RESUMO
BACKGROUND: Remote ischemic perconditioning (RIPerC) has been demonstrated to protect grafts from hepatic ischemia-reperfusion injury (IRI). This study investigated the role of exosomes in RIPerC of liver grafts in rats. METHODS: Twenty-five rats (including 10 donors) were randomly divided into five groups (n = 5 each group): five rats were used as sham-operated controls (Sham), ten rats were for orthotopic liver transplantation (OLT, 5 donors and 5 recipients) and ten rats were for OLT + RIPerC (5 donors and 5 recipients). Liver architecture and function were evaluated. RESULTS: Compared to the OLT group, the OLT + RIPerC group exhibited significantly improved liver graft histopathology and liver function (P < 0.05). Furthermore, the number of exosomes and the level of P-Akt were increased in the OLT + RIPerC group. CONCLUSIONS: RIPerC effectively improves graft architecture and function, and this protective effect may be related to the increased number of exosomes. The upregulation of P-Akt may be involved in underlying mechanisms.
Assuntos
Exossomos , Transplante de Fígado , Traumatismo por Reperfusão , Ratos , Animais , Transplante de Fígado/efeitos adversos , Proteínas Proto-Oncogênicas c-akt , Exossomos/patologia , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/patologia , Isquemia , Fígado/cirurgia , Fígado/patologia , ReperfusãoRESUMO
BACKGROUND: Nonalcoholic fatty liver disease and its advanced stage, nonalcoholic steatohepatitis (NASH), are the major cause of hepatocellular carcinoma (HCC) and other end-stage liver disease. However, the potential mechanism and therapeutic strategies have not been clarified. This study aimed to identify potential roles of miRNA/mRNA axis in the pathogenesis and drug combinations in the treatment of NASH. METHODS: Microarray GSE59045 and GSE48452 were downloaded from the Gene Expression Omnibus and analyzed using R. Then we obtained differentially expressed genes (DE-genes). DAVID database was used for Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway analysis. Protein-protein interaction (PPI) networks were used for the identification of hub genes. We found upstream regulators of hub genes using miRTarBase. The expression and correlation of key miRNA and its targets were detected by qPCR. Drug Pair Seeker was employed to predict drug combinations against NASH. The expression of miRNA and hub genes in HCC was identified in the Cancer Genome Atlas database and Human Protein Atlas database. RESULTS: Ninety-four DE-genes were accessed. GO and KEGG analysis showed that these predicted genes were linked to lipid metabolism. Eleven genes were identified as hub genes in PPI networks, and they were highly expressed in cells with vigorous lipid metabolism. hsa-miR-335-5p was the upstream regulator of 9 genes in the 11 hub genes, and it was identified as a key miRNA. The hub genes were highly expressed in NASH models, while hsa-miR-335-5p was lowly expressed. The correlation of miRNA-mRNA was established by qPCR. Functional verification indicated that hsa-miR-335-5p had inhibitory effect on the development of NASH. Finally, drug combinations were predicted and the expression of miRNA and hub genes in HCC was identified. CONCLUSIONS: In the study, potential miRNA-mRNA pathways related to NASH were identified. Targeting these pathways may be novel strategies against NASH.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Hepatopatia Gordurosa não Alcoólica , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Biologia Computacional , Combinação de Medicamentos , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , MicroRNAs/genética , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , RNA Mensageiro/genéticaRESUMO
BACKGROUND: The safety and efficacy of superior vena cava (SVC) isolation using second-generation cryoballoon (CB) ablation remain unknown. METHODS: A total of 26 (3.2%) patients with SVC-related paroxysmal atrial fibrillation (AF) from a consecutive series of 806 patients who underwent second-generation CB were included. Pulmonary vein isolation was initially achieved by CB ablation. If the SVC trigger was determined, the electrical isolation of SVC isolation was performed using the second-generation CB. RESULTS: Real-time SVC potential was observed in all patients. Isolation of the SVC was successfully accomplished in 21 (80.8%) patients. The mean number of freeze cycles in each patient was 2.1 ± 1.1. The mean time to isolation and ablation duration were 22.5 ± 14.2 seconds and 94.5 ± 22.3 seconds, respectively. A transient phrenic nerve (PN) injury was observed in five patients (19.2%). There were two patients (7.7%) experienced reversible sinus node injury during the first application. During a mean follow-up period of 13.2 ± 5.8 months, four patients (15.4%) had atrial arrhythmia recurrences. CONCLUSION: Isolation of SVC using the second-generation 28-mm CB is feasible when SVC driver during AF is identified. Vigilant monitoring of PN function during CB ablation of SVC is needed to avoid PN injury.
Assuntos
Fibrilação Atrial/cirurgia , Cateteres Cardíacos , Criocirurgia/instrumentação , Veia Cava Superior/cirurgia , Potenciais de Ação , Idoso , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/fisiopatologia , Criocirurgia/efeitos adversos , Desenho de Equipamento , Feminino , Traumatismos Cardíacos/etiologia , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Traumatismos dos Nervos Periféricos/etiologia , Nervo Frênico/lesões , Recidiva , Estudos Retrospectivos , Nó Sinoatrial/lesões , Fatores de Tempo , Resultado do Tratamento , Veia Cava Superior/diagnóstico por imagem , Veia Cava Superior/fisiopatologiaRESUMO
BACKGROUND: Liver cirrhosis results from many forms of chronic damage, characterized by accumulation of extracellular matrix. The present study aimed to explore a potential non-invasive biomarker and its mechanism in the progression of liver cirrhosis. METHODS: Gene Expression Omnibus (GEO) dataset (GSE15654, n = 216) was analyzed to screen genes associated with progression of liver cirrhosis. A total of 181 plasma samples, including healthy control (HC, n = 20), chronic hepatitis B (CHB, n = 77) and HBV-related liver cirrhosis (LC, n = 84), were enrolled for validation. In vitro and in vivo experiments were employed for the mechanistic investigation. RESULTS: GEO dataset analysis showed that relatively low mRNA-expression of CC motif chemokine ligand 16 (CCL16) was associated with elevated Child-Pugh score (P = 0.034) and worse prognosis (P = 0.025). Plasma CCL16 level decreased in a stepwise pattern, with a median concentration of 10.29, 6.57 and 4.47 ng/mL in the HC, CHB and LC groups, respectively (P<0.001). Low plasma CCL16 was significantly related to hepatic dysfunction both in the CHB and LC groups (P<0.05). Combination of CCL16 and ALT showed improved distinguishing capability for LC compared to either alone. In vitro, CCL16 expression was downregulated by lipopolysaccharide and hypoxia. Overexpression of CCL16 from human normal liver cell line (LO2) reduced the extracellular matrix associated proteins (Col1 and Col4) in human hepatic stellate cell line (LX-2). In vivo, the pathological feature of cirrhosis was alleviated by the hepatocyte-specific expression of CCL16. CONCLUSIONS: CCL16 could be a feasible plasma marker to predict the occurrence and progression of liver cirrhosis. CCL16 might impact liver cirrhosis through inactivating hepatic stellate cells.
Assuntos
Quimiocinas CC/metabolismo , Células Estreladas do Fígado/metabolismo , Hepatócitos/metabolismo , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática/metabolismo , Fígado/metabolismo , Adulto , Animais , Biomarcadores/metabolismo , Estudos de Casos e Controles , Linhagem Celular , Quimiocinas CC/genética , Colágeno Tipo I/metabolismo , Colágeno Tipo IV/metabolismo , Bases de Dados Genéticas , Feminino , Células Estreladas do Fígado/patologia , Hepatócitos/patologia , Humanos , Fígado/patologia , Cirrose Hepática/genética , Cirrose Hepática/patologia , Cirrose Hepática Experimental/genética , Cirrose Hepática Experimental/patologia , Masculino , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , PrognósticoRESUMO
BACKGROUND: The downstaging of hepatocellular carcinoma (HCC) has been confirmed to benefit liver transplantation (LT) patients whose tumors are beyond the transplantation criteria. Milan criteria (MC), a tumor size and number-based assessment, is currently used as the endpoint in these patients. However, many studies believe that tumor biological behavior should be added to the evaluation criteria for downstaging efficacy. Hence, this study aimed to explore the feasibility of Hangzhou criteria (HC), which introduced tumor grading and alpha-fetoprotein in addition to tumor size and number, as an endpoint of downstaging. METHODS: We performed a multicenter and retrospective study of 206 patients accepted locoregional therapy (LRT) as downstaging/bridge treatment prior to LT in three centers of China. RESULTS: Recipients were divided into four groups: failed downstaging to the HC (group A, n = 46), successful downstaging to the HC (group B, n = 30), remained within the HC all the time (group C, n = 113), and tumor progressed (group D, n = 17). The 3-year HCC recurrence probabilities of groups B and C were not significantly different (10.3% vs. 11.6%, P = 0.87). The HCC recurrent rate was significantly higher in group A (52.3%) compared with that in group B/C (Pâ¯<â¯0.05). Seven patients (7/76, 9.2%) whose tumor exceeded the the HC were successfully downstaged to the MC, and 39.5% (30/76) to the the HC. In group B, 23 patients remained beyond the MC and their survivals were as well as those of patients within the MC. CONCLUSIONS: Compared to the MC, HC downstaging criteria can give more HCC patients access to LT and furthermore, the outcome of these patients is the same as those matching MC downstaging criteria. Hangzhou downstaging criteria therefore is applicable in clinical practice.
Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Transplante de Fígado , Seleção de Pacientes , Adulto , Idoso , Carcinoma Hepatocelular/cirurgia , China , Feminino , Humanos , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos RetrospectivosRESUMO
BACKGROUND: While the left sinus of Valsalva (LSV) is a frequent origin of ventricular arrhythmias (VAs). Uncommonly, VAs with right bundle branch block (RBBB) morphology may be successfully terminated from the LSV. OBJECTIVE: We aimed to investigate the electrocardiographic and electrophysiologic characteristics of VAs with RBBB which were successfully eliminated from the LSV. METHODS: We identified patients with VAs successfully ablated from the LSV from January 2014 to December 2017 and compared electrophysiologic characteristics and ablation sites of those VAs with RBBB versus a control group of patients with left bundle branch block morphology. RESULTS: We identified 18 patients with RBBB and predominant "R" waves in the precordial leads. In 12 (66.7%) patients, a small "s" wave in lead V2 and positive "R" in the remaining pericardial leads could be seen. Overall, a single "V" potential was seen in 72.2% of patients in the study group, while discrete potentials were recorded in 80% of the patients in the control group. The majority (88.9%) of the VAs could only be terminated at the nadir of the LSV in the study group. After mean follow-up of 33 ± 14 months, 93.8% and 92% were free of VAs after initial ablation in study and control group, respectively (P = 0.99). CONCLUSION: Some VAs with predominant monophasic "R" wave in precordial leads could be terminated from LSV, especially a small "s" wave in lead V2 was recorded. The nadir of LSV is highly successful for RBBB VAs and single electrogram was recorded at the target for most of the cases.
Assuntos
Bloqueio de Ramo/cirurgia , Ablação por Cateter , Eletrocardiografia , Técnicas Eletrofisiológicas Cardíacas , Frequência Cardíaca , Seio Aórtico/cirurgia , Taquicardia Ventricular/cirurgia , Complexos Ventriculares Prematuros/cirurgia , Potenciais de Ação , Adulto , Idoso , Bloqueio de Ramo/diagnóstico , Bloqueio de Ramo/fisiopatologia , Ablação por Cateter/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Seio Aórtico/fisiopatologia , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/fisiopatologia , Resultado do Tratamento , Complexos Ventriculares Prematuros/diagnóstico , Complexos Ventriculares Prematuros/fisiopatologia , Adulto JovemRESUMO
INTRODUCTION: The procedural findings and clinical outcome of second-generation cryoballoon (CB2) ablation in patients with variant pulmonary vein (PV) anatomy have not been fully investigated. METHODS: A total of 424 consecutive patients who underwent PV isolation with CB2 were included. Computed tomographic (CT) scan was performed in all patients before the procedure. The study population was divided into common PV, accessory PV, and nonvariant PV groups according to the CT scan. Procedural findings and clinical outcome between the three groups were compared. RESULTS: Variant PV anatomy was observed in 118 of 424 (27.8%) patients. PV isolation was successfully achieved in all patients in three groups with low rates of need for touch-up ablation (P = 0.974). Total procedure time was longer in the accessory PV group compared with nonvariant PV group (53.7 ± 12.9 vs 49.5 ± 8.8 minutes; P < 0.001). More number of applications per patient were required in accessory PV group compared with the nonvariant PV and common PV groups (7.5 ± 2.1 vs 6.5 ± 1.6, P < 0.001; 7.5 ± 2.1 vs 6.8 ± 1.4, P = 0.027, respectively). No significant difference in phrenic nerve (PN) injury was observed between the three groups (P = 0.693). During mean follow-up duration of 16.1 ± 3.3 months, there was no significant difference in rates of atrial fibrillation (AF) recurrences in the three groups (13 of 43 common PV group, 21 of 75 accessory PV group, and 80 of 306 nonvariant PV group, P = 0.178). CONCLUSION: Variant PV patterns are common in patients undergoing ablation for drug-resistant AF. CB2 ablation appears to be a reasonable strategy in the setting of the variant PV anatomy with a small increase in procedure time and the number of cryoapplications.
Assuntos
Fibrilação Atrial/cirurgia , Criocirurgia , Veias Pulmonares/anormalidades , Veias Pulmonares/cirurgia , Potenciais de Ação , Adulto , Idoso , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/fisiopatologia , Angiografia por Tomografia Computadorizada , Criocirurgia/efeitos adversos , Feminino , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Veias Pulmonares/diagnóstico por imagem , Veias Pulmonares/fisiopatologia , Recidiva , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
Background: Current opinion suggests that expansion of cancer stem cells (CSCs) and activation of pro-tumoral inflammation cascade correlate with cancer progression. Materials and methods: We explored the possible contributions of MRC-5 cancer-associated fibroblasts to the expression profiles of CSC markers and inflammation-associated cell surface molecules. The liver cancer cell lines Bel-7402, SMMC-7721, MHCC-LM3, and HepG2 cultured in conditioned medium (CM) from MRC-5 served as test groups, whereas the liver cancer cell lines cultured in normal medium served as control groups. Results: Flow cytometry revealed that the proportions of CD90+ cells were significantly higher in MHCC-LM3-(MRC-5)-CM and HepG2-(MRC-5)-CM cells, and moderately higher in Bel-7402-(MRC-5)-CM and SMMC-7721-(MRC-5)-CM cells, than in controls. The CD90+/CD45- proportions were elevated in Bel-7402-(MRC-5)-CM and MHCC-LM3-(MRC-5)-CM cells, but reduced in HepG2-(MRC-5)-CM and SMMC-7721-(MRC-5)-CM cells, as compared to controls. Western blotting indicated that Nanog was downregulated in MHCC-LM3-(MRC-5)-CM and HepG2-(MRC-5)-CM cells, compared to controls; that POU5F1 (OCT4/3) was downregulated in MHCC-LM3-(MRC-5)-CM, but upregulated in Bel-7402-(MRC-5)-CM and HepG2-(MRC-5)-CM cells, compared to controls, and that CK19 was upregulated in Bel-7402-(MRC-5)-CM and MHCC-LM3-(MRC-5)-CM cells, compared to controls. Proportions of cells expressing Toll-like receptor-1+ (TLR1) and TLR4 were significantly higher in MHCC-LM3-(MRC-5)-CM cells, and moderately higher in HepG2-(MRC-5)-CM cells, than controls. However, the TLR1+ and TLR4+ proportions were lower in Bel-7402-(MRC-5)-CM and SMMC-7721-(MRC-5)-CM cells than controls. Proportions of CD25+ cells were reduced in HepG2-(MRC-5)-CM and SMMC-7721-(MRC-5)-CM cells, but elevated in MHCC-LM3-(MRC-5)-CM and Bel-7402-(MRC-5)-CM cells, compared to controls. Proportion of CD61+ cells was higher in liver cancer cells cultured in MRC-5-CM than in controls. Proportion of CD14+ cells was lower in HCC cells cultured in MRC-5-CM than in controls. Conclusion: MRC-5 extensively affected the production of CSC markers and inflammation-associated cell surface molecules. Tumor-targeting molecular therapies should consider these findings.
Assuntos
Biomarcadores Tumorais/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Inflamação/metabolismo , Células-Tronco Neoplásicas/metabolismo , Fibroblastos Associados a Câncer/patologia , Linhagem Celular Tumoral , Meios de Cultivo Condicionados/farmacologia , Citometria de Fluxo , Células Hep G2 , Humanos , Integrina beta3/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Fator 3 de Transcrição de Octâmero/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor 1 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Microambiente Tumoral , Ensaio Tumoral de Célula-TroncoRESUMO
BACKGROUND: Retinoblastoma binding protein 4 (RBBP4) plays an essential role in the development of multiple cancers. However, its relationship with prognosis in colon cancer and colon cancer hepatic metastasis has not been elucidated. The aim of this study was to explore the relationship between RBBP4 expression and prognosis of colon cancer patients and to evaluate RBBP4 as a new prognostic marker in these patients. METHODS: Eighty colon cancer patients underwent surgical resection of the colon were enrolled. Among them, forty colon cancer patients suffered with hepatic metastasis. The colon cancer tissues, para-colon cancer tissues, and hepatic metastatic cancer tissues were collected from the pathological department for further analysis. The expression of RBBP4 proteins was examined by immunohistochemistry and correlated with clinicopathological parameters. The Cancer Genome Atlas (TCGA) database was used to validate the expression and explore its relationship with clinical characteristics. RESULTS: RBBP4 was up-regulated in the colon cancer tissues compared with the para-colon cancer tissues. The analysis of TCGA database verified the upregulation of RBBP4 in the colon cancer tissues and RBBP4 overexpression was correlated with nerve invasion and poor outcomes of chemotherapy. Moreover, the positive rate of RBBP4 expression in 40 colon cancer patients with hepatic metastasis was higher in the hepatic metastatic cancer tissues (39/40, 97.5%) than in the colon cancer tissues (26/40, 65.0%). Our clinicopathological analysis showed that RBBP4 expression was significantly correlated with vascular invasion, hepatic metastasis, and lymph node involvement (all P < 0.05). Additionally, the survival analysis demonstrated that RBBP4 over-expression was correlated with poor prognosis. CONCLUSIONS: RBBP4 was upregulated in the colon cancer. RBBP4 may be a novel predictor for poor prognosis of colon cancer and colon cancer hepatic metastasis.
Assuntos
Colo/metabolismo , Neoplasias do Colo/metabolismo , Neoplasias Hepáticas/metabolismo , RNA Mensageiro/metabolismo , Proteína 4 de Ligação ao Retinoblastoma/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Vasos Sanguíneos/patologia , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Feminino , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Prognóstico , Proteína 4 de Ligação ao Retinoblastoma/genética , Taxa de Sobrevida , Regulação para CimaRESUMO
BACKGROUND: Primary hepatic neuroendocrine neoplasms (PHNENs) are extremely rare and few articles have compared the prognosis of PHNENs with other neuroendocrine neoplasms (NENs). This study aimed to investigate the different prognosis between PHNENs and pancreatic NEN (PanNENs) and evaluate the relevant prognosis-related factors. METHODS: From January 2012 to October 2016, a total of 44 NENs patients were enrolled and divided into two groups according to the primary tumor location which were named group PHNENs (liver; nâ¯=â¯12) and group PanNENs (pancreas; nâ¯=â¯32). Demographic, clinical characteristics and survival data were compared between the two groups with Kaplan-Meier method and log-rank tests. Prognostic factors were analyzed using the Cox regression model. RESULTS: The overall survival of group PHNENs and group PanNENs were 25.4⯱â¯6.7 months and 39.8⯱â¯3.7 months, respectively (Pâ¯=â¯0.037). The cumulative survival of group PanNENs was significantly higher than that of group PHNENs (Pâ¯=â¯0.029). Univariate analysis revealed that sex, albumin, total bilirubin, total bile acid, aspartate aminotransferase, alkaline phosphatase, α-fetoprotein and carbohydrate antigen 19-9, histological types, treatments and primary tumor site were the prognostic factors. Further multivariate analysis indicated that albumin (Pâ¯=â¯0.008), histological types NEC (Pâ¯=â¯0.035) and treatments (Pâ¯=â¯0.005) were the independent prognostic factors. Based on the histological types, the cumulative survival of patients with well-differentiated neuroendocrine tumor was significant higher than that of patients with poorly differentiated neuroendocrine carcinoma in group PHNENs (Pâ¯=â¯0.022), but not in group PanNENs (Pâ¯>â¯0.05). According to the different treatments, patients who received surgery had significantly higher cumulative survival than those with conservative treatment in both groups (Pâ¯<â¯0.05). CONCLUSIONS: PHNENs have lower survival compared to PanNENs. Histological types and treatments affect the prognosis. Surgical resection still remains the first line of treatment for resectable lesions and can significantly improve the survival.
Assuntos
Carcinoma Neuroendócrino/terapia , Neoplasias Hepáticas/terapia , Neoplasias Pancreáticas/terapia , Adulto , Idoso , Carcinoma Neuroendócrino/mortalidade , Carcinoma Neuroendócrino/patologia , China/epidemiologia , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Our previous study showed that 17-beta-hydroxysteroid dehydrogenase 13 (HSD17B13) is down-regulated in hepatocellular carcinoma (HCC). But its function in HCC remains unknown. This study aimed to reveal the function of HSD17B13 and its clinical significance in HCC. METHODS: mRNA levels of HSD17B13 were analyzed in cohort 1 (30 normal, 30 HBV cirrhosis, 60 HBV-related HCC and 60 peritumoral tissue) by real-time PCR. HSD17B13 protein was evaluated in cohort 2 (15 normal, 33 HBV-cirrhosis, 12 dysplastic nodules, 34 HBV-related HCC, and 9 metastatic HCC) using immunohistochemistry. The association between HSD17B13 and the survival of HCC patients was analyzed in cohort 3 (nâ¯=â¯88). The inhibitory mechanism of HSD17B13 on HCC was explored . RESULTS: The mRNA of HSD17B13 and its protein expression were significantly down-regulated in HCC compared to non-tumor specimens (P < 0.001). The sensitivity, specificity and area under curve (AUC) values of HSD17B13 expression levels for HCC detection were 81.7%, 83.7% and 0.856, respectively (P < 0.001). Lower HSD17B13 in peritumoral tissue was an independent risk factor of worse recurrence free survival of HCC patients (HR: 0.41; 95% CI: 0.20-0.83; P = 0.014). The study in Huh 7 and SK-HEP-1 cells showed that HSD17B13 induced an accumulation of cells in G1 phase and reduction of cells in S and G2 phases via up-regulating the expression of P21, P27 and MMP2. CONCLUSIONS: Lower HSD17B13 in peritumoral tissues was associated with worse recurrence free survival and overall survival of HCC patients. HSD17B13 delayed G1/S progression of HCC cells. HSD17B13 may be a therapeutic target for the treatment of HCC.
Assuntos
17-Hidroxiesteroide Desidrogenases/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/enzimologia , Neoplasias Hepáticas/enzimologia , Recidiva Local de Neoplasia , 17-Hidroxiesteroide Desidrogenases/genética , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Proliferação de Células , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Progressão da Doença , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Transdução de Sinais , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Ischemia reperfusion injury (IRI) causes postoperative complications and influences the outcome of the patients undergoing liver surgery and transplantation. Postconditioning (PostC) is a known manual conditioning to decrease the hepatic IRI. Here we aimed to optimize the applicable PostC protocols and investigate the potential protective mechanism. METHODS: Thirty Sprague-Dawley rats were randomly divided into 3 groups: the sham group (nâ¯=â¯5), standard orthotopic liver transplantation group (OLT, nâ¯=â¯5), PostC group (OLT followed by clamping and re-opening the portal vein for different time intervals, nâ¯=â¯20). PostC group was then subdivided into 4 groups according to the different time intervals: (10â¯sâ¯×â¯3, 10â¯sâ¯×â¯6, 30â¯sâ¯×â¯3, 60â¯sâ¯×â¯3, nâ¯=â¯5 in each subgroup). Liver function, histopathology, malondialdehyde (MDA), myeloperoxidase (MPO), expressions of p-Akt and endoplasmic reticulum stress (ERS) related genes were evaluated. RESULTS: Compared to the OLT group, the grafts subjected to PostC algorithm (without significant prolonging the total ischemic time) especially with short stimulus and more cycles (10â¯sâ¯×â¯6) showed significant alleviation of morphological damage and graft function. Besides, the production of reactive oxidative agents (MDA) and neutrophil infiltration (MPO) were significantly depressed by PostC algorithm. Most of ERS related genes were down-regulated by PostC (10â¯sâ¯×â¯6), especially ATF4, Casp12, hspa4, ATF6 and ELF2, while p-Akt was up-regulated. CONCLUSIONS: PostC algorithm, especially 10â¯sâ¯×â¯6 algorithm, showed to be effective against rat liver graft IRI. These protective effects may be associated with its antioxidant, inhibition of ERS and activation of p-Akt expression of reperfusion injury salvage kinase pathway.
Assuntos
Algoritmos , Pós-Condicionamento Isquêmico/métodos , Transplante de Fígado/efeitos adversos , Fígado/cirurgia , Veia Porta/cirurgia , Traumatismo por Reperfusão/prevenção & controle , Animais , Constrição , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/genética , Regulação da Expressão Gênica , Fígado/metabolismo , Fígado/patologia , Masculino , Malondialdeído/metabolismo , Infiltração de Neutrófilos , Estresse Oxidativo , Peroxidase/metabolismo , Fosforilação , Veia Porta/fisiopatologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Transdução de Sinais , Fatores de TempoRESUMO
BACKGROUND: Post-transplant model for predicting mortality (PMPM, calculated as -5.359+1.988Xln (serum creatinine [mg/dL])+1.089Xln (total bilirubin [mg/dL])) score has been proved to be a simple and accurate model for predicting the prognosis after liver transplantation (LT) in a single center study. Here we aim to verify this model in a large cohort of patients. METHODS: A total of 2727 patients undergoing LT with end-stage liver cirrhosis from January 2003 to December 2010 were included in this retrospective study. Data were collected from the China Liver Transplant Registry (CLTR). PMPM score was calculated at 24-h and 7-d following LT. According to the PMPM score at 24-h, all patients were divided into the low-risk group (PMPM score ≤-1.4, n=2509) and the high-risk group (PMPM score >-1.4, n=218). The area under receiver operator characteristic curve (AUROC) was calculated for evaluating the prognostic accuracy. RESULTS: The 1-, 3-, and 5-year patient survival rates in the low-risk group were significantly higher than those in the high-risk group (90.23%, 88.01%, and 86.03% vs 63.16%, 59.62%, and 56.43%, respectively, P<0.001). In the high-risk group, 131 patients had a decreased PMPM score (≤-1.4) at 7-d, and their cumulative survival rate was significantly higher than the other 87 patients with sustained high PMPM score (>-1.4) (P<0.001). For predicting 3-month mortality, PMPM score showed a much higher AUROC than post-transplant MELD score (P<0.05). CONCLUSION: PMPM score is a simple and effective tool to predict short-term mortality after liver transplantation in patients with benign liver diseases, and an indicator for prompt salvaging treatment as well.
Assuntos
Bilirrubina/sangue , Creatinina/sangue , Técnicas de Apoio para a Decisão , Doença Hepática Terminal/cirurgia , Cirrose Hepática/cirurgia , Transplante de Fígado , Adulto , Área Sob a Curva , Biomarcadores/sangue , China , Doença Hepática Terminal/sangue , Doença Hepática Terminal/diagnóstico , Doença Hepática Terminal/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Cirrose Hepática/sangue , Cirrose Hepática/diagnóstico , Cirrose Hepática/mortalidade , Transplante de Fígado/efeitos adversos , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Curva ROC , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Fatores de Tempo , Resultado do TratamentoAssuntos
Fígado , Lisofosfolipídeos , Fosfotransferases (Aceptor do Grupo Álcool) , Traumatismo por Reperfusão , Transdução de Sinais , Esfingosina/análogos & derivados , Animais , Fígado/irrigação sanguínea , Lisofosfolipídeos/metabolismo , Microcirculação , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Ratos , Traumatismo por Reperfusão/metabolismo , Esfingosina/metabolismoRESUMO
BACKGROUND: Because of an increasing discrepancy between the number of potential liver graft recipients and the number of organs available, scientists are trying to create artificial liver to mimic normal liver function and therefore, to support the patient's liver when in dysfunction. 3D printing technique meets this purpose. The present study was to test the feasibility of 3D hydrogel scaffolds for liver engineering. METHODS: We fabricated 3D hydrogel scaffolds with a bioprinter. The biocompatibility of 3D hydrogel scaffolds was tested. Sixty nude mice were randomly divided into four groups, with 15 mice in each group: control, hydrogel, hydrogel with L02 (cell line HL-7702), and hydrogel with hepatocyte growth factor (HGF). Cells were cultured and deposited in scaffolds which were subsequently engrafted into livers after partial hepatectomy and radiation-induced liver damage (RILD). The engrafted tissues were examined after two weeks. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, total bilirubin, CYP1A2, CYP2C9, glutathione S-transferase (a-GST), and UDP-glucuronosyl transferase (UGT-2) were compared among the groups. Hematoxylin-eosin (HE) staining and immunohistochemistry of cKit and cytokeratin 18 (CK18) of engrafted tissues were evaluated. The survival time of the mice was also compared among the four groups. RESULTS: 3D hydrogel scaffolds did not impact the viability of cells. The levels of ALT, AST, albumin, total bilirubin, CYP1A2, CYP2C9, a-GST and UGT-2 were significantly improved in mice engrafted with 3D scaffold loaded with L02 compared with those in control and scaffold only (P<0.05). HE staining showed clear liver tissue and immunohistochemistry of cKit and CK18 were positive in the engrafted tissue. Mice treated with 3D scaffold+L02 cells had longer survival time compared with those in control and scaffold only (P<0.05). CONCLUSION: 3D scaffold has the potential of recreating liver tissue and partial liver functions and can be used in the reconstruction of liver tissues.
Assuntos
Hepatócitos/transplante , Transplante de Fígado/métodos , Impressão Tridimensional , Engenharia Tecidual/métodos , Alicerces Teciduais , Animais , Biomarcadores/metabolismo , Técnicas de Cultura de Células , Linhagem Celular , Proliferação de Células , Forma Celular , Sobrevivência Celular , Estudos de Viabilidade , Sobrevivência de Enxerto , Hepatócitos/metabolismo , Humanos , Hidrogéis , Regeneração Hepática , Camundongos Nus , Fenótipo , Fatores de TempoRESUMO
BACKGROUND: Increasing evidence indicates that downregulation of cell adhesion molecule 1 (CADM1) contributes to tumorigenesis in various cancers. The present study was undertaken to investigate the CADM1 expression pattern in human hepatocellular carcinoma (HCC), and to elucidate the mechanism underlying CADM1-mediated tumor suppression. METHODS: CADM1 expression in HCC cell lines was measured by quantitative real-time PCR. The function of CADM1 in the context of tumor suppression in HCC cells was determined using proliferation assays, cell cycle analysis, EdU incorporation assays, in vitro colony formation analysis, and in vivo tumorigenicity assays. The mechanism by which CADM1 acts as a tumor suppressor gene in HCC was investigated using Western blotting analysis. RESULTS: Downregulation of CADM1 expression is frequently detected in both HCC cells and clinical samples. Restoration of CADM1 expression in HCC cell lines significantly inhibits cell growth and negatively regulates the G1/S transition. CADM1 overexpression can inhibit the tumorigenicity of HCC cells both in vitro and in vivo. Western blotting analysis revealed that ectopic expression of CADM1 in HCC cells is associated with increased expression of Retinoblastoma (Rb) protein. CONCLUSIONS: Our results showed that suppression of tumorigenesis by CADM1 may be mediated by the Rb-E2F pathway, involving upregulation of Rb protein levels. This pathway could therefore represent an attractive target for HCC therapy.
Assuntos
Carcinoma Hepatocelular/metabolismo , Moléculas de Adesão Celular/metabolismo , Fator de Transcrição E2F1/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular , Imunoglobulinas/metabolismo , Neoplasias Hepáticas/metabolismo , Proteína do Retinoblastoma/metabolismo , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Molécula 1 de Adesão Celular , Moléculas de Adesão Celular/genética , Proliferação de Células , Fator de Transcrição E2F1/genética , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Imunoglobulinas/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , RNA Interferente Pequeno , Proteína do Retinoblastoma/genética , Transdução de Sinais , Fatores de Tempo , Transfecção , Carga TumoralRESUMO
BACKGROUND: Four tumor markers for hepatocellular carcinoma (HCC), alpha-fetoprotein (AFP), glypican-3 (GPC3), vascular endothelial growth factor (VEGF) and des-gamma-carboxy prothrombin (DCP), are closely associated with tumor invasion and patient's survival. This study estimated the predictability of preoperative tumor marker levels along with pathological parameters on HCC recurrence after hepatectomy. METHODS: A total of 140 patients with HCC who underwent hepatectomy between January 2012 and August 2012 were enrolled. The demographics, clinical and follow-up data were collected and analyzed. The patients were divided into two groups: patients with macroscopic vascular invasion (MaVI+) and those without MaVI (MaVI-). The predictive value of tumor markers and clinical parameters were evaluated by univariate and multivariate analysis. RESULTS: In all patients, tumor size (>8 cm) and MaVI were closely related to HCC recurrence after hepatectomy. For MaVI+ patients, VEGF (>900 pg/mL) was a significant predictor for recurrence (RR=2.421; 95% CI: 1.272-4.606; P=0.007). The 1- and 2-year tumor-free survival rates for MaVI+ patients with VEGF ≤900 pg/mL versus for those with VEGF >900 pg/mL were 51.5% and 17.6% versus 19.0% and 4.8% (P<0.001). For MaVI- patients, DCP >445 mAu/mL and tumor size >8 cm were two independent risk factors for tumor recurrence (RR=2.307, 95% CI: 1.132-4.703, P=0.021; RR=3.150, 95% CI: 1.392-7.127, P=0.006; respectively). The 1- and 2-year tumor-free survival rates for the patients with DCP ≤445 mAu/mL and those with DCP >445 mAu/mL were 90.4% and 70.7% versus 73.2% and 50.5% respectively (P=0.048). The 1- and 2-year tumor-free survival rates for the patients with tumor size ≤8 cm and >8 cm were 83.2% and 62.1% versus 50.0% and 30.0%, respectively (P=0.003). CONCLUSIONS: The MaVI+ patients with VEGF ≤900 pg/mL had a relatively high tumor-free survival than those with VEGF >900 pg/mL. In the MaVI- patients, DCP >445 mAu/mL and tumor size >8 cm were predictive factors for postoperative recurrence.
Assuntos
Biomarcadores Tumorais/sangue , Biomarcadores/sangue , Vasos Sanguíneos/patologia , Carcinoma Hepatocelular/sangue , Neoplasias Hepáticas/sangue , Recidiva Local de Neoplasia , Precursores de Proteínas/sangue , Fator A de Crescimento do Endotélio Vascular/sangue , Adulto , Idoso , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Distribuição de Qui-Quadrado , China , Intervalo Livre de Doença , Feminino , Glipicanas/sangue , Hepatectomia , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Protrombina , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Carga Tumoral , alfa-Fetoproteínas/metabolismoRESUMO
A refractive index insensitive temperature sensor is proposed base on cascading single mode fiber with few mode fiber(FMF). During the sensor preparation, the splicing current is set to 100 mA, and a section of FMF is no core-offset splicing between two single-mode fibers. Therefore, it can motivate the transmission mode preferably and form optical fiber Mach-Zehnder interferometer. The mode phase difference in FMF will be changed according to the outside environment. It will cause interference fringe shift. The parameter to be measured can be achieved by detecting the amount shift of interference spectrum. The FMF can transmit four modes with LP01, LP11, LP21, LP02. The transmission spectrum is also analyzed, which shows that they have two modes of LP01 and LP11 in sensor with the length of 81.5 mm. In the refractive index and temperature sensing experiment, the cascading FMF sensor with the length of 81.5 mm is used. The results show that the transmission spectrum of sensor appears obvious blue shift as temperature is increasing, the temperature sensitivity can be up to -85.9 pm·â-1 within the range of 27.6~93.8 â with good linearity. The refractive index sensitivity is 3.697 34 nm·RIU-1 within the range of 1.347 1~1.443 9. There is no obvious shift phenomenon in the transmission spectrum with the feature of refractive index insensitive. Therefore, compared with the traditional cladding mode and multimode interferometric fiber-optic sensor, the proposed sensor based on FMF is easier to control and analyze transmission mode has the advantages of simple structure, easy process and high sensitivity. It can avoid cross-sensitivity between temperature and refractive index measurement. Thus, it can be used for temperature detection of power system, biomedicine, aerospace and other fields.