記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND ANDAIM: Human telomerase reverse transcriptase (TERT) promoter mutations were the most prevalent mutations in patients with hepatocellular carcinoma (HCC). We tried to detect the mutations with plasma circulating tumor DNA (ctDNA) in patients with advanced HCC and elucidated their clinical utility. METHODS: Circulating tumor DNA in plasma was extracted from 130 patients with advanced HCC who were treated with systemic chemotherapy (n = 86) or transcatheter arterial chemoembolization (n = 44), and TERT promoter mutations were examined with digital droplet polymerase chain reaction. The correlations between these mutations and the clinical outcome of patients were analyzed. RESULTS: Of the 130 patients examined, 71 patients (54.6%) were positive for TERT promoter mutations in ctDNA, of which 64 patients were -124bp G > A and 10 were -146bp G > A. The presence of TERT promoter mutations was correlated with large intrahepatic tumor size (P = 0.05) and high des-gamma carboxyprothrombin (P = 0.005). Overall survival of the patients with the mutations was significantly shorter than those without them (P < 0.001), and the patients with high (≥ 1%) fractional abundance of the mutant alleles showed shorter survival than those with low (< 1%) fractional abundance. Multivariate analysis revealed that TERT promoter mutation (hazard ratio [HR]: 1.94; 95% confidence interval [CI], 1.18-3.24; P < 0.01), systemic chemotherapy (HR: 2.38; 95% CI, 1.29-4.57; P < 0.01), and vascular invasion (HR: 2.16; 95% CI, 1.22-3.76; P < 0.01) were significant factors for poor overall survival. CONCLUSIONS: TERT promoter mutations in ctDNA were associated with short survival and could be a valuable biomarker for predicting the prognosis of patients with advanced HCC.

DOI： 10.1111/jgh.15227

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

AIM: Tolvaptan is a newly available diuretic that has a specific function in water reabsorption inhibition. Given that spironolactone or furosemide induces the aggravation of cirrhotic hyponatremia and dehydration, tolvaptan affects the management strategy of liver cirrhosis. Representative predictive markers of its response include renal function-related markers such as urea nitrogen or creatinine. However, vascular function-related markers have not been well investigated. We investigated the effect of the vascular function-related marker asymmetric dimethylarginine (ADMA) and the effective arterial blood volume (EABV) marker, fractional excretion of sodium (FENa), on the early tolvaptan response and survival in liver cirrhosis. METHODS: We prospectively recruited 49 patients who required add-on tolvaptan for refractory ascites or edema. Laboratory data were obtained immediately before and 1 day after tolvaptan administration. Patients exhibiting >1.5 kg weight loss after 1 week were categorized as early responders to tolvaptan. Patients were followed for a median of 200 days and were assessed for survival. RESULTS: Early responders showed lower creatinine levels (<1.0 mg/dL), and higher ADMA levels (≥0.61 nmol/mL) than others in a multivariate analysis. Patients with a shorter survival were positive for hepatocellular carcinoma and had a low FENa (<0.35%). CONCLUSION: Early responders showed higher ADMA levels reflecting vascular stricture, suggesting that higher vascular tonus is required for a tolvaptan early response. Patients with a shorter survival showed a lower FENa, reflecting a lower EABV and suggesting that adequate EABV is required for the prolonged survival after tolvaptan administration.

DOI： 10.1111/hepr.13573

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/hepr.13573

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) is a promising method for controlling tumors, although it does not entirely eliminate recurrence. Oxidative stress is associated with the progression of hepatocarcinogenesis, while also acting as an anticancer response. The objective of the present study was to investigate the factors influencing post-RFA outcomes. We recruited 235 newly diagnosed HCC patients who received RFA for single tumors. The patients with recurrence were sub-grouped into early and segmental recurrence groups. The characteristics of the sub-grouped patients were evaluated, including by measuring oxidative stress marker reactive oxygen metabolites and antioxidant marker OXY-adsorbent tests. The factors associated with poor survival were a high Child-Pugh score and early recurrence within 2 years in the same segment. The patients who experienced recurrence within 2 years in the same segment showed a larger tumor diameter than did others. According to a multivariate analysis, the OXY values were also significantly low in these patients. In conclusion, maintaining the antioxidant reservoir function with a high OXY value might be necessary to prevent early recurrence within the RFA-treated segment.

DOI： 10.18926/AMO/60364

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KARGER  

Introduction: Molecular targeting drugs are recommended as second-line treatment for intrahepatic advanced hepatocellular carcinoma (HCC). However, in Asia, hepatic arterial infusion chemotherapy (HAIC) is also considered as a second-line treatment because it improves the survival of responders. The aim of this study was to predict responders and non-responders to HAIC with low-dose cisplatin plus 5-fluorouracil (LFP) using tumor markers. Objective and Methods: The data of 47 patients who received LFP for the first time in our hospital were analyzed retrospectively. We evaluated the association between treatment response by Response Evaluation Criteria in Solid Tumors and the changing ratio of the serum concentration of α-fetoprotein (AFP), Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), and des-γ-carboxy prothrombin (DCP) 2 weeks after LFP initiation. Results: The number of patients showing a complete response (CR), a partial response (PR), stable disease (SD), and progressive disease (PD) was 0 (0%), 20 (43%), 18 (38%), and 9 (19%), respectively. The AFP ratio showed significant positive correlations for PR vs. SD (p = 0.004) and PR vs. PD (p = 0.003). The DCP ratio correlated significantly for PR vs. SD (p = 0.02). The optimal cutoff values for responders were 0.79 for the AFP ratio and 0.53 for the DCP ratio. Prediction using both or either cutoff value showed 93% sensitivity, 53% specificity, a 94% negative predictive value, and a 57% positive predictive value. Conclusion: Optimal cutoff values for AFP and DCP ratios enable prediction of nonresponders to HAIC with LFP. This simple and early assessment method allows the use of HAIC and molecular targeting drugs for HCC treatment.

DOI： 10.1159/000506941

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The physiological role of the reduced expression of immortalized cells (REIC)/Dickkopf-3 (Dkk-3) protein in patients with hepatocellular carcinoma (HCC) remains unclear. In this study, we evaluated the effect of the REIC/Dkk-3 protein on HCC cell proliferation and assessed the relationship between the serum REIC/Dkk-3 protein level and the prognosis in patients with HCC. We evaluated the REIC/Dkk-3 protein-induced anticancer effects on Huh7 and Hep3B cells (HCC cell lines) in the presence of peripheral blood mononuclear cells (PBMCs), and found that combination treatment with REIC/Dkk-3 protein and PBMCs reduced the proliferation of HCC cells (Hep3B: 82.0%±16.3%; Huh7: 72.6%±9.1%). We also studied 194 HCC patients who underwent primary liver resection or primary radiofrequency ablation from 2008 to 2017. Serum REIC/Dkk-3 protein levels were measured by an enzyme-linked immunosorbent assay and compared to the prognostic data. The 3-year disease-free survival of the REIC/Dkk-3 high group was significantly higher than that in the REIC/Dkk-3 low group. In conclusion, this is the first study investigating the relationship between HCC patient survival and serum REIC/Dkk-3 protein levels in a large population. Based on the results, the serum REIC/Dkk-3 protein level should be considered a new prognostic marker for patients with HCC.

DOI： 10.18926/AMO/59957

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: We previously demonstrated that the reduced expression in immortalized cells (REIC)/dikkopf-3 (Dkk-3) gene was downregulated in various malignant tumors, and that an adenovirus vector carrying the REIC/Dkk-3 gene, termed Ad-REIC induced cancer-selective apoptosis in pancreatic cancer and hepatocellular carcinoma. OBJECTIVE: In this study, we examined the therapeutic effects of Ad-REIC in biliary cancer using a second- generation Ad-REIC (Ad-SGE-REIC). METHODS: Human biliary cancer cell lines (G-415, TFK-1) were used in this study. The cell viability and apoptotic effect of Ad-SGE-REIC were assessed in vitro using an MTT assay and Hoechst staining. The anti-tumor effect in vivo was assessed in a mouse xenograft model. We also assessed the therapeutic effects of Ad-SGE-REIC therapy with cisplatin. Cell signaling was assessed by Western blotting. RESULTS: Ad-SGE-REIC reduced cell viability, and induced apoptosis in biliary cancer cell lines via the activation of the c-Jun N-terminal kinase pathway. Ad-SGE-REIC also inhibited tumor growth in a mouse xenograft model. This effect was further enhanced in combination with cisplatin. CONCLUSION: Ad-SGE-REIC induced apoptosis and inhibited tumor growth in biliary cancer cells. REIC/Dkk-3 gene therapy using Ad-SGE-REIC is an attractive therapeutic tool for biliary cancer.

DOI： 10.2174/1566523220666200309125709

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hepatocellular carcinoma and intrahepatic cholangiocarcinoma are the most common types of primary liver cancers. Moreover, the liver is the second most frequently involved organ in cancer metastasis after lymph nodes. The tumor microenvironment is crucial for the development of both primary and secondary liver cancers. The hepatic microenvironment consists of multiple cell types, including liver sinusoidal endothelial cells, Kupffer cells, natural killer cells, liver-associated lymphocytes, and hepatic stellate cells (HSCs). The microenvironment of a normal liver changes to a tumor microenvironment when tumor cells exist or tumor cells migrate to and multiply in the liver. Interactions between tumor cells and non-transformed cells generate a tumor microenvironment that contributes significantly to tumor progression. HSCs play a central role in the tumor microenvironment crosstalk. As this crosstalk is crucial for liver carcinogenesis and liver-tumor development, elucidating the mechanism underlying the interaction of HSCs with the tumor microenvironment could provide potential therapeutic targets for liver cancer.

DOI： 10.1007/978-3-030-37184-5_4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Mutations in the human telomerase reverse transcriptase (hTERT) gene promoter have been reported in hepatocellular carcinoma (HCC); however, analyses of these mutations in liquid biopsies have been technically difficult because of the high GC content of the regions of interest within this promoter. We evaluated the feasibility and prognostic value of hTERT promoter mutations identified in circulating cell-free DNA (cfDNA) from the serum of patients with HCC. OBJECTIVE: A cohort of HCC patients (n = 36) who were curatively treated by surgical resection between June 2003 and September 2014 were enrolled in this study. METHODS: The presence of hTERT promoter mutations in cfDNA from the patients' serum was analyzed via modified droplet digital polymerase chain reaction, and associations were sought between specific promoter mutations and patients' disease-free survival (DFS). RESULTS: The G>A hTERT mutation at -124 bp was detected in the serum of 25 patients (69%). Although no marked differences were observed between the characteristics of the serum mutation-positive and serum mutation-negative patient groups, the DFS of patients with the mutation was significantly shorter than that of the serum mutation-negative patients (p = 0.02). Among 18 clinicopathologic and background liver factors examined, the presence of the -124 bp G>A mutation was an independent and significant predictor of patients' DFS (hazard ratio = 3.01, 95% confidence interval 1.11-10.5, p = 0.03) in multivariate analyses. CONCLUSIONS: The -124 bp G>A hTERT promoter mutation was observed in the serum of 69% of HCC patients who underwent surgical resection and was an independent predictor of disease progression in HCC.

DOI： 10.1159/000506135

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2217/fon-2019-0115

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.18926/AMO/56935

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/jgh.14535

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記述言語：英語  

DOI： 10.2169/internalmedicine.1957-18

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.18926/AMO/56457

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1248/yakushi.18-00170

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3892/ol.2018.9301

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DOI： 10.1016/j.clinre.2018.01.003

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BioMed Central Ltd.  

Background: Portopulmonary hypertension (POPH) is characterized by pulmonary vasoconstriction, while hepatopulmonary syndrome (HPS) is characterized by vasodilation. Definite POPH is a risk factor for the survival after orthotopic liver transplantation (OLT), as the congestive pressure affects the grafted liver, while subclinical pulmonary hypertension (PH) has been acknowledged as a non-risk factor for deceased donor OLT. Given that PH measurement requires cardiac catheterization, the tricuspid regurgitation pressure gradient (TRPG) measured by echocardiography is used to screen for PH and congestive pressure to the liver. We investigated the impact of a subclinical high TRPG on the survival of small grafted living donor liver transplantation (LDLT). Methods: We retrospectively analyzed 84 LDLT candidates. Patients exhibiting a TRPG ≥25 mmHg on echocardiography were categorized as potentially having liver congestion (subclinical high TRPG
n=34). The mean pulmonary artery pressure (mPAP) measured after general anesthesia with FIO20.6 (mPAP-FIO20.6) was also assessed. Patients exhibiting pO2&lt
80 mmHg and an alveolar-arterial oxygen gradient (AaDO2)≥15 mmHg were categorized as potentially having HPS (subclinical HPS
n=29). The clinical course after LDLT was investigated according to subclinical high TRPG. Results: A subclinical high TRPG (p=0.012) and older donor age (p=0.008) were correlated with a poor 40-month survival. Although a higher mPAP-FIO20.6 was expected to correlate with a worse survival, a high mPAP-FIO20.6 with a low TRPG was associated with high frequency complicating subclinical HPS and a good survival, suggesting a reduction in the PH pressure via pulmonary shunt. Conclusion: In cirrhosis patients, mPAP-FIO20.6 may not accurately reflect the congestive pressure to the liver, as the pressure might escape via pulmonary shunt. A subclinical high TRPG is an important marker for predicting a worse survival after LDLT, possibly reflecting congestive pressure to the grafted small liver.

DOI： 10.1186/s12876-018-0793-z

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DOI： 10.18926/AMO/55662

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Background and Aim: Reduced expression in immortalized cells (REIC)/dickkopf-3 (Dkk-3) is a tumor suppressor gene that is downregulated in various cancers. In our previous study of prostate cancer, the REIC/Dkk-3-expressing adenoviral vector (Ad-REIC) was found to induce cancer-selective apoptosis. This study recently developed a novel super gene expression (SGE) system and used this system to re-construct an Ad-REIC vector, termed the Ad-SGE-REIC, to achieve more effective therapeutic outcomes. In this study, the therapeutic effects of Ad-SGE-REIC on hepatocellular carcinoma (HCC) was assessed.
Methods: Human HCC cell lines (HLE, Huh7, HepG2, HLF, SK-Hep1, and PLC), human HCC tissues, and mouse HCC cell line (Hepa1-6) were used in this study. REIC/Dkk-3 expression was assessed by immunoblotting and immunohistochemistry. The relative cell viability and the apoptotic effect were examined in vitro, and the anti-tumor effects of Ad-SGE-REIC treatment were analyzed in the mouse xenograft model. This study additionally assessed anti-tumor immunological effects on the immunocompetent mice.
Results: REIC/Dkk-3 expression was decreased in HCC cell lines and HCC tissues. Ad-SGE-REIC reduced cell viability and induced apoptosis in HCC cell lines (HLE and Huh7), inhibited tumor growth in the mouse xenograft model, and demonstrated in vivo anti-cancer immunostimulatory effects on the HCC cell line (Hepa1-6).
Conclusions: Ad-SGE-REIC treatment not only enhanced cell killing effects in vitro but also elicited significant therapeutic effects, with tumor growth suppression, in vivo. REIC/Dkk-3 gene therapy using Ad-SGE-REIC potentially represents an innovative new therapeutic tool for HCC.

DOI： 10.1111/jgh.13757

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Background and Aim Pathological grading is important in defining the therapeutic strategy in pancreatic neuroendocrine neoplasm (PNEN) but is difficult for unresectable cases. Endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA) is useful in the diagnosis of PNEN, but its usefulness for pathological grading is not well established. No studies have examined the diagnostic ability of dynamic computed tomography (CT) for pathological grading of PNEN. We investigated the usefulness of EUS-FNA and dynamic CT in the diagnosis and pathological grading of PNEN.
Methods In this retrospective study, 39 PNEN patients finally diagnosed via EUS-FNA and/or surgical resection underwent dynamic CT. Pathological samples were diagnosed based on WHO2010; staging was based on the European Neuroendocrine Tumor Society classification. The proportion of the quantification value in the tumor to the pancreatic parenchyma in arterial phase was defined as the CT ratio. Immunohistochemical staining with CD31 was performed to evaluate microvessel density (MVD). We evaluated the relationship between pathological grade, CT ratio, and MVD.
Results By using EUS-FNA, 35 of 39 (90%) cases were diagnosed as PNEN. As for pathological grade, 15 of 35 (43%) cases could be identified correctly. CT ratio could predict pathological Grade 3 disease. The sensitivity, specificity, and diagnostic accuracy were 100%, 94%, and 95%. MVD was significantly correlated with CT ratio (r=0.83, P&lt;0.0001) and pathological grade (P=0.0074).
Conclusions Computed tomography ratio has a relationship with pathological grade in PNEN, which would help decide therapeutic strategy in unresectable cases and cases in which pathological grading is difficult.

DOI： 10.1111/jgh.13594

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Background and Aim: Transcatheter arterial chemoembolization (TACE) is a standard therapy for the treatment of intermediate-stage hepatocellular carcinoma (HCC). In this study, we tried to elucidate the possibility of using radiofrequency ablation (RFA) as an alternative treatment of intermediate-stage HCC.
Methods: Among 246 patients who were initially diagnosed with intermediate-stage HCC, 76 who were treated with TACE (TACE group) and 91 who were treated with RFA (RFA group) were enrolled in this study. The risk for survival was analyzed with the Cox Proportional Hazard Model, and the survival rates were compared using propensity score matching.
Results: About half (50.6%) of the intermediate-stage HCC patients in the RFA group were diagnosed with Barcelona Clinic Liver Cancer substage-B1 (BCLC-B1) compared with only 19.7% of the patients in the TACE group. Survival of the RFA group was longer than that of TACE group in patients with BCLC-B1 and BCLC-B2. In contrast, no difference between groups was observed in patients with BCLC-B3/4. Multivariate analysis revealed that large tumor size (&gt; 30 mm, hazard ratio = 1.685, P = 0.043), high des-gamma-carboxyprothrombin (&gt; 100 mAU/mL, hazard ratio = 1.920, P = 0.012), and TACE group (hazard ratio = 1.896, P = 0.016) were significant risk factors for survival. Overall 3-year survival of the patients in the RFA group (69.5%) was significantly longer than that of patients in the TACE group (51.5%) after propensity score matching (P = 0.032). No significant adverse events were observed in either group.
Conclusions: RFA was useful for the treatment of less advanced intermediate-stage HCC and could be an alternative to TACE in selected cases.

DOI： 10.1111/jgh.13586

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記述言語：英語  

DOI： 10.3892/or.2017.5419

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

The molecular pathogenesis of non-alcoholic steatohepatitis (NASH) is not well defined. The objective of the present study was to identify disease progression-related cytokines and investigate the molecular pathogenesis of such changes in NASH.
A study population of 20 non-alcoholic fatty liver (NAFL) and 59 NASH patients diagnosed by liver biopsy and 15 healthy volunteers was recruited. The serum pro- and anti-inflammatory cytokines were measured by a multiple enzyme-linked immunosorbent assay. The hepatic mRNA expressions of cytokines were measured by real-time PCR. A monocyte cell line was stimulated with Toll-like receptor (TLR) ligand under a high glucose and insulin condition, and cellular cytokine mRNA expression was quantified.
One group of cytokines was higher in NAFL and NASH than in controls, while another group was higher in NASH than in NAFL and controls. The NASH-specific second group included interleukin (IL)-15 and interferon-gamma-inducible protein (IP)-10. In particular, IP-10 was higher in NAFL than in controls and higher in NASH than in NAFL and controls. The sensitivity to diagnose NASH was 90%, with specificity of 50%. Insulin resistance reflecting a high glucose and insulin condition resulted in higher IP-10 mRNA expression in the monocyte cell line only with concomitant TLR-2 stimulation.
IP-10 is a sensitive marker of the need for liver biopsy. Insulin resistance with bacteria-related TLR-2 stimulation might induce IP-10 production from monocytes. Insulin resistance and intestinal barrier function should be intensively controlled to prevent progression from NAFL to NASH.

DOI： 10.1007/s12072-016-9773-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

AimRecurrence of hepatocellular carcinoma (HCC) is observed frequently, even after curative treatments. The aim of this study is to elucidate the risk factors for recurrence of HCC after radiofrequency ablation (RFA), focusing on the carcinogenic potential of the liver assessed by -fetoprotein (AFP).
MethodsWe enrolled 357 consecutive patients who underwent complete ablation by RFA for primary HCC (3cm, 3 tumors) and analyzed the correlation between 17 critical parameters, including AFP and HCC recurrence.
ResultsRecurrence was observed in 236 patients during a mean observation period of 54.3months. Multivariate analysis revealed that multiple tumors (risk ratio [RR]=1.70, 95% confidence interval [CI]=1.27-2.26, P&lt;0.001), high AFP (&gt;10ng/mL, RR=1.45, 95% CI=1.09-1.94, P&lt;0.001) and high des--carboxyprothrombin (&gt;40 mAU/mL, RR=1.52, 95% CI=1.13-2.02, P&lt;0.005) were significantly correlated with recurrence. AFP was selected as a significant factor even when the cut-off level was set lower (5ng/mL). The risk of recurrence increased linearly according to the increase of the lowest AFP level after RFA and the adjusted ratios relative to AFP less than 5ng/mL were 1.56, 2.14, 2.57 and 3.13 in AFP 5-10ng/mL, 10-20ng/mL, 20-50ng/mL and over 50ng/mL, respectively. In addition, the recurrence rate was predicted by the AFP level after RFA, regardless of the level before the treatment.
ConclusionAFP less than 5ng/mL after curative RFA was an important predictor of a better prognosis and was considered to indicate the low carcinogenic potential of the non-cancerous liver.

DOI： 10.1111/hepr.12636

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Background and AimReduced expression in immortalized cells/dickkopf-3 (REIC/DKK3) is a reported tumor suppressor gene and has potential to become an innovative therapy for various cancers. We examined the antitumor immunological effects of human REIC/DKK3 protein against pancreatic cancer.
MethodsActivation of extracellular signal-regulated kinases 1 and 2, mammalian target of rapamycin, and signal transducer and activator of transcription 3 by REIC/DKK3 protein was assessed in human peripheral blood mononuclear cells using immunoblotting. Pancreatic cancer cell lines (AsPC-1 and MIA Paca-2) were cocultured with peripheral blood mononuclear cells, and the anticancer effects of REIC/DKK3 protein were assessed using the methyl thiazole tetrazolium, cytotoxicity, and enzyme-linked immunospot assays. The antitumor immunological effects of the combined treatment with REIC/DKK3 protein and peripheral blood mononuclear cells were also assessed in a pancreatic cancer model using non-obese diabetic/severe combined immunodeficiency mice.
ResultsThe REIC/DKK3 protein activated extracellular signal-regulated kinases 1 and 2, mammalian target of rapamycin, and signal transducer and activator of transcription 3 in peripheral blood mononuclear cells. REIC/DKK3 protein inhibited in vitro cancer cell viability and enhanced cytotoxicity when incubated with peripheral blood mononuclear cells. REIC/DKK3 protein induced significant production of interferon gamma from lymphocytes incubated with pancreatic cancer cells, indicating that CD8+ T cells were activated in the peripheral blood mononuclear cells when cocultured with AsPC-1 and MIA Paca-2 in the presence of REIC/DKK3 protein. Combined treatment with REIC/DKK3 protein and peripheral blood mononuclear cells produced in vivo anticancer immunostimulatory effects on pancreatic cancer cells.
ConclusionsThe REIC/DKK3 protein and peripheral blood mononuclear cells synergistically enhanced anticancer immunological effects against pancreatic cancer cells. The observed immunomodulatory effect of combined treatment likely occurs in adenovirus-mediated REIC/DKK3 gene therapy and provides important clues to the therapeutic mechanisms involving immune cells.

DOI： 10.1111/jgh.13259

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPANDIDOS PUBL LTD  

Runt-related transcription factor 3 (RUNX3) is known to function as a tumor suppressor in gastric cancer and other types of cancers, including hepatocellular carcinoma (HCC). However, its role has not been fully elucidated. In the present study, we aimed to evaluate the role of RUNX3 in HCC. We used the human HCC cell lines Hep3B, Huh7 and HLF; RUNX3 cDNA was introduced into Hep3B and Huh7 cells, which were negative for endogenous RUNX3 expression, and RUNX3 siRNA was transfected into HLF cells, which were positive for endogenous RUNX3. We analyzed the expression of RUNX3 and multidrug resistance-associated protein (MRP) by immunoblotting. MTT assays were used to determine the effects of RUNX3 expression on 5-fluorouracil (5-FU) and cisplatin (CDDP) sensitivity. Finally, 23 HCC specimens resected from patients with HCC at Okayama University Hospital were analyzed, and correlations among immunohistochemical expression of RUNX3 protein and MRP protein were evaluated in these specimens. Exogenous RUNX3 expression reduced the expression of MRP1, MRP2, MRP3 and MRP5 in the RUNX3-negative cells, whereas knockdown of RUNX3 in the HLF cells stimulated the expression of these MRPs. An inverse correlation between RUNX3 and MRP expression was observed in the HCC tissues. Importantly, loss of RUNX3 expression contributed to 5-FU and CDDP resistance by inducing MRP expression. These data have important implications in the study of chemotherapy resistance in HCC.

DOI： 10.3892/or.2016.4681

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DOI： 10.1016/S0016-5085(16)33891-4

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記述言語：英語  

DOI： 10.1016/S0016-5085(16)31025-3

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japanese Society of Gastroenterology  

A woman in her 50s was admitted to our hospital because of multiple tumors detected in her liver. She was diagnosed with combined hepatocellular cholangiocarcinoma using gadolinium-ethoxybenzyldiethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) and biopsy of the liver tumors. We judged the tumors to be unresectable because they were found in both lobes of the liver, with a tumor thrombus being found in the main left portal vein. The pathological findings showed that the tumors exhibited characteristics of hepatocellular carcinoma Therefore, sorafenib was administered
however, 6 months later, the disease progressed. Consequently, she received second-line chemotherapy with a one-shot intra-arterial injection of cisplatin, but this too was ineffective, and her general condition worsened. As hence, we changed the regimen to 5-fluorouracil continuous infusion and consecutive low dose cisplatin (LFP) therapy. After one cycle of chemotherapy with LFP, Gd-EOB-DTPA-enhanced MRI showed markedly decreased sizes and numbers of tumors. To date, she has completed six cycles of LFP therapy, and almost all her tumors are no longer visible on MRI. She has recovered to a good state and has achieved long-term survival. Thus, this case indicates that although LFP therapy is generally selected for cases of advanced hepatocellular carcinoma, it also appears to be effective for long-term disease control in cases of hepatocellular cholangiocarcinoma.

DOI： 10.11405/nisshoshi.113.2050

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN SOC INTERNAL MEDICINE  

To investigate the mechanism of phytobezoar dissolution by Coca-Cola (R), persimmon phytobezoar pieces removed from a 60-year-old Japanese woman were analyzed by energy dispersive X-ray spectroscopy. The amount of calcium significantly decreased after dissolution treatment using Coca-Cola (R), suggesting a potential contribution of calcium to dissolution mechanisms. Moreover, immersion in Coca-Cola (R) for 120 hours on the exterior surface revealed that Coca-Cola (R) did not permeate persimmon phytobezoars. This is the first study to investigate the mechanisms of persimmon phytobezoar permeability and dissolution induced by Coca-Cola (R).

DOI： 10.2169/internalmedicine.55.6985

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：INT MEDICAL PRESS LTD  

Background: The efficacy of a direct-acting antiviral agent (DAA) is compromised by the development of drug resistance. The associations between resistance-associated virus (RAV) and therapeutic outcomes have not been well-understood.
Methods: A total of 30 patients with HCV genotype-1b were enrolled and treated for 24 weeks with asunaprevir (ASV) and daclatasvir (DCV). Viral sequences in non-structural (NS) regions 3 and 5A in serum and liver tissue before treatment were examined with direct sequencing, next-generation sequencing (NGS) and the PCR-invader method to evaluate the importance of drug-resistance in the prediction of the outcomes of ASV plus DCV therapy.
Results: Of 30 patients (22 treatment-naive patients, 2 interferon-intolerant patients and 6 non-responders), 25 patients (83.3%) achieved sustained virological response (SVR) 24 weeks after the treatment. Viral breakthrough occurred in three treatment-naive patients and one non-responder. One treatment-naive patient experienced viral relapse. Among 25 patients without RAV, 24 obtained SVR, whereas 5 patients had RAV with a 1.3 to 88% frequency, resulting in various therapeutic outcomes. As for HCV compartments, similar RAVs were detected in serum and liver tissue for a patient obtaining SVR despite HCV NS5A Y93H and another developed viral breakthrough although no RAV was detected. Direct sequencing could not detect RAVs in low frequency (1.3 to 12%) for three of four patients.
Conclusions: Low frequency of RAVs might not affect the outcomes of ASV plus DCV therapy. Deep sequencing and PCR-invader methods can detect clinically significant RAVs for ASV plus DCV therapy.

DOI： 10.3851/IMP2976

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：TAYLOR & FRANCIS LTD  

Background: Pancreatico-biliary malignancies exhibit similar characteristics, including obesity-related features and poor prognosis, and require new treatment strategies. Oxidative stress is known to induce DNA damage and carcinogenesis, and its reduction is viewed as being favorable. However, it also has anti-infection and anti-cancer functions that need to be maintained. To reveal the effect of oxidative stress on cancer progression, we evaluated oxidative stress and anti-oxidative balance in pancreatic cancer (PC) and cholangiocarcinoma (CC) patients, as well as the effect of add-on antioxidant treatment to chemotherapy in a mouse cholangiocarcinoma model.
Methods: We recruited 84 CC and 80 PC patients who were admitted to our hospital. Serum levels of reactive oxygen metabolites (ROM) and the anti-oxidative OXY-adsorbent test were determined and the balance of these tests was defined as an oxidative index. A diabetic mouse-based cholangiocarcinoma model was utilized to evaluate the effects of add-on antioxidant therapy on cholangiocarcinoma chemotherapy.
Results: Serum ROM was higher and anti-oxidant OXY was lower in CC patients with poor outcomes. These parameters were not significantly different in PC patients. In mice, vitamin E administration induced antioxidant hemeoxygenase (HO)-1 protein expression in cancer tissue, while the number of stem-like cells increased. L-carnitine administration improved intestinal microbiome and biliary acid balance, upregulated the hepatic mitochondrial membrane uptake related gene Cpt1 in non-cancerous tissue, and did not alter stem-like cell numbers.
Conclusion: Oxidative stress balance was dysregulated in cholangiocarcinoma with poor outcome. The mitochondrial function-supporting agent L-carnitine is a good candidate to control oxidative stress conditions.

DOI： 10.3109/10715762.2016.1172071

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

AimMost of the modification of N-glycosylation reported in cancers including hepatocellular carcinoma (HCC) were based on the examinations of a small number of patients or particular proteins. The aim of this study is to reveal changes in whole serum N-glycan profiles systematically during the process of hepatocarcinogenesis and to elucidate their clinical application.
MethodsWe analyzed sera from 105 patients with chronic hepatitis/liver cirrhosis (CH/LC) and age-/sex-matched healthy volunteers (HLT), as well as from 114 patients with HCC. Serum N-glycan profiles were measured comprehensively by a new, quantitative, high-throughput method and compared with clinical parameters.
ResultsThe total amount of N-glycan expression was significantly higher in patients with CH/LC than in HLT; however, no differences were observed between CH/LC and HCC patients. In HCC patients, multi-antennary glycans with fucose residues, particularly m/z 3195, were increased compared with CH/LC patients. The expression of m/z 3195 was high, especially in patients with a high number of intrahepatic lesions (&gt;3), large tumor size (&gt;3cm), macroscopic vascular invasion or metastasis. The ratio of pairs of glycans on the same path of the biosynthesis pathway (m/z 3195/1914) showed a higher area under the receiver-operator curve of 0.810 than any other single glycan to distinguish HCC from CH/LC.
ConclusionWe demonstrate the full spectrum of the alterations of serum N-glycans comprehensively in patients with liver disease, and elucidate the possible use of glycans as novel biomarkers of liver disease progression.

DOI： 10.1111/hepr.12441

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPANDIDOS PUBL LTD  

Microenvironment plays an important role in epithelial-mesenchymal transition (EMT) and sternness of cells in hepatocellular carcinoma (HCC). Epithelial cell adhesion molecule (EpCAM) is known as a tumor stemness marker of HCC. To investigate the relationship between microenvironment and sternness, we performed an in vitro co-culture assay. Four HCC cell lines (HepG2, Hep3B, HuH-7 and PLC/PRF/5) were co-cultured with the TWNT-1 immortalized hepatic stellate cells (HSCs), which create a microenvironment with HCC. Cell proliferation ability was analyzed by flow cytometry (FCM) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, while migration ability was assessed by a wound healing assay. Expression of EpCAM was analyzed by immunoblotting and FCM. HCC cell lines were co-cultured with TWNT-1 treated with small interfering RNA (siRNA) for TGF-beta and HB-EGF; we then analyzed proliferation, migration ability and protein expression using the methods described above. Proliferation ability was unchanged in HCC cell lines co-cultured with TWNT-1. Migration ability was increased in HCC cell lines (HepG2, Hep3B, HuH-7 and PLC/PRF/5) directly (216.2 +/- 67.0, 61.0 +/- 22.0, 124.0 +/- 66.2 and 51.5 +/- 40.3%) and indirectly (102.5 +/- 22.0, 84.6 +/- 30.9, 86.1 +/- 25.7 and 73.9 +/- 29.7%) co-cultured with TWNT-1 compared with the HCC uni-culture. Immunoblot analysis revealed increased EpCAM expression in the HCC cell lines co-cultured with TWNT-1. Flow cytometry revealed that the population of E-cadherin(-)/N-cadherin(+) and EpCAM-positive cells increased and accordingly, EMT and stemness in the HCC cell line were activated. These results were similar in the directly and indirectly co-cultured samples, indicating that humoral factors were at play. Conversely, HCC cell lines co-cultured with siRNA-treated TWNT-1 showed decreased migration ability, a decreased population of EpCAM-positive and E-cadherin(-)/N-cadherin(+) cells. Taken together, humoral factors secreted from TWNT-1 promote upregulation of EpCAM and EMT in hepatic cancer cells.

DOI： 10.3892/or.2015.4126

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OKAYAMA UNIV MED SCHOOL  

We conducted a retrospective cohort study to investigate the predisposing factors for local recurrence and complications after percutaneous radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC). HCC patients (n = 397) consecutively treated with RFA (256 males, 141 females, median age 69 years) were enrolled. In these patients, 1,455 nodules (median size 17 mm) were ablated. Predisposing factors for overall recurrence and local recurrence in the context of tumor location and complications were examined. Local recurrence was observed for 113 of the 1,455 nodules. The 1-, 3- and 5-year local recurrence rates were 2.2%, 7.4% and 9.5%, respectively. A multivariate Cox proportional hazard analysis revealed that large tumor size (&gt; 2cm), tumor location (adjacent to the major portal branch or hepatic vein), and small ablated margin (&lt; 3mm) were independent predisposing factors for local recurrence after RFA (HR = 1.70-2.81). Tumor location (adjacent to the major portal branch, hepatic vein, or diaphragm) was also revealed as a risk factor for liver damage due to RFA. HCC adjacent to the major portal vein or hepatic vein was associated with a higher risk for local recurrence and for complications; therefore, special precautions are necessary when applying RFA to HCC near vessels even when the tumors are located at an easy-to-puncture site.

DOI： 10.18926/AMO/53558

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Background. Post orthotopic liver transplantation (OLT) viral hepatitis is an immunological condition where immune cells induce hepatitis during conditions of immune-suppression. The immune-regulatory programmed death-1 (PD-1)/PD-ligand 1 system is acknowledged to play important roles in immune-mediated diseases. However, the PD-1/PD-L2 interaction is not well characterized, with PD-L2 also exhibiting an immunostimulatory function. We hypothesized that this atypical molecule could affect the recurrence of post-OLT hepatitis. To test this hypothesis, we conducted immunohistochemical staining analysis and in vitro analysis of PD-L2. Methods. The expression of PD-L2 was evaluated in liver biopsy specimens from patients with chronic hepatitis B (n = 15), post-OLT hepatitis B (n = 8), chronic hepatitis C (n = 48), and post-OLT hepatitis C (CH-C-OLT) (n = 14). The effect of calcineurin inhibitors (CNIs) and hepatitis C virus (HCV) on PD-L2 expression was investigated in hepatoma cell lines. Results. The PD-L2 was highly expressed on CH-C-OLT hepatocytes. Treatment of hepatoma cell lines with CNIs resulted in increased PD-L2 expression, especially in combination with HCV core or NS3 protein. Transfection of cell lines with PD-L2 containing plasmid resulted in high intercellular adhesion molecule-1 (ICAM-1) expression, which might enhance hepatitis activity. Conclusions. The PD-L2 is highly expressed on CH-C-OLT hepatocytes, whereas HCV proteins, in combination with CNIs, induce high expression of PD-L2 resulting in elevated expression of ICAM-1. These findings demonstrate the effect of CNIs on inducing PD-L2 and subsequent ICAM-1 expression, effects that may produce inflammatory cell infiltration in post-OLT hepatitis C.

DOI： 10.1097/TP.0000000000000572

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KARGER  

Background/objectives: Diagnosing the invasiveness of intraductal papillary mucinous neoplasms (IPMNs) is difficult, especially by blood test. Alterations in serum glycan profiles have been reported for several cancers, but changes in serum glycan profiles have not been investigated in patients with IPMNs. The objectives of this study were to determine the serum N-glycan profile and to investigate its clinical utility in patients with IPMNs.
Methods: We measured serum N-glycan profiles in 79 patients with IPMNs, including 13 invasive IPMNs, by performing comprehensive glycome analysis and assessed the relationship between N-glycan changes and clinical parameters.
Results: Seventy glycans were identified and their expression profiles were significantly different depending on the cyst size, the presence of an enhancing solid component, and the histological grade of the IPMN. Nine glycans were highly expressed in patients with invasive IPMNs. The glycan m/z 3195, which is a fucosylated tri-antennary glycan, had the highest diagnostic value for distinguishing invasive IPMNs from non-invasive IPMNs (area under the receiver operating characteristic curve = 0.803). Multivariate analyses revealed high levels of m/z 3195 [odds ratio (OR), 20.5; 95% confidence interval (CI) 2.60-486.4] and the presence of enhancing solid components (OR, 35.8; 95% Cl, 5.39-409.6) were significant risk factors for invasive IPMNs.
Conclusions: We performed a comprehensive evaluation of the changes in serum N-glycan profiles in patients with IPMNs for the first time. We determined that increased expression of fucosylated complex-type glycans, especially m/z 3195, is a potential marker for invasive IPMNs. Copyright (C) 2015, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.

DOI： 10.1016/j.pan.2015.05.470

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Objectives: The objectives of this study were to examine the whole serum N-glycan profile of patients with unresectable pancreatic cancer and to evaluate the ability of glycans to predict gemcitabine treatment efficacy and patient survival.
Methods: We collected serum from 52 patients with advanced pancreatic cancer before they began gemcitabine monotherapy. The serum glycan profile was measured through comprehensive quantitative high-throughput glycome analysis and compared with the treatment efficacy and patient survival.
Results: Of the 61 glycans detected, the serum levels of glycan 4310 (molecular weight [m/z] 1549.566), 6301 (m/z 2032.724), and 9200 (m/z 2010.692) were high in patients with a short time to tumor progression (TTP). Multivariate analysis revealed that a high glycan 9200 concentration was an independent risk factor for shorter TTP (hazard ratio, 2.11; 95% confidence interval, 1.07-4.17) and poor overall survival (hazard ratio, 2.56; 95% confidence interval, 1.08-6.19). The median TTP of patients with up-regulation of 9200 after gemcitabine treatment was shorter than for the remaining patients (91 vs 301 days; P = 0.0005). A similar relationship was observed for overall survival (median, 181 vs 561 days; P = 0.001).
Conclusions: Glycan 9200 is a possible biomarker predicting gemcitabine efficacy survival in patients with unresectable pancreatic cancer.

DOI： 10.1097/MPA.0000000000000321

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Background and AimsSerum glycans have been reported to be promising diagnostic markers for many inflammatory diseases and cancers. The aims of this study were to investigate whole glycan expression in patients with non-alcoholic fatty liver diseases and to evaluate the potential use of glycan profiles as new clinical biomarkers to distinguish non-alcoholic steatohepatitis (NASH) from simple steatosis (SS).
MethodsWe collected sera from 42 histologically proven NASH and 15 SS patients prior to treatment. Serum glycan profiles were measured by comprehensive, quantitative, high-throughput glycome analysis, and diagnostic values of serum glycans for NASH prediction were examined.
ResultsAmong the 41 serum glycans examined, the expression levels of 8 glycans in NASH were significantly higher than those of SS. Out of these eight glycans, three glycans (m/z 1955, 2032, and 2584) showed high areas under the receiver operating characteristic curve (0.833, 0.863, and 0.866, respectively) for distinguishing NASH from SS. In multivariate analyses with clinical parameters and serum glycans, these three glycans were significant predictive factors for distinguishing NASH from SS. The odds ratio of m/z 1955, 2032, and 2584 were 48.5, 6.46, and 11.8, respectively. These glycans also correlated significantly with lobular inflammation, ballooning, and fibrosis, but not with steatosis.
ConclusionWe clearly demonstrated whole-serum glycan profiles in NASH patients, and the feasibility of serum glycans (m/z 1955, 2032, and 2584) as new noninvasive biomarkers for distinguishing NASH from SS.

DOI： 10.1111/jgh.12726

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Background and AimInappropriate innate immune responses have been suggested to contribute to the pathogenesis of primary sclerosing cholangitis (PSC). We evaluated the associations of expressions of toll-like receptor (TLR) 4, TLR9, and nucleotide-binding oligomerization domain-containing protein (NOD)-like receptor family pyrin domain containing 3 (NLRP3) in the biliary epithelial cells (BECs) with clinical features of PSC patients.
MethodsWe retrospectively evaluated the expressions of TLR4, TLR9, and NLRP3 in the intrahepatic BECs by immunohistochemical staining in 21 PSC patients and 10 normal controls. In PSC, 17 patients underwent liver biopsy, and, in the other four patients, liver specimens were obtained at the time of liver transplantation.
ResultsTLR9 expressions in BECs were higher in PSC patients than in normal controls. TLR9 expressions were correlated with Ludwig fibrosis scores in PSC patients. TLR4 and NLRP3 expressions were similar between PSC patients and normal controls. Seventeen PSC patients undergoing liver biopsy were followed up during a median period of 55.7 months. Four reached to liver transplantation and four developed cholangiocarcinoma. Patients developing cholangiocarcinoma showed lower NLRP3 expressions than the others. Patients reaching to liver transplantation showed higher TLR9 expressions. Expression levels of TLR9 and NLRP3 were not correlated with liver biochemical tests and Mayo risk scores.
ConclusionsIn PSC, excessive immune responses through TLR9 signaling may be associated with the disease progression. Insufficient immune response through NLRP3 signaling may be associated with the development of cholangiocarcinoma. Evaluation of TLR9 and NLRP3 expressions in BECs may be useful for predicting the prognosis as an auxiliary marker.

DOI： 10.1111/jgh.12711

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

The presence of portal vein tumor thrombosis (PVTT) is a poor prognostic factor for patients with hepatocellular carcinomas (HCC). The purpose of this study was to determine the treatment effect of irradiation in combination with hepatic arterial infusion chemotherapy (HAIC) for these patients.
We retrospectively examined the outcome of 67 HCC patients with PVTT of the main trunk or first branch who received HAIC alone or with concurrent irradiation for PVTT (CCRT).
Thirty-four patients received HAIC, and 33 patients received CCRT. The time to progression (TTP) of PVTT in the CCRT group was significantly longer than in the HAIC group (p &lt; 0.01), and the TTP of intrahepatic nodules in the CCRT group tended to be longer than in the HAIC group (p = 0.06). The objective response rates of intrahepatic nodules (52 vs. 18 %, p &lt; 0.01) and PVTT (45 vs. 18 %, p = 0.01) were both significantly higher in the CCRT group than in the HAIC group, respectively. No significant difference in overall survival was found between the two groups (p = 0.14); however, the median survival time in the CCRT group was longer than that in the HAIC group (12.4 vs. 5.7 months, respectively).
CCRT might be a promising treatment for advanced-stage HCC with PVTT. CCRT prolonged the TTP of intrahepatic nodules and PVTT, and it improved the objective response rate of intrahepatic nodules and PVTT.

DOI： 10.1007/s12072-014-9592-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN SOC INTERNAL MEDICINE  

Objective Hepatopulmonary syndrome (HPS) is characterized by vascular dilatation and hyperdynamic circulation, while portopulmonary hypertension (POPH) is characterized by vasoconstriction with fibrous obliteration of the vascular bed. Vasoactive molecules such as nitric oxide (NO) are candidate factors for cirrhotic complications associated with these diseases. However, oxidative stress balance is not well characterized in HPS and POPH. The present objective is to investigate the oxidative stress and anti-oxidative stress balance and NO pathway balance in patients with potential HPS and POPH.
Methods We recruited patients with decompensated cirrhosis (n = 69) admitted to our hospital as liver transplantation candidates. Patients exhibiting partial pressure of oxygen lower than 80 mmHg and alveolararterial oxygen gradient (AaDO(2)) &gt;= 15 mmHg were categorized as potentially having HPS (23 of 69 patients). Patients exhibiting a tricuspid regurgitation pressure gradient &gt;= 25 mmHg were categorized as potentially having POPH (29 of 61 patients). Serum reactive oxygen metabolites were measured and anti-oxidative OXY-adsorbent test (OXY) were performed, and the balance of these tests was defined as the oxidative index. The correlation between these values and the clinical characteristics of the patients were assessed in a cross-sectional study.
Results Potential HPS patients exhibited no correlation with oxidative stress markers. Potential POPH patients exhibited lower OXY (p = 0.037) and higher oxidative index values (p = 0.001). Additionally, the vascular NO synthase enzyme inhibiting protein, asymmetric dimethylarginine, was higher in potential POPH patients (p = 0.049). The potential POPH patients exhibited elevated AaDO(2), suggesting the presence of pulmonary shunting.
Conclusion Potential POPH patients exhibited elevated oxidative stress with decreased anti-oxidative function accompanied by inhibited NO production. Anti-oxidants represent a candidate treatment for potential POPH patients.

DOI： 10.2169/internalmedicine.54.4889

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

AimRecently, a relationship between platelets and cancer metastasis has been reported. The aim of this study is to elucidate the risk factors for extrahepatic metastasis (EHM), with emphasis on association with platelets in patients, with hepatocellular carcinoma (HCC).
MethodsWe examined risk factors for EHM in 1613 consecutive, newly diagnosed HCC patients by logistic regression analysis (case-control study). We also examined the factors by Cox proportional hazard model in a retrospective cohort fashion in 803 patients who received non-curative treatment for HCC.
ResultsIn the case-control study, multivariate analysis revealed that high platelet counts (odds ratio [OR]=4.84; 95% confidence interval [CI]=1.29-29.54; P=0.01), high tumor number and the presence of macroscopic vascular invasion were significantly associated with EHM. In the cohort study, EHM was diagnosed in 71 patients during the study period (mean observation time=23.3 months). On multivariate analysis, high tumor number, high des--carboxyprothrombin (DCP) and Child-Pugh class A were significantly correlated with EHM, and the patients with high platelet counts tended to develop EHM (OR=1.73; 95% CI=0.99-3.14; P=0.055).
ConclusionHCC patients with high platelet counts, as well as large numbers of tumors, high serum DCP and Child-Pugh class A, are at risk for EHM.

DOI： 10.1111/hepr.12315

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OKAYAMA UNIV MED SCHOOL  

A 67-year-old Japanese man underwent enterotomy because of enterolith ileus. Component analysis by infrared spectroscopy revealed that the enterolith was composed of a high concentration of deoxycholic acid. We further analyzed and compared the ultrastructure of the enterolith and a commercially available powdered form of deoxycholic acid by means of scanning electron microscopy and energy dispersive X-ray spectroscopy. Energy dispersive X-ray spectroscopy analysis revealed that the ratios of carbon and oxygen in the enterolith were equal to those in the deoxycholic acid powder. Scanning electron microscopy analysis showed rectangular prism-shaped particles on the surface of the enterolith. This structure was similar to that of the deoxycholic acid powder. The surgically removed enterolith had a twisted and coiled appearance. Possible mechanisms underlying the formation of this unique form are discussed.

DOI： 10.18926/AMO/53026

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Radiofrequency ablation (RFA) is frequently used to treat early stage hepatocellular carcinoma. Two of the most cumbersome side-effects of the ablation procedure are intractable pain and vagotonia when deep sedation is not used. We describe local injection of anesthetic into Glisson's sheath as a new technique for overcoming these problems. Lidocaine was injected into Glisson's sheath when radiofrequency ablation of hepatocellular carcinomas, which were located adjacent to Glisson's sheath, could not be continued due to severe pain (n=8) or bradycardia (n=3). In all three patients who showed vagotonia with bradycardia during the ablations, injection of lidocaine prevented bradycardia, allowing completion of the radiofrequency ablation. Pain was reduced in all eight patients who experienced pain during ablation. No side-effects were observed during the procedures. Injection of anesthetic into Glisson's sheath is simple and effective for reducing intractable pain and vagotonia associated with RFA.

DOI： 10.1111/hepr.12321

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OKAYAMA UNIV MED SCHOOL  

Nursing support might help patients with chronic hepatitis C (CHC) remain in good mental and physical condition during interferon (IFN) therapy. However, the effects of nursing support have not been studied adequately in this context. This case-control study evaluated the effects of nursing support during IFN therapy. Twenty-four CHC patients who received pegylated IFN and ribavirin were enrolled. Nurses advised patients on the maintenance of their mental and physical condition at weekly visits, based on the results of written questionnaires. An additional 24 patients who received IFN therapy without nursing support and who were matched for age, sex, platelet count, viral serogroup and IFN regimen were selected with propensity score matching as controls. The patients with nursing support during IFN therapy achieved higher sustained virological responses (79%) than those without nursing support (58%). Adherence to the IFN and ribavirin regimens at 24 weeks of therapy were slightly higher in the patients with nursing support than those without it, but these differences were not statistically significant. Adherence to ribavirin after 24 weeks of therapy was significantly higher in those with nursing support than those without it (93% and 66%, p = 0.045). These results suggested that nursing support services could contribute to the virological responses of CHC patients by promoting drug-regimen adherence.

DOI： 10.18926/AMO/52894

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OKAYAMA UNIV MED SCHOOL  

It is not known how the immune system targets hepatitis C virus (HCV)-infected HLA-mismatched hepatocytes under immune-suppressed conditions after orthotopic liver transplantation (OLT). In addition, the relationship between the HCV-specific immune response and IL28B variants as predictors of HCV clearance has not been well-characterized. We determined the IL28B polymorphisms for 57 post-OLT HCV carriers, and we assessed the HCV-specific immune responses by measuring the peripheral blood mononuclear cell-derived HCV-specific interferon-gamma (IFN-gamma) response using an enzyme-linked immunospot assay. At 1-3 years after OLT, patients with no active hepatitis showed higher total spots on the immunospot assay. At &gt; 3 years after OLT, patients with resolved HCV showed higher levels of core, NS3, NS5A, and total spots compared to the chronic hepatitis patients. The IL28B major genotype in the donors correlated with higher spot counts for NS5A and NS5B proteins at 1-3 years after OLT. In the post-OLT setting, the HCV-specific immune response could be strongly induced in patients with no active hepatitis with an IL28B major donor or sustained virological response. Strong immune responses in the patients with no active hepatitis could only be maintained for 3 years and diminished later. It may be beneficial to administer IFN treatment starting 3 years after OLT, to induce the maximum immunological effect.

DOI： 10.18926/AMO/52898

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記述言語：英語   出版者・発行元：ELSEVIER MASSON  

DOI： 10.1016/j.clinre.2013.11.005

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease characterized by lobular inflammation, hepatocellular ballooning, and fibrosis with an inherent risk for progression to cirrhosis and hepatocellular carcinoma (HCC). Mitochondrial dysfunction appears to play a role in the progression from simple steatosis to NASH. L-carnitine (L-b-hydroxy-g-N-trimethylaminobutyric acid), an essential nutrient that converts fat into energy in mitochondria, has been shown to ameliorate liver damage. The aim of the present study was to explore the preventive and therapeutic effect of L-carnitine in NASH model mice. Eight-week-old male STAM mice, a NASH-cirrhosis-hepatocarcinogenic model, were divided into 3 experimental groups and fed as follows: 1) high-fat diet (HFD) (control group); 2) HFD mixed with 0.28% L-carnitine (L-carnitine group); and 3) HFD mixed with 0.01% alpha-tocopherol (alpha-tocopherol group). After 4 or 8 weeks, mice were sacrificed. Blood samples and livers were collected, and hepatic tumors were counted and measured. Livers were subjected to histological study, immunohistochemical staining of 4-hydroxynonenal and ferritin, determination of 8-OHdG levels, mRNA and protein expressions for multiple genes, and metabolomic analysis. The intestinal microbiome was also analyzed. L-carnitine increased hepatic expression of genes related to long-chain fatty acid transport, mitochondrial beta-oxidation, and antioxidant enzymes following suppression of hepatic oxidative stress markers and inflammatory cytokines in NASH, and mice treated with L-carnitine developed fewer liver tumors. Although alpha-tocopherol resulted in NASH improvement in the same manner as L-carnitine, it increased periodontitis-related microbiotic changes and hepatic iron transport-related gene expression and led to less effective for anti-hepatocarcinogenesis. Conclusion: L-carnitine prevents progression of non-alcoholic steatohepatitis in a mouse model by upregulating the mitochondrial beta-oxidation and redox system.

DOI： 10.1371/journal.pone.0100627

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Background and AimThe reduced expression in immortalized cells REIC/the dickkopf 3 (Dkk-3) gene, tumor suppressor gene, is downregulated in various malignant tumors. In a prostate cancer study, an adenovirus vector carrying the REIC/Dkk-3 gene (Ad-REIC) induces apoptosis. In the current study, we examined the effects of REIC/Dkk-3 gene therapy in pancreatic cancer.
MethodsREIC/Dkk-3 expression was assessed by immunoblotting and immunohistochemistry in the pancreatic cancer cell lines (ASPC1, MIAPaCa2, Panc1, BxPC3, SUIT-2, KLM1, and T3M4) and pancreatic cancer tissues. The Ad-REIC agent was used to investigate the apoptotic effect in vitro and antitumor effects in vivo. We also assessed the therapeutic effects of Ad-REIC therapy with gemcitabine.
ResultsThe REIC/Dkk-3 expression was lost in the pancreatic cancer cell lines and decreased in pancreatic cancer tissues. Ad-REIC induced apoptosis and inhibited cell growth in the ASPC1 and MIAPaCa2 lines in vitro, and Ad-REIC inhibited tumor growth in the mouse xenograft model using ASPC1 cells. The antitumor effect was further enhanced in combination with gemcitabine. This synergistic effect may be caused by the suppression of autophagy via the enhancement of mammalian target of rapamycin signaling.
ConclusionsAd-REIC induces apoptosis and inhibits tumor growth in pancreatic cancer cell lines. REIC/Dkk-3 gene therapy is an attractive therapeutic tool for pancreatic cancer.

DOI： 10.1111/jgh.12501

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Aim
We investigated whether continuous sorafenib administration keeps suppressing the growth of hepatocellular carcinoma (HCC) after first progressive disease (PD), and whether it prolongs patients' survival.
Methods
The size of metastatic lesions was measured in 36 patients with advanced HCC treated with sorafenib. The tumor growth rates before and after radiological PD as well as survival were compared between the patients who continued (n = 23) and stopped (n = 13) sorafenib at first radiological PD.
Results
The growth rate did not differ between before and after PD in patients who continued sorafenib, while it increased after PD in patients who stopped sorafenib at PD (P = 0.002). Survival beyond first progression was longer in patients who continued sorafenib than in those who stopped it at PD (P = 0.012), and this tendency was observed even when the analysis was limited to Child-Pugh class A patients (P = 0.085).
Conclusion
Sorafenib administration beyond first radiological PD could continuously suppress HCC growth and may have survival benefit.

DOI： 10.1111/hepr.12123

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記述言語：英語   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

DOI： 10.1097/MCG.0b013e3182a39116

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Background and AimRecently, the association of the dysfunction of programmed cell death (PD)-1 expressed on activated lymphocytes with the pathogenesis of autoimmune hepatitis (AIH) has been speculated. This study aimed to investigate the association of serum anti-PD-1 antibodies with clinical characteristics of type 1 AIH.
MethodsSerum samples before the initiation of prednisolone treatment were obtained from 52 type 1 AIH patients, 24 patients with drug-induced liver injury (DILI), 30 patients with acute viral hepatitis (AVH), 11 patients with primary sclerosing cholangitis (PSC), and 62 healthy volunteers. Titers of serum anti-PD-1 antibodies were measured by indirect enzyme-linked immunosorbent assay. The cutoff level was represented by a mean absorbance+2 standard deviations in healthy volunteers.
ResultsPrevalence of serum anti-PD-1 antibodies was 63% in type 1 AIH patients, 8% in DILI patients, 13% in AVH patients, 18% in PSC patients, and 3% in healthy volunteers. In type 1 AIH patients, titers of serum anti-PD-1 antibodies were correlated with serum levels of bilirubin (r=0.31, P=0.030) and alanine aminotransferase (r=0.31, P=0.027) but not serum immunoglobulin G levels. Positivity for serum anti-PD-1 antibodies was associated with the later normalization of serum alanine aminotransferase levels after the initiation of prednisolone and the disease relapse.
ConclusionsSerum anti-PD-1 antibodies would be useful for the discrimination of type 1 AIH from DILI, AVH, and PSC as an auxiliary diagnostic marker. Furthermore, anti-PD-1 antibodies may be associated with clinical characteristics of type 1 AIH.

DOI： 10.1111/jgh.12340

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer-Verlag Tokyo  

A 44-year-old male was pointed out liver function abnormality by medical check-up. Blood examination and computed tomography showed liver cirrhosis. Then, he was referred to our hospital for further examination. After blood test, viral markers revealed previous infection of hepatitis B virus (HBV). We estimated the etiology of his liver disease as previous HBV infection. On laparoscopic examination, his liver surface was nodular with mixed yellowish nodules and ash gray to copper-colored nodules in the diameter of 3-10 mm. There were large regenerative nodules in segments 3 and 4. Large regenerative nodules and irregular steatosis were contradictory to HBV-related liver cirrhosis, so then we supposed Wilson's disease. The amount of copper excretion in the urine was 326.6 μg (&gt
100 μg/24 h). After D-penicillamine administration, urinary copper excretion increased to 2151.5 μg/24 h. Though hepatic copper concentration was 174.5 μg/g wet tissue (&gt
200 μg/g wet tissue), his laboratory data fulfilled the Leipzig diagnostic criteria proposed by EASL. Laparoscopic examination with liver biopsy has advantages to survey many disease-specific findings on liver surface and to obtain adequate liver sample. Laparoscopic examination is one of the effective procedures for diagnosing relatively rare liver disease like Wilson's disease. © 2014 Springer.

DOI： 10.1007/s12328-014-0465-7

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記述言語：英語   出版者・発行元：WILEY-BLACKWELL  

DOI： 10.1371/journal.pone.0100627

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: A combination of hepatitis B immunoglobulin and nucleos(t)ide analogues is the current standard of care for controlling hepatitis B recurrence after orthotopic liver transplantation (OLT). However, frequent immunoglobulin treatment is expensive and inconvenient. This study investigated the efficacy of hepatitis B virus (HBV) vaccination in preventing the recurrence of hepatitis B after living donor OLT. Methods: Twenty-seven patients who had undergone living donor OLT participated in the study
five had acute HBV infected liver failure (ALF-OLT) and 22 had HBV related liver cirrhosis (LC-OLT). Hepatitis B surface antigen (HBsAg)-containing vaccine was administered to them for at least 1 year after transplantation and continued once monthly for up to 36 months post-OLT. Patients who had anti-HBs antibody titers above 100 mIU/mL for a minimum of 6 months without immunoglobulin administration were defined as good responders
the others were defined as poor responders. Interferon-γ enzyme-linked immunospot assays against HBs and HBc antigens were used to assay cellular immune responses. Results: All five of the ALF-OLT patients had good responses after a median of four (range 2.5-5) vaccinations. Nine of the 22 LC-OLT patients had good responses after a median of 19 (range 11.5-30) vaccinations. Among the LC-OLT group, those with livers donated by relatively higher-aged, marital and high-titer anti-HBs antibody donors were good responders. LC-OLT patients classed as good responders showed interferon-γ responses comparable to those of the ALF-OLT patients. Conclusions: The ALF-OLT and LC-OLT patients who received livers from relatively higher-aged, marital, high-titer anti-HBs antibody donors were the best candidates for HBV vaccine administration. Boosting donors before transplantation may facilitate later vaccine response of the recipients. © 2013 The Author(s).

DOI： 10.1007/s00535-013-0763-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background:The aims of this study were to determine the change of whole-serum N-glycan profile in ulcerative colitis (UC) patients and to investigate its clinical utility.Methods:We collected serum from 75 UC patients at the time of admission and the same number of age/sex-matched healthy volunteers. Serum glycan profile was measured by comprehensive quantitative high-throughput glycome analysis and was compared with disease activity and prognosis.Results:Out of 61 glycans detected, 24 were differentially expressed in UC patients. Pathway analysis demonstrated that highly sialylated multi-branched glycans and agalactosyl bi-antennary glycans were elevated in UC patients
in addition, the glycan ratio m/z 2378/1914, which also increased in UC, showed the highest Area under Receiver Operating Characteristic curve (0.923) for the diagnosis of UC. Highly sialylated multi-branched glycans and the glycan ratio m/z 2378/1914 were higher in the patients with total colitis, Clinical Activity Index &gt
10, Mayo endoscopic score 3, or a steroid-refractory status. In particular, the glycan ratio m/z 2378/1914 (above median) was an independent prognostic factor for the need for an operation (hazard ratio, 2.67
95% confidence interval, 1.04-7.84).Conclusions:Whole-serum glycan profiles revealed that the glycan ratio m/z 2378/1914 and highly sialylated multi-branched glycans increase in UC patients, and are correlated with disease activity. The glycan ratio m/z 2378/1914 was an independent predictive factor of the prognosis of UC. © 2013 Miyahara et al.

DOI： 10.1371/journal.pone.0074861

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/bjc.2013.554

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その他リンク： http://www.nature.com/articles/bjc2013554

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/hepr.12055

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER JAPAN KK  

Most of the glycan changes reported in cancers were based on the examinations of a small number of patients or particular proteins. The aim of this study was to determine the changes of the serum N-glycan profile comprehensively in a large number of pancreatic cancer patients and investigate its clinical utility.
Glycan levels in the serum of 92 pancreatic cancer patients and 243 healthy volunteers (HLT) were examined by comprehensive quantitative high-throughput glycome analysis and were compared with clinical parameters.
Out of 66 glycans detected, 15 were differentially expressed in pancreatic cancer, and 10 out of the 15 glycans were significantly up-regulated in cases with distant metastasis. There was a clear increase in overall expression of serum glycans, especially highly-branched glycans with fucose moieties, in pancreatic cancer. Among these 15 glycans, a tri-antennary complex type glycan (m/z 3195) showed the highest area under the receiver operating characteristic curve (AUROC = 0.799) for the diagnosis of pancreatic cancer. The ratio of pairs of glycans on the same path of the biosynthesis pathway (m/z 3195/1914) was found to be significantly higher in pancreatic cancer than in HLT (median = 1.11 and 0.41, respectively; p &lt; 0.0001, AUROC = 0.831). For this pair ratio, the hazard ratio for survival (2.60, 95 % CI = 1.44-4.79) was higher than that of any single glycan and 1-year survival of patients with a high and low ratio was 36.9 and 69.2 %, respectively, (p = 0.001).
Comprehensive glycome analysis can be used to know the presence of pancreatic cancer, distant metastasis, and patient prognosis, simultaneously.

DOI： 10.1007/s00535-012-0732-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Background and Aim: Follistatin (FST) is a glycoprotein expressed in most organs, which interacts with activins or other members of the transforming growth factor beta family. Recently, several reports have shown that FST regulates a variety of processes during tumor progression. Here, serum FST in patients with liver diseases was measured, and its clinical utility as a biomarker was assessed.
Methods: Serum was collected from 162 patients (91 hepatocellular carcinoma [HCC], 43 liver cirrhosis, and 28 chronic hepatitis) as well as from 16 healthy volunteers. FST was quantified by enzyme-linked immunosorbent assays, and levels were compared with clinical parameters including survival of the HCC patients.
Results: Median serum FST levels in HCC, liver cirrhosis, chronic hepatitis, and healthy volunteers were 1168, 1606, 1324, and 1661 pg/mL, respectively, not significantly different. In HCC patients, higher serum FST was associated with greater age, hepatitis C virus antibody-negativity, large tumor size, g-glutamyl transpeptidase, des-gamma carboxyprothrombin and presence of portal vein tumor thrombus. Survival of HCC patients with high FST levels was significantly shorter than for those with low levels (P = 0.004). Multivariate analysis revealed that in addition to large tumor size and presence of portal vein thrombus, high FST levels were independently correlated with poor prognosis (hazard ratio = 2.41, 95% confidence interval = 1.16-5.00, P = 0.02).
Conclusions: Serum FST levels are significantly associated with HCC prognosis and could represent a predictive biomarker in this disease.

DOI： 10.1111/jgh.12167

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OKAYAMA UNIV MED SCHOOL  

The aim of this study was to evaluate the histologic diagnosis of hypovascular hepatic lesions showing hypointensity on hepatobiliary phase images of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI (EOB-MRI). In 38 patients with hepatocellular carcinoma (HCC) after curative treatments and 18 patients with liver cirrhosis, 105 hypovascular nodules that were hypointense at the hepatobiliary phase of EOB-MRI were biopsied and the clinical usefulness of these EOB-MRI findings for the diagnosis of HCC was examined. Of the 105 nodules (median diameter = 12 nun), 78 (74.3%), 11(10.5%), and 16 (15.2%) were diagnosed as HCC, dysplastic, and non-neoplastic, respectively. The positive predictive value (PPV) of hypointensity at the hepatobiliary phase of EOB-MRI for the diagnosis of HCC increased to 77-90% when combined with the following factors: washout appearance on the delayed phase of triple-phase CT, hyperintensity in diffusion-weighted image of MRI, or the appearance of a hypoechoic part in ultrasonography. PPV increased to 100% when all 3 factors were positive. A relatively large proportion of hypovascular lesions that showed hypo-intensity in the hepatobiliary phase were confirmed to be HCC, and the accuracy of HCC increased when combined with other imaging findings.

DOI： 10.18926/AMO/51068

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPANDIDOS PUBL LTD  

Hepatocellular carcinoma is the third most frequent cause of cancer-related death worldwide; and its incidence rate is increasing. Clinical and molecular medical analyses have revealed substantial information on hepatocarcinogenesis. Hepatocarcinogenesis is a stepwise process during which multiple genes are altered. Genetic changes and their biological consequences in human HCC can be divided into at least 4 groups: i) tumor suppressor genes (p53, retinoblastoma, phosphatase tensin homolog and runt-related transcription factor 3), ii) oncogenes (myc, K-ras, BRAF), iii) reactivation of developmental pathways (Wnt, hedgehog), and iv) growth factors and their receptors (transforming growth factor-a, insulin-like growth factor-2 receptor). An experimental model of human hepatocarcinogenesis such as in vitro neoplastic transformation of human hepatocytes has not been successfully achieved yet, but several immortalized human hepatocyte cell lines have been established. These immortalized human hepatocytes will become useful tools for the elucidation of hepatocarcinogenesis, especially for the initial step of multistep hepatocarcinogenesis.

DOI： 10.3892/ijo.2013.1829

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background The single nucleotide polymorphism (SNP) rs738409 in patatin-like phospholipase domain-containing protein 3 (PNPLA3) is associated with hepatic fat accumulation and disease progression in patients with nonalcoholic fatty liver disease and alcoholic liver disease (ALD). This study was conducted to determine whether PNPLA3 rs738409 SNPs affect development and prognosis of hepatocellular carcinoma (HCC) in patients with various liver diseases. Methods We enrolled 638 consecutive Japanese patients newly diagnosed with HCC between 2001 and 2010: 72 patients with hepatitis B virus (HBV), 462 with hepatitis C virus (HCV), and 104 with non-B non-C (NBNC). Results NBNC patients exhibited large tumors of advanced TNM stages at HCC diagnosis, and had significantly poorer prognosis than HBV or HCV patients (P&lt
0.001 and &lt
0.001, respectively
log-rank test). The G/G genotype of PNPLA3 rs738409 SNP had significantly higher distribution in NBNC patients (P&lt
0.001) and was significantly associated with higher body mass index (BMI) and an increased aspartate aminotransferase to platelet ratio index. No significant differences were observed in survival with differences in PNPLA3 SNP genotypes among the patients, although ALD patients with the G/G genotype of PNPLA3 SNP and low BMI had significantly poorer survival than those with high BMI (P = 0.028). Conclusions The G/G genotype of PNPLA3 rs738409 SNP was more frequently distributed, and associated with BMI and fibrosis among NBNC-HCC patients but not among HBV or HCV patients. These genotypes might affect HCC prognosis in ALD patients, but not in HBV, HCV, or NAFLD patients. © Springer 2012.

DOI： 10.1007/s00535-012-0647-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：John Wiley and Sons Ltd  

Background &amp
Aim: Runt-related transcription factor 3 (RUNX3) is a tumor suppressor gene that is expressed in gastric and other cancers including pancreatic cancer. However, the precise function of RUNX3 in pancreatic cancer has not been fully elucidated. In this study, we aimed to determine the effect of decreased RUNX3 expression in pancreatic cancer. Methods: This study included 36 patients with primary pancreatic cancer, who had undergone pancreaticoduodenectomy. All patients were treated with 1000mg/m2 gemcitabine after the surgery. The pancreatic cancer cell lines PANC-1, MIAPaCa-2, BxPC-3, SUIT-2, and KLM-1 were used for immunoblotting analysis of RUNX3 and multidrug resistance protein (MRP) expressions. Ectopic RUNX3 expression was achieved by cDNA transfection of the cells, and small interfering RNA (siRNA) against RUNX3 was used to knock down endogenous RUNX3. Cell growth in the presence of gemcitabine was assessed using the MTT assay. Results: Patients with RUNX3-positive and RUNX3-negative pancreatic cancer had a median survival of 1006 and 643 days, respectively. Exogenous RUNX3 expression reduced the expression of MRP1, MRP2, and MRP5 in endogenous RUNX3-negative cells, whereas RUNX3 siRNA increased the expressions of these genes in endogenous RUNX3-positive cells. Exogenous RUNX3 expression decreased gemcitabine IC50 in RUNX3-negative cells. Conclusion: Loss of RUNX3 expression contributes to gemcitabine resistance by inducing MRP expression, thereby resulting in poor patient survival. © 2013 Federation of European Biochemical Societies.

DOI： 10.1016/j.molonc.2013.04.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Loss or decreased expression of runt-related transcription factor 3 (RUNX3), a tumor suppressor gene involved in gastric and other cancers, has been frequently observed in hepatocellular carcinoma (HCC). The objective of this study was to identify the regulatory mechanism of the epithelialmesenchymal transition (EMT) by RUNX3 in HCC. Human HCC cell lines, Hep3B, Huh7, HLF and SK-Hep1, were divided into low- and high-EMT lines, based on their expression of TWIST1 and SNAI2, and were used in this in vitro study. Ectopic RUNX3 expression had an anti-EMT effect in low-EMT HCC cell lines characterized by increased E-cadherin expression and decreased N-cadherin and vimentin expression. RUNX3 expression has previously been reported to reduce jagged-1 (JAG1) expression; therefore, JAG1 ligand peptide was used to reinduce EMT in RUNX3-expressing low-EMT HCC cells. Immunohistochemical analyses were performed for RUNX3, E-cadherin, N-cadherin and TWIST1 in 33 human HCC tissues, also divided into low- and high-EMT HCC, based on TWIST1 expression. E-cadherin expression was correlated positively and N-cadherin expression was correlated negatively with RUNX3 expression in low-EMT HCC tissues. Correlations between EMT markers and RUNX3 mRNA expression were analyzed using Oncomine datasets. Similarly, mRNA expression of E-cadherin was also significantly correlated with that of RUNX3 in low-EMT HCC, while mRNA expression of JAG1 was negatively correlated with that of RUNX3. These results suggest a novel mechanism by which loss or decreased expression of RUNX3 induces EMT via induction of JAG1 expression in low-EMT HCC.

DOI： 10.1002/ijc.27575

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Aim: Hepatocellular carcinoma (HCC) is a common clinical problem all over the world. Fucosylated hemopexin (Fuc-Hpx) is a newly reported glycoprotein for the diagnosis of HCC, however, its clinical implications are unclear. The aim of this study was to elucidate the clinical utility of Fuc-Hpx in Japanese patients with HCC.
Methods: The sera from 331 HCC patients, 45 with liver cirrhosis (LC), 85 with chronic hepatitis (CH) and 22 healthy people were examined for the expression of Fuc-Hpx; the level was compared with clinical parameters as well as hemopexin (Hpx) expression. The expressions of Fuc-Hpx in 12 HCC tissues and corresponding adjacent non-cancerous liver tissues were also examined.
Results: No correlation was observed between Hpx and Fuc-Hpx level. The median Fuc-Hpx levels in healthy people and CH, LC and HCC patients were 3.8, 3.7, 6.1 and 7.6 AU/mL, respectively (CH vs LC, P = 0.002; CH vs HCC, P &lt; 0.001; LC vs HCC, P = 0.02). Multivariate analysis revealed that low albumin, low prothrombin time and the presence of HCC were significantly correlated with high Fuc-Hpx (P = 0.013, =0.001 and &lt;0.001, respectively). Among the HCC patients, albumin was correlated with high Fuc-Hpx; however, none of the tumor factors, such as tumor size, tumor number and tumor stage, was correlated with Fuc-Hpx level. The expression of Fuc-Hpx in cancer tissue was not different from that in non-cancerous tissue.
Conclusion: Fuc-Hpx is a valuable biomarker for HCC but it might be a marker for hypercarcinogenic liver rather than a marker for tumor-bearing liver.

DOI： 10.1111/j.1872-034X.2012.01044.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Background: Bioartificial liver systems, designed to support patients with liver failure, are composed of bioreactors and functional hepatocytes. Immunological rejection of the embedded hepatocytes by the host immune system is a serious concern that crucially degrades the performance of the device. Induced pluripotent stem (iPS) cells are considered a desirable source for bioartificial liver systems, because patient-derived iPS cells are free from immunological rejection. The purpose of this paper was to test the feasibility of a bioartificial liver system with iPS cell-derived hepatocyte-like cells.
Methods: Mouse iPS cells were differentiated into hepatocyte-like cells by a multi-step differentiation protocol via embryoid bodies and definitive endoderm. Differentiation of iPS cells was evaluated by morphology, PCR assay, and functional assays. iPS cell-derived hepatocyte-like cells were cultured in a bioreactor module with a pore size of 0.2 mu m for 7 days. The amount of albumin secreted into the circulating medium was analyzed by ELISA. Additionally, after a 7-day culture in a bioreactor module, cells were observed by a scanning electron microscope.
Results: At the final stage of the differentiation program, iPS cells changed their morphology to a polygonal shape with two nucleoli and enriched cytoplasmic granules. Transmission electron microscope analysis revealed their polygonal shape, glycogen deposition in the cytoplasm, microvilli on their surfaces, and a duct-like arrangement. PCR analysis showed increased expression of albumin mRNA over the course of the differentiation program. Albumin and urea production was also observed. iPS-Heps culture in bioreactor modules showed the accumulation of albumin in the medium for up to 7 days. Scanning electron microscopy revealed the attachment of cell clusters to the hollow fibers of the module. These results indicated that iPS cells were differentiated into hepatocyte-like cells after culture for 7 days in a bioreactor module with a pore size of 0.2 mu m.
Conclusion: We consider the combination of a bioreactor module with a 0.2-mu m pore membrane and embedded hepatocytes differentiated from iPS cells to be a promising option for bioartificial liver systems. This paper provides the basic concept and preliminary data for an iPS cell-oriented bioartificial liver system. PACS code: 87. Biological and medical physics, 87.85.-d Biomedical engineering, 87.85.Lf Tissue engineering, 87.85.Tu Modeling biomedical systems.

DOI： 10.1186/1475-925X-11-93

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OKAYAMA UNIV MED SCHOOL  

Hepatitis C virus (HOT) infection induces several changes in hepatocytes, such as oxidative stress, steatosis, and hepatocarcinogenesis. Although considerable progress has been made during recent years, the mechanisms underlying these functions remain unclear. We employed proteomic techniques in HCV replicon-harboring cells to determine the effects of HCV replication on host-cell protein expression. We examined two-dimensional electrophoresis (2-DE) and mass spectrometry to compare and identify differentially expressed proteins between HCV subgenomic replicon-harboring cells and their "cured" cells. One of the identified proteins was confirmed using enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. Full-length HCV genome RNA replicating and cured cells were also assessed using ELISA. Replicon-harboring cells showed higher expression of retinal dehydrogenase 1 (RALDH-1), which converts retinol to retinoic acid, and the cured cells showed higher expression of retinol-binding protein (RBP), which transports retinol from the liver to target tissues. The alteration in RBP expression was also confirmed by ELISA and Western blot analysis. We conclude that protein expression profiling demonstrated that HCV replicon eradication affected retinol-related protein expression.

DOI： 10.18926/AMO/49042

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/j.1440-1746.2012.07173.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Oxidative stress is a strong contributor to the progression from simple fatty liver to nonalcoholic steatohepatitis (NASH). Molecular hydrogen is an effective antioxidant that reduces cytotoxic reactive oxygen species. In this study, we investigated the effects of hydrogen-rich water and the drug pioglitazone on the progression of NASH in mouse models. A methionine-cholinedeficient (MCD) diet mouse model was prepared. Mice were divided into three experimental groups and fed for 8 weeks as follows: (1) MCD diet + control water (CW group); (2) MCD diet + hydrogen-rich water (HW group); and (3) MCD diet mixed with pioglitazone (PGZ group). Plasma alanine aminotransferase levels, hepatic expression of tumor necrosis factor-a, interleukin-6, fatty acid synthesisrelated genes, oxidative stress biomarker 8-hydroxydeoxyguanosine (8-OHdG), and apoptosis marker terminal deoxynucleotidyl transferasemediated deoxyuridine triphosphate nick-end labeling (TUNEL)positive cells in the liver were decreased in the HW and PGZ groups. The HW group showed a smaller decrease in hepatic cholesterol; however, stronger antioxidative effects in serum and lower peroxisome proliferator-activated receptor-a expression in the liver were seen in comparison with the PGZ group. We then investigated the effects of hydrogen in the prevention of hepatocarcinogenesis in STAM mice, known as the NASH-related hepatocarcinogenesis model. Eight-week-old male STAM mice were divided into three experimental groups as follows: (1) control water (CW-STAM); (2) hydrogen-rich water (HW-STAM); and (3) pioglitazone (PGZ-STAM). After 8 weeks, hepatic tumors were evaluated. The number of tumors was significantly lower in the HW-STAM and PGZ-STAM groups than in the CW-STAM group. The maximum tumor size was smaller in the HW-STAM group than in the other groups. Conclusion: Consumption of hydrogen-rich water may be an effective treatment for NASH by reducing hepatic oxidative stress, apoptosis, inflammation, and hepatocarcinogenesis. (HEPATOLOGY 2012;56:912921)

DOI： 10.1002/hep.25782

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Herein, a case of immunoglobulin G4 (IgG4)-related sclerosing cholangitis is reported. IgG4 was diagnosed based on observations from peroral cholangioscopy and laparoscopy, and these methods are proposed for definitive and precise diagnosis of this disease. A 76-year-old male patient with inguinal Paget's disease had intrahepatic bile duct dilatations detected with computed tomography at his periodic check-up. Magnetic resonance cholangiography showed stenosis of the upper common bile duct and poststenotic dilatation of left intrahepatic bile ducts. The portal tract and bilateral intrahepatic bile ducts were surrounded by a low-density area, facing a tumor-like lesion at segment 2. Cytological examinations of the stenotic and dilated lesions revealed no cellular atypia. Histological examination of the tumor showed normal liver tissue with infiltration of lymphocytes, indicating an inflammatory pseudotumor. Peroral cholangioscopy excluded the possibility of biliary cancer and indicated that the stenotic legion was of submucosal, not mucosal, origin. Laparoscopic observations showed discoloration with wide yellowish-white lobular markings and wide depressed lesions at segments 2 and 7. Liver histology showed mild cholangitis with infiltration of IgG4-positive plasma cells around the bile ducts. Serum IgG4 levels were elevated. From these findings, the patient was diagnosed with IgG4-related sclerosing cholangitis. After treatment with prednisolone, blood liver enzymes and IgG4 rapidly normalized, bile duct dilatations improved, and the hepatic pseudotumor disappeared. The cholangitis did not recur. In this case, biliary cancer was ruled out by observation with peroral cholangioscopy, and the spread of cholangitis in the liver periphery was verified with laparoscopy; this information could not be obtained with other modalities.

DOI： 10.1111/j.1443-1661.2012.01300.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER TOKYO  

Radiofrequency ablation (RFA) is a standard therapy for the treatment of hepatocellular carcinoma (HCC) with 3 or fewer tumors of up to 3 cm (early-stage HCC); when RFA is unsuccessful or unfeasible, transcatheter arterial chemoembolization (TACE) has often been performed. However, little information about the outcome of TACE for early-stage HCC has been reported and it is hard to decide whether to perform additional treatment following TACE in these difficult conditions. The aim of this study was to determine the risk factors for local or intrahepatic distant recurrence after TACE in early-stage HCC.
Among 1,560 newly diagnosed HCC patients who were admitted to Okayama University Hospital, 43 patients with early-stage HCC who received only TACE in at least one nodule were enrolled in this study. We analyzed the risk factors for local and distant recurrence by the Cox proportional hazard model.
The local recurrence rates and intrahepatic distant recurrence rates at 3 months, 6 months, and 1 year were 18.6, 33.4, and 61.8%, and 2.8, 2.8, and 10.2%, respectively. Among 12 parameters examined as possible risk factors for recurrence, heterogeneous Lipiodol uptake (risk ratio 3.38; 95% confidence interval 1.14-10.60) and high serum des-gamma-carboxy prothrombin (DCP) (2.58; 1.03-7.14) were significantly correlated with local recurrence, and the presence of multiple tumors (10.64; 1.76-93.75) was significantly correlated with intrahepatic distant recurrence.
Heterogeneous Lipiodol uptake, high serum DCP, and multiple tumors are risk factors for recurrence in patients with early-stage HCC who have undergone palliative TACE.

DOI： 10.1007/s00535-011-0492-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00535-011-0508-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: Von Hippel-Lindau disease is an autosomal dominant genetic disorder characterized by neoplasms developing in multiple organs. Although the pancreas is one of the most frequently involved organs, the frequency of pancreatic cysts, cystadenomas, neuroendocrine tumors and diabetes has not been sufficiently evaluated clue to the low prevalence of this disease. In this paper, we review and retrospectively analyze 11 patients with von Hippel-Lindau disease. Methodology: Eleven patients (6 males, 5 females) who underwent CT or MRI scans at Okayama University Hospital between 2002 and 2009 were enrolled in this study. Their pancreatic CT scans, MRI scans, biochemical test results and clinical histories were retrospectively reviewed. Results: All patients had one or more pancreatic involvements. Nine of the 11 patients had multiple pancreatic cysts, 2 had dilatation of the main pancreatic duct, 3 had a non-functioning pancreatic endocrine tumor (one patient required pancreatoduodenectomy due to the endocrine carcinoma) and 3 had diabetes mellitus. Pancreatic cystadenomas were not detected in this case series. Conclusions: The prevalence of pancreatic involvement was 100% in this study. Regular screening and scheduled follow-up for pancreatic lesions and diabetes should be performed on individuals predisposed to von Hippel-Lindau disease.

DOI： 10.5754/hge10236

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KARGER  

Background/Aims: In patients with septic shock, the degree of liver dysfunction is correlated with serum levels of soluble intercellular adhesion molecule (sICAM)-1. We aimed to assess the usefulness of serum levels of soluble adhesion molecules as prognostic factors for acute liver failure (ALF). Methods: Serum levels of soluble platelet endothelial cell adhesion molecule (sPECAM)-1, sICAM-3, soluble endothelial (sE) selectin, sICAM-1, soluble platelet selectin, and soluble vascular cell adhesion molecule-1 on admission were measured in 37 ALF patients and 34 healthy controls. Results: Twenty-two ALF patients (59%) reached to fatal outcomes. Serum levels of sPECAM-1, sICAM-3, sE-selectin and sICAM-1 were higher in ALF patients than healthy controls. In 37 ALF patients, by the multivariate logistic regression analysis, ratio of direct to total bilirubin (per 0.1 increase; OR 0.11, 95% CI 0.01-0.99), serum sPECAM-1 level (per 100 ng/ml increase; OR 4.37, 95% CI 1.23-15.5) and serum sICAM-1 level (per 100 ng/ml increase; OR 0.49, 95% CI 0.27-0.89) were associated with fatal outcomes. Using receiver operating characteristics curve, each area under the curve of serum sPECAM-1 and sICMA-1 levels as prognostic factors was 0.71 and 0.74, respectively. Conclusion: Serum sPECAM-1 and sICAM-1 levels may be useful for predicting the prognosis of ALF. Copyright (c) 2012 S. Karger AG, Basel

DOI： 10.1159/000339496

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

Purpose The combination of hepatitis B immunoglobulin (HBIg) and nucleos(t)ide analogues has been accepted as the best treatment to control hepatitis B recurrence after orthotopic liver transplantation (OLT). However, the optimal dose of HBIg remains unclear. We have previously reported that high-dose HBIg in the early period followed by low-dose HBIg with nucleos(t)ide analogues offers reliable and cost-effective control of hepatitis B recurrence. The aim of this study was to investigate intrahepatic hepatitis B virus (HBV) reinfection status with our clinically successful protocol.
Methods We quantified levels of intrahepatic HBV covalently closed circular (ccc) deoxyribonucleic acid (DNA) and serum hepatitis B core-related antigen (HBcrAg), a new serological marker that can estimate intrahepatic cccDNA levels. Nucleos(t)ide analogues were administered in all cases.
Results No patients showed recurrence of hepatitis B surface antigen (HBsAg) or HBV-DNA. However, HBV, cccDNA, and HBcrAg were positive in 57% and 48% of patients after OLT, respectively. Pre-OLT serum HBV-DNA and HBcrAg levels correlated linearly with post-OLT cccDNA levels (r = 0.534, P &lt; 0.05, and r = 0.634, P &lt; 0.05, respectively). High serum HBV-DNA and HBcrAg levels, particularly with &gt; 3 log(10) copies/mL and &gt; 4 log(10) IU/mL, respectively, at the time of OLT, were associated with high levels of post-OLT cccDNA. Even with our successful protocol, nearly half of patients showed HBV reinfection.
Conclusions Patients with high serum HBV-DNA and HBcrAg levels before OLT (particularly &gt; 3 log(10) copies/mL and &gt; 4 log(10) IU/mL, respectively) should be followed with care for HBV recurrence.

DOI： 10.1007/s12072-011-9265-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Background and Aim: Sorafenib, the first agent demonstrated to have efficacy to improve the survival of patients with advanced hepatocellular carcinoma (HCC), is an active multikinase inhibitor affecting angiogenesis and tumor proliferation. We analyzed cytokines related to angiogenesis or cell proliferation, and tried to determine their utility as biomarkers of sorafenib treatment effect for HCC.
Methods: Nine serum cytokines (angiopoietin-2 [Ang-2], follistatin, granulocyte colony-stimulating factor [G-CSF], hepatocyte growth factor [HGF], interleukin-8 [IL-8], leptin, platelet-derived growth factor-BB, platelet endothelial cell adhesion molecule-1, and vascular endothelial growth factor) were measured in 30 HCC patients treated with sorafenib, and the effects of treatment were compared using modified Response Evaluation Criteria in Solid Tumors.
Results: All but IL-8 were significantly higher at baseline in patients with progressive disease. Progression-free survival was significantly shorter in patients with high levels of Ang-2, G-CSF, HGF, and leptin, and the hazard ratios were 2.51, 6.89, 2.55, and 4.14, respectively. As the number of cytokines at a high level increased, the treatment response deteriorated. Disease progression was seen in three of 12 (25.0%) patients with zero to two high biomarkers, two of six (33.3%) patients with 3-5 high biomarkers, and 10 of 12 (83.3%) patients with six to eight high biomarkers (P = 0.008). The prognosis of all patients with eight high biomarkers was progressive disease.
Conclusion: High levels of serum cytokines at baseline were correlated with poor effects of sorafenib treatment in patients with HCC.

DOI： 10.1111/j.1440-1746.2011.06887.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Background: Hepatitis B virus (HBV) is a major cause of hepatocarcinogenesis. To identify mutations relevant to hepatocellular carcinoma (HCC) development, we compared the full genome sequences of HBV from the sera of patients with and without HCC.
Methods: We compared the full genome sequences of HBV isolates from 37 HCC patients (HCC group 1) and 38 patients without HCC (non-HCC group 1). We also investigated part of the core promoter region sequences from 40 HCC patients (HCC group 2) and 68 patients without HCC. Of the 68 patients who initially did not have HCC, 52 patients remained HCC-free during the follow-up period (non-HCC group 2), and 16 patients eventually developed HCC (pre-HCC group 2). Serum samples collected from patients were subjected to PCR, and the HBV DNA was directly sequenced.
Results: All patients had genotype C. A comparison of the nucleotide sequences of the HBV genome between HCC group 1 and non-HCC group 1 revealed that the prevalence of G1613A and C1653T mutations in the core promoter region was significantly higher in the HCC group. These mutations tended to occur simultaneously in HCC patients. Multivariate analysis with group 2 revealed that the presence of HCC was associated with aging and the double mutation. Future emergence of HCC was associated with aging and the presence of a single G1613A mutation.
Conclusions: G1613A and C1653T double mutations were frequently found in patients with HCC. A single G1613A mutation was associated with future emergence of HCC. These mutations may serve as useful markers in predicting HCC development.

DOI： 10.1186/1471-2407-11-458

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPANDIDOS PUBL LTD  

Runt-related transcription factor 3 (RUNX3) is a candidate tumor suppressor gene that is downregulated in various cancers. In the present study, we analyzed the regulatory function of RUNX3 on Jagged-1 (JAG1) expression and cancer stem cell (CSC) signaling in hepatocellular carcinoma (HCC). Eleven HCC cell lines and 30 human HCC tissues were used. RUNX3 and JAG1 expression levels were analyzed by immunoblotting and immunohistochemistry. Ectopic RUNX3 expression was induced by introducing RUNX3 cDNA into the RUNX3-negative HCC cell line Hep3B and Huh7 cells. Furthermore endogenous RUNX3 expression was knocked down by RUNX3 siRNA in SK-Hep-1 cells. In order to analyze JAG1 transcriptional regulation, we conducted reporter assays, chromatin immunoprecipitation (ChIP) assays and electrophoretic mobility shift assays (EMSAs). Tumorigenicity was analyzed using a SCID mouse liver injection model. An inverse correlation was observed between RUNX3 expression and JAG1 expression in most HCC cell lines and tissues. Restoring RUNX3 expression decreased the expression of JAG1 in Hep3B and Huh7 cells, whereas JAG1 expression was upregulated in RUNX3 siRNA-treated SK-Hep-1 cells. Reporter assays, ChIP assays and EMSAs revealed that RUNX3 directly bound to the transcriptional regulatory region of JAG1 and suppressed JAG1 transcription. Moreover, RUNX3 restoration downregulated CSCs by suppressing JAG1-mediated Notch signaling. The tumorigenic capacity of RUNX3-expressing Hep3B cells was lower compared to that of control Hep3B cells. RUNX3 expression suppressed JAG1 expression and resulted in downregulation of tumorigenesis by suppression of JAG1-mediated CSCs.

DOI： 10.3892/or.2011.1336

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Background and Aim: Fucosylated alpha-fetoprotein (AFP-L3) is known to be a marker of poor prognosis in patients with hepatocellular carcinoma (HCC). However, it has been difficult to measure AFP-L3 under low AFP (&lt;= 20 ng/mL). The aim of this study was to elucidate the role of AFP-L3 in HCC patients with low AFP conditions.
Methods: One hundred and ninety six consecutive newly developed HCC patients with low AFP (&lt;= 20 ng/mL) were examined for serum AFP-L3 expression by a newly-developed micro-total analysis system that could stably measure AFP-L3 in low AFP circumstances, and its clinical importance was analyzed.
Results: Positivity of AFP-L3 in HCC patients was 13.3% at a cut-off level of 10%. Five-year survivals of HCC patients with AFP-L3 (&lt; 10%) and AFP-L3 (&gt;= 10%) were 69.4% and 41.1%, respectively (P = 0.001). Among 18 clinical parameters, low alanine aminotransferase, large tumor size, presence of portal vein tumor thrombus, high AFP and high des-gamma carboxy prothrombin were observed in the high AFP-L3 (&gt;= 10%) group. Multivariate analysis revealed that high aspartate aminotransferase (AST) (risk ratio [RR] = 3.24, 95% confidence interval [Cl] = 1.27-8.26), the presence of ascites (RR = 3.44, 95% Cl = 1.22-9.34), multiple tumor number (RR = 3.06, 95% CI = 1.33-7.17), and high AFP-L3 (RR = 8.36, 95% Cl = 2.79-25.5) were risk factors for survival. High AFP-L3 was also a risk factor for survival in HCC patients who received radiofrequency ablation (P = 0.048).
Conclusions: AFP-L3 is a strong prognostic factor for survival even in HCC patients with low AFP (&lt;= 20 ng/mL).

DOI： 10.1111/j.1440-1746.2011.06720.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER TOKYO  

We wished to determine whether pegylated interferon (PEG-IFN) therapy after curative treatment of hepatocellular carcinoma (HCC) prevents a recurrence of HCC.
Thirty-seven HCC patients with hepatitis C virus (HCV) infection who were treated with PEG-IFN after curative treatment (PEG-IFN group) and 145 controls without IFN therapy (non-IFN group) were enrolled. The overall survival and recurrence-free survival rates were compared between the groups, and the predisposing factors for recurrence and survival were analyzed. The rates were also examined by propensity score (PS) matched analysis that could minimize selection biases.
The median follow-up period was 3.7 years. The 5-year survival rate in the PEG-IFN group (91%) was significantly higher than that in the non-IFN group (56%; P &lt; 0.01). The rate of the second recurrence but not that of the first recurrence of HCC in the sustained virological responder (SVR) group was lower than that in the non-IFN group (P = 0.03). Improvement of survival by PEG-IFN and low rate of second recurrence in the SVR group were also observed in PS matched analysis. Multivariate analysis revealed that PEG-IFN therapy and high serum albumin were good prognostic factors for survival. Although low serum albumin and large and multiple tumors were risk factors for the first recurrence, non-SVR and low serum albumin were risk factors for the second recurrence.
PEG-IFN-therapy after curative treatment of HCC improved the rate of survival, and SVR was found to be closely correlated with the prevention of recurrence.

DOI： 10.1007/s10147-010-0150-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Congenital hepatic fibrosis (CHF) and bile duct hamartomas (von Meyenburg complexes) are hepatobiliary fibropolycystic diseases. There have been several reports of liver neoplasias arising in hepatobiliary fibropolycystic diseases. However, most of them were cholangiocarcinomas and cases involving hepatocellular carcinoma (HCC) are rare. A 51-year-old woman was found to have multiple hepatic tumors by ultrasonography and enhanced computed tomography (CT) during a regular work-up for the recurrence of lung cancer and thyroid cancer, which had been surgically removed 4 and 3 years ago, respectively. Nodules were observed at S3, S5, and S6 (2 cm in diameter). All of the nodules were hyperattenuated at the early arterial phase, and the main tumor at S5 showed hypoattenuation at the delayed phase on dynamic CT and magnetic resonance imaging (MRI). HCC was suspected from these findings. She also suffered from multiple small cystic lesions in the liver. The surgically removed liver showed HCC arising in CHF, which is a rare histological finding.

DOI： 10.1111/j.1872-034X.2010.00761.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Runt-related transcription factor 3 (RUNX3) is reported as a tumor suppressor gene for gastric cancer, and may be important in the development of hepatocellular carcinoma (HCC). RUNX3 expression is frequently lost or decreased by hemizygous deletion or hypermethylation of its promoter lesion in HCC. The significance of decreased expression of RUNX3 in HCC has not been fully elucidated, but is likely related to dysfunction of cell cycle regulation, decrement of apoptosis, enhancement of angiogenesis, and development of epithelial mesenchymal transition. RUNX3 is a promising candidate as a tumor suppressor gene for HCC. J. Cell. Biochem. 112: 745-749,2011. (C) 2010 Wiley-Liss, Inc.

DOI： 10.1002/jcb.22973

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OKAYAMA UNIV MED SCHOOL  

The purpose of this study was to build a prognostic model of hepatocellular carcinoma (HCC) using time-dependent covariates to re-evaluate the prognosis at any stage of the disease. The subjects were consecutive HCC patients who were treated at our institute between 1995 and 2007. We constructed time-fixed and time-dependent prognostic models with a training group (n = 336) and compared the prognostic abilities between conventional Cancer of the Liver Italian Program (CLIP) scores, Japan Integrated Staging (JIS) scores, an Okuda classification, and our prognostic models in the testing group (n = 227) with the c-index. The time-dependent prognostic model consisted of main tumor size, tumor number, portal vein invasion, distant metastasis, alpha-fetoprotein, des-gamma-carboxy prothrombin (DCP), bilirubin, and albumin and the weighted scores were set for each factor depending on the hazard ratio for the prognosis. The prognostic index was determined by summing the scores. The c-index values for the CLIP scores, JIS scores, Okuda classification, and our time dependent model were 0.741, 0.727, 0.609, and 0.870, respectively. These results indicate that our time-dependent model can estimate the prognosis of HCC more precisely than traditional time-fixed models and can be used to re-predict the prognosis of HCC.

DOI： 10.18926/AMO/43825

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL PUBLISHING, INC  

Background and Aims:
In animal models for acute liver injury, the administration of some angiogenic factors such as vascular endothelial growth factor (VEGF) and granulocyte-colony stimulating factor (G-CSF) are shown to reduce liver injury and improve liver proliferative capacity. The aim of the present study was to assess the role of angiogenic factors in fulminant hepatic failure (FHF).
Methods:
Serum levels of nine angiogenic factors (angiopoietin-2, follistatin, G-CSF, hepatocyte growth factor [HGF], interleukin-8, leptin, platelet-derived growth factor [PDGF]-BB, platelet endothelial cell adhesion molecule-1 and VEGF) were measured using the Bio-Plex Protein Array System in 30 patients, 17 of whom were diagnosed with FHF, 13 with acute hepatitis (AH), and 20 controls.
Results:
Serum levels of PDGF-BB and VEGF were lower in FHF patients than AH patients and controls (PDGF-BB; 2050 +/- 1572 pg/mL vs 4521 +/- 2419 pg/mL vs 8506 +/- 5500 pg/mL, VEGF; 39 +/- 38 pg/mL vs 144 +/- 122 pg/mL vs 205 +/- 121 pg/mL). By using univariate logistic regression models, serum levels of PDGF-BB and VEGF were associated with poor outcomes. Serum PDGF-BB levels were strongly correlated with serum VEGF levels (r = 0.70). Furthermore, serum PDGF-BB levels were significantly correlated with platelet counts (r = 0.79), PT activity (r = 0.37) and D.Bil/T.Bil ratio (r = 0.50), while serum VEGF levels were significantly correlated with platelet counts (r = 0.68) and PT activity (r = 0.38).
Conclusions:
We consider that serum levels of PDGF-BB and VEGF are worth investigating as biomarkers for predicting outcomes of FHF patients.

DOI： 10.1111/j.1440-1746.2010.06441.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Background: Runt-related transcription factor 3 (RUNX3) is known as a tumor suppressor gene for gastric cancer and other cancers, this gene may be involved in the development of hepatocellular carcinoma (HCC).
Methods: RUNX3 expression was analyzed by immunoblot and immunohistochemistry in HCC cells and tissues, respectively. Hep3B cells, lacking endogenous RUNX3, were introduced with RUNX3 constructs. Cell proliferation was measured using the MTT assay and apoptosis was evaluated using DAPI staining. Apoptosis signaling was assessed by immunoblot analysis.
Results: RUNX3 protein expression was frequently inactivated in the HCC cell lines (91%) and tissues (90%). RUNX3 expression inhibited 90 +/- 8% of cell growth at 72 h in serum starved Hep3B cells. Forty-eight hour serum starvation-induced apoptosis and the percentage of apoptotic cells reached 31 +/- 4% and 4 +/- 1% in RUNX3-expressing Hep3B and control cells, respectively. Apoptotic activity was increased by Bim expression and caspase-3 and caspase-9 activation.
Conclusion: RUNX3 expression enhanced serum starvation-induced apoptosis in HCC cell lines. RUNX3 is deleted or weakly expressed in HCC, which leads to tumorigenesis by escaping apoptosis.

DOI： 10.1186/1471-2407-11-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER TOKYO  

For patients with chronic hepatitis due to hepatitis B virus (HBV), factors predicting hepatocellular carcinoma (HCC) other than high levels of HBV-DNA and alanine aminotransferase (ALT) are needed to prevent HCC development, as many patients with chronic HBV infection fulfill these conditions. The purpose of this study was to clarify factors predictive of HCC development for those patients.
The study was a systematic cohort analysis of 303 consecutive patients with hepatitis B e-antigen, receiving laparoscopic examination for assessment of liver disease. Laparoscopic, histological, and clinical characteristics were investigated as related to HCC development.
HCC occurred in 27 patients during a mean follow-up of 8.0 +/- A 5.0 years, at the age of 37-72 years. Significant associations with HCC development were shown for liver cirrhosis, histological activity grade, reddish markings, and older age. Multivariate analysis revealed that HCC development was strongly associated with older age and male gender (P = 0.002 and P = 0.043, respectively). HCC occurred more frequently in patients of age a parts per thousand yen30 years even with early stage than in patients of age &lt; 30 years (P = 0.031). Severe reddish markings, a laparoscopic finding of widespread parenchymal destruction, were highly associated with HCC development in patients of age a parts per thousand yen30 years at diagnosis (odds ratio = 1.67, P = 0.034), while histological activity grade and ALT level were not (P = 0.075 and P = 0.69, respectively).
HCC development is associated with older age, male gender, and liver cirrhosis. Reddish markings, rather than histological activity or ALT level, can be useful to predict HCC for HBV patients of age a parts per thousand yen30 years.

DOI： 10.1007/s00535-010-0266-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Dendritic cells (DCs) in chronic hepatitis C patients display impaired function, although the details remain unclear. To investigate the hepatitis C virus (HCV) protein that has the most impact on DC function, we compared five recombinant proteins and seven HCV protein genes in modulating DC phenotype and function. Immature DCs (iDCs) were established from healthy donor peripheral blood monocytes with granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-4. Lipopolysaccharide was used to establish mature DCs (mDCs). Cells were then pulsed with HCV recombinant proteins or transfected with HCV plasmids and subsequently assayed for cell surface marker expression by flow cytometry. For cytokine and proliferative T-cell response analysis, DCs were cultured with autologous CD4 T cells and tuberculin purified protein derivative (PPD). Mean fluorescent intensity of CD86 was reduced in HCV protein-pulsed iDCs. Proliferative T-cell responses and Th1 cytokine concentrations were reduced with HCV nonstructural proteins (NS), particularly with HCV NS4. HCV nonstructural proteins, particularly NS4, change the iDC phenotype and reduce antigen-specific T-cell stimulatory function with Th1 cytokine reductions.

DOI： 10.1111/j.1365-2893.2009.01213.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL PUBLISHING, INC  

Background/aim: There are many reports dealing with the risk factors for hepatocellular carcinoma (HCC) recurrence. However, in most of these reported studies, factors were analysed only at the initial treatment stage, and the predisposing factors for the recurrence during follow-up have not been well studied. The aim of this study is to evaluate the predisposing factors after treatments. Methods: Two hundred and seventy-one consecutive HCC patients curatively treated between January 1994 and March 2004 were followed up and analysed. The recurrence rate was estimated by the Kaplan-Meier method and the predisposing factors were evaluated by time-fixed Cox regression analysis and by time-dependent covariate analysis using multiple parameters. Results: The mean follow-up period was 4.86 years and recurrence was observed in 169 patients (62.4%). The recurrence rates were 27.9, 65.1 and 84.3% at 1, 3 and 5 years respectively. Among the variables determined before treatment, predisposing factors for recurrence were low serum albumin [&lt;= 3.5 g/dl, hazard ratio (HR) = 1.47, 95% confidence interval (CI) = 1.07-2.01] and multiple tumour number (HR = 2.04, 95% CI = 1.46-2.84) by time-fixed multivariate analysis. In the time-dependent analysis, six variables with 12 013 plots were examined. The multivariate analysis revealed that high des-g-carboxy prothrombin (DCP &gt;= 40mAU/ml, HR = 2.33, 95% CI = 1.61-3.39), high a-fetoprotein (AFP &gt;= 100 ng/ml, HR = 2.01, 95% CI = 1.3-3.35) and high alanine aminotransferase (ALT &gt;= 40 IU/L, HR = 1.52, 95% CI = 1.1-2.1) were significant predisposing factors for recurrence. Conclusion: Predisposing factors for the recurrence of HCC after treatment are different from those before treatments and special cautions are required when AFP, DCP or ALT is high during follow-up.

DOI： 10.1111/j.1478-3231.2010.02252.x

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DOI： 10.1111/j.1365-2036.2009.04179.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: The aim of this study is to elucidate the effectiveness of radiofrequency ablation (RFA) for the treatment of metastatic liver cancers.
Methodology: From 74 patients with metastatic liver cancers treated by RFA, 40 patients including 23 colon cancer who had received curative resection of the primary tumor were analyzed.
Results: Recurrence of the tumor was observed in 29 (72.5%) patients. The most prevalent site of recurrence was the liver in both colon cancer (10/15, 66.7%) and non-colon cancer patients (12/14, 85.7%). Among the recurrence in the liver, the rate of intrahepatic distant recurrence (recurrence outside of the RFA-treated segment) was high in both colon cancer (55.6%) and non-colon cancer patients (69.0%). Local recurrence (recurrence at the RFA-treated segment) rate was low (32.6% and 32.9%, respectively) and none of single tumor less than 2cm in diameter showed local recurrence. The intrahepatic recurrence was single in 67.6% of the patients and 59.1% of the patients were re-treated by RFA.
Conclusions: RFA is a less-invasive method for the treatment of metastatic liver tumors and can be performed repetitively. Although the rate of intra-hepatic distant recurrence and extra-hepatic recurrence was high, good local control can be achieved by RFA.

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記述言語：英語   出版者・発行元：OKAYAMA UNIV MED SCHOOL  

Serum des-gamma-carboxy prothrombin (DCP) is commonly used to detect hepatocellular carcinoma (HCC). This review focuses on the clinical features of DCP-positive HCC and the molecular function of DCP in HCC. DCP-positive HCC demonstrates more aggressive clinicopathological features than DCP-negative HCC. Analysis of the biological effects of DCP revealed that DCP acts as a growth factor in both an autocrine and paracrine manner. DCP stimulates HCC cell proliferation through the Met-Janus kinase 1-signal transducer and activator of transcription 3 signaling pathway, whereas for vascular endothelial cells, it stimulates cell proliferation and migration through the kinase insert domain receptor-phospholipase C-gamma-mitogen-activated protein kinase signaling pathway.

DOI： 10.18926/AMO/31826

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Background: Twist, a transcription factor of the basic helix-loop-helix class, is reported to regulate cancer metastasis. It is known to induce epithelial-mesenchymal transition (EMT). In this study, we evaluated the expression of twist and its effect on cell migration in hepatocellular carcinoma (HCC).
Methods: We examined twist expression using immunohistochemistry in 20 tissue samples of hepatocellular carcinoma, and assessed twist expression in HCC cell lines by RT-PCR and Western blot analysis. Ectopic twist expression was created by introducing a twist construct in the twist-negative HCC cell lines. Endogenous twist expression was blocked by twist siRNA in the twist-positive HCC cell lines. We studied EMT related markers, E-cadherin, Vimentin, and N-cadherin by Western blot analysis. Cell proliferation was measured by MTT assay, and cell migration was measured by in vitro wound healing assay. We used immunofluorescent vinculin staining to visualize focal adhesion.
Results: We detected strong and intermediate twist expression in 7 of 20 tumor samples, and no significant twist expression was found in the tumor-free resection margins. In addition, we detected twist expression in HLE, HLF, and SK-Hep1 cells, but not in PLC/RPF/5, HepG2, and Huh7 cells. Ectopic twist-expressing cells demonstrated enhanced cell motility, but twist expression did not affect cell proliferation. Twist expression induced epithelial-mesenchymal transition together with related morphologic changes. Focal adhesion contact was reduced significantly in ectopic twist-expressing cells. Twist-siRNA-treated HLE, HLF, and SK-Hep1 cells demonstrated a reduction in cell migration by 50, 40 and 18%, respectively.
Conclusion: Twist induces migratory effect on hepatocellular carcinoma by causing epithelial-mesenchymal transition.

DOI： 10.1186/1471-2407-9-240

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Intracranial hemangiopericytoma is an uncommon soft tissue sarcoma. We report a case of a 54-year-old Japanese female with hepatic metastasis from primary intracranial hemangiopericytoma. At age 44 years the patient underwent primary resection of the intracranial tumor, followed by no adjuvant therapy. At age 53 years she underwent resection of bone metastases in her left upper arm and tenth right rib. The following year, three hepatic tumors with high vascularity were detected by ultrasonography, computed tomography scans, and magnetic resonance imaging. An ultrasound-guided liver biopsy specimen confirmed the diagnosis of hepatic metastases from the primary intracranial hemangiopericytoma. A combination therapy of transcatheter arterial chemoembolization and radiofrequency ablation was performed against the hepatic metastasis. After 5 years, there has been no local recurrence in the liver. © 2008 Springer.

DOI： 10.1007/s12328-008-0033-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCI LTD  

Using GGCX gene-specific real-time PCR, exon 2 deletion splice variant of vitamin K-dependent gamma-glutamyl carboxylase (GGCX) mRNA was identified in HCC cell lines. Expressions of wild type and exon 2 deletion variant of GGCX were analyzed with relevance to DCP production in HCC cell lines. Hep3B, HepG2, HuH1, HuH7, and PLC/PRF/5 produced DCP, while SK-Hep-1, HLE, HLF, and JHH1 produced no detectable level of DCP. DCP-producing cells expressed exon 2 deletion variant of GGCX mRNA and protein, while DCP-negative cells expressed no detectable level of exon 2 deletion variant of GGCX. These results suggest that exon 2 deletion splice variant of GGCX causes dysfunction of GGCX enzyme activity resulting in DCP production in HCC cell lines. (C) 2008 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.molonc.2008.06.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KARGER  

Aims: To prospectively study whether occult hepatitis B virus (HBV) infection can promote the development of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)-related chronic liver disease. In addition, to evaluate the difference among HBV DNA-negative patients and patients with high and low HBV copy numbers. Methods: A total of 167 patients with HCV-related chronic liver disease without HBV surface antigen ( HBsAg) were studied. HBV DNA in liver tissue was determined using polymerase chain reaction (PCR). Results: HBV DNA was detected in 9 of 167 patients (5.4%) by single PCR and in 25 patients (15.0%) by nested PCR. HCC developed in 12 of 167 patients (7.2%). Ten of 142 HBV DNA-negative patients (7.0%) and 2 of 9 patients with a high HBV copy number (22.2%) developed HCC, whereas none of 16 patients with a low HBV copy number developed HCC. The incidence rate of HCC in patients with a high HBV copy number was significantly higher than in HBV DNA-negative patients and patients with low HBV copy number. Conclusion: A high amount of HBV DNA in liver tissue of HBsAg-negative patients with HCV-related liver disease might be associated with HCC development. Copyright (c) 2008 S. Karger AG, Basel.

DOI： 10.1159/000121363

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PROFESSOR D A SPANDIDOS  

Patients with sporadic microsatellite instable colorectal cancers, in most of which the function of the hMLH1 mismatch repair gene is impaired, do not gain a survival benefit from 5-fluorouracil (5-FU)-based chemotherapy. However, the effect of hMLH1 on the cytotoxicity induced by 5-FU has not yet been sufficiently confirmed. In this study, we assessed the effect of hMLH1 on cytotoxicity and apoptosis induced by 5-FU using newly developed cell lines. We constructed two cell lines: SW480 (originally hMLH1-proficient), in which the expression of hMLH1 was reduced using a small interfering RNA (siRNA) technique, and HCT116 (originally hMLH1-deficient), in which the expression of hMLH1 can be regulated by doxycycline. Using these, cell lines, a clonogenic survival assay, 4',6-diamidino-2-phenylindole (DAPI) staining and an Annexin-V assay were performed. Moreover, the incorporation of 5-FU into DNA was determined using tritium-labeled 5-FU. In both of our two cell lines, hMLH1-deficient cells exhibited approximately 2.4-fold clonal surviving fraction compared to hMLH1-proficient cells for 10 days after the administration of 5-FU. Additionally, hMLH1-deficient cells treated with 5-FU exhibited 34-45% less apoptosis than hMLH1-proficient cells according to the results of DAPI staining and Annexin-V assay. Furthermore, hMLH1-deficient cells treated with 5-FU exhibited an approximately 2-fold greater incorporation of 5-FU into DNA than control cells, suggesting that the recognition of 5-FU-incorporated DNA is impaired in hMLH1-deficient cells, resulting in reduced apoptosis. Our conclusions were that decreased expression of hMLH1 in colon cancer cells reduced the apoptosis induced by 5-M, suggesting that hMLH1 is a key determinant of 5-FU chemosensitivity.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING  

Background: Cimetidine, a histamine-2 (H-2) receptor antagonist, has been demonstrated to have anticancer effects on colorectal cancer, melanoma and renal cell carcinoma. In the current study, we clarified that cimetidine inhibits both epidermal growth factor (EGF)-induced cell proliferation and migration in hepatocellular carcinoma (HCC) cell lines.
Method: HCC cell lines (Hep3B, HLF, SK-Hep-1, JHH-2, PLC/PRF/5 and HLE) were used and cell proliferation was assessed by [H-3]-thymidine incorporation assay. Cell migration was measured by in vitro cell migration assay. Biological effects of cimetidine were assessed with human EGF receptor (EGFR)-expressing mouse fibroblast cells (NR6-WT). The autophosphorylation of EGFR and the activation of other downstream effectors were analyzed by immunoprecipitation and immunoblotting. The concentration of intracellular cyclic AMP (cAMP) was measured by competitive enzyme immunoassay.
Results: Cimetidine inhibited both EGF-induced cell proliferation and migration in Hep3B, HLF, SK-Hep-1 and JHH-2, while cimetidine did not affect EGF-induced cell proliferation and migration in PLC/PRF/5 and HLE. Cimetidine was revealed to disrupt the EGF-induced autophosphorylation of EGFR and its downstream effectors, mitogen activated protein kinases and phospholipase C-gamma. To define the molecular basis of this negative regulation, we identified that cimetidine significantly decreased intracellular cAMP levels and that decrement of cAMP inhibited autophosphorylation of EGFR. The cell permeable cAMP analog, CPT-cAMPS reversed the cimetidine-induced inhibition of EGF-induced cell proliferation and cell migration by restoring autophosphorylation of EGFR.
Conclusion: Cimetidine inhibited EGF-induced cell proliferation and migration in HCC cell lines by decreasing the concentration of intracellular cAMP levels. Cimetidine may be a candidate chemopreventive agent for HCC.

DOI： 10.1111/j.1440-1746.2006.04541.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Des-gamma-carboxyl prothrombin (DCP) is a well recognized tumor marker for hepatocellular carcinoma. Previously, we have demonstrated that DCP stimulates cell proliferation in hepatocellular carcinoma cell lines through Met-Janus kinase 1 signal transducer and activator of transcription 3 signaling pathway. In the present study, we demonstrated that DCP induces both cell proliferation and migration in human umbilical vein endothelial cells. DCP was found to bind with the kinase insert domain receptor (KDR), alternatively referred to as vascular endothelial growth factor receptor-2. Furthermore, DCP induced autophosphorylation of KDR and its downstream effector phospholipase C-gamma and mitogen-activated protein kinase (MAPK). To support these results, we showed that DCP-induced cell proliferation and cell migration were inhibited by KDR short interfering RNA, KDR kinase inhibitor, or MAPK inhibitor. In conclusion, these results indicate that DCP is a novel type of vascular endothelial growth factor that possesses potent mitogenic and migrative activities.

DOI： 10.1074/jbc.M609358200

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN SOC INTERNAL MEDICINE  

We encountered a case of peritoneal dissemination of hepatocellular carcinoma, successfully treated with a combination therapy of interferon-alpha-2b and oral tegafur/uracil. A 67-year-old Japanese man who underwent a hepatectomy developed peritoneal dissemination. A combination therapy of subcutaneous interferon-alpha-2b and intravenous 5-fluorouracil was started. Four weeks later, he felt severe general fatigue and nausea, and intravenous 5-fluorouracil was replaced with oral tegafur/uracil. At 3 months after the initiation of chemotherapy, enhanced computed tomography showed markedly reduced peritoneal dissemination. A combination therapy of interferon-alpha-2b and oral tegafur/uracil is facile and may be effective for extrahepatic metastasis of hepatocellular carcinoma.

DOI： 10.2169/internalmedicine.46.6362

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PROFESSOR D A SPANDIDOS  

Interferon (IFN) combined with 5-Fluorouracil (5-FU) treatment has recently been reported to show beneficial effects in patients with advanced hepatocellular carcinoma. IFNa is usually provided for this combination therapy. In this study, we investigated the molecular mechanisms of apoptosis induction in hepatoma cell lines with IFNa and 5-FU combination therapy from the view point of 5-FU's additive effect on interferon-related signaling pathways. Five hepatoma cell lines (Hep3B, Huh7, HLE, PLC/PRF/5, and HepG2) were tested for apoptosis inducibility by IFN alpha in the absence or presence of 5-FU. Hep3B was the most apoptosis sensitive to IFN plus 5-FU treatment. The JAK/STAT pathway transcriptional factor ISRE was activated more synergistically when 5-FU was added to IFN alpha treatments. Caspase-3, -9, and especially caspase-8 activity was higher with IFN a plus 5-FU than IFN or 5-FU alone. Inhibition of caspase-8, -9, c-Jun N-terminal kinase (INK), phosphatidylinositide 3-kinase (PI3K), and p38 mitogen-activated protein kinase (p38 MAPK) revealed that caspase-8 inhibition was the most effective at decreasing the apoptotic effects of IFN and/or 5-FU. In JAK1 and ISGF3y-silenced Hep3B cells, the apoptosis induction and caspase-8 activation levels by IFN, even in combination with 5-FU, were abrogated. In conclusion, caspase-8 is the most important factor that controls IFN and 5-FU-induced apoptosis in hepatoma cell lines.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：W B SAUNDERS CO-ELSEVIER INC  

Background & Aims: Laterally spreading tumors (LST), characterized by superficial extension along the colonic lumen, have recently been detected by colonoscopy. However, genetic and epigenetic characteristics of these tumors were scarcely reported. Methods: A total of 205 sporadic colorectal adenoma tissues (157 protruded-type, 23 granular-type LST (G-LST), 12 flat-type LST (FLST), and 13 flat-type smaller than 1 cm) were collected. CpG island methylator phenotype (CIMP) was determined by examination of methylation status at p16, methylated in tumor (MINT) 1, 2, 12, and 31 loci. K-ras codon 12 and 13 point mutations were also examined. The relationship between macroscopic appearance and CIMP status or K-ras mutations was analyzed. Results: Among adenomas larger than 1 cm, CpG island methylation involving 2 or more loci (CIMP-high) was more likely to be observed in G-LST (14/23, 61%) than in protruded-type adenomas (18/73, 25%) (P=.002). The prevalence of K-ras mutations in G-LST (18/23, 78%) was significantly higher than that in protruded-type adenomas (18/73, 25%) (P &lt;.0001). Moreover, the prevalence of CIMP-high and K-ras mutations in G-LST located in the proximal colon was much higher (11/13, 85%; and 12/13, 92%, respectively). In contrast, F-LST exhibited low prevalence of CIMP-high (1/12, 8%) and K-ras mutations (2/12, 16%). Conclusions: High prevalence of CIMP-high and K-ras mutations in G-LST, especially in the proximal colon, could strongly suggest that G-LST appearance is associated with a unique carcinogenic pathway.

DOI： 10.1053/j.gastro.2006.04.027

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER JAPAN KK  

Background. Long-term lamivudine treatment induces the emergence of lamivudine-resistant hepatitis B virus (HBV). The objective of this study was to develop a fluorescent biprobe hybridization (FBH) assay for the detection and quantification of HBV mutants in the clinical course of lamivudine-treated patients and to evaluate its clinical usefulness. Methods. We developed an FBH assay to detect mutations in the HBV DNA polymerase gene. The assay's detection sensitivity was determined using a dilution series of wild-type/mutant plasmid DNA. Blood samples obtained from 27 lamivudine-treated patients were analyzed. Results. Mutant DNA levels as low as 10% of total HBV DNA were detected (sensitivity = 100%, specificity = 80%). HBV mutants were detected in five of the 27 patients during an average follow-up of 20 months after lamivudine administration. In one of the five patients, the YIDD mutant was detected at the initiation of lamivudine treatment, while the remaining four patients were identified as having YIDD mutants within 3 months after beginning lamivudine administration. Of the five patients with an HBV mutant, four developed breakthrough hepatitis more than 10 months after the detection of HBV mutants, following the reappearance or a re-increase of HBV DNA, characterized by a predominance of the mutant. The YIDD mutant was detected in one patient, even when the titer of the serum HBV DNA was below the detection limit of commercially available quantitative polymerase chain reaction. Conclusions. The FBH assay is an efficient method for detecting and quantifying HBV mutants, as early as 3 months after lamivudine administration.

DOI： 10.1007/s00535-006-1834-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Des-gamma-carboxyl prothrombin (DCP) is a well recognized tumor marker for hepatocellular carcinoma (HCC). In the present study, we demonstrate that DCP has a mitogenic effect on HCC cell lines. Purified DCP stimulated DNA synthesis of Hep3B and SK-Hep-1 cells in a dose-dependent manner. DCP was found to bind with cell surface receptor Met causing Met autophosphorylation and also to activate STAT3 signaling pathway through Janus kinase 1. Luciferase gene reporter analysis showed that DCP induced STAT3-related transcription. Small interfering RNAs against both STAT3 and Met abrogated DCP-induced cell proliferation. DCP did not affect the mitogen-activated protein kinase pathway, Myc signaling pathway, or phosphoinositide 3-kinase/Akt pathway. Based on these results, we believe that DCP acts as an autologous mitogen for HCC cell lines. The Met-Janus kinase 1-STAT3 signaling pathway may be a major signaling pathway for DCP-induced cell proliferation.

DOI： 10.1074/jbc.M406714200

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Background: Insulin-like growth factor binding protein (IGFBP)-3 functions as a carrier of insulin-like growth factors (IGFs) in circulation and a mediator of the growth suppression signal in cells. There are two reported p53 regulatory regions in the IGFBP3 gene; one upstream of the promoter and one intronic. We previously reported a hot spot of promoter hypermethylation of IGFBP-3 in human hepatocellular carcinomas and derivative cell lines. As the hot spot locates at the putative upstream p53 consensus sequences, these p53 consensus sequences are really functional is a question to be answered.
Methods: In this study, we examined the p53 consensus sequences upstream of the IGFBP-3 promoter for the p53 induced expression of IGFBP-3. Deletion, mutagenesis, and methylation constructs of IGFBP-3 promoter were assessed in the human hepatoblastoma cell line HepG2 for promoter activity.
Results: Deletions and mutations of these sequences completely abolished the expression of IGFBP-3 in the presence of p53 overexpression. In vitro methylation of these p53 consensus sequences also suppressed IGFBP-3 expression. In contrast, the expression of IGFBP-3 was not affected in the absence of p53 overexpression. Further, we observed by electrophoresis mobility shift assay that p53 binding to the promoter region was diminished when methylated.
Conclusion: From these observations, we conclude that four out of eleven p53 consensus sequences upstream of the IGFBP-3 promoter are essential for the p53 induced expression of IGFBP-3, and hypermethylation of these sequences selectively suppresses p53 induced IGFBP-3 expression in HepG2 cells.

DOI： 10.1186/1471-2407-5-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OKAYAMA UNIV MED SCHOOL  

The prevalence of hepatitis C virus (HCV) genotypes in Myanmar in comparison with the rest of Southeast Asia is not well known. Serum samples were obtained from 201 HCV antibody-positive volunteer blood donors in and around the Myanmar city of Yangon. Of these, the antibody titers of 101 samples were checked by serial dilution using HCV antibody PA test II and Terasaki microplate as a low-cost method. To compare antibody titers by this method and RNA identification, we also checked HCV-RNA using the Amplicor 2.0 test. Most high-titer groups were positive for HCV-RNA. Of the 201 samples, 110 were successfully polymerase chain reaction (PCR) amplified. Among them, 35 (31.8%) were of genotype 1, 52 (47.3%) were of genotype 3, and 23 (20.9%) were of type 6 variants, and phylogenetic analysis of these type 6 variants revealed that 3 new type 6 subgroups exist in Myanmar. We named the subgroups M6-1, M6-2, and M6-3. M6-1 and M6-2 were relatively close to types 8 and 9, respectively. M6-3, though only found in one sample, was a brand-new subgroup. These subtypes were not seen in Vietnam, where type 6 group variants are widely spread. These findings may be useful for analyzing how and when these subgroups were formed.

DOI： 10.18926/AMO/32110

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC MICROBIOLOGY  

How m-calpain is activated in cells has challenged investigators because in vitro activation requires near-millimolar calcium. Previously, we demonstrated that m-calpain activation by growth factors requires extracellular signal-regulated kinase (ERK); this enables tail deadhesion and allows productive motility. We now show that ERK directly phosphorylates and activates m-calpain both in vitro and in vivo. We identified serine 50 as required for epidermal growth factor (EGF)-induced calpain activation in vitro and in vivo. Replacing the serine with alanine limits activation by EGF and subsequent cell deadhesion and motility. A construct with the serine converted to glutamic acid displays constitutive activity in vivo; expression of an estrogen receptor fusion construct produces a tamoxifen-sensitive enzyme. Interestingly, EGF-induced m-calpain activation occurs in the absence of increased intracellular calcium levels; EGF triggers calpain even in the presence of intracellular calcium chelators and in calcium-free media. These data provide evidence that m-calpain can be activated through the ERK cascade via direct phosphorylation and that this activation may occur in the absence of cytosolic calcium fluxes.

DOI： 10.1128/MCB.24.6.2499-2512.2004

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC MICROBIOLOGY  

We have shown previously that the ELR-negative CXC chemokines interferon-inducible protein 10, monokine induced by gamma interferon, and platelet factor 4 inhibit epidermal growth factor (EGF)-induced m-calpain activation and thereby EGF-induced fibroblast cell motility (H. Shiraha, A. Glading, K. Gupta, and A. Wells, J. Cell Biol. 146:243-253, 1999). However, how this cross attenuation could be accomplished remained unknown since the molecular basis of physiological m-calpain regulation is unknown. As the initial operative attenuation signal from the CXCR3 receptor was cyclic AAIP (cAMP), we verified that this second messenger blocked EGF-induced motility of fibroblasts (55% +/- 4.5% inhibition) by preventing rear release during active locomotion. EGF-induced calpain activation was inhibited by cAMP activation of protein kinase A (PKA), as the PKA inhibitors H-89 and Rp-8Br-cAMPS abrogated cAMP inhibition of both motility and calpain activation. We hypothesized that PKA might negatively modulate m-calpain in an unexpected manner by directly phosphorylating m-calpain. A mutant human large subunit of m-calpain was genetically engineered to negate a putative PKA consensus sequence in the regulatory domain III (ST369/370AA) and was expressed in NR6WT mouse fibroblasts to represent about 30% of total m-calpain in these cells. This construct was not phosphorylated by PICA in vitro while a wild-type construct was, providing proof of the principle that m-calpain can be directly phosphorylated by PKA at this site. cAMP suppressed EGF-induced calpain activity of cells overexpressing a control wild-type human m-calpain (83% +/- 3.7% inhibition) but only marginally suppressed that of cells expressing the PKA-resistant mutant human m-calpain (25% +/- 5.5% inhibition). The EGF-induced motility of the cells expressing the PKA-resistant mutant also was not inhibited by cAMP. Structural modeling revealed that new constraints resulting from phosphorylation at serine 369 would restrict domain movement and help "freeze" m-calpain in an inactive state. These data point to a novel mechanism of negative control of calpain activation, direct phosphorylation by PKA.

DOI： 10.1128/MCB.22.8.2716-2727.2002

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC  

Connective tissue growth factor (CTGF) it regulated by TGF-beta1 during wound healing. The present study examined the expression of CTGF during regeneration after 70% partial hepatectomy (PH) or D-galactosamine (GalN)-injured liver in rats. CTGF, TGF-beta1, and type I collagen mRNAs were semiquantified by a ribonuclease protection assay. After PH, TGF-beta1 and type I collagen were increased at 2-6 h and at 12-48 h. CTGF increased at 6 h and returned to the control level thereafter. The ribonuclease protection assay of cultured hepatic stellate cells (HSC) and in situ hybridization suggest that the cells express CTGF along sinusoid might be HSCs. After GalN administration, CTGF increased at 2-96 h with a shoulder peak at 6-12 h followed by a main peak at 24 h. TGF-beta1 and type I collagen were up-regulated with kinetics similar to those of CTGF. The different kinetics between PH and GalN regenerations indicate that regulation of CTGF in the two processes is different. Higher TGF-beta1 expression after inflammatory/necrotic process in the GalN regeneration may caused the prolonged CTGF expression. (C) 2000 Academic Press.

DOI： 10.1006/bbrc.2000.3693

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Wound healing is compromised in aging adults in part due to decreased responsiveness of fibroblasts to extracellular signals. However, the cellular mechanisms underlying this phenomenon are not known. Aged dermal fibroblasts with reduced remaining replicative capacities demonstrated decreased epidermal growth factor (EGF)-induced cell migrative and cell proliferative capacities, as reported previously. Thus, as cells approach senescence, programmed in vivo or in vitro, EGF responsiveness is preferentially lost. To define the rate-limiting signaling event, we found that the activity of two different EGF receptor (EGFR)-signaling pathways to cell migration (phospholipase-C gamma) and/or mitogenesis (extracellular signal/regulated-mitogen-activated kinases) were decreased in near senescent cells despite unchanged levels of effector molecules. Aged cells presented decreased levels of EGFR, although insulin receptor and transferrin receptor levels were relatively unchanged. EGFR, mRNA levels and production of new transcripts decreased during aging, suggesting that this preferential loss of EGFR was due to diminished production, which more than counteracts the reduced ligand-induced receptor loss. Since these data suggested that the decrement in EGF was rate-limiting, higher levels of EGFR were established in near senescent cells by electroporation of EGFR cDNA. These cells presented higher levels of EGFR and recovered their EGF-induced migration and proliferation responsiveness. Thus, the defect in EGF responsiveness of aged dermal fibroblasts is secondary to reduced EGFR message transcription. Our experimental model suggests that EGFR gene delivery might be an effective future therapy for compromised wound healing.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ROCKEFELLER UNIV PRESS  

During wound healing, fibroblasts are recruited from the surrounding tissue to accomplish repair. The requisite migration and proliferation of the fibroblasts is promoted by growth factors including those that activate the epidermal growth factor receptor (EGFR), Counterstimulatory factors in wound fluid are postulated to limit this response; among these factors is the ELR-negative CXC chemokine, interferon inducible protein-10 (IP-10),We report here that IP-10 inhibited EGF- and heparin-binding EGF-like growth factor-induced Hs68 human dermal fibroblast motility in a dose-dependent manner (to 52% and 44%, respectively, at 50 ng/ml IP-10), whereas IP-10 had no effect on either basal or EGFR-mediated mitogenesis (96 +/- 15% at 50 ng/ml). These data demonstrate for the first time a counterstimulatory effect of IP-10 on a specific induced fibroblast response, EGFR-mediated motility.
To define the molecular basis of this negative transmodulation of EGFR signaling, we found that IP-10 did not adversely impact receptor or immediate postreceptor signaling as determined by tyrosyl phosphorylation of EGFR and two major downstream effecters phospholipase C-gamma and erk mitogen-activated protein kinases, Morphological studies suggested which biophysical steps may be affected by demonstrating that IP-10 treatment resulted in an elongated cell morphology reminisce:nt of failure to detach the uropod; in support of this, IP-10 pretreatment inhibited EGF-induced cell detachment. These data suggested that calpain activity may be involved. The cell permeant agent, calpain inhibitor I, limited EGF-induced motility and de-adhesion similarly to IP-10, IP-10 also prevented EGF induced calpain activation (reduced by 71 +/- 7%).That this inhibition of EGF-induced calpain activity was secondary to IP-10 initiating a cAMP-protein kinase A-calpain cascade is supported by the following evidence: (a:) the cell permeant analogue 8-(4-chlorophenylthio)-cAMP (CPT-cAMP) prevented EGF-induced calpain activity and motility; (b) other ELR-negative CXC chemokines, monokine induced by IFN-gamma and platelet factor 4 that also generate cAMP, inhibited EGF-induced cell migration and calpain activation; and (c) the protein kinase A inhibitor Rp-8-Br-cANIPS abrogated IP-10 inhibition of cell migration, cell detachment, and calpain activation. Our findings provide a model by which IP-10 suppresses EGF-induced cell motility by inhibiting EGF-induced detachment of the trailing edges of motile cells.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：H G E UPDATE MEDICAL PUBL LTD.  

Two hepatitis B virus (HBV) carriers who had antibodies to HBV surface antigen (anti-HBs) were studied. Case 1 was a 47 year old woman positive for hepatitis B e antigen (HBeAg), and case 2 was a 61 year old man positive for antibody to HBeAg (anti-HBe) and DNA-polymerase (DNA-p). Neither case had received the HBV vaccine. The nucleotide sequences of the HBV-DNA extracted from the patients' sera were determined within the pre-S2 and S genes. Seven out of nine S gene clones from case I and six out of nine S gene clones from case 2 had an amino acid replacement from Thr or lie to Ser at codon 126 in the alpha-determinant of the S gene. Amino acid substitution of codon 145 of the S gene previously reported was not observed. Although two previous reports on HBV escape mutant carriers with both anti-HBs and HBeAg described some deletions in the pre-Sa gene, our cases did not show these deletions. Our analysis indicated that carriers with the HBV escape mutant did not always have pre-Sa gene deletions. We found two HBV escape mutant carriers who had amino acid substitutions at codon 126 in the S gene due to point mutation without any deletions in the pre-S2 gene.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：H G E UPDATE MEDICAL PUBL LTD.  

Background/Aims: Fibroglycan (FG) is a major heparan sulfate proteoglycan. (HSPG) in. the rat Liver that is mainly distributed on. the surface of hepatocytes. HSPG may play some important roles in the regeneration of liver by interacting with various growth factors such as bFGF and HB-EGF. However, little is known about the function. of FG. We reported that after injury caused by D-galactosamine, regeneration started on the following day and peaked on day 2. To clarify the function. of FG in Liver regeneration, we investigated the gene expression of FG during regeneration after D-galactosamine injury.
Materials and Methods: Rats were given D-galactosamine on day 0. Liver RNA was collected from day 0 to day 7. The gene expression of FG and beta-actin (as a representative cytoskeleton) was examined by Northern and/or Slot blotting.
Results: FG gene expression was markedly decreased on. day 2, but totally recovered on day 3. In contrast, beta-actin. gene expression was markedly increased on day 2 and returned to the normal level on. day 3. Expression, of the FG and beta-actin genes was reciprocal.
Conclusion: FG expression is transiently suppressed when cytoskeleton gene expression is enhanced at the early phase of liver regeneration.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：H G E UPDATE MEDICAL PUBL LTD.  

Background: Inactivation of the retinoblastoma (Rb) gene is considered to play a fundamental role in the genesis and progression of several human cancers. In retinoblastoma, the inactivation of Rb promoter by mutations or hypermethylation has been reported. Although genetic changes of Rb gene have been described in hepatocellular carcinoma (HCC) an, epigenetic change such as hypermethylation of the Rb promoter as reported in, retinoblastoma has not been described.
Materials and Methods: We examined the hypermethylation in the promoter region of Rb gene by restriction fragment length polymorphism in 19 HCCs, as well as the expression of Rb mRNA and protein by RT-PCR and by immunoblotting, respectively.
Results: We found no evidence of hypermethylation. in the promoter region, of the Rb gene in all HCCs analyzed. However, the expression of Rb mRNA and protein was lost in one HCC, and no mutation was detected in the Rb promoter region of this patient. The inactivation of Rb promoter by hypermethylation or by inhibition of binding of transcription factors due to point mutations did not contribute to the loss of mRNA and protein in. the patient.
Conclusions: Hypermethylation in the Rb promoter region appeared to have little causal effect on HCC.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JOHN WILEY & SONS INC  

We designed a bioartificial liver support system in which encapsulated multicellular spheroids of rat hepatocytes were utilized as a bioreactor in a hollow fiber cartridge. The spheroids, formed in a positively charged polystyrene dish that contained hormonally defined medium, were encapsulated into microdroplets of agarose that contained about 9 x 10(7) rat hepatocytes. The medium, including 150 mt reservoir volume, was circulated in a closed circuit in which the cartridge was inserted. The pH and levels of dissolved oxygen were monitored and automatically regulated so that they were maintained within a constant range for 72 h. Albumin accumulated in the circuit at the rate of 2.0 mg/L/h in this system. When the bioreactor cells in the system were replaced with Hep G2 cells, a human hepatoblastoma cell line, albumin accumulated at the rate of 0.15 mg/L/h. The spheroids of primary culture hepatocytes had 13 times higher albumin-producing capacity than the aggregates of Hep G2. The serum of a patient with fulminant hepatic failure was circulated in this system with the spheroids of primary culture hepatocytes. The concentration of branched amino acid (BCAA) in the circuit significantly increased during the 48 h circulation, while the concentration of aromatic amino acid (AAA) and methionine decreased. The ratio of BCAA/AAA increased from 0.640 to 0.772, indicating that the hepatocyte spheroids had improved the imbalance of the amino acid profile in the serum. These findings indicate that this system may be a useful model for an artificial liver support. (C) 1996 John Wiley & Sons, Inc.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：H G E UPDATE MEDICAL PUBL LTD.  

Background/Aims: We investigate whether hepatitis C virus (HCV) forms a circulating immune complex (CIC) in patients with chronic HCV infection.
Materials and Methods: We examined HCV-RNA immunoprecipitated with anti-human IgG, A and M antibodies by reverse transcription-polymerase chain I reaction.
Results: In thirty-nine (91%) of 43 patients, composed of 35 chronic hepatitis (CH) and 8 liver cirrhosis (LC), HCV-RNA was detected in the CIC. All 43 patients analyzed were classified into the following three categories; HCV-RNA was detected only in the supernatant (S pattern, 4 patients), both in the supernatant and the precipitate (SP pattern, 27 patients), and only in the precipitate (P pattern, 12 patients). SP pattern was most common in chronic HCV infection, and the frequency of SP pattern decreased with the progression of Liver disease. P pattern was significantly more frequent in patients with higher gamma-globulin Levels, histologically indicated LC, and antibody to HCV envelope protein.
Conclusion: We found that HCV formed a CIC in most patients with chronic HCV infection, and that the formation of CIC might be related to the stage of chronic HCV injection.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OKAYAMA UNIV MED SCHOOL  

Adult rat hepatocytes assemble to form multicellular spheroids under non-adherent environments such as immobilized chondroitin sulfate-proteoglycan in primary culture. Previously, we demonstrated that hepatocyte spheroids exhibited various differentiated structures as observed in the liver tissue. It was also shown that hepatocyte growth was highly suppressed and several differentiated functions, including albumin production and gluconeogenesis, preserved in spheroids. To investigate differentiated functions of cultured hepatocytes in relation to cell morphology, we compared the expression of the albumin and transferrin genes in spheroids with those in monolayers by Northern blot analysis. Production of these proteins in the culture medium was simultaneously examined by ELISA. Gene expression and protein production of both albumin and transferrin were better preserved in spheroids. We also examined changes in the expression of liver-specific genes in response to IL-6. Reduced mRNA levels of both albumin and transferrin was only found in spheroids and no change was observed in monolayers. These results suggest that the regulation of tissue-specific gene expression is better preserved in spheroids, in which hepatocytes are in close contact with each other.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Liver biopsies were carried out using three different needles, a Vim‐Silverman needle 2.5 mm in outer caliber, an 18‐Gauge (18G) Majima needle, and a 17‐Gauge (17G) Majima needle. The biopsies were obtained from nearby locations on the liver surface under laparoscopic observation, to ascertain differences in histological diagnosis according to the size of the biopsy specimen. The biopsy specimens obtained with the Vim‐Silverman needle were wider than those obtained with the other two needles. The agreement in histological diagnoses of the liver, obtained with the Vim‐Silverman needle versus the 18G Majima needle, was 26.0%, while that between the Vim‐Silverman needle and the 17G Majima needle was 40.0%. Histological diagnosis tended to be underestimated in small biopsy specimens in advanced chronic liver diseases. A questionnaire survey, conducted in 92 hospitals affiliated with Okayama University Medical School, revealed US‐guided liver biopsy to be the practice of choice in 57 of 92 (62.0%) hospitals, and 18G needles were used in US‐guided liver biopsy in 35 of 78 (45.2%) hospitals. Copyright © 1995, Wiley Blackwell. All rights reserved

DOI： 10.1111/j.1443-1661.1995.tb00172.x

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記述言語：日本語   出版者・発行元：JAPANESE SOCIETY FOR ARTIFICIAL ORGANS  

DOI： 10.11392/jsao1972.24.Supplement_S57

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記述言語：日本語   出版者・発行元：JAPANESE SOCIETY FOR ARTIFICIAL ORGANS  

DOI： 10.11392/jsao1972.23.Supplement_S86

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総ページ数：1冊   記述言語：英語

CiNii Books

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総ページ数：1冊  

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J-GLOBAL

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記述言語：日本語   出版者・発行元：日本消化器病学会-四国支部  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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J-GLOBAL

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記述言語：日本語   出版者・発行元：(株)メディカルレビュー社  

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記述言語：日本語   出版者・発行元：日本消化器病学会-中国支部  

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記述言語：日本語   出版者・発行元：日本消化器病学会-中国支部  

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(株)メディカルレビュー社  

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記述言語：日本語   出版者・発行元：(一社)日本TDM学会  

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：日本語   出版者・発行元：(公社)日本薬学会  

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記述言語：日本語   出版者・発行元：(公社)日本薬学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

出張肝臓病教室では、岡山大学病院の肝疾患サポートチームが職域に出向き、職員全員を対象として肝炎検診受検や肝臓専門機関受診の重要性を説明した。12回の出張肝臓病教室を603人が受講し、アンケート回答に欠損のない565人の回答を分析した。肝臓病で通院中の人は3人(0.5%)、健康診断で今まで肝機能異常を指摘されたことがない人が468人(82.8%)、健康診断で肝臓に関する検査結果を意識してみていない人が263人(46.5%)であった。肝臓病教室を受講して肝炎ウイルス検査を受けようと思った人が300人(53.1%)、既に受けている人が154人(27.3%)で、111人(19.6%)は受けないと回答した。講演が職場の肝臓病に対する偏見や誤解の解消に非常に役立つと思った人が347人(61.4%)、少し役に立つと思った人が208人(36.8%)であった。出張肝臓病教室に参加した306名中288名(94.1%)が肝炎検診を受検し、HBs抗原陽性者3名(1%)、HCV抗体陽性者3名(1%)であった。陽性者6名全員が肝炎専門医療機関を受診した。

DOI： 10.2957/kanzo.58.304

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER SOC CLINICAL ONCOLOGY  

DOI： 10.1200/JCO.2017.35.15_suppl.e15674

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：W B SAUNDERS CO-ELSEVIER INC  

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DOI： 10.1016/S0016-5085(17)33922-7

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：W B SAUNDERS CO-ELSEVIER INC  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

非肝臓専門診療科で実施される肝炎ウイルス検査の結果が受検者に適切に説明されるように、当院では2013年に電子カルテ上で検査陽性を知らせるアラートの自動表示システムを導入した。このシステムを利用して担当医が説明した割合は28%と不十分であったため、検査実施診療科了解のもと検査陽性者へ検査報告書を郵送し、検査陽性者への報告率は89%と改善した。肝臓専門医への紹介状と返信用書類を同封、郵送半年後に肝臓専門医受診を確認できていない場合は再送し、肝炎専門医受診把握率は49%から72%に改善した(p&lt;0.001)。検査報告書再送で肝精査の必要性に気づき肝臓専門医を受診し、肝炎治療を受けた症例もあった。肝炎ウイルス検査陽性者への報告を徹底することは肝臓専門医受診率の向上や適切な肝炎治療の受療に有用である。(著者抄録)

DOI： 10.2957/kanzo.58.427

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

肝移植後C型肝炎に対するDirect Acting Antivirals(DAA)治療効果を検討した。Genotypelは29症例で、ダクラタスビル+アスナプレビル(DCV+ASV)5例、ソホスブビル+レジパスビル(SOF+LDV)25例(含DCV+ASV無効1例)、Genotype2が2症例でSOF+リバビリン治療を行った。DCV+ASVは5例中4例で治療完遂、3例でSustained viral response(SVR)24を達成。SOF+LDVは全例SVR24を達成、移植後2ヵ月以内の肝炎再燃例も含まれているが問題なく治療完遂可能であった。Genotype2はSVR24を達成。SOF中心レジメンで100%のSVR24達成率であり、移植後早期においても問題なくウイルス駆除達成可能であった。C型肝硬変の肝移植適応評価においてC型肝炎のネガティブインパクトはなくなったと言っても過言ではない。(著者抄録)

DOI： 10.2957/kanzo.58.599

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

症例は50歳代、女性。肝左葉を占める、肝内多発転移・門脈腫瘍塞栓をともなう混合型肝癌と診断された。肝細胞癌成分が有意と判断し、肝細胞癌に準じた化学療法を導入した。Sorafenib・CDDP肝動注療法では病勢と全身状態の悪化を認めたが、Low-dose FP(LFP)療法は奏効を認め、長期生存が得られている。今回LFP療法が、切除不能な混合型肝癌の治療の選択肢としても有効である可能性が示唆された。(著者抄録)

DOI： 10.11405/nisshoshi.113.2050

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：W B SAUNDERS CO-ELSEVIER INC  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：W B SAUNDERS CO-ELSEVIER INC  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：W B SAUNDERS CO-ELSEVIER INC  

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DOI： 10.1038/cgt.2016.31

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：W B SAUNDERS CO-ELSEVIER INC  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：W B SAUNDERS CO-ELSEVIER INC  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：W B SAUNDERS CO-ELSEVIER INC  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：W B SAUNDERS CO-ELSEVIER INC  

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：日本語   出版者・発行元：(株)日本臨床社  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：岡山医学会  

柿胃石の成分分析における標準物質としてタンニン酸、柿渋および各種の柿を用い、その有用性を赤外吸収分光法にて検討した。その結果、未精製の柿渋の波形が柿胃石症例の波形に最も近いことが明らかとなった。以上の結果から、未精製の柿渋が柿胃石の成分分析における標準物質として有用であることが示唆された。

DOI： 10.4044/joma.126.127

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記述言語：日本語   出版者・発行元：(株)アークメディア  

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記述言語：英語   出版者・発行元：ELSEVIER SCI LTD  

DOI： 10.1016/j.molonc.2014.03.007

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記述言語：日本語   出版者・発行元：日本膵臓学会  

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記述言語：日本語   出版者・発行元：日本膵臓学会  

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記述言語：日本語   出版者・発行元：日本膵臓学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：W B SAUNDERS CO-ELSEVIER INC  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY-BLACKWELL  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY-BLACKWELL  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY-BLACKWELL  

Web of Science

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

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記述言語：日本語   出版者・発行元：(株)南江堂  

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記述言語：日本語   出版者・発行元：(株)メディカルトリビューン  

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記述言語：日本語   出版者・発行元：(株)メディカルレビュー社  

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記述言語：日本語   出版者・発行元：(株)南江堂  

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記述言語：日本語   出版者・発行元：(株)メディカルトリビューン  

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記述言語：日本語   出版者・発行元：日本膵臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

症例は15歳男児。高校入学時の検診で貧血を指摘され、近医を受診。血液検査にて肝機能障害を認め、CT検査では肝脾腫、少量腹水を認めた。抗核抗体・抗平滑筋抗体陽性、IgG高値であり前医で自己免疫性肝炎(autoimmune hepatitis:AIH)を強く疑われたため、プレドニゾロン(prednisolone:PSL)20mg/日による治療を開始され、更なる精査目的に当科紹介。エコー下肝生検を施行し、新犬山分類F4A3の肝硬変像とAIHに一致する病理所見を得た。PSL開始後の肝機能の改善が不充分であり、PSL40mg/日への増量やアザチオプリンの併用も試みたが効果不十分であった。さらにメチルプレドニゾロンパルス療法を追加したところ肝機能は改善した。本症例は腹部症状や黄疸はなく貧血を契機にAIHと診断された症例であり、診断時には肝硬変に至っていた貴重な症例と考える。(著者抄録)

DOI： 10.2957/kanzo.54.698

Scopus

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記述言語：日本語   出版者・発行元：エーザイ(株)  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(株)インナービジョン  

このたび、東芝社から超音波診断装置「Aplio 500(TUS-A500)」(図1)に対応した、改良型マイクロコンベックスプローブ「PVT-382BT」(図2)が発売されることとなった。当科では、肝がんのラジオ波焼灼療法(radiofrequency ablation:RFA)や肝生検に際し、専らマイクロコンベックスプローブを使用している。本稿では、まずマイクロコンベックスプローブが必要な理由について述べ、続いて「PVT-382BT」の開発最終段階試用機の使用経験について紹介する。(著者抄録)

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：日本語   出版者・発行元：(有)科学評論社  

門脈腫瘍栓合併肝細胞癌に対し動注療法および放射線療法を施行した41例(男36例、女5例、平均65歳)の成績を報告した。対象は肝予備能が比較的保たれ、遠隔転移の合併がないStage IVAが主であった。肝実質内の結節に対する動注療法はlow dose FPが22例、5-FU+CDDP+IFNが8例、5-FU単剤が8例、5-FU+IFNが3例で、放射線療法は動注療法の初回導入時に同時併用し、門脈腫瘍栓の肝門部先端に対して三次元照射(2Gy×25回)を行った。生存期間の中央値(MST)は9.9ヵ月、1年生存率42%であった。門脈腫瘍栓に対する治療効果はCR 2%、PR 42%、SD 49%、PD 7%で、奏効率44%、病勢コントロール率93%、1年後の無増悪率59%であった。肝内結節と門脈腫瘍栓の治療効果別に見ると、いずれも奏効した症例のMSTは12.3ヵ月、門脈腫瘍栓のみ奏効が7.5ヵ月、いずれも無効が6.5ヵ月で、これらの間に有意差が認められた。

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記述言語：日本語   出版者・発行元：(株)メディカルレビュー社  

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記述言語：日本語   出版者・発行元：(一社)日本移植学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY-BLACKWELL  

Web of Science

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY-BLACKWELL  

Web of Science

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記述言語：日本語   出版者・発行元：(一社)日本消化器内視鏡学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：W B SAUNDERS CO-ELSEVIER INC  

Web of Science

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(有)科学評論社  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(公社)日本超音波医学会  

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記述言語：日本語   出版者・発行元：(株)医学書院  

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記述言語：日本語   出版者・発行元：(株)医学書院  

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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