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Design and discovery of a highly potent ultralong-acting GLP-1 and glucagon co-agonist for attenuating renal fibrosis

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1283-1301页

作者： Qian Zhao Jiale Dong Han Liu Hui Chen Huan Yu Shuyin Ye Shuangjin Yu Yu Li Longhui Qiu Nazi Song Hongjiao Xu Qi Liu Zhiteng Luo Yuyi Li Rui Wang Guodong Chen Xianxing Jiang School of Pharmaceutical Sciences Guangdong Provincial Key Laboratory of Chiral Molecule and Drug DiscoverySun Yat-sen UniversityGuangzhou 510006China Organ Transplant Center the First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510006China Zhongshan School of Medicine Sun Yat-sen UniversityGuangzhou 510006China Shenzhen Turier Biotech.Co. Ltd.Shenzhen 518118China School of Life Sciences Key Laboratory of Preclinical Study for New Drugs of Gansu ProvinceSchool of Basic Medical Sciences&Research Unit of Peptide ScienceChinese Academy of Medical SciencesLanzhou UniversityLanzhou 730000China

The role of co-agonists of glucagon-like peptide-1 receptor(GLP-1R)and glucagon receptor(GCGR)in chronic kidney disease(CKD)remains *** we found that GLP-1R and GCGR expression levels were lower in the kidneys of mice with CKD compared to healthy mice and were correlated with disease ***,GLP-1R or GCGR knockdown aggravated the progression of kidney injury in both diabetic db/db mice and non-diabetic mice undergoing unilateral ureteral obstruction(UUO).Based on the importance of GLP-1R and GCGR in CKD,we reported a novel monomeric peptide,1907-B,with dual-agonism on both GLP-1R and *** data confirmed that 1907-B had a longer half-life than long-acting semaglutide in rats or cynomolgus monkeys(~2-3 fold)and exhibited better therapeutic contribution to CKD than best-in-class monoagonists,semaglutide,or glucagon,in db/db mice and UUO *** lock-of-function models,including selective pharmacological activation and genetic knockdown,confirmed that 1907-B’s effects on ameliorating diabetic nephropathy in db/db mice,as well as inhibiting kidney fibrosis in UUO mice,were mediated through GLP-1 and glucagon *** findings highlight that 1907-B,a novel GLP-1R and GCGR co-agonist,exerts multifactorial improvement in kidney injuries and is an effective and promising therapeutic option for CKD treatment.

关键词： GLP-1 receptor Glucagon receptor Chronic kidney disease Diabetic nephropathy Kidney fibrosis Dual-agonism

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Changing the 3-decade routine of preoperative radiotherapy for locally advanced rectal cancer: New wine for new bottle?

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中华医学杂志(英文版) 2024年第16期137卷 2024 Feb 26页

作者： Dou Ruoxu Zhang Jianwei Wang Jianping Deng Yanhong Department of Gastrointestinal Surgery The Fifth Affiliated Hospital Sun Yat-sen University Zhuhai Guangdong China Department of Medical Oncology The Sixth Affiliated Hospital Sun Yat-sen University Guangzhou Guangdong China Biomedical Innovation Center The Sixth Affiliated Hospital Sun Yat-sen University Guangzhou Guangdong China Department of General Surgery The Sixth Affiliated Hospital Sun Yat-sen University Guangzhou Guangdong China Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases The Sixth Affiliated Hospital Sun Yat-sen University Guangzhou Guangdong China

Effect of plateletcrit and methylenetetrahydrofolate reductase(MTHFR)C677T genotypes on folic acid efficacy in stroke prevention

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Signal Transduction and Targeted Therapy 2024年第6期9卷 2694-2701页

作者： Yuncong Shi Zhengzhipeng Zhang Binyan Wang Yu Wang Xiangyi Kong Yong sun Aimin Li Yimin Cui Yan Zhang Jianping Li Yong Huo Hui Huang Cardiovascular Department The Eighth Affiliated HospitalJoint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic DiseasesSun Yat-sen UniversityShenzhenChina Shenzhen Evergreen Medical Institute ShenzhenChina Shenzhen Tailored Medical Laboratory ShenzhenChina Department of Cardiology Beijing Anzhen HospitalCapital Medical UniversityBeijingChina Department of Neurosurgery The First Affiliated Hospital of Kangda College of Nanjing Medical UniversityLianyungangChina Institute of Clinical Pharmacology Peking University First HospitalBeijingChina Department of Cardiology Peking University First HospitalBeijingChina

Previous studies have shown that low platelet count combined with high plasma total homocysteine(tHcy)increased stroke risk and can be lowered by 73% with folic ***,the combined role of other platelet activation parameters and the methylenetetrahydrofolate reductase(MTHFR)C677T genotypes on stroke risk and folic acid treatment benefit remain to be *** study aimed to investigate if platelet activation parameters and MTHFR genotypes jointly impact folic acid treatment efficacy in first stroke *** were derived from the China Stroke Primary Prevention *** study includes a total of 11,185 adult hypertensive patients with relevant platelet activation parameters and MTHFR genotype *** simultaneously considering both platelet activation parameters(plateletcrit,platelet count,mean platelet volume,platelet distribution width)and MTHFR genotypes,patients with both low plateletcrit(Q1)and the TT genotype had the highest stroke incidence rate(5.6%)in the enalapril *** subgroup significantly benefited from folic acid treatment,with a 66% reduction in first stroke(HR:0.34;95%CI:0.14-0.82;p=0.016).Consistently,the subgroup with low plateletcrit(Q1)and the CC/CT genotype also benefited from folic acid treatment(HR:0.40;95%CI:0.23-0.70;p=0.001).In Chinese hypertensive adults,low plateletcrit can identify those who may greatly benefit from folic acid treatment,in particular,those with the TT genotype,a subpopulation known to have the highest stroke risk.

关键词： prevention treatment MTHFR

XELOX(capecitabine plus oxaliplatin)plus bevacizumab(anti-VEGF-A antibody)with or without adoptive cell immunotherapy in the treatment of patients with previously untreated metastatic colorectal cancer:a multicenter,open-label,randomized,controlled,phase 3 trial

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Signal Transduction and Targeted Therapy 2024年第5期9卷 2104-2113页

作者： Qiu-Zhong Pan Jing-Jing Zhao Liang Liu Dong-Sheng Zhang Li-Ping Wang Wen-Wei Hu De-Sheng Weng Xiang Xu Yi-Zhuo Li Yan Tang Wei-Hong Zhang Jie-Yao Li Xiao Zheng Qi-Jing Wang Yong-Qiang Li Tong Xiang Li Zhou Shuang-Ning Yang Chen Wu Rong-Xing Huang Jia He Wei-Jiao Du Lu-Jun Chen Yue-Na Wu Bin Xu Qiong Shen Yi Zhang Jing-Ting Jiang Xiu-Bao Ren Jian-Chuan Xia State Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for CancerCollaborative Innovation Center for Cancer MedicineSun Yat-Sen University Cancer CenterGuangzhouGuangdong 510060PR China Department of Biotherapy Sun Yat-Sen University Cancer CenterGuangzhouGuangdong 510060PR China Tianjin Medical University Cancer Institute and hospital National Clinical Research Center for CancerTianjin 300060PR China Key Laboratory of Cancer Immunology and Biotherapy Tianjin 300060PR China Department of Biotherapy/Immunology Tianjin Medical University Cancer Institute and HospitalTianjin 300060PR China Department of Medical Oncology Sun Yat-sen University Cancer CenterGuangzhou 510060PR China Department of Oncology the First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052PR China Department of Tumor Biological Treatment the Third Affiliated Hospital of Soochow UniversityChangzhouJiangsu 213003PR China Jiangsu Engineering Research Center for Tumor Immunotherapy ChangzhouJiangsu 213003PR China Institute for Cell Therapy of Soochow University ChangzhouJiangsu 213003PR China Department of Stem Cell&Regenerative Medicine State Key Laboratory of TraumaBurn and Combined InjuryDaping HospitalArmy Medical UniversityChongqing 400042PR China Imaging Diagnosis and Interventional Center Sun Yat-sen University Cancer CenterGuangzhouGuangdong 510060PR China

Fluoropyrimidine-based combination chemotherapy plus targeted therapy is the standard initial treatment for unresectable metastatic colorectal cancer(mCRC),but the prognosis remains *** phase 3 trial(***:NCT03950154)assessed the efficacy and adverse events(AEs)of the combination of PD-1 blockade-activated DC-CIK(PD1-T)cells with XELOX plus bevacizumab as a first-line therapy in patients with mCRC.A total of 202 participants were enrolled and randomly assigned in a 1:1 ratio to receive either first-line XELOX plus bevacizumab(the control group,n=102)or the same regimen plus autologous PD1-T cell immunotherapy(the immunotherapy group,n=100)every 21 days for up to 6 cycles,followed by maintenance treatment with capecitabine and *** main endpoint of the trial was progression-free survival(PFS).The median follow-up was 19.5 *** PFS was 14.8 months(95%CI,11.6-18.0)for the immunotherapy group compared with 9.9 months(8.0-11.8)for the control group(hazard ratio[HR],0.60[95%CI,0.40-0.88];p=0.009).Median overall survival(OS)was not reached for the immunotherapy group and 25.6 months(95%CI,18.3-32.8)for the control group(HR,0.57[95%CI,0.33-0.98];p=0.043).Grade 3 or higher AEs occurred in 20.0%of patients in the immunotherapy group and 23.5%in the control groups,with no toxicity-associated deaths *** addition of PD1-T cells to first-line XELOX plus bevacizumab demonstrates significant clinical improvement of PFS and OS with well tolerability in patients with previously untreated mCRC.

关键词： PD1 immunotherapy bevacizumab

Clinical guidelines for indications,techniques,and complications of autogenous bone grafting

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Chinese Medical Journal 2024年第1期137卷 5-7页

作者： Jianzheng Zhang Shaoguang Li Hongying He Li Han Simeng Zhang Lin Yang Wenxing Han Xiaowei Wang Jie Gao Jianwen Zhao Weidong Shi Zhuo Wu Hao Wang Zhicheng Zhang Licheng Zhang Wei Chen Qingtang Zhu Tiansheng sun Peifu Tang Yingze Zhang Senior Department of Orthopedics PLA General HospitalBeijing 100048China The National Clinical Research Center for Orthopedics Sports Medicine&RehabilitationBeijing 100048China The Trauma Orthopedic Branch of Chinese Orthopedic Association ShijiazhuangHebei 050051China Department of Orthopedic Surgery The Third Hospital of Hebei Medical UniversityShijiazhuangHebei 050051China Department of Microsurgical Trauma The First Affiliated Hospital of Sun Yat-sen UniversityGuangzhouGuangdong 510080China

Autogenous bone grafts have long been considered the“gold standard”and most effective material in bone regeneration procedures.[1]Autogenous bone grafts are used to repair bone defects caused by nonunion,infection,tumor resection,and spinal and joint fusion.[2]It has been reported that more than 200,000 autologous bone grafts are performed in the United States each year.[3]Although there are no specific statistics on the annual number of bone grafts performed in China,autologous bone grafting is the most common surgical technique in *** iliac crest remains the most common donor site,along with the fibula,ribs,tibial metaphysis,proximal humerus,distal radius,and greater trochanter.[4,5]Various bone-graft options provide different amounts and qualities of cortical,cancellous,and corticocancellous bone.[6,7]Autogenous bone graft is osteogenic,histocompatible,provides structural support.

关键词： grafting graft union

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Investigation of Student Nurses’Attitudes towards End-of-Life Care and Their Influencing Factors

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Open Journal of Nursing 2024年第5期14卷 183-191页

作者： Lei Peng Jingxian Wang Jia Wang Qiangqiang Liu Department of Emergency Medicine The First Affiliated Hospital of Sun Yat-sen University Guangzhou China

Background: This cross-sectional investigative study aimed to determine student nurses’ attitudes towards end-of-life care. Methods: This study used a descriptive research design with stratified sampling to survey student nurses enrolled in one of four nursing colleges in China from January 2023 to December 2023. Student nurses’ general demographic and prior related information, attitudes towards death and attitudes towards end-of-life care were determined using a general information questionnaire, the Death Attitude Profile—Revised scale and the Professional End-of-Life Attitude Scale (PEAS), respectively. Results: The total PEAS score was 122.91 ± 16.123. Significant differences were noted in the attitude towards end-of-life care scores according to sources of end-of-life care knowledge (P Conclusions: Student nurses lacked an optimistic attitude towards end-of-life care, which was influenced by differences in the sources of end-of-life care knowledge.

关键词： Nursing Students End-of-Life Care Attitude

RNA modifications in cellular metabolism:implications for metabolism-targeted therapy and immunotherapy

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1565-1594页

作者： Wei-Wei Liu Si-Qing Zheng Tian Li Yun-Fei Fei Chen Wang Shuang Zhang Fei Wang Guan-Min Jiang Hao Wang Department of Laboratory Medicine The First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiChina School of Clinical Medicine Shandong UniversityJinanChina Core Unit of National Clinical Research Center for Laboratory Medicine HefeiChina Neurosurgical Department The First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiChina Department of Clinical Laboratory The Fifth Affiliated HospitalSun Yat-sen UniversityZhuhaiChina

Cellular metabolism is an intricate network satisfying bioenergetic and biosynthesis requirements of *** studies have been constantly making inroads in our understanding of pathophysiology,and inspiring development of *** a crucial component of epigenetics at post-transcription level,RNA modification significantly determines RNA fates,further affecting various biological processes and cellular *** be noted,immunometabolism defines the metabolic alterations occur on immune cells in different stages and immunological *** this review,we characterize the distribution features,modifying mechanisms and biological functions of 8 RNA modifications,including N6-methyladenosine(m6A),N6,2'-O-dimethyladenosine(m6Am),N1-methyladenosine(m1A),5-methylcytosine(m5C),N4-acetylcytosine(ac4C),N7-methylguanosine(m7G),Pseudouridine(V),adenosine-to-inosine(A-to-l)editing,which are relatively the most studied *** regulatory roles of these RNA modification on metabolism in diverse health and disease contexts are comprehensively described,categorized as glucose,lipid,amino acid,and mitochondrial *** we highlight the regulation of RNA modifications on immunometabolism,further influencing immune *** all,we provide a thorough discussion about clinical implications of RNA modification in metabolism-targeted therapy and immunotherapy,progression of RNA modification-targeted agents,and its potential in RNAtargeted ***,we give legitimate perspectives for future researches in this field from methodological requirements,mechanistic insights,to therapeutic applications.

关键词： metabolism targeted alterations

NHE7 upregulation potentiates the uptake of small extracellular vesicles by enhancing maturation of macropinosomes in hepatocellular carcinoma

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Cancer Communications 2024年第2期44卷 251-272页

作者： Yue Yao Yi Xu Liang Yu Ting-Mao Xue Zhi-Jie Xiao Pui-Chi Tin Hiu-Ling Fung Hoi-Tang Ma Jing-Ping Yun Judy Wai Ping Yam Department of Pathology School of Clinical MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong KongP.R.China Department of Endocrinology and Metabolism Second Affiliated Hospital of Harbin Medical UniversityHarbinHeilongjingP.R.China Department of Hepatopancreatobiliary Surgery Second Affiliated Hospital of Harbin Medical UniversityHarbinHeilongjingP.R.China State Key Laboratory of Oncology in South China Cancer Center of Sun Yat-sen UniversityGuangzhouGuangdongP.R.China Department of Hepatobiliary Surgery II Zhujiang HospitalSouthern Medical UniversityGuangzhouGuangdongP.R.China Scientific Research Center The Seventh Affiliated HospitalSun Yat-sen UniversityShenzhenGuangdongP.R.China State Key Laboratory of Liver Research The University of Hong KongHong KongP.R.China Department of Pathology Cancer Center of Sun Yat-sen UniversityGuangzhouGuangdongP.R.China

Background:Small extracellular vesicles(sEVs)mediate intercellular commu-nication that contributes to hepatocellular carcinoma(HCC)progression via multifaceted *** success of cell entry determines the effect of sEV on recipient ***,we aimed to delineate the mechanisms underlying the uptake of sEV in ***:AF,Alexa Fluor;ANOVA,analysis of variance;ATP9A,ATPase Phospholipid Transporting 9A;BCECF-AM,2’,7’-bis-(2-barboxyethyl)-5-(and-6)-carboxyfluorescein,acetoxymethyl ester;BSA,bovine serum albumin;CCMR,Centre for Comparative Medicine Research;CRISPR,clustered regularly interspaced short palindromic repeats;CTL,ctrl;CXCR4,C-X-C Chemokine Receptor Type 4;DAPI,4′,6-diamidino-2-phenylindole;DFS,disease-free survival;DMEM,Dulbecco’s Modified Eagle Medium;DMSO,dimethyl sulfoxide;Dox,doxycycline;EEA1,early endosome antigen 1;EIPA,5-(N-ethyl-N-isopropyl)-amiloride;FBS,fetal bovine serum;FITC,fluorescein isothiocyanate;GAPDH,glyceraldehyde-3-phosphate dehydrogenase;GM130,Golgi matrix protein 130;HCC,hepatocellular carcinoma;HEPES,4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid;HPRT1,hypoxanthine phosphoribosyltransferase 1;H-score,histoscore;IAA,indole-3-acetic acid;KD,knockdown;KO,knockout;mAID,mini-auxin-inducible degron;MTT,3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide;NHE7,Na(+)/H(+)exchanger 7;ns,non-significant;OD,optical density;OS,overall survival;PBS,phosphate-buffered saline;PCR,polymerase chain reaction;pHe,endosomal pH;pHi,intracellular pH;PKH67,Paul Karl Horan 67;Rab21,Ras-associated binding protein 21;RIPA,radioimmunoprecipitation assay;SAM,synergistic activation mediator;SEMs,standard error of the means;sEVs,small extracellular vesicles;sgRNA,single-guide RNA;shRNA,short-hairpin RNA;SLC9,solute carrier gene 9;SLiCE,Seamless Ligation Cloning Extract;TCGA,The Cancer Genome Atlas;TCL,total cell lysates;TGN,trans-Golgi network;TMA,tissue microarray;TMR,tetramethyl rhodamine;TSG101,tumor susceptibility gene *** Yao an

关键词： hepatocellular carcinoma small extracellular vesicles macropinocytosis pH regulation sodium-hydrogen exchanger

Real-time myocardial contrast echocardiography and its applications in evaluation for coronary artery disease

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Chinese Medical Journal 2004年第9期117卷 1388-1394页

作者：杨莉 Department of Cardiology Second Affiliated Hospital Sun Yatsen University Guangzhou 510120 China

Recent improvements in the design of microbubbles and the technology for their detection have enabled myocardial opacification to be achieved by low-energy real-time intravenous MCE. Microbubble replenishment rate and peak intensity after bubble destruction by high-energy ultrasound, as assessed by real-time imaging, provide reliable parameters of regional microcirculatory flow. Real-time imaging offers a rapid and easy means of assessing regional myocardial perfusion with MCE. With the introduction of real-time imaging, wall motion and myocardial perfusion can be assessed together, without the need of time-consuming combination of imaging modes. Recent studies using real-time MCE have underscored its potential in the identification of coronary artery disease, quantification of coronary stenosis severity, assessment of myocardial viability, determination of risk and infarct size, and evaluation of reflow and no-reflow or low-reflow after AMI. However, some limitations, such as basal attenuation and motion artefacts, still exist in the current state of the technique. Further studies, using real-time MCE in normal humans and patients with various stages of coronary artery disease, for quantification of myocardial perfusion and flow reserve in comparison to a reference standard such as quantitative positron emission tomography, will be needed to establish the validity of real-time MCE. If the encouraging preliminary clinical results are confirmed in daily routine patients, real-time MCE may become the method of choice for myocardial perfusion assessment in the near future.

关键词： contrast echocardiography · myocardial perfusion · coronary arteriosclerosis

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