Objective: Esophageal squamous cell carcinoma(ESCC) is one of the dominant malignances worldwide, but currently there is less focus on the microbiota with ESCC and its precancerous lesions.Methods: Paired esophageal b...Objective: Esophageal squamous cell carcinoma(ESCC) is one of the dominant malignances worldwide, but currently there is less focus on the microbiota with ESCC and its precancerous lesions.Methods: Paired esophageal biopsy and swab specimens were obtained from 236 participants in Linzhou, China.Data from 16 S ribosomal RNA gene sequencing were processed using quantitative insights into microbial ecology(QIIME2) and R Studio to evaluate differences. The Wilcoxon rank sum test and Kruskal-Wallis rank sum test were used to compare diversity and characteristic genera by specimens and participant groups. Ordinal logistic regression model was used to build microbiol prediction model.Results: Microbial diversity was similar between biopsy and swab specimens, including operational taxonomic unit(OTU) numbers and Shannon index. There were variations and similarities of esophageal microbiota among different pathological characteristics of ESCC. Top 10 relative abundance genera in all groups include Streptococcus, Prevotella, Veillonella, Actinobacillus, Haemophilus, Neisseria, Alloprevotella, Rothia, Gemella and Porphyromonas. Genus Streptococcus, Haemophilus, Neisseria and Porphyromonas showed significantly difference in disease groups when compared to normal control, whereas Streptococcus showed an increasing tendency with the progression of ESCC and others showed a decreasing tendency. About models based on all combinations of characteristic genera, only taken Streptococcus and Neisseria into model, the prediction performance was the ideal one, of which the area under the curve(AUC) was 0.738.Conclusions: Esophageal biopsy and swab specimens could yield similar microbial characterization. The combination of Streptococcus and Neisseria has the potential to predict the progression of ESCC, which is needed to confirm by large-scale, prospective cohort studies.展开更多
Fibroblast activation protein(Fap)is a serine protease that degrades denatured type I collagen,α2-antiplasmin and FGF21.Fap is highly expressed in bone marrow stromal cells and functions as an osteogenic suppressor a...Fibroblast activation protein(Fap)is a serine protease that degrades denatured type I collagen,α2-antiplasmin and FGF21.Fap is highly expressed in bone marrow stromal cells and functions as an osteogenic suppressor and can be inhibited by the bone growth factor Osteolectin(Oln).Fap is also expressed in synovial fibroblasts and positively correlated with the severity of rheumatoid arthritis(RA).However,whether Fap plays a critical role in osteoarthritis(OA)remains poorly understood.Here,we found that Fap is significantly elevated in osteoarthritic synovium,while the genetic deletion or pharmacological inhibition of Fap significantly ameliorated posttraumatic OA in mice.Mechanistically,we found that Fap degrades denatured type II collagen(Col II)and Mmp13-cleaved native Col II.Intra-articular injection of r Fap significantly accelerated Col II degradation and OA progression.In contrast,Oln is expressed in the superficial layer of articular cartilage and is significantly downregulated in OA.Genetic deletion of Oln significantly exacerbated OA progression,which was partially rescued by Fap deletion or inhibition.Intra-articular injection of r Oln significantly ameliorated OA progression.Taken together,these findings identify Fap as a critical pathogenic factor in OA that could be targeted by both synthetic and endogenous inhibitors to ameliorate articular cartilage degradation.展开更多
To the Editor:Esophageal cancer(EC)ranks ninth and fifth among the leading cause of global cancer-related morbidity and mortality,respectively.[1]Esophageal squamous cell carcinoma(ESCC)is the predominant histologic s...To the Editor:Esophageal cancer(EC)ranks ninth and fifth among the leading cause of global cancer-related morbidity and mortality,respectively.[1]Esophageal squamous cell carcinoma(ESCC)is the predominant histologic subtype of EC in China.Population screening effectively decreases the morbidity and mortality of ESCC,highlighting the necessity of early detection and early diagnosis.展开更多
A two-dimensional(2D)cell culture-based model is widely applied to study tumorigenic mechanisms and drug screening.However,it cannot authentically simulate the threedimensional(3D)microenvironment of solid tumors and ...A two-dimensional(2D)cell culture-based model is widely applied to study tumorigenic mechanisms and drug screening.However,it cannot authentically simulate the threedimensional(3D)microenvironment of solid tumors and provide reliable and predictable data in response to in vivo,thus leading to the research ilusionis and failure of drug screening.In this study,honeycomb-like gelatin methacryloyl(GelMA)hydrogel microspheres are developed by synchronous photocrosslinking microluidic technique to construct a 3D model of osteosarcoma.The in vitro study shows that ostcosarcoma cells(K7M2)culured in 3D GelMA microspheres have stronger tumorous stemness。proliferation and migration abilitics,more osteoclastogenetic ability,and reistance to chemotherapeutic drugs(DOX)than that of cells in 2D cultures.More imporantly,the 3D-cultured K7M2 cells show more tumorigenicity in immunologically sound mice,characterized by shorter tumorigenesis time,larger tumor volumc,severe bone destruction,and higher mortality.In conclusion,honeycomb like porous microsphere scaffolds are constructed with uniform structure by micofluidic technology to massively produce tumor cells with original phenotypes.Those microspheres could recapitulate the physiology microenvironment of tumors.maintain ell-cell and cell-extracellular matrix interactions,and thus provide an efective and convenient strategy for tumor pathogenesis and drug screening research.展开更多
Inhaled drug-containing nanocarriers have been well applied as an important strategy in pulmonary dis-eases.Acute lung injury(ALI)is characterized by abnormal lung tension and complex pathogenesis,with high mortality ...Inhaled drug-containing nanocarriers have been well applied as an important strategy in pulmonary dis-eases.Acute lung injury(ALI)is characterized by abnormal lung tension and complex pathogenesis,with high mortality because of the limitations of targeted intervention.Accordingly,in the present study,we first identified that the mechanosensitive ion channel Piezo1 participated in the ALI-associated processes induced by lipopolysaccharide(LPS)in vitro and in vivo.Then,chitosan-stabilized bovine serum albu-min nanoparticles(NCs)emulsified with the Piezo1 inhibitor GsMTx4(NC-GsMTx4)were generated and exhibited excellent biocompatibility and biological function.Through aerosol inhalation,NC-GsMTx4 im-proved lung injury and inhibited cell apoptosis in LPS-stressed ALI mice and alleviated pulmonary fibrosis during the later stage of ALI.Mechanistically,GsMTx4 could regulate inflammation and apoptosis in lung epithelial cells via NF-κB and ERK1/2 signaling.In summary,our findings provide new insights into the pathological mechanisms of Piezo1 in ALI progression,and nebulized inhalation of NC-GsMTx4 offers a prospective platform for targeting Piezo1 to treat ALI efficiently and conveniently.展开更多
Phototheranostics have attracted tremendous attention in cancer diagnosis and treatment because of the noninvasiveness and promising effectiveness.Developing advanced phototheranostic agents with long emission wavelen...Phototheranostics have attracted tremendous attention in cancer diagnosis and treatment because of the noninvasiveness and promising effectiveness.Developing advanced phototheranostic agents with long emission wavelength,excellent biocompatibility,great tumor-targeting capability,and efficient therapeutic effect is highly desirable.However,the mutual constraint between imaging and therapeutic functions usually hinders their wide applications in biomedical field.To balance this contradiction,we herein rationally designed and synthesized three novel tumor-targeted NIR-Ⅱ probes(QR-2PEG_(321),QR-2PEG_(1000),and QR-2PEG_(5000)) by conjugating three different chain lengths of PEG onto an integrin α_(v)β_(3)-targeted NIR-Ⅱ heptamethine cyanine fluorophore,respectively.In virtue of the essential amphiphilic characteristics of PEG polymers,these probes display various degree of aggregation in aqueous buffer accompanying with differential NIR-Ⅱ imaging and photothermal(PTT) therapeutic performance.Both in vitro and in vivo results have demonstrated that probe QR-2PEG_(5000) has the best NIR-Ⅱ imaging performance with prominent renal clearance,whereas QR-2PEG_(321)possesses excellent photoacoustic signal as well as PTT effect,which undoubtedly provides a promising toolbox for tumor diagnosis and therapy.We thus envision that these synthesized probes have great potential to be explored as a toolkit for precise diagnosis and treatment of malignant tumors.展开更多
SPONGE(Simulation Package tOward Next GEneration molecular modeling)is a software package for molecular dynamics(MD)simulation of solution and surface molecular systems.In this version of SPONGE,the all-atom potential...SPONGE(Simulation Package tOward Next GEneration molecular modeling)is a software package for molecular dynamics(MD)simulation of solution and surface molecular systems.In this version of SPONGE,the all-atom potential energy functions used in AMBER MD packages are used by default and other all-atom/coarse-grained potential energy functions are also supported.SPONGE is designed to extend the timescale being approached in MD simulations by utilizing the latest CUDA-enabled graphical processing units(GPU)and adopting highly efficient enhanced sampling algorithms,such as integrated tempering,selective integrated tempering and enhanced sampling of reactive trajectories.It is highly modular and new algorithms and functions can be incorporated con veniently.Particularly,a specialized Python plugin can be easily used to perform the machine learning MD simulation with MindSpore,TensorFlow,PyTorch or other popular machine learning frameworks.Furthermore,a plugin of Finite-Element Method(FEM)is also available to handle metallic surface systems.All these advanced features increase the power of SPONGE for modeling and simulation of complex chemical and biological systems.展开更多
Hazelnut husk brown rot has been identified as a new disease in Liaoning Province in recent years.The objective of this study as to identify the pathogen.[Method]In this study,a standard sample of hazelnut husk brown ...Hazelnut husk brown rot has been identified as a new disease in Liaoning Province in recent years.The objective of this study as to identify the pathogen.[Method]In this study,a standard sample of hazelnut husk brown rot was collected from Songmudao Base in Dalian City,Liaoning Province.The pathogen was identified by the studies of the morphology,pathogenicity,and analyses of ITS and LSU sequences.The pathogen was isolated and purified,which was confirmed by Koch’s postulates.The symptoms after inoculation were the same as those collected directly from a diseased tree,which showed that it was the pathogenic fungus.The cultural characteristics and conidia and the morphology of the pathogenic fungi were similar to those of Botrytis cinerea’s.The ITS sequences and LSU sequences were compared to the associated strain sequences in GenBank,with 100%identity to Botrytis cinerea(GenBank accession number:MN589848.1)and Botrytis cinerea(GenBank accession number:KU140653.1),respectively.The infection status of the pathogen on the hazelnut husks was also observed.The studies suggested that the pathogen leading to the hazelnut husk brown rot as a new disease in Liaoning Province was Botrytis cinerea.展开更多
基金the National Natural Science Foundation of China (No.81974493)the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (No.2016-I2M-3-001)。
文摘Objective: Esophageal squamous cell carcinoma(ESCC) is one of the dominant malignances worldwide, but currently there is less focus on the microbiota with ESCC and its precancerous lesions.Methods: Paired esophageal biopsy and swab specimens were obtained from 236 participants in Linzhou, China.Data from 16 S ribosomal RNA gene sequencing were processed using quantitative insights into microbial ecology(QIIME2) and R Studio to evaluate differences. The Wilcoxon rank sum test and Kruskal-Wallis rank sum test were used to compare diversity and characteristic genera by specimens and participant groups. Ordinal logistic regression model was used to build microbiol prediction model.Results: Microbial diversity was similar between biopsy and swab specimens, including operational taxonomic unit(OTU) numbers and Shannon index. There were variations and similarities of esophageal microbiota among different pathological characteristics of ESCC. Top 10 relative abundance genera in all groups include Streptococcus, Prevotella, Veillonella, Actinobacillus, Haemophilus, Neisseria, Alloprevotella, Rothia, Gemella and Porphyromonas. Genus Streptococcus, Haemophilus, Neisseria and Porphyromonas showed significantly difference in disease groups when compared to normal control, whereas Streptococcus showed an increasing tendency with the progression of ESCC and others showed a decreasing tendency. About models based on all combinations of characteristic genera, only taken Streptococcus and Neisseria into model, the prediction performance was the ideal one, of which the area under the curve(AUC) was 0.738.Conclusions: Esophageal biopsy and swab specimens could yield similar microbial characterization. The combination of Streptococcus and Neisseria has the potential to predict the progression of ESCC, which is needed to confirm by large-scale, prospective cohort studies.
基金National Key R&D Program of China(2022YFA1103200,2017YFA0106400,2021YFA1100900)Ministry of Science and Technology of China(2020YFC2002804)+3 种基金National Natural Science Foundation of China(91749124,81772389,82070108)Major Program of Development Fund for Shanghai Zhangjiang National Innovation Demonstration Zone(ZJ2018-ZD-004)Fundamental Research Funds for the Central Universities(22120190149 and kx0200020173386)Peak Disciplines(Type IV)of Institutions of Higher Learning in Shanghai。
文摘Fibroblast activation protein(Fap)is a serine protease that degrades denatured type I collagen,α2-antiplasmin and FGF21.Fap is highly expressed in bone marrow stromal cells and functions as an osteogenic suppressor and can be inhibited by the bone growth factor Osteolectin(Oln).Fap is also expressed in synovial fibroblasts and positively correlated with the severity of rheumatoid arthritis(RA).However,whether Fap plays a critical role in osteoarthritis(OA)remains poorly understood.Here,we found that Fap is significantly elevated in osteoarthritic synovium,while the genetic deletion or pharmacological inhibition of Fap significantly ameliorated posttraumatic OA in mice.Mechanistically,we found that Fap degrades denatured type II collagen(Col II)and Mmp13-cleaved native Col II.Intra-articular injection of r Fap significantly accelerated Col II degradation and OA progression.In contrast,Oln is expressed in the superficial layer of articular cartilage and is significantly downregulated in OA.Genetic deletion of Oln significantly exacerbated OA progression,which was partially rescued by Fap deletion or inhibition.Intra-articular injection of r Oln significantly ameliorated OA progression.Taken together,these findings identify Fap as a critical pathogenic factor in OA that could be targeted by both synthetic and endogenous inhibitors to ameliorate articular cartilage degradation.
基金National Natural Science Foundation of China(No.81974493)National Science&Technology Fundamental Resources Investigation Program of China(No.2019FY101101)National Key Research and Development Program of Precision Medicine(No.2016YFC091404)
文摘To the Editor:Esophageal cancer(EC)ranks ninth and fifth among the leading cause of global cancer-related morbidity and mortality,respectively.[1]Esophageal squamous cell carcinoma(ESCC)is the predominant histologic subtype of EC in China.Population screening effectively decreases the morbidity and mortality of ESCC,highlighting the necessity of early detection and early diagnosis.
基金supported by grants from the National Natural Science Foundation of China(81930051,81772313,and 81972059)the Social Development,Project of Jiangsu Province(BK2019668)+2 种基金the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD),the Shanghai Jiao Tong University“Medical and Research”Program(ZH2018ZDA04)Foundation of National Facility for Translational Medicine(Shanghai)(TMSK-2020-117)and Translational Research Grant of NCRCH(2020WSB08).
文摘A two-dimensional(2D)cell culture-based model is widely applied to study tumorigenic mechanisms and drug screening.However,it cannot authentically simulate the threedimensional(3D)microenvironment of solid tumors and provide reliable and predictable data in response to in vivo,thus leading to the research ilusionis and failure of drug screening.In this study,honeycomb-like gelatin methacryloyl(GelMA)hydrogel microspheres are developed by synchronous photocrosslinking microluidic technique to construct a 3D model of osteosarcoma.The in vitro study shows that ostcosarcoma cells(K7M2)culured in 3D GelMA microspheres have stronger tumorous stemness。proliferation and migration abilitics,more osteoclastogenetic ability,and reistance to chemotherapeutic drugs(DOX)than that of cells in 2D cultures.More imporantly,the 3D-cultured K7M2 cells show more tumorigenicity in immunologically sound mice,characterized by shorter tumorigenesis time,larger tumor volumc,severe bone destruction,and higher mortality.In conclusion,honeycomb like porous microsphere scaffolds are constructed with uniform structure by micofluidic technology to massively produce tumor cells with original phenotypes.Those microspheres could recapitulate the physiology microenvironment of tumors.maintain ell-cell and cell-extracellular matrix interactions,and thus provide an efective and convenient strategy for tumor pathogenesis and drug screening research.
基金supported by the Science and Technology Plan of Jiangxi Provincial Health Commission(No.SKJP220201115)Live Science and Technology of Suzhou(No.SS201862)the Prior-ity Academic Program Development of Jiangsu Higher Education Institutions(PAPD).Translational Research Grant of NCRCH(No.2020WSB08).
文摘Inhaled drug-containing nanocarriers have been well applied as an important strategy in pulmonary dis-eases.Acute lung injury(ALI)is characterized by abnormal lung tension and complex pathogenesis,with high mortality because of the limitations of targeted intervention.Accordingly,in the present study,we first identified that the mechanosensitive ion channel Piezo1 participated in the ALI-associated processes induced by lipopolysaccharide(LPS)in vitro and in vivo.Then,chitosan-stabilized bovine serum albu-min nanoparticles(NCs)emulsified with the Piezo1 inhibitor GsMTx4(NC-GsMTx4)were generated and exhibited excellent biocompatibility and biological function.Through aerosol inhalation,NC-GsMTx4 im-proved lung injury and inhibited cell apoptosis in LPS-stressed ALI mice and alleviated pulmonary fibrosis during the later stage of ALI.Mechanistically,GsMTx4 could regulate inflammation and apoptosis in lung epithelial cells via NF-κB and ERK1/2 signaling.In summary,our findings provide new insights into the pathological mechanisms of Piezo1 in ALI progression,and nebulized inhalation of NC-GsMTx4 offers a prospective platform for targeting Piezo1 to treat ALI efficiently and conveniently.
基金financial support from the Training Program of the Major Research Plan of the National Natural Science Foundation of China (No. 91959123)National Natural Science Foundation of China (No. 22077092)+2 种基金Key Research and Development Program of Social Development of Jiangsu Province (No. BE2018655)the Open Project Program of the State Key Laboratory of Radiation Medicine and Protection (Nos. GZK1202132, GZK1202140 and GZK1202017)funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions。
文摘Phototheranostics have attracted tremendous attention in cancer diagnosis and treatment because of the noninvasiveness and promising effectiveness.Developing advanced phototheranostic agents with long emission wavelength,excellent biocompatibility,great tumor-targeting capability,and efficient therapeutic effect is highly desirable.However,the mutual constraint between imaging and therapeutic functions usually hinders their wide applications in biomedical field.To balance this contradiction,we herein rationally designed and synthesized three novel tumor-targeted NIR-Ⅱ probes(QR-2PEG_(321),QR-2PEG_(1000),and QR-2PEG_(5000)) by conjugating three different chain lengths of PEG onto an integrin α_(v)β_(3)-targeted NIR-Ⅱ heptamethine cyanine fluorophore,respectively.In virtue of the essential amphiphilic characteristics of PEG polymers,these probes display various degree of aggregation in aqueous buffer accompanying with differential NIR-Ⅱ imaging and photothermal(PTT) therapeutic performance.Both in vitro and in vivo results have demonstrated that probe QR-2PEG_(5000) has the best NIR-Ⅱ imaging performance with prominent renal clearance,whereas QR-2PEG_(321)possesses excellent photoacoustic signal as well as PTT effect,which undoubtedly provides a promising toolbox for tumor diagnosis and therapy.We thus envision that these synthesized probes have great potential to be explored as a toolkit for precise diagnosis and treatment of malignant tumors.
基金the National Key R&D Program of China(2017YFA0204702)the National Natural Science Foundation of China(21821004,21873007 and 21927901)CAAI-Huawei MindSpore Open Fund for financial support.
文摘SPONGE(Simulation Package tOward Next GEneration molecular modeling)is a software package for molecular dynamics(MD)simulation of solution and surface molecular systems.In this version of SPONGE,the all-atom potential energy functions used in AMBER MD packages are used by default and other all-atom/coarse-grained potential energy functions are also supported.SPONGE is designed to extend the timescale being approached in MD simulations by utilizing the latest CUDA-enabled graphical processing units(GPU)and adopting highly efficient enhanced sampling algorithms,such as integrated tempering,selective integrated tempering and enhanced sampling of reactive trajectories.It is highly modular and new algorithms and functions can be incorporated con veniently.Particularly,a specialized Python plugin can be easily used to perform the machine learning MD simulation with MindSpore,TensorFlow,PyTorch or other popular machine learning frameworks.Furthermore,a plugin of Finite-Element Method(FEM)is also available to handle metallic surface systems.All these advanced features increase the power of SPONGE for modeling and simulation of complex chemical and biological systems.
基金This work was financially supported by the Liaoning Provincial Natural Science Foundation of China(Grant No.2021-MS-057).
文摘Hazelnut husk brown rot has been identified as a new disease in Liaoning Province in recent years.The objective of this study as to identify the pathogen.[Method]In this study,a standard sample of hazelnut husk brown rot was collected from Songmudao Base in Dalian City,Liaoning Province.The pathogen was identified by the studies of the morphology,pathogenicity,and analyses of ITS and LSU sequences.The pathogen was isolated and purified,which was confirmed by Koch’s postulates.The symptoms after inoculation were the same as those collected directly from a diseased tree,which showed that it was the pathogenic fungus.The cultural characteristics and conidia and the morphology of the pathogenic fungi were similar to those of Botrytis cinerea’s.The ITS sequences and LSU sequences were compared to the associated strain sequences in GenBank,with 100%identity to Botrytis cinerea(GenBank accession number:MN589848.1)and Botrytis cinerea(GenBank accession number:KU140653.1),respectively.The infection status of the pathogen on the hazelnut husks was also observed.The studies suggested that the pathogen leading to the hazelnut husk brown rot as a new disease in Liaoning Province was Botrytis cinerea.
