RESUMO
Cholangiocarcinoma (CCA) is one of the most difficult malignancies to treat as the therapeutic options are limited. Although several driver genes have been identified, most remain unknown. In this study, we identified a failed axon connection homolog (FAXC), whose function is unknown in mammals, by analyzing serially passaged CCA xenograft models. Knockdown of FAXC reduced subcutaneous tumorigenicity in mice. FAXC was bound to annexin A2 (ANXA2) and c-SRC, which are tumor-promoting genes. The FAXC/ANXA2/c-SRC complex forms in the mitochondria. FAXC enhances SRC-dependent ANXA2 phosphorylation at tyrosine-24, and the C-terminal amino acid residues (351-375) of FAXC are required for ANXA2 phosphorylation. Transcriptome data from a xenografted CCA cell line revealed that FAXC correlated with epithelial-mesenchymal transition, hypoxia, and KRAS signaling genes. Collectively, these findings advance our understanding of CCA tumorigenesis and provide candidate therapeutic targets.
Assuntos
Anexina A2 , Neoplasias dos Ductos Biliares , Carcinogênese , Colangiocarcinoma , Mitocôndrias , Quinases da Família src , Animais , Humanos , Masculino , Camundongos , Anexina A2/metabolismo , Anexina A2/genética , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/genética , Carcinogênese/genética , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Colangiocarcinoma/metabolismo , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Camundongos Nus , Mitocôndrias/metabolismo , Fosforilação , Transdução de Sinais , Quinases da Família src/metabolismo , Quinases da Família src/genéticaRESUMO
Cholangiocarcinoma is a fatal disease with limited therapeutic options. We screened genes required for cholangiocarcinoma tumorigenicity and identified FADS2, a delta-6 desaturase. FADS2 depletion reduced in vivo tumorigenicity and cell proliferation. In clinical samples, FADS2 was expressed in cancer cells but not in stromal cells. FADS2 inhibition also reduced the migration and sphere-forming ability of cells and increased apoptotic cell death and ferroptosis markers. Lipidome assay revealed that triglyceride and cholesterol ester levels were decreased in FADS2-knockdown cells. The oxygen consumption ratio was also decreased in FADS2-depleted cells. These data indicate that FADS2 depletion causes a reduction in lipid levels, resulting in decrease of energy production and attenuation of cancer cell malignancy.
RESUMO
Gastric cancer is the fifth most common malignancy worldwide. However, targeted therapy for advanced gastric cancer is still limited. Here, we report BEX2 (Brain expressed X-linked 2) as a poor prognostic factor in two gastric cancer cohorts. BEX2 expression was increased in spheroid cells, and its knockdown decreased aldefluor activity and cisplatin resistance. BEX2 was found to upregulate CHRNB2 (Cholinergic Receptor Nicotinic Beta 2 Subunit) expression, a cancer stemness-related gene, in a transcriptional manner, and the knockdown of which also decreases aldefluor activity. Collectively, these data are suggestive of the role of BEX2 in the malignant process of gastric cancer, and as a promising therapeutic target.
Assuntos
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Prognóstico , Linhagem Celular Tumoral , Oncogenes , Proteínas do Tecido Nervoso/metabolismoRESUMO
In this study, a 76-year-old man initially diagnosed with branch-duct pancreatic intraductal papillary mucinous tumor is presented. During follow-up, stenosis was discovered in the main pancreatic duct of the tail. A nodular lesion was found in the pancreatic duct consistent with the stenosis. Distal pancreatectomy was performed since it was suspected to be malignant. Histopathology revealed polymorphic mononuclear cells proliferated with osteoclast-like giant cells in the nodule. The patient was finally diagnosed with anaplastic pancreatic cancer with osteoclast-like giant cells, a relatively rare tumor. It is reported herein with a review of the literature.
Assuntos
Adenocarcinoma Mucinoso , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Adenocarcinoma Mucinoso/diagnóstico por imagem , Adenocarcinoma Mucinoso/cirurgia , Idoso , Carcinoma Ductal Pancreático/diagnóstico por imagem , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/cirurgia , Constrição Patológica , Seguimentos , Células Gigantes/patologia , Humanos , Masculino , Osteoclastos/patologia , Pancreatectomia , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/cirurgia , Neoplasias PancreáticasRESUMO
Cancer stem cells (CSCs) are responsible for therapy resistance and share several properties with normal stem cells. Here, we show that brain-expressed X-linked gene 2 (BEX2), which is essential for dormant CSCs in cholangiocarcinoma, is highly expressed in human hepatocellular carcinoma (HCC) lesions compared with the adjacent normal lesions and that in 41 HCC cases the BEX2high expression group is correlated with a poor prognosis. BEX2 localizes to Ki67-negative (nonproliferative) cancer cells in HCC tissues and is highly expressed in the dormant fraction of HCC cell lines. Knockdown of BEX2 attenuates CSC phenotypes, including sphere formation ability and aldefluor activity, and BEX2 overexpression enhances these phenotypes. Moreover, BEX2 knockdown increases cisplatin sensitivity, and BEX2 expression is induced by cisplatin treatment. Taken together, these data suggest that BEX2 induces dormant CSC properties and affects the prognosis of patients with HCC.
Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Idoso , Aldeído Desidrogenase/metabolismo , Animais , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Colangiocarcinoma/metabolismo , Cisplatino/farmacologia , Feminino , Inativação Gênica , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Proteínas do Tecido Nervoso/genética , Organoides , Prognóstico , Esferoides CelularesRESUMO
Cancer stem cells (CSCs) are believed to cause cancer metastasis and recurrence. BEX2 (brain expressed X-linked gene 2) is a CSC-related gene that is expressed in dormant CSCs in cholangiocarcinoma and induces resistance against chemotherapy. The aim of the present study was to identify small compounds that have activity to inhibit BEX2 expression and result in the attenuation of CSC-related phenotypes. We screened 9600 small chemical compounds in high-throughput screening using cholangiocarcinoma cell line HuCCT1 expressing BEX2 protein fused with NanoLuc, and identified a compound, BMPP (1, 3-Benzenediol, [4-(4-methoxyphenyl)-1H-pyrazol-3-yl]). BMPP was found to exert decreasing effects on BEX2 protein expression and G0 phase population of the tumor cells, and increasing effects on ATP levels and chemotherapeutic sensitivity of the cells. These findings indicate that BMPP is a valuable chemical compound for reducing dormant CSC-related phenotypes. Thus, the identification of BMPP as a potential CSC suppressor provides scope for the development of novel therapeutic modalities for the treatment of cancers with BEX2 overexpressing CSCs.
Assuntos
Antineoplásicos/análise , Antineoplásicos/farmacologia , Descoberta de Drogas , Células-Tronco Neoplásicas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Antineoplásicos/química , Linhagem Celular Tumoral , Ensaios de Triagem em Larga Escala , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Accumulating evidence indicates that CD109, a glycosylphosphatidylinositol-anchored glycoprotein, is highly expressed in human epithelial carcinomas of multiple organs including the pancreas, but its functional role in carcinoma development has not yet been fully clarified. The aim of this study was to investigate the role of CD109 in the malignancy of pancreatic ductal adenocarcinoma (PDAC). METHODS: PDAC specimens of 145 cases were immunostained for CD109, and correlations between CD109 expression and clinicopathological conditions were analyzed. CD109 expression in PANC-1 cells, a PDAC-derived cell line, was decreased by siRNA or shRNA and its effect on the malignancy of PANC-1 cells was examined. RESULTS: Suppression of CD109 expression in PANC-1 cells resulted in reduction of in vitro cell motility and tumorigenicity in xenografts. Based on these results, we investigated the relationship between CD109 expression and metastasis of PDAC using tumor tissue specimens. Among 106 recurrent cases of 145 PDAC, there was a tendency for CD109-positive cases to be accompanied by distant metastasis. CONCLUSIONS: CD109 plays a critical role in the promotion of tumorigenic ability and cellular motility relating to metastasis of PDAC cells.
Assuntos
Antígenos CD/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Proteínas de Neoplasias/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Proteínas Ligadas por GPI/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , RNA Interferente Pequeno/farmacologia , Cicatrização , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
It is important to determine the genotypes or serotypes of hepatitis C virus (HCV) in patients before treatment with direct-acting antiviral agents (DAAs), because the effects of DAAs differ among genotypes. In Japan, two tests for HCV typing are available clinically, but only serotyping, not genotyping, is approved by the public health insurance. Although most serotype-1 Japanese patients are infected with genotype 1b HCV, it is known that a small proportion of patients show different results from two typing methods. This study focused on such patients and the effectiveness of treatment with daclatasvir plus asunaprevir (DCV/ASV) was evaluated. We analyzed 644 DCV/ASV-treated patients with serotype 1 or genotype 1b, and among them, 166 serotype-1 patients received a commercial-based direct sequencing (DS) test for resistant-associated variants of genotype 1b HCV. We found four patients (2.4%) with DS test failure, suggesting that the PCR primers targeting genotype 1b may not match. Importantly, none of the four patients achieved a sustained virological response. Our in-house DS test analyzing the 5'-untranslated region and coding regions for NS4 and NS5B of HCV showed that three of the four patients were infected with genotype 2 HCV, and one patient was infected with genotype 1a HCV. No recombinant virus of different genotypes was found. This study indicates that a subset of serotype-1 hepatitis C patients is infected with HCV of genotype 2 or 1a in Japan and that DCV/ASV is not effective for such patients. Thus, attention should be paid to DAA treatment without HCV genotyping.
Assuntos
Hepacivirus/classificação , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Imidazóis/uso terapêutico , Isoquinolinas/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Carbamatos , Progressão da Doença , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/efeitos dos fármacos , Hepacivirus/isolamento & purificação , Humanos , Imidazóis/farmacologia , Isoquinolinas/farmacologia , Masculino , Pessoa de Meia-Idade , Filogenia , Pirrolidinas , Sorotipagem , Sulfonamidas/farmacologia , Fatores de Tempo , Resultado do Tratamento , Valina/análogos & derivados , Proteínas não Estruturais Virais/genéticaRESUMO
BACKGROUND: The genotype B of hepatitis B virus (HBV) was reported to associate with fulminant hepatitis (FH). We aimed to clarify the characteristics of HBV obtained from FH patients in an area of Japan where genotype B HBV is prevalent. METHODS: Using serum samples of 16 HBV-associated FH patients, partial HBV sequences were determined. The effects of HBV mutation/insertion/deletion were evaluated using an in vitro HBV replication system. RESULTS: Of the 16 HBV isolates, 31% belonged to subgenotype B1/Bj, 38% were subgenotype B2/Ba, and 31% were subgenotype C2/Ce. Notably, the single nucleotide insertion/deletion that resulted in a frameshift of the precore protein was found exclusively in 60% of B1/Bj strains. An in vitro study showed that all of the frameshift mutants had significantly higher amounts of HBV DNA than did the wild type. One of the isolates had a novel insertion of A between nucleotides 1900 and 1901, which resulted in a 3-nucleotide change within the Kozak sequence of the core protein and enhanced the core protein expression in vitro. CONCLUSIONS: The frameshift insertion/deletion in the precore region enhanced HBV replication and might be associated with the development of FH by the subgenotype B1/Bj HBV.
Assuntos
Mutação da Fase de Leitura/genética , Vírus da Hepatite B/genética , Vírus da Hepatite B/fisiologia , Falência Hepática Aguda/virologia , Replicação Viral , Adulto , Idoso , DNA Viral/metabolismo , Feminino , Genótipo , Células Hep G2 , Vírus da Hepatite B/patogenicidade , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Mutagênese Insercional/genética , Análise de Sequência de DNA , Deleção de Sequência/genética , Proteínas do Core Viral/genética , Proteínas do Core Viral/metabolismoRESUMO
Organ allocation in Japan remains difficult due to the shortage of deceased-donor livers. The screening tool for controlling nutritional status (CONUT) has been considered to be an established assessment model for evaluating nutritional aspects in surgical patients. However, the application of this CONUT for evaluating the prognosis of patients with end-stage liver diseases has not been evaluated. We assessed the predictability of the prognoses of 58 patients with end-stage liver disease using various prognostic models. The patients registered at the transplantation center of Tohoku University Hospital for the waiting list of Japan Organ Transplant Network for liver transplantation were retrospectively analyzed. The prognoses of the patients were evaluated using the following 5 models: CONUT, the model for ELD with incorporation of sodium (MELD-Na), Child-Turcotte-Pugh score (CTP), prognostic nutritional indices (Onodera: PNI-O), and the Japan Medical Urgency criteria of the liver (JMU). Cox's proportional hazard model, log-rank test and concordance(c)-static were used for the statistics. The indices were 17.74 ± 5.80 for MELD-Na, 9.21 ± 2.19 for CTP, 33.92 ± 11.16 for PNI-O, and 7.57 ± 3.09 for CONUT. Univariate analysis revealed the significance of CONUT (p = 0.017, Odds: 1.325) but not MELD-Na, CTP, JMU or PNI-O for prediction. The cumulative survival rate was clearly discriminated at CONUT point 7. The c-static was 0.081 for the 6-month (M) survival rate, 0.172 for 12M, 0.517 for 36M, 0.821 for 48M, and 0.938 for 60M for CONUT. In conclusion, CONUT shows best predictability for the distant prognoses of patients with ELD.
Assuntos
Doença Hepática Terminal/diagnóstico , Doença Hepática Terminal/epidemiologia , Avaliação Nutricional , Estado Nutricional , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Curva ROC , Análise de Sobrevida , Fatores de TempoRESUMO
BACKGROUND: HBcAg-specific regulatory T (T(reg)) cells play an important role in the pathogenesis of chronic hepatitis B. Soluble heat shock proteins, especially soluble heat shock protein 60 (sHSP60), could affect the function of T(reg) cells via Toll-like receptor. METHODS: We analyzed the relationship between soluble heat shock protein production and hepatitis B virus (HBV) replication with both clinical samples from HBeAg-positive patients with chronic hepatitis B (n= 24) and HBeAb-positive patients with chronic hepatitis B (n= 24) and in vitro HBV-replicating hepatocytes. Thereafter, we examined the biological effects of sHSP60 with isolated T(reg) cells. RESULTS: The serum levels of sHSP60 in patients with chronic hepatitis B were statistically significantly higher than those in patients with chronic hepatitis C (P<.01), and the levels of sHSP60 were correlated with the HBV DNA levels (r = 0.532; P<.001) but not with the alanine aminotransferase levels. Moreover, the levels of sHSP60 in HBV-replicating HepG2 cells were statistically significantly higher than those in control HepG2 cells. Preincubation of CD4(+) CD25(+) cells with recombinant HSP60 (1 ng/mL) statistically significantly increased the frequency of HBcAg-specific interleukin 10-secreting T(reg) cells. The frequency of IL7R(-)CD4(+)CD25(+) cells, the expression of Toll-like receptor 2, and the suppressive function of T(reg) cells had declined during entecavir treatment. CONCLUSION: The function of HBcAg-specific T(reg) cells was enhanced by sHSP60 produced from HBV-infected hepatocytes. Entecavir treatment suppressed the frequency and function of T(reg) cells; this might contribute to the persistence of HBV infection.
Assuntos
Chaperonina 60/genética , Vírus da Hepatite B/imunologia , Vírus da Hepatite B/fisiologia , Hepatócitos/fisiologia , Linfócitos T Reguladores/imunologia , Adulto , Células Apresentadoras de Antígenos/imunologia , Antígenos Virais/imunologia , Carcinoma Hepatocelular/imunologia , Linhagem Celular Tumoral , Chaperonina 60/sangue , Chaperonina 60/farmacologia , DNA Viral/sangue , Feminino , Genótipo , Antígenos do Núcleo do Vírus da Hepatite B/imunologia , Antígenos E da Hepatite B/análise , Vírus da Hepatite B/genética , Hepatite B Crônica/sangue , Hepatite B Crônica/genética , Hepatite B Crônica/imunologia , Hepatócitos/virologia , Humanos , Tolerância Imunológica , Interleucina-10/metabolismo , Neoplasias Hepáticas/imunologia , Masculino , Plasmídeos/genética , Proteínas Recombinantes/farmacologia , Linfócitos T Reguladores/virologia , TransfecçãoRESUMO
BACKGROUND & AIMS: Excessive trans-fatty acids (TFA) consumption has been thought to be a risk factor mainly for coronary artery diseases while less attention has been paid to liver disease. We aimed to clarify the impact of TFA-rich oil consumption on the hepatic pathophysiology compared to natural oil. METHODS: Mice were fed either a low-fat (LF) or high-fat (HF) diet made of either natural oil as control (LF-C or HF-C) or partially hydrogenated oil, TFA-rich oil (LF-T or HF-T) for 24 weeks. We evaluated the liver and body weight, serological features, liver lipid content and composition, liver histology and hepatic lipid metabolism-related gene expression profile. In addition, primary cultures of mice Kupffer cells (KCs) were evaluated for cytokine secretion and phagocytotic ability after incubation in cis- or trans-fatty acid-containing medium. RESULTS: The HF-T-fed mice showed significant increases of the liver and body weights, plasma alanine-aminotransferase, free fatty acid and hepatic triglyceride content compared to the HF-C group, whereas the LF-T group did not differ from the LF-C group. HF-T-fed mice developed severe steatosis, along with increased lipogenic gene expression and hepatic TFA accumulation. KCs showed increased tumor necrosis factor secretion and attenuated phagocytotic ability in the TFA-containing medium compared to its cis-isomer. CONCLUSIONS: Excessive consumption of the TFA-rich oil up-regulated the lipogenic gene expression along with marked hepatic lipid accumulation. TFA might be pathogenic through causing severe steatosis and modulating the function of KCs. The quantity and composition of dietary lipids could be responsible for the pathogenesis of non-alcoholic steatohepatitis.
Assuntos
Gorduras na Dieta/metabolismo , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Ácidos Graxos trans/metabolismo , Adipocinas/metabolismo , Animais , Células Cultivadas , Citocinas/metabolismo , Gorduras na Dieta/efeitos adversos , Modelos Animais de Doenças , Fígado Gorduroso/fisiopatologia , Feminino , Células de Kupffer/citologia , Células de Kupffer/efeitos dos fármacos , Células de Kupffer/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/fisiologia , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Fagocitose/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ácidos Graxos trans/efeitos adversos , Ácidos Graxos trans/farmacologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Although chronic infection of hepatitis B virus (HBV) is currently managed with nucleot(s)ide analogues or interferon-alpha, the control of HBV infection still remains a clinical challenge. Peroxisome proliferator-activated receptor (PPAR) is a ligand-activated transcription factor, that plays a role in glucose and lipid metabolism, immune reactions, and inflammation. In this study, the suppressive effect of PPAR ligands on HBV replication was examined in vitro using a PPARalpha ligand, bezafibrate, and a PPARgamma ligand, rosiglitazone. The effects were examined in HepG2 cells transfected with a plasmid containing 1.3-fold HBV genome. Whereas bezafibrate showed no effect against HBV replication, rosiglitazone reduced the amount of HBV DNA, hepatitis B surface antigen, and hepatitis B e antigen in the culture supernatant. Southern blot analysis showed that the replicative intermediates of HBV in the cells were also inhibited. It was confirmed that GW9662, an antagonist of PPARgamma, reduced the suppressive effect of rosiglitazone on HBV. Moreover, rosiglitazone showed a synergistic effect on HBV replication with lamivudine or interferon-alpha-2b. In conclusion, this study showed that rosiglitazone inhibited the replication of HBV in vitro, and suggested that the combination therapy of rosiglitazone and nucleot(s)ide analogues or interferon could be a therapeutic option for chronic HBV infection.
Assuntos
Antivirais/farmacologia , Vírus da Hepatite B/efeitos dos fármacos , PPAR gama/agonistas , Tiazolidinedionas/farmacologia , Replicação Viral/efeitos dos fármacos , Antivirais/uso terapêutico , Quimioterapia Combinada , Hepatite B/tratamento farmacológico , Vírus da Hepatite B/genética , Humanos , Interferon-alfa/farmacologia , Interferon-alfa/uso terapêutico , Lamivudina/farmacologia , Lamivudina/uso terapêutico , Ligantes , Rosiglitazona , Tiazolidinedionas/uso terapêuticoRESUMO
Cancer stem cells (CSCs) define a subpopulation of cancer cells that are resistant to therapy. However, little is known of how CSC characteristics are regulated. We previously showed that dormant cancer stem cells are enriched with a CD274low fraction of cholangiocarcinoma cells. Here we found that BEX2 was highly expressed in CD274low cells, and that BEX2 knockdown decreased the tumorigenicity and G0 phase of cholangiocarcinoma cells. BEX2 was found to be expressed predominantly in G0 phase and starvation induced the USF2 transcriptional factor, which induced BEX2 transcription. Comprehensive screening of BEX2 binding proteins identified E3 ubiquitin ligase complex proteins, FEM1B and CUL2, and a mitochondrial protein TUFM, and further demonstrated that knockdown of BEX2 or TUFM increased mitochondria-related oxygen consumption and decreased tumorigenicity in cholangiocarcinoma cells. These results suggest that BEX2 is essential for maintaining dormant cancer stem cells through the suppression of mitochondrial activity in cholangiocarcinoma.
Assuntos
Neoplasias dos Ductos Biliares/metabolismo , Colangiocarcinoma/metabolismo , Regulação Neoplásica da Expressão Gênica , Mitocôndrias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Proteínas Culina/genética , Proteínas Culina/metabolismo , Humanos , Mitocôndrias/genética , Mitocôndrias/patologia , Proteínas do Tecido Nervoso/genética , Consumo de Oxigênio/fisiologiaRESUMO
BACKGROUND: Recent studies have shown that indigenous hepatitis E virus (HEV) strains cause hepatitis E in industrialized countries. We aimed to clarify the characteristics of HEV infection in sporadic hepatitis patients during the last decade in Miyagi, northeast Japan. METHODS: We analyzed 94 serum samples obtained from acute or fulminant hepatitis patients of non-A, non-B, and non-C etiology between 1999 and 2008. Antibody to HEV (anti-HEV) was assayed, and patients who were positive for IgM- and/or IgA-class anti-HEV were diagnosed with hepatitis E. HEV RNA was tested in these patients, and phylogenetic analysis was performed. The occurrence of hepatitis E was compared with that of hepatitis A. RESULTS: Eight acute hepatitis patients (8.5%) were diagnosed with hepatitis E, and HEV RNA was detectable in seven patients. Five isolates of HEV were segregated into genotype 3 and the remaining two isolates into genotype 4. The year of the occurrence of hepatitis E was distributed almost equally from 1999 to 2008, whereas the cases of acute hepatitis A (n = 16) have decreased markedly in the last several years. In 2004-2008, the occurrence of hepatitis E was greater than that of hepatitis A (five cases vs. one case). As for seasonality, hepatitis E occurred more frequently from September to December than hepatitis A (five cases vs. four cases), although less frequently from January to April (one case vs. seven cases). CONCLUSION: The occurrence of hepatitis E has not decreased during the last decade in northeast Japan, in contrast to hepatitis A.
Assuntos
Vírus da Hepatite E/imunologia , Hepatite E/epidemiologia , RNA Viral/sangue , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Genótipo , Hepatite A/epidemiologia , Hepatite E/imunologia , Vírus da Hepatite E/genética , Humanos , Imunoglobulina A/sangue , Imunoglobulina M/sangue , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Estações do Ano , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND: Many studies have reported the efficiency of transient elastography, a noninvasive, reproducible, and reliable method for predicting liver fibrosis, in patients with chronic hepatitis C (CHC) and B (CHB), but there are few reports about nonviral chronic liver disease (CLD) such as primary biliary cirrhosis (PBC), nonalcoholic steatohepatitis (NAFLD), and autoimmune hepatitis (AIH). We therefore compared the efficiency of transient elastography between CHC and nonviral CLD. METHODS: We assessed the accuracy of liver stiffness measurement (LSM) using Fibroscan, and compared these values with those of hyaluronic acid, type 4 collagen, platelet count, prothrombin index, and AST/platelet ratio index (APRI) as indices for the diagnosis of liver fibrosis in 114 patients with a variety of chronic liver diseases: CHC (n = 51), CHB (n = 11), NAFLD (n = 17), PBC (n = 20), and AIH (n = 15). The histology was assessed according to the METAVIR score by two pathologists. RESULTS: The number of fibrosis stage (F0/1/2/3/4) with CHC was 9/15/12/6/10, and that with nonviral CLD was 10/21/11/4/6, respectively. The ability, assessed by area under receiver operating characteristic (AUROC) curve, to predict liver fibrosis F >or= 2 for LSM, HA, type 4 collagen, platelet count, prothrombin index, and APRI, was 0.92, 0.81, 0.87, 0.85, 0.85, and 0.92 in CHC patients, respectively; and 0.88, 0.72, 0.81, 0.67, 0.81, and 0.77 in nonviral CLD patients, respectively. CONCLUSIONS: In patients with nonviral CLD, LSM was most helpful in predicting significant fibrosis (F >or= 2). Transient elastography is a reliable method for predicting significant liver fibrosis, not only in CHC patients but also in nonviral CLD patients.
Assuntos
Técnicas de Imagem por Elasticidade , Cirrose Hepática/diagnóstico , Fígado/patologia , Biópsia por Agulha , Fígado Gorduroso/diagnóstico , Fígado Gorduroso/patologia , Feminino , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/patologia , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/patologia , Hepatite Autoimune/diagnóstico , Hepatite Autoimune/patologia , Humanos , Cirrose Hepática Biliar/diagnóstico , Cirrose Hepática Biliar/patologia , Masculino , Pessoa de Meia-Idade , Curva ROC , Sensibilidade e EspecificidadeRESUMO
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.
RESUMO
A 27-year-old Caucasian female with hepatitis C virus (HCV) infection treated with interferon (IFN) who developed severe autoimmune hepatitis (AIH) is described. The infecting viral strain was of genotype Ib and the pre-treatment HCV viral load was at a high level. The patient was treated with pegylated IFN-alpha 2b and ribavirin, and her HCV-RNA became negative at wk 12, but after that she developed fulminant hepatic failure. The patient recovered after steroid pulse therapy consisting of methylprednisolone 1000 mg/d for three days which was administered twice. A needle liver biopsy revealed the typical pathological findings of AIH.
Assuntos
Antivirais/efeitos adversos , Hepatite C/complicações , Hepatite Autoimune/etiologia , Interferon-alfa/efeitos adversos , Falência Hepática Aguda/induzido quimicamente , Ribavirina/uso terapêutico , Adulto , Antivirais/uso terapêutico , Biópsia , Quimioterapia Combinada , Feminino , Hepatite C/tratamento farmacológico , Hepatite Autoimune/diagnóstico , Humanos , Interferon alfa-2 , Interferon-alfa/uso terapêutico , Fígado/patologia , Falência Hepática Aguda/diagnóstico , Polietilenoglicóis , Proteínas RecombinantesRESUMO
Hepatitis B virus (HBV) reactivation from resolved infection is a serious problem which can frequently lead to severe hepatitis. Generally, it occurs several months after the start of immunosuppressive therapy; however, it sometimes occurs a few years later, even after cessation of therapy. Here we report a patient with de novo HBV infection who had received corticosteroid therapy for pemphigus vulgaris for 6 years. Full-genome HBV sequence analysis using serial serum samples revealed that the patient was infected with HBV subgenotype C2, which had the G1896R mixed mutation in the precore region. Interestingly, it had the immune escape mutations P120A and G145R in the S gene. Because both hepatitis B surface antigen and antibodies to hepatitis B surface antigen (HBsAb) were positive at the onset of the de novo infection, it was considered that HBV with these mutations escaped from neutralization by the pre-existing HBsAbs. This case indicates that HBV reactivation with an immune escape mutant can occur long after immunosuppressive therapy.
Assuntos
Corticosteroides/efeitos adversos , Vírus da Hepatite B/genética , Hepatite B/imunologia , Hepatite B/virologia , Imunossupressores/efeitos adversos , Mutação , Ativação Viral , Corticosteroides/administração & dosagem , Idoso , Esquema de Medicação , Humanos , Imunossupressores/administração & dosagem , Masculino , Pênfigo/tratamento farmacológico , FilogeniaRESUMO
BACKGROUND AND AIMS: The innate immune cells can not normally respond to the pathogen in patients with decompensated cirrhosis. Previous studies reported that antigen-presenting cells take up L-Cystine (L-Cys) and secrete substantial amounts of L-Glutamate (L-Glu) via the transport system Xc- (4F2hc+xCT), and that this exchange influences the immune responses. The aim of this study is to investigate the influence of the plasma L-Cys/L-Glu imbalance observed in patients with advanced cirrhosis on the function of circulating monocytes. METHODS: We used a serum-free culture medium consistent with the average concentrations of plasma amino acids from patients with advanced cirrhosis (ACM), and examined the function of CD14+ monocytes or THP-1 under ACM that contained 0-300 nmol/mL L-Cys with LPS. In patients with advanced cirrhosis, we actually determined the TNF-alpha and xCT mRNA of monocytes, and evaluated the correlation between the plasma L-Cys/L-Glu ratio and TNF-alpha. RESULTS: The addition of L-Cys significantly increased the production of TNF alpha from monocytes under ACM. Monocytes with LPS and THP-1 expressed xCT and a high level of extracellular L-Cys enhanced L-Cys/L-Glu antiport, and the intracellular GSH/GSSG ratio was decreased. The L-Cys transport was inhibited by excess L-Glu. In patients with advanced cirrhosis (nâ=â19), the TNF-alpha and xCT mRNA of monocytes were increased according to the Child-Pugh grade. The TNF-alpha mRNA of monocytes was significantly higher in the high L-Cys/L-Glu ratio group than in the low ratio group, and the plasma TNF-alpha was significantly correlated with the L-Cys/L-Glu ratio. CONCLUSIONS: A plasma L-Cys/L-Glu imbalance, which appears in patients with advanced cirrhosis, increased the TNF-alpha from circulating monocytes via increasing the intracellular oxidative stress. These results may reflect the immune abnormality that appears in patients with decompensated cirrhosis.