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| 1 | The establishment of polypeptide PSMA-targeted chimericantigen receptor-engineered natural killer cells forcastration-resistant prostate cancer and the induction of ferroptosis-related cell death显示文摘Background:The mortality of castration-resistant prostate cancer(CRPC)is high due to lack of an effective treatment.Chimeric antigen receptor(CAR)-based therapy is a promising immunotherapeutic strategy.Here,we aimed to design a novel CAR-natural killer(NK)cells with a clinically significant tumoricidal effect on CRPC.Methods:We constructed novel CAR-NK92MI cells with a CD244-based recombinant lentiviral vector.Different intracellular segments(CD244,NKG2D,or CD3ζ)were screened to identify the best candidate according to cell lysis assay and CD107a expression levels.To enhance the affinity of the CAR to the tumor antigen,we compared an antibody specific for prostate-specific membrane antigen(anti-PSMA)with PSMA-targeted polypeptide(p-PSMA),which was screened by phage display combinatorial library.Then,CAR-NK92MI cells with both a high affinity for PSMA and a strong tumoricidal capacity were generated.In addition,we verified their tumor-killing effect in vitro and in vivo.The release of cytokine by NK92MI cells was compared with that by CAR-NK92MI cells through flow cytometry and enzyme-linked immunosorbent assay.Moreover,ferroptosis-related cell death was explored as a possible underlying mechanism.Results:Three different CAR intracellular regions CAR1(CD244),CAR2(CD244,NKG2D)and CAR3(CD244,NKG2D,and CD3ζ)were constructed.CAR2 was chosen to confer a stronger tumoricidal ability on CAR-NK92MI cells.Compared with anti-PSMA,p-PSMA exhibited enhanced affinity for the tumor antigen.Thus,p-PSMA-CAR-NK92MI cells,which expressed CAR with a polypeptide-based antigen-binding region,an intracellular CD244 and a NKG2D costimulatory domain,were generated.They could selectively and successfully kill PSMA+target cells and exhibited specific lysis rate of 73.19%for PSMA-positive C4-2 cells and 33.04%for PSMA-negative PC3 cells.Additionally,p-PSMA-CAR-NK92MI cells had significantly higher concentrations of IFN-γ,TNF-αand granzyme B than NK92MI cells.In a CRPC cancer xenograft model,p-PSMA-CAR-NK92MI cells significantly inhibited tumor growth and exerted a more consistent killing effect than NK92MI cells.Moreover,ferroptosis is a potential mechanism through which CAR-NK92MI cells attack cancer cells,and is triggered by IFN-γ.Conclusions:p-PSMA-CAR-NK92MI cells can effectively kill CRPCPSMA+cells in vitro and in vivo.This strategy may provide additional treatment options for patients with CRPC. | Liyuan Wu Fei Liu Le Yin Fangming Wang Hui Shi Qinxin Zhao Feiya Yang Dong Chen Xiying Dong Yuchun Gu Nianzeng Xing | 2022 | Cancer Communications2022，42，8： | 2 |
| 2 | A hierarchical vascularized engineered bone inspired by intramembranous ossification for mandibular regeneration显示文摘Mandibular defects caused by injuries,tumors,and infections are common and can severely affect mandibular function and the patient's appearance.However,mandible reconstruction with a mandibular bionic structure remains challenging.Inspired by the process of intramembranous ossification in mandibular development,a hierarchical vascularized engineered bone consisting of angiogenesis and osteogenesis modules has been produced.Moreover,the hierarchical vascular network and bone structure generated by these hierarchical vascularized engineered bone modules match the particular anatomical structure of the mandible.The ultra-tough polyion complex has been used as the basic scaffold for hierarchical vascularized engineered bone for ensuring better reconstruction of mandible function.According to the results of in vivo experiments,the bone regenerated using hierarchical vascularized engineered bone is similar to the natural mandibular bone in terms of morphology and genomics.The sonic hedgehog signaling pathway is specifically activated in hierarchical vascularized engineered bone,indicating that the new bone in hierarchical vascularized engineered bone underwent a process of intramembranous ossification identical to that of mandible development.Thus,hierarchical vascularized engineered bone has a high potential for clinical application in mandibular defect reconstruction.Moreover,the concept based on developmental processes and bionic structures provides an effective strategy for tissue regeneration. | Xin Ye Jianxiang He Shaolong Wang Qianglong Han Dongqi You Bin Feng Feiya Zhao Jun Yin Mengfei Yu Huiming Wang Huayong Yang | 2022 | International Journal of Oral Science2022，14，3： | 1 |
| 3 | Stigmatization and Scientific Inquiry in the Tracing of the Origin of the 1918 Influenza Pandemic in the United States显示文摘The United States was hard hit by the great influenza pandemic of 1918.The national policy of putting the war first,the unprecedented scale of military training,and the worldwide troop movements and engagement created the conditions for the spread of the pandemic and at the same time seriously weakened US preparedness.The unprecedented pandemic threw American society into extreme panic and spawned all kinds of hypotheses about the pandemic’s geographic origin.Some of the press turned scientifically“tracing the flu”into a succession of pejorative geopolitical exonyms,stigmatizing it as“Spanish flu,”“Russian flu,”“German poisoning,”“Chinese plague,”etc.The groundless ascription of a geographic origin to the influenza pandemic was questioned at the time by insightful American medical professionals and even by Chinese medical experts.In the aftermath of the pandemic,tracking its source became a professional issue of pure medical science,with the search for the pathogen of the pandemic becoming a priority.The discovery and genetic sequencing of the 1918 influenza virus by scientists in the US and other countries led to landmark advances in the discovery of the pathogen,so the importance of tracing it back to its place of origin has taken a back seat.Although evidence of the geographic origin of the 1918 influenza pandemic is not conclusive,medical science has developed enough to disprove the ridiculous“geographic tracking”in the US during the pandemic. | Tao Feiya Zou Zetao Yang Enlu 李光辉 | 2022 | Social Sciences in China2022，43，2： | 0 |
| 4 | Membrane dual-targeting probes:A promising strategy for fluorescence-guided prostate cancer surgery and lymph node metastases detection显示文摘Fluorescence-guided surgery(FGS)with tumor-targeted imaging agents,particularly those using the near-infrared wavelength,has emerged as a real-time technique to highlight the tumor location and margins during a surgical procedure.For accurate visualization of prostate cancer(PCa)boundary and lymphatic metastasis,we developed a new approach involving an efficient self-quenched near-infrared fluorescence probe,Cy-KUE-OA,with dual PCa-membrane affinity.Cy-KUE-OA specifically targeted the prostate-specific membrane antigen(PSMA),anchored into the phospholipids of the cell membrane of PCa cells and consequently showed a strong Cy7-de-quenching effect.This dual–membrane-targeting probe allowed us to detect PSMA-expressing PCa cells both in vitro and in vivo and enabled clear visualization of the tumor boundary during fluorescence-guided laparoscopic surgery in PCa mouse models.Furthermore,the high PCa preference of Cy-KUE-OA was confirmed on surgically resected patient specimens of healthy tissues,PCa,and lymph node metastases.Taken together,our results serve as a bridge between preclinical and clinical research in FGS of PCa and lay a solid foundation for further clinical research. | Ling-Ling Wu Qinxin Zhao Qinghua Wang Qingyang Zhang Feiya Yang Bo Zheng Hai-Yu Hu Nianzeng Xing | 2023 | Acta Pharmaceutica Sinica B2023，13，3： | 0 |
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