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Alternative splicing and related RNA binding proteins in human health and disease

Signal Transduction and Targeted Therapy 2024年第3期9卷 839-871页

作者： Yining Tao Qi Zhang Haoyu Wang Xiyu Yang Haoran Mu department of Orthopedics Shanghai General HospitalShanghai Jiao Tong University School of Medicine200000 ShanghaiChina Shanghai Bone tumor Institution 200000 ShanghaiChina department of Biochemistry and Molecular Cell Biology Shanghai Key Laboratory for Tumor Microenvironment and InflammationShanghai Jiao Tong University School of Medicine200000 ShanghaiChina

Alternative splicing(AS)serves as a pivotal mechanism in transcriptional regulation,engendering transcript diversity,and modifications in protein structure and *** varying tissues,developmental stages,or under specific conditions,AS gives rise to distinct splice *** implies that these isoforms possess unique temporal and spatial roles,thereby associating AS with standard biological activities and *** these,AS-related RNA-binding proteins(RBPs)play an instrumental role in regulating alternative splicing *** physiological conditions,the diversity of proteins mediated by AS influences the structure,function,interaction,and localization of proteins,thereby participating in the differentiation and development of an array of tissues and *** pathological conditions,alterations in AS are linked with various diseases,particularly *** changes can lead to modifications in gene splicing patterns,culminating in changes or loss of protein *** instance,in cancer,abnormalities in AS and RBPs may result in aberrant expression of cancer-associated genes,thereby promoting the onset and progression of *** and RBPs are also associated with numerous neurodegenerative diseases and autoimmune ***,the study of AS across different tissues holds significant *** review provides a detailed account of the recent advancements in the study of alternative splicing and AS-related RNA-binding proteins in tissue development and diseases,which aids in deepening the understanding of gene expression complexity and offers new insights and methodologies for precision medicine.

关键词： organs alterations thereby

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STING agonist-conjugated metal-organic framework induces artificial leukocytoid structures and immune hotspots for systemic antitumor responses

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National Science Review 2024年第7期11卷 189-204页

作者： Taokun Luo Xiaomin Jiang Yingjie Fan Eric Yuan Jinhong Li Langston Tillman Wenbin Lin department of Chemistry University of Chicago department of Radiation and Cellular Oncology and the Ludwig Center for metastasis Research University of Chicago

Radiotherapy is widely used for cancer treatment, but its clinical utility is limited by radioresistance and its inability to target metastases. Nanoscale metal-organic frameworks(MOFs) have shown promise as high-Z nanoradiosensitizers to enhance radiotherapy and induce immunostimulatory regulation of the tumor microenvironment. We hypothesized that MOFs could deliver small-molecule therapeutics to synergize with radiotherapy for enhanced antitumor efficacy. Herein, we develop a robust nanoradiosensitizer,GA-MOF, by conjugating a STING agonist, 2,3-cyclic guanosine monophosphate–adenosine monophosphate(GA), on MOFs for synergistic radiosensitization and STING activation. GA-MOF demonstrated strong anticancer efficacy by forming immune-cell-rich nodules(artificial leukocytoid structures) and transforming them into immunostimulatory hotspots with radiotherapy. Further combination with an immune checkpoint blockade suppressed distant tumors through systemic immune activation. Our work not only demonstrates the potent radiosensitization of GA-MOF, but also provides detailed mechanisms regarding MOF distribution, immune regulatory pathways and long-term immune effects.

关键词： metal-organic framework radiosensitization STING agonist artificial leukocytoid structures immune hotspots immunotherapy nanomedicine

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Spatial relationship of tertiary lymphoid structures and tumor-associated neutrophils in bladder cancer and prognostic potential for anti-PD-L1 immunotherapy

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Cancer Communications 2024年第4期44卷 499-503页

作者： Xuechun Wang Anna Juncker-Jensen Gang Huang Mate Levente Nagy Xuemin Lu Liang Cheng Xin Lu department of Biological Sciences Boler-Parseghian Center for Rare and Neglected DiseasesHarper Cancer Research InstituteUniversity of Notre DameNotre DameINUSA NeoGenomics Laboratories Inc.Aliso ViejoCAUSA department of Pathology and Laboratory Medicine Brown University Warren Alpert Medical SchoolLifespan Academic Medical CenterLegorreta Cancer Center at Brown UniversityProvidenceRIUSA tumor microenvironment and metastasis Program Indiana University Melvin and Bren Simon Comprehensive Cancer CenterIndianapolisINUSA

Dear Editor,Tertiary lymphoid structures(TLSs)are organized clus-ters of immune cells found in non-lymphoid tissues of chronic inflammation,including solid tumors[1].High endothelial venules(HEVs)positive for peripheral node addressin(PNAd)are present in TLSs and may pro-vide highway entry for ***-residing TLSs may be formed by the concerted actions of cytokines and chemokines,a finding supported by the relation between a 12-chemokine signature and TLSs[2].

关键词： bladder lymphoid inflammation

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DNA Damage-driven Inflammatory Cytokines:Reprogramming of tumor Immune microenvironment and Application of Oncotherapy

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Current Medical Science 2024年第2期44卷 261-272页

作者： Meng-jie WANG Yu XIA Qing-lei GAO department of Obstetrics and Gynecology National Clinical Research Center for Obstetrics and GynecologyTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China Key Laboratory of Cancer Invasion and metastasis(Ministry of Education) Hubei Key Laboratory of Tumor Invasion and MetastasisTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China

DNA damage occurs across tumorigenesis and tumor *** intrinsic DNA damage can not only increase the risk of mutations responsible for tumor generation but also initiate a cellular stress response to orchestrate the tumor immune microenvironment(TIME)and dominate tumor *** evidence documents that multiple signaling pathways,including cyclic GMP-AMP synthase-stimulator of interferon genes(cGAS-STING)and ataxia telangiectasia-mutated protein/ataxia telangiectasia and Rad3-related protein(ATM/ATR),are activated downstream of DNA damage and they are associated with the secretion of diverse *** cytokines possess multifaced functions in the anti-tumor immune ***,it is necessary to deeply interpret the complex TIME reshaped by damaged DNA and tumor-derived cytokines,critical for the development of effective tumor *** manuscript comprehensively reviews the relationship between the DNA damage response and related cytokines in tumors and depicts the dual immunoregulatory roles of these *** also summarize clinical trials targeting signaling pathways and cytokines associated with DNA damage and provide future perspectives on emerging technologies.

关键词： DNA damage tumor immune microenvironment inflammatory cytokines cancer therapy

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Human umbilical cord mesenchymal stem cell-derived exosomes loaded into a composite conduit promote functional recovery after peripheral nerve injury in rats

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Neural Regeneration Research 2024年第4期19卷 900-907页

作者： Haoshuai Tang Junjin Li Hongda Wang Jie Ren Han Ding Jun Shang Min Wang Zhijian Wei Shiqing Feng department of Othopaedics Tianjin Medical University General Hospital International Science and Technology Cooperation Base of Spinal Cord Injury Tianjin Key Laboratory of Spine and Spinal Cord InjuryDepartment of OrthopedicsTianjin Medical University General Hospital Tianjin Key Laboratory of Lung Cancer metastasis and tumor microenvironment Tianjin Lung Cancer InstituteTianjin Medical University General Hospital department of Othopaedics Qilu Hospital of Shandong UniversityShandong University Centre for OthopedicsAdvanced Medical Research InstituteShandong University Orthopedic Research Center of Shandong University&Advanced Medical Research Institute Cheeloo College of MedicineShandong University

Complete transverse injury of peripheral nerves is challenging to *** secreted by human umbilical cord mesenchymal stem cells are considered to play an important role in intercellular communication and regulate tissue *** previous studies,a collagen/hyaluronic acid sponge was shown to provide a suitable regeneration environment for Schwann cell proliferation and to promote axonal *** three-dimensional(3D)composite conduit contains a collagen/hyaluronic acid inner sponge enclosed in an electrospun hollow poly(lactic-co-glycolic acid)***,whether there is a synergy between the 3D composite conduit and exosomes in the repair of peripheral nerve injury remains *** this study,we tested a comprehensive strategy for repairing long-gap(10 mm)peripheral nerve injury that combined the 3D composite conduit with human umbilical cord mesenchymal stem cell-derived *** effectiveness was evaluated by sciatic functional index,sciatic nerve compound muscle action potential recording,recovery of muscle mass,measuring the cross-sectional area of the muscle fiber,Masson trichrome staining,and transmission electron microscopy of the regenerated nerve in *** results showed that transplantation of the 3D composite conduit loaded with human umbilical cord mesenchymal stem cell-derived exosomes promoted peripheral nerve regeneration and restoration of motor function,similar to autograft *** CD31-positive endothelial cells were observed in the regenerated nerve after transplantation of the loaded conduit than after transplantation of the conduit without exosomes,which may have contributed to the observed increase in axon regeneration and distal nerve ***,the use of a 3D composite conduit loaded with human umbilical cord mesenchymal stem cell-derived exosomes represents a promising cell-free therapeutic option for the treatment of peripheral nerve injury.

关键词： axon growth collagen exosome human umbilical cord mesenchymal stem cells hyaluronic acid muscular atrophy nerve guidance conduits peripheral nerve regeneration

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An engineered DNA aptamer-based PROTAC for precise therapy of p53-R175H hotspot mutant-driven cancer

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Science Bulletin 2024年第13期69卷 2122-2135页

作者： Lingping Kong Fanlu Meng Ping Zhou Ruixin Ge Xiaoshan Geng Zhihao Yang Guo Li Linlin Zhang Jing Wang Jinfeng Ma Cheng Dong Jun Zhou Sijin Wu Diansheng Zhong Songbo Xie department of Medical Oncology Tianjin Medical University General HospitalTianjin 300052China Center for Cell Structure and Function Collaborative Innovation Center of Cell Biology in Universities of ShandongCollege of Life SciencesShandong Normal UniversityJinan 250014China The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics Key Laboratory of Immune Microenvironment and Disease(Ministry of Education)School of Basic Medical SciencesTianjin Medical UniversityTianjin 300070China Tianjin Key Laboratory of Lung Cancer metastasis and tumor microenvironment Lung Cancer InstituteTianjin Medical University General HospitalTianjin 300052China Haihe Laboratory of Cell Ecosystem State Key Laboratory of Medicinal Chemical BiologyCollege of Life SciencesNankai UniversityTianjin 300071China Wisdom Lake Academy of Pharmacy Xi’an Jiaotong-Liverpool UniversitySuzhou 215028China department of Ophthalmology Tianjin Medical University General HospitalLaboratory of Molecular OphthalmologyTianjin Key Laboratory of Ocular TraumaTianjin Medical UniversityTianjin 300052China

Targeting oncogenic mutant p53 represents an attractive strategy for cancer treatment due to the high frequency of gain-of-function mutations and ectopic expression in various cancer *** extensive efforts,the absence of a druggable active site for small molecules has rendered these mutants therapeutically *** we develop a selective and effective proteolysis-targeting chimera(PROTAC)for p53-R175H,a common hotspot mutant with dominant-negative and oncogenic *** a novel iterative molecular docking-guided post-SELEX(systematic evolution of ligands by exponential enrichment)approach,we rationally engineer a high-performance DNA aptamer with improved affinity and specificity for *** this resulting aptamer as a binder for PROTACs,we successfully developed a selective p53-R175H degrader,named ***53m induces the ubiquitin–protea some-dependent degradation of p53-R175H while sparing wildtype ***,dp53m demonstrates significant antitumor efficacy in p53-R175H-driven cancer cells both in vitro and in vivo,without ***,dp53m significantly and synergistically improves the sensitivity of these cells to cisplatin,a commonly used chemotherapy *** findings provide evidence of the potential therapeutic value of dp53m in p53-R175H-driven cancers.

关键词： P53 Aptamer PROTAC Cancer Drug resistance

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Aspirin suppresses hepatocellular carcinoma progression by inhibiting platelet activity

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World Journal of Gastrointestinal Oncology 2024年第6期16卷 2742-2756页

作者： Li-Jun Zhao Zhi-Yin Wang Wei-Ting Liu Li-Li Yu Hao-Nan Qi Jie Ren Chen-Guang Zhang Hematology Laboratory The First Affiliated Hospital of Xinxiang Medical UniversityXinxiang 453100Henan ProvinceChina Xinxiang Key Laboratory of tumor microenvironment and Immunotherapy School of Medical TechnologyXinxiang Medical UniversityXinxiang 453003Henan ProvinceChina School of Public Health Xinxiang Medical UniversityXinxiang 453003Henan ProvinceChina

BACKGROUND Hepatocellular carcinoma(HCC)is the most common malignant liver disease in the ***(PLTs)are known to play a key role in the maintenance of liver homeostasis and the pathophysiological processes of a variety of liver *** is the most classic antiplatelet ***,the molecular mechanism of platelet action and whether aspirin can affect HCC progression by inhibiting platelet activity need further *** To explore the impact of the antiplatelet effect of aspirin on the development of *** Platelet-rich plasma,platelet plasma,pure platelet,and platelet lysate were prepared,and a coculture model of PLTs and HCC cells was ***-8 analysis,apoptosis analysis,Transwell analysis,and real-time polymerase chain reaction(RT-PCR)were used to analyze the effects of PLTs on the growth,metastasis,and inflammatory microenvironment of ***-PCR and Western blot were used to detect the effects of platelet activation on tumor-related signaling *** was used to block the activation and aggregation of PLTs both in vitro and in vivo,and the effect of PLTs on the progression of HCC RESULTS PLTs significantly promoted the growth,invasion,epithelial-mesenchymal transition,and formation of an inflammatory microenvironment in HCC *** PLTs promoted HCC progression by activating the mitogenactivated protein kinase/protein kinase B/signal transducer and activator of transcription three(MAPK/AKT/STAT3)signaling ***,aspirin inhibited HCC progression in vitro and in vivo by inhibiting platelet *** PLTs play an important role in the pathogenesis of HCC,and aspirin can affect HCC progression by inhibiting platelet *** results suggest that antiplatelet therapy has promising application prospects in the treatment and combined treatment of HCC.

关键词： Platelets Antiplatelet therapy Hepatocellular carcinoma Aspirin Antitumor

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PDCD2 as a prognostic biomarker in glioma correlates with malignant phenotype

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Genes & Diseases 2024年第5期11卷 390-406页

作者： Fengsheng Dai Yixiao Yuan Jiaqi Hao Xing Cheng Xiangyi Zhou Li Zhou Rui Tian Yi Zhao Tingxiu Xiang department of Oncology The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400010China Chongqing Key Laboratory of Translational Research for Cancer metastasis and Individualized Treatment Chongqing University Cancer HospitalChongqing 400030China department of Neurosurgery Xiangya HospitalCentral South UniversityChangshaHunan 410008China Hunan International Scientific and Technological Cooperation Base of Brain tumor Research Xiangya HospitalCentral South UniversityChangshaHunan 410008China department of Neuro-Oncology Chongqing University Cancer HospitalChongqing 400030China

Programmed cell death 2(PDCD2)is related to cancer progression and chemotherapy *** role of PDCD2 in solid cancers(excluding hematopoietic malignancies)and their diagnosis and prognosis remains *** TCGA,CGGA,GEPIA,cBioPortal,and GTEx databases were analyzed for expression,prognostic value,and genetic modifications of PDCD2 in cancer *** enrichment analysis,CCK8,colony formation assay,transwell assay,and xenograft tumor model were undertaken to study the PDCD2’s biological function in glioma(GBMLGG).The PDCD2 gene was associated with solid cancer *** the functional enrichment analysis results,PDCD2 was shown to participate in several important GBMLGG biological *** cells may be inhibited in their proliferation,migration,invasion,and xenograft tumor growth by knocking down *** research can provide new insights into solid cancer prognostic biomarkers of PDCD2.

关键词： Biomarker Glioma Programmed cell death 2 Progression Solid cancer

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The role of proteasomes in tumorigenesis

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Genes & Diseases 2024年第4期11卷 155-169页

作者： Xiangyi Zhou Ruqing Xu Yue Wu Li Zhou Tingxiu Xiang department of Oncology The First Affliated Hospital of Chongqing Medical UniversityChongqing 400016China Chongqing Key Laboratory of Translational Research for Cancer metastasis and Individualized Treatment Chongqing University Cancer HospitalChongqing 400030China

Protein homeostasis is the basis of normal life activities,and the proteasomefamily plays an extremely important function in this *** proteasome 2os is a concentric circle structure with twoαrings and twoβrings *** proteasome 2os can perform both ATP-dependent and non-ATP-dependent ubiquitination proteasome degradation by binding to various subunits(such as 19S,11S,and 200 PA),which is performed by its active subunitβ1,β2,andβ*** proteasome can degrade misfolded,excess proteins tomaintain *** the same time,it can be utilized by tumors to degrade over-proliferate and unwanted proteins to support their *** can affect the development of tumors from several aspects including tumor signaling pathways such as NF-kB and p53,cell cycle,immune regulation,and drug ***-encoding genes have been found to be overexpressed in a variety of tumors,providing a potential novel target for cancer *** addition,proteasome inhibitors such as bortezomib,carfilzomib,and ixazomib have been put into clinical application as the first-line treatment of multiple *** and more studies have shown that it also has different therapeutic effects in other tumors such as hepatocellular carcinoma,non-small cell lung cancer,glioblastoma,and ***,proteasome inhibitors are not much effective due to their tolerance and singleness in other ***,further studies on their mechanisms of action and drug interactions are needed to investigate their therapeutic potential.

关键词： Bortezomib Cancer therapy Immunoproteasome Multiplemyeloma Proteasome 20S Proteasome inhibitor Thymoproteasom

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Gut microbial metabolite targets HDAC3-FOXK1-interferon axis in fibroblast-like synoviocytes to ameliorate rheumatoid arthritis

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Bone Research 2024年第2期12卷 421-437页

作者： Hongzhen Chen Xuekun Fu Xiaohao Wu Junyi Zhao Fang Qiu Zhenghong Wang Zhuqian Wang Xinxin Chen Duoli Xie Jie Huang Junyu Fan Xu Yang Yi Song Jie Li Dongyi He Guozhi Xiao Aiping Lu Chao Liang department of Systems Biology School of Life SciencesSouthern University of Science and TechnologyGuangdong Provincial Key Laboratory of Cell Microenvironment and Disease ResearchShenzhen Key Laboratory of Cell MicroenvironmentShenzhen 518055China Institute of Integrated Bioinfomedicine and Translational Science(IBTS) School of Chinese MedicineHong Kong Baptist UniversityHong Kong SAR 999077China department of Biochemistry School of MedicineSouthern University of Science and TechnologyGuangdong Provincial Key Laboratory of Cell Microenvironment and Disease ResearchShenzhen Key Laboratory of Cell MicroenvironmentShenzhen 518055China Division of Immunology and Rheumatology Stanford UniversityStanfordCA 94305USA VA Palo Alto Health Care System Palo AltoCA 94304USA Institute of Plant and Food Science Department of BiologySouthern University of Science and TechnologyShenzhen 518055China department of Rheumatology Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghai University of Traditional Chinese MedicineShanghaiChina department of Computational Biology St.Jude Children’s Research HospitalMemphisTNUSA department of Laboratory Medicine Peking University Shenzhen HospitalShenzhenChina Guangdong-Hong Kong-Macao Joint Lab on Chinese Medicine and Immune Disease Research Guangzhou 510006China Shanghai University of Traditional Chinese Medicine Shanghai 200032China State Key Laboratory of Proteomics National Center for Protein Sciences(Beijing)Beijing Institute of Lifeomics100850 BeijingChina

Rheumatoid arthritis(RA)is an autoimmune *** studies hold an opinion that gut microbiota is environmentally acquired and associated with RA ***,accumulating evidence demonstrates that genetics also shape the gut *** is known that some strains of inbred laboratory mice are highly susceptible to collagen-induced arthritis(CIA),while the others are resistant to ***,we show that transplantation of fecal microbiota of CIA-resistant C57BL/6J mice to CIA-susceptible DBA/1J mice confer CIA resistance in DBA/1J mice.C57BL/6J mice and healthy human individuals have enriched *** than DBA/1J mice and RA *** of *** prevents CIA in DBA/1J *** identify that *** mainly produces propionate and C57BL/6J mice and healthy human individuals have higher level of ***-like synoviocytes(FLSs)in RA are activated to undergo tumor-like *** disrupts HDAC3-FOXK1 interaction to increase acetylation of FOXK1,resulting in reduced FOXK1 stability,blocked interferon signaling and deactivation of *** treat CIA mice with propionate and show that propionate attenuates ***,a combination of propionate with anti-TNF etanercept synergistically relieves *** results suggest that *** or propionate could be an alternative or complementary approach to the current therapies.

关键词： HDAC3 cytes interferon

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