Sepsis is a life-threatening organ dysfunction that is associated with a high risk of death.Xuebijing(XBJ)injection,a Chinese herbal compound preparation,has been widely used for the treatment of sepsis in China.The p...Sepsis is a life-threatening organ dysfunction that is associated with a high risk of death.Xuebijing(XBJ)injection,a Chinese herbal compound preparation,has been widely used for the treatment of sepsis in China.The purpose of this research is to decipher the underlying multi-target pharmacological mechanism of XBJ in the treatment of sepsis using a systems pharmacology approach.Compounds in XBJ were collected by literature retrieval.The corresponding putative targets of XBJ were screened from the Traditional Chinese Medicine Systems Pharmacology(TCMSP),Swiss Target Prediction(STP),and Search Tool for Interacting Chemicals(STITCH)databases.Sepsis-related targets were summarized using the Genecards,DrugBank,and Online Mendelian Inheritance in Man(OMIM)databases.The intersection targets were obtained with Venny 2.1.Subsequently,protein-protein interaction(PPI)networks were constructed with the STRING database and Cytoscape 3.7.1.Then,degree,betweenness,and closeness were calculated to recognize the core targets in the PPI network.Moreover,the pharmacological mechanism of XBJ against sepsis was predicted via gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment.After the literature review,the 33 most commonly cited chemical ingredients,were screened out as major compounds.Bioinformatics analysis revealed that the major compounds of XBJ modulated 218 common targets associated with sepsis.Through PPI network analysis,41 genes,including IL-6,AKT1,STAT3,TP53,and MAPK1,were identified as core targets.The results of GO and KEGG enrichment revealed that the potential biological functions of XBJ against sepsis were mainly involved in cytokine receptor binding,cytokine activity,growth factor receptor binding,growth factor activity,and chemokine activity.The crucial pathways were closely associated with initial immune activation(CLR/TLR4-NF-κB/MAPK pathway),the acute inflammatory response(TNFMAPK/caspase and IL-MAPK/STAT pathways),and the late inflammation and coagulation process(HMGB1-RAGE and HIF-1 signaling pathways).This study revealed that the multiple components of XBJ exert multitarget effects against sepsis by regulating initial immune activation,the acute inflammatory response,and the late inflammation and coagulation process.展开更多
In this study, the three-dimensional physical model of pleated air filtration media was simplified to porous media model, and the calculation parameters of porous media were obtained based on experimental data. The mo...In this study, the three-dimensional physical model of pleated air filtration media was simplified to porous media model, and the calculation parameters of porous media were obtained based on experimental data. The model of V-shaped pleated air filter media is constructed, the height of the media pleat is 50 mm and the pleat thickness is 4 mm, the pleat angle is 3.7°. The Hertz-Mindlin contact model was modified by Johnson Kendall Roberts (JKR) adhesion contact model. The deposition process of particles in media was simulated based on computational fluid dynamics (CFD) theory and discrete element method (DEM). Results show that the CFD–DEM coupling method can be effectively applied to the macro research of pleated air filter media. The particles will form dust layer and dendrite structure on the fiber surface, and the dust layer will affect the subsequent air flow organization, and the dendrite structure will eventually form a “particle wall”. The formation of the “particle wall” will prevent the particles from moving further in the fluid domain, which makes area of pleated angle become the “low efficiency” part about the particle deposition. Compared with area of pleated angle, the particles are concentrated in the opening area and the middle area of the pleated to agglomerate and deposit.展开更多
在自元古代以来的长期地质演化过程中,扬子地块西南部形成了多样化的富含In、Ge、Ga、Cd、Re、Sn、Li、Nb、REE(rare earth element)和PGE(platinum group elements)等不同种类关键金属元素的矿床类型.通过总结以往的研究,本文认为该区...在自元古代以来的长期地质演化过程中,扬子地块西南部形成了多样化的富含In、Ge、Ga、Cd、Re、Sn、Li、Nb、REE(rare earth element)和PGE(platinum group elements)等不同种类关键金属元素的矿床类型.通过总结以往的研究,本文认为该区除晚二叠世与峨眉山地幔柱活动有关的Cu-Ni-PGE岩浆硫化物矿床和新生代与印-亚大陆后碰撞造山作用有关的碳酸岩型REE矿床外,富含关键金属元素矿床的成矿作用主要显示四大特点:(1)古-中元古代发育我国首个被确认的富稀土IOCG成矿省;(2)燕山晚期与花岗岩有关的富In锡石硫化物矿床在面积很小的区域大爆发成矿;(3)印支期和燕山早期花岗岩浆活动微弱,富Ge低温Pb-Zn矿床和低温Au-As-Sb-Hg-Tl矿床广泛发育;(4)埃迪卡拉纪以来的海相沉积岩尤其是黑色页岩和碳酸盐岩广布,多时代富Li、Nb、Zr、Ga、Re、REE、PGE等的沉积和/或风化-沉积矿床大面积分布.在此基础上,进一步总结了区域地质事件与成矿事件的相互关系,提出了一些重要成矿系统值得进一步探索的领域.展开更多
Lightweight design is important for the Thermal Protection System(TPS) of hypersonic vehicles in that it protects the inner structure from severe heating environment. However, due to the existence of uncertainties in ...Lightweight design is important for the Thermal Protection System(TPS) of hypersonic vehicles in that it protects the inner structure from severe heating environment. However, due to the existence of uncertainties in material properties and geometry, it is imperative to incorporate uncertainty analysis into the design optimization to obtain reliable results. In this paper, a six sigma robust design optimization based on Successive Response Surface Method(SRSM) is established for the TPS to improve the reliability and robustness with considering the uncertainties. The uncertain parameters related to material properties and thicknesses of insulation layers are considered and characterized by random variables following normal distributions. By employing SRSM, the values of objective function and constraints are approximated by the response surfaces to reduce computational cost. The optimization is an iterative process with response surfaces updating to find the true optimal solution. The optimization of the nose cone of hypersonic vehicle cabin is provided as an example to illustrate the feasibility and effectiveness of the proposed method.展开更多
The chemotherapy combined with photothermal therapy has been a favorable approach for the treatment of breast cancer.In present study,nanoparticles with the characteristics of photothermal/matrix metalloproteinase-2(M...The chemotherapy combined with photothermal therapy has been a favorable approach for the treatment of breast cancer.In present study,nanoparticles with the characteristics of photothermal/matrix metalloproteinase-2(MMP-2)dual-responsive,tumor targeting,and size-variability were designed for enhancing the antitumor efficacy and achieving"on-demand"drug release markedly.Based on the thermal sensitivity of gelatin,we designed a size-variable gelatin nanoparticle(GNP)to encapsulate indocyanine green(ICG)and doxorubicin(DOX).Under an 808 nm laser irradiation,GNP-DOX/ICG responded photothermally and swelled in size from 71.58?4.28 to 160.80?9.51 nm,which was beneficial for particle retention in the tumor sites and release of the loaded therapeutics.Additionally,GNP-DOX/ICG showed a size reduction of the particles to 33.24?4.11 nm and further improved drug release with the degradation of overexpressed MMP-2 in tumor.In the subsequently performed in vitro experiments,it was confirmed that GNP-DOX/ICG could provide a therapeutic effect that was enhanced and synergistic.Consequently,GNP-DOX/ICG could efficiently suppress the growth of 4 T1 tumor in vivo.In conclusion,this study may provide a promising strategy in the rational design of drug delivery nanosystems based on gelatin for chemo-photothermal therapy to achieve synergistically enhanced therapeutic efficacy against breast cancer.展开更多
Background:Pressure ulcers(PUs)are a major clinical problem that constitutes a tremendous economic burden on healthcare systems.Deep tissue injury(DTI)is a unique serious type of pressure ulcer that arises in skeletal...Background:Pressure ulcers(PUs)are a major clinical problem that constitutes a tremendous economic burden on healthcare systems.Deep tissue injury(DTI)is a unique serious type of pressure ulcer that arises in skeletal muscle tissue.DTI arises in part because skeletal muscle tissues are more susceptible than skin to external compression.Unfortunately,few effective therapies are currently available for muscle injury.Basic fibroblast growth factor(bFGF),a potent mitogen and survival factor for various cells,plays a crucial role in the regulation of muscle development and homeostasis.The main purpose of this study was to test whether local administration of bFGF could accelerate muscle regeneration in a rat DTI model.Methods:Male Sprague Dawley(SD)rats(age 12 weeks)were individually housed in plastic cages and a DTI PU model was induced according to methods described before.Animals were randomly divided into three groups:a normal group,a PU group treated with saline,and a PU group treated with bFGF(10μg/0.1 ml)subcutaneously near the wound.Results:We found that application of bFGF accelerated the rate of wound closure and promoted cell proliferation and tissue angiogenesis.In addition,compared to saline administration,bFGF treatment prevented collagen deposition,a measure of fibrosis,and up-regulated the myogenic marker proteins MyHC and myogenin,suggesting bFGF promoted injured muscle regeneration.Moreover,bFGF treatment increased levels of myogenesis-related proteins p-Akt and p-mTOR.Conclusions:Our findings show that bFGF accelerated injured skeletal muscle regeneration through activation of the PI3K/Akt/mTOR signaling pathway and suggest that administration of bFGF is a potential therapeutic strategy for the treatment of skeletal muscle injury in PUs.展开更多
The unique photo-thermal energy conversion property of polar bear hairs has long been regarded as an essential element to enable this creature to survive in extremely cold conditions. However, the relevant research wa...The unique photo-thermal energy conversion property of polar bear hairs has long been regarded as an essential element to enable this creature to survive in extremely cold conditions. However, the relevant research was ineffectual to provide sufficient evidence of its solar energy harvesting property. In this paper, the properties of polar bear hairs were analyzed and compared systematically with those of domestic sheep wool through the measurements in the aspects of photo-thermal conversion effi- ciency, scanning electron microscope, fluorescence spectral and transmission of UV-visible spectra. Moreover, this study was much more focused on exploring ultraviolet utilization property of polar bear hair than previous research. The research results demonstrated that the photo-thermal property of polar bear hair was superior to those of wool fiber, especially in harvesting ultraviolet part. The potential benefits of this research lie in the development of bionic solar energy collective devices, especially in artificial solar energy collection fibers and textile products.展开更多
It is a formidable challenge to fabricate healable polymeric materials with high mechanical strength and stiffness due to the highly suppressed diffusion of their polymer chains.Herein,a high-strength,highly stiff,and...It is a formidable challenge to fabricate healable polymeric materials with high mechanical strength and stiffness due to the highly suppressed diffusion of their polymer chains.Herein,a high-strength,highly stiff,andrepairable/healable supramolecular polymercomposite was fabricatedby complexingpoly(acrylic acid)(PAA)and poly(allylamine hydrochloride)(PAH)in aqueous solutions,followed by molding into desired shapes.Exquisitely tuning the electrostatic and H-bonding interactions between PAA and PAH led to associative phase-separation and in situ formation of nanostructures in the resultant PAA–PAH composites.展开更多
Background:DNA methylation and gene expression are known to play important roles in the etiology of human diseases such as prostate cancer(PCa).However,it has not yet been possible to incorporate information of DNA me...Background:DNA methylation and gene expression are known to play important roles in the etiology of human diseases such as prostate cancer(PCa).However,it has not yet been possible to incorporate information of DNA methylation and gene expression into polygenic risk scores(PRSs).Here,we aimed to develop and validate an improved PRS for PCa risk by incorporating genetically predicted gene expression and DNA methylation,and other genomic information using an integrative method.Methods:Using data from the PRACTICAL consortium,we derived multiple sets of genetic scores,including those based on available single-nucleotide polymorphisms through widely used methods of pruning and thresholding,LDpred,LDpred-funt,AnnoPred,and EBPRS,as well as PRS constructed using the genetically predicted gene expression and DNA methylation through a revised pruning and thresholding strategy.In the tuning step,using the UK Biobank data(1458 prevalent cases and 1467 controls),we selected PRSs with the best performance.Using an independent set of data from the UK Biobank,we developed an integrative PRS combining information from individual scores.Furthermore,in the testing step,we tested the performance of the integrative PRS in another independent set of UK Biobank data of incident cases and controls.Results:Our constructed PRS had improved performance(C statistics:76.1%)over PRSs constructed by individual benchmark methods(from 69.6%to 74.7%).Furthermore,our new PRS had much higher risk assessment power than family history.The overall net reclassification improvement was 69.0%by adding PRS to the baseline model compared with 12.5%by adding family history.Conclusions:We developed and validated a new PRS which may improve the utility in predicting the risk of developing PCa.Our innovative method can also be applied to other human diseases to improve risk prediction across multiple outcomes.展开更多
基金This work was supported by start-up funds from Beijing University of Chinese Medicine to Jianxun Wang(grant number 1000041510051).
文摘Sepsis is a life-threatening organ dysfunction that is associated with a high risk of death.Xuebijing(XBJ)injection,a Chinese herbal compound preparation,has been widely used for the treatment of sepsis in China.The purpose of this research is to decipher the underlying multi-target pharmacological mechanism of XBJ in the treatment of sepsis using a systems pharmacology approach.Compounds in XBJ were collected by literature retrieval.The corresponding putative targets of XBJ were screened from the Traditional Chinese Medicine Systems Pharmacology(TCMSP),Swiss Target Prediction(STP),and Search Tool for Interacting Chemicals(STITCH)databases.Sepsis-related targets were summarized using the Genecards,DrugBank,and Online Mendelian Inheritance in Man(OMIM)databases.The intersection targets were obtained with Venny 2.1.Subsequently,protein-protein interaction(PPI)networks were constructed with the STRING database and Cytoscape 3.7.1.Then,degree,betweenness,and closeness were calculated to recognize the core targets in the PPI network.Moreover,the pharmacological mechanism of XBJ against sepsis was predicted via gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment.After the literature review,the 33 most commonly cited chemical ingredients,were screened out as major compounds.Bioinformatics analysis revealed that the major compounds of XBJ modulated 218 common targets associated with sepsis.Through PPI network analysis,41 genes,including IL-6,AKT1,STAT3,TP53,and MAPK1,were identified as core targets.The results of GO and KEGG enrichment revealed that the potential biological functions of XBJ against sepsis were mainly involved in cytokine receptor binding,cytokine activity,growth factor receptor binding,growth factor activity,and chemokine activity.The crucial pathways were closely associated with initial immune activation(CLR/TLR4-NF-κB/MAPK pathway),the acute inflammatory response(TNFMAPK/caspase and IL-MAPK/STAT pathways),and the late inflammation and coagulation process(HMGB1-RAGE and HIF-1 signaling pathways).This study revealed that the multiple components of XBJ exert multitarget effects against sepsis by regulating initial immune activation,the acute inflammatory response,and the late inflammation and coagulation process.
文摘In this study, the three-dimensional physical model of pleated air filtration media was simplified to porous media model, and the calculation parameters of porous media were obtained based on experimental data. The model of V-shaped pleated air filter media is constructed, the height of the media pleat is 50 mm and the pleat thickness is 4 mm, the pleat angle is 3.7°. The Hertz-Mindlin contact model was modified by Johnson Kendall Roberts (JKR) adhesion contact model. The deposition process of particles in media was simulated based on computational fluid dynamics (CFD) theory and discrete element method (DEM). Results show that the CFD–DEM coupling method can be effectively applied to the macro research of pleated air filter media. The particles will form dust layer and dendrite structure on the fiber surface, and the dust layer will affect the subsequent air flow organization, and the dendrite structure will eventually form a “particle wall”. The formation of the “particle wall” will prevent the particles from moving further in the fluid domain, which makes area of pleated angle become the “low efficiency” part about the particle deposition. Compared with area of pleated angle, the particles are concentrated in the opening area and the middle area of the pleated to agglomerate and deposit.
文摘在自元古代以来的长期地质演化过程中,扬子地块西南部形成了多样化的富含In、Ge、Ga、Cd、Re、Sn、Li、Nb、REE(rare earth element)和PGE(platinum group elements)等不同种类关键金属元素的矿床类型.通过总结以往的研究,本文认为该区除晚二叠世与峨眉山地幔柱活动有关的Cu-Ni-PGE岩浆硫化物矿床和新生代与印-亚大陆后碰撞造山作用有关的碳酸岩型REE矿床外,富含关键金属元素矿床的成矿作用主要显示四大特点:(1)古-中元古代发育我国首个被确认的富稀土IOCG成矿省;(2)燕山晚期与花岗岩有关的富In锡石硫化物矿床在面积很小的区域大爆发成矿;(3)印支期和燕山早期花岗岩浆活动微弱,富Ge低温Pb-Zn矿床和低温Au-As-Sb-Hg-Tl矿床广泛发育;(4)埃迪卡拉纪以来的海相沉积岩尤其是黑色页岩和碳酸盐岩广布,多时代富Li、Nb、Zr、Ga、Re、REE、PGE等的沉积和/或风化-沉积矿床大面积分布.在此基础上,进一步总结了区域地质事件与成矿事件的相互关系,提出了一些重要成矿系统值得进一步探索的领域.
基金supported by the National Key Research and Development Program of China (No. 2016YFB0200700)the National Nature Science Foundation of China (No. 11872089, No. 11572024, No. 11432002)Defence Industrial Technology Development Programs of China (No. JCKY2016601B001, No. JCKY2016204B101, No. JCKY2017601B001) for the financial supports
文摘Lightweight design is important for the Thermal Protection System(TPS) of hypersonic vehicles in that it protects the inner structure from severe heating environment. However, due to the existence of uncertainties in material properties and geometry, it is imperative to incorporate uncertainty analysis into the design optimization to obtain reliable results. In this paper, a six sigma robust design optimization based on Successive Response Surface Method(SRSM) is established for the TPS to improve the reliability and robustness with considering the uncertainties. The uncertain parameters related to material properties and thicknesses of insulation layers are considered and characterized by random variables following normal distributions. By employing SRSM, the values of objective function and constraints are approximated by the response surfaces to reduce computational cost. The optimization is an iterative process with response surfaces updating to find the true optimal solution. The optimization of the nose cone of hypersonic vehicle cabin is provided as an example to illustrate the feasibility and effectiveness of the proposed method.
基金supported by the National Natural Science Foundation of China(81873014,China)Natural Science Foundation of Zhejiang Province(LQ18E030003,China)+1 种基金China Postdoctoral Science Foundation(2017M621890,China)the Science and Technology Innovation Team Project of Zhejiang Province(2019R410057,China)
文摘The chemotherapy combined with photothermal therapy has been a favorable approach for the treatment of breast cancer.In present study,nanoparticles with the characteristics of photothermal/matrix metalloproteinase-2(MMP-2)dual-responsive,tumor targeting,and size-variability were designed for enhancing the antitumor efficacy and achieving"on-demand"drug release markedly.Based on the thermal sensitivity of gelatin,we designed a size-variable gelatin nanoparticle(GNP)to encapsulate indocyanine green(ICG)and doxorubicin(DOX).Under an 808 nm laser irradiation,GNP-DOX/ICG responded photothermally and swelled in size from 71.58?4.28 to 160.80?9.51 nm,which was beneficial for particle retention in the tumor sites and release of the loaded therapeutics.Additionally,GNP-DOX/ICG showed a size reduction of the particles to 33.24?4.11 nm and further improved drug release with the degradation of overexpressed MMP-2 in tumor.In the subsequently performed in vitro experiments,it was confirmed that GNP-DOX/ICG could provide a therapeutic effect that was enhanced and synergistic.Consequently,GNP-DOX/ICG could efficiently suppress the growth of 4 T1 tumor in vivo.In conclusion,this study may provide a promising strategy in the rational design of drug delivery nanosystems based on gelatin for chemo-photothermal therapy to achieve synergistically enhanced therapeutic efficacy against breast cancer.
基金This study was supported by research grants from the Zhejiang Provincial Natural Science Funding(LY14H150008)the National Natural Science Funding of China(81372064,81472165,and 81572237)+2 种基金the Zhejiang Provincial Program of Medical and Health Science(2014KYA131)the Wenzhou Program of Science and Technology(Y20140003)the State Key Basic Research Development Program(2012CB518105)
文摘Background:Pressure ulcers(PUs)are a major clinical problem that constitutes a tremendous economic burden on healthcare systems.Deep tissue injury(DTI)is a unique serious type of pressure ulcer that arises in skeletal muscle tissue.DTI arises in part because skeletal muscle tissues are more susceptible than skin to external compression.Unfortunately,few effective therapies are currently available for muscle injury.Basic fibroblast growth factor(bFGF),a potent mitogen and survival factor for various cells,plays a crucial role in the regulation of muscle development and homeostasis.The main purpose of this study was to test whether local administration of bFGF could accelerate muscle regeneration in a rat DTI model.Methods:Male Sprague Dawley(SD)rats(age 12 weeks)were individually housed in plastic cages and a DTI PU model was induced according to methods described before.Animals were randomly divided into three groups:a normal group,a PU group treated with saline,and a PU group treated with bFGF(10μg/0.1 ml)subcutaneously near the wound.Results:We found that application of bFGF accelerated the rate of wound closure and promoted cell proliferation and tissue angiogenesis.In addition,compared to saline administration,bFGF treatment prevented collagen deposition,a measure of fibrosis,and up-regulated the myogenic marker proteins MyHC and myogenin,suggesting bFGF promoted injured muscle regeneration.Moreover,bFGF treatment increased levels of myogenesis-related proteins p-Akt and p-mTOR.Conclusions:Our findings show that bFGF accelerated injured skeletal muscle regeneration through activation of the PI3K/Akt/mTOR signaling pathway and suggest that administration of bFGF is a potential therapeutic strategy for the treatment of skeletal muscle injury in PUs.
文摘The unique photo-thermal energy conversion property of polar bear hairs has long been regarded as an essential element to enable this creature to survive in extremely cold conditions. However, the relevant research was ineffectual to provide sufficient evidence of its solar energy harvesting property. In this paper, the properties of polar bear hairs were analyzed and compared systematically with those of domestic sheep wool through the measurements in the aspects of photo-thermal conversion effi- ciency, scanning electron microscope, fluorescence spectral and transmission of UV-visible spectra. Moreover, this study was much more focused on exploring ultraviolet utilization property of polar bear hair than previous research. The research results demonstrated that the photo-thermal property of polar bear hair was superior to those of wool fiber, especially in harvesting ultraviolet part. The potential benefits of this research lie in the development of bionic solar energy collective devices, especially in artificial solar energy collection fibers and textile products.
基金the National Key R&D Program of China(2018YFC1105401)and China’s Thousand Talent Plan,L.Y.thanks the National Natural Science Foundation of China(NSFC grant no.21704067)J.S.thanks the National Natural Science Foundation of China(NSFC grant no.21774049)for financial support.
文摘It is a formidable challenge to fabricate healable polymeric materials with high mechanical strength and stiffness due to the highly suppressed diffusion of their polymer chains.Herein,a high-strength,highly stiff,andrepairable/healable supramolecular polymercomposite was fabricatedby complexingpoly(acrylic acid)(PAA)and poly(allylamine hydrochloride)(PAH)in aqueous solutions,followed by molding into desired shapes.Exquisitely tuning the electrostatic and H-bonding interactions between PAA and PAH led to associative phase-separation and in situ formation of nanostructures in the resultant PAA–PAH composites.
基金NIH,Grant/Award Number:R03 AG070669Canadian Institutes of Health Research,European Commission’s Seventh Framework Programme grant agreement,Grant/Award Number:HEALTH-F2-2009-223175+11 种基金Cancer Research UK,Grant/Award Numbers:C5047/A7357,C1287/A10118,C1287/A16563,C5047/A3354,C5047/A10692,C16913/A6135The National Institute of Health(NIH)Cancer Post-Cancer GWAS,Grant/Award Number:1 U19 CA 148537-01The National Health and Medical Research Council,Australia,Grant/Award Numbers:126402,209057,251533,396414,450104,504700,504702,504715,623204,940394,614296US National Institutes of Health(NIH),Grant/Award Number:U19 CA 148537Prostate cancer SuscEptibility(ELLIPSE),Grant/Award Number:X01HG007492Center for Inherited Disease Research(CIDR),Grant/Award Number:HHSN268201200008INIH NCI,Grant/Award Number:U01 CA188392European Community’s Seventh Framework Programme,Grant/Award Number:223175Post-Cancer GWAS initiative,Grant/Award Numbers:1U19 CA148537,1U19 CA148065,1U19 CA148112U.S.National Institutes of Health,National Cancer Institute,Grant/Award Numbers:U01-CA98233,U01-CA98710,U01-CA98216,U01-CA98758Swedish Cancer Foundation,Grant/Award Numbers:09-0677,11-484,12-823Swedish Research Council,Swedish Research Council,Grant/Award Numbers:K2010-70X-20430-04-3,2014-2269。
文摘Background:DNA methylation and gene expression are known to play important roles in the etiology of human diseases such as prostate cancer(PCa).However,it has not yet been possible to incorporate information of DNA methylation and gene expression into polygenic risk scores(PRSs).Here,we aimed to develop and validate an improved PRS for PCa risk by incorporating genetically predicted gene expression and DNA methylation,and other genomic information using an integrative method.Methods:Using data from the PRACTICAL consortium,we derived multiple sets of genetic scores,including those based on available single-nucleotide polymorphisms through widely used methods of pruning and thresholding,LDpred,LDpred-funt,AnnoPred,and EBPRS,as well as PRS constructed using the genetically predicted gene expression and DNA methylation through a revised pruning and thresholding strategy.In the tuning step,using the UK Biobank data(1458 prevalent cases and 1467 controls),we selected PRSs with the best performance.Using an independent set of data from the UK Biobank,we developed an integrative PRS combining information from individual scores.Furthermore,in the testing step,we tested the performance of the integrative PRS in another independent set of UK Biobank data of incident cases and controls.Results:Our constructed PRS had improved performance(C statistics:76.1%)over PRSs constructed by individual benchmark methods(from 69.6%to 74.7%).Furthermore,our new PRS had much higher risk assessment power than family history.The overall net reclassification improvement was 69.0%by adding PRS to the baseline model compared with 12.5%by adding family history.Conclusions:We developed and validated a new PRS which may improve the utility in predicting the risk of developing PCa.Our innovative method can also be applied to other human diseases to improve risk prediction across multiple outcomes.
