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1.
Aging (Albany NY) ; 122020 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-32039832

RESUMO

This work aimed to investigate tumor-infiltrating immune cells (TIICs) and immune-associated genes in the tumor microenvironment of osteosarcoma. An algorithm known as ESTIMATE was applied for immune score assessment, and osteosarcoma cases were assigned to the high and low immune score groups. Immune-associated genes between these groups were compared, and an optimal immune-related risk model was built by Cox regression analyses. The deconvolution algorithm (referred to as CIBERSORT) was applied to assess 22 TIICs for their amounts in the osteosarcoma microenvironment. Osteosarcoma cases with high immune score had significantly improved outcome (P<0.01). The proportions of naive B cells and M0 macrophages were significantly lower in high immune score tissues compared with the low immune score group (P<0.05), while the amounts of M1 macrophages, M2 macrophages, and resting dendritic cells were significantly higher (P<0.05). Important immune-associated genes were determined to generate a prognostic model by Cox regression analysis. Interestingly, cases with high risk score had poor outcome (P<0.01). The areas under the curve (AUC) for the risk model in predicting 1, 3 and 5-year survival were 0.634, 0.781, and 0.809, respectively. Gene set enrichment analysis suggested immunosuppression in high-risk osteosarcoma patients, in association with poor outcome.

2.
J Biomol Struct Dyn ; : 1-9, 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31918625

RESUMO

In recent years, deep neural networks have begun to receive much attention, which has obvious advantages in feature extraction and modeling. However, in the using of deep neural networks for the QSAR modeling process, the selection of various parameters (number of neurons, hidden layers, transfer functions, data set partitioning, number of iterations, etc.) becomes difficult. Thus, we proposed a new and easy method for optimizing the model and selecting Deep Neural Networks (DNN) parameters through uniform design ideas and orthogonal design methods. By using this approach, 222 chloroquine (CQ) derivatives with half maximal inhibitory concentration values reported in different kinds of literature were selected to establish DNN models and a total number of 128,000 DNN models were built to determine the optimized parameters for selecting the better models. Comparing with linear and Artificial Neural Network (ANN) models, we found that DNN models showed better performance.Communicated by Ramaswamy H. Sarma.

3.
Onco Targets Ther ; 12: 9093-9104, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31806994

RESUMO

Purpose: Diosgenin (DSG) is the precursor of steroid hormones and plays a crucial part in the proliferation of various carcinomas including human colorectal cancer and gastric carcinoma. Nevertheless, its specific features and mechanisms in human cholangiocarcinoma (CCA) remain unknown. Methods: MTS assay, colony-forming assay, and EdU assay were performed to determine the role of DSG on the progression of human CCA cells. The distributions of cell cycle, the ratio of apoptosis, and the mitochondrial membrane potential (ΔΨm) were studied by flow cytometry (FCM). AO/EB and Hoechst 33258 staining were performed to observe the morphological features of cell apoptosis. TEM was performed to observe the ultrastructures of QBC939 and HuCCT1 cells. The mRNA and protein expression of mitochondrial apoptotic pathway and GSK3ß/ß-catenin pathway were further confirmed by qPCR and Western blotting. The xenograft tumor model of HuCCT1 cells was built. Immunohistochemistry of tumor tissues was performed. Results: Our results indicated that DSG inhibited the progression of six CCA cell lines. In vivo tumor studies also indicated that DSG significantly inhibited tumor growth in xenografts in nude mice. The expression of mitosis-promoting factor cyclinB1 was decreased along with the elevating level of cell cycle inhibitor p21, resulting in arresting CCA cell cycles at G2/M phase. Furthermore, DSG induced apoptosis with the increased expressions of cytosol cytochrome C, cleaved-caspase-3, cleaved-PARP1 and the Bax/Bcl-2 ratio. Mechanistically, our study showed that GSK3ß/ß-catenin pathway was involved in the apoptosis of CCA cells. Thus, DSG might provide a new clue for the drug therapy of CCA. Conclusion: In our data, DSG was found to have efficient antitumor potential of human CCA cells in vitro and in vivo.

4.
Int J Mol Sci ; 20(24)2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31842360

RESUMO

Drought stress is a major obstacle to agriculture. Although many studies have reported on plant drought tolerance achieved via genetic modification, application of plant growth-promoting rhizobacteria (PGPR) to achieve tolerance has rarely been studied. In this study, the ability of three isolates, including Bacillus amyloliquefaciens 54, from 30 potential PGPR to induce drought tolerance in tomato plants was examined via greenhouse screening. The results indicated that B. amyloliquefaciens 54 significantly enhanced drought tolerance by increasing survival rate, relative water content and root vigor. Coordinated changes were also observed in cellular defense responses, including decreased concentration of malondialdehyde and elevated concentration of antioxidant enzyme activities. Moreover, expression levels of stress-responsive genes, such as lea, tdi65, and ltpg2, increased in B. amyloliquefaciens 54-treated plants. In addition, B. amyloliquefaciens 54 induced stomatal closure through an abscisic acid-regulated pathway. Furthermore, we constructed biofilm formation mutants and determined the role of biofilm formation in B. amyloliquefaciens 54-induced drought tolerance. The results showed that biofilm-forming ability was positively correlated with plant root colonization. Moreover, plants inoculated with hyper-robust biofilm (ΔabrB and ΔywcC) mutants were better able to resist drought stress, while defective biofilm (ΔepsA-O and ΔtasA) mutants were more vulnerable to drought stress. Taken altogether, these results suggest that biofilm formation is crucial to B. amyloliquefaciens 54 root colonization and drought tolerance in tomato plants.

5.
Medicine (Baltimore) ; 98(45): e17920, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31702672

RESUMO

There is little information concerning the predictive ability of the preoperative platelet to albumin ratio (PAR) in hepatocellular carcinoma (HCC) patients after liver resection. In the current study, we aimed to assess the prognostic power of the PAR in HCC patients without portal hypertension (PH) following liver resection.Approximately 628 patients were included in this study. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive value of the PAR for both recurrence-free survival (RFS) and overall survival (OS). Univariate and multivariate analyses were used to identify the independent risk factors for both RFS and OS.During the follow-up period, 361 patients experienced recurrence, and 217 patients died. ROC curve analysis suggested that the best cut-off value of the PAR for RFS was greater than 4.8. The multivariate analysis revealed that microvascular invasion (MVI), tumor size >5 cm, high aspartate aminotransferase-to-platelet count ratio index (APRI) and high PAR were four independent risk factors for both RFS and OS. Patients with a low PAR had significantly better RFS and OS than those with a high PAR.The PAR may be a useful marker to predict the prognosis of HCC patients after liver resection. HCC patients with a high preoperative PAR had a higher recurrent risk and lower long-term survival rate than those with a low preoperative PAR.


Assuntos
Albuminas/metabolismo , Plaquetas/metabolismo , Carcinoma Hepatocelular/mortalidade , Neoplasias Hepáticas/mortalidade , Recidiva Local de Neoplasia/epidemiologia , Adulto , Biomarcadores/sangue , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Feminino , Hepatectomia/mortalidade , Hepatectomia/estatística & dados numéricos , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Valor Preditivo dos Testes , Período Pré-Operatório , Intervalo Livre de Progressão , Curva ROC
6.
Arch Toxicol ; 93(11): 3207-3218, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31552475

RESUMO

Prediction of pEC50 values of dioxins binding with the aryl hydrocarbon receptor (AhR) is of great significance for exploring how dioxins induce toxicity in human body and evaluating their environmental behaviors and risks. To reveal the factors that influence the toxicity of dioxins, provide more accurate mathematical models for predicting the pEC50 values of dioxins, and supplement the toxicity database of persistent organic pollutants, qualitative structure-activity relationship (SAR) and two-dimensional quantitative structure-activity relationship (2D-QSAR) were used in this study. The research objects in this study were 60 organic compounds with pEC50 values and 162 compounds without pEC50 values, which included polychlorinated dibenzofurans (PCDFs), polychlorinated dibenzo-p-dioxins (PCDDs), and polybrominated dibenzo-p-dioxins (PBDDs). The qualitative structure-activity relationship (SAR) was performed first and concluded that halogen substitutions at any of the 2, 3, 7, and 8 sites increased the pEC50 value of the compound. Moreover, two-dimensional quantitative structure-activity relationship (2D-QSAR) models were established by employing multiple linear regression (MLR) method and artificial neural network (ANN) algorithm to investigate the factors affecting the pEC50 values of dioxins molecules. MLR was used to establish the well-understood linear model and ANN was used to establish a more accurate non-linear model. Both models have good fitting, robustness, and predictive ability. Importantly, the ability of dioxins binding to AhR is mainly determined by molecular descriptors including E1m, SM09_AEA (dm), RDF065u, F05 [Cl-Cl], and Neoplastic-80. In addition, the pEC50 values of the 162 dioxins without toxicity data were predicted by MLR and ANN models, respectively.

7.
PLoS One ; 14(7): e0219219, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31269063

RESUMO

Posthepatectomy liver failure (PHLF) is the most leading cause of mortality following hepatectomy in patients with hepatocellular carcinoma (HCC). Platelet count was reported to be a simple but useful indicator of liver cirrhosis and function of spleen. Spleen stiffness (SS) was used to evaluate the morphological change of spleen and was reported to be related to liver cirrhosis and portal hypertension. However, the predictive value of platelet to spleen stiffness ratio (PSR) on PHLF remains unknown. A retrospective study was performed to analyze 158 patients with HCC following hepatectomy from August 2015 to February 2016. Univariate and multivariate analyses were performed to evaluate the value of each risk factor for predicting PHLF. The predictive efficiency of the risk factors was evaluated by receiver operating characteristic (ROC) curve. PHLF occured in 23 (14.6%) patients. PSR (P<0.001, odds ratio (OR) = 0.622, 95% confidence interval (CI) 0.493~0.784), hepatic inflow occlusion (HIO) (P = 0.003, OR = 1.044, 95% CI 1.015~1.075) and major hepatectomy (P = 0.019, OR = 5.967, 95% CI 1.346~26.443) were demonstrated to be the independent predictive factors for development of PHLF in a multivariate analysis. Results of the present study suggested PSR is a novel and non-invasive model for predicting PHLF in patients with HCC.

8.
Int J Biol Macromol ; 136: 1247-1257, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31247228

RESUMO

Bone defects arise from trauma, skeletal diseases or tumor resections have become a critical clinical challenge. Biocomposite materials as artificial bone repair materials provide a promising approach for bone regeneration. In this study, we used silk fibroin (SF), carboxymethyl chitosan (CMCS), cellulose nanocrystals (CNCs) and strontium substituted hydroxyapatite (Sr-HAp) to prepare the biocomposite scaffolds of SF/CMCS, SF/CMCS/CNCs, SF/CMCS/CNCs/Sr-HAp. The characterization results showed that all the SF-based scaffolds have a porous sponge-like structure with porosities over 80%. In addition, there was a significant increase in compressive strength of SF/CMCS/Sr-HAp/CNCs scaffold when compared to that of SF/CMCS scaffolds, while maintaining high porosity with lower swelling ratio. All the SF-based scaffolds were non-toxic and had a good hemocompatibility. Comparing to the SF/CMCS scaffold, the scaffolds with addition of Sr-HAp and/or CNCs showed enhanced protein adsorption and ALP activity. In addition, higher expression of osteogenic gene markers such as RUNX2, ALP, OCN, OPN, BSP and COL-1 further substantiated the applicability of SF/CMCS/Sr-HAp/CNCs scaffolds for bone related applications. Hence, this study suggests that SF/CMCS/Sr-HAp/CNCs scaffolds have a potential in non-loading bone repair application.


Assuntos
Osso e Ossos/citologia , Celulose/química , Quitosana/análogos & derivados , Fibroínas/química , Hidroxiapatitas/química , Nanopartículas/química , Estrôncio/química , Engenharia Tecidual , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Quitosana/química , Humanos , Teste de Materiais , Nanocompostos/química , Osteogênese/efeitos dos fármacos , Tecidos Suporte/química
9.
Medicine (Baltimore) ; 98(18): e15458, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31045820

RESUMO

Posthepatectomy liver failure (PHLF) is the main cause of perioperative death, and liver cirrhosis is one of the most important risk factors for PHLF. Spleen stiffness (SS) is a novel ultrasonic indicator for liver cirrhosis and portal hypertension, however, it is not clear that whether it has a significant influence on PHLF. Future remnant liver volume (FRLV) is a significant factor for liver regeneration after hepatectomy, spleen volume (SV) could also predict the degree of liver cirrhosis, and recent literatures reported that SV to FRLV ratio (SV/FRLV) could predict small for size syndrome (SFSS) in liver transplantation, however, the relationship between SV/FRLV and PHLF in patients receiving hepatectomy is not known. Systemic inflammatory response (SIR) plays a significant role in the pathogenesis and progression of liver cirrhosis, however, it is not very clear about the exact relationship between SIR and PHLF.We prospectively collected the medical data of consecutive patients diagnosed with hepatocellular carcinoma (HCC) who underwent hepatectomy from August 2015 to February 2016. Preoperative measurements of SS, liver stiffness (LS), SV, FRLV, and SIR were performed on all patients. A univariate analysis was performed to find the risk factors of PHLF and a multivariate analysis was used to identify independent risk factors. The predictive efficiency of the risk factors was evaluated by receiver operating characteristic (ROC) curve.Twenty three (23) (14.6%) patients developed PHLF. Univariate analysis found several variables significantly related to PHLF, they were as follows: tumor diameter (P = .01), cirrhosis (P = .001), neutrophil to lymphocyte ratio (NLR) (P = .018), LS (P = .001), SS (P = .001), SV/FRLV (P < .001), operation duration (P = .003), transfusion (P = .009), hepatic inflow occlusion (HIO) (P = .001). Finally, SV/FRLV (P < .001, hazard ratio (HR) = 26.356, 95% confidence interval (CI) 1.627-425.21), SS (P = .009, HR = 1.077, 95%CI 1.017-1.141), and HIO time (P = .002, HR = 1.043, 95%CI 1.014-1.072) were determined as the independent risk factors of PHLF by multivariate analysis.SS and SV/FRLV help to predict the development of PHLF in patients with hepatocellular carcinoma.


Assuntos
Carcinoma Hepatocelular/diagnóstico por imagem , Hepatectomia/efeitos adversos , Falência Hepática/etiologia , Neoplasias Hepáticas/diagnóstico por imagem , Complicações Pós-Operatórias/etiologia , Ultrassonografia/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Elasticidade , Feminino , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Tamanho do Órgão , Valor Preditivo dos Testes , Estudos Prospectivos , Curva ROC , Fatores de Risco , Baço/diagnóstico por imagem , Baço/patologia , Resultado do Tratamento
10.
J Ethnopharmacol ; 240: 111936, 2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31078692

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Sishen Wan (SSW) is a commercial and frequently used Chinese patent medicine listed in the Chinese Pharmacopeia, which is usually used to treat chronic colitis. AIM OF THE STUDY: We explored the pharmacological mechanism of Sishen Wan attenuated experimental chronic colitis by inhibiting Wnt/ß-catenin pathway. MATERIALS AND METHODS: Experimental chronic colitis was induced by trinitrobenzene sulfonic acid (TNBS). The therapeutic effect of SSW were analyzed by index of colonic weight, colonic length, pathological score. Cytokines expression were analyzed by ELISA, while the apoptosis level was checked by TUNEL staining. These proteins of Wnt/ß-catenin signaling pathway was analyzed by Western blot assay. RESULTS: Rats with TNBS-induced chronic colitis were treated by SSW for 10 days. The efficacy of SSW was demonstrated by improved macroscopic and microscopic colonic damage. SSW increased the level of ATP in colonic mucosa, while SSW inhibited ß-catenin, ubiquitination of Nemo-like-kinase-associated ring finger protein and T-cell factor, and expression of Wnt/ß-catenin downstream proteins (including c-Myc, cyclo-oxygenase-2, cyclin D1, survivin, signal transducer and activator of transcription 3 and zipper-interacting protein kinase), and improved lymphoid enhancer factor ubiquitination and ß-TrCP activity, followed by excessive apoptosis of colonic epithelial cells. CONCLUSIONS: SSW effectively attenuated experimental chronic colitis induced by TNBS, which was realized by inhibition of the Wnt/ß-catenin signaling pathway.


Assuntos
Anti-Inflamatórios/farmacologia , Colite/imunologia , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Anti-Inflamatórios/uso terapêutico , Doença Crônica , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/patologia , Colo/efeitos dos fármacos , Colo/imunologia , Colo/patologia , Citocinas/imunologia , Masculino , Ratos Sprague-Dawley , Ácido Trinitrobenzenossulfônico , Proteína Wnt3A/imunologia , beta Catenina/imunologia
11.
Artigo em Inglês | MEDLINE | ID: mdl-30743159

RESUMO

OBJECTIVE(S): The aim of this study was to compare the patient characteristics, type of genetic disease and inheritance, volume of activity, practice patterns and pregnancy outcomes, in private versus publically funded IVF pre-implantation genetic testing (PGT) for translocation (IVF-PGT-SR) and aneuploidy (PGT-A) periods. STUDY DESIGN: This study retrospectively analyzed data during both privately funded period (PRP) and publically funded period (PUP) of assisted reproductive technology (ART) for a total of 275 patients. 83 patients underwent IVF-PGT-SR and 192 patients underwent IVF-PGT-A. Given that PGT-SR is a chromosomal abnormality hereditary in nature, whereas PGT-A is sporadic in addition to the contrasting funding policies, the two cohorts were analyzed separately. To achieve the proposed objective, the two groups under analysis were grouped in accordance with their respective coverage systems for infertility. RESULTS: Among translocation patients, 94 normal/balanced embryos were obtained from 47 IVF-PGT cycles in PRP whereas 145 embryos were obtained from 92 IVF-PGT cycles in PUP. The average number of embryos transferred per embryo transfer cycle was significantly lower in PUP in comparison to PRP (1.13 vs. 1.74, p < 0.0001). 13 singletons and 2 sets of twins were conceived in PRP. 14 singletons were conceived in PUP. Regardless of funding period, there were more reciprocal translocation carriers (79.4% in PRP and 76.4% in PUP) and more male carriers (82.4% in PRP and 60% in PUP), of which the majority had abnormal sperm parameters. Among aneuploidy patients, on average 2.5 embryos in PRP and 1.4 embryos in PUP were transferred per ET cycle (p = 0.05). There was a 13.3% increase in number of IVF-PGT-A attempts per patient in PRP compared to PUP. Live birth rate per IVF-PGT-A was higher in PRP (29.7% vs. 15%, P = 0.02), which consisted of 48 singletons and 18 multiparous pregnancies in PRP and 9 singletons in PUP. CONCLUSION(S): Public coverage of ART is associated with a greater utilization ART, as well as a reduced number in embryo transfer (ET) per cycle, a lower proportion of cycles resulting in successful pregnancy and a lower multiple birth rate. Our study ultimately shines light on the effect of providers' and patients' monetary conscious on pregnancy outcome.


Assuntos
Fertilização In Vitro/economia , Organização do Financiamento/estatística & dados numéricos , Testes Genéticos/economia , Resultado da Gravidez/economia , Diagnóstico Pré-Implantação/economia , Adulto , Transferência Embrionária/estatística & dados numéricos , Feminino , Organização do Financiamento/métodos , Humanos , Gravidez , Técnicas de Reprodução Assistida/estatística & dados numéricos , Estudos Retrospectivos , Resultado do Tratamento
12.
Mol Med Rep ; 19(3): 1739-1746, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30628700

RESUMO

The present study aimed to evaluate the effects of Krüppel­like factor 2 (KLF2) on the differentiation of endothelial progenitor cells (EPCs) to endothelial cells (ECs) induced by shear stress, and to investigate the corresponding mechanisms. Cultured rat late EPCs were exposed to shear stress (12 dyn/cm2) for different lengths of time. Reverse transcription­quantitative polymerase chain reaction (RT­qPCR) was used to measure the initial KLF2 mRNA levels in each group. Subsequently, the EPCs were treated with anti­integrin ß1 or ß3 antibodies to block integrin ß1 and ß3, respectively, or cytochalasin D to destroy F­actin, and the subsequent expression levels of KLF2 in EPCs were measured. Then, KLF2 small interfering RNAs (siRNAs) were transfected into EPCs, and RT­qPCR was used to measure the mRNA expression level of KLF2. Additionally, flow cytometry was applied to evaluate the protein levels of cluster of differentiation 31 (CD31) and the von Willebrand factor (vWF), and the regulatory effects of KLF2 in the promoter region of vWF were determined via a luciferase assay. High shear stress upregulated KLF2 expression, while blocking integrin ß1/ß3 or destroying F­actin resulted in a corresponding decrease in KLF2 expression. Downregulation of KLF2 expression by siKLF2 inhibited the differentiation of EPCs to ECs under shear stress conditions, while the expression of EC­specific markers decreased, including CD31 and vWF. Various lengths of the vWF promoter region induced vWF expression, and EPCs co­transfected with KLF2 significantly increased the vWF expression levels compared with the group treated with vWF alone (P<0.01). In conclusion, shear stress may upregulate KLF2 expression, which may be associated with the integrin­actin cytoskeleton system. Most importantly, the shear stress­induced differentiation of EPCs may be mediated by KLF2.


Assuntos
Diferenciação Celular/genética , Células Progenitoras Endoteliais/metabolismo , Endotélio Vascular/crescimento & desenvolvimento , Fatores de Transcrição Kruppel-Like/genética , Estresse Mecânico , Actinas/genética , Animais , Anticorpos Anti-Idiotípicos/administração & dosagem , Citocalasina D/metabolismo , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Células Progenitoras Endoteliais/citologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Integrina beta1/imunologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Ratos , Fator de von Willebrand/genética
13.
J Cell Biochem ; 120(1): 562-574, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30191596

RESUMO

As a potent and selective drug, brigatinib exhibits high efficacy against wild-type and mutant anaplastic lymphoma kinase (ALK) proteins to treat non-small cell lung cancer. In this work, the mechanisms of brigatinib binding to wild type and four mutant ALKs were investigated to gain insight into the dynamic energetic and structural information with respect to the design of novel inhibitors. Comparison between ALK-brigatinib and ALK-crizotinib suggests that the scaffold of brigatinib is well anchored to the residue Met1199 of hinge region by two hydrogen bonds, and the residue Lys1150 has the strong electrostatic interaction with the dimethylphosphine oxide moiety in brigatinib. These ALK mutations have significant influences on the flexibility of P-loop region and DFG sequences, but do not impair the hydrogen bonds between brigatinib and the residue Met1199 of hinge region. And mutations (L1196M, G1269A, F1174L, and R1275Q) induce diverse conformational changes of brigatinib and the obvious energy variation of residues Glu1167, Arg1209, Asp1270, and Asp1203. Together, the detailed explanation of mechanisms of those mutations with brigatinib further provide several guidelines for the development of more effective ALK inhibitors.

14.
Pathol Oncol Res ; 25(3): 849-858, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30361906

RESUMO

Vasculogenic mimicry (VM) is a new pattern of blood supplement independent of endothelial vessels, which is related with tumor invasion, metastasis and prognosis. However, the role of VM in the prognosis of cancer patients is controversial. This study aimed to perform a meta-analysis of the published data to attempt to clarify the prognostic value of VM in the digestive cancer. Relevant studies were retrieved from the PubMed, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure and VIP databases published before March 29, 2018. Studies were included if they detected VM in the digestive cancer and analyzed the overall survival (OS) or disease-free survival (DFS) according to VM status. Two independent reviewers screened the studies, extracted data, and evaluated the quality of included studies with the Newcastle-Ottawa scale. Meta-analysis was performed using STATA 12.0 software. A total of 22 studies with 2411 patients were included in this meta-analysis. Meta-analysis showed that VM was related with the poor OS (HR = 2.30, 95% CI: 2.06-2.56, P < 0.001) and DFS (HR = 2.60, 95% CI: 2.07-3.27, P < 0.001) of patients with digestive cancer. Subgroup analysis showed VM was related with tumor differentiation, lymph node metastasis and TNM stage. Moreover, the present meta-analysis was reliable, and there was no obvious publication bias. This meta-analysis suggested that VM was a poor prognosis of digestive cancer patients. Further large and well-designed studies are required.


Assuntos
Neoplasias Gastrointestinais/patologia , Neovascularização Patológica/patologia , Diferenciação Celular/fisiologia , Intervalo Livre de Doença , Humanos , Metástase Linfática/patologia , Prognóstico
15.
Molecules ; 23(10)2018 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-30332835

RESUMO

Gx-50 is a bioactive compound for the treatment of Alzheimer's disease (AD) found in Sichuan pepper (Zanthoxylum bungeanum). In order to find a stronger anti-AD lead compound, 20 gx-50 (1⁻20) analogs have been designed and synthesized, and their molecular structures were determined based on nuclear magnetic resonance (NMR) and mass spectrometry (MS) analysis, as well as comparison with literature data. Compounds 1⁻20 were evaluated for their anti-AD potential by using DPPH radical scavenging assay for considering their anti-oxidant activity, thioflavin T (ThT) fluorescence assay for considering the inhibitory or disaggregate potency of Aß, and transgenic Drosophila model assay for evaluating their rescue effect on memory loss. Finally, compound 13 was determined as a promising anti-AD candidate.


Assuntos
Peptídeos beta-Amiloides/química , Antioxidantes/síntese química , Cinamatos/síntese química , Transtornos da Memória/tratamento farmacológico , Zanthoxylum/química , Peptídeos beta-Amiloides/efeitos dos fármacos , Animais , Animais Geneticamente Modificados , Antioxidantes/química , Antioxidantes/farmacologia , Cinamatos/química , Cinamatos/farmacologia , Modelos Animais de Doenças , Drosophila , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Transtornos da Memória/genética , Estrutura Molecular
16.
Angew Chem Int Ed Engl ; 57(47): 15510-15516, 2018 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-30255542

RESUMO

A simple and efficient synthesis of NBN-doped conjugated polycyclic aromatic hydrocarbons (such as diazaborinines) has been accomplished by a catalyst-free intermolecular dehydration reaction at room temperature between boronic acid and diamine moieties with yields up to 99 %. Polycyclic aromatic hydrocarbons with a six-membered NBN ring are a new class of aggregation-induced emissive luminogens. Extremely sensitive detection of ppb levels of TNT by phenyl naphthodiazaborinine is straightforward. Visual detection of TNT is illustrated by fabrication of TNT test strips, which can detect as little as 100 ng of TNT powder. This simple and sensitive detection of TNT has potential applications in the area of public safety and security against terrorist activities.

17.
Dig Dis Sci ; 63(12): 3348-3358, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30155836

RESUMO

BACKGROUND: Aberrant expression of retinoic acid receptor α (RARα) was correlated with diverse carcinomas such as acute promyelocytic leukemia and colorectal carcinoma. Nevertheless, the function and mechanism of RARα in esophageal carcinoma (EC) remain unclear. AIM: To investigate the expression of RARα in EC and its effect in the tumorigenesis of EC. METHODS AND RESULTS: In immunohistochemistry study, RARα was overexpressed in human EC tissues, and its overexpression was closely related to the pathological differentiation, lymph node metastasis, and clinical stages in EC patients. Functionally, RARα knockdown suppressed the proliferation and metastasis of EC cells through downregulating the expression of PCNA, Ki67, MMP7, and MMP9, as well as enhanced drug susceptibility of EC cells to 5-fluorouracil and cisplatin. Mechanistically, RARα knockdown inhibited the activity of Wnt/ß-catenin pathway through reducing the phosphorylation level of GSK3ß at Ser-9 and inducing phosphorylation level at Tyr-216, which resulted in downregulation of its downstream targets such as MMP7, MMP9, and P-gP. CONCLUSIONS: Our results demonstrated that RARα knockdown suppressed the tumorigenicity of EC via Wnt/ß-catenin pathway. RARα might be a potential molecular target for EC clinical therapy.


Assuntos
Neoplasias Esofágicas , Regulação Neoplásica da Expressão Gênica , Receptor alfa de Ácido Retinoico/metabolismo , Via de Sinalização Wnt/fisiologia , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Feminino , Técnicas de Inativação de Genes/métodos , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Ensaio Tumoral de Célula-Tronco/métodos
18.
Medicine (Baltimore) ; 97(29): e11599, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30024565

RESUMO

There is little information regarding the predictive ability of albumin-bilirubin grades (ALBI) plus platelet-to-lymphocyte ratio (PLR) in patients with hepatocellular carcinoma (HCC) following liver resection. In this study, we aimed to evaluate the prognostic power of the ALBI-PLR score in patients with hepatitis B virus-related (HBV-related) HCC within Barcelona Clinic Liver Cancer (BCLC) stage A after liver resection.Around 475 patients were included in this study. Patients with preoperative ALBI grades 1, 2, or 3 were allocated a score of 0, 1, or 2, respectively. Patients with preoperative PLR >150 or ≤150 were allocated a score of 0 or 1, respectively. The ALBI-PLR score was the summary of the ALBI and PLR scores.During the follow-up period, 256 patients experienced recurrence, and 150 patients died. Multivariate analysis revealed tumor size, multiple tumors, positive HBV-DNA load, cirrhosis, and ALBI-PLR score as being independently associated with postoperative recurrence, whereas tumor size, high preoperative α-fetoprotein level, and ALBI-PLR score were independent risk factors for postoperative mortality. HCC patients with high ALBI-PLR score had poor recurrence-free and overall survival.The preoperative ALBI-PLR score is a surrogate marker for predicting HBV-related HCC patient's prognosis after liver resection. A high ALBI-PLR score is associated with a high incidence of postoperative recurrence and mortality.


Assuntos
Bilirrubina/sangue , Carcinoma Hepatocelular/sangue , Neoplasias Hepáticas/sangue , Contagem de Linfócitos/métodos , Contagem de Plaquetas/métodos , Albumina Sérica/análise , Adulto , Idoso , Biomarcadores Tumorais/análise , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Feminino , Seguimentos , Hepatectomia , Hepatite B/complicações , Humanos , Estimativa de Kaplan-Meier , Fígado/patologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco
19.
Int J Biol Macromol ; 118(Pt A): 1149-1156, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30001602

RESUMO

As an attractive therapeutic target for non-small-cell lung cancer (NSCLC), anaplastic lymphoma kinase (ALK) has got increased attention, and the selectivity of ALK inhibitors is an enormous challenge. Recently, 2,4-Diarylaminopyrimidines with high inhibitory activity over InsR/IGF1R were reported as ALK inhibitors, which harboring phosphine oxide moiety. In this work, it is the first time to reveal that the incorporation of dimethylphosphine oxide moiety and the smaller active pocket of ALK is key factor in the selectivity of inhibitor 11q toward ALK over IGF1R/InsR. The results of molecular simulation indicate that the subtle change in the binding pocket of ALK is mainly associated with the flexibility of P-loop and the own residues K1150 and D1270. The replacement of the dimethylphosphine oxide and methylpiperazine of inhibitor 11q would alter the major inhibitory effects of binding and activation. The results further combined 3D-QSAR can not only profile the binding mechanism between the 2,4-Diarylaminopyrimidines inhibitors and ALK, but also supply the useful information for the rational design of a more potential small molecule inhibitor bound to ALK receptor.


Assuntos
Desenho de Drogas , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Quinase do Linfoma Anaplásico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Receptores Proteína Tirosina Quinases/química
20.
Front Pharmacol ; 9: 283, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29636693

RESUMO

Erzhi Pill (EZP) is one of the basic prescriptions for treating liver diseases in traditional Chinese medicine. However, its mechanism of action is still undefined. The PI3K/AKT/Raptor/Rictor signaling pathway is closely related to apoptosis and plays a significant role in the pathogenesis of liver disease. To define the mechanism of the hepatoprotective effect of EZP in the treatment of liver disease, hepatic injury induced by 2-acetylaminofluorene/partial hepatectomy was treated by EZP for 14 days. The therapeutic effect of EZP was confirmed by the decreased production of aspartate aminotransferase and alanine aminotransferase, recovery of pathological liver injury, followed by inhibition of pro-inflammatory cytokines and transforming growth factor-ß1. Bromodeoxyuridine assay and TUNEL staining indicated that apoptosis was suppressed and the numbers of cells in S phase and G0/G1phase were decreased. The crucial proteins in the PI3K/AKT/Raptor/Rictor signaling pathway were deactivated in rats with experimental liver injury treated by EZP. These results indicated that the hepatoprotective effect of EZP via inhibition of hepatocyte apoptosis was closely related to repression of the PI3K/Akt/Raptor/Rictor signaling pathway.

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