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1.
Arch Virol ; 165(1): 33-42, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31630275

RESUMO

Hepatocellular carcinoma (HCC) is a major public health issue in Africa. In Tunisia, hepatitis B virus (HBV) is known to be an important risk factor for HCC in the south of the country, but the role played by hepatitis C virus (HCV) still remains unclear. The aim of the current case-control study was to identify risk factors for HCC development in the northern part of the country. Clinical and biological data including viral hepatitis status (serological and molecular) and non-infectious risk factors from 73 patients with HCC and 70 control subjects without hepatic diseases were collected. The mean age of the patients was 63 ± 10 years, and the ratio of males to females was 1.1. HCC occurred in cirrhotic liver in 72.0% of the cases. HCV infection was the dominant risk factor (64.3% of cases); the presence of HBV was observed in 53.4% of the cases. Occult hepatitis B and C were implicated, respectively, in 30.1% and 9.6% of the cases. HCV genotype 1b was predominant. Patients originating from western Tunisia formed a homogeneous group, characterized by significantly higher rates of tattoos or scarifications (83%) and HCV infection (80%) than those from other parts of the country. Chronic HCV infection is currently the primary risk factor for HCC in Tunisia; HBV infection remains frequent in its overt or occult infection forms. Traditional esthetic practices apparently contribute to increasing the burden of terminal liver diseases in western Tunisia.


Assuntos
Carcinoma Hepatocelular/epidemiologia , Hepatite B/epidemiologia , Hepatite C/epidemiologia , Cirrose Hepática/virologia , Neoplasias Hepáticas/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/virologia , Estudos de Casos e Controles , Feminino , Genótipo , Hepatite B/complicações , Hepatite C/complicações , Humanos , Cirrose Hepática/complicações , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Medição de Risco , Tunísia/epidemiologia
2.
J Surg Res ; 245: 302-308, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31421377

RESUMO

BACKGROUND: Epithelial-mesenchymal transition genes have prognostic influence on hepatocellular carcinoma (HCC). Previously, the following four epithelial-mesenchymal transition-related genes were considered to be significantly influential: E-cadherin (CDH1), inhibitor of DNA binding 2 (ID2), matrix metalloproteinase 9 (MMP9), and transcription factor 3 (TCF3). A prognostic prediction model, NRISK4 = (-0.333 × [CDH1] - 0.400 × [ID2] + 0.339 × [MMP9] + 0.387 × [TCF3]) was constructed, but from patients with HCC with predominantly hepatitis B virus infection. We therefore aim to validate if this model also fits patients with HCC and hepatitis C virus (HCV) infection. METHODS: We collected HCC tissue samples from 67 patients with HCV infection. Discrimination of the NRISK4 was re-estimated using receiver operating curve analysis and we redefined the appropriate cutoff value. Using this cutoff value, patients were divided into two groups (high/low risk patients) and we compared their clinicopathological factors and prognosis. RESULTS: Area under the curve of NRISK4 prediction was 0.70 and an appropriate cutoff value was 3.19 in this cohort. Patients were divided into high- (n = 25) and low-risk (n = 42) patients for prognosis. There were no significant differences in tumor factors between the two groups. Cancer-specific survival rates at 5 y after surgery on high- and low-risk patients were 45% and 68%, respectively (P = 0.02). At 2 y after surgery, recurrence rates were 68% and 37% among high- and low-risk patients, respectively (P = 0.01). Aggressive recurrences were highly observed in the high-risk patients (P = 0.01). CONCLUSIONS: NRISK4 model could also successfully validate prognosis of patients with HCC with HCV infection similarly to in the previous report of patients with hepatitis B virus infection, especially in the early period after surgery.


Assuntos
Carcinoma Hepatocelular/mortalidade , Transição Epitelial-Mesenquimal/genética , Hepatite C/complicações , Neoplasias Hepáticas/mortalidade , Recidiva Local de Neoplasia/epidemiologia , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/cirurgia , Carcinoma Hepatocelular/virologia , Intervalo Livre de Doença , Feminino , Seguimentos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Hepatectomia , Hepatite C/genética , Hepatite C/virologia , Humanos , Fígado/patologia , Fígado/cirurgia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/virologia , Masculino , Valor Preditivo dos Testes , Prognóstico , Medição de Risco/métodos , Fatores de Risco , Taxa de Sobrevida
3.
Gene ; 724: 144157, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31629820

RESUMO

Cellular microRNAs are known to modulate the life-cycle of different viruses. Surprisingly, very little data exists on AAV-induced changes to the cellular microRNAome in general and in hepatic and retinal cells, in particular. We reasoned that inducible microRNA in response to recombinant AAV infection may regulate immediate and long-lived cellular responses necessary for the cell's own survival as well as its ability to control several aspects of viral life-cycle. To study this, we performed a global small RNA sequencing analysis in Adeno-associated virus (AAV) serotypes 2 and 3 infected hepatic and retinal cell models. This screen identified multiple differentially expressed microRNAs, in AAV infected Huh-7 and ARPE-19 cells. Among these, one microRNA (miR-4488) was found to be significantly down regulated (-2.24 fold for AAV2 and -3.32 fold for ARPE-19) in AAV infected cells. An enrichment and pathway analysis of miR-4488 predicted its possible effects on gene targets involved in multiple biological processes including cell-cycle regulation, endoplasmic reticulum stress response and lipid-signalling pathways. Moreover, validation studies in miR-4488 mimic or sponge transfected cells revealed modulation of these target pathways in a cell-specific manner. Further studies demonstrated that overexpression of miR-4488, modestly increased gene expression (126-128%) from AAV2 and AAV3 vectors in Huh-7 cells whereas miR-4488 inhibition in ARPE-19 cells had a similar increase (142-158%) on AAV2 or AAV3 transduction. Our results highlight that recombinant AAV mediated microRNA expression is cell-type and serotype-specific and can target specific host cellular biological pathways.


Assuntos
Dependovirus/genética , MicroRNAs/genética , Infecções por Parvoviridae/genética , Epitélio Pigmentado da Retina/virologia , Transdução Genética/métodos , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Ciclo Celular/genética , Linhagem Celular , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático/genética , Perfilação da Expressão Gênica , Humanos , Metabolismo dos Lipídeos/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Parvovirinae/genética , Reprodutibilidade dos Testes , Epitélio Pigmentado da Retina/citologia , Transgenes
4.
Gastroenterology ; 158(1): 215-225.e6, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31574268

RESUMO

BACKGROUND & AIMS: There have been conflicting results from studies comparing the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection treated with tenofovir disoproxil fumarate (TDF) vs those treated with entecavir. We compared the effects of TDF vs entecavir on HCC risk in a large cohort of patients with chronic HBV infection in China. METHODS: We performed a retrospective study of consecutive adults with chronic HBV infection who initially received treatment with entecavir or TDF, for at least 6 months, from January 2008 through June 2018. Patients who had cancers or liver transplantation before or within the first 6 months of treatment were excluded. Propensity score weighting and 1:5 matching were used to balance the clinical characteristics between the 2 groups. Fine-Gray model was used to adjust for competing risk of death and liver transplantation. RESULTS: We analyzed data from 29,350 patients (mean age, 52.9 ± 13.2 years; 18,685 men [63.7%]); 1309 were first treated with TDF (4.5%) and 28,041 were first treated with entecavir (95.5%). TDF-treated patients were younger (mean age, 43.2 years vs 53.4 years) and a lower proportion had cirrhosis (38 patients [2.9%] vs 3822 patients treated with entecavir [13.6%]). At a median follow-up time of 3.6 years after treatment began (interquartile range, 1.7-5.0 years), 8 TDF-treated patients (0.6%) and 1386 entecavir-treated patients (4.9%) developed HCC. Patients' clinical characteristics were comparable after propensity score weighting. TDF treatment was associated with a lower risk of HCC than entecavir treatment after propensity score weighting (weighted subdistribution hazard ratio, 0.36; 95% confidence interval 0.16-0.80; P = .013) and 1:5 matching (weighted subdistribution hazard ratio, 0.39; 95% confidence interval 0.18-0.84; P = .016). CONCLUSIONS: In a retrospective analysis of 29,350 patients with chronic HBV infection in China, treatment with TDF was associated with a lower risk of HCC than treatment with entecavir, over a median follow-up time of 3.6 years.


Assuntos
Antivirais/administração & dosagem , Carcinoma Hepatocelular/prevenção & controle , Guanina/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Neoplasias Hepáticas/prevenção & controle , Tenofovir/administração & dosagem , Adulto , Assistência ao Convalescente , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/virologia , China/epidemiologia , Progressão da Doença , Feminino , Guanina/administração & dosagem , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/patologia , Hepatite B Crônica/virologia , Humanos , Incidência , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/virologia , Cirrose Hepática/epidemiologia , Cirrose Hepática/prevenção & controle , Cirrose Hepática/virologia , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
5.
BMC Med Genet ; 20(1): 201, 2019 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-31864292

RESUMO

BACKGROUND: Vitamin D derivatives and their receptor (VDR) are potent modulators of immune responses in various diseases including malignancies as well as in metabolic and infectious disorders. The impact of vitamin D receptor polymorphisms on clinical outcomes of hepatitis B virus (HBV) infection is not well understood. This study aims to investigate the potential role of VDR polymorphisms (TaqI, FokI, ApaI, and BsmI) in Vietnamese HBV infected patients and to correlate these polymorphisms with the progression of HBV-related liver disease. METHODS: Four hundred forty-three HBV infected patients of the three clinically well-defined subgroups chronic hepatitis B (CHB, n = 183), liver cirrhosis (LC, n = 89) and hepatocellular carcinoma (HCC, n = 171) and 238 healthy individuals (HC) were enrolled. VDR polymorphisms were genotyped by DNA sequencing and in-house validated ARMS assays. Logistic regression models were applied in order to determine the association of VDR polymorphisms with manifest HBV infection as well as with progression of related liver diseases mulin different genetic models. RESULTS: The VDR ApaI CA genotype was less frequent in HCC than in CHB patients in different genetic models (codominant model, OR = 0.5, 95%CI = 0.3-0.84, P = 0.004; dominant model, OR = 0.46, 95%CI = 0.27-0.76, P = 0.0023). In the recessive model, the genotype ApaI AA was found more frequently among HCC compared to CHB patients (OR = 2.56, 95%CI = 1.01-6.48, P = 0.04). Similarly, the ApaI CA genotype was less frequent in HCC than in non-HCC group codominant model, OR = 0.6, 95%CI = 0.4-0.98, dominant model, P = 0.04 and OR = 0.6, 95%CI = 0.38-0.90, P = 0.017). The ApaI genotypes CA and AA was significantly associated with higher levels of liver enzymes, bilirubin, and HBV DNA (P < 0.05). No association between TaqI, FokI and BsmI polymorphisms and any clinical outcome as well as liver disease progression was found. CONCLUSIONS: Among the four investigated VDR polymorphisms, ApaI is associated with clinical outcome and liver disease progression in Vietnamese HBV infected patients.


Assuntos
Carcinoma Hepatocelular/genética , Desoxirribonucleases de Sítio Específico do Tipo II/metabolismo , Vírus da Hepatite B/isolamento & purificação , Neoplasias Hepáticas/genética , Polimorfismo de Nucleotídeo Único , Receptores de Calcitriol/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Estudos de Casos e Controles , Progressão da Doença , Genótipo , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Vietnã
6.
Medicine (Baltimore) ; 98(44): e17867, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31689880

RESUMO

AIMS: Interleukin(IL)-22 plays an important role in promoting liver regeneration and repair, but its role in chronic HBV-related liver diseasesis not clear. The goal of this study was to evaluate associations between eight IL22 single nucleotide polymorphisms (SNPs) and the development of chronic HBV cirrhosis and HBV-related HCC within a Chinese Han population. METHODS: We investigated associations between single nucleotide polymorphisms (SNPs) in the IL22 gene (rs1026788, rs2227472, rs2227491, rs2227485, rs1179249, rs2046068,rs2227473, and rs7314777) and the risk of HBV-related chronic liver diseases within a Han population in Northeast China. A total of 649 participants were included in the study, including 103 patients with CHB, 264 patients with LC, and 282 patients with HCC. The odds ratios (OR) and corresponding 95% confidence intervals (CI) were calculated using chi-square test. Haplotype analysis was conducted by haploview software. RESULTS: Genotype and allele distributions of SNPs rs1179249 and rs2227472 differed between LC and CHB groups (both P < 0.05).The G alleles of SNP rs2227491 and rs1026788 were more frequent in the LC group than in the CHB group (P = 0.046, P = 0.041 respectively). A IL22 haplotype consisting of the minor alleles of SNP rs1179249 and the major alleles of seven other SNPs occurred less frequently in the LC and HCC groups than in the CHB group (28.2%, 33.94%, and 37.86%, respectively, P < 0.05). Moreover, there were no significant associations between smoking or drinking and IL22 SNPs on the risk of HCC (P > 0.05). CONCLUSION: IL22 genetic variations were associated with chronic HBV infection progression, especially in the HBV-LC group. The IL22 genetic variations may help clinicians initiate the correct treatment strategy at the CHB stage.


Assuntos
Carcinoma Hepatocelular/virologia , Hepatite B Crônica/genética , Interleucinas/genética , Cirrose Hepática/virologia , Neoplasias Hepáticas/virologia , Polimorfismo de Nucleotídeo Único , Adulto , Consumo de Bebidas Alcoólicas/efeitos adversos , Grupo com Ancestrais do Continente Asiático/genética , Carcinoma Hepatocelular/genética , Estudos de Casos e Controles , Progressão da Doença , Feminino , Hepatite B Crônica/complicações , Humanos , Cirrose Hepática/genética , Neoplasias Hepáticas/genética , Masculino , Pessoa de Meia-Idade , Mutação Puntual , Estudos Retrospectivos , Fumar/efeitos adversos
7.
Cancer Treat Rev ; 81: 101907, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31715422

RESUMO

The aberrant activation of RAS-derived mitogen-activated protein kinase (MAPK) signaling pathway plays a prominent role in tumorigenesis of an array of malignancies. The reasons are usually the upstream activated mutations including mitogen-activated protein kinase kinase 1/2 (MEK1/2). As oncogenic mutations, MEK1 mutations have been observed in a variety of malignancies including melanoma, histiocytic neoplasms, colorectal cancer and lung cancer. Presently, the use of trametinib, a highly selective MEK1/2 inhibitor, was limited to BRAF mutations, according to the approvals of FDA. Therefore, we consider that this is a question worth studying that whether malignancies with MEK1 mutations are sensitive to the treatment of trametinib. This review discussed the function of MEK1 mutations, retrieved the frequency and distribution of MEK1 mutations in various malignancies, and reviewed the basic experiments and clinical case reports on trametinib in the treatment of cell lines or patients with MEK1 mutations. Most studies have demonstrated that trametinib was effective to cells or tumor patients harboring MEK1 mutations, which suggest that the MEK1 mutations might be potential indications of trametinib therapy. In addition, it was also reported that resistance was observed in the treatment of trametinib, suggesting that different MEK1 mutations may have different response to trametinib, and further studies are necessary to distinguish that which MEK1 mutations are appropriate for the treatment with trametinib and which are not.


Assuntos
Antineoplásicos/uso terapêutico , MAP Quinase Quinase 1/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Animais , Antineoplásicos/farmacologia , Grupo com Ancestrais do Continente Asiático/genética , Histiocitose de Células de Langerhans/tratamento farmacológico , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 1/metabolismo , Camundongos , Células NIH 3T3 , Neoplasias/tratamento farmacológico , Neoplasias/genética , Inibidores de Proteínas Quinases/farmacologia , Piridonas/farmacologia , Pirimidinonas/farmacologia
8.
BMC Infect Dis ; 19(1): 875, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640596

RESUMO

BACKGROUND: Hepatitis C virus (HCV) infection is a major cause of chronic liver disease globally. Direct acting antivirals (DAAs) have proven effective in curing HCV. However, the current standard of care (SOC) in Botswana remains PEGylated interferon-α (IFN-α) with ribavirin. Several mutations have been reported to confer resistance to interferon-based treatments. Therefore, there is a need to determine HCV genotypes in Botswana, as these data will guide new treatment guidelines and understanding of HCV epidemiology in Botswana. METHODS: This was a retrospective cross-sectional pilot study utilizing plasma obtained from 55 participants from Princess Marina Hospital in Gaborone, Botswana. The partial core region of HCV was amplified, and genotypes were determined using phylogenetic analysis. RESULTS: Four genotype 5a and two genotype 4v sequences were identified. Two significant mutations - K10Q and R70Q - were observed in genotype 5a sequences and have been associated with increased risk of hepatocellular carcinoma (HCC), while R70Q confers resistance to interferon-based treatments. CONCLUSION: Genotypes 5a and 4v are circulating in Botswana. The presence of mutations in genotype 5 suggests that some patients may not respond to IFN-based regimens. The information obtained in this study, in addition to the World health organization (WHO) recommendations, can be utilized by policy makers to implement DAAs as the new SOC for HCV treatment in Botswana.


Assuntos
Hepacivirus/genética , Hepatite C/virologia , Mutação , Filogenia , Adulto , Antivirais/uso terapêutico , Botsuana , Carcinoma Hepatocelular/virologia , Estudos Transversais , Farmacorresistência Viral , Feminino , Genótipo , Hepacivirus/efeitos dos fármacos , Hepacivirus/isolamento & purificação , Hepatite C/tratamento farmacológico , Humanos , Interferon-alfa/uso terapêutico , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Retrospectivos , Ribavirina/uso terapêutico
9.
Medicine (Baltimore) ; 98(43): e17394, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31651841

RESUMO

Child-Pugh (CP) grade A patients with early stage hepatocellular carcinoma (HCC) are candidates for curative surgery, while some patients still have a poor outcome. The aim of this study was to investigate the prognostic values of 2 new evaluation models for liver function, named albumin-bilirubin (ALBI) and platelet-albumin-bilirubin (PALBI) grades, in CP grade A patients with HCC.In this retrospective cohort study, we reviewed 134 cases of CP grade A patients with hepatitis B-associated HCC who underwent radical surgery. ALBI and PALBI grades were calculated based on preoperative serologic examinations. Overall survival (OS) and recurrence-free survival (RFS) were estimated by Kaplan-Meier curve and Cox regression. The prognostic performances of the models were estimated by using the concordance index (C-index).During a median follow-up time of 27 months, 27.6% (37/134) of patients died and 26.1% (35/134) experienced recurrence. Kaplan-Meier analyses showed that ALBI and PALBI grades were significantly associated with OS and RFS. Multivariate analyses further revealed that both ALBI and PALBI grades were independent predictors for survival. Furthermore, the prognostic values of the combination of tumor size with ALBI (C-index = 0.754, 95% confidence interval [CI]: 0.675-0.849) or with PALBI (C-index = 0.762, 95% CI: 0.664-0.844) may be comparable with both Barcelona Clinic Liver Cancer and Cancer of Liver Italian Program staging systems.The ALBI and PALBI grades, in particular the combination with tumor size, are effective models for discriminating survival in CP grade A patients with HCC.


Assuntos
Bilirrubina/sangue , Plaquetas/metabolismo , Carcinoma Hepatocelular/mortalidade , Hepatectomia/mortalidade , Neoplasias Hepáticas/mortalidade , Albumina Sérica/análise , Adulto , Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/virologia , Feminino , Hepatite B/complicações , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do Tratamento
10.
Zhonghua Gan Zang Bing Za Zhi ; 27(9): 721-724, 2019 Sep 20.
Artigo em Chinês | MEDLINE | ID: mdl-31594101

RESUMO

Clinically, hepatocellular carcinoma (HCC) is one of the most common malignant tumors with a high rate of morbidity and mortality. Hepatitis B virus infection is the main cause of hepatocellular carcinoma in China and it is a serious threat to people's health. Antiviral drugs such as nucleos(t)ide analogues and interferon can inhibit viral replication and liver fibrosis progression and reduce the occurrence of hepatitis B-related HCC. This article reviews the effects of different antiviral therapy on the occurrence of hepatitis B-related hepatocellular carcinoma in recent years.


Assuntos
Antivirais/uso terapêutico , Carcinoma Hepatocelular/virologia , Hepatite B/tratamento farmacológico , Neoplasias Hepáticas/virologia , China , Vírus da Hepatite B , Humanos , Cirrose Hepática/prevenção & controle , Cirrose Hepática/virologia
11.
Rev Med Suisse ; 15(666): 1802-1806, 2019 Oct 09.
Artigo em Francês | MEDLINE | ID: mdl-31599521

RESUMO

Discovered in 1977, Hepatitis D is the most severe form of chronic hepatitis, with rapid development of cirrhosis, hepatic failure and hepatocellular carcinoma. Despite all this, it is still largely underdiagnosed and there is no standardised management. The current treatment options are scarce and bear frequent side-effects, but the early diagnosis and an optimal follow-up with identification of the patients suitable for treatment improve significantly their survival rate and quality of life. Moreover, new promising treatments are entering phase III trials and offer new perspectives for our patients.


Assuntos
Hepatite D/terapia , Carcinoma Hepatocelular/virologia , Ensaios Clínicos Fase III como Assunto , Hepatite D/diagnóstico , Humanos , Cirrose Hepática/virologia , Neoplasias Hepáticas/virologia , Taxa de Sobrevida
12.
Medicine (Baltimore) ; 98(38): e17275, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31568008

RESUMO

Single nucleotide polymorphisms (SNPs) of the interleukin 28B (IL28B) gene has proven to be associated with the clinical outcome of patients with chronic hepatitis virus B or C (HBV or HCV) infections. However, whether IL28B SNPs have an influence on the risk of hepatocellular carcinoma (HCC) among patients with HBV or HCV infection remains controversial. Therefore, this study aims to determine the association between IL28B polymorphisms and the risk of HCC in individuals with HBV or HCV infection.PubMed, EMBASE, and Chinese National Knowledge Infrastructure (CNKI) databases were used to identify studies meeting the selection requirements using the terms "interleukin 28B", "IFN-lambda-3", "IFNL3", "single nucleotide polymorphisms", "SNPs", "hepatocellular carcinoma", "HCC", "liver cancer".A total of 24 eligible original studies (1 cohort study and 23 case-control studies) involved 20238 individuals (HCC group = 8725 vs control group = 11,513) were included. Both IL28B rs12979860 CC and rs8099917 TT genotypes were significantly associated with a decreased risk of HCC among patients with HBV or HCV infection (OR = 0.71, 95% CI = 0.57-0.88; OR = 0.82, 95% CI = 0.72-0.94, respectively). Egger test and Begg test revealed no' publication bias (P > .05). Sensitivity analyses suggested the robustness of the results in this meta-analysis.Both IL28B rs12979860 CC and rs8099917 TT genotypes are protective factors for the development of HCC among patients with HBV or HCV infection. Future prospective studies examining the impact of IL28B polymorphisms on the risk of HCC and investigating the underlying mechanism for the protective role of IL28B polymorphisms in HCC development are warranted.


Assuntos
Carcinoma Hepatocelular/genética , Predisposição Genética para Doença/genética , Hepatite B/complicações , Hepatite C/complicações , Interferons/genética , Neoplasias Hepáticas/genética , Polimorfismo de Nucleotídeo Único/genética , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/virologia , Hepacivirus , Hepatite B/genética , Vírus da Hepatite B , Hepatite C/genética , Humanos , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/virologia
13.
Braz J Infect Dis ; 23(5): 343-351, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31542378

RESUMO

OBJECTIVE: The clinical significance of coexistence of HBsAg/anti-HBs in chronic hepatitis B (CHB) patients remains controversial. This study was aimed to assess the association of this serological pattern with hepatocellular carcinoma (HCC) in patients with CHB. METHODS: In this cross-section study, 206 CHB patients with coexistence of HBsAg/anti-HBs and 206 CHB patients with HBsAg alone were included to evaluate the risk of HCC development by logistic regression analysis. In addition, a retrospective cohort of 260 patients with CHB was recruited to estimate the cumulative incidence of HCC by Kaplan-Meier analysis. RESULTS: The serological pattern of coexistence of HBsAg/anti-HBs, with high levels of ("High") HBsAg/low levels of ("Low") anti-HBs, were considered as independent risk factors for HCC. In particular, patients with "High" HBsAg/"High" anti-HBs [odds ratio (OR), 4.295; 95% confidence interval (CI), 1.104-16.699; p = 0.035] and "Low" HBsAg/ "High" anti-HBs (OR, 3.207; 95%CI, 1.299-7.919; p = 0.012) exhibited significantly higher risk for HCC development. However, only "Low" HBsAg /"High" anti-HBs might increase risk of HCC in CHB patients with high HBV load (logrank p < 0.001) in our cohort study. CONCLUSION: The coexistence of "Low" HBsAg /"High" anti-HBs might increase the risk of HCC development in CHB patients with high HBV load, which reflected that the long-term interaction between immune response and virus might lead to the development of HCC. The identification of the patients with poor prognosis will help clinicians to refine the therapeutic decisions and individualize follow-up strategies.


Assuntos
Carcinoma Hepatocelular/virologia , Anticorpos Anti-Hepatite B/sangue , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/imunologia , Hepatite B Crônica/sangue , Neoplasias Hepáticas/virologia , Biomarcadores/sangue , Carcinoma Hepatocelular/sangue , Estudos Transversais , Progressão da Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/sangue , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Carga Viral
14.
Zhonghua Yi Xue Za Zhi ; 99(35): 2781-2784, 2019 Sep 17.
Artigo em Chinês | MEDLINE | ID: mdl-31550803

RESUMO

Objective: To explore the risk factors in HBV-associated hepatocellular carcinoma (HCC) patients with early recurrence after ablation and to establish predictive model. Methods: A total of 81 patients with HBV-related HCC who underwent ablation from January 2016 to December 2016 were included in Beijing Youan Hospital, including 66 males and 15 females. Standard medical records were collected, which were summarized as follows: demographic data, liver function, the number and size of tumors and the modality of ablation. Univariate and multivariate analysis were performed to identify the independent risk factors.The ROC curve was used to determine prognostic value. Cox proportional hazards model was used to establish predictive model, and the scores of risk factors were assigned according to HR value. Patients were divided into high-risk group and low-risk group in accordance with scores.The analysis of early recurrence rate was performed by the Kaplan-Meier method. Results: Tumor number, fibrinogen (Fib) and platelet-lymphocyte rate (PLR) were independently correlated with recurrence-free survival (RFS). The AUCs of Fib, PLR and Fib-PLR were 72.9%, 71.5% and 81.8%. The recurrence rates of the low-risk group were 4.9%,7.3% and 29.3% at 6 months,12 months and 24 months while 14.6%,43.9% and 78.1% in high-risk group. Two groups revealed statistically significant differences (all P<0.05). Conclusion: Tumor number, Fib, and PLR may be used as a set of predictive indicator of early recurrence in HBV-associated HCC patients after ablation.


Assuntos
Carcinoma Hepatocelular/sangue , Fibrinogênio/análise , Hepatite B/sangue , Neoplasias Hepáticas/sangue , Contagem de Linfócitos , Contagem de Plaquetas , Carcinoma Hepatocelular/virologia , Feminino , Humanos , Neoplasias Hepáticas/virologia , Masculino , Recidiva Local de Neoplasia , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos
15.
Nat Rev Gastroenterol Hepatol ; 16(10): 631-641, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31477873

RESUMO

Chronic hepatitis B virus (HBV) infection is a serious problem owing to its worldwide distribution and potential adverse sequelae that include cirrhosis and/or hepatocellular carcinoma. Current antiviral therapies have much improved outcomes, but few patients achieve the ultimate goal of hepatitis B surface antigen (HBsAg) loss (functional cure). As hepatitis B e antigen (HBeAg)-negative chronic HBV infection is the final phase prior to HBsAg loss, the management of patients in this phase together with quantification of HBsAg has attracted increasing clinical and research interest. This Review integrates the findings from research in HBsAg kinetics and discusses how they might inform our understanding and management of HBeAg-negative chronic HBV infection. Studies have shown that HBsAg levels are highly predictive of the presence of inactive HBV infection and that serial changes in HBsAg levels might predict HBsAg loss within 1-3 years. Data also suggest that quantitative HBsAg monitoring is important during hepatitis flare and antiviral therapy, especially in the timing of the decision to stop therapy and to start off-therapy retreatment. These findings have shed new light on the natural course of HBV infection and might lead to optimization of the management of HBeAg-negative chronic HBV infection and contribute to the paradigm shift from indefinite to finite therapy for patients with HBV infection.


Assuntos
Carcinoma Hepatocelular/virologia , Antígenos da Hepatite B/imunologia , Vírus da Hepatite B/fisiologia , Hepatite B Crônica/imunologia , Cirrose Hepática/virologia , Neoplasias Hepáticas/virologia , Antivirais/uso terapêutico , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/prevenção & controle , Progressão da Doença , Antígenos de Superfície da Hepatite B/imunologia , Antígenos E da Hepatite B/imunologia , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Humanos , Cirrose Hepática/imunologia , Cirrose Hepática/prevenção & controle , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/prevenção & controle
16.
Transplant Proc ; 51(7): 2397-2402, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31402255

RESUMO

PURPOSE: Despite advances in prevention techniques, screening, and new technologies in both diagnosis and treatment, the incidence and mortality of hepatocellular carcinoma (HCC) continue to rise. To obtain the best treatment result for HCC, early diagnosis is the key. In this study, we investigated the accuracy of noninvasive fibrosis markers, which have been typically used to predict liver fibrosis in recent years, in the prediction of HCC development in patients with chronic hepatitis B and chronic hepatitis B + D-induced cirrhosis. METHODS: Between 2004 and 2018, 1216 patients with chronic liver disease were retrospectively reviewed, and 331 patients (27%) with hepatitis B and hepatitis B+D virus-related cirrhosis were enrolled in our study. Patients were divided into 2 groups based on HCC diagnosis (HCC and non-HCC group). Eleven noninvasive fibrosis markers were evaluated in the groups. These markers included 3 alpha-fetoprotein (AFP)-based models (PAPAS index, Fibro-alpha, and BRC score) and 8 non-AFP based models (Lok index, FIB-4, Fibro-O index, APRI, King's score, Forns index, Bonacini score, and HUI model) for each Child-Pugh score in the prediction of HCC. RESULTS: AFP-based models were higher in HCC group patients, and statistically significant outcomes were detected with these methods in each Child-Pugh score group for HCC prediction (P < .05). Non-AFP based-methods showed different and inconsistent results in each Child-Pugh score group. CONCLUSION: These easily applied fibrosis markers, particularly AFP-based models, may provide an effective, simple, and low-cost way to predict HCC development in patients with hepatitis B and hepatitis B + D cirrhosis.


Assuntos
Carcinoma Hepatocelular/virologia , Hepatite B Crônica/complicações , Hepatite D Crônica/complicações , Cirrose Hepática/complicações , Neoplasias Hepáticas/virologia , Adulto , Biomarcadores/análise , Feminino , Humanos , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Resultado do Tratamento
17.
PLoS Pathog ; 15(8): e1007988, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31386698

RESUMO

Adeno-associated viruses (AAV) are Dependoparvoviruses that have shown promise as recombinant vectors for gene therapy. While infectious pathways of AAV are well studied, gaps remain in our understanding of host factors affecting vector genome expression. Here, we map the role of ring finger protein 121 (RNF121), an E3 ubiquitin ligase, as a key regulator of AAV genome transcription. CRISPR-mediated knockout of RNF121 (RNF121 KO) in different cells markedly decreased AAV transduction regardless of capsid serotype or vector dose. Recombinant AAV transduction is partially rescued by overexpressing RNF121, but not by co-infection with helper Adenovirus. Major steps in the AAV infectious pathway including cell surface binding, cellular uptake, nuclear entry, capsid uncoating and second strand synthesis are unaffected. While gene expression from transfected plasmids or AAV genomes is unaffected, mRNA synthesis from AAV capsid-associated genomes is markedly decreased in RNF121 KO cells. These observations were attributed to transcriptional arrest as corroborated by RNAPol-ChIP and mRNA half-life measurements. Although AAV capsid proteins do not appear to be direct substrates of RNF121, the catalytic domain of the E3 ligase appears essential. Inhibition of ubiquitin-proteasome pathways revealed that blocking Valosin Containing Protein (VCP/p97), which targets substrates to the proteasome, can selectively and completely restore AAV-mediated transgene expression in RNF121 KO cells. Expanding on this finding, transcriptomic and proteomic analysis revealed that the catalytic subunit of DNA PK (DNAPK-Cs), a known activator of VCP, is upregulated in RNF121 KO cells and that the DNA damage machinery is enriched at sites of stalled AAV genome transcription. We postulate that a network of RNF121, VCP and DNA damage response elements function together to regulate transcriptional silencing and/or activation of AAV vector genomes.


Assuntos
Carcinoma Hepatocelular/virologia , Proteína Quinase Ativada por DNA/metabolismo , Dependovirus/genética , Genoma Viral , Proteínas de Membrana/metabolismo , Transdução Genética , Proteína com Valosina/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proteína Quinase Ativada por DNA/genética , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteoma , Transcriptoma , Células Tumorais Cultivadas , Ubiquitina/metabolismo , Ubiquitinação , Proteína com Valosina/genética , Internalização do Vírus
18.
PLoS Pathog ; 15(8): e1007874, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31393946

RESUMO

Hepatitis B virus (HBV) is a common cause of liver diseases, including chronic hepatitis, steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). HBV chronically infects about 240 million people worldwide, posing a major global health problem. The current standard antiviral therapy effectively inhibits HBV replication but does not eliminate the virus unlike direct-acting antivirals (DAA) for curing hepatitis C. Our previous studies have demonstrated that human apolipoprotein E (apoE) plays important roles in hepatitis C virus infection and morphogenesis. In the present study, we have found that apoE is also associated with HBV and is required for efficient HBV infection. An apoE-specific monoclonal antibody was able to capture HBV similar to anti-HBs. More importantly, apoE monoclonal antibody could effectively block HBV infection, resulting in a greater than 90% reduction of HBV infectivity. Likewise, silencing of apoE expression or knockout of apoE gene by CRISPR/Cas9 resulted in a greater than 90% reduction of HBV infection and more than 80% decrease of HBV production, which could be fully restored by ectopic apoE expression. However, apoE silencing or knockout did not significantly affect HBV DNA replication or the production of nonenveloped (naked) nucleocapsids. These findings demonstrate that human apoE promotes HBV infection and production. We speculate that apoE may also play a role in persistent HBV infection by evading host immune response similar to its role in the HCV life cycle and pathogenesis. Inhibitors interfering with apoE biogenesis, secretion, and/or binding to receptors may serve as antivirals for elimination of chronic HBV infection.


Assuntos
Apolipoproteínas E/metabolismo , Carcinoma Hepatocelular/virologia , Anticorpos Anti-Hepatite B/imunologia , Vírus da Hepatite B/patogenicidade , Hepatite B/virologia , Neoplasias Hepáticas/virologia , Replicação Viral , Apolipoproteínas E/antagonistas & inibidores , Apolipoproteínas E/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Células Hep G2 , Hepatite B/complicações , Vírus da Hepatite B/imunologia , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , RNA Interferente Pequeno/genética
19.
Transplant Proc ; 51(7): 2482-2485, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31405736

RESUMO

BACKGROUND: Chronic hepatitis C virus (HCV) infection is a global health problem, and the need for liver transplants is ever-growing. For optimal surgical success, risk factors must be identified and HCV viral load must be reduced to a minimum to avoid complications. In this study, we aimed to investigate the role of HCV viral load on the post-transplant biliary complications. METHOD: Between 2004 and 2018, the cases of 114 liver transplant recipients with HCV infection were retrospectively reviewed. Data collection included demographic variables, preoperative and postoperative amount of serum HCV RNA copies, preoperative diagnosis of hepatocellular carcinoma (HCC), and postoperative biliary complications in the early and late period. After missing values were excluded, the remaining 97 patients were divided into 2 groups according to preoperative HCV RNA status (Group A: HCV RNA [+] and Group B: HCV RNA [-]). RESULTS: Demographic parameters were similar among both groups. There were 67 patients in Group A and 30 patients in Group B. The overall rate of biliary complications was higher in Group A without statistical significance (20% [n = 14] vs 13% [n = 4], respectively, P = .573). Biliary stricture occurrence in the late period was also higher in Group A. In HCC (+) patients (n = 26), biliary complications were significantly higher compared to HCC (-) patients (34% vs 12%, P = .018). However, in patients with biliary complications, the rate of multiple duct anastomoses was higher with no statistical significance (45% vs 26%, respectively, P = .14). CONCLUSION: The biliary complications on patient survival has been previously established, and this is mostly evident in those patients with viral etiology and hepatocellular carcinoma. As was also suggested in our study, hepatocellular carcinoma and positive viral status should be considered as predisposing factors for postoperative biliary complications after liver transplantation. However, the rate of multiple duct anastomoses should also be taken into consideration. New standards of antiviral medications and bridge therapy for HCC may improve transplant outcomes.


Assuntos
Carcinoma Hepatocelular/complicações , Hepatite C Crônica/virologia , Neoplasias Hepáticas/complicações , Transplante de Fígado/efeitos adversos , Complicações Pós-Operatórias/etiologia , Adulto , Idoso , Procedimentos Cirúrgicos do Sistema Biliar/efeitos adversos , Procedimentos Cirúrgicos do Sistema Biliar/métodos , Carcinoma Hepatocelular/cirurgia , Carcinoma Hepatocelular/virologia , Feminino , Hepacivirus , Hepatite C Crônica/complicações , Humanos , Incidência , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/virologia , Transplante de Fígado/métodos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Carga Viral
20.
Int J Mol Sci ; 20(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370326

RESUMO

Two polymorphisms in the promoter region of macrophage migration inhibitory factor (MIF) - rs755622 and rs5844572 - exhibit prognostic relevance in inflammatory diseases. The aim of this study was to investigate a correlation between these MIF promoter polymorphisms and the severity of hepatitis C virus (HCV)-induced liver fibrosis. Our analysis included two independent patient cohorts with HCV-induced liver fibrosis (504 and 443 patients, respectively). The genotype of the single nucleotide polymorphism (SNP) -173 G/C and the repeat number of the microsatellite polymorphism -794 CATT5-8 were determined in DNA samples and correlated with fibrosis severity. In the first cohort, homozygous carriers of the C allele in the rs755622 had lower fibrosis stages compared to heterozygous carriers or wild types (1.25 vs. 2.0 vs. 2.0; p = 0.03). Additionally, ≥7 microsatellite repeats were associated with lower fibrosis stages (

Assuntos
Carcinoma Hepatocelular/genética , Predisposição Genética para Doença , Hepatite C Crônica/genética , Oxirredutases Intramoleculares/genética , Cirrose Hepática/genética , Neoplasias Hepáticas/genética , Fatores Inibidores da Migração de Macrófagos/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/virologia , Estudos de Coortes , Técnicas de Imagem por Elasticidade , Feminino , Expressão Gênica , Frequência do Gene , Hepacivirus/patogenicidade , Hepacivirus/fisiologia , Hepatite C Crônica/complicações , Hepatite C Crônica/diagnóstico por imagem , Hepatite C Crônica/virologia , Heterozigoto , Homozigoto , Humanos , Fígado/metabolismo , Fígado/patologia , Fígado/virologia , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/etiologia , Cirrose Hepática/virologia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/virologia , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Polimorfismo Genético , Regiões Promotoras Genéticas , Índice de Gravidade de Doença
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