Dear Editor, The current flu epidemic caused by influenza A H1N1 （A/H1N1） virus, which first appeared in Mexico emerged as a communicable human disease in late March and rapidly spread throughout the world in April ...Dear Editor, The current flu epidemic caused by influenza A H1N1 （A/H1N1） virus, which first appeared in Mexico emerged as a communicable human disease in late March and rapidly spread throughout the world in April 2009. Due to the rapid transport systems in modern times, the epidemic affected about 121 countries in less than 4 months （http：//www.who.int/csr/don/2009_07_16/en/）.展开更多
Objective To characterize Chinese families in which both parents and at least one child are diagnosed with malignant diseases and provide reference for cancer screening or early detection in people whose both parents ...Objective To characterize Chinese families in which both parents and at least one child are diagnosed with malignant diseases and provide reference for cancer screening or early detection in people whose both parents are diagnosed with cancer.Methods Medical records of all clients to the center of cancer screening and prevention of the National Cancer Center/Cancer Hospital between January 2008 and February 2018 were screened to select families in which both parents and at least one child were diagnosed with malignant diseases.The cancer profiles of fathers,mothers,sons and daughters,their age distribution at diagnosis,and similarity of cancers between two generations were analyzed.The proportions of each cancer in males and females of the cohort were compared with corresponding data from the National Cancer Center Registry of China(NCCRC)in 2013.Results Totally 13S families were identified from records of 33200 clients.Proportion of lung cancer in fathers(40/135,29.6%)and in mothers(38/135,28.1%)were higher than the national data(23.9%in males and 14.9%in females,respectively).The proportion of breast cancer in daughters(35/109,32.1%)was higher than that of mothers(14/135,10.4%)and the national data(17.1%),In 71 father-son pairs of cancer,46.5%(33/71)were of the same systematic disease,and 16.9%(12/71)were of the same cancer.These two indexes were 31.2%(n=34)and 10.1%(n=l 1),respectively in the 109 father-daughter pairs of cancer,36.6%(n=26)and 8.5%(n=6)respectively in the 71 mother-son pairs of cancer,and 31.2%(n=34)and 20.2%(n=20)respectively in the 109 mother-daughter pairs of cancer.Sons were more likely to suffer from cancers originated from the same system as father s cancer than daughters(χ^(2)=4.299,P<0.05),and daughters were more likely to suffer from the same cancer as their mother's cancer than sons(χ^(2)=4.506,P<0.05).The age(mean±standard deviation)of the daughters(52.4±12.7)and the sons(59.4±10.9)at diagnosis were significantly younger than the fathers(65.5±12.2)and the mothers(65.7±12.5)(all P<0.001)・Conclusions For people whose both parents are diagnosed as cancer,screening or early detection examinations should cover a full range of cancers rather than the cancers their father and mother have suffered,or cancers stemmed from the same system as their parents cancers.We suggest screening or early detection program for these special population start earlier than that for the general population,with emphasis on cancers derived from digestive system for males and women-specific cancers,i.e.,breast cancer,ovarian cancer,cervical cancer and uterine cancer for females.展开更多
TiO2 decorated with partially crystallized Pd nanoparticles （Pd/TiO2-P） was successfully prepared by atmospheric-pressure dielectric barrier discharge cold plasma. The XRD and XPS analyses proved that Pd ions were r...TiO2 decorated with partially crystallized Pd nanoparticles （Pd/TiO2-P） was successfully prepared by atmospheric-pressure dielectric barrier discharge cold plasma. The XRD and XPS analyses proved that Pd ions were reduced to partially crystallized metallic Pd nanoparticles in Pd/TiO2-P. The XPS spectra also indicated that an enhanced metal-support interaction was formed due to the existence of partially crystallized Pd nanoparticles with lower coordination number in Pd/TiO2-P. Photocatalytic activity of Pd/TiO2-P was much higher than that of TiO2 samples decorated with well crystallized Pd nanoparticles.展开更多
Inducing the degradation of KRAS represents a novel strategy to combat cancers with KRAS mutation.In this study,we identify ubiquitin-specific protease 2(USP2)as a novel deubiquitinating enzyme of KRAS in multiple mye...Inducing the degradation of KRAS represents a novel strategy to combat cancers with KRAS mutation.In this study,we identify ubiquitin-specific protease 2(USP2)as a novel deubiquitinating enzyme of KRAS in multiple myeloma(MM).Specifically,we demonstrate that gambogic acid(GA)forms a covalent bond with the cysteine 284 residue of USP2 through an allosteric pocket,inhibiting its deubiquitinating activity.Inactivation or knockdown of USP2 leads to the degradation of KRAS,resulting in the suppression of MM cell proliferation in vitro and in vivo.Conversely,overexpressing USP2 stabilizes KRAS and partially abrogates GA-induced apoptosis in MM cells.Furthermore,elevated USP2 levels may be associated with poorer prognoses in MM patients.These findings highlight the po-tential of the USP2/KRAS axis as a therapeutic target in MM,suggesting that strategically inducing KRAS degradation via USP2 inhibition could be a promising approach for treating cancers with KRAS mutations.展开更多
With the rapid development of unmanned aerial vehicle technology,unmanned aerial vehicles(UAVs)have been widely used in the field of agricultural plant protection.Compared with fuel-driven UAVs,electrically driven rot...With the rapid development of unmanned aerial vehicle technology,unmanned aerial vehicles(UAVs)have been widely used in the field of agricultural plant protection.Compared with fuel-driven UAVs,electrically driven rotorcrafts have many advantages such as lower cost,simpler operation,good maneuverability and cleaner power,which them popular in the plant protection.However,electrical rotorcrafts still face battery problems in actual operation,which limits its working time and application.Aiming at this issue,this paper studied the influence of rotorcraft flight parameters on energy consumption through series of carefully designed flight experiments.First of all,the linear motion experiments have been designed that the rotorcraft was made to perform speed tests and acceleration test with the speed varied from 2∼9 m/s.Secondly,the turning maneuver experiments are carried out under the different circular routes,a rotorcraft was made to conduct successive steering maneuvers at a certain speed of 2 m/s.With the collected tests data,the relation of the energy consumption and the flight dynamic parameter are analyzed through correlation analysis,and the test results of different pairs of experiments have been compared.The research results of this paper would encourage the agricultural rotorcraft to make less maneuvers during operation,which can also provide practical experience and data support for subsequent optimization of flight parameters and reduction of energy consumption.展开更多
Existing traditional Chinese medicine(TCM)-related databases are still insufficient in data standardization,integrity and precision,and need to be updated urgently.Herein,an Encyclopedia of Traditional Chinese Medicin...Existing traditional Chinese medicine(TCM)-related databases are still insufficient in data standardization,integrity and precision,and need to be updated urgently.Herein,an Encyclopedia of Traditional Chinese Medicine version 2.0(ETCM v2.0,http://www.tcmip.cn/ETCM2/front/#/)was constructed as the latest curated database hosting 48,442 TCM formulas recorded by ancient Chinese medical books,9872 Chinese patent drugs,2079 Chinese medicinal materials and 38,298 ingredients.To facilitate the mechanistic research and new drug discovery,we improved the target identification method based on a two-dimensional ligand similarity search module,which provides the confirmed and/or potential targets of each ingredient,as well as their binding activities.Importantly,five TCM formulas/Chinese patent drugs/herbs/ingredients with the highest Jaccard similarity scores to the submitted drugs are offered in ETCM v2.0,which may be of significance to identify prescriptions/herbs/ingredients with similar clinical efficacy,to summarize the rules of prescription use,and to find alternative drugs for endangered Chinese medicinal materials.Moreover,ETCM v2.0 provides an enhanced Java Script-based network visualization tool for creating,modifying and exploring multi-scale biological networks.ETCM v2.0 may be a major data warehouse for the quality marker identification of TCMs,the TCM-derived drug discovery and repurposing,and the pharmacological mechanism investigation of TCMs against various human diseases.展开更多
A highly effective medicine is urgently required to cure coronavirus disease 2019(COVID-19).For the purpose,we developed a molecular docking based webserver,namely D3 Targets-2019-nCoV,with two functions,one is for pr...A highly effective medicine is urgently required to cure coronavirus disease 2019(COVID-19).For the purpose,we developed a molecular docking based webserver,namely D3 Targets-2019-nCoV,with two functions,one is for predicting drug targets for drugs or active compounds observed from clinic or in vitro/in vivo studies,the other is for identifying lead compounds against potential drug targets via docking.This server has its unique features,(1)the potential target proteins and their different conformations involving in the whole process from virus infection to replication and release were included as many as possible;(2)all the potential ligand-binding sites with volume larger than 200 A^3 on a protein structure were identified for docking;(3)correlation information among some conformations or binding sites was annotated;(4)it is easy to be updated,and is accessible freely to public(https://www.d3 pharma.com/D3 Targets-2019-nCoV/index.php).Currently,the webserver contains 42 proteins[20 severe acute respiratory syndrome-related coronavirus 2(SARS-CoV-2)encoded proteins and 22 human proteins involved in virus infection,replication and release]with 69 different conformations/structures and 557 potential ligand-binding pockets in total.With 6 examples,we demonstrated that the webserver should be useful to medicinal chemists,pharmacologists and clinicians for efficiently discovering or developing effective drugs against the SARS-CoV-2 to cure COVID-19.展开更多
Dear Editor,SARS-coronavirus-2(SARS-CoV-2)Omicron variant(B.1.1.529)is of great concern to the world due to its multiple mutations that may have an impact on transmissibility and immune evasion.1 Compared to the wild ...Dear Editor,SARS-coronavirus-2(SARS-CoV-2)Omicron variant(B.1.1.529)is of great concern to the world due to its multiple mutations that may have an impact on transmissibility and immune evasion.1 Compared to the wild type(WT),Omicron carries as many as 30 single point mutations,3 deletion mutation and one insertion mutation on its spike protein.Strikingly,there are 15 mutations observed in the Omicron receptor-binding domain(RBD),10 of which are in the receptor-binding motif(RBM)that human angiotensin-converting enzyme 2(ACE2)and most monoclonal antibodies(mAbs)interact directly with.As a comparison,the currently dominant variant Delta(B.1.617.2)has only 2 mutations(L452R and T478K)in its RBM and additional K417N and E484K mutations sometimes.Therefore,Omicron variant may significantly impact the binding affinity to ACE2 and effectiveness of currently available mAbs.Consequently,Omicron mutant has aroused wide concern,many countries have taken measures on entry restrictions to prevent its rapid spread.However,the transmissibility and immune evasion risk of Omicron have not been properly evaluated.展开更多
7-epi-Taxane has been achieved efficiently in gram scale from natural taxane via inversion of the 7-hydroxyl group simply using Ag20 as catalyst and DMF as solvent. The catalyst could he quantitatively recovered by fi...7-epi-Taxane has been achieved efficiently in gram scale from natural taxane via inversion of the 7-hydroxyl group simply using Ag20 as catalyst and DMF as solvent. The catalyst could he quantitatively recovered by filtra- tion without loss of catalytic activity. This condition is also applicable to the direct epimerization of taxane derivatives （e.g., docetaxel and paclitaxel） to 7-epi-taxane derivatives （e.g., 7-epi-docetaxel and 7-epi-paclitaxel）. Furthermore, 33 ester derivatives of 7-epi-taxane with different amino acid moieties at the position of C-13 were successfully synthesized via esterification without protecting C-7-OH. Bioassay results revealed that compounds 13 and 18 have good selectivity against prostatic cancer cell line DU145, with ICs0 value as low as 15.9 nmol/L for 18.展开更多
Effective drugs with broad spectrum safety profile to all people are highly expected to combat COVID-19 caused by SARS-CoV-2.Here we report that nelfinavir,an FDA approved drug for the treatment of HIV infection,is ef...Effective drugs with broad spectrum safety profile to all people are highly expected to combat COVID-19 caused by SARS-CoV-2.Here we report that nelfinavir,an FDA approved drug for the treatment of HIV infection,is effective against SARS-CoV-2 and COVID-19.Preincubation of nelfinavir could inhibit the activity of the main protease of the SARS-CoV-2(IC50=8.26μM),while its antiviral activity in Vero E6 cells against a clinical isolate of SARS-CoV-2 was determined to be 2.93μM(EC50).In comparison with vehicle-treated animals,rhesus macaque prophylactically treated with nelfinavir had significantly lower temperature and significantly reduced virus loads in the nasal and anal swabs of the animals.At necropsy,nelfinavir-treated animals had a significant reduction of the viral replication in the lungs by nearly three orders of magnitude.A prospective clinic study with 37 enrolled treatment-naive patients at Shanghai Public Health Clinical Center,which were randomized(1:1)to nelfinavir and control groups,showed that the nelfinavir treatment could shorten the duration of viral shedding by 5.5 days(9.0 vs.14.5 days,P=0.055)and the duration of fever time by 3.8 days(2.8 vs.6.6 days,P=0.014)in mild/moderate COVID-19 patients.The antiviral efficiency and clinical benefits in rhesus macaque model and in COVID-19 patients,together with its well-established good safety profile in almost all ages and during pregnancy,indicated that nelfinavir is a highly promising medication with the potential of preventative effect for the treatment of COVID-19.展开更多
Diffuse large B-cell lymphoma(DLBCL)is a highly heterogeneous malignant tumor characterized by diffuse growth.DCZ0858 is a novel small molecule with excellent antitumor effects in DLBCL.This study explored in depth th...Diffuse large B-cell lymphoma(DLBCL)is a highly heterogeneous malignant tumor characterized by diffuse growth.DCZ0858 is a novel small molecule with excellent antitumor effects in DLBCL.This study explored in depth the inhibitory effect of DCZ0858 on DLBCL cell lines.Cell Counting Kit-8(CCK-8)and plate colony formation assays were used to evaluate cell proliferation levels.Flow cytometry was employed to analyze apoptosis and the cell cycle,and western blotting was used to quantify the expression of cell cycle regulators.The results indicated that DCZ0858 inhibited cell growth in a concentration-dependent and time-dependent manner while inducing no significant toxicity in normal cells.Moreover,DCZ0858 initiated cell apoptosis via both internal and external apoptotic pathways.DCZ0858 also induced cell cycle arrest in the G0/G1 phase,thereby controlling cell proliferation.Further investigation of the molecular mechanism showed that the JAK2/STAT3 pathway was involved in the DCZ0858-mediated antitumor effects and that JAK2 was the key target for DCZ0858 treatment.Knockdown of JAK2 partly weakened the DCZ0858-mediated antitumor effect in DLBCL cells,while JAK2 overexpression strengthened the effect of DCZ0858 in DLBCL cells.Moreover,a similar antitumor effect was observed for DCZ0858 and the JAK2 inhibitor ruxolitinib,and combining the two could significantly enhance cancer-suppressive signaling.Tumor xenograft models showed that DCZ0858 inhibited tumor growth in vivo and had low toxicity in important organs,findings that were consistent with the in vitro data.In summary,DCZ0858 is a promising drug for the treatment of DLBCL.展开更多
文摘Dear Editor, The current flu epidemic caused by influenza A H1N1 （A/H1N1） virus, which first appeared in Mexico emerged as a communicable human disease in late March and rapidly spread throughout the world in April 2009. Due to the rapid transport systems in modern times, the epidemic affected about 121 countries in less than 4 months （http：//www.who.int/csr/don/2009_07_16/en/）.
基金the National Key R&D Program of China(2017YFC1308700)Peking Union Medical College Discipline Development Project(201920200303).
文摘Objective To characterize Chinese families in which both parents and at least one child are diagnosed with malignant diseases and provide reference for cancer screening or early detection in people whose both parents are diagnosed with cancer.Methods Medical records of all clients to the center of cancer screening and prevention of the National Cancer Center/Cancer Hospital between January 2008 and February 2018 were screened to select families in which both parents and at least one child were diagnosed with malignant diseases.The cancer profiles of fathers,mothers,sons and daughters,their age distribution at diagnosis,and similarity of cancers between two generations were analyzed.The proportions of each cancer in males and females of the cohort were compared with corresponding data from the National Cancer Center Registry of China(NCCRC)in 2013.Results Totally 13S families were identified from records of 33200 clients.Proportion of lung cancer in fathers(40/135,29.6%)and in mothers(38/135,28.1%)were higher than the national data(23.9%in males and 14.9%in females,respectively).The proportion of breast cancer in daughters(35/109,32.1%)was higher than that of mothers(14/135,10.4%)and the national data(17.1%),In 71 father-son pairs of cancer,46.5%(33/71)were of the same systematic disease,and 16.9%(12/71)were of the same cancer.These two indexes were 31.2%(n=34)and 10.1%(n=l 1),respectively in the 109 father-daughter pairs of cancer,36.6%(n=26)and 8.5%(n=6)respectively in the 71 mother-son pairs of cancer,and 31.2%(n=34)and 20.2%(n=20)respectively in the 109 mother-daughter pairs of cancer.Sons were more likely to suffer from cancers originated from the same system as father s cancer than daughters(χ^(2)=4.299,P<0.05),and daughters were more likely to suffer from the same cancer as their mother's cancer than sons(χ^(2)=4.506,P<0.05).The age(mean±standard deviation)of the daughters(52.4±12.7)and the sons(59.4±10.9)at diagnosis were significantly younger than the fathers(65.5±12.2)and the mothers(65.7±12.5)(all P<0.001)・Conclusions For people whose both parents are diagnosed as cancer,screening or early detection examinations should cover a full range of cancers rather than the cancers their father and mother have suffered,or cancers stemmed from the same system as their parents cancers.We suggest screening or early detection program for these special population start earlier than that for the general population,with emphasis on cancers derived from digestive system for males and women-specific cancers,i.e.,breast cancer,ovarian cancer,cervical cancer and uterine cancer for females.
基金supported by the National Natural Science Foundation of China(21173028)the Science and Technology Research Project of Liaoning Provincial Education Department(L2013464)+1 种基金the Scientific Research Foundation for the Doctor of Liaoning Province(20131004)the Program for Liaoning Excellent Talents in University(LR2012042)
文摘TiO2 decorated with partially crystallized Pd nanoparticles （Pd/TiO2-P） was successfully prepared by atmospheric-pressure dielectric barrier discharge cold plasma. The XRD and XPS analyses proved that Pd ions were reduced to partially crystallized metallic Pd nanoparticles in Pd/TiO2-P. The XPS spectra also indicated that an enhanced metal-support interaction was formed due to the existence of partially crystallized Pd nanoparticles with lower coordination number in Pd/TiO2-P. Photocatalytic activity of Pd/TiO2-P was much higher than that of TiO2 samples decorated with well crystallized Pd nanoparticles.
基金supported in part by grants from the National Natural Science Foundation of China(82170145,82322067,82100156,and 82374583)CAMS Innovation Fund for Medical Sciences(CIFMS):2019-I2M-5-051+3 种基金Shanghai Science and Technology Commission(20ZR1430600,20JC1410100)Shanghai Municipal Commission of Health and Family Planning,NO.ZY(2021-2023)-0208Shandong Provincial Natural Science Foundation(ZR2020QH095)China Postdoctoral Science Foundation funded project(2023M742311).
文摘Inducing the degradation of KRAS represents a novel strategy to combat cancers with KRAS mutation.In this study,we identify ubiquitin-specific protease 2(USP2)as a novel deubiquitinating enzyme of KRAS in multiple myeloma(MM).Specifically,we demonstrate that gambogic acid(GA)forms a covalent bond with the cysteine 284 residue of USP2 through an allosteric pocket,inhibiting its deubiquitinating activity.Inactivation or knockdown of USP2 leads to the degradation of KRAS,resulting in the suppression of MM cell proliferation in vitro and in vivo.Conversely,overexpressing USP2 stabilizes KRAS and partially abrogates GA-induced apoptosis in MM cells.Furthermore,elevated USP2 levels may be associated with poorer prognoses in MM patients.These findings highlight the po-tential of the USP2/KRAS axis as a therapeutic target in MM,suggesting that strategically inducing KRAS degradation via USP2 inhibition could be a promising approach for treating cancers with KRAS mutations.
基金This work was supported by the National Natural Science Foundation of China(No.61803203)。
文摘With the rapid development of unmanned aerial vehicle technology,unmanned aerial vehicles(UAVs)have been widely used in the field of agricultural plant protection.Compared with fuel-driven UAVs,electrically driven rotorcrafts have many advantages such as lower cost,simpler operation,good maneuverability and cleaner power,which them popular in the plant protection.However,electrical rotorcrafts still face battery problems in actual operation,which limits its working time and application.Aiming at this issue,this paper studied the influence of rotorcraft flight parameters on energy consumption through series of carefully designed flight experiments.First of all,the linear motion experiments have been designed that the rotorcraft was made to perform speed tests and acceleration test with the speed varied from 2∼9 m/s.Secondly,the turning maneuver experiments are carried out under the different circular routes,a rotorcraft was made to conduct successive steering maneuvers at a certain speed of 2 m/s.With the collected tests data,the relation of the energy consumption and the flight dynamic parameter are analyzed through correlation analysis,and the test results of different pairs of experiments have been compared.The research results of this paper would encourage the agricultural rotorcraft to make less maneuvers during operation,which can also provide practical experience and data support for subsequent optimization of flight parameters and reduction of energy consumption.
基金supported by Key project at the National Natural Science Foundation of China(Grant Nos.81830111 and 82030122,China)the Innovation Project of China Academy of Chinese Medical Sciences(Grant No.CI2021A04907,China)。
文摘Existing traditional Chinese medicine(TCM)-related databases are still insufficient in data standardization,integrity and precision,and need to be updated urgently.Herein,an Encyclopedia of Traditional Chinese Medicine version 2.0(ETCM v2.0,http://www.tcmip.cn/ETCM2/front/#/)was constructed as the latest curated database hosting 48,442 TCM formulas recorded by ancient Chinese medical books,9872 Chinese patent drugs,2079 Chinese medicinal materials and 38,298 ingredients.To facilitate the mechanistic research and new drug discovery,we improved the target identification method based on a two-dimensional ligand similarity search module,which provides the confirmed and/or potential targets of each ingredient,as well as their binding activities.Importantly,five TCM formulas/Chinese patent drugs/herbs/ingredients with the highest Jaccard similarity scores to the submitted drugs are offered in ETCM v2.0,which may be of significance to identify prescriptions/herbs/ingredients with similar clinical efficacy,to summarize the rules of prescription use,and to find alternative drugs for endangered Chinese medicinal materials.Moreover,ETCM v2.0 provides an enhanced Java Script-based network visualization tool for creating,modifying and exploring multi-scale biological networks.ETCM v2.0 may be a major data warehouse for the quality marker identification of TCMs,the TCM-derived drug discovery and repurposing,and the pharmacological mechanism investigation of TCMs against various human diseases.
基金supported by the National Key Research and Development Program of China(2017YFB0202601 and 2016YFA0502301)
文摘A highly effective medicine is urgently required to cure coronavirus disease 2019(COVID-19).For the purpose,we developed a molecular docking based webserver,namely D3 Targets-2019-nCoV,with two functions,one is for predicting drug targets for drugs or active compounds observed from clinic or in vitro/in vivo studies,the other is for identifying lead compounds against potential drug targets via docking.This server has its unique features,(1)the potential target proteins and their different conformations involving in the whole process from virus infection to replication and release were included as many as possible;(2)all the potential ligand-binding sites with volume larger than 200 A^3 on a protein structure were identified for docking;(3)correlation information among some conformations or binding sites was annotated;(4)it is easy to be updated,and is accessible freely to public(https://www.d3 pharma.com/D3 Targets-2019-nCoV/index.php).Currently,the webserver contains 42 proteins[20 severe acute respiratory syndrome-related coronavirus 2(SARS-CoV-2)encoded proteins and 22 human proteins involved in virus infection,replication and release]with 69 different conformations/structures and 557 potential ligand-binding pockets in total.With 6 examples,we demonstrated that the webserver should be useful to medicinal chemists,pharmacologists and clinicians for efficiently discovering or developing effective drugs against the SARS-CoV-2 to cure COVID-19.
基金This work was supported by the Natural Science Foundation of Shanghai(21ZR1475600)National Key R&D Program of China(2016YFA0502301&2017YFB0202601)+2 种基金the National Science Foundation of China(U1811462)the open fund from the State Key Laboratory of High-Performance Computing(No.201901-11)The work was partially carried out on the new generation Tianhe Supercomputer.
文摘Dear Editor,SARS-coronavirus-2(SARS-CoV-2)Omicron variant(B.1.1.529)is of great concern to the world due to its multiple mutations that may have an impact on transmissibility and immune evasion.1 Compared to the wild type(WT),Omicron carries as many as 30 single point mutations,3 deletion mutation and one insertion mutation on its spike protein.Strikingly,there are 15 mutations observed in the Omicron receptor-binding domain(RBD),10 of which are in the receptor-binding motif(RBM)that human angiotensin-converting enzyme 2(ACE2)and most monoclonal antibodies(mAbs)interact directly with.As a comparison,the currently dominant variant Delta(B.1.617.2)has only 2 mutations(L452R and T478K)in its RBM and additional K417N and E484K mutations sometimes.Therefore,Omicron variant may significantly impact the binding affinity to ACE2 and effectiveness of currently available mAbs.Consequently,Omicron mutant has aroused wide concern,many countries have taken measures on entry restrictions to prevent its rapid spread.However,the transmissibility and immune evasion risk of Omicron have not been properly evaluated.
文摘7-epi-Taxane has been achieved efficiently in gram scale from natural taxane via inversion of the 7-hydroxyl group simply using Ag20 as catalyst and DMF as solvent. The catalyst could he quantitatively recovered by filtra- tion without loss of catalytic activity. This condition is also applicable to the direct epimerization of taxane derivatives （e.g., docetaxel and paclitaxel） to 7-epi-taxane derivatives （e.g., 7-epi-docetaxel and 7-epi-paclitaxel）. Furthermore, 33 ester derivatives of 7-epi-taxane with different amino acid moieties at the position of C-13 were successfully synthesized via esterification without protecting C-7-OH. Bioassay results revealed that compounds 13 and 18 have good selectivity against prostatic cancer cell line DU145, with ICs0 value as low as 15.9 nmol/L for 18.
基金supported by the Natural Science Foundation of Shanghai (21ZR1475600)Science and Technology Commission of Shanghai Municipality (20431900100)+4 种基金Shanghai Science and Technology Committee (19430750100)National Key R&D Program of China (2016YFA0502301 and 2021YFC2301204)Drug development for the newly emerging viral infectious diseases (SIMM010107)Fundamental Research Funds for the Central Universities (2022ZFJH003)Zhejiang Provincial Key Research&Development Program of China (2021C03043 and No.2021C03039).
文摘Effective drugs with broad spectrum safety profile to all people are highly expected to combat COVID-19 caused by SARS-CoV-2.Here we report that nelfinavir,an FDA approved drug for the treatment of HIV infection,is effective against SARS-CoV-2 and COVID-19.Preincubation of nelfinavir could inhibit the activity of the main protease of the SARS-CoV-2(IC50=8.26μM),while its antiviral activity in Vero E6 cells against a clinical isolate of SARS-CoV-2 was determined to be 2.93μM(EC50).In comparison with vehicle-treated animals,rhesus macaque prophylactically treated with nelfinavir had significantly lower temperature and significantly reduced virus loads in the nasal and anal swabs of the animals.At necropsy,nelfinavir-treated animals had a significant reduction of the viral replication in the lungs by nearly three orders of magnitude.A prospective clinic study with 37 enrolled treatment-naive patients at Shanghai Public Health Clinical Center,which were randomized(1:1)to nelfinavir and control groups,showed that the nelfinavir treatment could shorten the duration of viral shedding by 5.5 days(9.0 vs.14.5 days,P=0.055)and the duration of fever time by 3.8 days(2.8 vs.6.6 days,P=0.014)in mild/moderate COVID-19 patients.The antiviral efficiency and clinical benefits in rhesus macaque model and in COVID-19 patients,together with its well-established good safety profile in almost all ages and during pregnancy,indicated that nelfinavir is a highly promising medication with the potential of preventative effect for the treatment of COVID-19.
基金supported by the National Natural Science Foundation of China(Nos.81529001,81570190,81670194,and 81870158)National Science&Technology Major Project“Key New Drug Creation and Manufacturing Program”,China(Number:2018ZX09711002).
文摘Diffuse large B-cell lymphoma(DLBCL)is a highly heterogeneous malignant tumor characterized by diffuse growth.DCZ0858 is a novel small molecule with excellent antitumor effects in DLBCL.This study explored in depth the inhibitory effect of DCZ0858 on DLBCL cell lines.Cell Counting Kit-8(CCK-8)and plate colony formation assays were used to evaluate cell proliferation levels.Flow cytometry was employed to analyze apoptosis and the cell cycle,and western blotting was used to quantify the expression of cell cycle regulators.The results indicated that DCZ0858 inhibited cell growth in a concentration-dependent and time-dependent manner while inducing no significant toxicity in normal cells.Moreover,DCZ0858 initiated cell apoptosis via both internal and external apoptotic pathways.DCZ0858 also induced cell cycle arrest in the G0/G1 phase,thereby controlling cell proliferation.Further investigation of the molecular mechanism showed that the JAK2/STAT3 pathway was involved in the DCZ0858-mediated antitumor effects and that JAK2 was the key target for DCZ0858 treatment.Knockdown of JAK2 partly weakened the DCZ0858-mediated antitumor effect in DLBCL cells,while JAK2 overexpression strengthened the effect of DCZ0858 in DLBCL cells.Moreover,a similar antitumor effect was observed for DCZ0858 and the JAK2 inhibitor ruxolitinib,and combining the two could significantly enhance cancer-suppressive signaling.Tumor xenograft models showed that DCZ0858 inhibited tumor growth in vivo and had low toxicity in important organs,findings that were consistent with the in vitro data.In summary,DCZ0858 is a promising drug for the treatment of DLBCL.
