Novel Biomarkers: Soluble Urokinase-Type Plasminogen Activator Receptor and Procalcitonin- and Histological Chorioamnionitis after Preterm Premature Rupture of Membranes.

Fetal inflammatory response syndrome or infection after preterm premature rupture of membranes (PPROM) increases neonatal morbidity in preterm deliveries. Biochemical markers from the amniotic fluid (AF) have been used to evaluate possible intra-amniotic infection during the asymptomatic phase after PPROM. This study aimed to describe whether soluble urokinase-type plasminogen activator receptor (suPAR) or procalcitonin (PCT) from AF or maternal sera could reveal fetal inflammatory response or infection after PPROM. AF and maternal serum samples were collected weekly after PPROM (23+ 0 - 34+ 6 gestational weeks) until delivery from twenty women and two women with possible chorioamnionitis with intact membranes. Levels of suPAR, PCT, interleukin-6 (IL-6), glucose, lactate dehydrogenase (LDH), and bacterial PCR were determined from AF and suPAR and PCT and IL-6 from maternal sera. Fetal infection or inflammation response were determined by the histology of the placenta after delivery. AF glucose was significantly lower and AF LDH higher in the fetal site histologic chorioamnionitis (HCA) group, while AF suPAR concentrations tended to be higher in this group. AF suPAR correlated significantly with AF glucose and LDH. Based on receiver operating characteristic (ROC) analysis, AF glucose had the best predictability for fetal site histological chorioamnionitis. The findings of AF PCT were insignificant considering HCA. AF glucose had the highest accuracy in predicting fetal site histologic chorioamnionitis. AF suPAR may be a promising marker; however, our findings were limited by a small study population.

High-sensitive troponin T, suPAR and Beta-2-microglobulin changes in concentration during hemodialysis.

Hemodialysis (HD) patients are at high risk of cardiovascular disease and death. Reliable biomarkers for risk stratification and detection of acute myocardial infarction (AMI) are therefore pivotal. Cardiac troponins (cTn) are the preferred biomarkers for AMI. It remains unclear, if cTn concentrations changes as a consequence of HD treatment itself during dialysis. In this study, cTn was compared with soluble urokinase plasminogen activator receptor (suPAR) and Beta-2-microglobulin (B2M). We performed a prospective study including 17 HD patients measuring high-sensitive cardiac troponin t (hs-cTnT), suPAR and B2M before and after a dialysis session and verified the results in a random subgroup of eight patients from the group by repeating their measurements before and after a dialysis session 15 weeks later. Biomarker concentrations after dialysis were adjusted according to hemodilution or concentration according to the hemoglobin concentration. The average hs-cTnT concentration decreased significantly by -9.9% after dialysis (95% CI: -13.6% to -6.2%). The average (paired) difference were - 6.7 ng/L (p = 0.0104) after dialysis comparing 25 HD treatment occasions. SuPAR was not significantly influenced by dialysis. B2M decreased by -58% after HD as an expected result from the molecular size of the biomarker. The hs-cTnT in average decreased by -9.9% after dialysis. This is a diagnostic challenge since the current guidelines suggest a 20% change in hs-cTnT in patients with acute myocardial infarction. Larger prospective studies investigating the different factors influencing hs-cTnT after HD are warranted. Adjusting biomarker concentrations according to hemodilution or concentration using the hemoglobin concentration, should be considered in future studies to determine more exact changes in concentrations of cTnT and other relevant biomarkers.

Thrombolytic therapy as a superior option: Insights from three cases of acute subdural hematoma following surgery for chronic subdural hematoma.

BACKGROUND: Chronic subdural hematoma (cSDH) ranks among the most prevalent neurosurgical conditions, with burr-hole drainage typically yielding favorable prognoses. Nevertheless, perioperative complications may arise, with remote intraparenchymal hemorrhage and subarachnoid hemorrhage occurring infrequently, while acute subdural hematoma (aSDH) remains a relatively common complication post-cSDH removal. The standard treatment for aSDH, typically large craniotomy, substantially elevates surgical risk. CASE DESCRIPTION: This study presents three cases of postoperative aSDH in elderly patients with cSDH, examining potential causative factors and proposing pertinent strategies. Three elderly patients, admitted urgently due to exacerbating symptoms, underwent preoperative assessment followed by emergency parietal burr-hole drainage. Regrettably, all three patients developed aSDH postoperatively. Various treatment approaches were employed: two cases received thrombolysis with 50,000 units of urokinase, while one case required a large craniotomy. Despite the patients achieving satisfactory outcomes without significant neurological deficits, this study advocates thrombolytic therapy as a potentially superior option for aSDH following cSDH surgery. CONCLUSION: Urokinase-mediated subdural thrombolysis enhances hematoma clearance rates, suggesting a shift towards minimally invasive treatments to mitigate greater trauma. However, the paucity of evidence necessitates extensive research to validate its safety and efficacy.

Risk factors for gastrointestinal bleeding in patients with intracerebral hemorrhage: A propensity score matching analysis.

BACKGROUND: Gastrointestinal bleeding (GIB) is a common complication of intracerebral hemorrhage (ICH). Rate pressure product (RPP) is an objective hemodynamic index that is closely related to the prognosis of cardia-cerebrovascular disease. The purpose of this study was to investigate the relationship between RPP and GIB in ICH patients. METHODS: We retrospectively analyzed data from ICH patients admitted to the neurosurgery department of Nanchang University affiliated with Ganzhou Hospital from January 2019 to December 2021. The patients were divided into a GIB group and a non-GIB group according to whether they had GIB. Propensity score matching was used to match between the two groups. Univariate analysis was used to select factors affecting GIB, and multivariate conditional logistic regression was used to analyze the independent factors associated with GIB. RESULTS: There were 1232 patients included in the study, including 182 in the GIB group and 1050 in the non-GIB group, and 182 pairs of patients were successfully matched through propensity score matching. The univariate analysis showed that high RPP, low Glasgow coma score (GCS), fibrinogen, D-dimer and PPIs were factors associated with GIB. Multivariate conditional logistic regression showed that high RPP, low GCS and urokinase were independent risk factors for GIB, and PPIs was a protective factor for GIB. CONCLUSIONS: High RPP, low GCS and urokinase were independent risk factors for GIB, and PPIs was a protective factor for GIB. Patients with a high risk of developing GIB should be monitored closely. Nevertheless, multicenter prospective studies with more patients are needed to further validate the results.

Ultrasound and Intrapleural Enzymatic Therapy for Complicated Pleural Effusion: A Case Series with a Literature Review.

Pleural effusion is the most common manifestation of pleural disease, and chest ultrasound is crucial for diagnostic workup and post-treatment monitoring. Ultrasound helps distinguish the various types of pleural effusion and enables the detection of typical manifestations of empyema, which presents as a complicated, septated effusion. This may benefit from drainage and the use of intrapleural enzyme therapy or may require more invasive approaches, such as medical or surgical thoracoscopy. The mechanism of action of intrapleural enzymatic therapy (IPET) is the activation of plasminogen to plasmin, which breaks down fibrin clots that form septa or the loculation of effusions and promotes their removal. In addition, IPET has anti-inflammatory properties and can modulate the immune response in the pleural space, resulting in reduced pleural inflammation and improved fluid reabsorption. In this article, we briefly review the literature on the efficacy of IPET and describe a case series in which most practical applications of IPET are demonstrated, i.e., as a curative treatment but also as an alternative, propaedeutic, or subsequent treatment to surgery.

Intrapleural Fibrinolytic Interventions for Retained Hemothoraces in Rabbits.

Bleeding within the pleural space may result in persistent clot formation called retained hemothorax (RH). RH is prone to organization, which compromises effective drainage, leading to lung restriction and dyspnea. Intrapleural fibrinolytic therapy is used to clear the persistent organizing clot in lieu of surgery, but fibrinolysin selection, delivery strategies, and dosing have yet to be identified. We used a recently established rabbit model of RH to test whether intrapleural delivery of single-chain urokinase (scuPA) can most effectively clear RH. scuPA, or single-chain tissue plasminogen activator (sctPA), was delivered via thoracostomy tube on day 7 as either one or two doses 8 h apart. Pleural clot dissolution was assessed using transthoracic ultrasonography, chest computed tomography, two-dimensional and clot displacement measurements, and gross analysis. Two doses of scuPA (1 mg/kg) were more effective than a bolus dose of 2 mg/kg in resolving RH and facilitating drainage of pleural fluids (PF). Red blood cell counts in the PF of scuPA, or sctPA-treated rabbits were comparable, and no gross intrapleural hemorrhage was observed. Both fibrinolysins were equally effective in clearing clots and promoting pleural drainage. Biomarkers of inflammation and organization were likewise comparable in PF from both groups. The findings suggest that single-agent therapy may be effective in clearing RH; however, the clinical advantage of intrapleural scuPA remains to be established by future clinical trials.

Soluble urokinase type plasminogen activator receptor (suPAR) and mortality in acute pulmonary embolism.

INTRODUCTION: The soluble urokinase-type plasminogen activator receptor (suPAR) potentially plays a role in immune-thrombosis, possibly by modulating plasmin activity or contributing to chemotaxis in a complex, poorly understood context. The role of suPAR levels in the short-term prognostic of patients with pulmonary embolism (PE) has not been evaluated. MATERIAL AND METHODS: This observational, prospective, single-center study enrolled consecutive patients aged 18 and above with confirmed acute symptomatic PE and no prior anticoagulant therapy. The primary objective was to assess the prognostic capacity of suPAR levels measured at the time of diagnosis in terms of mortality. RESULTS: Fifty-two patients, with a mean age of 73.8 years (±17), were included, with gender distribution evenly split at 50%. Seven (13.5%) patients died. The ROC curve for mortality yielded an AUC of 0.72 (95% CI 0.48-0.96), with an optimal suPAR cut-off of 5.5ng/mL. Bivariate analysis for suPAR>5.5ng/mL was associated with a crude odds ratio of 10 (95% CI 1.63-61.27; p=0.01) for 30-day mortality. Survival analysis showed a 30-day mortality hazard ratio of 8.33 (95% CI 1.69-40.99; p<0.01). CONCLUSION: suPAR emerges as a potential biomarker for short-term mortality prediction and holds the potential for enhanced stratification in patients with acute symptomatic PE.

An engineered ultrahigh affinity bi-paratopic uPAR targeting agent confers enhanced tumor targeting.

Urokinase-type plasminogen activator receptor (uPAR) is overexpressed on tumor cells in multiple types of cancer and contributes to disease progression and metastasis. In this work, we engineered a novel bi-paratopic uPAR targeting agent by fusing the binding domains of two native uPAR ligands: uPA and vitronectin, with a flexible peptide linker. The linker length was optimized to facilitate simultaneous engagement of both domains to their adjacent epitopes on uPAR, resulting in a high affinity and avid binding interaction. Furthermore, the individual domains were affinity-matured using yeast surface display and directed evolution, resulting in a bi-paratopic protein with affinity in the picomolar to femtomolar range. This engineered uPAR targeting agent demonstrated significantly enhanced tumor localization in mouse tumor models compared to the native uPAR ligand and warrants further investigation as a diagnostic and therapeutic agent for cancer.

Biomarker-guided detection of acute kidney injury in abdominal aortic surgery: the new and the old.

Introduction: Acute kidney injury (AKI) is a common complication in patients undergoing major vascular surgery. Despite significant research efforts in this area, the incidence of AKI remains high, posing a significant challenge to healthcare systems, especially in situations where resources are limited. Early prediction of AKI severity and individualized postoperative care is therefore essential. Methods: The primary objective of this exploratory study was to assess the diagnostic value of urine cell-cycle arrest biomarkers [(TIMP-2) × (IGFBP7)] and soluble urokinase plasminogen activator receptor (suPAR) for predicting moderate or severe AKI within 24 h after open aortic surgery, and compared to routine kidney biomarkers. Seventy-five patients undergoing elective aortic surgery were included. Clinical parameters, urine and blood samples were collected preoperatively, immediately postoperatively, and 24 h later. AKI was defined using KDIGO criteria. Individual and combined diagnostic performance of biomarkers were evaluated. Results: Of the 75 patients, 61% developed AKI, of which 28% developed moderate or severe AKI within 24 h of surgery. Baseline demographics, comorbidities and kidney parameters did not differ between patients with moderate or severe AKI (AKI II/III) and none or mild AKI (AKI 0/I), except for higher preoperative suPAR levels in later AKI II/III patients. Urine osmolality, Cystatin C and serum creatinine had the highest predictive power for AKI II/III with AUCs of 0.75-0.72. (TIMP-2) × (IGFBP7), and neither (TIMP-2) × (IGFBP7) nor suPAR individually showed superior diagnostic value. Combining CysC or SCr with urine osmolality and 6 h urine output gave the best performance with AUCs of 0.86 (95% CI, 0.74-0.96) and 0.85 (95% CI, 0.75-0.95) respectively. Conclusion: Our study suggests that routine parameters like urine osmolality, CysC, SCr and 6 h urine output perform best in predicting postoperative AKI after aortic surgery compared to the new biomarkers (TIMP-2) × (IGFBP7) and suPAR. Combining biomarkers, particularly CysC or SCr with urine output, urine osmolality, may enhance diagnostic accuracy. Further validation in larger cohorts and clinical settings is warranted to establish their clinical utility.

Mesenchymal stem/stromal cells alleviate early-stage pulmonary fibrosis in a uPAR-dependent manner.

Pulmonary fibrosis, a debilitating lung disorder characterised by excessive fibrous tissue accumulation in lung parenchyma, compromises respiratory function leading to a life-threatening respiratory failure. While its origins are multifaceted and poorly understood, the urokinase system, including urokinase-type plasminogen activator (uPA) and its receptor (uPAR), plays a significant role in regulating fibrotic response, extracellular matrix remodelling, and tissue repair. Mesenchymal stem/stromal cells (MSCs) hold promise in regenerative medicine for treating pulmonary fibrosis. Our study aimed to investigate the potential of MSCs to inhibit pulmonary fibrosis as well as the contribution of uPAR expression to this effect. We found that intravenous MSC administration significantly reduced lung fibrosis in the bleomycin-induced pulmonary fibrosis model in mice as revealed by MRI and histological evaluations. Notably, administering the MSCs isolated from adipose tissue of uPAR knockout mice (Plaur-/- MSCs) attenuated lung fibrosis to a lesser extent as compared to WT MSCs. Collagen deposition, a hallmark of fibrosis, was markedly reduced in lungs treated with WT MSCs versus Plaur-/- MSCs. Along with that, endogenous uPA levels were affected differently; after Plaur-/- MSCs were administered, the uPA content was specifically decreased within the blood vessels. Our findings support the potential of MSC treatment in attenuating pulmonary fibrosis. We provide evidence that the observed anti-fibrotic effect depends on uPAR expression in MSCs, suggesting that uPAR might counteract the uPA accumulation in lungs.

Hyperfibrinolysis during the treatment of rhabdomyosarcoma.

Background: Coagulopathies are frequently observed in alveolar rhabdomyosarcoma (ARMS), with disseminated intravascular coagulation (DIC) being the most common presentation. However, hyperfibrinolysis represents a distinct but often overlapping and potentially life-threatening subset of coagulation disorders that requires specific diagnostic and management approaches. Key Clinical Question: How can clinicians identify hyperfibrinolysis and what are the implications for management? Clinical Approach: This case report describes a 25-year-old man with metastatic ARMS arising from the prostate who developed persistent gross hematuria one week after initiating chemotherapy. A comprehensive coagulation workup was performed, including assessment of platelet count, prothrombin time, activated partial thromboplastin time, fibrinogen, D-dimer, and fibrin degradation products. Management included repletion of fibrinogen and the use of anti-fibrinolytic agents. Conclusion: Recognizing hyperfibrinolysis in ARMS patients is crucial for appropriate management. Clinicians should maintain a high index of suspicion for hyperfibrinolysis in ARMS patients presenting with severe coagulation abnormalities, particularly those with prostatic involvement or undergoing chemotherapy. In cases of primary hyperfibrinolysis, antifibrinolytic agents may be considered, whereas they are generally contraindicated in DIC.

Non-Surgical Bleeding and Transurethral Resection of the Prostate (TURP) Syndrome after TURP Surgery: A Case Report and Literature Review.

Patients undergoing transurethral resection of the prostate (TURP) surgery can develop TURP syndrome and post-TURP bleeding. Post-TURP bleeding can be surgical, from arteries or venous sinuses, or non-surgical, due to coagulopathy preventing clot formation. Non-surgical post-TURP bleeding may be due to high concentrations of urokinase and tissue plasminogen activator (tPA) in the urine that cause fibrinolytic changes and increase bleeding risk. Urine urokinase and tPA may have both local and systemic fibrinolytic effects that may prevent blood clot formation locally at the site of surgery, and cause fibrinolytic changes systemically through leaking into the blood stream. Another post-TURP complication that may happen is TURP syndrome, due to absorption of hypotonic glycine fluid through the prostatic venous plexus. TURP syndrome may present with hyponatremia, bradycardia, and hypotension, which may be preceded by hypertension. In this case report, we had a patient with benign prostatic hyperplasia (BPH) who developed both TURP syndrome and non-surgical post-TURP bleeding. These complications were transient for one day after surgery. The local effect of urine urokinase and tPA explains the non-surgical bleeding after TURP by preventing clot formation and inducing bleeding. Coagulation studies showed fibrinolytic changes that may be explained by urokinase and tPA leakage into the blood stream. In conclusion, non-surgical bleeding after TURP can be explained by the presence of fibrinolytic agents in the urine, including urokinase and tPA. There is a deficiency in existing studies explaining the pathophysiology of the fibrinolytic changes and risk of bleeding after TURP. Herein, we discuss the possible pathophysiology of developing fibrinolytic changes after TURP. More research effort should be directed to explore this area to investigate the appropriate medications to treat and prevent post-TURP bleeding. We suggest monitoring patients' coagulation profiles and electrolytes after TURP because of the risk of developing severe acute hyponatremia, TURP syndrome, fibrinolytic changes, and non-surgical bleeding. In our review of the literature, we discuss current clinical trials testing the use of an antifibrinolytic agent, Tranexamic acid, locally in the irrigation fluid or systemically to prevent post-TURP bleeding by antagonizing the fibrinolytic activity of urine urokinase and tPA.

Association between the Serum Soluble Urokinase Plasminogen Activator Receptor and Peripheral Arterial Stiffness According to the Cardio-Ankle Vascular Index in Patients Undergoing Kidney Transplantation.

Background: High soluble urokinase plasminogen activator receptor (suPAR) levels are correlated with cardiovascular (CV) disease. Arterial stiffness is associated with aging-related vascular diseases and is an independent risk factor for CV morbidity and mortality. It can be measured by the cardio-ankle vascular index (CAVI). We evaluated the association between serum suPAR levels and arterial stiffness according to the CAVI in kidney transplantation (KT) recipients. Methods: In this study, 82 patients undergoing KT were enrolled. Serum suPAR levels were analyzed using an enzyme immunoassay. The CAVI was measured using a plethysmograph waveform device, and patients with a CAVI of ≥ 9.0 were assigned to the peripheral arterial stiffness (PAS) group. Results: Twenty KT patients (24.4%) had PAS, were of older age (p = 0.042), and had higher serum triglyceride (p = 0.023) and suPAR levels (p < 0.001) than the normal group. After adjusting for factors significantly associated with PAS by multivariate logistic regression analysis, serum suPAR levels (odds ratio [OR] 1.072, 95% confidence interval (CI) 1.023-1.123; p = 0.004) were independently associated with PAS in KT patients. The logarithmically transformed suPAR level (log-suPAR) was also positively correlated with the left or right CAVI values (all p < 0.001) from the results of the Spearman correlation analysis in KT patients. Conclusions: Serum suPAR levels are positively associated with left or right CAVI values and are independently associated with PAS in KT patients.

Generation and Characterization of Novel Pan-Cancer Anti-uPAR Fluorescent Nanobodies as Tools for Image-Guided Surgery.

Fluorescence molecular imaging plays a vital role in image-guided surgery. In this context, the urokinase plasminogen activator receptor (uPAR) is an interesting biomarker enabling the detection and delineation of various tumor types due to its elevated expression on both tumor cells and the tumor microenvironment. In this study, anti-uPAR Nanobodies (Nbs) are generated through llama immunization with human and murine uPAR protein. Extensive in vitro characterization and in vivo testing with radiolabeled variants are conducted to assess their pharmacokinetics and select lead compounds. Subsequently, the selected Nbs are converted into fluorescent agents, and their application for fluorescence-guided surgery is evaluated in various subcutaneous and orthotopic tumor models. The study yields a panel of high-affinity anti-uPAR Nbs, showing specific binding across multiple types of cancer cells in vitro and in vivo. Lead fluorescently-labeled compounds exhibit high tumor uptake with high contrast at 1 h after intravenous injection across all assessed uPAR-expressing tumor models, outperforming a non-targeting control Nb. Additionally, rapid and accurate tumor localization and demarcation are demonstrated in an orthotopic human glioma model. Utilizing these Nbs can potentially enhance the precision of surgical tumor resection and, consequently, improve survival rates in the clinic.

PAI-1 deficiency drives pulmonary vascular smooth muscle remodeling and pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by vasoconstriction and remodeling of small pulmonary arteries (PAs). Central to the remodeling process is a switch of pulmonary vascular cells to a proliferative, apoptosis-resistant phenotype. Plasminogen activator inhibitors-1 and -2 (PAI-1 and PAI-2) are the primary physiological inhibitors of urokinase-type and tissue-type plasminogen activators (uPA and tPA), but their roles in PAH are unsettled. Here, we report that: 1) PAI-1, but not PAI-2, is deficient in remodeled small PAs and in early-passage PA smooth muscle and endothelial cells (PASMCs and PAECs) from subjects with PAH compared with controls; 2) PAI-1-/- mice spontaneously develop pulmonary vascular remodeling associated with upregulation of mTORC1 signaling, pulmonary hypertension (PH), and right ventricle (RV) hypertrophy; and 3) pharmacological inhibition of uPA in human PAH PASMCs suppresses proproliferative mTORC1 and SMAD3 signaling, restores PAI-1 levels, reduces proliferation, and induces apoptosis in vitro, and prevents the development of SU5416/hypoxia-induced PH and RV hypertrophy in vivo in mice. These data strongly suggest that downregulation of PAI-1 in small PAs promotes vascular remodeling and PH due to unopposed activation of uPA and consequent upregulation of mTOR and transforming growth factor-ß (TGF-ß) signaling in PASMCs, and call for further studies to determine the potential benefits of targeting the PAI-1/uPA imbalance to attenuate and/or reverse pulmonary vascular remodeling and PH.NEW & NOTEWORTHY This study identifies a novel role for the deficiency of plasminogen activator inhibitor (PAI)-1 and resultant unrestricted uPA activity in PASMC remodeling and PH in vitro and in vivo, provides novel mechanistic link from PAI-1 loss through uPA-induced Akt/mTOR and TGFß-Smad3 upregulation to pulmonary vascular remodeling in PH, and suggests that inhibition of uPA to rebalance the uPA-PAI-1 tandem might provide a novel approach to complement current therapies used to mitigate this pulmonary vascular disease.

Urokinase-Type Plasminogen Activator Receptor (uPAR) in Inflammation and Disease: A Unique Inflammatory Pathway Activator.

The urokinase-type plasminogen activator receptor (uPAR) is a unique protease binding receptor, now recognized as a key regulator of inflammation. Initially, uPA/uPAR was considered thrombolytic (clot-dissolving); however, recent studies have demonstrated its predominant immunomodulatory functions in inflammation and cancer. The uPA/uPAR complex has a multifaceted central role in both normal physiological and also pathological responses. uPAR is expressed as a glycophosphatidylinositol (GPI)-linked receptor interacting with vitronectin, integrins, G protein-coupled receptors, and growth factor receptors within a large lipid raft. Through protein-to-protein interactions, cell surface uPAR modulates intracellular signaling, altering cellular adhesion and migration. The uPA/uPAR also modifies extracellular activity, activating plasminogen to form plasmin, which breaks down fibrin, dissolving clots and activating matrix metalloproteinases that lyse connective tissue, allowing immune and cancer cell invasion and releasing growth factors. uPAR is now recognized as a biomarker for inflammatory diseases and cancer; uPAR and soluble uPAR fragments (suPAR) are increased in viral sepsis (COVID-19), inflammatory bowel disease, and metastasis. Here, we provide a comprehensive overview of the structure, function, and current studies examining uPAR and suPAR as diagnostic markers and therapeutic targets. Understanding uPAR is central to developing diagnostic markers and the ongoing development of antibody, small-molecule, nanogel, and virus-derived immune-modulating treatments that target uPAR.

suPAR in cardiovascular disease.

Soluble urokinase plasminogen activator receptor (suPAR), the soluble counterpart of urokinase plasminogen activator receptor, is found in the circulation at various levels. suPAR and its parent molecule, cell surface uPAR, exhibit similar structure and extracellular functional roles facilitating fibrinolysis, cellular adhesion, and migration. Studies have assessed the correlation between suPAR in cardiovascular disease (CVD). It is postulated that suPAR may serve as an indicator of inflammatory activation and burden during CVD progression. Increased suPAR independently predicts poorer outcomes in acute coronary syndromes, in heart failure, as well as in coronary artery disease and atherosclerosis. To guide translation into clinical utization, suPAR has been assessed in numerous CVD settings for improved risk discrimination independently or in association with established traditional risk factors. Whilst the involvement of suPAR has been explored in other diseases such as kidney diseases and cancer, there is only emerging evidence of suPAR's mechanistic involvement in cardiovascular disease. In this review, we provide a background into suPAR and its potential role as a biomarker in CVD.

PLAU promotes cell proliferation and migration of head and neck cancer via STAT3 signaling pathway.

It was reported that within the head and neck cancer (HNC) cell line CAL21 the epithelial-mesenchymal transition (EMT) and cell proliferation were promoted by Urokinase-Type Plasminogen Activator (PLAU) proteinase through TNFRSF12A. Additionally, in this paper HNC cell lines refer to Fadu and Tu686. A novel PLAU-STAT3 axis was found to be involved in HNC cell line proliferation and metastasis. PLAU expression in HNC samples was upregulated, besides, the elevated expression of PLAU was linked to the lower overall survival (OS) and disease-free survival (DFS). Ectopic PLAU expression promoted cell proliferation and migration, while PLAU knockdown exhibited opposite results. RNA-seq data identified the JAK-STAT signaling pathway, confirmed by western blotting. A recovery assay using S3I-201, a selective inhibitor of signal transducer and activator of transcription 3 (STAT3), indicated that PLAU promoted HNC cell line progression via STAT3 signaling in vitro. The oncogenic role of PLAU in HNC tumor growth in vivo was confirmed using xenograft models. In summary, we identified the tumorigenic PLAU function in the HNC progress. PLAU may represent a potential prognostic biomarker of HNC and the PLAU-STAT3 pathway might be considered a therapeutic target of HNC.

A proteomics-based survey reveals thrombospondin-4 as a ligand regulated by the mannose receptor in the injured lung.

Receptor-mediated cellular uptake of specific ligands constitutes an important step in the dynamic regulation of individual protein levels in extracellular fluids. With a focus on the inflammatory lung, we here performed a proteomics-based search for novel ligands regulated by the mannose receptor (MR), a macrophage-expressed endocytic receptor. WT and MR-deficient mice were exposed to lipopolysaccharide, after which the protein content in their lung epithelial lining fluid was compared by tandem mass tag-based mass spectrometry. More than 1200 proteins were identified in the epithelial lining fluid using this unbiased approach, but only six showed a statistically different abundance. Among these, an unexpected potential new ligand, thrombospondin-4 (TSP-4), displayed a striking 17-fold increased abundance in the MR-deficient mice. Experiments using exogenous addition of TSP-4 to MR-transfected CHO cells or MR-positive alveolar macrophages confirmed that TSP-4 is a ligand for MR-dependent endocytosis. Similar studies revealed that the molecular interaction with TSP-4 depends on both the lectin activity and the fibronectin type-II domain of MR and that a closely related member of the TSP family, TSP-5, is also efficiently internalized by the receptor. This was unlike the other members of this protein family, including TSPs -1 and -2, which are ligands for a close MR homologue known as urokinase plasminogen activator receptor-associated protein. Our study shows that MR takes part in the regulation of TSP-4, an important inflammatory component in the injured lung, and that two closely related endocytic receptors, expressed on different cell types, undertake the selective endocytosis of distinct members of the TSP family.

Efficacy and safety of intracoronary pro-urokinase combined with low-pressure balloon pre-dilatation during percutaneous coronary intervention in patients with anterior ST-segment elevation myocardial infarction.

BACKGROUND: The efficacy and safety of low-pressure balloon pre-dilatation before intracoronary pro-urokinase (pro-UK) in preventing no-reflow during percutaneous coronary intervention (PCI) remains unknown. This study aimed to evaluate the clinical outcomes of intracoronary pro-UK combined with low-pressure balloon pre-dilatation in patients with anterior ST-segment-elevation myocardial infarction (STEMI). METHODS: This was a randomized, single-blind, investigator-initiated trial that included 179 patients diagnosed with acute anterior STEMI. All patients were eligible for PCI and were randomized into two groups: intracoronary pro-UK combined with (ICPpD group, n = 90) or without (ICP group, n = 89) low-pressure balloon pre-dilatation. The main efficacy endpoint was complete epicardial and myocardial reperfusion. The safety endpoints were major adverse cardiovascular events (MACEs), which were analyzed at 12 months follow-up. RESULTS: Patients in the ICPpD group presented significantly higher TIMI myocardial perfusion grade 3 (TMPG3) compared to those in the ICP group (77.78% versus 68.54%, P = 0.013), and STR ≥ 70% after PCI 30 min (34.44% versus 26.97%, P = 0.047) or after PCI 90 min (40.0% versus 31.46%, P = 0.044). MACEs occurred in 23 patients (25.56%) in the ICPpD group and in 32 patients (35.96%) in the ICP group. There was no difference in hemorrhagic complications during hospitalization between the groups. CONCLUSION: Patients with acute anterior STEMI presented more complete epicardial and myocardial reperfusion with adjunctive low-pressure balloon pre-dilatation before intracoronary pro-UK during PCI. TRIAL REGISTRATION: 2019xkj213.