Objective:Previous studies reported that 4-1BB-based CD19 chimeric antigen receptor(CAR)-T cells were more beneficial for the clinical outcomes than CD28-based CAR-T cells,especially the lower incidence rate of severe...Objective:Previous studies reported that 4-1BB-based CD19 chimeric antigen receptor(CAR)-T cells were more beneficial for the clinical outcomes than CD28-based CAR-T cells,especially the lower incidence rate of severe adverse events.However,the median progression-free survival(mPFS)of 4-1BB-based product Kymriah was shorter than that of CD28-based Yescarta(2.9 months vs.5.9 months),suggesting that Kymriah was limited in the long-term efficacy.Thus,a safe and durable 4-1BB-based CD19 CAR-T needs to be developed.Methods:We designed a CD19-targeted CAR-T(named as IM19)which consisted of an FMC63 scFv,4-1BB and CD3ζintracellular domain and was manufactured into a memory T-enriched formulation.A phase I/II clinical trial was launched to evaluate the clinical outcomes of IM19 in relapsed or refractory(r/r)B cell non-Hodgkin lymphoma(B-NHL).Dose-escalation investigation(at a dose of 5×10^(5)/kg,1×10^(6)/kg and 3×106/kg)was performed in 22 r/r B-NHL patients.All patients received a single infusion of IM19 after 3-day conditional regimen.Results:At month 3,the overall response rate(ORR)was 59.1%,the complete response rate(CRR)was 50.0%.The mPFS was 6 months and the 1-year overall survival rate was 77.8%.Cytokine release syndrome(CRS)occurred in 13 patients(59.1%),with 54.5%of grade 1−2 CRS.Only one patient(4.5%)experienced grade 3 CRS and grade 3 neurotoxicity.Conclusions:These results demonstrated the safety and durable efficacy of a 4-1BB-based CD19 CAR-T,IM19,which is promising for further development and clinical investigation.展开更多
BACKGROUND： Studies have shown that neurogenesis in the dentate gyrus plays an important role in learning and memory. However, studies have not determined whether the superior cervical ganglion or the sympathetic ner...BACKGROUND： Studies have shown that neurogenesis in the dentate gyrus plays an important role in learning and memory. However, studies have not determined whether the superior cervical ganglion or the sympathetic nerve system influences hippocampal neurogenesis or learning and memory in adult rats. OBJECTIVE： To observe differences in dentate gyrus neurogenesis, as well as learning and memory, in adult rats following superior cervical ganglionectomy. DESIGN, TIME AND SETTING： A randomized, controlled, animal study was performed at the Immunohistochemistry Laboratory of the School of Life Sciences in Lanzhou University from July 2006 to July 2007. MATERIALS： Doublecortin polyclonal antibody was provided by Santa Cruz Biotechnology, USA; avidin-biotin-peroxidase complex was purchased from Zhongshan Goldenbride Biotechnology, China; Morris water maze was bought from Taimeng Technology, China. METHODS： A total of 20 adult, male, Wistar rats were randomly divided into surgery and control groups, with 10 rats in each group. In the surgery group, the bilateral superior cervical ganglions were transected. In the control group, the superior cervical ganglions were only exposed, but no ganglionectomy was performed. MAIN OUTCOME MEASURES： To examine distribution, morphology, and number of newborn neurons in the dentate gyrus using doublecortin immunohistochemistry at 36 days following surgical procedures. To examine ability of learning and memory in adult rats using the Morris water maze at 30 days following surgical procedures. RESULTS： Doublecortin immunohistochemical results showed that a reduction in the number of doublecortin-positive neurons in the surgery group compared to the control group （P 〈 0.05）, while the distribution of doublecortin-positive neurons was identical in the two groups. The surgery group exhibited significantly worse performance in learning and spatial memory tasks compared to the control group （P 〈 0.05）. CONCLUSION： Superior cervical ganglienectomy inhibited neurogenesis in the dentate gyrus and decreased learning and memory abilities in adult rats.展开更多
Quercetin （Que） is a natural multifunctional bioflavonoid, and has shown great potential for reducing adverse side effects and enhancing antitumor efficacy of chemotherapeutic drugs. However, its clinical applicatio...Quercetin （Que） is a natural multifunctional bioflavonoid, and has shown great potential for reducing adverse side effects and enhancing antitumor efficacy of chemotherapeutic drugs. However, its clinical application is limited due to very low solubility and structural instability in physiological systems. Herein, we co-delivered hydrophobic quercetin and hydrophilic doxorubicin （Dox） by developing a biocompatible nanocarrier comprising of an amphiphilic polymer, methoxy poly（ethylene glycol） and poly（D, L-lactide-co-glycolide）, respectively. The antitumor and prophylactic efficacy of this system was evaluated in cellular and animal models. Our findings illustrated that the Dox-Que nanoparticulate formulation protected normal vascular endothelial cells from either free or nanoparticulate doxorubicin-induced cytotoxicity and increased cancer cell death. Compared with free doxorubicin and its nanoformulation, co-delivery of quercetin and doxorubicin using our nanosystem synergistically inhibited tumor growth, while maintaining normal levels of cardiac function indicators in serum and recovering the histopathological damages in heart tissue. This study demonstrates a promising strategy for enhancing anti-cancer drug efficacy and reducing chemotherapy-induced toxicity on normal nanoparticulate tissues.展开更多
Platinum(Pt)-based electrocatalysts remain the only practical cathode catalysts for proton exchange membrane water electrolysis(PEMWE),due to their excellent catalytic activity for acidic hydrogen evolution reaction(H...Platinum(Pt)-based electrocatalysts remain the only practical cathode catalysts for proton exchange membrane water electrolysis(PEMWE),due to their excellent catalytic activity for acidic hydrogen evolution reaction(HER),but are greatly limited by their low reserves and high cost.Here,we report an interfacial engineering strategy to obtain a promising low-Pt loading catalyst with atomically Pt-doped molybdenum carbide quantum dots decorated on conductive porous carbon(Pt-MoCx@C)for high-rate and stable HER in PEMWE.Benefiting from the strong interfacial interaction between Pt atoms and the ultra-small MoCx quantum dots substrate,the Pt-MoCx catalyst exhibits a high mass activity of 8.00 A·mgPt−1,5.6 times higher than that of commercial 20 wt.%Pt/C catalyst.Moreover,the strong interfacial coupling of Pt and MoCx substrate greatly improves the HER stability of the Pt-MoCx catalyst.Density functional theory studies further confirm the strong metal-support interaction on Pt-MoCx,the critical role of MoCx substrate in the stabilization of surface Pt atoms,as well as activation of MoCx substrate by Pt atoms for improving HER durability and activity.The optimized Pt-MoCx@C catalyst demonstrates>2000 h stability under a water-splitting current of 1000 mA·cm^(−2)when applied to the cathode of a PEM water electrolyzer,suggesting the potential for practical applications.展开更多
This study presents the first definitive anatomical description of the tongue and lingual papillae of the cattleyak.Data on tongues from 12 healthy cattle-yaks were collected.The results show that five types of papill...This study presents the first definitive anatomical description of the tongue and lingual papillae of the cattleyak.Data on tongues from 12 healthy cattle-yaks were collected.The results show that five types of papillae were identifiable on the tongue surface of the cattle-yak.Among these,three types were mechanical papillae(filiform,conical,and lenticular),and two types were gustatory papillae(vallate and fungiform).Some morphological features of the cattle-yak tongue were similar to those of domestic ruminants,but the lingual prominence was higher and more developed.For example,more mechanical papillae were present and they were covered by a thicker,keratinized epithelium,the conical papillae possibly perform an immune function,the fungiform papillae have more mucus-secreting pores,and the sublingual glands were more developed.This research will provide a further and detailed source of morphological information about the cattle-yak that is currently lacking in species-specific studies on the morphology of the Bovidae family.展开更多
基金supported by the Beijing Natural Science Foundation (No. 7202026)Capital’s Funds for Health Improvement and Research (No. 2020-2Z-2157)
文摘Objective:Previous studies reported that 4-1BB-based CD19 chimeric antigen receptor(CAR)-T cells were more beneficial for the clinical outcomes than CD28-based CAR-T cells,especially the lower incidence rate of severe adverse events.However,the median progression-free survival(mPFS)of 4-1BB-based product Kymriah was shorter than that of CD28-based Yescarta(2.9 months vs.5.9 months),suggesting that Kymriah was limited in the long-term efficacy.Thus,a safe and durable 4-1BB-based CD19 CAR-T needs to be developed.Methods:We designed a CD19-targeted CAR-T(named as IM19)which consisted of an FMC63 scFv,4-1BB and CD3ζintracellular domain and was manufactured into a memory T-enriched formulation.A phase I/II clinical trial was launched to evaluate the clinical outcomes of IM19 in relapsed or refractory(r/r)B cell non-Hodgkin lymphoma(B-NHL).Dose-escalation investigation(at a dose of 5×10^(5)/kg,1×10^(6)/kg and 3×106/kg)was performed in 22 r/r B-NHL patients.All patients received a single infusion of IM19 after 3-day conditional regimen.Results:At month 3,the overall response rate(ORR)was 59.1%,the complete response rate(CRR)was 50.0%.The mPFS was 6 months and the 1-year overall survival rate was 77.8%.Cytokine release syndrome(CRS)occurred in 13 patients(59.1%),with 54.5%of grade 1−2 CRS.Only one patient(4.5%)experienced grade 3 CRS and grade 3 neurotoxicity.Conclusions:These results demonstrated the safety and durable efficacy of a 4-1BB-based CD19 CAR-T,IM19,which is promising for further development and clinical investigation.
基金the Key Project of Scientific Research of Ministry of Education, No.106153
文摘BACKGROUND： Studies have shown that neurogenesis in the dentate gyrus plays an important role in learning and memory. However, studies have not determined whether the superior cervical ganglion or the sympathetic nerve system influences hippocampal neurogenesis or learning and memory in adult rats. OBJECTIVE： To observe differences in dentate gyrus neurogenesis, as well as learning and memory, in adult rats following superior cervical ganglionectomy. DESIGN, TIME AND SETTING： A randomized, controlled, animal study was performed at the Immunohistochemistry Laboratory of the School of Life Sciences in Lanzhou University from July 2006 to July 2007. MATERIALS： Doublecortin polyclonal antibody was provided by Santa Cruz Biotechnology, USA; avidin-biotin-peroxidase complex was purchased from Zhongshan Goldenbride Biotechnology, China; Morris water maze was bought from Taimeng Technology, China. METHODS： A total of 20 adult, male, Wistar rats were randomly divided into surgery and control groups, with 10 rats in each group. In the surgery group, the bilateral superior cervical ganglions were transected. In the control group, the superior cervical ganglions were only exposed, but no ganglionectomy was performed. MAIN OUTCOME MEASURES： To examine distribution, morphology, and number of newborn neurons in the dentate gyrus using doublecortin immunohistochemistry at 36 days following surgical procedures. To examine ability of learning and memory in adult rats using the Morris water maze at 30 days following surgical procedures. RESULTS： Doublecortin immunohistochemical results showed that a reduction in the number of doublecortin-positive neurons in the surgery group compared to the control group （P 〈 0.05）, while the distribution of doublecortin-positive neurons was identical in the two groups. The surgery group exhibited significantly worse performance in learning and spatial memory tasks compared to the control group （P 〈 0.05）. CONCLUSION： Superior cervical ganglienectomy inhibited neurogenesis in the dentate gyrus and decreased learning and memory abilities in adult rats.
基金Acknowledgments This work was supported by the National Basic Research Program of China （2012CB934004）, the National Funds for Distinguished Young Scientists （31325010）, the Key Research Program of the Chinese Academy of Sciences （KGZD-EW-T06） and the National Natural Science Foundation of China （31300822）.
文摘Quercetin （Que） is a natural multifunctional bioflavonoid, and has shown great potential for reducing adverse side effects and enhancing antitumor efficacy of chemotherapeutic drugs. However, its clinical application is limited due to very low solubility and structural instability in physiological systems. Herein, we co-delivered hydrophobic quercetin and hydrophilic doxorubicin （Dox） by developing a biocompatible nanocarrier comprising of an amphiphilic polymer, methoxy poly（ethylene glycol） and poly（D, L-lactide-co-glycolide）, respectively. The antitumor and prophylactic efficacy of this system was evaluated in cellular and animal models. Our findings illustrated that the Dox-Que nanoparticulate formulation protected normal vascular endothelial cells from either free or nanoparticulate doxorubicin-induced cytotoxicity and increased cancer cell death. Compared with free doxorubicin and its nanoformulation, co-delivery of quercetin and doxorubicin using our nanosystem synergistically inhibited tumor growth, while maintaining normal levels of cardiac function indicators in serum and recovering the histopathological damages in heart tissue. This study demonstrates a promising strategy for enhancing anti-cancer drug efficacy and reducing chemotherapy-induced toxicity on normal nanoparticulate tissues.
基金the National Natural Science Foundation of China(Nos.22171287,21901136,51972342,51972345,22105226,and 51872056)Taishan Scholar Project of Shandong Province(Nos.tsqn202103046 and ts20190922)+3 种基金Natural Science Foundation of Shandong Province(Nos.ZR2022QE175 and ZR2019ZD51)Fundamental Research Funds for the Central Universities(Nos.20CX06024A,22CX01002A-1,and 21CX06002A)China Postdoctoral Science Foundation(Nos.2019M650027 and 2019TQ0169)National Natural Science Foundation of Beijing(No.2204082),and Shandong Province Postdoctoral Innovative Talent Support Program(No.SDBX20200004).
文摘Platinum(Pt)-based electrocatalysts remain the only practical cathode catalysts for proton exchange membrane water electrolysis(PEMWE),due to their excellent catalytic activity for acidic hydrogen evolution reaction(HER),but are greatly limited by their low reserves and high cost.Here,we report an interfacial engineering strategy to obtain a promising low-Pt loading catalyst with atomically Pt-doped molybdenum carbide quantum dots decorated on conductive porous carbon(Pt-MoCx@C)for high-rate and stable HER in PEMWE.Benefiting from the strong interfacial interaction between Pt atoms and the ultra-small MoCx quantum dots substrate,the Pt-MoCx catalyst exhibits a high mass activity of 8.00 A·mgPt−1,5.6 times higher than that of commercial 20 wt.%Pt/C catalyst.Moreover,the strong interfacial coupling of Pt and MoCx substrate greatly improves the HER stability of the Pt-MoCx catalyst.Density functional theory studies further confirm the strong metal-support interaction on Pt-MoCx,the critical role of MoCx substrate in the stabilization of surface Pt atoms,as well as activation of MoCx substrate by Pt atoms for improving HER durability and activity.The optimized Pt-MoCx@C catalyst demonstrates>2000 h stability under a water-splitting current of 1000 mA·cm^(−2)when applied to the cathode of a PEM water electrolyzer,suggesting the potential for practical applications.
基金the Research Foundation of the National Natural Science Foundation of China for financial support(Grant numbers:31060141 and 31000190)supported by the Fundamental Research Funds for the Central Universities of Lanzhou University.
文摘This study presents the first definitive anatomical description of the tongue and lingual papillae of the cattleyak.Data on tongues from 12 healthy cattle-yaks were collected.The results show that five types of papillae were identifiable on the tongue surface of the cattle-yak.Among these,three types were mechanical papillae(filiform,conical,and lenticular),and two types were gustatory papillae(vallate and fungiform).Some morphological features of the cattle-yak tongue were similar to those of domestic ruminants,but the lingual prominence was higher and more developed.For example,more mechanical papillae were present and they were covered by a thicker,keratinized epithelium,the conical papillae possibly perform an immune function,the fungiform papillae have more mucus-secreting pores,and the sublingual glands were more developed.This research will provide a further and detailed source of morphological information about the cattle-yak that is currently lacking in species-specific studies on the morphology of the Bovidae family.
