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1.
Artigo em Inglês | MEDLINE | ID: mdl-32169996

RESUMO

BACKGROUND: Although the poor prognosis and increasing incidence of pancreatic cancer highlight the need for prevention strategies, few lifestyle risk factors for pancreatic cancer have yet been identified. Soybeans contain various bioactive compounds. However, the association between soy food intake and pancreatic cancer risk remains unknown. METHODS: The Japan Public Health Center-based Prospective Study is a cohort study conducted in a general Japanese population. To determine the association of soy food intake and pancreatic cancer incidence, we analyzed 90,185 participants who responded to a questionnaire on medical history and lifestyle factors, including dietary factors based on a food frequency questionnaire in 1995-1998, using Cox proportional hazards models. RESULTS: During a median follow-up of 16.9 years, 577 cases of pancreatic cancer were identified. In the multivariate-adjusted model, total soy food intake was statistically significantly associated with an increased risk of pancreatic cancer [HR for the highest vs. lowest intake quartile: 1.48; 95% confidence interval (CI), 1.15-1.92; P trend = 0.007]. Among soy foods, nonfermented soy food intake showed a statistically significant positive association with pancreatic cancer (HR, 1.41; 95% CI, 1.09-1.81; P trend = 0.008), whereas fermented soy food intake showed no association (HR, 0.96; 95% CI, 0.73-1.26; P trend = 0.982). CONCLUSIONS: Higher intake of soy foods, particularly nonfermented soy foods, might increase pancreatic cancer risk. IMPACT: This study is the first to report an association between the intake of various soy foods and pancreatic cancer risk. Further studies are required to confirm our findings.

2.
Cancer Sci ; 110(11): 3603-3614, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31482651

RESUMO

Red meat and processed meat have been suggested to increase risk of colorectal cancer (CRC), especially colon cancer. However, it remains unclear whether these associations differ according to meat subtypes or colon subsites. The present study addressed this issue by undertaking a pooled analysis of large population-based cohort studies in Japan: 5 studies comprising 232 403 participants (5694 CRC cases) for analysis based on frequency of meat intake, and 2 studies comprising 123 635 participants (3550 CRC cases) for analysis based on intake quantity. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using the Cox proportional hazards model and then pooled using the random effect model. Comparing the highest vs lowest quartile, beef intake was associated with an increased risk of colon cancer in women (pooled HR 1.20; 95% CI, 1.01-1.44) and distal colon cancer (DCC) risk in men (pooled HR 1.30; 95% CI, 1.05-1.61). Frequent intake of pork was associated with an increased risk of distal colon cancer in women (pooled HR 1.44; 95% CI, 1.10-1.87) for "3 times/wk or more" vs "less than 1 time/wk". Frequent intake of processed red meat was associated with an increased risk of colon cancer in women (pooled HR 1.39; 95% CI, 0.97-2.00; P trend = .04) for "almost every day" vs "less than 1 time/wk". No association was observed for chicken consumption. The present findings support that intake of beef, pork (women only), and processed red meat (women only) might be associated with a higher risk of colon (distal colon) cancer in Japanese.


Assuntos
Neoplasias do Colo/etiologia , Carne/efeitos adversos , Neoplasias Retais/etiologia , Animais , Grupo com Ancestrais do Continente Asiático , Índice de Massa Corporal , Bovinos , Colo , Intervalos de Confiança , Feminino , Manipulação de Alimentos , Humanos , Japão , Masculino , Carne/classificação , Aves Domésticas , Carne Vermelha/efeitos adversos , Medição de Risco , Fatores Sexuais , Suínos
3.
Int J Cancer ; 144(8): 1858-1866, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30255932

RESUMO

Oxidative stress and chronic inflammation are potential pathogenic factors of pancreatic cancer. Although fruits and vegetables are abundant in antioxidants and anti-inflammatory constituents, the reported associations between fruit and vegetable intake and pancreatic cancer risk have been inconsistent. Here, we investigated the association between fruit and vegetable intake and pancreatic cancer risk as part of the Japan Public Health Center-based Prospective Study. The analysis included 90,185 participants who responded to a medical and lifestyle questionnaire during 1995-1998. Associations between fruit and vegetable intake and pancreatic cancer risk were evaluated with Cox proportional hazards models. Additional analyses were stratified by smoking status and body mass index. During follow-up (median duration, 16.9 years), 577 participants were diagnosed with pancreatic cancer. In multivariate-adjusted models, pancreatic cancer risk was inversely associated with total fruit intake (highest vs. lowest intake quartile; hazard ratio [HR]: 0.74, 95% confidence interval [CI]: 0.57-0.95, p-trend: 0.116) and positively associated with total vegetable intake (HR: 1.30, 95% CI: 1.01-1.66, p-trend: 0.151). For total fruit intake, the inverse association with pancreatic cancer risk was more apparent in never smokers (HR: 0.67, 95% CI: 0.47-0.97, p-trend: 0.034). For total vegetable intake, the positive association was statistically significant in ever smokers (HR: 1.49, 95% CI: 1.01-2.19, p-trend: 0.043) and statistically nonsignificant in never smokers. In summary, total fruit intake and total vegetable intake had inverse and positive associations, respectively, with pancreatic cancer risk. Vegetable intake may correlate with increased risk partly because of the influence of smoking on vegetable intake.


Assuntos
Comportamento Alimentar , Frutas , Neoplasias Pancreáticas/epidemiologia , Fumar Tabaco/epidemiologia , Verduras , Adulto , Idoso , Feminino , Seguimentos , Humanos , Japão/epidemiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais/estatística & dados numéricos , Pâncreas/patologia , Estudos Prospectivos , Fatores de Risco
4.
Liver Int ; 39(8): 1566-1576, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30566759

RESUMO

BACKGROUND & AIMS: The association of serum liver enzyme levels with all-cause mortality in individuals without hepatitis B virus or hepatitis C virus infection is inconsistent. We aimed to investigate all-cause and non-liver disease mortality according to levels of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyltransferase (GGT) stratified by hepatitis virus infection status in a Japanese cohort. METHODS: Participants were 7243 men and 13 513 women aged 40-69 years at the baseline survey in 1993-1994. Multivariate-adjusted hazard ratios of death from the baseline health check-up to December 2012 were calculated with a Cox proportional hazards model controlling for potential confounding factors. RESULTS: During follow-up, 2235 deaths in men and 1901 deaths in women were identified. All serum liver enzymes were associated with all-cause mortality in each sex and hepatitis virus infection status. In participants without infection, those with more than twice the upper level of normal (ULN), which was defined as 30 IU/L for AST and ALT and 50 IU/L for GGT, had a higher risk of non-liver disease mortality compared to those below the ULN (HR 1.69; 95% confidence interval 1.13-2.53, 1.49; 1.02-2.18, 1.39; 1.11-1.73, 1.72; 1.08-2.74 and 1.72; 1.10-2.69 for AST, ALT, and GGT in men and AST and GGT in women, respectively), except for ALT in women. CONCLUSIONS: In participants without hepatitis virus infection, serum liver enzyme levels were positively associated with all-cause mortality. Similar associations were also found for non-liver disease mortality.

5.
Hepatol Res ; 48(13): 1069-1080, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29934990

RESUMO

AIM: The consideration of patients' needs in terms of research outcomes is emphasized in research promotion to eradicate hepatitis B virus according to the Basic Act on Hepatitis Measures in Japan. This study analyzed patients' attitudes toward experienced antiviral therapies for chronic hepatitis B and their need for future therapies. METHODS: A self-administered questionnaire comprising 124 questions was completed among patients with chronic hepatitis B from 61 core-center hospitals designated to implement and research policies on hepatitis in 47 prefectures from August 2013 to January 2014 (n = 3021, response rate = 51%). RESULTS: In decision-tree models with 333 variables generated from the questionnaire data, patients' satisfaction with therapy and reduction in anxiety about therapy were dependent on favorable therapeutic effects, sufficient information provided by the physician, and fewer lifestyle disturbances. Medical expenses were not selected at a superior branch because subsidy for antiviral therapy started in 2010. In correspondence analysis of free text answers, patients' need for therapy and support mechanisms differed among their attributes, including a great need for novel therapy in older men, hope for avoidance of lifestyle disturbance in younger men, and alleviation of painful experience with the disease in women. CONCLUSIONS: Continual provision of sufficient information is necessary to improve the utility of antiviral therapy for chronic hepatitis B as well as for favorable therapeutic effects. The patients believed that novel drugs and support would reduce the diverse burden of the disease on their lives.

6.
Cytokine ; 88: 29-36, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27541605

RESUMO

AIM: Telaprevir (TVR) remarkably improves the efficacy of interferon treatment for chronic hepatitis C. Interleukin-28B (IL28B) genotype and interferon-gamma-inducible protein-10 (IP-10) level predict virologic response to peg-interferon (Peg-IFN)/ribavirin (RBV) therapy. We aimed to investigate the usefulness of pretreatment serum IP-10 levels and IL28B genotyping in predicting sustained virologic response (SVR) to TVR-based triple therapy. METHODS: In this multi-center study, patients infected with hepatitis C virus genotype 1 with high viral load (⩾5.0logIU/mL) were treated with TVR for 12weeks and Peg-IFN/RBV for 24weeks in Japan. IL28B genotype, serum IP-10 levels, other clinical parameters, and drug dosages were assessed before treatment. RESULTS: We included 121 patients who were treated with TVR for at least 8weeks and Peg-IFN/RBV for 24weeks. The median IP-10 levels were significantly lower in rapid virologic response (RVR) or SVR in the IL28B non-TT genotype group, with no significant difference in the TT genotype group. RVR rates were significantly lower in the group with higher serum IP-10 levels (>450pg/mL). In the non-TT IL28B genotype group, RVR and SVR rates were significantly lower in the group with higher IP-10 levels. SVR rates in the group with lower IP-10 levels (<450pg/mL) increased to 82% for those showing RVR, but reduced to 27% in the group with higher IP-10 levels for those not showing RVR. CONCLUSIONS: Determination of serum IP-10 levels before treatment could be useful for predicting favorable virologic response to TVR-based triple therapy, especially in patients with IL28B non-TT genotype.


Assuntos
Quimiocina CXCL10/sangue , Genótipo , Hepacivirus , Hepatite C Crônica , Interleucinas/genética , Oligopeptídeos/administração & dosagem , Idoso , Feminino , Técnicas de Genotipagem , Hepatite C Crônica/sangue , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/genética , Humanos , Interferons , Masculino , Pessoa de Meia-Idade
7.
BMC Public Health ; 15: 566, 2015 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-26088426

RESUMO

BACKGROUND: Many patients with chronic hepatitis C have been treated with interferon (IFN) therapy in Japan, especially after the introduction of subsidies for medical expenses in 2008. However, its performance and outcome have never been evaluated. Therefore, a nationwide, mail-based, retrospective cohort study was conducted. METHODS: Regional disparities in the demographic features, treatment performance, and virological response were evaluated using an intent-to-treat design. The participating prefectures were classified into nine regions from north to south (Hokkaido/Tohoku, Kanto, Shin-etsu, Hokuriku, Tokai, Kinki, Chugoku, Shikoku, and Kyushu). Multivariate logistic regression analysis was performed to select predictive factors for treatment performance and outcome. RESULTS: From December 2009 to May 2013, 16,854 patients with chronic hepatitis C were registered from 37 prefectures in Japan (median age: 60 years; 50.4% male; 74.8% IFN-naïve; HCV genotype [1 or 2]/viral load [high (≥5 log IU/mL) or low (<5 log IU/mL)]: 1/high = 58.2%, 1/low = 5.2%, 2/high = 27.3%, 2/low = 7.5%; 83.4% treated with peginterferon-α and ribavirin). Mean age, proportion of elderly patients (≥65 years), male sex, IFN-experienced, and HCV genotype were significantly different among the nine regions (all P < 0.001). Regional disparities were independently selected as one of the predictive factors for treatment performance and outcome in patients treated with peginterferon-α and ribavirin, which revealed two regions that required further investigation. CONCLUSIONS: Regional disparities still exist in IFN therapy, and are strongly associated with treatment performance and outcome. Since the accessibility to medical resources for individual patients seemed to be different among the nine regions, public health actions should be focused on how to construct and properly manage consultation networks between base hospitals and local clinics, especially in those regions with low population density.


Assuntos
Antivirais/uso terapêutico , Disparidades em Assistência à Saúde , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Adulto , Idoso , Esquema de Medicação , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus , Humanos , Imunoterapia , Japão , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis , Estudos Retrospectivos , Ribavirina/uso terapêutico , Carga Viral/efeitos dos fármacos
8.
J Gastroenterol ; 50(8): 894-902, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25501286

RESUMO

BACKGROUND: Hepatitis C virus (HCV) is one of the major causes of liver cancer. The single nucleotide polymorphisms within the IFNL3 gene, which encodes interferon (IFN)-λ(3), are strongly associated with the response to pegylated IFN-α (PEG-IFN-α) plus ribavirin (RBV) therapy in chronic hepatitis C (C-CH) patients. However, the roles of IFN-λ(3) in chronic HCV infection are still elusive. In this study, we aimed to identify clinical and immunological factors influencing IFN-λ(3) and evaluated whether serum IFN-λ(3) levels are involved or not involved in the response to PEG-IFN-α plus RBV therapy. METHODS: We enrolled 119 C-CH patients with HCV genotype 1 infection who underwent 48 weeks of PEG-IFN-α plus RBV therapy. As controls, 23 healthy subjects and 56 patients with non-HCV viral hepatitis were examined. Serum IFN-λ(3) was quantified by chemiluminescence enzyme immunoassay, and 27 cytokines or chemokines were assayed by the multiplexed BioPlex system. RESULTS: Serum IFN-λ(3) levels were higher in C-CH patients or acute hepatitis E patients than in healthy volunteers. Such levels did not differ between the IFNL3 genotypes. In C-CH patients, serum IFN-λ(3) was positively correlated with aspartate aminotransferase, alanine aminotransferase, α-fetoprotein, histological activity, fibrosis index, IFN-γ-inducible protein 10, and platelet-derived growth factor. Multivariate analysis showed that IFNL3 single nucleotide polymorphisms, fibrosis score, and macrophage inflammatory protein 1α were involved in the sustained viral clearance in PEG-IFN-α plus RBV therapy; however, serum IFN-λ(3) levels were not involved. CONCLUSION: Serum IFN-λ(3) levels are increased in C-CH patients regardless of the IFNL3 genotype. IFN-λ(3) is a biomarker reflecting the activity and fibrosis of liver disease, but is not correlated with the responsiveness to PEG-IFN-α plus RBV therapy.


Assuntos
Hepatite C Crônica/sangue , Mediadores da Inflamação/sangue , Interleucinas/sangue , Cirrose Hepática/sangue , Adulto , Idoso , Antivirais/uso terapêutico , Biomarcadores/sangue , Estudos de Casos e Controles , Quimioterapia Combinada , Feminino , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Humanos , Interferon-alfa/uso terapêutico , Interferons , Interleucinas/genética , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/uso terapêutico , Polimorfismo de Nucleotídeo Único , Proteínas Recombinantes/uso terapêutico , Ribavirina/uso terapêutico
9.
Cancer Sci ; 101(10): 2145-55, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20707805

RESUMO

Accumulating evidence suggests that cancer stem cells (CSC) play an important role in tumorigenicity. Epithelial cell adhesion molecule (EpCAM) is one of the markers that identifies tumor cells with high tumorigenicity. The expression of EpCAM in liver progenitor cells prompted us to investigate whether CSC could be identified in hepatocellular carcinoma (HCC) cell lines. The sorted EpCAM(+) subpopulation from HCC cell lines showed a greater colony formation rate than the sorted EpCAM(-) subpopulation from the same cell lines, although cell proliferation was comparable between the two subpopulations. The in vivo evaluation of tumorigenicity, using supra-immunodeficient NOD/scid/γc(null) (NOG) mice, revealed that a smaller number of EpCAM(+) cells (minimum 100) than EpCAM(-) cells was necessary for tumor formation. The bifurcated differentiation of EpCAM(+) cell clones into both EpCAM(+) and EpCAM(-) cells was obvious both in vitro and in vivo, but EpCAM(-) clones sustained their phenotype. These clonal analyses suggested that EpCAM(+) cells may contain a multipotent cell population. Interestingly, the introduction of exogenous EpCAM into EpCAM(+) clones, but not into EpCAM(-) clones, markedly enhanced their tumor-forming ability, even though both transfectants expressed a similar level of EpCAM. Therefore, the difference in the tumor-forming ability between EpCAM(+) and EpCAM(-) cells is probably due to the intrinsic biological differences between them. Collectively, our results suggest that the EpCAM(+) population is biologically quite different from the EpCAM(-) population in HCC cell lines, and preferentially contains a highly tumorigenic cell population with the characteristics of CSC.


Assuntos
Antígenos de Neoplasias/fisiologia , Carcinoma Hepatocelular/química , Moléculas de Adesão Celular/fisiologia , Neoplasias Hepáticas/química , Células-Tronco Neoplásicas/fisiologia , Animais , Antígenos de Neoplasias/análise , Antígenos de Neoplasias/química , Antígenos de Neoplasias/genética , Carcinoma Hepatocelular/patologia , Moléculas de Adesão Celular/análise , Moléculas de Adesão Celular/química , Moléculas de Adesão Celular/genética , Linhagem Celular Tumoral , Molécula de Adesão da Célula Epitelial , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Estrutura Terciária de Proteína
10.
Intern Med ; 48(16): 1387-90, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19687584

RESUMO

Interferon (IFN) therapies, including IFN, peginterferon (PEG-IFN) and ribavirin (RBV) plus PEG-IFN combination, are widely used for patients with chronic hepatitis C. We encountered a patient with chronic hepatitis C in whom previous IFN or PEG-IFN alone had not induced type 1 diabetes (T1D), while the addition of RBV to PEG-IFN did induce T1D. The patient had HLA types conferring highly susceptibility to T1D. Thus, adding RBV to PEG-IFN may render chronic hepatitis C patients, with T1D-susceptible HLA types, more prone to developing T1D than IFN or PEG-IFN alone. To prevent T1D development, we recommend HLA typing prior to initiating RBV plus PEG-IFN administration.


Assuntos
Diabetes Mellitus Tipo 1/sangue , Hepatite C Crônica/sangue , Interferon-alfa/administração & dosagem , Polietilenoglicóis/administração & dosagem , Ribavirina/administração & dosagem , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Tipo 1/induzido quimicamente , Quimioterapia Combinada , Feminino , Hepatite C Crônica/tratamento farmacológico , Humanos , Interferon alfa-2 , Interferon-alfa/efeitos adversos , Pessoa de Meia-Idade , Polietilenoglicóis/efeitos adversos , Proteínas Recombinantes , Ribavirina/efeitos adversos
11.
Hepatol Res ; 38(11): 1098-111, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18684128

RESUMO

AIMS: Galectins are multifunctional lectins binding to the beta-galactoside of glycoproteins that affect diverse physiological and pathophysiological processes such as development, inflammation and tumor growth. In hepatocellular carcinoma (HCC), the over-expression of galectin-1, 3, and 4 has been reported, although their function and correlation with tumor progression remain unknown. Thus, we aimed to assess the role of galectin-3 during HCC progression. METHODS: Specimens were obtained during curative operations and used for immunohistochemical analysis of galectin-3 (n = 52), and statistically assessed for correlations with the clinical profiles and the prognoses of the patients. The serum galectin-3 levels from the patients with liver diseases including HCC were assessed by ELISA. RESULTS: In total, galectin-3 expression was found in 34 of 52 tumors (65%) and was statistically correlated with histological differentiation and vascular invasion. Kaplan-Meier's analysis showed that patients with galectin-3 expression tended to relapse in the earlier phase and had worse overall survival. In particular, a higher expression rate of nuclear galectin-3 showed a markedly worse prognosis, and it was independent in the multivariate analysis for overall survival. Serum galectin-3 levels were significantly increased in HCC compared with chronic liver disease. The sensitivity and specificity of galectin-3 were equivalent to alpha-fetoprotein and Vitamin K absence or antagonist II, and the combination of HCC biomarkers with galectin-3 improved the diagnostic performance. CONCLUSIONS: Galectin-3 expression was involved in the tumor progression and related to the prognosis of HCC. Our observations suggested that galectin-3 could be a novel tumor marker and therapeutic target.

12.
Hepatol Res ; 38(8): 842-6, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18498361

RESUMO

We report a case of a HIV and hepatitis B virus (HBV)-co-infected patient to whom entecavir (ETV) was administered initially before the notification regarding the potential mutagenesis effect on HIV against the nucleoside analog. Since initial evaluations indicated the advanced stage of chronic hepatitis B and preserved numbers of peripheral CD4+ lymphocytes without the manifestation of immunodeficiency, priority was given to the management of HBV. We started HBV therapy with ETV at a dose of 0.5 mg daily without using any HIV drugs. The viral loads of both HBV and HIV-1 decreased gradually during the 5 months following the initial administration of ETV. HBV was well controlled by the gradual replacement of ETV with highly-active antiretroviral therapy against HIV with a regimen including atazanavir, emtricitabine, and tenofovir. HBV was genotyped as A2 with the quasispecies pool consisting of the -1G precore/core deletion mutant strain.

13.
Hepatol Res ; 38(4): 415-20, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18021227

RESUMO

Severe hepatitis with an indistinct etiology manifested in a 16-year-old boy who had no particular history. The histological features of the liver and clinical course of the patient were similar to those of patients with autoimmune hepatitis characterized by interface hepatitis and severe lobular inflammation of the liver and recurrent exacerbations of hepatitis. We administered intravenous glycyrrhizin preparation daily or three times a week combined with the oral administration of ursodeoxycholic acid daily throughout the term after the initial onset of disease for the control of disease activity. The normalization of the concentration of alanine aminotransferase in serum was achieved in response to the therapy during the course. The serum concentration of immunoglobulins of the patient gradually decreased from the onset of the disease to an unacceptable level without globulin preparation during the following period of 17 months. Immunological tests revealed impairment of immunoglobulin production bythe B cell population of the patient, which led to the diagnosis of the patient as common variable immunodeficiency (CVID). The patient, with improved liver histology after 27 months from the onset of disease, benefited from the current combination therapy without severe infection through the avoidance of overimmunosuppression. CVID is defined as a heterogeneous syndrome characterized by various degrees of hypogammaglobulinemia without any specific predisposing causes, frequently associated with autoimmunity. Diagnostic criteria and therapeutic options of persistent hepatitis with CVID are to be established, as discussed in the current report.

14.
Hepatol Res ; 37(4): 286-94, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17397517

RESUMO

AIM: Bile duct paucity, ductopenia, is a feature of end-stage chronic cholangiopathies such as primary biliary cirrhosis. The limited proliferative ability of cholangiocytes after specific injury is thought to be the principal cause of ductopenia, although the detailed mechanisms involved are unclear. It has been reported that human amniotic epithelial cells (AEC) express differentiation markers of hepatic parenchymal cells, suggesting a resemblance of AEC to hepatic progenitor cells. The aim of the present study was to develop a mouse model of experimental cholestasis to assess the capability of mouse AEC to trans-differentiate into cholangiocytes. METHODS: Enhanced green fluorescent protein (EGFP)-transgenic C57BL/6 pregnant female mice were used as the source of AEC. At 11.5 gestational days, 1 x 10(5) AEC were isolated from EGFP-transgenic mouse embryos and transferred into C57BL/6 mice. Chronic cholestasis was induced by 0.1%alpha-naphthylisothiocyanate (ANIT) feeding immediately after the transfer of AEC. The proliferation of cholangiocytes in the livers was assessed morphologically and immunohistochemically (cytokeratin 7; CK7). The proliferative activity was also quantified immunohistochemically by proliferating cell nuclear antigen (PCNA) protein expression. EGFP of transferred AEC was confirmed by fluorescent laser microscopy and immunofluorescent staining for EGFP. Also, Notch2 and Hes1 expression was evaluated to examine the roles of the differentiation markers in this process. RESULTS: Marked proliferation of cholangiocytes was observed in ANIT-fed mice confirmed by quantitative CK7 (3-4 fold vs control) and PCNA (11-20 fold vs control) staining. EGFP and CK7 double positive cells in interlobular bile ducts were confirmed in the livers of AEC-transferred recipients. Positivity of EGFP was further confirmed by the immunofluorescent staining for EGFP. Moreover, both Notch2 and Hes1 expression was confirmed in the proliferative bile duct in this model. CONCLUSIONS: Significant ductular proliferation was observed in ANIT-fed mice. EGFP-positive cholangiocytes were confirmed in this chronic cholestasis model. AEC transfer was able to contribute to the repopulating of proliferating cholangiocytes under cholestasis, suggesting AEC might be a candidate cell source for stem cell administration in future clinical applications to re-model interlobular bile ducts.

15.
Hepatogastroenterology ; 54(79): 2113-6, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18251171

RESUMO

We report the case of a patient having hepatocellular carcinoma with tumor invasion to the inferior vena cava and with multiple pulmonary metastases who was treated with repeated one-shot administration of epirubicin, cisplatin, and mitomycin C by hepatic artery and bronchial artery, which led to complete remission. A 72-year-old woman was diagnosed with infiltrative hepatocellular carcinoma with Vv3, multiple intrahepatic metastases, and multiple pulmonary metastases associated with compensated liver cirrhosis. One-shot infusion of epirubicin, cisplatin, and mitomycin C was performed through proper hepatic artery and bronchial artery for twice at eight weeks of intervals. Pulmonary metastases disappeared and intrahepatic lesions indicated marked shrinkage leaving a scar-like lesion with decreases in tumor markers. After six months and 20 months, tumor markers indicated increasing tendency but no evident recurrence was found by computed tomography or hepatic arteriography. One-shot infusion of the same regimens through proper hepatic artery was performed and tumor markers decreased to normal levels. After 14 months of the last therapy, no evidence of recurrence has been found on image analysis or in tumor markers. This arterial infusion therapy is well tolerated for the patients with compensated liver cirrhosis and might be promising for the effective treatment of advanced hepatocellular carcinoma with pulmonary metastases.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Infusões Intra-Arteriais , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/secundário , Veia Cava Inferior/patologia , Idoso , Artérias Brônquicas , Carcinoma Hepatocelular/diagnóstico por imagem , Feminino , Artéria Hepática , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Invasividade Neoplásica , Indução de Remissão , Retratamento , Tomografia Computadorizada por Raios X
16.
J Gastroenterol ; 41(10): 1005-10, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17096070

RESUMO

BACKGROUND: The model for end-stage liver disease (MELD) is useful for assessing the recipients of liver transplants, namely, deceased-donor transplantation. The application of MELD for living donor liver transplantation (LDLT) is under investigation. Thus, the aim of this study was to analyze the impact of the MELD score in LDLT in Japan. METHODS: Seventeen adult cases of LDLT during 2001 to 2005 were enrolled. Indications for LDLT were primary biliary cirrhosis, seven; liver cirrhosis, two; hepatocellular carcinoma (HCC), three; metabolic liver disease, one; primary sclerosing cholangitis, two; Caroli's disease, one; and biliary atresia, one. Total medical charges during the operative periods were retrospectively evaluated. The united network of organ sharing (UNOS) modified was obtained using preoperative clinical data. RESULTS: The average medical expense of the 17 cases was approximately 97,901 US dollar. The UNOS-modified MELD score was 22.1. A statistically significant positive correlation was found between the MELD score and medical expense (P = 0.0086, rho = 0.657), and between the MELD score and the length of stay in the intensive care unit (ICU) (P = 0.0396, rho = 0.515). The cause of the liver disease leading to transplantation was not related to MELD score, medical expense, or length of ICU stay. CONCLUSIONS: Although not originally designed for the application to LDLT, the MELD score is useful for predicting medical expenses in LDLT. Similar to those of deceased-donor liver transplantation, the disadvantage of high medical expenses associated with a high MELD score allow consideration of an earlier elective operation in suitable cases.


Assuntos
Falência Hepática , Transplante de Fígado/economia , Doadores Vivos , Modelos Econômicos , Adulto , Custos e Análise de Custo , Feminino , Seguimentos , Humanos , Unidades de Terapia Intensiva/economia , Tempo de Internação/economia , Falência Hepática/diagnóstico , Falência Hepática/economia , Falência Hepática/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença
17.
Tohoku J Exp Med ; 210(1): 29-36, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16960342

RESUMO

Hepatitis B virus (HBV) infection, which causes liver cirrhosis and hepatocellular carcinoma, remains a major health problem in Asian countries. Recent development of vaccine for prevention is reported to be successful in reducing the size of chronically infected carriers, although the standard medical therapies have not been established up to now. In this report, we encountered a patient with decompensated HBV-related cirrhosis who exhibited the dramatic improvements after antiviral therapy. The patient was a 50-year-old woman. Previous conventional medical treatments were not effective for this patient, thus this patient had been referred to our hospital. However, the administration of lamivudine, a reverse transcriptase inhibitor, for 23 months dramatically improved her liver severity. During this period, no drug resistant mutant HBV emerged, and the serum HBV-DNA level was continuously suppressed. These virological responses were also maintained even after the antiviral therapy was discontinued. Moreover, both hepatitis B surface antigen and e antigen were observed to have disappeared in this patient. The administration of lamivudine to patients with HBV-related cirrhosis, like our present case, should be considered as an initial medical therapeutic option, especially in countries where liver transplantation is not reliably available.


Assuntos
Hepatite B Crônica/tratamento farmacológico , Lamivudina/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Fármacos Anti-HIV/uso terapêutico , Feminino , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/sangue , Hepatite B Crônica/complicações , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/virologia , Cirrose Hepática/etiologia , Pessoa de Meia-Idade , Resultado do Tratamento , Carga Viral
18.
World J Gastroenterol ; 12(29): 4757-60, 2006 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-16937453

RESUMO

A 29-year-old nurse with a hepatitis C virus (HCV) infection caused by needle-stick injury was treated with interferon-beta starting about one year after the onset of acute hepatitis. The patient developed acute hepatitis C with symptoms of general fatigues, jaundice, and ascites 4 wk after the needle-stick injury. When these symptoms were presented, the patient was pregnant by artificial insemination. She hoped to continue her pregnancy. After delivery, biochemical liver enzyme returned to normal levels. Nevertheless, HCV RNA was positive and the pathological finding indicated a progression to chronicity. The genotype was 1b with low viral load. Daily intravenous injection of interferon-beta at the dosage of six million units was started and continued for eight weeks. HCV was eradicated without severe adverse effects. In acute hepatitis C, delaying therapy is considered to reduce the efficacy but interferon-beta therapy is one of the useful treatments for hepatitis C infection in chronic phase.


Assuntos
Hepacivirus/patogenicidade , Hepatite C/tratamento farmacológico , Hepatite C/etiologia , Ferimentos Penetrantes Produzidos por Agulha/complicações , Doença Aguda , Adulto , Antivirais/uso terapêutico , Progressão da Doença , Feminino , Hepacivirus/genética , Hepatite C/fisiopatologia , Hepatite C/transmissão , Humanos , Transmissão de Doença Infecciosa do Paciente para o Profissional , Interferon beta/uso terapêutico , RNA Viral/análise , RNA Viral/genética
19.
Liver Int ; 26(4): 457-66, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16629650

RESUMO

BACKGROUND: Ductopenia is observed in end-stage human cholestatic diseases. The limited capability of cholangiocytes for proliferation is suggested to be the principal reason. Recently, bone marrow cells (BMCs) have been reported to behave as hepatic stem cells; however, their capability to differentiate into cholangiocytes in cholestasis remains unclear. METHODS: Normal mice were lethally irradiated to suppress the proliferation of self-BMCs; thereafter, the BMCs from enhanced green fluorescent protein (EGFP)-transgenic mice were transferred to recipients. Chronic cholestasis was induced by 0.1%alpha-naphtylisothiocyanate (ANIT) feeding. The proliferation of cholangiocytes and oval cells was assessed morphologically and immunohistchemically (cytokeratin-7 (CK-7), A6). Proliferative activity (proliferating cell nuclear antigen (PCNA) protein expression), hepatic growth factor (HGF) receptor (c-Met), stem cell factor receptor (c-kit), Notch2 and Hes1 expression were also evaluated. RESULTS: Marked cholangiocyte proliferation was observed in ANIT-fed mice. However, no EGFP/CK-7 double positive cells were identified in any of the liver specimens after BMCs transfer (Tx). In hepatic parenchyma, there were scattered EGFP-positive cells, although none of them were positive for CK-7. CONCLUSIONS: In spite of the significant ductular proliferations after ANIT feeding, no EGFP-positive cholangiocytes were confirmed by any other means in this chronic cholestasis model. Thus, different from hepatocytes, BMCs Tx seems not to contribute to the differentiation of cholangiocytes. Future studies are feasible to clarify the origin of proliferative cholangiocytes observed in this chronic cholestatic ductular hyperplasia model.


Assuntos
Ductos Biliares/citologia , Ductos Biliares/fisiologia , Células da Medula Óssea/citologia , Diferenciação Celular , Colestase/patologia , Regeneração , 1-Naftilisotiocianato , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Ductos Biliares/patologia , Células da Medula Óssea/metabolismo , Transplante de Medula Óssea , Proliferação de Células , Colestase/induzido quimicamente , Colestase/metabolismo , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Hiperplasia/patologia , Queratina-7 , Queratinas/genética , Queratinas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas dos Microfilamentos , Proteínas Tirosina Quinases/análise , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Receptores Notch/genética , Receptores Notch/metabolismo , Fatores de Transcrição HES-1
20.
J Hepatol ; 44(6): 1055-65, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16469407

RESUMO

BACKGROUND/AIMS: Over-expression of IL-6 has been implicated in cholangiocarcinoma growth but the cellular mechanisms involved are unknown. Our aims were to assess the mechanisms by which over-expression of IL-6 promotes transformed cell growth in malignant cholangiocytes. METHODS: Stably transfected cell lines over-expressing IL-6 were derived from malignant human cholangiocytes. Transformed cell growth was assessed by anchorage independent growth in vitro and by xenograft growth in nude mice. Expression of the anti-apoptotic protein Mcl-1 was quantitated by immunoblot analysis and by real-time PCR. Gene silencing was performed using siRNA. Dominant negative upstream kinase activators and isoform-specific constructs were used to evaluate the involvement of p38 MAP kinase signaling pathways. RESULTS: Over-expression of IL-6 increased xenograft growth, anchorage independent growth and cell survival but did not significantly alter cell proliferation. The basal expression of Mcl-1 was increased in IL-6 over-expressing cells. Selective knockdown of Mcl-1 by siRNA increased gemcitabine-induced cytotoxicity. Moreover, IL-6 increased Mcl-1 mRNA and protein expression via a p38 MAPK dependent mechanism. CONCLUSIONS: These data demonstrate a major role of survival signaling pathways in mediating the effects of IL-6 over-expression in cholangiocarcinoma growth. Mcl-1 is identified as a mediator of IL-6-induced tumor cell survival and shown to be transcriptionally regulated by IL-6 via a p38 MAPK dependent pathway. We conclude that modulation of IL-6 mediated survival signaling pathways involving the p38 MAPK or downstream targets such as Mcl-1 may prove useful therapeutic strategies for human cholangiocarcinoma.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/patologia , Colangiocarcinoma/patologia , Regulação Neoplásica da Expressão Gênica , Interleucina-6/metabolismo , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Ativação Transcricional , Animais , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/metabolismo , Ductos Biliares Intra-Hepáticos/metabolismo , Sobrevivência Celular/genética , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Inativação Gênica , Humanos , Interleucina-6/genética , Camundongos , Proteína de Sequência 1 de Leucemia de Células Mieloides , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Transdução de Sinais , Transcrição Genética , Transformação Genética , Células Tumorais Cultivadas , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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