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Antigen-induced chimeric antigen receptor multimerization amplifies on-tumor cytotoxicity

Signal Transduction and Targeted Therapy 2024年第1期9卷 259-270页

作者： Yan Sun Xiu-Na Yang Shuang-Shuang Yang Yi-Zhu Lyu Bing Zhang Kai-Wen Liu Na Li Jia-chen Cui Guang-Xiang Huang cheng-Lin Liu Jie Xu Jian-Qing Mi Zhu chen Xiao-Hu Fan sai-juan chen Shuo chen Shanghai Institute of Hematology National Research Center for Translational MedicineState Key Laboratory of Medical GenomicsRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200025China Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China Department of Hematology Second Hospital of Dalian Medical UniversityDalian 116023China National Facility for Protein Science Shanghai Shanghai Advanced Research InstituteChinese Academy of SciencesShanghai 201210China Legend Biotech China Nanjing 211112China Shanghai Immune Therapy Institute Shanghai Cancer InstituteState Key Laboratory of Oncogenes and Related GenesRenji Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200127China Wondercel Biotechnology Shenzhen 518052China

Ligand-induced receptor dimerization or oligomerization is a widespread mechanism for ensuring communication specificity,safeguarding receptor activation,and facilitating amplification of signal transduction across the cellular membrane.However,cell-surface antigeninduced multimerization(dubbed AIM herein)has not yet been consciously leveraged in chimeric antigen receptor(CAR)engineering for enriching T cell-based therapies.We co-developed ciltacabtagene autoleucel(cilta-cel),whose CAR incorporates two B-cell maturation antigen(BCMA)-targeted nanobodies in tandem,for treating multiple myeloma.Here we elucidated a structural and functional model in which BCMA-induced cilta-cel CAR multimerization amplifies myeloma-targeted T cell-mediated cytotoxicity.Crystallographic analysis of BCMA–nanobody complexes revealed atomic details of antigen–antibody hetero-multimerization whilst analytical ultracentrifugation and small-angle X-ray scattering characterized interdependent BCMA apposition and CAR juxtaposition in solution.BCMA-induced nanobody CAR multimerization enhanced cytotoxicity,alongside elevated immune synapse formation and cytotoxicity-mediating cytokine release,towards myeloma-derived cells.Our results provide a framework for contemplating the AIM approach in designing next-generation CARs.

关键词： cytotoxicity Antigen elevated

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Intensive care unit-acquired weakness: Recent insights

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Journal of Intensive Medicine 2024年第1期4卷 73-80页

作者： juan chen Man Huang Department of General Intensive Care Unit The Second Affiliated Hospital of Zhejiang University School of MedicineHangzhou 310009ZhejiangChina

Intensive care unit-acquired weakness(ICU-AW)is a common complication in critically ill patients and is associated with a variety of adverse outcomes.These include the need for prolonged mechanical ventilation and ICU stay;higher ICU,in-hospital,and 1-year mortality;and increased in-hospital costs.ICU-AW is associated with multiple risk factors including age,underlying disease,severity of illness,organ failure,sepsis,immobilization,receipt of mechanical ventilation,and other factors related to critical care.The pathological mechanism of ICUAW remains unclear and may be considerably varied.This review aimed to evaluate recent insights into ICU-AW from several aspects including risk factors,pathophysiology,diagnosis,and treatment strategies;this provides new perspectives for future research.

关键词： Intensive care unit-acquired weakness Muscle weakness Muscle atrophy Risk factor Mechanism Treatment

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Impact of Alcian blue and periodic acid Schiff expression on the prognosis of gastric signet ring cell carcinoma

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World Journal of Gastrointestinal Oncology 2024年第3期16卷 687-698页

作者： juan Lin Zhu-Feng chen Guo-Dong Guo Xin chen Shengli Clinical Medical College Fujian Medical UniversityFuzhou 350001Fujian ProvinceChina Department of Pathology Fujian Provincial HospitalFuzhou 350001Fujian ProvinceChina Department of Internal Medicine Fujian Provincial HospitalFuzhou 350001Fujian ProvinceChina

BACKGROUND The Alcian blue(AB)and periodic acid Schiff(PAS)stains are representative mucus markers in gastric signet ring cell carcinoma(SRCC).They are low-cost special staining methods used to detect acidic mucus and neutral mucus,respectively.However,the clinical importance of the special combined AB and PAS stain is unclear.AIM To investigate AB expression,PAS expression and the AB-to-PAS(A/P)ratio in gastric SRCC patients and to assess patient prognosis.METHODS Paraffin-embedded sections from 83 patients with gastric SRCC were stained with AB and PAS,and signet ring cell positivity was assessed quantitatively.Immuno-histochemical staining for Ki67,protein 53(P53)and human epidermal growth factor receptor 2(HER2)was performed simultaneously.The cancer-specific survival(CSS)rate was estimated via Kaplan-Meier analysis.Cox proportional hazards models were used for univariate and multivariate survival analyses.RESULTS Kaplan-Meier survival analysis revealed that the 3-year CSS rate was significantly greater in the high-PAS-expression subgroup than in the low-PAS-expression subgroup(P0.5 group(P=0.042).Univariate Cox regression analysis revealed that the factors affecting prognosis included tumor diameter,lymph node metastasis,vessel carcinoma embolus,tumor stage,the A/P ratio and the expression of Ki67,P53 and the PAS.Cox multivariate regression analysis confirmed that low PAS expression[hazard ratio(HR)=3.809,95%confidence interval(CI):1.563-9.283,P=0.003]and large tumor diameter(HR=2.761,95%CI:1.086-7.020,P=0.033)were independent risk factors for poor prognosis.CONCLUSION A/P>0.5 is potentially a risk factor for prognosis,and low PAS expression is an independent risk factor in the prognosis of gastric SRCC.PAS expression and the A/P ratio could help in predicting the clinical prognosis of patients with SRCC.

关键词： Alcian blue Periodic acid-Schiff Prognosis Gastric Signet ring cell carcinoma

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Effect of relative humidity on the desulfurization performance of calcium-based desulfurizer

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Journal of Environmental Sciences 2024年第4期138卷 179-188页

作者： juan Lǖ Yu Fu Haiyan Yu HuanWang Zhe Wang Haiyan chen School of Environment and Resource Southwest University of Science and TechnologyMianyang 621010China Guangyuan Emergency Management bureau Guangyuan 628000China

Low desulfurization efficiency impedes the wide application of dry desulfurization technology,which is a low-cost and simple process,and one significant solution is the development and manufacture of high-performance desulfurizers.In this study,firstly,a steam jet mill was used to digest quicklime;then,we utilized numerical simulation to study the flow field distribution and analyze the driving factors of quicklime digestion;and lastly,the desulfurization performance of the desulfurizer was evaluated under different relative humidities.The results show that the desulfurizer prepared via the steam jet mill had better apparent activity than traditional desulfurizers.Also,the entire jet flow field of the steam jet mill is in a supersonic and highly turbulent flow state,with high crushing intensity and good particle acceleration performance.Sufficient contact with the nascent surface maximizes the formation of slaked lime.The experiments demonstrated that the operating time with 100%desulfurization efficiency and the“break-through”time for the desulfurizer prepared via the steam jet mill is longer than that of traditional desulfurizers,and has significant advantages,especially at low flue gas relative humidity.Compared with traditional desulfurizers,the desulfurizer prepared via steam jet mill expands the range of acceptable flue gas temperature,and the failure temperature is 1.625 times that of traditional desulfurizers.This work breaks through the technical bottleneck of low dry desulfurization efficiency,which is an important step in pushing forward the application of dry desulfurization.

关键词： Dry desulfurization Relative humidity Desulfurization efficiency High-efficiency desulfurizer Quicklime digestion

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Nitrogen-doped titanium dioxide/schwertmannite nanocomposites as heterogeneous photo-Fenton catalysts with enhanced efficiency for the degradation of bisphenol A

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Journal of Environmental Sciences 2024年第9期143卷 1-11页

作者： Xing-Xing Qiao Yu-Hang Xu Xiang-Ji Liu sai-Le chen Zhou Zhong Ya-Feng Li Jian Lü Fujian Provincial Key Laboratory of Soil Environmental Health and Regulation College of Resources and EnvironmentFujian Agriculture and Forestry UniversityFuzhou 350002China State Key Laboratory of Photocatalysis on Energy and Environment Fuzhou UniversityFuzhou 350116China

Potential health risks related to environmental endocrine disruptors(EEDs)have aroused research hotspots at the forefront of water treatment technologies.Herein,nitrogen-doped titanium dioxide/schwertmannite nanocomposites(N-TiO_(2)/SCH)have been successfully developed as heterogeneous catalysts for the degradation of typical EEDs via photo-Fenton processes.Due to the sustainable Fe(Ⅲ)/Fe(Ⅱ)conversion induced by photoelectrons,as-prepared N-TiO_(2)/SCH nanocomposites exhibit much enhanced efficiency for the degradation of bisphenol A(BPA;ca.100% within 60 min under visible irradiation)in a wide pH range of 3.0-7.8,which is significantly higher than that of the pristine schwertmannite(ca.74.5%)or N-TiO_(2)(ca.10.8%).In this photo-Fenton system,the efficient degradation of BPA is mainly attributed to the oxidation by hydroxyl radical(·OH)and singlet oxygen(^(1)O_(2)).Moreover,the possible catalytic mechanisms and reaction pathway of BPA degradation are systematically investigated based on analytical and photoelectrochemical analyses.This work not only provides a feasible means for the development of novel heterogeneous photo-Fenton catalysts,but also lays a theoretical foundation for the potential application of mineral-based materials in wastewater treatment.

关键词： Titanium dioxide Schwertmannite Fenton reaction Environmental endocrine disruptors Photocatalysis

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Perspective and challenges of mycorrhizal symbiosis in orchid medicinal plants

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Chinese Herbal Medicines 2024年第2期16卷 172-179页

作者： Chunyan Leng Mengyan Hou Yongmei Xing juan chen Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine Ministry of EducationInstitute of Medicinal Plant DevelopmentChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100193China

The family Orchidaceae is of the most diverse taxon in the plant kingdom,and most of its members are highly valuable herbal medicines.Orchids have a unique mycorrhizal symbiotic relationship with specific fungi for carbohydrate and nutrient supplies in their whole lifecycle.The large-scale cultivation of the medicinal plant Gastodia elata is a successful example of using mycorrhizal symbiotic technology.In this review,we adopted G.elata and Dendrobium officinale as examples to describe the characteristics of orchid mycorrhiza and mycorrhizal benefits for host plants’growth and health(e.***.biotic and abiotic stress and secondary metabolite accumulation).The challenges in applying mycorrhizal technology to the cultivation of orchid medicinal plants in the future were also discussed.This review aims to serve as a theoretical guide for the cultivation of mycorrhizal technology in medicinal orchid plants.

关键词： Dendrobium officinale Kimura&Migo ecological cultivation Gastodia elata Blume mycorrhiza orchid medicinal plants symbiosis mechanisms

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Application of Global Leadership Initiative on Malnutrition criteria in patients with liver cirrhosis

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Chinese Medical Journal 2024年第1期137卷 97-104页

作者： Minjie Jiang juan chen Muchen Wu Jing Wu Xiaotong Xu juan Li Can Liu Yaping Zhao Xin Hua Qinghua Meng Department of Hepatology Beijing You-An HospitalCapital Medical UniversityBeijing 100069China Beijing Institute of Hepatology Beijing 100069China Department of Medical Oncology Beijing You-An HospitalCapital Medical UniversityBeijing 100069China Department of Nutrition Beijing You-An HospitalCapital Medical UniversityBeijing 100069China

Background:The Global Leadership Initiative on Malnutrition(GLIM)criteria were published to build a global consensus on nutritional diagnosis.Reduced muscle mass is a phenotypic criterion with strong evidence to support its inclusion in the GLIM consensus criteria.However,there is no consensus regarding how to accurately measure and define reduced muscle mass in clinical settings.This study aimed to investigate the optimal reference values of skeletal muscle mass index for diagnosing sarcopenia and GLIM-defined malnutrition,as well as the prevalence of GLIM-defined malnutrition in hospitalized cirrhotic patients.Methods:This retrospective study was conducted on 1002 adult patients with liver cirrhosis between January 1,2018,and February 28,2022,at Beijing You-An Hospital,Capital Medical University.Adult patients with a clinical diagnosis of liver cirrhosis and who underwent an abdominal computed tomography(CT)examination during hospitalization were included in the study.These patients were randomly divided into a modeling group(cohort 1,667 patients)and a validation group(cohort 2,335 patients).In cohort 1,optimal cut-off values of skeletal muscle index at the third lumbar skeletal muscle index(L3-SMI)were determined using receiver operating characteristic analyses against in-hospital mortality in different gender groups.Next,patients in cohort 2 were screened for nutritional risk using the Nutritional Risk Screening 2002(NRS-2002),and malnutrition was diagnosed by GLIM criteria.Additionally,the reference values of reduced muscle mass in GLIM criteria were derived from the L3-SMI values from cohort 1.Multivariate logistic regression analysis was used to analyze the association between GLIM-defined malnutrition and clinical outcomes.Results:The optimal cut-off values of L3-SMI were 39.50 cm 2/m 2 for male patients and 33.06 cm 2/m 2 for female patients.Based on the cut-off values,31.63%(68/215)of the male patients and 23.3%(28/120)of the female patients had CT-determined sarcopenia in cohort 2.The prevalence of GL

关键词： Malnutrition Liver cirrhosis Sarcopenia Clinical outcomes GLIM criteria

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Safety and efficacy of omalizumab for antihistamine-resistant chronic urticaria in children:a case series and literature review

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World Journal of Pediatrics 2024年第3期20卷 294-298页

作者： Wei-Fang Zhu chen Wang Jian-Jun Qiao Lan-juan Li Department of Dermatology First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China State Key Laboratory for Diagnosis and Treatment of Infectious Diseases National Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China

Chronic urticaria(CU)is a common skin disease characterized by the occurrence of wheals,with or without angioedema,lasting more than 6 weeks.The prevalence of CU is about 0.7%[1],but higher in children,with an incidence of 1.38%[1].The occurrence of severe pruritus and unpredictable wheals may severely impact patients'quality of life,cause psychological problems,including sleep disorders and depression,and lead to economic burden due to limitation on daily life and work[2,3].

关键词： edema prevalence children

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Effects of seepage pressure on the mechanical behaviors and microstructure of sandstone

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Journal of Rock Mechanics and Geotechnical Engineering 2024年第6期16卷 2033-2051页

作者： Xuewei Liu Juxiang chen Bin Liu sai Wang Quansheng Liu Jin Luo State Key Laboratory of Geomechanics and Geotechnical Engineering Institute of Rock and Soil MechanicsChinese Academy of SciencesWuhan430071China Faculty of Engineering China University of GeosciencesWuhan430074China Key Laboratory of Safety for Geotechnical and Structural Engineering of Hubei Province School of Civil EngineeringWuhan UniversityWuhan430072China

Surrounding rocks of underground engineering are subjected to long-term seepage pressure,which can deteriorate the mechanical properties and cause serious disasters.In order to understand the impact of seepage pressure on the mechanical property of sandstone,uniaxial compression tests,P-wave velocity measurements,and nuclear magnetic resonance(NMR)tests were conducted on saturated sandstone samples with varied seepage pressures(i.e.0 MPa,3 MPa,4 MPa,5 MPa,6 MPa,7 MPa).The results demonstrate that the mechanical parameters(uniaxial compressive strength,peak strain,elastic modulus,and brittleness index),total energy,elastic strain energy,as well as elastic strain energy ratio,decrease with increasing seepage pressure,while the dissipation energy and dissipation energy ratio increase.Moreover,as seepage pressure increases,the micro-pores gradually transform into meso-pores and macro-pores.This increases the cumulative porosity of sandstone and decreases P-wave velocity.The numerical results indicate that as seepage pressure rises,the number of tensile cracks increases progressively,the angle range of microcracks is basically from 50-120to 80-100,and as a result,the failure mode transforms to the tensile-shear mixed failure mode.Finally,the effects of seepage pressure on mechanical properties were discussed.The results show that decrease in the effective stress and cohesion under the action of seepage pressure could lead to deterioration of strength behaviors of sandstone.

关键词： Rock mechanics Mechanical property Seepage pressure Numerical simulation Microcracks

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A Dynamic Covalent Bonding-based Nanoplatform for Intracellular Co-Delivery of Protein Drugs and Chemotherapeutics with Enhanced Anti-Cancer Effect

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Chinese Journal of Polymer Science 2024年第5期42卷 559-569,I0005页

作者： sai-Nan Liu Jia-Hui Meng Li-Yun Cui Hua chen Lin-Qi Shi Ru-Jiang Ma Key Laboratory of Functional Polymer Materials of Ministry of Education Institute of Polymer ChemistryTianjin Key Laboratory of Functional Polymer MaterialsState Key Laboratory of Medicinal Chemical BiologyFrontiers Science Center for New Organic MatterCollege of ChemistryNankai UniversityTianjin300071China Haihe Laboratory of Sustainable Chemical Transformations Tianjin300192China

Efficient intracellular delivery of protein drugs is critical for protein therapy.The combination of protein drugs with chemotherapeutics represents a promising strategy in enhancing anti-cancer effect.However,co-delivery systems for efficient delivery of these two kinds of drugs are still lacking because of their different properties.Herein,we show a well-designed delivery system based on dynamic covalent bond for efficient intracellular co-delivery of ribonuclease A(RNase A)and doxorubicin(DOX).Two polymers,PEG-b-P(Asp-co-AspDA)and PAE-b-P(Asp-co-AspPBA),and two 2-acetylphenylboronic acid(2-APBA)-functionalized drugs,2-APBA-RNase A and 2-APBA-DOX,self-assemble into mixed-shell nanoparticles(RNase A/DOX@MNPs)via dynamic phenylboronic acid(PBA)-catechol bond between PBA and dopamine(DA)moieties.The PBA-catechol bond endows the nanoparticles with high stability and excellent stimulus-responsive drug release behavior.Under the slight acidic environment at tumor tissue,RNase A/DOX@MNPs are positively charged,promoting their endocytosis.Upon cellular uptake into endosome,further protonation of PAE chains leads to the rupture of endosomes because of the proton sponge effect and the cleavage of PBA-catechol bond promotes the release of two drugs.In cytoplasm,the high level of GSH removed the modification of 2-APBA on drugs.The restored RNase A and DOX show a synergistic and enhanced antic-cancer effect.This system may be a promising platform for intracellular co-delivery of protein drugs and chemotherapeutics.

关键词： Drug co-delivery Combination therapy Dynamic covalent bond

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