Cuproptosis, a recently identified form of regulated cell death triggered by excess intracellular copper, has emerged as a promising cytotoxic strategy for cancer therapy. However, the therapeutic efficacy of copper ionophores such as elesclomol (ES) is often hindered by cellular copper homeostasis mechanisms that limit copper influx and cuproptosis induction. To address this challenge, we developed a nanoagent utilizing outer membrane vesicle (OMV) derived from Akkermansia muciniphila (Akk) for co-delivery of antioxidant 1 copper chaperone (Atox1)-targeting siRNA and ES (siAtox1/ES@OMV) to tumors. In vitro, we demonstrated that Atox1 knockdown via siRNA significantly disrupted copper export mechanisms, resulting in elevated intracellular copper levels. Simultaneously, ES facilitated efficient copper influx and mitochondrial transport, leading to Fe-S cluster depletion, increased proteotoxic stress, and robust cuproptosis. In vivo, siAtox1/ES@OMV achieved targeted tumor delivery and induced pronounced cuproptosis. Furthermore, leveraging the immunomodulatory properties of OMVs, siAtox1/ES@OMV promoted T-cell infiltration and the activation of tumor-reactive cytotoxic T cells, enhancing tumor immune responses. The combination of siAtox1/ES-induced cuproptosis and immunogenic cell death synergistically suppressed tumor growth in both subcutaneous breast cancer and orthotopic rectal cancer mouse models. This study highlights the potential of integrating copper homeostasis disruption with a copper ionophore using an immunomodulatory OMV-based vector, offering a promising combinatorial strategy for cancer therapy.

Background: Autoimmune mechanisms have important roles in the pathogenesis of alopecia areata (AA). Objective: This study aimed to evaluate the exact biological and clinical importance of immunogenes in AA patients using bioinformatic methods. Methods: Five AA scalp gene expression profiles were obtained from the Gene Expression Omnibus database. Differentially-expressed genes (DEGs) between AA and control groups were identified. An immune-related gene diagnostic signature (IRGDS) was established by protein-protein interaction network analysis, least absolute shrinkage and selection operator and logistic regression analysis. Results: A total of 102 immune-related DEGs were identified. We developed an IRGDS composed of CD8A, CSF1R and CXCL10 for AA molecular pathological assessment and diagnosis (area under the receiver operating characteristic curve [AUC]=0.962). We also validated the diagnostic value of the IRGDS in an external cohort (AUC=0.955). Patients with high IRGDS scores presented with a higher abundance of immune cell infiltration and expression of genes associated with immune recruitment and immune activation, suggesting adverse biological alterations. Conclusion In our study, an IRGDS model with accurately diagnostic capacity for AA was established, and biological alterations were deciphered in AA. The IRGDS may be used as an auxiliary diagnostic marker for AA.

Objective:To assess the current state of care for Severe Postpartum Hemorrhage(SPPH)in refer-ral centers and non-referral centers,and to propose enhanced strategies for the regional prevention and manage-ment of SPPH.Methods:The clinical data of patients with SPPH,defined as postpartum blood loss≥1500 ml or transfusion of blood products≥1000 ml,in two districts of Beijing from January 2021 to June 2023 were retrospec-tively analyzed.A total of 201 cases of SPPH were included and they were divided into 125 cases in the referral center group and 76 cases in the non-referral center group based on whether they were city level referral centers.The clinical characteristics between these two groups were compared.Furthermore,a stratified analysis was con-ducted using a Logistic regression model to identify the risk factors associated with massive postpartum hemor-rhage,defined as postpartum hemorrhage≥4000 ml,transfusion requirements exceeding suspended red blood cells(RBC)>10 U and(or)plasma>1000 ml.Results:Analysis of cases presenting with SPPH between the two study groups showed that patients in the referral center group exhibited advanced maternal age,smaller gestation-al weeks at delivery and a higher proportion of high-risk factors compared to those in the non-referral center group,and the difference was statistically significant(P<0.05).The primary cause of SPPH in the referral center group was placental factors,while uterine atony was identified as the main factor in the non-referral center group,and this difference was statistically significant(P<0.05).Additionally,within the non-referral center group,there was a higher amount of blood loss during cesarean section,lower proportion of B-Lynch suture/vascular suture ligation,and higher proportion of uterine packing(P<0.05).Furthermore,compared to the referral center group,there were significantly higher incidences of plasma transfution volume,return to operating room for further inter-vention or exploratory laparotomy procedures after initial delivery and complications related to postpartum hemor-rhage observed in the non-referral center group(P<0.05).Moreover,it was noted that there were more cases of massive postpartum hemorrhagic disease reported in the non-referral center group than in the referral center group(P<0.05).In massive postpartum hemorrhage cases analyzed,referring centers had a higher percentage of patients presenting with multiple high-risk factors for postpartum hemorrhage during pregnancy when compared to non-referring centers(71.4%vs.33.3%,P<0.05).Placental factors accounted for majority causes leading to hemorrhage within referring centers(57.1%),whereas both uterine atony and placental factors played major roles within non-referring centers′cases(42.9%,28.6%).The multivariate Logistic regression analysis revealed that non-referral center delivery(aOR 3.47,95%CI 1.40-9.18)and a history of multiple intrauterine operations(aOR 12.63,95%CI 1.24-131.30)were identified as significant risk factors for massive postpartum hemor-rhage.Conclusions:The outcomes of high-risk pregnant women referral management in the region exhibit an im-provement,necessitating the reinforcement of training in non-referral midwifery institutions regarding identification of high-risk factors,surgical suture techniques,and comprehensive SPPH management to avert excessive bleed-ing and blood transfusion.

Objective:To explore the characteristics and typology of self-care behavior among patients with chronic heart failure (CHF), and analyze their influencing factors.Methods:A cross-sectional study was used. A total of 318 patients with CHF who were hospitalized in the Heart Center of Zhongshan Hospital, Fudan University from November 2022 to July 2023 were selected by continuous enrollment method. The General Information Questionnaire, Heart Failure Self-care Index Scale, Brief Illness Perception Questionnaire, Self-efficacy for Managing Chronic Disease 6-item Scale, Perceived Social Support Scale, Atlanta Heart Failure Knowledge Test-V2 and Self-Care Confidence Scale were used to investigate. Latent profile analysis was utilized to delineate the characteristics and subtypes of self-care behaviors in CHF patients and examine the influencing factors.Results:A total of 291 patients were included in this study, including 190 males and 101 females, aged 67 (61, 74) years old. The analysis identified three latent categories of self-care behaviors among CHF patients: 26 cases in high self-care group, 131 cases in moderate self-care with deficiencies in maintenance and symptom perception group, and 134 cases in low self-care group.Ordered multicategorical Logistic regression analysis revealed that age ( OR=1.023, 95% CI 1.001-1.046, P<0.05), self-care confidence ( OR=0.859, 95% CI 0.817-0.904, P<0.01), and social support ( OR=0.966, 95% CI 0.940-0.993, P<0.05) were the factors influencing the potential categories of self-care behavior in CHF patients. Conclusions:The study identifies distinct categorical characteristics of self-care behaviors in patients with CHF. Healthcare professionals can leverage these findings to identify the self-care behavior characteristics and influencing factors for each patient category at an early stage, thereby providing personalized and precise support strategies to help patients enhance self-care behaviors.

【Objective】 To screen the sterilizing-grade filters applicable for production of human coagulation factor Ⅷ/von Willebrand factor complex(FⅧ/VWF)and study the sterilization filtration process. 【Methods】 Four sterilizing-grade filters for FⅧ/VWF were evaluated through indicators such as filtration capacity, filtration flux, recovery rate of FⅧ activity, recovery rate of VWF activity, recovery rate of VWF antigen, recovery rate of protein and VWF molecular distribution. The sterilizing-grade filter with the best filtration performance was selected for further study. The study was designed by general full-factor design to determine the appropriate filitered protein concentration and filitered speed range through evaluating the total filtered protein amount, recovery rate of protein and filtration efficiency, and then the process operation parameters was determined. 【Results】 The filtration flux of Sartobran P, Sartopore 2 XLG, Sartopore Platinum and Sartopore 2 XLI were 1.71±0.01, 1.80±0.01, 1.34±0.01, and 1.81±0.04 L·(m²)^-1·min^-1, respectively; the recovery rates (%) of FⅧ activity were 97.09±2.82, 99.22±0.99, 96.87±1.85 and 93.76±1.21, respectively; the recovery rates (%) of VWF activity were 98.12±1.42, 99.95±1.85, 94.80±1.62 and 92.09±1.67, respectively. Between Sartopore 2 XLG and Sartobran P, the difference of filtration flux (P<0.001) was statistically significant; between Sartopore 2 XLG and Sartopore Platinum, the differences of the filtration flux (P<0.001) and VWF potency recovery rate (P<0.05) were statistically significant; between Sartopore 2 XLG and Sartopore 2 XLI, the differences of FⅧ potency recovery rate (P<0.01) and VWF potency recovery rate (P<0.01) were statistically significant. The optimal process operating space of Sartopore 2 XLG was protein concentration of 0.45-0.58 mg/mL, and filtration rate of 1.48-2.95 L·(m²)^-1·min^-1. 【Conclusion】 Sartopore 2 XLG is the most suitable filter for the production of FⅧ/VWF and the DoE test proves that it has good process operation space.

OBJECTIVE: To investigate the serum microRNA (miRNA) expression and examine the impact of miRNA expression profiles on T helper type 17 (Th17)/regulatory T cells (Treg) imbalance among patients with cystic echinococcosis, so as to provide insights into the illustration of the mechanisms underlying chronic Echinococcus granulosus infections, and long-term pathogenesis. METHODS: Total RNA was extracted from the sera of cystic echinococcosis patients and healthy controls, and subjected to high-throughput sequencing with the Illumina sequencing platform. Known miRNAs were annotated and new miRNAs were predicted using the miRBase database and the miRDeep2 tool, and differentially expressed miRNAs were identified. The target genes of differentially expressed miRNAs were predicted using the software miRanda and TargetScan, and the intersection was selected for Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Among the differentially expressed miRNAs with the 20 highest fold changes, miRNAs that targeted genes relating to key transcription factors RORC and FOXP3 that determine the production of Th17 and Treg cells or their important regulatory pathways (PI3K-Akt and mTOR pathways) were matched. RESULTS: A total of 53 differentially expressed miRNAs were screened in sera of cystic echinococcosis patients and healthy controls, including 47 up-regulated miRNAs and 6 down-regulated miRNAs. GO enrichment analysis showed that these differentially expressed miRNA were involved DNA transcription and translation, cell components, cell morphology, neurodevelopment and metabolic decomposition, and KEGG pathway analysis showed that the differentially expressed miRNA were mainly involved in MAPK, PI3K-Akt and mTOR signaling pathways. Among the differentially expressed miRNAs with the 20 highest fold changes, there were 3 miRNAs that had a potential for target regulation of RORC, and 15 miRNAs that had a potential to target the PI3K-Akt and mTOR signaling pathways. CONCLUSIONS Significant changes are found in serum miRNA expression profiles among patients with E. granulosus infections, and differentially expressed miRNAs may lead to Th17/Treg imbalance through targeting the key transcription factors of Th17/Treg or PI3K-Akt and mTOR pathways, which facilitates the long-term parasitism of E. granulosus in hosts and causes a chronic disease.
Echinococcosis/genetics* ; Gene Expression Profiling ; Humans ; MicroRNAs/metabolism* ; Phosphatidylinositol 3-Kinases/genetics* ; Proto-Oncogene Proteins c-akt/genetics* ; T-Lymphocytes, Regulatory ; TOR Serine-Threonine Kinases/genetics* ; Th17 Cells ; Transcription Factors/genetics*

Herein, we define the role of ferroptosis in the pathogenesis of diabetic cardiomyopathy (DCM) by examining the expression of key regulators of ferroptosis in mice with DCM and a new ex vivo DCM model. Advanced glycation end-products (AGEs), an important pathogenic factor of DCM, were found to induce ferroptosis in engineered cardiac tissues (ECTs), as reflected through increased levels of Ptgs2 and lipid peroxides and decreased ferritin and SLC7A11 levels. Typical morphological changes of ferroptosis in cardiomyocytes were observed using transmission electron microscopy. Inhibition of ferroptosis with ferrostatin-1 and deferoxamine prevented AGE-induced ECT remodeling and dysfunction. Ferroptosis was also evidenced in the heart of type 2 diabetic mice with DCM. Inhibition of ferroptosis by liproxstatin-1 prevented the development of diastolic dysfunction at 3 months after the onset of diabetes. Nuclear factor erythroid 2-related factor 2 (NRF2) activated by sulforaphane inhibited cardiac cell ferroptosis in both AGE-treated ECTs and hearts of DCM mice by upregulating ferritin and SLC7A11 levels. The protective effect of sulforaphane on ferroptosis was AMP-activated protein kinase (AMPK)-dependent. These findings suggest that ferroptosis plays an essential role in the pathogenesis of DCM; sulforaphane prevents ferroptosis and associated pathogenesis via AMPK-mediated NRF2 activation. This suggests a feasible therapeutic approach with sulforaphane to clinically prevent ferroptosis and DCM.

［摘要］ 目的：探讨穿膜蛋白125（transmembrane protein125，TMEM125）在肺腺癌组织与A549 细胞中的表达，以及影响细胞 的增殖和侵袭能力的分子机制。方法：从癌症基因组图谱（the cancer genome atlas，TCGA）数据库收集肺腺癌数据包，下载临床 信息及基因表达谱数据。分析TMEM125 在肺腺癌组织中的表达及其与患者总生存期的相关性。构建TMEM125 过表达A549 细胞株，以CCK-8 法、细胞划痕实验检测TMEM125 过表达对肿瘤细胞的增殖和迁移能力的影响；流式细胞术检测TMEM125 过 表达对A549 细胞的细胞周期和凋亡的影响。WB检测TMEM125 过表达对下游NF-κB信号通路、凋亡蛋白的影响；免疫共沉淀 法（co-immunoprecipitation，Co-IP）检测TMEM125 与NF- κB 抑制因子结合Ras 样2（NF- κB inhibitor interacting Ras-like 2， NKIRAS2）的相互作用。利用TNFα（10 ng/ml）处理TMEM125 过表达A549 细胞，CKK-8、流式细胞术及WB检测其对细胞增殖、 凋亡以及NF-κB信号通路相关蛋白表达的影响。去甲基化试剂地西他滨处理A549 细胞，qPCR和WB检测TMEM125 基因和蛋 白的表达。结果：TMEM125 mRNA在肺腺癌组织中表达水平显著低于正常组织（P<0.001），启动子甲基化水平显著高于正常组 织（P<0.001），并且低、中表达患者总生存期显著低于高表达患者（P<0.001）。过表达TMEM125 抑制了A549 细胞的增殖和迁移 （P<0.01），增加细胞G2/M 期，促进细胞凋亡（P<0.01）；过表达TMEM125 与NKIRAS2 相互作用，显著抑制NF- κB 的活性 （P<0.01）；地西他滨处理A549 细胞可促进TMEM125 表达并且抑制细胞增殖（P<0.01）。结论：启动子高甲基化水平降低了 TMEM125 基因表达，导致其抑制NF-κB活性功能和抑制细胞增殖的作用下降，并且降低了细胞对地西他滨的敏感性。

Objective To evaluate the value of cardiac MR imaging in chronic ischemie mitral regurgitation (IMR) in patients with myocardial infarction. Methods All patients clinically diagnosed with coronary heart disease and myocardial infarction in our hospital from January 2016 to September 2018 were retrospectively selected, myocardial infarction time more than 3 months and confirmed to have necrotic myocardium by cardiac magnetic resonance examination. All patients underwent echocardiography at the same time. Based on the results of echocardiography, patients were divided into the myocardial infarction group without IMR (40 cases), the mild IMR group (39 cases) and the moderate to severe IMR group (51 cases). Cardiac MR and delayed enhancement (LGE) scan images were analyzed. Cardiac function indexes were measured and left ventricular LGE positive segments were recorded. The indexes of myocardial global longitudinal strain (GLS), global peripheral strain (GCS) and global radial strain (GRS) of left ventricle of IMR patients were measured by feature tracking(FT). Cardiovascular history, coronary artery stenosis and location of myocardial infarction were compared by chi?square test between the without IMR, mild IMR and moderate to severe IMR groups.Univariate analysis of variance was used to compare the measurement data of left ventricular myocardial infarction volume, left heart function and left ventricular myocardial globle strain, and LSD test was used for pair?wise comparison. Results There was no difference in age, sex and cardiovascular history among the three groups. Comparison of myocardial infarction patients in the three groups: (1) There was no statistically significant difference in the myocardial infarction volume between the three groups (P=0.052), while the myocardial infarction volume tended to increase as the grade of mitral regurgitation increased. The number of patients with myocardial infarction in the inferior wall and the inferolateral wall in the moderate to severe IMR group were significantly higher than those of the other two groups (P<0.05), and there was no significant difference in the volume of myocardial infarction between the without IMR group and mild IMR group, and no difference in the number of patients with inferior wall and inferolateral wall. (2) Cardiac function measured by CMR: ejection fraction (EF) was significantly reduced in the moderate to severe IMR group compared with the without IMR group and the mild IMR group (P<0.05), the end diastolic volume (EDV) increased significantly and the end systolic volume (ESV) increased significantly (P<0.05). Mass of myocardium increased significantly (P<0.05); Stroke volume (SV) and cardiac output (CO) there was no significant difference among the three groups. (3) Comparison of the moderate to severe IMR group to the without IMR group and the mild IMR group respectively: left ventricular GLS and GRS decreased (P<0.05), the difference of the GCS was no statistically significant. There was no statistical difference in the three strain values between the without IMR group and the mild IMR group. Conclusion The globe myocardial strain of the left ventricle in myocardial infarction patients with chronic moderate to severe IMR was significantly impaired, the myocardial infarction in the inferior wall and the inferolateral wall in the level of the papillary muscle may be correlated with chronic moderate to severe IMR, and the myocardial infarction volume of the left ventricle may also be related.

Objective: To evaluate the value of cardiac MR imaging in chronic ischemie mitral regurgitation (IMR) in patients with myocardial infarction. Methods: All patients clinically diagnosed with coronary heart disease and myocardial infarction in our hospital from January 2016 to September 2018 were retrospectively selected, myocardial infarction time more than 3 months and confirmed to have necrotic myocardium by cardiac magnetic resonance examination. All patients underwent echocardiography at the same time. Based on the results of echocardiography, patients were divided into the myocardial infarction group without IMR (40 cases), the mild IMR group (39 cases) and the moderate to severe IMR group (51 cases). Cardiac MR and delayed enhancement (LGE) scan images were analyzed. Cardiac function indexes were measured and left ventricular LGE positive segments were recorded. The indexes of myocardial global longitudinal strain (GLS), global peripheral strain (GCS) and global radial strain (GRS) of left ventricle of IMR patients were measured by feature tracking(FT). Cardiovascular history, coronary artery stenosis and location of myocardial infarction were compared by chi-square test between the without IMR, mild IMR and moderate to severe IMR groups.Univariate analysis of variance was used to compare the measurement data of left ventricular myocardial infarction volume, left heart function and left ventricular myocardial globle strain, and LSD test was used for pair-wise comparison. Results: There was no difference in age, sex and cardiovascular history among the three groups. Comparison of myocardial infarction patients in the three groups: (1) There was no statistically significant difference in the myocardial infarction volume between the three groups (P=0.052), while the myocardial infarction volume tended to increase as the grade of mitral regurgitation increased. The number of patients with myocardial infarction in the inferior wall and the inferolateral wall in the moderate to severe IMR group were significantly higher than those of the other two groups (P<0.05), and there was no significant difference in the volume of myocardial infarction between the without IMR group and mild IMR group, and no difference in the number of patients with inferior wall and inferolateral wall. (2) Cardiac function measured by CMR: ejection fraction (EF) was significantly reduced in the moderate to severe IMR group compared with the without IMR group and the mild IMR group (P<0.05), the end diastolic volume (EDV) increased significantly and the end systolic volume (ESV) increased significantly (P<0.05). Mass of myocardium increased significantly (P<0.05); Stroke volume (SV) and cardiac output (CO) there was no significant difference among the three groups. (3) Comparison of the moderate to severe IMR group to the without IMR group and the mild IMR group respectively: left ventricular GLS and GRS decreased (P<0.05), the difference of the GCS was no statistically significant. There was no statistical difference in the three strain values between the without IMR group and the mild IMR group. Conclusion The globe myocardial strain of the left ventricle in myocardial infarction patients with chronic moderate to severe IMR was significantly impaired, the myocardial infarction in the inferior wall and the inferolateral wall in the level of the papillary muscle may be correlated with chronic moderate to severe IMR, and the myocardial infarction volume of the left ventricle may also be related.