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PURPOSE: The incidence of post-transplant poral vein stenosis (PVS) is higher in pediatric liver transplantation, probably resulting from various portal vein (PV) reconstruction methods or other factors. METHODS: 332 patients less than 12 years old when receiving liver transplantation (LT) were enrolled in this research. Portal vein reconstruction methods include anastomosis to the left side of the recipient PV trunk (type 1, n = 170), to the recipient left and right PV branch patch (type 2, n = 79), using vein graft interposition (type 3, n = 32), or end-to-end PV anastomosis (type 4, n = 50). The incidence of PVS was analyzed in terms to different PV reconstruction methods and other possible risk factors. RESULTS: PVS occurred in 35 (10.5%) patients. Of the 32 patients using vein graft, 20 patients received a cryopreserved vein graft, 11 (55%) developed PVS, while the remaining 12 patients received a fresh iliac vein for PV interposition and none of them developed PVS. 9 patients whose liver donor was under 12 years old developed PVS, with an incidence of 18.8%. CONCLUSION: Cryopreserved vein graft interposition and a liver donor under 12 are independent risk factors for PVS in pediatric LT.
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Trasplante de Hígado , Vena Porta , Complicaciones Posoperatorias , Humanos , Trasplante de Hígado/métodos , Vena Porta/cirugía , Factores de Riesgo , Masculino , Femenino , Niño , Preescolar , Estudios de Casos y Controles , Lactante , Constricción Patológica , Complicaciones Posoperatorias/epidemiología , Incidencia , Estudios Retrospectivos , Anastomosis Quirúrgica/métodos , Enfermedades Vasculares/etiología , Enfermedades Vasculares/cirugíaRESUMEN
Superficial surgical site infections (SSIs) are one of the most common postoperative complications of hepatectomy for liver cancer. The objective of this study is to clarify the risk factors and determine a clinical prediction score for SSIs after partial hepatectomy for malignant tumour. A total of 812 consecutive patients were enrolled who underwent partial hepatectomy for liver malignant tumour from January 2017 to December 2017. Univariate and multivariate analyses were conducted to identify the risk factors for SSIs. Clinical prediction score was then constructed using coefficients of identified significant predictors. Risk stratification was then carried out by receiver operating characteristic curve analysis. Of all the 812 patients, SSIs were observed in 31 (3.82%) patients. A multivariate analysis identified four predictors as independent risk factors for SSIs, which were splenomegaly, perioperative blood transfusion, intensive care unit (ICU) admission, and low postoperative serum albumin concentration (<35 g/L). Clinical prediction score ranged from 0 to 4.6 with its discrimination concordance (C) statistic of 0.70 (95% confidence interval [CI] 0.59, 0.81). Risk stratification classified these patients into low, moderate, and high risk in SSIs. This risk score system may credibly stratify the risk of SSIs with relatively high sensitivity and specificity. Splenomegaly, history of blood transfusion, ICU admission, and postoperative serum albumin concentration less than 35 g/L could be used to predict SSIs with acceptable discrimination. This clinical risk score system may be useful in prediction of SSIs after hepatectomy for malignant tumours.
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Hepatectomía/efectos adversos , Hepatectomía/estadística & datos numéricos , Neoplasias Hepáticas/cirugía , Medición de Riesgo/métodos , Infección de la Herida Quirúrgica/epidemiología , Infección de la Herida Quirúrgica/etiología , Adulto , Anciano , Anciano de 80 o más Años , China/epidemiología , Reglas de Decisión Clínica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Curva ROC , Estudios Retrospectivos , Factores de RiesgoRESUMEN
This study aims to investigate how microRNA-375 (miR-375) improves immune function by regulating liver macrophages (Kupffer cells) in mice with liver failure. Forty mice were divided into ConA-1h, ConA-3h, ConA-6h, and control groups, with 10 mice in each group. Mice models of liver failure were established by injecting concanavalin A (ConA) solution via the tail veins of mice, and then primary Kupffer cells were isolated and cultured. Reverse transcription quantitative polymerase chain reaction, Western blot analysis, and enzyme-linked immunosorbent assay were conducted to examine the expressions of miR-375, astrocyte elevated gene-1 (AEG-1), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and IL-1ß in Kupffer cells of mice with liver failure as well as after silencing of miR-375. Flow cytometry was used to determine cell apoptosis. During the liver failure process, miR-375, IL-6, TNF-α, and IL-1ß expressions were increased over time, while AEG-1 expression decreased over time in the control, ConA-1h, ConA-3h, and ConA-6h groups. Opposite alternations were observed after silencing of miR-375. Dual-luciferase reporter gene assay showed that AEG-1 was a target gene of miR-375. Flow cytometry determination showed that the ratio of apoptotic Kupffer cells decreased after silencing of miR-375. Overexpression of AEG-1 could rescue the suppression of IL-6, TNF-α, and IL-1ß expressions in Kupffer cells after the short-term induction of ConA and further inhibit cell apoptosis. Our study provides evidence that miR-375 could regulate Kupffer cells to improve immune function in mice with liver failure.
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Apoptosis , Silenciador del Gen , Macrófagos del Hígado/metabolismo , Fallo Hepático/metabolismo , Glicoproteínas de Membrana/genética , MicroARNs/genética , Regulación hacia Arriba/genética , Animales , Concanavalina A/farmacología , Modelos Animales de Enfermedad , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Fallo Hepático/inducido químicamente , Masculino , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , MicroARNs/metabolismo , Transfección , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND/AIMS: Pancreatic cancer is an aggressive malignancy as a result of highly metastatic potential. The current study was carried out to alter the expression of LINC01121 in pancreatic cancer, with the aim of elucidating its effects on the biological processes of cell proliferation, migration, invasion, and apoptosis. We hypothesized that both the GLP1R gene and cAMP/PKA signaling pathway participate in the aforementioned process. METHODS: Microarray data (GSE14245, GSE27890 and GSE16515) and annotating probe files linked to pancreatic cancer were downloaded through the GEO database. The Multi Experiment Matrix (MEM) site was used to predict the target gene of lncRNA. Both pancreatic cancer tissues (n = 56) and paracancerous tissues (n = 45) were collected from patients diagnosed with pancreatic cancer. Immunohistochemistry was applied to identify the positive expression rate of GLP1R protein. Isolated pancreatic cancer cells and PANC-1 cells were independently classified into the blank, negative control (NC), LINC01121 vector, siRNA-LINC01121, siRNA-GLP1R and siRNA-LINC01121 + siRNA-GLP1R groups. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis were applied to detect the expressions of LINC01121, GLP1R, cAMP, PKA, CREB, Bcl-2, Bad and PCNA. Cell proliferation, migration, invasion, cycle progression, and apoptosis were examined by MTT assay, scratch test, Transwell assay and flow cytometry analyses of Annexin V-FITC/PI staining. RESULTS: Observations were made indicating that LINC01121 was highly expressed, while low expressions of GLP1R in pancreatic cancer were detected based on microarray data, which was largely in consistent with the data collected of LINC01121 and GLP1R within the tissues. The target prediction program and luciferase activity analysis was testament to the notion suggesting that GLP1R was indeed a target of LINC01121. In contrast to the blank and NC groups, the LINC01121 vector group exhibited increased expressions of LINC01121; decreased mRNA and protein levels of GLP1R, Bad, cAMP, and PKA; increased protein levels of CREB, Bcl-2, PCNA, p-PKA and p-CREB; increased cell proliferation, migration and invasion; and decreased cell apoptosis. There was no significant difference detected among the blank, NC, and siRNA-LINC01121 + siRNA-GLP1R groups, except that decreased LINC01121 expression was determined in the siRNA-LINC01121 + siRNA-GLP1R group. Parallel data were observed in the pancreatic cancer cells and PANC-1 cells. CONCLUSION: The current study presents evidence indicating that LINC01121 might inhibit apoptosis while acting to promote proliferation, migration, and invasion of pancreatic cancer cells, supplementing the stance held that LINC01121 functions as a tumor promoter by means of its involvement in the process of translational repression of the GLP1R and inhibition of the cAMP/PKA signaling pathway.
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Apoptosis , Movimiento Celular , Proliferación Celular , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Pancreáticas/metabolismo , ARN Largo no Codificante/metabolismo , ARN Neoplásico/metabolismo , Sistemas de Mensajero Secundario , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Neoplasias Pancreáticas/patologíaRESUMEN
TLR4 (Toll-like receptor 4) and B7-H1, which were known to be restricted to immune cells in the past, were found to be aberrantly expressed in a majority of tumor cells, facilitating tumor evasion from immune surveillance. Our study demonstrated that activation of TLR4 signaling in bladder cancer cells up-regulated B7-H1 expression. Furthermore, this regulation was significantly attenuated by ERK or JNK inhibitor. Our results elucidated the molecule mechanism of regulation of B7-H1 expression through TLR4 signaling and may suggest new strategies of down-regulating the cancer-associated B7-H1 expression for bladder cancer treatment.
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Antígenos CD/biosíntesis , Carcinoma de Células Transicionales/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Proteínas de Neoplasias/fisiología , Receptor Toll-Like 4/fisiología , Neoplasias de la Vejiga Urinaria/metabolismo , Antracenos/farmacología , Antígenos CD/genética , Antígeno B7-H1 , Carcinoma de Células Transicionales/patología , Línea Celular Tumoral , Cromonas/farmacología , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Quinasas MAP Reguladas por Señal Extracelular/fisiología , Flavonoides/farmacología , Humanos , Imidazoles/farmacología , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas JNK Activadas por Mitógenos/fisiología , Receptores de Lipopolisacáridos/fisiología , Lipopolisacáridos/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Morfolinas/farmacología , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Fosfatidilinositol 3-Quinasas/fisiología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Piridinas/farmacología , Regulación hacia Arriba/efectos de los fármacos , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
PURPOSE: Aberrant tumor cell B7-H1 expression, a member of B7 family that can predominantly stimulate interleukin 10 (IL-10) products, contributed to the tumor immune evasion and tumor progression. This study was designed to investigate the expression of B7-H1 and IL-10 in normal pancreas tissues and pancreatic carcinoma samples, and to evaluate clinical significance of B7-H1 expression in pancreatic carcinoma. METHODS: First, the B7-H1 and IL-10 expression in 40 pancreatic carcinoma samples and 8 healthy pancreas specimens using reverse transcription-PCR (RT-PCR) and western-blotting was detected. Localization of B7-H1 and IL-10 was confirmed by immunohistochemical (IHC) staining. Next, the association between B7-H1 expression and tumor differentiation and tumor stage was analyzed. Finally, the correlation between tumor-associated B7-H1 and IL-10 was evaluated. RESULTS: Pancreatic carcinoma samples demonstrated the up-regulated expression of B7-H1 and IL-10 at mRNA and protein level compared with normal pancreas tissues. IHC staining revealed that B7-H1 and IL-10 was almost localized in tumor cells. Analysis of relationship between B7-H1 and tumor clinicopathological characteristics showed that B7-H1 expression was significantly associated with poor tumor differentiation (P < 0.01) and advanced tumor stage (P < 0.01). Meanwhile, tumor-associated B7-H1 expression was also correlated with IL-10 products (P < 0.01, R (2) = 0.6985, mRNA level; P < 0.01, R (2) = 0.7236, protein level) in tumor cells. CONCLUSIONS: Our findings for the first time demonstrated up-regulated B7-H1 expression in human pancreatic carcinoma tissues, which might play a role in tumor progression and invasiveness. This expression seemed to be related to the ability of B7-H1 to promoting IL-10 secretion.
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Antígenos CD/genética , Carcinoma/genética , Carcinoma/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Regulación hacia Arriba , Antígenos CD/análisis , Antígenos CD/metabolismo , Antígeno B7-H1 , Carcinoma/inmunología , Diferenciación Celular , Femenino , Humanos , Interleucina-10/análisis , Interleucina-10/genética , Interleucina-10/inmunología , Masculino , Procesos Neoplásicos , Neoplasias Pancreáticas/inmunología , ARN Mensajero/metabolismoRESUMEN
BACKGROUND: Honokiol has been known to have antitumour activity. This study was conducted to evaluate the antiproliferative potential of honokiol against the hepG2 heptocellular cell line and its mechanism of action. METHODS: hepG2 cells were treated with honokiol of 0-40 microg/ml concentration. The cytotoxic effect of honokiol was determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The apoptosis was evaluated by flow cytometry. Western blots were used to analyse the expression of various proteins (procaspase-9, procaspase-3, cleaved caspase-3, cytochrome c, Bcl-2, Bax, Bad, Bcl-X(L) and p38). RESULTS: Honokiol induced apoptosis with a decreased expression of procaspase-3 and -9 and an increased expression of active caspase-3. Exposure of hepG2 cells to honokiol resulted in the downregulation of Bcl-X(L) and Bcl-2 expression and the release of mitochondrial cytochrome c to the cytosol. In addition, honokiol activated the p38 mitogen-activated protein kinase (MAPK) pathway, and the inhibition of this pathway by SB203580 reduced honokiol-induced apoptosis and activation of caspase-3. CONCLUSION: Honokiol induces apoptosis of hepG2 human hepatocellular carcinoma cells through activation of the p38 MAPK pathway, and, in turn, activation of caspase-3.
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Apoptosis/efectos de los fármacos , Compuestos de Bifenilo/farmacología , Proliferación Celular/efectos de los fármacos , Lignanos/farmacología , Transducción de Señal/fisiología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Apoptosis/fisiología , Western Blotting , Carcinoma Hepatocelular , Caspasas/metabolismo , Línea Celular Tumoral , Citometría de Flujo , Humanos , Imidazoles , Piridinas , Sales de Tetrazolio , TiazolesRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is characterized by remarkable desmoplasia with infiltration of distinct cellular components. Cancer-associated fibroblasts (CAFs) has been shown to be among the most prominent cells and played a significant role in shaping the tumor microenvironment by interacting with other type of cells. Here, we aimed to investigate the effect of CAFs in modulating phenotype of tumor-associated macrophages (TAM). Under treatment of CAFs conditioned medium (CM) or direct co-culture with CAFs, monocytes exhibited enhanced expression of CD206 and CD163 compared with control group (P < 0.01). The induction of M2 polarization was mediated by increased reactive oxygen species (ROS) production in monocytes as ROS elimination abolished the effect of CAFs (P < 0.05). The supernatant analysis showed that pancreatic CAFs produced increased macrophage colony-stimulating factor (M-CSF). Upon treatment of M-CSF neutralizing antibody, the ROS generation and M2 polarization of CAFs CM-stimulated monocytes were significantly inhibited (P < 0.05). In addition, the CAFs-induced M2 macrophages significantly enhanced pancreatic tumor cell growth, migration, and invasion. Collectively, our data revealed that pancreatic CAFs were able to induce a tumor-promoting TAM phenotype partly through secreted M-CSF and enhanced ROS production in monocytes, indicating possible treatment strategies by targeting stromal cell interaction within PDAC microenvironment.
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Fibroblastos Asociados al Cáncer/patología , Carcinoma Ductal Pancreático/patología , Factor Estimulante de Colonias de Macrófagos/metabolismo , Macrófagos/citología , Neoplasias Pancreáticas/patología , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Fibroblastos Asociados al Cáncer/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Línea Celular Tumoral , Movimiento Celular , Polaridad Celular , Proliferación Celular , Técnicas de Cocultivo , Medios de Cultivo Condicionados/farmacología , Regulación Neoplásica de la Expresión Génica , Humanos , Lectinas Tipo C/metabolismo , Macrófagos/metabolismo , Macrófagos/patología , Receptor de Manosa , Lectinas de Unión a Manosa/metabolismo , Neoplasias Pancreáticas/metabolismo , Receptores de Superficie Celular/metabolismo , Células Tumorales Cultivadas , Microambiente TumoralRESUMEN
OBJECTIVE: To investigate the correlations of two hepatocyte growth factor (HGF) gene polymorphisms (rs5745652 and rs2074725) and their protein expression levels with the efficacy of transhepatic arterial chemotherapeutic embolism (TACE) and prognosis in patients with primary liver cancer (PLC). METHODS: From March 2011 to June 2012, 109 PLC patients (the case group) who chose TACE as primary treatment and 80 healthy people (the control group) who had undergone physical examination in The First Affiliated Hospital, Zhejiang University were selected during the same period. Gene polymorphisms of HGF rs5745652 and HGF rs2074725 were detected. Serum HGF level, treating efficacy, survival quality, and 3-year survival rate for PLC patients who received TACE were observed. RESULTS: There were significant differences in genotype and allele frequencies of HGF rs5745652 and HGF rs2074725, between the case and control groups (all P<0.05). Compared with CT+TT genotype of HGF rs5745652, patients carrying CC genotype had lower serum HGF levels, higher efficacy, better survival quality, and prolonged 3-year survival rate (all P<0.05). In rs2074725, patients carrying CA+AA genotype had lower serum HGF levels, higher efficacy, better survival quality, and prolonged 3-year survival rate compared with patients carrying rs2074725 CC genotype (all P<0.05). Gene polymorphisms of HGF rs5745652 and HGF rs2074725, tumor size, and Barcelona Clinic Liver Cancer stage were independent prognostic factors for PLC (P<0.05). CONCLUSION: Our results indicated that HGF gene polymorphisms affect TACE efficacy and survival quality of PLC patients. Patients with HGF CC genotype of rs5745652 and CA+AA genotype of rs2074725 had decreased HGF level, better curative effect, high survival quality, and a good prognosis after TACE treatment.
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We investigated the prognostic role of regulatory T cells (Tregs) in patients with hepatocellular carcinoma (HCC). Relevant evidence regarding prognostic significance of Tregs was systematically searched in MEDLINE and Embase databases. A meta-analysis was performed to compare survival in patients with high or low Tregs level (either in peripheral blood or tumor). Eighteen studies were identified that fulfilled for the eligibility criteria and were included for data synthesis. Our pooled hazard ratios (HRs) demonstrated that increased Tregs intratumoral accumulation was significantly associated with worse overall survival (HR=2.04, 95% confidence interval (CI): 1.72-2.42) and disease-free survival (HR=1.82, 95% CI: 1.58-2.09). Three studies evaluated the role of Tregs in peripheral blood, and all of them showed that increased peripheral Tregs correlated with shortened disease-free and overall survival. Collectively, our results showed that the increased Tregs count is tightly associated with the shortened survivals. Its measurement in either primary tumor or even circulation might be a candidate marker of prognostic significance in HCC patients.
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Carcinoma Hepatocelular/inmunología , Neoplasias Hepáticas/inmunología , Linfocitos T Reguladores/inmunología , Carcinoma Hepatocelular/mortalidad , Supervivencia sin Enfermedad , Humanos , Neoplasias Hepáticas/mortalidad , Pronóstico , Sesgo de PublicaciónRESUMEN
PURPOSE: B7-DC on tumor cells was demonstrated to promote tumor immunity; however, the precise mechanism responsible for the aberrant B7-DC expression remains unknown. Interferon gamma (IFN-γ) can induce B7-DC expression on macrophages and has been shown to regulate anti-tumor immunity by various mechanisms. This study was designed to investigate the relationship of IFN-γ and B7-DC on tumor cells and further explored the signal transduction pathways involved. METHODS: RT-PCR and flow cytometry were used for the analysis of B7-DC expression on various tumor cells. The phosphorylation of p38, ERK1/2, JNK, Akt, and JAK2 was determined by Western blot. RESULTS: IFN-γ markedly up-regulated B7-DC expression on various tumor cells and resulted in the phosphorylation of JAK2, JNK, ERK, p38, and Akt. Inhibition of ERK or JNK pathway significantly decreased IFN-c-induced B7-DC expression, whereas inhibition of phosphorylation of Akt, p38, and JAK2 had very little effect on IFN-γ-induced B7-DC expression. CONCLUSIONS: Our findings demonstrate that the pretreatment of tumor cells with IFN-γ enhances B7-DC expression through ERK and JNK pathways.
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Antígeno B7-1/metabolismo , Interferón gamma/metabolismo , MAP Quinasa Quinasa 4/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Neoplasias/metabolismo , Transducción de Señal , Análisis de Varianza , Antígeno B7-1/genética , Western Blotting , Línea Celular Tumoral , Citometría de Flujo , Regulación Neoplásica de la Expresión Génica , Humanos , Janus Quinasa 2/metabolismo , Fosforilación , Proteína 2 Ligando de Muerte Celular Programada 1 , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
PURPOSE: Toll-like receptor 4 (TLR4) was found to be aberrantly expressed in bladder cancer, inducing some genes expression and facilitating tumor progression. Recent data suggest that tumor associated Interleukin-6 (IL-6) correlates with tumor size and grade in bladder cancer. However, the molecule mechanisms of the induction of IL-6 response in bladder cancer cells are not well elucidated. In this study, we manage to find out whether TLR4 signaling is involved in the production of IL-6 by human bladder cancer cells, and the detailed molecule mechanisms by which IL-6 is up-regulated. METHODS: We selected human bladder cancer T24 cell line in the present study, and examined its expression of TLR4 and CD14 by using flow cytometry. TLR4 signaling was activated by lipopolysaccharide (LPS) and IL-6 secretion in culture supernatants was tested by using ELISA kit. The expression of p38, ERK, JNK and Akt were determined by western-blot analysis using specific antibodies. RESULTS: Our study demonstrated that CD14 and TLR4 were constitutively expressed in T24 cells and activation of TLR4 signaling by LPS resulted in phosphorylation of MAPK and PI3K pathways and up-regulation of IL-6 in dose- and time-dependent manner. Pretreatment of cells with SB203580 (inhibitor of p38) and PD98059 (inhibitor of ERK) attenuated LPS-induced IL-6 expression, whereas LY294002 (inhibitor of PI3K) markedly amplified the LPS-stimulated synthesis of IL-6. CONCLUSIONS: Our results demonstrate that activation of TLR4 signaling in bladder cancer cells induces tumor-associated IL-6 expression via activation of p38 and ERK, whereas activation of PI3K/Akt exerts an opposing action.