes positive for Ki-67 increased. Furthermore, the concentrations of Cu and Zn in tumor tissues decreased with the degree of histological differentiation in human hepatocellular carcinoma.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：John Wiley and Sons Inc.  

Liver fibrosis/cirrhosis is characterized by hyper-accumulation of fibrous tissue components and is commonly observed in later or terminal states of chronic hepatic diseases. In ongoing work, we found that the administration of human recombinant hepatocyte growth factor (hrHGF) suppressed the onset of liver fibrosis/cirrhosis in several distinct models and accelerated the recovery from liver fibrosis/cirrhosis in rats. Repeated administration of porcine serum for 10 weeks to rats induced liver fibrosis without any accompanying hepatocellular injuries
in addition, the intravenous (i.v.) administration of hepatocyte growth factor (HGF) to these rats suppressed increases in fibrous components and hydroxyproline contents in the liver, thus preventing the onset of liver fibrosis. Repeated administration of dimethylnitrosamine (DMN) for four weeks induced liver cirrhosis, as characterized by the hyperaccumulation of fibrous components, infiltration of mononuclear leukocytes, and hepatic dysfunction. When HGF was injected daily for four weeks along with DMN-treatment, the onset of DMN- induced hepatic fibrosis/cirrhosis was suppressed
the numbers of infiltrating mononuclear cells, fibrous tissue components, and hydroxyproline content in the liver were decreased. When HGF was injected for two weeks following four weeks of DMN-treatment, HGF accelerated the recovery from liver cirrhosis and prevented death due to hepatic dysfunction. Likewise, HGF-injection suppressed the onset of liver fibrosis, when liver fibrosis had been induced by long-term treatment with carbon tetrachloride (CCl4). Thus, the administration of HGF holds great promise for treating subjects with liver fibrosis/cirrhosis as a result of chronic hepatic injury.

DOI： 10.1002/hep.510260111

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MUNKSGAARD INT PUBL LTD  

Circulating hyaluronan is mostly derived from lymph, fibroblast and Ito cells in the liver; and more than 90% of hyaluronan is degraded in hepatic sinusoidal endothelial cells. Thus, elevated serum hyaluronan is regarded as an indication of hepatic fibrosis with activated Ito cells and dysfunctional sinusoidal endothelial cells. We studied the distribution of hyaluronan in human liver sinusoids to determine the influences on elevated hyaluronan levels in sera. Histochemical examination was made using hyaluronan-binding protein (HABP) and serial sections of liver tissue for staining of alpha-smooth muscle actin (ASMA) (an indicator of activated Ito cells) and of ulex europaeus agglutinin I lectin (UEA-1) (closely related to hepatic sinusoidal capillarization). Positive staining, indicating the presence of hyaluronan, was noted in fibrous regions around the portal tracts, areas of focal necrosis in the liver parenchyma, and walls of the sinusoids in chronic hepatitis. In this group, hyaluronan-positive areas corresponded to positive ASMA staining and faint staining of UEA-1. On the contrary, in liver cirrhosis, UEA-1-positive areas were essentially identical to hyaluronan-positive areas and to ASMA-negative areas in sinusoidal walls. Hyaluronan and ASMA could be detected in the same areas of sinusoidal walls in chronic hepatitis, but not in liver cirrhosis. Hyaluronan appears to be mainly related to the staining of activated Ito cells in chronic hepatitis. Therefore, we concluded that in chronic hepatitis, the production of hyaluronan was accelerated in Ito cells; however, degradation of hyaluronan by sinusoidal endothelial cells continued. On the contrary, in liver cirrhosis, hyaluronan production decreased in Ito cells, and a marked transformation of sinusoidal endothelial cells with hepatic sinusoidal capillarization indicated loss of the ability to degrade hyaluronan. These different mechanisms in chronic hepatitis and liver cirrhosis may operate in the sinusoidal walls and may cause the elevation of hyaluronan in sera.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press  

Hepatic fibrosis/cirrhosis is a common hepatic disease characterized by the hyper-accumulation of connective tissue components, and hepatic necrosis. Chronic alcohol inges-tion, viral infection, and metabolic disorders are contributing factors and there has been no effective treatment. Hepatocyte growth factor (HGF), originally identified as a potent mitogen for mature hepatocytes, is a long-sought hepatotrophic factor for liver regeneration. Administration of human recombinant HGF into rats with hepatic fibrosis/cirrhosis caused by dimethylnitrosamine (DMN) elicited mitogenic action for hepatocytes, stimulated hepatic collagenase activity, and prevented the onset and progression of hepatic fibrosis/cirrhosis. Accumulation of fibrous tissue components in the liver due to DMN-treatment were markedly decreased in HGF-injected rats. Moreover, HGF completely abrogated death caused by severe hepatic cirrhosis and dysfunction. We postulate that HGF may prove to be an effective treatment for human liver fibrosis/cirrhosis and for chronic hepatic failure. © 1995 by the Journal of Biochemistry.

DOI： 10.1093/oxfordjournals.jbchem.a124958

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Hepatocyte growth factor (HGF) is the most potent mitogen of mature hepatocytes in primary culture, and is a molecule composed of 69 kD alpha-chain and 34 kD beta-chain. HGF predominantly acts on various epithelial cells as a mitogen, motogen and a morphogen. HGF mRNA and HGF protein increases rapidly in the liver and plasma of rats with liver injury such as hepatitis, ischemia, physical crush and partial hepatectomy. Production of HGF in the liver occurs in Kupffer cells, sinusoidal endothelial cells, and Ito cells, but not in hepatocytes. HGF mRNA is also rapidly increased in the intact organs such as lung, kidney and spleen. Thus, HGF may act as a hepatotrophic factor for liver regeneration through two mechanisms: a paracrine mechanism and an endocrine mechanism. Moreover, intravenously injected HGF enhances liver regeneration and protects hepatitis in vivo. Consequently, HGF may prove to be useful for the clinical treatment of patients with liver disease. Recently, we found a factor which specially appears in the blood of rats with organ injury and increases the synthesis of HGF, and it was named &quot;injurin&quot;. IL-1 alpha and IL-1 beta are also positive regulators for the exp

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Hepatocyte growth factor (HGF) is the most potent mitogen of mature hepatocytes in primary culture, and is a molecule composed of 69 kD alpha-chain and 34 kD beta-chain. HGF predominantly acts on various epithelial cells as a mitogen, motogen and a morphogen. HGF mRNA and HGF protein increases rapidly in the liver and plasma of rats with liver injury such as hepatitis, ischemia, physical crush and partial hepatectomy. Production of HGF in the liver occurs in Kupffer cells, sinusoidal endothelial cells, and Ito cells, but not in hepatocytes. HGF mRNA is also rapidly increased in the intact organs such as lung, kidney and spleen. Thus, HGF may act as a hepatotrophic factor for liver regeneration through two mechanisms: a paracrine mechanism and an endocrine mechanism. Moreover, intravenously injected HGF enhances liver regeneration and protects hepatitis in vivo. Consequently, HGF may prove to be useful for the clinical treatment of patients with liver disease. Recently, we found a factor which specially appears in the blood of rats with organ injury and increases the synthesis of HGF, and it was named &quot;injurin&quot;. IL-1 alpha and IL-1 beta are also positive regulators for the exp

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MUNKSGAARD INT PUBL LTD  

Tenascin is an oligomeric glycoprotein of the extracellular matrix synthesized during embryonic development. It is prominently expressed in a variety of tumors. The role of tenascin in liver tissue is, however, unknown. We used immunocytochemistry to define the localization of tenascin and compare this with the localization of non-collagenous proteins, such as laminin and fibronectin, in normal human liver and pathological liver from patients with chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. In normal liver, tenascin expression was localized along the sinusoidal and vascular wall. In fibrotic liver, tenascin was also observed in the region between the hepatic parenchyma and the fibrosing portal tracts, especially in areas of piecemeal necrosis in chronic hepatitis. Immuno-EM study of liver tissue in chronic hepatitis strongly suggested the synthesis and secretion of tenascin by fat-storing cells into the space of Disse. In hepatocellular carcinoma, tenascin was expressed in both the capsule and lobular septa, but not in the sinusoidal walls of the tumors. These results led us to postulate a close relationship between the occurrence of this protein and disease processes such as fibrosis and cancer invasion.

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：English   Publisher：日本癌学会  

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Language：Japanese   Publisher：(株)ニュー・サイエンス社  

エクソソームは、細胞・細胞間コミュニケーションを司る機能をもつ不溶性粒子である。近年ではエクソソームががん診断・治療に有用な生体ツールであることが明らかにされて以降、その実用性に関する注目が集まっている。肝がんは化学療法耐性を伴う、予後不良な悪性疾患であり、エクソソームを用いた治療への期待は高い。肝がん由来のエクソソームはがん進展や転移能を促進し、薬剤耐性獲得にも関与しているため、今後はエクソソーム分泌阻害剤による肝がん治療法の開発が待たれている。(著者抄録)

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：新潟医学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY-BLACKWELL  

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Language：Japanese   Publisher：新潟大学医学部保健学科  

【目的】肝細胞癌(肝がん)は、化学療法の効果が乏しい予後不良な悪性疾患である。本研究では、新規の分子標的薬オーロラキナーゼ阻害剤の肝がんに対する作用機序を解析した。【方法】肝がん細胞株HepG2にオーロラキナーゼ阻害剤AZD1152を添加し、細胞シグナルをウエスタン・ブロットで解析した。また分子標的薬ソラフェニブをAZD1152と併用して、アポトーシス誘導率や細胞増殖を観察した。【結果】AZD1152単剤は、がん細胞の増殖は抑制するものの、細胞殺傷効果は認められなかった。AZD1152添加後のがん細胞では、ストレスキナーゼERKが著明に活性化しており、ERK阻害剤やソラフェニブを併用するとアポトーシス細胞数がAZD1152単剤に比べ約20倍に増加した(p&lt;0.01)。【総括】AZD1152は肝がんに対する殺傷効果が極めて弱く、ERK活性化がその原因であることが示唆された。ソラフェニブはERK阻害作用を有しており、有意にオーロラキナーゼ阻害剤の効果を増強した。(著者抄録)

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Language：Japanese   Publisher：日本膵・胆管合流異常研究会  

J-GLOBAL

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Language：Japanese   Publisher：(一社)日本肝臓学会  

J-GLOBAL

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：新潟医学会  

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Language：Japanese   Publisher：新潟大学医学部保健学科  

近年，アポトーシス細胞が周囲の細胞に生存・増殖を促す「代償性増殖作用」をもつことが明らかとなったが，そのメカニズムについては未だ不明な点が多い。最近の研究報告により，アポトーシスを進行させる因子であるカスパーゼが，ストレスキナーゼJNKやプロスタグランジンE2を介して，細胞増殖を誘導させる作用を併せ持つことが明らかになった。また酸化ストレスに関与するインターロイキン-11も，代償性増殖に関与する可能性が報告されており，本機構が多彩な因子によって調節されている可能性が推測されている。今後，さらなる研究の発展により，代償性増殖を利用した医療の発展に期待がもたれる。Recent studies have suggested that dying apoptotic cells are involved in various types of extracellular stimuli, termed compensatory proliferation. For example, caspase-9 (Dronc), a type of enzyme which induced cell apoptosis, stimulates JNK or prostaglandin E2, leading to the pronounced cell proliferation. Moreover, interleukin-11, which is produced by reactive oxygen stress, has been also found to be involved in the compensatory proliferation. For more understanding the mechanism of cell death and proliferation, further investigation of the compensatory proliferation is awaited.

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Language：Japanese   Publisher：新潟大学医学部保健学科  

【目的】非アルコール性脂肪肝炎（NASH）は，近年急速に増加している原因不明の肝疾患である。本研究では，肝がん治療に有効とされる分子標的薬ラパマイシンの標的シグナルp70S6キナーゼが，NASH肝がんの病態に関与している可能性について検討した。 【方法】根治的外科手術療法を施行したNASH肝がん22例の病変組織に対して，リン酸化型（活性型）p70S6キナーゼの免疫組織化学染色を行い，臨床因子・予後の比較検討を行った。 【結果】NASH肝がん22例中12例（54.5%）がリン酸化型p70S6キナーゼを高発現しており，組織未分化度と相関した（p = 0.047）。リン酸化型P70S6キナーゼ高発現群は，外科切除後３年以内再発率が有意に増加していた（p = 0.045）。 【総括】p70S6キナーゼを高発現しているNASH肝がんは，再発頻度が高い傾向がある。同シグナルを阻害する分子標的薬ラパマイシンは，本疾患の再発防止に有効である可能性が示唆された。Objective: Non-alcoholic steatohepatitis（NASH）is a recently identified liver disease which causes hepatocellular carcinoma（HCC）. In this study, we addressed whether p70S6 kinase（p70S6K）, a main target of the anti-cancer agent rapamycin, is involved in the clinicopathological factors in NASH-related HCC. Methods: HCC tissue samples were obtained from 22 NASH patients with radical surgical treatment. Phosphorylation level of p70S6K was analyzed by immunohistochemical analysis, and the correlation with the clinicopathological factors were examined. Results: Phosphorylated p70S6K was detected in 54.5%（12/22）of NASH-related HCCs. The levels of phosphop70S6K were correlated with histological grade of HCC（p = 0.047）, but not with clinical factors. Phosphorylation of p70S6K was correlated with increased cancer recurrence after 3 years of the treatment（p= 0.045）. Conclusion: Phosphorylation level of p70S6K was correlated with cancer recurrence of NASH-related HCC. Rapamycin might be a useful agent for treating NASH-associated HCC.

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Other Link： http://hdl.handle.net/10191/38942

Language：Japanese   Publisher：新潟医学会  

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症例は67歳男性。食欲不振と体重減少を主訴に受診、上部消化管内視鏡検査で進行胃癌、腹部computed tomography(CT)にてリンパ節および肝転移を認めた。当初、リンパ節および肝転移を伴う胃中分化管状腺癌と診断、S-1+シスプラチン(CDDP)併用療法、つぎにS-1+パクリタキセル(PTX)併用療法による化学療法が奏功、肝転移巣が消失したため、胃原発巣切除術を行ったところ切除標本は胃内分泌細胞癌であった。おそらく腺癌が先行発生し、癌細胞の分化により出現する増殖能の高い腫瘍性内分泌細胞が、腺癌粘膜深部から塊状増殖し、内分泌細胞癌が形成されたと考えられた。胃内分泌細胞癌は非常にまれな疾患で、かつ悪性度の高い予後不良な疾患であるが、発症から約3年経過、現在無再発生存中である。予後不良といわれる胃内分泌細胞癌であっても化学療法が奏功する可能性があり、かつ外科的手術の時期を判断することが重要である。(著者抄録)

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Language：Japanese   Publisher：日本臨床分子医学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY-BLACKWELL  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY-BLACKWELL  

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Language：English   Publishing type：Book review, literature introduction, etc.   Publisher：SPRINGER TOKYO  

Hepatocellular carcinoma (HCC) is the most common primary cancer worldwide. The only current drug available for clinical treatment of HCC is sorafenib, which inhibits multiple signaling kinases including Raf family members, platelet-derived growth factor receptor, vascular endothelial growth factor receptors 1 and 2, c-Kit, and Fms-like tyrosine kinase 3. Many studies have revealed that the mechanism underlying the antitumor effect of sorafenib is complex. Because sorafenib inhibits C-Raf more potently than B-Raf, the therapeutic efficacy of sorafenib is strongly influenced by the relative expression and activity of B-Raf and C-Raf and the complex interactions between these factors. Moreover, Rafindependent signaling mechanisms have recently emerged as important pathways of sorafenib-induced cell death. Basic research studies have suggested that using sorafenib as part of a combination therapy may improve its effect, although this has yet to be confirmed by clinical evidence. Further studies of the functional mechanism of sorafenib are required to advance the development of targeted therapy for HCC. To aid future work on sorafenib, we here review the current literature pertaining to sorafenib signaling and its clinical efficacy in both monotherapy and combination therapy.

DOI： 10.1007/s00795-011-0558-z

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【目的】非アルコール怪脂肪性肝疾患 (nonalcoholic fatty liver disease, 以下NAFLD) における肝細胞癌に対する外科治療成績を明らかにする. 【対象・方法】肝細胞癌に対して肝切除を施行した225例を対象とし, HBs抗原単独陽性群 (以下, B群) 61例, HCV抗体単独陽性群 (以下, C群) 147例, NAFLD群17例の3群に分類した. 3群間における臨床病理学的背景因子, 術後遠隔成績を比較検討した. 【結果】NAFLD群はB群, C群と比較して有意に高齢であり (P &lt;0.001), body mass index は高く (P &lt;0.001), 腫瘍径が大きかった (P =0.002). NAFLD群17例中8例は組織学的に非アルコール性脂肪肝炎 (nonalcoholic steatohepatitis, 以下NASH) と診断された. 術後合併症発生率, 在院死亡率は, B群 (各々28%, 8%), C群 (各々31%, 1.4%) と比較してNAFLD群 (各々59%, 12%) で有意に高かった (各々P =0.043, P =0.030). NAFLD群での在院死亡は2例であり, NASHに関連した肝硬変に合併した肝細胞癌に対して肝右葉切除が施行されていた. 術後累積5年無再発生存率は, B群39%, C群29%, NAFLD群66%であった. 術後累積無再発生存率はNAFLD群が単変量解析 (P =0.048), 多変量解析 (P =0.020) の両者で有意に良好な成績であった. 【結論】NAFLD関連肝細胞癌に対する外科治療は予後を改善する. NASH関連肝硬変患者に対して肝葉切除を行う際には細心の注意が必要である.

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Hepatocellular carcinoma (HCC) has an aggressive clinical course with frequent recurrence and metastasis. Orthotopic liver transplantation has been the only curative tool for unresectable HCC; therefore, recent advances in molecular targeted therapy may improve the prognosis of HCC. The multiple kinase inhibitor sorafenib and the macrolide antibiotic rapamycin are currently the most promising agents for treating unresectable HCC. A large population-based clinical trial revealed that sorafenib significantly prolonged the overall survival of HCC patients. However, subsequent clinical studies showed that sorafenib rarely reduced tumor volume and inadequately prolonged survival of patients with severe liver damage. To improve its therapeutic effect, the development of a predictive biomarker and a sorafenib-based combination is awaited. Another molecular targeting agent, rapamycin, has now been considered as a putative agent for preventing tumor recurrence in post-liver transplantation HCC patients, because it not only has immunosuppressive activity but also exerts an anti-tumor effect. In the near future, a combination of molecular targeting agents, such as sorafenib and rapamycin, may become a standard protocol for treating unresectable HCC. For specifying cases with more effective and less harmful modalities, further investigation in clinical and basic research to identify unexpected effects are needed.

DOI： 10.1007/s00795-011-0547-2

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE BV  

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症例は62歳女性。1型高ウイルス量のC型慢性肝炎に対し、ペグインターフェロン(PEG-IFN)α2aとリバビリンの併用療法を行った。治療開始後より肝酵素値の上昇が見られた。治療終了後の肝生検では結節形成を認め肝硬変の所見であった。PEG-IFN治療中に観察されるALT上昇の多くは軽度であり臨床的な問題点にはなりにくいが、長期に継続した場合、このような転帰をとる例があることは認知されるべきあると考え報告する。(著者抄録)

DOI： 10.11405/nisshoshi.108.267

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Language：Japanese   Publisher：日本消化器免疫学会  

炎症性腸疾患(IBD)は炎症の再発、寛解を繰り返し、腸管の線維化に伴う腸管の狭窄をもたらす。われわれは、B6マウスに3% Dextran Sulfate Sodium(DSS)を自由飲水させ慢性DSS腸炎を惹起しIL-10遺伝子発現プラスミドの注腸治療を検討した。治療群では、無治療群に比べ、腸炎は臨床的、組織学的に改善し、腸管線維化の抑制が見られた。治療群において慢性DSS腸炎が改善したことより、IL-10遺伝子発現プラスミド注腸は、IBDの慢性腸管炎症と線維化に対する新たな治療法になり得ると考えた。(著者抄録)

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Language：Japanese   Publisher：(一社)日本内科学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：JOHN WILEY & SONS INC  

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Language：English   Publishing type：Book review, literature introduction, etc.   Publisher：SPRINGER TOKYO  

Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers worldwide. The main HCC-associated diseases are chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV), and HBV-associated HCC is still prevalent in Asia. Many studies have suggested that HBV X protein (HBX), which is the most common ORF integrated into the host genome, plays a crucial role in hepatocarcinogenesis. However, the accumulated evidence regarding HBX-mediated signaling pathways is not concordant, and it is difficult to understand the mechanistic nature of HBX-associated hepatocarcinogenesis. For example, HBX was reported to inactivate the early responses to DNA damage via p53-dependent and -independent pathways by interacting with several DNA damage-binding proteins and was also reported to sensitize cells to p53-mediated apoptosis via ataxia-telangiectasia and Rad3-related (ATR)-dependent signaling. HBX also interferes with the centrosome replication process, resulting in rearrangement of chromosomes with micronuclei. Moreover, HBX was found to sensitize protein kinases such as Ras/Raf/mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), stress-activated protein kinase/NH2-terminal-Jun kinase (SAPK/JNK), protein kinase B (PKB/Akt), and Janus kinase/STAT (JAK/STAT), indicating that a variety of signaling pathways may be activated by HBX. In this review, we focus on the roles of HBX in DNA damage repair during HCC development, with a view to achieving a better understanding of the significance of HBX in the early steps of hepatocarcinogenesis.

DOI： 10.1007/s00795-009-0457-8

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腸管狭窄の原因である腸管線維化は炎症性腸疾患(IBD)の重篤な合併症であり、いまだ有効な治療法を欠いている。我々はB6マウスに3% Dextran sulfate sodium(DSS)を自由飲水させ慢性DSS腸炎を惹起し、肥満細胞膜安定剤トラニラストの注腸治療を検討した。無治療群に比べ、治療群において腸炎は臨床的、組織学的に改善し、腸管線維化の抑制効果もみられた。治療群で腸炎が有意に改善したことより、トラニラスト注腸がIBDの慢性腸管炎症と線維化の有効な治療戦略となりうると示唆された。(著者抄録)

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IL-10遺伝子治療は炎症性腸疾患(IBD)の有力な治療法として注目されてきたが、IL-10の全身投与による副作用が問題となっている。我々はB6マウスに3% Dextran sulfate sodium(DSS)を自由飲水させ腸炎を惹起し、IL-10遺伝子発現プラスミドの注腸投与による治療効果を検討した。無治療群に比し、治療群では腸炎は臨床的、組織学的に改善がみられた。IL-10遺伝子発現プラスミド注腸により、DSS腸炎を改善できた。IL-10遺伝子注腸治療はIBD治療法になり得ると考えられた。(著者抄録)

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Language：Japanese   Publisher：一般財団法人 日本消化器病学会  

A 73-year-old man with chronic hepatitis C was Successfully treated for hepatocellular carcinoma (HCC) by localized treatment During the follow-up period, abdominal computed tomography (CT) revealed no HCC recurrence in the liver. However, 9 months after the treatment, abdominal lymph nodes appeared enlarged on CT. Laparoscopic biopsy of the lymph nodes showed that the lesion was HCC, and TS-1/cisplatin chemotherapy was performed. However, extra-hepatic lymph nodes rapidly grew, leading to obstructive jaundice and finally death 10 months after of HCC metastasis. Although abdominal lymph node metastasis of HCC has been widely considered to be rare, the confirmation of effective therapy is awaited because histological studies have suggested that this pathologic lesion may occur more often than expected.

DOI： 10.11405/nisshoshi.106.397

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Language：Japanese   Publisher：日本消化器免疫学会  

生体肝移植症例の移植肝生着とDCとの関連性について検討することを目的とし,移植前後で経時的に肝臓内樹状細胞(DC)の変動を解析した.生体肝移植を施行したレシピエント12例,およびそのドナー12例を対象とした.移植後の拒絶反応の有無は,血液生化学的データと肝生検による病理組織学的検討により診断した.肝組織および末梢血よりFicoll比重遠心法でリンパ球を分離後,各種蛍光モノクローナル抗体で染色しフローサイトメトリーで解析した.正常肝内DCは成熟あるいは活性化型が多く,未熟型が多い末梢血中DCとは異なるフェノタイプを示した.拒絶反応の有無により移植肝内DCの違いを認め,移植肝生着に関与していることが示唆された

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Language：Japanese   Publisher：(株)アークメディア  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本内科学会  

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Language：Japanese   Publisher：(株)中外医学社  

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Language：Japanese   Publisher：(株)アークメディア  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：日本癌学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：日本炎症・再生医学会  

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Language：Japanese   Publisher：日本消化器免疫学会  

四塩化炭素によるマウス急性肝障害モデルに対し,ハイドロダイナミクス法を用いて肝臓にHGF(肝細胞増殖因子)遺伝子導入を行った群とControl gene導入群を作製し,治療効果を比較した.HGF遺伝子導入群は血清ALT値が有意に低く,組織学的には傷害がより軽度であり,免疫組織学的にはBrdU陽性細胞数の増加と炎症細胞の肝浸潤抑制がより顕著であった.また,Control gene導入群でTUNEL陽性細胞数が増加したのに対してHGF遺伝子導入群では有意に減少した

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一社)日本内科学会  

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Language：Japanese   Publisher：(株)癌と化学療法社  

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Language：Japanese   Publisher：(株)癌と化学療法社  

78歳男.肝被膜下表面のS3-4およびS3に存在する径12mm大と5mm大の肝細胞癌再発巣に対し,制癌剤動注療法後にLRFAを施行した.腹腔鏡下に病変を直視することはできなかったが,トロカールから挿入したセクタ型超音波探触子によって2つの病変が確認でき,正確な焼灼が行えた

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Language：Japanese   Publisher：(株)日本メディカルセンター  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：JOHN WILEY & SONS INC  

Web of Science

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：日本癌学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：日本炎症・再生医学会  

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Language：Japanese   Publisher：(株)東京医学社  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：W B SAUNDERS CO  

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Language：Japanese   Publisher：新潟大学  

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Language：Japanese   Publisher：新潟医学会  

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Language：Japanese   Publisher：新潟医学会  

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Language：Japanese   Publisher：新潟医学会  

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Language：Japanese   Publisher：新潟医学会  

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Language：Japanese   Publisher：(株)東京医学社  

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Language：Japanese   Publisher：(株)東京医学社  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：W B SAUNDERS CO  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：W B SAUNDERS CO  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：新潟大学  

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Language：Japanese   Publisher：新潟医学会  

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Language：Japanese   Publisher：日本癌学会  

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Language：Japanese   Publisher：(株)癌と化学療法社  

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Language：Japanese   Publisher：(株)癌と化学療法社  

71歳女.胆道系優位の肝機能異常を認め,抗ミトコンドリア抗体は陰性であったが,抗核抗体および抗平滑筋抗体は陽性であり,自己免疫性肝炎の国際診断基準によるスコアは11点であった.腹腔鏡では溝状陥凹を有する起伏状変化の上に,大小不同の半球状結節が散在する肝表面像で,自己免疫性肝炎に近い像であった.組織では門脈域にpiecemeal necrosisを伴う細胞浸潤を認め,granulomaは認めないものの,ductpeniaと変性した隔壁胆管を認め,原発性胆汁性肝硬変も否定できない所見であった.これらの所見から,自己免疫性肝炎と原発性胆汁性肝硬変の境界に位置する症例と考え,ursodesoxycholic acid 300mg/日を投与し,経過をみているが,現在まで肝機能の悪化は認めていない

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Language：Japanese   Publisher：(株)癌と化学療法社  

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Language：Japanese   Publisher：(株)癌と化学療法社  

腹腔鏡下マイクロ波凝固治療(laparoscopic microwave coagulation therapy:LMCT)が有用であった表在型肝癌を3例(症例1:69歳女,症例2:70歳男,症例3:72歳女)を経験した.全例共にS3区域肝表面に存在する肝細胞癌であった.症例1の腫瘍は径6mmで肝表面に突出しており,腹腔鏡施行時に発見された.症例2の腫瘍は径2cmで,肝表面に腫瘍を視認できなかったが,腹腔鏡下超音波走査により描出可能であった.症例の3の腫瘍は径1cmで肝表面に突出しており,腹腔鏡で視認できたが,腹膜癒着のためLMCTのみでは十分なtreated marginを確保できず,LMCT施行時に経皮エタノール注入(PEIT)を追加した.いずれの症例も術後,画像検査で十分なtreated marginが得られた

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Language：Japanese   Publisher：(株)癌と化学療法社  

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Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

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Language：Japanese   Publisher：日本胆道学会  

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Language：Japanese   Publisher：日本癌学会  

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Language：Japanese   Publisher：(株)中山書店  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：日本癌学会  

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Language：Japanese   Publisher：新潟医学会  

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Language：Japanese   Publisher：新潟医学会  

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Language：Japanese   Publisher：(一社)日本ハイパーサーミア学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：日本ハイパーサーミア学会  

組織内癌温熱療法の一つである針電極によるRF加温の場合, 加温領域が狭いという問題があった.本研究では, 加温対象に食塩水を注入し, 導電率を高めることによって, 加温領域を拡大することを試みた.切離した豚の肝臓を対象として加温実験を行った結果, 食塩水の濃度が高いほど, また針電極の直径が太いほど加温領域が拡大した.Interstitial hyperthermia by using a needle electrode has problem that heating range is too narrow to apply for massive tissues. In this study, we tried to extend the heating range by using high-conductivity saline pouring into the heating object. In experiments of RF power heating using pig livers, the higher salt concentration or the thicker the diameter of the needle electrode, the wider the heating range.

DOI： 10.3191/thermalmedicine.13.68

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DOI： 10.3191/thermalmedicine.13.68

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Language：Japanese   Publisher：(株)東京医学社  

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Language：Japanese   Publisher：新潟医学会  

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Language：Japanese   Publisher：(株)東京医学社  

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Language：Japanese   Publisher：(株)東京医学社  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：日本癌学会  

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Language：Japanese   Publisher：(公社)日本生化学会  

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Language：Japanese   Publisher：(株)北隆館  

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Language：Japanese   Publisher：(株)日本臨床社  

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Language：Japanese   Publisher：新潟医学会  

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Language：Japanese   Publisher：一般社団法人 日本肝臓学会  

核1個当りのAgNOR個数は,正常肝1.34±0.11 (mean±SD),慢性肝炎1.83±0.22,肝硬変1.93±0.40,細小肝癌2.64±0.52,進行性肝細胞癌3.93±0.60であった.細小肝癌は,肝硬変に比し,統計学的に有意差(p&lt;0.01)をもって個数の増加が認められた.進行性肝細胞癌との間にも有意差(p&lt;0.01)を認めた

DOI： 10.2957/kanzo.33.76

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Language：Japanese   Publisher：克誠堂出版(株)  

24歳男,ショック状態を呈したRPE.この時,経過中に一過性に尿崩症を併発し,その他に脳下垂体ホルモンの低下をきたした

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：新潟医学会  

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Language：Japanese   Publisher：新潟医学会  

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Language：Japanese   Publisher：新潟医学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：一般社団法人 日本肝臓学会  

DOI： 10.2957/kanzo.32.967

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Language：Japanese   Publisher：新潟医学会  

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Language：Japanese   Publisher：新潟医学会  

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