1.Optimized lipid nanoparticles enable effective CRISPR/Cas9-mediated gene editing in dendritic cells for enhanced immunotherapy.
Kuirong MAO ; Huizhu TAN ; Xiuxiu CONG ; Ji LIU ; Yanbao XIN ; Jialiang WANG ; Meng GUAN ; Jiaxuan LI ; Ge ZHU ; Xiandi MENG ; Guojiao LIN ; Haorui WANG ; Jing HAN ; Ming WANG ; Yong-Guang YANG ; Tianmeng SUN
Acta Pharmaceutica Sinica B 2025;15(1):642-656
Immunotherapy has emerged as a revolutionary approach to treat immune-related diseases. Dendritic cells (DCs) play a pivotal role in orchestrating immune responses, making them an attractive target for immunotherapeutic interventions. Modulation of gene expression in DCs using genome editing techniques, such as the CRISPR-Cas system, is important for regulating DC functions. However, the precise delivery of CRISPR-based therapies to DCs has posed a significant challenge. While lipid nanoparticles (LNPs) have been extensively studied for gene editing in tumor cells, their potential application in DCs has remained relatively unexplored. This study investigates the important role of cholesterol in regulating the efficiency of BAMEA-O16B lipid-assisted nanoparticles (BLANs) as carriers of CRISPR/Cas9 for gene editing in DCs. Remarkably, BLANs with low cholesterol density exhibit exceptional mRNA uptake, improved endosomal escape, and efficient single-guide RNA release capabilities. Administration of BLANmCas9/gPD-L1 results in substantial PD-L1 gene knockout in conventional dendritic cells (cDCs), accompanied by heightened cDC1 activation, T cell stimulation, and significant suppression of tumor growth. The study underscores the pivotal role of cholesterol density within LNPs, revealing potent influence on gene editing efficacy within DCs. This strategy holds immense promise for the field of cancer immunotherapy, offering a novel avenue for treating immune-related diseases.
2.A novel chalcone derivative C13 inhibits the growth of human gastric cancer cells through suppressing ErbB4/PI3K/AKT signaling pathway
Peng TAN ; Yun-feng ZHANG ; Long-yan WANG ; Hui-ming HUANG ; Fei WANG ; Xue-jiao WEI ; Zhu-guo WANG ; Jun LI ; Zhong-dong HU
Acta Pharmaceutica Sinica 2024;59(4):957-964
3ʹ-Hydroxy-4ʹ-methoxy-2-hydroxy-5-bromochalcone (hereinafter referred to as C13) is a novel chalcone derivative obtained in the process of structural modification of DHMMF, the antitumor active compound of
3.Establishment and Exploration of Core Competency Oriented Training Program for Neurology Resident
Lixin ZHOU ; Ying TAN ; Fei HAN ; Ming YAO ; Linzhi LUO ; Jun NI ; Bin PENG ; Liying CUI ; Yicheng ZHU
Medical Journal of Peking Union Medical College Hospital 2024;15(4):973-980
Resident training is a necessary path to cultivate excellent clinical doctors. Based on the
4.Robotic visualization system-assisted microsurgical reconstruction of the reproductive tract in male rats
Zheng LI ; Jian-Jun DONG ; Ming LIU ; Xun-Zhu WU ; Ren-Feng JIA ; San-Wei GUO ; Kai MENG ; Chen-Cheng YAO ; Er-Lei ZHI ; Gang LIU ; Da-Xian TAN ; Zheng LI ; Peng LI
National Journal of Andrology 2024;30(8):675-680
Objective:To evaluate the safety and efficiency of robotic visualization system(RVS)-assisted microsurgical re-construction of the reproductive tract in male rats and the satisfaction of the surgeons.Methods:We randomly divided 8 adult male SD rats into an experimental and a control group,the former treated by RVS-assisted microsurgical vasoepididymostomy(VE)or vaso-vasostomy(VV),and the latter by VE or VV under the standard operating microscope(SOM).We compared the operation time,me-chanical patency and anastomosis leakage immediately after surgery,and the surgeons'satisfaction between the two groups.Results:No statistically significant difference was observed the operation time between the experimental and the control groups,and no anasto-mosis leakage occurred after VV in either group.The rate of mechanical patency immediately after surgery was 100%in both groups,and that of anastomosis leakage after VE was 16.7%in the experimental group and 14.3%in the control.Compared with the control group,the experimental group achieved dramatically higher scores on visual comfort(3.00±0.76 vs 4.00±0.53,P<0.05),neck/back comfort(2.75±1.16 vs 4.38±1.06,P<0.01)and man-machine interaction(3.88±1.55 va 4.88±0.35,P<0.05).There were no statistically significant differences in the scores on image definition and operating room suitability between the two groups.Conclusion:RVS can be used in microsurgical reconstruction of the reproductive tract in male rats and,with its advantages over SOM in ergonomic design and image definition,has a potential application value in male reproductive system micosurgery.
5.Effect analysis of myectomy guided by personalized three-dimensional reconstruction and printing in the treatment of obstructive hypertrophic cardiomyopathy.
Pei Jian WEI ; Jian LIU ; Tong TAN ; Wei ZHU ; Jian ZHUANG ; Hui Ming GUO
Chinese Journal of Surgery 2023;61(1):54-60
Objective: To examine the clinical efficacy of myectomy guided by personalized three-dimensional reconstruction and printing for patients with obstructive hypertrophic cardiomyopathy. Methods: The clinical data of 28 patients with obstructive hypertrophic cardiomyopathy, who underwent septal myectomy guided by personalized three-dimensional reconstruction and printing in the Department of Cardiaovascular Surgery, Guangdong Provincial People's Hospital from May 2020 to December 2021, were retrospectively analyzed. There were 14 males and 14 females, aging (51.1±14.0) years (range: 18 to 72 years). Enhanced cardiac computed tomography images were imported into Mimics software for preoperative three-dimensional reconstruction. The direction of the short axial plane of each segment was marked perpendicularly to the interventricular septum on the long axial plane of the digital cardiac model, then the thickness was measured on each short axial plane. A figurative digital model was used to determine the extent of resection and to visualize mitral valve and papillary muscle abnormalities. Correlation between the length, width, thickness, and volume of the predicted resected myocardium and those of the surgically resected myocardium was assessed by Pearson correlation analysis or Spearman correlation analysis. The accuracy of detecting mitral valve and papillary muscle abnormalities of transthoracic echocardiography and three-dimensional reconstruction was also compared. Results: There was no death or serious complications like permanent pacemaker implantation, re-sternotomy for bleeding, low cardiac output syndrome, stroke, or multiple organ dysfunction syndromes in the whole group. Namely, the obstruction of the left ventricular outflow tract was effectively relieved. The systolic anterior motion of the anterior mitral valve leaflet was absent in all patients after myectomy. The length, width, and thickness of the predicted resected myocardium by three-dimensional reconstruction were significantly positively correlated with the length (R=0.65, 95%CI: 0.37 to 0.82, P<0.01), width (R=0.39, 95%CI: 0.02 to 0.67, P<0.01), and thickness (R=0.82, 95%CI: 0.65 to 0.92, P<0.01) of the surgically resected myocardium, while the relation of the volume of the predicted resected myocardium and the volume of the surgically resected myocardium was a strong positive correlation (R=0.88, 95%CI: 0.76 to 0.94, P<0.01). Importantly, the interventricular septal myocardial thickness measured by preoperative transthoracic echocardiography showed a moderate positive correlation with the volume of surgically resected myocardium (R=0.52, 95%CI: 0.19 to 0.75, P<0.01). During a follow-up of (14.4±6.8) months (range: 3 to 22 months), no death occurred, and 1 patient was readmitted for endocardial radiofrequency ablation due to atrial fibrillation. Conclusion: Personalized three-dimensional reconstruction and printing can not only visualize the intracardiac structure but also guide septal myectomy by predicting the thickness, volume, and extent of resected myocardium to achieve ideal resection.
Female
;
Humans
;
Male
;
Cardiomyopathy, Hypertrophic/diagnosis*
;
Imaging, Three-Dimensional
;
Printing, Three-Dimensional
;
Retrospective Studies
;
Treatment Outcome
;
Ventricular Septum
;
Adolescent
;
Young Adult
;
Adult
;
Middle Aged
;
Aged
6.Early outcomes of thoracoscopic trans-mitral myectomy in obstructive hypertrophic cardiomyopathy patients with left midventricular obstruction.
Pei Jian WEI ; Jian LIU ; Tong TAN ; Wei ZHU ; Jian ZHUANG ; Hui Ming GUO
Chinese Journal of Surgery 2023;61(3):214-219
Objective: To examine the early effect of thoracoscopic trans-mitral myectomy for hypertrophic cardiomyopathy patients with left midventricular obstruction. Methods: From April 2020 to July 2021, 10 hypertrophic cardiomyopathy patients with left midventricular obstruction underwent thoracoscopic trans-mitral myectomy at Guangdong Provincial People's Hospital. The whole group of patients consisted of 7 males and 3 females aged (52.0±16.4) years (range: 18 to 68 years). The EuroSCORE Ⅱ predicted mortality rate was 1.78% (1.20%) (M(IQR)) (range: 0.96% to 4.86%). The clinical data were collected and analyzed retrospectively to evaluate the clinical efficacy by comparing preoperative and postoperative echocardiographic parameters using paired t-test, paired Wilcoxon test or Fisher exact test, including left ventricular outflow tract peak pressure gradient, maximum interventricular septum thickness, systolic anterior motion of the anterior mitral leaflet and so on. The safety was determined by summarizing the incidence of perioperative and follow-up complications. Results: All the procedures successed with no conversion to median sternotomy, septal defect, ventricular rupture. There was no in-hospital 30-day death, neither serious complications like permanent pacemaker implantation, re-sternotomy for bleeding, low cardiac output syndrome, stroke, or multiple organ dysfunction syndrome. The left ventricular outflow tract obstruction was effectively relieved in all patients expect a patient developed residual obstruction. Compared with that of pre-operation, the thickness of the interventricular septum was significantly reduced from (22.1±4.0) mm to (10.3±1.7) mm (t=10.693, P<0.01), while the left ventricular outflow tract peak pressure gradient was significantly reduced from (81.7±21.1) mmHg to 12.3 (11.5) mmHg (Z=-2.805, P<0.01) (1 mmHg=0.133 kPa). Conclusion: Thoracoscopic trans-mitral myectomy is an effective and safe procedure for hypertrophic cardiomyopathy patients with left midventricular obstruction.
Male
;
Female
;
Humans
;
Retrospective Studies
;
Echocardiography
;
Treatment Outcome
;
Cardiomyopathy, Hypertrophic/complications*
;
Ventricular Septum
7.A case of low-grade fibromyxoid sarcoma of the temporal bone.
Ming Yang MAO ; Guo Dong FENG ; Yu CHEN ; Xiao Hua SHI ; Xu TIAN ; Tong SU ; Hui Ying SUN ; Zhen Tan XU ; Wen Sheng REN ; Zhu Hua ZHANG ; Zhi Qiang GAO ; Zheng Yu JIN
Chinese Journal of Otorhinolaryngology Head and Neck Surgery 2023;58(1):64-67
8.Vitamin D receptor (VDR) mediates the quiescence of activated hepatic stellate cells (aHSCs) by regulating M2 macrophage exosomal smooth muscle cell-associated protein 5 (SMAP-5).
Xuwentai LIU ; Yue WU ; Yanyi LI ; Kaiming LI ; Siyuan HOU ; Ming DING ; Jingmin TAN ; Zijing ZHU ; Yingqi TANG ; Yuming LIU ; Qianhui SUN ; Cong WANG ; Can ZHANG
Journal of Zhejiang University. Science. B 2023;24(3):248-261
An effective therapeutic regimen for hepatic fibrosis requires a deep understanding of the pathogenesis mechanism. Hepatic fibrosis is characterized by activated hepatic stellate cells (aHSCs) with an excessive production of extracellular matrix. Although promoted activation of HSCs by M2 macrophages has been demonstrated, the molecular mechanism involved remains ambiguous. Herein, we propose that the vitamin D receptor (VDR) involved in macrophage polarization may regulate the communication between macrophages and HSCs by changing the functions of exosomes. We confirm that activating the VDR can inhibit the effect of M2 macrophages on HSC activation. The exosomes derived from M2 macrophages can promote HSC activation, while stimulating VDR alters the protein profiles and reverses their roles in M2 macrophage exosomes. Smooth muscle cell-associated protein 5 (SMAP-5) was found to be the key effector protein in promoting HSC activation by regulating autophagy flux. Building on these results, we show that a combined treatment of a VDR agonist and a macrophage-targeted exosomal secretion inhibitor achieves an excellent anti-hepatic fibrosis effect. In this study, we aim to elucidate the association between VDR and macrophages in HSC activation. The results contribute to our understanding of the pathogenesis mechanism of hepatic fibrosis, and provide potential therapeutic targets for its treatment.
Humans
;
Hepatic Stellate Cells/pathology*
;
Receptors, Calcitriol
;
Liver Cirrhosis/pathology*
;
Macrophages/metabolism*
9.High-throughput screening of SARS-CoV-2 main and papain-like protease inhibitors.
Yi ZANG ; Mingbo SU ; Qingxing WANG ; Xi CHENG ; Wenru ZHANG ; Yao ZHAO ; Tong CHEN ; Yingyan JIANG ; Qiang SHEN ; Juan DU ; Qiuxiang TAN ; Peipei WANG ; Lixin GAO ; Zhenming JIN ; Mengmeng ZHANG ; Cong LI ; Ya ZHU ; Bo FENG ; Bixi TANG ; Han XIE ; Ming-Wei WANG ; Mingyue ZHENG ; Xiaoyan PAN ; Haitao YANG ; Yechun XU ; Beili WU ; Leike ZHANG ; Zihe RAO ; Xiuna YANG ; Hualiang JIANG ; Gengfu XIAO ; Qiang ZHAO ; Jia LI
Protein & Cell 2023;14(1):17-27
The global COVID-19 coronavirus pandemic has infected over 109 million people, leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment. Here, we screened about 1.8 million small molecules against the main protease (Mpro) and papain like protease (PLpro), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851Mpro inhibitors and 205 PLpro inhibitors with low nmol/l activity of the best hits. Among these inhibitors, eight small molecules showed dual inhibition effects on both Mpro and PLpro, exhibiting potential as better candidates for COVID-19 treatment. The best inhibitors of each protease were tested in antiviral assay, with over 40% of Mpro inhibitors and over 20% of PLpro inhibitors showing high potency in viral inhibition with low cytotoxicity. The X-ray crystal structure of SARS-CoV-2 Mpro in complex with its potent inhibitor 4a was determined at 1.8 Å resolution. Together with docking assays, our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.
Humans
;
Antiviral Agents/chemistry*
;
COVID-19
;
COVID-19 Drug Treatment
;
High-Throughput Screening Assays
;
Molecular Docking Simulation
;
Protease Inhibitors/chemistry*
;
SARS-CoV-2/enzymology*
;
Viral Nonstructural Proteins
10.Efficacy and safety of LY01005 versus goserelin implant in Chinese patients with prostate cancer: A multicenter, randomized, open-label, phase III, non-inferiority trial.
Chengyuan GU ; Zengjun WANG ; Tianxin LIN ; Zhiyu LIU ; Weiqing HAN ; Xuhui ZHANG ; Chao LIANG ; Hao LIU ; Yang YU ; Zhenzhou XU ; Shuang LIU ; Jingen WANG ; Linghua JIA ; Xin YAO ; Wenfeng LIAO ; Cheng FU ; Zhaohui TAN ; Guohua HE ; Guoxi ZHU ; Rui FAN ; Wenzeng YANG ; Xin CHEN ; Zhizhong LIU ; Liqiang ZHONG ; Benkang SHI ; Degang DING ; Shubo CHEN ; Junli WEI ; Xudong YAO ; Ming CHEN ; Zhanpeng LU ; Qun XIE ; Zhiquan HU ; Yinhuai WANG ; Hongqian GUO ; Tiwu FAN ; Zhaozhao LIANG ; Peng CHEN ; Wei WANG ; Tao XU ; Chunsheng LI ; Jinchun XING ; Hong LIAO ; Dalin HE ; Zhibin WU ; Jiandi YU ; Zhongwen FENG ; Mengxiang YANG ; Qifeng DOU ; Quan ZENG ; Yuanwei LI ; Xin GOU ; Guangchen ZHOU ; Xiaofeng WANG ; Rujian ZHU ; Zhonghua ZHANG ; Bo ZHANG ; Wanlong TAN ; Xueling QU ; Hongliang SUN ; Tianyi GAN ; Dingwei YE
Chinese Medical Journal 2023;136(10):1207-1215
BACKGROUND:
LY01005 (Goserelin acetate sustained-release microsphere injection) is a modified gonadotropin-releasing hormone (GnRH) agonist injected monthly. This phase III trial study aimed to evaluated the efficacy and safety of LY01005 in Chinese patients with prostate cancer.
METHODS:
We conducted a randomized controlled, open-label, non-inferiority trial across 49 sites in China. This study included 290 patients with prostate cancer who received either LY01005 or goserelin implants every 28 days for three injections. The primary efficacy endpoints were the percentage of patients with testosterone suppression ≤50 ng/dL at day 29 and the cumulative probability of testosterone ≤50 ng/dL from day 29 to 85. Non-inferiority was prespecified at a margin of -10%. Secondary endpoints included significant castration (≤20 ng/dL), testosterone surge within 72 h following repeated dosing, and changes in luteinizing hormone, follicle-stimulating hormone, and prostate specific antigen levels.
RESULTS:
On day 29, in the LY01005 and goserelin implant groups, testosterone concentrations fell below medical-castration levels in 99.3% (142/143) and 100% (140/140) of patients, respectively, with a difference of -0.7% (95% confidence interval [CI], -3.9% to 2.0%) between the two groups. The cumulative probabilities of maintaining castration from days 29 to 85 were 99.3% and 97.8%, respectively, with a between-group difference of 1.5% (95% CI, -1.3% to 4.4%). Both results met the criterion for non-inferiority. Secondary endpoints were similar between groups. Both treatments were well-tolerated. LY01005 was associated with fewer injection-site reactions than the goserelin implant (0% vs . 1.4% [2/145]).
CONCLUSION:
LY01005 is as effective as goserelin implants in reducing testosterone to castration levels, with a similar safety profile.
TRIAL REGISTRATION
ClinicalTrials.gov, NCT04563936.
Humans
;
Male
;
Antineoplastic Agents, Hormonal/therapeutic use*
;
East Asian People
;
Gonadotropin-Releasing Hormone/agonists*
;
Goserelin/therapeutic use*
;
Prostate-Specific Antigen
;
Prostatic Neoplasms/drug therapy*
;
Testosterone

Result Analysis
Print
Save
E-mail