The encapsulation of lunar samples is a core research area in the third phase of the Chinese Lunar Exploration Program.The seal assembly,opening and closing mechanism(OCM),and locking mechanism are the core components...The encapsulation of lunar samples is a core research area in the third phase of the Chinese Lunar Exploration Program.The seal assembly,opening and closing mechanism(OCM),and locking mechanism are the core components of the encapsulation device of the lunar samples,and the requirements of a tight seal,lightweight,and low power make the design of these core components difficult.In this study,a combined sealing assembly,OCM,and locking mechanism were investigated for the device.The sealing architecture consists of rubber and an Ag-In alloy,and a theory was built to analyze the seal.Experiments of the electroplate Au coating on the knife-edge revealed that the hermetic seal can be significantly improved.The driving principle for coaxial double-helical pairs was investigated and used to design the OCM.Moreover,a locking mechanism was created using an electric initiating explosive device with orifice damping.By optimizing the design,the output parameters were adjusted to meet the requirements of the lunar explorer.The experimental results showed that the helium leak rate of the test pieces were not more than 5×10^(-11) Pa·m^(3)·s^(-1),the minimum power of the OCM was 0.3 W,and the total weight of the principle prototype was 2.9 kg.The explosive driven locking mechanism has low impact.This investigation solved the difficulties in achieving tight seal,light weight,and low power for the lunar explorer,and the results can also be used to explore other extraterrestrial objects in the future.展开更多
BACKGROUND Colorectal laterally spreading tumors(LSTs)with malignant potential require en bloc resection by endoscopic submucosal dissection(ESD),but lesions with deep submucosal invasion(SMI)are endoscopically unrese...BACKGROUND Colorectal laterally spreading tumors(LSTs)with malignant potential require en bloc resection by endoscopic submucosal dissection(ESD),but lesions with deep submucosal invasion(SMI)are endoscopically unresectable.AIM To investigate the factors associated with high-grade dysplasia(HGD)/carcinoma and deep SMI in colorectal LSTs.METHODS The endoscopic and histological results of consecutive patients who underwent ESD for colorectal LSTs in our hospital from June 2013 to March 2019 were retrospectively analyzed.The characteristics of LST subtypes were compared.Risk factors for HGD/carcinoma and deep SMI(invasion depth≥1000μm)were determined using multivariate logistic regression.RESULTS A total of 323 patients with 341 colorectal LSTs were enrolled.Among the four subtypes,non-granular pseudodepressed(NG-PD)LSTs(85.5%)had the highest rate of HGD/carcinoma,followed by the granular nodular mixed(G-NM)(77.0%),granular homogenous(29.5%),and non-granular flat elevated(24.2%)subtypes.Deep SMI occurred commonly in NG-PD LSTs(12.9%).In the adjusted multivariate analysis,NG-PD[odds ratio(OR=16.8,P<0.001)and G-NM(OR=7.8,P<0.001)subtypes],size≥2 cm(OR=2.2,P=0.005),and positive non-lifting sign(OR=3.3,P=0.024)were independently associated with HGD/carcinoma.The NG-PD subtype(OR=13.3,P<0.001)and rectosigmoid location(OR=8.7,P=0.007)were independent risk factors for deep SMI.CONCLUSION Because of their increased risk for malignancy,it is highly recommended that NG-PD and G-NM LSTs are removed en bloc through ESD.Given their substantial risk for deep SMI,surgery needs to be considered for NG-PD LSTs located in the rectosigmoid,especially those with positive nonlifting signs.展开更多
Constructing a model for international carbon emissions trading is an effective method to curb global warming through a market mechanism.Although the international carbon emissions market generates substantial profits...Constructing a model for international carbon emissions trading is an effective method to curb global warming through a market mechanism.Although the international carbon emissions market generates substantial profits,the relevant trading mechanism has been far from perfect.The perfect mechanism for international carbon emissions trading should be a revealing preference game.In other words,only if all players in this game truly show their information and preferences can the Nash outcome be Pareto efficient and fair.China should actively participate in the international carbon emissions trading game;promote efficiency,justice,rationality,and the quality of being manipulation-free in the carbon emissions market;and play a more important role in perfecting the international carbon emissions trading mechanism.展开更多
Several studies have suggested the pivotal roles of eutrophic lakes in carbon(C)cycling at regional and global scales.However,how the co-metabolism effect on lake sediment organic carbon(OC)mineralization changes in r...Several studies have suggested the pivotal roles of eutrophic lakes in carbon(C)cycling at regional and global scales.However,how the co-metabolism effect on lake sediment organic carbon(OC)mineralization changes in response to integrated inputs of labile OC and nutrients is poorly understood.This knowledge gap hinders our ability to predict the carbon sequestration potential in eutrophic lakes.Therefore,a 45-day microcosm experiment was conducted to examine the dominant mechanisms that underpin the co-metabolism response to the inputs of labile C and nutrients in lacustrine sediments.Results indicate that the labile C addition caused a rapid increase in the positive co-metabolism effect during the initial stage of incubation,and the co-metabolism effect was positively correlated with the C input level.The positive co-metabolism effect was consistently higher under high C input,which was 152%higher than that under low C input.The higherβ-glucosidase activity after nutrient addition,which,in turn,promoted the OC mineralization in sediments.In addition different impacts of nutrients on the co-metabolism effect under different C inputs were observed.Compared with the low nutrient treatments,the largest co-metabolism effect under high C with high nutrient treatment was observed by the end of the incubation.In the high C treatment,the intensity of the co-metabolism effect(CE)under high nitrogen treatment was 1.88 times higher than that under low nitrogen condition.However,in the low C treatment,the amount of nitrogen had limited impact on co-metabolism effect.Our study thus proved that the microorganisms obviously regulate sediment OC turnover via stoichiometric flexibility to maintain a balance between resources and microbial requirements,which is meaningful for evaluating the OC budget and lake eutrophication management in lacustrine sediments.展开更多
The acceleration of decay induced by frequency measurements,namely the quantum anti-Zeno effect(AZE),was first predicted by Kofman and Kurizki [Nature 405(2000) 546].The effect of the frequency measurements on nuclear...The acceleration of decay induced by frequency measurements,namely the quantum anti-Zeno effect(AZE),was first predicted by Kofman and Kurizki [Nature 405(2000) 546].The effect of the frequency measurements on nuclear β decay rate is analyzed based on the time-dependent perturbation theory.We present a detailed calculation of the decay rates of ^(3)H,^(60)Co(β^(-)type),^(22)Na,^(106)Ag(β^(+) type) and ^(18)F,^(57)Co and ^(111)Sn(EC type)under frequency measurements.It is found that the effects of frequency measurements on the decay rates of β^(+)and β^(-)cases are different from the case of EC,and the smaller the β decay energy is,the more favorable it is to observe the AZE in experiment.Based on our analysis,it is suggested that possible experimental candidates should have a small decay energy and a reasonable half life(such as ^(3)H) for observing the AZE in β decay.展开更多
Idiopathic pulmonary fibrosis(IPF)is a progressive lung disease with unclear etiology and limited treatment options.The median survival time for IPF patients is approximately 2–3 years and there is no effective inter...Idiopathic pulmonary fibrosis(IPF)is a progressive lung disease with unclear etiology and limited treatment options.The median survival time for IPF patients is approximately 2–3 years and there is no effective intervention to treat IPF other than lung transplantation.As important components of lung tissue,endothelial cells(ECs)are associated with pulmonary diseases.However,the role of endothelial dysfunction in pulmonary fibrosis(PF)is incompletely understood.Sphingosine-1-phosphate receptor 1(S1PR1)is a G protein-coupled receptor highly expressed in lung ECs.Its expression is markedly reduced in patients with IPF.Herein,we generated an endothelial-conditional S1pr1 knockout mouse model which exhibited inflammation and fibrosis with or without bleomycin(BLM)challenge.Selective activation of S1PR1 with an S1PR1 agonist,IMMH002,exerted a potent therapeutic effect in mice with bleomycin-induced fibrosis by protecting the integrity of the endothelial barrier.These results suggest that S1PR1 might be a promising drug target for IPF therapy.展开更多
Glioblastoma(GBM)is a highly aggressive and lethal brain tumor with an immunosuppressive tumor microenvironment(TME).In this environment,myeloid cells,such as myeloid-derived suppressor cells(MDSCs),play a pivotal rol...Glioblastoma(GBM)is a highly aggressive and lethal brain tumor with an immunosuppressive tumor microenvironment(TME).In this environment,myeloid cells,such as myeloid-derived suppressor cells(MDSCs),play a pivotal role in suppressing antitumor immunity.Lipometabolism is closely related to the function of myeloid cells.Here,our study reports that acetyl-CoA acetyltransferase 1(ACAT1),the key enzyme of fatty acid oxidation(FAO)and ketogenesis,is significantly downregulated in the MDSCs infiltrated in GBM patients.To investigate the effects of ACAT1 on myeloid cells,we generated mice with myeloid-specific(LyzM-cre)depletion of ACAT1.The results show that these mice exhibited a remarkable accumulation of MDSCs and increased tumor progression both ectopically and orthotopically.The mechanism behind this effect is elevated secretion of C-X-C motif ligand 1(CXCLI)of macrophages(Mo).Overall,our findings demonstrate that ACAT1 could serve as a promising drug target for GBM by regulating the function of MDSCs in the TME.展开更多
Psoriasis is characterized by abnormal proliferation of keratinocytes,as well as infiltration of immune cells into the dermis and epidermis,causing itchy,scaly and erythematous plaques of skin.The understanding of thi...Psoriasis is characterized by abnormal proliferation of keratinocytes,as well as infiltration of immune cells into the dermis and epidermis,causing itchy,scaly and erythematous plaques of skin.The understanding of this chronic inflammatory skin disease remains unclear and all available treatments have their limitations currently.Here,we showed that IMMH002,a novel orally active S1 P1 modulator,desensitized peripheral pathogenic lymphocytes to egress signal from secondary lymphoid organs and thymus.Using different psoriasis animal models,we demonstrated that IMMH002 could significantly relieve skin damage as revealed by PAS I score and pathological injure evaluation.Mechanistically,IMMH002 regulated CD3+T lymphocytes re-distribution by inducing lymphocytes’homing,thus decreased T lymphocytes allocation in the peripheral blood and skin but increased in the thymus.Our results suggest that the novel SIP1 agonist,IMMH002,exert extraordinary capacity to rapidly modulate T lymphocytes distribution,representing a promising drug candidate for psoriasis treatment.展开更多
Tumor-associated macrophages(TAMs)generally display an immunosuppressive M2 phenotype and promote tumor progression and metastasis,suggesting their potential value as a target in cancer immunotherapy.Chlorogenic acid(...Tumor-associated macrophages(TAMs)generally display an immunosuppressive M2 phenotype and promote tumor progression and metastasis,suggesting their potential value as a target in cancer immunotherapy.Chlorogenic acid(CHA)has been identified as a potent immunomodulator that promotes the polarization of TAMs from an M2 to an M1 phenotype.However,rapid clearance in vivo and low tumor accumulation have compromised the immunotherapeutic efficacy of CHA in clinical trials.In this study,mannosylated liposomes are developed for targeted delivery of CHA to TAMs.The immunoregulatory effects of CHA,along with the overall antitumor efficacy of CHA-encapsulated mannosylated liposomes,are investigated through in vitro and in vivo experiments.The prepared CHA-encapsulated mannosylated liposomes exhibit an ideal particle size,favorable stability,and preferential accumulation in tumors via the mannose receptor-mediated TAMs-targeting effects.Further,CHA-encapsulated mannosylated liposomes inhibit G422 glioma tumor growth by efficiently promoting the polarization of the pro-tumorigenic M2 phenotype to the anti-tumorigenic M1 phenotype.Overall,these findings indicate that CHA-encapsulated mannosylated liposomes have great potential to enhance the immunotherapeutic efficacy of CHA by inducing a shift from the M2 to the M1 phenotype.展开更多
Dear Editor,The pathophysiologic al mechanisms underlying mood disorders including major depressive disorder(MDD)remain to be fully characterized.Iron is a key component in the development of the central nervous syste...Dear Editor,The pathophysiologic al mechanisms underlying mood disorders including major depressive disorder(MDD)remain to be fully characterized.Iron is a key component in the development of the central nervous system and iron deficiency has been linked to impairments of mood and cognition[1].展开更多
Background:Endoscopic retrograde cholangiopancreatography(ERCP)is the endoscopic modality of choice for the treatment of biliary and pancreatic diseases.However,patients with cirrhosis,particularly those with decompen...Background:Endoscopic retrograde cholangiopancreatography(ERCP)is the endoscopic modality of choice for the treatment of biliary and pancreatic diseases.However,patients with cirrhosis,particularly those with decompensated cirrhosis,are believed to be at increased risk for complications associated with ERCP.There is a paucity of literature describing the outcomes of ERCP for patients with cirrhosis.This study aimed to investigate the outcomes of ERCP for cirrhosis patients,especially adverse events,and evaluated its safety and efficacy.Methods:We performed a multicenter,retrospective study of all patients at Beijing Friendship Hospital affiliated to Capital Medical University,Xijing Hospital affiliated to Air Force Military Medical University,Beijing Youan Hospital affiliated to Capital Medical University,and the Fifth Medical Center of the People’s Liberation Army General Hospital from June 2003 to August 2019.The adverse events of inpatient ERCP for patients with(n=182)and without liver cirrhosis(controls;n=385)were compared.Results:A total of 567 patients underwent ERCP between January 2003 and December 2019 were enrolled in this study.Compared to patients without cirrhosis,patients with cirrhosis were at higher risk for postoperative complications(odds ratio[OR],4.172;95%confidence interval[CI],1.232–7.031;P<0.001)such as postoperative pancreatitis(OR,2.026;95%CI,1.002–4.378;P=0.001)and cholangitis(OR,3.903;95%CI,1.001–10.038;P=0.036).The main indications for ERCP for patients with cirrhosis in this study included choledocholithiasis(101 cases;55.5%),benign bile duct strictures(46 cases;25.3%),and malignant bile duct strictures(28 cases;15.4%).Among them,23 patients(12.6%)underwent balloon dilation and 79 patients(43.4%)underwent sphincterotomy.Of the patients with cirrhosis,delayed bleeding occurred in ten patients(5.5%),postoperative pancreatitis occurred in 80 patients(44.0%),and postoperative cholangitis occurred in 25 patients(13.7%).An additional multivariate analysis showed that the total bilirubin(TBIL)level(OR,4.58;95%CI,2.37–6.70)and Child-Pugh score of C(OR,3.11;95%CI,1.04–5.37)were risk factors for postoperative complications in patients with cirrhosis.Conclusions:Compared with the general population of patients undergoing ERCP,patients with cirrhosis were more prone to postoperative pancreatitis and cholangitis.TBIL levels and Child-Pugh scores were risk factors for postoperative complications in patients with cirrhosis.展开更多
PD-1 and PD-L1 antibodies have brought about extraordinary clinical benefits for cancer patients,and their indications are expanding incessantly.Currently,most PD-1/PD-L1 agents are administered intravenously,which ma...PD-1 and PD-L1 antibodies have brought about extraordinary clinical benefits for cancer patients,and their indications are expanding incessantly.Currently,most PD-1/PD-L1 agents are administered intravenously,which may be uncomfortable for some cancer patients.Herein,we develop a novel oral-delivered small molecular,YPD-29B,which specifically targets human PD-L1.Our data suggested that YPD-29B could potently and selectively block the interaction between PD-L1 and PD-1,but did not inhibit any other immune checkpoints.Mechanistically,YPD-29B induced human PD-L1 dimerization and internalization,which subsequently activated T lymphocytes and therefore overcomes immunity tolerance in vitro.YDP-29B was modified as the YPD-30 prodrug to improve druggability.Using humanized mice with human PD-1 xenografts of human PD-L1 knock-in mouse MC38 cancer cells,we demonstrated that YPD-30 exhibited significant antitumor activity and was well tolerated in vivo.Taken together,our results indicate that YPD-30 serves as a promising therapeutic candidate for anti-human PD-L1 cancer immunotherapy.展开更多
Glioblastoma is carcinogenesis of glial cells in central nervous system and has the highest incidence among primary brain tumors.Brain metastasis,such as breast cancer and lung cancer,also leads to high mortality.The ...Glioblastoma is carcinogenesis of glial cells in central nervous system and has the highest incidence among primary brain tumors.Brain metastasis,such as breast cancer and lung cancer,also leads to high mortality.The available medicines are limited due to blood-brain barrier.Abnormal activation of phosphatidylinositol 3-kinases(PI3 K)signaling pathway is prevalent in glioblastoma and metastatic tumors.Here,we characterized a 2-amino-4-methylquinazoline derivative XH30 as a potent PI3 K inhibitor with excellent anti-tumor activity against human glioblastoma.XH30 significantly repressed the proliferation of various brain cancer cells and decreased the phosphorylation of key proteins of PI3 K signaling pathway,induced cell cycle arrest in G1 phase as well.Additionally,XH30 inhibited the migration of glioma cells and blocked the activation of PI3 K pathway by interleukin-17 A(IL-17 A),which increased the migration of U87 MG.Oral administration of XH30 significantly suppressed the tumor growth in both subcutaneous and orthotopic tumor models.XH30 also repressed tumor growth in brain metastasis models of lung cancers.Moreover,XH30 reduced IL-17 A and its receptor IL-17 RA in vivo.These results indicate that XH30 might be a potential therapeutic drug candidate for glioblastoma migration and brain metastasis.展开更多
基金Supported by Research Foundation of CLEP of China (Grant No.TY3Q20110003)。
文摘The encapsulation of lunar samples is a core research area in the third phase of the Chinese Lunar Exploration Program.The seal assembly,opening and closing mechanism(OCM),and locking mechanism are the core components of the encapsulation device of the lunar samples,and the requirements of a tight seal,lightweight,and low power make the design of these core components difficult.In this study,a combined sealing assembly,OCM,and locking mechanism were investigated for the device.The sealing architecture consists of rubber and an Ag-In alloy,and a theory was built to analyze the seal.Experiments of the electroplate Au coating on the knife-edge revealed that the hermetic seal can be significantly improved.The driving principle for coaxial double-helical pairs was investigated and used to design the OCM.Moreover,a locking mechanism was created using an electric initiating explosive device with orifice damping.By optimizing the design,the output parameters were adjusted to meet the requirements of the lunar explorer.The experimental results showed that the helium leak rate of the test pieces were not more than 5×10^(-11) Pa·m^(3)·s^(-1),the minimum power of the OCM was 0.3 W,and the total weight of the principle prototype was 2.9 kg.The explosive driven locking mechanism has low impact.This investigation solved the difficulties in achieving tight seal,light weight,and low power for the lunar explorer,and the results can also be used to explore other extraterrestrial objects in the future.
基金Supported by Beijing Nova Program,No.Z201100006820147Beijing Municipal Administration of Hospitals’Youth Program,No.QML20180102。
文摘BACKGROUND Colorectal laterally spreading tumors(LSTs)with malignant potential require en bloc resection by endoscopic submucosal dissection(ESD),but lesions with deep submucosal invasion(SMI)are endoscopically unresectable.AIM To investigate the factors associated with high-grade dysplasia(HGD)/carcinoma and deep SMI in colorectal LSTs.METHODS The endoscopic and histological results of consecutive patients who underwent ESD for colorectal LSTs in our hospital from June 2013 to March 2019 were retrospectively analyzed.The characteristics of LST subtypes were compared.Risk factors for HGD/carcinoma and deep SMI(invasion depth≥1000μm)were determined using multivariate logistic regression.RESULTS A total of 323 patients with 341 colorectal LSTs were enrolled.Among the four subtypes,non-granular pseudodepressed(NG-PD)LSTs(85.5%)had the highest rate of HGD/carcinoma,followed by the granular nodular mixed(G-NM)(77.0%),granular homogenous(29.5%),and non-granular flat elevated(24.2%)subtypes.Deep SMI occurred commonly in NG-PD LSTs(12.9%).In the adjusted multivariate analysis,NG-PD[odds ratio(OR=16.8,P<0.001)and G-NM(OR=7.8,P<0.001)subtypes],size≥2 cm(OR=2.2,P=0.005),and positive non-lifting sign(OR=3.3,P=0.024)were independently associated with HGD/carcinoma.The NG-PD subtype(OR=13.3,P<0.001)and rectosigmoid location(OR=8.7,P=0.007)were independent risk factors for deep SMI.CONCLUSION Because of their increased risk for malignancy,it is highly recommended that NG-PD and G-NM LSTs are removed en bloc through ESD.Given their substantial risk for deep SMI,surgery needs to be considered for NG-PD LSTs located in the rectosigmoid,especially those with positive nonlifting signs.
基金This work was funded by Humanity and Social Science Youth foundation of Ministry of Education of China:Research on the Practices and Theoretical Innovation of Improving People's Wellbeing in the New Era[Grant number.18YJC710023]Major Projects of Social Science Fund of Jilin University:Research on China's Social Welfare System[Grant number.2019XXJD10]Major Projects of Trade Union of Jilin Province:Research on the Evaluation System of Harmonious Labor Relations[Grant number.2016LD007].
文摘Constructing a model for international carbon emissions trading is an effective method to curb global warming through a market mechanism.Although the international carbon emissions market generates substantial profits,the relevant trading mechanism has been far from perfect.The perfect mechanism for international carbon emissions trading should be a revealing preference game.In other words,only if all players in this game truly show their information and preferences can the Nash outcome be Pareto efficient and fair.China should actively participate in the international carbon emissions trading game;promote efficiency,justice,rationality,and the quality of being manipulation-free in the carbon emissions market;and play a more important role in perfecting the international carbon emissions trading mechanism.
基金Supported by the National Natural Science Foundation of China(No.42077294)the Special basic research service for the Central Level Public Welfare Research Institute(No.GYZX210517)+1 种基金the Major Science and Technology Program for Water Pollution Control and Treatment(Nos.2017ZX07203-003,2017ZX07301006)the Excellent Young Talents Fund Program of Higher Education Institutions of Anhui Province(No.gxyqZD2020047)。
文摘Several studies have suggested the pivotal roles of eutrophic lakes in carbon(C)cycling at regional and global scales.However,how the co-metabolism effect on lake sediment organic carbon(OC)mineralization changes in response to integrated inputs of labile OC and nutrients is poorly understood.This knowledge gap hinders our ability to predict the carbon sequestration potential in eutrophic lakes.Therefore,a 45-day microcosm experiment was conducted to examine the dominant mechanisms that underpin the co-metabolism response to the inputs of labile C and nutrients in lacustrine sediments.Results indicate that the labile C addition caused a rapid increase in the positive co-metabolism effect during the initial stage of incubation,and the co-metabolism effect was positively correlated with the C input level.The positive co-metabolism effect was consistently higher under high C input,which was 152%higher than that under low C input.The higherβ-glucosidase activity after nutrient addition,which,in turn,promoted the OC mineralization in sediments.In addition different impacts of nutrients on the co-metabolism effect under different C inputs were observed.Compared with the low nutrient treatments,the largest co-metabolism effect under high C with high nutrient treatment was observed by the end of the incubation.In the high C treatment,the intensity of the co-metabolism effect(CE)under high nitrogen treatment was 1.88 times higher than that under low nitrogen condition.However,in the low C treatment,the amount of nitrogen had limited impact on co-metabolism effect.Our study thus proved that the microorganisms obviously regulate sediment OC turnover via stoichiometric flexibility to maintain a balance between resources and microbial requirements,which is meaningful for evaluating the OC budget and lake eutrophication management in lacustrine sediments.
基金Supported by the National Natural Science Foundation of China(Grant Nos.11822503 and 11575082)the Fundamental Research Funds for the Central Universities(Nanjing University)。
文摘The acceleration of decay induced by frequency measurements,namely the quantum anti-Zeno effect(AZE),was first predicted by Kofman and Kurizki [Nature 405(2000) 546].The effect of the frequency measurements on nuclear β decay rate is analyzed based on the time-dependent perturbation theory.We present a detailed calculation of the decay rates of ^(3)H,^(60)Co(β^(-)type),^(22)Na,^(106)Ag(β^(+) type) and ^(18)F,^(57)Co and ^(111)Sn(EC type)under frequency measurements.It is found that the effects of frequency measurements on the decay rates of β^(+)and β^(-)cases are different from the case of EC,and the smaller the β decay energy is,the more favorable it is to observe the AZE in experiment.Based on our analysis,it is suggested that possible experimental candidates should have a small decay energy and a reasonable half life(such as ^(3)H) for observing the AZE in β decay.
基金supported by National Key Research&Development Program from the Ministry of Science and Technology of the PRC(No.2019YFE0111800,China)National Natural Science Foundation of China(No.81872923,China)+1 种基金Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(No.2021-JKCS-016,China)The Science and Technology Development Fund,Macao SAR(No.0074/2019/AMJ,China).
文摘Idiopathic pulmonary fibrosis(IPF)is a progressive lung disease with unclear etiology and limited treatment options.The median survival time for IPF patients is approximately 2–3 years and there is no effective intervention to treat IPF other than lung transplantation.As important components of lung tissue,endothelial cells(ECs)are associated with pulmonary diseases.However,the role of endothelial dysfunction in pulmonary fibrosis(PF)is incompletely understood.Sphingosine-1-phosphate receptor 1(S1PR1)is a G protein-coupled receptor highly expressed in lung ECs.Its expression is markedly reduced in patients with IPF.Herein,we generated an endothelial-conditional S1pr1 knockout mouse model which exhibited inflammation and fibrosis with or without bleomycin(BLM)challenge.Selective activation of S1PR1 with an S1PR1 agonist,IMMH002,exerted a potent therapeutic effect in mice with bleomycin-induced fibrosis by protecting the integrity of the endothelial barrier.These results suggest that S1PR1 might be a promising drug target for IPF therapy.
基金supported by National Key R&D Program of China(No.2019YFE0111800)National Natural Science Foundation of China(Nos.T2192972,81872923,and 81903904)the CAMS Innovation Fund(2022-I2M-1-014,China).
文摘Glioblastoma(GBM)is a highly aggressive and lethal brain tumor with an immunosuppressive tumor microenvironment(TME).In this environment,myeloid cells,such as myeloid-derived suppressor cells(MDSCs),play a pivotal role in suppressing antitumor immunity.Lipometabolism is closely related to the function of myeloid cells.Here,our study reports that acetyl-CoA acetyltransferase 1(ACAT1),the key enzyme of fatty acid oxidation(FAO)and ketogenesis,is significantly downregulated in the MDSCs infiltrated in GBM patients.To investigate the effects of ACAT1 on myeloid cells,we generated mice with myeloid-specific(LyzM-cre)depletion of ACAT1.The results show that these mice exhibited a remarkable accumulation of MDSCs and increased tumor progression both ectopically and orthotopically.The mechanism behind this effect is elevated secretion of C-X-C motif ligand 1(CXCLI)of macrophages(Mo).Overall,our findings demonstrate that ACAT1 could serve as a promising drug target for GBM by regulating the function of MDSCs in the TME.
基金supported by the CAMS Innovation Fund for Medical Sciences(2016-I2M-3-008,China)National Natural Science Foundation of China(NSFC Nos.81872923 and 81473096)+1 种基金Beijing Natural Science Foundation(No.7172140,China)The Drug Innovation Major Project(No.2018ZX09711001-003,China).
文摘Psoriasis is characterized by abnormal proliferation of keratinocytes,as well as infiltration of immune cells into the dermis and epidermis,causing itchy,scaly and erythematous plaques of skin.The understanding of this chronic inflammatory skin disease remains unclear and all available treatments have their limitations currently.Here,we showed that IMMH002,a novel orally active S1 P1 modulator,desensitized peripheral pathogenic lymphocytes to egress signal from secondary lymphoid organs and thymus.Using different psoriasis animal models,we demonstrated that IMMH002 could significantly relieve skin damage as revealed by PAS I score and pathological injure evaluation.Mechanistically,IMMH002 regulated CD3+T lymphocytes re-distribution by inducing lymphocytes’homing,thus decreased T lymphocytes allocation in the peripheral blood and skin but increased in the thymus.Our results suggest that the novel SIP1 agonist,IMMH002,exert extraordinary capacity to rapidly modulate T lymphocytes distribution,representing a promising drug candidate for psoriasis treatment.
基金financially supported by the National Science and Technology Major Project of China(Grant No.2018ZX09721003 , 2018ZX09711001)the Fundamental Research Funds for the Central Universities(Grant No.3332019069)the Young Scientists Fund of the National Natural Science Foundation of China(Grant No.81703566).
文摘Tumor-associated macrophages(TAMs)generally display an immunosuppressive M2 phenotype and promote tumor progression and metastasis,suggesting their potential value as a target in cancer immunotherapy.Chlorogenic acid(CHA)has been identified as a potent immunomodulator that promotes the polarization of TAMs from an M2 to an M1 phenotype.However,rapid clearance in vivo and low tumor accumulation have compromised the immunotherapeutic efficacy of CHA in clinical trials.In this study,mannosylated liposomes are developed for targeted delivery of CHA to TAMs.The immunoregulatory effects of CHA,along with the overall antitumor efficacy of CHA-encapsulated mannosylated liposomes,are investigated through in vitro and in vivo experiments.The prepared CHA-encapsulated mannosylated liposomes exhibit an ideal particle size,favorable stability,and preferential accumulation in tumors via the mannose receptor-mediated TAMs-targeting effects.Further,CHA-encapsulated mannosylated liposomes inhibit G422 glioma tumor growth by efficiently promoting the polarization of the pro-tumorigenic M2 phenotype to the anti-tumorigenic M1 phenotype.Overall,these findings indicate that CHA-encapsulated mannosylated liposomes have great potential to enhance the immunotherapeutic efficacy of CHA by inducing a shift from the M2 to the M1 phenotype.
基金the National Natural Science Foundation of China(81871852,81200935,81671867 and 81971794)the Liaoning Revitalization Talents Program(XLYC1807137)+1 种基金the Scientific Research Foundation for Returned Scholars of the Ministry of Education of China(20151098)the Natural Science Foundation of Liaoning Province,China(20170541030)。
文摘Dear Editor,The pathophysiologic al mechanisms underlying mood disorders including major depressive disorder(MDD)remain to be fully characterized.Iron is a key component in the development of the central nervous system and iron deficiency has been linked to impairments of mood and cognition[1].
文摘Background:Endoscopic retrograde cholangiopancreatography(ERCP)is the endoscopic modality of choice for the treatment of biliary and pancreatic diseases.However,patients with cirrhosis,particularly those with decompensated cirrhosis,are believed to be at increased risk for complications associated with ERCP.There is a paucity of literature describing the outcomes of ERCP for patients with cirrhosis.This study aimed to investigate the outcomes of ERCP for cirrhosis patients,especially adverse events,and evaluated its safety and efficacy.Methods:We performed a multicenter,retrospective study of all patients at Beijing Friendship Hospital affiliated to Capital Medical University,Xijing Hospital affiliated to Air Force Military Medical University,Beijing Youan Hospital affiliated to Capital Medical University,and the Fifth Medical Center of the People’s Liberation Army General Hospital from June 2003 to August 2019.The adverse events of inpatient ERCP for patients with(n=182)and without liver cirrhosis(controls;n=385)were compared.Results:A total of 567 patients underwent ERCP between January 2003 and December 2019 were enrolled in this study.Compared to patients without cirrhosis,patients with cirrhosis were at higher risk for postoperative complications(odds ratio[OR],4.172;95%confidence interval[CI],1.232–7.031;P<0.001)such as postoperative pancreatitis(OR,2.026;95%CI,1.002–4.378;P=0.001)and cholangitis(OR,3.903;95%CI,1.001–10.038;P=0.036).The main indications for ERCP for patients with cirrhosis in this study included choledocholithiasis(101 cases;55.5%),benign bile duct strictures(46 cases;25.3%),and malignant bile duct strictures(28 cases;15.4%).Among them,23 patients(12.6%)underwent balloon dilation and 79 patients(43.4%)underwent sphincterotomy.Of the patients with cirrhosis,delayed bleeding occurred in ten patients(5.5%),postoperative pancreatitis occurred in 80 patients(44.0%),and postoperative cholangitis occurred in 25 patients(13.7%).An additional multivariate analysis showed that the total bilirubin(TBIL)level(OR,4.58;95%CI,2.37–6.70)and Child-Pugh score of C(OR,3.11;95%CI,1.04–5.37)were risk factors for postoperative complications in patients with cirrhosis.Conclusions:Compared with the general population of patients undergoing ERCP,patients with cirrhosis were more prone to postoperative pancreatitis and cholangitis.TBIL levels and Child-Pugh scores were risk factors for postoperative complications in patients with cirrhosis.
基金supported by the National Natural Science Foundation of China(No.81872923)the CAMS Innovation Fund for Medical Sciences(2016-I2M-3-008,China)The Drug Innovation Major Project(No.2018ZX09711001-003,China)。
文摘PD-1 and PD-L1 antibodies have brought about extraordinary clinical benefits for cancer patients,and their indications are expanding incessantly.Currently,most PD-1/PD-L1 agents are administered intravenously,which may be uncomfortable for some cancer patients.Herein,we develop a novel oral-delivered small molecular,YPD-29B,which specifically targets human PD-L1.Our data suggested that YPD-29B could potently and selectively block the interaction between PD-L1 and PD-1,but did not inhibit any other immune checkpoints.Mechanistically,YPD-29B induced human PD-L1 dimerization and internalization,which subsequently activated T lymphocytes and therefore overcomes immunity tolerance in vitro.YDP-29B was modified as the YPD-30 prodrug to improve druggability.Using humanized mice with human PD-1 xenografts of human PD-L1 knock-in mouse MC38 cancer cells,we demonstrated that YPD-30 exhibited significant antitumor activity and was well tolerated in vivo.Taken together,our results indicate that YPD-30 serves as a promising therapeutic candidate for anti-human PD-L1 cancer immunotherapy.
基金supported by the CAMS Innovation Fund(2016I2M-3-008,China)The Drug Innovation Major Project(2018ZX09711001-003-011 and 2018ZX09711001-005-017,China)the Non-Profit Central Research Institute Fund of Chinese Academy of Medical Sciences(Grant 2018PT35003,China)。
文摘Glioblastoma is carcinogenesis of glial cells in central nervous system and has the highest incidence among primary brain tumors.Brain metastasis,such as breast cancer and lung cancer,also leads to high mortality.The available medicines are limited due to blood-brain barrier.Abnormal activation of phosphatidylinositol 3-kinases(PI3 K)signaling pathway is prevalent in glioblastoma and metastatic tumors.Here,we characterized a 2-amino-4-methylquinazoline derivative XH30 as a potent PI3 K inhibitor with excellent anti-tumor activity against human glioblastoma.XH30 significantly repressed the proliferation of various brain cancer cells and decreased the phosphorylation of key proteins of PI3 K signaling pathway,induced cell cycle arrest in G1 phase as well.Additionally,XH30 inhibited the migration of glioma cells and blocked the activation of PI3 K pathway by interleukin-17 A(IL-17 A),which increased the migration of U87 MG.Oral administration of XH30 significantly suppressed the tumor growth in both subcutaneous and orthotopic tumor models.XH30 also repressed tumor growth in brain metastasis models of lung cancers.Moreover,XH30 reduced IL-17 A and its receptor IL-17 RA in vivo.These results indicate that XH30 might be a potential therapeutic drug candidate for glioblastoma migration and brain metastasis.
