Although diverse signal-amplified methods have been committed to improve the sensitivity of surface plasmon resonance(SPR)biosensing,introducing convenient and robust signal amplification strategy into SPR biosensing ...Although diverse signal-amplified methods have been committed to improve the sensitivity of surface plasmon resonance(SPR)biosensing,introducing convenient and robust signal amplification strategy into SPR biosensing remains challenging.Here,a novel nanozyme-triggered polymerization amplification strategy was proposed for constructing highly sensitive surface plasmon resonance(SPR)immunosensor.In detail,Au@Pd core-shell nanooctahedra nanozyme with superior peroxidase(POD)-like activity was synthesized and utilized as a label probe.Simultaneously,Au@Pd core-shell nanooctahedra nanozyme can catalyze the decomposition of H_(2)O_(2)to form hydroxyl radicals(·OH)that triggers the polymerization of aniline to form polyaniline attaching on the surface of sensor chip,significantly amplifying SPR responses.The sensitivity of SPR immunosensor was enhanced by nanozyme-triggered polymerization amplification strategy.Using human immunoglobulin G(HIgG)as a model,the constructed SPR immunosensor obtains a wide linear range of 0.005–1.0μg/m L with low detection limit of 0.106 ng/m L.This research provides new sights on establishing sensitive SPR immunosensor and may evokes more inspiration for developing signal amplification methods based on nanozyme in biosensing.展开更多
Background:Makorin ring finger protein 3 gene(MKRN3)gene mutation is the most common genetic cause of central precocious puberty(CPP)in children.Due to the lack of ideal MKRN3-modified animal model(MKRN3-modified mice...Background:Makorin ring finger protein 3 gene(MKRN3)gene mutation is the most common genetic cause of central precocious puberty(CPP)in children.Due to the lack of ideal MKRN3-modified animal model(MKRN3-modified mice enter puberty only 4–5 days earlier than normal mice),the related research is limited.Methods:Therefore,the MKRN3-modified rabbit was developed using CRISPR(clus-tered regularly interspaced short palindromic repeats)gene editing technology.The genotype identification and phenotype evaluation of MKRN3-modified rabbits were carried out.Results:The first estrus of MKRN3-modified female rabbits was observed~27 days earlier than that of wild-type female rabbits,with a typical CPP phenotype.This study found increased gonadotropin releasing hormone(GnRH)and decreased gonadotropin inhibiting hormone(GnIH)in the hypothalamus of the CPP rabbit model with MKRN3 gene mutation.Although this study failed to fully clarify the pathogenesis of CPP caused by MKRN3 mutation,it found some differentially expressed genes and potential pathways through transcriptome sequencing.Conclusions:This study established a novel CPP model:paternal MKRN3 gene-modified rabbit.It is hoped that the establishment of this model will help researchers better understand,treat,and prevent CPP in the future.展开更多
Emiliania huxleyi is the most prominent modern coccolithophore,a group of marine unicellular eukaryotes that play a critical role in ocean biogeochemistry.Coccolithoviruses are large double stranded DNA viruses,which ...Emiliania huxleyi is the most prominent modern coccolithophore,a group of marine unicellular eukaryotes that play a critical role in ocean biogeochemistry.Coccolithoviruses are large double stranded DNA viruses,which is responsible for the demise of large oceanic blooms formed by E.huxleyi.E.huxleyi virus(EhVs)acquired a series of enzyme-coding genes predicted to be involved in the sphingolipid biosynthesis by horizontal gene transfer between virus-host.Currently,there is limited experimental validation identifying the functions of these genes in EhV.Genetic transformation of eukaryotic cells is a powerful tool to get an insight into gene functions of the studied organisms.Serine palmitoyltransferase(SPT)catalyzes the first committed step in de novo sphingolipid biosynthetic pathway.Here,a novel vector system for the transformation of E.huxleyi was designed.It contained fragments of promoter and terminator sequences of E.huxleyi endogenic fucoxanthin chlorophyll a/c-binding protein gene“fcp”and harbored EhV-99B1 spt gene.The resultant recombinant transformation vectors pEhux-I-spt and pEhux-II were co-transferred into E.huxleyi BOF92 by electroporation.Transformants were obtained upon glufosinate-ammonium selection,and confirmed by Southern hybridization,genome PCR,qRT-PCR and Western blot screening of spt gene,which indicated that spt gene was integrated into the nuclear genome and was expressed at the mRNA and protein levels.The expression of the viral spt gene led to differences in lipid compositions analyzed using thin-layer chromatography(TLC).The results present the genetic transformation system for E.huxleyi,providing additional genetic resource with potential for exploring basic biological questions such as the virus-host interactions.展开更多
Lipidomics approach by UPLC-Q-Exactive-MS was used for the identification,quantification,comparison,and characterization of sphingolipids in virus infected marine Emiliania huxleyi BOF92 cells.The results show that 16...Lipidomics approach by UPLC-Q-Exactive-MS was used for the identification,quantification,comparison,and characterization of sphingolipids in virus infected marine Emiliania huxleyi BOF92 cells.The results show that 16 significantly changed sphingolipids(including Cer,CerG1,and SPHm)were identified during viral infection.Our data confirmed previously recognized facts that viral infection led to a shift toward virus-specific sphingolipids,which is consistent with the down-regulation of genes involved in the host de novo sphingolipid biosynthesis.Moreover,we revealed the upregulation of virusencoded homologous genes participating in de novo sphingolipids biosynthesis and virus-specific hydroxylated long chain bases(LCBs)as phytoCer,suggesting the competitive inhibition of host sphingolipid synthesis to produce the required building blocks for viral production,replication,and assembly.Additionally,Cer 40꞉1;2,Cer 40꞉2;2 isomer,and CerG139꞉0;2,Cer 39꞉0;2 as novel metabolite markers might indicate the general dysfunctions in E.huxleyi in response to viral infection.Our results show that viral infection led to a profound remodeling of host sphingolipidome,by which viruses depend on the hijacking of host sphingolipid metabolism to support the viral life cycle.展开更多
In the present study, we aimed to explore the structure-activity relationship for the new amphiphilic material rhamnoside with antibacterial biofilm activity, and provide the basis for selecting rhamnoside with the op...In the present study, we aimed to explore the structure-activity relationship for the new amphiphilic material rhamnoside with antibacterial biofilm activity, and provide the basis for selecting rhamnoside with the optimum antibacterial biofilm activity. A series of alkyl rhamnosides with different carbon chain lengths were obtained by a simple and effective synthesis method. The structure was characterized by ~1H NMR spectrum, and their critical micelle concentration(CMC) was measured by fluorescence probe method. The hydrophilic and lipophilic balance(HLB) value was obtained by calculation. The minimal inhibitory concentration(MIC) of Staphylococcus aureus was determined by the broth double dilution method. The effect of biofilm inhibition and biofilm disruption was assayed by crystal violet method. The results showed that with the increase of carbon chain length, the CMC and HLB of alkyl rhamnosides displayed a linear downward trend, indicating that the lipophilicity and surface activity of the alkyl rhamnoside were increased. At the same time, the antibacterial activity in vitro produced the maximum, ie, 12-hydroxydecanoyl rhamnoside had the strongest antibacterial activity in vitro. Similarly, this material also exhibited the strongest antibacterial biofilm activity in vitro. The results of this study demonstrated that the most potent active material was obtained through the structure-activity relationship and it could be applied antibacterial biofilms in clinical practice.展开更多
Pollination biology studies of the endangered herbal medicines Dendrobium chrysotoxum were conducted in natural pollination conditions using flower observation,pollinator observation and artificial pollination experim...Pollination biology studies of the endangered herbal medicines Dendrobium chrysotoxum were conducted in natural pollination conditions using flower observation,pollinator observation and artificial pollination experiments.Populations of D.chrysotoxum with fragrance and nectar were pollinated by Ctenoplectra davidi Valhalla(Hymenoptera:Apidae)species.The floral structure of D.chrysotoxum adapted precisely to its pollinators.Flowers had a low capsule setting(0.17%)under natural conditions.However,compared to open pollination,artificial pollination experiments showed a significant increase in capsule setting,and D.chrysotoxum was cross-compatible and self-compatible,but there was pollinator limitation also.This study will provide important information for the preservation of this endangered species.展开更多
Preclinical studies have indicated that the combination of mTORC1/2 inhibitors with PD-1 antibodies exhibits synergistic effects on solid tumors.However,no clinical data supporting this combination have been reported....Preclinical studies have indicated that the combination of mTORC1/2 inhibitors with PD-1 antibodies exhibits synergistic effects on solid tumors.However,no clinical data supporting this combination have been reported.Therefore,we conducted a clinical trial(NCT 04337463)to investigate the efficacy and safety of combining onatasertib,an mTORC1/2 inhibitor,with toripalimab,a PD-1 antibody in patients with advanced solid tumors.This open-label,phase 1/2 clinical trial included dose escalation and dose expansion cohorts to evaluate safety,tolerability,objective response rate(ORR),disease control rate(DCR)and progression-free survival(PFS).A total of 46 patients were enrolled and received onatasertib at doses of 15 mg,20 mg,or 30 mg once daily(QD),combined with toripalimab 240 mg every 3 weeks(Q3W).No dose-limiting toxicities were observed,and the most common grade 3 or 4 treatment emergent adverse events were lymphopenia(23.9%)and rash(19.6%).The overall ORR was 26.1%,with a DCR of 73.9%,and a median PFS of 4.3 months.In cervical cancer patients,regardless of PD-L1 expression,the ORR was 52.4%,DCR was 90.5%and median PFS was 5.8 months.Notably,the 15 mg combination dose demonstrated a median PFS of 7.8 months.In conclusion,the safety profile of onatasertib in combination with toripalimab was manageable and showed encouraging clinical activity in advanced solid tumors,particularly among cervical cancer patients,irrespective of PD-L1 expression.The recommended phase 2 dose for the combination was determined to be onatasertib 15 mg QD and toripalimab 240 mg Q3W.展开更多
Heterotopic ossification(HO)is the abnormal formation of bone in extraskeletal sites.However,the mechanisms linking HO pathogenesis with bone mass dysfunction remain unclear.Here,we showed that mice harboring injury-i...Heterotopic ossification(HO)is the abnormal formation of bone in extraskeletal sites.However,the mechanisms linking HO pathogenesis with bone mass dysfunction remain unclear.Here,we showed that mice harboring injury-induced and BMP4-dependent HO exhibit bone mass loss similar to that presented by patients with HO.Moreover,we found that injury-induced hyperinflammatory responses at the injury site triggered HO initiation but did not result in bone mass loss at 1 day post-injury(dpi).In contrast,a suppressive immune response promoted HO propagation and bone mass loss by 7 dpi.Correcting immune dysregulation by PD1/PDL1 blockade dramatically alleviated HO propagation and bone mass loss.We further demonstrated that fetuin-A(FetA),which has been frequently detected in HO lesions but rarely observed in HO-adjacent normal bone,acts as an immunomodulator to promote PD1 expression and M2 macrophage polarization,leading to immunosuppression.Intervention with recombinant FetA inhibited hyperinflammation and prevented HO and associated bone mass loss.Collectively,our findings provide new insights into the osteoimmunological interactions that occur during HO formation and suggest that FetA is an immunosuppressor and a potential therapeutic option for the treatment of HO.展开更多
In the present study,we aimed to prepare sustained-release microspheres for injection of neurokinin-1(NK-1)receptor antagonist APT011,and to evaluate their physicochemical properties,in vitro sustained-release effect ...In the present study,we aimed to prepare sustained-release microspheres for injection of neurokinin-1(NK-1)receptor antagonist APT011,and to evaluate their physicochemical properties,in vitro sustained-release effect and preliminary stability.APT011-loaded sustained-release microspheres were prepared using W/O/W double emulsion-solvent evaporation technique.The L9(34)orthogonal experiment was used to optimize the APT011 sustained-release microsphere formulation.Microscope photographs showed that APT011-loaded microspheres were spherical,and the particle size was^90μm with uniform size distribution.XRD results indicated that APT011 existed in the microspheres in an amorphous form.DSC results showed that there was no significant interaction between APT011 and blank microspheres.APT011-loaded microspheres had a significant sustained-release effect,which maintained release for at least 2 months.Preliminary study results indicated that the loading content and release percentage at 0.5 h were not markedly altered below 40°C and under high lighting condition.APT011-loaded microspheres prepared in our study exhibited excellent physicochemical properties and sustained-release characteristics and preliminary stability,demonstrating real potential for the clinical practice.展开更多
Objective： To establish angiogenesis model of xenografts of lung cancer cell in nude mouse and investigate the expression of the neuropilin-1 （NRP-1） protein in tumors and its role in progression and angiogenesis o...Objective： To establish angiogenesis model of xenografts of lung cancer cell in nude mouse and investigate the expression of the neuropilin-1 （NRP-1） protein in tumors and its role in progression and angiogenesis of lung cancer. Methods： Human lung adenocarcinoma cells A549 were analyzed for the expression of vascular endothelial growth factor- 165 （VEGF16s） mRNA using RT-PCR in vitro. Two groups of nude mice were subcutaneously inoculated with A549 at different tumor-loading time. Two groups of xenografts were identified by hematoxylin and eosin （HE） staining, their microvessel density （MVD） were analyzed meanwhile. Two groups were analyzed for the expression of NRP-1 protein and their mean absorbency by using immunohistochemistry and automatic image analysis system respectively. Results： A549 expressed VEGF165 mRNA, and xenografts of A549 in nude mice were successfully established and confirmed by HE staining. The atypia of cancer cells and angiogenesis were occurred in two groups. Two groups of MVD were 13.06 ± 1.58, 23.61 ± 3.11 （vessels/mm^2） （P 〈 0.01）. NRP-1 protein was expressed in cytoplasm of vascular endothelium cells and partial tumor cells. Two groups of mean absorbency of NRP-1 were 0.1095 ± 0.0228, 0.1784 ± 0.0151 （P 〈 0.01）. Conclusion： The angiogenesis models of xenografts in nude mice with lung cancer cell A549 expressing VEGF165 mRNA at different tumor-loading times were established successfully. The expression of NRP-1 protein and MVD were increased with the tumor progression. Our results demonstrate that NRP-1 protein in tung cancer is related to angiogenesis.展开更多
Cervical cancer (CC) is the fourth most commonly diagnosed female malignancy and a leading cause of cancer-related mortality worldwide, especially in developing countries. Despite the use of advanced screening and pre...Cervical cancer (CC) is the fourth most commonly diagnosed female malignancy and a leading cause of cancer-related mortality worldwide, especially in developing countries. Despite the use of advanced screening and preventive vaccines, more than half of all CC cases are diagnosed at advanced stages, when therapeutic options are extremely limited and side effects are severe. Given these circumstances, new and effective treatments are needed. In recent years, exciting progress has been made in immunotherapies, including the rapid development of immune checkpoint inhibitors. Checkpoint blockades targeting the PD-1/PD-L1 axis have achieved effective clinical responses with acceptable toxicity by suppressing tumor progression and improving survival in several tumor types. In this review, we summarize recent advances in our understanding of the PD-1/PD-L1 signaling pathway, including the expression patterns of PD-1/PD-L1 and potential PD-l/PD-Ll-related therapeutic strategies for CC.展开更多
基金supported by National Natural Science Foundation of China(Nos.22474124,21575125)the National Natural Science Foundation of Jiangsu Province(No.BK20221370)+4 种基金Key University Natural Science Foundation of Jiangsu-Province(No.20KJA150004)the Project for Science and Technology of Yangzhou(No.YZ2022074)Project for Yangzhou City and Yangzhou University corporation(No.YZ2023204)the Open Research Fund of State Key Laboratory of Analytical Chemistry for Life Science(No.SKLACLS2405)Postgraduate Research&Practice Innovation Program of Jiangsu Province(No.KYCX22_3462)。
文摘Although diverse signal-amplified methods have been committed to improve the sensitivity of surface plasmon resonance(SPR)biosensing,introducing convenient and robust signal amplification strategy into SPR biosensing remains challenging.Here,a novel nanozyme-triggered polymerization amplification strategy was proposed for constructing highly sensitive surface plasmon resonance(SPR)immunosensor.In detail,Au@Pd core-shell nanooctahedra nanozyme with superior peroxidase(POD)-like activity was synthesized and utilized as a label probe.Simultaneously,Au@Pd core-shell nanooctahedra nanozyme can catalyze the decomposition of H_(2)O_(2)to form hydroxyl radicals(·OH)that triggers the polymerization of aniline to form polyaniline attaching on the surface of sensor chip,significantly amplifying SPR responses.The sensitivity of SPR immunosensor was enhanced by nanozyme-triggered polymerization amplification strategy.Using human immunoglobulin G(HIgG)as a model,the constructed SPR immunosensor obtains a wide linear range of 0.005–1.0μg/m L with low detection limit of 0.106 ng/m L.This research provides new sights on establishing sensitive SPR immunosensor and may evokes more inspiration for developing signal amplification methods based on nanozyme in biosensing.
基金National Natural Science Foundation of China,Grant/Award Number:82101937Guangdong Medical Science and Technology Research Fund Project,China,Grant/Award Number:B2024069Guangzhou Science and Technology Plan Project,China,Grant/Award Number:2024A04J4923 and SL2023A04J02229。
文摘Background:Makorin ring finger protein 3 gene(MKRN3)gene mutation is the most common genetic cause of central precocious puberty(CPP)in children.Due to the lack of ideal MKRN3-modified animal model(MKRN3-modified mice enter puberty only 4–5 days earlier than normal mice),the related research is limited.Methods:Therefore,the MKRN3-modified rabbit was developed using CRISPR(clus-tered regularly interspaced short palindromic repeats)gene editing technology.The genotype identification and phenotype evaluation of MKRN3-modified rabbits were carried out.Results:The first estrus of MKRN3-modified female rabbits was observed~27 days earlier than that of wild-type female rabbits,with a typical CPP phenotype.This study found increased gonadotropin releasing hormone(GnRH)and decreased gonadotropin inhibiting hormone(GnIH)in the hypothalamus of the CPP rabbit model with MKRN3 gene mutation.Although this study failed to fully clarify the pathogenesis of CPP caused by MKRN3 mutation,it found some differentially expressed genes and potential pathways through transcriptome sequencing.Conclusions:This study established a novel CPP model:paternal MKRN3 gene-modified rabbit.It is hoped that the establishment of this model will help researchers better understand,treat,and prevent CPP in the future.
基金Supported by the National Natural Science Foundation of China(Nos.41576166,21707042,31771972)the Fujian Province Natural Science Foundation of China(Nos.2019J01696,2017J01447,2017J01636)。
文摘Emiliania huxleyi is the most prominent modern coccolithophore,a group of marine unicellular eukaryotes that play a critical role in ocean biogeochemistry.Coccolithoviruses are large double stranded DNA viruses,which is responsible for the demise of large oceanic blooms formed by E.huxleyi.E.huxleyi virus(EhVs)acquired a series of enzyme-coding genes predicted to be involved in the sphingolipid biosynthesis by horizontal gene transfer between virus-host.Currently,there is limited experimental validation identifying the functions of these genes in EhV.Genetic transformation of eukaryotic cells is a powerful tool to get an insight into gene functions of the studied organisms.Serine palmitoyltransferase(SPT)catalyzes the first committed step in de novo sphingolipid biosynthetic pathway.Here,a novel vector system for the transformation of E.huxleyi was designed.It contained fragments of promoter and terminator sequences of E.huxleyi endogenic fucoxanthin chlorophyll a/c-binding protein gene“fcp”and harbored EhV-99B1 spt gene.The resultant recombinant transformation vectors pEhux-I-spt and pEhux-II were co-transferred into E.huxleyi BOF92 by electroporation.Transformants were obtained upon glufosinate-ammonium selection,and confirmed by Southern hybridization,genome PCR,qRT-PCR and Western blot screening of spt gene,which indicated that spt gene was integrated into the nuclear genome and was expressed at the mRNA and protein levels.The expression of the viral spt gene led to differences in lipid compositions analyzed using thin-layer chromatography(TLC).The results present the genetic transformation system for E.huxleyi,providing additional genetic resource with potential for exploring basic biological questions such as the virus-host interactions.
基金Supported by the National Natural Science Foundation of China(Nos.42076086,41576166)the Natural Science Foundation of Fujian Province(No.2020J05138)+1 种基金the Education and Research Project for Young and Middle-aged Teachers of Fujian Province(No.JAT190343)the Cultivation Plan for Distinguished Young Scholars in Fujian Universities。
文摘Lipidomics approach by UPLC-Q-Exactive-MS was used for the identification,quantification,comparison,and characterization of sphingolipids in virus infected marine Emiliania huxleyi BOF92 cells.The results show that 16 significantly changed sphingolipids(including Cer,CerG1,and SPHm)were identified during viral infection.Our data confirmed previously recognized facts that viral infection led to a shift toward virus-specific sphingolipids,which is consistent with the down-regulation of genes involved in the host de novo sphingolipid biosynthesis.Moreover,we revealed the upregulation of virusencoded homologous genes participating in de novo sphingolipids biosynthesis and virus-specific hydroxylated long chain bases(LCBs)as phytoCer,suggesting the competitive inhibition of host sphingolipid synthesis to produce the required building blocks for viral production,replication,and assembly.Additionally,Cer 40꞉1;2,Cer 40꞉2;2 isomer,and CerG139꞉0;2,Cer 39꞉0;2 as novel metabolite markers might indicate the general dysfunctions in E.huxleyi in response to viral infection.Our results show that viral infection led to a profound remodeling of host sphingolipidome,by which viruses depend on the hijacking of host sphingolipid metabolism to support the viral life cycle.
基金National Natural Science Foundation of China(Grant No.81573381)CAMS Initiative for Innovative Medicine(Grant No.CAMS-I2M-1-012)
文摘In the present study, we aimed to explore the structure-activity relationship for the new amphiphilic material rhamnoside with antibacterial biofilm activity, and provide the basis for selecting rhamnoside with the optimum antibacterial biofilm activity. A series of alkyl rhamnosides with different carbon chain lengths were obtained by a simple and effective synthesis method. The structure was characterized by ~1H NMR spectrum, and their critical micelle concentration(CMC) was measured by fluorescence probe method. The hydrophilic and lipophilic balance(HLB) value was obtained by calculation. The minimal inhibitory concentration(MIC) of Staphylococcus aureus was determined by the broth double dilution method. The effect of biofilm inhibition and biofilm disruption was assayed by crystal violet method. The results showed that with the increase of carbon chain length, the CMC and HLB of alkyl rhamnosides displayed a linear downward trend, indicating that the lipophilicity and surface activity of the alkyl rhamnoside were increased. At the same time, the antibacterial activity in vitro produced the maximum, ie, 12-hydroxydecanoyl rhamnoside had the strongest antibacterial activity in vitro. Similarly, this material also exhibited the strongest antibacterial biofilm activity in vitro. The results of this study demonstrated that the most potent active material was obtained through the structure-activity relationship and it could be applied antibacterial biofilms in clinical practice.
基金funded by the Basic Research Priorities Program of Yunnan Provincethe Applied Basic Research Programs of Science and Technology Department for Young Scholars(No.2019FD005)Technological Innovation Talents Cultivation Project of Yunnan Province(No.202205AD160043)Technological Innovation Talents Cultivation Project of Dehong City(No.2021RC007).
文摘Pollination biology studies of the endangered herbal medicines Dendrobium chrysotoxum were conducted in natural pollination conditions using flower observation,pollinator observation and artificial pollination experiments.Populations of D.chrysotoxum with fragrance and nectar were pollinated by Ctenoplectra davidi Valhalla(Hymenoptera:Apidae)species.The floral structure of D.chrysotoxum adapted precisely to its pollinators.Flowers had a low capsule setting(0.17%)under natural conditions.However,compared to open pollination,artificial pollination experiments showed a significant increase in capsule setting,and D.chrysotoxum was cross-compatible and self-compatible,but there was pollinator limitation also.This study will provide important information for the preservation of this endangered species.
文摘Preclinical studies have indicated that the combination of mTORC1/2 inhibitors with PD-1 antibodies exhibits synergistic effects on solid tumors.However,no clinical data supporting this combination have been reported.Therefore,we conducted a clinical trial(NCT 04337463)to investigate the efficacy and safety of combining onatasertib,an mTORC1/2 inhibitor,with toripalimab,a PD-1 antibody in patients with advanced solid tumors.This open-label,phase 1/2 clinical trial included dose escalation and dose expansion cohorts to evaluate safety,tolerability,objective response rate(ORR),disease control rate(DCR)and progression-free survival(PFS).A total of 46 patients were enrolled and received onatasertib at doses of 15 mg,20 mg,or 30 mg once daily(QD),combined with toripalimab 240 mg every 3 weeks(Q3W).No dose-limiting toxicities were observed,and the most common grade 3 or 4 treatment emergent adverse events were lymphopenia(23.9%)and rash(19.6%).The overall ORR was 26.1%,with a DCR of 73.9%,and a median PFS of 4.3 months.In cervical cancer patients,regardless of PD-L1 expression,the ORR was 52.4%,DCR was 90.5%and median PFS was 5.8 months.Notably,the 15 mg combination dose demonstrated a median PFS of 7.8 months.In conclusion,the safety profile of onatasertib in combination with toripalimab was manageable and showed encouraging clinical activity in advanced solid tumors,particularly among cervical cancer patients,irrespective of PD-L1 expression.The recommended phase 2 dose for the combination was determined to be onatasertib 15 mg QD and toripalimab 240 mg Q3W.
基金supported by the National Key Research and Development Program of China(reference number 2019YFA0801800)the Natural Science Foundation of China(reference numbers 32070916,82102573,8157152,81472087,81670097 and 81870085)the Natural Science Foundation of Anhui Province(reference numbers 1508085MC45 and 1908085QH359).
文摘Heterotopic ossification(HO)is the abnormal formation of bone in extraskeletal sites.However,the mechanisms linking HO pathogenesis with bone mass dysfunction remain unclear.Here,we showed that mice harboring injury-induced and BMP4-dependent HO exhibit bone mass loss similar to that presented by patients with HO.Moreover,we found that injury-induced hyperinflammatory responses at the injury site triggered HO initiation but did not result in bone mass loss at 1 day post-injury(dpi).In contrast,a suppressive immune response promoted HO propagation and bone mass loss by 7 dpi.Correcting immune dysregulation by PD1/PDL1 blockade dramatically alleviated HO propagation and bone mass loss.We further demonstrated that fetuin-A(FetA),which has been frequently detected in HO lesions but rarely observed in HO-adjacent normal bone,acts as an immunomodulator to promote PD1 expression and M2 macrophage polarization,leading to immunosuppression.Intervention with recombinant FetA inhibited hyperinflammation and prevented HO and associated bone mass loss.Collectively,our findings provide new insights into the osteoimmunological interactions that occur during HO formation and suggest that FetA is an immunosuppressor and a potential therapeutic option for the treatment of HO.
基金National Science&Technology Major Project“Key New Drug Creation and Manufacturing”(Grant No.2019ZX09201001-003-007)。
文摘In the present study,we aimed to prepare sustained-release microspheres for injection of neurokinin-1(NK-1)receptor antagonist APT011,and to evaluate their physicochemical properties,in vitro sustained-release effect and preliminary stability.APT011-loaded sustained-release microspheres were prepared using W/O/W double emulsion-solvent evaporation technique.The L9(34)orthogonal experiment was used to optimize the APT011 sustained-release microsphere formulation.Microscope photographs showed that APT011-loaded microspheres were spherical,and the particle size was^90μm with uniform size distribution.XRD results indicated that APT011 existed in the microspheres in an amorphous form.DSC results showed that there was no significant interaction between APT011 and blank microspheres.APT011-loaded microspheres had a significant sustained-release effect,which maintained release for at least 2 months.Preliminary study results indicated that the loading content and release percentage at 0.5 h were not markedly altered below 40°C and under high lighting condition.APT011-loaded microspheres prepared in our study exhibited excellent physicochemical properties and sustained-release characteristics and preliminary stability,demonstrating real potential for the clinical practice.
基金Province Science and Technology of Hubei Key Program Foundation (No. 2003AA301C05)
文摘Objective： To establish angiogenesis model of xenografts of lung cancer cell in nude mouse and investigate the expression of the neuropilin-1 （NRP-1） protein in tumors and its role in progression and angiogenesis of lung cancer. Methods： Human lung adenocarcinoma cells A549 were analyzed for the expression of vascular endothelial growth factor- 165 （VEGF16s） mRNA using RT-PCR in vitro. Two groups of nude mice were subcutaneously inoculated with A549 at different tumor-loading time. Two groups of xenografts were identified by hematoxylin and eosin （HE） staining, their microvessel density （MVD） were analyzed meanwhile. Two groups were analyzed for the expression of NRP-1 protein and their mean absorbency by using immunohistochemistry and automatic image analysis system respectively. Results： A549 expressed VEGF165 mRNA, and xenografts of A549 in nude mice were successfully established and confirmed by HE staining. The atypia of cancer cells and angiogenesis were occurred in two groups. Two groups of MVD were 13.06 ± 1.58, 23.61 ± 3.11 （vessels/mm^2） （P 〈 0.01）. NRP-1 protein was expressed in cytoplasm of vascular endothelium cells and partial tumor cells. Two groups of mean absorbency of NRP-1 were 0.1095 ± 0.0228, 0.1784 ± 0.0151 （P 〈 0.01）. Conclusion： The angiogenesis models of xenografts in nude mice with lung cancer cell A549 expressing VEGF165 mRNA at different tumor-loading times were established successfully. The expression of NRP-1 protein and MVD were increased with the tumor progression. Our results demonstrate that NRP-1 protein in tung cancer is related to angiogenesis.
基金This work was supported by the National Natural Science Foundation of China (No. 81373867).
文摘Cervical cancer (CC) is the fourth most commonly diagnosed female malignancy and a leading cause of cancer-related mortality worldwide, especially in developing countries. Despite the use of advanced screening and preventive vaccines, more than half of all CC cases are diagnosed at advanced stages, when therapeutic options are extremely limited and side effects are severe. Given these circumstances, new and effective treatments are needed. In recent years, exciting progress has been made in immunotherapies, including the rapid development of immune checkpoint inhibitors. Checkpoint blockades targeting the PD-1/PD-L1 axis have achieved effective clinical responses with acceptable toxicity by suppressing tumor progression and improving survival in several tumor types. In this review, we summarize recent advances in our understanding of the PD-1/PD-L1 signaling pathway, including the expression patterns of PD-1/PD-L1 and potential PD-l/PD-Ll-related therapeutic strategies for CC.
