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Gene replacement therapy in Bietti crystalline corneoretinal dystrophy:an open-label,single-arm,exploratory trial

Signal Transduction and Targeted Therapy 2024年第5期9卷 2275-2284页

作者： Jinyuan Wang Jinlu Zhang Shicheng Yu Hongyan Li Shaohong Chen Jingting Luo Haibo Wang Yuxia Guan Haihan Zhang Shiyi Yin Huili Wang Heping Li Junle Liu Jingyuan Zhu Qiong Yang Ying Sha Chuan Zhang Yuhang Yang Xuan Yang Xifang Zhang Xiuli Zhao Likun Wang Liping Yang Wenbin Wei Beijing Tongren Eye Center Beijing Key Laboratory of Intraocular Tumor Diagnosis and TreatmentBeijing Ophthalmology&Visual Sciences Key LabMedical Artificial Intelligence Research and Verification Key Laboratory of the Ministry of Industry and Information TechnologyBeijing Tongren HospitalCapital Medical University100730 BeijingChina School of Clinical Medicine Tsinghua University100084 BeijingChina Chigenovo Co. Ltd.102206 BeijingChina Department of Ophthalmology Peking University Third HospitalBeijing Key Laboratory of Restoration of Damaged Ocular NervePeking University Third Hospital100191 BeijingChina Department of Ophthalmology The Third People’s Hospital of Dalian116091 DalianChina Department of Biomedical Informatics School of Basic Medical SciencesPeking University Health Science Center100191 BeijingChina Institute of Systems biomedicine Department of PathologySchool of Basic Medical SciencesPeking University Health Science Center100191 BeijingChina

Bietti crystalline corneoretinal dystrophy is an inherited retinal disease caused by mutations in CYP4V2,which results in blindness in the working-age population,and there is currently no available ***,we report the results of the first-in-human clinical trial(NCT04722107)of gene therapy for Bietti crystalline corneoretinal dystrophy,including 12 participants who were followed up for 180-365 *** open-label,single-arm exploratory trial aimed to assess the safety and efficacy of a recombinant adeno-associated-virus-serotype-2/8 vector encoding the human CYP4V2 protein(rAAV2/8-hCYP4V2).Participants received a single unilateral subretinal injection of 7.5×10^(10)vector genomes of rAAV2/***,73 treatment-emergent adverse events were reported,with the majority(98.6%)being of mild or moderate intensity and considered to be procedure-or corticosteroid-related;no treatment-related serious adverse events or local/systemic immune toxicities were *** with that measured at baseline,77.8%of the treated eyes showed improvement in best-corrected visual acuity(BCVA)on day 180,with a mean±standard deviation increase of 9.0±10.8 letters in the 9 eyes analyzed(p=0.021).By day 365,80%of the treated eyes showed an increase in BCVA,with a mean increase of 11.0±10.6 letters in the 5 eyes assessed(p=0.125).Importantly,the patients’improvement observed using multifocal electroretinogram,microperimetry,and Visual Function Questionnaire-25 further supported the beneficial effects of the *** conclude that the favorable safety profile and visual improvements identified in this trial encourage the continued development of rAAV2/8-hCYP4V2(named ZVS101e).

关键词： cor dystrophy crystalline

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The induction of PANoptosis in KRAS-mutant pancreatic ductal adenocarcinoma cells by a multispecific platinum complex

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Science China Chemistry 2022年第10期65卷 1978-1984页

作者： Xin Yuan Shuren Zhang Xuanmeng Zhong Hao Yuan Dongfan Song Xiaoyu Wang Hanyang Yu Zijian Guo State Key Laboratory of Coordination Chemistry School of Chemistry and Chemical EngineeringChemistry and Biomedicine Innovation Center(ChemBIC)Nanjing UniversityNanjing 210023China Department of Biomedical Engineering College of Engineering and Applied SciencesChemistry and Biomedicine Innovation Center(ChemBIC)Nanjing UniversityNanjing 210023China

Oncogenic KRAS reprograms pancreatic ductal adenocarcinoma(PDAC) cells to a state that is awfully resistant to *** alternative coping strategy is to trigger a nonapoptotic cell ***,a multi specific platinum complex SEP was constructed by conjugating a quinone derivative seratrodast to a prodrug of ***,SEP-treated KRAS-mutant PDAC cells showed the characteristics of pyroptosis,apoptosis and necroptosis,similar to PANoptosis(a newfound inflammatory cell death).Mechanistically,SEP could enter cancer cells effectively,then damage nuclear DNA,boost mitochondrial superoxide anion radicals and affect various signaling pathways related to redox homeostasis and tumor *** our best knowledge,SEP is the first metal complex,even small molecule,to elicit PANoptosis(pyroptosis,apoptosis and necroptosis) in cancer cells,providing a new strategy to overcome apoptotic resistance of KRAS-mutant PDAC.

关键词： metallodrug pancreatic ductal adenocarcinoma PANoptosis cell death platinum prodrug

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GLUL stabilizes N-Cadherin by antagonizing β-Catenin to inhibit the progresses of gastric cancer

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Acta Pharmaceutica Sinica B 2024年第2期14卷 698-711页

作者： Qiwei Jiang Yong Li Songwang Cai Xingyuan Shi Yang Yang Zihao Xing Zhenjie He Shengte Wang Yubin Su Meiwan Chen Zhesheng Chen Zhi Shi Department of Cell Biology&Institute of biomedicine National Engineering Research Center of Genetic MedicineState Key Laboratory of Bioactive Molecules and Druggability AssessmentMOE Key Laboratory of Tumor Molecular BiologyGuangdong Provincial Key Laboratory of Bioengineering MedicineCollege of Life Science and TechnologyJinan UniversityGuangzhou 510632China Department of Gastrointestinal Surgery&General Surgery the Guangdong Provincial People’s HospitalGuangdong Academy of Medical SciencesGuangzhou 510080China Department of Thoracic Surgery The First Affiliated Hospital of Jinan UniversityGuangzhou 510632China Department of Radiation Oncology The Fifth Hospital of Guangzhou Medical UniversityGuangzhou 510150China State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao 519000China Department of Pharmaceutical Sciences College of Pharmacy and Health SciencesSt.John’s UniversityQueensNY 11439USA

Glutamate-ammonia ligase(GLUL, also known as glutamine synthetase) is a crucial enzyme that catalyzes ammonium and glutamate into glutamine in the ATP-dependent condensation. Although GLUL plays a critical role in multiple cancers, the expression and function of GLUL in gastric cancer remain unclear. In the present study, we have found that the expression level of GLUL was significantly lower in gastric cancer tissues compared with adjacent normal tissues, and correlated with N stage and TNM stage, and low GLUL expression predicted poor survival for gastric cancer patients. Knockdown of GLUL promoted the growth, migration, invasion and metastasis of gastric cancer cells in vitro and in vivo, and vice versa, which was independent of its enzyme activity. Mechanistically, GLUL competed with β-Catenin to bind to N-Cadherin, increased the stability of N-Cadherin and decreased the stability of β-Catenin by alerting their ubiquitination. Furthermore, there were lower N-Cadherin and higher β-Catenin expression levels in gastric cancer tissues compared with adjacent normal tissues. GLUL protein expression was correlated with that of N-Cadherin, and could be the independent prognostic factor in gastric cancer. Our findings reveal that GLUL stabilizes N-Cadherin by antagonizing β-Catenin to inhibit the progress of gastric cancer.

关键词： Gastric cancer GLUL N-Cadherin β-Catenin Enzyme

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Mass Spectrometry-Based Targeted Metabolomics Revealed the Regulatory Roles of Magnesium on Biofilm Formation in Escherichia coli by Targeting Functional Metabolites

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Journal of Analysis and Testing 2022年第2期6卷 89-97页

作者： Tian-Yu Wang Rui Guo Long-Long Hu Jing-Jing Liu Hai-Tao Lu Key Laboratory of Systems biomedicine(Ministry of Education) Shanghai Center for Systems BiomedicineShanghai Jiao Tong UniversityShanghai 200240China Laboratory for Functional Metabolomics Science Shanghai Jiao Tong UniversityShanghai 200240China

Biofi lms often impose harmful infl uences in many niches involving food contamination,antibiotics resistance,and environmental ***,eradicating biofi lms remains diffi cultly because the formation mechanism of biofi lms is still incompletely clarifi ***,we attempted to explore the regulatory role of magnesium(Mg^(2+))on biofi lm formation in Escherichia coli(***)using phenotype visualization with targeted metabolomics *** found that Mg^(2+)could exert signifi cant infl uence on biofi lm formation with a concentration dependency by regulating phenotypic morphology and triggering metabolic modifi cations of biofi *** imaging revealed that increasing concentration of Mg^(2+)gradually inhibited biofi lm formation,Mg^(2+)was observed to restore the microstructure of *** strain in biofi lms to that in the relevant planktonic *** addition,our metabolomics analysis characterized 20 diff erential metabolites and associated two metabolic pathways including nucleotide metabolism and amino acid metabolism that were notably modifi ed during biofi lm formation under the treatments of varied Mg^(2+).Altogether,our work provides a novel insight into the infl uence of Mg^(2+)on biofi lm formation at a metabolic level,which is implicated in the novel solution to disturb biofi lm formation through the regulation of Mg^(2+)and functional metabolite interaction.

关键词： Biofilms Magnesium Precision-targeted metabolomics Metabolic modifications Escherichia coli

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Bridging the gap:axonal fusion drives rapid functional recovery of the nervous system

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Neural Regeneration Research 2018年第4期13卷 591-594页

作者： Jean-Sébastien Teoh Michelle Yu-Ying Wong Tarika Vijayaraghavan Brent Neumann Neuroscience program Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental BiologyMonash University

Injuries to the central or peripheral nervous system frequently cause long-term disabilities because damaged neurons are unable to efficiently *** inherent deficiency necessitates the need for new treatment options aimed at restoring lost function to *** to humans,a number of species possess far greater regenerative capabilities,and can therefore provide important insights into how our own nervous systems can be *** particular,several invertebrate species have been shown to rapidly initiate regeneration post-injury,allowing separated axon segments to *** process,known as axonal fusion,represents a highly efficient repair mechanism as a regrowing axon needs to only bridge the site of damage and fuse with its separated counterpart in order to re-establish its original *** recent findings in the nematode Caenorhabditis elegans have expanded the promise of axonal fusion by demonstrating that it can restore complete function to damaged ***,we revealed the importance of injury-induced changes in the composition of the axonal membrane for mediating axonal fusion,and discovered that the level of axonal fusion can be enhanced by promoting a neuron＇s intrinsic growth potential.A complete understanding of the molecular mechanisms controlling axonal fusion may permit similar approaches to be applied in a clinical setting.

关键词： axonal fusion axon regeneration nervous system repair nerve injury phosphatidylserine functional repair axonal transport Caenorhabditis elegans

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A Non-canonical Excitatory PV RGC–PV SC Visual Pathway for Mediating the Looming-evoked Innate Defensive Response

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Neuroscience Bulletin 2024年第3期40卷 310-324页

作者： Man Yuan Sen Jin Gao Tan Siyuan Song Yizong Liu Huadong Wang Yin Shen Eye Center Renmin Hospital of Wuhan UniversityWuhan UniversityWuhan430060China The Brain Cognition and Brain Disease Institute Shenzhen Key Laboratory of Viral Vectors for BiomedicineShenzhen Institute of Advanced TechnologyChinese Academy of Sciences(CAS)Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research InstitutionsNational Medical Products Administration Key Laboratory for Research and Evaluation of Viral Vector Technology in Cell and Gene Therapy Medicinal ProductsShenzhen Key Laboratory of Quality Control Technology for Virus-Based TherapeuticsGuangdong Provincial Medical Products AdministrationShenzhen518055China Jan and Dan Duncan Neurological Research Institute Baylor College of MedicineHouston77030USA State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics Key Laboratory of Magnetic Resonance in Biological SystemsWuhan Center for Magnetic ResonanceInnovation Academy for Precision Measurement Science and TechnologyCASWuhan430071China Frontier Science Center of Immunology and Metabolism Medical Research InstituteWuhan UniversityWuhan430071China

Parvalbumin-positive retinal ganglion cells(PV+RGCs)are an essential subset of RGCs found in various ***,their role in transmitting visual information remains ***,we characterized PV+RGCs in the retina and explored the functions of the PV+RGC-mediated visual *** applying multiple viral tracing strategies,we investigated the downstream of PV+RGCs across the whole ***,we found that the PV+RGCs provided direct monosynaptic input to PV+excitatory neurons in the superficial layers of the superior colliculus(SC).Ablation or suppression of SC-projecting PV+RGCs abolished or severely impaired the flight response to looming visual stimuli in mice without affecting visual ***,using transcriptome expression profiling of individual cells and immunofluorescence colocalization for RGCs,we found that PV+RGCs are predominant glutamatergic ***,our findings indicate the critical role of PV+RGCs in an innate defensive response and suggest a non-canonical subcortical visual pathway from excitatory PV+RGCs to PV+SC neurons that regulates looming visual *** results provide a potential target for intervening and treating diseases related to this circuit,such as schizophrenia and autism.

关键词： Parvalbumin-positive retinal ganglion cell Innate fear Superior colliculus Excitatory-excitatory neuronal connection Looming-evoked defensive response Subcortical pathway

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Two birds with one stone:Amine-functionalized MSNs@Eu(OH)CO_(3) nanoprobe for efficient dissolution-enhanced afterglow bioassay

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Nano Research 2022年第9期15卷 8360-8366页

作者： Fuying Zhang Donghao Hu Xianlong Su Zhengdao Hong Wei Feng Ming Xu Fuyou Li Department of Chemistry&State Key Laboratory of Molecular Engineering of Polymers&Institute of biomedicine Science Fudan UniversityShanghai 200433China

ABSTRACT The efficient detection of tumor markers is crucial to early cancer diagnosis and ***,we propose a unique“two birds with one stone”dissolution-enhanced afterglow bioassay based on amino-functionalized mesoporous SiO2 nanoparticles(MSNs-NH2)encapsulated Eu(OH)CO_(3)*** nanoprobes(i)stably conjugate to the antibody and(ii)are highly soluble in the acidic enhancer solution,and provide a high Eu3+*** released Eu3+ions further activate the photochemical afterglow system to determine the alpha-fetoprotein(AFP)levels in clinical serum *** the use of a real-time excitation source,the interference of autofluorescence and scattering from blood can be *** demonstrated limit of detection(LOD)for AFP was as low as 0.12 ng·mL^(−1).This covalently connected dissolution-enhanced luminescent bioassay(DELBA)and novel afterglow system shows tremendous potential for ultrasensitive and rapid clinical diagnosis.

关键词： bioassay photochemical afterglow mesoporous SiO2 nanoparticles(MSNs) nanocomposites dissolution-enhanced

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Aptamer-Based Cell-Surface Profiling with Single-Cell Resolution Enables Precise Cancer Characterization

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CCS Chemistry 2024年第1期6卷 196-207页

作者： Liujun Xu Yawei Feng Tong Wang Shenhuan Li Kangli Xu Yue Sun Yi Luo Yishan Ye Yan Miao Yun Dong Zhenzhen Guo Qing Zhang Benshang Li He Huang Xue-Qiang Wang Liping Qiu Weihong Tan Molecular Science and biomedicine Laboratory State Key Laboratory of Chemo/Biosensing and ChemometricsCollege of Chemistry and Chemical EngineeringCollege of BiologyAptamer Engineering Center of Hunan ProvinceHunan UniversityChangshaHunan 410082 The Key Laboratory of Zhejiang Province for Aptamers and Theranostics Zhejiang Cancer HospitalHangzhou Institute of MedicineChinese Academy of SciencesHangzhouZhejiang 310022 Institute of Molecular Medicine Renji HospitalShanghai Jiao Tong University School of MedicineCollege of Chemistry and Chemical EngineeringShanghai Jiao Tong UniversityShanghai 200240 Bone Marrow Transplantation Center The First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou 310003 Institute of Hematology Zhejiang UniversityHangzhou 310003 Department of Hematology and Oncology Shanghai Children’s Medical CenterShanghai Jiao Tong University School of MedicineShanghai Jiao Tong UniversityShanghai 200127

Molecular profiling of cell-surface proteins is a powerful strategy for precise cancer *** mass cytometry(MC)enables synchronous detection of over 40 cellular parameters,its full potential in disease classification is challenged by the limited types of recognition probes currently *** this work,we synthesize a panel of heavy isotopeconjugated aptamers to profile cancer-associated signatures on the surface of hematological malignancy(HM)*** on 15 molecular signatures,we performed cell-surface profiling that allowed the precise classification of 8 HM cell *** with machine-learning technology,this aptamer-based MC platform also achieved multiclass identification of HM subtypes in clinical sampleswith 100%accuracy in the training cohort and 80%accuracy in the test ***,we report an effective and practical strategy for precise cancer classification at the singlecell level,paving the way for its clinical use in the near future.

关键词： molecular profiling cancer diagnosis mass cytometry aptamers machine learning

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Treatment Sequencing Strategies in Lung Cancer

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中国肺癌杂志 2022年第5期25卷 323-336页

作者： Daniel Humberto Pozza Ramon Bezerra Andrade de Mello Department of biomedicine Faculty of Medicine and i3sUniversity of Porto4200-319 PortoPortugal Discipline of Medical Oncology Post-graduation Program in MedicineNine of July University(UNINOVE)São PauloBrazil./Nine of July HospitalSão PauloBrazi

Background and objective The advances in the lung cancer screening methods and therapeutics,together with awareness towards deleterious habits,such as smoking,is increasing the overall survival with better quality of life for the ***,lung cancer is still one of the most common and fatal neoplasm with a high incidence and consequently burden to public health ***,based on guidelines and recent phasesⅡandⅢclinical trials studies,this manuscript summarizes the current treatment sequencing strategies in lung *** A comprehensive search of related articles was performed focused on phasesⅡandⅢclinical trials *** The lung cancer management should take into consideration the tumor characteristics,histology,molecular pathology and be discussed in a multidisciplinary *** cancer treatment options comprises surgery whenever possible,radiotherapy associate with/or chemotherapy and immunotherapy as monotherapy,or combined with chemotherapy and best palliative *** The screening predictability in more patients,smoking reduction,early diagnosis,better disease understanding and individualized,more effective and tolerable therapeutics are related to an increasing in overall survival and quality of *** the near future improvement of personalized therapy in precision medicine is expected,enhancing new predictive biomarkers,optimal doses and optimal treatment sequencing as well as anti-cancer vaccines development.

关键词： Lung neoplasms Immunotherapy Clinical trials Targeted therapies Pembrolizumab Nivolumab Atezolizumab Necitumumab Brigatinib

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Innovation leading development:a glimpse into three-dimensional bioprinting in Israel

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Bio-Design and Manufacturing 2024年第3期7卷 358-382页

作者： Lujing Gao Zixuan Liu Daniel Dikovsky Jiqian Wang Deqing Mei Lihi Adler-Abramovich Ehud Gazit Kai Tao State Key Laboratory of Heavy Oil Processing and Centre for Bioengineering and Biotechnology College of Chemistry and Chemical EngineeringChina University of Petroleum(East China)Qingdao 266580China Future Science Research Institute Hangzhou Global Scientific and Technological Innovation CentreHangzhou 311200China Zhejiang-Israel Joint Laboratory of Self-Assembling Functional Materials Hangzhou 311200China Redefine Meat Ltd. Rehovot 7670110Israel State Key Laboratory of Fluid Power and Mechatronic Systems School of Mechanical EngineeringZhejiang UniversityHangzhou 310058China Key Laboratory of Advanced Manufacturing Technology of Zhejiang Province School of Mechanical EngineeringZhejiang UniversityHangzhou 310058China Department of Oral Biology The Maurice and Gabriela Goldschleger School of Dental MedicineFaculty of Medical&Health SciencesTel Aviv UniversityTel Aviv 6997801Israel The Center for Nanoscience and Nanotechnology Tel Aviv UniversityTel Aviv 6997801Israel Department of Materials Science and Engineering Iby and Aladar FleischmanTel Aviv UniversityTel Aviv 6997801Israel The Shmunis School of biomedicine and Cancer Research George S.Wise Faculty of Life SciencesTel Aviv UniversityTel Aviv 6997801Israel

Three-dimensional(3D)printing has attracted increasing research interest as an emerging manufacturing technology for devel-oping sophisticated and exquisite architecture through hierarchical *** has also been employed in various advanced industrial *** development of intelligent biomedical engineering has raised the requirements for 3D printing,such as flexible manufacturing processes and technologies,biocompatible constituents,and alternative ***,state-of-the-art 3D printing mainly involves inorganics or polymers and generally focuses on traditional industrial fields,thus severely limiting applications demanding biocompatibility and *** this regard,peptide architectonics,which are self-assembled by programmed amino acid sequences that can be flexibly functionalized,have shown promising potential as bioinspired inks for 3D ***,the combination of 3D printing and peptide self-assembly poten-tially opens up an alternative avenue of 3D bioprinting for diverse advanced ***,a small but innovative nation,has significantly contributed to 3D bioprinting in terms of scientific studies,marketization,and peptide architectonics,including modulations and applications,and ranks as a leading area in the 3D bioprinting *** review summarizes the recent progress in 3D bioprinting in Israel,focusing on scientific studies on printable components,soft devices,and tissue *** paper further delves into the manufacture of industrial products,such as artificial meats and bioinspired supramolecular architectures,and the mechanisms,physicochemical properties,and applications of peptide ***,Israel contributes significantly to the field of 3D bioprinting and should thus be appropriately recognized.

关键词： Israel 3D bioprinting Biomanufacturing Peptide self-assembly Integration of industry,education and research

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