Ankylosing spondylitis (AS) is linked to an increased prevalence of myocardial infarction (MI). However, research dedicated to elucidating the pathogenesis of AS-MI is lacking. In this study, we explored the biomarkers for enhancing the diagnostic and therapeutic efficiency of AS-MI. Datasets were obtained from the Gene Expression Omnibus database. We employed weighted gene co-expression network analysis and machine learning models to screen hub genes. A receiver operating characteristic curve and a nomogram were designed to assess diagnostic accuracy. Gene set enrichment analysis was conducted to reveal the potential function of hub genes. Immune infiltration analysis indicated the correlation between hub genes and the immune landscape. Subsequently, we performed single-cell analysis to identify the expression and subcellular localization of hub genes. We further constructed a transcription factor (TF)-microRNA (miRNA) regulatory network. Finally, drug prediction and molecular docking were performed. S100A12 and MCEMP1 were identified as hub genes, which were correlated with immune-related biological processes. They exhibited high diagnostic value and were predominantly expressed in myeloid cells. Furthermore, 24 TFs and 9 miRNA were associated with these hub genes. Enzastaurin, meglitinide, and nifedipine were predicted as potential therapeutic agents. Our study indicates that S100A12 and MCEMP1 exhibit significant potential as biomarkers and therapeutic targets for AS-MI, offering novel insights into the underlying etiology of this condition.
Humans ; Spondylitis, Ankylosing/complications* ; Systems Biology/methods* ; Myocardial Infarction/diagnosis* ; Biomarkers/metabolism* ; MicroRNAs/genetics* ; Gene Regulatory Networks ; Gene Expression Profiling ; Machine Learning

Objective:To investigate endothelial cell heterogeneity in diabetic cardiomyopathy (DCM) and identify potential therapeutic targets of dapagliflozin in cardiac vascular endothelial cells.Methods:ePharmaLib reverse virtual screening was performed on 15 148 protein crystals to identified the binding interactions between human-derived proteins and dapagliflozin. Subsequently, single-cell RNA sequencing data (PRJNA1069235) from wild-type mice (control group) and db/db mice (DCM group) were integrated, then dimensionality reduction and clustering analysis were performed to identify endothelial cell subpopulations in the heart tissue of DCM mice, followed by functional annotation. Cell-cell communication analysis was explored to investigate fibroblast-endothelial cell interactions. The Agilent Mouse ceRNA Microarray chip was used to perform transcriptomic analysis of heart tissue from mice fed a high-fat diet and treated with dapagliflozin. Intersection analysis of reverse virtual screening results, single-cell RNA sequencing results and chip analysis data was performed to identify common differentially expressed genes. In vitro, human umbilical vein endothelial cells were divided into blank control group, tumor necrosis factor-α (TNF-α) group (TNF-α 10 mg/L), dapagliflozin low concentration group (TNF-α 10 mg/L+dagliazin 2 μmol/L), dapagliflozin medium concentration group (TNF-α 10 mg/L+dagliazin 5 μmol/L) and dapagliflozin high concentration group (TNF-α 10+dagliazin 10 μmol/L). Western blot and real-time reverse transcriptase polymerase chain reaction were used to detect the expression of inflammatory factors and differential genes.Results:ePharmaLib reverse virtual screening identified 168 human-derived proteins with potential binding affinity to dapagliflozin, and single-cell analysis identifiedf 6 types of endothelial cell subpopulations. Compared with the control group, the abundance of capillary endothelial cells was significantly lower in DCM group, while the abundance of microvascular and venous endothelial cells was significantly higher ( P all<0.05). Cell-cell communication analysis showed significant expression of Pgf-Vegfr1 ligand-receptor pair. In addition, 15 differentially expressed genes were identified by intersection analysis of 168 dapagliflozin-binding proteins. Including Bcl2, Baz2b, Nos3, Ephb4, Cdk8, Pparg, Pde2a, Fgfr2, Fto, Stk24, Dlg1, Gsk3b, Pdpk1, Fas and Tnks2. Notably, Baz2b, Pparg, Fto and Gsk3b were differentially expressed in all cell subpopulations. Six differential genes, including Pde7a, Dlg1, Gsk3b, Nampt, Met and Adk, were obtained by the intersection of the chip analysis data with the virtual screening results of dapagliflozin. In vitro, compared to the human umbilical vein endothelial cells of TNF-α group, the expression levels of interleukin-6, interleukin-1β and p-P65 proteins and messenger RNA of Bcl2, Nos3, Cdk8, Pde2a, Dlg1, Pdpk1, Tnks2, Baz2b, Pparg, Fas, Pde7a and Nampt were significantly lower than dapagliflozin high concentration group ( P all<0.05). Conclusions:Dapagliflozin may inhibit endothelial cell inflammatory responses and improve endothelial dysfunction in DCM by regulating key genes such as Dlg1, Bcl2, Nos3, Pde7a and Nampt.

Objective:Investigate key genes influencing vascular calcification through bioinformatics analysis and experimental validation.Methods:Three vascular calcification datasets (GSE159832, GSE229679 and GSE37558) were obtained from the Gene Expression Omnibus database. Subsequently, gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG), and conventional gene set enrichment analysis (GSEA) were performed on the common differential expressed genes(DEGs). For in vitro validation, a vascular smooth muscle cell calcification model was established by stimulating mouse primary vascular smooth muscle cells with high phosphate and calcium chloride (Pi+CaCl 2). Cells were divided into a control group and a Pi+CaCl 2 group. To investigate the role of TK1, cells were transfected with TK1-targeting siRNA (siTK1) or control siRNA (siControl) prior to Pi+CaCl 2 stimulation, creating siControl+Pi+CaCl 2 and siTK1+Pi+CaCl 2 groups. The association between key DEGs and vascular calcification was assessed at the protein and mRNA levels using Western blot and quantitative real-time PCR, respectively. Changes in the phosphorylation of the downstream effector, AKT (p-AKT/AKT), were also measured. Results:A total of 2275, 449, and 381 DEGs were identified from the three vascular calcification datasets (GSE159832, GSE229679, and GSE37558), respectively. Two common DEGs-phosphoserine aminotransferase 1 and thymidine kinase 1 (TK1)-were identified across all datasets. GO enrichment analysis revealed that TK1 was significantly enriched in pathways related to ribosome biogenesis, assembly, and rRNA processing and maturation. GSEA-KEGG analysis indicated significant enrichment in the PI3K-AKT signaling pathway, pathways in cancer, neurodegenerative diseases, cytoskeleton, and smooth muscle contraction. Conventional GSEA of TK1 further confirmed significant enrichment in pathways including dynein, epithelial tight junctions, axon guidance, and vascular smooth muscle contraction pathways. At the experimental level, both protein and mRNA expression of TK1, along with the p-AKT/AKT ratio, were significantly lower in the Pi+CaCl 2 group compared to the control group (all P<0.05). Furthermore, compared to the siControl+Pi+CaCl 2 group, the siTK1+Pi+CaCl 2 group exhibited decreased expression of differentiation markers, increased expression of calcification markers, and a further reduced p-AKT/AKT ratio (all P<0.05). Conclusion:Integrated bioinformatics and cellular validation demonstrate a correlation between TK1 expression and vascular calcification, suggesting a potential protective role for TK1 in this pathological process.

Objective To investigate the impact of sintilimab combined with TP chemotherapy regimen on immune function and prognostic survival in patients with advanced esophageal cancer.Methods A total of 82 patients with advanced esophageal cancer who received treatment in the hospital from January 2022 to October 2023 were enrolled.They were divided into two groups with 41 cases in each group using the random number table method.The control group was given the TP chemotherapy regimen,while the observation group was treated with sintilimab in addition to the TP chemotherapy regimen used in the control group.The treatment cycle was 21 days,and both groups received 4 cycles of treatment.After that,the observation group received sintilimab monotherapy for maintenance treatment for at least 1 year.The disease control rate(DCR)and objective response rate(ORR)of the patients were recorded.The immune function,levels of inflammatory factors and tumor markers before and after treatment were compared between the two groups.The swallowing function and quality of life of the patients before and after treatment were evaluated using the Swallowing Safety Assessment(SSA)and the Quality of Life Instruments for Cancer Patients-Esophageal Cancer(QLICP-ES).The occurrence of adverse reactions was also recorded.After the start of treatment,the patients were followed up for 18 months,and the overall survival(OS)and survival rate were recorded.Results In the observation group,the partial remission rate and disease control rate were 53.66%and 87.80%respectively,both higher than those in the control group.After treatment,the levels of CD3+and CD4+in the observation group were(50.48±5.61)%and(37.96±4.69)%respectively,which were higher than(44.73±5.12)%and(33.15±4.21)%in the control group.The immune function of the observation group was improved compared with the control group,while the levels of inflammatory factors and tumor markers were lower than those in the control group.The swallowing function and quality of life were significantly improved compared with the control group(P<0.05).The 18-month follow-up results showed that the median overall survival(OS)in the observation group was 16(9,17)months,and that in the control group was 9(7,14)months.The OS in the observation group was longer than that in the control group(χ2=13.394,P<0.001).The 18months survival rates in the observation group and the control group were 60.98%(25/41)and 36.59%(15/41)respec-tively,with the observation group being higher than the control group(χ2=4.881,P=0.027).Conclusion The sintilimab combined with TP chemotherapy regimen is beneficial for improving immune function and enhancing the survival status of patients with advanced esophageal cancer.

Objective To investigate the intracranial hemodynamic parameters with transcranial color-coded duplex sonography(TCCS)in elderly patients with acute ischemic stroke(AIS)after endovascular therapy,and analyze their association with functional outcomes.Methods A total of 360 elderly AIS patients undergoing endovascular therapy in our hospital from March 1,2020 to January 31,2024 were prospectively included,and according to the score of modified Rankin scale(mRS)at 90 d,they were divided into a poor function group(mRS score 3-6,145 cases)and good function group(mRS score≤2,215 cases).TCCS was conducted on all the patients in 12 h after endovascular therapy to evaluate intracranial blood flow status.Peak systolic velocity(PSV),end-diastolic velocity(EDV),mean blood flow velocity(MFV),pulsatility index(PI),MFV ratio and PSV ratio,adjusted PSV ratio and adjusted MFV ratio were recorded in all pa-tients.Receiver operator characteristic(ROC)curve analysis was employed to analyze the value of TCCS parameters in predicting poor functional outcomes,and the AUC values and cut-off values were also analyzed.Results The PSV ratio,MFV ratio,adjusted PSV ratio and adjusted MFV ra-tio were significantly higher in the poor function group than the good function group(P＜0.01).The predictive performance of PSV ratio and MFV ratio were not good enough for poor functional outcome in the AIS patients(AUC＜0.750),while the adjusted PSV ratio and adjusted MFV ratio showed better predictive performance(P＜0.01).Multivariate logistic regression analysis showed that NIHSS score at admission ≥14.00,ASPECT score at admission≥8.00,adjusted PSV ratio＞1.39 and adjusted MFV ratio＞1.40 were independent risk factors for poor functional outcomes in AIS patients(P＜0.01).ROC curve analysis indicated that combined NIHSS score at admission+ASPECT score at admission showed poor value in predicting poor functional outcome in the AIS(AUC=0.780,95％CI:0.734-0.822),the predictive performance of combination of above two scores+adjusted PSV ratio+adjusted MFV ratio was significantly improved(AUC=0.976,95％CI:0.955-0.989),with higher sensitivity and specificity(Z=8.261,P＜0.01).Conclusion Early TCCS detection in elderly AIS patients after endovascular treatment is an effective method for identifying poor functional outcomes at 90 d,with the advantages of non invasiveness and easy op-eration.And,better predictive performance is obtained when adjusted PSV ratio and adjusted MFV ratio are combined with conventional predictors.

Objective To investigate the intracranial hemodynamic parameters with transcranial color-coded duplex sonography(TCCS)in elderly patients with acute ischemic stroke(AIS)after endovascular therapy,and analyze their association with functional outcomes.Methods A total of 360 elderly AIS patients undergoing endovascular therapy in our hospital from March 1,2020 to January 31,2024 were prospectively included,and according to the score of modified Rankin scale(mRS)at 90 d,they were divided into a poor function group(mRS score 3-6,145 cases)and good function group(mRS score≤2,215 cases).TCCS was conducted on all the patients in 12 h after endovascular therapy to evaluate intracranial blood flow status.Peak systolic velocity(PSV),end-diastolic velocity(EDV),mean blood flow velocity(MFV),pulsatility index(PI),MFV ratio and PSV ratio,adjusted PSV ratio and adjusted MFV ratio were recorded in all pa-tients.Receiver operator characteristic(ROC)curve analysis was employed to analyze the value of TCCS parameters in predicting poor functional outcomes,and the AUC values and cut-off values were also analyzed.Results The PSV ratio,MFV ratio,adjusted PSV ratio and adjusted MFV ra-tio were significantly higher in the poor function group than the good function group(P＜0.01).The predictive performance of PSV ratio and MFV ratio were not good enough for poor functional outcome in the AIS patients(AUC＜0.750),while the adjusted PSV ratio and adjusted MFV ratio showed better predictive performance(P＜0.01).Multivariate logistic regression analysis showed that NIHSS score at admission ≥14.00,ASPECT score at admission≥8.00,adjusted PSV ratio＞1.39 and adjusted MFV ratio＞1.40 were independent risk factors for poor functional outcomes in AIS patients(P＜0.01).ROC curve analysis indicated that combined NIHSS score at admission+ASPECT score at admission showed poor value in predicting poor functional outcome in the AIS(AUC=0.780,95％CI:0.734-0.822),the predictive performance of combination of above two scores+adjusted PSV ratio+adjusted MFV ratio was significantly improved(AUC=0.976,95％CI:0.955-0.989),with higher sensitivity and specificity(Z=8.261,P＜0.01).Conclusion Early TCCS detection in elderly AIS patients after endovascular treatment is an effective method for identifying poor functional outcomes at 90 d,with the advantages of non invasiveness and easy op-eration.And,better predictive performance is obtained when adjusted PSV ratio and adjusted MFV ratio are combined with conventional predictors.

Objective To investigate the impact of sintilimab combined with TP chemotherapy regimen on immune function and prognostic survival in patients with advanced esophageal cancer.Methods A total of 82 patients with advanced esophageal cancer who received treatment in the hospital from January 2022 to October 2023 were enrolled.They were divided into two groups with 41 cases in each group using the random number table method.The control group was given the TP chemotherapy regimen,while the observation group was treated with sintilimab in addition to the TP chemotherapy regimen used in the control group.The treatment cycle was 21 days,and both groups received 4 cycles of treatment.After that,the observation group received sintilimab monotherapy for maintenance treatment for at least 1 year.The disease control rate(DCR)and objective response rate(ORR)of the patients were recorded.The immune function,levels of inflammatory factors and tumor markers before and after treatment were compared between the two groups.The swallowing function and quality of life of the patients before and after treatment were evaluated using the Swallowing Safety Assessment(SSA)and the Quality of Life Instruments for Cancer Patients-Esophageal Cancer(QLICP-ES).The occurrence of adverse reactions was also recorded.After the start of treatment,the patients were followed up for 18 months,and the overall survival(OS)and survival rate were recorded.Results In the observation group,the partial remission rate and disease control rate were 53.66%and 87.80%respectively,both higher than those in the control group.After treatment,the levels of CD3+and CD4+in the observation group were(50.48±5.61)%and(37.96±4.69)%respectively,which were higher than(44.73±5.12)%and(33.15±4.21)%in the control group.The immune function of the observation group was improved compared with the control group,while the levels of inflammatory factors and tumor markers were lower than those in the control group.The swallowing function and quality of life were significantly improved compared with the control group(P<0.05).The 18-month follow-up results showed that the median overall survival(OS)in the observation group was 16(9,17)months,and that in the control group was 9(7,14)months.The OS in the observation group was longer than that in the control group(χ2=13.394,P<0.001).The 18months survival rates in the observation group and the control group were 60.98%(25/41)and 36.59%(15/41)respec-tively,with the observation group being higher than the control group(χ2=4.881,P=0.027).Conclusion The sintilimab combined with TP chemotherapy regimen is beneficial for improving immune function and enhancing the survival status of patients with advanced esophageal cancer.

Objective:To investigate endothelial cell heterogeneity in diabetic cardiomyopathy (DCM) and identify potential therapeutic targets of dapagliflozin in cardiac vascular endothelial cells.Methods:ePharmaLib reverse virtual screening was performed on 15 148 protein crystals to identified the binding interactions between human-derived proteins and dapagliflozin. Subsequently, single-cell RNA sequencing data (PRJNA1069235) from wild-type mice (control group) and db/db mice (DCM group) were integrated, then dimensionality reduction and clustering analysis were performed to identify endothelial cell subpopulations in the heart tissue of DCM mice, followed by functional annotation. Cell-cell communication analysis was explored to investigate fibroblast-endothelial cell interactions. The Agilent Mouse ceRNA Microarray chip was used to perform transcriptomic analysis of heart tissue from mice fed a high-fat diet and treated with dapagliflozin. Intersection analysis of reverse virtual screening results, single-cell RNA sequencing results and chip analysis data was performed to identify common differentially expressed genes. In vitro, human umbilical vein endothelial cells were divided into blank control group, tumor necrosis factor-α (TNF-α) group (TNF-α 10 mg/L), dapagliflozin low concentration group (TNF-α 10 mg/L+dagliazin 2 μmol/L), dapagliflozin medium concentration group (TNF-α 10 mg/L+dagliazin 5 μmol/L) and dapagliflozin high concentration group (TNF-α 10+dagliazin 10 μmol/L). Western blot and real-time reverse transcriptase polymerase chain reaction were used to detect the expression of inflammatory factors and differential genes.Results:ePharmaLib reverse virtual screening identified 168 human-derived proteins with potential binding affinity to dapagliflozin, and single-cell analysis identifiedf 6 types of endothelial cell subpopulations. Compared with the control group, the abundance of capillary endothelial cells was significantly lower in DCM group, while the abundance of microvascular and venous endothelial cells was significantly higher ( P all<0.05). Cell-cell communication analysis showed significant expression of Pgf-Vegfr1 ligand-receptor pair. In addition, 15 differentially expressed genes were identified by intersection analysis of 168 dapagliflozin-binding proteins. Including Bcl2, Baz2b, Nos3, Ephb4, Cdk8, Pparg, Pde2a, Fgfr2, Fto, Stk24, Dlg1, Gsk3b, Pdpk1, Fas and Tnks2. Notably, Baz2b, Pparg, Fto and Gsk3b were differentially expressed in all cell subpopulations. Six differential genes, including Pde7a, Dlg1, Gsk3b, Nampt, Met and Adk, were obtained by the intersection of the chip analysis data with the virtual screening results of dapagliflozin. In vitro, compared to the human umbilical vein endothelial cells of TNF-α group, the expression levels of interleukin-6, interleukin-1β and p-P65 proteins and messenger RNA of Bcl2, Nos3, Cdk8, Pde2a, Dlg1, Pdpk1, Tnks2, Baz2b, Pparg, Fas, Pde7a and Nampt were significantly lower than dapagliflozin high concentration group ( P all<0.05). Conclusions:Dapagliflozin may inhibit endothelial cell inflammatory responses and improve endothelial dysfunction in DCM by regulating key genes such as Dlg1, Bcl2, Nos3, Pde7a and Nampt.

Objective:Investigate key genes influencing vascular calcification through bioinformatics analysis and experimental validation.Methods:Three vascular calcification datasets (GSE159832, GSE229679 and GSE37558) were obtained from the Gene Expression Omnibus database. Subsequently, gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG), and conventional gene set enrichment analysis (GSEA) were performed on the common differential expressed genes(DEGs). For in vitro validation, a vascular smooth muscle cell calcification model was established by stimulating mouse primary vascular smooth muscle cells with high phosphate and calcium chloride (Pi+CaCl 2). Cells were divided into a control group and a Pi+CaCl 2 group. To investigate the role of TK1, cells were transfected with TK1-targeting siRNA (siTK1) or control siRNA (siControl) prior to Pi+CaCl 2 stimulation, creating siControl+Pi+CaCl 2 and siTK1+Pi+CaCl 2 groups. The association between key DEGs and vascular calcification was assessed at the protein and mRNA levels using Western blot and quantitative real-time PCR, respectively. Changes in the phosphorylation of the downstream effector, AKT (p-AKT/AKT), were also measured. Results:A total of 2275, 449, and 381 DEGs were identified from the three vascular calcification datasets (GSE159832, GSE229679, and GSE37558), respectively. Two common DEGs-phosphoserine aminotransferase 1 and thymidine kinase 1 (TK1)-were identified across all datasets. GO enrichment analysis revealed that TK1 was significantly enriched in pathways related to ribosome biogenesis, assembly, and rRNA processing and maturation. GSEA-KEGG analysis indicated significant enrichment in the PI3K-AKT signaling pathway, pathways in cancer, neurodegenerative diseases, cytoskeleton, and smooth muscle contraction. Conventional GSEA of TK1 further confirmed significant enrichment in pathways including dynein, epithelial tight junctions, axon guidance, and vascular smooth muscle contraction pathways. At the experimental level, both protein and mRNA expression of TK1, along with the p-AKT/AKT ratio, were significantly lower in the Pi+CaCl 2 group compared to the control group (all P<0.05). Furthermore, compared to the siControl+Pi+CaCl 2 group, the siTK1+Pi+CaCl 2 group exhibited decreased expression of differentiation markers, increased expression of calcification markers, and a further reduced p-AKT/AKT ratio (all P<0.05). Conclusion:Integrated bioinformatics and cellular validation demonstrate a correlation between TK1 expression and vascular calcification, suggesting a potential protective role for TK1 in this pathological process.

Objective:To investigate the level of self-management and daily physical activity in patients with type 2 diabetes mellitus (T2DM) of Zang and Han nationalities in Tibetan, China, and to compare the difference in daily management between T2DM patients of Zang and Han nationalities, to develop reasonable and effective chronic disease management strategies for long-term out-of-hospital management of T2DM patients of Zang nationalities.Methods:A total of 265 T2DM patients with glycosylated hemoglobin (HbA1c) ≥ 7% who were admitted to the Endocrinology Ward of the Hospital of Chengdu Office of People's Government of Tibet Autonomous Region from November 2020 to April 2021 and who were from different regions of Tibet were included in this study according to inclusion and exclusion criteria. The general data of all included patients were collected. Glucose and lipid metabolism-related indicators were determined. The Generalized Diabetes Self-Management Efficacy Scale and International Physical Activity Questionnaires (IPAQ) were used to evaluate patients' levels of self-management and daily physical activity.Results:The hemoglobin level in T2DM patients of Zang nationality was (154.09 ± 24.11) g/L, which was significantly higher than that in T2DM patients of Han nationality ( P < 0.05). The total cholesterol, fasting blood glucose, and low-density lipoprotein in T2DM patients of Zang nationality were (4.63 ± 1.41) mmol/L, (7.94 ± 2.19) mmol/L, and (2.75 ± 1.11) mmol/L, respectively, which significantly higher compared with T2DM patients of Han nationality (all P < 0.05). Compared with T2DM patients of Han nationality, T2DM patients of Zang nationality had lower self-management scores (81.40 ± 15.44) points, diet control scores (17.26 ± 4.97) points, physical exercise scores (11.67 ± 4.42) points, prevention and treatment of high and low blood sugar score (12.21 ± 5.72) points. The differences were statistically significant (all P < 0.05). Moderate-intensity physical activity was a significant difference between T2DM patients of Zang and Han nationalities ( P < 0.05). Conclusion:Compared with T2DM patients of Han nationality, T2DM patients of Zang nationality have lower overall self-management levels, including diet control, physical exercise, prevention and management of high and low blood glucose, and moderate-intensity physical activity. Targeted individualized education should be carried out according to the Tibetan cultural characteristics, to further develop an intervention method and an out-of-hospital management strategy for chronic disease, which are suitable for T2DM patients of Zang nationality.