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Signal Transduction and Targeted Therapy 2021年第9期6卷 2870-2882页

作者： Ruoxi Xie Zijun Wu Fanxin Zeng Huawei Cai Dan Wang Lei Gu Hongyan Zhu Su Lui Gang Guo Bin Song Jinxing Li Min Wu Qiyong Gong Huaxi MR Research center(HMRRC) Department of RadiologyFunctional and Molecular Imaging Key Laboratory of Sichuan ProvinceWest China HospitalSichuan UniversityChengduChina Research Unit of Psychoradiology Chinese Academy of Medical SciencesChengduChina department of Clinic Medical center Dazhou Central HospitalDazhouChina Laboratory of clinical Nuclear Medicine Department of Nuclear MedicineWest China HospitalSichuan UniversityChengduChina State Key Laboratory of biotherapy and Cancer center West China HospitalSichuan Universityand Collaborative Innovation Center for BiotherapyChengduChina department of Chemical Engineering Stanford UniversityStanfordCaliforniaUSA

Glioblastoma(GBM),one of the most common primary intracranial malignant tumours,is very difficult to be completely excised by surgery due to its irregular ***,we use an MRI/NIR fluorescence dual-modal imaging nanoprobe that includes superparamagnetic iron oxide nanoparticles(SPIONs)modified with indocyanine(Cy7)molecules and peptides(ANG orDANG)to locate malignant gliomas and guide accurate *** peptides/Cy7-SPIONs probes displayed excellent tumour-homing properties and barrier penetrating abilities in vitro.

关键词： tumour malignant surgery

Simultaneous enhancement of cellular and humoral immunity by the lymph node-targeted cholesterolized TLR7 agonist liposomes

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Acta Pharmaceutica Sinica B 2024年第10期14卷 4577-4590页

作者： Dandan Wan Ziyi Bai Yu Zhang Li Chen Haiying Que Tianxia Lan Weiqi Hong Jiayu Huang Cai He Yuquan Wei Qiang Pu Xiawei Wei Laboratory of Aging Research and Cancer Drug Target State Key Laboratory of Biotherapy and Cancer CenterNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengdu 610041China department of Thoracic Surgery National Frontier Center of Disease Molecular NetworkWest China HospitalSichuan UniversityChengdu 610041China

Toll-like receptor(TLR)agonists,as promising adjuvants and immunotherapeutic agents,have the potential to enhance immune responses and modulate antigen-dependent T-cell immune memory through activation of distinct signaling ***,their clinical application is hindered by uncontrolled systemic inflammatory ***,it is imperative to create a vaccine adjuvant for TLR receptors that ensures both safety and *** this study,we designed lymph node-targeted cholesterolized TLR7 agonist cationic liposomes(1V209-Cho-Lip^(+))to mitigate undesired side ***-delivery of the model antigen OVA and cholesterolized TLR7 agonist facilitated DC maturation through TLR activation while ensuring optimal presentation of the antigen to CD8^(+)T *** main aim of the present study is to evaluate the adjuvant effectiveness of 1V209-Cho-Lip^(+)in tumor *** immunization with 1V209-Cho-Lip^(+)+OVA,we observed a pronounced"depot effect"and enhanced trafficking to secondary lymphoid *** vaccination with 1V209-Cho-Lip^(+)^(+)OVA significantly delays tumor development,prolongs mouse survival,and establishes durable immunity against tumor ***,1V209-Cho-Lip^(+)+OVA,while used therapeutic tumor vaccine,has demonstrated its efficacy in inhibiting tumor progression,and when combined with anti-PD-1,it further enhances antitumor ***,the co-delivery of antigen and lymph node-targeted cholesterolized TLR7 agonist shows great promise as a cancer vaccine.

关键词： TLR7 agonist Cationic liposomes Lymph node Cancer nanovaccines Immunotherapy Cross-presentation Cellular immunity Humoral immunity

HDAC I/IIb selective inhibitor Purinostat Mesylate combined with GLS1 inhibition effectively eliminates CML stem cells

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Bioactive Materials 2023年第3期21卷 483-498页

作者： Qiang Qiu Linyu yang Yunyu Feng Zejiang Zhu Ning Li Li Zheng Yuanyuan Sun Cong Pan Huandi Qiu Xue Cui Wei He Fang Wang Yuyao Yi Minghai Tang Zhuang Yang Yunfan Yang Zhihui Li Lijuan Chen Yiguo Hu State Key Laboratory of biotherapy and Cancer center West China HospitalSichuan Universityand Collaborative Innovation Center for BiotherapyChengduPR China Thyroid and Parathyroid Surgery center State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduPR China department of Hematology and Research Laboratory of Hematology West China HospitalSichuan UniversityChengduPR China center of Infectious Diseases West China HospitalSichuan UniversityChengduPR China Guizhou Normal College GuiyangPR China

Purinostat Mesylate(PM)is a novel highly selective and active HDAC I/IIb inhibitor,and the injectable formulation of PM(PMF)based on the compound prescription containing cyclodextrin completely can overcome PM’s poor solubility and improves its stability and pharmacokinetic ***,we showed that PM effectively repressed the survival of Ph+leukemia cells and CD34+leukemia cells from CML patients in *** vivo studies demonstrated that PMF significantly prevented BCR-ABL(T315I)induced CML progression by restraining leukemia stem cells(LSCs),which are insensitive to chemotherapy and responsible for CML *** studies revealed that targeting HDAC I/IIb repressed several important factors for LSCs survival including c-Myc,β-Catenin,E2f,Ezh2,Alox5,and mTOR,as well as interrupted some critical biologic ***,PMF increased glutamate metabolism in LSCs by increasing *** combination of PMF and glutaminase inhibitor BPTES synergistically eradicated LSCs by altering multiple key proteins and signaling pathways which are critical for LSC survival and ***,our findings represent a new therapeutic strategy for eliminating LSCs by targeting HDAC I/IIb and glutaminolysis,which potentially provides a guidance for PMF clinical trials in the future for TKI resistance CML patients.

关键词： Chronic myelogenous leukemia Leukemia stem cell Selective HDAC I/IIb inhibitor GLS1 Mouse model

A tumor cell membrane-coated self-amplified nanosystem as a nanovaccine to boost the therapeutic effect of anti-PD-L1 antibody

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Bioactive Materials 2023年第3期21卷 299-312页

作者： Zhilin Li Hao Cai Zhiqian Li Long Ren Xuelei Ma Hongyan Zhu Qiyong Gong Hu Zhang Zhongwei Gu Kui Luo Laboratory of Stem Cell Biology Department of RadiologyHuaxi MR Research Centner(HMRRC)Department of BiotherapyCancer CenterNational Clinical Research Center for GeriatricsFrontiers Science Center for Disease-related Molecular NetworkState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu610041China Amgen Bioprocessing Centre Keck Graduate InstituteClaremontCA91711USA Functional and Molecular Imaging Key Laboratory of Sichuan Province And Research Unit of PsychoradiologyChinese Academy of Medical SciencesChengdu610041China

To improve the response rate of immune checkpoint inhibitors such as anti-PD-L1 antibody in immunosup-pressive cancers like triple-negative breast cancer(TNBC),induction of immunogenic cell death(ICD)at tumor sites can increase the antigenicity and adjuvanticity to activate the immune microenvironment so that tumors become sensitive to the intervention of immune checkpoint ***,a self-amplified biomimetic nanosystem,mEHGZ,was constructed by encapsulation of epirubicin(EPI),glucose oxidase(Gox)and hemin in ZIF-8 nanoparticles and coating of the nanoparticles with calreticulin(CRT)over-expressed tumor cell *** acts as an ICD inducer,Gox and hemin medicate the cascade generation of reactive oxygen species(ROS)to strengthen the ICD effect,and CRT-rich membrane as“eat me”signal promote presentation of the released antigens by dendritic cells(DCs)to invoke the tumor-immunity *** biomimetic delivery system displays an amplified ICD effect via Gox oxidation,hydroxyl radical generation and glutathione(GSH)*** induced potent ICD effect promotes DCs maturation and cytotoxic T lymphocytes(CTLs)infiltration,reversing an immunosuppressive tumor microenvironment to an immunoresponsive *** with the nanosystem in combination with anti-PD-L1 antibody results in distinctive inhibition of tumor growth and lung metastasis,supporting that a potent ICD effect can significantly boost the therapeutic efficacy of the anti-PD-L1 *** self-amplified biomimetic nanoplatform offers a promising means of raising the response rate of immune checkpoint inhibitors.

关键词： Cell membrane Biomimetic nanosystem Immunogenic cell death Immunotherapy anti-PD-L1 antibody

Tumor biomarkers for diagnosis,prognosis and targeted therapy

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Signal Transduction and Targeted Therapy 2024年第6期9卷 2391-2476页

作者： Yue Zhou Lei Tao Jiahao Qiu Jing Xu Xinyu Yang Yu Zhang Xinyu Tian Xinqi Guan Xiaobo Cen Yinglan Zhao department of biotherapy Cancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China West China School of Pharmacy Sichuan UniversityChengdu 610041China School of Medicine Tibet UniversityLhasa 850000China National Chengdu center for Safety Evaluation of Drugs State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China

Tumor biomarkers,the substances which are produced by tumors or the body’s responses to tumors during tumorigenesis and progression,have been demonstrated to possess critical and encouraging value in screening and early diagnosis,prognosis prediction,recurrence detection,and therapeutic efficacy monitoring of *** the past decades,continuous progress has been made in exploring and discovering novel,sensitive,specific,and accurate tumor biomarkers,which has significantly promoted personalized medicine and improved the outcomes of cancer patients,especially advances in molecular biology technologies developed for the detection of tumor ***,we summarize the discovery and development of tumor biomarkers,including the history of tumor biomarkers,the conventional and innovative technologies used for biomarker discovery and detection,the classification of tumor biomarkers based on tissue origins,and the application of tumor biomarkers in clinical cancer *** particular,we highlight the recent advancements in biomarker-based anticancer-targeted therapies which are emerging as breakthroughs and promising cancer therapeutic *** also discuss limitations and challenges that need to be addressed and provide insights and perspectives to turn challenges into opportunities in this ***,the discovery and application of multiple tumor biomarkers emphasized in this review may provide guidance on improved precision medicine,broaden horizons in future research directions,and expedite the clinical classification of cancer patients according to their molecular biomarkers rather than organs of origin.

关键词： diagnosis breakthrough biomarkers

A folic acid-decorated nanoparticles loaded JQ1 for oral squamous cell carcinoma therapy

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Chinese Chemical Letters 2024年第3期35卷 332-336页

作者： Dequan Zeng Zhongkai Ma Xin Zan Ting Luo Xiang Wang Xiang Gao Xianghui Fu School of Health Management Xihua UniversityChengdu 610039China State Key Laboratory of Oral Diseases National Clinical Research Center for Oral DiseasesWest China College of StomatologySichuan 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 Breast Disease center Cancer CenterWest China HospitalSichuan UniversityChengdu 610041China

Oral squamous cell carcinoma(OSCC)is known as one of the most malignant tumors with high recurrence and fatality *** poor tumor-targeting ability of traditional chemotherapeutic drugs has been a grand challenge for anti-OSCC *** that,a large quantity of tumor associated macrophages in OSCC tissues further diminish the anti-tumor effects of these ***,we produced a therapeutic nano drug delivery system(FA-PEG-PLA-JQ1)through encapsulating JQ1[a small-molecule inhibitor of bromodomain containing protein 4(BRD4)]into the folic acid(FA)-modified nanoparticle(PEG-PLA),which could prolong the half-life of JQ1 and target the tumor *** then,JQ1 released from this nanoparticle could prevent OSCC growth inducing tumor cell apoptosis,inhibiting tumor angiogenesis and the polarization of M2 type *** conclusion,our date demonstrated the therapeutic benefits of FA-PEG-PLA-JQ1 against OSCC in vivo or in vitro,which could be a novel treatment strategy for OSCC in coming days.

关键词： Folic acid Nanoparticles JQ1 Oral squamous cell carcinoma Macrophages

Beyond ribosomal function:RPS6 deficiency suppresses cholangiocarcinoma cell growth by disrupting alternative splicing

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Acta Pharmaceutica Sinica B 2024年第9期14卷 3931-3948页

作者： Wenkang Fu Yanyan Lin Mingzhen Bai Jia Yao Chongfei Huang Long Gao Ningning Mi Haidong Ma Liang Tian Ping Yue Yong Zhang Jinduo zhang Yanxian Ren Liyun Ding Lunzhi Dai Joseph WLeung Jinqiu Yuan Wenhua Zhang Wenbo Meng The First School of clinical Medicne Lanzhou UniversityLanzhou 730030China department of General Surgery the First Hospital of Lanzhou UniversityLanzhou 730030China Key Laboratory of biotherapy and Regenerative Medicine of Gansu Province the First Hospital of Lanzhou UniversityLanzhou 730000China School of Physical Science and Technology Lanzhou UniversityLanzhou 730000China National clinical Research center for Geriatrics and department of General Practice State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China Division of Gastroenterology UC Davis Medical Center and Sacramento VA Medical CenterSacramentoCA 95817USA clinical Research center Big Data Centerthe Seventh Affiliated HospitalSun Yat-sen UniversityShenzhen 518107China School of Life Sciences Lanzhou UniversityLanzhou 730000China

Cholangiocarcinoma(CCA)is a bile duct malignancy with a dismal *** study systematically investigated the role of the ribosomal protein S6(RPS6)gene,which is dependent in *** found that RPS6 upregulation in CCA tissues was correlated with a poor *** investigations have shown that alterations in RPS6 expression,both gain-and loss-of function could affect the proliferation of CCA *** xenograft tumor models,RPS6 overexpression enhances tumorigenicity,whereas RPS6 silencing reduces *** analysis using RNA-seq and proteomics elucidated downstream signaling pathways of RPS6 depletion by affecting the cell cycle,especially DNA *** followed by mass spectrometry has identified numerous spliceosome complex proteins associated with *** profiling revealed that RPS6 affects numerous alternative splicing(AS)events,and combined with RNA immunoprecipitation sequencing,revealed that minichromosome maintenance complex component 7(MCM7)binds to RPS6,which regulates its AS and increases oncogenic activity in *** RPS6 with vivo phosphorodiamidate morpholino oligomer(V-PMO)significantly inhibited the growth of CCA cells,patient-derived organoids,and subcutaneous xenograft *** together,the data demonstrate that RPS6 is an oncogenic regulator in CCA and that RPS6-V-PMO could be repositioned as a promising strategy for treating CCA.

关键词： Cholangiocarcinoma Ribosomal protein S6 Alternative splicing p53 Minichromosome maintenance complex component 7 Vivo morpholino Patient-derived organoids

CRISPR/Cas9-mediated correction of human genetic disease

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Science China(Life Sciences) 2017年第5期60卷 447-457页

作者： Ke Men Xingmei Duan Zhiyao He Yang Yang Shaohua Yao Yuquan Wei State Key Laboratory of biotherapy and Cancer center/Collaborative Innovation center for biotherapy West China Hospital Sichuan University Chengdu 610041 China Individualized Medication Key Laboratory of Sichuan Province Department of Pharmacy Hospital of the University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital Sichuan Translational Medicine Hospital Chengdu 610072 China department of Pharmacy State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu 610041 China

The clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated(Cas) protein 9 system(CRISPR/Cas9) provides a powerful tool for targeted genetic editing. Directed by programmable sequence-specific RNAs,this system introduces cleavage and double-stranded breaks at target sites precisely. Compared to previously developed targeted nucleases, the CRISPR/Cas9 system demonstrates several promising advantages, including simplicity, high specificity,and efficiency. Several broad genome-editing studies with the CRISPR/Cas9 system in different species in vivo and ex vivo have indicated its strong potential, raising hopes for therapeutic genome editing in clinical settings. Taking advantage of non-homologous end-joining(NHEJ) and homology directed repair(HDR)-mediated DNA repair, several studies have recently reported the use of CRISPR/Cas9 to successfully correct disease-causing alleles ranging from single base mutations to large insertions. In this review, we summarize and discuss recent preclinical studies involving the CRISPR/Cas9-mediated correction of human genetic diseases.

关键词： CRISPR/Cas9 genome editing genetic disease gene therapy

Symptomatic Radiation Pneumonitis in NSCLC Patients Receiving EGFR-TKIs and Concurrent Oncedaily Thoracic Radiotherapy:Predicting the Value of clinical and Dose-volume Histogram Parameters

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中国肺癌杂志 2022年第6期25卷 409-419页

作者： Xuexi YANG Ting MEI Min YU Youling GONG department of Thoracic Oncology and State Key Laboratory of biotherapy Cancer CenterWest China HospitalSichuan UniversityChengdu 610041China

Background and objectives:The incidence of symptomatic radiation pneumonitis(RP)and its relationship with dose-volume histogram(DVH)parameters in non-small cell lung cancer(NSCLC)patients receiving epidermal growth factor receptortyrosine kinase inhibitors(EGFR-TKIs)and concurrent once-daily thoracic radiotherapy(TRT)remain *** aim to analyze the values of clinical factors and dose-volume histogram(DVH)parameters to predict the risk for symptomatic RP in these ***:Between 2011 and 2019,we retrospectively analyzed and identified 85 patients who had received EGFR-TKIs and oncedaily TRT simultaneously(EGFR-TKIs group)and 129 patients who had received concurrent chemoradiotherapy(CCRT group).The symptomatic RP was recorded according to the Common Terminology Criteria for Adverse Event(CTCAE)criteria(grade 2 or above).Statistical analyses were performed using SPSS ***:In total,the incidences of symptomatic(grade≥2)and severe RP(grade≥3)were 43.5%(37/85)and 16.5%(14/85)in EGFR-TKIs group vs 27.1%(35/129)and 10.1%(13/129)in CCRT group *** 1:1 ratio between EGFR-TKIs group and CCRT group was matched by propensity score matching,chi-square test suggested that the incidence of symptomatic RP in the MATCHED EGFR-TKIs group was higher than that in the matched CCRT group(χ^(2)=4.469,P=0.035).In EGFRTKIs group,univariate and multivariate analyses indicated that the percentage of ipsilateral lung volume receiving≥30 Gy(ilV_(30))[odds ratio(OR):1.163,95%CI:1.036-1.306,P=0.011]and the percentage of total lung volume receiving≥20 Gy(tlV_(20))(OR:1.171,95%CI:1.031-1.330,P=0.015),with chronic obstructive pulmonary disease(COPD)or not(OR:0.158,95%CI:0.041-0.600,P=0.007),were independent predictors of symptomatic *** to patients with lower iIV_(30)/tlV_(20)values(ilV_(30)and tlV_(20)cut-off point values)and COPD had a significantly h

关键词： Lung neoplasms EGFR-TKIs Radiation pneumonitis Risk factor Dose-volume histogram parameters

Nucleic acids and analogs for bone regeneration

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Bone Research 2018年第4期6卷 331-339页

作者： Yuxin Zhang Wenjuan Ma Yuxi Zhan Chenchen Mao Xiaoru Shao Xueping Xie Xiawei Wei Yunfeng Lin State Key Laboratory of Oral Diseases National Clinical Research Center for Oral Diseases Department of Oral Surgery West China Hospital of Stomatology Sichuan University Lab of Aging Research and Nanotoxicology State Key Laboratory of Biotherapy West China Hospital Sichuan University

With the incidence of different bone diseases increasing, effective therapies are needed that coordinate a combination of various technologies and biological materials. Bone tissue engineering has also been considered as a promising strategy to repair various bone defects. Therefore, different biological materials that can promote stem cell proliferation, migration, and osteoblastic differentiation to accelerate bone tissue regeneration and repair have also become the focus of research in multiple fields. Stem cell therapy, biomaterial scaffolds, and biological growth factors have shown potential for bone tissue engineering; however, off-target effects and cytotoxicity have limited their clinical use. The application of nucleic acids(deoxyribonucleic acid or ribonucleic acid)and nucleic acid analogs(peptide nucleic acids or locked nucleic acids), which are designed based on foreign genes or with special structures, can be taken up by target cells to exert different effects such as modulating protein expression, replacing a missing gene, or targeting specific gens or proteins. Due to some drawbacks, nucleic acids and nucleic acid analogs are combined with various delivery systems to exert enhanced effects, but current studies of these molecules have not yet satisfied clinical requirements. In-depth studies of nucleic acid or nucleic acid analog delivery systems have been performed, with a particular focus on bone tissue regeneration and repair. In this review, we mainly introduce delivery systems for nucleic acids and nucleic acid analogs and their applications in bone repair and regeneration. At the same time, the application of conventional scaffold materials for the delivery of nucleic acids and nucleic acid analogs is also discussed.

关键词： Nucleic regeneration defects