Background/Aims: Lenvatinib resistance remains a critical barrier in advanced hepatocellular carcinoma (HCC) therapy. However, the underlying mechanisms and strategies for reversing resistance remain incompletely understood. Methods: Integrated transcriptomics of lenvatinib-resistant patient tumors and an acquired-resistance murine model identified a novel macrophage subpopulation. Functional validation employed CRISPR-SAM screening, conditioned medium (CM) assays, subcutaneous/orthotopic xenografts, patient-derived organoids (PDOs), and patient-derived xenografts (PDXs). Mechanistic studies included ChIP-qPCR, co-immunoprecipitation, and pharmacologic targeting. Clinical relevance was assessed in a retrospective cohort. Results: Resistant HCC exhibited significant enrichment of a COLEC12high TAM subset , which correlated with poor survival and treatment response. These TAMs secreted neuregulin-1 (NRG1) , activating HER2/HER3-AKT signaling in tumor cells to drive cancer stemness and lenvatinib resistance. Mechanistically, in TAMs COLEC12 sequestered STAT1 in the cytoplasm, preventing its phosphorylation, and thereby derepressing STAT3-mediated NRG1 transcription. Depletion of NRG1 reversed the stemness phenotypes and resensitized tumors to lenvatinib both in vitro and in vivo. Clinically, high NRG1 expression predicted an inferior lenvatinib response and shorter survival. Crucially, the bispecific anti-HER2/HER3 antibody zenocutuzumab restored lenvatinib efficacy in PDOs, PDXs, and murine models. Conclusions Our work establishes the COLEC12high TAM/NRG1 axis as a master regulator of therapeutic resistance and identifies NRG1 as a predictive biomarker, providing a clinically actionable strategy to overcome lenvatinib resistance in HCC.

Objective To evaluate the efficacy and safety of the antibody-drug conjugate(ADC)vedotinumab combined with programmed cell death protein 1(PD-1)inhibitors as neoadjuvant therapy in patients with bladder cancer.Methods This retrospective study included 54 patients with bladder cancer who underwent neoadjuvant therapy at the Department of Urology,Peking University First Hospital,between Jun.2023 and Jun.2025.Among them,26 patients received vedotinumab combined with a PD-1 inhibitors,and 28 patients received gemcitabine plus cisplatin(GC).Clinical data,pathological complete response(pCR)rates,and pathological downstaging rates were collected.Treatment-related adverse events(TRAEs)were also assessed in both groups.Results There were no statistically significant differences between the two groups in terms of age,sex,smoking history,tumor grade and stage,depth of invasion,or human epidermal growth factor receptor 2(HER2)expression,indicating good baseline comparability(P＞0.05).The pCR rate in the vedotinumab plus PD-1 inhibitor group was 57.69％(15/26),significantly higher than that of the GC group at 25.00％(7/28)(P＜0.05).Pathological downstaging occurred in 5 patients in either group,with no statistically significant difference(P＞0.05).The main TRAEs in the vedotinumab plus PD-1 inhibitor group were peripheral sensory neuropathy and rash,and no grade 3-4 severe adverse events were observed.In contrast,the GC group predominantly experienced bone marrow suppression,with 4 cases of grade 3-4 adverse events.Conclusion Vedotinumab combined with PD-1 inhibitors demonstrated significantly superior efficacy and favorable safety compared with the conventional GC regimen as neoadjuvant therapy for bladder cancer.

Objective To evaluate the efficacy and safety of the antibody-drug conjugate(ADC)vedotinumab combined with programmed cell death protein 1(PD-1)inhibitors as neoadjuvant therapy in patients with bladder cancer.Methods This retrospective study included 54 patients with bladder cancer who underwent neoadjuvant therapy at the Department of Urology,Peking University First Hospital,between Jun.2023 and Jun.2025.Among them,26 patients received vedotinumab combined with a PD-1 inhibitors,and 28 patients received gemcitabine plus cisplatin(GC).Clinical data,pathological complete response(pCR)rates,and pathological downstaging rates were collected.Treatment-related adverse events(TRAEs)were also assessed in both groups.Results There were no statistically significant differences between the two groups in terms of age,sex,smoking history,tumor grade and stage,depth of invasion,or human epidermal growth factor receptor 2(HER2)expression,indicating good baseline comparability(P＞0.05).The pCR rate in the vedotinumab plus PD-1 inhibitor group was 57.69％(15/26),significantly higher than that of the GC group at 25.00％(7/28)(P＜0.05).Pathological downstaging occurred in 5 patients in either group,with no statistically significant difference(P＞0.05).The main TRAEs in the vedotinumab plus PD-1 inhibitor group were peripheral sensory neuropathy and rash,and no grade 3-4 severe adverse events were observed.In contrast,the GC group predominantly experienced bone marrow suppression,with 4 cases of grade 3-4 adverse events.Conclusion Vedotinumab combined with PD-1 inhibitors demonstrated significantly superior efficacy and favorable safety compared with the conventional GC regimen as neoadjuvant therapy for bladder cancer.

Objective:To verify the performance of the immunoturbidimetric assay(ITMA)kit of detecting oxidized low-density lipoprotein(ox-LDL).Methods:In accordance with the requirements of China National Accreditation Service for Conformity Assessment[(CNAS)-GL037:2019]and the National Health Industry Standards,the precision,trueness,linear range and reportable range of ITMA test kit for ox-LDL were verified on AU5800 fully automatic biochemical analyzer,which were compared with enzyme linked immunosorbent assay(ELISA)of Mercodia comparison reagents for ox-LDL through experiment of methodological comparison.Results:The coefficients of variation(CV)values of within-run and between-run precisions of the two concentration levels of quality control materials in the ITMA reagent kit for ox-LDL were respectively(3.74%,3.36%)and(4.75%,5.49%).The trueness bias of the two concentration levels of standards were respectively 0.46%and 1.78%,and the linear range was(15-120 U/L),which verification regression coefficient was R2=0.999 5 with a slope of 0.989.The maximum dilution multiple was 4 times,and the upper limitation of the clinically reportable range was 240.00 U/L.The manufacturer-provided biological reference interval was 0-64.49 U/L,and the coincidence rate was 100%.The results of hemoglobin,bilirubin,triglycerides,high density lipoprotein(HDL),low density lipoprotein(LDL)and rheumatoid factor were respectively 10 mg/ml,342 μmol/L,10.0 mg/ml,100 mg/dl,200 mg/dl,<200 IU/ml.The stationary duration was there was not influence within 30 h after opened the kit.The correlation between ITMA and ELISA detection methods was excellent(R2=0.9766).The positive and negative coincidence rates of clinical identification were respectively 92.3%and 96.5%.Conclusion:The performances of ox-LDL ITMA test kit based on fully automatic biochemical analyzer can all meet the requirement of clinical application,which shows excellent consistency with the results of ELISA method.

Objective To investigate the early prediction efficacy of adiponectin(ADPN)for gestational diabetes mellitus(GDM),and to explore new indicators for the early diagnosis of GDM and risk models for early prediction.Methods A cohort of 486 pregnant women in early pregnancy(7-12 weeks)was selected from July to November 2023 at Beijing Tongren Hospital,Capital Medical University.According to the diagnostic criteria of GDM recommended by the International Association for the study of Diabetes and Pregnancy Study Group(IADPSG)in 2010,mid-pregnancy pregnancies were divided into GDM group(150 cases)and non-GDM group(336 case).ADPN,insulin(IR),fasting glucose(GLU),and glycated albumin(GA)were collected in early pregnancy,and the homeostatic model assessment of adiponectin(HOMA-AD),homeostatic model assessment of insulin resistance index(HOMA-IR)and hepatic steatosis index(HSI)were calculated.The differences in ADPN,HOMA-AD,and HOMA-IR between the two groups were analyzed and compared,and the value of each type of index in predicting GDM was analyzed with the receiver operating characteristics(ROC)curve,and the predictive risk model was established by combining the relevant indexes.Results There was a statistically significant difference between the GDM and non-GDM groups in ADPN in early pregnancy(P＜0.05).The results of the ROC curve analysis showed that the area under the curve(AUC)of ADPN for early prediction of GDM positivity was 0.723,with a cutoff value 13.38 mg/L.There was a statistically significant difference between the GDM and non-GDM groups in HOMA-AD(P=0.000).The AUC of HOMA-AD for early prediction of GDM was 0.815,with the cutoff value 3.024.Combining GLU,HOMA-AD,HOMA-IR,and HSI in a Logistic regression model improved predictive performance across several metrics,with the final test set of AUC=0.829,accuracy=0.740,sensitivity=0.913,negative predictive value=0.833.Conclusion ADPN levels were reduced in the GDM group compared to the non-GDM group,and the diagnostic efficacy of a single ADPN was poor when it was used for early prediction of the onset of GDM.The HOMA-AD level of the GDM group was lower than that of the non-GDM group,and HOMA-AD was negatively correlated with the disease,which was more effective than ADPN,HOMA-IR,and HIS in the early prediction of GDM.HOMA-AD could be used in combination with these indexes to establish a diagnostic and predictive model to improve the effectiveness of the prediction.

Objective To investigate the early prediction efficacy of adiponectin(ADPN)for gestational diabetes mellitus(GDM),and to explore new indicators for the early diagnosis of GDM and risk models for early prediction.Methods A cohort of 486 pregnant women in early pregnancy(7-12 weeks)was selected from July to November 2023 at Beijing Tongren Hospital,Capital Medical University.According to the diagnostic criteria of GDM recommended by the International Association for the study of Diabetes and Pregnancy Study Group(IADPSG)in 2010,mid-pregnancy pregnancies were divided into GDM group(150 cases)and non-GDM group(336 case).ADPN,insulin(IR),fasting glucose(GLU),and glycated albumin(GA)were collected in early pregnancy,and the homeostatic model assessment of adiponectin(HOMA-AD),homeostatic model assessment of insulin resistance index(HOMA-IR)and hepatic steatosis index(HSI)were calculated.The differences in ADPN,HOMA-AD,and HOMA-IR between the two groups were analyzed and compared,and the value of each type of index in predicting GDM was analyzed with the receiver operating characteristics(ROC)curve,and the predictive risk model was established by combining the relevant indexes.Results There was a statistically significant difference between the GDM and non-GDM groups in ADPN in early pregnancy(P＜0.05).The results of the ROC curve analysis showed that the area under the curve(AUC)of ADPN for early prediction of GDM positivity was 0.723,with a cutoff value 13.38 mg/L.There was a statistically significant difference between the GDM and non-GDM groups in HOMA-AD(P=0.000).The AUC of HOMA-AD for early prediction of GDM was 0.815,with the cutoff value 3.024.Combining GLU,HOMA-AD,HOMA-IR,and HSI in a Logistic regression model improved predictive performance across several metrics,with the final test set of AUC=0.829,accuracy=0.740,sensitivity=0.913,negative predictive value=0.833.Conclusion ADPN levels were reduced in the GDM group compared to the non-GDM group,and the diagnostic efficacy of a single ADPN was poor when it was used for early prediction of the onset of GDM.The HOMA-AD level of the GDM group was lower than that of the non-GDM group,and HOMA-AD was negatively correlated with the disease,which was more effective than ADPN,HOMA-IR,and HIS in the early prediction of GDM.HOMA-AD could be used in combination with these indexes to establish a diagnostic and predictive model to improve the effectiveness of the prediction.

ObjectiveTo explore the mechanism of Jiebiao Qingli decoction （JQD） in treating pneumonia caused by influenza A virus （IAV） infection. MethodsA total of 132 Balb/c mice were randomly assigned into normal control （NC）， model control （IAV）， oseltamivir （OSV， 37.5 mg·kg^-1）， and high-， medium-， low-dose JQD （H-， M-， and L-JQD： 6.05， 3.02， and 1.51 g·kg^-1， respectively） groups. The NC group was treated with normal saline nasal drops， and the other groups were intranasally inoculated with A/Brisbane/02/2018 （H1N1） ［pdm09-like virus （H1N1）］ for the modeling of IAV infection. Two hours post-modeling， the NC and IAV groups were administrated with normal saline by gavage， while other groups received corresponding drugs for 7 d. The body mass， survival status， and deaths of mice were recorded daily during the administration of the drugs. On days 3 and 7， the lung index was measured for mice in each group. Pathological changes in the lung tissue were observed via hematoxylin-eosin staining. Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） was conducted to measure the viral load （IAV-M） and the mRNA levels of Toll-like receptor 7 （TLR7）， p38 mitogen-activated protein kinase （p38 MAPK）， and nuclear factor-kappa B （NF-κB） in the lung tissue. Western blot was employed to measure the protein levels of p38 MAPK and NF-κB. Enzyme-linked immunosorbent assay was used to quantify serum levels of interleukin-2 （IL-2）， interleukin-6 （IL-6）， and tumor necrosis factor-alpha （TNF-α）. ResultsCompared with the NC group， the IAV group showed reduced survival quality and survival days （P<0.01）， lung congestion， inflammatory cell infiltration， elevated lung index （P<0.01）， increased viral load （P<0.01）， upregulated TLR7， p38 MAPK， and NF-κB levels （P<0.05， P<0.01）， decreased IL-2 level （P<0.01）， and elevated IL-6 and TNF-α levels （P<0.01）. Compared with the IAV group， H-JQD prolonged survival days （P<0.05）. All JQD groups alleviated pathological changes in the lung tissue and reduced the lung index （P<0.01）. M-JQD and H-JQD decreased the viral load （P<0.01）. H-JQD downregulated the mRNA levels of TLR7， p38 MAPK， and NF-κB （P<0.05， P<0.01） and the protein levels of p38 MAPK and NF-κB （P<0.01）， increased the serum IL-2 level （P<0.01）， and lowered the IL-6 and TNF-α levels （P<0.05， P<0.01）. M-JQD downregulated the mRNA level of NF-κB （P<0.01） and the protein level of p38 MAPK （P<0.05）， elevated the IL-2 level （P<0.01）， and lowered the TNF-α level （P<0.01）. ConclusionM- and H-JQD can prevent and control IAV infection-induced pneumonia dose-dependently by inhibiting the TLR7/MAPK/NF-κB signaling pathway， increasing IL-2， and reducing excessive secretion of IL-6 and TNF-α.

ObjectiveTo explore the mechanism of Jiebiao Qingli decoction （JQD） in treating pneumonia caused by influenza A virus （IAV） infection. MethodsA total of 132 Balb/c mice were randomly assigned into normal control （NC）， model control （IAV）， oseltamivir （OSV， 37.5 mg·kg^-1）， and high-， medium-， low-dose JQD （H-， M-， and L-JQD： 6.05， 3.02， and 1.51 g·kg^-1， respectively） groups. The NC group was treated with normal saline nasal drops， and the other groups were intranasally inoculated with A/Brisbane/02/2018 （H1N1） ［pdm09-like virus （H1N1）］ for the modeling of IAV infection. Two hours post-modeling， the NC and IAV groups were administrated with normal saline by gavage， while other groups received corresponding drugs for 7 d. The body mass， survival status， and deaths of mice were recorded daily during the administration of the drugs. On days 3 and 7， the lung index was measured for mice in each group. Pathological changes in the lung tissue were observed via hematoxylin-eosin staining. Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） was conducted to measure the viral load （IAV-M） and the mRNA levels of Toll-like receptor 7 （TLR7）， p38 mitogen-activated protein kinase （p38 MAPK）， and nuclear factor-kappa B （NF-κB） in the lung tissue. Western blot was employed to measure the protein levels of p38 MAPK and NF-κB. Enzyme-linked immunosorbent assay was used to quantify serum levels of interleukin-2 （IL-2）， interleukin-6 （IL-6）， and tumor necrosis factor-alpha （TNF-α）. ResultsCompared with the NC group， the IAV group showed reduced survival quality and survival days （P<0.01）， lung congestion， inflammatory cell infiltration， elevated lung index （P<0.01）， increased viral load （P<0.01）， upregulated TLR7， p38 MAPK， and NF-κB levels （P<0.05， P<0.01）， decreased IL-2 level （P<0.01）， and elevated IL-6 and TNF-α levels （P<0.01）. Compared with the IAV group， H-JQD prolonged survival days （P<0.05）. All JQD groups alleviated pathological changes in the lung tissue and reduced the lung index （P<0.01）. M-JQD and H-JQD decreased the viral load （P<0.01）. H-JQD downregulated the mRNA levels of TLR7， p38 MAPK， and NF-κB （P<0.05， P<0.01） and the protein levels of p38 MAPK and NF-κB （P<0.01）， increased the serum IL-2 level （P<0.01）， and lowered the IL-6 and TNF-α levels （P<0.05， P<0.01）. M-JQD downregulated the mRNA level of NF-κB （P<0.01） and the protein level of p38 MAPK （P<0.05）， elevated the IL-2 level （P<0.01）， and lowered the TNF-α level （P<0.01）. ConclusionM- and H-JQD can prevent and control IAV infection-induced pneumonia dose-dependently by inhibiting the TLR7/MAPK/NF-κB signaling pathway， increasing IL-2， and reducing excessive secretion of IL-6 and TNF-α.

Objective:To verify the performance of the immunoturbidimetric assay(ITMA)kit of detecting oxidized low-density lipoprotein(ox-LDL).Methods:In accordance with the requirements of China National Accreditation Service for Conformity Assessment[(CNAS)-GL037:2019]and the National Health Industry Standards,the precision,trueness,linear range and reportable range of ITMA test kit for ox-LDL were verified on AU5800 fully automatic biochemical analyzer,which were compared with enzyme linked immunosorbent assay(ELISA)of Mercodia comparison reagents for ox-LDL through experiment of methodological comparison.Results:The coefficients of variation(CV)values of within-run and between-run precisions of the two concentration levels of quality control materials in the ITMA reagent kit for ox-LDL were respectively(3.74%,3.36%)and(4.75%,5.49%).The trueness bias of the two concentration levels of standards were respectively 0.46%and 1.78%,and the linear range was(15-120 U/L),which verification regression coefficient was R2=0.999 5 with a slope of 0.989.The maximum dilution multiple was 4 times,and the upper limitation of the clinically reportable range was 240.00 U/L.The manufacturer-provided biological reference interval was 0-64.49 U/L,and the coincidence rate was 100%.The results of hemoglobin,bilirubin,triglycerides,high density lipoprotein(HDL),low density lipoprotein(LDL)and rheumatoid factor were respectively 10 mg/ml,342 μmol/L,10.0 mg/ml,100 mg/dl,200 mg/dl,<200 IU/ml.The stationary duration was there was not influence within 30 h after opened the kit.The correlation between ITMA and ELISA detection methods was excellent(R2=0.9766).The positive and negative coincidence rates of clinical identification were respectively 92.3%and 96.5%.Conclusion:The performances of ox-LDL ITMA test kit based on fully automatic biochemical analyzer can all meet the requirement of clinical application,which shows excellent consistency with the results of ELISA method.

Objective:To explore risk factors associated with the live birth in patients with long-acting follicular phase in fresh single embryo transfer cycle and to construct nomogram prediction model for providing a reference for clinical decision-making and individualized treatment.Methods:An assisted reproduction population-based retrospective cohort analysis of the clinical data of 2 795 patients with long-acting follicular phase in fresh single embryo transfer cycle who underwent in vitro fertilization/intracytoplasmic sperm injection and embryo transfer (IVF/ICSI-ET) was performed in the Reproductive Center of the Third Affiliated Hospital of Zhengzhou University from January 2017 to December 2020. These patients were randomly divided into modeling group and validation group according to 3∶1. Univariate and multivariate logistic regression were used to screen potential risk factors for newborn live birth after fresh single embryo transfer. The nomogram model was established according to the regression coefficients. Besides, area under the receiver operator characteristic (ROC) curve, calibration curve and decision curve analysis were used to evaluate the discrimination and calibration of the model. Results:Through multiple logistic regression analysis, female age, progestational polycystic ovary syndrome (PCOS), the level of progestrogen on the day of human chorionic gonadotropin (hCG) injection, high-quality embryo rate, type of embryos transferred were independent risk factors associated with live birth. Stratified analysis found age ≥36 years together with the level of progestrogen ≥5.20 nmol/L on the day of hCG injection could reduce the probability of live birth signally, and statistically significant interaction was found ( P=0.043). The level of progestrogen ≥5.20 nmol/L on the day of hCG injection together with high-quality embryo rate <59.60% could reduce the probability of live birth signally, and statistically significant interaction was found ( P=0.010). The area under the curve (AUC) of modeling group and validation group was 0.637 (95% CI: 0.615-0.658) and 0.617 (95% CI: 0.579-0.654), respectively. The calibration curve showed that the predicted value of the model was in good agreement with the actual value. The decision curve analysis indicated the most benefical clinical effect with the nomogram for live birth under threshold probabilities of 24.05%-68.75%, it had a good diagnostic value for clinical decision. Conclusion:Female age, progestational PCOS, the level of progestrogen on the day of hCG injection, high-quality embryo rate, type of embryos transferred were independent risk factors associated with live birth in patients with long-acting follicular phase in fresh single embryo transfer cycle. Female age ≥36 years and high-quality embryo rate <59.60% together with the level of progestrogen ≥5.26 nmol/L on the day of hCG injection respectively could reduce the probability of live birth. The nomogram predictive model based on the above factors contribute to predict the probability of live birth.