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Regulating ion transport is a prevailing strategy to suppress lithium dendrite growth, in which the distribution of ion regulatory sites plays an important role. Here a hyperbranched polyamidoamine (HBPA) grafted polyethylene (PE) composite separator (HBPA-g-PE) is reported. The densely and uniformly distributed positive -NH2 and negative -CHNO- groups efficiently restrict the anion migration and promote Li+ transport at the surface of the lithium metal anode. The obtained Li foil symmetric cell delivers a stable cycle performance with a low-voltage hysteresis of 130 mV for over 1500 h (3000 cycles) at an ultrahigh current density of 20 mA cm-2 and a practical areal capacity of 5 mAh cm-2. Moreover, HBPA-g-PE separator enables a practical lithium-sulfur battery to achieve over 200-cycle stable performance with initial and retained capacity of 700 and 455 mAh g-1, at a high sulfur loading of 4 mg cm-2 and a low electrolyte content/sulfur loading ratio of 8 µL mg-1.
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Electro-Fenton processes aim at producing oxidizing radicals with fewer added chemicals and residues but are still unable to completely eliminate both. This study demonstrates that a reagent-free electro-Fenton process that runs solely on oxygen and electricity can be achieved by sequential dual-cathode electrocatalysis. H2O2 is produced on an electrodeposited PEDOT on carbon cloth (PEDOT/CC) cathode and subsequently converted to hydroxyl radicals on a stainless-steel-mesh cathode. The dual-cathode system demonstrates efficient decolorization and total organic carbon (TOC) removal toward organic dyes at optimized cathodic potentials of -0.9 V for PEDOT/CC and -0.8 V for the stainless-steel mesh. The sequential dual-cathode process also displays high reusability, no iron leaching, high removal efficiency using air instead of oxygen, and low installation and operation costs. This work demonstrates a preeminent and commercially viable example of pollution control rendered by the "catalysis instead of chemical reagent" philosophy of green chemistry.
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BACKGROUND: Hepatocellular carcinoma (HCC) is the fifth most frequently diagnosed malignancy and the third leading cause of cancer death globally. T cells are significantly correlated with the progression, therapy and prognosis of cancer. Limited systematic studies regarding the role of T-cell-related markers in HCC have been performed. METHODS: T-cell markers were identified with single-cell RNA sequencing (scRNA-seq) data from the GEO database. A prognostic signature was developed with the LASSO algorithm in the TCGA cohort and verified in the GSE14520 cohort. Another three eligible immunotherapy datasets, GSE91061, PRJEB25780 and IMigor210, were used to verify the role of the risk score in the immunotherapy response. RESULTS: With 181 T-cell markers identified by scRNA-seq analysis, a 13 T-cell-related gene-based prognostic signature (TRPS) was developed for prognostic prediction, which divided HCC patients into high-risk and low-risk groups according to overall survival, with AUCs of 1 year, 3 years, and 5 years of 0.807, 0.752, and 0.708, respectively. TRPS had the highest C-index compared with the other 10 established prognostic signatures, suggesting a better performance of TRPS in predicting the prognosis of HCC. More importantly, the TRPS risk score was closely correlated with the TIDE score and immunophenoscore. The high-risk score patients had a higher percentage of SD/PD, and CR/PR occurred more frequently in patients with low TRPS-related risk scores in the IMigor210, PRJEB25780 and GSE91061 cohorts. We also constructed a nomogram based on the TRPS, which had high potential for clinical application. CONCLUSION: Our study proposed a novel TRPS for HCC patients, and the TRPS could effectively indicate the prognosis of HCC. It also served as a predictor for immunotherapy.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Prognóstico , Transcriptoma , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Linfócitos T , ImunoterapiaRESUMO
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths among cancer patients. Vascular endothelial growth factor A (VEGFA) is involved in regulating biological processes, such as angiogenesis and vascular permeability, and is very closely related to the pathogenesis of various tumours, especially vascular-rich, solid tumours. Clinical data of patients with HCC and other tumours were analysed through public databases, such as the TCGA database, Gene Expression Omnibus database, Human Protein Atlas database, STRING, Tumour Immune Estimation Resource and Kaplan-Meier Plotter. The tumour tissues and adjacent normal tissues of patients with HCC from Hunan Provincial People's Hospital were collected to verify the expression of VEGFA by immunohistochemistry, immunofluorescence, Western blotting and qPCR. VEGFA expression is elevated in multiple tumour types and correlates with the prognosis of tumour patients. VEGFA is involved in regulating the tumour microenvironment and immune cell function in tumour development. Inhibition of VEGFA reduces proliferation, invasion, and migration and promotes apoptosis in HCC cells. VEGFA is a potential predictive biomarker for the diagnosis and prognosis of HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Prognóstico , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Biomarcadores Tumorais/genética , Microambiente Tumoral/genéticaRESUMO
BACKGROUND: The actin filament-associated protein (AFAP) family genes include AFAP1/AFAP-110, AFAP1L1 and AFAP1L2/XB130. Increasing evidence indicates these three AFAP family members participate in tumor progression, but their clinical significance and molecular mechanisms in gastric cancer (GC) remain unclear. METHODS: We first analyzed expression of AFAP family genes using public datasets and verified the results. The clinical significance of AFAP family genes in GC patients was also analyzed. In vitro and in vivo experiments were applied to explore the function of AFAP1L1. Enrichment analysis was used to explore potential molecular mechanisms. We then performed additional experiments, such as cell adhesion assay, co-immunoprecipitation and so on to confirm the downstream molecular mechanisms of AFAP1L1. RESULTS: Public data analyses and our verification both showed AFAP1L1 was the only AFAP family members that was significantly upregulated in GC compared with normal gastric tissues. Besides, only AFAP1L1 could predict poor prognosis and act as an independent risk factor for GC patients. In addition, AFAP1L1 promotes GC cells proliferation, migration, invasion in vitro and tumor growth, metastasis in vivo by inducing epithelial-to-mesenchymal transition (EMT). In terms of mechanism, AFAP1L1 interacts with VAV guanine nucleotide exchange factor 2 (VAV2) to activate Rho family GTPases CDC42, which finally promotes expression of integrin subunit alpha 5 (ITGA5) and activation of integrin signaling pathway. CONCLUSION: AFAP1L1 promotes GC progression by inducing EMT through VAV2-mediated activation of CDC42 and ITGA5 signaling pathway, indicating AFAP1L1 may be a promising prognostic biomarker and therapeutic target for GC patients.
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Neoplasias Gástricas , Humanos , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Integrinas/metabolismo , Proteínas dos Microfilamentos/genética , Invasividade Neoplásica , Proteínas Proto-Oncogênicas c-vav/genética , Proteínas Proto-Oncogênicas c-vav/metabolismo , Transdução de Sinais , Neoplasias Gástricas/patologiaRESUMO
Acute pancreatitis (AP) is a common and potentially life-threatening inflammatory disease of the pancreas. Reactive oxygen species (ROS) play a key role in the occurrence and development of AP. With increasing ROS levels, the degree of oxidative stress and the severity of AP increase. However, diagnosing AP still has many drawbacks, including difficulties with early diagnosis and undesirable sensitivity and accuracy. Herein, we synthesized a semiconducting polymer nanoplatform (SPN) that can emit ROS-correlated chemiluminescence (CL) signals. The CL intensity increased in solution after optimization of the SPN. The biosafety of the SPN was verified in vitro and in vivo. The mechanism and sensitivity of the SPN for AP early diagnosis and severity assessment were evaluated in three groups of mice using CL intensity, serum marker evaluations and hematoxylin and eosin staining assessments. The synthetic SPN can be sensitively combined with different concentrations of ROS to produce different degrees of high-intensity CL in vitro and in vivo. Notably, the SPN shows an excellent correlation between CL intensity and AP severity. This nanoplatform represents a superior method to assess the severity of AP accurately and sensitively according to ROS related chemiluminescence signals. This research overcomes the shortcomings of AP diagnosis in clinical practice and provides a novel method for the clinical diagnosis of pancreatitis in the future.
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Pancreatite , Camundongos , Animais , Pancreatite/diagnóstico , Espécies Reativas de Oxigênio , Polímeros , Doença Aguda , Diagnóstico PrecoceRESUMO
Enabling efficient and durable charge storage under high sulfur loading and lean electrolyte remains a paramount challenge for Li-S battery technology to truly demonstrate its commercial viability. This work reports an amphoteric polymer binder, whose negatively and positively charged moieties allow for coregulation of both lithium cations and heteropolar lithium polysulfides through multiple intermolecular interactions. These interactions and the physical properties lead to simultaneously improved Li+ transport, polysulfide adsorption and catalysis, cathode robustness and anode stability. Therefore, this multifunctional binder endows Li-S batteries with compelling overall performances even under rigorous conditions. At low sulfur loading and copious electrolyte, the cell shows a low capacity-fading rate of 0.056% cycle-1 upon 700 cycles. At sulfur loading of 6.8 mg cm-2 and low E/S of 6 µL mg-1 , the cell still delivers stable areal capacities between 4.2 and 4.8 mAh cm-2 in 50 cycles without obvious decay at 0.2 C. The commercial feasibility of this work is further manifested by its zero added weight, low material cost, and ease of manufacturing and scale-up. The efficacy and simplicity of this work symbolize an example of lab-scale battery research aiming at improved technology and manufacturing readiness level.
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SOX9, as a transcript factor, has been confirmed to boost proliferation and epithelial-mesenchymal transition (EMT) of hepatocellular carcinoma (HCC), but the underlying mechanism remains incompletely elucidated. A bioinformatics analysis web, Jaspar, manifested that SOX9 can transcriptionally regulate an lncRNA, MKLN1-AS. To determine the role of MKLN1-AS in HCC, this study measured MKLN1-AS expression in HCC and the paracancerous tissues and conducted a series of assays, including MTT, colony formation, and transwell assays, in vitro. EMT of HCC was evaluated by E-cadherin and vimentin protein levels. The regulatory effect of SOX9 on MKLN1-AS was determined using dual luciferase reporter and ChIP assays. Both MKLN1-AS and SOX9 were up-regulated in HCC tissues compared to paracancerous tissues. SOX9 promoted cell viability, proliferation, invasion, and EMT of HCCs, but these promoting effects of SOX9 were attenuated after the knockdown of MKLN1-AS. Overexpression of SOX9 increased MKLN1-AS in HCCs, whereas silencing SOX9 decreased MKLN1-AS expression. According to dual luciferase reporter and ChIP assays, SOX9 can bind to the promoter of MKLN1-AS gene to stimulate the expression. MKLN1-AS is transcriptionally regulated by SOX9 and mediates the effects of SOX9 on the proliferation and EMT of HCCs.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , RNA Longo não Codificante , Humanos , Carcinoma Hepatocelular/metabolismo , Transição Epitelial-Mesenquimal/genética , Neoplasias Hepáticas/metabolismo , RNA Longo não Codificante/genética , Proliferação de Células , Linhagem Celular Tumoral , Movimento Celular , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genéticaRESUMO
BACKGROUNDS/AIMS: Hepatocellular carcinoma is recognized as the most common subtype of hepatic cancer. Muskelin 1 antisense RNA (MKLN1-AS) shows prognostic value in hepatitis B virus-hepatocellular carcinoma. The aim of this study is to investigate the detailed biological role of MKLN1-AS and Yes-associated transcriptional regulator 1 (YAP1)-related mechanisms. METHODS: Based on online databases (GEPIA, TCGA, and GEO), the expression of MKLN1-AS and YAP1 in patients with hepatocellular carcinoma was analyzed. The IntaRNA algorithm was used to predict complementary sites between MKLN1-AS and YAP1 mRNA. Hepatocellular carcinoma tumor tissues and cells were collected for the quantification of MKLN1-AS and YAP1. FISH was performed to explore the location of MKLN1-AS in cells. The effects of MKLN1-AS and YAP1 on proliferation, migration and invasionof hepatocellular carcinoma were determined in vitro and in vivo. Actinomycin D and RNA immunoprecipitation were resorted to confirm the regulatory role of MKLN1-AS in YAP1 expression. RESULTS: The up-regulation of MKLN1-AS contributed to the poor prognosis of patients with hepatocellular carcinoma. MKLN1-AS and YAP1 were overexpressed in hepatocellular carcinoma tissues and cells. MKLN1-AS positively modulated YAP1 expression through targeting and stabilizing YAP1 mRNA.MKLN1-AS was predominantly located in the cytoplasm of the cells. MKLN1-AS intensified proliferation, migration and invasion of hepatocellular carcinoma cells via YAP1. MKLN1-AS also caused hepatocarcinogenesis through inducing YAP1 expression in vivo. CONCLUSIONS: MKLN1-AS overexpression enhances the stability of YAP1 mRNA, which is necessary for the oncogenic activity of MKLN1-AS. MKLN1-AS can be utilized in the diagnosis and prognosis of hepatocellular carcinoma as an upstream factor of YAP1.
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Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/patologia , Moléculas de Adesão Celular/genética , Regulação Neoplásica da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/genética , RNA Antissenso/genética , RNA Longo não Codificante/genética , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Apoptose , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Proliferação de Células , Feminino , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Prognóstico , Taxa de Sobrevida , Fatores de Transcrição/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas de Sinalização YAPRESUMO
A delay line consisting of a balanced side-coupled integrated spaced sequence of resonators and phase change material VO2 films is employed to realize continuously tunable delays with ultrafast response and low distortion. Simulation results show that a tunable delay of up to 80 ps with a 10% broadening, 150 GHz bandwidth, and 0.087 dB/ps delay loss is achieved from this structure. Taking advantage of photoinduced phase transition of VO2 films, this device obtains a switching time of less than 0.6 ps and effective compensation for group delay dispersion. This delay line shows advantages in the high-bit-rate all-optical processing systems.
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BACKGROUND: The World Health Organization's updated classification of digestive system neuroendocrine tumors in 2010 first proposed the classification of mixed adenoneuroendocrine carcinoma (MANEC). The incidence of biliary malignant tumors with neuroendocrine tumors accounts for less than 1% of all neuroendocrine tumors. Moreover, the incidence of hilar bile duct with MANEC is very rare. CASE PRESENTATION: A 65-year-old female patient came to our hospital for repeated abdominal pain for more than 4 months and skin sclera yellow staining for 1 week. Contrast-enhanced computed tomography imaging and magnetic resonance results suggested a hilar tumor for Bismuth-Corlette Type II. The patient underwent radical surgery for hilar cholangiocarcinoma. Finally, the patient was diagnosed with hilar bile duct MANEC, staged 1 (pT1N0M0) based on the eighth edition of the AJCC. Histopathology showed that the tumor was a biliary tumor with both adenocarcinoma and neuroendocrine carcinoma. No evidence of recurrence and metastasis after 20 months of follow-up. CONCLUSIONS: We first reported a MANEC that originated in the hilar bile duct. As far as we known, there were few reports of biliary MANEC, and the overall prognosis was poor. We also found that the higher the Ki-67 index, the worse the prognosis of this type of patient. Radical surgery is the most effective treatment.
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Adenocarcinoma , Neoplasias dos Ductos Biliares , Carcinoma Neuroendócrino , Idoso , Neoplasias dos Ductos Biliares/cirurgia , Ductos Biliares Intra-Hepáticos , Carcinoma Neuroendócrino/diagnóstico por imagem , Carcinoma Neuroendócrino/cirurgia , Feminino , Humanos , Fígado , Recidiva Local de NeoplasiaRESUMO
PURPOSE: To investigate the efficacy and safety of flurbiprofen axetil in postoperative analgesia in upper abdominal surgery. METHODS: This was a multicenter, randomized, positive drug parallel controlled double-blind clinical study. Patients undergoing upper abdominal surgery were randomly divided to receive flurbiprofen axetil or tramadol. The VAS pain scores at rest and on coughing (pulmonary function training) were assessed immediately before drug usage (T1) to evaluate the efficacy of postoperative analgesia. Repeat assessment of the VAS was performed after T1. The timing of the recovery of the gastrointestinal function and the preoperative and postoperative IL-6, cortisol, and blood glucose levels were recorded as secondary endpoints. Vital signs and the occurrence of adverse reactions were evaluated for the assessment of safety. RESULTS: A total of 240 patients were enrolled in the current study; 119 used flurbiprofen axetil for postoperative analgesia. The VAS scores at rest and on coughing did not differ between the two groups to a statistically significant extent (P > 0.05). However, the reduction of the VAS score at rest in the flurbiprofen axetil group was greater than that in the tramadol group at 4-24 h after T1. The reduction of the VAS score on coughing at 8 h after T1 was greater in the flurbiprofen axetil group. The incidence of adverse reactions was significantly lower in the flurbiprofen axetil group, with only one adverse reaction recorded. In contrast, 18 adverse reactions were reported in the tramadol group. CONCLUSION: Flurbiprofen axetil showed superior efficacy to tramadol in early postoperative analgesia after upper abdominal surgery. Flurbiprofen axetil was associated with a significantly lower incidence of adverse reactions in comparison to tramadol.
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Anti-Inflamatórios não Esteroides/uso terapêutico , Flurbiprofeno/análogos & derivados , Dor Pós-Operatória/tratamento farmacológico , Abdome/cirurgia , Adolescente , Adulto , Idoso , Anti-Inflamatórios não Esteroides/efeitos adversos , Método Duplo-Cego , Feminino , Flurbiprofeno/efeitos adversos , Flurbiprofeno/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Tramadol , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND/AIMS: Acute pancreatitis contributes to high mortality in pancreatitis patients, and miRNAs play a vital role in the development of acute pancreatitis (AP), however, its precise biological role remains largely elusive. METHODS: To clarify the potential mechanisms of miRNAs in AP, we built mouse models of mild acute pancreatitis (MAP) and moderate/ severe acute pancreatitis (SAP). MiRNA microarray analysis and Real-time quantitative PCR (qRT-PCR) were used to analyze the expression of miRNA in MAP/SAP. TargetScan software, dual-luciferase gene reporter assays and Western blotting were used to assess the target genes of miR-155-5p in AP. RESULTS: miR-155-5p was significantly decreased in MAP/SAP mice compared to controls. In pancreatic acinar AR42J cells transfected with miR-155-5p mimic, the expression of Rela and Traf3 notably decreased in both the caerulein- and TLC-S-induced groups compared with the negative control (NC); however, the expression of Rela and Traf3 notably increased after transfection with miR-155-5p inhibitor. Combined analysis using the TargetScan software and dual-luciferase gene reporter assays indicated that Rela and Traf3 were both targeted by miR-155-5p. Meanwhile, the expression of Ptgs2 also decreased after transfection of the AR42J cells with miR-155-5p mimic. The opposite results were found when miR-155-5p inhibitor was transfected into the AR42J cells. In addition, we treated caerulein- and TLC-S-induced AR42J cells with the Rela inhibitor helenalin and found that the expression of Rela, Traf3 and Ptgs2 decreased compared with the NC, while the expression of miR-155-5p did not show any significant difference. Furthermore, we found that miR-155-5p was significantly down-regulated in pancreatitis patients. CONCLUSION: miR-155-5p inversely regulated AP development through the Rela/Traf3/Ptgs2 signaling pathway.
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Células Acinares/patologia , MicroRNAs/genética , Pancreatite/genética , Fator 3 Associado a Receptor de TNF/genética , Fator de Transcrição RelA/genética , Células Acinares/metabolismo , Adulto , Idoso , Animais , Linhagem Celular , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Pancreatite/patologia , Ratos , TranscriptomaRESUMO
To improve the dynamic random error compensation accuracy of the Micro Electro Mechanical System (MEMS) gyroscope at different angular rates, an adaptive filtering approach based on the dynamic variance model was proposed. In this paper, experimental data were utilized to fit the dynamic variance model which describes the nonlinear mapping relations between the MEMS gyroscope output data variance and the input angular rate. After that, the dynamic variance model was applied to online adjustment of the Kalman Filter measurement noise coefficients. The proposed approach suppressed the interference from the angular rate in the filtering results. Dynamic random errors were better estimated and reduced. Turntable experiment results indicated that the adaptive filtering approach compensated for the MEMS gyroscope dynamic random error effectively both in the constant angular rate condition and the continuous changing angular rate condition, thus achieving adaptive dynamic random error compensation.
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In order to tackle the inaccurate step length measurement of people with different heights and in different motion states, a height-adaptive method of step length measurement based on motion parameters is proposed in this paper. This method takes people's height, stride frequency, and changing accelerometer output while walking into integrated consideration, and builds a dynamic and parameterized model of their step length. In this study, these parameters were calibrated with thirty sets of experiment data from people with different heights and in different motion states, which were then verified experimentally by motion data of randomly selected subjects, regardless of speed and height. The experiment results indicate that the height-adaptive step length measurement was realized, thus eliminating the influence of height exerted on step length measurement.
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Cholangiocarcinoma (CCA) is a malignant tumor originating in the bile duct and its branching epithelium. Due to its high heterogeneity, there are no specific clinical indications at the early stage, the diagnosis is often in advanced CCA. With surgical resection, the 5-year postoperative survival rate (long-term survival rate) is very poor. The regimen of gemcitabine combined with platinum has been used as the first-line chemotherapy for advanced patients. In recent years, targeted therapy for a variety of malignant tumors has made great progress, showing good efficacy and safety in advanced CCA. However, the current targeted therapy of CCA still has many challenges, such as adverse reactions, drug resistance, and individual differences. Therefore, the researches need to further explore the targeted therapy mechanism of CCA malignancies in depth, develop more effective and safe drugs, and accurately formulate plans based on patient characteristics to further improve patient prognosis in the future. This article reviews the recent progress of targeted therapy for CCA, aiming to provide a strategy for the research and clinical work of targeted therapy for CCA.
For these patients without surgical indications, chemotherapy and radiation therapy are the main treatment options, among which gemcitabine combined with cisplatin is the standard recognized chemotherapy regimen.With the gradual maturity of gene detection technology, the molecular pathology of CCA has gradually been revealed and precision oncology has become a promising method for the treatment of CCA.
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Neoplasias dos Ductos Biliares , Colangiocarcinoma , Humanos , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/patologia , Gencitabina , Prognóstico , Ductos Biliares Intra-Hepáticos/patologiaRESUMO
Cholangiocarcinoma (CCA) is a type of malignant tumor originating from the intrahepatic, periportal, or distal biliary system. The treatment means for CCA is limited, and its prognosis is poor. Spatholobi Caulis (SC) is reported to have effects on anti-inflammatory and anti-tumor, but its role in CCA is unclear. First, the potential molecular mechanism of SC for CCA treatment was explored based on network pharmacology, and the core targets were verified by molecular docking and molecular dynamics simulation. Then, we explored the inhibitory effect of SC on the malignant biological behavior of CCA in vitro and in vivo and also explored the related signaling pathways. The effect of combination therapy of SC and cisplatin (DDP) in CCA was also explored. Finally, we conducted a network pharmacological study and simple experimental verification on luteolin, one of the main components of SC. Network pharmacology analysis showed that the core targets of SC on CCA were AKT1, CASP3, MYC, TP53, and VEGFA. Molecular docking and molecular dynamics simulation indicated a good combination between the core target protein and the corresponding active ingredients. In vitro, SC inhibited proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of CCA cells. In vivo experiments, the results were consistent with in vitro experiments, and there was no significant hepatorenal toxicity of SC at our dosage. Based on KEGG enrichment analysis, we found PI3K/AKT signaling pathway might be the main signaling pathway of SC action on CCA by using AKT agonist SC79. To explore whether SC was related to the chemotherapy sensitivity of CCA, we found that SC combined with DDP could more effectively inhibit the progression of cholangiocarcinoma. Finally, we found luteolin may inhibit the proliferation and invasion of CCA cells. Our study demonstrates for the first time that SC inhibits the progression of CCA by suppressing EMT through the PI3K-AKT signaling pathway, and SC could enhance the effectiveness of cisplatin therapy for CCA.
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Neoplasias dos Ductos Biliares , Colangiocarcinoma , Cisplatino , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Farmacologia em Rede , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/patologia , Humanos , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/metabolismo , Animais , Cisplatino/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Masculino , Luteolina/farmacologia , Luteolina/uso terapêutico , Camundongos Nus , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Camundongos Endogâmicos BALB CRESUMO
BACKGROUND: Mitochondrial dysfunction and metabolic reprogramming can lead to the development and progression of hepatocellular carcinoma (HCC). Ferredoxin 1 (FDX1) is a small mitochondrial protein and recent studies have shown that FDX1 plays an important role in tumor cuproptosis, but its role in HCC is still elusive. In this study, we aim to investigate the expression and novel functions of FDX1 in HCC. METHODS: FDX1 expression was first analyzed in publicly available datasets and verified by immunohistochemistry, qRT-PCR and Western blot. In vitro and in vivo experiments were applied to explore the functions of FDX1. Non-targeted metabolomics and RNA-sequencing were used to determine molecular mechanism. mRFP-GFP-LC3 lentivirus transfection, Mito-Tracker Red and Lyso-Tracker Green staining, transmission electron microscopy, flow cytometry, JC-1 staining, etc. were used to analyze mitophagy or ROS levels. Hydrodynamic tail vein injection (HTVi) and patient-derived organoid (PDO) models were used to analyze effect of FDX1 overexpression. RESULTS: FDX1 expression is significantly downregulated in HCC tissues. FDX1 downregulation promotes HCC cell proliferation, invasion in vitro and growth, metastasis in vivo. In addition, FDX1 affects metabolism of HCC cells and is associated with autophagy. We then confirmed that FDX1 deficiency increases ROS levels, activates mitophagy and the PI3K/AKT signaling pathway in HCC cells. Interestingly, scavenging ROS attenuates the tumor-promoting role and mitophagy of FDX1 downregulation. The results of HTVi and PDO models both find that FDX1 elevation significantly inhibits HCC progression. Moreover, low FDX1 expression is associated with shorter survival and is an independent risk factor for prognosis in HCC patients. CONCLUSIONS: Our research had investigated novel functions of FDX1 in HCC. Downregulation of FDX1 contributes to metabolic reprogramming and leads to ROS-mediated activation of mitophagy and the PI3K/AKT signaling pathway. FDX1 is a potential prognostic biomarker and increasing FDX1 expression may be a potential therapeutic approach to inhibit HCC progression.