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.

ObjectiveTo investigate the effects of rhizosphere organic acids secreted by the roots of Salvia miltiorrhiza on continuous cropping obstacles. MethodsThe mixed solution of organic acids in the rhizosphere of S. miltiorrhiza in continuous cropping and rotation cropping was added to the hairy roots subcultured for 21 days， and samples were collected on days 0， 2， 4， 6， 8， and 10. The changes of biomass， effective components， primary metabolites， secondary metabolites， antioxidant enzymes， and hormones in hairy roots of S. miltiorrhiza were observed and determined. ResultsCompared with the rotation cropping group and the blank control group， the simulation of organic acid secretion from the roots of S. miltiorrhiza had a significant inhibitory effect on the growth of hairy roots and decreased the content of effective components as well as total sugar and total protein in primary metabolites. Compared with the blank control group， the rotation cropping group and the continuous cropping group showed total sugar and total protein content decreases of 33.9% and 5.1%， respectively. On the other hand， the secretion of organic acids from S. miltiorrhiza roots significantly promoted the accumulation of total phenolic acids and total tanshinone， which showed increases of 14.6% and 1.6%， respectively， in continuous cropping group and rotation cropping group compared with the blank control group. ConclusionThe organic acid environment under continuous cropping significantly inhibited the growth of hairy roots and the accumulation of primary metabolites， while promoting the synthesis and accumulation of secondary metabolites of S. miltiorrhiza.

Acupotomy therapy demonstrates the definite clinical efficacy on knee osteoarthritis (KOA). After reviewing systematically the mechanism studies on acupotomy for KOA over the past 5 years, It is revealed that acupotomy synergistically intervenes in the pathological progression of KOA through multi-target approaches, such as regulating cartilage homeostasis, restoring skeletal muscle function, alleviating synovial inflammatory responses, remodeling subchondral bone, and neuromodulation. But the current research still limits to single-tissue phenotypic observation, and is insufficiency in the in-depth exploration of multi-tissue synergistic interactions and molecular upstream-downstream regulatory mechanisms. Future studies should focus on the inheritance and innovation of acupotomy theory, and integrating multi-omics analytical technologies, artificial intelligence, and novel biochemical detection methods. The mechanism research targets on the interaction mechanisms among tissues, direct effects of acupotomy, immune-inflammatory regulatory mechanisms, and analgesic mechanisms, so as to comprehensively elucidate the therapeutic mechanism of acupotomy for KOA.
Humans ; Acupuncture Therapy ; Osteoarthritis, Knee/genetics* ; Animals

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.

Diabetic retinopathy, a prevalent and vision-threatening microvascular complication of diabetes mellitus, is the leading cause of blindness among middle-aged and elderly individuals. Natural diterpenoids isolated from Siegesbeckia pubescens demonstrate potent anti-inflammatory properties. This study aimed to identify novel bioactive diterpenoids from S. pubescens and investigate their effects on oxidative stress and inflammatory responses in diabetic retinopathy, both in vitro and in vivo. Three new ent-pimarane-type diterpenoids (1-3) and six known compounds (4-9) were isolated from the aerial parts of S. pubescens. Their structures were elucidated through spectroscopic data interpretation, and absolute configurations were determined by comparing calculated and experimental electronic circular dichroism (ECD) spectra. Among these compounds, 14β,16-epoxy-ent-3β,15α,19-trihydroxypimar-7-ene (5) exhibited the most potent protective effect against high glucose and interleukin-1β (IL-1β)-stimulated human retinal endothelial cells. Mechanistically, compound 5 promoted endothelial cell survival while ameliorating oxidative stress and inflammatory response in diabetic retinopathy, both in vivo and in vitro. These findings not only suggest that diterpenoids such as compound 5 are important anti-inflammatory constituents in S. pubescens, but also indicate that compound 5 may serve as a lead compound for preventing or treating vascular complications associated with diabetic retinopathy.
Diabetic Retinopathy/metabolism* ; Humans ; Oxidative Stress/drug effects* ; Animals ; Diterpenes, Kaurane/administration & dosage* ; Asteraceae/chemistry* ; Male ; Endothelial Cells/drug effects* ; Abietanes/administration & dosage* ; Molecular Structure ; Mice ; Anti-Inflammatory Agents/chemistry* ; Plant Extracts/chemistry* ; Mice, Inbred C57BL

Objective: To screen and identify the key active molecules, signaling pathways, and therapeutic targets of Shuxuening (SXN) injection for treating liver cirrhosis (LC) and to evaluate its therapeutic potential using a mouse model. Methods: Target genes of SXN and LC were retrieved from public databases, and enrichment analysis was performed. A protein–protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), and hub genes were identified using Molecular Complex Detection (MCODE). LC was induced in rats and mice via intraperitoneal injections of diethylnitrosamine and carbon tetrachloride (CCl4) for 12 weeks. Starting at week 7, SXN was administered intraperitoneally to the mice in the treatment group. Serum and liver tissues of the mice were collected for the detection of indicators, pathological staining, and expression analysis of hub targets using quantitative real-time polymerase chain reaction (qRT-PCR). Results: We identified 368 overlapping genes (OLGs) between SXN and LC targets. These OLGs were subsequently used to build a PPI network and to screen for hub genes. Enrichment analysis showed that these genes were associated with cancer-related pathways, including phosphoinositide-3-kinase/Akt and mitogen-activated protein kinase signaling and various cellular processes, such as responses to chemicals and metabolic regulation. In vivo experiments demonstrated that SXN treatment significantly improved liver function and pathology in CCl4-induced LC mice by reducing inflammation and collagen deposition. Furthermore, qRT-PCR demonstrated that SXN regulated the expression of MAPK8, AR and CASP3 in the livers of LC mice. Conclusion This study highlighted the therapeutic effects of SXN in alleviating LC using both bioinformatics and experimental methods. The observed effect was associated with modulation of hub gene expression, particularly MAPK8, and CASP3.

Objective:To analyze the breast cancer-related parameters and the ultrasonic features of positive axillary lymph nodes,to discuss the risk factors for axillary lymphnode metastatic burden,and to provide basis for preoperative evaluation of breast cancer patients.Methods:The ultrasonic and clinicopathological data of 574 breast cancer patients with axillary lymph node metastasis confirmed by surgery and pathology were retrospectively analyzed.According to the status of axillary lymphnode metastasis,the patients were divided into low nodal burden(LNB)group(n=283)and high nodal burden(HNB)group(n=291).The affected side,tumor quadrant,distance to skin,maximum diameter,internal echogenicity,shape,margin,calcification,blood supply,posterior echo,lymphnode long diameter,lymphnode short diameter,lymphnode aspect ratio,number of suspicious metastases,intranodal blood supply,lymphnode hilum morphology,age,pathological type,histological grade,molecular subtype,and the expressions of estrogen receptor(ER),progesterone receptor(PR),Ki-67,human epidermal growth factor receptor 2(HER2),and P53 were compared between two groups.Logistic regression was used to analyze the risk factors for axillary lymph node metastatic burden in the breast cancer patients;receiver operating characteristic(ROC)curve and area under the curve(AUC)were used to evaluate the predictive value.Results:The univariate analysis results showed that there were statistically significant differences in tumor quadrant,distance to skin,molecular subtype,HER2 positive expression,lymphnode long diameter,lymph node short diameter,lymph node aspect ratio,number of suspicious metastases,and lymphnode hilum morphology between two groups(P<0.05).The multivariate Logistic regression analysis results showed that tumor located in the upper outer quadrant(OR=0.648,P=0.021),distance to skin<5 mm(OR=0.283,P=0.016),Luminal A(OR=1.564,P=0.044),lymphnode long diameter≥20 mm(OR=2.050,P<0.01),lymphnode short diameter≥8.6 mm(OR=2.430,P<0.01),lymph node aspect ratio<2(OR=1.585,P<0.01),and indistinct lymphnode hilum structure(OR=2.092,P<0.01)were the independent risk factors for axillary lymphnode metastatic burden.The ROC curve analysis results showed that compared with the ultrasonic features of positive axillary lymph nodes,the AUC of the combination of breast cancer-related parameters and ultrasonic features of positive axillary lymphnodes was larger(Z=2.72,P=0.006 5),and it had higher predictive value for axillary lymphnode metastatic burden.Conclusion:The tumor quadrant,distance to skin,molecular subtype,lymphnode long diameter,lymph node short diameter,lymphnode aspect ratio,and lymphnode hilum structure are the independent risk factors for axillary lymphnode metastatic burden,and they have certain predictive value for axillary lymphnode metastatic burden.

Objective To discuss the prediction value of the early efficacy of hepatic arterial infusion chemotherapy(HAIC)in treating stage Ⅱ-Ⅲ hepatocellular carcinoma(HCC).Methods The clinical data of 81 patients with stage Ⅱ-Ⅲ HCC,who received at least 3 times of HAIC at the Nanchang Municipal Central Hospital of China from November 2021 to March 2024,were retrospectively analyzed.CT or MRI was used to compare patient's local tumor response after each treatment cycle.Based on modified Response Evaluation Criteria in Solid Tumors(mRECIST),the curative effects of patients after receiving the first,the second,and the last HAIC treatment were compared between each other.The prediction value of the early efficacy of HAIC in treating patients with stage Ⅱ-Ⅲ HCC was analyzed.Results In the 67 patients,the efficacy of the last time HAIC was equal or similar to that of the first time HAIC,and in the remaining 14 patients the efficacy of the last time HAIC was different from that of the first time HAIC,with an efficacy prediction rate of 82.72％.The efficacy of the last time HAIC was equal or similar to that of the second time HAIC in 71 patients,and in the remaining 10 patients the efficacy of the last time HAIC was different from that of the second time HAIC,with an efficacy prediction rate of 87.65％.Conclusion In treating stage Ⅱ-Ⅲ HCC with HAIC,the early efficacy can be used to predict the final efficacy after completion of the total treatment course.

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 explore the diagnostic value of fetal echocardiography (ECHO) for ventricular septal defect (VSD) and the causes of missed diagnosis and misdiagnosis by analyzing the standard of ECHO sections and image quality.Methods:A retrospective analysis was conducted on 94 VSD fetuses diagnosed by ECHO at Xiangtan Maternal and Child Health Care Hospital from January 2022 to June 2024. Clinical data including the anatomic subtypes, associated anomalies, chromosomal karyotype results, pregnancy outcomes, and neonatal ECHO results were collected and analyzed. Besides, by reviewing the ultrasound images from the institution's ultrasound workstation, a descriptive analysis was conducted on the ECHO section criteria and image quality in the missed and misdiagnosed cases.Results:Among 10 984 fetuses undergoing ECHO, a total of 94 cases of fetal VSD were detected (0.7%), including 45 (48%) isolated VSD and 49 (52%) non-isolated VSD cases. Anatomic distribution revealed perimembranous type predominance (67, 71%), followed by muscular (24, 26%), subarterial types (2, 2%), and perimembranous+muscular type (1, 1%). Among 29 missed diagnosis cases (fetal ECHO-negative but neonatal ECHO-confirmed VSDs), all were isolated VSD, muscular types accounted for 19 (66%), perimembranous types for 8 (27%), and subarterial types for 2 (7%). The causes of missed diagnosis include: technical limitation in 14 cases (48%), restricted cardiac acoustic window in 11 cases (38%), and operator-dependent factors in four cases (14%). All 18 misdiagnosed cases occurred in isolated VSD, with 15 cases of perimembranous and three cases of muscular types. The causes of misdiagnosis include: nine cases due to non-perpendicular beam alignment to perimembranous septum, six cases due to excessively high color flow gain,and three cases due to the misinterpretation of the right ventricular outflow tract flow above the aortic valve as VSD septal perforation blood flow. The sensitivity and specificity of fetal ECHO for diagnosing VSD were 76.42% and 99.83%. Among the 94 cases of fetal VSD, 38 cases (40%) underwent chromosomal karyotype analysis and chromosomal microarray analysis, which identified chromosomal karyotype abnormalities or pathogenic gene variants in 4/16 non-isolated VSDs (all perimembranous), while no anomalies were detected in 22 isolated VSDs. Pregnancy outcomes showed 31 terminations due to associated structural or chromosomal abnormalities versus 63 live births. In the live births, who underwent echocardiography in the neonatal period, 19 cases (30%) showed no VSD and were considered to have undergone spontaneous in utero closure, and persistent defects were found in 44 (70%).Conclusions:Fetal ECHO demonstrates high sensitivity and specificity in the diagnosis of fetal VSD. Critical quality control measures include individualized parameter adjustment and systematic multiplanar continuous scanning to minimize diagnostic errors. Isolated small and medium-sized muscular and perimembranous VSD usually have a good prognosis.