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1.
J Transl Med ; 19(1): 379, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34488791

RESUMO

BACKGROUND: Since interferon regulatory factor (IRF) family functions in immune response to viral infection, its role in colorectal cancer (CRC) has not been inspected before. This study tries to investigate members of IRF family using bioinformatics approaches in aspect of differential expressions, biological function, tumor immune infiltration and clinical prognostic value for patients with CRC. METHODS: Transcriptome profiles data, somatic mutations and clinical information of CRC were obtained from COAD/READ dataset of The Cancer Genome Atlas (TCGA) as a training set. Gene expression data (GSE17536 and GSE39582) were downloaded from the Gene Expression Omnibus as a validating set. A random forest algorithm was used to score the risk for every case. Analyzing gene and function enrichment, constructing protein-protein interaction and noncoding RNA network, identifying hub-gene, characterizing tumor immune infiltration, evaluating differences in tumor mutational burden (TMB) and sensitivity to chemotherapeutics or immunotherapy were performed by a series of online tools and R packages. Immunohistochemical (IHC) examinations were carried out validation in tissue samples. RESULTS: Principal-component analysis (PCA) suggested that the transcript expression levels of nine members of IRF family differed between normal colorectum and CRC. The risk score constructed by IRF family not only acted as an independent factor for predicting survival in CRC patients with different biological processes, signaling pathways and TMB, but also indicated different immunotherapy response with diverse immune and stromal cells infiltration. IRF3 and IRF7 were upregulated in CRC and suggested a shorter survival time in patients with CRC. Differentially expressed members of IRF family exhibited varying degrees of immune cell infiltration. IHC analysis showed a positive association between IRF3 and IRF7 expression and tumor-infiltrating immune cells, including CD4+ T cell and CD68+ macrophages. CONCLUSIONS: On account of differential expression, IRF family members can help to predict both response to immunotherapy and clinical prognosis of patients with CRC. Our bioinformatic investigation not only gives a preliminary picture of the genetic features as well as tumor microenvironment, but it may provide a clue for further experimental exploration and verification on IRF family members in CRC.


Assuntos
Neoplasias Colorretais , Fatores Reguladores de Interferon , Biomarcadores Tumorais , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Fatores Reguladores de Interferon/genética , Prognóstico , Microambiente Tumoral
2.
J Transl Med ; 19(1): 347, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389031

RESUMO

BACKGROUND: Tumor-associated macrophages (TAM) are immunosuppressive cells that contribute to impaired anti-cancer immunity. Iron plays a critical role in regulating macrophage function. However, it is still elusive whether it can drive the functional polarization of macrophages in the context of cancer and how tumor cells affect the iron-handing properties of TAM. In this study, using hepatocellular carcinoma (HCC) as a study model, we aimed to explore the effect and mechanism of reduced ferrous iron in TAM. METHODS: TAM from HCC patients and mouse HCC tissues were collected to analyze the level of ferrous iron. Quantitative real-time PCR was used to assess M1 or M2 signature genes of macrophages treated with iron chelators. A co-culture system was established to explore the iron competition between macrophages and HCC cells. Flow cytometry analysis was performed to determine the holo-transferrin uptake of macrophages. HCC samples from The Cancer Genome Atlas (TCGA) were enrolled to evaluate the prognostic value of transferrin receptor (TFRC) and its relevance to tumor-infiltrating M2 macrophages. RESULTS: We revealed that ferrous iron in M2-like TAM is lower than that in M1-like TAM. In vitro analysis showed that loss of iron-induced immunosuppressive M2 polarization of mouse macrophages. Further experiments showed that TFRC, the primary receptor for transferrin-mediated iron uptake, was overexpressed on HCC cells but not TAM. Mechanistically, HCC cells competed with macrophages for iron to upregulate the expression of M2-related genes via induction of HIF-1α, thus contributing to M2-like TAM polarization. We further clarified the oncogenic role of TFRC in HCC patients by TCGA. TFRC is significantly increased in varieties of malignancies, including HCC, and HCC patients with high TFRC levels have considerably shortened overall survival. Also, TFRC is shown to be positively related to tumor-infiltrating M2 macrophages. CONCLUSIONS: Collectively, we identified iron starvation through TFRC-mediated iron competition drives functional immunosuppressive polarization of TAM, providing new insight into the interconnection between iron metabolism and tumor immunity.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Linhagem Celular Tumoral , Humanos , Ferro , Camundongos , Macrófagos Associados a Tumor
3.
J Clin Pharm Ther ; 46(3): 820-831, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33751618

RESUMO

WHAT IS KNOWN AND OBJECTIVES: Various population pharmacokinetic (PopPK) models for vancomycin in children and adolescents have been constructed to optimize the therapeutic regimen of vancomycin. However, little is known about their predictive performance when extrapolated to different clinical centres. Therefore, the aim of this study was to externally validate the predictability of vancomycin PopPK model when extrapolated to different clinical centres and verify its applicability in an independent data set. METHODS: The published models were screened from the literature and evaluated using an external data set of a total of 451 blood concentrations of vancomycin measured in 220 Chinese paediatric patients. Prediction- and simulation-based diagnostics and Bayesian forecasting were performed to evaluate the predictive performance of the models. RESULTS: Ten published PopPK models were assessed. Prediction-based diagnostics showed that none of the investigated models met all the standards (median prediction error (MDPE) ≤ ±20%, median absolute prediction error (MAPE) ≤30%, PE% within ±20% (F20 ) ≥35% and PE% within ±30% (F30 ) ≥50%), indicating unsatisfactory predictability. In simulation-based diagnostics, both the visual predictive checks (VPC) and the normalized prediction distribution error (NPDE) indicated misspecification in all models. Bayesian forecasting results showed that the accuracy and precision of individual predictions could be significantly improved with one or two prior observations, but frequent monitoring might not be necessary in the clinic, since Bayesian forecasting identified that greater number of samples did not significantly improve the predictability. Model 3 established by Moffett et al showed better predictability than other models. WHAT IS NEW AND CONCLUSION: The 10 published models performed unsatisfactorily in prediction- and simulation-based diagnostics; none of the published models was suitable for designing the initial dosing regimens of vancomycin. Pharmacokinetic characteristics and covariates, such as weight, renal function, age and underlying disease should be taken into account when extrapolating the vancomycin model. Bayesian forecasting combined with therapeutic drug monitoring based on model 3 can be used to adjust vancomycin dosing regimens.

4.
Hepatol Int ; 15(1): 155-165, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33385299

RESUMO

BACKGROUND AND AIMS: Rifaximin has been recommended as a prophylactic drug for hepatic encephalopathy (HE) and spontaneous bacterial peritonitis (SBP). This study aims to explore whether low-dose rifaximin can prevent overall complications and prolong survival in cirrhotic patients. METHODS: In this multi-centre randomized open-labelled prospective study, 200 patients with decompensated cirrhosis were randomly assigned at a ratio of 1:1. Patients in rifaximin group were administered 400 mg rifaximin twice daily for 6 months, and all other therapeutic strategies were kept unchanged in both groups as long as possible. The primary efficacy endpoints were the incidence of overall complications and liver transplantation-free survival. The secondary endspoints were the incidence of each major cirrhosis-related complication, as well as the Child-Pugh score and class. RESULTS: The major baseline characteristics were similar in the two groups except for HE. The cumulative incidence and frequency of overall complications were significantly lower in rifaximin group than in the control group (p < 0.001). Though liver transplantation-free survival was not significantly different between the two groups, subgroup analysis showed rifaximin markedly prolonged liver transplantation-free survival in patients with Child-Pugh score ≥ 9 (p = 0.007). Moreover, rifaximin markedly reduced the episodes of ascites exacerbation (p < 0.001), HE (p < 0.001) and gastric variceal bleeding (EGVB, p = 0.031). The incidence of adverse events was similar in the two groups. CONCLUSION: Low-dose rifaximin significantly decreases the occurrence of overall complications, leading to prolonged survival in patients with advanced stages of cirrhosis in this trail. Further study should be carried out to compare the effect of this low-dose rifaximin with normal dose (1200 mg/day) rifaximin in preventing cirrhosis-related complications. CLINICAL TRIAL NUMBER: NCT02190357.

5.
Adv Healthc Mater ; 9(21): e2000650, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33000919

RESUMO

Sorafenib (SOR), a multi-kinase inhibitor for advanced hepatocellular carcinoma (HCC), reveals a limited therapeutic effect due to a lack of selectivity and evident drug resistance. In the present study, bismuth-based mesoporous nanomaterial (NBOF) is loaded with SOR and then coated with polyethylene glycol and folic acid conjugates (P-FA) to form an NBOF@SOR-P-FA nanocarrier system. The system achieves significantly enhanced anti-cancer efficacy by combining chemotherapy with radiotherapy. To evaluate the effect of synergistic treatment, cytotoxicity detection, Live/Dead staining, apoptotic assay, and Western blot analysis are performed. The results suggest that NBOF@SOR-P-FA significantly inhibits HCC cell proliferation and promotes cell apoptosis. Also, the NBOF@SOR-P-FA exhibits excellent biocompatibility by hemolysis and serum biochemical tests and produces a substantially enhanced contrast efficiency as compared to iohexol by computed tomography imaging. More importantly, the profound suppression of tumor growth and potentiation of apoptosis are observed in a mouse subcutaneous tumor model. Collectively, these results indicate that the bismuth-based nanotheranostic platform could enhance the therapeutic effect of sorafenib and serve as an innovative method for HCC treatment.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Bismuto/farmacologia , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Quimiorradioterapia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Niacinamida , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico
6.
Oncogene ; 39(35): 5768-5781, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32719439

RESUMO

Cumulative evidence suggests that microRNAs (miRNAs) promote gene expression in cancers. However, the pathophysiologic relevance of miRNA-mediated RNA activation in hepatocellular carcinoma (HCC) remains to be established. Our previous miRNA expression profiling in seven-paired HCC specimens revealed miR-93-5p as an HCC-related miRNA. In this study, miR-93-5p expression was assessed in HCC tissues and cell lines by quantitative real-time PCR and fluorescence in situ hybridization. The correlation of miR-93-5p expression with survival and clinicopathological features of HCC was determined by statistical analysis. The function and potential mechanism of miR-93-5p in HCC were further investigated by a series of gain- or loss-of-function experiments in vitro and in vivo. We identified that miR-93-5p, overexpressed in HCC specimens and cell lines, leads to poor outcomes in HCC cases and promotes proliferation, migration, and invasion in HCC cell lines. Mechanistically, rather than decreasing target mRNA levels as expected, miR-93-5p binds to the 3'-untranslated region (UTR) of mitogen-activated protein kinase kinase kinase 2 (MAP3K2) to directly upregulate its expression and downstream p38 and c-Jun N-terminal kinase (JNK) pathway, thereby leading to cell cycle progression in HCC. Notably, we also demonstrated that c-Jun, a downstream effector of the JNK pathway, enhances miR-93-5p transcription by targeting its promoter region. Besides, downregulation of miR-93-5p significantly retarded tumor growth, while overexpression of miR-93-5p accelerated tumor growth in the HCC xenograft mouse model. Altogether, we revealed a miR-93-5p/MAP3K2/c-Jun positive feedback loop to promote HCC progression in vivo and in vitro, representing an RNA-activating role of miR-93-5p in HCC development.


Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , MAP Quinase Quinase Quinase 2/metabolismo , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Regiões 3' não Traduzidas , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Células Hep G2 , Xenoenxertos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , MAP Quinase Quinase Quinase 2/biossíntese , MAP Quinase Quinase Quinase 2/genética , Masculino , Camundongos , Camundongos Nus , MicroRNAs/genética , Invasividade Neoplásica , Fosforilação , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-jun/genética , Transfecção , Regulação para Cima
7.
J Clin Pharm Ther ; 45(6): 1278-1287, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32557716

RESUMO

WHAT IS KNOWN AND OBJECTIVES: Augmented renal clearance (ARC) is characterized by enhanced renal clearance, which leads to insufficient vancomycin exposure and treatment failure. In haematologic malignancy patients, determination of optimal vancomycin dosage is essential because of high stake of life-threatening bacterial infection and increased clearance. The aim of this study was to describe vancomycin pharmacokinetic parameters in haematologic malignancy with augmented renal clearance children and define the appropriate dosing regimen to achieve an AUC0-24h /MIC ≥400. METHODS: Hematologic malignancy with ARC children was enrolled in this retrospective study. The vancomycin PPK model was established by non-linear mixed-effects modelling programme. Goodness-of-fit (GOF) plots, non-parametric bootstrap, normalized prediction distribution error (NPDE) and visual predictive checks (VPCs) were carried out for internal evaluation of the final model. Monte Carlo simulation method was used to stimulate the optimal dosage regimens. RESULTS: Fifty-three patients with 106 samples were included. A one-compartment model with first-order elimination was developed, and the final model was as follows: CL (L/h) = 6.32×(WT/70)0.75  × e0.0467 ; V(L) = 39.6×(WT/70), where WT denotes weight (kg). The internal validation of the model showed a good prediction performance. Monte Carlo simulation results showed that when MIC was 0.5 mg/L or 1 mg/L, the recommended doses to achieve a target of AUC0-24h /MIC ≥400 were 25 to 40 and 50 to 75 mg/kg/d, respectively. With decreasing weight, the recommended dosage to achieve an AUC0-24h /MIC ≥400 increased. WHAT IS NEW AND CONCLUSION: A one-compartment vancomycin PPK model was established in haematologic malignancy with augmented renal clearance children with weight with allometric scaling as a significant covariate. When MIC was 1 mg/L, current recommended paediatric dosages were insufficient in haematologic malignancy with augmented renal clearance children and should be increased.

8.
Eur J Drug Metab Pharmacokinet ; 45(4): 535-546, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32304024

RESUMO

BACKGROUND AND OBJECTIVES: Renal function has an important influence on the pharmacokinetics of vancomycin, and serum cystatin C (CysC) exhibits accurate predictive performance as a marker for renal function. This study aimed to develop a population pharmacokinetics (PopPK) model of vancomycin based on serum CysC in pediatric patients. In addition, vancomycin dosage was optimized with the area under the serum concentration-time curve over 24 h (AUC0-24)/minimum inhibitory concentration (MIC) ratio in the target range of 400-700 and the steady-state trough concentration (Css,trough). METHODS: Data were retrospectively obtained from pediatric patients aged 2-18 years who received vancomycin treatment for infection from January 2014 to June 2019. PopPK analysis and Monte Carlo simulations were conducted using nonlinear mixed effects model (NONMEM) software. RESULTS: A total of 220 children were included. Serum CysC and age were significant covariates affecting the pharmacokinetics of vancomycin. The final typical value of clearance was 2.25 L/h; the volume of distribution was 8.17 L. The average probability of target attainment values of AUC0-24/MIC ratios within 400-700 in the 2-7, 7-12, and 12-18 years age groups were 66.1%, 68.1% and 66.5%, respectively. The median Css,trough values of vancomycin for the 2-7, 7-12, and 12-18 years age groups were 7.49-11.84, 5.98-11.32, and 5.15-11.39 mg/L, respectively, and were highly correlated with AUC0-24/MIC ratios in the range of 400-700 when the MIC was 1 mg/L. CONCLUSIONS: The pharmacokinetic parameters for vancomycin in pediatric patients were estimated using a serum CysC model. The simulated dosages provide a reference for vancomycin therapy.


Assuntos
Antibacterianos/farmacocinética , Cistatina C/sangue , Modelos Biológicos , Vancomicina/farmacocinética , Adolescente , Fatores Etários , Antibacterianos/administração & dosagem , Biomarcadores/sangue , Criança , Pré-Escolar , Cálculos da Dosagem de Medicamento , Feminino , Humanos , Testes de Função Renal , Masculino , Estudos Retrospectivos , Vancomicina/administração & dosagem
9.
Ann Surg Oncol ; 27(5): 1546-1557, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32157528

RESUMO

BACKGROUND: The mechanistic target of rapamycin (mTOR) pathway, containing mTOR complex 1 (mTORC1) and mTORC2, is dysregulated in multiple cancers, including hepatocellular carcinoma (HCC). Mammalian lethal with sec-13 protein 8 (mLST8) is a shared constituent of both mTORC1 and mTORC2, yet little is known regarding its role in HCC development. METHODS: mLST8 expression was detected in a total of 186 pairs of HCC and adjacent non-tumor specimens. The correlation between mLST8 level and clinicopathological features or prognostic significance were analyzed. The role of mLST8 on biological functions was also preliminarily studied. RESULTS: The study revealed that the mLST8 level was dramatically higher in HCC specimens than in adjacent non-tumor specimens. mLST8 overexpression positively correlated with tumor size, differentiation, and vessel invasion. Cases with elevated mLST8 level had more unfavorable overall survival (OS) and disease-free survival (DFS) than those with downregulated mLST8 level. Multivariate analysis demonstrated that mLST8 upregulation was an independent predictive marker for OS and DFS. Calibration curves from nomogram models indicated an excellent coherence between nomogram prediction and actual situation. Decision curve analysis proved that mLST8-based nomograms presented much higher predictive accuracy when compared with conventional clinical staging systems. Mechanistically, mLST8 enhanced cell proliferation and invasion through the AKT (protein kinase B) pathway. CONCLUSIONS: Our study demonstrates that mLST8 exerts an oncogenic role in HCC and may become a promising prognostic biomarker and therapeutic target for HCC patients.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Homólogo LST8 da Proteína Associada a mTOR/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Linhagem Celular Tumoral , Proliferação de Células/genética , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Nomogramas , Prognóstico , Regulação para Cima , Adulto Jovem
10.
ACS Appl Mater Interfaces ; 12(15): 17193-17206, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32207914

RESUMO

Sorafenib, a multitargeted kinase inhibitor, has been reported to elicit a limited therapeutic effect in hepatocellular carcinoma (HCC). Currently, phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is emerging as a powerful modality for cancer therapy. However, few studies have been reported the effectiveness of the combination of sorafenib with PDT and PTT in HCC. Herein, we designed and synthesized bovine serum albumin (BSA)-coated zinc phthalocyanine (ZnPc) and sorafenib (SFB) nanoparticle (ZnPc/SFB@BSA). The obtained ZnPc/SFB@BSA was able to trigger PDT, PTT, and chemotherapy. After irradiation by a 730 nm light, ZnPc/SFB@BSA significantly suppressed HCC cell proliferation and metastasis while promoted cell apoptosis in vitro. Furthermore, intravenous injection of ZnPc/SFB@BSA led to dramatically reduced tumor growth in an orthotopic xenograft HCC model. More importantly, ZnPc/SFB@BSA presented low toxicity and adequate blood compatibility. Therefore, a combination of ZnPc with sorafenib via BSA-assembled nanoparticle can markedly suppress HCC growth, representing a promising strategy for HCC patients.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/terapia , Indóis/química , Neoplasias Hepáticas/terapia , Nanocápsulas/química , Compostos Organometálicos/química , Fármacos Fotossensibilizantes/uso terapêutico , Sorafenibe/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Indóis/metabolismo , Indóis/uso terapêutico , Luz , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Camundongos , Camundongos Nus , Compostos Organometálicos/metabolismo , Compostos Organometálicos/uso terapêutico , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fototerapia , Espécies Reativas de Oxigênio , Soroalbumina Bovina/química , Sorafenibe/metabolismo , Sorafenibe/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Eur J Drug Metab Pharmacokinet ; 45(1): 135-149, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31541402

RESUMO

BACKGROUND: Most of the current published population pharmacokinetic (PopPK) models are based on serum creatinine, but we often encounter an underestimation of its concentration in our clinical work. Therefore, we established a cystatin C-based model of vancomycin. OBJECTIVES: The purpose of this study was to externally verify the PopPK model of vancomycin based on the glomerular filtration rate (GFR) estimated by serum cystatin C in our previous study and to compare the prediction performance of cystatin C (Cys C) and serum creatinine (SCR)-based models. METHODS: The external data set consists of adults receiving vancomycin treatment at The First Affiliated Hospital of Guangxi Medical University. We summarized and restored published models based on serum creatinine values from the literature and used our external data set for initial screening. Visual and external verifications were used to further select candidate models for comparison. The mean prediction error (ME), mean absolute error (MAE) and root mean squared error (RMSE) were the primary outcomes for the overall comparison. Group comparisons of patients with different glomerular filtration rates (GFRs), ages and body mass index (BMI) levels were obtained by the Bayesian method. RESULTS: A total of 156 patients with 233 samples were collected as an external data set. Sixteen published models were summarized and restored. After screening, four candidate models suitable for the external data set were finally obtained for comparison. The cystatin C-based model has a smaller ME value in the overall comparison. In the group comparison, serum creatinine-based models were underestimated in the prediction for patient groups with age ≥ 60 years, abnormal BMI values and GFR < 90 ml/min/1.73 m2, for which the cystatin C-based model could solve this problem. CONCLUSION: After comparison, we suggest that cystatin C is a superior renal function marker to serum creatinine for vancomycin PopPK models.


Assuntos
Antibacterianos/farmacocinética , Biomarcadores/sangue , Creatinina/sangue , Cistatina C/sangue , Monitoramento de Medicamentos/métodos , Vancomicina/farmacocinética , Adulto , Idoso , Antibacterianos/administração & dosagem , China , Estudos de Coortes , Feminino , Taxa de Filtração Glomerular , Humanos , Rim/fisiologia , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Estudos Prospectivos , Vancomicina/administração & dosagem
12.
J Clin Pharm Ther ; 45(1): 88-96, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31463971

RESUMO

WHAT IS KNOWN AND OBJECTIVES: Some previous studies have indicated that serum cystatin C (Cys C) is a better marker than serum creatinine (SCR) for assessing the glomerular filtering rate (GFR). However, in almost all population pharmacokinetic models of vancomycin, the GFR is usually estimated from SCR. Therefore, the aim of this study was to compare the GFR estimated from SCR (sGFR) with the GFR estimated from Cys C (cGFR) and investigate which one can describe the characteristics of vancomycin population pharmacokinetics better in Chinese neurosurgical adult patients. METHODS: Patients from the Neurosurgery Department aged ≥18 years were enrolled retrospectively. Among these patients, the data from 222 patients were used to establish two population pharmacokinetic models based on sGFR and cGFR, separately. The data from another 95 patients were used for the external validation of these two models. Non-linear mixed-effect modelling (NONMEM) 7.4.3 was used for the population pharmacokinetic analysis. RESULTS: We developed two one-compartment models with first-order absorption based on Cys C and SCR, separately. In the Cys C model, age, body weight and cGFR were significant covariates on the clearance rate (CL) of vancomycin (typical value, 6.4 L/hour). In the SCR model, age and sGFR were significant covariates on the CL (typical value, 6.46 L/hour). The external validation results showed that the predictive performance of the two models was similar. WHAT IS NEW AND CONCLUSION: In this study, the predictive performance of two models was similar in neurosurgical patients. We did not find a significant improvement in the predictive performance of the model when GFR was estimated from Cys C.


Assuntos
Antibacterianos/farmacocinética , Modelos Biológicos , Procedimentos Neurocirúrgicos/métodos , Vancomicina/farmacocinética , Adulto , Fatores Etários , Antibacterianos/administração & dosagem , Biomarcadores/metabolismo , Creatinina/sangue , Cistatina C/sangue , Feminino , Taxa de Filtração Glomerular , Humanos , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Dinâmica não Linear , Estudos Retrospectivos , Vancomicina/administração & dosagem
13.
Dig Dis Sci ; 65(1): 168-177, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31350707

RESUMO

PURPOSE: The interferon regulatory factor 2 (IRF-2) acted as a tumor suppressor. We inspected IRF-2 as a predictor of prognosis in gastric cancer (GC) patients and tried to find out the potential molecular mechanism. METHODS: In this study, the association between IRF-2 expression and clinical or prognosis significance was investigated in 86 pairs of tumor and the adjacent normal gastric tissues from GC patients. After establishing the stable cell lines, the Transwell assays were deduced to evaluate the malignancy of tumor. Then, microarray assay was carried out and the GO/KEGG pathway analyses were conducted to identify IRF-2's target gene. The relationship between IRF-2 and matrix metalloproteinases 1 (MMP-1) was also investigated by the immunohistochemistry in 15 pairs of tumor and adjacent normal gastric tissues. RESULTS: We found that IRF-2 expression level in GC was significantly correlated with the prognosis of the patients. Transwell assays suggested an impaired ability of invasion and migration in IRF-2-overexpressed GC cells and a progressive malignant phenotype in IRF-2-knockdown GC cells. Ninety differentially expressed genes were found between IRF-2-overexpressed GC cells and its normal control sets by microarray. We demonstrated that MMP-1 was canonical in the network of differentially expressed genes by GO and KEGG pathway analysis and its expression level was markedly decreased in IRF-2-overexpressed cells of MKN-45 and increased in IRF-2-knockdown cells of SGC-7901. The expression of MMP-1 was inversely correlated with IRF-2 in GAC TMA specimens. CONCLUSION: IRF-2 may inhibit GC progression by down-regulating MMP-1 level.


Assuntos
Movimento Celular , Fator Regulador 2 de Interferon/metabolismo , Metaloproteinase 1 da Matriz/metabolismo , Neoplasias Gástricas/enzimologia , Idoso , Linhagem Celular Tumoral , Regulação para Baixo , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Fator Regulador 2 de Interferon/genética , Masculino , Metaloproteinase 1 da Matriz/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Transdução de Sinais , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia
14.
J Cell Biochem ; 121(4): 2938-2949, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31692072

RESUMO

BACKGROUND: Calcium-binding tyrosine phosphorylation-regulated protein (CABYR) is a group of isoforms produced by alternative splicing and is overexpressed in human malignancies including hepatocellular carcinoma (HCC). However, the prognostic value and biological functions of its major protein isoforms, named CABYR-a/b (combined CABYR-a and CABYR-b), in HCC remain to be established. METHODS: CABYR-a/b expression was detected in HCC tissues and cell lines by quantitative real-time polymerase chain reaction and Western blot analysis. The correlation of CABYR-a/b expression with clinical characteristics and its prognosis impact were determined by statistical analysis. Finally, the biological functions and molecular mechanism of CABYR-a/b were also investigated using molecular biology approaches. RESULTS: The present research found that CABYR-a/b was markedly elevated in HCC specimens and cell lines. Upregulated CABYR-a/b level had positive association with tumor size and differentiation in patients. Moreover, cases with elevated CABYR-a/b level had poorer overall survival (OS) and disease-free survival (DFS) than those with reduced CABYR-a/b level. Multivariate analysis and prognostic nomograms demonstrated that CABYR-a/b overexpression was an independent predictive indicator for OS and DFS. The calibration curve for the odds of OS and DFS demonstrated that the prediction by nomograms was in excellent accordance with actual situation. CABYR-a/b downregulation suppressed cell proliferation and induced G1-phase arrest via decreasing cyclin D1 and cyclin dependent kinase 4, while promoted apoptosis by reducing B-cell lymphoma 2 (Bcl-2) and increasing Bcl-2-associated death promoter. CONCLUSION: Our research indicates that CABYR-a/b exerts an oncogenic effect on HCC development and may become a new prognostic indicator for patients with HCC.

15.
Int J Mol Med ; 44(5): 1844-1854, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31485608

RESUMO

Long non­coding RNAs (lncRNAs) have been shown to contribute to progression and prognosis of hepatocellular carcinoma (HCC). However, expression profiling and interaction of lncRNAs with messenger RNAs (mRNAs) and microRNAs (miRNAs) remain largely unknown in HCC. The expression profiling of lncRNAs, mRNA and miRNAs was obtained using microarray. The Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analysis were used to characterize potential functions of differentially expressed mRNAs. Cytoscape was applied to construct an lncRNA­miRNA­mRNA co­expression network and candidate lncRNAs were validated via quantitative PCR in 30 pairs of HCC and adjacent tumor­free tissues. In this study, 1,056 upregulated and 1,288 downregulated lncRNAs were identified, while 2,687 mRNAs and 6 miRNAs were aberrantly expressed in HCC compared with adjacent tumor­free tissues. Potential functions of differentially expressed mRNAs were demonstrated to significantly participate in modulating critical genes in the cell cycle, such as cyclin E1 and cyclin B2. After screening, 95 lncRNAs, 5 miRNAs and 36 mRNAs were recruited for construction of lncRNA­mRNA­miRNA co­expression network in the cell cycle pathway. Subsequently, the top 5 lncRNAs that potentially modulate critical genes in the cell cycle were selected as the candidates for further verification. Kaplan­Meier curves using the Cancer Genome Atlas database showed that 13 targeted mRNAs were associated with overall survival of HCC patients. Finally, three lncRNAs, including ENST00000522221, lnc­HACE1­6:1 and lnc­ICOSLG­11:1, are significantly upregulated in HCC tissues compared with adjacent tumor­free tissues. These findings suggest that lncRNAs play essential roles in the pathogenesis of HCC via regulating coding genes and miRNAs, and may be important targets for diagnosis and treatment of this disease.


Assuntos
Carcinoma Hepatocelular/genética , Ciclo Celular/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Hepáticas/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Ontologia Genética , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade
16.
Drug Des Devel Ther ; 13: 2249-2270, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31308634

RESUMO

Background: It is reported that various diseases such as non-alcoholic fatty liver disease (NAFLD) are associated with imbalance of microbiome. And FXR has been well investigated in liver diseases. Purpose: The objective of this study was to identify the role of farnesoid X receptor agonist obeticholic acid via targeting gut microbiota in NAFLD. Patients and methods: Male C57BL/6 mice were fed either a normal-chow diet or a high-fat diet (HFD). Obeticholic acid(30mg/(kg·d)) and/or a combination of antibiotics were administered orally by gavage to mice for 12 weeks. Gut microbiota profiles were established through 16S rRNA amplicon sequencing. The effects of obeticholic acid on liver inflammation, the gut barrier, endotoxemia, gut microbiome and composition of the bile acid were also investigated. Results: Obeticholic acid treatment can significantly improve obesity, circulation metabolism disorders, liver inflammation and fibrosis, and intestinal barrier damage caused by HFD. Removal of normal commensal bacteria can weaken the effect of obeticholic acid. The gut microbial structure was changed, and abundance of Blautia was increased significantly after treated with obeticholic acid. After obeticholic acid treatment, the concentration of taurine-bound bile acid caused by HFD was reduced in the liver. Conclusion: Taken together, these data suggest that obeticholic acid has aprotective effect on NAFLD via changing the components of gut microbiota, specifically increasing the abundance of Blautia.


Assuntos
Ácido Quenodesoxicólico/análogos & derivados , Microbioma Gastrointestinal/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Substâncias Protetoras/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Animais , Ácidos e Sais Biliares/antagonistas & inibidores , Ácidos e Sais Biliares/biossíntese , Ácido Quenodesoxicólico/química , Ácido Quenodesoxicólico/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/microbiologia , Substâncias Protetoras/química
17.
Cancer Manag Res ; 11: 2927-2934, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31114341

RESUMO

Background: Aberrant expression of pepsinogen C (PGC) has been observed in human cancers. However, its role in hepatocellular carcinoma (HCC) remains to be established. The goal of this study is to illustrate PGC expression and to evaluate its clinical relevance in HCC. Materials and methods: PGC expression was examined in 75 pairs of HCC and adjacent non-tumor tissues using tissue microarray. The correlations between its expression and clinical parameters were also analyzed. Results: PGC overexpression was significantly associated with larger tumor size (≥5 cm; P=0.017) and incomplete encapsulation (P<0.0001). Cox regression model demonstrated that PGC expression and tumor size were independent prognostic factors for overall survival (OS) and disease-free survival (DFS) in HCC. The subgroup analysis by Kaplan-Meier uncovered that OS and DFS were much worse in high PGC level group than in low PGC level group with large tumor size subgroup, while no difference of OS was noted between the two groups with low tumor size subgroup. Conclusion: PGC plays a tumorigenesis role in HCC progression, which may lead to a novel insight to the potential biomarker and novel therapeutic strategies for HCC patients.

18.
Biochim Biophys Acta Rev Cancer ; 1871(2): 379-391, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30951815

RESUMO

The mechanistic target of rapamycin (mTOR) pathway coordinates organismal growth and homeostasis in response to growth factors, nutrients, and cellular energy stage. The pathway regulates several major cellular processes and is implicated in various pathological conditions, including hepatocellular carcinoma (HCC). This review summarizes recent advances of the mTOR pathway, highlights the potential of the mTOR pathway as a therapeutic target, and explores clinical trials targeting the mTOR pathway in HCC. Although the review focuses on the mTOR pathway involved in HCC, more comprehensive discussions (eg, developing a rational design for future trials targeting the mTOR pathway) are also applicable to other tumors.


Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Humanos , Transdução de Sinais/fisiologia
19.
J Pharm Pharmacol ; 71(6): 945-955, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30873627

RESUMO

OBJECTIVES: This study aimed to establish a vancomycin population pharmacokinetics (PPK) model based on serum cystatin C and to optimize dosing for achieving targeted steady-state trough concentrations (Css ) of 10-15 and 15-20 mg/l. METHODS: Patients aged ≥18 years were prospectively enrolled. A vancomycin PPK model was built with glomerular filtration rate (GFR) as a renal covariate estimated by cystatin C. A new group of patients were used for external evaluation. PPK analysis and Monte Carlo simulations were performed using nonlinear mixed effect modelling programme. KEY FINDINGS: Two hundreds of patients with 514 samples were included. The final model was CL (L/h) = (5.07 × (GFR/105.5)0.524 × (AGE/48.5)-0.309 × (WT/60)0.491 ); V (l) = 46.3. Internal and external evaluations demonstrated good stability and predictability. The average probability of target attainment (PTA) of optimal dosing regimens for targeted Css achieving 10-15 and 15-20 mg/l were 51.2% and 40.6%, respectively. An average PTA ≥71% for targeted concentration of 10-20 mg/l was obtained. CONCLUSIONS: A vancomycin PPK model with cystatin C as the renal marker has good stability and predictability. The new proposed dosing regimens were predicted to achieve a good PTA.


Assuntos
Antibacterianos/administração & dosagem , Cistatina C/sangue , Modelos Biológicos , Vancomicina/administração & dosagem , Adulto , Idoso , Antibacterianos/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Taxa de Filtração Glomerular/fisiologia , Humanos , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Método de Monte Carlo , Dinâmica não Linear , Estudos Prospectivos , Vancomicina/farmacocinética
20.
Chem Commun (Camb) ; 55(28): 4063-4066, 2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30882802

RESUMO

The salen-Co(iii) motif was inserted into imidazolium-functionalized multivariate cationic zirconium metal-organic frameworks (MOFs). The salen-Co(iii), as a Lewis acid site, and the Br- of imidazolium, as a nucleophile, are synergistically catalytic for the enhanced cycloaddition reaction of carbon dioxide with epoxides.

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