RESUMO
Neutrophilic superhalide-anion-triggered chalcogen conversion-based Zn batteries, despite latent high-energy merit, usually suffer from a short lifespan caused by dendrite growth and shuttle effect. Here, a superhalide-anion-motivator reforming strategy is initiated to simultaneously manipulate the anode interface and Se conversion intermediates, realizing a bipolar regulation toward longevous energy-type Zn batteries. With ZnF2 chaotropic additives, the original large-radii superhalide zincate anion species in ionic liquid (IL) electrolytes are split into small F-containing species, boosting the formation of robust solid electrolyte interphases (SEI) for Zn dendrite inhibition. Simultaneously, ion radius reduced multiple F-containing Se conversion intermediates form, enhancing the interion interaction of charged products to suppress the shuttle effect. Consequently, Zn||Se batteries deliver a ca. 20-fold prolonged lifespan (2000 cycles) at 1 A g-1 and high energy/power density of 416.7 Wh kgSe-1/1.89 kW kgSe-1, outperforming those in F-free counterparts. Pouch cells with distinct plateaus and durable cyclability further substantiate the practicality of this design.
RESUMO
Gliomas are the most common tumours in the central nervous system. In the present study, we aimed to find a promising anti-glioma compound and investigate the underlying molecular mechanism. Glioma cells were subjected to the 50 candidate compounds at a final concentration of 10 µM for 72 h, and CCK-8 was used to evaluate their cytotoxicity. NPS-2143, an antagonist of calcium-sensing receptor (CASR), was selected for further study due to its potent cytotoxicity to glioma cells. Our results showed that NPS-2143 could inhibit the proliferation of glioma cells and induce G1 phase cell cycle arrest. Meanwhile, NPS-2143 could induce glioma cell apoptosis by increasing the caspase-3/6/9 activity. NPS-2143 impaired the immigration and invasion ability of glioma cells by regulating the epithelial-mesenchymal transition process. Mechanically, NPS-2143 could inhibit autophagy by mediating the AKT-mTOR pathway. Bioinformatic analysis showed that the prognosis of glioma patients with low expression of CASR mRNA was better than those with high expression of CASR mRNA. Gene set enrichment analysis showed that CASR was associated with cell adhesion molecules and lysosomes in glioma. The nude mice xenograft model showed NPS-2143 could suppress glioma growth in vivo. In conclusion, NPS-2143 can suppress the glioma progression by inhibiting autophagy.
Assuntos
Glioma , Naftalenos , Proteínas Proto-Oncogênicas c-akt , Animais , Humanos , Camundongos , Apoptose , Autofagia , Linhagem Celular Tumoral , Proliferação de Células , Glioma/tratamento farmacológico , Glioma/genética , Glioma/metabolismo , Camundongos Nus , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , Serina-Treonina Quinases TOR/metabolismo , Naftalenos/farmacologiaRESUMO
BACKGROUND: Cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) homozygous deletion has been verified as an independent and critical biomarker of negative prognosis and short survival in isocitrate dehydrogenase (IDH)-mutant astrocytoma. Therefore, noninvasive and accurate discrimination of CDKN2A/B homozygous deletion status is essential for the clinical management of IDH-mutant astrocytoma patients. PURPOSE: To develop a noninvasive, robust preoperative model based on MR image features for discriminating CDKN2A/B homozygous deletion status of IDH-mutant astrocytoma. STUDY TYPE: Retrospective. POPULATION: Two hundred fifty-one patients: 107 patients with CDKN2A/B homozygous deletion and 144 patients without CDKN2A/B homozygous deletion. FIELD STRENGTH/SEQUENCE: 3.0 T/1.5 T: Contrast-enhanced T1-weighted spin-echo inversion recovery sequence (CE-T1WI) and T2-weighted fluid-attenuation spin-echo inversion recovery sequence (T2FLAIR). ASSESSMENT: A total of 1106 radiomics and 1000 deep learning features extracted from CE-T1WI and T2FLAIR were used to develop models to discriminate the CDKN2A/B homozygous deletion status. Radiomics models, deep learning-based radiomics (DLR) models and the final integrated model combining radiomics features with deep learning features were developed and compared their preoperative discrimination performance. STATISTICAL TESTING: Pearson chi-square test and Mann Whitney U test were used for assessing the statistical differences in patients' clinical characteristics. The Delong test compared the statistical differences of receiver operating characteristic (ROC) curves and area under the curve (AUC) of different models. The significance threshold is P < 0.05. RESULTS: The final combined model (training AUC = 0.966; validation AUC = 0.935; test group: AUC = 0.943) outperformed the optimal models based on only radiomics or DLR features (training: AUC = 0.916 and 0.952; validation: AUC = 0.886 and 0.912; test group: AUC = 0.862 and 0.902). DATA CONCLUSION: Whether based on a single sequence or a combination of two sequences, radiomics and DLR models have achieved promising performance in assessing CDKN2A/B homozygous deletion status. However, the final model combining both deep learning and radiomics features from CE-T1WI and T2FLAIR outperformed the optimal radiomics or DLR model. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.
Assuntos
Astrocitoma , Aprendizado Profundo , Humanos , Homozigoto , Isocitrato Desidrogenase/genética , Radiômica , Estudos Retrospectivos , Deleção de Sequência , Astrocitoma/diagnóstico por imagem , Astrocitoma/genética , Imageamento por Ressonância Magnética , Inibidor p16 de Quinase Dependente de Ciclina/genéticaRESUMO
OBJECTIVES: To develop a high-accuracy MRI-based deep learning method for predicting cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) homozygous deletion status in isocitrate dehydrogenase (IDH)-mutant astrocytoma. METHODS: Multiparametric brain MRI data and corresponding genomic information of 234 subjects (111 positives for CDKN2A/B homozygous deletion and 123 negatives for CDKN2A/B homozygous deletion) were obtained from The Cancer Imaging Archive (TCIA) and The Cancer Genome Atlas (TCGA) respectively. Two independent multi-sequence networks (ResFN-Net and FN-Net) are built on the basis of ResNet and ConvNeXt network combined with attention mechanism to classify CDKN2A/B homozygous deletion status using MR images including contrast-enhanced T1-weighted imaging (CE-T1WI) and T2-weighted imaging (T2WI). The performance of the network is summarized by three-way cross-validation; ROC analysis is also performed. RESULTS: The average cross-validation accuracy (ACC) of ResFN-Net is 0.813. The average cross-validation area under curve (AUC) of ResFN-Net is 0.8804. The average cross-validation ACC and AUC of FN-Net is 0.9236 and 0.9704, respectively. Comparing all sequence combinations of the two networks (ResFN-Net and FN-Net), the sequence combination of CE-T1WI and T2WI performed the best, and the ACC and AUC were 0.8244, 0.8975 and 0.8971, 0.9574, respectively. CONCLUSIONS: The FN-Net deep learning networks based on ConvNeXt network achieved promising performance for predicting CDKN2A/B homozygous deletion status of IDH-mutant astrocytoma. CLINICAL RELEVANCE STATEMENT: A novel deep learning network (FN-Net) based on preoperative MRI was developed to predict the CDKN2A/B homozygous deletion status. This network has the potential to be a practical tool for the noninvasive characterization of CDKN2A/B in glioma to support personalized classification and treatment planning. KEY POINTS: ⢠CDKN2A/B homozygous deletion status is an important marker for glioma grading and prognosis. ⢠An MRI-based deep learning approach was developed to predict CDKN2A/B homozygous deletion status. ⢠The predictive performance based on ConvNeXt network was better than that of ResNet network.
Assuntos
Astrocitoma , Neoplasias Encefálicas , Aprendizado Profundo , Glioma , Humanos , Isocitrato Desidrogenase/genética , Homozigoto , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Mutação , Deleção de Sequência , Imageamento por Ressonância Magnética/métodos , Astrocitoma/diagnóstico por imagem , Astrocitoma/genética , Glioma/genética , Inibidor p16 de Quinase Dependente de Ciclina/genéticaRESUMO
Bipolar organic cathode materials (OCMs) implementing cation/anion storage mechanisms are promising for high-energy aqueous Zn batteries (AZBs). However, conventional organic functional group active sites in OCMs usually fail to sufficiently unlock the high-voltage/capacity merits. Herein, we initially report dynamically ion-coordinated bipolar OCMs as cathodes with chalcogen active sites to solve this issue. Unlike conventional organic functional groups, chalcogens bonded with conjugated group undergo multielectron-involved positive-valence oxidation and negative-valence reduction, affording higher redox potentials and reversible capacities. With phenyl diselenide (PhSe-SePh, PDSe) as a proof of concept, it exhibits a conversion pathway from (PhSe)- to (PhSe-SePh)0 and then to (PhSe)+ as unveiled by characterization and theoretical simulation, where the diselenide bonds are periodically broken and healed, dynamically coordinating with ions (Zn2+ and OTF-). When confined into ordered mesoporous carbon (CMK-3), the dissolution of PDSe intermediates is greatly inhibited to obtain an ultralong lifespan without voltage/capacity compromise. The PDSe/CMK-3 || Zn batteries display high reversibility capacity (621.4â mAh gPDSe -1), distinct discharge plateau (up to 1.4â V), high energy density (578.3â Wh kgPDSe -1), and ultralong lifespan (12 000 cycles) at 10â A g-1, far outperforming conventional bipolar OCMs. This work sheds new light on conversion-type active site engineering for high-voltage/capacity bipolar OCMs towards high-energy AZBs.
RESUMO
For zinc-metal batteries, the instable chemistry at Zn/electrolyte interphasial region results in severe hydrogen evolution reaction (HER) and dendrite growth, significantly impairing Zn anode reversibility. Moreover, an often-overlooked aspect is this instability can be further exacerbated by the interaction with dissolved cathode species in full batteries. Here, inspired by sustained-release drug technology, an indium-chelated resin protective layer (Chelex-In), incorporating a sustained-release mechanism for indium, is developed on Zn surface, stabilizing the anode/electrolyte interphase to ensure reversible Zn plating/stripping performance throughout the entire lifespan of Zn//V2O5 batteries. The sustained-release indium onto Zn electrode promotes a persistent anticatalytic effect against HER and fosters uniform heterogeneous Zn nucleation. Meanwhile, on the electrolyte side, the residual resin matrix with immobilized iminodiacetates anions can also repel detrimental anions (SO4 2- and polyoxovanadate ions dissolved from V2O5 cathode) outside the electric double layer. This dual synergetic regulation on both electrode and electrolyte sides culminates a more stable interphasial environment, effectively enhancing Zn anode reversibility in practical high-areal-capacity full battery systems. Consequently, the bio-inspired Chelex-In protective layer enables an ultralong lifespan of Zn anode over 2800â h, which is also successfully demonstrated in ultrahigh areal capacity Zn//V2O5 full batteries (4.79â mAh cm-2).
RESUMO
Hydrogel electrolytes (HEs) hold great promise in tackling severe issues emerging in aqueous zinc-ion batteries, but the prevalent salting-out effect of kosmotropic salt causes low ionic conductivity and electrochemical instability. Herein, a subtle molecular bridging strategy is proposed to enhance the compatibility between PVA and ZnSO4 from the perspective of hydrogen-bonding microenvironment re-construction. By introducing urea containing both an H-bond acceptor and donor, the broken H-bonds between PVA and H2O, initiated by the SO42--driven H2O polarization, could be re-united via intense intermolecular hydrogen bonds, thus leading to greatly increased carrying capacity of ZnSO4. The urea-modified PVA-ZnSO4 HEs featuring a high ionic conductivity up to 31.2 mS cm-1 successfully solves the sluggish ionic transport dilemma at the solid-solid interface. Moreover, an organic solid-electrolyte-interphase can be derived from the in-situ electro-polymerization of urea to prohibit H2O-involved side reactions, thereby prominently improving the reversibility of Zn chemistry. Consequently, Zn anodes witness an impressive lifespan extension from 50 h to 2200 h at 0.1 mA cm-2 while the Zn-I2 full battery maintains a remarkable Coulombic efficiency (>99.7%) even after 8000 cycles. The anti-salting-out strategy proposed in this work provides an insightful concept for addressing the phase separation issue of functional HEs.
RESUMO
Gradual disability of Zn anode and high negative/positive electrode (N/P) ratio usually depreciate calendar life and energy density of aqueous Zn batteries (AZBs). Herein, within original Zn2+-free hydrated electrolytes, a steric hindrance/electric field shielding-driven "hydrophobic ion barrier" is engineered towards ultradurable (002) plane-exposed Zn stripping/plating to solve this issue. Guided by theoretical simulations, hydrophobic adiponitrile (ADN) is employed as a steric hindrance agent to ally with inert electric field shielding additive (Mn2+) for plane adsorption priority manipulation, thereby constructing the "hydrophobic ion barrier". This design robustly suppresses the (002) plane/dendrite growth, enabling ultradurable (002) plane-exposed dendrite-free Zn stripping/plating. Even being cycled in ZnâZn symmetric cell over 2150â h at 0.5â mA cm-2, the efficacy remains well-kept. Additionally, ZnâZn symmetric cells can be also stably cycled over 918â h at 1â mA cm-2, verifying uncompromised Zn stripping/plating kinetics. As-assembled anode-less ZnâVOPO4 â 2H2O full cells with a low N/P ratio (2 : 1) show a high energy density of 75.2â Wh kg-1 full electrode after 842â cycles at 1â A g-1, far surpassing counterparts with thick Zn anode and low cathode loading mass, featuring excellent practicality. This study opens a new avenue by robust "hydrophobic ion barrier" design to develop long-life anode-less Zn batteries.
RESUMO
OBJECTIVES: To develop a clinical radiomics-integrated model based on 18 F-fluorodeoxyglucose positron emission tomography ([18F]FDG PET) and multi-modal MRI for predicting alpha thalassemia/mental retardation X-linked (ATRX) mutation status of IDH-mutant lower-grade gliomas (LGGs). METHODS: One hundred and two patients (47 ATRX mutant-type, 55 ATRX wild-type) diagnosed with IDH-mutant LGGs (CNS WHO grades 1 and 2) were retrospectively enrolled. A total of 5540 radiomics features were extracted from structural MR (sMR) images (contrast-enhanced T1-weighted imaging, CE-T1WI; T2-weighted imaging, and T2WI), functional MR (fMR) images (apparent diffusion coefficient, ADC; cerebral blood volume, CBV), and metabolic PET images ([18F]FDG PET). The random forest algorithm was used to establish a clinical radiomics-integrated model, integrating the optimal multi-modal radiomics model with three clinical parameters. The predictive effectiveness of the models was evaluated by receiver operating characteristic (ROC) and decision curve analysis (DCA). RESULTS: The optimal multi-modal model incorporated sMR (CE-T1WI), fMR (ADC), and metabolic ([18F]FDG) images ([18F]FDG PET+ADC+ CE-T1WI) with the area under curves (AUCs) in the training and test groups of 0.971 and 0.962, respectively. The clinical radiomics-integrated model, incorporating [18F]FDG PET+ADC+CE-T1WI, three clinical parameters (KPS, SFSD, and ATGR), showed the best predictive effectiveness in the training and test groups (0.987 and 0.975, respectively). CONCLUSIONS: The clinical radiomics-integrated model with metabolic, structural, and functional information based on [18F]FDG PET and multi-modal MRI achieved promising performance for predicting the ATRX mutation status of IDH-mutant LGGs. KEY POINTS: ⢠The clinical radiomics-integrated model based on [18F]FDG PET and multi-modal MRI achieved promising performance for predicting ATRX mutation status in LGGs. ⢠The study investigated the value of multicenter clinical radiomics-integrated model based on [18F]FDG PET and multi-modal MRI in LGGs regarding ATRX mutation status prediction. ⢠The integrated model provided structural, functional, and metabolic information simultaneously and demonstrated with satisfactory calibration and discrimination in the training and test groups (0.987 and 0.975, respectively).
Assuntos
Neoplasias Encefálicas , Glioma , Deficiência Intelectual , Talassemia alfa , Humanos , Fluordesoxiglucose F18 , Estudos Retrospectivos , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Glioma/diagnóstico por imagem , Glioma/genética , Glioma/metabolismo , Imageamento por Ressonância Magnética/métodos , Mutação , Proteína Nuclear Ligada ao X/genéticaRESUMO
The artificial solid electrolyte interphase (SEI) plays a pivotal role in Zn anode stabilization but its long-term effectiveness at high rates is still challenged. Herein, to achieve superior long-life and high-rate Zn anode, an exquisite electrolyte additive, lithium bis(oxalate)borate (LiBOB), is proposed to in situ derive a highly Zn2+ -conductive SEI and to dynamically patrol its cycling-initiated defects. Profiting from the as-constructed real-time, automatic SEI repairing mechanism, the Zn anode can be cycled with distinct reversibility over 1800â h at an ultrahigh current density of 50â mA cm-2 , presenting a record-high cumulative capacity up to 45â Ah cm-2 . The superiority of the formulated electrolyte is further demonstrated in the Zn||MnO2 and Zn||NaV3 O8 full batteries, even when tested under harsh conditions (limited Zn supply (N/P≈3), 2500â cycles). This work brings inspiration for developing fast-charging Zn batteries toward grid-scale storage of renewable energy sources.
RESUMO
Aqueous rechargeable Mg batteries (ARMBs) usually fail from severe anode passivation, alternatively, executing quasi-underpotential Mg plating/stripping chemistry (UPMC) on a proper heterogeneous metal substrate is a crucial remedy. Herein, a stable UPMC on Zn substrate is initially achieved in new hydrated eutectic electrolytes (HEEs), delivering an ultralow UPMC overpotential and high energy/voltage plateau of ARMBs. The unique eutectic property remarkably expands the lower limit of electrochemical stability window (ESW) of HEEs and undermines the competition between hydrogen evolution/corrosion reactions and UPMC, enabling a reversible UPMC. The UPMC is carefully revealed by multiple characterizations, which shows a low overpotential of 50â mV at 0.1â mA cm-2 over 550â h. With sulfonic acid-doped polyaniline (SPANI) cathodes, UPMC-based full cells show high energy/power densities of 168.6â Wh kg-1 /2.1â kWh kg-1 and voltage plateau of 1.3â V, far overwhelming conventional aqueous systems.
RESUMO
The anode-cathode interplay is an important but rarely considered factor that initiates the degradation of aqueous zinc ion batteries (AZIBs). Herein, to address the limited cyclability issue of V-based AZIBs, Al2 (SO4 )3 is proposed as decent electrolyte additive to manipulate OH- -mediated cross-communication between Zn anode and NaV3 O8 â 1.5H2 O (NVO) cathode. The hydrolysis of Al3+ creates a pH≈0.9 strong acidic environment, which unexpectedly prolongs the anode lifespan from 200 to 1000â h. Such impressive improvement is assigned to the alleviation of interfacial OH- accumulation by Al3+ adsorption and solid electrolyte interphase formation. Accordingly, the strongly acidified electrolyte, associated with the sedated crossover of anodic OH- toward NVO, remarkably mitigate its undesired dissolution and phase transition. The interrupted OH- -mediated communication between the two electrodes endows Zn||NVO batteries with superb cycling stability, at both low and high scan rates.
RESUMO
OBJECTIVES: Voriconazole is the most commonly used antifungal agent in clinical application. Previous studies suggested that voriconazole was extensively metabolized by CYP450 enzyme system, including CYP2C19, CYP2C9 and CYP3A4, which contributed to the individual variability of the pharmacokinetic process of voriconazole. This study aimed to investigate the effects of CYP2C19, CYP2C9 and CYP3A4 gene polymorphisms on plasma voriconazole concentrations in Chinese pediatric patients. METHODS: This study prospectively evaluated pediatric patients administrating voriconazole for the treatment or prophylaxis of invasive fungal infections from October 2018 to July 2020. Seven single-nucleotide polymorphisms in CYP2C19 (CYP2C19*2, CYP2C19*3, and CYP2C19*17), CYP2C9 (CYP2C9*3, CYP2C9*13) and CYP3A4 (CYP3A4*22, rs4646437) were detected by real-time fluorescent PCR with TaqMan probes. The voriconazole trough plasma concentration was determined by UPLC-MS/MS. RESULTS: A total of 68 pediatric patients were enrolled in this study. Our results showed that voriconazole plasma concentrations of patients with CYP2C19*2 or CYP2C19*3 allele were significantly higher than that with wild-type carriers (P < 0.0001, P = 0.004, respectively). However, CYP2C9*3 and CYP3A4 rs4646437 were not significantly associated with voriconazole plasma levels. The CYP2C19*17, CYP2C9*13 and CYP3A4*22 alleles were not observed in our study. Additionally, multiple linear regression analysis indicated that CYP2C19*2 and CYP2C19*3 alleles remained predictors of voriconazole plasma concentration (r2 = 0.428; P < 0.0001). For CYP2C19 metabolizer phenotype, trough concentration of voriconazole was significantly lower in NM group compared with IM (P < 0.0001) and PM (P = 0.004) groups. CONCLUSION: Voriconazole plasma levels in pediatric patients are mainly affected by CYP2C19 gene polymorphisms.
Assuntos
Citocromo P-450 CYP3A , Espectrometria de Massas em Tandem , Antifúngicos/farmacocinética , Criança , China , Cromatografia Líquida , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP3A/genética , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Voriconazol/farmacocinéticaRESUMO
Untreated invasive fungal infection is one of the important risk factors affecting the prognosis of pediatric patients with hematologic tumors. Voriconazole (VOR) is the first-line antifungal drug for the treatment of Aspergillus infections. In order to reduce the risk of adverse drug reactions while producing an ideal antifungal effect, therapeutic drug monitoring was performed to maintain the VOR plasma concentration in a range of 1,000-5,500 ng/ml. In the present study, a reliable, accurate, sensitive and quick ultra-high performance liquid chromatograph-tandem mass spectrometry (UPLC-MS/MS) method was developed for the determination of the VOR level. Protein precipitation was performed using acetonitrile, and then the chromatographic separation was carried out by UPLC using a C18 column with the gradient mobile phases comprising 0.1% methanoic acid in acetonitrile (A) and 0.1% methanoic acid in water (B). In the selective reaction monitor mode, the mass spectrometric detection was carried out using an TSQ Endura triple quadruple mass spectrometer. The performance of this UPLC-MS/MS method was validated as per the National Medical Products Administration for Bioanalytical Method Validation. Additionally, the plasma concentrations of VOR in pediatric patients with hematologic tumors were detected using this method, and the analyzed results were used for personalized therapy.
Assuntos
Neoplasias Hematológicas , Espectrometria de Massas em Tandem , Acetonitrilas , Antifúngicos/uso terapêutico , Criança , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida/métodos , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos , Voriconazol/uso terapêuticoRESUMO
Developing advanced electrode materials with enhanced charge-transfer kinetics is the key to realizing fast energy storage technologies. Commonly used modification strategies, such as nanoengineering and carbon coating, are mainly focused on electron transfer and bulk Li+ diffusion. Nonetheless, the desolvation behavior, which is considered as the rate-limiting process for charge-storage, is rarely studied. Herein, we designed a nitridation layer on the surface of Wadsley-Roth phase FeNb11O29 (FNO-x@N) to act as a desolvation promoter. Theoretical calculations demonstrate that the adsorption and desolvation of solvated Li+ is efficiently improved at FNO-x@N/electrolyte interphase, leading to the reduced desolvation energy barrier. Moreover, the nitridation layer can also help to prevent solvent cointercalation during Li+ insertion, leading to advantageous shrinkage of block area and reduced volume change of lattice cell during cycling. Consequently, FNO-x@N exhibits a high-rate capacity of 129.7 mAh g-1 with negligible capacity decay for 10â¯000 cycles.
RESUMO
Gliomas are the most common form of malignant tumour in the central nervous system. However, the molecular mechanism of the tumorigenesis and progression of gliomas remains unclear. In this study, we used the GEO database to identify genes differentially expressed in gliomas and predict the prognosis of glioma. We observed that ASPM mRNA was increased obviously in glioma tissue, and higher ASPM mRNA expression predicted worse disease prognosis. ASPM was highly expressed in glioma cell lines U87-MG and U251, and knockdown of ASPM expression in these cells significantly repressed the proliferation, migration and invasion ability and induced G0/G1 phase arrest. In addition, down-regulation of ASPM suppressed the growth of glioma in nude mice. Five potential binding sites for transcription factor FoxM1 were predicted in the ASPM promoter. FoxM1 overexpression significantly increased the expression of ASPM and promoted the proliferation and migration of glioma cells, which was abolished by ASPM ablation. ChIP and dual-luciferase reporter analysis confirmed that FoxM1 bound to the ASPM promoter at -236 to -230 bp and -1354 to -1348 bp and activated the transcription of ASPM directly. Collectively, our results demonstrated for the first time that aberrant ASPM expression mediated by transcriptional regulation of FoxM1 promotes the malignant properties of glioma cells.
Assuntos
Proteína Forkhead Box M1/genética , Glioma/genética , Proteínas do Tecido Nervoso/genética , Transcrição Gênica/genética , Animais , Carcinogênese/genética , Carcinogênese/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Glioma/patologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Prognóstico , Regiões Promotoras Genéticas/genéticaRESUMO
BACKGROUND: Cumulative evidence has shown that the non-invasive modality of coronary computed tomography angiography (CCTA) has evolved as an alternative to invasive coronary angiography, which can be used to quantify plaque burden and stenosis and identify vulnerable plaque, assisting in diagnosis, prognosis and treatment. With the increasing elderly population, many patients scheduled for non-cardiovascular surgery may have concomitant coronary artery disease (CAD). The aim of this study was to investigate the usefulness of preoperative CCTA to rule out or detect significant CAD in this cohort of patients and the impact of CCTA results to clinical decision-making. METHODS: 841 older patients (age 69.5 ± 5.8 years, 74.6% males) with high risk non-cardiovascular surgery including 771 patients with unknown CAD and 70 patients with suspected CAD who underwent preoperative CCTA were retrospectively enrolled. Multivariate logistic regression analysis was performed to determine predictors of significant CAD and the event of cancelling scheduled surgery in patients with significant CAD. RESULTS: 677 (80.5%) patients had non-significant CAD and 164 (19.5%) patients had significant CAD. Single-, 2-, and 3- vessel disease was found in 103 (12.2%), 45 (5.4%) and 16 (1.9%) patients, respectively. Multivariate analysis demonstrated that positive ECG analysis and Agatston score were independently associated with significant CAD, and the optimal cutoff of Agatston score was 195.9. The event of cancelling scheduled surgery was increased consistently according to the severity of stenosis and number of obstructive major coronary artery. Multivariate analysis showed that the degree of stenosis was the only independent predictor for cancelling scheduled surgery. In addition, medication using at perioperative period increased consistently according to the severity of stenosis. CONCLUSIONS: In older patients referred for high risk non-cardiovascular surgery, preoperative CCTA was useful to rule out or detect significant CAD and subsequently influence patient disposal. However, it might be unnecessary for patients with negative ECG and low Agatston score. Trial registration Retrospectively registered.
Assuntos
Angiografia por Tomografia Computadorizada , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Estenose Coronária/diagnóstico por imagem , Programas de Triagem Diagnóstica , Tomografia Computadorizada Multidetectores , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Fatores Etários , Idoso , Tomada de Decisão Clínica , Doença da Artéria Coronariana/terapia , Estenose Coronária/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
PURPOSE: There is a large inter-individual variation in the efficacy of valproic acid (VPA) against epilepsy. The genetic polymorphism influence of sodium channels on VPA response remains a matter of debate. The aim of the study was to explore the effect of SCN1A and SCN2A gene polymorphisms on VPA response in the treatment of epilepsy among Chinese patients. METHODS: A total of 354 epileptic patients with VPA treatment were genotyped for five single nucleotide polymorphisms (SNP), including SCN1A rs10188577 T>C, rs2298771 T>C, rs3812718 G>A, and SCN2A rs2304016 A>G, rs17183814 G>A. A binary logistic regression analysis was performed to evaluate the association of genotype with VPA antiepileptic effects, adjusting the influence of confounding factors. RESULTS: Genotype distributions of all selected SNPs were consistent with the Hardy-Weinberg equilibrium in epilepsy patients. SCN1A rs3812718 and SCN2A rs2304016 were found to be significantly associated with VPA response, both in monotherapy and in VPA-based polytherapy. Patients with the rs3812718 A allele were more frequently seen in the VPA-responsive group (P < 0.05), and the rs2304016 G allele was related to an increased risk of resistance to VPA therapy (P < 0.05). CONCLUSIONS: Our study revealed that SCN1A rs3812718 and SCN2A rs2304016 polymorphisms might be markers of VPA response in Chinese epilepsy patients. TRIAL REGISTRATION: ChiCTR-1800016477.
Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Epilepsia/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Polimorfismo de Nucleotídeo Único , Ácido Valproico/uso terapêutico , Adolescente , Adulto , Povo Asiático/genética , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Genótipo , Técnicas de Genotipagem , Humanos , Masculino , Adulto JovemRESUMO
BACKGROUND/AIMS: In the current study, we performed an integrated analysis of genome-wide methylation and gene expression data to find novel prognostic genes for lower-grade gliomas (LGGs). METHODS: First, TCGA methylation data were used to identify prognostic genes associated with promoter methylation. Second, candidate genes that were stably regulated by promoter methylation were explored. Third, Cox proportional hazards regression analysis was used to generate a prognostic signature, and the signature genes were used to construct a survival risk score system. RESULTS: Three genes (EMP3, GSX2 and EMILIN3) were selected as signature genes. These three signature genes were used to construct a survival risk score system. The high-risk group exhibited significantly worse overall survival (OS) and relapse-free survival (RFS) as compared to the low-risk group in the TCGA dataset. The association of the three-gene prognostic signature with patient' survival was then validated using the CGGA dataset. Moreover, Kaplan-Meier plots showed that the three-gene prognostic signature risk remarkably stratified grade II and grade III patients in terms of both OS and RFS in the TCGA cohort. There was also a significant difference between the low- and high-risk groups in IDH wild-type glioma patients, indicating that the three-gene signature may be able to help in predicting prognosis for patients with IDH wild-type gliomas. CONCLUSION: We identified and validated a three-gene (EMP3, GSX2 and EMILIN3) prognostic signature in LGGs by integrating multidimensional genomic data from the TCGA and CGGA datasets, which may help in fine-tuning the current histology-based tumors classification system and providing better stratification for future clinical trials.
Assuntos
Antígenos de Superfície/genética , Neoplasias do Sistema Nervoso Central/genética , Metilação de DNA , Glioma/genética , Proteínas de Homeodomínio/genética , Glicoproteínas de Membrana/genética , Adulto , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Glioma/diagnóstico , Glioma/patologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Recidiva Local de Neoplasia/genética , Prognóstico , Regiões Promotoras Genéticas , TranscriptomaRESUMO
Ticagrelor is a direct-acting P2Y12 receptor antagonist. It is rapidly absorbed and partly metabolized to the active metabolite AR-C124910XX by CYP3A4 and CYP3A5. Three genetic loci (SLCO1B1, CYP3A4, and UGT2B7) were reported to affect ticagrelor pharmacokinetics. This study aimed to investigate the possible effects of SLCO1B1 and CYP3A4/5 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy Chinese male volunteers. Eighteen healthy male volunteers who participated in pharmacogenetics study of ticagrelor were genotyped for SLCO1B1 rs113681054, SLCO1B1*5 (rs4149056), CYP3A4*1G (rs2242480), and CYP3A5*3 (rs776746). All subjects received a single 180 mg loading dose of ticagrelor and then series blood samples were collected from 0 to 48 h. Plasma concentrations of ticagrelor and AR-C124910XX were determined by the high performance liquid chromatography-tandem mass spectrometry method. Inhibition in platelet aggregation (IPA) was assessed and the area under the time-effect curve (AUEC) for the IPA was calculated as pharmacodynamic parameters. No significant difference in ticagrelor pharmacokinetics among genotypes of the two genes was observed. The AUEC did not differ significantly among genotypes of candidate single nucleotide polymorphisms (SNPs). Our data suggest that common genetic variants in SLCO1B1 and CYP3A4/5 may have no effect on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy Chinese volunteers.