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Ultrasound-responsive spherical nucleic acid against c-Myc/PD-L1 to enhance anti-tumoral macrophages in triple-negative breast cancer progression

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Science China(life Sciences) 2024年第4期67卷 698-710页

作者： Runtian Wang Gaigai li Fangyan Gao Feng Xu xintong li Jian Zhang Jinbo li Xiaoxiang Guan Department of Oncology The First Affiliated Hospital of Nanjing Medical UniversityNanjing 210029China State Key Laboratory of Analytical Chemistry for life Sciences Jiangsu Key Laboratory of Advanced Organic MaterialsSchool of Chemistry and Chemical EngineeringChemistry and Biomedicine Innovation Center(ChemBIC)Nanjing UniversityNanjing 210023China Department of Medical Oncology Fudan University Shanghai Cancer CenterDepartment of OncologyShanghai Medical CollegeFudan UniversityShanghai 200032China Jiangsu Key Lab of Cancer Biomarkers Prevention and TreatmentCollaborative Innovation Center for Cancer Personalized MedicineNanjing Medical UniversityNanjing 211166China

Triple-negative breast cancer(TNBC)is the most challenging breast cancer subtype because of its aggressive behavior and limited therapeutic targets.c-Myc is hyperactivated in the majority of TNBC tissues,however,it has been considered an“undruggable”target due to its disordered structure.Herein,we developed an ultrasound-responsive spherical nucleic acid(SNA)against c-Myc and PD-L1 in TNBC.It is a self-assembled and carrier-free system composed of a hydrophilic small-interfering RNA(si RNA)shell and a hydrophobic core made of a peptide nucleic acid(PNA)-based antisense oligonucleotide(ASO)and a sonosensitizer.We accomplished significant enrichment in the tumor by enhanced permeability and retention(EPR)effect,the controllable release of effective elements by ultrasound activation,and the combination of targeted therapy,immunotherapy and physiotherapy.Our study demonstrated significant anti-tumoral effects in vitro and in vivo.Mass cytometry showed an invigorated tumor microenvironment(TME)characterized by a significant alteration in the composition of tumor-associated macrophages(TAM)and decreased proportion of PD-1-positive(PD-1+)T effector cells after appropriate treatment of the ultrasound-responsive SNA(USNA).Further experiments verified that tumor-conditioned macrophages residing in the TME were transformed into the anti-tumoral population.Our finding offers a novel therapeutic strategy against the“undruggable”c-Myc,develops a new targeted therapy for c-Myc/PD-L1 and provides a treatment option for the TNBC.

关键词： triple-negative breast cancer c-Myc spherical nucleic acid self-assembly

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Estrogen receptor beta suppresses the androgen receptor oncogenic effects in triple-negative breast cancer

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Chinese Medical Journal 2024年第3期137卷 338-349页

作者： Feng Xu Kun Xu lingling Fan xintong li Yiqiu liu Fang Yang Chengjun Zhu Xiaoxiang Guan Department of Oncology The First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu 210029China Department of Oncology Jiangsu Cancer HospitalThe Affiliated Cancer Hospital of Nanjing Medical UniversityJiangsu Institute of Cancer ResearchNanjingJiangsu 210009China The Comprehensive Cancer Center of Nanjing Drum Tower Hospital Affiliated Hospital of Medical SchoolNanjing UniversityNanjingJiangsu 210008China Jiangsu Key Lab of Cancer Biomarkers Prevention and TreatmentCollaborative Innovation Center for Personalized Cancer MedicineNanjing Medical UniversityNanjingJiangsu 211166China

Background:Triple-negative breast cancer(TNBC)is an aggressive type of breast cancer associated with poor prognosis and limited treatment options.The androgen receptor(AR)has emerged as a potential therapeutic target for luminal androgen receptor(LAR)TNBC.However,multiple studies have claimed that anti-androgen therapy for AR-positive TNBC only has limited clinical benefits.This study aimed to investigate the role of AR in TNBC and its detailed mechanism.Methods:Immunohistochemistry and TNBC tissue sections were applied to investigate AR and nectin cell adhesion molecule 4(NECTIN4)expression in TNBC tissues.Then,in vitro and in vivo assays were used to explore the function of AR and estrogen receptor beta(ERβ)in TNBC.Chromatin immunoprecipitation sequencing(ChIP-seq),co-immunoprecipitation(co-IP),molecular docking method,and luciferase reporter assay were performed to identify key molecules that affect the function of AR.Results:Based on the TNBC tissue array analysis,we revealed that ERβand AR were positive in 21.92%(32/146)and 24.66%(36/146)of 146 TNBC samples,respectively,and about 13.70%(20/146)of TNBC patients were ERβpositive and AR positive.We further demonstrated the pro-tumoral effects of AR on TNBC cells,however,the oncogenic biology was significantly suppressed when ERβtransfection in LAR TNBC cell lines but not in AR-negative TNBC.Mechanistically,we identified that NECTIN4 promoter–42 bp to–28 bp was an AR response element,and that ERβinteracted with AR thus impeding the AR-mediated NECTIN4 transcription which promoted epithelial–mesenchymal transition in tumor progression.Conclusions:This study suggests that ERβfunctions as a suppressor mediating the effect of AR in TNBC prognosis and cell proliferation.Therefore,our current research facilitates a better understanding of the role and mechanisms of AR in TNBC carcinogenesis.

关键词： Androgen receptor Estrogen receptor beta Triple-negative breast cancer NECTIN4 Oncogenic effects Tumor progression

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Characterization and prediction of tailpipe ammonia emissions from in-use China 5/6 light-duty gasoline vehicles

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Frontiers of Environmental Science & Engineering 2024年第1期18卷 71-81页

作者： Lewei Zeng Fengbin Wang Shupei Xiao Xuan Zheng xintong li Qiyuan Xie Xiaoyang Yu Cheng Huang Qingyao Hu Yan You Ye Wu College of Chemistry and Environmental Engineering Shenzhen UniversityShenzhen 518060China State Key Laboratory of Engines Tianjin UniversityTianjin 300072China China Automotive Technology and Research Center Co.Ltd. Tianjin 300300China CATARC Automotive Test Center(Guangzhou)Co.Ltd. Guangzhou 511300China State Environmental Protection Key Laboratory of Cause and Prevention of Urban Air Pollution Complex Shanghai Academy of Environmental SciencesShanghai 200233China National Observation and Research Station of Coastal Ecological Environments in Macao Macao Environmental Research InstituteMacao University of Science and TechnologyMacao SAR 999078China School of Environment State Key Joint Laboratory of Environment Simulation and Pollution ControlTsinghua UniversityBeijing 100084China

On-road tailpipe ammonia (NH3) emissions contribute to urban secondary organic aerosol formation and have direct or indirect adverse impacts on the environment and human health. To understand the tailpipe NH3 emission characteristics, we performed comprehensive chassis dynamometer measurements of NH3 emission from two China 5 and two China 6 light-duty gasoline vehicles (LDGVs) equipped with three-way catalytic converters (TWCs). The results showed that the distance-based emission factors (EFs) were 12.72 ± 2.68 and 3.18 ± 1.37 mg/km for China 5 and China 6 LDGVs, respectively. Upgrades in emission standards were associated with a reduction in tailpipe NH3 emission. In addition, high NH3 EFs were observed during the engine warm-up period in cold-start cases owing to the intensive emissions of incomplete combustion products and suitable catalytic temperature in the TWCs. Notably, based on the instantaneous NH3 emission rate, distinct NH3–emitting events were detected under high/extra high velocity or rapid acceleration. Furthermore, NH3 emission rates correlated well with engine speed, vehicle specific power, and modified combustion efficiency, which were more easily accessible. These strong correlations were applied to reproduce NH3 emissions from China 5/6 LDGVs. The predicted NH3 EFs under different dynamometer and real-world cycles agreed well with existing measurement and prediction results, revealing that the NH3 EFs of LDGVs in urban routes were within 8.55–11.62 mg/km. The results presented here substantially contribute to improving the NH3 emission inventory for LDGVs and predicting on-road NH3 emissions in China.

关键词： NH3 instantaneous emissions Catalytic temperature Vehicle specific power Combustion efficiency Emission prediction

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Grain size refinement of additive manufactured Ce-TZP ceramics by coupled two-step pre-sintering and HIP

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Journal of Advanced Ceramics 2024年第5期13卷 621-629页

作者： Ruoshi Zhao Hongbing Yang xintong liu Hezhen li Chang-An Wang Jing Ma Yanhao Dong State Key Lab of New Ceramics and Fine Processing School of Materials Science and EngineeringTsinghua UniversityBeijing 100084China

Ceria-stabilized tetragonal zirconia polycrystal(Ce-TZP)has exceptional fracture toughness and flaw tolerance due to facile t‒m phase transformation toughening.However,its wider-range applications are limited by its relatively low strength due to its large grain size and low transformation stress,which results in yield-like failure.Here,we combined additive manufacturing(AM),pressureless two-step sintering,and hot isostatic pressing(HIP),and addressed the challenging grain size refinement problem in Ce-TZPs.We successfully produced dense ultrafine-grained Ce-TZP ceramics with an average grain size below 500 nm,a three-point bending strength above 800 MPa,and a single-edge-notch-beam fracture toughness in the range of 11‒12 MPa·m^(1/2).The critical roles of processing design,mixed Ce valences,and under-vs.over-stabilization of tetragonal polymorphs were noted.Our work offers insights and strategies for the future development of stronger and tougher Ce-TZP ceramics that can compete with tetragonal yttria-stabilized zirconia in various applications,including additive manufacturing.

关键词： zirconia additive manufacturing(AM) two-step sintering hot isostatic pressing(HIP) grain size refinement

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The Application of Solid Waste in Thermal Insulation Materials: A Review

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Journal of Renewable Materials 2024年第2期12卷 329-347页

作者： Ming liu Pinghua Zhu Xiancui Yan Haichao li xintong Chen School of Environmental Science and Engineering Changzhou UniversityChangzhou213164China School of Urban Construction Changzhou UniversityChangzhou213164China

As socioeconomic development continues,the issue of building energy consumption has attracted significant attention,and improving the thermal insulation performance of buildings has become a crucial strategic measure.Simultaneously,the application of solid waste in insulation materials has also become a hot topic.This paper reviews the sources and classifications of solid waste,focusing on research progress in its application as insulation materials in the domains of daily life,agriculture,and industry.The research shows that incorporating household solid waste materials,such as waste glass,paper,and clothing scraps into cementitious thermal insulation can significantly reduce the thermal conductivity of the materials,leading to excellent thermal insulation properties.Insulation materials prepared from agricultural solid waste,such as barley straw,corn stalk,chicken feather,and date palm fibers,possess characteristics of lightweight and strong thermal insulation.Industrial solid waste,including waste tires,iron tailings,and coal bottom ash,can also be utilized in the preparation of insulation materials.These innovative applications not only have positive environmental significance by reducing waste emissions and resource consumption,but also provide efficient and sustainable insulation solutions for the construction industry.However,to further optimize the mix design and enhance the durability of insulation materials,continuous research is required to investigate the mechanisms through which solid waste impacts the performance of insulation materials.

关键词： Solid waste building energy consumption insulation material sustainability

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Exosomes derived from microglia overexpressing miR-124-3p alleviate neuronal endoplasmic reticulum stress damage after repetitive mild traumatic brain injury

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Neural Regeneration Research 2024年第9期19卷 2010-2018页

作者： Yan Wang Dai li Lan Zhang Zhenyu Yin Zhaoli Han xintong Ge Meimei li Jing Zhao Shishuang Zhang Yan Zuo Xiangyang Xiong Han Gao Qiang liu Fanglian Chen Ping Lei Department of Geriatrics Tianjin Medical University General HospitalTianjinChina Tianjin Geriatrics Institute Tianjin Medical University General HospitalTianjinChina Tianjin Neurological Institute Tianjin Medical University General HospitalTianjinChina

We previously reported that miR-124-3p is markedly upregulated in microglia-derived exosomes following repetitive mild traumatic brain injury.However,its impact on neuronal endoplasmic reticulum stress following repetitive mild traumatic brain injury remains unclear.In this study,we first used an HT22 scratch injury model to mimic traumatic brain injury,then co-cultured the HT22 cells with BV2 microglia expressing high levels of miR-124-3p.We found that exosomes containing high levels of miR-124-3p attenuated apoptosis and endoplasmic reticulum stress.Furthermore,luciferase reporter assay analysis confirmed that miR-124-3p bound specifically to the endoplasmic reticulum stress-related protein IRE1α,while an IRE1αfunctional salvage experiment confirmed that miR-124-3p targeted IRE1αand reduced its expression,thereby inhibiting endoplasmic reticulum stress in injured neurons.Finally,we delivered microglia-derived exosomes containing miR-124-3p intranasally to a mouse model of repetitive mild traumatic brain injury and found that endoplasmic reticulum stress and apoptosis levels in hippocampal neurons were significantly reduced.These findings suggest that,after repetitive mild traumatic brain injury,miR-124-3 can be transferred from microglia-derived exosomes to injured neurons,where it exerts a neuroprotective effect by inhibiting endoplasmic reticulum stress.Therefore,microglia-derived exosomes containing miR-124-3p may represent a novel therapeutic strategy for repetitive mild traumatic brain injury.

关键词： apoptosis C/EBP homologous protein endoplasmic reticulum stress exosome inositol-requiring enzyme 1α microglia miR-124-3p neuron repetitive mild traumatic brain injury X-box binding protein 1

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Modeling of microstructure evolution of AZ80 magnesium alloy during hot working process using a unified internal state variable method

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Journal of Magnesium and Alloys 2022年第1期10卷 299-313页

作者： Zexing Su Chaoyang Sun Mingjia Wang lingyun Qian xintong li School of Mechanical Engineering University of Science and Technology Beijing30 Xueyuan RoadHaidian DistrictBeijing 100083China Beijing Key Laboratory of lightweight Metal Forming Beijing 100083China College of Nuclear Equipment and Nuclear Engineering Yantai UniversityYantai 264005China Shunde Graduate School of University of Science and Technology Beijing Foshan528000China

In this paper, a unified internal state variable(ISV) model for predicting microstructure evolution during hot working process of AZ80 magnesium alloy was developed. A novel aspect of the proposed model is that the interactive effects of material hardening, recovery and dynamic recrystallization(DRX) on the characteristic deformation behavior were considered by incorporating the evolution laws of viscoplastic flow, dislocation activities, DRX nucleation and boundary migration in a coupled manner. The model parameters were calibrated based on the experimental data analysis and genetic algorithm(GA) based objective optimization. The predicted flow stress, DRX fraction and average grain size match well with experimental results. The proposed model was embedded in the finite element(FE) software DEFORM-3 D via user defined subroutine to simulate the hot compression and equal channel angular extrusion(ECAE) processes. The heterogeneous microstructure distributions at different deformation zones and the dislocation density evolution with competitive deformation mechanisms were captured.This study can provide a theoretical solution for the hot working problems of magnesium alloy.

关键词： AZ80 magnesium alloy Internal state variable model Microstructure evolution Dynamic recrystallization Hot working process Finite element simulation

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Sesamin is an effective spleen tyrosine kinase inhibitor against IgE-mediated food allergy in computational， cell-based and animal studies

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Food Science and Human Wellness 2024年

作者： Yu li Xuerui Chen Longhua Xu xintong Tan Dapeng li Dongxiao Sun-Waterhouse Feng li School of Chemical Sciences The University of Auckland Key Laboratory of Food Nutrition and Human Health in Universities of Shandong College of Food Science and Engineering Shandong Agricultural University

Food allergy has become a global concern. Spleen tyrosine kinase (SYK) inhibitors are promising therapeutics against allergic disorders. In this study， a total of 300 natural phenolic compounds were firstly subjected to virtual screening. Sesamin and its metabolites， sesamin monocatechol (SC-1) and sesamin dicatechol (SC-2)， were identified as potential SYK inhibitors， showing high binding affinity and inhibition efficiency towards SYK. Compared with R406 (a traditional SYK inhibitor)， sesamin， SC-1， and SC-2 had lower binding energy and inhibition constant (Ki) during molecular docking， exhibited higher bioavailability， safety， metabolism/clearance rate， and distribution uniformity ADMET predictions， and showed high stability in occupying the ATP-binding pocket of SYK during molecular dynamics simulations. In anti-dinitrophenyl-immunoglobulin E (Anti-DNP-IgE)/dinitrophenyl-human serum albumin (DNP-HSA)-stimulated rat basophilic leukemia (RBL-2H3) cells， sesamin in the concentration range of (5 – 80) μmol/L influenced significantly the degranulation and cytokine release， with 54.00% inhibition against β-hexosaminidase release and 58.45% decrease in histamine. In BALB/c mice， sesamin could ameliorate Anti-DNP-IgE/DNP-HSA-induced passive cutaneous anaphylaxis and ovalbumin (OVA)-induced active systemic anaphylaxis reactions， reduce the levels of allergic mediators (immunoglobulins and pro-inflammatory cytokines)， partially correct the imbalance of T helper (Th) cells differentiation in the spleen， and inhibit the phosphorylation of SYK and its downstream signaling proteins， including p38 mitogen-activated protein kinases (p38 MAPK)， extracellular signal-regulated kinases (ERK)， and p65 nuclear factor-κB (p65 NF-κB) in the spleen. Thus， sesamin may be a safe and versatile SYK inhibitor that can alleviate IgE-mediated food allergies.

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The nuclear export receptor OsXPO1 is required for rice development and involved in abiotic stress responses

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The Crop Journal 2023年第1期11卷 71-78页

作者： Qiufei Peng Jieyu Qiu xintong li Xuezhong Xu Xinxiang Peng Guohui Zhu Guangdong Laboratory for lingnan Modern Agriculture College of Life SciencesSouth China Agricultural UniversityGuangzhou 510640GuangdongChina Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms Guangzhou 510640GuangdongChina

The transport of proteins to and from the nucleus is necessary for many cellular processes and is one of the ways plants respond to developmental signals and environmental stresses.Nucleocytoplasmic trafficking of proteins is mediated by the nuclear transport receptor(NTR).Although NTR has been extensively studied in humans and Arabidopsis,it has rarely been identified and functionally characterized in rice.In this study,we identified exportin 1 in rice(OsXPO1)as a nuclear export receptor.OsXPO1shares high protein identity with its functional homologs in Arabidopsis and other organisms.OsXPO1localized to both the nucleus and the cytoplasm,directly interacted with the small GTPases OsRAN1and OsRAN2 in the nucleus,and mediated their nuclear export.Loss-of-function osxpo1 mutations were lethal at the seedling stage.Suppression of OsXPO1 expression in RNA interference lines produced multifaceted developmental defects,including arrested growth,premature senescence,abnormal inflorescence,and brown and mouth-opened spikelets.Overexpression of OsXPO1 in rice reduced plant height and seed-setting rate,but increased plant tolerance in response to PEG-mimicked drought stress and salt stress.These results indicate that OsXPO1 is a nuclear export receptor and acts in regulating plant development and abiotic stress responses.

关键词： Exportin 1 Nucleocytoplasmic transport Plant development Abiotic stress

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Optimization of depreciation subsidy policy strategies for electric two-wheelers for improving traffic safety

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Transportation Safety and Environment 2022年第3期4卷 107-118页

作者： xintong li Helai Huang Chunyang Han Guangming Xu Jaeyoung Lee Cheng Hu School of Traffic and Transportation Engineering Central South UniversityChangsha 410075HunanChina Department of Automation Tsinghua UniversityBeijing 100084China.

To improve the traffic safety of electric two-wheelers(ETW),China has promulgated ETW standardization policies.This policy requires local governments to take measures to guide the illegal ETWs out of use.Governments have implemented a depreciation subsidy scheme to encourage users to scrap illegal ETWs early.When designing the subsidy scheme,effectively improving the ETWs’traffic safety at the road network level while saving government expenses is essential for the sustainable implementation of the policy.This study proposes an optimization method for depreciation subsidy design incorporating traffic safety evaluation.Based on the policy scheme,this study formulates a risk assessment model for the ETW traffic network to characterize the effect of the subsidy on improving safety.Then,we use the bi-level programming approach to model the subsidy strategy design problem.The upper-level problem reflects the goal of policymakers to maximize safety improvement and minimize government expenses.The lower-level problem describes the route choices of ETW users.The optimal subsidy design under different safety-expense trade-offs is analysed based on the Nguyen and Dupuis network and a real network extracted from Changsha City in China.The results show that specific subsidy schemes effectively improve road safety without a large government spending.When themarket price or service life of ETWs increases,the government spending on the same safety goal increases.The government should comprehensively consider the safety effect of financial expense and the situation of the local ETW market before selecting reasonable subsidy strategies.

关键词： Electric two-wheeler(ETW) depreciation subsidy optimization traffic safety evaluation dual-objective bi-level programming

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