Most cancers are currently incurable, partly due to abnormal post-translational modifications (PTMs). In this study, we initially used multiple myeloma (MM) as a working model and found that SUMOylation activating enzyme subunit 1 (SAE1) promotes the malignancy of MM. Through proteome microarray analysis, SAE1 was identified as a potential target for bioactive colcemid or its derivative colchicine. Elevated levels of SAE1 were associated with poor clinical survival and increased MM proliferation in vitro and in vivo. Additionally, SAE1 directly SUMOylated and upregulated the total protein expression of p27, leading to LLPS-mediated nuclear export of p27. Our study also demonstrated the involvement of SAE1 in other types of cancer cells, and provided the first monomer crystal structure of SAE1 and its key binding model with colchicine. Colchicine also showed promising results in the Patient-Derived Tumor Xenograft (PDX) model. Furthermore, a controlled clinical trial with 56 MM patients demonstrated the clinical efficacy of colchicine. Our findings reveal a novel mechanism by which tumor cells evade p27-induced cellular growth arrest through p27 SUMOylation-mediated nuclear export. SAE1 may serve as a promising therapeutic target, and colchicine may be a potential treatment option for multiple types of cancer in clinical settings.

OBJECTIVES: To study the mechanism mediating the protective effect of asiaticoside (AS) against myocardial ischemia-reperfusion injury (MIRI) in rats. METHODS: Fifty SD rats were randomized into sham-operated group, MIRI model group and AS treatment group. AS treatment was administered at low, moderate and high doses by daily gavage for 2 weeks before MIRI modeling (n=10). Serum levels of lactate dehydrogenase (LDH), creatine kinase isoenzyme (CK-MB), interleukin-18 (IL-18) and IL-1β, the volume of myocardial infarction and ischemia, and myocardial pathologies of the rats were determined or observed. The protein expression levels of NLRP3, ASC, caspase-1, GSDMD, GSDMD-N, IL-1β and IL-18 in the myocardial tissues were detected using Western blotting. The changes in the expression levels of these proteins were also detected in H9C2 cells with AS pretreatment prior to hypoxia-reoxygenation (H/R) injury. RESULTS: The rats models of MIRI exhibited significant myocardial infarction and ischemia with increased serum levels of LDH and CK-MB and myocardial expressions of NLRP3, ASC, caspase-1, GSDMD, GSDMD-N, IL-1β and IL-18. AS pretreatment effectively reduced myocardial infarction volume in the rat models and significantly reduced serum LDH and CK-MB levels and the protein levels in the myocardial tissue in a dose-dependent manner. In the H9C2 cell model of H/R injury, AS pretreatment significantly suppressed the elevation of the protein expressions of NLRP3, ASC, caspase-1, GSDMD, GSDMD-N, IL-1β and IL-18. Molecular docking studies showed that AS had a strong binding affinity with NLRP3. CONCLUSIONS Asiaticoside can alleviate MIRI in rats possibly by inhibiting NLRP3 inflammasome-mediated pyroptosis.
Animals ; Myocardial Reperfusion Injury/metabolism* ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Pyroptosis/drug effects* ; Rats, Sprague-Dawley ; Rats ; Inflammasomes/metabolism* ; Triterpenes/pharmacology* ; Interleukin-18/metabolism* ; Male ; Interleukin-1beta/metabolism* ; Caspase 1/metabolism*

Myocardial infarction (MI) is the leading cause of cardiovascular disease-related death worldwide. Nonetheless, existing therapeutic approaches for MI are hampered by issues such as reliance on pharmacological agents and suboptimal patient adherence. Caffeic acid (CA) is a bioactive polyphenolic compound with important anti-inflammatory, anti-bacterial and anti-oxidant functions. Still, its specific role and mechanism in treating cardiovascular disease remain to be further studied. In recent years, a large number of studies have shown that the kelch-like ECH-associated protein 1/nuclear factor erythroid 2 related factor 2 (Keap1/Nrf2) pathway is a key factor in the occurrence and development of cardiovascular diseases. In this study, H₂O₂-induced oxidative stress model of H9c2 cells and left anterior descending branch (LAD) conjunctival induced acute myocardial infarction reperfusion (AMI/R) model were used to evaluate the protective effect of CA on the heart. The interaction between CA and Keap1 was analyzed by CA-labeled fluorescence probe, target fishing, isothermal titration calorimetry (ITC), protein crystallography and surface plasmon resonance (SPR). Our results suggested that CA binds Keap1 and degrades Keap1 in a p62-dependent manner, further promoting nuclear transcription of Nrf2 and thus effectively reducing oxidative stress. In addition, based on the three-dimensional eutectic structure, it was confirmed that CA directly targets Keap1 protein by interacting with residues M550 and N532, inducing conformation changes in Keap1 protein. We also found that the CA analog chlorogenic acid (GCA) can bind Keap1. In conclusion, this study elucidates a novel molecular mechanism and structural basis for the protective effects of CA against oxidative damage via the Keap1-Nrf2 pathway.

Portal hypertension is a major complication of cirrhosis. The current gold standard for diagnosis is the hepatic venous pressure gradient, but it possesses limitations such as invasiveness. In recent years, non-invasive tests have made significant progress in terms of evaluating and prognostication of portal hypertension. This article reviews the diagnostic value and related research advancements of different non-invasive tests in assessing portal hypertension in patients with cirrhosis.

Objective:To evaluate the predictive performance of machine learning methods for predicting the risk of death in traumatic hemorrhage, and address the low prediction accuracy of traditional trauma scores, provide a reference for developing a more robust prediction method for severe trauma patients.Methods:Clinical data of severe trauma patients from the National Trauma Medical Center between April 1, 2023, and March 31, 2024 were collected. ElasticNet, Recursive Feature Elimination, and Mutual Information-based feature selection methods were used to screen variables and compared with traditional hypothesis testing methods. Built the prediction models for mortality risk in traumatic hemorrhage using Logistic Regression, ElasticNet, and Support Vector Machine (SVM) and compared the predictive performance.Results:The study included 5,601 trauma patients, the results of the variable screening and importance ranking were consistent with three feature selection methods. The classification accuracy and AUC values for the three models were as follows: Overall accuracy was 83.2%, survival accuracy was 84.0%, death accuracy was 76.3%, and an AUC was 0.86 in logistic regression; Overall accuracy was 78.9%, survival accuracy was 78.5%, death accuracy was 81.7%, and an AUC was 0.88 in ElasticNet; Overall accuracy was 84.7%, survival accuracy was 86.1%, death accuracy was 72.4%, and an AUC was 0.86 in SVM. The prediction performance of three models is quite little.Conclusion:Machine learning methods can effectively improve the prediction of death risk for traumatic hemorrhage,and has wide applications.

Objective:To investigate the factors influencing recurrence and metastasis and prognosis of early breast cancer patients after surgery and the significance of all-foci radiotherapy after recurrence and metastasis.Methods:A retrospective cohort study was conducted. A total of 554 patients with stage T 1-2N 0M 0 breast cancer after surgery who were admitted to Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University from January 2006 to January 2019 were collected. The clinicopathological features were compared between patients with and without recurrence and metastasis after surgery. Kaplan-Meier method was used to analyze the overall survival (OS) and disease-free survival (DFS) of patients. The univariate analysis of prognostic factors was conducted using log rank test, while the multivariate analysis was conducted using Cox proportional hazards model. Patients with recurrence and metastasis are grouped according to whether the recurrence and metastasis lesions had received radiotherapy, patients with radiotherapy for all recurrence and metastasis lesions were classified as the all-foci radiotherapy group, patients with radiotherapy for partial recurrence and metastasis lesions were classified as non-all-foci radiotherapy group, and patients without radiotherapy for all recurrence and metastasis lesions were classified as non-radiotherapy group. The OS and progression free survival (PFS) were compared between groups. Results:The 554 patients were (49±10) years old, including 56 patients (10.1%) with recurrence and metastasis after surgery. There were statistically significant differences in menopausal status, pathological type, differentiation degree, estrogen receptor or progesterone receptor expression, pathological stage, postoperative adjuvant chemotherapy, postoperative adjuvant radiotherapy, and postoperative adjuvant endocrine therapy (all P < 0.05). The 5-year OS and DFS were 96.9% and 95.9%, respectively. The multivariate Cox regression analysis showed that the high differentiation ( HR = 0.300, P = 0.011), no postoperative adjuvant radiotherapy ( HR = 0.097, P < 0.001) and no postoperative endocrine therapy ( HR = 0.421, P = 0.040) were independent risk factors for DFS. The high differentiation ( HR = 0.266, P = 0.003) and no postoperative adjuvant radiotherapy ( HR = 0.225, P = 0.003) were independent risk factors for OS. OS in all-foci radiotherapy group was better than that in non-all-foci radiotherapy group, and the difference was statistically significant ( χ2 = 6.73, P = 0.010), but there was no significant difference in PFS between the two groups ( χ2 = 3.51, P = 0.061). There was no statistically significant difference in OS and PFS between the all-foci radiotherapy group and the non-radiotherapy group (both P > 0.05). Conclusions:Menopausal status, pathological classification, differentiation degree, estrogen receptor or progesterone receptor expression, pathological stage, postoperative adjuvant chemotherapy, postoperative adjuvant radiotherapy, and postoperative adjuvant endocrine therapy may affect the occurrence of postoperative recurrence and metastasis in stage T 1-2N 0M 0 breast cancer patients after surgery. The prognosis of stage T 1-2N 0M 0 breast cancer patient with high differentiation, no postoperative adjuvant radiotherapy and no postoperative endocrine therapy is poor. The OS of early breast cancer patients with recurrence and metastasis may be prolonged by all-foci radiotherapy compared with non-all-foci radiotherapy.

Objective To retrospectively study the characteristics and short-term outcomes of patients with decompensated liver cirrhosis accompanied by diastolic cardiac dysfunction,and to inform the clinical diagnosis and treatment of decompensated liver cirrhosis.Methods We retrospectively analyzed the clinical data of patients with liver cirrhosis and diastolic heart dysfunction admitted to Nanfang Hospital of Southern Medical University from April 1,2019 to July 31,2023.The patients were divided into compensated cirrhosis group(n=37)and decompensated cirrhosis group(n=226),and those with decompensated cirrhosis were further divided into subgroups of patients with heart dysfunction(n=84)and patients without heart dysfunction(n=142).We compared two groups using the independent samples t-test and Mann-Whitney U test for continuous data in normal distribution and data in skewed distribution,respectively;compared multiple groups using the Kruskal-Wallis H test,with subsequent paired comparisons using the Wilcoxon test;compared categorical data between two groups using the chi-square test or corrected chi-square test;identified the factors affecting patient survival using a Logistic regression model;and plotted Kaplan-Meier survival curves,with inter-group comparisons using the log-rank test.Results A total of 263 eligible patients were ultimately included,among whom 226 patients were diagnosed with decompensated liver cirrhosis(84 patients with diastolic dysfunction).Between the diastolic dysfunction group and non-diastolic dysfunction group,significant differences were detected in age(t=-4.566,P<0.05),activated partial thromboplastin time(Z=-3.026,P<0.05),prothrombin time(Z=-2.450,P<0.05),international normalized ratio(Z=2.779,P<0.05),and the proportion of moderate esophageal varices(χ2=4.273,P<0.05).During hospitalization,35 patients experienced new or aggravated ascites(18 with cardiac dysfunction and 17 without cardiac dysfunction),6 patients experienced new gastroesophageal variceal bleeding,and 9 patients experienced new or aggravated hepatic encephalopathy(3 with cardiac dysfunction and 6 without cardiac dysfunction).Jaundice was the most common decompensation event upon admission,and electrophysiological abnormalities were the most common electrocardiogram findings upon admission.During the 90-day follow-up period,30 individuals(12 with cardiac dysfunction and 18 without cardia dysfunction)died.The logistic regression analysis showed that age(odds ratio[OR]=1.075,95%confidence interval[CI]:1.033-1.119,P<0.001),N-terminal pro-B-type natriuretic peptide(NT-proBNP,OR=0.996,95%CI:0.992-0.999,P=0.016),and mild/moderate ascites(OR=0.270,95%CI:0.092-0.789,P=0.017)were independent predictive factors for cirrhotic cardiomyopathy.Conclusion Timely attention should be paid to elderly patients with decompensated liver cirrhosis and diastolic heart dysfunction who have a decline in NT-proBNP and mild to moderate ascites.Symptomatic treatment such as diuretics may improve diastolic heart dysfunction.

Objective To investigate the role of multimodal magnetic resonance imaging(MRI)features in predicting vascular invasion and prognosis in cervical cancer.Methods A total of 180 cervical cancer patients were included in this study.According to the postoperative vascular invasion status,patients were categorized into vascular invasion-positive group(n=61)and vascular invasion-negative group(n=119).All patients underwent comprehensive MRI protocols including diffusion-weighted imaging(DWI),diffusion tensor imaging(DTI),and dynamic contrast-enhanced MRI(DCE-MRI)scans to analyze intergroup differences in imaging parameters.The diagnostic efficacy of multimodal MRI(DWI,DTI,and DCE-MRI)in detecting vascular invasion and predicting prognosis was evaluated.Results Statistically significant differences in ADCDWI were observed between vascular invasion-positive group and vascular invasion-negative group(P<0.01).The vascular invasion-positive group exhibited significantly lower ADCDTI and FA as compared with vascular invasion-negative group,accompanied by elevated Ktrans,VE,and Kep(P<0.01).Compared with survival group,non-survivor group demonstrated higher ADCDWI,Ktrans,VE and Kep,alongside lower ADCDTI and FA.The sensitivity of multimodal MRI for vascular invasion detection and mortality prediction was higher than that of unimodal detection approaches.Conclusion Multimodal MRI features have significant predictive value for vascular invasion and prognosis in cervical cancer,serving as a critical foundation for clinical decision-making.

Integrated medical curriculum is an important direction for the development of medical education. While integrated theoretical courses have been practiced for many years, integrated experiments are still in the exploratory stage. Taking the integrated experiments of medical microbiology and immunology in Xi'an Jiaotong University as an example, this article introduces the design concept, implementation details, effectiveness evaluation, improvements, and prospects of integrated experiments established based on clinical practice principles, so as to provide a reference for further optimization of integrated experiments in the future.

Objective To investigate the characteristics of lens diameter in different axial positions and their rela-tionship with ocular biometric parameters using swept-source optical coherence tomography.Methods A total of 180 pa-tients(180 eyes)with age-related cataract who were scheduled for phacoemulsification combined with intraocular lens im-plantation from July to December 2023 were included,and the operated eyes were used as the observation eyes.The lens diameter data of patients were obtained by scanning at 16 axial positions using the swept-source optical coherence tomo-graphy device CASIA2.The patients were divided into three groups according to the scanning axial positions of the maxi-mum and minimum lens diameters:horizontal group,oblique group,and vertical group.The distribution differences of the maximum and minimum lens diameters among the three groups were compared.Ocular biometric parameters,including ax-ial length(AL),white-to-white distance,anterior chamber depth(ACD),and lens thickness(LT),were measured using the IOL Master 700.Correlation analysis was used to assess the relationship between lens diameter and age,ocular biomet-ric parameters.Multiple linear regression analysis was used to evaluate the impact of age and ocular biometric parameters on lens diameter.Results The maximum lens diameter[10.13(9.20,10.80)mm]was significantly larger than the min-imum lens diameter[9.26(8.21,9.91)mm],with a statistically significant difference(Z=-7.387,P＜0.001).There were no statistically significant differences in the maximum and minimum lens diameters among the three groups(H=1.575,P=0.455;H=0.927,P=0.629).The distribution difference of the maximum lens diameters between the oblique group and the horizontal group was statistically significant(x2=6.035,P=0.014);differences in other group comparisons were not statistically significant(all P＞0.022).The proportion of the maximum lens diameter occurring in the oblique group(55.2％)was significantly higher than that in the horizontal group(38.0％).The maximum lens diameter was more commonly found in the oblique group.The lens diameter was positively correlated with age and LT(rs=0.217,P＜0.05;rs=0.538,P＜0.001),and negatively correlated with ACD(rs=-0.379,P＜0.001).Comparison of standardized regres-sion coefficients(β')showed that LT had the greatest impact on lens diameter,followed by AL;both LT and AL had a sig-nificant positive impact on lens diameter(β'=0.483,P＜0.001;β'=0.314,P＜0.001).Conclusion The distribution frequency of the maximum lens diameter in the oblique group(30°-60° and 120°-150°)was significantly higher than that in the horizontal group.There was a positive correlation between lens diameter and age and LT,and a negative correlation between lens diameter and ACD.Among all the factors affecting lens diameter,LT and AL are the most critical factors,with LT having a more significant impact on lens diameter than AL.