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Ciclopirox inhibits SARS-CoV-2 replication by promoting the degradation of the nucleocapsid protein

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2505-2519页

作者： Xiafei Wei Yuzheng Zhou Xiaotong Shen Lujie Fan Donglan Liu Xiang Gao Jian Zhou Yezi Wu Yunfei Li Wei Feng Zheng Zhang institute for Hepatology National Clinical Research Center for Infectious DiseaseShenzhen Third People's HospitalSouthern University of Science and TechnologyShenzhen 518112China Guangzhou Laboratory Guangzhou Medical UniversityGuangzhou 511495China 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

The nucleocapsid protein(NP)plays a crucial role in SARS-CoV-2 replication and is the most abundant structural protein with a long *** its vital role in severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)assembly and host inflammatory response,it remains an unexplored target for drug *** this study,we identified a small-molecule compound(ciclopirox)that promotes NP degradation using an FDA-approved library and a drug-screening cell *** significantly inhibited SARS-CoV-2 replication both in vitro and in vivo by inducing NP *** induced abnormal NP aggregation through indirect interaction,leading to the formation of condensates with higher viscosity and lower *** condensates were subsequently degraded via the autophagy-lysosomal pathway,ultimately resulting in a shortened NP half-life and reduced NP *** results suggest that NP is a potential drug target,and that ciclopirox holds substantial promise for further development to combat SARS-CoV-2 replication.

关键词： SARS-CoV-2 Nucleocapsid protein Viral replication Ciclopirox Abnormal aggregation Protein degradation Autophagy-lysosome Drug target

EGFR-mutant non-small cell lung cancer patients harboring CDK4 amplification show favorable response to afatinib:Two case reports

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Chinese Medical Journal 2024年第12期137卷 1465-1467页

作者： Shuting Zhan Bo Cheng Xiwen Liu Jianfu Li Ge Bai Qi Cai Huiting Wang Yang Xiang Chunyan Li Jianxing He Wenhua Liang Department of Thoracic Surgery and Oncology The First Affiliated Hospital of Guangzhou Medical University&Guangzhou Institute of Respiratory HealthState Key Laboratory of Respiratory Disease&National Clinical Research Center for Respiratory DiseaseGuangzhouGuangdong 510120China National Center for respiratory Medicine State Key Laboratory of Respiratory DiseaseNational Clinical Research Center for Respiratory DiseasesGuangzhou Institute of Respiratory Health&The First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouGuangdong 510120China Southern Medical University GuangzhouGuangdong 510120China Department of respiratory and Critical Care Medicine The Tenth Affiliated Hospital of Southern Medical UniversityDongguanGuangdong 523108China

To the Editor:Epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)show significant efficacy in patients with advanced-stage non-small cell lung cancer(NSCLC)with sensitive EGFR mutations and significantly prolong the survival of these ***,drug resistance emerges in most *** studies indicated that cyclin-dependent kinase 4/6(CDK4/6)gene amplification was one of the resistance mechanisms of the EGFR-TKI osimertinib,weakening its *** options for EGFR-mutant NSCLC patients with CDK4 amplification are limited to add CDK4 inhibitors.

关键词： CDK4 NSCLC EGFR

Initial COVID-19 severity influenced by SARS-CoV-2-specific T cells imprints T-cell memory and inversely affects reinfection

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Signal Transduction and Targeted Therapy 2024年第6期9卷 2791-2803页

作者： Gang Yang Jinpeng Cao Jian Qin Xinyue Mei Shidong Deng Yingjiao Xia Jun Zhao Junxiang Wang Tao Luan Daxiang Chen Peiyu Huang Cheng Chen Xi Sun Qi Luo Jie Su Yunhui Zhang Nanshan Zhong Zhongfang Wang The Affiliated Hospital of Kunming University of Science and Technology.Department of respiratory and Critical Care Medicine The First People’s Hospital of Yunnan provinceKunmingYunnanChina Guangzhou National Laboratory BiolandGuangzhouGuangdongChina State Key Laboratory of respiratory disease&National Clinical Research Center for respiratory disease Guangzhou Institute of Respiratory Healththe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou Medical UniversityGuangzhouChina

The immunoprotective components control COVID-19 disease severity,as well as long-term adaptive immunity maintenance and subsequent reinfection risk discrepancies across initial COVID-19 severity,remain ***,we longitudinally analyzed SARS-CoV-2-specific immune effectors during the acute infection and convalescent phases of 165 patients with COVID-19 categorized by *** found that early and robust SARS-CoV-2-specific CD4^(+)and CD8^(+)T cell responses ameliorate disease progression and shortened hospital stay,while delayed and attenuated virus-specific CD8^(+)T cell responses are prominent severe COVID-19 *** antiviral antibody generation rather than titer level associates with severe ***,initial COVID-19 severity imprints the long-term maintenance of SARS-CoV-2-specific adaptive immunity,demonstrating that severe convalescents exhibited more sustained virus-specific antibodies and memory T cell responses compared to mild/moderate ***,initial COVID-19 severity inversely correlates with SARS-CoV-2 reinfection ***,our study unravels the complicated interaction between temporal characteristics of virus-specific T cell responses and COVID-19 severity to guide future SARS-CoV-2 wave management.

关键词： severity immunity infection

Prevalence of bacteria, fungi, and virus coinfections with SARS-CoV-2 Omicron variant among patients with severe COVID-19 in Guangzhou, China, winter 2022

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Biosafety and Health 2024年第2期6卷 92-97页

作者： Qinghong Fan Mengling Jiang Jun Zhang Guofang Tang Ming Gao Yingfen Wen Xizi Deng Jun Dai Honghao Lai Peng Qian Yaqing Lin Ruiying He Liya Li Yueping Li Zhengtu Li Xuesong Liu Yimin Li Na Yu Yun Lan Fengyu Hu Feng Li institute of Infectious diseases Guangzhou Eighth People's HospitalGuangzhou Medical UniversityGuangzhou 510440China State Key Laboratory of respiratory disease National Clinical Research Center for Respiratory DiseaseGuangzhou Institute of Respiratory Healththe First Affiliated Hospital of GuangzhouMedicalUniversityGuangzhou510120China Guangzhou Laboratory Guangzhou 510700China

The status of coinfection during the national outbreak of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)Omicron BA.5.2 or BF.7 in China in the winter of 2022,which is suspected to contribute substantially to the overloaded severe cases,needs to be *** analyzed the coinfection status of 385 severe patients infected with the Omicron variant in Guangzhou using metagenomic *** found that 317(82.3%)patients were coinfected with at least one additional pathogen(s),including bacteria(58.7%),fungi(27.1%)and viruses(73.5%).Pseudomonas aeruginosa(***)(24.2%),Staphylococcus aureus(***)(14.0%),andKlebsiella pneumoniae(***)(13.4%)ranked as the top three coinfected *** fumigatus(***)(39.5%),Pneumocystis jirovecii(***)(24.4%)andCanidia albicans(***)(22.1%)were the top three coinfected ***-Barr virus(EBV)(63.1%),Human herpesvirus 7(HHV-7)(34.8%),and Herpes simplex virus 1(HSV-1)(32.6%)were the top three coinfected *** note,the detection of multiple coinfections of potential pathogenic bacteria,fungi,and viruses,despite lacking consistent patterns,highlighted a complicated synergistic contribution to disease *** study presents the most comprehensive spectrum of bacterial,fungal,and viral coinfections in Omicron-associated severe coronavirus disease 2019(COVID-19),implying that the coinfection of conditional pathogens might synergistically deteriorate the Omicron infection outcomes.

关键词： SARS-CoV-2 Omicron BA.5.2 Omicron BF.7 Coinfection Severeinfection

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

Heparin-binding protein as a predictor of mortality in patients with diabetes mellitus and community-acquired pneumonia in intensive care unit:a propensity score matched study

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World Journal of Emergency Medicine 2024年第4期15卷 263-272页

作者： Yuhan Sun Baoqing Sun Zhigang Ren Mingshan Xue Changju Zhu Qi Liu Translational Medicine Center Department of Emergency Medicinethe First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052China State Key Laboratory of respiratory disease National Clinical Research Center for Respiratory DiseaseGuangzhou Institute of Respiratory Healththe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510230China Department of Infectious disease the First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052China Henan Medical Key Laboratory of Emergency and Trauma Research Department of Emergency Medicinethe First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052China

BACKGROUND:Patients with diabetes mellitus(DM)are vulnerable to community-acquired pneumonia(CAP),which have a high mortality *** aimed to investigate the value of heparin-binding protein(HBP)as a prognostic marker of mortality in patients with DM and ***:This retrospective study included CAP patients who were tested for HBP at intensive care unit(ICU)admission from January 2019 to April *** were allocated to the DM or non-DM group and paired with propensity score *** characteristics and clinical outcomes up to 90 days were *** primary outcome was the 10-day *** operating characteristic(ROC)curves,Kaplan-Meier analysis,and Cox regression were used for statistical ***:Among 152 enrolled patients,60 pairs were successfully *** was no significant difference in 10-day mortality,while more patients in the DM group died within 28 d(P=0.024)and 90 d(P=0.008).In the DM group,HBP levels at ICU admission were higher in 10-day non-survivors than in 10-day survivors(median 182.21[IQR:55.43-300]ng/ml *** 66.40[IQR:34.13-107.85]ng/mL,P=0.019),and HBP levels could predict the 10-day mortality with an area under the ROC curve of *** cut-off value,sensitivity,and specificity were 160.6 ng/mL,66.7%,and 90.2%,*** Cox regression analysis indicated that HBP was an independent prognostic factor for 10-day(HR 7.196,95%CI:1.596-32.455,P=0.01),28-day(HR 4.381,95%CI:1.449-13.245,P=0.009),and 90-day mortality(HR 4.581,95%CI:1.637-12.819,P=0.004)in patients with ***:Plasma HBP at ICU admission was associated with the 10-day,28-day,and 90-day mortality,and might be a prognostic factor in patients with DM and CAP.

关键词： Community-acquired pneumonia Diabetes mellitus Heparin-binding protein Propensity score match

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

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

The activity and immune dynamics of PD-1 inhibition on high-risk pulmonary ground glass opacity lesions:insights from a single-arm,phase II trial

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Signal Transduction and Targeted Therapy 2024年第5期9卷 2202-2214页

作者： Bo Cheng Caichen Li Jianfu Li Longlong Gong Peng Liang Ying Chen Shuting Zhan Shan Xiong Ran Zhong Hengrui Liang Yi Feng Runchen Wang Haixuan Wang Hongbo Zheng Jun Liu Chengzhi Zhou Wenlong Shao Yuan Qiu Jiancong Sun Zhanhong Xie Zhu Liang Chenglin Yang Xiuyu Cai Chunxia Su Wei Wang Jianxing He Wenhua Liang Department of Thoracic Surgery and Oncology the First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou Institute of Respiratory HealthState Key Laboratory of Respiratory DiseaseNational Clinical Research Center for Respiratory DiseaseGuangzhouChina Medical Department Genecast Biotechnology Co.LtdWuxiChina Department of Radiation Oncology the First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina Department of respiratory Medicine the First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou Institute of Respiratory HealthState Key Laboratory of Respiratory DiseaseNational Clinical Research Center for Respiratory DiseaseGuangzhouChina Department of Cardiothoracic Surgery Affiliated Hospital of Guangdong Medical UniversityZhanjiangChina Department of Thoracic Surgery National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital&Shenzhen HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeShenzhenChina Department of VIP Inpatient Sun Yat-sen University Cancer CenterState Key Laboratory of Oncology in South ChinaSun Yat-sen UniversityGuangzhouChina Department of Medical Oncology Shanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghaiChina

Immune checkpoint inhibitors targeting the programmed cell death-1(PD-1)protein significantly improve survival in patients with advanced non-small-cell lung cancer(NSCLC),but its impact on early-stage ground-glass opacity(GGO)lesions remains *** is a single-arm,phase II trial(NCT04026841)using Simon’s optimal two-stage design,of which 4 doses of sintilimab(200 mg per 3 weeks)were administrated in 36 enrolled multiple primary lung cancer(MPLC)patients with persistent high-risk(Lung-RADS category 4 or had progressed within 6 months)*** primary endpoint was objective response rate(ORR).T/B/NK-cell subpopulations,TCR-seq,cytokines,exosomal RNA,and multiplexed immunohistochemistry(mIHC)were monitored and compared between responders and ***,two intent-to-treat(ITT)lesions(pure-GGO or GGO-predominant)showed responses(ORR:5.6%,2/36),and no patients had progressive disease(PD).No grade 3-5 TRAEs *** total response rate considering two ITT lesions and three non-intent-to-treat(NITT)lesions(pure-solid or solid-predominant)was 13.9%(5/36).The proportion of CD8^(+)T cells,the ratio of CD8^(+)/CD4^(+),and the TCR clonality value were significantly higher in the peripheral blood of responders before treatment and decreased over ***,the mIHC analysis showed more CD8^(+)T cells infiltrated in ***,responders’cytokine concentrations of EGF and CTLA-4 increased during *** exosomal expression of fatty acid metabolism and oxidative phosphorylation gene signatures were down-regulated among ***,PD-1 inhibitor showed certain activity on high-risk pulmonary GGO lesions without safety *** effects were associated with specific T-cell re-distribution,EGF/CTLA-4 cytokine compensation,and regulation of metabolism pathways.

关键词： lesions metabolism doses