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2.
Nat Immunol ; 22(10): 1268-1279, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34556885

RESUMO

Metabolic inflammation is closely linked to obesity, and is implicated in the pathogenesis of metabolic diseases. FTO harbors the strongest genetic association with polygenic obesity, and IRX3 mediates the effects of FTO on body weight. However, in what cells and how IRX3 carries out this control are poorly understood. Here we report that macrophage IRX3 promotes metabolic inflammation to accelerate the development of obesity and type 2 diabetes. Mice with myeloid-specific deletion of Irx3 were protected against diet-induced obesity and metabolic diseases via increasing adaptive thermogenesis. Mechanistically, macrophage IRX3 promoted proinflammatory cytokine transcription and thus repressed adipocyte adrenergic signaling, thereby inhibiting lipolysis and thermogenesis. JNK1/2 phosphorylated IRX3, leading to its dimerization and nuclear translocation for transcription. Further, lipopolysaccharide stimulation stabilized IRX3 by inhibiting its ubiquitination, which amplified the transcriptional capacity of IRX3. Together, our findings identify a new player, macrophage IRX3, in the control of body weight and metabolic inflammation, implicating IRX3 as a therapeutic target.


Assuntos
Proteínas de Homeodomínio/metabolismo , Inflamação/metabolismo , Macrófagos/metabolismo , Obesidade/metabolismo , Fatores de Transcrição/metabolismo , Adipócitos/metabolismo , Adulto , Animais , Peso Corporal/fisiologia , Linhagem Celular , Diabetes Mellitus Tipo 2/metabolismo , Dieta/métodos , Células HEK293 , Humanos , Masculino , Doenças Metabólicas/metabolismo , Camundongos , Células RAW 264.7 , Células THP-1 , Termogênese/fisiologia , Transcrição Genética/fisiologia , Adulto Jovem
3.
J Transl Med ; 19(1): 389, 2021 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-34507559

RESUMO

BACKGROUND: Lung adenocarcinoma (LUAD) is a common subtype of lung cancer with high recurrence rate and fatality. Circ_0001361 has been recognized as key regulators in various malignancies, but its roles in LUAD remain ambiguous. METHODS: Circ_0001361, miR-525-5p, and VMA21 levels were assessed by RT-qPCR. The growth and metastasis of LUAD cells were detected by MTT, colony formation, wound scratch, and transwell assays, respectively. The interaction between circ_0001361/VMA21 and miR-525-5p was detected by dual luciferase, RNA immunoprecipitation, and RNA pull-down assays. VMA21 protein level was detected by Western blotting. Nude mouse xenograft model was established to determine the role of circ_0001361 in tumor growth in vivo. RESULTS: Circ_0001361 was up-regulated, while miR-525-5p was down-regulated in LUAD tissues and cells. Functional experiments demonstrated that circ_0001361 drove LUAD cell growth and metastasis. Mechanistically, circ_0001361 functioned as a sponge of miR-525-5p to up-regulate downstream target VMA21 level. MiR-525-5p/VMA21 axis was involved in circ_0001361-mediated malignant phenotypes of LUAD cells. Finally, inhibition of circ_0001361 restrained in vivo xenograft tumor growth via regulating miR-525-5p/VMA21 axis. CONCLUSION: Our findings elucidate that circ_0001361 facilitates the tumorigenesis and development of LUAD through miR-525-5p/VMA21 axis, providing evidence for circ_0001361 as a potential prognosis biomarker and therapeutic target for clinical treatment of LUAD.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , MicroRNAs/metabolismo , ATPases Vacuolares Próton-Translocadoras/metabolismo , Adenocarcinoma de Pulmão/genética , Animais , Humanos , Neoplasias Pulmonares/genética , Camundongos , MicroRNAs/genética , Recidiva Local de Neoplasia , RNA Circular , ATPases Vacuolares Próton-Translocadoras/genética
4.
Drug Des Devel Ther ; 15: 3605-3616, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34447241

RESUMO

Purpose: Prostate cancer (PCa) is the second leading cause of cancer-related death among men in developed countries. Cabazitaxel (CBZ) is recommended as one of the most active chemotherapy agents for PCa. This study aimed to develop a hyaluronic acid (HA) decorated, cabazitaxel-prodrug (HA-CBZ) and orlistat (ORL) co-loaded nano-system against the prostate cancer in vitro and in vivo. Methods: Cabazitaxel-prodrug was firstly synthesized by conjugating HA with CBZ through the formation of ester bonds. HA contained ORL and CBZ prodrug co-loaded lipid-polymer hybrid nanoparticles (ORL/HA-CBZ/LPNs) were constructed and characterized in terms of particle size, zeta potential, drug loading capacity and stability. The antitumor efficiency and systemic toxicity of LPNs were evaluated in vitro and in vivo. Results: The resulting ORL/HA-CBZ/LPNs were 150.9 nm in particle size with narrow distribution and high entrapment efficiency. The minimum combination index of 0.57 was found at a drug ratio of 1:2 (ORL:HA-CBZ, w/w) in the drug co-loaded formulations, indicating the strongest synergism effect. ORL/HA-CBZ/LPNs demonstrated an enhanced in vitro and in vivo antitumor effect compared with single drug loaded LPNs and free drug formulations. Conclusion: ORL/HA-CBZ/LPNs showed remarkable synergism cytotoxicity and the best tumor inhibition efficiency in mice with negligible systemic toxicity. ORL/HA-CBZ/LPNs can be highly useful for targeted prostate cancer therapy.

5.
Biomed Pharmacother ; 141: 111830, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34146851

RESUMO

Lung cancer treatment using cisplatin (DDP) in combination with other drugs are effective for the treatment of non-small cell lung cancer (NSCLC). The aim of this study was to prepare a layer-by-layer nanoparticles (NPs) for the co-loading of DDP and oridonin (ORI) and to evaluate the antitumor activity of the system in vitro and in vivo. Novel DDP and ORI co-loaded layer-by-layer NPs (D/O-NPs) were constructed. The mean diameter, surface change stability and drug release behavior of NPs were evaluated. In vitro cytotoxicity of D/O-NPs was investigated against DDP resistant human lung cancer cell line (A549/DDP cells), and in vivo anti-tumor efficiency of D/O-NPs was tested on mice bearing A549/DDP cells xenografts. D/O-NPs have a diameter of 139.6 ± 4.4 nm, a zeta potential value of +13.8 ± 1.6 mV. D/O-NPs could significantly enhance in vitro cell toxicity and in vivo antitumor effect against A549/DDP cells and lung cancer animal model compared to the single drug loaded NPs and free drugs. The results demonstrated that the D/O-NPs could be used as a promising lung cancer treatment system.

6.
Front Plant Sci ; 11: 600820, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33304374

RESUMO

The mammalian BREAST CANCER 2 (BRCA2) gene is a tumor suppressor that plays a crucial role in DNA repair and homologous recombination (HR). Here, we report the identification and characterization of OsBRCA2, the rice orthologue of human BRCA2. Osbrca2 mutant plants exhibit normal vegetative growth but experience complete male and female sterility as a consequence of severe meiotic defects. Pairing, synapsis and recombination are impaired in osbrca2 male meiocytes, leading to chromosome entanglements and fragmentation. In the absence of OsBRCA2, localization to the meiotic chromosome axes of the strand-invasion proteins OsRAD51 and OsDMC1 is severely reduced and in vitro OsBRCA2 directly interacts with OsRAD51 and OsDMC1. These results indicate that OsBRCA2 is essential for facilitating the loading of OsRAD51 and OsDMC1 onto resected ends of programmed double-strand breaks (DSB) during meiosis to promote single-end invasions of homologous chromosomes and accurate recombination. In addition, treatment of osbrca2-1 seedlings with mitomycin C (MMC) led to hypersensitivity. As MMC is a genotoxic agent that creates DNA lesions in the somatic cells that can only be repaired by HR, these results suggest that OsBRCA2 has a conserved role in DSB repair and HR in rice.

7.
J Cancer ; 11(17): 4933-4946, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32742441

RESUMO

Increasing studies on malignant tumors have proposed a new competing endogenous RNA (ceRNA) regulatory mechanism that mRNA, miRNA and lncRNA interact with each other. However, the mRNA-miRNA-lncRNA associated ceRNA network in gastric cancer remains unknown. We used online bioinformatic softwares to predict the hub genes and their upstream miRNAs and lncRNAs in gastric cancer, and then performed survival analyses. After collecting gastric cancer tissue samples and performing PCR experiments, the correlations among predicted mRNA, miRNA and lncRNA were further verified. A total of 101 up-regulated significant differentially expressed genes (DEGs) and 219 down-regulated significant DEGs in gastric cancer were confirmed. Functional enrichment analyses of these significant DEGs indicated that they were potentially enriched in some pathways involved in tumor malignant biological processes or metabolism. Then, we identified 20 hub genes in the PPI networks. Combined with expression and survival analyses, 8 up-regulated genes and 1 down-regulated gene were identified as central genes and acted as important prognostic roles in gastric cancer. 17 miRNAs were confirmed that might potentially regulate the expressions of these central genes. But only 8 out of them indicated better outcome in gastric cancer. Further, 79 lncRNAs were predicted that might have the potence to combine with the 8 central miRNAs. The lncRNA H19 was eventually defined as a central lncRNA by survival analyses. Stimultaneously, we found that there were certain interactions among lncRNA, miRNA and mRNAs in 50 gastric cancer tissues by qRT-PCR. Moreover, the high expression of H19 is associated with advanced TNM stage, primary tumor and lymph nodes, indicating a poor prognosis. In summary, we uncovered the prognostic value of COL3A1/FBN1/COL5A2/SPARC-mir-29a-3p-H19 ceRNA network in gastric cancer.

8.
Ital J Pediatr ; 46(1): 113, 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32758256

RESUMO

Hepatoblastoma (HB) is the most common malignant liver tumor in children. Abnormal activation of the Wnt/ß-catenin signaling pathway plays an important role in the formation and development of HB. Genes in HB show a global hypomethylation change, accompanied by hypermethylation of specific tumor suppressor genes (TSGs). This article reviews the hypermethylation changes in several TSGs, such as RASSF1A, SOCS1, APC, HHIP, and P16, and analyzes the pathways and mechanisms of TSGs regulating gene expression. The role of the methylation-regulating enzymes DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) family members enzymes in the methylation changes of HB was analyzed, and it was speculated that the occurrence of HB is partly due to the obstruction of liver differentiation in the early stage of differentiation. The origin cells may be incompletely differentiated hepatocytes remaining in the liver of children after birth. Therefore, further studying the role of methylation regulating enzymes in methylation changes in HB is a promising future research direction.


Assuntos
Metilação de DNA , Genes Supressores de Tumor/fisiologia , Hepatoblastoma/etiologia , Hepatoblastoma/patologia , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/patologia , Humanos
9.
Medicine (Baltimore) ; 98(42): e17590, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31626130

RESUMO

To date, a small number of studies concerning the effects and safety of tenofovir disoproxil fumarate (TDF) in Chinese individuals were conducted. In this study, we aimed to assess the antiviral effects and nephrotoxicity of TDF in Chinese patients with chronic hepatitis B virus (HBV) infection.Patients with chronic HBV infection were prospectively recruited and TDF treatment was given for 96 weeks. HBV serologic markers, HBV DNA, creatinine and phosphorus were collected.Fifty-seven treatment-naïve and 48 treatment-experienced patients were recruited. Irrespective of the prior treatment history, more than 95% of patients achieved virological response during 96 weeks treatment with TDF. Estimated glomerular filtration rate (eGFR) significantly declined in the first year of treatment in patients with chronic hepatitis B or younger age (<65 years old) (both P < .05), while that was not achieved in patients with liver cirrhosis or older age (≥65 years old) (both P > .05). For patients who were treatment-naïve or treated previously with adefovir dipivoxil, eGFR declined at the 48th week; however, eGFR was partially recovered at the 96th week. Furthermore, multivariable analysis showed that basal eGFR <90 mL/min/1.73 m (P = .001; odds ratio: 4.821; 95% confidence interval: 1.904-12.206) is the only independent risk factor for eGFR <90 mL/min/1.73 m at the 96th week.TDF has potent antiviral effect in both treatment-naïve and treatment-experienced patients.


Assuntos
Vírus da Hepatite B/fisiologia , Hepatite B Crônica/tratamento farmacológico , Tenofovir/uso terapêutico , Carga Viral , Adulto , Antivirais/uso terapêutico , China/epidemiologia , DNA Viral/análise , Feminino , Seguimentos , Antígenos E da Hepatite B/análise , Hepatite B Crônica/epidemiologia , Hepatite B Crônica/virologia , Humanos , Incidência , Masculino , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
10.
Cancer Sci ; 110(9): 2960-2972, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31301086

RESUMO

In recent years, circular RNAs (circRNAs) have been revealed to have important roles in carcinogenesis. Metastasis is the leading cause of lung adenocarcinoma (LUAC) death. However, the contributions of circRNA to the metastasis of LUAC remain largely unknown. Based on circBase data and our biobank tissues, we identified circCRIM1 (a circRNA derived from exons 2, 3 and 4 of the CRIM1 gene, hsa_circ_0002346) as having a significantly decreased expression in LUAC samples compared with matched normal control samples. Both in vivo and in vitro experiments revealed that circCRIM1 suppresses the invasion and metastasis of LUAC. In vitro precipitation of circRNAs, luciferase reporter assay, and biotin-coupled microRNA capture were carried out to investigate the Ago2-dependent interaction of circCRIM1 and microRNA (miR)-93/miR-182. Mechanistically, we found that circCRIM1 could promote the expression of leukemia inhibitory factor receptor, a well-known tumor suppressor, by sponging miR-93 and miR-182. In the clinical and pathological analyses, the downregulation of circCRIM1 in LUAC was significantly correlated with lymphatic metastasis and TNM stage, which served as an independent risk factor for the overall survival of patients with LUAC. Our study showed that circCRIM1 inhibits the invasion and metastasis of lung adenocarcinoma cancer cells, which makes it a potential therapeutic target.


Assuntos
Adenocarcinoma de Pulmão/genética , Biomarcadores Tumorais/metabolismo , Subunidade alfa de Receptor de Fator Inibidor de Leucemia/genética , Neoplasias Pulmonares/genética , MicroRNAs/metabolismo , RNA/metabolismo , Adenocarcinoma de Pulmão/mortalidade , Adenocarcinoma de Pulmão/patologia , Animais , Receptores de Proteínas Morfogenéticas Ósseas , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidade alfa de Receptor de Fator Inibidor de Leucemia/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Proteínas de Membrana/genética , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Prognóstico , RNA/genética , RNA Circular , RNA Interferente Pequeno/metabolismo , Análise de Sobrevida , Análise Serial de Tecidos , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Exp Mol Pathol ; 110: 104276, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31233732

RESUMO

Secreted protein acidic and rich in cysteine (SPARC) plays a crucial role in the malignant progression of a number of human cancers. However, the roles of SPARC in lung squamous cell carcinoma (LSCC) remain elusive. In this present study, we first detected SPARC expression and investigated the relationship between SPARC expression and the clinicopathological attributes of LSCC patients. Then we constructed SPARC-overexpression model in LSCC cell line to explore the characteristics of SPARC in LSCC development both in vitro and in vivo. The data demonstrated a remarkably higher level of SPARC in LSCC tissues than in corresponding non-cancerous tissues and elevated SPARC expression was significantly correlated with poor outcome in LSCC patients. Moreover, a serial of phenotypic experiments indicated that SPARC overexpression substantially facilitated the growth and inhibited the apoptosis in LSCC cells and xenografts. Taken together, our results suggest that SPARC is a novel prognostic marker for LSCC prognosis and SPARC significantly promotes LSCC tumorigenesis. Targeting SPARC may provide a novel therapeutic strategy for LSCC management.


Assuntos
Carcinogênese/genética , Carcinoma de Células Escamosas/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Osteonectina/genética , Animais , Carcinogênese/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Osteonectina/metabolismo , Prognóstico , Transplante Heterólogo , Carga Tumoral/genética
12.
Ann Hepatol ; 18(2): 393-396, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31010795

RESUMO

Wilson's disease (WD), resulting from homozygote and compound heterozygote mutations in ATB7B, is an autosomal recessive disease. WD associated acute liver failure (ALF) is fatal, and a revised Wilson's disease prognostic index (RWPI) >11 is a reliable indication of liver transplantation (LT) or artificial liver support (ALS). We described a WD patient who initially presented with ALF and severe hemolytic anemia. A single heterozygote c.2333G>T mutation (p. Arg778Leu, R778L) in ATP7B was screened by whole exome sequencing and validated by Sanger sequencing. Rapid diagnostic criteria (ALP/TBIL <4 and AST/ALT >2.2) are suitable for early diagnosis. Although the RWPI amounted to 15, the patient recovered after intermittent plasma transfusion and subsequent chelating therapy without LT or ALS. In conclusion, WD patients with a single R778L heterozygote mutation can present with ALF as the initial clinical manifestation, and intermittent plasma transfusion combined with chelating therapy may alleviate fulminant WD without LT or ALS.


Assuntos
Anemia Hemolítica/terapia , Transfusão de Sangue , Quelantes/uso terapêutico , ATPases Transportadoras de Cobre/genética , Degeneração Hepatolenticular/genética , Falência Hepática Aguda/terapia , Mutação , Penicilamina/uso terapêutico , Adolescente , Anemia Hemolítica/diagnóstico , Anemia Hemolítica/genética , Terapia Combinada , Transfusão de Eritrócitos , Feminino , Predisposição Genética para Doença , Degeneração Hepatolenticular/complicações , Degeneração Hepatolenticular/diagnóstico , Heterozigoto , Humanos , Falência Hepática Aguda/diagnóstico , Falência Hepática Aguda/genética , Resultado do Tratamento
13.
J Infect Dev Ctries ; 13(11): 1062-1067, 2019 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-32087080

RESUMO

INTRODUCTION: The impact of mutations in the reverse transcriptase region of HBV on serum HBsAg titer and its correlation with HBV DNA is largely unknown. METHODOLOGY: A total of 644 patients, with a history of lamivudine or adefovir dipivoxil resistance who underwent genotypic resistance tests, were enrolled in this study. Serum HBsAg, hepatitis B e antigen and HBV DNA were quantified, and the HBV RT region was sequenced and analyzed. Then, the patients were divided into five sub-groups, including M204I/V, L180M+M204I/V, A181T/V, N236T and A181T/V+N236T according to the mutation spectra. RESULTS: HBsAg was lower in the wild-type and A181T/V+N236T groups as compared to the M204I/V, L180M+M204I/V and N236T groups. HBsAg was positively correlated with HBV DNA levels in the wild-type group (r = 0.322, p < 0.01), as well as in the M204I/V, L180M+M204I/V, A181T/V, and N236T subgroups, while no correlation was found in the A181T/V+N236T subgroup (r = 0.159, p = 0.217). Moreover, for patients with N236T mutation, HBsAg was positively correlated with HBV DNA level in the HBeAg negative group (r = 0.435, p = 0.016), but not in the HBeAg positive group (r = 0.105, p = 0.594). For patients with A181T/V or N236T mutation, HBsAg was positively correlated with HBV DNA in older patients (≥ 40 years), but not in younger patients (< 40 years). CONCLUSIONS: Serum HBsAg titer and its correlation with HBV DNA may be affected by mutations in the reverse transcriptase region of HBV, that should be re-evaluated in patients with antiviral resistance.


Assuntos
Farmacorresistência Viral/genética , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/genética , Hepatite B Crônica/virologia , Mutação , DNA Polimerase Dirigida por RNA/genética , Adulto , Antivirais/uso terapêutico , Estudos de Coortes , DNA Viral/genética , Farmacorresistência Viral/efeitos dos fármacos , Antígenos de Superfície da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Humanos , Lamivudina/uso terapêutico , Pessoa de Meia-Idade
14.
Gene ; 671: 170-177, 2018 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-29704631

RESUMO

Circular RNAs (circRNAs) are a group of non-protein-coding RNAs that are generated from back-splicing. Recent evidence indicates that circRNAs play important roles in tissue development, gene regulation, and carcinogenesis. It was recently demonstrated that circular RNAs can function as sponges for miRNAs. In our study, the clinical implications of circRNF13 were assessed in 50 pathologically diagnosed lung adenocarcinoma samples and their paired peripheral normal lung tissues by using quantitative polymerase chain reaction. We validated that circRNF13 was almost 2.98-fold down-regulated in cancer tissues. The expression level of circRNF13 was significantly negatively correlated with TNM staging and lymph node metastasis. In vitro experiments indicated that circRNF13 repressed the invasion and metastasis of lung adenocarcinoma cell lines. Cell fraction analyses and fluorescence in situ hybridization detected that circRNF13 was mostly located in the cytoplasm. Bioinformatic analyses and RIP experiments revealed that circRNF13 could interact with Ago2, an RNA binding protein, and could function as sponge for miR-93-5p. Our data suggest that circRNF13 represents a potential novel biomarker and a therapeutic target of lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão/genética , Regulação para Baixo , Neoplasias Pulmonares/genética , MicroRNAs/genética , RNA/genética , Células A549 , Idoso , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Prognóstico , RNA Circular , Análise de Sobrevida
15.
Virus Genes ; 54(1): 41-47, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29119303

RESUMO

The objective of this study was to analyze the prevalence of drug-resistant HBV mutants in patients with treatment failure during the past seven years (2010-2016). 4055 HBV-infected patients who underwent HBV polymerase gene mutation test from 2010 to 2016 were enrolled. The nucleos(t)ide analogues (NAs) resistance mutation positions, including rtL180, rtA181, rtT184, rtS202, rtM204, rtI233, rtN236, rtI169, rtV173, and rtM250 were analyzed. Genotypic resistance mutations were detected in 30.8% (1248/4055) of the patients with treatment failure. Rates of drug-resistant mutations associated with LAM, ADV, ETV, and multidrug were 27.23% (1104/4055), 9.67% (392/4055), 3.69% (150/4055), and 0.79% (32/4055). Among the primary NA-resistant mutations, rtM204I (13.44%, 545/4055) occurred more frequently, followed by rtM204V, rtN236T, rtA181T, and rtA181V. For single-base mutations, rtL180M and rtA181V increased gradually during the past seven years, while rtM204I/V and rtN236T decreased after 2015. The development of drug-resistant mutations positively correlated with the consumption of ETV (r = 0.964, P = 0.002), and weakly correlated with that of LAM (r = 0.679, P = 0.109) and ADV (r = 0.429, P = 0.354). Moreover, single-base mutation rtA181V and multi-base mutations (rtL180M + M204I and rtL180M + M204V + M204I) were more common in HBV genotype C than those in genotype B (1.94% vs. 0.66%, 1.84% vs. 0.16%, 1.02% vs. 0.16%, respectively). NA-related mutations in HBV RT region increased in the past seven years, especially for LAM. Frequencies of rtL180M and rtA181T/V increased gradually in the past seven years, to which we should pay more attention.


Assuntos
Antivirais/uso terapêutico , Farmacorresistência Viral , Evolução Molecular , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Frequência do Gene , Genoma Viral , Vírus da Hepatite B/isolamento & purificação , Humanos , Mutação , Falha de Tratamento
16.
Mol Med Rep ; 16(2): 2269-2273, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28627683

RESUMO

Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an endogenous adaptor of innate and adaptive immune responses, and serves a crucial role in tumor necrosis factor receptor and toll­like/interleukin­1 receptor signaling. Although studies have demonstrated that TRAF6 has oncogenic activity, its potential contributions to breast cancer in human remains largely uninvestigated. The present study examined the expression levels and function of TRAF6 in breast carcinoma (n=32) and adjacent healthy (n=25) tissue samples. Compared with adjacent healthy tissues, TRAF6 protein expression levels were significantly upregulated in breast cancer tissues. Reverse transcription­quantitative polymerase chain reaction analysis revealed a significant upregulation of the cellular proliferative marker Ki­67 and proliferation cell nuclear antigen expression levels in breast carcinoma specimens. Furthermore, protein expression levels of the accessory molecule, transforming growth factor ß­activated kinase 1 (TAK1), were significantly increased in breast cancer patients, as detected by western blot analysis. As determined by MTT assay, TRAF6 exerted profoundly proliferative effects in the MCF­7 breast cancer cell line; however, these detrimental effects were ameliorated by TAK1 inhibition. Notably, protein kinase B (AKT)/glycogen synthase kinase (GSK)3ß phosphorylation levels were markedly upregulated in breast cancer samples, compared with adjacent healthy tissues. In conclusion, an altered TRAF6­TAK1 axis and its corresponding downstream AKT/GSK3ß signaling molecules may contribute to breast cancer progression. Therefore, TRAF6 may represent a potential therapeutic target for the treatment of breast cancer.


Assuntos
Glicogênio Sintase Quinase 3 beta/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Fosforilação , Antígeno Nuclear de Célula em Proliferação/metabolismo , Transdução de Sinais , Fator 6 Associado a Receptor de TNF/genética , Regulação para Cima
17.
Cancer Biomark ; 19(4): 365-373, 2017 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-28582841

RESUMO

BACKGROUND: Sal-like protein 4 (SALL4) is recognized as a potential biomarker for assessing cancer prognosis. Many experiments have been done to explore the aberrant expression of SALL4 in cancer patients. OBJECTIVE: To explore the association between SALL4 expression and cancer prognosis. METHODS: A systematically comprehensive search was performed through PubMed, Web of Science, and CNKI. The prognostic value of SALL4 expression in cancer patients was evaluated by pooled hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: The overexpression of SALL4 was identified to be significantly associated with a poor prognosis in cancer patients (pooled HR: 2.02, 95% CI: 1.67-2.46). This association was also detected in digestive system neoplasms subgroup (pooled HR: 1.91, 95% CI: 1.52-2.39) and reproductive system neoplasms subgroup (pooled HR: 1.95, 95% CI: 1.17-3.26). In the geography subgroup analysis, a statistical association was confirmed in the Chinese subgroup (pooled HR: 1.982, 95% CI: 1.526-2.576). In the respect of disease progression, there was a certain degree of relationship between higher expression of SALL4 and recurrence-free survival (RFS) (pooled HR: 1.617, 95% CI: 1.190-2.196). CONCLUSION: SALL4 is a promising prognostic biomarker for cancer, and is appropriate for the assessment of cancer prognosis in the Chinese people.


Assuntos
Neoplasias/metabolismo , Fatores de Transcrição/biossíntese , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Progressão da Doença , Humanos , Pessoa de Meia-Idade , Neoplasias/genética , Prognóstico , Análise de Sobrevida , Fatores de Transcrição/genética
18.
World J Clin Oncol ; 8(2): 158-167, 2017 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-28439497

RESUMO

AIM: To evaluate the treatment effects of recombinant human interleukin-12 (rhIL-12) on radiotherapy complications, such as severe myelosuppression or pancytopenia, the decline or imbalance of immune function, etc. METHODS: The patients received high-dose and short-course precise radiotherapy, such as Cyber knife and image-guided radiotherapy (IGRT), which can cause myelosuppression or pancytopenia and immune function decline within a short time. One-hundred subjects were enrolled in the study, and 50 were randomized to a treatment group which used rhIL-12 and 50 were randomized to a control group which used symptomatic and supportive therapy after radiotherapy. The 50 subjects in the treatment group were further divided into five subgroups and intervened with rhIL-12 at a dose of 50, 100, 150, 200 or 250 ng/kg respectively. The dose-effect relationship was observed. RESULTS: RhIL-12 significantly attenuated the decrease of peripheral blood cells in the treatment group, and immune function was improved after treatment. Due to the different radiation doses, there was a fluctuation within 12 h after treatment but mostly showing an increasing trend. As to the clinical manifestations, 2 patients in the 250 ng/kg subgroup showed low fever after administration, 1 patient in the 200 ng/kg subgroup and 2 patients in the 250 ng/kg subgroup showed mild impairment of liver function during the observation period. CONCLUSION: RhIL-12 has effective therapeutic and protective effects on complications following radiotherapy, such as the decline of blood cells, myelosuppression and the decline or imbalance of immune function, which indicated good prospects for development and application.

19.
Gene ; 623: 5-14, 2017 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-28438694

RESUMO

Anthracycline/taxane-based chemotherapy regimens are usually used as neoadjuvant chemotherapies to decrease tumour size and prevent metastasis of advanced breast cancer. However, patients have a high risk of developing chemo-resistance during treatment through still unknown mechanisms. Glutathione S-transferase P1 (GSTP1), which belongs to the family of phase II metabolic enzymes, has been reported to function in detoxifying several anti-cancer drugs by conjugating them with glutathione. Previous studies have identified GSTP1 as a predictor of prognosis and chemo-resistance in breast cancer patients, but the mechanisms governing GSTP1-dependent drug resistance are still unclear. We have found that GSTP1 expression is much higher in adriamycin-resistant cells and their corresponding exosomes. The role of GSTP1-containing exosomes in conferring drug resistance was analysed through cell apoptosis and immunofluorescence staining assays. Furthermore, we analysed 42 cases of paired breast cancer tissues collected before and after anthracycline/taxane-based neoadjuvant chemotherapy by immunohistochemistry. Higher GSTP1 expression was shown in the progressive disease (PD)/stable disease (SD) group than in the partial response (PR)/complete response (CR) group both in the samples collected before and after the chemotherapy treatment. Interestingly, GSTP1 partly re-localized from the cell nucleus to the cytoplasm upon treatment, and similar results were obtained for the exosomal marker Tumour susceptibility gene 101 protein (TSG101), which also increased in the cytoplasm after chemotherapy. After analysing the serum exosomes of 30 patients treated with anthracycline/taxane-based neoadjuvant chemotherapy, we discovered that the levels of GSTP1 in exosomes from patients in the PD/SD group were significantly higher than those in the PR/CR group. Here, for the first time, we investigated a novel role for GSTP1-containing exosomes and their capability to transfer drug resistance and evaluated their clinical use in predicting chemo-resistance.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Resistencia a Medicamentos Antineoplásicos , Exossomos/metabolismo , Glutationa S-Transferase pi/metabolismo , Transporte Ativo do Núcleo Celular , Antibióticos Antineoplásicos/farmacologia , Antibióticos Antineoplásicos/uso terapêutico , Apoptose , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Núcleo Celular/metabolismo , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Exossomos/efeitos dos fármacos , Feminino , Humanos , Células MCF-7
20.
Tumour Biol ; 39(3): 1010428317692204, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28347244

RESUMO

The microRNA family, miR-30, plays diverse roles in regulating key aspects of neoplastic transformation, metastasis, and clinical outcomes in different types of tumors. Accumulating evidence proves that miR-30 family is pivotal in the breast cancer development by controlling critical signaling pathways and relevant oncogenes. Here, we review the roles of miR-30 family members in the tumorigenesis, metastasis, and drug resistance of breast cancer, and their application to predict the prognosis of breast cancer patients. We think miR-30 family members would be promising biomarkers for breast cancer and may bring a novel insight in molecular targeted therapy of breast cancer.


Assuntos
Neoplasias da Mama/genética , MicroRNAs/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinogênese/genética , Carcinogênese/metabolismo , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , MicroRNAs/metabolismo , Metástase Neoplásica , Transdução de Sinais/genética
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