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OBJECTIVE: Whether and how the PI3K-AKT pathway, a central node of metabolic homeostasis, is responsible for high-fat-induced non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) remain a mystery. Characterisation of AKT regulation in this setting will provide new strategies to combat HCC. DESIGN: Metabolite library screening disclosed that palmitic acid (PA) could activate AKT. In vivo and in vitro palmitoylation assay were employed to detect AKT palmitoylation. Diverse cell and mouse models, including generation of AKT1C77S and AKT1C224S knock-in cells, Zdhhc17 and Zdhhc24 knockout mice and Akt1C224S knock-in mice were employed. Human liver tissues from patients with NASH and HCC, hydrodynamic transfection mouse model, high-fat/high-cholesterol diet (HFHCD)-induced NASH/HCC mouse model and high-fat and methionine/choline-deficient diet (HFMCD)-induced NASH mouse model were also further explored for our mechanism studies. RESULTS: By screening a metabolite library, PA has been defined to activate AKT by promoting its palmitoyl modification, an essential step for growth factor-induced AKT activation. Biologically, a high-fat diet could promote AKT kinase activity, thereby promoting NASH and liver cancer. Mechanistically, palmitoyl binding anchors AKT to the cell membrane in a PIP3-independent manner, in part by preventing AKT from assembling into an inactive polymer. The palmitoyltransferases ZDHHC17/24 were characterised to palmitoylate AKT to exert oncogenic effects. Interestingly, the anti-obesity drug orlistat or specific penetrating peptides can effectively attenuate AKT palmitoylation and activation by restricting PA synthesis or repressing AKT modification, respectively, thereby antagonising liver tumorigenesis. CONCLUSIONS: Our findings elucidate a novel fine-tuned regulation of AKT by PA-ZDHHC17/24-mediated palmitoylation, and highlight tumour therapeutic strategies by taking PA-restricted diets, limiting PA synthesis, or directly targeting AKT palmitoylation.
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Carcinoma Hepatocelular , Dieta Alta en Grasa , Lipoilación , Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Proteínas Proto-Oncogénicas c-akt , Animales , Proteínas Proto-Oncogénicas c-akt/metabolismo , Dieta Alta en Grasa/efectos adversos , Ratones , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/etiología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/patología , Humanos , Ácido Palmítico/metabolismo , Carcinogénesis/metabolismo , Ratones Noqueados , Modelos Animales de Enfermedad , Masculino , Transducción de SeñalRESUMEN
BACKGROUND AND AIMS: To clarify high-risk factors and develop a nomogram model to predict biochemical resolution or biochemical nonresolution (BNR) in patients with chronic DILI. APPROACH AND RESULTS: Retrospectively, 3655 of 5326 patients with chronic DILI were enrolled from nine participating hospitals, of whom 2866 underwent liver biopsy. All of these patients were followed up for over 1 year and their clinical characteristics were retrieved from electronic medical records. The endpoint was BNR, defined as alanine aminotransferase or aspartate aminotransferase >1.5× upper limit of normal or alkaline phosphatase >1.1× ULN, at 12 months from chronic DILI diagnosis. The noninvasive high-risk factors for BNR identified by multivariable logistic regression were used to establish a nomogram, which was validated in an independent external cohort. Finally, 19.3% (707 of 3655) patients presented with BNR. Histologically, with the increase in liver inflammation grades and fibrosis stages, the proportion of BNR significantly increased. The risk of BNR was increased by 21.3-fold in patients with significant inflammation compared to none or mild inflammation (p < 0.001). Biochemically, aspartate aminotransferase and total bilirubin, platelets, prothrombin time, sex, and age were associated with BNR and incorporated to construct a nomogram model (BNR-6) with a concordance index of 0.824 (95% CI, 0.798-0.849), which was highly consistent with liver histology. These results were successfully validated both in the internal cohort and external cohort. CONCLUSIONS: Significant liver inflammation is a robust predictor associated with biochemical nonresolution. The established BNR-6 model provides an easy-to-use approach to assess the outcome of chronic DILI.
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Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Hepatitis , Aspartato Aminotransferasas , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/diagnóstico , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/patología , Hepatitis/patología , Humanos , Inflamación/patología , Hígado/patología , Estudios RetrospectivosRESUMEN
BACKGROUND AND AIMS: Lipoprotein Z (LP-Z) is an abnormal free cholesterol (FC)-enriched LDL-like particle discovered from patients with cholestatic liver disease. This study aims to define the diagnostic value of LP-Z in alcohol-associated hepatitis (AH) and interrogate the biology behind its formation. APPROACH AND RESULTS: We measured serum levels of LP-Z using nuclear magnetic resonance spectroscopy, a well-established clinical assay. Serum levels of LP-Z were significantly elevated in four AH cohorts compared with control groups, including heavy drinkers and patients with cirrhosis. We defined a Z-index, calculated by the ratio of LP-Z to total apolipoprotein B-containing lipoproteins, representing the degree of deviation from normal VLDL metabolism. A high Z-index was associated with 90-day mortality independent from the Model for End-Stage Liver Disease (MELD) and provided added prognosticative value. Both a Z-index ≤ 0.6 and a decline of Z-index by ≥0.1 in 2 weeks predicted 90-day survival. RNA-sequencing analyses of liver tissues demonstrated an inverse association in the expression of enzymes responsible for the extrahepatic conversion of VLDL to LDL and AH disease severity, which was further confirmed by the measurement of serum enzyme activity. To evaluate whether the FC in LP-Z could contribute to the pathogenesis of AH, we found significantly altered FC levels in liver explant of patients with AH. Furthermore, FC in reconstituted LP-Z particles caused direct toxicity to human hepatocytes in a concentration-dependent manner, supporting a pathogenic role of FC in LP-Z. CONCLUSIONS: Impaired lipoprotein metabolism in AH leads to the accumulation of LP-Z in the circulation, which is hepatotoxic from excessive FC. A Z-index ≤ 0.6 predicts 90-day survival independent from conventional biomarkers for disease prognostication.
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Enfermedad Hepática en Estado Terminal , Hepatitis Alcohólica , Apolipoproteínas B , Colesterol , Humanos , Lipoproteína(a) , Lipoproteínas , Índice de Severidad de la EnfermedadRESUMEN
Herein, a broadband photodetector (BPD) is constructed with consistent and stable detection abilities for deep ultraviolet to near-infrared spectral range. The BPD integrates the GaN template with a hybrid organic semiconductor, PM6:Y6, via the spin-coating process, and is fabricated in the form of asymmetric metal-semiconductor-metal structure. Under an optimal voltage, the device shows consistent photoresponse within 254 to 850â nm, featuring high responsivity (10 to 60â A/W), photo-to-dark-current ratio over 103, and fast response time. These results show the potential of such organic/GaN heterojunctions as a simple and effective strategy to build BPDs for a reliable photo-sensing application in the future.
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BACKGROUND AND AIMS: Myofibroblasts play a pivotal role in the development and progression of HCC. Here, we aimed to explore the role and mechanism of myofibroblast Musashi RNA binding protein 2 (MSI2) in HCC progression. APPROACH AND RESULTS: Myofibroblast infiltration and collagen deposition were detected and assessed in the tissues from 117 patients with HCC. Transgenic mice (Msi2ΔCol1a1 ) with floxed Msi2 allele and collagen type I alpha 1 chain (Col1a1)-ligand inducible Cre recombinases (CreER) were constructed to generate a myofibroblast-specific Msi2 knockout model. Mouse HCC cells were orthotopically transplanted into the Msi2ΔCol1a1 or the control mice (Msi2F/F ). We found that the deposition of collagen fibers, the main product of myofibroblasts, predicted a poor prognosis for HCC; meanwhile, we detected high MSI2 expression in the peritumoral infiltrated myofibroblasts. Conditional deletion of Msi2 in myofibroblasts significantly inhibited the growth of orthotopically implanted HCC, reduced both intrahepatic and lung metastasis, and prolonged the overall survival of tumor-bearing mice (P = 0.002). In vitro analysis demonstrated that myofibroblasts promoted cell proliferation, invasion, and epithelial-mesenchymal transformation of HCC cells, whereas Msi2 deletion in myofibroblasts reversed these effects. Mechanically, Msi2 knockout decreased myofibroblast-derived IL-6 and IL-11 secretion by inhibiting the extracellular signal-regulated kinase 1/2 pathway, and thus attenuated the cancer stem cell-promoting effect of myofibroblasts. Interestingly, we found that the simultaneous knockout of Msi2 in myofibroblasts and knockdown of Msi2 in HCC cells could not further attenuate the implanted HCC progression. CONCLUSIONS: Myofibroblast-specific Msi2 knockout abrogated the tumor-promoting function of myofibroblasts and inhibited HCC progression in mouse models. Targeting myofibroblast MSI2 expression may therefore prove to be a therapeutic strategy for HCC treatment in the future.
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Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Miofibroblastos/metabolismo , Proteínas de Unión al ARN/metabolismo , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Técnicas de Silenciamiento del Gen , Humanos , Hígado/patología , Ratones , Ratones Noqueados , Miofibroblastos/patología , Proteínas de Unión al ARN/genéticaRESUMEN
To investigate mechanisms that TMEM2 activation inhibits hepatitis B virus (HBV) infection in hepatocarcinoma (HCC) cells, co-immunoprecipitation (Co-IP) and mass spectrometry were used in screening interacting proteins for TMEM2. Levels of casein kinase 2 subunit α3 (CSNK2A3) in HCC cells were found to be inhibited or overexpressed using siRNAs and pcDNA3.1-CSNK2A3, respectively. Effect of CSNK2A3 expression on cell proliferation was analyzed using MTS, while its effect on HBV infection was measured using ddPCR and IHC. Western blotting and JAK inhibitor ruxolitinib were also used to determine whether TMEM2-regulated CSNK2A3 expression and HBV infection were affected by JAK-STAT signaling. Co-IP and mass spectrometry results showed that CSNK2A3 interacts with TMEM2. Moreover, overexpression of CSNK2A3 significantly inhibited cell proliferation, while inhibition of CSNK2A3 promoted proliferation of HCC cells. In addition, overexpression of CSNK2A3 was observed to significantly enhance HBV infection, while siRNA knockdown of CSNK2A3 inhibited HBV infection. Notably, effect of CSNK2A3 overexpression on HBV infection was suppressed by TMEM2 overexpression. Further mechanistic analyses have revealed that TMEM2 could antagonize the effects of CSNK2A3 on cell proliferation and HBV infection via JAK-STAT pathway activation. In conclusion, TMEM2 has been determined to bind to CSNK2A3 to inhibit HBV infection via activation of the JAK-STAT pathway.
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Quinasa de la Caseína II/metabolismo , Epilepsia del Lóbulo Temporal/prevención & control , Hepatitis B/prevención & control , Janus Quinasa 1/metabolismo , Proteínas de la Membrana/metabolismo , Factores de Transcripción STAT/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Carcinoma Hepatocelular/complicaciones , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/virología , Estudios de Casos y Controles , Quinasa de la Caseína II/genética , Epilepsia del Lóbulo Temporal/genética , Epilepsia del Lóbulo Temporal/metabolismo , Epilepsia del Lóbulo Temporal/patología , Hepatitis B/metabolismo , Hepatitis B/patología , Hepatitis B/virología , Virus de la Hepatitis B/fisiología , Humanos , Janus Quinasa 1/genética , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/virología , Proteínas de la Membrana/genética , PPAR gamma/genética , PPAR gamma/metabolismo , Factores de Transcripción STAT/genética , Células Tumorales CultivadasRESUMEN
BACKGROUND: For patients with hepatocellular carcinoma (HCC) with microvascular invasion (MVI) after curative resection, the effects of various postoperative adjuvant therapies are not summarized in detail, and the comparison between the effects of various adjuvant therapies is still unclear. Thus, we collected existing studies on postoperative adjuvant therapies for patients with HCC with MVI after curative resection and analyzed the effects of various adjuvant therapies. METHOD: We collected all studies on postoperative adjuvant therapy for patients with HCC with MVI after curative resection from PubMed, EMBASE, Cochrane Library and SinoMed ending on May 1, 2019. Overall survival (OS) and disease-free/recurrence-free survival (RFS) between each group were compared in these studies by calculating the pooled hazard ratio (HR) and 95% confidence interval (CI). All statistical analyses were assessed by two authors independently. RESULT: A total of 13 studies were included in this study, including 824 postoperative adjuvant transarterial chemoembolization (pa-TACE) patients, 90 postoperative radiotherapy patients, 57 radiofrequency ablation (RFA)/re-resection patients, 16 sorafenib patients and 886 postoperative conservative treatment patients. The results showed that pa-TACE significantly improved OS and RFS compared with postoperative conservative treatment in patients with HCC with MVI after curative resection (HR: 0.64, 95% CI: 0.55-0.74, p < 0.001; HR: 0.70, 95% CI: 0.62-0.78, p < 0.001, respectively). There was no significant difference in OS between pa-TACE and radiotherapy in patients with HCC with MVI (HR: 1.75, 95% CI: 0.92-3.32, p = 0.087). RFS in patients with HCC with MVI after pa-TACE was worse than that after postoperative adjuvant radiotherapy (HR: 2.29, 95% CI: 1.43-3.65, p < 0.001). The prognosis of pa-TACE and RFA/re-resection in patients with MVI with recurrent HCC had no significant differences (HR: 0.65, 95% CI: 0.09-4.89, p = 0.671). Adjuvant treatments significantly improved the OS and RFS of patients compared with the postoperative conservative group (HR: 0.580, 95% CI: 0.480-0.710, p < 0.001; HR: 0.630, 95% CI: 0.540-0.740, p < 0.001, respectively). CONCLUSION: Compared with postoperative conservative treatment, pa-TACE, postoperative radiotherapy and sorafenib can improve the prognosis of patients with hepatocellular carcinoma with microvascular invasion after curative resection. Postoperative radiotherapy can reduce the recurrence of patients with HCC with MVI after curative resection compared with pa-TACE.
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BACKGROUND: The recurrence of stones after endoscopic minimally invasive cholecystolithotomy (EMIC) remains a hazardous problem in patients with cholelithasis. We sought to evaluate the risk factors for recurrence after cholecystolithotomy and to provide a theoretical basis for the indication for cholecystolithotomy. METHODS: We searched the Cochrane Library, PubMed, EMBASE, WanFang Data, CNKI and VIP Data to identify controlled trials related to cholelithasis that were published between 2007 and 2016. The odds ratios (ORs) were calculated with 95% confidence intervals (CIs). Stata12.0 was used to test the heterogeneity and publication bias. RESULTS: Eight studies involving 1663 participants were selected. No significant differences were observed in hazardous factors including advanced age, gender and diabetes mellitus compared with the control groups. However, family history of cholelithasis, multiple calculi, gallbladder wall thickening (GBWT) over 3 mm, a preference for greasy food, dysfunction of the gallbladder and not taking oral ursodeoxycholic acid post-EMIC yielded pooled ORs (95% CI) of 3.28 (2.30, 4.66), 4.24 (2.76, 6.50), 18.4 (7.23, 46.83), 1.90 (1.20, 3.01), 26.16 (10.15, 62.34) and 2.90 (1.36, 6.15), respectively. CONCLUSIONS: A family history of cholelithasis, multiple calculi, a GBWT ≥ 3 mm, a preference for greasy food, dysfunction of the gallbladder and not taking oral ursodeoxycholic acid post-EMIC are hazardous factors for stones and sludge after cholecystolithotomy.
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Colecistectomía Laparoscópica/métodos , Colelitiasis/cirugía , China , Colelitiasis/etiología , Humanos , Oportunidad Relativa , Recurrencia , Factores de Riesgo , Resultado del TratamientoRESUMEN
BACKGROUND: The treatment of hepatocellular carcinoma (HCC) is complicated and challenging because of the frequent presence of cirrhosis. Therefore, we propose a novel surgical approach to minimize the invasiveness and risk in patients with HCC, hypersplenism, and esophagogastric varices. METHODS: This was a retrospective study carried out in 25 patients with HCC and hypersplenism and who underwent simultaneous laparoscopic-guided radio-frequency ablation and laparoscopic splenectomy with endoscopic variceal ligation. Tumor size was restricted to a single nodule of <3 cm. Characteristics of the patients (cirrhosis etiology, liver function, tumor size, spleen size), surgery (complications, blood loss, time of stay), and follow-up (recurrence and survival) were examined. RESULTS: Mean operative time was 128 ± 18 min. Mean blood loss was 206 ± 57 mL. Length of stay was 7.0 ± 1.5 days. Mean total costs were 8064 USD. Cytopenia and thrombocytopenia recovered quickly after surgery. No procedure was converted to open surgery. Two patients showed worsening liver function after surgery, three patients showed worsening of ascites, and five patients suffered from portal vein thrombosis. The 1-year tumor-free survival was 78.8 %, and the 21-month tumor-free survival was 61.4 %. According to a literature review, these outcomes were comparable to those of simultaneous open hepatic resection and splenectomy. CONCLUSIONS: Laparoscopic-guided radio-frequency ablation with laparoscopic splenectomy and endoscopic variceal ligation could be an available technique for patients with HCC <3 cm, hypersplenism, and esophagogastric varices. This approach may help to minimize the surgical risks and results in a fast increase in platelet counts with an acceptable rate of complications.
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Carcinoma Hepatocelular/cirugía , Ablación por Catéter/métodos , Neoplasias Hepáticas/cirugía , Esplenectomía/métodos , Adulto , Anciano , Pérdida de Sangre Quirúrgica , Carcinoma Hepatocelular/complicaciones , Carcinoma Hepatocelular/patología , Ablación por Catéter/efectos adversos , Supervivencia sin Enfermedad , Várices Esofágicas y Gástricas/etiología , Várices Esofágicas y Gástricas/cirugía , Femenino , Estudios de Seguimiento , Humanos , Hiperesplenismo/cirugía , Laparoscopía , Tiempo de Internación , Ligadura , Cirrosis Hepática/complicaciones , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/prevención & control , Recurrencia Local de Neoplasia/patología , Tempo Operativo , Recuento de Plaquetas , Estudios Retrospectivos , Esplenectomía/efectos adversos , Resultado del TratamientoRESUMEN
AIM: Cancer is not only influenced by specific tumor cells but also by the stromal microenvironment. Upon liver damage, activated hepatic stellate cells (aHSC) become highly proliferative myofibroblast-like cells and are thought to secrete molecules that influence development of hepatocellular carcinoma (HCC). The aim of this study was to investigate the role of aHSC in the development of HCC. METHODS: To assess if aHSC secreted factor(s) that promote microvascular endothelial cell (MEC) tube formation, MEC were plated with aHSC-conditioned medium and tube formation analyzed by light microscopy. An established transendothelial migration assay with MEC was used to evaluate the role of aHSC in migration and metastasis. A novel in vitro and in vivo orthotopic mouse HCC tumor model was used to investigate angiogenic, proliferative and metastatic activity of aHSC. RESULTS: We found that aHSC promoted angiogenesis both in vitro and in vivo through vascular endothelial growth factor (VEGF). aHSC-conditioned medium increased the ability of MEC to form tubes which was dependent upon aHSC-secreted VEGF. In addition, HCC orthogenic tumors derived from co-injection of H22 cells plus aHSC into the hepatic lobes of mice had greater cell proliferation and vascularization, as evaluated by the presence of CD34 and VEGF expression, than tumors resulting from H22 injections alone. aHSC also migrated from the primary tumor to sites of metastasis. CONCLUSION: Our findings support aHSC playing multiple roles in HCC development and metastasis.
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BACKGROUND AND AIM: Hepatitis B virus core promoter (CP) mutations can increase risk of hepatocellular carcinoma. The CP region overlaps with the HBV X (HBx) gene, which has been associated with hepatocarcinogenesis. The cyclin kinase inhibitor P53 is an important regulator of cell cycle progression. We determined whether HBx mutants that result from mutations in the CP deregulate P53. METHODS: A HBx combination (combo) mutant with changes in the CP region that corresponded to A1762T/G1764A (TA), T1753A, and T1768A was constructed and expressed in L-02 and Hep3B cells. The effects of CP mutations on expression and degradation of P53, and the effects on cell cycle progression and proliferation were analyzed. RESULTS: The combo mutant decreased levels of P53 and increased cyclin D1 expression, accelerated P53 degradation in L-02 cells, accelerated cell cycle progression, and increased expression of S-phase kinase-associated protein 2 (Skp2) in L-02 and Hep3B cells. Silencing of Skp2 abrogated the effects of CP mutations on P53 expression. The kinetics of P53 expression correlated with changes in cell cycle distribution. CONCLUSIONS: The HBx mutant with a combination of CP mutations can up-regulate Skp2, which then down-regulates P53 via ubiquitin-mediated proteasomal degradation, increasing the risk of hepatocellular carcinoma.
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Carcinoma Hepatocelular/virología , Transformación Celular Viral , Virus de la Hepatitis B/genética , Hepatitis B/virología , Neoplasias Hepáticas/virología , Mutación , Proteínas Quinasas Asociadas a Fase-S/metabolismo , Transactivadores/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteínas del Núcleo Viral/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Ciclo Celular , Línea Celular Tumoral , Proliferación Celular , Ciclina D1/metabolismo , Regulación Neoplásica de la Expresión Génica , Genotipo , Hepatitis B/complicaciones , Virus de la Hepatitis B/patogenicidad , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Fenotipo , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteolisis , Interferencia de ARN , Proteínas Quinasas Asociadas a Fase-S/genética , Factores de Tiempo , Transfección , Proteína p53 Supresora de Tumor/genética , Ubiquitinación , Proteínas Reguladoras y Accesorias ViralesRESUMEN
OBJECTIVE: To explore the risk factors of portal hypertensive gastropathy (PHG) in patients with hepatitis B associated cirrhosis and establish a Logistic regression model of noninvasive prediction. METHODS: The clinical data of 234 hospitalized patients with hepatitis B associated cirrhosis from March 2012 to March 2014 were analyzed retrospectively. The dependent variable was the occurrence of PHG while the independent variables were screened by binary Logistic analysis. Multivariate Logistic regression was used for further analysis of significant noninvasive independent variables. Logistic regression model was established and odds ratio was calculated for each factor. The accuracy, sensitivity and specificity of model were evaluated by the curve of receiver operating characteristic (ROC). RESULTS: According to univariate Logistic regression, the risk factors included hepatic dysfunction, albumin (ALB), bilirubin (TB), prothrombin time (PT), platelet (PLT), white blood cell (WBC), portal vein diameter, spleen index, splenic vein diameter, diameter ratio, PLT to spleen volume ratio, esophageal varices (EV) and gastric varices (GV). Multivariate analysis showed that hepatic dysfunction (X1), TB (X2), PLT (X3) and splenic vein diameter (X4) were the major occurring factors for PHG. The established regression model was Logit P=-2.667+2.186X1-2.167X2+0.725X3+0.976X4. The accuracy of model for PHG was 79.1% with a sensitivity of 77.2% and a specificity of 80.8%. CONCLUSION: Hepatic dysfunction, TB, PLT and splenic vein diameter are risk factors for PHG and the noninvasive predicted Logistic regression model was Logit P=-2.667+2.186X1-2.167X2+0.725X3+0.976X4.
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Hepatitis B , Hipertensión Portal , Várices Esofágicas y Gástricas , Humanos , Cirrosis Hepática , Modelos Logísticos , Oportunidad Relativa , Vena Porta , Valor Predictivo de las Pruebas , Curva ROC , Estudios Retrospectivos , Factores de Riesgo , Bazo , GastropatíasRESUMEN
OBJECTIVE: To investigate the treatment effect of laparoscopic hepatectomy and microwave ablation for colorectal liver metastases. METHODS: We retrospectively analyzed 126 patients who received treatment for colorectal liver metastases in our hospital during Jan. 2009 to Jan. 2015, and these patients were divided into laparoscopic surgical group (40 cases), microwave group (42 cases) and open surgical group (44 cases). The overall survival rate and disease-free survival rate were compared by using the Kaplan-Meier method. RESULTS: The operation time in three groups were (120±35), (55±20), (100±30) min, respectively. The blood loss in the three groups were (300±120), (100±25), (250±95) ml, respectively. The operation time, blood loss and hospital stay in microwave group were less than the other two groups (P<0.05). There was no significant difference in survival time and postoperative complications in these groups (P>0.05). CONCLUSIONS: Laparoscopic hepatectomy and microwave ablation in the treatment of colorectal liver metastases is effective compared to open hepatectomy. So the minimal invasive surgical techniques had benefit for patients with liver metastases from colorectal cancer.
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Neoplasias Colorrectales , Hepatectomía , Supervivencia sin Enfermedad , Humanos , Laparoscopía , Tiempo de Internación , Neoplasias Hepáticas , Microondas , Tempo Operativo , Complicaciones Posoperatorias , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Purpose: Osteoarthritis (OA) is the most common joint disease worldwide and is the primary cause of disability and chronic pain in older adults.Ferroptosis is a type of programmed cell death characterized by aberrant iron metabolism and reactive oxygen species accumulation; however, its role in OA is not known. Methods: To identify ferroptosis markers co-expressed in articular cartilage and synovium samples from patients with OA, in silico analysis was performed.Signature genes were analyzed and the results were evaluated using a ROC curve prediction model.The biological function, correlation between Signature genes, immune cell infiltration, and ceRNA network analyses were performed. Signature genes and ferroptosis phenotypes were verified through in vivo animal experiments and clinical samples. The expression levels of non-coding RNAs in samples from patients with OA were determined using qRT-PCR. ceRNA network analysis results were confirmed using dual-luciferase assays. Results: JUN, ATF3, and CDKN1A were identified as OA- and ferroptosis-associated signature genes. GSEA analysis demonstrated an enrichment of these genes in immune and inflammatory responses, and amino acid metabolism. The CIBERSORT algorithm showed a negative correlation between T cells and these signature genes in the cartilage, and a positive correlation in the synovium. Moreover, RP5-894D12.5 and FAM95B1 regulated the expression of JUN, ATF3, and CDKN1A by competitively binding to miR-1972, miR-665, and miR-181a-2-3p. In vivo, GPX4 was downregulated in both OA cartilage and synovium; however, GPX4 and GSH were downregulated, while ferrous ions were upregulated in patient OA cartilage and synovium samples, indicating that ferroptosis was involved in the pathogenesis of OA. Furthermore, JUN, ATF3, and CDKN1A expression was downregulated in both mouse and human OA synovial and cartilage tissues. qRT-PCR demonstrated that miR-1972, RP5-894D12.5, and FAM95B1 were differentially expressed in OA tissues. Targeted interactions between miR-1972 and JUN, and a ceRNA regulatory mechanism between RP5-894D12.5, miR-1972, and JUN were confirmed by dual-luciferase assays. Conclusion: This study identified JUN, ATF3, and CDKN1A as possible diagnostic biomarkers and therapeutic targets for joint synovitis and OA. Furthermore, our finding indicated that RP5-894D12.5/miR-1972/JUN was a potential ceRNA regulatory axis in OA, providing an insight into the connection between ferroptosis and OA.
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[This corrects the article DOI: 10.3389/fonc.2022.916104.].
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Tumor-associated macrophages (TAMs) play a pivotal role in shaping the tumor microenvironment. Lactic acid (LA) has been identified as an influential factor in promoting immune escape and tumor progression. However, the mechanisms through which LA modulates TAMs in colorectal cancer (CRC) remain poorly understood. We used qRT-PCR to quantify the expression of LA-related genes (LDHA and LAMP2) in CRC tumor tissues and adjacent nontumor tissues (n = 64). The biological effects and mechanisms of LA on macrophages and tumors were evaluated via qRT-PCR, Western blot, RNA-seq, wound healing assay, colony formation assay in vitro, and allograft mouse tumor models in vivo. We found the expression of LDHA and LAMP2 was highly elevated in the tumor regions and positively associated with a poor clinical stage of CRC. A high concentration of LA was generated under hypoxia; it could promote tumor progression and metastasis with the involvement of macrophages. The inhibition of LA release impaired this protumor phenomenon. Mechanically, LA induced M2 macrophages through the AKT/ERK signaling pathway; subsequently, M2 macrophages secreted CCL8 and facilitated the proliferation and metastasis of CRC cells by activating the CCL8/CCR5/mTORC1 axis. This effect was inhibited by the antagonist or knockdown of CCR5. In conclusion, lactate-induced CCL8 in TAMs accelerated CRC proliferation and metastasis through the CCL8/CCR5/mTORC1 axis.
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MicroRNAs (miRNAs) reportedly play significant roles in the progression of various cancers and hold huge potential as both diagnostic tools and therapeutic targets. Given the ongoing uncertainty surrounding the precise functions of several miRNAs in cholangiocarcinoma (CCA), this research undertakes a comprehensive analysis of CCA data sourced from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. The present study identified a novel miRNA, specifically miR-26b-3p, which exhibited prognostic value for individuals with CCA. Notably, miR-26b-3p was upregulated within CCA samples, with an inverse correlation established with patient prognosis (Hazard Ratio = 8.19, p = 0.018). Through a combination of functional enrichment analysis, analysis of the LncRNA-miR-26b-3p-mRNA interaction network, and validation by qRT PCR and western blotting, this study uncovered the potential of miR-26b-3p in potentiating the malignant progression of CCA via regulation of essential genes (including PSMD14, XAB2, SLC4A4) implicated in processes such as endoplasmic reticulum (ER) stress and responses to misfolded proteins. Our findings introduce novel and valuable insights that position miR-26b-3p-associated genes as promising biomarkers for the diagnosis and treatment of CCA.
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Over the last decades, imaging technologies have got significant developments and become indispensable in the surgical management of liver cancers. Real-time navigation afforded by intraoperative images has a significant impact on the success of liver surgeries. Fluorescence imaging in the near-infrared spectrum has shown potential for tumor detection and image-guided surgery in clinics. While predominantly focused on indocyanine green (ICG) imaging, there is also accelerated development of more specific molecular tracers. Compared to passive targeting contrast agents ICG, active targeting and activatable probes both shed new light for intraoperative navigation owing to the higher degree of specificity for the tumor target. A variety of fluorescence imaging probes have been developed to target biomarkers unique to cancer cells or tumor microenvironment and demonstrated promising results. In this review, we provide a comprehensive update on preclinical development and clinical applications of fluorescence imaging in the surgical management of liver cancers. By highlighting the current status, we aim to offer insight into the challenges and opportunities for further investigation.
Asunto(s)
Neoplasias Hepáticas , Cirugía Asistida por Computador , Colorantes Fluorescentes , Humanos , Verde de Indocianina , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/cirugía , Imagen Óptica/métodos , Cirugía Asistida por Computador/métodos , Microambiente TumoralRESUMEN
With microtrauma becoming a consensus, in order to improve surgical treatment capability, the clinical application of laparoscopic multiorgan resection is becoming more and more complicated and diversified. Recently, we successfully presented a case of transvaginal specimen extraction surgery that included laparoscopic anatomical left hemihepatectomy combined with laparoscopic total hysterectomy and bilateral adnexectomy and the pelvic and para-aortic lymphadenectomy. The patient, a 75-year-old woman, was hospitalized with abnormal vaginal discharge and bleeding. The pathologic diagnosis of uterine curettage was endometrioid adenocarcinoma. After completing examinations such as color Doppler ultrasound, CEUS, MRCP and thoracoabdominal enhanced spiral CT, preoperative diagnosis was considered as endometrial cancer and a space-occupying lesion in the liver (primary or secondary site)?. No lymphatic or distant metastasis had been found. We also excluded Lynch syndrome by digestive endoscopy and gene sequencing. After a multidisciplinary consultation, the patient underwent surgery under general anesthesia on 24 September 2021. The operation was completed uneventfully in 6 hours, then the patient was transferred to the ICU for follow-up monitoring. The patient began to eat and was able to leave bed on the 4th postoperative day. According to immunohistochemistry, the patient's postoperative diagnosis was intrahepatic cholangiocarcinoma (ICC) and endometrial cancer. Compared with open surgery, laparoscopic multiorgan resection with natural orifice specimen extraction surgery (NOSES) has many advantages such as fewer traumas, shorter recovery time, and better postoperative quality of life. However, combined large-scale laparoscopic surgeries of different organs can be challenging for surgeons and anesthesiologists. No similar cases have been searched.
RESUMEN
Fibroblast growth factor 2 (FGF-2) and its main receptor FGFR1 have been shown to promote hepatic stellate cell (HSC) activation and proliferation. However, scant information is available on the anti-fibrogenic activity of FGFR1 inhibitors. The aim of this study was to assess the impact of a selective FGFR1 tyrosine kinase inhibitor NP603 on HSC proliferation and hepatic fibrosis. We demonstrated that rat primary HSCs secreted significant amounts of FGF-2, and its tyrosine phosphorylation of FGFR1 was attenuated by NP603. NP603 inhibited HSC activaton by measuring the expression of α-smooth muscle actin (α-SMA) and the production of type I collagen using ELISA. Furthermore, NP603 (25 µM) in vitro strongly suppressed HSC growth induced by FGF-2 (10 ng/ml) and FCS. This effect correlated with the suppression of extracellular-regulated kinase (ERK) activity and its downstream targets cyclin D1 and p21. In addition, PO NP603 (20 mg·kg(-1)·day(-1)) administration significantly decreased hepatic collagen deposition and α-SMA expression in CCl(4)-treated rats. Collectively, these studies suggest that selective blocking of the FGFR1-mediated pathway could be a promising therapeutic approach for the treatment of hepatic fibrosis.