Dear Editor,Although effective vaccines and antiviral therapies are available,hepatitis B virus(HBV)infection is still a serious global health threat.Persistent HBV infection remains the principal cause of liver cirrh...Dear Editor,Although effective vaccines and antiviral therapies are available,hepatitis B virus(HBV)infection is still a serious global health threat.Persistent HBV infection remains the principal cause of liver cirrhosis and hepatocellular carcinoma(HCC).HBV is a small DNA virus,owning a~3.2 kb genome that encodes several proteins:viral DNA polymerase,core antigen(HBcAg),E antigen(HBeAg),three surface antigens(PreS1/PreS2/HBsAg),and a regulatory X protein(HBx)(Lamontagne et al.,2016).X protein,named for its lack of homology with any known proteins,is a 154 aa protein that plays an essential role in HBV biology and regulates the development of HCC(Yang et al.,2022).Although previous studies have strongly expanded our understanding of HBx,the regulation of HBx is not completely elucidated.展开更多
Aqueous Zn metal batteries have become competitive electrochemical energy storage systems owing to their material abundance,low cost,high capacity,and nontoxicity.Nevertheless,the notorious Zn dendrites and poor anode...Aqueous Zn metal batteries have become competitive electrochemical energy storage systems owing to their material abundance,low cost,high capacity,and nontoxicity.Nevertheless,the notorious Zn dendrites and poor anode reversibility caused by the insulating by-products and“dead Zn”are still formidable challenges for their practical application.Herein,an SnS-based layer coated on the Zn anode is reported to tackle these problems.The semiconducting SnS with a higher work function can drive the electrons from the Zn anode,which constructs a polarized interface between the SnS layer and Zn.The semiconducting importance of the coating layer is verified through theoretical simulations,which can migrate the polarization layer from the electrode surface to a wellprotected spot beneath the coating layer.This polarization interface is effective in homogenizing the Zn^(2+)flux and repelling the anions from electrochemical corrosion.Compared with the bare Zn,the SnS-coated Zn anode exhibits a notable 14.7-fold enhancement in plating/stripping lifetime(over 3000 h),high reversibility(with CE of 99.74%),and superior stability in full cells when paired with vanadium-and manganese-based cathodes.展开更多
Pleural and peritoneal metastasis accompanied by malignant pleural effusion(MPE)or malignant ascites(MA)is frequent in patients with advanced solid tumors that originate from the lung,breast,gastrointestinal tract and...Pleural and peritoneal metastasis accompanied by malignant pleural effusion(MPE)or malignant ascites(MA)is frequent in patients with advanced solid tumors that originate from the lung,breast,gastrointestinal tract and ovary.Regional delivery of CAR-T cells represents a new strategy to control tumor dissemination in serous cavities.However,malignant effusions constitute an immune-suppressive environment that potentially induces CAR-T cell dysfunction.Here,we demonstrated that the anti-tumor cytotoxicity of conventional 2nd-generation CAR-T cells was significantly inhibited by both the cellular and non-cellular components of MPE/MA,which was primarily attributed to impaired CAR-T cell proliferation and cytokine production in MPE/MA environment.Interestingly,we found that PD-L1 was widely expressed on freshly-isolated MPE/MA cells.Based on this feature,a novel PD-L1-targeting chimeric switch receptor(PD-L1.BB CSR)was designed,which can bind to PD-L1,switching the inhibitory signal into an additional 4-1BB signal.When co-expressed with a 2nd-generation CAR,PD-L1.BB CSR-modified CAR-T cells displayed superior fitness and enhanced functions in both culture medium and MPE/MA environment,causing rapid and durable eradication of pleural and peritoneal metastatic tumors in xenograft models.Further investigations revealed elevated expressions of T-cell activation,proliferation,and cytotoxicity-related genes,and we confirmed that PD-L1 scFv and 4-1BB intracellular domain,the two important components of PD-L1.BB CSR,were both necessary for the functional improvements of CAR-T cells.Overall,our study shed light on the clinical application of PD-L1.BB CSR-modified dual-targeting CAR-T cells.Based on this study,a phase I clinical trial was initiated in patients with pleural or peritoneal metastasis(NCT04684459).展开更多
基金funded by the National Science and Technology Innovation 2030 Major Project of China(No.2021ZD0203900)the Ministry of Science and Technology of China(No.2019YFA0802103)+3 种基金the National Natural Science Foundation of China(No.92253302)the Department of Science and Technology of Zhejiang Province(No.2021C03104)the Guangzhou Science Innovation and Development Program(No.201803010092)athe Shenzhen-Hong Kong Institute of Brain Science(No.NYKFKT2019006).
文摘Dear Editor,Although effective vaccines and antiviral therapies are available,hepatitis B virus(HBV)infection is still a serious global health threat.Persistent HBV infection remains the principal cause of liver cirrhosis and hepatocellular carcinoma(HCC).HBV is a small DNA virus,owning a~3.2 kb genome that encodes several proteins:viral DNA polymerase,core antigen(HBcAg),E antigen(HBeAg),three surface antigens(PreS1/PreS2/HBsAg),and a regulatory X protein(HBx)(Lamontagne et al.,2016).X protein,named for its lack of homology with any known proteins,is a 154 aa protein that plays an essential role in HBV biology and regulates the development of HCC(Yang et al.,2022).Although previous studies have strongly expanded our understanding of HBx,the regulation of HBx is not completely elucidated.
基金support from the National Natural Science Foundation of China(No.51874362,52002270)the China Postdoctoral Science Foundation(No.2020M670661).
文摘Aqueous Zn metal batteries have become competitive electrochemical energy storage systems owing to their material abundance,low cost,high capacity,and nontoxicity.Nevertheless,the notorious Zn dendrites and poor anode reversibility caused by the insulating by-products and“dead Zn”are still formidable challenges for their practical application.Herein,an SnS-based layer coated on the Zn anode is reported to tackle these problems.The semiconducting SnS with a higher work function can drive the electrons from the Zn anode,which constructs a polarized interface between the SnS layer and Zn.The semiconducting importance of the coating layer is verified through theoretical simulations,which can migrate the polarization layer from the electrode surface to a wellprotected spot beneath the coating layer.This polarization interface is effective in homogenizing the Zn^(2+)flux and repelling the anions from electrochemical corrosion.Compared with the bare Zn,the SnS-coated Zn anode exhibits a notable 14.7-fold enhancement in plating/stripping lifetime(over 3000 h),high reversibility(with CE of 99.74%),and superior stability in full cells when paired with vanadium-and manganese-based cathodes.
基金National Science and Technology Major Project(2018ZX09733001-003-004)National Natural Science Foundation of China(81673001 and 81872489).
文摘Pleural and peritoneal metastasis accompanied by malignant pleural effusion(MPE)or malignant ascites(MA)is frequent in patients with advanced solid tumors that originate from the lung,breast,gastrointestinal tract and ovary.Regional delivery of CAR-T cells represents a new strategy to control tumor dissemination in serous cavities.However,malignant effusions constitute an immune-suppressive environment that potentially induces CAR-T cell dysfunction.Here,we demonstrated that the anti-tumor cytotoxicity of conventional 2nd-generation CAR-T cells was significantly inhibited by both the cellular and non-cellular components of MPE/MA,which was primarily attributed to impaired CAR-T cell proliferation and cytokine production in MPE/MA environment.Interestingly,we found that PD-L1 was widely expressed on freshly-isolated MPE/MA cells.Based on this feature,a novel PD-L1-targeting chimeric switch receptor(PD-L1.BB CSR)was designed,which can bind to PD-L1,switching the inhibitory signal into an additional 4-1BB signal.When co-expressed with a 2nd-generation CAR,PD-L1.BB CSR-modified CAR-T cells displayed superior fitness and enhanced functions in both culture medium and MPE/MA environment,causing rapid and durable eradication of pleural and peritoneal metastatic tumors in xenograft models.Further investigations revealed elevated expressions of T-cell activation,proliferation,and cytotoxicity-related genes,and we confirmed that PD-L1 scFv and 4-1BB intracellular domain,the two important components of PD-L1.BB CSR,were both necessary for the functional improvements of CAR-T cells.Overall,our study shed light on the clinical application of PD-L1.BB CSR-modified dual-targeting CAR-T cells.Based on this study,a phase I clinical trial was initiated in patients with pleural or peritoneal metastasis(NCT04684459).
