RESUMO
Liver fibrosis is a very common condition seen in millions of patients with various liver diseases, and yet no effective treatments are available owing to poorly characterized molecular pathogenesis. Here, we show that leukocyte cell-derived chemotaxin 2 (LECT2) is a functional ligand of Tie1, a poorly characterized endothelial cell (EC)-specific orphan receptor. Upon binding to Tie1, LECT2 interrupts Tie1/Tie2 heterodimerization, facilitates Tie2/Tie2 homodimerization, activates PPAR signaling, and inhibits the migration and tube formations of EC. In vivo studies showed that LECT2 overexpression inhibits portal angiogenesis, promotes sinusoid capillarization, and worsens fibrosis, whereas these changes were reversed in Lect2-KO mice. Adeno-associated viral vector serotype 9 (AAV9)-LECT2 small hairpin RNA (shRNA) treatment significantly attenuates fibrosis. Upregulation of LECT2 is associated with advanced human liver fibrosis staging. We concluded that targeting LECT2/Tie1 signaling may represent a potential therapeutic target for liver fibrosis, and serum LECT2 level may be a potential biomarker for the screening and diagnosis of liver fibrosis.
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Células Endoteliais/metabolismo , Hepatócitos/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Cirrose Hepática/metabolismo , Fígado/metabolismo , Receptores de TIE/metabolismo , Animais , Biomarcadores/metabolismo , Capilares/metabolismo , Células Endoteliais/citologia , Células Endoteliais/patologia , Células HEK293 , Hepatócitos/citologia , Hepatócitos/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Fígado/irrigação sanguínea , Fígado/patologia , Cirrose Hepática/diagnóstico , Camundongos Endogâmicos C57BLRESUMO
Metastasis-associated in colon cancer 1 (MACC1) is an oncogene associated with the progression and metastasis of many solid cancer entities. High expression of MACC1 is found in colorectal cancer (CRC) tissues. So far, the role of MACC1 in CRC cell pyroptosis and resistance to irinotecan is unclear. The cleavage of Gasdermin-E (GSDME) is the main executors of activated pyroptosis. We found that GSDME enhanced CRC cell pyroptosis and reduced their resistance to irinotecan, while MACC1 inhibited the cleavage of GSDME and CRC cell pyroptosis, promoted CRC cell proliferation, and enhanced the resistance of CRC cells to irinotecan. Therefore, CRC cells with high MACC1 expression and low GSDME expression had higher resistance to irinotecan, while CRC cells with low MACC1 expression and high GSDME expression had lower resistance to irinotecan. Consistently, by analyzing CRC patients who received FOLFIRI (Fluorouracil + Irinotecan + Leucovorin) in combination with chemotherapy in the GEO database, we found that CRC patients with low MACC1 expression and high GSDME expression had higher survival rate. Our study suggests that the expression of MACC1 and GSDME can be used as detection markers to divide CRC patients into irinotecan resistant and sensitive groups, helping to determine the treatment strategy of patients.
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Neoplasias Colorretais , Gasderminas , Humanos , Irinotecano/farmacologia , Piroptose , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Transativadores/genética , Transativadores/metabolismoRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) is the second malignancy worldwide. POLA2 initiates DNA replication, regulates cell cycle and gene repair that promote tumorigenesis and disease progression. However, the prognostic and biological function roles of POLA2 in HCC had not been conclusively determined. METHODS: The expression levels and prognosis role of POLA1 and POLA2 in HCC were analyzed based on TCGA-LIHC database and recruited 24 HCC patients. Gene mutations were analyzed using "maftools" package. POLA2 and immune cells correlations were analyzed by TIMER. POLA2 co-expressed genes functional enrichment were evaluated using Metascape. The mRNA and protein level of POLA2 was detected in HCC cells and tissues. Cell migration, invasion, proliferation, cell cycle and HCC cell lines derived xenograft model were performed to investigate POLA2 biological function. RESULTS: POLA2 was significantly high expressed in HCC than in normal liver tissue in both TCGA-LIHC and our collected HCC samples. In validation cohort, POLA2 significantly related to tumor differentiation, tumor size and Ki-67 (p < 0.05). In TCGA-LIHC cohort, overexpression of POLA2 predicted a low OS and associated with different clinical stages. Multivariate Cox regression showed overexpression of POLA2 effectively distinguished the prognosis at different T, N, M, stages and grades of HCC. POLA2 expression correlated with mutation burden, immune cells infiltration and immune-associated genes expression of HCC. Functional enrichment revealed that POLA2 co-expressed genes were linked to cellular activity, plasma membrane protein complex and leukocyte activity, immune response-regulated cell surface receptor signaling pathway, and immune response-regulated signaling pathway. Moreover, POLA2 was also positively co-expressed with some immune checkpoints (CD274, CTL-4, HAVCR2, PDCD1, PDCD1LG2, TIGIT, and LAG3) (p < 0.001). Gene knockdown revealed that POLA2 promoted proliferation, migration, invasion, and cell cycle of SMMC-7721 and HepG2. The HCC xenograft tumor model also demonstrated remarkably tumor size inhibition, tumor proliferation inhibtion and tumor necrosis promotion when POLA2 knockdown. CONCLUSIONS: POLA2 influenced immune microenvironment and tumor progression of HCC indicated that it might be a potential molecular marker for prognostic evaluation or a therapeutic target for HCC.
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Hepatocyte-derived inducible nitric oxide synthase (iNOS) was proved to impart protection against liver ischemia reperfusion (I/R) injury in our prior analysis. However, the mechanism for this hepatoprotection remains incompletely understood. Bone marrow chimeric mice were generated using expression of iNOS in a hepatocyte-selective manner against an iNOS-knockout background. The function of heme oxygenase 1 (HO-1) in iNOS-stimulated hepatoprotection and the molecular mechanisms were explored in vitro and in vivo, respectively. Hepatocyte-derived iNOS conferred protection from I/R injury and anoxia/reoxygenation stimulation. Mechanistically, iNOS activated nuclear factor erythroid 2-related factor 2 (Nrf-2) and subsequently, stimulated the transcription of HO-1. Results from our study led to the conclusion that HO-1 is another potent mediator of iNOS-mediated protection after liver I/R.
Assuntos
Heme Oxigenase-1/metabolismo , Hepatócitos/enzimologia , Fígado/patologia , Óxido Nítrico Sintase Tipo II/metabolismo , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/patologia , Animais , Núcleo Celular/metabolismo , Células Cultivadas , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/metabolismo , Transporte Proteico , Regulação para Cima/genéticaRESUMO
Although the role of inducible nitric oxide synthase (iNOS) in hepatic ischemia/reperfusion (I/R) injury remains controversial and confusing, with both harmful and beneficial effects in animal studies, the mechanism of these incongruous actions remains unclear. In the current study, we generated bone marrow chimeric mice with hepatocyte-restricted expression of iNOS. Chimeric mice and primary hepatocytes were subjected to I/R or anoxia/reoxygenation stimulation, respectively. The role of iNOS in liver I/R injury and the underlying molecular mechanisms were investigated. Hepatocyte-derived iNOS resulted in hepatoprotection from I/R injury, as well as in vitro experiments. Mechanistically, iNOS upregulates Heat shock protein (HSP) 70 by augmenting heat shock factor 1 (HSF1) binding to the HSP70 gene promoter. Importantly, inhibition of HSP70 partly reversed the iNOS overexpression-mediated hepatoprotection. The present findings demonstrate that hepatocellular iNOS protects from hepatic I/R injury through the HSF1-dependent activation of the HSP70. The upregulation of hepatocellular iNOS may offer a promising strategy for protecting against I/R injury.
Assuntos
Proteínas de Choque Térmico HSP70/metabolismo , Fatores de Transcrição de Choque Térmico/metabolismo , Fígado/irrigação sanguínea , Óxido Nítrico Sintase Tipo II/metabolismo , Traumatismo por Reperfusão/metabolismo , Animais , Proteínas de Choque Térmico HSP70/genética , Hepatócitos/metabolismo , Hepatócitos/patologia , Fígado/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico Sintase Tipo II/genética , Regiões Promotoras Genéticas , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologia , Regulação para CimaRESUMO
Multiple molecular events are involved in non-alcoholic steatohepatitis (NASH). There is no consensus on the role of inducible nitric oxide synthase (iNOS) in the progression of NASH. The present study therefore investigated the role of iNOS in NASH pathogenesis using bone marrow-transplanted iNOS chimeric mice under high-fat diet (HFD) conditions. The chimeric mice were fed a HFD for 16â¯wk, and primary hepatocytes were stimulated with oleic acid (OA). The molecular mechanisms underlying the role of iNOS in NASH were investigated. Marked hepatic steatosis and injury observed in the HFD mice and OA-stimulated hepatocytes were reduced by hepatocyte-derived iNOS. Mechanistically, iNOS upregulated heme oxygenase 1 (HO-1) by augmenting nuclear factor erythroid 2-related factor 2 (Nrf-2) binding to the HO-1 gene promoter. In conclusion, hepatocyte-derived iNOS may play a protective role against the progression of NASH by upregulating HO-1 through Nrf-2. Upregulation of hepatocellular iNOS may represent a potentially new therapeutic paradigm to combat NASH.
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Heme Oxigenase-1/metabolismo , Hepatócitos/metabolismo , Fígado/metabolismo , Proteínas de Membrana/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Animais , Ativação Enzimática , Feminino , Fígado/enzimologia , Fígado/patologia , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/enzimologia , Hepatopatia Gordurosa não Alcoólica/metabolismoRESUMO
OBJECTIVES: Multiple intrahepatic calculi, especially calculi in both sides of the liver, cannot be completely resolved by traditional surgery. In addition, morbidity after liver resection remains high. ERAS programs have been suggested that could relieve surgical stress and accelerate postoperative recovery. This study aimed to evaluate the safety and efficacy of choledocholithotomy combined with holmium laser lithotripsy in the treatment of multiple intrahepatic calculi within ERAS programs. METHODS: In all, 109 patients with multiple intrahepatic calculi were enrolled between January 2012 and September 2016, 42 of whom received choledocholithotomy combined with holmium laser lithotripsy. The remaining 67 patients underwent choledocholithotomy combined with choledochoscopic mechanical lithotripsy. Perioperative outcomes were compared and analyzed. RESULTS: Patient characteristics and preoperative details were similar between the groups (P > 0.05). The implementation of holmium laser lithotripsy could reduce the calculi residual rate (7.1% vs. 22.4%, P = 0.037), and even the liver resection rate (16.7% vs. 35.8%, P = 0.031). Additionally, holmium laser lithotripsy did not result in a higher morbidity (11.9% vs. 16.4%, P = 0.517), readmission rate (0% vs. 6%, P = 0.158), hospital stay (P = 0.189), hospital cost (P = 0.998), transfusion rate (P = 0.576), or operative time (P = 0.638). CONCLUSIONS: Holmium laser lithotripsy is feasible and efficient for treating multiple intrahepatic calculi within ERAS programs, which could reduce the liver resection rate and render refractory hepatic calculi easy to eliminate. In addition, holmium laser lithotripsy could be well coupled to the ERAS program to relieve surgical stress and accelerate postoperative recovery. Lasers Surg. Med. 51:161-166, 2019. © 2018 Wiley Periodicals, Inc.
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Coledocolitíase/terapia , Litotripsia a Laser/métodos , Hepatopatias/terapia , Coledocolitíase/diagnóstico por imagem , Coledocolitíase/cirurgia , Terapia Combinada , Feminino , Hólmio , Humanos , Litotripsia a Laser/instrumentação , Hepatopatias/diagnóstico por imagem , Hepatopatias/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Hepatocellular carcinoma (HCC) is a hypervascular cancer without effective treatment. Here we report that polypeptide of NC1 domain of type VIII collagen (Vastatin) is an endogenous polypeptide expressed in normal liver tissue but lost in the liver of most HCC patients (73.1%). Its expression level is negatively associated with tumor size (P = 0.035) and metastasis (P = 0.016) in HCC patients. To evaluate its potential use as a therapeutic, we constructed a recombinant adeno-associated virus carrying Vastatin (rAAV-Vastatin) to treat HCC in an orthotopic Buffalo rat model. rAAV-Vastatin treatment significantly prolonged the median survival, inhibited tumor growth, and completely prevented metastasis in HCC-bearing rats by decreasing microvessel density and increasing tumor necrosis. No detectable toxicity in nontumor-bearing mice was observed. To investigate its molecular mechanisms, we performed DNA microarray, western blotting assays, and bioinformatic analysis to determine its effect on global gene expression patterns and signal transduction pathways. Our results indicated that rAAV-Vastatin significantly reduced the expressions of Pck1, JAG2, and c-Fos, thus inhibiting the cellular metabolism, Notch and AP-1 signaling pathways, respectively. Hence, we demonstrated for the first time that Vastatin is a novel, safe, and effective antiangiogenic therapeutic and a potential biomarker for HCC.
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Inibidores da Angiogênese/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Colágeno Tipo VIII/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Adulto , Idoso , Inibidores da Angiogênese/metabolismo , Animais , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Colágeno Tipo VIII/metabolismo , Dependovirus/genética , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Feminino , Expressão Gênica , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Necrose , Gradação de Tumores , Metástase Neoplásica , Neovascularização Patológica/genética , Ratos , Receptores Notch/metabolismo , Transdução de Sinais , Fator de Transcrição AP-1/metabolismo , Transdução Genética , Carga Tumoral , Ensaios Antitumorais Modelo de XenoenxertoAssuntos
Doenças dos Ductos Biliares , Ductos Biliares Intra-Hepáticos , Endoscopia do Sistema Digestório , Cálculos Biliares , Litotripsia a Laser , Irrigação Terapêutica , Adulto , Idoso , Doenças dos Ductos Biliares/cirurgia , Ductos Biliares Intra-Hepáticos/cirurgia , Colelitíase/cirurgia , Endoscopia do Sistema Digestório/métodos , Feminino , Cálculos Biliares/cirurgia , Humanos , Lasers de Estado Sólido/uso terapêutico , Litotripsia a Laser/métodos , Masculino , Pessoa de Meia-Idade , Neodímio , Pressão , Estudos Retrospectivos , Irrigação Terapêutica/métodosRESUMO
BACKGROUND/AIMS: To discuss the clinical significance of combined application of laparoscopic cholecystectomy (LC) and endoscopic retrograde cholangiopancreatography (ERCP) for one-stage treatment of cholelithiasis complicated with common bile duct stones. METHODOLOGY: To retrospectively analyze 40 cases with cholelithiasis complicated with common bile duct stones treated with LC plus intraoperative ERCP between May 2005 and September 2012 and to evaluate the clinical efficacy in the treatment of cholelithiasis complicated with common bile duct stones. RESULTS: Among 40 cases, 36 successfully underwent LC plus intraoperative ERCP and 4 were transferred to open surgery. Eighteen patients with preoperative abnormal liver function showed declined indexes post-operatively. Compared with LC, more patients had abdominal distention and vomiting. Seven patients presented with transient increase in the levels of serum amylase with no incidence of acute pancreatitis. One had hematochezia and recovered after conservative treatment with no incidence of bile leakage and perforation and other severe complications. CONCLUSIONS: LC combined with intraoperative ERCP is safe and efficacious in the primary treatment of cholelithiasis complicated with common bile duct stones to avoid open surgery and double surgeries.
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Colangiopancreatografia Retrógrada Endoscópica , Colecistectomia Laparoscópica , Coledocolitíase/cirurgia , Colelitíase/cirurgia , Cálculos Biliares/cirurgia , Adulto , Idoso , Colangiopancreatografia Retrógrada Endoscópica/efeitos adversos , Colecistectomia Laparoscópica/efeitos adversos , Coledocolitíase/diagnóstico , Coledocolitíase/etiologia , Colelitíase/complicações , Colelitíase/diagnóstico , Feminino , Cálculos Biliares/diagnóstico , Cálculos Biliares/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Adulto JovemAssuntos
Carcinoma Hepatocelular/cirurgia , Hepatectomia/métodos , Neoplasias Hepáticas/cirurgia , Idoso , Perda Sanguínea Cirúrgica , Carcinoma Hepatocelular/virologia , Diafragma , Hepatite B Crônica/complicações , Humanos , Laparoscopia , Tempo de Internação , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , ToracoscopiaRESUMO
AIM: To investigate the roles of P21-activated kinase 5 (PAK5) in proliferation and tumorigenicity of human hepatocellular carcinoma (HCC). METHODS: HCC and matched paraneoplastictis tissue samples were obtained from 30 patients. Human HCC cell lines SMMC7721, HepG2, Hep3B, SK-HEP-1, Huh-7, and liver cell line HL-7702 were examined. The expression of PAK5 gene was studied using real-time qPCR and Western blotting. Cell proliferation was quantified with the MTT assay. Cell cycle was analyzed with flow cytometry. The tumorigenicity of Lv-shRNA-transfected HepG2 cells was evaluated in BALB/cA nude mice. RESULTS: The mRNA level of PAK5 was significantly higher in 25 out of 30 HCC samples compared to the matched paraneoplastic tissues. The HCC cell lines showed varying expression of PAK5 protein, and the highest level was found in the HepG2 cells. PAK5 gene silencing in HepG2 cells markedly reduced the cell proliferation and colony formation, and induced cell cycle arrest in the G1 phase. Furthermore, PAK5 gene silencing suppressed the tumor formation in nude mice, and significantly decreased the expression of HCC-related genes Cyclin D1 and beta-catenin. CONCLUSION: PAK5 may play essential roles in the initiation and progression of human HCC. Thus, it may be an effective therapeutic target or perhaps serve as a clinical diagnostic or prognostic marker in human HCC.
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Carcinogênese/metabolismo , Carcinoma Hepatocelular/enzimologia , Proliferação de Células , Neoplasias Hepáticas/enzimologia , Quinases Ativadas por p21/fisiologia , Animais , Carcinoma Hepatocelular/patologia , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, it has a poor prognosis due to its highly invasive and metastatic nature. Consequently, identifying effective prognostic markers and potential therapeutic targets has been extensively investigated. METTL5, an 18S rRNA methyltransferase, is abnormally high in HCC. But its biological function and prognostic significance in HCC remain largely unelucidated. This study aimed to investigate the role of METTL5 in HCC progression, and elucidate its possible molecular mechanisms in HCC via transcriptome sequencing, providing new insights for identifying new HCC prognostic markers and therapeutic targets. METHODS: The METTL5 expression in HCC and paracancerous tissues was analyzed using HCC immunohistochemical microarrays and bioinformatic retrieval methods to correlate METTL5 with clinicopathological features and survival prognosis. We constructed a METTL5 knockdown hepatocellular carcinoma cell line model and an animal model to determine the effect of METTL5 on hepatocellular carcinoma progression. Subsequently, RNA sequencing was performed to analyze the molecular mechanism of METTL5 in HCC based on the sequencing results, and relevant experiments were performed to verify it. RESULTS: We found that METTL5 expression was elevated in hepatocellular carcinoma tissues and correlated with poor patient prognosis, and in the analysis of clinicopathological features showed a correlation with TNM staging. In hepatocellular carcinoma cell lines with knockdown of METTL5, the malignant biological behavior was significantly reduced both in vitro and in vivo. Based on the sequencing results as well as the results of GO functional enrichment analysis and KEGG pathway enrichment analysis, we found that METTL5 could promote the generation and release of neutrophil extracellular capture network (NETs) and might further accelerate the progression of HCC. CONCLUSION: The m6A methyltransferase METTL5 is overexpressed in hepatocellular carcinoma (HCC) and correlates with poor prognosis. METTL5 accelerates malignant progression of HCC by promoting generation and release of the neutrophil extracellular traps (NETs) network, providing new insights for clinical biomarkers and immunotherapeutic targets in HCC prognosis.
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Adenina , Carcinoma Hepatocelular , Armadilhas Extracelulares , Neoplasias Hepáticas , Animais , Humanos , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Metiltransferases/genéticaRESUMO
OBJECTIVE: To explore the safety and feasibility of laparoscopic right hemihepatectomy via an anterior-inferior approach through retrohepatic tunnel in the dissection of short hepatic veins (SHVs). METHODS: After partial freeing of right liver, anterior peritoneum of inferior cava vena (ICV) was opened. Retrohepatic space was dissected via an anterior-inferior approach to establish the posterior tunnel partially. Then the first branch of right side SHVs could be freed and ligated after its exposure through the right part of retrohepatic tunnel. The above procedure was repeated until the right side SHVs or the third hepatic portal became partially or completely blocked. If right side SHVs were completely freed and ligament of right liver fully isolated, right hepatic vein could be exposed and ligated and selective blockage of the second hepatic portal blood flow accomplished. This technique was applied in 7 cases of laparoscopic right hemihepatectomy through curettage transaction and aspiration with laparoscopic Peng's multifunctional operative dissector (LPMOD). RESULTS: Six patients were treated successfully. In one case of right hepatic hemangioma, small margin auxiliary hematischesis was attempted because of troublesome hemostasis of middle hepatic vein branch. All of them underwent partial dissection of right side of SHVs. Two cases had complete dissection in which right hepatic vein was freed and ligated, the second hepatic porta blood flow controlled and right hemihepatectomy anatomically achieved. Operative duration was 300-540 min [mean, 399.1 ± 74.7]. The time of dissecting hepatic porta was 30-75 min [mean, 50.7 ± 16.2]. The time of dissecting SHVs was 35-95 min [mean, 57.1 ± 22.1]. The time of liver transection was 60-160 min [mean, 115.9 ± 32.3]. Operative blood loss had a volume at 600-3000 ml [mean, 1485.7 ± 809.2]. The postoperative hospital stay was 10-18 days [mean, 12.4 ± 2.6]. The postoperative time for ambulation, diet and flatus was 2-4, 1-4 and 2-4 days respectively. No severe postoperative complications occurred. CONCLUSION: During laparoscopic right hemihepatectomy, dissecting SHVs is both safe and feasible through a retrohepatic tunnel via an anterior-inferior approach.
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Hepatectomia , Veias Hepáticas/cirurgia , Laparoscopia , Perda Sanguínea Cirúrgica , Humanos , Tempo de Internação , Ligadura , Hepatopatias , Veia Cava InferiorRESUMO
Introduction: As one of the most common malignant tumors in clinical practice, hepatocellular carcinoma (HCC) is a major threat to human health, where alpha-fetoprotein (AFP) is widely used for early screening and diagnoses. However, the level of AFP would not elevate in about 30-40% of HCC patients, which is clinically referred to as AFP-negative HCC, with small tumors at an early stage and atypical imaging features, making it difficult to distinguish benign from malignant by imaging alone. Methods: A total of 798 patients, with the majority being HBV-positive, were enrolled in the study and were randomized 2:1 to the training and validation groups. Univariate and multivariate binary logistic regression analyses were used to determine the ability of each parameter to predict HCC. A nomogram model was constructed based on the independent predictors. Results: A unordered multicategorical logistic regression analyses showed that the age, TBIL, ALT, ALB, PT, GGT and GPR help identify non-hepatic disease, hepatitis, cirrhosis, and hepatocellular carcinoma. A multivariate logistic regression analyses showed that the gender, age, TBIL, GAR, and GPR were independent predictors for the diagnosis of AFP-negative HCC. And an efficient and reliable nomogram model (AUC=0.837) was constructed based on independent predictors. Discussion: Serum parameters help reveal intrinsic differences between non-hepatic disease, hepatitis, cirrhosis, and HCC. The nomogram based on clinical and serum parameters could be used as a marker for the diagnosis of AFP-negative HCC, providing an objective basis for the early diagnosis and individualized treatment of hepatocellular carcinoma patients.
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Ischemia reperfusion injury remains a major barrier to liver transplantation, especially using grafts from donation after circulatory death, and it is also a pressing issue to be solved in clinical practice. Kupffer cell polarization toward a proinflammatory M1 phenotype is an early trigger of liver ischemia-reperfusion injury. However, the molecular mechanism regulating Kupffer cell polarization has not yet been fully elucidated. We induced liver ischemia reperfusion injury in mice and obtained samples from patients undergoing liver transplantation, serum and hepatocytes-derived extracellular vesicles were isolated by differential ultracentrifugation. Kupffer cell polarization was examined by flow cytometry and immunofluorescence histochemistry. RNA-seq was conducted to detect the differentially expressed miRNAs in extracellular vesicles. The role and mechanism of exosomal miR-122-5p in liver ischemia-reperfusion injury were determined both in vitro and in vivo. We identified ischemia reperfusion induced extracellular vesicles as a major cause of hepatic inflammation and tissue damage using adoptive transfer and release inhibition. The study also demonstrated that hepatocyte-derived exosomal miR-122-5p mediates liver ischemia reperfusion injury by polarizing Kupffer cell via PPARδ down-regulation and NF-κB pathway activation using profiling and functional analysis. Moreover, inhibiting miR-122-5p with antagomir suppressed Kupffer cell M1 polarization and attenuated liver ischemia reperfusion injury. Overall, our study demonstrated that hepatocyte-derived exosomal miR-122-5p played a critical role in promoting hepatic ischemia reperfusion injury through modulating PPARδ signaling and NF-κB pathway to introduce M1 polarization of Kupffer cell. Inhibition of miR-122-5p exhibited a protective effect against liver ischemia reperfusion injury, suggesting a potential therapeutic target for liver transplantation.
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MicroRNAs , PPAR delta , Traumatismo por Reperfusão , Animais , Camundongos , Hepatócitos/metabolismo , Células de Kupffer/metabolismo , Fígado/metabolismo , MicroRNAs/metabolismo , NF-kappa B/metabolismo , PPAR delta/metabolismo , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo , HumanosRESUMO
OBJECTIVE: To investigate the clinical significance of human leukocyte antigen (HLA)-E levels in oesophageal squamous cell carcinoma (ESCC). METHODS: The levels of HLA-E immunostaining in ESCC lesions and 47 corresponding adjacent normal tissues were measured using immunohistochemistry. The correlation between the levels of immunostaining and clinical parameters was analysed. RESULTS: This study analysed 110 paraffin-embedded primary tumour lesions and 47 case-controlled paracancerous tissues that were surgically resected from 110 patients with ESCC. Positive immunostaining for HLA-E was observed in 88.2% (97 of 110) of ESCC lesions and 29.8% (14 of 47) of normal oesophageal tissues. There was no correlation between HLA-E immunostaining in ESCC lesions and clinicopathological characteristics such as lymph node metastasis, tumour-node-metastasis stage and differentiation grade. Kaplan-Meier survival analysis revealed a significantly better prognosis in patients with higher levels of HLA-E immunostaining than in those with lower levels of HLA-E immunostaining; overall survival was 28.6 months (95% confidence interval [CI], 23.2, 34.0) versus 15.3 months (95% CI, 11.5, 19.1), respectively. Furthermore, multivariate analysis showed that the HLA-E level was an independent prognostic factor in patients with ESCC. CONCLUSION: A higher level of HLA-E immunostaining was associated with favourable survival in patients with ESCC.
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Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Carcinoma de Células Escamosas/diagnóstico , Neoplasias Esofágicas/diagnóstico , Antígenos HLA , Humanos , PrognósticoRESUMO
OBJECTIVE: Conventional laparoscopic cholecystectomy (CLC) is usually performed with four incisions. Minimally invasive surgery for gallbladder disease with less pain and smaller scars has become increasingly popular. This study reported a new, two-incision laparoscopic cholecystectomy (TILC) using conventional instruments. METHODS: In this prospective study, 43 patients were recruited to undergo TILC and were compared with 43 historical cases undergoing CLC. We evaluated operative time, postoperative pain, cosmesis and complications. RESULTS: There was no significant difference in gender, age, body mass index, bile duct damage, blood loss and postoperative hospital stay between the two groups. The mean operation time was longer with TILC than with CLC, but the difference was not statistically different. Postoperative pain scores were significantly lower with TILC than with CLC. The mean cosmetic satisfaction score was significantly higher with TILC than that with CLC. There was no significant difference in the incidence of complications between the two groups. CONCLUSION: Our work demonstrates that TILC generates less postoperative pain and significantly improved cosmesis for patients. TILC is a safe and feasible alternative to CLC.
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Colecistectomia Laparoscópica , Doenças da Vesícula Biliar , Doenças da Vesícula Biliar/cirurgia , Humanos , Tempo de Internação , Duração da Cirurgia , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/prevenção & controle , Estudos Prospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Recently, hepatocellular carcinoma (HCC) has been ranked as the second leading cause of cancer-associated death. However, the underlying molecular mechanisms of HCC progression remain unclear. Vesicular overexpressed in cancer pro-survival protein 1 (VOPP1) could be upregulated in a quantity of human cancers, including squamous cell carcinoma (SCC), gastric cancer, and glioblastoma. However, the precise functional mechanism of VOPP1 in HCC remains poorly understood. The present study aimed to investigate the role of VOPP1 in HCC proliferation. METHODS: Immunohistochemistry (IHC), Western blot and Reverse-transcription polymerase chain reaction (RT-PCR) were used to analyze the protein and mRNA expressions of VOPP1, mitogen-activated protein kinase (MAPK) 14, ribosomal protein S6 kinase ß1 (RPS6KB1), cylindromatosis (CYLD) and Twist family bHLH transcription factor 1 (TWIST1). The cell proliferation and apoptosis were tested using Celigo cell imaging analyzer and annexin V-APC apoptosis detection kit respectively. Colony formation and tumor xenograft assays were performed to understand their roles in tumorigenicity. RESULTS: The expression of VOPP1 in HCC samples was higher than that in adjacent noncancerous tissues by immunohistochemistry. In addition, the down-regulation of VOPP1 using shRNA inhibited cell proliferation and tumour growth, and induced cell apoptosis in vitro and in vivo. Furthermore, VOPP1 silencing increased the expression of MAPK14 and RPS6KB1, indicating that the MAPK and mTOR signalling pathways might be involved in VOPP1-mediated cancer cell proliferation. CONCLUSION: The present data indicate that VOPP1 may play an important role in the progression of HCC by targeting the MAPK and mTOR signalling pathways, and that VOPP1 may potentially be a candidate as a novel molecular target for HCC therapy.
Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Proteínas Oncogênicas/genética , Fatores de Transcrição/metabolismo , Adulto , Idoso , Proliferação de Células , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: We evaluated the feasibility and efficacy of laparoscopic hepatectomy (LH) combined with endoscopic papillary balloon dilation (EPBD) for removing intra- and extrahepatic bile duct stones. METHODS: A total of 26 patients with intra- and extrahepatic bile duct stones underwent LH and EPBD. Selective hemi-hepatic vascular occlusion was used to complete the LH. EPBD was performed under the guidance of a guidewire, and stones were removed with a stone basket or balloon. RESULTS: A one-stage LH with EPBD lithotomy was successfully performed in 26 cases. No residual bile duct stones, intestinal or bile duct perforations were found. In addition, no severe post-operative bleeding, severe pancreatitis or mortality occurred. Post-operative hyperamylasemia was observed in five cases and bile leakage in one case. Post-operative hospital stays lasted 7-11 days. CONCLUSION: LH combined with EPBD applied to intra- and extrahepatic bile duct stones was feasible, effective and safe, resulting in rapid recovery and few post-operative complications.