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Branched glycopolymer prodrug-derived nanoassembly combined with a STING agonist activates an immuno-supportive status to boost anti-PD-L1 antibody therapy

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2194-2209页

作者： Zhilin Li Qianfeng Zhang Zhiqian Li Long Ren Dayi Pan Qiyong Gong Zhongwei Gu Hao Cai Kui Luo Department of Radiology Huaxi MR Research Center(HMRRC)Clinical Research Center for BreastDepartment of Breast SurgeryDepartment of Thoracic Surgery and Institute of Thoracic OncologyFrontiers Science Center for Disease-Related Molecular NetworkState Key Laboratory of BiotherapyWest China Hospital Sichuan UniversityChengdu 610041China Functional and Molecular Imaging Key Laboratory of Sichuan Province and Research Unit of PsychoradiologyChinese Academy of Medical SciencesChengdu 610041China Department of Radiology West China Xiamen Hospital of Sichuan UniversityXiamen 361021China Key Laboratory of Medicinal Chemistry for Natural Resource Ministry of EducationYunnan Key Laboratory of Research and Development for Natural ProductsSchool of PharmacyYunnan UniversityKunming 650500China

Despite the great potential of anti-PD-L1 antibodies for immunotherapy,their low response rate due to an immunosuppressive tumor microenvironment has hampered their *** address this issue,we constructed a cell membrane-coated nanosystem(mB4S)to reverse an immunosuppressive microenvironment to an immuno-supportive one for strengthening the anti-tumor *** this system,Epirubicin(EPI)as an immunogenic cell death(ICD)inducer was coupled to a branched glycopolymer via hydrazone bonds and diABZI as a stimulator of interferon genes(STING)agonist was encapsulated into *** internalization of mB4S,EPI was acidic-responsively released to induce ICD,which was characterized by an increased level of calreticulin(CRT)exposure and enhanced ATP ***,diABZI effectively activated the STING *** with mB4S in combination with an anti-PD-L1 antibody elicited potent immune responses by increasing the ratio of matured dendritic cells(DCs)and CD8+T cells,promoting cytokines secretion,up-regulating M1-like tumor-associated macrophages(TAMs)and down-regulating immunosuppressive myeloid-derived suppressor cells(MDSCs).Therefore,this nanosystem for co-delivery of an ICD inducer and a STING agonist achieved promotion of DCs maturation and CD8+T cells infiltration,creating an immuno-supportive microenvironment,thus potentiating the therapy effect of the anti-PD-L1 antibody in both 4T1 breast and CT26 colon tumor mice.

关键词： Glycopolymer Polymer prodrug Immunogenic cell death Nanoassembly Epirubicin STING pathway Immuno-supportive microenvironment Immunotherapy

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Comparison of clinical features and outcomes of proliferative,fibrotic,and mixed subtypes of IgG4-related disease:A retrospective cohort study

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Chinese Medical Journal 2024年第3期137卷 303-311页

作者： Linyi Peng Xinlu Zhang Jiaxin Zhou Jieqiong Li Zheng Liu Hui Lu Yu Peng Yunyun Fei Yan Zhao Xiaofeng Zeng Wen Zhang Department of Rheumatology and clinical Immunology Peking Union Medical College HospitalNational Clinical Research Center for Dermatologic and Immunologic DiseasesState Key Laboratory of Complex Severe and Rare DiseasesThe Ministry of Education Key LaboratoryBeijing 100730China Institute of clinical Medicine Peking Union Medical College Hospital(PUMCH)Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100730China

Background:Immunoglobulin G4-related disease(IgG4-RD)is a recently recognized immune-mediated disorder that can affect almost any organ in the human ***4-RD can be categorized into proliferative and fibrotic subtypes based on patients’clinicopathological *** study aimed to compare the clinical manifestations,laboratory findings,and treatment outcomes of IgG4-RD among different ***:We prospectively enrolled 622 patients with newly diagnosed IgG4-RD at Peking Union Medical College hospital from March 2011 to August *** patients were divided into three groups according to their clinicopathological characteristics:proliferative,fibrotic,and mixed *** compared demographic features,clinical manifestations,organ involvement,laboratory tests,and treatment agents across three *** then assessed the differences in treatment outcomes among 448 patients receiving glucocorticoids alone or in combination with ***,risk factors of relapse were revealed by applying the univariate and multivariate Cox regression ***:We classified the 622 patients into three groups consisting of 470 proliferative patients,55 fibrotic patients,and 97 mixed patients,*** found that gender distribution,age,disease duration,and frequency of allergy history were significantly different among *** terms of organ involvement,submandibular and lacrimal glands were frequently involved in the proliferative subtype,while retroperitoneum was the most commonly involved site in both fibrotic subtype and mixed *** comparison of laboratory tests revealed that eosinophils(P=0.010),total IgE(P=0.006),high-sensitivity C-reactive protein(P<0.001),erythrocyte sedimentation rate(P<0.001),complement C4(P<0.001),IgG(P=0.001),IgG1(P<0.001),IgG4(P<0.001),and IgA(P<0.001),at baseline were significantly different among three *** with proliferative and mixed subtypes,the fibrotic subtype showed the

关键词： IgG4-related disease Proliferative subtype Fibrotic subtype clinical features Treatment outcome

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Efficacy and safety of Y- 2 sublingual tablet for patients with acute ischaemic stroke: protocol of a phase III randomised double- blind placebo- controlled multicentre trial

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Stroke & Vascular Neurology 2024年第1期9卷 90-95页

作者： Yu Fu Renhong Tang Rong Chen Anxin Wang Jinsheng Ren Shunwei Zhu Xiaofei Feng Dongsheng Fan Deparment of Neurology Peking University Third HospitalBeijingChina State Key Laboratory of Neurology and Oncology Drug development NanjingJiangsuChina Simcere Pharmaceutical Group Limited NanjingJiangsuChina Neurodawn Pharmaceutical Co. LtdNanjingJiangsuChina Department of Neurology Beijing Tiantan HospitalCapital Medical UniversityBeijingChina China National clinical research Center for Neurological Diseases Beijing Tiantan HospitalCapital Medical UniversityBeijingChina

Background and purpose clinical studies have demonstrated that edaravone dexborneol can improve the functional outcomes in patients with acute ischaemic stroke(AIS).The present clinical trial aimed at testing the efficacy and safety of Y-2 sublingual tablet on 90-day functional outcome in patients with *** and design This is a randomised,double-blind,placebo-controlled,multicentre,parallel-group trial of Y-2 sublingual tablet on patients with *** estimated 914 patients at age of 18–80 years with AIS within 48 hours after symptom onset from 40 hospitals will be randomly assigned to receive Y-2 sublingual tablet or placebo for 14 *** are at score 6–20 points on National Institutes of Health Stroke Scale(NIHSS)and had a modified Rankin Scale(mRS)≤1 before this stroke,except mechanical thrombectomy and neuroprotective agents *** outcomes The primary outcome is the proportion of patients with mRS≤1 on day 90 after *** efficacy outcomes include mRS score on day 90,the proportion of patients with mRS≤2 on day 90;the change of NIHSS score from baseline to day 14 and the proportion of patients with NIHSS score≤1 at the days 14,30 and *** This trial will provide valuable evidence for the efficacy and safety of Y-2 sublingual table for improving 90 days the functional outcomes in patients with *** registration number NCT04950920.

关键词： patients protective centre

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development and validation of a novel non-invasive test for diagnosing nonalcoholic fatty liver disease in Chinese children

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World Journal of Pediatrics 2024年第4期20卷 413-421页

作者： Zhe-Wen Qin Qian-Nan Ren Hong-Xi Zhang Ya-Ru Liu Ke Huang Wei Wu Guan-Ping Dong Yan Ni Jun-Fen Fu Division of Endocrinology National Clinical Research Center for Child HealthNational Children’s Regional Medical CenterThe Children’s HospitalDepartment of EndocrinologyNational Clinical Research Center for Child HealthNational Children’s Regional Medical CenterThe Children’s HospitalZhejiang University School of MedicineHangzhou310052China

With the exploding prevalence of obesity,many children are at risk of developing nonalcoholic fatty liver *** anthropometric and laboratory parameters,our study aimed to develop a model to quantitatively evaluate liver fat content(LFC)in children with *** A well-characterized cohort of 181 children between 5 and 16 years of age were recruited to the study in the Endocrinology Department as the derivation *** external validation cohort comprised 77 *** assessment of liver fat content was performed using proton magnetic resonance *** and laboratory metrics were measured in all subjects.B-ultrasound examination was carried out in the external validation *** Kruskal-Wallis test,Spearman bivariate correlation analyses,univariable linear regressions and multivariable linear regression were used to build the optimal predictive *** The model was based on indicators including alanine aminotransferase,homeostasis model assessment of insulin resistance,triglycerides,waist circumference and Tanner *** adjusted R^(2)of the model was 0.589,which presented high sensitivity and specificity both in internal[sensitivity of 0.824,specificity of 0.900,area under curve(AUC)of 0.900 with a 95%confidence interval:0.783–1.000]and external validation(sensitivity of 0.918 and specificity of 0.821,AUC of 0.901 with a 95%confidence interval:0.818–0.984).Conclusions Our model based on five clinical indicators was simple,non-invasive,and inexpensive;it had high sensitivity and specificity in predicting LFC in ***,it may be useful for identifying children with obesity who are at risk for developing nonalcoholic fatty liver disease.

关键词： Biochemical markers Children Magnetic resonance spectroscopy Nonalcoholic fatty liver disease Pediatric obesity

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RARRES2 regulates lipid metabolic reprogramming to mediate the development of brain metastasis in triple negative breast cancer

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Military Medical research 2024年第1期11卷 34-49页

作者： Yi-Qun Li Fang-Zhou Sun Chun-Xiao Li Hong-Nan Mo Yan-Tong Zhou Dan Lv Jing-Tong Zhai Hai-Li Qian Fei Ma Department of Medical Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China

Background Triple negative breast cancer(TNBC),the most aggressive subtype of breast cancer,is characterized by a high incidence of brain metastasis(BrM)and a poor *** the most lethal form of breast cancer,BrM remains a major clinical challenge due to its rising incidence and lack of effective treatment *** evidence suggested a potential role of lipid metabolic reprogramming in breast cancer brain metastasis(BCBrM),but the underlying mechanisms are far from being fully *** Through analysis of BCBrM transcriptome data from mice and patients,and immunohistochemical validation on patient tissues,we identified and verified the specific down-regulation of retinoic acid receptor responder 2(RARRES2),a multifunctional adipokine and chemokine,in BrM of *** investigated the effect of aberrant RARRES2 expression of BrM in both in vitro and in vivo *** signaling pathway components were evaluated using multi-omics *** were performed to elucidate the regulation of lipid metabolic reprogramming of *** We found that downregulation of RARRES2 is specifically associated with BCBrM,and that RARRES2 deficiency promoted BCBrM through lipid metabolic ***,reduced expression of RARRES2 in brain metastatic potential TNBC cells resulted in increased levels of glycerophospholipid and decreased levels of triacylglycerols by regulating phosphatase and tensin homologue(PTEN)-mammalian target of rapamycin(mTOR)-sterol regulatory element-binding protein 1(SREBP1)signaling pathway to facilitate the survival of breast cancer cells in the unique brain *** Our work uncovers an essential role of RARRES2 in linking lipid metabolic reprogramming and the development of ***2-dependent metabolic functions may serve as potential biomarkers or therapeutic targets for BCBrM.

关键词： RARRES2 Lipid metabolic reprogramming Brain metastasis(BrM) Breast cancer

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Roles of THEM4 in the Akt pathway:a double-edged sword

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第7期25卷 541-556页

作者： Wen XIE Weidong LIU Lei WANG Bin ZHU Cong ZHAO Ziling LIAO Yihan LI Xingjun JIANG Jie LIU Caiping REN NHC Key Laboratory of Carcinogenesis Department of NeurosurgeryXiangya HospitalCentral South UniversityChangsha 410008China National clinical research Center for Geriatric Disorders Xiangya HospitalCentral South UniversityChangsha 410008China The Key Laboratory of Carcinogenesis and Cancer Invasion of the Ministry of Education Cancer Research InstituteSchool of Basic Medical ScienceCentral South UniversityChangsha 410078China Department of Critical Care Medicine Hainan Hospital of Chinese PLA General HospitalHainan Province Clinical Medical CenterSanya 572013China

The protein kinase B(Akt)pathway can regulate the growth,proliferation,and metabolism of tumor cells and stem cells through the activation of multiple downstream target genes,thus affecting the development and treatment of a range of *** superfamily member 4(THEM4),a member of the thioesterase superfamily,is one of the Akt kinase-binding *** studies on the mechanism of cancers and other diseases have shown that THEM4 binds to Akt to regulate its ***,THEM4 was considered an endogenous inhibitor of Akt,which can inhibit the phosphorylation of Akt in diseases such as lung cancer,pancreatic cancer,and liver cancer,but subsequently,THEM4 was shown to promote the proliferation of tumor cells by positively regulating Akt activity in breast cancer and nasopharyngeal carcinoma,which contradicts previous *** these two distinct views,this review summarizes the important roles of THEM4 in the Akt pathway,focusing on THEM4 as an Akt-binding protein and its regulatory relationship with Akt phosphorylation in various diseases,especially *** work provides a better understanding of the roles of THEM4 combined with Akt in the treatment of diseases.

关键词： Protein kinase B(Akt) Thioesterase superfamily member 4(THEM4) Tumor proliferation Tumor metastasis

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MicroRNA-146a-loaded magnesium silicate nanospheres promote bone regeneration in an inflammatory microenvironment

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Bone research 2024年第1期12卷 153-164页

作者： Jiakang Yang Jing Shuai Lixuen Siow Jingyi Lu Miao Sun Wenyue An Mengfei Yu Baixiang Wang Qianming Chen Stomatology hospital School of StomatologyZhejiang University School of MedicineZhejiang Provincial Clinical Research Center for Oral DiseasesKey Laboratory of Oral Biomedical Research of Zhejiang ProvinceCancer Center of Zhejiang UniversityHangzhou 310000China

Reconstruction of irregular oral-maxillofacial bone defects with an inflammatory microenvironment remains a challenge,as chronic local inflammation can largely impair bone ***,we used magnesium silicate nanospheres(MSNs)to load microRNA-146a-5p(miR-146a)to fabricate a nanobiomaterial,MSN+miR-146a,which showed synergistic promoting effects on the osteogenic differentiation of human dental pulp stem cells(hDPSCs).In addition,miR-146a exhibited an anti-inflammatory effect on mouse bone marrow-derived macrophages(BMMs)under lipopolysaccharide(LPS)stimulation by inhibiting the NF-κB pathway via targeting tumor necrosis factor receptor-associated factor 6(TRAF6),and MSNs could simultaneously promote M2 polarization of ***-146a was also found to inhibit osteoclast ***,the dual osteogenic-promoting and immunoregulatory effects of MSN+miR-146a were further validated in a stimulated infected mouse mandibular bone defect model via delivery by a photocuring ***,the MSN+miR-146a complex revealed good potential in treating inflammatory irregular oralmaxillofacial bone defects.

关键词： inflammatory healing stimulation

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Pan-cancer immunogenic death analysis identifies key roles of CXCR3 and CCL18 in hepatocellular carcinoma

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Genes & Diseases 2024年第2期11卷 568-570页

作者： Jia Guo Xin Sun Guowei Pan Ce Li Xin He Xiaofang Che Zan Teng Xiujuan Qu Yunpeng Liu Bowen Yang Department of Medical Oncology Provincial Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning ProvinceLiaoning Provincial Clinical Research Center for CancerClinical Cancer Research Center of ShenyangThe First Hospital of China Medical UniversityShenyangLiaoning 110001China research Center for Universal Health School of Public HealthChina Medical UniversityShenyangLiaoning 110122China

Immunogenic death is a form of programmed cell death that is common in the development and progression of ***,its impact on tumor progression differs depending on the location of the ***,it also plays an important role in antitumor immunity because the process of immunogenic death can release substances that activate immunity.1 Therefore,in this study,the key mechanism of mediating immunogenic death in hepatocellular carcinoma(HCC)was found from the excavation of the immunogenic death characteristics of pan-cancer and the in-depth investigation of its effects on different tumor types(Fig.1A).

关键词： death CXCR3 immunity

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Application of Fusobacterium nucleatum as a biomarker in gastrointestinal malignancies

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World Journal of Gastrointestinal Oncology 2024年第6期16卷 2271-2283页

作者： Long-Chen Yu Ya-Ping Li Yue-Ming Xin Mai Mao Ya-Xin Pan Yi-Xuan Qu Zheng-Dong Luo Yi Zhang Xin Zhang Department of clinical Laboratory Qilu Hospital of Shandong UniversityShandong Engineering Research Center of Biomarker and Artificial Intelligence ApplicationJinan 250012Shandong ProvinceChina

The morbidity and mortality of gastrointestinal(GI)malignancies are among the highest in the world,posing a serious threat to human *** of the insidious onset of the cancer,it is difficult for patients to be diagnosed at an early stage,and it rapidly progresses to an advanced stage,resulting in poor treatment and *** nucleatum(***)is a gram-negative,sporefree anaerobic bacterium that primarily colonizes the oral cavity and is implicated in the development of colorectal,esophageal,gastric,and pancreatic cancers via various intricate *** development in novel research suggests that *** may function as a biomarker in GI *** the abundance of *** in stool,saliva,and serum samples of patients may aid in the diagnosis,risk assessment,and prognosis monitoring of GI *** editorial systematically describes the biological roles and mechanisms of *** in GI malignancies focusing on the application of *** as a biomarker in the diagnosis and prognosis of GI malignancies to promote the clinical translation of *** and GI tumors-related research.

关键词： Gastrointestinal malignancies Fusobacterium nucleatum Biomarker Diagnosis Prognosis

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Advances in single-cell sequencing technology in microbiome research

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Genes & Diseases 2024年第4期11卷 201-219页

作者： Yinhang Wu Jing Zhuang Yifei Song Xinyi Gao Jian Chu Shuwen Han Huzhou Central hospital Affiliated Central Hospital Huzhou UniversityHuzhouZhejiang 313000China Key Laboratory of Multiomics research and clinical Transformation of Digestive Cancer of Huzhou HuzhouZhejiang 313000China The Fifth Affiliated clinical Medical College of Zhejiang Chinese Medical University HangzhouZhejiang 313000China Zhejiang Provincial People's hospital and Affiliated People's hospital Hangzhou Medical CollegeHangzhouZhejiang 310000China

With the rapid development of histological techniques and the widespread applica-tion of single-cell sequencing in eukaryotes,researchers desire to explore individual *** and functional expression,which deepens our understanding of *** this review,the history of the development of microbial detection technologies was revealed and the difficulties in the application of single-cell sequencing in microorganisms were dissected as ***,the characteristics of the currently emerging microbial single-cell sequencing(Microbe-seq)technology were summarized,and the prospects of the application of Microbe-seq in microorganisms were distilled based on the current development *** its mature development,the Microbe-seq technology was still in the optimization stage.A retrospective study was conducted,aiming to promote the widespread application of single-cell sequencing in microorganisms and facilitate further improvement in the technol-ogy.

关键词： Bacterialantibiotic resistance Host immunity Host-phage interaction Microbial single-cell sequencing Microorganisms Single cell Single-cell sequencing technology

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