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Hepatic arterial infusion chemotherapy with anti-angiogenesis agents and immune checkpoint inhibitors for unresectable hepatocellular carcinoma and meta-analysis

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World Journal of Gastroenterology 2024年第4期30卷 318-331页

作者： Yu-Zhe Cao Guang-Lei Zheng tian-qi zhang Hong-Yan Shao Jia-Yu Pan Zi-Lin Huang Meng-Xuan Zuo Department of Minimally Invasive Interventional Therapy Sun Yat-sen University Cancer CenterGuangzhou 510060Guangdong ProvinceChina Department of Minimally Invasive Interventional Therapy State Key Laboratory of Oncology in South ChinaGuangzhou 510060Guangdong ProvinceChina Department of Minimally Invasive Interventional Therapy Guangdong Provincial Clinical Research Center for CancerGuangzhou 510060Guangdong ProvinceChina

BACKGROUND Hepatic arterial infusion chemotherapy(HAIC)has been proven to be an ideal choice for treating unresectable hepatocellular carcinoma(uHCC).HAIC-based treatment showed great potential for treating uHCC.However,large-scale studies on HAIC-based treatments and meta-analyses of first-line treatments for uHCC are lacking.AIM To investigate better first-line treatment options for uHCC and to assess the safety and efficacy of HAIC combined with angiogenesis inhibitors,programmed cell death of protein 1(PD-1)and its ligand(PD-L1)blockers(triple therapy)under real-world conditions.METHODS Several electronic databases were searched to identify eligible randomized controlled trials for this meta-analysis.Study-level pooled analyses of hazard ratios(HRs)and odds ratios(ORs)were performed.This was a retrospective single-center study involving 442 patients with uHCC who received triple therapy or angiogenesis inhibitors plus PD-1/PD-L1 blockades(AIPB)at Sun Yat-sen University Cancer Center from January 2018 to April 2023.Propensity score matching(PSM)was performed to balance the bias between the groups.The Kaplan-Meier method and cox regression were used to analyse the survival data,and the log-rank test was used to compare the suvival time between the groups.RESULTS A total of 13 randomized controlled trials were included.HAIC alone and in combination with sorafenib were found to be effective treatments(P values for ORs:HAIC,0.95;for HRs:HAIC+sorafenib,0.04).After PSM,176 HCC patients were included in the analysis.The triple therapy group(n=88)had a longer median overall survival than the AIPB group(n=88)(31.6 months vs 14.6 months,P<0.001)and a greater incidence of adverse events(94.3%vs 75.4%,P<0.001).CONCLUSION This meta-analysis suggests that HAIC-based treatments are likely to be the best choice for uHCC.Our findings confirm that triple therapy is more effective for uHCC patients than AIPB.

关键词： Unresectable hepatocellular carcinoma Hepatic arterial infusion chemotherapy Angiogenesis inhibitors Programmed cell death protein 1 Programmed death ligand 1

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Facile Synthesis of Polyisothioureas via Alternating Copolymerization of Aziridines and Isothiocayanates

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Chinese Journal of Polymer Science 2024年第3期42卷 292-298,I0005页

作者： Hao-tian zhang Ming-Xin Niu qi zhang Chen-Yang Hu Xuan Pang Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied ChemistryChinese Academy of SciencesChangchun 130022China Department of Materials Science and Engineering Jilin UniversityChangchun 130025China School of Applied Chemistry and Engineering University of Science and Technology of ChinaHefei 230026China

Isothiourea is an important class of sulfur-containing molecules showing unique catalytic and biological activities. As such,polyisothiourea is envisioned to be an interesting type of polymer that potentially exhibits a number of interesting properties. However, there is no access to synthesizing well-defined polyisothiourea, and currently isothiourea-containing polymers are mainly prepared by immobilizing onto other polymer's side chain. Herein, we report the first facile synthesis of polyisothioureas via alternating copolymerization of aziridines and isothiocayanates. Mediated by the catalytic system of phosphazene superbases/alcohol, a broad scope of aziridines and isothiocayanates could be transformed into polyisothioureas with adjustable substitutions(11 examples). The structures of obtained polyisothioureas were fully characterized with ^(1)H-NMR, ^(13)C-NMR, and ^(1)H-^(13)C HMBC NMR. Moreover, the polyisothioureas show tunable thermal properties depending on substitutions on the isothiourea linkages. The novel structure of these polyisothioureas will enable a powerful platform for the discovery of nextgeneration functional plastics.

关键词： Polyisothioureas Alternative copolymer Aziridines Isothiocayanates

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Silvestrol alleviates glioblastoma progression through ERK pathway modulation and MANBA and NRG-1 expression

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BIOCELL 2024年第7期48卷 1081-1093页

作者： LAN ZHOU qi zhang BO tian FENG YANG Neurosurgery Department The First Affiliated Hospital of Chongqing Medical and Pharmaceutical CollegeChongqingChina Neurosurgery Department Changdu People’s Hospital of TibetChangduChina

Background:Glioblastoma,a notably malignant tumor within the central nervous system,is distinguished by its aggressive behavior.Silvestrol,a robust inhibitor of the RNA helicase eukaryotic initiation factor 4A(eIF4A),has shown significant potential as an anticancer compound.Yet,the impact of silvestrol on glioblastoma,especially its molecular mechanisms,has not been fully elucidated.Methods:This investigation employed a variety of in vitro assays,such as cell counting kit-8(CCK-8),clonogenic,5-ethynyl-2′-deoxyuridine(EDU),wound healing,and flow cytometry,to evaluate cell cycle progression,apoptosis,cell viability,and migration.Western blot analysis was also performed to study the apoptosis and extracellular regulated kinase(ERK)pathways.After the ERK pathway was inhibited,differentially expressed genes(DEGs)in U87 cells were identified,followed by an analysis of target genes using the gene expression profiling interactive analysis(GEPIA)database.Results:Silvestrol significantly suppressed the proliferation,migration,and colony formation of glioma cells.It caused cell cycle arrest and enhanced apoptosis in these cells.Additionally,silvestrol stimulated the ERK pathway,with these effects being reversible by an ERK phosphorylation inhibitor.Transcriptome combined with GEPIA,GSCA,UALCAN,TIMER database screened 4 potential drug targets of silvestrol:chromosome 1 open reading frame 226(C1ORF226),mannosidase beta A(MANBA),IQ motif and Sec7 domain 2(IQSEC2),neuregulin 1(NRG-1).Among them,C1ORF226 was lower risk gene while MANBA,IQSEC2,and NRG-1 were high-risk genes.Furthermore,silvestrol notably reduced MANBA mRNA levels,which could be reversed by inhibiting ERK phosphorylation.Furthermore,silvestrol markedly decreased NRG-1 protein levels,with an additional reduction observed when the ERK pathway was blocked.Conclusion:Silvestrol’s anti-glioma effects are primarily due to the suppression of MANBA expression via the ERK pathway and possibly by hindering the translation of NRG-1 protein,thus reducing its expression.The do

关键词： Glioblastoma Silvestrol ERK pathway MANBA NRG-1

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Buckling Optimization of Curved Grid Stiffeners through the Level Set Based Density Method

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Computer Modeling in Engineering & Sciences 2024年第7期140卷 711-733页

作者： Zhuo Huang Ye tian Yifan zhang Tielin Shi qi Xia State Key Laboratory of Digital Manufacturing Equipment and Technology Huazhong University of Science and TechnologyWuhan430074China

Stiffened structures have great potential for improvingmechanical performance,and the study of their stability is of great interest.In this paper,the optimization of the critical buckling load factor for curved grid stiffeners is solved by using the level set based density method,where the shape and cross section(including thickness and width)of the stiffeners can be optimized simultaneously.The grid stiffeners are a combination ofmany single stiffenerswhich are projected by the corresponding level set functions.The thickness and width of each stiffener are designed to be independent variables in the projection applied to each level set function.Besides,the path of each single stiffener is described by the zero iso-contour of the level set function.All the single stiffeners are combined together by using the p-norm method to obtain the stiffener grid.The proposed method is validated by several numerical examples to optimize the critical buckling load factor.

关键词： Stiffener buckling optimization shape and cross section level set based density

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Joint Effects of Multipollutant Mixtures on Mortality in Chengdu,China

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Biomedical and Environmental Sciences 2024年第1期37卷 112-116页

作者： zhang Ying tian qi qi HU Wen Dong zhang Shao Bo WANG Shi Gong ZHENG Can Jun Plateau Atmosphere and Environment Key Laboratory of Sichuan Province School of Atmospheric SciencesChengdu University of Information TechnologyChengdu 610225SichuanChina Yunnan R&D Institute of Natural Disaster on Chengdu University of Information Technology Kunming 650034YunnanChina Chengdu Plain Urban Meteorology and Environment Sichuan Provincial Field Scientific Observation and Research Station Chengdu 610225SichuanChina Chinese Center for Disease Control and Prevention National Institute for Communicable Disease Control and PreventionBeijing 102206China

Significant epidemiological research has revealed that exposure to air pollution is substantially associated with numerous detrimental health consequences^([1-3]).The negative health effects of individual air pollutants(e.g.,fine particulate matter:PM_(2.5);nitrogen dioxide:NO_(2);carbon monoxide,CO;or ozone:O_(3))have been widely explored^([4]).However,humans are constantly exposed to multipollutant mixtures in real life,and biological responses to inhaled pollutants are likely to depend on the interplay of pollutant mixtures.Therefore,it is critical and imperative to explore the joint effects of multipollutant mixtures on human beings.

关键词： mixtures monoxide consequences

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Revealing the Structure-Property Difference of Natural Rubber Prepared by Different Methods: Protein and Gel Content are Key Factors

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Chinese Journal of Polymer Science 2024年第4期42卷 457-467页

作者： Shao-qi Huang Jun-qi zhang Yong Zhu Ling-Min Kong Lu-Sheng Liao Fu-Quan zhang Zheng-tian Xie Jin-Rong Wu State Key Laboratory of Polymer Materials Engineering College of Polymer Science and EngineeringSichuan UniversityChengdu610065China Hainan Provincial Key Laboratory of Natural Rubber Processing Agricultural Products Processing Research Institute of Chinese Academy of Tropical Agricultural SciencesZhanjiang524001China

Natural rubber (NR) is widely used in various fields including aerospace, military industry and transportation due to its superior elasticity and comprehensive mechanical properties. Nonetheless, the commercial NR prepared by different methods usually exhibits different mechanical properties, primarily due to variations in processing conditions during the conversion from latex to bulk rubber material. Consequently, this poses challenges in scientific research and industrial production of NR. In order to assess the properties of various commercially available NR and identify key structural and compositional components, this study systematically compares and analyzes four representative NR raw materials: air dried sheet (ADS), ribbed smoked sheets (RSS), constant viscidity NR (CV), and whole field latex rubber (WF). The investigation focuses on evaluating their static mechanical behavior, SIC behavior, wear resistance, and fatigue resistance. The findings indicate that protein and gel content exhibit a crucial influence on the NR properties. These constituents contribute to the formation of a high-crosslinking density region, generating a heterogeneous network structure within the rubber. This structure amplifies strains during deformation, leading to earlier and stronger strain-induced crystallization (SIC). Among the four commercial NR brands, RSS demonstrates superior overall mechanical and dynamic properties owing to its high protein and gel content. This study serves as a valuable reference for comprehending the differences in properties among various commercial NR, thereby offering guidance for the actual processing and selection of NR.

关键词： Natural rubber Processingmethod Protein Gel content Property

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In situ autophagy regulation in synergy with phototherapy for breast cancer treatment

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2317-2332页

作者： Huijuan zhang Xiangyang Xuan Yaping Wang Zijun qi Kexuan Cao Yingmei tian Chaoqun Wang Junbiao Chang Zhenzhong zhang Lin Hou School of Pharmaceutical Sciences Zhengzhou UniversityZhengzhou 450001China Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases Zhengzhou 450001China Collaborative Innovation Center of New Drug Research and Safety Evaluation Zhengzhou 450001China School of Chemistry and Molecular Engineering Zhengzhou UniversityZhengzhou 450001China

Autophagy is an important factor in reducing the efficacy of tumor phototherapy(including PTT and PDT).Accurate regulation of autophagy in tumor cells is a new strategy to improve the anti-tumor efficiency of PTT/PDT.This project intended to construct a tumor-activated autophagy regulator to efficiently block PTT/PDT-induced autophagy and realize synergistic sensitization to tumor phototherapy.To achieve this goal,we first synthesized TRANSFERRIN(Tf)biomimetic mineralized nano-tellurium(Tf-Te)as photosensitizer and then used disulfide bond reconstruction technology to induce Tf-Te self-assembly.The autophagy inhibitor hydroxychloroquine(HCQ)and iron ions carried by Tf were simultaneously loaded to prepare a tumor-responsive drug reservoir Tf-Te/HCQ.After entering breast cancer cells through the“self-guidance system”,Tf-Te/HCQ can generate hyperpyrexia and ROS under NIR laser irradiation,to efficiently induce PTT/PDT effect.Meanwhile,the disulfide bond broke down in response to GSH,and the nanoparticles disintegrated to release Fe2+and HCQ at fixed points.They simultaneously induce lysosomal alkalinization and increased osmotic pressure,effectively inhibit autophagy,and synergistically enhance the therapeutic effect of phototherapy.In vivo anti-tumor results have proved that the tumor inhibition rate of Tf-Te/HCQ can be as high as 88.6%on 4T1 tumor-bearing mice.This multifunctional drug delivery system might provide a new alternative for more precise and effective tumor phototherapy.

关键词： Autophagy Tumor phototherapy Synergistic sensitization HCQ TRANSFERRIN Disulfide bond reconstruction GSH Biomimetic mineralized nano-tellurium

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Mechanism Exploration of Euphorbia fischeriana Steud. for Liver Cancer Based on Aspartic Acid Identification in Metabolomics

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Chinese Journal of Integrative Medicine 2024年第6期30卷 507-514页

作者： ZHAO Jing tian Xin-chen zhang Jia-qi HUANG Chen SUN Yan qiAO Sen JIANG Shu-long Clinical Medical Laboratory Center Jining First People’s HospitalJiningShandong Province272000China Cheeloo College of Medicine Shandong UniversityJinan250000China

Objective:To investigate the anti-liver cancer effects and aspartic acid(Asp)-related action mechanism of Euphorbia fischeriana Steud.(LD).Methods:The mice model of liver cancer was established by injection of H22 cells.After 5 days,mice were randomly divided into model group,sorafenib group(20 mg/kg),LD high-dose(LDH,1.36 g/kg) group,LD medium-dose(LDM,0.68 g/kg) group,and LD low-dose(LDL,0.34 g/kg)group,10 mice each group.Drugs were intragastrically administered to the mice once daily for 10 days,respectively.Body weight,tumor size and tumor weight were recorded.Hepatic index was calculated.Pathological changes of liver cancer tissues were evaluated by hematoxylin and eosin staining and TUNEL staining.Liquid chromatography-mass spectrometer was used to analyze different metabolites between the model and LDH groups.Results:After LD treatment,tumor weight,tumor size and hepatic index were reduced compared with the model group.Necrocytosis and karyorrhexis of tumor cells were found.Moreover,61 differential metabolites(18 up-regulated,43 down-regulated) were affirmed and 20 pathways of KEGG(P<0.05) were gotten.In addition,Bel-7402,HepG2 and H22 cell viabilities were significantly increased after adding Asp into the medium.And then,the cell proliferation effect induced by Asp was ameliorated by LD.Conclusion:The anti-liver cancer efficacy of LD extract was validated in H22 mice model,and inhibition of Asp level might be the underlying mechanism.

关键词： liver cancer Euphorbia fischeriana Steud. aspartic acid metabolomics

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Buckling optimization of curvilinear fiber-reinforced composite structures using a parametric level set method

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Frontiers of Mechanical Engineering 2024年第1期19卷 149-160页

作者： Ye tian Tielin SHI qi XIA State Key Laboratory of Intelligent Manufacturing Equipment and Technology Huazhong University of Science and TechnologyWuhan 430074China

Owing to their excellent performance and large design space,curvilinear fiber-reinforced composite structures have gained considerable attention in engineering fields such as aerospace and automobile.In addition to the stiffness and strength of such structures,their stability also needs to be taken into account in the design.This study proposes a level-set-based optimization framework for maximizing the buckling load of curvilinear fiber-reinforced composite structures.In the proposed method,the contours of the level set function are used to represent fiber paths.For a composite laminate with a certain number of layers,one level set function is defined by radial basis functions and expansion coefficients for each layer.Furthermore,the fiber angle at an arbitrary point is the tangent orientation of the contour through this point.In the finite element of buckling,the stiffness and geometry matrices of an element are related to the fiber angle at the element centroid.This study considers the parallelism constraint for fiber paths.With the sensitivity calculation of the objective and constraint functions,the method of moving asymptotes is utilized to iteratively update all the expansion coefficients regarded as design variables.Two numerical examples under different boundary conditions are given to validate the proposed approach.Results show that the optimized curved fiber paths tend to be parallel and equidistant regardless of whether the composite laminates contain holes or not.Meanwhile,the buckling resistance of the final design is significantly improved.

关键词： buckling optimization curvilinear fiber composite structure level set method manufacturing constraint

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NQO1 Mediates Lenvatinib Resistance by Regulating ROS-induced Apoptosis in Hepatocellular Carcinoma

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Current Medical Science 2024年第1期44卷 168-179页

作者： Wei XUE Ting WANG Wen-jing tian Si-qi PANG Hua-feng zhang Wei-dong JIA Department of General Surgery The First Affiliated Hospital of University of Science and Technology of ChinaDivision of Life Science and MedicineUniversity of Science and Technology of ChinaHefei 230027China Institute of Health and Medicine Hefei Comprehensive National Science CenterHefei 230601China The Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease School of Basic Medical SciencesDivision of Life Science and MedicineUniversity of Science and Technology of ChinaHefei 230027China

Objective Hepatocellular carcinoma(HCC)is the third leading cause of cancer-associated death worldwide.As a first-line drug for advanced HCC treatment,lenvatinib faces a significant hurdle due to the development of both intrinsic and acquired resistance among patients,and the underlying mechanism remains largely unknown.The present study aims to identify the pivotal gene responsible for lenvatinib resistance in HCC,explore the potential molecular mechanism,and propose combinatorial therapeutic targets for HCC management.Methods Cell viability and colony formation assays were conducted to evaluate the sensitivity of cells to lenvatinib and dicoumarol.RNA-Seq was used to determine the differences in transcriptome between parental cells and lenvatinib-resistant(LR)cells.The upregulated genes were analyzed by GO and KEGG analyses.Then,qPCR and Western blotting were employed to determine the relative gene expression levels.Afterwards,the intracellular reactive oxygen species(ROS)and apoptosis were detected by flow cytometry.Results PLC-LR and Hep3B-LR were established.There was a total of 116 significantly upregulated genes common to both LR cell lines.The GO and KEGG analyses indicated that these genes were involved in oxidoreductase and dehydrogenase activities,and reactive oxygen species pathways.Notably,NAD(P)H:quinone oxidoreductase 1(NQO1)was highly expressed in LR cells,and was involved in the lenvatinib resistance.The high expression of NQO1 decreased the production of ROS induced by lenvatinib,and subsequently suppressed the apoptosis.The combination of lenvatinib and NQO1 inhibitor,dicoumarol,reversed the resistance of LR cells.Conclusion The high NQO1 expression in HCC cells impedes the lenvatinib-induced apoptosis by regulating the ROS levels,thereby promoting lenvatinib resistance in HCC cells.

关键词： hepatocellular carcinoma lenvatinib resistance NAD(P)H quinone oxidoreductase 1 reactive oxygen species apoptosis dicoumarol

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