OBJECTIVE To evaluate the cost-effectiveness of iruplinalkib for ALK-positive non-small cell lung cancer （NSCLC） patients who had not previously received ALK-tyrosine kinase inhibitors （TKIs） from the perspective of the Chinese healthcare system. METHODS Based on the INSPIRE clinical trial， a three-health state partitioned survival model was developed to simulate the progression of disease， with model cycle of 3 weeks and a life-year time range of 15 years； the discount rate was 5%. For the treatment of ALK-positive advanced NSCLC， total cost， quality-adjusted life year （QALY）， and incremental cost- effectiveness ratio （ICER） were compared between iruplinalkib and crizotinib； using 1-3 times China’s per capita gross domestic product （GDP） （89 358-268 074 yuan） in 2023 as the willingness-to-pay （WTP） threshold， the cost-effectiveness of two regimens were compared. The sensitivity analysis and scenario analysis （altering the distribution of survival curves， utility values） were conducted to assess model robustness. RESULTS Compared with the crizotinib regimen， the ICER for the iruplinalkib regimen was 194 412.74 yuan/QALY， which was below the WTP threshold of three times China’s per capita GDP in 2023 yuan）. The results under the scenario of altering the survival curve distribution were consistent with the base case analysis. However， after increasing the utility value of the disease progression state， the ICER exceeded the WTP threshold， and iruplinalkib no longer had a cost-effective advantage. The results of the one-way sensitivity analysis indicated that the cost of iruplinalkib and the utility values of disease progression states had a significant impact on the ICER. The probabilistic sensitivity analysis confirmed the robustness of the base case analysis results. CONCLUSIONS From the perspective of China’s healthcare system， compared with crizotinib regimen， the therapy with iruplinalkib is cost-effective for ALK-positive NSCLC patients who have not previously received ALK-TKIs.

BACKGROUND: Inflammation plays a critical role in severe cerebral venous thrombosis (CVT) pathogenesis, but the benefits of anti-inflammatory therapies remain unclear. This study aimed to investigate the association between steroid therapy combined with anticoagulation and the prognosis of acute/subacute severe CVT patients. METHODS: A prospective cohort study enrolled patients with acute/subacute severe CVT at Xuanwu Hospital (July 2020-January 2024). Patients were allocated into steroid and non-steroid groups based on the treatment they received. Functional outcomes (modified Rankin scale [mRS]) were evaluated at admission, discharge, and 6 months after discharge. Serum high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), cerebrospinal fluid (CSF) IL-6, and intracranial pressure were measured at admission and discharge in the steroid group. Fundoscopic Frisén grades were assessed at admission and 6 months after discharge. Univariate and multivariate logistic regression were used to evaluat associations between steroid use and favorable outcomes (mRS ≤2) at the 6-month follow-up. Paired tests assessed changes in hs-CRP and other variables before and after treatment, and Spearman's correlations were used to analyze relationships between these changes and functional improvements. RESULTS: A total of 107 and 58 patients in the steroid and non-steroid groups, respectively, were included in the analysis. Compared with the non-steroid group, the steroid group had a higher likelihood of achieving an mRS score of 0-2 (93.5% vs . 82.5%, odds ratio [OR] = 2.98, P  = 0.037) at the 6-month follow-up. After adjusting for confounding factors, the result remained consistent. Pulsed steroid therapy did not increase mortality during hospitalization or follow-up, nor did it lead to severe steroid-related complications (all P  >0.05). Patients in the steroid group showed a significant reduction in serum hs-CRP, IL-6, CSF IL-6, and intracranial pressure at discharge compared to at admission, as well as a significant reduction in the fundoscopic Frisén grade at the 6-month follow-up compare to at admission (all P  <0.001). A reduction in serum inflammatory marker levels during hospitalization positively correlated with improvements in functional outcomes ( P  <0.05). CONCLUSION: Short-term steroid use may be an effective and safe adjuvant therapy for acute/subacute severe CVT when used alongside standard anticoagulant treatments, which are likely due to suppression of the inflammatory response. However, these findings require further validation in randomized controlled trials. TRAIL REGISTRATION ClinicalTrials.gov , NCT05990894.
Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Anticoagulants/therapeutic use* ; C-Reactive Protein/metabolism* ; Interleukin-6/metabolism* ; Intracranial Thrombosis/drug therapy* ; Prospective Studies ; Steroids/therapeutic use* ; Venous Thrombosis/drug therapy*

Cells and exosomes derived from them are extensively used as biological carrier systems. Cells demonstrate superior targeting specificity and prolonged circulation facilitated by their rich array of surface proteins, while exosomes, due to their small size, cross barriers and penetrate tumors efficiently. However, challenges remain, cells' large size restricts tissue penetration, and exosomes have limited targeting accuracy and short circulation times. To address these challenges, we developed a novel concept termed exosomal spheres. This approach involved incorporating platelet-derived exosomes shielded with phosphatidylserine (PS) and linked via pH-sensitive bonds for drug delivery applications. The study demonstrated that, compared with exosomes, the exosomal spheres improved blood circulation through the upregulation of CD47 expression and shielding of phosphatidylserine, thereby minimizing immune clearance. Moreover, the increased expression of P-selectin promoted adhesion to circulating tumor cells, thereby enhancing targeting efficiency. Upon reaching the tumor site, the hydrazone bonds of exosome spheres were protonated in the acidic tumor microenvironment, leading to disintegration into uniform-sized exosomes capable of deeper tumor penetration compared to platelets. These findings suggested that exosome spheres addressed the challenges and offered significant potential for efficient and precise drug delivery.

With the rapid advancement of vaccines, the research and application of vaccine adjuvants have garnered significant attention. Despite the development of numerous vaccine adjuvants, their applications in human vaccines remain limited due to either insufficient efficacy or severe side effects. Consequently, there is growing interest in developing bioactive compounds derived from traditional Chinese medicines (TCMs) as vaccine adjuvants, owing to their natural biocompatibility, diversity, and safety. Here, we systematically review the current application status and potential value of TCM-based bioactive compounds in vaccine adjuvants. Firstly, we elaborate on the types and characteristics of active ingredients, such as polysaccharides, saponins, flavonoids, acids, and alkaloids. The mechanisms by which these compounds function as vaccine adjuvants are then discussed, including their roles in enhancing humoral immunity, cellular immunity, and relieving the immune suppression in the microenvironment. Additionally, we summarize the current strategies for structural modification and platform optimization to adapt to different application scenarios. Finally, we offer insights into the future development directions for these potential adjuvants, highlighting research priorities, technical approaches, and application prospects. In conclusion, natural vaccine adjuvants derived from TCMs present broad application prospects and hold promise for future vaccine development.

In recent years， the potential anti-tumor effects of metformin have attracted widespread attention in the field of cancer treatment. This article summarizes the research progress of metformin in the treatment of malignant tumors，finding its potential application in the treatment of malignant tumors in the digestive system （biliary tract cancer，gastric cancer，esophagus cancer，colorectal cancer，pancreatic cancer，liver cancer） and reproductive system （prostate cancer，ovarian cancer，breast cancer， cervical cancer），non-small cell lung cancer，renal cell carcinoma，and melanoma. Metformin can inhibit the proliferation of tumor cells and extend the overall survival of patients. Its mechanisms of action include，but are not limited to，inhibiting the activity of mitochondrial complex Ⅰ，activating adenosine monophosphate-activated protein kinase/p53 signaling pathway，and blocking the cell cycle. Additionally，the combined use of metformin with chemotherapy drugs has shown potential for reducing toxicity and enhancing efficacy. It can enhance the sensitivity of biliary tract cancer，ovarian cancer，and melanoma cells to chemotherapy drugs， improve the drug resistance of gastric and colorectal cancer cells to chemotherapy，and reduce the toxic reactions of breast cancer patients during chemotherapy. Metformin is also used as an immunomodulator，applied in the immunotherapy of patients with esophagus cancer，colorectal cancer，cervical cancer，non-small cell lung cancer，and melanoma.

Objective·To compare the prognostic effects of radical resection of esophageal cancer,concurrent chemoradiotherapy and simple follow-up observation on the prognosis of patients with T1b invasion of superficial esophageal squamous cell carcinoma after endoscopic submucosal dissection(ESD).Methods·From May 2016 to May 2021,the clinical data of 67 patients with esophageal squamous cell carcinoma who were pathologically confirmed as pT1b after ESD and treated in Shanghai Chest Hospital were retrospectively analyzed.According to the additional treatment after ESD,the patients were divided into additional surgery group(S group),chemoradio-therapy group(CRT group)and observation group(O group).χ2 test was used to compare the clinical baseline data and pathological information of the three groups of patients.The Kaplan-Meier survival curve and log-rank test were used to compare the disease free survival(DFS)and recurrence free survival(RFS)of the three groups of patients,and the Cox proportional hazards regression model was used on DFS and RFS by univariate and multivariate analysis.Results·Among all 67 patients,there were 23 cases in the S group,19 cases in the CRT group,and 25 cases in the O group.There was no significant difference in age(P=0.080),gender(P=0.078),tumor length(P=0.485),tumor location(P=0.655),lesion circumferential ratio(P= 0.310),histological grading(P=0.084),depth of tumor invasion(P=0.066)and lymphovascular invasion(P=0.279)among the three groups.During(42.6±16.7)months of follow-up,tumor recurrence was observed in 10 cases(14.9%),including 6 patients(60%)with local recurrence,2 patients(20%)with regional lymph recurrence and 2 patients(20%)with distant metastasis.The median recurrence time of group S,group CRT,and group O was 40.1,36.6,and 22.1 months,and the 3-year DFSs were 100%,89.5%,and 74.5%(P-trend=0.040).Multivariate Cox analysis showed that additional esophagectomy was the key to improving independent protective factors of RFS(HR=0.097,95%CI 0.010?0.956,P=0.046).Conclusion·For patients with superficial esophageal squamous cell carcinoma confirmed as pT1b after ESD,additional surgery can significantly reduce the possibility of long-term recurrence.

Objective To screen out the biomarkers linked to prognosis of breast invasive carcinoma based on the analysis of transcriptome data by random forest(RF),extreme gradient boosting(XGBoost),light gradient boosting machine(LightGBM),and categorical boosting(CatBoost).Methods We obtained the ex-pression data of breast invasive carcinoma from The Cancer Genome Atlas and employed DESeq2,t-test,and Cox univariate analysis to identify the differentially expressed protein-coding genes associated with survival prog-nosis in human breast invasive carcinoma samples.Furthermore,RF,XGBoost,LightGBM,and CatBoost mod-els were established to mine the protein-coding gene markers related to the prognosis of breast invasive cancer and the model performance was compared.The expression data of breast cancer from the Gene Expression Omnibus was used for validation.Results A total of 151 differentially expressed protein-coding genes related to survival prog-nosis were screened out.The machine learning model established with C3orf80,UGP2,and SPC25 demonstrated the best performance.Conclusions Three protein-coding genes(UGP2,C3orf80,and SPC25)were screened out to identify breast invasive carcinoma.This study provides a new direction for the treatment and diagnosis of breast invasive carcinoma.

Objective:To observe the effect of metformin on intestinal metabolites and its protective effect on lung injury in an elderly sepsis rat.Methods:SD rats were fed at the Animal Laboratory Center of Zhengzhou University, fourteen elderly SD rats were randomly divided into three groups: sham surgery (age-Sham, AgS group, n=4), cecal ligation and perforation induced sepsis (age-Cecal ligation and puncture, AgCLP group, n=5), and oral administration of metformin (100 mg/kg) after 1 h of CLP treatment (age-Metformin, AgMET group, n=5). Collected rat feces 24 h after modeling, and analyzed the composition and inter group differences of metabolites in the feces using liquid chromatography tandem mass spectrometry non targeted metabolomics. Collected rat lung tissues and detected the expression levels of inflammation related genes and pathological changes in the tissue. The visualization of metabolic changes between groups were presented using orthogonal partial least squares discriminant analysis, heatmaps, and unsupervised principal component analysis, respectively. MetaboAnalyst 3.0 was used to evaluate the Pathway analysis of metabolites, and this software was based on the KEGG database and the human metabolome database. Results:The expressions of CCL4 ( F=203.00, P<0.001), CXCL1( F=65.69, P<0.001), IL-6 ( F=38.94, P<0.002), TNF-α ( F=14.85, P=0.005) between two groups of rats were significantly different (all P<0.05). However, there was no significant difference in CCL2 expression between AgCLP group and AgMET group. Furthermore, compared with the AgS group, the relative intensities of 17 metabolites such as 7-methylxanthine, N-Arachidonylglycine and Manolide in AgCLP group were significantly increased, whereas the 9 metabolites such as Phenazone, Gly-Phe and Valyproline were significantly decreased, and metformin treatment could reverse these changes of the above metabolites. Correlation analysis showed that the IL-6 and TNF-α levels were positively correlated with the relative strength of 7-Methylxanthine, N-Arachidonylglycine and other metabolites, but negatively correlated with the Phenazone and Gly-Phe. CCL4 and CXCL1 were positively correlated with Manolide, but negatively correlated with Valyproline. Conclusion:The results of this study showed that metformin improved sepsis induced acute lung injury and regulates the host intestinal metabolites, which might provide a potential and effective treatment for elderly sepsis induced acute lung injury.

Objective:To explore the effects of hinokiol on the cell cyle and apoptosis of CNE1 nasopharyngeal carcinoma cells and the relevant molecular mechanism.Methods:The CNE1 cells were cultured in vitro and incubated with different concentrations of honokiol, and the cells were divided into blank control group, 10 μmol/L, 20 μmol/L and 40 μmol/L hinokiol treatment groups, and 10 μg/ml cisplatin group. Cell viability was determined by methylthiazolyldiphenyl- tetrazolium bromide (MTT) method, the cell cycle distribution was detected by flow cytometry, mitochondrial membrane potential was detected by mitochondrial membrane potential test kit, apoptosis was detected by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) method, and the proteins expression of proliferating cell nuclear antigen (PCNA) and G 1/S specific cyclin D1 (cyclin D1) were detected by immunoblotting. RNA-Seq was conducted in the hinokiol-treated cells. The mRNA expression of yes-associated protein delta (YAP) was detected by quantitative reverse transcription polymerase chain reaction (RT-qPCR). The proteins expression of phosphor-YAP (p-YAP) and nuclear YAP were detected by immunoblotting, the nuclear distribution of YAP protein was detected by immunofluorescence in the cells with or without treated with the mammalian STE20-like kinase 1/2 (MST1/2) inhibitor (XMU-MP-1), hinokiol, and XMU-MP-1+hinokiol. Statistical analysis of the data was conducted using GraphPad Prism 8.0 software. Resluts Compared with the control group, the cell viablity of CNE1 cells, the levels of mitochondrial membrane potential, the proteins expression of PCNA and cyclin D1 in hinokiol treatment groups were markedly decreased (all P values<0.05), while the proportion of G 0/G 1 phase cells and the ratio of TUNEL-positive cells were significantly increased (both P values<0.05). Transcriptome analysis showed that differential genes were mainly enriched in Wnt signaling pathway, tumor necrosis factor pathway, and Hippo signaling pathway. The mRNA level of YAP and the protein expression of YAP in the nucleus were decreased and the level of p-YAP protein was increased in cells treated with hinokiol, which were significantly different from control group (all P values<0.05). Compared with the hinokiol group, XMU-MP-1+hinokiol groups showed the decrease of p-YAP protein expression (1.157±0.076 vs 0.479±0.038, t=37.120, P<0.05), the increase of YAP protein expression in the nucleus (0.143±0.012 vs 0.425±0.031, t=29.181, P<0.05), the reduced proportion of cells in G 0/G 1 phase [(72.494±3.309)% vs (58.747±2.865)%, t=17.265, P<0.05], and the decrease of apoptosis ratio [(53.158±3.376)% vs (29.621±2.713)%, t=28.584, P<0.05]. Conclusion:Hinokiol can arrest the cell cycle and induce the cell apoptosis of CNE1 cells via Hippo/YAP signaling pathway.