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OBJECTIVES: Pegylated interferon α-2b (PegIFNα-2b) therapy can help inactive hepatitis B surface antigen (HBsAg) carriers (IHCs) achieve clinical cure. To explore and compare the efficacy, safety, and relevant influential factors of PegIFNα-2b monotherapy and PegIFNα-2b-based immunotherapy for IHCs. METHODS: This exploratory, prospective, single-center, randomized controlled trial enrolled 40 IHCs who were randomized into group A (PegIFNα-2b treatment for 68 weeks) and group B (two cycles of PegIFNα-2b treatment with a lead-in period of GM-CSF and vaccine treatment before each cycle). The primary endpoint was 68-week HBsAg loss rate. RESULTS: At week 68, the HBsAg loss rates were 45.45% [full analysis set (FAS)] and 46.67% [per-protocol set (PPS)]. There was no statistically significant difference in HBsAg loss rate between groups A and B ( Pâ >â 0.05). Univariate analysis revealed that age ≤40 years old, baseline HBsAg <200â IU/ml, and 24-week HBsAg decline ≥2 log 10 IU/ml were significantly associated with HBsAg loss in FAS population ( P â <â 0.05). Multivariate analysis showed that only 24-week HBsAg decline ≥2 log 10 IU/ml was the independent influencing factor in both FAS and PPS populations ( P â <â 0.05). The adverse events were common and mild, and the therapies were well-tolerated. CONCLUSION: Treatment of IHCs with PegIFNα-2b-based therapy could result in a high HBsAg loss rate. The HBsAg loss rate of combined immunotherapy was similar to that of PegIFNα-2b monotherapy, and the safety was good. CLINICALTRIALSGOV ID: NCT05451420.
Assuntos
Antígenos de Superfície da Hepatite B , Hepatite B Crônica , Humanos , Adulto , Antivirais/efeitos adversos , Estudos Prospectivos , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/efeitos adversos , Polietilenoglicóis/efeitos adversos , Imunoterapia , Proteínas Recombinantes/efeitos adversos , Resultado do Tratamento , Antígenos E da Hepatite B , Vírus da Hepatite BRESUMO
Activation of hepatic stellate cells (HSCs) is an important event during the progress of liver fibrosis. MicroRNA (miR)-15b and miR-16 have been found to be involved in activation of HSCs. However, the roles of miR-15b/16 in liver fibrosis remain unclear. The expression of miR-15b/16 was decreased in TGF-ß1-stimulated LX-2 cells. Overexpression of miR-15b/16 in LX-2 cells suppressed TGF-ß1-induced cell proliferation and the expression levels of tissue inhibitor of metalloproteinase type 1, collagen type I, and α-smooth muscle actin. The activation of Smad2/3 caused by TGF-ß1 was repressed by miR-15b/16 overexpression. The two miRNAs directly bound to the 3'-UTR of lysyl oxidase-like 1 (LOXL1) and suppressed the LOXL1 expression. Furthermore, knockdown of LOXL1 attenuated miR-15b/16 downregulation-induced cell proliferation, fibrogenic response and phosphorylation of Smad2/3. Collectively, miR-15b/16 exhibited anti-fibrotic activity through regulation of Smad2/3 pathway.
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Aminoácido Oxirredutases/genética , MicroRNAs/genética , Regiões 3' não Traduzidas/genética , Aminoácido Oxirredutases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Colágeno Tipo I/metabolismo , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Células Estreladas do Fígado/metabolismo , Humanos , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , MicroRNAs/metabolismo , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
BACKGROUND: Patients on oral antiviral (OAV) therapy remain at hepatocellular carcinoma (HCC) risk. Risk prediction tools distinguishing treated patients with residual HCC risk are limited. The aim of this study was to develop an accurate, precise, simple-to-use HCC risk score using routine clinical variables among a treated Asian cohort. METHODS: Adult Asian chronic hepatitis B (CHB) patients on OAV were recruited from 25 centers in the United States and the Asia-Pacific region. Excluded persons were coinfected with hepatitis C, D, or human immunodeficiency virus, had HCC before or within 1 year of study entry, or their follow-up was <1 year. Patients were randomized to derivation and validation cohorts on a 2:1 ratio. Statistically significant predictors from multivariate modeling formed the Real-world Effectiveness from the Asia Pacific Rim Liver Consortium for HBV (REAL-B) score. RESULTS: A total of 8048 patients were randomized to the derivation (n = 5365) or validation group (n = 2683). The REAL-B model included 7 variables (male gender, age, alcohol use, diabetes, baseline cirrhosis, platelet count, and alpha fetoprotein), and scores were categorized as follows: 0-3 low risk, 4-7 moderate risk, and 8-13 high risk. Area under receiver operating characteristics were >0.80 for HCC risk at 3, 5, and 10 years, and these were significantly higher than other risk models (p < .001). CONCLUSIONS: The REAL-B score provides 3 distinct risk categories for HCC development in Asian CHB patients on OAV guiding HCC surveillance strategy.
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Antivirais/efeitos adversos , Antivirais/uso terapêutico , Carcinoma Hepatocelular/etiologia , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Neoplasias Hepáticas/etiologia , Projetos de Pesquisa , Administração Oral , Adulto , Antivirais/administração & dosagem , Ásia/etnologia , Povo Asiático , Estudos de Coortes , DNA Viral/genética , Confiabilidade dos Dados , Feminino , Hepatite B Crônica/etnologia , Hepatite B Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Curva ROC , Distribuição Aleatória , Medição de RiscoRESUMO
MicroRNAs (miRs) are important regulators of the tumorigenesis and metastasis of various cancers. In the present study, the roles and underlying mechanisms of miR4255p in the development of hepatocellular carcinoma (HCC) were investigated. RTqPCR analysis revealed that miR4255p was upregulated in HCC tissues and cell lines. A functional study in vitro using MTT assays, colony formation and Transwell assays demonstrated that overexpression of miR4255p promoted the proliferation, migration, and invasion of HCC cells, prevented cell apoptosis and accelerates the epithelialmesenchymal transition process, whereas miR4255p knockdown induced opposing effects. A further mechanistic study revealed that forkhead box D3 (FOXD3) was a direct target of miR4255p, and gain and lossoffunction of FOXD3 studies demonstrated that FOXD3 suppressed HCC cell proliferation, migration, and invasion. Furthermore, rescue experiments revealed that overexpression of FOXD3 counteracted the positive effects of miR4255p on HCC malignant behaviors. Collectively, the present results demonstrated that miR4255p promoted HCC cell proliferation, migration, and invasion by suppressing FOXD3 expression, potentially providing a novel target for the treatment of HCC.
Assuntos
Carcinoma Hepatocelular/genética , Fatores de Transcrição Forkhead/genética , Neoplasias Hepáticas/genética , MicroRNAs/genética , Idoso , Apoptose , Carcinogênese/genética , Carcinoma Hepatocelular/patologia , Movimento Celular/genética , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologiaRESUMO
BACKGROUND: PEST-containing nuclear protein (PCNP), a novel nuclear protein, is involved in cell proliferation and tumorigenesis. However, the precise mechanism of action of PCNP in the process of tumor growth has not yet been fully elucidated. METHODS: ShRNA knockdown and overexpression of PCNP were performed in human neuroblastoma cells. Tumorigenic and metastatic effects of PCNP were examined by tumor growth, migration, and invasion assays in vitro, as well as xenograft tumor assay in vivo. RESULTS: PCNP over-expression decreased the proliferation, migration, and invasion of human neuroblastoma cells and down-regulation of PCNP showed reverse effects. PCNP over-expression increased protein expressions of cleaved caspase-3, cleaved caspase-8, cleaved caspase-9, and cleaved poly adenosine diphosphate-ribose polymerase, as well as ratios of B-cell lymphoma-2 (Bcl-2)-associated X protein/Bcl-2 and Bcl-2-associated death promoter/B-cell lymphoma-extra large in human neuroblastoma cells, however PCNP knockdown exhibited reverse trends. PCNP over-expression increased phosphorylations of extracellular signal-regulated protein kinase 1/2, p38, c-Jun N-terminal kinase, as well as decreased phosphorylations of phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR), nevertheless PCNP knockdown exhibited opposite effects. Furthermore, PCNP over-expression significantly reduced the growth of human neuroblastoma xenograft tumors by down-regulating angiogenesis, whereas PCNP knockdown markedly promoted the growth of human neuroblastoma xenograft tumors through up-regulation of angiogenesis. CONCLUSIONS: PCNP mediates the proliferation, migration, and invasion of human neuroblastoma cells through mitogen-activated protein kinase and PI3K/AKT/mTOR signaling pathways, implying that PCNP is a therapeutic target for patients with neuroblastoma.
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Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neuroblastoma/metabolismo , Proteínas Nucleares/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Apoptose/genética , Movimento Celular/genética , Proliferação de Células , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Imuno-Histoquímica , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neuroblastoma/genética , Neuroblastoma/patologia , Proteínas Nucleares/genéticaRESUMO
In the previous study, it was found that long intergenic noncoding RNA-p21 (lincRNA-p21) was downregulated in hepatocellular carcinoma (HCC) and lincRNA-p21 overexpression inhibited tumor invasion through inducing epithelial-mesenchymal transition. However, the underlying mechanism was not fully elaborated. In this study, lincRNA-p21 expression was measured in 12 paired HCC and nontumor adjacent normal tissues by quantitative real-time polymerase chain reaction. The effects of lincRNA-p21 on HCC cells were studied using lentivirus expressing lincRNA-p21 vector in vitro. The association between lincRNA-p21 level and miR-9 level was tested with the Spearman rank correlation. The effects of miR-9 on HCC cells were studied by using miR-9 inhibitor in vitro. Luciferase assay was used to validate the target of miR-9. The results showed that lincRNA-p21 was downregulated in human HCC tissues and cell lines. LincRNA-p21 overexpression significantly inhibited HCC cell migration and invasion in vitro. Besides, lincRNA-p21 negatively regulated miR-9 expression level, and miR-9 was upregulated in human HCC tissues and cells. MiR-9 knockdown inhibited HCC cell migration and invasion in vitro. Finally, the luciferase assay results showed that E-cadherin was a direct target of miR-9. The expression level of E-cadherin was found to be regulated by lincRNA-p21 and miR-9. Altogether, the results suggested that lincRNA-p21 inhibits migration and invasion of HCC cells through regulating miR-9-mediated E-cadherin cascade signaling pathway.
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OBJECTIVE: To investigate the effects of adefovir dipivoxil (ADV) on blood phosphorus metabolism in patients with chronic hepatitis B (CHB). METHODS: Patients with hepatitis B surface antigen (HBsAg)-positive CHB were treated with ADV alone, ADV combined with interferon (IFN), or ADV combined with lamivudine (LAM). Changes in levels of calcium, phosphate, urea, and creatinine were assessed at treatment weeks 4, 12, 24, 48, 72 and 96. Statistical analysis was carried out with SPSS 16 software; influential factors were analyzed by ANOVA and non-conditional logistic regression analysis. RESULTS: During the course of treatments, 32 (42.6%) of the patients presented with low phosphorus. The highest incidence of low phosphorus was found to have occurred at treatment week 24 (25.0%, 27.5% and 36.4% respectively, with no statistical difference between three groups, x2=0.225, P>0.225). Patients with hypophosphatemia did not show a significant difference in serum phosphorus levels from the other patients (F=1.853, P=0.169). Logistic regression showed a correlation between low phosphorus and sex (x2=7.876, P<0.05), age (t=2.479, P<0.05), and serum creatinine (t =-2.256, P<0.05), but not with blood urea nitrogen or blood calcium (P>0.05). CONCLUSION: ADV antiviral treatment can decrease the blood phosphorous levels of CHB patients, particularly over extended time of treatment, and the occurrence of low phosphorus is more common than of mild phosphorus decrease.Male and elderly patients may be at greater risk of this complication. The incidence and severity of low phosphorus is not significantly different for the different ADV-based treatment regimens.
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Hepatite B Crônica , Adenina/análogos & derivados , Idoso , Antivirais , Creatinina , Quimioterapia Combinada , Humanos , Interferons , Lamivudina , Masculino , Organofosfonatos , FósforoRESUMO
Staphylococcus sciuri subsp. sciuri strain Z8 was isolated from a skin wound infection of a patient with infective endocarditis. To the best of our knowledge, the genome sequence of the species S. sciuri has not been previously studied. The complete genome sequence of strain Z8 includes a genome of 2,620,868 bp (32.43% GC content) without any plasmids.
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OBJECTIVE: To explore the clinical features and gene mutation profiles of patients with chronic hepatitis B (CHB) and Gilbert's syndrome. METHODS: Thirty-three patients with CHB and Gilbert's syndrome were enrolled in the study. Serum markers of liver function and histological features of disease-related liver injury were assessed by standard methods. Gene mutations were detected by PCR and direct DNA sequencing.Statistical analysis was carried out with the chi-square and t tests. RESULTS: Sequencing of the Gilbert syndrome-associated gene, UGT 1A 1, revealed mutations in the upstream promoter phenobarbital-responsive element module (PBREM) (-3279 mutation, 23 cases), in the promoter TATA box (a TA insertion mutation, 21 cases), and in the coding region of exon 1 (a GGA-AGA Gly71Arg mutation, 18 cases); there was no statistical difference found for any of the three mutations among this patient population (x2 =1.640, P more than 0.05). CONCLUSION: The traditional methods of diagnosis for patients with CHB and Gilbert's syndrome remain a technical challenge in the clinic, and gene detection may represent a more favorable method for diagnosing this patient population.