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PHLDA2 reshapes the immune microenvironment and induces drug resistance in hepatocellular carcinoma

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Oncology Research 2024年第6期32卷 1063-1078页

作者： KUN FENG HAO PENG QINGPENG LV yewei zhang Hepatopancreatobiliary Center The Second Affiliated Hospital of Nanjing Medical UniversityNanjing210000China Medical School Southeast UniversityNanjing210000China

Hepatocellular carcinoma(HCC)is a malignancy known for its unfavorable *** dysregulation of the tumor microenvironment(TME)can affect the sensitivity to immunotherapy or chemotherapy,leading to treatment *** elucidation of PHLDA2’s involvement in HCC is imperative,and the clinical value of PHLDA2 is also ***,bioinformatics analysis was performed in multiple cohorts to explore the phenotype and mechanism through which PHLDA2 may affect the progression of ***,the expression and function of PHLDA2 were examined via the qRT-PCR,Western Blot,and MTT *** findings indicate a substantial upregulation of PHLDA2 in HCC,correlated with a poorer *** methylation levels of PHLDA2 were found to be lower in HCC tissues compared to normal liver ***,noteworthy associations were observed between PHLDA2 expression and immune infiltration in *** addition,PHLDA2 upregulation is closely associated with stemness features and immunotherapy or chemotherapy resistance in *** vitro experiments showed that sorafenib or cisplatin significantly up-regulated PHLDA2 mRNA levels,and PHLDA2 knockdown markedly decreased the sensitivity of HCC cells to chemotherapy ***,we found that TGF-βinduced the expression of PHLDA2 in *** GSEA and in vitro experiment indicated that PHLDA2 may promote the HCC progression via activating the AKT signaling *** study revealed the novel role of PHLDA2 as an independent prognostic factor,which plays an essential role in TME remodeling and treatment resistance in HCC.

关键词： HCC Immune infiltration Drug resistance TME PHLDA2

Engineered extracellular vesicles for targeted reprogramming of cancer-associated fibroblasts to potentiate therapy of pancreatic cancer

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Signal Transduction and Targeted Therapy 2024年第7期9卷 3077-3096页

作者： Pengcheng Zhou Xuanlong Du Weilu Jia Kun Feng yewei zhang Department of General Surgery Affiliated Hospital of Nantong UniversityNantongChina School of Medicine Southeast UniversityNanjingChina Nanjing Medical University NanjingChina Hepatobiliary and Pancreatic Center The Second Affiliated Hospital of Nanjing Medical UniversityNanjingChina

Pancreatic cancer is one of the deadly malignancies with a significant mortality rate and there are currently few therapeutic options for *** tumor microenvironment(TME)in pancreatic cancer,distinguished by fibrosis and the existence of cancer-associated fibroblasts(CAFs),exerts a pivotal influence on both tumor advancement and resistance to *** advancements in the field of engineered extracellular vesicles(EVs)offer novel avenues for targeted therapy in pancreatic *** study aimed to develop engineered EVs for the targeted reprogramming of CAFs and modulating the TME in pancreatic *** obtained from bone marrow mesenchymal stem cells(BMSCs)were loaded with miR-138-5p and the anti-fibrotic agent pirfenidone(PFD)and subjected to surface modification with integrinα5-targeting peptides(named IEVs-PFD/138)to reprogram CAFs and suppress their pro-tumorigenic ***α5-targeting peptide modification enhanced the CAF-targeting ability of ***-138-5p directly inhibited the formation of the FERMT2-TGFBR1 complex,inhibiting TGF-βsignaling pathway *** addition,miR-138-5p inhibited proline-mediated collagen synthesis by directly targeting the FERMT2-PYCR1 *** combination of miR-138-5p and PFD in EVs synergistically promoted CAF reprogramming and suppressed the pro-cancer effects of *** experiments using the orthotopic stroma-rich and patient-derived xenograft mouse models yielded promising *** particular,IEVs-PFD/138 effectively reprogrammed CAFs and remodeled TME,which resulted in decreased tumor pressure,enhanced gemcitabine perfusion,tumor hypoxia amelioration,and greater sensitivity of cancer cells to ***,the strategy developed in this study can improve chemotherapy *** IEVs-PFD/138 as a targeted therapeutic agent to modulate CAFs and the TME represents a promising therapeutic approach for pancreatic cancer.

关键词： inhibited targeted chemotherapy

Theoretical and experimental investigations on an X-shaped vibration isolator with active controlled variable stiffness

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Applied Mathematics and Mechanics(English Edition) 2024年第8期45卷 1371-1386页

作者： Zeyu CHAI J.T.HAN Xuyuan SONG Jian ZANG yewei zhang Zhen zhang College of Aerospace Engineering Shenyang Aerospace UniversityShenyang 110136China Jacobs School of Engineering University of California San DiegoSan Diego CA 92122U.S.A. Key Laboratory of Vibration and Control of Aero-Propulsion System Ministry of EducationNortheastern UniversityShenyang 110819China

A novel X-shaped variable stiffness vibration isolator(X-VSVI)is *** Runge-Kutta method,harmonic balance method,and wavelet transform spectra are introduced to evaluate the performance of the X-VSVI under various *** layer number,the installation angle of the X-shaped structure,the stiffness,and the active control parameters are systematically *** addition,a prototype of the X-VSVI is manufactured,and vibration tests are carried *** results show that the proposed X-VSVI has a superior adaptability to that of a traditional X-shaped mechanism,and shows excellent vibration isolation performance in response to different amplitudes and forms of ***,the vibration isolation efficiency of the device can be improved by appropriate adjustment of parameters.

关键词： bionic vibration isolation X-shaped structure variable stiffness structure nonlinear dynamics prototype experiment

Semaphorin 3C (Sema3C) reshapes stromal microenvironment to promote hepatocellular carcinoma progression

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SIGNAL TRANSDUCTION AND TARGETED THERAPY 2024年第1期9卷 1-20页

作者： Peng, Hao Yang, Meng Feng, Kun Lv, Qingpeng zhang, yewei Southeast Univ Med Sch Nanjing 210009 Peoples R China Chinese Acad Med Sci & Peking Union Med Coll Peking Union Med Coll Hosp State Key Lab Complex Severe & Rare Dis Dept Ultrasound Beijing 100730 Peoples R China Nanjing Med Univ Hepatopancreatobiliary Ctr Affiliated Hosp 2 Nanjing 210009 Peoples R China

More than 90% of hepatocellular carcinoma (HCC) cases develop in the presence of fibrosis or cirrhosis, making the tumor microenvironment (TME) of HCC distinctive due to the intricate interplay between cancer-associated fibroblasts (CAFs) and cancer stem cells (CSCs), which collectively regulate HCC progression. However, the mechanisms through which CSCs orchestrate the dynamics of the tumor stroma during HCC development remain elusive. Our study unveils a significant upregulation of Sema3C in fibrotic liver, HCC tissues, peripheral blood of HCC patients, as well as sorafenib-resistant tissues and cells, with its overexpression correlating with the acquisition of stemness properties in HCC. We further identify NRP1 and ITGB1 as pivotal functional receptors of Sema3C, activating downstream AKT/Gli1/c-Myc signaling pathways to bolster HCC self-renewal and tumor initiation. Additionally, HCC cells-derived Sema3C facilitated extracellular matrix (ECM) contraction and collagen deposition in vivo, while also promoting the proliferation and activation of hepatic stellate cells (HSCs). Mechanistically, Sema3C interacted with NRP1 and ITGB1 in HSCs, activating downstream NF-kB signaling, thereby stimulating the release of IL-6 and upregulating HMGCR expression, consequently enhancing cholesterol synthesis in HSCs. Furthermore, CAF-secreted TGF-beta 1 activates AP1 signaling to augment Sema3C expression in HCC cells, establishing a positive feedback loop that accelerates HCC progression. Notably, blockade of Sema3C effectively inhibits tumor growth and sensitizes HCC cells to sorafenib in vivo. In sum, our findings spotlight Sema3C as a novel biomarker facilitating the crosstalk between CSCs and stroma during hepatocarcinogenesis, thereby offering a promising avenue for enhancing treatment efficacy and overcoming drug resistance in HCC.

关键词： CANCER-ASSOCIATED FIBROBLASTS HEPATIC STELLATE CELLS STEM-CELLS ACTIVATION POPULATIONS METASTASIS MECHANISMS PATHWAYS FIBROSIS PI3K/AKT

Tumor microenvironment-activated theranostic nanoreactor for NIR-II Photoacoustic imaging-guided tumor-specific photothermal therapy

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Fundamental Research 2024年第1期4卷 178-187页

作者： Nan Yang Hui Li Changyu Cao Lei Zhao Xuejiao Song Wenjun Wang Wenjing Xu yewei zhang Peng Chen Xiaochen Dong Key Laboratory of Flexible Electronics(KLOFE)and Institute of Advanced Materials(IAM) School of Physical and Mathematical SciencesNanjing Tech University(NanjingTech)Nanjing 211816China School of Physical Science and Information Technology Liaocheng UniversityLiaocheng 252059China Department of Hepatobiliary and Pancreatic Surgery the Second Affiliated Hospital of Nanjing Medical UniversityNanjing 210011China School of Chemical and Biomedical Engineering Lee Kong Chian School of MedicineNanyang Technological University62 Nanyang DriveSingapore 637459Singapore

Theranostic agents that can be sensitively and specifically activated by the tumor microenvironment(TME)have recently attracted considerable *** this study,TME-activatable 3,3′,5,5′-tetramethylbenzidine(TMB)-copper peroxide(CuO_(2))@poly(lactic-co-glycolic acid)(PLGA)@red blood cell membrane(RBCM)(TCPR)nanoparticles(NPs)for second near-infrared photoacoustic imaging-guided tumor-specific photothermal therapy were developed by co-loading CuO_(2)NPs and TMB into PLGA camouflaged by *** an efficient H_(2)O_(2)supplier,once exposed to a proton-rich TME,CuO_(2)NPs can generate H_(2)O_(2)and Cu^(2+),which are further reduced to Cu^(+) by endogenous ***,the Cu^(+)-mediated Fenton-like reaction produces cytotoxic·OH to kill the cancer cells and induce TMB-mediated photoacoustic and photothermal *** with the RBCM modification-prolonged blood circulation,TCPR NPs display excellent specificity and efficiency in suppressing tumor growth,paving the way for more accurate,safe,and efficient cancer theranostics.

关键词： Nanoparticles Photoacoustic imaging Second near-infrared region Tumor microenvironment Self-sufficient H_(2)O_(2)

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区域轨道交通路网图系统的设计和实现

铁路通信信号工程技术 2024年第5期21卷 70-74页

作者：张晔伟北京全路通信信号研究设计院集团有限公司北京100070

针对区域轨道交通协同运输一体化的需求,提出构建区域轨道交通路网图系统。将接入区域路网的线路基础设备状态、客流数据、列车开行情况、列车设备状态以及气象状况等各专业信息以车站和区间为节点进行拆分,并对拆分后的数据计算和重构... 详细信息

针对区域轨道交通协同运输一体化的需求,提出构建区域轨道交通路网图系统。将接入区域路网的线路基础设备状态、客流数据、列车开行情况、列车设备状态以及气象状况等各专业信息以车站和区间为节点进行拆分,并对拆分后的数据计算和重构,生成以车站和区间为单位的节点数据模型,在同一个底图上进行显示,从而对区域路网内各线路的列车分布、实时客流、设备状态以及安全预警等信息提供直观、全面的展示,为人工决策提供便利,为整个系统智能决策和智能指挥提供数据基础。

关键词：路网图区域轨道交通协同运输

Energy harvesting via nonlinear energy sink for whole-spacecraft

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Science China(Technological Sciences) 2019年第9期62卷 1483-1491页

作者： zhang yewei LU YanNan CHEN LiQun Faculty of Aerospace Engineerings Shenyang Aerospace UniversityShenyang 110136China School of Science Harbin Institute of TechnologyShenzhen 518055China

This paper presents nonlinear energy sink with giant magnetostrictive-piezoelectric material for energy harvesting of the wholespacecraft vibration reduction system. The whole-spacecraft vibration attenuation system can effectively reduce vibration and achieve self-tuning enhanced energy harvesting range. The open-circuit voltage generated at low frequency is affected by the magnetic field force, alternating magnetic field and relative displacement. In order to acquire a steady periodic solution of the energy harvesting system, a combination of the harmonic balance method and pseudo arc length continuation technique is *** numerical outcomes are consistent with the analytical outcomes in a certain range, which also proves the accuracy and reliability of the results. The amplitude and voltage of the energy harvesting system are analyzed by parameters such as cubic stiffness, viscous damping, and external excitation acceleration. In addition, this paper provides a new idea for broadband energy harvesting.

关键词： nonlinear energy sink giant magnetostrictive-piezoelectric material pseudo arc length continuation technique energy harvesting

Research on linear/nonlinear viscous damping and hysteretic damping in nonlinear vibration isolation systems

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Applied Mathematics and Mechanics(English Edition) 2020年第7期41卷 983-998页

作者： Zhong zhang Muqing NIU Kai YUAN yewei zhang Science and Technology on Reliability and Environment Engineering Laboratory Beijing Institute of Structure and Environment EngineeringBeijing 100076China School of Science Harbin Institute of TechnologyShenzhen 518055China College of Aerospace Engineering Shenyang Aerospace UniversityShenyang 110136China

A nonlinear vibration isolation system is promising to provide a high-efficient broadband isolation *** this paper,a generalized vibration isolation system is established with nonlinear stiffness,nonlinear viscous damping,and Bouc-Wen(BW)hysteretic *** approximate analytical analysis is performed based on a harmonic balance method(HBM)and an alternating frequency/time(AFT)domain *** evaluate the damping effect,a generalized equivalent damping ratio is defined with the stiffness-varying characteristics.A comprehensive comparison of different kinds of damping is made through numerical *** is found that the damping ratio of the linear damping is related to the stiffness-varying characteristics while the damping ratios of two kinds of nonlinear damping are related to the responding *** linear damping,hysteretic damping,and nonlinear viscous damping are suitable for the small-amplitude,medium-amplitude,and large-amplitude conditions,*** hysteretic damping has an extra advantage of broadband isolation.

关键词： vibration isolation nonlinear damping Bouc-Wen(BW)model harmonic balance method(HBM)

Aeroelastic Properties and Nonlinear Vibration Control of a Simply-Supported Lattice Sandwich Beam Embedded with Nitinol-Steel Wire Ropes

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Acta Mechanica Solida Sinica 2022年第5期35卷 755-764页

作者： yewei zhang Xichao Chen Donghui Li Jian Zang College of Aerospace Engineering Shenyang Aerospace UniversityShenyang110136China

As a novel vibration absorber,Nitinol-steel wire rope(NiTi-ST)has rarely been studied on vibration suppression for lattice sandwich beams in supersonic *** this paper,NiTi-ST with nonlinear stiffness and hysteretic damping is embedded in a lattice sandwich beam to control the beam's *** nonlinear restoring and hysteretic damping force of NiTi-ST are treated as *** dynamic equation is established based on Hamilton's *** amplitude responses of the beam with different NiTi-ST configurations are *** vibration-suppression effects and energy dissipation of lattice sandwich beam with different NiTi-ST configurations under different air velocities are also *** frequency-domain and time-domain methods are used to analyze the structural aeroelastic *** results show that the use of NiTi-ST can significantly suppress excessive vibration of a lattice sandwich beam in supersonic airflow.

关键词： Lattice sandwich beam Nonlinear vibration control Nitinol-steel wire rope Supersonic airflow