OBJECTIVE To investigate the effect of pharmaceutical services guided by root cause analysis （RCA） in a problem-oriented manner combined with knowledge-attitude-practice （KAP） theory on reducing the incidence of protocol violations of investigational medicinal products in pediatric clinical trials. METHODS A total of 617 participants from 69 drug clinical trial projects conducted in our hospital from January 2016 to December 2020 were selected as the control group， and 868 participants from 72 drug clinical trial projects from January 2022 to December 2025 as the observation group. RCA was performed on the protocol violations of investigational medicinal product in the control group to identify the types and underlying causes. The control group received routine pharmaceutical services for drug clinical trials， while the observation group was provided with precision pharmaceutical services from the three dimensions of knowledge， attitude and practice on the basis of routine pharmaceutical services， according to the root causes identified by RCA. The occurrence of investigational medicinal products protocol violations was compared between the two groups. RESULTS The total incidence of protocol violations of investigational medicinal products， as well as the incidences of minor and major protocol violations， were all significantly lower in the observation group than in the control group （ P ＜0.001）. The main types of protocol violations in both groups included missed/under-/over-dosing of medications， non-adherence to administration time， failure to adjust dosage as required， and combined medication/vaccination in violation of the protocol. Regarding the responsible subjects of protocol violations， the incidences of protocol violations attributed to participants and their guardians as well as investigators and accidental factors were significantly lower in the observation group than in the control group （ P ＜0.001， P ＜0.001， P ＝0.025）. However， there were no statistically significant differences in the incidences of protocol violations caused by sponsor-related reasons between the two groups （ P ＞0.05）. CONCLUSIONS Pharmaceutical services led by pharmacists， based on problem-oriented RCA and combined with KAP theory， can effectively reduce the protocol violations of investigational medicinal products rate in pediatric clinical trials， thereby safeguarding the safety and rights of study participants.

Objective To investigate the clinical significance of the miR-543/syntrophin beta 1(SNTB1)axis in colorectal cancer(CRC)and its influence on the tumor immune microenvironment.Methods The expression of SNTB1 in CRC tissues was analyzed using public data,such as,The Cancer Genome Atlas(TCGA),Genotype-Tissue Expression(GTEx),and Human Protein Atlas(HPA).Then Kaplan-Meier survival analysis,univariate Cox regression analysis and correlation analysis were performed to evaluate the prognostic value of SNTB1 and its relationship with immune microenvironment in CRC.The targeting relationship between miR-543 and SNTB1 was confirmed through online databases and fluorescence assays in HT-29 cells.For in vitro experiments,after transfecting si-SNTB1,miR-543 mimics and/or SNTB1 overexpression plasmids,HT-29 cells were co-cultured with CD8+T cells,the expression of miR543 and SNTB1 and the viability and cytotoxicity of CD8+T cells were assessed with qRT-PCR,Western blotting,flow cytometry,ELISA,and lactate dehydrogenase(LDH)release assay.Results Analysis of public databases revealed significantly higher expression of SNTB1 in CRC tissues than normal tissues(P<0.001).The CRC patients with high SNTB1 expression exhibited poorer prognosis when compared with those with low expression level(P<0.05).Moreover,high SNTB1 expression was negatively correlated with immune scores in the tumor microenvironment and immune cell infiltration,especially CD8+T cells(P<0.05).Furthermore,Knockdown of SNTB1 in HT-29 cells enhanced the cytotoxic activity of CD8+T cells(P<0.01).Online database and in vitro experiments confirmed that miR-543 targets SNTB1,while the expression of miR-543 was decreased in colorectal cancer(P<0.001).Transfection with the miR-543 mimic inhibited the expression of SNTB1 in HT-29 cells(P<0.001),while overexpressing SNTB1 counteracted the promotion effect of miR-543 mimics on CD8+T cell-mediated cytotoxicity(P<0.05).Conclusion MiR-543 activates CD8+T cells and enhances their cytotoxicity against HT-29 cells by directly targeting SNTB1.

ObjectiveTo reveal the changing pattern of fungal communities and isoflavone content during the fermentation of Sojae Semen Praeparatum. MethodsInternal transcribed spacer （ITS） amplicon sequencing was used to analyze the changes in fungal communities during the fermentation. High-performance liquid chromatography （HPLC） was employed to determine the composition and content of isoflavones. Spearman correlation analysis was conducted to identify fungal communities positively correlated with isoflavone content. ResultsDuring the fermentation of Sojae Semen Praeparatum， the abundance of Penicillium continued to increase and became the dominant genus from the "yellow cladding" to the early "secondary fermentation" stage （9 days）. However， in the mid-to-late "secondary fermentation" stage （12-21 days）， the abundance of Penicillium decreased， while the abundance of Barnettozyma increased rapidly， becoming the dominant genus during the later stages （18-21 days）. Alpha diversity analyses showed that fungal diversity was higher in the "secondary fermentation" stage than in the "yellow cladding" stage. Beta diversity analyses showed greater variability in fungal communities during the "yellow cladding" stage， with relatively stable fungal communities during the "secondary fermentation" stage. The aglycone isoflavone content exhibited a gradual increase， rising from 5.56% at the start of fermentation to 96.84% by the end. In contrast， the glucoside isoflavone content experienced a corresponding decline， decreasing from 94.44% to 3.16%. Spearman analysis showed that Penicillium， Barnettozyma， and Ilyonectria were positively correlated with the contents of daidzein， glycitein， and genistein， and promoted the conversion of isoflavones from glucoside to aglycone forms. ConclusionThe fungal communities of Penicillium， Barnettozyma， and Ilyonectria promote the conversion of isoflavones from glucoside to aglycone forms during the fermentation of Sojae Semen Praeparatum. The findings provide an important reference for improving the scalability and quality of Sojae Semen Praeparatu fermentation.

Objective:This study starts from the main problems existing in the current stage of the development of pediatric clinical research in China and focuses on the construction of a clinical research management system. By innovating the platform management model and enhancing personnel skills, we can provide support and assurance for improving the clinical research platform and its sustainable development in the future.Methods:This study established an integrated management platform for Industry-Sponsored Initiated Clinical Research Trial (IST) and Investigator Initiated Clinical Research (IIT) and implement integrated management of IST and IIT projects. At the same time, in response to the weak links in quality management, synchronous training of management and research talents should be implemented to achieve dual improvement in project management quality and platform service efficiency throughout the process.Results:We had optimized the clinical research organization structure, improved the management system, and strengthened the quality supervision of IIT projects by establishing rules and systems to improve the quality and efficiency of project management.Conclusions:Based on analyzing the current situation in China and referring to international experience, we have built a clinical research management platform in line with the development of the hospital, and implemented centralized management of the entire process of IST and IIT projects, strengthened project process quality control, which is expected to provide a reference for peers.

Objective:In response to the current situation where Investigator-Initiated Trial (IIT) management system of pediatric medical institutions in our country is inadequate and the management of high-risk projects needs to be strengthened, a pediatric hospital in Beijing has been selected as a pilot to develop a system and process suitable for IIT management. We aim to explore personalized management models for different types of research projects, especially high-risk ones, to improve the quality of pediatric IIT, reduce research risks, and enhance management efficiency.Methods:By analyzing the current management situation of high-risk pediatric IIT, optimization strategies were proposed to improve the internal IIT project management system and processes of the pilot unit, and effective management measures are promoted.Results:By revising the IIT project management system, improving the project application and approval processes, strengthening process quality control and personnel training, the risk control and quality supervision of such projects had been enhanced, thereby improving project quality and ensuring the rights and interests of research participants.Conclusions:After the pilot unit trialed a series of management measures for high-risk IIT projects, researchers' risk awareness has significantly increased, and project quality has been effectively improved. The Results provide a reference and model for peers in establishing management rules and also offer theoretical and practical foundations for improving the management system of high-risk clinical research.

Objective:To investigate the effects of echinatin(Ech)on the malignant biological behavior and immune escape of lung cancer A549 cells and its underlying mechanisms.Methods:Normal lung epithelial cells(BEAS-2B)and A549 cells were routinely cultured and treated with different concentrations of Ech for 24h.Cell viability was assessed using the MTT assay,and concentrations of 20,30,and 40 μmol/L were selected for subsequent experiments.A549 cells were divided into the following groups:control group(0 μmol/L Ech),low-(20 μmol/L),medium-(30 μmol/L),and high-concentration(40 μmol/L)Ech groups(Ech-L,Ech-M,Ech-H),and high-dose Ech combined with the pathway inhibitor H-151(1.0 μmol/L)group(Ech-H+H-151).Cell proliferation,migration,and invasion were evaluated using the EdU assay,wound-healing assay,and Transwell assay,respectively.Western blotting(WB)assay was applied to detect the expression of proteins related to proliferation,migration,invasion,and the STING/TBK1/IRF3 signaling pathway.Subsequently,A549 cells were co-cultured with CD8+T cells,and trypan blue staining was used to detect CD8+T cell viability.The levels of type Ⅰ interferon(IFN-Ⅰ)in the co-culture supernatants were detected by WB,while the levels of programmed death ligand 1(PD-L1),interleukin-10(IL-10),interleukin-4(IL-4),and transforming growth factor-β(TGF-β)were determined using ELISA.Results:Ech inhibited the viability of A549 cells in a dose-dependent manner(all P<0.05)but had no significant effect on the viability of BEAS-2B cells.Ech dose-dependently inhibited the proliferation,migration and invasion of A549 cells(all P<0.05),as well as the protein expression of cyclinD1,Ki67,MMP2,MMP9,STING,p-TBK1 and p-IRF3(all P<0.05).These effects were partially reversed by H-151.Ech dose-dependently promoted the survival of CD8+T cells co-cultured with A549 cells(all P<0.05),enhanced IFN-Ⅰexpression(all P<0.05),and inhibited the secretion of PD-L1,IL-10,IL-4,and TGF-β(all P<0.05),with H-151 partially reversing these effects(all P<0.05).Conclusion:Ech inhibits malignant biological behavior and immune escape of lung cancer A549 cells by activating the STING/TBK1/IRF3 signaling pathway.

Objective:This study starts from the main problems existing in the current stage of the development of pediatric clinical research in China and focuses on the construction of a clinical research management system. By innovating the platform management model and enhancing personnel skills, we can provide support and assurance for improving the clinical research platform and its sustainable development in the future.Methods:This study established an integrated management platform for Industry-Sponsored Initiated Clinical Research Trial (IST) and Investigator Initiated Clinical Research (IIT) and implement integrated management of IST and IIT projects. At the same time, in response to the weak links in quality management, synchronous training of management and research talents should be implemented to achieve dual improvement in project management quality and platform service efficiency throughout the process.Results:We had optimized the clinical research organization structure, improved the management system, and strengthened the quality supervision of IIT projects by establishing rules and systems to improve the quality and efficiency of project management.Conclusions:Based on analyzing the current situation in China and referring to international experience, we have built a clinical research management platform in line with the development of the hospital, and implemented centralized management of the entire process of IST and IIT projects, strengthened project process quality control, which is expected to provide a reference for peers.

Objective:In response to the current situation where Investigator-Initiated Trial (IIT) management system of pediatric medical institutions in our country is inadequate and the management of high-risk projects needs to be strengthened, a pediatric hospital in Beijing has been selected as a pilot to develop a system and process suitable for IIT management. We aim to explore personalized management models for different types of research projects, especially high-risk ones, to improve the quality of pediatric IIT, reduce research risks, and enhance management efficiency.Methods:By analyzing the current management situation of high-risk pediatric IIT, optimization strategies were proposed to improve the internal IIT project management system and processes of the pilot unit, and effective management measures are promoted.Results:By revising the IIT project management system, improving the project application and approval processes, strengthening process quality control and personnel training, the risk control and quality supervision of such projects had been enhanced, thereby improving project quality and ensuring the rights and interests of research participants.Conclusions:After the pilot unit trialed a series of management measures for high-risk IIT projects, researchers' risk awareness has significantly increased, and project quality has been effectively improved. The Results provide a reference and model for peers in establishing management rules and also offer theoretical and practical foundations for improving the management system of high-risk clinical research.

Objective To investigate the effect and underlying mechanisms of G-protein-coupled receptor 39(GPR39)activation on neuroinflammation and brain injury after experimental intracerebral hemorrhage in mice.Methods Mouse model of intracerebral hemorrhage(ICH)was established by intracerebral injection of autologous blood.A total of 176 male C57/BL6 mice were randomly divided into 8 groups:Sham group(n=42),ICH group(n=34),ICH+Vehicle group(n=32),ICH+TC-G 1008 group(n=44),ICH+GPR39 siRNA group(n=6),ICH+Scramble siRNA group(n=6),ICH+TC-G 1008+666-15 group(n=6),and ICH+TC-G 1008+Vehicle 2 group(n=6).GPR39-specific agonist TC-G 1008 was administered via oral gavage at 1 and 25 h post-ICH modeling.Additionally,GPR39 siRNA and cAMP response element binding protein(CREB)inhibitor 666-15 were intracerebroventricularly injected 24 h before induction of ICH to inhibit the expression levels of GPR39 and p-CREB.At 48 h after ICH,modified Garcia test,forelimb placement test and corner turn test were used to evaluate the short-term neurological deficits in mice.Brain water content was determined by wet/dry method.Immunofluorescence assay was performed to detect the co-localization of GPR39 in neurons and microglia in the brain tissue surrounding the hematoma,as well as the expression of NOD-like receptor thermal protein domain associated protein 3(NLRP3)in neurons.ELISA was employed to measure IL-1β,TNF-α and myeloperoxidase(MPO)levels in peri-hematoma tissue.TUNEL staining was performed to quantify apoptotic neurons around the hematoma.Nissl staining was utilized to evaluate neuronal damage.Western blotting was conducted to detect the expression of GPR39,p-CREB,CREB,NLRP3,Cleaved caspase-1(C-caspase-1),and gasdermin-D protein(GSDMD)in peri-hematoma brain tissue.Results GPR39 expression peaked at 48 h post-ICH in mice(P＜0.05),and it was expressed in both neurons and microglia.Activation of GPR39 by TC-G 1008(24 mg/kg)significantly improved the modified Garcia score,and increased success rate of left forelimb placement and the number of left turns(P＜0.05).Brain edema in the ipsilateral basal ganglia(BG)and cortex(CX)was significantly reduced(P＜0.05).The numbers of apoptotic and damaged neurons around the hematoma were obviously decreased(P＜0.05).The expression of pyroptosis-related molecules,including NLRP3,C-caspase-1 and GSDMD and the levels of inflammation-related factors,including IL-1β,TNF-α and MPO were notably decreased(P＜0.05).However,knockdown of GPR39 and downregulation of p-CREB expression significantly increased the expression of pyroptosis related molecules and inflammatory-related factors in peri-hematoma brain tissue post-ICH in mice(P＜0.05).Conclusion GPR39 activation may inhibit neuroinflammation and brain injury after ICH in mice partly through the CREB signaling pathway.Therefore,GPR39 may be a potential therapeutic target for mitigating neuroinflammation and brain damage after ICH.

By reviewing the ancient and modern literature， the name， origin， scientific name evolution， place of origin， quality， harvesting， processing， efficacy and toxicity of Asteris Radix et Rhizoma（ARR） were systematically sorted out， so as to provide reference for the development and utilization of the relevant famous classical formulas. According to textual research， ARR was first contained in Shennong Bencaojing， all generations are Ziwan for its proper name， and there are still aliases such as Ziyuan， Ziqian and Xiaobianer. Its mainstream origin in successive generations was Aster tataricus， and there are also Ligularia fischeri and others in local area of use. The medicinal parts of ARR are root and rhizome， but in modern times， the rhizome is mostly used for propagation and cultivation， so some of ARR medicinal materials only have the root without the rhizome. The earliest recorded ancient origin of ARR was now Fangxian（Hubei）， Zhengding and Handan（Heibei）， then the range of production areas gradually expanded， the mainstream production areas from the Song dynasty to the Ming and Qing dynasties included Hebei， Jiangsu， Anhui， Henan and other places， since modern times， two major producing areas have been formed in Anguo， Hebei province and Bozhou， Anhui province. From the quality evaluation， it is clear that from ancient times， flexible roots and purple color are the best. The ancient harvesting was mainly in lunar February or March， and then dried in the shade， and the modern harvesting is mostly in spring and autumn， and the roots are braided into pigtails and then dried in the sun or dried in the sun after 1-2 d. The ancient and modern processing method of ARR are basically the same， mainly honey processing， there are still methods of frying， steaming， vinegar sizzling， etc. Based on the results， it is recommended that the dried roots and rhizomes of A. tataricus should be used in clinical and the development of related famous classical formulas， and those whose original formulas specify the processing requirements can be processed according to the relevant requirements， while whose processing requirements are not specified should be used in the form of raw products.