OBJECTIVE To evaluate the cost-effectiveness of anlotinib combined with penpulimab versus sorafenib as first- line treatment for unresectable hepatocellular carcinoma （uHCC） from the perspective of China’s healthcare system. METHODS Based on data from the APOLLO study， a partitioned survival model was established with a 21-day model cycle to simulate patient survival status over 10 years under anlotinib combined with penpulimab regimen or sorafenib monotherapy. Quality-adjusted life year （QALY） was used as the core evaluation parameter to assess the incremental cost-effectiveness ratio （ICER） of different treatment regimens. Using 3 times China’s per capita gross domestic product （GDP） in 2024 （287 247 yuan/QALY） as the willingness-to-pay （WTP） threshold， cost-utility analysis was performed to evaluate the cost-effectiveness of the treatment regimens. Sensitivity analysis was conducted to validate the robustness of the baseline analysis conclusion. Scenario analysis was performed to consider the impact of anlotinib and penpulimab assistance programs on the results； the price reduction of penpulimab to ensure the cost-effectiveness of the combination regimen was examined under varying WTP thresholds （specifically， 1， 2， and 3 times China’s per capita GDP in 2024）. RESULTS The baseline analysis revealed that the ICER of anlotinib combined with penpulimab regimen relative to the sorafenib regimen was 338 611.20 yuan/QALY， which exceeded the WTP threshold set in this study. Univariate sensitivity analysis indicated that the utility value of progression free survival and penpulimab price significantly influenced the baseline analysis results. Probabilistic sensitivity analysis validated the robustness of the baseline results. The results of scenario analysis indicated that when considering the assistance programs for anlotinib and penpulimab， the obtained ICER values were all below the WTP threshold set at 3 times China’s per capita GDP in 2024. When the price of penpulimab was reduced by 58%， 35%， and 13%， the ICER values were below the WTP threshold， which was 1， 2 and 3 times the per capita GDP of China in 2024， respectively. CONCLUSIONS From the perspective of China’s healthcare system， anlotinib combined with penpulimab regimen for first-line treatment of uHCC lacks cost-effectiveness compared to sorafenib regimen. However， this conclusion would be reversed if the anlotinib and penpulimab assistance programs are taken into account or if the price of penpulimab is reduced by more than 13% and above.

Combined with elastic network model (ENM), the perturbation response scanning (PRS) has emerged as a robust technique for pinpointing allosteric interactions within proteins. Here, we proposed the PRS analysis of drug-target networks (DTNs), which could provide a promising avenue in network medicine. We demonstrated the utility of the method by introducing a deep learning and network perturbation-based framework, for drug repurposing of multiple sclerosis (MS). First, the MS comorbidity network was constructed by performing a random walk with restart algorithm based on shared genes between MS and other diseases as seed nodes. Then, based on topological analysis and functional annotation, the neurotransmission module was identified as the "therapeutic module" of MS. Further, perturbation scores of drugs on the module were calculated by constructing the DTN and introducing the PRS analysis, giving a list of repurposable drugs for MS. Mechanism of action analysis both at pathway and structural levels screened dihydroergocristine as a candidate drug of MS by targeting a serotonin receptor of serotonin 2B receptor (HTR2B). Finally, we established a cuprizone-induced chronic mouse model to evaluate the alteration of HTR2B in mouse brain regions and observed that HTR2B was significantly reduced in the cuprizone-induced mouse cortex. These findings proved that the network perturbation modeling is a promising avenue for drug repurposing of MS. As a useful systematic method, our approach can also be used to discover the new molecular mechanism and provide effective candidate drugs for other complex diseases.

Increasing evidence showed that histone deacetylase 6 (HDAC6) dysfunction is directly associated with the onset and progression of various diseases, especially cancers, making the development of HDAC6-targeted anti-tumor agents a research hotspot. In this study, artificial intelligence (AI) technology and molecular simulation strategies were fully integrated to construct an efficient and precise drug screening pipeline, which combined Voting strategy based on compound-protein interaction (CPI) prediction models, cascade molecular docking, and molecular dynamic (MD) simulations. The biological potential of the screened compounds was further evaluated through enzymatic and cellular activity assays. Among the identified compounds, Cmpd.18 exhibited more potent HDAC6 enzyme inhibitory activity (IC₅₀ = 5.41 nM) than that of tubastatin A (TubA) (IC₅₀ = 15.11 nM), along with a favorable subtype selectivity profile (selectivity index ≈ 117.23 for HDAC1), which was further verified by the Western blot analysis. Additionally, Cmpd.18 induced G2/M phase arrest and promoted apoptosis in HCT-116 cells, exerting desirable antiproliferative activity (IC₅₀ = 2.59 μM). Furthermore, based on long-term MD simulation trajectory, the key residues facilitating Cmpd.18's binding were identified by decomposition free energy analysis, thereby elucidating its binding mechanism. Moreover, the representative conformation analysis also indicated that Cmpd.18 could stably bind to the active pocket in an effective conformation, thus demonstrating the potential for in-depth research of the 2-(2-phenoxyethyl)pyridazin-3(2H)-one scaffold.

Combined with elastic network model(ENM),the perturbation response scanning(PRS)has emerged as a robust technique for pinpointing allosteric interactions within proteins.Here,we proposed the PRS analysis of drug-target networks(DTNs),which could provide a promising avenue in network medicine.We demonstrated the utility of the method by introducing a deep learning and network perturbation-based framework,for drug repurposing of multiple sclerosis(MS).First,the MS comorbidity network was constructed by performing a random walk with restart algorithm based on shared genes between MS and other diseases as seed nodes.Then,based on topological analysis and functional annotation,the neurotransmission module was identified as the"therapeutic module"of MS.Further,perturbation scores of drugs on the module were calculated by constructing the DTN and introducing the PRS analysis,giving a list of repurposable drugs for MS.Mechanism of action analysis both at pathway and structural levels screened dihydroergocristine as a candidate drug of MS by targeting a serotonin receptor of se-rotonin 2B receptor(HTR2B).Finally,we established a cuprizone-induced chronic mouse model to evaluate the alteration of HTR2B in mouse brain regions and observed that HTR2B was significantly reduced in the cuprizone-induced mouse cortex.These findings proved that the network perturbation modeling is a promising avenue for drug repurposing of MS.As a useful systematic method,our approach can also be used to discover the new molecular mechanism and provide effective candidate drugs for other complex diseases.

Objective To compare the efficacy of stenting in the treatment of idiopathic intracranial hypertension(IIH)complicated by different types of venous sinus stenosis(VSS).Methods The clinical data of 48 patients with IIH complicated by VSS,who received stenting therapy at the First Affiliated Hospital of Zhengzhou University of China from January 2019 to September 2023,were retrospectively analyzed.According to the type of VSS,the patients were divided into intrinsic stenosis group(n=20)and the extrinsic stenosis group(n=28).The improvement of symptoms,Frisén grade of papilledema,lumbar puncture opening pressure(LPOP),trans-stenosis pressure gradient(△P)of VSS,and surgery-related complications were compared between the two groups.Results The mean age of the patients in the intrinsic stenosis group was greater than that of the patients in the extrinsic stenosis group(41.60 years vs.35.25 years,P=0.049).The length of the narrowed segment in the extrinsic stenosis group was 22.5 mm,which was significantly longer than 19.0 mm in the intrinsic stenosis group(P=0.007).The postoperative Frisén grade of papilledema in the extrinsic stenosis group was obviously lower than that in the intrinsic stenosis group(P=0.037).No statistically significant differences in the other clinical data existed between the two groups(all P＞0.05).After stenting,all of the median △P,mean LPOP,and median Frisén grade of papilledema were decreased significantly when compared with their preoperative values(all P＜0.001),and the postoperative 3-day median Frisén grade of papilledema in the extrinsic stenosis group was much lower(P=0.037).The patients were followed up for one year,the clinical symptoms of the patients in both groups were improved to varying degrees.At the time of discharge,the proportion of patients having no symptoms of papilledema in the extrinsic stenosis group was 57.1％,which was higher than 22.2％in the intrinsic stenosis group(P=0.049),and no statistically significant differences in the improvements of other symptoms existed between the two groups(all P＞0.05).There was no significant difference in the incidence of complications between the two groups(P=0.563).Conclusion Venous sinus stenting can effectively treat patients with IIH complicated by different types of VSS.

Objective To compare the clinical efficacy of medication and stenting in treating patients with idiopathic intracranial hypertension complicated by venous sinus stenosis.Methods The clinical data of 74 patients with idiopathic intracranial hypertension complicated by venous sinus stenosis,who were admitted to the First Affiliated Hospital of Zhengzhou University of China from January 2020 to June 2023,were retrospectively analyzed.The patients were divided into medication group(n=35,receiving drug therapy)and stenting group(n=39,receiving stent implantation therapy).Before and after treatment,lumbar puncture and fundus examinations were performed,and the postoperative improvements in intracranial pressure and papillary oedema were evaluated.The changes in the median papillary oedema Frisén grade and the average opening pressure of lumbar puncture were compared between the two groups during hospitalization period.The improvement degrees of the clinical symptoms determined at discharge,as well as at the 6 months and 12 months after discharge were compared between the two groups.The incidence of complications during the follow-up period in the two groups was recorded.Results The time interval from onset to treatment in the stenting group was longer than that in the medication group(2 months vs.one month,P=0.021),and the differences in the other baseline data between the two groups were not statistically significant(all P＞0.05).After treatment,different degrees of improvement were obtained in both groups(all P＞0.05).At the time of discharge,the degree of median papillary oedema in the stenting group was Frisén grade I,which was lower than Frisén grade Ⅱ in the medication group(P=0.011);the average opening pressure of lumbar puncture in the stenting group was 205.26 mm H2O,which was lower than 248.14 mm H2O in the medication group(P=0.002).The proportions of patients having no symptom or showing symptom improvement in the stenting group and in the medication group at the time of discharge were 74.4％and 45.7％respectively(P=0.017),which at the time of 6 months after discharge were 84.6％and 48.6％respectively(P=0.001)and at the time of 12 months after discharge were 87.2％and 57.1％respectively(P=0.004).No statistically significant difference in the incidence of complications existed between the two groups(10.3％and 8.6％respectively,P=1.000).Conclusion For the treatment of patients with idiopathic intracranial hypertension complicated by venous sinus stenosis,stent implantation therapy is superior to medication therapy in quickly and effectively relieving papillary oedema,decreasing lumbar puncture opening pressure,and improving their corresponding symptoms and signs,with satisfactory patient's prognosis and clinical safety.

Increasing evidence showed that histone deacetylase 6(HDAC6)dysfunction is directly associated with the onset and progression of various diseases,especially cancers,making the development of HDAC6-targeted anti-tumor agents a research hotspot.In this study,artificial intelligence(AI)technology and molecular simulation strategies were fully integrated to construct an efficient and precise drug screening pipeline,which combined Voting strategy based on compound-protein interaction(CPI)prediction models,cascade molecular docking,and molecular dynamic(MD)simulations.The biological potential of the screened compounds was further evaluated through enzymatic and cellular activity assays.Among the identified compounds,Cmpd.18 exhibited more potent HDAC6 enzyme inhibitory activity(IC50=5.41 nM)than that of tubastatin A(TubA)(IC50=15.11 nM),along with a favorable subtype selectivity profile(selectivity index ≈ 117.23 for HDAC1),which was further verified by the Western blot analysis.Additionally,Cmpd.18 induced G2/M phase arrest and promoted apoptosis in HCT-116 cells,exerting desirable antiproliferative activity(IC50=2.59 μM).Furthermore,based on long-term MD simulation trajectory,the key residues facilitating Cmpd.18's binding were identified by decomposition free energy analysis,thereby elucidating its binding mechanism.Moreover,the representative conformation analysis also indicated that Cmpd.18 could stably bind to the active pocket in an effective conformation,thus demonstrating the potential for in-depth research of the 2-(2-phenoxyethyl)pyridazin-3(2H)-one scaffold.

Gastric cancer is one of the most common malignant tumors of the digestive tract worldwide,and its early diagnosis and treatment have always been the focus of clinical research.In recent years,the rapid progress and wide application of proteomics technology have opened up a new perspective for the early screening,diagnosis,prognosis assessment,and mechanism exploration of gastric cancer.With the rapid development of bioinformatics,a series of innovative methods and cutting-edge results based on proteomics related to gastric cancer have emerged.This article reviewed the application progress of proteomics in gastric cancer from three dimensions:experimental techniques,analysis strategies,and major achievements,and discussed the challenges and opportunities in this field.In the future,with the integration of technologies and the deepening of interdisciplinary research,proteomics of gastric cancer is expected to make more breakthroughs,achieve clinical transformation,and provide more precise diagnosis and treatment plans for patients.

Objective To investigate the current status of family resilience of children with cancer and analyze its influencing factors,to provide a basis for medical staff to formulate intervention plans.Methods Using a convenient sampling method,children with cancer who were hospitalized in 2 tertiary hospitals in Henan Province from January to April 2024 were selected for the survey.A general information questionnaire,family resilience assessment scale,quality of life family version,ZBI caregiver burden interview,and social support rating scale were used to understand the current status of family resilience of children with cancer and to explore the related influencing factors by univariate analysis and multiple stepwise linear regression analysis.Results A total of 280 questionnaires were distributed and 265 valid questionnaires were recovered,with a valid questionnaire recovery rate of 94.64％.The total score of family resilience for primary caregivers of children with cancer was(185.63±30.66).The multiple stepwise linear regression analysis results showed that the children's self-care ability,caregiver's work status,family care burden,and social support level were the influencing factors for family resilience of children with cancer(P＜0.05),and the explanatory variance was 51.3％.Conclusion The family resilience of children with cancer is at a medium level.The worse the children's self-care ability and the heavier the family care burden,the worse the family resilience;the caregiver's work status and good social support are helpful for the family resilience of children with cancer.Healthcare workers should develop intervention programs to address these factors to enhance the family resilience of children with cancer.

Objective To construct a graded nursing program for exercise rehabilitation of children with hematopoietic stem cell transplantation(HSCT)and carry out a preliminary application,aiming to provide a basis for healthcare personnel to guide the exercise rehabilitation of children with HSCT.Methods Literature analysis and Delphi expert correspondence were used to construct a graded nursing program of exercise rehabilitation for children with HSCT.Through the convenience sampling method,children with HSCT in the hematology department of a tertiary-level children's hospital in Suzhou City were selected as the study subjects from June-December 2023,of which 26 children with HSCT from September-December 2023 served as an experimental group,and 23 children with HSCT from June-August 2023 as a control group.The experimental group was applied with the graded nursing program of exercise rehabilitation,and the control group was applied with the conventional nursing care.The comparison of cardiorespiratory fitness and adverse events between the 2 groups after 8 weeks of exercise intervention was conducted,and the adherence to the exercise intervention programme in the experimental group was recorded.Results The final constructed graded care program of exercise rehabilitation for children with HSCT included 6 primary indicators,20 secondary indicators,and 44 tertiary indicators.Finally,21 children in the experimental group and 23 children in the control group were included in the study.After the intervention,the 6 min walking distance of the experimental group increased compared with that of the control group,and the difference was statistically significant(P＜0.001).85.71％of children in the experimental group had good exercise compliance,and there was no adverse events in both groups.Conclusion The constructed graded nursing program of exercise rehabilitation for children with HSCT is scientific,reasonable,safe and feasible,which can improve the cardiorespiratory capacity of children with HSCT and provide the basis for their exercise rehabilitation.