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Ischemia-reperfusion injury (IRI) is one of the most common complications in liver transplantation. METTL3 regulates inflammation and cellular stress response by modulating RNA m6A modification level. Here, the study aimed to investigate the role and mechanism of METTL3 in IRI after rat orthotopic liver transplantation. The total RNA m6A modification and METTL3 expression level was consistently down-regulated after 6â¯h or 24â¯h reperfusion in OLT, which is negatively associated with the hepatic cell apoptosis. Functionally, METTL3 pretreatment in donor significantly inhibited liver grafts apoptosis, improved liver function and depressed the proinflammatory cytokine/chemokine expression. Mechanistically, METTL3 inhibited apoptosis of grafts via upregulating HO-1. Moreover, m6A dot blot and MeRIP-qPCR assay revealed that METTL3 promoted HO-1 expression in an m6A-dependent manner. In vitro, METTL3 alleviated hepatocytes apoptosis by upregulating HO-1 under hypoxia/reoxygenation condition. Taken together, these findings demonstrate that METTL3 ameliorates rat OLT-stressed IRI by inducing HO-1 in an m6A-dependent manner, highlighting a potential target for IRI in liver transplantation.
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Transplante de Fígado , Traumatismo por Reperfusão , Ratos , Animais , Transplante de Fígado/efeitos adversos , Fígado/metabolismo , Inflamação/metabolismo , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo , RNA/metabolismoRESUMO
AIMS: To determine the relationship between microvascular invasion (MVI) and the clinical features of hepatocellular carcinoma (HCC) and provide a method to evaluate MVI status by neutral network analysis. METHODS: The patients were divided into two groups (MVI-positive group and MVI-negative group). Univariate analysis and multivariate logistic regression analysis were carried out to identify the independent risk factors for MVI positivity. Neural network analysis was used to analyze the different importance of the risk factors in MVI prediction. RESULTS: We enrolled 1697 patients in this study. We found that the independent prognostic factors were age, NEU, multiple tumors, AFP level and tumor diameter. By neural network analysis, we proposed that the level of AFP was the most important risk factor for HCC in predicting MVI status (the AUC was 0.704). However, age was the most important risk factor for early-stage HCC with a single tumor (the AUC was 0.605). CONCLUSION: Through the neutral network analysis, we could conclude that the level of AFP is the most important risk factor for MVI-positive patients and the age is the most important risk factor for early-stage HCC with a single tumor.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , alfa-Fetoproteínas , Estudos Retrospectivos , Invasividade NeoplásicaRESUMO
BACKGROUND: This study aimed to find effective treatments for the patient within UCSF criteria. METHODS: This study enrolled 1006 patients meeting UCSF criteria, undergoing hepatic resection (HR), divided into two groups: single tumor group and multiple tumors group. We compared and analyzed the risk factors between these two groups' long-term outcomes, through log-rank test, cox proportional hazards model and using neural network analysis to identify the independent risk factors. RESULTS: The 1-, 3-, and 5-year OS rates in single tumor were significantly higher than multiple tumors (95.0%, 73.2% and 52.3% versus 93.9%, 69.7% and 38.0%, respectively, p < 0.001). The 1-, 3- and 5-year RFS rates were 90.3%, 60.7%, and 40.1% in single tumor and 83.4%, 50.7% and 23.8% in multiple tumors, respectively (p < 0.001). And tumor type, anatomic resection and MVI were the independent risk factors for the patient within UCSF criteria. MVI was the most important risk factor affecting OS and RFS rates in neural network analysis. The method of hepatic resection and the number of tumors were also affected OS and RFS rates. CONCLUSION: Anatomic resections should be applied to patients within UCSF criteria, especially for patients with single MVI negative tumours.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Transplante de Fígado , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Hepatectomia/efeitos adversos , São Francisco , Transplante de Fígado/efeitos adversos , Estudos Retrospectivos , Recidiva Local de Neoplasia/cirurgiaRESUMO
BACKGROUND: Transcription factor 3 (TCF3) plays pivotal roles in embryonic development, stem cell maintenance and carcinogenesis. However, its role in hepatocellular carcinoma (HCC) remains largely unknown. This study aimed to analyze the correlation between TCF3 expression and clinicopathological features of HCC, and further explore the underlying mechanism in HCC progression. METHODS: The expression of TCF3 was collected from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) HCC datasets, and further confirmed by immunostaining and Western blotting assays. The correlation between TCF3 expression and the clinicopathological features was evaluated. Bioinformatical analysis and in vitro experiments were conducted to explore the potential role of TCF3 in HCC development. RESULTS: Both the mRNA and protein levels of TCF3 were significantly higher in HCC tumor tissues compared to tumor adjacent tissues (P < 0.001 and P < 0.01). Analysis based on TCGA datasets showed that TCF3 was positively correlated with tumor clinical stage and grade, and patients with high TCF3 expression had shorter overall survival (P = 0.012), disease-specific survival (P = 0.022) and progression-free survival (P = 0.013). Similarly, the immunostaining results revealed that the high expression of TCF3 was closely correlated with tumor size (P = 0.001) and TNM stage (P = 0.002), and TCF3 was an independent risk factor of HCC. In vitro study exhibited that TCF3 knockdown dramatically suppressed cancer cell proliferation, and the underlying mechanism might be that the silencing of TCF3 reduced the expression of critical regulating proteins towards cell cycle and proteins involved in Wnt signaling pathways. CONCLUSIONS: TCF3 expression is significantly elevated in HCC and positively associated with the tumor size and TNM stage, as well as poor prognosis of HCC patients. The mechanism might be that TCF3 promotes cancer cell proliferation via activating Wnt signaling pathway.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Fator 3 de Transcrição , Via de Sinalização Wnt , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/patologia , Prognóstico , Fator 3 de Transcrição/genética , Fator 3 de Transcrição/metabolismoRESUMO
Background and Objective: The study aims to investigate the correlation between Hepatitis B 'e' antigen (HBeAg) and HBV DNA levels, and to find a convenient tool to estimate the HBV DNA level for clinicians. Materials and Methods: We enrolled 1020 patients in this cross-sectional study and divided them into four groups: an HbeAg-positive and -negative group, and high and low HBV DNA levels groups. Results: Alanine aminotransferase (ALT), Albumin (ALB) and HBeAg are independent risk factors for CHB patients. When the level of HBeAg is higher than 16.15 S/CO, it is four times more likely that the patients will have high levels of HBV DNA than those who do not. The ALT and TB are independent risk factors in HBeAg-negative patients with a high HBV DNA level. We have drawn three predictive models to estimate the HBV DNA levels for those with the chronic hepatitis B virus (CHB), and those that are HBeAg-positive and HBeAg-negative (Y1 = 0.004 × ALT(IU/L) + 1.412 × HBeAg (S/CO) - 0.029 × ALB (g/L) + 0.779, the AUC is 0.672, and the cutoff value is -0.072, there the sensitivity is 0.615, the specificity is 0.648, PPV is 65.182% and NPV is 60.837%; Y2 = 0.007 × HBeAg (S/CO) - 0.016 × HGB (g/L) + 3.070, the AUC is 0.724, and the cutoff value is 1.216, where the sensitivity is 0.626, the specificity is 0.897, PPV is 94.118% and NPV is 34.437%; Y3 = -0.005 × ALT(IU/L) + 0.006 × TB (umol/L) + 0.385, the AUC is 0.661, and the cutoff value is 0.263, where the sensitivity is 0.677, the specificity is 0.587, PPV is 66.820% and NPV is 40.774%, respectively). We propose that HBeAg is the most important risk factor for the patient with a high HBV DNA level, however, it is not as important in the HBeAg-positive group. Conclusions: HBeAg is an independent risk factor that reflects the level of HBV DNA with a strong correlation. Patient with HBeAg (-) should combine TB and ALT to estimate the level of HBV DNA.
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Antígenos E da Hepatite B , Hepatite B Crônica , Alanina Transaminase , Albuminas , Estudos Transversais , DNA Viral , Vírus da Hepatite B/genética , Hepatite B Crônica/diagnóstico , HumanosRESUMO
The performance enhancement of inverted perovskite solar cells applying nickel oxide (NiOx ) as the hole transport layer (HTL) has been limited by impurity ions (such as nitrate ions). Herein, we have proposed a strategy to obtain high-quality NiOx nanoparticles via an ionic liquid-assisted synthesis method (NiOx -IL). Experimental and theoretical results illustrate that the cation of the ionic liquid can inhibit the adsorption of impurity ions on nickel hydroxide through a strong hydrogen bond and low adsorption energy, thereby obtaining NiOx -IL HTL with high conductivity and strong hole-extraction ability. Importantly, the removal of impurity ions can effectively suppress the redox reaction between the NiOx film and the perovskite film, thus slowing down the deterioration of device performance. Consequently, the modified inverted device shows a striking efficiency exceeding 22.62 %, and superior stability maintaining 92 % efficiency at a maximum power point tracking under one sun illumination for 1000â h.
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There are two causes of graft compression in the large-for-size syndrome (LFSS). One is a shortage of intra-abdominal space for the liver graft, and the other is the size discrepancy between the anteroposterior dimensions of the liver graft and the lower right hemithorax of the recipient. The former could be treated using delayed fascial closure or mesh closure, but the latter may only be treated by reduction of the right liver graft to increase space. Given that split liver transplantation has strict requirements regarding donor and recipient selections, reduced-size liver transplantation, in most cases, may be the only solution. However, surgical strategies for the reduction of the right liver graft for adult liver transplantations are relatively unfamiliar. Herein, we introduce a novel strategy of HuaXi-ex vivo right posterior sectionectomy while preserving the right hepatic vein in the graft to prevent LFSS and propose its initial indications.
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Transplante de Fígado , Adulto , Veias Hepáticas , Humanos , Fígado , Transplante de Fígado/efeitos adversos , Transplante de Fígado/métodos , Doadores Vivos , Projetos Piloto , Doadores de TecidosRESUMO
OBJECTIVE: To evaluate the efficacy of internal fixation of lateral and medial borders for displaced scapular body fractures via the minimally invasive approach. METHODS: The internal fixation of lateral and medial borders via minimally invasive approach was applied in surgical treatment of 23 patients with scapular body comminuted fractures from January 2014 to June 2018. The lateral approach was made straightly orienting over the lateral border of scapula. The dissection was taken down to the deltoid fascia. The deltoid was retracted cephalically, revealing the external rotators. Blunt dissection was used down to the lateral border between infraspinatus and teres minor, exposing the fracture site. The medial incision was done along the medial border of the scapula over site of the fracture. Dissections were taken down to the fascia and the periosteum. A subperiosteal dissection was then performed to elevate the infraspinatus to the degree necessary to visualize the fracture. The medial and lateral borders of scapula body were fixed with plates and screws in a frame-like way. RESULTS: One patient developed the delayed healing of the incisions due to liquefactive fat necrosis. The other 22 patients showed no complications of the incisions. The glenopolar angle (GPA) of fractured scapula was increased from preoperative (25±12) degrees to postoperative (41±5) degrees (P<0.01). The healing time of fractures healed was 3-8 months, with an average time of (4.4±1.3) months. CONCLUSIONS: The lateral-medial combined fixation through minimally invasive surgical approach for the scapula body fractures allows visualization of fracture reduction without extensive muscular or subcutaneous flaps, and is associated with successful fracture healing and high functional scores of the shoulder.
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Fixação de Fratura , Fraturas Ósseas , Procedimentos Cirúrgicos Minimamente Invasivos , Escápula , Fraturas do Ombro , Fixação Interna de Fraturas/normas , Consolidação da Fratura , Fraturas Ósseas/cirurgia , Humanos , Procedimentos Cirúrgicos Minimamente Invasivos/normas , Escápula/lesões , Escápula/cirurgia , Fraturas do Ombro/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: Interleukin-37b (IL-37b), a vital negative regulator of the innate immune system, has been reported to be a tumor inhibitor in different type of cancers. However, little is known about the relationship between IL-37b and hepatocellular carcinoma (HCC). The present study aimed to investigate the potential roles of IL-37b in HCC progression. METHODS: Subjects (nâ¯=â¯237) were recruited, and serum IL-37b was measured using ELISA. The tumor-suppressive capacity and underlying mechanisms of IL-37b in HCC were investigated in vitro and in vivo. RESULTS: Compared to healthy controls, serum IL-37b levels were elevated in chronic hepatitis B (CHB) patients but decreased significantly in HBV-HCC patients, especially for those with portal venous tumor thrombus. Low level serum IL-37b in HBV-HCC patients correlated with high HCC stage and poor overall survival and disease-free survival. In vitro and in vivo, recombinant human IL-37b inhibited proliferation and metastasis in HCC cells. Furthermore, IL-37b inhibited epithelial mesenchymal transition in HCC cells in vitro by downregulating IL-6, pSTAT3 (Y705), N-cadherin, and vimentin expression and by upregulating E-cadherin expression. These effects were partially reversed by transfection of adenovirus encoding human IL-6. CONCLUSIONS: IL-37b inhibits HCC growth, metastasis and epithelial mesenchymal transition by regulating IL-6/STAT3 signaling. Serum IL-37b may be a biomarker for HBV-HCC and its staging.
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Carcinoma Hepatocelular/genética , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Interleucina-1/genética , Neoplasias Hepáticas/genética , Fator de Transcrição STAT3/metabolismo , Adulto , Idoso , Análise de Variância , Biópsia por Agulha , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Estudos de Casos e Controles , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Hepatite B Crônica/sangue , Hepatite B Crônica/genética , Hepatite B Crônica/patologia , Humanos , Imuno-Histoquímica , Interleucina-6/metabolismo , Estimativa de Kaplan-Meier , Cirrose Hepática/sangue , Cirrose Hepática/genética , Cirrose Hepática/patologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Valores de Referência , Medição de Risco , Fator de Transcrição STAT3/genética , Transdução de Sinais , Análise de SobrevidaRESUMO
BACKGROUND: In a previous study, we found that melatonin inhibits MG-63 osteosarcoma cell proliferation; however, the underlying mechanisms remain elusive. Mitogen-activated protein kinase (MAPK) and Akt signaling pathways play key roles in the anticancer effects of melatonin. AIMS: The present study investigated whether MAPK and Akt signaling pathways are involved in melatonin's antiproliferative actions on the human MG-63 osteosarcoma cells. METHODS/RESULTS: Western blot analysis confirmed that melatonin significantly inhibited phosphorylation of ERK1/2 but not p38, JNK, or Akt. The expression of ERK1/2, p38, JNK, and Akt was not altered by melatonin. PD98059 and melatonin alone, and especially in combination, significantly inhibited cell proliferation. The changes included G1 and G2/M phase arrest of the cell cycle, and a downregulation of the expression at both the protein and mRNA levels of cyclin D1 and CDK4 (related to the G1 phase) and of cyclin B1 and CDK1 (related to the G2/M phase) as measured by flow cytometry after propidium iodide staining, and both western blot and real-time PCR, respectively. Furthermore, the combination of PD98059 and melatonin synergistically and markedly augmented the action of either agent alone. Co-immunoprecipitation further confirmed that there was an interaction between p-ERK1/2 and cyclin D1, CDK4, cyclin B1, or CDK1, which was blunted in the presence of melatonin or PD98059. CONCLUSION: These findings suggest that melatonin's antiproliferative action is mediated by inhibition of the ERK1/2 signaling pathway rather than the p38, JNK, or Akt pathways.
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Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Melatonina/farmacologia , Osteossarcoma/enzimologia , Osteossarcoma/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclina B1/genética , Ciclina B1/metabolismo , Ciclina D1/genética , Ciclina D1/metabolismo , Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/metabolismo , Regulação para Baixo/efeitos dos fármacos , Flavonoides/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Fosforilação/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Objective: To analyze ITS region and matK gene sequences of three medicinal Phlomis plants,in order to provide molecular basis for identifying and protecting their wild resources. Methods: PCR and sequencing were conducted on Phlomis likiangensis,Phlomis melanantha and Phlomis betonicoides wild populations by primers pairs ITS4 / ITS5 and matKXF / matK5 R. Results: The smallest inter-K2 P genetic distance was further than the largest intra-K2 P genetic distance in Phlomis likiangensis, Phlomis melanantha and Phlomis betonicoides. Different samples of three medicinal Phlomis plants were gathered together and could be distinguished from other exogenous species by Neighbor-Joining( NJ) tree. Phlomis likiangensis, Phlomis melanantha and Phlomis betonicoides had three, three and one sites on ITS2 for their effective identification, and had three,three and three sites on ITS1 for their effective identification respectively. Phlomis betonicoides had three sites on matK for its effective identification, while Phlomis likiangensis or Phlomis melanantha needed multiple sites for their effective identification. Conclusion: The study implies that ITS1,ITS2 and matK fragments could be used for molecular identification of Phlomis likiangensis, Phlomis melanantha and Phlomis betonicoides.
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Código de Barras de DNA Taxonômico , Phlomis , China , DNA de Plantas , Plantas Medicinais , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas pp60(c-src)RESUMO
[4-(3,6-dimethyl-9H-carbazol-9yl)butyl]phosphonic acid (Me-4PACz) self-assembled molecules (SAM) are an effective method to solve the problem of the buried interface of NiOx in inverted perovskite solar cells (PSCs). However, the Me-4PACz end group (carbazole core) cannot forcefully passivate defects at the bottom of the perovskite film. Here, a Co-SAM strategy is employed to modify the buried interface of PSCs. Me-4PACz is doped with phosphorylcholine chloride (PC) to form a Co-SAM to improve the monolayer coverage and reduce leakage current. The phosphate group and chloride ions (Cl-) in PC can inhibit NiOx surface defects. Meantime, the quaternary ammonium ions and Cl- in PC can fill organic cations and halogen vacancies in the perovskite film to enable defects passivation. Moreover, Co-SAM can promote the growth of perovskite crystals, collaboratively solve the problem of buried defects, suppress nonradiative recombination, accelerate carrier transmission, and relieve the residual stress of the perovskite film. Consequently, the Co-SAM modified devices show power conversion efficiencies as high as 25.09% as well as excellent device stability with 93% initial efficiency after 1000 h of operation under one-sun illumination. This work demonstrates the novel approach for enhancing the performance and stability of PSCs by modifying Co-SAM on NiOx.
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BACKGROUND: Our previous randomized controlled trial (RCT) have demonstrated that intermittent Pringle's maneuver (IPM) with a 25-min ischemic interval can be applied safely and efficiently in open or laparoscopic hepatectomy in patients with hepatocellular carcinoma (HCC) patients. But prolonging the hepatic inflow blocking time will inevitably aggravate the ischemia-reperfusion injury (IRI) caused by systemic response. This RCT aims to evaluate the effect of administration of dexamethasone versus placebo before clamping the hilar pedicle on postoperative liver function, inflammatory response, and perioperative outcomes among HCC patients undergoing liver resection with 25-min hepatic inflow occlusion. METHODS AND ANALYSIS: This will be a randomized, dual-arm, parallel-group, double-blinded trial. All eligible and consecutive patients are coming from a regional medical center who are diagnosed with HCC and underwent radical R0/R1 resection. All participates are randomly allocated in dexamethasone group or placebo group. All surgeons, anesthesiologists, and outcome assessors will be blinded to allocation status. Primary endpoints are transaminase-based postoperative hepatic injury on seven consecutive days after surgery and assessed by their peak values as well as area under the curve (AUC) of the postoperative course of aminotransferases. Secondary endpoints are postoperative total bilirubin (TBil), coagulation function, inflammatory cytokines and their respective peaks, intraoperative blood loss, postoperative hospital stay, morbidity, and mortality. The above parameters will be compared using the corresponding statistical approach. Subgroup analysis will be performed according to the liver cirrhosis and major hepatectomy. DISCUSSION: Based on our previous study, we will explore further the effect of glucocorticoid administration on attenuating the surgical stress response in order to follow securely 25-min hepatic inflow occlusion. Therefore, the trial protocol is reasonable and the results of the trial may be clinically significant. TRIAL REGISTRATION: This trial was registered on 3 December 2022, in the Chinese Clinical Trial Registry ( http://www.chictr.org.cn ), ChiCTR2200066381. The protocol version is V1.0 (20221104).
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Perda Sanguínea Cirúrgica , Carcinoma Hepatocelular/cirurgia , Dexametasona/uso terapêutico , Hepatectomia/efeitos adversos , Hepatectomia/métodos , Neoplasias Hepáticas/cirurgia , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Encapsulation engineering is an effective strategy to improve the stability of perovskite solar cells. However, current encapsulation materials are not suitable for lead-based devices because of their complex encapsulation processes, poor thermal management, and inefficient lead leakage suppression. In this work, we design a self-crosslinked fluorosilicone polymer gel, achieving nondestructive encapsulation at room temperature. Moreover, the proposed encapsulation strategy effectively promotes heat transfer and mitigates the potential impact of heat accumulation. As a result, the encapsulated devices maintain 98% of the normalized power conversion efficiency after 1000 h in the damp heat test and retain 95% of the normalized efficiency after 220 cycles in the thermal cycling test, satisfying the requirements of the International Electrotechnical Commission 61215 standard. The encapsulated devices also exhibit excellent lead leakage inhibition rates, 99% in the rain test and 98% in the immersion test, owing to excellent glass protection and strong coordination interaction. Our strategy provides a universal and integrated solution for achieving efficient, stable, and sustainable perovskite photovoltaics.
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Introduction: Obesity and diabetes are common chronic metabolic disorders which can cause an imbalance of the intestinal flora and gut-liver metabolism. Several studies have shown that probiotics, including Escherichia coli Nissle 1917 (EcN), promote microbial balance and metabolic health. However, there are no studies on how EcN outer membrane vesicles (EcN-OMVs) influence the intestinal microflora and affect the metabolic disorders of obesity and diabetes. Methods: In this study, we evaluated the effects of EcN-OMVs on high-fat diet (HFD)-induced obesity and HFD + streptozotocin (STZ)-induced diabetes. Results: EcN-OMVs could reduce body weight, decrease blood glucose, and increase plasma insulin in obese mice. Similarly, EcN-OMVs treatment could modify the ratio of Firmicutes/Bacteroidetes in the gut, elevate intestinal short-chain fatty acid (SCFA)-producing flora, and influence the SCFA content of the intestine. Furthermore, the intestinal metabolites ornithine and fumaric acid, hepatic ω-6 unsaturated fatty acids, and SCFAs were significantly increased after administering EcN-OMVs. Discussion: Overall, this study showed that EcN-OMVs might act as post-biotic agents that could modulate gut-liver metabolism and ameliorate the pathophysiology of obesity and diabetes.
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Pyroptosis, a way of pro-inflammatory death, plays a significant part in the tumor microenvironment (TME). A recent study has shown that the hepatitis C virus changes the TME by inducing pyroptosis against hepatocellular carcinoma (HCC). However, compared to TME in hepatitis C virus-infected HCC, the exploration of immune characteristics and response to immunotherapy associated with the pyroptosis phenotype is still insufficient in hepatitis B virus-related HCC (HBV-HCC). Our study constructed pyroptosis-score (PYS) via principal-component analysis (PCA) to unveil the link between pyroptosis and tumor immunity in 369 HBV-HCC patients. Compared with the low-PYS group, subjects with higher PYS were associated with poor prognosis but were more susceptible to anti-PD-L1 treatment. In addition, we found that PYS can serve independently as a prognostic factor for HBV-HCC, making it possible for us to identify specific small molecule drugs with a potential value in inhibiting tumors via targeting pyroptosis. Also, the target genes predicted by the Weighted gene co-expression network analysis (WGCNA) and pharmacophore model were enriched in the HIF-1 signaling pathway and NF-kB transcription factor activity, which were related to the mechanism of inflammation-driven cancer. The PYS is extremely important in predicting prognosis and responses to immunotherapy. New treatment strategies for inflammation-driven cancers may be found by targeting pyroptosis.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/patologia , Genômica , Vírus da Hepatite B/genética , Humanos , Inflamação , Neoplasias Hepáticas/patologia , Piroptose/genética , Microambiente Tumoral/genéticaRESUMO
BACKGROUND: The feasibility and safety of using longer ischemic interval during intermittent Pringle maneuver for hepatectomy in patients with hepatocellular carcinoma are still unclear. The aim of this study was to compare the short-term outcomes of hepatectomy using intermittent Pringle maneuver with an ischemic interval of 25 minutes versus 15 minutes in hepatocellular carcinoma patients. METHODS: A total of 344 patients with hepatocellular carcinoma undergoing hepatectomy were randomized to receive the intermittent Pringle maneuver with a 15-minute (n = 172) or 25-minute (n = 172) ischemic interval. Primary endpoint was transaminase-based postoperative hepatic injury, assessed by their peak values as well as area under the curve of the postoperative course of aminotransferases. Secondary endpoints included the intraoperative blood loss, transection speed, morbidity, mortality, and postoperative inflammatory reaction. RESULTS: There were no significant differences between the 2 groups in the postoperative aminotransferase serum levels or their area under the curve values, but the 25-minute intermittent Pringle maneuver group was associated with significantly higher speed for liver transection (1.38 vs 1.23 cm2/min, P = .002) and a lower blood loss during transection (109 vs 166 mL, P < .001) than the 15-minute intermittent Pringle maneuver group. Postoperative complications, inflammatory cytokines serum levels, and 90-day mortality were comparable. Stratification analysis showed that the 25-minute intermittent Pringle maneuver did not aggravate the hepatic injury but resulted in a lower blood loss during transection and higher transection speed in hepatocellular carcinoma patient undergoing laparoscopic or open hepatectomy. CONCLUSION: Intermittent Pringle maneuver with a 25-minute ischemic interval can be applied safely and efficiently in open or laparoscopic hepatectomy in patients with hepatocellular carcinoma patients.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Perda Sanguínea Cirúrgica/prevenção & controle , Carcinoma Hepatocelular/cirurgia , Hepatectomia/efeitos adversos , Hepatectomia/métodos , HumanosRESUMO
BACKGROUND: Hepatic ischemia-reperfusion injury (IRI) is an unavoidable outcome of liver transplantation, during which neutrophil extracellular traps (NETs) may play a critical role in the IRI-induced immune response to inflammation. The purpose of this study was to identify the function of recombinant human thrombomodulin (rTM) in the remission of hepatic IRI after liver transplantation and elucidate the specific mechanism. METHODS: NET formation (NETosis) was detected in the serum of liver transplantation patients and rats following liver transplantation. Hematoxylin-eosin staining, terminal deoxynucleotidyl transferase 2´-deoxyuridine, 5´-triphosphate nick-end labeling staining, immunohistochemistry, and immunofluorescence were used to assess the effect of rTM on NETosis in vitro and in vivo. RESULTS: We found that rTM markedly inhibited neutrophil formation in NETs, reduced apoptosis in hepatocytes, alleviated rat hepatic IRI, and improved liver function. In vitro, rTM inhibited neutrophil formation in NETs, and lipopolysaccharide (a Toll-like receptor 4 agonist) reversed the inhibitory effect of rTM on NETosisN. rTM blocked a Toll-like receptor 4 and the downstream extracellular signal-regulated kinase/c-Jun NH2 terminal kinase and nicotinamide adenine dinucleotide phosphate (NADPH)/reactive oxygen species/peptidylarginine deiminase 4 signaling pathways to protect against hepatic IRI and inhibit NETosis. In addition, we demonstrated that combined treatment with rTM and an NADPH oxidative inhibitor had a better effect than either treatment alone. CONCLUSIONS: NETs are a potential therapeutic target in hepatic IRI, and rTM could be used to prevent IR-induced hepatic injury. In addition, cotargeting NETosis-related signaling pathways might be a novel therapeutic strategy for hepatic IRI treatment.
Assuntos
Armadilhas Extracelulares , Transplante de Fígado , Traumatismo por Reperfusão , Animais , Humanos , Fígado/metabolismo , Transplante de Fígado/efeitos adversos , Ratos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/prevenção & controle , Trombomodulina/metabolismo , Receptor 4 Toll-Like/metabolismoRESUMO
Background: Dysregulation of long non-coding (lncRNA) has been reported in various solid tumors. HOXA cluster antisense RNA 2 (HOXA-AS2) is a newly identified lncRNA with abnormal expression in several human malignancies. However, its prognostic value remains controversial. This meta-analysis synthesized available data to clarify the association between HOXA-AS2 expression levels and clinical prognosis in multiple cancers. Methods: Four public databases (Embase, PubMed, Web of Science, The Cochrane Library) were used to identify eligible studies. Hazard ratios (HRs) and odds ratios (ORs) with their 95% confidence intervals (CIs) were combined to assess the correlation of HOXA-AS2 expression with survival outcomes and clinicopathological features of cancer patients. Publication bias was measured using Begg's funnel plot and Egger's regression test, and the stability of the combined results was measured using sensitivity analysis. Additionally, multiple public databases were screened and extracted to validate the results of this meta-analysis. Results: The study included 20 studies, containing 1331 patients. The meta-analysis showed that the overexpression of HOXA-AS2 was associated with poor overall survival (HR = 2.06, 95% CI 1.58-2.69, p < 0.001). In addition, the high expression of HOXA-AS2 could forecast advanced tumor stage (OR = 3.89, 95% CI 2.90-5.21, p < 0.001), earlier lymph node metastasis (OR = 3.48, 95% CI 2.29-5.29, p < 0.001), larger tumor size (OR = 2.36, 95% CI 1.52-3.66, p < 0.001) and earlier distant metastasis (OR = 3.54, 95% CI 2.00-6.28, p < 0.001). However, other clinicopathological features, including age (OR = 1.09, 95% CI 0.86-1.38, p = 0.467), gender (OR = 0.92, 95% CI 0.72-1.18, p = 0.496), depth of invasion (OR = 2.13, 95% CI 0.77-5.90, p = 0.146) and differentiation (OR = 1.02, 95% CI 0.65-1.59, p = 0.945) were not significantly different from HOXA-AS2 expression. Conclusion: Our study showed that the overexpression of HOXA-AS2 was related to poor overall survival and clinicopathological features. HOXA-AS2 may serve as a potential prognostic indicator and therapeutic target for tumor treatment.