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1.
Virology ; 540: 75-87, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31743858

RESUMO

Epstein-Barr virus (EBV), a major human oncogenic pathogen, establishes life-long persistent infections. In latently infected B lymphocytes, the virus persists as an episome in the nucleus. Periodic reactivation of latent virus is controlled by both viral and cellular factors. Our recent studies showed that interferon regulatory factor 8 (IRF8) is required for EBV lytic reactivation while protein inhibitor of activated STAT1 (PIAS1) functions as an EBV restriction factor to block viral reactivation. Here, we show that IRF8 directly binds to the EBV genome and regulates EBV lytic gene expression together with PU.1 and EBV transactivator RTA. Furthermore, our study reveals that PIAS1 antagonizes IRF8/PU.1-mediated lytic gene activation through binding to and inhibiting IRF8. Together, our study establishes IRF8 as a transcriptional activator in promoting EBV reactivation and defines PIAS1 as an inhibitor of IRF8 to limit lytic gene expression.

2.
Molecules ; 25(1)2019 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-31877851

RESUMO

This study was conducted to develop a self-assembled direct competitive enzyme-linked immunosorbent assay (dcELISA) kit for the detection of deoxynivalenol (DON) in food and feed grains. Based on the preparation of anti-DON monoclonal antibodies, we established a standard curve with dcELISA and optimized the detection conditions. The performance of the kit was evaluated by comparison with high-performance liquid chromatography (HPLC). The minimum detection limit of DON with the kit was 0.62 ng/mL, the linear range was from 1.0 to 113.24 ng/mL and the half-maximal inhibition concentration (IC50) was 6.61 ng/mL in the working buffer; there was a limit of detection (LOD) of 62 ng/g, and the detection range was from 100 to 11324 ng/g in authentic agricultural samples. We examined four samples of wheat bran, wheat flour, corn flour and corn for DON recovery. The average recovery was in the range of 77.1% to 107.0%, and the relative standard deviation (RSD) ranged from 4.2% to 11.9%. In addition, the kit has the advantages of high specificity, good stability, a long effective life and negligible sample matrix interference. Finally, wheat samples from farms in the six provinces of Henan, Anhui, Hebei, Shandong, Jiangsu and Gansu in China were analyzed by the kit. A total of 30 samples were randomly checked (five samples in each province), and the results were in good agreement with the standardized HPLC method. These tests showed that the dcELISA kit had good performance and met relevant technical requirements, and it had the characteristics of accuracy, reliability, convenience and high-throughput screening for DON detection. Therefore, the developed kit is suitable for rapid screening of DON in marketed products.

3.
Anticancer Drugs ; 30(9): 925-932, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31517732

RESUMO

Hypoxia has crucial roles in cancer development and progression. Our previous study indicated that cell migration was increased in a hypoxic microenvironment in GBC-SD gallbladder cancer (GBC) cells. Oridonin, a bioactive diterpenoid compound that is isolated from the plant Rabdosia rubescens, has been identified as an anticancer agent in various types of cancer. However, its roles in cell proliferation, apoptosis, and migration in a hypoxic microenvironment and the associated regulatory mechanisms have not yet to be fully elucidated in GBC. The present study investigated the effect of oridonin on cell proliferation, apoptosis, the cell cycle and cell migration in GBC in vitro and in vivo. Furthermore, the role of oridonin in hypoxia-induced cell migration and its underlying mechanisms were explored in GBC. The results indicated that treatment with oridonin significantly suppressed cell proliferation and the metastatic ability of GBC-SD cells in a dose-dependent manner, increased the level of cell apoptosis and induced cell cycle arrest at the G0/G1 phase. Further experiments demonstrated that oridonin could inhibit hypoxia-induced epithelial-mesenchymal transition and cell migration by downregulating the expression levels of hypoxia-inducible factor (HIF)-1α/matrix metallopeptidase (MMP)-9. In addition, oridonin suppressed GBC cell growth and downregulated the expression levels of HIF-1α and MMP-9 in a GBC-SD cell xenograft model. Taken together, these results suggest that oridonin possesses anticancer properties in GBC. Notably, oridonin can suppress tumor epithelial-mesenchymal transition and cell migration by targeting the HIF-1α/MMP-9 signaling pathway.

4.
Medicine (Baltimore) ; 98(32): e15837, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31393341

RESUMO

Peripherally inserted central catheters (PICCs) can provide nutritional and medical support for very low birth weight or critically ill newborns. The aim of this study was to retrospectively analyze the use of PICCs in our clinic for critically ill newborns to evaluate the relationship between catheter related factors and the occurrence of complications.Retrospective analysis was conducted for all newborns consecutively admitted at the Neonatal Intensive Care Unit (NICU), Chongqing Health Center for Women and Children, who underwent PICC insertion between May 2011 and March 2018. Data collected included total puncture success rate, one puncture success rate, infection rate, complication rate, unplanned catheter withdrawal rate, device days, and catheter indwelling time.Five-hundred eighty-eight infants (304 males and 284 females) aged 3.4 ±â€Š3.9 days, mean gestational age of 30.9 ±â€Š2.7 weeks and a mean body mass of 1.38 ±â€Š0.47 kg at insertion were included. Total puncture success rate was 99.65%, one puncture success rate was 77.77%. The mean catheter retention was 13.6 ±â€Š6.7 days: more than 30 days in 15 (2.61%) cases, 20 to 30 days in 60 (10.43%) cases, 10 to 19 days in 372 (64.70%) cases, and 62 days in 1 case. Complications occurred in 63 (10.71%) cases: with PICC insertion within 24 hours after birth in 29 (15.43%), within 48 hours in 13 (6.63%), and after 48 hours in 21 (10.99%) cases. Catheter tip culture was positive in 3 cases and there was 1 case of catheter-related bloodstream infection.Nursing measures of the maintenance of body temperature and the evaluation of blood vessels were important conditions for improving the success rate of one puncture in critically ill neonates. PICC catheterization as early as 48 hours will not increase the difficulty of PICC puncture. Nor did it increase the incidence of PICC complications.


Assuntos
Cateterismo Periférico/estatística & dados numéricos , Cateteres de Demora/estatística & dados numéricos , Estado Terminal , Unidades de Terapia Intensiva Neonatal/estatística & dados numéricos , Infecções Relacionadas a Cateter/epidemiologia , Infecções Relacionadas a Cateter/prevenção & controle , Cateteres de Demora/efeitos adversos , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Recém-Nascido de muito Baixo Peso , Masculino , Estudos Retrospectivos
5.
mSphere ; 4(4)2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31391281

RESUMO

Human papillomaviruses induce a host of anogenital cancers, as well as oropharyngeal cancer (HPV+OPC); human papillomavirus 16 (HPV16) is causative in around 90% of HPV+OPC cases. Using telomerase reverse transcriptase (TERT) immortalized foreskin keratinocytes (N/Tert-1), we have identified significant host gene reprogramming by HPV16 (N/Tert-1+HPV16) and demonstrated that N/Tert-1+HPV16 support late stages of the viral life cycle. Expression of the cellular dNTPase and homologous recombination factor sterile alpha motif and histidine-aspartic domain HD-containing protein 1 (SAMHD1) is transcriptionally regulated by HPV16 in N/Tert-1. CRISPR/Cas9 removal of SAMHD1 from N/Tert-1 and N/Tert-1+HPV16 demonstrates that SAMHD1 controls cell proliferation of N/Tert-1 only in the presence of HPV16; the deletion of SAMHD1 promotes hyperproliferation of N/Tert-1+HPV16 cells in organotypic raft cultures but has no effect on N/Tert-1. Viral replication is also elevated in the absence of SAMHD1. This new system has allowed us to identify a specific interaction between SAMHD1 and HPV16 that regulates host cell proliferation and viral replication; such studies are problematic in nonimmortalized primary keratinocytes due to their limited life span. To confirm the relevance of our results, we repeated the analysis with human tonsil keratinocytes (HTK) immortalized by HPV16 (HTK+HPV16) and observed the same hyperproliferative phenotype following CRISPR/Cas9 editing of SAMHD1. Identical results were obtained with three independent CRISPR/Cas9 guide RNAs. The isogenic pairing of N/Tert-1 with N/Tert-1+HPV16, combined with HTK+HPV16, presents a unique system to identify host genes whose products functionally interact with HPV16 to regulate host cellular growth in keratinocytes.IMPORTANCE HPVs are causative agents in human cancers and are responsible for around of 5% of all cancers. A better understanding of the viral life cycle in keratinocytes will facilitate the development of novel therapeutics to combat HPV-positive cancers. Here, we present a unique keratinocyte model to identify host proteins that specifically interact with HPV16. Using this system, we report that a cellular gene, SAMHD1, is regulated by HPV16 at the RNA and protein levels in keratinocytes. Elimination of SAMHD1 from these cells using CRISPR/Cas9 editing promotes enhanced cellular proliferation by HPV16 in keratinocytes and elevated viral replication but not in keratinocytes that do not have HPV16. Our study demonstrates a specific intricate interplay between HPV16 and SAMHD1 during the viral life cycle and establishes a unique model system to assist exploring host factors critical for HPV pathogenesis.

6.
Cell Rep ; 28(2): 449-459.e5, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31291580

RESUMO

To ensure a successful infection, herpesviruses have developed elegant strategies to counterbalance the host anti-viral responses. Sterile alpha motif and HD domain 1 (SAMHD1) was recently identified as an intrinsic restriction factor for a variety of viruses. Aside from HIV-2 and the related simian immunodeficiency virus (SIV) Vpx proteins, the direct viral countermeasures against SAMHD1 restriction remain unknown. Using Epstein-Barr virus (EBV) as a primary model, we discover that SAMHD1-mediated anti-viral restriction is antagonized by EBV BGLF4, a member of the conserved viral protein kinases encoded by all herpesviruses. Mechanistically, we find that BGLF4 phosphorylates SAMHD1 and thereby inhibits its deoxynucleotide triphosphate triphosphohydrolase (dNTPase) activity. We further demonstrate that the targeting of SAMHD1 for phosphorylation is a common feature shared by beta- and gamma-herpesviruses. Together, our findings uncover an immune evasion mechanism whereby herpesviruses exploit the phosphorylation of SAMHD1 to thwart host defenses.

7.
Poult Sci ; 98(10): 4457-4464, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31162616

RESUMO

Infectious bursal disease virus (IBDV) often infects young chickens and causes severe immunosuppression and inflammatory injury. Betaine is an antiviral and anti-inflammatory ingredient that may exert functions through epigenetic regulation. However, the effects of betaine on an IBDV-induced bursal injury and their underlying mechanisms have not been investigated. In this study, betaine was supplemented to the drinking water of newly hatched commercial broilers for 3 wk. Afterward, the chickens were infected with the IBDV. After 5 D of infection, the bursal lesions were examined. The mRNA expression levels of IBDV VP2 gene, pro-inflammatory cytokines, and interferons were detected. Furthermore, the 5-methylcytosine level of the CpG island in the promoter region of IL-6 and interferon regulatory factor 7 (IRF7) were determined. The IBDV induced the depletion of lymphocytes and inflammation in the bursal follicles. IBDV infection considerably elevated the mRNA levels of VP2, IL-6, types I (IFNα and IFNß) and II (IFNγ) interferons, and IRF7. The CpG island methylation in the promoter regions of IL-6 and IRF7 were substantially decreased after IBDV infection. Betaine administration attenuated the IBDV-induced bursal lesions. Meanwhile, the IBDV-induced mRNA expression levels of IL-6, IFNß, and IRF7 were suppressed by betaine consumption. Furthermore, the hypomethylation effects of IBDV infection to the promoter regions of IL-6 and IRF7 genes were eliminated and relieved by betaine administration. Our results indicated that the IBDV-induced expression levels of IL-6 and IRF7 genes are associated with the suppression of methylation in the promoter region. Betaine administration through drinking water may alleviate the IBDV-induced bursal injury via epigenetic regulation.


Assuntos
Antivirais/farmacologia , Betaína/farmacologia , Infecções por Birnaviridae/veterinária , Vírus da Doença Infecciosa da Bursa/efeitos dos fármacos , Doenças das Aves Domésticas/tratamento farmacológico , Animais , Proteínas Aviárias/metabolismo , Infecções por Birnaviridae/tratamento farmacológico , Infecções por Birnaviridae/virologia , Metilação de DNA , Fator Regulador 7 de Interferon/metabolismo , Interleucina-6/metabolismo , Doenças das Aves Domésticas/virologia , Distribuição Aleatória
8.
Int J Oncol ; 55(1): 331-339, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31180536

RESUMO

Thyroid cancer is among the most common types of malignant tumor of the endocrine system. The role of metformin in the inhibition of cancer cell proliferation and induction of apoptosis is widely accepted. The present study explored the effect and the underlying mechanisms of metformin on human thyroid cancer TPC­1 cells. Following treatment of TPC­1 cells with different concentrations of metformin, cell proliferation and apoptosis were analyzed by cell counting kit­8 (CCK­8) assay and flow cytometry, respectively. Reverse transcription­quantitative PCR and western blotting were used to detect alterations in the mRNA and protein expression levels, respectively, for heat shock protein family A member 5 (HSPA5, also known as Bip), DNA damage­inducible transcript 3 (DDIT3, also known as CHOP) and caspase­12. The results demonstrated that treatment with metformin inhibited proliferation and induced apoptosis in a concentration and time­dependent manner. In addition, treatment with metformin increased the expression of Bip, CHOP and caspase­12 in vitro, activating endoplasmic reticulum (ER) stress. Thapsigargin treatment enhanced the apoptosis induced by metformin. Inhibition of ER stress by 4­phenylbutyrate reversed the metformin­induced apoptosis. Finally, treatment with metformin inhibited thyroid cancer growth and increased the expression of Bip and CHOP in a TPC­1 cell xenograft model. These results indicated that metformin increased the apoptotic rate of thyroid cancer cells via ER stress­associated mechanisms.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Metformina/farmacologia , Câncer Papilífero da Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia
9.
Oncol Rep ; 41(6): 3587, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31002375

RESUMO

The authors have noted that the address given for the Affiliated Hospital of Zhengzhou University in the above article was presented incorrectly: This should have been written as the First Affiliated Hospital of Zhengzhou University. Therefore, the author affiliations for this paper should have appeared as follows: Jianwen Ye1,2, Kunlun Chen1,2, Lei Qi3, Renfeng Li1,2, Hongwei Tang2, Chuang Zhou1,2 and Wenlong Zhai1,2. 1Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University; 2Key Laboratory of Digestive Organ Transplantation of Henan Province; Open and Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities; Zhengzhou Key Laboratory of Hepatobiliary and Pancreatic Disease and Organ Transplantation; 3Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China. The authors regret that this was not corrected prior to the publication of the paper, and apologize to the readers for any inconvenience caused. [the original article was published in Oncology Reports 40: 3501­3510, 2018; DOI: 10.3892/ijmm.2015.2162].

10.
Oncol Rep ; 40(6): 3501-3510, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30272364

RESUMO

Hypoxia plays a crucial role in cancer development and progression. Overexpression of hypoxia-inducible factor-1α (HIF­1α) has been demonstrated in a hypoxic microenvironment in various tumor types. Metformin has been identified as an antitumor drug in various tumor types. However, its role in cellular migration in a hypoxic microenvironment, and the associated regulatory mechanism, have yet to be fully elucidated. The present study aimed to investigate the clinical significance of HIF­1α, and its biological role, in gallbladder cancer (GBC). Furthermore, the role of metformin in cellular migration, and its underlying mechanism in GBC, were also identified. Real­time quantitative polymerase chain reaction analysis and immunohistochemistry experiments revealed that HIF­1α was significantly upregulated in GBC tissues. HIF­1α overexpression was closely associated with lymph node metastasis and tumor­lymph node­metastasis (TNM) stages. HIF­1α was able to promote cell migration in a hypoxic microenvironment by overexpressing vascular endothelial growth factor (VEGF) in GBC­SD cells, an effect which was partly reversed by small­interfering RNA HIF­1α (siHIF­1α) and 2­methoxyestradiol. Further experiments demonstrated that metformin inhibited hypoxia­induced migration via HIF­1α/VEGF in vitro. In addition, metformin suppressed GBC growth and downregulated the expression of HIF­1α and VEGF in a GBC­SD cell xenograft model. Taken together, these results suggest that HIF­1α may contribute to tumor migration via the overexpression of VEGF in GBC, while metformin is able to inhibit tumor migration by targeting the HIF­1α/VEGF pathway.


Assuntos
Neoplasias da Vesícula Biliar/tratamento farmacológico , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Metformina/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/metabolismo , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias da Vesícula Biliar/genética , Neoplasias da Vesícula Biliar/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Metformina/farmacologia , Estadiamento de Neoplasias , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Expert Rev Gastroenterol Hepatol ; 12(5): 515-523, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29543072

RESUMO

BACKGROUND: Compared with overall survival, conditional survival is a more relevant measure of prognosis in surviving patients over time. The aim of this study was to describe the conditional survival of patients with hepatocellular carcinoma according to different prognostic variables through an analysis of a national population-based cancer registry. METHODS: We analyzed data from 3,082 hepatocellular carcinoma patients who were diagnosed between 2004 and 2014. RESULTS: The conditional overall and cause-specific survival improved from 37.6% to 68.9% and 45% to 79.1%, respectively, in the entire study population. The conditional overall and cause-specific survival improved from 32.6% to 69.3% and 40.1% to 74.8%, respectively, in patients aged 65 to 74 years. The conditional overall and cause-specific survival improved from 8.4% to 44.1% and 12.1% to 66.1%, respectively, in the stage IVB group. The conditional overall and cause-specific survival improved from 32.8% to 71.4% and 40.3% to 78.4%, respectively, in the positive/elevated AFP group. CONCLUSIONS: Conditional survival exhibited an improved prognosis over time. For hepatocellular carcinoma patients who survived for a specific period of time after diagnosis, more dramatic improvements occurred in patients aged 65-74 years, patients with AJCC stage IVB, and patients with a positive/elevated AFP value.


Assuntos
Carcinoma Hepatocelular/epidemiologia , Neoplasias Hepáticas/epidemiologia , Idoso , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/terapia , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Programa de SEER , Fatores de Tempo , Estados Unidos/epidemiologia , alfa-Fetoproteínas/metabolismo
12.
PLoS Pathog ; 14(1): e1006868, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29357389

RESUMO

Interferon regulatory factor 8 (IRF8), also known as interferon consensus sequence-binding protein (ICSBP), is a transcription factor of the IRF family. IRF8 plays a key role in normal B cell differentiation, a cellular process that is intrinsically associated with Epstein-Barr virus (EBV) reactivation. However, whether IRF8 regulates EBV lytic replication remains unknown. In this study, we utilized a CRISPR/Cas9 genomic editing approach to deplete IRF8 and found that IRF8 depletion dramatically inhibits the reactivation of EBV upon lytic induction. We demonstrated that IRF8 depletion suppresses the expression of a group of genes involved in apoptosis and thus inhibits apoptosis induction upon lytic induction by B cell receptor (BCR) stimulation or chemical induction. The protein levels of caspase-1, caspase-3 and caspase-8 all dramatically decreased in IRF8-depleted cells, which led to reduced caspase activation and the stabilization of KAP1, PAX5 and DNMT3A upon BCR stimulation. Interestingly, caspase inhibition blocked the degradation of KAP1, PAX5 and DNMT3A, suppressed EBV lytic gene expression and viral DNA replication upon lytic induction, suggesting that the reduced caspase expression in IRF8-depleted cells contributes to the suppression of EBV lytic replication. We further demonstrated that IRF8 directly regulates CASP1 (caspase-1) gene expression through targeting its gene promoter and knockdown of caspase-1 abrogates EBV reactivation upon lytic induction, partially through the stabilization of KAP1. Together our study suggested that, by modulating the activation of caspases and the subsequent cleavage of KAP1 upon lytic induction, IRF8 plays a critical role in EBV lytic reactivation.


Assuntos
Linfócitos B/imunologia , Caspase 1/genética , Herpesvirus Humano 4/fisiologia , Fatores Reguladores de Interferon/fisiologia , Ativação Linfocitária , Ativação Viral/genética , Linfócitos B/virologia , Células Cultivadas , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/virologia , Regulação Enzimológica da Expressão Gênica , Células HEK293 , Humanos , Ativação Linfocitária/efeitos dos fármacos , Latência Viral/genética
13.
Bioorg Med Chem Lett ; 28(4): 742-747, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29342415

RESUMO

A series of novel N,N-bis(3-aminopropyl)methylamine bridged bis-naphthalimide derivatives NI1-NI8 containing saturated nitrogenous heterocycles were designed and synthesized, their cytotoxic activities against Hela, MCF-7, A549 and MGC-803 cells were investigated, Compounds NI1-NI4 modified with piperidine and piperazine exhibited good and selective cytotoxic activity, for instance, compounds NI1 and NI4 showed potent cytotoxic activity against Hela cells and MGC-803 cells with the IC50 values of 2.89, 060, 2.73 and 1.60 µM, respectively, better than the control drug (Amonafide). However, compounds NI5-NI8 conjugated with pyrrole derivatives showed weak cytotoxic activities against the all tested cell lines. Furthermore, their DNA binding properties, fluorescence imaging and cell cycle were investigated. Interestingly, compounds NI1 and NI4 showed fluorescence enhancement because of the strong binding with Ct-DNA, and exhibited fluorescence imaging with Hela cells on the lysosomes.


Assuntos
Antineoplásicos/farmacologia , Corantes Fluorescentes/farmacologia , Lisossomos/metabolismo , Naftalimidas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , DNA/química , Ensaios de Seleção de Medicamentos Antitumorais , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Humanos , Microscopia Confocal , Microscopia de Fluorescência , Naftalimidas/síntese química , Naftalimidas/química , Conformação de Ácido Nucleico , Piperazinas/síntese química , Piperazinas/química , Piperazinas/farmacologia , Piperidinas/síntese química , Piperidinas/química , Piperidinas/farmacologia , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Temperatura de Transição , Peixe-Zebra
14.
J Surg Res ; 222: 55-68, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29273376

RESUMO

BACKGROUND: The American Joint Committee on Cancer (AJCC) eighth edition staging system for hepatocellular carcinoma (HCC) has incorporated several significant changes. This study aims to evaluate the newly proposed staging system and assess its strengths and weaknesses. MATERIALS AND METHODS: Using the Surveillance, Epidemiology, and End Results database, we identified patients with pathologically confirmed stage I-III HCC diagnosed between 2004 and 2014. RESULTS: After all exclusion criteria were applied, AJCC seventh and eighth edition staging was possible in 4931 patients. According to the AJCC eighth edition staging system, stages IB and II did not differ significantly in terms of overall survival (OS) and cause-specific survival (CSS) (P = 0.928 and 0.872, respectively). On the basis of the above results, we reclassified T1a, T1b, and T2 into several subgroups. According to the modified AJCC eighth edition staging system, OS and CSS among the five groups of patients differed significantly. For OS predication, the Akaike information criterion values for the AJCC seventh, eighth, and modified eighth edition staging systems were 29,288.24, 29,282.85, and 27,182.21, respectively, and the c-indices for the AJCC seventh, eighth, and modified eighth edition staging systems were 0.5716, 0.5805, and 0.6082, respectively. Regarding CSS, the Akaike information criterion values for the AJCC seventh, eighth, and modified eighth edition staging systems were 21,701.11, 21,682.12, and 20,313.26, respectively, and the c-indices for the AJCC seventh, eighth, and modified eighth edition staging systems were 0.5983, 0.6117, and 0.6436, respectively. CONCLUSIONS: This is the first large-scale validation of the AJCC eighth edition staging system for patients undergoing hepatectomy. Our study revealed that there was a lack of discrepancy in the outcomes for stage IB and II tumors for AJCC eighth edition staging system of HCC. Our modified AJCC eighth edition staging system allows for finer stratification of patients undergoing hepatectomy according to more detailed tumor size and vascular invasion classifications.


Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Fígado/patologia , Idoso , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/cirurgia , Estudos de Coortes , Feminino , Hepatectomia , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Programa de SEER , Estados Unidos/epidemiologia
15.
Cell Rep ; 21(12): 3445-3457, 2017 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-29262325

RESUMO

Epstein-Barr virus (EBV) in tumor cells is predominately in the latent phase, but the virus can undergo lytic reactivation in response to various stimuli. However, the cellular factors that control latency and lytic replication are poorly defined. In this study, we demonstrated that a cellular factor, PIAS1, restricts EBV lytic replication. PIAS1 depletion significantly facilitated EBV reactivation, while PIAS1 reconstitution had the opposite effect. Remarkably, we found that various lytic triggers promote caspase-dependent cleavage of PIAS1 to antagonize PIAS1-mediated restriction and that caspase inhibition suppresses EBV replication through blocking PIAS1 cleavage. We further demonstrated that a cleavage-resistant PIAS1 mutant suppresses EBV replication upon B cell receptor activation. Mechanistically, we demonstrated that PIAS1 acts as an inhibitor for transcription factors involved in lytic gene expression. Collectively, these results establish PIAS1 as a key regulator of EBV lytic replication and uncover a mechanism by which EBV exploits apoptotic caspases to antagonize PIAS1-mediated restriction.


Assuntos
Herpesvirus Humano 4/fisiologia , Proteínas Inibidoras de STAT Ativados/metabolismo , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo , Replicação Viral , Caspases/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Células HEK293 , Humanos , Proteínas Inibidoras de STAT Ativados/genética , Proteólise , Receptores de Antígenos de Linfócitos B/metabolismo , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/genética , Fatores de Transcrição/metabolismo
16.
Oncotarget ; 8(60): 102474-102485, 2017 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-29254263

RESUMO

Background: The impact of sarcopenia on outcomes following treatment for primary liver tumors remains contentious. Therefore, we performed a systematic literature review and meta-analysis to evaluate the clinical significance of sarcopenia in the treatment of patients with primary liver tumors. Data sources: A systematic literature search was performed in English through February 1, 2017 in databases. Results: There were significant differences between patients with and without sarcopenia in overall 1- and 3-year survival (1 year: OR: 0.43; 95% CI: 0.27-0.68; P=0.0004; 3 year: OR: 0.67; 95% CI: 0.47-0.96; P=0.03). However, overall 5-year survival showed no significant difference between the groups (OR: 0.61; 95% CI: 0.35-1.07; P=0.08). Patients with sarcopenia showed a significant 53% reduction in disease-free survival within 5 years (OR: 0.47; 95% CI: 0.28-0.79; P=0.005). Also, sarcopenia had a significantly negative impact on recurrence in patients with primary liver tumors (RR: 2.71; 95% CI: 1.46-5.05; P=0.002). Regarding complications rate, we concluded that there was a statistically significant difference between two groups in overall complications rate (RR: 2.52; 95% CI: 1.50-4.22; P=0.0005). However, the major complications rate showed no significant difference between the groups (RR: 1.19; 95% CI: 0.65-2.20; P=0.57). Conclusions: Sarcopenia seemed to have a negative effect on overall survival in patients with primary liver tumors in the early phase post-treatment, but further research is needed to investigate the prognostic impact on overall survival over the longer term. Moreover, sarcopenia could significantly increase the incidence rates of post-treatment recurrence and overall complications in patients with primary liver tumors.

17.
Sci Rep ; 7(1): 5666, 2017 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-28720773

RESUMO

In situ high energy X-ray pair distribution function (PDF) measurements, microtomography and reverse Monte Carlo simulations were used to characterize the local structure of liquid gallium up to 1.9 GPa. This pressure range includes the well-known solid-solid phase transition from Ga-I to Ga-II at low temperature. In term of previous research, the local structure of liquid gallium within this domain was suggested a mixture of two local structures, Ga I and Ga II, based on fitting experimental PDF to known crystal structure, with a controversy. However, our result shows a distinctly different result that the local structure of liquid gallium resembles the atomic arrangement of both gallium phase II and III (the high pressure crystalline phase). A melting mechanism is proposed for Ga, in which the atomic structure of phase Ι breaks up at the onset of melting, providing sufficient free volume for atoms to rearrange, to form the melt.

18.
Cell Physiol Biochem ; 42(1): 222-230, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28535506

RESUMO

BACKGROUND: Long non-coding RNAs (lncRNAs) have been shown to play important roles in a wide range of pathophysiological processes, including cancer progression. Our previous study has shown that AFAP1-AS1 was upregulated and acted as an oncogene in hepatocellular carcinoma. However, the expression and biological functions of lncRNA AFAP1-AS1 in intrahepatic cholangiocarcinoma (CCA) remains largely unknown. METHODS: The expression level of AFAP1-AS1 was measured in 56 pairs of human cholangiocarcinoma tumor tissues and corresponding adjacent normal bile duct tissues. The correlation between AFAP1-AS1 and the clinicopathological features were evaluated by chi-square test. The effects of AFAP1-AS1 on CCA cells were determined by CCK-8 assay, clone formation assay, flow cytometry and transwell assay. Finally, to determine the effect of AFAP1-AS1 on tumor growth in vivo, AFAP1-AS1 knockdowned CCLP-1 cells were subcutaneously into nude mice to evaluate tumor growth. RESULTS: In this study, we found that lncRNA AFAP1-AS1 was increased in CCA tissues and patients with high AFAP1-AS1 expression had a shorter overall survival. SiRNA-mediated AFAP1-AS1 knockdown significantly decreased cell proliferation of the CCA cells, with downregulation of C-myc and Cycling D1 in vitro. Furthermore, AFAP1-AS1 silencing inhibited cell migration partly due to decrease the expression of MMP-2 and MMP-9. In addition, CCLP-1 cells with AFAP1-AS1 knockdown were injected into nude mice to investigate the effect of AFAP1-AS1 on the tumorigenesis in vivo. CONCLUSIONS: Taken together, our findings suggested that AFAP1-AS1 might promote the CCA progression and provided a novel potential therapeutic target for CCA.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/patologia , RNA Longo não Codificante/metabolismo , Animais , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/mortalidade , Carcinogênese , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Colangiocarcinoma/metabolismo , Colangiocarcinoma/mortalidade , Progressão da Doença , Regulação para Baixo , Feminino , Humanos , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Interferência de RNA , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo , Transplante Heterólogo
19.
Sci Rep ; 7: 46762, 2017 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-28440339

RESUMO

The Yb62.5Zn15Mg17.5Cu5 metallic glass is investigated using synchrotron x-ray total scattering method up to 38.4 GPa. The polyamorphic transformation from low density to high density with a transition region between 14.1 and 25.2 GPa is observed, accompanying with a volume collapse reflected by a discontinuousness of isothermal bulk modulus. This collapse is caused by that distortional icosahedron short range order precedes to perfect icosahedron, which might link to Yb 4f electron delocalization upon compression, and match the result of in situ electrical resistance measurement under high pressure conditions. This discovery in Yb-based metallic glass, combined with the previous reports on other metallic glass systems, demonstrates that pressure induced polyamorphism is the general behavior for typical lanthanide based metallic glasses.

20.
OMICS ; 21(1): 27-37, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28271981

RESUMO

Epstein-Barr virus (EBV) is a human γ-herpesvirus associated with cancer, including Burkitt lymphoma, nasopharyngeal, and gastric carcinoma. EBV reactivation in latently infected B cells is essential for persistent infection whereby B cell receptor (BCR) activation is a physiologically relevant stimulus. Yet, a global view of BCR activation-regulated protein ubiquitination is lacking when EBV is actively replicating. We report here, for the first time, the long-term effects of IgG cross-linking-regulated protein ubiquitination and offer a basis for dissecting the cellular environment during the course of EBV lytic replication. Using the Akata-BX1 (EBV+) and Akata-4E3 (EBV-) Burkitt lymphoma cells, we monitored the dynamic changes in protein ubiquitination using quantitative proteomics. We observed temporal alterations in the level of ubiquitination at ∼150 sites in both EBV+ and EBV- B cells post-IgG cross-linking, compared with controls with no cross-linking. The majority of protein ubiquitination was downregulated. The upregulated ubiquitination events were associated with proteins involved in RNA processing. Among the downregulated ubiquitination events were proteins involved in apoptosis, ubiquitination, and DNA repair. These comparative and quantitative proteomic observations represent the first analysis on the effects of IgG cross-linking at later time points when the majority of EBV genes are expressed and the viral genome is actively being replicated. In all, these data enhance our understanding of mechanistic linkages connecting protein ubiquitination, RNA processing, apoptosis, and the EBV life cycle.


Assuntos
Herpesvirus Humano 4/patogenicidade , Proteômica/métodos , Linfócitos B/metabolismo , Linhagem Celular Tumoral , Interações Hospedeiro-Patógeno , Humanos , Ubiquitinação
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