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.

OBJECTIVE To evaluate the cost-effectiveness of toripalimab combined with paclitaxel （albumin binding type） in the treatment of metastatic or recurrent triple-negative breast cancer （TNBC）. METHODS Based on the data of TORCHLIGHT clinical trial， a three-state partitioned survival model including progression-free survival， disease progression， and death was established. The simulation cycle was 21 days， the study duration was 10 years， and the discount rate was 5%. Using quality- adjusted life year （QALY） and cost as output indicators， a cost-effectiveness analysis method was adopted to calculate the incremental cost-effectiveness ratio （ICER） of toripalimab combined with paclitaxel （albumin binding type） versus placebo combined with paclitaxel （albumin binding type）. Using three times the per capita gross domestic product （GDP） of China in 2023 as the willingness-to-pay（WTP） threshold（268 074 yuan/QALY）， the cost-effectiveness of the above two regimens was evaluated， and the sensitivity analysis was conducted. RESULTS ICER of toripalimab combined with paclitaxel （albumin binding type） versus placebo combined with paclitaxel （albumin binding type） in the treatment of Chinese metastatic or recurrent TNBC patients was 176 347.17 yuan/QALY， which was lower than the WTP threshold set in this study， demonstrating the cost-effectiveness of this regimen. The results of the single-factor sensitivity analysis showed that the parameters such as the cost of toripalimab， discount rate， and utility value of the progression-free survival state had a great impact on the ICER. The results of the probabilistic sensitivity analysis indicated that the results of the basic analysis were robust. CONCLUSIONS When three times the per capita GDP of China in 2023 is used as the WTP threshold， compared with the regimen of placebo combined with paclitaxel （albumin binding type）， toripalimab combined with paclitaxel （albumin binding type） is cost-effective in the treatment of metastatic or recurrent TNBC.

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.

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.

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 observe the effects of modified Xuanfuhua Decoction on pain behaviour and spinal cord neuroinflammation mediated by phosphorylated mitogen-activated protein kinase p38 (p38MAPK) signaling pathway in rats with sciatic nerve injury; To analyse the mechanism of its effects.Methods:Totally 108 SD rats were randomly divided into sham-operation group, model group, pregabalin group, decoction low-, medium- and high-dosage groups, with 18 rats in each group. The CCI model was established by ligation of sciatic nerve in other groups except sham-operation group. On the postoperative day, the decoction low-, medium-, high-dosage groups were gavaged with 2.5, 5.0 and 10.0 g/kg of modified Xuanfuhua Decoction concentrate, respectively. The pregabalin group was gavaged with 15 mg/kg of pregabalin. The sham-operation group and the model group were gavaged with equal amounts of saline once/d for 15 days. Pain behavioural assays were performed before, on the 3rd, 7th, 11th and 15th day of administration respectively. The levels of interleukin (IL)-1β, tumour necrosis factor-α (TNF-α), IL-10 were detected by ELISA method. The expressions of Toll-like receptor 4 (TLR4), nuclear factor-κB p65 (NF-κB p65) were detected by immunohistochemistry staining. The phosphorylated p38MAPK (p-p38MAPK) were measured in the spinal cord by Western blot.Results:Compared with the model group, the scores of spontaneous pain in decoction high-dosage group decreased ( P<0.05), the thermal foot shrinkage latency (TWL) was prolonged ( P<0.05), and the mechanical foot shrinkage reflex threshold (MWT) increased ( P<0.05); the levels of IL-1β and TNF-α in spinal cord tissue of decoction low-, medium- and high-dosage groups decreased ( P<0.05), the level of IL-10 increased ( P<0.05), the average gray values of TLR4 and NF-κB p65 in spinal cord decreased ( P<0.05), and the expression of P-P38MAPK protein decreased ( P<0.05). Conclusion:Modified Xuanfuhua Decoction can effectively improve neurogenic pain in CCI rats, and the mechanism may be related to inhibition of p38MAPK-TLR4 signaling pathway activation-mediated spinal cord neuroinflammation.

Objective To explore the correlation between serum glycosylated hemoglobin(HbA1c),lym-phocyte activation gene-3(LAG-3)and thyroid nodules in patients with type 2 diabetes mellitus(T2DM).Methods A total of 120 T2DM patients with thyroid nodules admitted to the Third Hospital of Hebei Medi-cal University from July 2021 to July 2022 were included as the study group,and 100 simple T2DM patients(without thyroid nodules)were included as the control group during the same period.According to the patho-logical examination results of thyroid nodules,the study group was grouped into a benign nodule group(85 ca-ses)and a malignant nodule group(35 cases).Enzyme linked immunosorbent assay was applied to detect the serum LAG-3 level of all study subjects.Fully automated glycated hemoglobin analyzer was applied to detect HbA1c level in all study subjects.Spearman method was applied to analyze the correlation between serum HbA1c,LAG-3,and thyroid imaging report and data system(TI-RADS)scores in patients with T2DM and thyroid nodules.Multivariate Logistic regression was applied to analyze the influencing factors of T2DM with thyroid nodules.Receiver operating characteristic(ROC)curve was applied to analyze the diagnostic value of HbA1c and LAG-3 levels in T2DM with thyroid nodules.Results Compared with the control group,the level of HbA1c in the study group was obviously higher(P<0.05),while the level of LAG-3 was obviously lower(P<0.05).Compared with the benign nodule group,the serum LAG-3 level in the malignant nodule group was obviously lower(P<0.05),while the level of LAG-3 was obviously lower(P<0.05).Spearman analysis showed a positive correlation between HbA1c level and TI-RADS score in T2DM patients with thyroid nod-ules(r=0.378,P<0.001),while the serum LAG-3 level was negatively correlated with TI-RADS score(r=-0.472,P<0.001).The results of multivariate Logistic regression analysis showed that HbA1c was a risk factor for the occurrence of thyroid nodules in T2DM patients(P<0.05),and LAG-3 was a protective factor for the occurrence of thyroid nodules in T2DM patients(P<0.05).The combination of HbA1c and LAG-3 in the diagnosis of T2DM with thyroid nodules was superior to their individual diagnosis(Zcombination-HbA1c=2.542,P=0.011;Zcombination-LAG-3=3.098,P=0.002).Conclusion Patients with T2DM combined with thyroid nodules have obviously lower serum LAG-3 level and higher HbA1c level,and the two are related to the malignancy of thyroid nodules.