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Immunostimulatory gene therapy combined with checkpoint blockade reshapes tumor microenvironment and enhances ovarian cancer immunotherapy

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Acta Pharmaceutica Sinica B 2024年第2期14卷 854-868页

作者： Yunzhu Lin Xiang Wang Shi He Zhongxin Duan Yunchu Zhang Xiaodong Sun yuzhu hu Yuanyuan Zhang Zhiyong Qian Xiang Gao Zhirong Zhang Key Laboratory of Drug Targeting and Drug Delivery Systems Ministry of EducationWest China School of PharmacySichuan UniversityChengdu 610041China Department of Pharmacy Evidence-based Pharmacy CenterWest China Second University HospitalKey Laboratory of Birth Defects and Related Diseases of Women and ChildrenSichuan UniversityChengdu 610041China Department of Neurosurgery and Institute of Neurosurgery State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengdu 610041China Department of Radiation Oncology State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengdu 610041China West China School of Basic Medical Sciences&Forensic Medicine Sichuan UniversityChengdu 610041China

Immune evasion has made ovarian cancer notorious for its refractory features, making the development of immunotherapy highly appealing to ovarian cancer treatment. The immune-stimulating cytokine IL-12 exhibits excellent antitumor activities. However, IL-12 can induce IFN-γ release and subsequently upregulate PDL-1 expression on tumor cells. Therefore, the tumor-targeting folate-modified delivery system F-DPC is constructed for concurrent delivery of IL-12 encoding gene and small molecular PDL-1 inhibitor(i PDL-1) to reduce immune escape and boost anti-tumor immunity. The physicochemical characteristics, gene transfection efficiency of the F-DPC nanoparticles in ovarian cancer cells are analyzed. The immune-modulation effects of combination therapy on different immune cells are also studied. Results show that compared with non-folate-modified vector, folate-modified F-DPC can improve the targeting of ovarian cancer and enhance the transfection efficiency of p IL-12. The underlying anti-tumor mechanisms include the regulation of T cells proliferation and activation, NK activation,macrophage polarization and DC maturation. The F-DPC/p IL-12/i PDL-1 complexes have shown outstanding antitumor effects and low toxicity in peritoneal model of ovarian cancer in mice. Taken together, our work provides new insights into ovarian cancer immunotherapy. Novel F-DPC/p IL-12/i PDL-1 complexes are revealed to exert prominent anti-tumor effect by modulating tumor immune microenvironment and preventing immune escape and might be a promising treatment option for ovarian cancer treatment.

关键词： IL-12encodinggene Checkpointblocker Nanoparticles Targeted delivery Tumormicroenvironment Immune escape Ovarian cancer Immunotherapy

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利用改进MobileNet V2网络识别水稻叶片病虫害的方法

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武汉轻工大学学报 2024年第3期43卷 76-81页

作者：胡玉珠刘昌华李盼武汉轻工大学数学与计算机学院武汉430023

针对传统水稻叶片病虫害分类效率不高、精度低和模型占用空间过大等问题,改进MobileNet V2网络,并结合迁移学习策略对水稻叶片病虫害进行识别。实验以4种常见水稻叶片病虫害作为研究对象,利用注意力机制对MobileNet V2进行改进,通过修... 详细信息

针对传统水稻叶片病虫害分类效率不高、精度低和模型占用空间过大等问题,改进MobileNet V2网络,并结合迁移学习策略对水稻叶片病虫害进行识别。实验以4种常见水稻叶片病虫害作为研究对象,利用注意力机制对MobileNet V2进行改进,通过修改模型残差结构引入通道注意力机制,并采用迁移学习策略对改进模型进行训练。实验表明,相比于原始模型,引入注意力机制并采用迁移学习的改进模型CAM_qianyi的准确率提升了0.82个百分点,达到了84.32%,其准确率也高于轻量化卷积神经网络ResNet18(82.54%)和未采用迁移学习的改进模型CAM(73.65%)。改进模型能准确提取水稻叶片病虫害特征,有效提高了识别效率和精度。

关键词：水稻叶片病虫害 MobileNet V2 迁移学习深度学习注意力机制

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A BRD4 PROTAC nanodrug for glioma therapy via the intervention of tumor cells proliferation,apoptosis and M2 macrophages polarization

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Acta Pharmaceutica Sinica B 2022年第6期12卷 2658-2671页

作者： Tingting Yang yuzhu hu Junming Miao Jing Chen Jiagang Liu Yongzhong Cheng Xiang Gao Department of Neurosurgery and Institute of Neurosurgery State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengdu 610041China Department of Medical Oncology State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengdu 610041China

Glioma is a primary aggressive brain tumor with high recurrence *** poor efficiency of chemotherapeutic drugs crossing the blood-brain barrier(BBB) is well-known as one of the main challenges for anti-glioma ***,massive infiltrated tumor-associated macrophages(TAMs) in glioma further thwart the drug ***,a therapeutic nanosystem(SPP-ARV-825) is constructed by incorporating the BRD4-degrading proteolytic targeting chimera(PROTAC) ARV-825 into the complex micelle(SPP) composed of substance P(SP) peptide-modified poly(ethylene glycol)-poly(D,L-lactic acid)(SP-PEG-PDLL A) and methoxy poly(ethylene glycol)-poly(D,L-lac tic acid)(mPEG-PDLL A,PP),which could penetrate BBB and target brain ***,released drug engenders antitumor effect via attenuating cells proliferation,inducing cells apoptosis and suppressing M2 macrophages polarization through the inhibition of IRF4 promoter transcription and phosphorylation of STAT6,STAT3 and *** together,our work demonstrates the versatile role and therapeutic efficacy of SPP-ARV-825 micelle against glioma,which may provide a novel strategy for glioma therapy in future.

关键词： Glioma BRD4 ARV-825 Micelle M2 macrophage

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Co-delivery of doxorubicin and curcumin via cRGD-peptide modified PEG-PLA self-assembly nanomicelles for lung cancer therapy

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Chinese Chemical Letters 2022年第5期33卷 2507-2511页

作者： Yunchu Zhang Tingting Li yuzhu hu Jing Chen Yihong He Xiang Gao Yan Zhang Department of Thoracic Oncology Cancer CenterState Key Laboratory of BiotherapyWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengdu 610041China Department of Neurosurgery and Institute of Neurosurgery State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengdu 610041China

Lung cancer is the most common malignancy in the world, with a high mortality rate. Nevertheless,therapies to act effectively against lung cancer remain elusive. So far, chemotherapy is still the frontline treatment of lung cancer. Doxorubicin(DOX) is a broad-spectrum anti-tumor drug. However, DOX often has serious side effects and causes multi-drug resistance, which greatly limits its clinical *** this work, biodegradable methoxy poly(ethylene glycol)-poly(lactic acid)(MPEG-PLA) and cyclo(ArgGly-Asp-D-Phe-Lys)(c RGD) polypeptide modified PEG-PLA(c RGD-PEG-PLA) copolymers were used for the co-delivery of curcumin(CUR) and DOX(CUR-DOX/c RGD-M). The particle size of the self-assembled drugloaded nanomicelle approximately was 27.4 nm and the zeta potential was -2.7mV. Interestingly, CUR can enhance the uptake of DOX by Lewis lung carcinoma(LL/2) cells. The experimental results in vivo and in vitro showed that CUR-DOX/c RGD-M combination therapy could promote apoptosis of lung cancer cells, and conspicuously inhibit the tumor growth. Our data indicate that CUR-DOX/c RGD-M will be biodegradable and sustainable, which may have potential clinical application value in the treatment of lung cancer.

关键词： Doxorubicin Curcumin Lung cancer Nanomicelle Co-delivery

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Local delivery of superagonist gene based on polymer nanoparticles for cancer immunotherapy

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Chinese Chemical Letters 2023年第3期34卷 356-360页

作者： Zehua Hong Xin Zan Ting Yu yuzhu hu Hongfeng Gou Songping Zheng Xiang Gao Peizhi Zhou Department of Neurosurgery and Institute of Neurosurgery State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan UniversityChengdu 610041China

Cancer is the leading cause that threatens human life expectancy due to the lack of effective *** immunotherapy has been explored to improve the body's immune system against cancer and accompanied by promising results in recent *** 15(IL-15),a pleiotropic immunomodulator,is critical for immune cells development and displays great anti-tumor potential in both preclinical and clinical *** this study,superagonist IL-15 plasmid(psIL-15)consisting of IL-15Rα-sushi-linker-IL-15 was constructed in order to secret superagonist IL-15(sIL-15)in tumor site.A gene delivery system through self-assembly by methylated polyethylene glycol-b-polylactic acid-b-methylated polyethylene glycol(m PEG-PLA-m PEG)and 1,2-dioleoyl-3-trimethylammonium-propane(DOTAP),named DMAM,was designed to deliver *** study showed that DMAM/psIL-15 could successfully deliver psIL-15 to tumor cells and the supernatants of the tumor cells could further stimulate lymphocytes proliferation as well as activation in *** delivery of DMAM/psIL-15 in animal models demonstrated significant tumor inhibition through enhancing immune cells responses,reducing angiogenesis,promoting tumor cell apoptosis and inhibiting proliferation,with no evidence of system *** results indicate that DMAM/psIL-15 may be a promising strategy for cancer immunotherapy.

关键词： IL-15 Immunotherapy Gene therapy Nanoparticles Tumor

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pIL-12 delivered by polymer based nanovector for anti-tumor genetherapy

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Chinese Chemical Letters 2023年第11期34卷 209-213页

作者： Lianbin Wen Xin Zan Qidi Pang yuzhu hu Songping Zheng Mengni Ran Xiang Gao Xiang Wang Bilan Wang Department of Geriatrics Sichuan Academy of Medical Sciences&Sichuan Provincial People’s HospitalChengdu 610072China Department of Neurosurgery West China HospitalSichuan UniversityChengdu 610041China Department of Infection Management Hospital of Chengdu University of Traditional Chinese MedicineChengdu 610072China Department of Radiation Oncology Cancer CenterWest China HospitalWest China Medical SchoolSichuan UniversityChengdu 610041China Department of Pharmacy West China Second University Hospital of Sichuan UniversityChengdu 610041China Pharmaceutical Department Chongqing University Three Gorges HospitalChongqing 404000China

Finding more effective and safe non-viral vectors to transfer genes into cancer cells has become the key of immune gene therapy for *** a triblock compound MPEG_(2000)-PDLLA_(4000)-MPEG_(2000) modified by cationic liposome DOTAP was used as a non-viral vector DOTAP/MPEG_(2000)-PDLLA_(4000)-MPEG_(2000)(DMPM)to effectively transfer interleukin(IL)-12 plasmid(pIL-12)into tumor ***-12 produced by transfected tumor cells successfully inducing lymphocyte proliferation and promoting interferon-γ(IFN-γ)secretion,which resulted in tumor cells *** ability of DMPM to transfer pIL-12 and the immune effect induced by IL-12 in cells had been *** anti-tumor effect,mechanism and safety of pIL-12/DMPM in mice cancer model were investigated in this *** results showed that the pIL-12 transferred by DMPM was highly expressed both in CT26 cells and B16-F10 ***-12 expressed in the culture supernatant of transfected tumor cells stimulated lymphocyte proliferation and promoted IFN-γ*** experimental result confirmed that pIL-12/DMPM therapy significantly reduced tumor growth in mice *** designed the nanocomposite DMPM to deliver pIL-12 for cancer treatment and explored its therapeutic efficacy and the underlying anti-tumor *** study suggested pIL-12 loaded by DMPM complex would be an effective strategy for cancer treatment.

关键词： Non-viral vector Cancer gene therapy pIL-12 Immune response Nanocomposite

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On the Strategies for Improving Students’English Speaking Competence in Nine-Year System Schools of China

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基础教育外语教学研究 2018年第6期 45-49页

作者： hu yuzhu Anhui Bengbu No.1 Experimental School Bengbu Anhui 233000China

For years,the aims of teaching English in China have been as changeable and diverse as the needs and interests of pupils or *** the most important aim for English learners as a foreign language is generally considered that learners are expecting to speak English as naturally as they can in real ***,based on students problems of speaking English in nine-year schools of China,this paper tries to find and explore three strategies of improving their speaking competence,which includes collective speaking,group work learning and real-life language teaching with the specific teaching activities for different levels students.

关键词： English speaking teaching speaking competence teaching activities

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Phase-mediated cobalt phosphide with unique core-shell architecture serving as efficient and bifunctional electrocatalyst for hydrogen evolution and oxygen reduction reaction

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Chinese Chemical Letters 2022年第8期33卷 3752-3756页

作者： Junsheng Chen Jianfeng huang Hai Wang Weihang Feng Tianmi Luo yuzhu hu Chengke Yuan Liyun Cao Yanni Jie Koji Kajiyoshi Yongqiang Feng School of Material Science and Engineering International S&T Cooperation Foundation of Shaanxi ProvinceXi'an Key Laboratory of Green Manufacture of Ceramic MaterialsShaanxi University of Science and TechnologyXi'an 710021China Kochi University Research Laboratory of Hydrothermal ChemistryKochi 780-8520Japan

Hydrogen evolution reaction(HER)and oxygen reduction reaction(ORR)have been considered as two critical processes in the field of electrocatalytic water-splitting for hydrogen production and fuel ***,the sluggish reaction kinetics of HER and ORR required efficient electrocatalyst such as Pt to promote such *** metal phosphides(TMPs)exhibit great potential to replace noble metal electrocatalysts to accelerate HER and ORR due to their high activity and easy ***,a highly-efficient bifunctional CoP electrocatalyst for HER and ORR,featuring a unique core-shell structure decorated on nitrogen-doped carbon matrix was designed and constructed via etching a cobalt-based zeolitic imidazolate framework(ZIF-67)with phytic acid(PA)followed by pyrolysis treatment(PA-ZIF-67-900).Experimental results revealed that the pure-phase single-crystalline Co P exhibited outstanding electrocatalytic performance in HER and ORR,superior to Co(PO_(3))_(2) in PA-ZIF-67-700,hybrid phase of Co(PO_(3))_(2) and CoP in PA-ZIF-67-800 and Co_(2)P-doped CoP in *** reach the current density of 10 mA/cm^(2)the as-synthesized Co P required an overpotential of 120 m V for HER in 1 mol/L KOH and half-wave potential of 0.85 V in O_(2)-saturated 0.1 mol/L *** work present new clue for construction of efficient and bifunctional electrocatalyst in the field of energy conversion and storage.

关键词： Electrocatalyst Hydrogen evolution reaction Oxygen reduction reaction Transitional metal phosphide CoP

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基于深度教学理念在眼战伤早期急救护理教学中的应用研究

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中华医学教育探索杂志 2024年第4期23卷 517-521页

作者：何季芳李姣姣钟玥袁财莉胡裕竹喻娟刘姣陆军特色医学中心眼科重庆400042

目的探讨深度教学理念引导下的眼战伤早期急救护理教学应用效果。方法64名参加眼战伤早期急救护理培训的眼科护士被分为两组,对照组26人,观察组38人。对照组理论部分采用清单式自主学习,操作技能采用传统示教法;观察组基于深度教学的理... 详细信息

目的探讨深度教学理念引导下的眼战伤早期急救护理教学应用效果。方法64名参加眼战伤早期急救护理培训的眼科护士被分为两组,对照组26人,观察组38人。对照组理论部分采用清单式自主学习,操作技能采用传统示教法;观察组基于深度教学的理念,从促进理解、启发反思、沉浸式体验3个维度进行教学设计并实施理论和实践教学。对比分析两组护士一般资料和实施前、后理论成绩,操作成绩及护士核心能力得分情况。采用SPSS 22.0进行t检验和卡方检验。结果两组护士在年龄、眼科工作年限、学历、职称等一般资料上差异无统计学意义。实施前两组护士理论成绩、操作成绩和护士核心能力得分比较差异均无统计学意义;实施后观察组护士理论成绩[(90.13±5.87)vs.(81.73±4.68),P<0.001],两项操作成绩[(95.63±2.81)vs.(87.31±4.51),P<0.001];[(96.24±2.74)vs.(89.08±4.50),P<0.001]均优于对照组;观察组护士核心能力量表的评判性思维得分[(34.00±1.93)vs.(30.58±3.01),P<0.001]和临床护理能力得分[(32.13±1.65)vs.(28.35±2.28),P<0.001]优于对照组。结论基于深度教学理念的教学模式有助于提升眼科护士关于眼战伤早期急救的相关知识、急救技能、临床反思及护理能力,利于提高军队临床护士的思想觉悟和练兵备战意识。

关键词：深度教学眼战伤早期急救沉浸式体验理解反思眼科护士

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Facile synthesis of defect-rich Fe-N-C hybrid from fullerene/ferrotetraphenylporphyrin as efficient oxygen reduction electrocatalyst for Zn-air battery

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Chinese Chemical Letters 2023年第5期34卷 616-620页

作者： Hai Wang Liyun Cao Yongqiang Feng Junsheng Chen Weihang Feng Tianmi Luo yuzhu hu Chengke Yuan Yajuan Zhao Yong Zhao Koji Kajiyoshi Yijun Liu Zhenjiang Li Jianfeng huang School of Material Science and Engineering International S&T Cooperation Foundation of Shaanxi ProvinceShaanxi University of Science and TechnologyXi'an 710021China Kochi University Research Laboratory of Hydrothermal ChemistryKochi 780-8520Japan Guangdong Mona Lisa Group Co. Ltd.Foshan 528211China College of Materials Science and Engineering Qingdao University of Science and TechnologyQingdao 266042China

Exploring remarkable oxygen reduction reaction(ORR)electrocatalysts for regenerative fuel cells and metal-air batteries is highly ***,a novel non-noble metal-based heterogeneous electrocatalyst with rich defects were successfully synthesized by liquid-liquid interfacial precipitation(LLIP)of fullerene(C_(60))and ferrotetraphenylporphyrin(FeTPP)followed by one step *** obtained product annealed at 700℃(C_(60)/FeTPP-700),when employed as ORR electrocatalyst,revealed a positive halfwave potential(E_(1/2))of 0.877 V *** hydrogen electrode(RHE),which was superior to that of the commercial 25%Pt/***,the assembled Zn-air battery(ZAB)using C_(60)/FeTPP-700 as an air-electrode catalyst exhibited a high power density of 153 m W/cm^(2),specific capacity of 668 mAh/g and long-term cycling stability for more than 250 *** results proved that the excellent electrocatalytic ORR activity of C_(60)/FeTPP-700 would attribute to the synergistic effect between FeN_xsites,Fe_(3)C/Fe nanoparticles and the structure *** work provides a feasible and simple method to prepare nonnoble metal-based ORR electrocatalysts for the application of energy storage and conversion.

关键词： Oxygen reduction reaction Electrocatalyst Fullerene Defect Zn-air battery

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