OBJECTIVE To evaluate the cost-utility of iguratimod combined with methotrexate in the treatment of patients with active rheumatoid arthritis （RA） who failed monotherapy with conventional synthetic disease-modifying antirheumatic drugs （csDMARDs）.METHODS A cost-utility analysis was performed. A Markov model was constructed from the perspective of China’s healthcare system with a cycle length of 6 months to simulate the costs and health outcomes [quality-adjusted life years （QALYs）] of iguratimod combined with methotrexate versus different combined csDMARDs regimens over a 30-year time horizon. Efficacy and safety data were synthesized from randomized controlled trials via network meta-analysis. Cost parameters were derived from the Menet Database， published literature and other sources. The discount rate was set at 4.5%， and the willingness-to-pay （WTP） threshold was twice China’s per capita gross domestic product in 2025 （199 330.00 yuan/QALY）. One-way sensitivity analysis， probabilistic sensitivity analysis and scenario analysis were conducted to verify the robustness of the results.RESULTS Compared with methotrexate+sulfasalazine and sulfasalazine+leflunomide， iguratimod+methotrexate was a dominant regimen. Compared with methotrexate+leflunomide， the incremental cost-effectiveness ratio of iguratimod+methotrexate was 60 577.10 yuan/QALY， which was lower than the WTP threshold. Sensitivity analyses and scenario analysis confirmed favorable robustness of the above findings.CONCLUSIONS From the perspective of China’s healthcare system， iguratimod+methotrexate is cost-effective for active RA patients failing csDMARD monotherapy， in comparison with methotrexate+leflunomide， methotrexate+sulfasalazine and sulfasalazine+leflunomide regimens.

ObjectiveTo observe the dynamic changes in heparin-binding protein (HBP), coagulation function indicators, and vascular endothelial injury markers in SD rats with sepsis, analyze the associations among these indicators, and elucidate the regulatory role of HBP in sepsis-associated coagulation disorders. MethodsEighteen specific pathogen-free (SPF) male SD rats aged 8–12 weeks were selected to establish a sepsis model using cecal ligation and puncture (CLP). Blood samples were collected from the heart at 0 hours before modeling and at 3, 6, and 9 hours post-modeling. Thromboelastography (TEG) with standard and heparinase cups was used to determine the difference in reaction time (R value) between the two cups (ΔR), thereby evaluating coagulation function and the endogenous heparin effect. Plasma levels of HBP, heparan sulfate (HS), syndecan-1 (SDC-1), and thrombomodulin (TM) were measured by enzyme-linked immunosorbent assay (ELISA). Samples with ΔR≥2 min were grouped as the ΔR≥2 min group, while those with ΔR<2 min were grouped as the ΔR<2 min group. Correlation and receiver operating characteristic (ROC) curve analyses were performed to evaluate the relationship between HBP and various indicators, as well as its predictive efficacy for ΔR values. ResultsΔR, HS, SDC-1 and HBP significantly increased after modeling compared with 0 hours (P<0.01). The HS, SDC-1, and HBP levels in the ΔR≥2 min group were significantly higher than those in the ΔR<2 min group (P<0.05 or P<0.01). HBP showed a significant positive correlation with ΔR and HS (P<0.05), while ΔR was significantly positively correlated with HS (r=0.799, P<0.01) and weakly positively correlated with SDC-1 (r=0.289, P<0.05). HS, HBP, and SDC-1 demonstrated significant predictive value for ΔR≥2 min (P<0.01). ConclusionIn the early stages of sepsis, the release of HS-like anticoagulant substances from the glycocalyx following its degradation can lead to coagulation disorders, while HBP can reflect the pathological process and play an important regulatory role in the occurrence and development of sepsis-related coagulation disorders.

ObjectiveTo construct a machine learning prediction model for grading blood stasis syndrome （BSS） in non-traumatic osteonecrosis of the femoral head （NONFH） based on magnetic resonance imaging （MRI） features， and to elucidate the dynamic evolution of blood stasis-related imaging features across the phlegm-stasis obstructing the collaterals syndrome， meridian obstruction syndrome， and liver-kidney depletion syndrome of NONFH. MethodsA total of 100 patients with NONFH were retrospectively enrolled and randomly divided into a training set （70 cases） and an internal validation set （30 cases） at a ratio of 7∶3. Patients were stratified into mild， moderate， and severe BSS groups. Macroscopic MRI features including degree of bone marrow edema， necrosis location， and necrosis area， and radiomic features including first-order， texture， and wavelet transform features were extracted. Optimal features were selected through correlation analysis and least absolute shrinkage and selection operator （LASSO） regression. Random forest algorithms were then used to construct a macroscopic imaging model， a radiomics model， and a combined model. An additional 30 NONFH patients enrolled prospectively served as an external validation set. Model performance was evaluated by the area under the receiver operating characteristic curve （AUC）， and the dynamic evolution of BSS was revealed by integrating model predictions with changes in imaging features. ResultsAmong the 100 patients， 10 had mild， 41 moderate， and 49 severe BSS. Among macroscopic features， the degree of bone marrow edema was significantly positively correlated with BSS grade （r=0.71， P＜0.05）， whereas necrosis location and area showed no correlation （P＞0.05）. Among radiomic features， wavelet-LHL gray-level co-occurrence matrix correlation， wavelet-HHL first-order mean， and wavelet-LLH gray-level run-length matrix gray-level non-uniformity were most strongly associated with BSS grade. Internal validation showed that the accuracy of the combined model （0.75） was superior to that of the macroscopic model （0.73） and the radiomics model （0.62）. External validation demonstrated that the combined model performed best， achieving an AUC of 0.884 （95%CI： 0.741-1.000）， with prediction accuracies of 0.86 and 0.90 for moderate and severe BSS， respectively， significantly outperforming the macroscopic model （AUC=0.737， 95%CI： 0.526-0.949）. Applying this model to the external validation set revealed that patients with meridian obstruction syndrome had the highest proportion of severe BSS （80.0%）， significantly higher than those with phlegm-stasis obstructing the collaterals syndrome （30.0%， 3/10） and liver-kidney depletion syndrome （10.0%， 1/10， P＜0.05）. The wavelet-LLH gray-level run-length matrix gray-level non-uniformity mean exhibited a "low-high-low" distribution （phlegm-stasis obstructing the collaterals syndrome， 1121.41±500.34； meridian obstruction syndrome， 1163.46±418.80； liver-kidney depletion syndrome， 1040.14±272.94； P＜0.05）. ConclusionThe combined macroscopic imaging-radiomics model for BSS in NONFH revealed a "mild-severe-mild" dynamic evolution across the phlegm-stasis obstructing the collaterals， meridian obstruction， and liver-kidney depletion syndromes from an imaging perspective.

This article retrospectively analyzed the clinical data of three recipients who developed acute antibody mediated rejection (AMR) after receiving different courses of immunotherapy prior to liver transplantation for hepatocellular carcinoma. It focused on their diagnostic and therapeutic processes, including the immunosuppressive induction regimen [rabbit anti-human thymocyte globulin (rATG) + methylprednisolone] , postoperative liver function changes, diagnostic methods for acute AMR (such as allograft liver biopsy, panel reactive antibody testing, and donor-specific antibody testing) , and the combination treatment strategies used (rATG, rituximab, intravenous immunoglobulin, and plasma exchange). The aim of this article is to summarize the clinical characteristics, diagnosis, and treatment experiences of acute AMR occurring after liver transplantation in patients with liver cancer who had received immunotherapy, explore the potential risks involved, and provide a reference for clinicians in managing such cases.

Aim To investigate the effects of the fangchinoline derivative LYY-32 on the biological prop-erties of the BLM642-1290 DNA helicase,in order to lay a foundation for further research on its antitumor activity.Methods Fluorescence polarization assay,malachite green-phosphate and ammonium molybdate colorime-try,and fluorescein-labeled DNA gel electrophoresis experiments were conducted to study the effects of fangchinoline derivative LYY-32 on the DNA binding activity,ATPase activity,and DNA unwinding activity of BLM642-1290 DNA helicase.The effects of LYY-32 on the DNA unwinding activity of DNA helicase in cells were studied using fluorescent techniques and time-lapse microscopy.Ultraviolet spectral scanning was used to investigate the effects of LYY-32 on the confor-mation of the BLM642-1290 DNA helicase.Results At a concentration of 10 μmol·L-1,the inhibition rate of LYY-32 on BLM642-1290 DNA helicase binding to dsDNA was 53.17％.At a concentration of 5 μmol·L-1,the inhibition rate of LYY-32 on BLM642-1290 DNA helicase binding to ssDNA was 88.49％.The inhibition rate of LYY-32 on the ATPase activity of BLM642-1290 DNA he-licase was 89.3％at a concentration of 50 μmol·L-1.When the concentration of LYY-32 exceeded 5μmol·L-1,its inhibition rate on the DNA unwinding activity of BLM642-1290 DNA helicase was 100％.LYY-32 also significantly inhibited the DNA unwinding ac-tivity of DNA helicase in cells.However,LYY-32 had no effect on the conformation of BLM642-1290 DNA heli-case.Conclusion The DNA binding activity,AT-Pase activity,and DNA unwinding activity of BLM642-1290 DNA helicase could be significantly inhibi-ted by the fangchinoline derivative LYY-32.

Objective:To investigate whether the highly expressed chemokine ligand 17(CCL17)in cervical cancer(CC)pro-motes the progression of CC through M2 macrophage polarization.Methods:The effect of CCL17 on the expression of IL-27 in CC cell line was detected by flow cytometry and ELISA.The effects of CCL17 and IL-27 on proliferation and differentiation of U937 cells were analyzed.The co-culture model of macrophages and CC cells were established to detect the effects of CCL17 on the proliferation of U937 and CC cells.Results:The CC cells secreted significantly higher levels of IL-27 after stimulation with CCL17.In addition,IL-27 but not CCL17 significantly upregulated interleukin 27 receptor(IL-27R,consisted of WSX-1 and GP130)on U937 cells.IL-27 de-rived from CC cells can promote the proliferation of U937 cells and induce the polarization of M2 macrophages.In the co-culture sys-tem,the level of IL-27 secreted by CC cells stimulated by CCL17 was significantly increased,and both CCL17 and IL-27 promoted the proliferation of CC and U937 cells,and the effect of CCL17 was partially reversed by αIL-27.Conclusion:CCL17 promotes the proliferation of macrophages and induces M2 polarization by stimulating CC cells to secrete IL-27,thereby enhancing the crosstalk be-tween CC cells and macrophages.Eventually,CCL17 participates in the malignant evolution of CC.

Objective To design and synthesize PROTAC degraders targeting the SARS-CoV-2 main protease （M^pro）based on PROTAC technology. Methods Compound 3w was used as the M^pro ligand, and the indole N atom in the solvent-exposed region was selected as the linker attachment site. A series of M^pro PROTACs were designed and synthesized by conjugating compound 3w with the CRBN ligand pomalidomide through alkane linkers of different lengths. The structures of the target compounds were confirmed by ¹H NMR, ¹³C NMR, and HRMS. Western Blot analysis was employed to evaluate their degradation activity and explore its mechanism in M^pro-HEK-293T cells. Results Four novel M^pro PROTACs（A1-A4）were successfully synthesized. The most potent compound A4 demonstrated M^pro degradation activity with a DC₅₀ value of 5.2 μmol/L, and its degradation mechanism was validated. Conclusion A novel class of M^pro PROTAC degraders were successfully designed and synthesized, and their protein degradation capability and mechanism of action were demonstrated. These results provided lead compounds for the research and development of antiviral degraders against SARS-CoV-2.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Colorectal cancer （CRC） ranks as the second leading cause of cancer death worldwide. Although preventive colonoscopy screening has improved the survival rate of CRC patients in the past few years， there are still many patients diagnosed after symptoms appear. The surgery for CRC carries high risks and high recurrence， and ideal therapies remain to be developed. The Janus kinase/signal transducer and activator of transcription （JAK/STAT） signaling pathway has become a focus of research due to its central role in cellular activities. As a classic oncogenic pathway， the JAK/STAT signaling pathway offers new possibilities for diagnosing and treating various malignancies， and it paves a new way for developing therapies for CRC. This pathway not only participates in basic cellular processes， such as proliferation， differentiation， and apoptosis but also plays a crucial role in immune responses and inflammation. Abnormal activation of the JAK/STAT signaling pathway is closely related to the occurrence and development of CRC. Studies have shown that the active components and compound prescriptions of traditional Chinese medicine （TCM） can inhibit the proliferation， invasion， migration， and angiogenesis while promoting the apoptosis and autophagy of CRC cells by interfering with the JAK/STAT signaling pathway. Furthermore， this pathway may also play a role in regulating the sensitivity of tumor cells to chemotherapy and radiotherapy， thus influencing the effectiveness of tumor treatment and impeding the progression of CRC. In recent years， research results have been updated rapidly， and previous literature summaries have failed to incorporate the latest findings， creating obstacles to accessing current literature. Therefore， this article supplements and summarizes information from the definition of the JAK/STAT pathway， association of this pathway with CRC， and TCM intervention of CRC. This review aims to provide references for future development of molecular biology regarding CRC and the research and development of new drugs.

Objective To investigate the impact of dietary protein intake on the prevalence of type 2 diabetes in adult residents, and to provide a reference for formulating diabetes prevention and control measures. Methods The research was based on cross-sectional survey data from the Nutrition and Health Follow-up Study of Chinese Residents in Chongqing (2021). Energy and nutrient intake was calculated in combination with the Chinese food composition table. Multivariate logistic regression was used to analyze the association between dietary protein and diabetes, and then restricted cubic spline regression (RCS) was used to analyze the dose-response relationship between dietary protein intake and the development of diabetes. Results Among the 1 415 adult residents, dietary intake of total protein, animal protein, and plant protein was 69.69g/d, 26.26g/d, and 43.43g/d, respectively. The ratio of protein to energy supply was 14.31%, and the prevalence of diabetes was 18.02%. Comparing with the residents in the first percentile of total dietary protein intake, the multivariable-adjusted odds ratios of those in the second and third percentile were 1.754 and 2.453 respectively. Comparing the residents in the third percentile with those in the first percentile, the multivariable-adjusted odds ratios of diabetes were 1.592 for protein energy supply ratio, and 1.558 for animal protein intake. Conclusion High protein intake, high protein energy supply ratio and high animal protein intake may increase the risk of diabetes, and different types of protein may have different effects on diabetes.