Background/Aims: Dysregulated cholesterol metabolism is a hallmark of hepatocellular carcinoma (HCC) that drives tumor initiation and progression. However, clinical targeting of cholesterol metabolism has yielded limited benefits due to stringent feedback in tumor cells. Identifying a central mediator capable of restoring cholesterol homeostasis within the cell’s intrinsically fine-tuned regulatory framework is urgently needed. Methods: We integrated a proteomic dataset from patients with cholesterol-dysregulated HCC into a global cholesterol metabolic regulatory network to identify potential therapeutic targets for disrupted cholesterol homeostasis. The prognostic significance of the candidate targets was further validated in an independent cohort through immunohistochemistry. Functional and mechanistic studies were conducted in vitro using HCC cell lines and in vivo using mouse models. The pharmacological efficacy of the candidate agent was evaluated in both subcutaneous and orthotopic HCC mouse models. Results: ER lipid raft-associated 1 (ERLIN1), a pivotal regulator of cholesterol metabolism reprogramming, was identified as an independent favorable prognostic indicator in HCC. ERLIN1 constrains HCC progression both in vitro and in vivo by stabilizing the INSIG1–SCAP–SREBP2 axis and maintaining the metabolic balance of intracellular cholesterol. Under hypoxia, impaired factor-inhibiting hypoxia-1-dependent hydroxylation of ASB11 at asparagine residues 90 and 92 enhances ASB11-mediated ERLIN1 degradation. Pharmacological targeting of this axis using zoledronic acid (ZoA) attenuated HCC progression by weakening the ASB11–ERLIN1 interaction and restoring cholesterol homeostasis. Conclusions ERLIN1 represents a druggable metabolic vulnerability in cholesterol-dysregulated HCC. Targeting the ASB11–ERLIN1 axis with the clinically approved ZoA reestablishes cholesterol homeostasis and offers a promising therapeutic strategy to overcome the current limitations of cholesterol-targeted HCC therapies.

Objective:To explore the dosimetry optimization strategy based on filter thickness and shape selection for the bulb superficial X-ray radiotherapy unit.Methods:Monte Carlo code TOPAS was used to model tubular equipment, and the dose distribution from six X-ray energies (50-150 kV) and five conventional aluminum filters (0.5-3.0 mm) with different thickness were simulated in the water model. The percentage depth dose (PDD) curve along the central axis, the center-axis profile dose at different depths, and the lateral dose distribution were analyzed. The dose distribution of three different designs of aluminum filters (conventional cylindrical, conical and oblique cylindrical filters) was compared to evaluate the effect of dosimetric optimization of different filter shapes.Results:Under the same energy, increasing the thickness of the filter can optimize the superficial skin dose, and the optimization effect of depth dose uniformity can be increased by 26% at a depth of 5.5 mm at 70 kV energy. The raised, flat and inclined dose distribution modes can be achieved by using conventional cylindrical, conical and inclined aluminum filters.Conclusions:By selecting the appropriate X-ray energy and filter thickness, an ideal dose distribution matching the tumor depth can be achieved. The application of personalized filters is also of great significance for diverse target areas.

Objective To systematically evaluate the performance and methodological quality of the risk prediction models for urinary incontinence after radical prostatectomy,so as to provide a reference for selecting the appropriate risk prediction tool.Methods A systematic search was conducted in PubMed,Web of Science,Cochrane Library,CINAHL,EMBASE,CNKI,Wanfang,VIP,and Chinese biomedical literature database from inception to Jan.23,2024.Two researchers independently conducted literature screening and data extraction,and the prediction model risk of bias assessment tool(PROBAST)was applied to assess the risk of bias and applicability of the included studies.MedCalc software was used to perform a meta-analysis of the area under curve(AUC)of the validation groups using the random effect model,and the publication bias and sensitivity analysis were also performed.Results A total of 8 studies were included,with a combined sample size of 7 216 cases.Six models reported the AUC values,and 7 models reported calibration.The applicability of 2 studies was acceptable,while 6 were poor.The most commonly used type of prediction model was logistic regression.After excluding models with extreme AUC values,the random-effects meta-analysis result was 0.840(95%confidence interval 0.786 to 0.895),with no heterogeneity(I2=0%,P=0.737).The bias risk was high in all 8 studies,mainly due to retrospective cohort data,transformation of continuous variables into binary variables,unaddressed missing data,selection of predictors based on univariate analysis,incomplete report of the model discrimination and calibration,and lack of external validation.Egger test result indicated no significant publication bias.Conclusion The development and validation process of the existing risk prediction models for urinary incontinence after radical prostatectomy is still imperfect.Future research should construct prediction models based on multicenter and large-sample data,strengthen the clinical applicability assessment of the models,and strictly follow the reporting standards and procedures,so as to establish high-quality risk prediction models for clinical practice.

Allogeneic haemopoietic stem cell transplantation (allo-HSCT)-related nephrotic syndrome is a rare complication, recognized as a clinical manifestation of chronic graft versus host disease (GVHD). T cell dysfunction is thought to play a significant role in the pathogenesis of allo-HSCT-related nephrotic syndrome, but the precise mechanism remains unclear. This paper reported a case of X-linked adrenoleukodystrophy (X-ALD) who had good control of the disease after allo-HSCT, but developed proteinuria and progressed to nephrotic syndrome after immunosuppressive therapy was tapered. Kidney biopsy revealed secondary membranous nephropathy, which responded well to treatment with glucocorticoids and tacrolimus. Limited literature exist on allo-HSCT-related nephrotic syndrome in children. This study provides a comprehensive summary of its mechanism, clinical features, pathology, diagnosis,and treatment, offering valuable insights for diagnosing and managing allo-HSCT-related nephrotic syndrome in pediatric patients.

Objective In view of the potential threat of adverse drug reaction(ADR)to patients'health and the limitations of traditional monitoring methods,this study investigates the construction method of an ADR knowledge graph based on a knowledge-driven technology path to promote the intelligent upgrading of pharmacovigilance field.Methods In this study,an adverse drug reaction knowledge base was established,and the data within the knowledge base were preprocessed.The BERT-CRF model was utilized to identify and extract the relevant entities,relationships and attribute information,and knowledge alignment was carried out by combining the rule method and statistical method.The knowledge fusion data was stored in the Neo4j graph database to construct the knowledge graph.Results Based on the established knowledge base,this study explored the method of constructing knowledge graph of adverse drug reaction by knowledge-driven technology,laying the groundwork for data mining and the development of intelligent auxiliary system tools based on knowledge graph.Conclusions The study on the construction method of an ADR knowledge graph based on a knowledge-driven technology path provides a new perspective and technical path for the intelligent upgrading of pharmacovigilance field.It holds important theoretical and practical significance for improving drug safety,protecting patients'health,and promoting the healthy development of pharmaceutical industry.

Objective To investigate the biomechanical characteristics of Salto Talaris tibial components with different heights at the bone-prosthesis interface during different gait support phases after total ankle replacement.Methods An ankle joint model was reconstructed using a weight-bearing CT from a 61-year-old female patient with ankle arthritis,and Salto Talaris tibial components with different heights(5,7,9,11 mm)were modelled to simulate the loading of the tibial-prosthesis during four gait support phases,and to analyse the micromotion and stresses at the bone-prosthesis interface.Results The 11 mm and 9 mm models had a poorer prosthesis stability,with the peak micromotion exceeding 50 μm and the peak internal tibial stresses of 30.75 MPa and 29.86 MPa,respectively,which exceeded the yield stress of the cancellous bone.The tibial stresses of the 7 mm and 5 mm models were within reasonable ranges and the average peak micromotions were only 42.66 μm and 40.32 μm.In contrast,the initial stability of the 5 mm model prosthesis was the best.Conclusions For total ankle replacement with Salto prosthesis,the height of the tibial component should be chosen appropriately,and the optimal height was about 5 mm.Excessive flexion and extension activities of the ankle joint should be avoided to maintain the stability of the prosthesis after surgery.This study provides a theoretical basis for the improvement of the structural parameters of the Salto prosthesis,which is valuable for the selection of clinical surgical prostheses and helps to improve the results of total ankle replacement.

BACKGROUND:D1-3-n-butylphthalide has antioxidant and anti-inflammatory effects and has been explored to have protective role in Parkinson's disease,but the underlying mechanisms are unknown.OBJECTIVE:To investigate the protective effect of D1-3-n-butylphthalide by the approach of network pharmacology,molecular docking,and cellular experimental validation.METHODS:(1)Network pharmacology and molecular docking:The database was used to screen the targets of D1-3-n-butylphthalide and Parkinson's disease.The intersection was taken from the construction of the target protein interaction network,and then screen the core targets.The GO and KEGG pathway enrichment was used to further analyze the core targets.The interaction between the target proteins and D1-3-n-butylphthalide was verified by molecular docking.(2)Cell validation:The passage 6 PC12 cells were divided into six groups for culture.The control group was cultured with conventional culture medium.The model group was cultured with N-methyl-4-phenylpyridinium iodide to induce Parkinson's disease model.The ML385 inhibitor group was added with nuclear factor E2-related factor 2 inhibitor ML385 on the basis of inducing Parkinson's disease model.The D1-3-n-butylphthalide treatment group was added with butylphthalide on the basis of inducing Parkinson's disease model.The D1-3-n-butylphthalide combined with ML385 treatment group was added with D1-3-n-butylphthalide and ML385 on the basis of inducing Parkinson's disease model.The D1-3-n-butylphthalide group was cultured with conventional culture medium containing butylphthalide alone.Cell proliferation,intracellular reduced glutathione and malondialdehyde levels,and protein expression of protein kinase B/glycogen synthase kinase 3β/nuclear factor E2-related factor 2(AKT/GSK-3β/Nrf2)signaling pathway were detected.RESULTS AND CONCLUSION:(1)A total of 52 targets were screened for the intersection of drugs and disease targets,and the core targets including the matrix metalloproteinase 9 and GSK-3β were involved the phosphatidylinositol 3-kinase(PI3K)/AKT and oxidative stress-related signaling pathways.The molecular docking binding energy of D1-3-n-butylphthalide and GSK-3β was-18.27 kJ/mol,which indicated that D1-3-n-butylphthalide had a good binding ability with GSK-3β.(2)Compared with the model group,the PC12 cell activity and reduced glutathione level in the D1-3-n-butylphthalide treatment group were increased(P＜0.05),the malondialdehyde level was decreased(P＜0.05),and the expression of p-AKT,p-GSK-3β,Nu-Nrf2,and T-Nrf2 proteins was increased(P＜0.05).Compared with the D1-3-n-butylphthalide group,the PC12 cell activity and reduced glutathione level in the D1-3-n-butylphthalide combined with ML385 treatment group were decreased(P＜0.05),the malondialdehyde level was increased(P＜0.05),and the expression of Nu-Nrf2 and T-Nrf2 proteins was decreased(P＜0.05).(3)These results demonstrate that D1-3-n-butylphthalide can inhibit oxidative stress and improve cell activity through the AKT/GSK-3β/Nrf2 signaling pathway,and has a protective effect on the Parkinson's cell model induced by N-methyl-4-phenylpyridinium iodide.

Objective In view of the potential threat of adverse drug reaction(ADR)to patients'health and the limitations of traditional monitoring methods,this study investigates the construction method of an ADR knowledge graph based on a knowledge-driven technology path to promote the intelligent upgrading of pharmacovigilance field.Methods In this study,an adverse drug reaction knowledge base was established,and the data within the knowledge base were preprocessed.The BERT-CRF model was utilized to identify and extract the relevant entities,relationships and attribute information,and knowledge alignment was carried out by combining the rule method and statistical method.The knowledge fusion data was stored in the Neo4j graph database to construct the knowledge graph.Results Based on the established knowledge base,this study explored the method of constructing knowledge graph of adverse drug reaction by knowledge-driven technology,laying the groundwork for data mining and the development of intelligent auxiliary system tools based on knowledge graph.Conclusions The study on the construction method of an ADR knowledge graph based on a knowledge-driven technology path provides a new perspective and technical path for the intelligent upgrading of pharmacovigilance field.It holds important theoretical and practical significance for improving drug safety,protecting patients'health,and promoting the healthy development of pharmaceutical industry.

Objective To investigate the biomechanical characteristics of Salto Talaris tibial components with different heights at the bone-prosthesis interface during different gait support phases after total ankle replacement.Methods An ankle joint model was reconstructed using a weight-bearing CT from a 61-year-old female patient with ankle arthritis,and Salto Talaris tibial components with different heights(5,7,9,11 mm)were modelled to simulate the loading of the tibial-prosthesis during four gait support phases,and to analyse the micromotion and stresses at the bone-prosthesis interface.Results The 11 mm and 9 mm models had a poorer prosthesis stability,with the peak micromotion exceeding 50 μm and the peak internal tibial stresses of 30.75 MPa and 29.86 MPa,respectively,which exceeded the yield stress of the cancellous bone.The tibial stresses of the 7 mm and 5 mm models were within reasonable ranges and the average peak micromotions were only 42.66 μm and 40.32 μm.In contrast,the initial stability of the 5 mm model prosthesis was the best.Conclusions For total ankle replacement with Salto prosthesis,the height of the tibial component should be chosen appropriately,and the optimal height was about 5 mm.Excessive flexion and extension activities of the ankle joint should be avoided to maintain the stability of the prosthesis after surgery.This study provides a theoretical basis for the improvement of the structural parameters of the Salto prosthesis,which is valuable for the selection of clinical surgical prostheses and helps to improve the results of total ankle replacement.

Objective:To investigate the predictive value of thyroid hormone sensitivity indicators for adverse pregnancy outcomes in pregnant women with gestational diabetes mellitus (GDM) complicated by hypothyroidism.Methods:A cross-sectional study was conducted to retrospectively analyze the clinical data of 80 pregnant women with GDM complicated by hypothyroidism who were admitted to the Department of Obstetrics, Second Affiliated Hospital of Shaanxi University of Chinese Medicine from February 2022 to February 2024. The patients were divided into two groups: the adverse outcome group ( n = 48) and the normal outcome group ( n = 32) based on the occurrence of adverse pregnancy outcomes. Logistic regression analysis was conducted to identify the risk factors for adverse pregnancy outcomes in these women. Additionally, receiver operating characteristic curve analysis was performed to evaluate the predictive value of thyroid hormone sensitivity indicators for adverse pregnancy outcomes. Results:In the adverse outcome group, the proportion of women with a pre-pregnancy body mass index ≥ 24 kg/m2, triglyceride level, activated partial thromboplastin time, fibrinogen level, thyroid-stimulating hormone level, and thyroid-stimulating hormone index were 58.33% (28/48), (5.77 ± 0.25) mmol/L, (31.79 ± 2.68) seconds, (4.39 ± 0.37) g/L, (5.05 ± 1.07) mU/L, and (3.15 ± 0.24), respectively, which were significantly higher than those in the normal outcome group ( χ2 = 4.41, t = -3.56, -3.23, -2.61, -4.17, -9.15, all P < 0.05). Conversely, the levels of free thyroxine, free triiodothyronine, thyrotroph T4 resistance index, and thyroid feedback quantile index in the adverse outcome group were (9.32 ± 1.04) pmol/L, (3.17 ± 0.42) pmol/L, (33.09 ± 4.26), and (0.19 ± 0.07), respectively, which were all significantly lower than those in the normal outcome group ( t = 4.44, 3.51, 4.31, 2.21, all P < 0.05). Logistic regression analysis revealed that pre-pregnancy body mass index [ OR = 2.673, 95% CI(1.057,6.761)], triglyceride level [ OR = 25.623, 95% CI(3.208,204.673)], activated partial thromboplastin time [ OR = 1.365, 95% CI(1.106,1.685)], fibrinogen level [ OR = 3.111, 95% CI(1.257,7.701)], thyroid-stimulating hormone level [ OR = 2.969, 95% CI(1.613,5.465)], free thyroxine level [ OR = 0.441, 95% CI(0.280,0.695)], free triiodothyronine level [ OR = 0.172, 95% CI(0.057,0.516)], thyroid-stimulating hormone index [ OR = 6.298, 95% CI(1.099, 36.094)], thyrotroph T4 resistance index [ OR = 0.799, 95% CI(0.704,0.907)], and thyroid feedback quantile index [ OR = 0.057, 95% CI(0.168,0.478)] were all factors that influence adverse pregnancy outcomes in pregnant women with GDM complicated by hypothyroidism (all P < 0.05). The area under the curve for predicting adverse pregnancy outcomes using the combined thyroid hormone sensitivity indicators was 0.809 [95% CI (0.704, 0.915), P < 0.001], with a sensitivity of 0.896, specificity of 0.687, and a maximum Youden index of 0.583. Conclusions:The thyroid hormone sensitivity indicators have a certain predictive value for adverse pregnancy outcomes in pregnant women with GDM complicated by hypothyroidism. These indicators can provide important reference for clinical prediction and intervention of adverse pregnancy outcomes in this patient population.