Lirispirolides A-L (1-12), twelve novel sesquiterpene-monoterpene heterodimers featuring distinctive carbon skeletons, were isolated from the branches and leaves of Chinese tulip tree [Liriodendron chinense (L. chinense)], a rare medicinal and ornamental plant endemic to China. The structural elucidation was accomplished through comprehensive spectroscopic analyses, quantum-chemical calculations, and X-ray crystallography. These heterodimers exhibit a characteristic 2-oxaspiro[4.5]decan-1-one structural motif, biosynthetically formed through intermolecular [4 + 2]-cycloaddition between a germacrane-type sesquiterpene and an ocimene-type monoterpene. The majority of the isolated compounds demonstrated significant anti-neuroinflammatory effects in lipopolysaccharide (LPS)-induced BV-2 microglial cells by reducing the production of pro-inflammatory mediators, specifically tumor necrosis factor-α (TNF-α) and nitric oxide (NO). Further investigation revealed that the lirispirolides' inhibition of NO release correlated with decreased messenger ribonucleic acid (mRNA) expression of inducible NO synthase (iNOS).
Sesquiterpenes/isolation & purification* ; Anti-Inflammatory Agents/isolation & purification* ; Animals ; Mice ; Tumor Necrosis Factor-alpha/genetics* ; Nitric Oxide/immunology* ; Microglia/immunology* ; Molecular Structure ; Liriodendron/chemistry* ; Monoterpenes/isolation & purification* ; Plants, Medicinal/chemistry* ; Cell Line ; Lipopolysaccharides ; Nitric Oxide Synthase Type II/immunology* ; Plant Extracts/pharmacology* ; China

To enhance the trustworthiness,security,and convenience of research data management and pro-mote the deep utilization of clinical research data,it introduces core technologies such as data sandboxing,ze-ro-trust architecture,elastic resource scheduling in cloud computing,and data lakes to construct a clinical research trusted data space with trusted management,resource interaction,and value co-creation capabilities.This trusted data space provides a secure and efficient platform for data processing and analysis through strict network access control,dynamic authentication,data anonymization,and digital watermarking technologies.It ensures the secure flow and precise traceability of research data throughout its lifecycle,effectively facilitating resource interaction and value co-creation.The implementation offers a valuable technical reference and practical guidance for other hospitals aiming to build trusted research data platforms.

Objectives:To explore whether short-course radiotherapy (SCRT)-based total neoadjuvant therapy (TNT) combined with PD-1 inhibitors could further promote tumor regression and improve the prognosis.Methods:This is a prospective, multicenter, two-arm randomized controlled, seamless phase Ⅱ/Ⅲ trial for proficient mismatch repair or microsatellite stable (pMMR/MSS) locally advanced rectal cancer (LARC). Eligible patients were randomly assigned to the iTNT (TNT+PD-1) group or the TNT group. Patients in the TNT group received SCRT (5 Gy×5) followed by 4 cycles of CAPOX or 6 cycles of mFOLFOX chemotherapy, with the iTNT group receiving SCRT followed by the same regime in combination with 4 cycles of Sintilimab. Total mesorectal excision (TME) surgery or watch and wait (W&W) was performed after neoadjuvant therapy and then 2 cycles of same regimen as before were recommended. The primary endpoints are the complete response (CR) rate for phase Ⅱ trial and 3-year disease-free survival (DFS) for phase Ⅲ trial. A total of 588 patients will be enrolled for the phase Ⅱ/Ⅲ trial. Short-term efficacy and safety data from the initial 100 treated patients were analyzed as planned.Results:From 2022-8-31 to 2023-5-24 the initial 100 patients were enrolled from 10 hospitals in China, 76.0%(76/100) patients were male, and the median age was 61 years (21-74 years). More patients had tumors located in the lower rectum (78.0%, 78/100), staged T3-4 (97.0%, 97/100) and N1-2 (93.0%, 93/100), and about half of the tumors invaded the mesorectal fascia (52.0%, 52/100) and with extramural vascular invasion (51.0%, 51/100). Analyses were performed according to the per-protocal (PP) set. All patients in the iTNT group ( n=52) and the TNT group ( n=48) completed SCRT; The 4-cycle chemotherapy±Sintilimab completion rates were 86.5% and 100.0% in the iTNT and TNT groups, respectively. In the iTNT group, 82.7% (43/52), 11.5% (6/52), and 5.8% (3/52) of the patients received 4, 3, and 2 cycles of PD-1 inhibitor. After TNT, 68 patients underwent radical surgery and 15 patients achieved cCR and adopted W&W. The pathological complete response (pCR) rates were 48.5% (16/33) and 17.1% (6/35) in the iTNT and TNT groups, with CR rates of 50.0% (25/50) and 26.1% (12/46), respectively. The incidence of treatment-related grade 3-4 adverse events was 26.9% (14/52, iTNT group) and 18.8% (9/48, TNT group), with thrombocytopenia and leukopenia being the most common. Among patients receiving immunotherapy, grade 3 immunotherapy-related adverse events occurred in 2 (3.8%, 2/52) patients: one case was pancreatitis, another case was hepatitis combined with myositis and myocarditis. Conclusion:The preliminary results show that SCRT-based TNT combined with PD-1 inhibitors could further improve the CR rate for LARC without unexpected serious adverse events.

To enhance the trustworthiness,security,and convenience of research data management and pro-mote the deep utilization of clinical research data,it introduces core technologies such as data sandboxing,ze-ro-trust architecture,elastic resource scheduling in cloud computing,and data lakes to construct a clinical research trusted data space with trusted management,resource interaction,and value co-creation capabilities.This trusted data space provides a secure and efficient platform for data processing and analysis through strict network access control,dynamic authentication,data anonymization,and digital watermarking technologies.It ensures the secure flow and precise traceability of research data throughout its lifecycle,effectively facilitating resource interaction and value co-creation.The implementation offers a valuable technical reference and practical guidance for other hospitals aiming to build trusted research data platforms.

Objectives:To explore whether short-course radiotherapy (SCRT)-based total neoadjuvant therapy (TNT) combined with PD-1 inhibitors could further promote tumor regression and improve the prognosis.Methods:This is a prospective, multicenter, two-arm randomized controlled, seamless phase Ⅱ/Ⅲ trial for proficient mismatch repair or microsatellite stable (pMMR/MSS) locally advanced rectal cancer (LARC). Eligible patients were randomly assigned to the iTNT (TNT+PD-1) group or the TNT group. Patients in the TNT group received SCRT (5 Gy×5) followed by 4 cycles of CAPOX or 6 cycles of mFOLFOX chemotherapy, with the iTNT group receiving SCRT followed by the same regime in combination with 4 cycles of Sintilimab. Total mesorectal excision (TME) surgery or watch and wait (W&W) was performed after neoadjuvant therapy and then 2 cycles of same regimen as before were recommended. The primary endpoints are the complete response (CR) rate for phase Ⅱ trial and 3-year disease-free survival (DFS) for phase Ⅲ trial. A total of 588 patients will be enrolled for the phase Ⅱ/Ⅲ trial. Short-term efficacy and safety data from the initial 100 treated patients were analyzed as planned.Results:From 2022-8-31 to 2023-5-24 the initial 100 patients were enrolled from 10 hospitals in China, 76.0%(76/100) patients were male, and the median age was 61 years (21-74 years). More patients had tumors located in the lower rectum (78.0%, 78/100), staged T3-4 (97.0%, 97/100) and N1-2 (93.0%, 93/100), and about half of the tumors invaded the mesorectal fascia (52.0%, 52/100) and with extramural vascular invasion (51.0%, 51/100). Analyses were performed according to the per-protocal (PP) set. All patients in the iTNT group ( n=52) and the TNT group ( n=48) completed SCRT; The 4-cycle chemotherapy±Sintilimab completion rates were 86.5% and 100.0% in the iTNT and TNT groups, respectively. In the iTNT group, 82.7% (43/52), 11.5% (6/52), and 5.8% (3/52) of the patients received 4, 3, and 2 cycles of PD-1 inhibitor. After TNT, 68 patients underwent radical surgery and 15 patients achieved cCR and adopted W&W. The pathological complete response (pCR) rates were 48.5% (16/33) and 17.1% (6/35) in the iTNT and TNT groups, with CR rates of 50.0% (25/50) and 26.1% (12/46), respectively. The incidence of treatment-related grade 3-4 adverse events was 26.9% (14/52, iTNT group) and 18.8% (9/48, TNT group), with thrombocytopenia and leukopenia being the most common. Among patients receiving immunotherapy, grade 3 immunotherapy-related adverse events occurred in 2 (3.8%, 2/52) patients: one case was pancreatitis, another case was hepatitis combined with myositis and myocarditis. Conclusion:The preliminary results show that SCRT-based TNT combined with PD-1 inhibitors could further improve the CR rate for LARC without unexpected serious adverse events.

Objective:To explore the clinical efficacy of pelvic floor biofeedback combined with electroacupuncture therapy in the treatment of chronic pelvic floor pain syndrome (CPPS).Methods:Ninety CPPS patients admitted to the Dongguan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Traditional Chinese Medicine from August 2022 to July 2023 were selected prospectively, and they were divided into two groups by random number table method, each group with 45 cases. The control group received pelvic floor biofeedback treatment alone, while the observation group received pelvic floor biofeedback combined with electroacupuncture treatment. The two groups were treated once a day, 10 times as a course of treatment. After two courses of treatment, the clinical efficacy, pain degree before and after treatment, inflammatory factor levels, SF-36 health questionnaire (SF-36) scores, pelvic floor surface myoelectric parameters, and incidence of adverse reactions were compared between the two groups.Results:The total effective rate in the observation group after treatment was higher than that in the control group: 95.56% (43/45) vs. 75.56% (34/45), there was statistical difference ( χ2 = 7.28, P<0.05). After treatment, the visual analogue scale (VAS) scores, levels of procalcitonin (PCT), interleukin-6 (IL-6) and C-reactive protein (CRP) in the two groups were decreased, and SF-36 scores were increased, there were statistical differences ( P<0.05); the VAS scores, PCT, IL-6 and CRP levels in the observation group were lower than those in the control group, and SF-36 scores was higher than that in the control group: (2.11 ± 0.24) scores vs. (2.87 ± 0.34) scores, (0.92 ± 0.08) ng/L vs. (1.26 ± 0.09) ng/L, (24.08 ± 2.52) μg/L vs. (28.49 ± 3.10) μg/L, (4.55 ± 0.51) mg/L vs. (6.06 ± 0.63) mg/L, (74.55 ± 7.29) scores vs. (70.18 ± 7.80) scores, there were statistical differences ( P<0.05). After treatment, the surface muscle potential of pelvic floor muscle were increased in the front resting stage, rapid contraction stage, tension contraction stage, endurance contraction stage and post-resting stage, and the above parameters in the observation group were higher than those in the control group: (3.56 ± 0.34)μV vs.(3.20 ± 0.37) μV, (35.26 ± 3.05) μV vs. (31.47 ± 3.08) μV, (34.22 ± 3.25) μV vs. (31.15 ± 3.01)μV, (29.77 ± 3.17) μV vs. (27.04 ± 2.68) μV, (3.21 ± 0.27) μV vs. (3.00 ± 0.34) μV, there were statistical differences ( P<0.05). The incidence rate of adverse reactions in the two groups had no statistical difference ( P>0.05). Conclusions:Pelvic floor biofeedback combined with electroacupuncture in the treatment of CPPS has good clinical effect, and can relief pain response, regulate the inflammatory response and pelvic floor function, and have high safety.

Objective:To explore the clinical efficacy of pelvic floor biofeedback combined with electroacupuncture therapy in the treatment of chronic pelvic floor pain syndrome (CPPS).Methods:Ninety CPPS patients admitted to the Dongguan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Traditional Chinese Medicine from August 2022 to July 2023 were selected prospectively, and they were divided into two groups by random number table method, each group with 45 cases. The control group received pelvic floor biofeedback treatment alone, while the observation group received pelvic floor biofeedback combined with electroacupuncture treatment. The two groups were treated once a day, 10 times as a course of treatment. After two courses of treatment, the clinical efficacy, pain degree before and after treatment, inflammatory factor levels, SF-36 health questionnaire (SF-36) scores, pelvic floor surface myoelectric parameters, and incidence of adverse reactions were compared between the two groups.Results:The total effective rate in the observation group after treatment was higher than that in the control group: 95.56% (43/45) vs. 75.56% (34/45), there was statistical difference ( χ2 = 7.28, P<0.05). After treatment, the visual analogue scale (VAS) scores, levels of procalcitonin (PCT), interleukin-6 (IL-6) and C-reactive protein (CRP) in the two groups were decreased, and SF-36 scores were increased, there were statistical differences ( P<0.05); the VAS scores, PCT, IL-6 and CRP levels in the observation group were lower than those in the control group, and SF-36 scores was higher than that in the control group: (2.11 ± 0.24) scores vs. (2.87 ± 0.34) scores, (0.92 ± 0.08) ng/L vs. (1.26 ± 0.09) ng/L, (24.08 ± 2.52) μg/L vs. (28.49 ± 3.10) μg/L, (4.55 ± 0.51) mg/L vs. (6.06 ± 0.63) mg/L, (74.55 ± 7.29) scores vs. (70.18 ± 7.80) scores, there were statistical differences ( P<0.05). After treatment, the surface muscle potential of pelvic floor muscle were increased in the front resting stage, rapid contraction stage, tension contraction stage, endurance contraction stage and post-resting stage, and the above parameters in the observation group were higher than those in the control group: (3.56 ± 0.34)μV vs.(3.20 ± 0.37) μV, (35.26 ± 3.05) μV vs. (31.47 ± 3.08) μV, (34.22 ± 3.25) μV vs. (31.15 ± 3.01)μV, (29.77 ± 3.17) μV vs. (27.04 ± 2.68) μV, (3.21 ± 0.27) μV vs. (3.00 ± 0.34) μV, there were statistical differences ( P<0.05). The incidence rate of adverse reactions in the two groups had no statistical difference ( P>0.05). Conclusions:Pelvic floor biofeedback combined with electroacupuncture in the treatment of CPPS has good clinical effect, and can relief pain response, regulate the inflammatory response and pelvic floor function, and have high safety.

BACKGROUND:Prosthesis loosening and wear are still the main problems in the failure of total ankle replacement,which are closely related to the micro-motion of the implant-bone interface,the contact stress of the articular surface and joint motion.The design of artificial joint components,including insert and tibial/talar stem prosthesis,is a key factor affecting the force,motion,and micromotion of the contact interface of the ankle joint.The development of new inserts is of great significance to improve the survival rate of artificial ankle joints. OBJECTIVE:The finite element model of the total ankle replacement model was constructed to detect the biomechanical properties of the porous structure-optimized inserts,and the effect of the porous structure-optimized inserts on reducing prosthesis micromotion and improving the contact behavior of the articular surface was analyzed. METHODS:Based on the CT scan data of the right ankle joint of a healthy adult and the INBONE Ⅱ system product manual,a three-dimensional model including bone and artificial joint system was established,and the total ankle replacement model(model A)was obtained after osteotomy and prosthesis installation,and then through four new types of inserts,G50,G60,D50,and D60,were obtained by transforming the porous structure of the original insert,and the original one was replaced with different inserts to establish an optimized total ankle replacement model(models B-E)corresponding to the inserts.The gait loads were applied on the five models to simulate the gait conditions.The differences in micromotion and articular surface contact behaviors at the implant-bone interface of all five models were compared. RESULTS AND CONCLUSION:(1)In the gait cycle,the micromotion of the prosthesis of the four optimized total ankle replacement models was lower than that of the original model.Compared with model A,the micromotion of the prosthesis in models B-E decreased by 5.4%,10.1%,8.1%,and 20.9%,respectively.The high micromotion area of t ??he tibial groove dome in the optimized model was significantly smaller than that of the original model.(2)The four optimized models obtained a larger articular surface contact area.Compared with model A,the average contact area of t ??he inserts in models B-E increased by 11.8%,14.7%,8.1%,and 32.6%,respectively.(3)Similar to the effect of increasing the contact area,compared with the original model,the contact stress of the optimized model decreased in varying degrees,and the value of model E decreased the most significantly(P<0.05),it is due to good mechanical properties and large porosity of the Diamond lattice that constitutes the D60-type insert.(4)The research results show that the use of porous structure to improve the inserts can improve the elasticity of the inserts and increase its ability to absorb joint impact,for favorable conditions are created for reducing micromotion at the implant-bone interface and improving joint contact behavior.

Objective To study the value of CYP2C19 gene polymorphism combined with biochemical indi-cators in predicting clopidogrel resistance(CR)in patients with cerebral infarction.Methods A total of 387 patients with cerebral infarction admitted to Beijing Tiantan Hospital,Capital Medical University from Januar-y 2021 to December 2023 were selected as the research subjects.According to the test results of platelet aggre-gation test-adenosine diphosphate(PAgT-ADP)after admission,the patients with cerebral infarction were di-vided into clopidogrel effective group(PAgT-ADP≤43％)and CR group(PAgT-ADP＞43％).The distribu-tion of CYP2C19 genotype in patients with cerebral infarction were observed.The age,gender and biochemical indicators,including urea,creatinine(Cr),uric acid(UA),alanine aminotransferase(ALT),aspartate amin-otransferase(AST),total bilirubin(TBIL),direct bilirubin(DBIL),indirect bilirubin(IBIL),lactate dehydro-genase(LDH),triglycerides(TG),total cholesterol(CHO),high-density lipoprotein cholesterol(HDL),low-density lipoprotein cholesterol(LDL),homocysteine(Hcy),of the two groups were retrospectively analyzed.Single factor analysis was conducted on statistical indicators,and a combined prediction model was constructed through multivariate Logistic regression analysis.Receiver operating characteristic(ROC)curve was plotted to analyze the efficacy of CYP2C19 gene metabolic types alone and in combination with biochemical indicators for predicting CR in patients with cerebral infarction.Results The gender,Cr,TBIL,DBIL,IBIL,Hcy and CYP2C19 gene metabolic types showed statistically significant differences between the CR group and the clo-pidogrel effective group(P＜0.05).Multivariate Logistic regression analysis showed that Cr,ALT,AST,TBIL,DBIL,IBIL,CHO,LDL and CYP2C19 gene metabolic types were independent predictors of CR(P＜0.05).ROC curve analysis results showed that the area under the curve of the combined prediction model for predicting CR in patients with cerebral infarction was 0.720,and the sensitivity and the specificity were 71.1％and 65.5％,respectively.The area under the curve of the CYP2C19 gene metabolic types for predicting CR in patients with cerebral infarction alone was 0.641,and the sensitivity and the specificity were 67.3％and 56.9％,respectively.There was a statistically significant difference in the area under the curve between the combined prediction model and the CYP2C19 gene metabolic type alone(P＜0.05).Conclusion The combi-nation of CYP2C19 gene polymorphism and biochemical indicators is helpful in predicting the occurrence of CR in patients with cerebral infarction,and has good predictive value especially for patients with CR and CYP2C19 gene metabolism showing normal metabolism.

Objective:To screen the differentially expressed immune-related genes(DEIRGs)in in-stent restenosis(ISR),and to analyze the immune cell infiltration in ISR,and to clarify the mechanism of occurrence and development of ISR.Methods:The mRNA gene expression data of GSE46560 dataset samples were downloaded from the Gene Expression Omnibus(GEO),and divided into ISR group and non-ISR group.The"Limma"package in R software was used to identify the differentially expressed genes(DEGs)which were then intersected with immune-related genes(IRGs)to identify the DEIRGs in ISR;R software was used for Gene Ontology(GO)functional enrichment andalysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)signaling pathway enrichment analysis on DEIRGs;the STRING database was used to construct the protein-protein interaction(PPI)network,which was visualized and analyzed for Hub genes by Cytoscape software;the receiver operating characteristic(ROC)curve of the Hub genes were plotted,and the area under the curve(AUC)was calculated and the diagnostic value was evaluated;CIBERSORT software was used to analyze the immune cell infiltration in ISR;Pearson correlation analysis was used to analyze the relationships between the immune cells and the relationships between the immune cells and key genes.Results:A total of 331 DEGs were identified(P<0.05,|log2FC|>1),including 176 upregulated genes and 155 downregulated genes,and 38 DEIRGs were obstained.The GO functional enrichment analysis results showed that the DEIRGs were mainly enriched in biological processes(BP)such as defense response,immune response,and immune system;in cellular components(CC),the DEIRGs were located primarily in the extracellular region and cytoplasmic membrane;and in molecular functions(MF),the DEIRGs were mainly involved in regulating signaling receptor binding and cytokine receptor activity.The KEGG signaling pathway enrichment analysis results indicated that the DEIRGs in ISR were primarily enriched in the phosphatidylinositol 3-kinase/protein kinase B(PI3K-AKT)and transforming growth factor-β(TGF-β)signaling pathways.In the PPI network,CD19 had the highest node among the top 10 Hub genes.Compared with non-ISR group,the expression level of the CD19 gene in the samples in ISR group was increased(P<0.05).The AUC value in the ROC curve of CD19 gene expression was 0.92(P<0.05).The immune cell infiltration analysis results showed that compared with non-ISR group,the infiltration level of T lymphocyte follicular helper(Tfh)cells in the patients in ISR group were increased(P<0.05),the infiltration levels of immature B lymphocytes,CD8+T lymphocytes,naive CD4+T lymphocytes,and M0 macrophages were increased,but the differences were not statistically significant(P>0.05),while the infiltration levels of memory B lymphocytes,activated memory CD4+T lymphocytes,regulatory T cells,resting natural killer(NK)cells,activated NK cells,monocytes,resting mast cells,and neutrophils were decreased,but the differences were not statistically significant(P>0.05).There were positive correlations between Tfh cells and M0 macrophages and resting mast cells(r=0.88,P<0.05;r=0.68,P<0.05),and there were negative correlations between Tfh cells and monocytes and neutrophils(r=-0.49,P<0.05;r=-0.42,P<0.05).Conclusion:CD19 may influence the occurrence and development of ISR by regulating the activation of the PI3K-AKT signaling pathway to affect the Tfh and B lymphocytes.CD19 can serve as a biomarker for the diagnosis of ISR.