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Correction of a CADAsIL point mutation using adenine base editors in hiPsCsandbloodvessel organoids

Journal of Genetics and Genomics 2024年第2期51卷 197-207页

作者： Jingwen Wang Lei Zhang Guanglan Wu Jinni Wu Xinyao Zhou Xiaolin Chen Yongxia Niu Yiren Jiao Qianyi Liu Puping Liang Guang shi Xueqing Wu Junjiu Huang MOE Key Laboratory of Gene Function and Regulation State Key Laboratory of BiocontrolSchool of Life SciencesSun Yat-sen UniversityGuangzhouGuangdong 510275China Key Laboratory of Reproductive Medicine of Guangdong Province The First Affiliated Hospital and School of Life SciencesSun Yat-sen UniversityGuangzhouGuangdong 510275China Center of Reproductive Medicine Children's Hospital of Shanxi and Women Health Center of ShanxiTaiyuanShanxi 030013China

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADAsIL) is a monogenic small vessel disease caused by mutations in the NOTCH3 gene. However, the pathogenesis of CADAsIL remains unclear, and patients have limited treatment options. Here, we use human induced pluripotent stem cells (hiPsCs) generated from the peripheral blood mononuclear cells of a patient with CADAsIL carrying a heterozygous NOTCH3 mutation (c.1261C>T, p.R421C) to develop a disease model. The correction efficiency of different adenine base editors (ABEs) is tested using the HEK293T-NOTCH3 reporter cell line. ABEmax is selected based on its higher efficiency and minimization of predicted off-target effects. Vascular smooth muscle cells (VsMCs) differentiated from CADAsIL hiPsCs show NOTCH3 deposition and abnormal actin cytoskeleton structure, and the abnormalities are recovered in corrected hiPsC-derived VsMCs. Furthermore, CADAsIL blood vessel organoids generated for in vivo modeling show altered expression of genes related to disease phenotypes, including the downregulation of cell adhesion, extracellular matrix organization, and vessel development. The dual adeno-associated virus (AAV) split-ABEmax system is applied to the genome editing of vascular organoids with an average editing efficiency of 8.82%. Collectively, we present potential genetic therapeutic strategies for patients with CADAsIL using blood vessel organoids and the dual AAV split-ABEmax system.

关键词： CADAsIL Induced pluripotent stem cells Adenine base editors AAV Blood vessel Organoid

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Weakly supervised Object Localization with Background suppression Erasing for Art Authentication and Copyright Protection

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Machine Intelligence Research 2024年第1期21卷 89-103页

作者： Chaojie Wu Mingyang Li Ying Gao Xinyan Xie Wing W.Y.Ng Ahmad Musyafa school of Computer science and Engineering South China University of TechnologyGuangzhou 511442China Guangdong Provincial Key Laboratory of Artificial Intelligence in Medical Image Analysis and Application Guangdong Provincial People's HospitalGuangzhou 510180China

The problem of art forgery and infringement is becoming increasingly prominent,since diverse self-media contents with all kinds of art pieces are released on the Internet every *** art paintings,object detection and localization provide an efficient and ef-fective means of art authentication and copyright ***,the acquisition of a precise detector requires large amounts of ex-pensive pixel-level *** alleviate this,we propose a novel weakly supervised object localization(WsOL)with background su-perposition erasing(BsE),which recognizes objects with inexpensive image-level ***,integrated adversarial erasing(IAE)for vanilla convolutional neural network(CNN)dropouts the most discriminative region by leveraging high-level semantic ***,a background suppression module(BsM)limits the activation area of the IAE to the object region through a self-guidance ***,in the inference phase,we utilize the refined importance map(RIM)of middle features to obtain class-agnostic loc-alization *** experiments are conducted on paintings,CUB-200-2011 and ILsVRC to validate the effectiveness of our BsE.

关键词： Weakly supervised object localization erasing method deep learning computer vision art authentication and copyright protection

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PD-L1-driven efficient enrichment and elimination of circulating cancer cells by magnetic Mose_(2) nanosheet

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Nano Research 2024年第5期17卷 4350-4358页

作者： Hongjie Huang Binhua Zou shanlin Zhu Xingchen Zhang Jiale Huang Jinlin Wang Xiaoling Li Tianfeng Chen The sixth Affiliated hospital Jinan UniversityDongguan 523566China Department of Chemistry Institute of Food Safety and NutritionJinan UniversityGuangzhou 510632China Department of Rehabilitation Medicine Nanfang HospitalSouthern Medical UniversityGuangzhou 510515China Pulmonary and Critical Care Medicine Guangzhou Institute of Respiratory HealthNational Clinical Research Center for Respiratory DiseaseNational Center for Respiratory MedicineState Key Laboratory of Respiratory DiseasesThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510120China

Circulating tumor cells(CTCs)are important biomarkers in the development and progression of lung cancer because they can reach other organs through the blood circulation and form distant metastases,exacerbating lung cancer *** presence of CTCs is also the main reason for the failure of nanomedicine-based lung cancer ***,magnetic Mose_(2) nanosheets loaded with programmed death-ligand 1(PD-L1),named PD-L1-MFP Ns,were employed here to precisely capture lung cancer CTCs in the blood circulation through the tumor-targeting effect of PD-L1 killing CTCs with highly effective photothermal therapy(PTT).In addition,by increasing the expression of cytomegalovirus UL16-binding protein(ULBP)ligands on tumor cells,the PD-L1-MFP Ns further activated natural killer(NK)cells and triggered NK cell-induced cancer immunotherapy,thereby enhancing the overall tumor-killing *** summary,this material designed to capture CTCs provides a substantial advancement for personalized PTT-triggered immunotherapy and has great clinical translational potential.

关键词： circulating tumor cells selenide photothermal therapy(PTT) natural killer(NK)cell immunotherapy

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CARD11 serves as a therapeutic biomarker for the drug therapies of ccRCC

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BIOCELL 2024年第5期48卷 817-834页

作者： KAIWEN TIAN HANZHONG CHEN QIANQIAN WANG FENGLIAN JIANG CHUNXIANG FENG TENG LI XIAOYONG PU YANLIN TANG JIUMIN LIU Department of Urology Guangdong Provincial People’s Hospital(Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhou510080China

Background:The incidence of clear cell renal cell carcinoma(ccRCC)is globally high;however,despite the introduction of innovative drug therapies,there remains a lack of effective biomarkers for evaluating treatment ***,Caspase recruiting domain-containing protein 11(CARD11)has garnered attention due to its significant association with tumor development and the immune ***:The expression of CARD11 mRNA and protein in ccRCC were analyzed by public database and *** focus of this study is on the epigenomic modifications of CARD11,its expression of ccRCC immunophenotype,and its correlation with response to immunotherapy and targeted ***,to investigate the mechanism of this molecule’s influence on different biological behaviors of cells,cell tests in vitro have been conducted to observe the impact of its expression ***:CARD11 expression was upregulated which may be mainly modified by body methylation and was correlated with poor prognosis in *** the tumor microenvironment of ccRCC,CARD11 expression was positively correlated with increased T lymphocyte infiltration and increased expression of inhibitory immune ***,ccRCC patients with high CARD11 expression had a better response to immunotherapy and targeted *** knockdown of CARD11 ultimately suppressed the proliferation,migration,and invasion capabilities of ccRCC cells while simultaneously enhancing tumor cell ***:We identified CARD11 as a novel therapeutic biomarker for immunotherapy and targeted therapy in ccRCC.

关键词： Clear cell renal cell carcinoma Tumor microenvironment CARD11 Immune checkpoint inhibitor Tyrosine kinase inhibitor

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ALKBH5 gene polymorphisms and risk of neuroblastoma in Chinese children from Jiangsu Province

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Cancer Innovation 2024年第2期3卷 72-79页

作者： Qian Guan Xinxin Zhang Jiabin Liu Chunlei Zhou Jinhong Zhu Haiyan Wu Zhenjian Zhuo Jing He Department of Pediatric surgery Guangzhou Institute of PediatricsGuangdong Provincial Key Laboratory of Research in Structural Birth Defect DiseaseGuangdong Provincial Clinical Research Center for Child HealthGuangzhou Women and Children's Medical CenterGuangzhou Medical UniversityGuangzhouGuangdongChina Department of Pathology Children's Hospital of Nanjing Medical UniversityNanjingJiangsuChina Department of Clinical Laboratory BiobankHarbin Medical University Cancer HospitalHarbinHeilongjiangChina Laboratory Animal Center School of Chemical Biology and BiotechnologyPeking University Shenzhen Graduate SchoolShenzhenGuangdongChina

Background:Neuroblastoma is one of the most common extracranial malignant solid tumors in *** homolog 5(ALKBH5)is an RNA N6-methyladenosine(m6A)demethylase that plays a critical role in tumorigenesis and *** assessed the association between single nucleotide polymorphisms(sNPs)in ALKBH5 and the risk of neuroblastoma in a case-control study including 402 patients and 473 non-cancer ***:Genotyping was determined by the TaqMan *** association between ALKBH5 polymorphisms(rs1378602 and rs8400)and the risk of neuroblastoma was evaluated using the odds ratio(OR)and 95%confidence interval(CI).Results:We found no strong association of ALKBH5 rs1378602 and rs8400 with neuroblastoma *** stratification analysis by age,sex,primary site,and clinical stage showed that the rs1378602 AG/AA genotype was associated with a lower risk of neuroblastoma in males(adjusted OR=0.58,95%CI=0.35–0.97,p=0.036)and children with retroperitoneal neuroblastoma(adjusted OR=0.58,95%CI=0.34–0.98,p=0.040).Conclusions:ALKBH5 sNPs do not seem to be associated with neuroblastoma *** studies are required to confirm this negative result and reveal the relationship between gene polymorphisms of the m6A modifier ALKBH5 and neuroblastoma.

关键词： ALKBH5 neuroblastoma polymorphism susceptibility

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FGF7 enhances the expression of ACE2 in human islet organoids aggravating sARs-CoV-2 infection

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signal Transduction and Targeted Therapy 2024年第5期9卷 2260-2274页

作者： Hao Meng Zhiying Liao Yanting Ji Dong Wang Yang Han Chaolin Huang Xujuan Hu Jingyi Chen Hengrui Zhang Zonghong Li Changliang Wang Hui sun Jiaqi sun Lihua Chen Jiaxiang Yin Jincun Zhao Tao Xu Huisheng Liu school of Biomedical Engineering Guangzhou Medical UniversityGuangzhou 511495 GuangdongChina guangzhou National Laboratory Guangzhou 510320 GuangdongChina state Key Laboratory of Respiratory Disease National Clinical Research Center for Respiratory DiseaseGuangzhou Institute of Respiratory HealthThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510120China Center for Translational Medicine Wuhan Jinyintan HospitalWuhan 430023 HubeiChina school of Biomedical sciences and Engineering South China University of TechnologyGuangzhou 510006 GuangdongChina

The angiotensin-converting enzyme 2(ACE2)is a primary cell surface viral binding receptor for sARs-CoV-2,so finding new regulatory molecules to modulate ACE2 expression levels is a promising strategy against *** the current study,we utilized islet organoids derived from human embryonic stem cells(hEsCs),animal models and COVID-19 patients to discover that fibroblast growth factor 7(FGF7)enhances ACE2 expression within the islets,facilitating sARs-CoV-2 infection and resulting in impaired insulin *** hEsC-derived islet organoids,we demonstrated that FGF7 interacts with FGF receptor 2(FGFR2)and FGFR1 to upregulate ACE2 expression predominantly inβ*** upregulation increases both insulin secretion and susceptibility ofβcells to sARs-CoV-2 *** FGFR counteracts the FGF7-induced ACE2 upregulation,subsequently reducing viral infection and replication in the ***,retrospective clinical data revealed that diabetic patients with severe COVID-19 symptoms exhibited elevated serum FGF7 levels compared to those with mild ***,animal experiments indicated that sARs-CoV-2 infection increased pancreatic FGF7 levels,resulting in a reduction of insulin concentrations in *** together,our research offers a potential regulatory strategy for ACE2 by controlling FGF7,thereby protecting islets from sARs-CoV-2 infection and preventing the progression of diabetes in the context of COVID-19.

关键词： ACE2 FGF7 islet

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sARs-CoV-2 immunity in animal models

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Cellular & Molecular Immunology 2024年第2期21卷 119-133页

作者： Zhao Chen Yaochang Yuan Qingtao Hu Airu Zhu Fenghua Chen shu Li Xin Guan Chao Lv Tian Tang Yiyun He Jinling Cheng Jie Zheng Xiaoyu Hu Jingxian Zhao Jincun Zhao Jing sun state Key Laboratory of Respiratory Disease National Clinical Research Centre for Respiratory DiseaseNational Centre for Respiratory MedicineGuangzhou Institute of Respiratory Healththe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouGuangdong 510182China GMU-GIBH Joint school of Life sciences Guangzhou Medical UniversityGuangzhou 510000China guangzhou National Laboratory GuangzhouGuangdong 510005China shanghai Institute for Advanced Immunochemical studies School of Life Science and TechnologyShanghaiTech UniversityShanghai 201210China Institute for Hepatology National Clinical Research Center for Infectious DiseaseShenzhen Third People’s Hospitalthe Second Affiliated HospitalSchool of MedicineSouthern University of Science and TechnologyShenzhen 518005China

The COVID-19 pandemic,which was caused by severe acute respiratory syndrome coronavirus 2(sARs-CoV-2),has become a worldwide health crisis due to its ***-CoV-2 infection results in severe respiratory illness and can lead to significant complications in affected *** complications encompass symptoms such as coughing,respiratory distress,fever,infectious shock,acute respiratory distress syndrome(ARDs),and even multiple-organ *** models serve as crucial tools for investigating pathogenic mechanisms,immune responses,immune escape mechanisms,antiviral drug development,and vaccines against ***,various animal models for sARs-CoV-2 infection,such as nonhuman primates(NHPs),ferrets,hamsters,and many different mouse models,have been *** model possesses distinctive features and *** this review,we elucidate the immune response elicited by sARs-CoV-2 infection in patients and provide an overview of the characteristics of various animal models mainly used for sARs-CoV-2 infection,as well as the corresponding immune responses and applications of these models.A comparative analysis of transcriptomic alterations in the lungs from different animal models revealed that the K18-hACE2 and mouse-adapted virus mouse models exhibited the highest similarity with the deceased COVID-19 ***,we highlighted the current gaps in related research between animal model studies and clinical investigations,underscoring lingering scientific questions that demand further clarification.

关键词： COVID-19 sARs-CoV-2 animal models immune response

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Transferrin receptor-targeted immunostimulant for photodynamic immunotherapy against metastatic tumors through b-catenin/CREB interruption

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Acta Pharmaceutica sinica B 2024年第9期14卷 4118-4133页

作者： Mengyi Yan Xiayun Chen Xiaotong Li Qianqian Liu Baixue Yu Yi Cen Wei Zhang Yibin Liu Xinxuan Li Ying Chen Tao Wang shiying Li The Fifth Affiliated hospital Guangdong Provincial Key Laboratory of Molecular Target&Clinical Pharmacologythe NMPA and State Key Laboratory of Respiratory Diseasethe School of Pharmaceutical SciencesGuangzhou Medical UniversityGuangzhou 511436China Department of Anesthesiology the Second Clinical School of Guangzhou Medical UniversityGuangzhou 511436China state Key Laboratory of Respiratory Diseases Guangdong Key Laboratory of Vascular DiseasesGuangzhou Institute of Respiratory Healththe first Affiliated HospitalGuangzhou Medical UniversityGuangzhou 510120China Department of Pulmonary and Critical Care Medicine Zhujiang HospitalSouthern Medical UniversityGuangzhou 510280China

The immunosuppressive phenotype of tumor cells extensively attenuates the immune activation effects of traditional *** this work,a transferrin receptor(TfR)targeted immunostimulant(PTI)is fabricated for photodynamic immunotherapy against metastatic tumors by interrupting b-catenin signal *** synthesize PTI,the photosensitizer conjugated TfR targeting peptide moiety(Palmitic-K(PpIX)-HAIYPRH)is unitized to encapsulate the transcription interrupter of *** the one hand,the recognition of PTI and TfR can promote drug delivery into tumor cells to destruct primary tumors through photodynamic therapy and initiate an immunogenic cell death with the release of tumorassociated *** the other hand,PTI will interrupt the binding between b-catenin andcAMP response element-binding protein(CREB),regulating the gene transcription to downregulate programmed death ligand 1(PD-L1)while upregulating CeC motif chemokine ligand 4(CCL4).Furthermore,the elevated CCL4 can recruit the dendritic cells to present tumor-specific antigens and promote T cells activation and infiltration,and the downregulated PD-L1 can avoid the immune evasion of tumor cells and activate systemic anti-tumor immunity to eradicate lung *** work may inspire the development of antibody antibody-free strategy to activate systemic immune response in consideration of immunosuppressive conditions.

关键词： Transferrin receptor b-Catenin signal pathway Tumor targeting Photodynamic therapy Immunotherapy Immunogenic cell death Programmed death ligand 1

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Targeting Therapeutic Windows for Rheumatoid Arthritis Prevention

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Chinese Journal of Integrative Medicine 2024年第9期30卷 842-851页

作者： GAO Kai-xin YANG Yi-hong LIANG Qi MEI Li-yan LIANG You-bang WANG Mao-jie CHEN Xiu-min HUANG Qing-chun WEN Ze-huai HUANG Run-yue section of Rheumatology and Immunology Research The Second Affiliated Hospital of Guangzhou University of Chinese MedicineGuangzhou510120China The second Clinical Medical College Guangzhou University of Chinese MedicineGuangzhou510405China state Key Laboratory of Dampness syndrome of Chinese Medicine The Second Affiliated Hospital of Guangzhou University of Chinese MedicineGuangzhou510120China Guangdong-Hong Kong-Macao Joint Lab on Chinese Medicine and Immune Disease Research Guangzhou University of Chinese MedicineGuangzhou510405China Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine syndrome Guangzhou510120China Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases Guangzhou510120China The Key Unit of Methodology of Clinical Research The Second Affiliated Hospital of Guangzhou University of Chinese MedicineGuangzhou510120China

Rheumatoid arthritis(RA)is a worldwide public health *** to delay or prevent the onset of RA have attracted much attention in recent years,and researchers are now exploring various prevention *** present,there is still no unified consensus for RA prevention,but targeting therapeutic windows and implementing interventions for at-risk individuals are extremely *** to the limited number of clinical trials on pharmacologic interventions,further studies are needed to explore and establish optimal intervention regimens and effective measures to prevent progression to *** this review,we introduce the RA disease process and risk factors,and present research on the use of both Western and Chinese medicine from clinical perspectives regarding RA ***,we describe several complete and ongoing clinical studies on the use of Chinese herbal formulae for the prevention of RA.

关键词： rheumatoid arthritis prevention Chinese medicine review

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Reconstruction of Postinfarcted Cardiac Functions Through Injection of Tanshinone ⅡA@Reactive Oxygen species-sensitive Microspheres Encapsulated in a Thermoreversible Hydrogel

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Energy & Environmental Materials 2024年第2期7卷 187-199页

作者： Ling Yu Yubin Liang Lei Gao Peipei Chen Zhiqiang Yu Minzhou Zhang Aleksander Hinek shuai Mao second Clinical College Guangzhou University of Chinese MedicineGuangzhou 510120China Department of Critical Care Medicine Guangdong Provincial Hospital of Chinese MedicineGuangzhou 510120China Guangdong Provincial Branch of National Clinical Research Centre for Chinese Medicine Cardiology Guangzhou 510120China Department of Radiation Medicine and Applied sciences University of California San DiegoLa JollaCalifornia 92093USA Department of Laboratory Medicine Dongguan Institute of Clinical Cancer ResearchAffiliated Dongguan HospitalSouthern Medical UniversityDongguan 523018China Translational Medicine Hospital for Sick ChildrenToronto M5G 0A4Canada

Myocardial damage resulting from acute myocardial infarction often leads to progressive heart failure and sudden death,highlighting the urgent clinical need for effective ***,tanshinoneⅡA has been identified as a promising therapeutic agent for myocardial ***,efficient delivery remains a major issue that limits clinical *** address this problem,an injectable thermosensitive poly(lactic acid-co-glycolic acid)-block-poly(ethylene glycol)-block-poly(lactic acid-co-glycolic acid)gel(PLGA-PEG-PLGA)system encapsulating tanshinoneⅡA-loaded reactive oxygen species-sensitive microspheres(Gel-Ms/tanshinoneⅡA)has been designed and synthesized in this *** thermosensitive hydrogel exhibits good mechanical properties after reaching body *** initially immobilized by the gel exhibit excellent reactive oxygen species-triggered release properties in a high-reactive oxygen species environment after myocardial infarction *** a result,encapsulated tanshinoneⅡA is effectively released into the infarcted myocardium,where it exerts local anti-pyroptotic and anti-inflammatory ***,the combined advantages of this technique contribute to the mitigation of left ventricular remodeling and the restoration of cardiac function following tanshinoneⅡ***,this novel,precision-guided intra-tissue therapeutic system allows for customized local release of tanshinoneⅡA,presenting a promising alternative treatment strategy aimed at inducing beneficial ventricular remodeling in the post-infarct heart.

关键词： myocardial infarction ROs-sensitive polymer tanshinoneⅡA thermoreversible hydrogel ventricular remodeling

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