OBJECTIVE: To explore the significance of thrombus biomarkers in evaluating the progression of immunoglobulin A vasculitis (IgAV) in children. METHODS: A total of 193 children who were diagnosed as IgAV from September 2021 to June 2023 in the Children's Hospital of Soochow University were enrolled. The levels of plasma thrombomodulin (TM), thrombin-antithrombin complex (TAT), plasmin-α2-plasmin inhibitor complex (PIC), tissue plasminogen activator-plasminogen activator inhibitor-1 complex (t-PAIC) and D-dimer (D-D) were analyzed retrospectively. And, 140 healthy children were selected as controls during the same period. The receiver operating characteristic (ROC) curves were drawn to analyze the role of thrombus parameters in estimating the progression of IgAV in children. Univariate and multivariate logistic regression analysis were used to assess the independent risk factors influencing the progression of pediatric IgAV in acute phase. RESULTS: The levels of D-D, TAT, PIC and t-PAIC in plasma of IgAV group were higher than those in control group (all P <0.001). The levels of D-D, TAT and PIC in acute phase children were significantly higher than those in non acute phase children (all P <0.001), while the levels of kidney injury related indicators such as 24h-UTP, urine albumin/creatinine ratio, positive urinary blood on dipstick, serum creatinine and cystatin C were lower (all P <0.05). ROC analysis showed that the area under curve (AUC) of PIC was 0.743 when the cut-off value was 0.93 μg/ml with 71.8% sensitivity and 78.3% specificity, while the AUC of D-D was 0.756 when the cut-off value was 550.0 μg/L with 81.3% sensitivity and 73.4% specificity. Univariate and multivariate logistic regression analysis showed that PIC≥0.93 μg/ml (OR =4.64, P =0.012) and D-D≥550.0 μg/L (OR =3.60, P =0.035) were the independent risk factors for the progression of IgAV in acute phase. CONCLUSION The pediatric patients with IgAV have shown hyperfibrinolysis in the acute stage. Furthermore, the levels of PIC and D-D should be of diagnostic value for evaluating the progression of IgAV in the acute phase.
Humans ; Biomarkers/blood* ; Child ; Fibrin Fibrinogen Degradation Products ; Retrospective Studies ; Thrombosis ; Female ; Male ; Disease Progression ; Thrombomodulin/blood* ; ROC Curve ; Vasculitis/blood* ; Antithrombin III ; Plasminogen Activator Inhibitor 1/blood* ; IgA Vasculitis/blood* ; alpha-2-Antiplasmin ; Adolescent ; Child, Preschool ; Fibrinolysin

Hereditary angioedema (HAE) is a rare,unpredictable,autosomal dominant disorder characterized by recurrent swelling in subcutaneous and submucosal tissue.In recent years,the pathophysiology and pathogenesis of HAE have been continuously studied and elucidated.In addition to the genes encoding complement 1 esterase inhibitors,new pathogenic variants have been identified in the genes encoding coagulation factor Ⅻ,plasminogen,angiopoietin-1,kininogen,heparan sulfate 3-O-sulfotransferase 6,and myoferlin in HAE.Moreover,different pathogenic variants have different mechanisms in causing HAE.In addition,the pathogenic genes of some patients remain unknown.This review summarizes the recent progress in the classification,epidemiology,pathophysiology,and pathogenesis of HAE,aiming to provide ideas for further fundamental research,clinical diagnosis,and drug development of HAE.
Humans ; Angioedemas, Hereditary/diagnosis* ; Angiopoietin-1/metabolism* ; Plasminogen/metabolism* ; Kininogens/metabolism* ; Complement C1 Inhibitor Protein/metabolism*

INTRODUCTION: Pleural infections are a significant cause of mortality. Intrapleural fibrinolytic therapy (IPFT) utilising alteplase and dornase is a treatment option for patients unsuitable for surgery. The optimal dose of alteplase is unknown, and factors affecting treatment success in an Asian population are unclear. We sought to determine the factors affecting treatment success in Tan Tock Seng Hospital, Singapore and evaluate the efficacy of lower doses of IPFT. METHOD: A retrospective analysis of patients with pleural infections treated with IPFT between July 2016 and November 2023 was performed. Treatment success was defined as survival without surgery at 3 months. Data, including patient demographics; comorbidities; RAPID (renal, age, purulence, infection source and dietary factor) scores; and radiological characteristics, were extracted from medical records and analysed. Linear mixed effects model and logistic regression were performed to determine factors affecting treatment success. RESULTS: A total of 131 cases were analysed. Of these, 51 (38.9%) reported positive pleural fluid culture, and the most common organism was Streptoccocus anginosus. Mean age was 65 years (standard deviation [SD] 15.5). Mean time from chest tube insertion to first dose of IPFT was 10.2 days (SD 11.5). Median starting dose of alteplase was 5 mg. Treatment success was reported in 112 cases (85.5%). There were no significant differences between the alteplase dose and radiological clearance. Patient age (odds ratio [OR] 0.94, confidence interval [CI] 0.89-0.98) and interval between chest tube insertion to first dose (OR 0.95, CI 0.91-0.99) were statistically significant variables for the treatment success. CONCLUSION Lower starting doses of alteplase remain effective in the treatment of pleural infection. Early IPFT may result in better outcomes.
Humans ; Tissue Plasminogen Activator/therapeutic use* ; Retrospective Studies ; Aged ; Fibrinolytic Agents/therapeutic use* ; Male ; Female ; Middle Aged ; Thrombolytic Therapy/methods* ; Treatment Outcome ; Singapore ; Pleural Effusion/drug therapy* ; Pleural Diseases/drug therapy* ; Cohort Studies ; Chest Tubes ; Deoxyribonuclease I ; Recombinant Proteins

The development, progression, and curative efficacy of head and neck squamous cell carcinoma (HNSCC) are influenced by complex interactions between epithelial and immune cells. Nevertheless, the specific changes in the nature of these interactions and their underlying molecular mechanisms in HNSCC are not yet fully understood. Cuproptosis, a form of programmed cell death that is dependent on copper, has been implicated in cancer pathogenesis. However, the understanding of cuproptosis in the context of HNSCC remains limited. In this study, we have discovered that cuproptosis-related long non-coding RNAs (CRLs) known as JPX play a role in promoting the expression of the oncogene urokinase-type plasminogen activator (PLAU) by competitively binding to miR-193b-3p in HNSCC. The increased activity of the JPX/miR-193b-3p/PLAU axis in malignant epithelial cells leads to enhanced cell proliferation, migration, and invasion in HNSCC. Moreover, the overexpression of PLAU in tumor epithelial cells facilitates its interaction with the receptor PLAUR, predominantly expressed on macrophages, thereby influencing the abnormal epithelial-immune interactome in HNSCC. Notably, the JPX inhibitor Axitinib and the PLAU inhibitor Palbociclib may not only exert their effects on the JPX/miR-193b-3p/PLAU axis that impacts the malignant tumor behaviors and the epithelial-immune cell interactions but also exhibit synergistic effects in terms of suppressing tumor cell growth and arresting cell cycle by targeting epidermal growth factor receptor (EGFR) and cyclin-dependent kinase (CDK4/6) for the treatment of HNSCC.
Humans ; MicroRNAs/metabolism* ; RNA, Long Noncoding/metabolism* ; Head and Neck Neoplasms/metabolism* ; Cell Proliferation ; Squamous Cell Carcinoma of Head and Neck/genetics* ; Urokinase-Type Plasminogen Activator/genetics* ; Cell Movement ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic ; Carcinoma, Squamous Cell/genetics* ; Neoplasm Invasiveness

OBJECTIVE: To establish a machine learning model to predict the risk of early neurological deterioration (END) based on the clinical and laboratory data of patients with acute ischemic stroke (AIS) before intravenous thrombolysis. METHODS: The clinical data of AIS patients who received intravenous thrombolytic with recombinant tissue plasminogen activator (rt-PA) at the Stroke Center of the First Hospital of Qinhuangdao City from January 2019 to July 2022 were retrospectively analyzed. Patients were divided into END group and non-END group according to whether END appeared after intravenous thrombolytic. Clinical data of patients at admission were collected, including demographic characteristics, clinical evaluation, comorbidification, drug use history, laboratory tests, etc. Univariate and multivariate Logistic regression analysis were performed to screen out the independent predictors of the END of AIS patients after intravenous thrombolytic. The study subjects were randomly divided into a training set and a test set in a 7 : 3 ratio. Four machine learning prediction models, including Logistic regression (LR), K-nearest neighbor (KNN), support vector machine (SVM) and random forest (RF), were established based on independent predictors. The receiver operator characteristic curve (ROC curve) was used to evaluate the predictive ability of each model in END. RESULTS: A total of 704 patients were enrolled, of whom 99 were identified as END and 605 as non-END. Univariate and multivariate Logistic regression analysis was used to screen out the National Institutes of Health stroke scale [NIHSS, odds ratio (OR) = 1.049, 95% confidence interval (95%CI) was 1.015-1.082, P = 0.004], systolic blood pressure (OR = 1.013, 95%CI was 1.004-1.022, P = 0.004), lymphocyte percentage (LYM%, OR = 0.903, 95%CI was 0.853-0.953, P < 0.001), platelet to lymphocyte ratio (PLR, OR = 1.007, 95%CI was 1.002-1.014, P = 0.013) were the independent predictors of END in AIS patients after intravenous thrombolysis. The area under the curve (AUC) of LR, KNN, SVM, and RF machine learning models in the test dataset were 0.789 (95%CI was 0.675-0.902), 0.797 (95%CI was 0.685-0.910), 0.851 (95%CI was 0.751-0.952) and 0.809 (95%CI was 0.699-0.919), respectively. The RF model had the highest sensitivity (95.7%). The accuracy (0.736), specificity (72.0%) and AUC of SVM model were the highest, and its overall prediction ability was better than the other three models. CONCLUSIONS Machine learning models have a potential role in early predicting the risk of END after intravenous thrombolysis in AIS patients, and can provide help in clinical decision-making for intravenous thrombolysis.
Humans ; Tissue Plasminogen Activator/therapeutic use* ; Ischemic Stroke/drug therapy* ; Brain Ischemia ; Retrospective Studies ; Thrombolytic Therapy ; Stroke ; Fibrinolytic Agents/therapeutic use*

The approach combining disease, syndrome, and symptom was employed to investigate the characteristic changes of blood stasis syndrome in a rat model of steroid-induced osteonecrosis of the femoral head(SONFH) during disease onset and progression. Seventy-two male SD rats were randomized into a healthy control group and a model group. The rat model of SONFH was established by injection of lipopolysaccharide(LPS) in the tail vein at a dose of 20 μg·kg~(-1)·d~(-1) on days 1 and 2 and gluteal intramuscular injection of methylprednisolone sodium succinate(MPS) at a dose of 40 mg·kg~(-1)·d~(-1) on days 3-5, while the healthy control group received an equal volume of saline. The mechanical pain test, tongue color RGB technique, gait detection, open field test, and inclined plane test were employed to assess hip pain, tongue color, limping, joint activity, and lower limb strength, respectively, at different time points within 21 weeks of modeling. At weeks 2, 4, 8, 12, 16, and 21 after modeling, histopathological changes of the femoral head were observed by hematoxylin-eosin(HE) staining and micro-CT scanning; four coagulation items were measured by rotational thromboelastometry; and enzyme-linked immunosorbent assay(ELISA) was employed to determine the levels of six blood lipids, vascular endothelial growth factor(VEGF), endothelin-1(ET-1), nitric oxide(NO), tissue-type plasminogen activator(t-PA), plasminogen activator inhibitor factor-1(PAI-1), bone gla protein(BGP), alkaline phosphatase(ALP), receptor activator of nuclear factor-κB(RANKL), osteoprotegerin(OPG), and tartrate-resistant acid phosphatase 5b(TRAP5b) in the serum, as well as the levels of 6-keto-prostaglandin 1α(6-keto-PGF1α) and thromboxane B2(TXB2) in the plasma. The results demonstrated that the pathological alterations in the SONFH rats were severer over time. The bone trabecular area ratio, adipocyte number, empty lacuna rate, bone mineral density(BMD), bone volume/tissue volume(BV/TV), trabecular thickness(Tb.Th), trabecular number(Tb.N), bone surface area/bone volume(BS/BV), and trabecular separation(Tb.Sp) all significantly increased or decreased over the modeling time after week 4. Compared with the healthy control group, the mechanical pain threshold, gait swing speed, stride, standing time, and walking cycle of SONFH rats changed significantly within 21 weeks after modeling, with the greatest difference observed 12 weeks after modeling. The time spent in the central zone, rearing score, and maximum tilt angle in the open field test of SONFH rats also changed significantly over the modeling time. Compared with the healthy control group, the R, G, and B values of the tongue color of the model rats decreased significantly, with the greatest difference observed 11 weeks after modeling. The levels of total cholesterol(TC), total triglycerides(TG), low-density lipoprotein-cholesterol(LDL-C), and apoprotein B(ApoB) in the SONFH rats changed significantly 4 and 8 weeks after modeling. The levels of VEGF, ET-1, NO, t-PA, PAI-1, 6-keto-PGF1α, TXB2, four coagulation items, and TXB2/6-keto-PGF1α ratio in the serum of SONFH rats changed significantly 4-16 weeks after modeling, with the greatest differences observed 12 weeks after modeling. The levels of BGP, TRAP5b, RANKL, OPG, and RANKL/OPG ratio in the serum of SONFH rats changed significantly 8-21 weeks after modeling. During the entire onset and progression of SONFH in rats, the blood stasis syndrome characteristics such as hyperalgesia, tongue color darkening, gait abnormalities, platelet, vascular, and coagulation dysfunctions were observed, which gradually worsened and then gradually alleviated in the disease course(2-21 weeks), with the most notable differences occurred around 12 weeks after modeling.
Rats ; Male ; Animals ; Femur Head/pathology* ; Plasminogen Activator Inhibitor 1/adverse effects* ; Vascular Endothelial Growth Factor A ; Femur Head Necrosis/pathology* ; Rats, Sprague-Dawley ; Steroids ; Pain ; Cholesterol

OBJECTIVE: To interpret the pharmacology of quercetin in treatment of atherosclerosis (AS). METHODS: Fourteen apolipoprotein E-deficient (ApoE^-/-) mice were divided into 2 groups by a random number table: an AS model (ApoE^-/-) group and a quercetin treatment group (7 in each). Seven age-matched C57 mice were used as controls (n=7). Quercetin [20 mg/(kg·d)] was administered to the quercetin group intragastrically for 8 weeks for pharmacodynamic evaluation. Besides morphological observation, the distribution of CD11b, F4/80, sirtuin 1 (Sirt1) and P21 was assayed by immunohistochemistry and immunofluorescence to evaluate macrophage infiltration and tissue senescence. Ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MSC/MS) was performed to study the pharmacology of quercetin against AS. Then, simultaneous administration of an apelin receptor antagonist (ML221) with quercetin was conducted to verify the possible targets of quercetin. Key proteins in apelin signaling pathway, such as angiotensin domain type 1 receptor-associated proteins (APJ), AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), tissue plasminogen activator (TPA), uncoupling protein 1 (UCP1) and angiotensin II receptor 1 (AT1R), were assayed by Western blot. RESULTS: Quercetin administration decreased lipid deposition in arterial lumen and improved the morphology of ApoE^-/- aortas in vivo. Quercetin decreased the densities of CD11b, F4/80 and P21 in the aorta and increased the level of serum apelin and the densities of APJ and Sirt1 in the aorta in ApoE^-/- mice (all P<0.05). Plasma metabolite profiling identified 118 differential metabolites and showed that quercetin affected mainly glycerophospholipids and fatty acyls. Bioinformatics analysis suggested that the apelin signaling pathway was one of the main pathways. Quercetin treatment increased the protein expressions of APJ, AMPK, PGC-1α, TPA and UCP1, while decreased the AT1R level (all P<0.05). After the apelin pathway was blocked by ML221, the effect of quercetin was abated significantly, confirming that quercetin attenuated AS by modulating the apelin signaling pathway (all P<0.05). CONCLUSION Quercetin alleviated AS lesions by up-regulation the apelin signaling pathway.
Mice ; Animals ; Apelin ; Tissue Plasminogen Activator/metabolism* ; Quercetin/therapeutic use* ; AMP-Activated Protein Kinases/metabolism* ; Sirtuin 1/metabolism* ; Signal Transduction/physiology* ; Atherosclerosis/metabolism* ; Apolipoproteins E

This study was designed to evaluate the protective effect of CPD1, a novel phosphodiesterase 5 inhibitor, on renal interstitial fibrosis after unilateral renal ischemia-reperfusion injury (UIRI). Male BALB/c mice were subjected to UIRI, and treated with CPD1 once daily (i.g, 5 mg/kg). Contralateral nephrectomy was performed on day 10 after UIRI, and the UIRI kidneys were harvested on day 11. Hematoxylin-eosin (HE), Masson trichrome and Sirius Red staining methods were used to observe the renal tissue structural lesions and fibrosis. Immunohistochemical staining and Western blot were used to detect the expression of proteins related to fibrosis. HE, Sirius Red and Masson trichrome staining showed that CPD1-treated UIRI mice had lower extent of tubular epithelial cell injury and deposition of extracellular matrix (ECM) in renal interstitium compared with those in the fibrotic mouse kidneys. The results from immunohistochemistry and Western blot assay indicated significantly decreased protein expressions of type I collagen, fibronectin, plasminogen activator inhibitor-1 (PAI-1) and α-smooth muscle actin (α-SMA) after CPD1 treatment. In addition, CPD1 dose-dependently inhibited the expression of ECM-related proteins induced by transforming growth factor β1 (TGF-β1) in normal rat kidney interstitial fibroblasts (NRK-49F) and human renal tubular epithelial cell line (HK-2). In summary, the novel PDE inhibitor, CPD1, displays strong protective effects against UIRI and fibrosis by suppressing TGF-β signaling pathway and regulating the balance between ECM synthesis and degradation through PAI-1.
Animals ; Humans ; Male ; Mice ; Rats ; Extracellular Matrix Proteins ; Fibrosis ; Kidney ; Kidney Diseases ; Phosphodiesterase 5 Inhibitors ; Plasminogen Activator Inhibitor 1

Objective: To evaluate the clinical value of new coagulation biomarkers including soluble thrombomodulin (sTM) and tissue plasminogen activator inhibitor complex (t-PAI·C) for the diagnosis and prognosis of sepsis in children. Methods: The prospective observational study enrolled 59 children who were diagnosed with sepsis including severe sepsis and septic shock in the Department of Pediatric Critical Care Medicine of Shanghai Children's Medical Center affiliated to the Medical College of Shanghai Jiao Tong University from June 2019 to June 2021. The sTM, t-PAI·C and conventional coagulation tests were detected on illness day one of sepsis. Twenty healthy children were selected as the control group, and the above parameters were detected on the day of inclusion. Children with sepsis were divided into survival group and non-survival group according to prognosis at discharge. Baseline comparisons between groups were performed using Mann-Whitney U test. Multivariate Logistic regression analysis was used to evaluate the risk factors for the diagnosis and prognosis of sepsis in children. Receiver operating characteristic (ROC) curve was conducted to evaluate the predictive values of above variables for the diagnosis and prognosis of sepsis in children. Results: The sepsis group included 59 patients (39 boys and 20 girls), aged 61(22, 136)months. There were 44 patients in the survival group and 15 patients in the non-survival group, respectively. The control group consisted of 20 boys, aged 107 (94,122) months. Patients in the sepsis group had higher sTM and t-PAI·C ((12 (9, 17)×10³ vs. 9(8, 10)×10³ TU/L, 10(6, 22) vs. 2 (1, 3) μg/L, Z=-2.15, -6.05, both P<0.05) compared with children in the control group. The t-PAI·C was superior to sTM for the diagnosis of sepsis. The areas under the curve (AUC) of t-PAI·C and sTM for the diagnosis of sepsis were 0.95 and 0.66, respectively, and the optimal cut-off value were 3 μg/L and 12×10³ TU/L, respectively. Patients in the survival group had lower sTM (10 (8, 14)×10³ vs. 17 (11, 36)×10³ TU/L, Z=-2.73, P=0.006) than those in the non-survival group. Logistic regression analysis showed that sTM was a risk factor for death at discharge (OR=1.14, 95%CI 1.04-1.27, P=0.006). The AUC of sTM and t-PAI·C for predicting death at discharge were 0.74 and 0.62, respectively, and the optimal cut-off values were 13×10³ TU/L and 6 μg/L, respectively. The AUC of sTM combined with platelet counts for predicting death at discharge was 0.89, which was superior to sTM and t-PAI·C. Conclusion: The sTM and t-PAI·C had clinical application values in diagnosing and predicting prognosis in pediatric sepsis.
Child ; Female ; Humans ; Male ; Biomarkers ; China ; Sepsis/diagnosis* ; Shock, Septic ; Tissue Plasminogen Activator ; Infant ; Child, Preschool

Hypoxia, as an important hallmark of the tumor microenvironment, is a major cause of oxidative stress and plays a central role in various malignant tumors, including glioblastoma. Elevated reactive oxygen species (ROS) in a hypoxic microenvironment promote glioblastoma progression; however, the underlying mechanism has not been clarified. Herein, we found that hypoxia promoted ROS production, and the proliferation, migration, and invasion of glioblastoma cells, while this promotion was restrained by ROS scavengers N-acetyl-L-cysteine (NAC) and diphenyleneiodonium chloride (DPI). Hypoxia-induced ROS activated hypoxia-inducible factor-1α (HIF-1α) signaling, which enhanced cell migration and invasion by epithelial-mesenchymal transition (EMT). Furthermore, the induction of serine protease inhibitor family E member 1 (SERPINE1) was ROS-dependent under hypoxia, and HIF-1α mediated SERPINE1 increase induced by ROS via binding to the SERPINE1 promoter region, thereby facilitating glioblastoma migration and invasion. Taken together, our data revealed that hypoxia-induced ROS reinforce the hypoxic adaptation of glioblastoma by driving the HIF-1α-SERPINE1 signaling pathway, and that targeting ROS may be a promising therapeutic strategy for glioblastoma.
Humans ; Cell Hypoxia ; Cell Line, Tumor ; Glioblastoma/pathology* ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism* ; Plasminogen Activator Inhibitor 1/metabolism* ; Reactive Oxygen Species/metabolism* ; Signal Transduction ; Tumor Microenvironment ; Brain Neoplasms/pathology*