Identification of immune cell-related prognostic genes characterized by a distinct microenvironment in hepatocellular carcinoma

BACKGROUND The development and progression of hepatocellular carcinoma(HCC)have been reported to be associated with immune-related genes and the tumor microenvir-onment.Nevertheless,there are not enough prognostic biomarkers and models available for clinical use.Based on seven prognostic genes,this study calculated overall survival in patients with HCC using a prognostic survival model and revealed the immune status of the tumor microenvironment(TME).AIM To develop a novel immune cell-related prognostic model of HCC and depict the basic profile of the immune response in HCC.METHODS We obtained clinical information and gene expression data of HCC from The Cancer Genome Atlas(TCGA)and International Cancer Genome Consortium(ICGC)datasets.TCGA and ICGC datasets were used for screening prognostic genes along with developing and validating a seven-gene prognostic survival model by weighted gene coexpression network analysis and least absolute shrinkage and selection operator regression with Cox regression.The relative analysis of tumor mutation burden(TMB),TME cell infiltration,immune check-points,immune therapy,and functional pathways was also performed based on prognostic genes.RESULTS Seven prognostic genes were identified for signature construction.Survival receiver operating characteristic curve analysis showed the good performance of survival prediction.TMB could be regarded as an independent factor in HCC survival prediction.There was a significant difference in stromal score,immune score,and estimate score between the high-risk and low-risk groups stratified based on the risk score derived from the seven-gene prognostic model.Several immune checkpoints,including VTCN1 and TNFSF9,were found to be associated with the seven prognostic genes and risk score.Different combinations of checkpoint blockade targeting inhibitory CTLA4 and PD1 receptors and potential chemotherapy drugs hold great promise for specific HCC therapies.Potential pathways,such as cell cycle regulation and metabolism of some amino acids,were also identified and analyzed.CONCLUSION The novel seven-gene(CYTH3,ENG,HTRA3,PDZD4,SAMD14,PGF,and PLN)prognostic model showed high predictive efficiency.The TMB analysis based on the seven genes could depict the basic profile of the immune response in HCC,which might be worthy of clinical application.

阿立哌唑治疗抽动障碍的药动学研究进展

抽动障碍是儿童期常见的以运动抽动和(或)发声抽动为主要特征的神经精神疾病,其发病机制与脑内局部多巴胺水平增高有关。阿立哌唑是新型的第3代非典型抗精神病药,是治疗抽动障碍的有效治疗药物之一。但目前阿立哌唑用于抽动障碍的治疗属于超说明书用药,且治疗窗尚不明确,药动学存在较大个体差异。为提高阿立哌唑治疗儿童抽动障碍的有效性和安全性,考察阿立哌唑在抽动障碍儿童群体中的药动学作用规律,探明其个体差异的产生机制意义重大。本文就目前阿立哌唑治疗儿童抽动障碍的药动学研究现状及意义作一综述。

Compact broadband high-resolution Compton spectroscopy for laser-driven high-flux gamma rays

A compact broadband Compton spectrometer with high spectral resolution has been designed to detect spectra of laser-driven high-flux gamma rays.The primary detection range of the gamma-ray spectrum is 0.5 MeV–13 MeV,although a secondary harder gamma-ray region of 13 MeV–30MeV can also be covered.The Compton-scattered electrons are spectrally resolved using a curved surface detector and a nonuniform magnetic field produced by a pair of step-like magnets.This design allows a compact structure,a wider bandwidth,especially in the lower-energy region of 0.5 MeV–2 MeV,and optimum spectral resolution.The spectral resolution is 5%–10%in the range 4 MeV–13 MeV and better than 25%in the range 0.5MeV–4MeV(with an Al converter of 0.25mmthickness and a collimator of 1 cm inner diameter).Low-Z plastic materials are used on the inner surface of the spectrometer to suppress noise due to secondary X-ray fluorescence.The spectrometer can be adjusted flexibly via a specially designed mechanical component.An algorithmbased on a regularizationmethod has also been developed to reconstruct the gamma-ray spectrum from the scattered electrons.

Therapeutic Effect of Prolyl Endopeptidase Inhibitor in High-fat Diet-induced Metabolic Dysfunction-associated Fatty Liver Disease

Background and Aims:Prolyl endopeptidase(PREP)is a serine endopeptidase that participates in many pathological processes including inflammation,oxidative stress,and autophagy.Our previous studies found that PREP knockout exhibited multiple benefits in high-fat diet(HFD)or methionine choline-deficient diet-induced metabolic dysfunctionassociated fatty liver disease(MAFLD).However,cumulative studies have suggested that PREP performs complex functions during disease development.Therefore,further understanding the role of PREP in MAFLD development is the foundation of PREP intervention.Methods:In this study,an HFD-induced MAFLD model at different time points(4,8,12,and 16 weeks)was used to explore dynamic changes in the PREP proline-glycine-proline(PGP)/N-acetyl-seryl-aspartyllysyl-proline(AcSDKP)system.To explore its potential value in MAFLD treatment,saline,or the PREP inhibitor,KYP-2047,was administered to HFD-induced MAFLD mice from the 10th to 16th weeks.Results:PREP activity and expression were increased in HFD-mice compared with control mice from the 12th week onwards,and increased PREP mainly resulted in the activation of the matrix metalloproteinase 8/9(MMP8/9)-PREP-PGP axis rather than the thymosin B4-meprin a/PREP-AcSDKP axis.In addition,KYP-2047 reduced HFD-induced liver injury and oxidative stress,improved lipid metabolism through the suppression of lipogenic genes and the induction of B-oxidation-related genes,and attenuated hepatic inflam-mation by decreasing MMP8/9 and PGP.Moreover,KYP2047 restored HFD-induced impaired autophagy and this was veri-fied in HepG2 cells.Conclusions:These findings suggest that increased PREP activity/expression during MAFLD de-velopment might be a key factor in the transition from sim-ple steatosis to steatohepatitis,and KYP-2047 might possess therapeutic potential for MAFLD treatment.