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Chronic subdural hematoma (CSDH) development involves inflammatory, angiogenetic, and fibrinolytic mechanisms, several components of which are now unraveled through intensive research. The urokinase plasminogen activator receptor (uPAR) is part of the plasminogen activator system and possesses inflammatory, angiogenetic, and fibrinolytic capabilities. As a first, this study aims to identify uPAR in the hematoma fluid, hematoma membrane, dura mater, and systemic blood from patients with CSDH and, if present, to investigate if the uPAR level at the time of surgery may be a predictor for later developing recurrent CSDH. uPAR expression in the hematoma membrane and dura mater was analyzed using immunohistochemistry and presented as the H-score of the positive immunostaining. The uPAR levels in the hematoma fluid and systemic blood were determined using a multiplex antibody bead kit (Luminex). Samples were collected at the time of the first CSDH surgery, and in the case of recurrent CSDH within 90 days, the samples were again collected at reoperation. A comparison of uPAR expression between the hematoma membrane and dura mater, as well as uPAR levels in systemic blood and hematoma fluid, was performed using the Wilcoxon rank sum test. We included 112 patients, 26 of whom had recurrent CSDH. The median hematoma uPAR level was 22,125 (14,845–33,237) and significantly higher than the median systemic blood level of 789 pg/L (465–2,088) (p < 0.001). Similarly, the uPAR level of the hematoma membrane was 14.3 (7.54–44.8) and significantly higher than the dural uPAR level of 0.81 (0.3–1.98) (p < 0.001). For the first time, we identified uPAR in the subdural fluid, hematoma membrane, dura mater, and systemic blood from patients with CSDH. The high expression of uPAR in the subdural fluid and hematoma membrane indicates that the mechanisms of CSDH are predominantly in the subdural fluid collection and surrounding hematoma membrane. [ABSTRACT FROM AUTHOR]

Objective: Minimally invasive surgery for spontaneous intracerebral hemorrhage is impeded by inadequate lysis of the target blood clot. Ultrasound is thought to expedite intravascular thrombolysis, thereby facilitating vascular recanalization. However, the impact of ultrasound on intracerebral blood clot lysis remains uncertain. This study aimed to explore the feasibility of combining ultrasound with urokinase to enhance blood clot lysis in an in vitro model of spontaneous intracerebral hemorrhage. Methods: The blood clots were divided into four groups: control group, ultrasound group, urokinase group, and ultrasound + urokinase group. Using our experimental setup, which included a key-shaped bone window, we simulated a minimally invasive puncture and drainage procedure for spontaneous intracerebral hemorrhage. The blood clot was then irradiated using ultrasound. Blood clot lysis was assessed by weighing the blood clot before and after the experiment. Potential adverse effects were evaluated by measuring the temperature variation around the blood clot in the ultrasound + urokinase group. Results: A total of 40 blood clots were observed, with 10 in each experimental group. The blood clot lysis rate in the ultrasound group, urokinase group, and ultrasound + urokinase group (24.83 ± 4.67%, 47.85 ± 7.09%, 61.13 ± 4.06%) was significantly higher than that in the control group (16.11 ± 3.42%) (p = 0.02, p < 0.001, p < 0.001). The blood clot lysis rate in the ultrasound + urokinase group (61.13 ± 4.06%) was significantly higher than that in the ultrasound group (24.83 ± 4.67%) (p < 0.001) or urokinase group (47.85 ± 7.09%) (p < 0.001). In the ultrasound + urokinase group, the mean increase in temperature around the blood clot was 0.26 ± 0.15°C, with a maximum increase of 0.38 ± 0.09°C. There was no significant difference in the increase in temperature regarding the main effect of time interval (F = 0.705, p = 0.620), the main effect of distance (F = 0.788, p = 0.563), or the multiplication interaction between time interval and distance (F = 1.100, p = 0.342). Conclusions: Our study provides evidence supporting the enhancement of blood clot lysis in an in vitro model of spontaneous intracerebral hemorrhage through the combined use of ultrasound and urokinase. Further animal experiments are necessary to validate the experimental methods and results. [ABSTRACT FROM AUTHOR]

Background: The role of the innate immune system has long been associated with Alzheimer's disease (AD). There is now accumulating evidence that the soluble Urokinase Plasminogen Activator Receptor pathway, and its genes, PLAU and PLAUR may be important in AD, and yet there have been few genetic association studies to explore this. Objective: This study utilizes the DNA bank of the Brains for Dementia Research cohort to investigate the genetic association of common polymorphisms across the PLAU and PLAUR genes with AD. Methods: TaqMan genotyping assays were used with standard procedures followed by association analysis in PLINK. Results: No association was observed between the PLAU gene and AD; however, two SNPs located in the PLAUR gene were indicative of a trend towards association but did not surpass multiple testing significance thresholds. Conclusions: Further genotyping studies and exploration of the consequences of these SNPs on gene expression and alternative splicing are warranted to fully uncover the role this system may have in AD. [ABSTRACT FROM AUTHOR]

Pediatric obesity and type 1 diabetes mellitus (T1DM) represent two common chronic diseases associated with chronic inflammation, endothelial dysfunction and long-term complications. The aim of the present study was to assess the possible diagnostic and prognostic value of soluble urokinase plasminogen activator receptor (suPAR), a marker of inflammation and impaired endothelial function, in children with the diseases. In this cross-sectional study, children and adolescents with T1DM (N = 41) or obesity (N = 37), aged < 18 years old, and without proteinuria were included, together with children of similar age and without evident morbidity that served as controls (N = 42). Serum samples were obtained during standard outpatient follow up and the urokinase-type plasminogen activator receptor (suPAR) concentrations were measured using a commercially available sandwich ELISA kit (DUP00, R&D systems). Clinical and biochemical indices that were also assessed include body mass index (BMI) z-score, Tanner stages, glycosylated haemoglobin (HbA1c), fasting lipid profile and serum creatinine. Mean serum suPAR levels were significantly higher in patients with obesity compared to patients with T1DM and controls, while children with T1DM had similar suPAR levels to controls. Also, serum suPAR levels showed a negative correlation with age (Spearman rho −0.359, p < 0.001) and serum creatinine levels (Spearman rho −0.334, p = 0.005), and a positive correlation with BMI z-score (Spearman rho 0.354, p = 0.009) in the whole cohort. Conclusion: Serum suPAR may be a useful predictive marker of inflammation or endothelial dysfunction for children with obesity and T1DM, as well as a promising therapeutic target. Further studies are needed in order to clarify whether the reported differences in suPAR levels could reflect a greater impairment of the inflammation status and endothelial function in children with obesity compared to children with T1DM. What is Known: • Paediatric obesity and type 1 diabetes are characterised by chronic inflammation and metabolic dysregulation. • Urokinase plasminogen activator receptor (uPAR) has been proposed as a useful biomarker for chronic inflammation and cardiovascular risk in adults. What is New: • Serum suPAR levels were increased in children and adolescents with obesity compared to those with T1DM and healthy controls; thus, obesity may affect the inflammatory status and endothelial function to a higher degree than T1DM during childhood. • Serum suPAR may serve as a diagnostic and predictive marker of inflammation and endothelial dysfunction for children and adolescents with obesity and T1DM. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Peste des petits ruminants is an acute and highly contagious disease caused by the Peste des petits ruminants virus (PPRV). Host proteins play a crucial role in viral replication. However, the effect of fusion (F) protein-interacting partners on PPRV infection is poorly understood. In this study, we found that the expression of goat plasminogen activator urokinase (PLAU) gradually decreased in a time- and dosedependent manner in PPRV-infected goat alveolar macrophages (GAMs). Goat PLAU was subsequently identified using co-immunoprecipitation and confocal microscopy as an F protein binding partner. The overexpression of goat PLAU inhibited PPRV growth and replication, whereas silencing goat PLAU promoted viral growth and replication. Additionally, we confirmed that goat PLAU interacted with a virus-induced signaling adapter (VISA) to antagonize F-mediated VISA degradation, increasing the production of type I interferon. We also found that goat PLAU reduced the inhibition of PPRV replication in VISA-knockdown GAMs. Our results show that the host protein PLAU inhibits the growth and replication of PPRV by VISA-triggering RIG-I-like receptors and provides insight into the host protein that antagonizes PPRV immunosuppression. IMPORTANCE The role of host proteins that interact with Peste des petits ruminants virus (PPRV) fusion (F) protein in PPRV replication is poorly understood. This study confirmed that goat plasminogen activator urokinase (PLAU) interacts with the PPRV F protein. We further discovered that goat PLAU inhibited PPRV replication by enhancing virus-induced signaling adapter (VISA) expression and reducing the ability of the F protein to degrade VISA. These findings offer insights into host resistance to viral invasion and suggest new strategies and directions for developing PPR vaccines. [ABSTRACT FROM AUTHOR]

Background Dengue cases continue to rise and can overwhelm healthcare systems during outbreaks. In dengue, neutrophil mediators, soluble urokinase plasminogen activator receptor (suPAR) and olfactomedin 4, and mast cell mediators, chymase and tryptase, have not been measured longitudinally across the dengue phases. The utility of these proteins as prognostic biomarkers for severe dengue has also not been assessed in an older adult population. Methods We prospectively enrolled 99 adults with dengue—40 dengue fever, 46 dengue with warning signs and 13 severe dengue, along with 30 controls. Plasma levels of suPAR, olfactomedin 4, chymase and tryptase were measured at the febrile, critical and recovery phases in dengue patients. Results The suPAR levels were significantly elevated in severe dengue compared to the other dengue severities and controls in the febrile (P <.001), critical (P <.001), and recovery (P =.005) phases. In the febrile phase, suPAR was a prognostic biomarker of severe dengue, with an AUROC of 0.82. Using a cutoff derived from Youden's index (5.4 ng/mL) and an estimated prevalence of severe dengue (16.5%) in our healthcare institution, the sensitivity was 71.4% with a specificity of 87.9% in the febrile phase, and the positive and negative predictive values were 54.7% and 95.8%, respectively. Olfactomedin 4 was elevated in dengue patients but not in proportion to disease severity in the febrile phase (P =.04) There were no significant differences in chymase and tryptase levels between dengue patients and controls. Conclusions In adult dengue, suPAR may be a reliable prognostic biomarker for severe dengue in the febrile phase. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Deviations in haemostasis are found in about 50 % of patients with cancer and up to 90% of those with metastatic disease. Many studies investigate the dynamics of the processes of coagulation and fibrinolysis and their role as a predictor of therapeutic response, early relapse, or metastasis risk. BACKGROUND: To investigate the serum levels of urokinase plasminogen activator (uPA) in patients with brain metastases treated with robotic stereotactic radiosurgery (SRS) with CyberKnife. MATERIAL AND METHODS: Serum levels of urokinase plasminogen activator (uPA) were measured in 66 patients with solid tumours, divided into two groups, with oligometastatic disease and brain metastases. In this prospective longitudinal study, the serum levels of uPA were measured before starting the therapy and at the first, third, and sixth months after patients were irradiated with the CyberKnife system. RESULTS: Analysis of serum uPA levels in the post-treatment period showed a statistically significant decrease between the baseline and the 6 months post-treatment time point in both patient groups. The baseline value of serum uPA in the group with lung cancer decreased by 62.7 %, and in the group with other types of cancer - by 60 %. Despite the significant reduction of serum uPA levels 6 months after the treatment, the levels remained significantly higher in both groups than in healthy controls. CONCLUSION: Ongoing research on uPA and cancer will enrich our knowledge and expand the possibilities for clinical utilization of the marker in the oncology setting. [ABSTRACT FROM AUTHOR]

Simple Summary: Cholangiocarcinoma (CCA) accounts for approximately 15% of primary liver cancers. CCA has a poor prognosis and, thus, more effective systemic treatments are needed. We tested opaganib and upamostat, drugs that target sphingosine kinase 2 and multiple serine proteases, primarily trypsins, which are highly expressed in CCA tumors. This study demonstrates the results of inhibiting these novel targets with these drugs individually and in combination in a patient-derived CCA xenograft mouse model. Upamostat is an orally available small-molecule serine protease inhibitor that is a highly potent inhibitor of trypsin 1, trypsin 2, trypsin 3 (PRSS1/2/3), and the urokinase-type plasminogen activator (uPA). These enzymes are expressed in many cancers, especially during tissue remodeling and subsequent tumor cell invasion. Opaganib (ABC294640), a novel, orally available small molecule is a selective inhibitor of the phosphorylation of sphingosine to sphingosine-1-phosphate (S-1-P) by sphingosine kinase 2 (SPHK2). Both sphingosine kinase 1 (SPHK1) and SPHK2 are known to regulate the proliferation-inducing compound S-1-P. However, SPHK2 is more critical in cancer pathogenesis. The goal of this project was to investigate the potential antitumor effects of upamostat and opaganib, individually and in combination, on cholangiocarcinoma (CCA) xenografts in nude mice. PAX165, a patient-derived xenograft (PDX) from a surgically resected CCA, expresses substantial levels of SPHK2, PRSS1, PRSS2, and PRSS3. Four groups of 18 mice each were treated with upamostat, opaganib, both, or vehicle. Mouse weights and PAX165 tumor volumes were measured. Tumor volumes in the upamostat, opaganib, and upamostat plus opaganib groups were significantly decreased compared to the control group. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy of urokinase (UK) treatment for tuberculous pleural effusion (TPE). Methods: We searched Chinese biomedical literature database, WanFang data, CNKI, PubMed, EMbase, Web of Science and The Cochrane Library for the randomized controlled trials (RCTs) of urokinase treatment for tuberculous pleurisy from January 2000 to February 2023. Pleural tuberculosis, urokinase and randomized controlled trial were used as keywords. The eligible studies were meta-analyzed by using Revman 5.4.1: risk of bias was assessed, mean difference (MD) and 95% CI were used for continuous variables, pooled studies were conducted using random-effects or fixed-effects models, forest plots were drawn to analyze efficacy, and funnel plots were drawn to discuss publication bias. Results: Twenty-nine RCTs were included. The meta-analyzed results showed that, on the basis of routine anti-tuberculosis, comparison between the treatment group treated with urokinase and the control group treated with antituberculosis alone, the time of pleural effusion absorption [MD-5.82, 95%CI (− 7.77, − 3.87); P<0.00001] and the residual pleural thickness [MD-1.31, 95%CI (− 1.70, − 0.91); P<0.00001], pleural effusion drainage volume [MD 822.81, 95%CI (666.46,977.96); P<0.00001], FVC%pred [MD 7.95, 95%CI (4.51,11.40); P<0.00001], FEV1%pred [MD 12.67, 95%CI (10.09,15.24); P<0.00001] were significantly different. Conclusion: The clinical effect of urokinase is better than that of antituberculous therapy alone: it can increase total pleural effusion, decrease residual pleural thickness, improve the pulmonary function, and shorten the time of pleural effusion absorption. [ABSTRACT FROM AUTHOR]

AbstractObjectiveMethodsResultsConclusionTo compare the efficacy of urokinase and alteplase intravenous thrombolysis in the treatment of acute phase cerebral infarction and investigate their impact on serum S-100β and nerve growth factor (NGF) levels.Parameters assessed included NIHSS score reduction, vascular recanalization rates, mRS, Barthel Index, and adverse reactions. Post-treatment blood samples were also collected for further analysis.The clinical treatment effectiveness and Vascular recanalization rate in Group A was higher than in Group B, with p < 0.05. After treatment, the NIHSS score in Group A was lower than in Group B (p < 0.05), and the mRS score was slightly lower, but the difference was not significant (p > 0.05). After treatment, the levels of IL-6, TNF-α, and CRP in Group A were lower than in the control group (p < 0.05). The S-100β level in Group A was lower than in Group B, and NGF level was higher than in Group B (p < 0.05). Group A had better prognosis.The efficacy and safety of both urokinase and alteplase intravenous thrombolysis for acute phase cerebral infarction have been demonstrated, yet disparities exist in neurological function recovery and regulation of biochemical indicators. Alteplase intravenous thrombolysis emerges as the superior option, displaying greater effectiveness and safety, alongside improved regulation of serum S-100β and NGF levels. Tailoring treatment plans to individual patient characteristics and drug mechanisms is essential. Given these findings, the promotion of alteplase intravenous thrombolysis in the management of acute phase cerebral infarction is justified. [ABSTRACT FROM AUTHOR]

Urokinase plasminogen activator receptor (uPAR) encoded by the PLAUR gene is known as a clinical marker for cell invasiveness in glioblastoma multiforme (GBM). It is additionally implicated in various processes, including angiogenesis and inflammation within the tumor microenvironment. However, there has not been a comprehensive study that depicts the overall functions and molecular cooperators of PLAUR with respect to intra-tumoral subtypes of GBM. Using single-cell RNA sequencing data from 37 GBM patients, we identified PLAUR as a marker gene for two distinct subtypes in GBM. One subtype is featured by inflammatory activities and the other subtype is marked by ECM remodeling processes. Using the whole-transcriptome data from single cells, we are able to uncover the molecular cooperators of PLAUR for both subtypes without presuming biological pathways. Two protein networks comprise the molecular context of PLAUR, with each of the two subtypes characterized by a different dominant network. We concluded that targeting PLAUR directly influences the mechanisms represented by these two protein networks, regardless of the subtype of the targeted cell. [ABSTRACT FROM AUTHOR]

Simple Summary: Neurotropic oncolytic viruses have shown promise for the treatment of brain tumors, as they are naturally capable of entering the brain and selectively killing cancer cells. In this study, the safety, immunologic responses, and anti-tumor effects of intravenous administration of a genetically modified strain of neurotropic oncolytic Newcastle disease virus (NDV) to 20 dogs with spontaneously occurring brain cancers are characterized. Viral treatment was safe, with common side effects limited to transient low-grade fever, chills, and diarrhea. Anti-tumor responses, defined by a post-treatment reduction in tumor size as measured with brain MRI scans, were observed in two dogs. NDV genetic material was detectable in canine tumor tissue after treatment, confirming the ability of NDV to infect tumors. All dogs rapidly developed antibodies to NDV, suggesting that the viral dosing schedule may require modification to improve anti-tumor effects. Neurotropic oncolytic viruses are appealing agents to treat brain tumors as they penetrate the blood–brain barrier and induce preferential cytolysis of neoplastic cells. The pathobiological similarities between human and canine brain tumors make immunocompetent dogs with naturally occurring tumors attractive models for the study of oncolytic virotherapies. In this dose-escalation/expansion study, an engineered Lasota NDV strain targeting the urokinase plasminogen activator system (rLAS-uPA) was administered by repetitive intravenous infusions to 20 dogs with intracranial tumors with the objectives of characterizing toxicities, immunologic responses, and neuroradiological anti-tumor effects of the virus for up to 6 months following treatment. Dose-limiting toxicities manifested as fever, hematologic, and neurological adverse events, and the maximum tolerated dose (MTD) of rLAS-uPA was 2 × 107 pfu/mL. Mild adverse events, including transient infusion reactions, diarrhea, and fever were observed in 16/18 of dogs treated at or below MTD. No infectious virus was recoverable from body fluids. Neutralizing antibodies to rLAS-uPA were present in all dogs by 2 weeks post-treatment, and viral genetic material was detected in post-treatment tumors from six dogs. Tumor volumetric reductions occurred in 2/11 dogs receiving the MTD. Systemically administered rLAS-uPA NDV was safe and induced anti-tumor effects in canine brain tumors, although modifications to evade host anti-viral immunity are needed to optimize this novel therapy. [ABSTRACT FROM AUTHOR]

Background: Improving noninvasive antenatal diagnosis of fetal inflammatory response syndrome (FIRS) can assist in the evaluation of prenatal risk and reduce perinatal outcomes. This study aimed to determine whether soluble urokinase-type plasminogen activator receptor (suPAR) in vaginally collected amniotic fluid is significant in identifying FIRS after preterm premature rupture of membranes before 34 weeks of gestation. Methods: This was a prospective cohort study of 114 pregnant women and their newborns after preterm premature rupture of membranes at 22–34+6 weeks of gestation. SuPAR was evaluated using an enzyme-linked immunosorbent assay in vaginally collected amniotic fluid. Patients were classified according to the presence or absence of FIRS. FIRS was defined by umbilical cord blood interleukin-6 level > 11 pg/mL or histological funisitis. The data were analyzed using the R package (R–4.0.5). Results: SuPAR was detected in all amniotic fluid samples with a median of 26.23 ng/mL (interquartile range (IQR), 15.19–51.14). The median level of suPAR was higher in the FIRS group than in the non-FIRS group, 32.36 ng/mL (IQR, 17.27–84.16) vs. 20.46 ng/mL (IQR, 11.49–36.63) (P = 0.01), respectively. The presence of histological chorioamnionitis significantly increased the suPAR concentration in the FIRS group (P < 0.001). The areas under the curve for FIRS and FIRS with histological chorioamnionitis were 0.65 and 0.74, respectively, with an optimum cutoff value of 27.60 ng/mL. Controlling for gestational age, the cutoff of suPAR more than 27.60 ng/mL predicted threefold higher odds for FIRS and sixfold higher odds for FIRS with histologic chorioamnionitis. Conclusion: Soluble urokinase-type plasminogen activator receptor in vaginally obtained amniotic fluid may assist in evaluating prenatal risk of FIRS in patients after preterm premature rupture of membranes before 34 weeks of gestation. [ABSTRACT FROM AUTHOR]

Vasospasm following an aneurysmal subarachnoid hemorrhage (SAH) causes serious neurological complications, despite surgical clipping of the aneurysm. Intrathecal urokinase (UK) infusion has been shown to effectively prevent symptomatic vasospasm in patients who have undergone endovascular obliteration of the ruptured aneurysms. To investigate whether intrathecal UK infusion can prevent symptomatic vasospasm in patients undergoing surgical or endovascular treatment. A total of 90 patients with severe aneurysmal SAH were enrolled and assigned to a surgical neck clipping (n = 56) or an endovascular coil embolization (n = 34) groups. After treatment, UK infusion from the lumbar drain was repeated in 32 patients in the surgical neck clipping group (group B) and all in the endovascular coil embolization group (group C) until complete resolution of the SAH was observed on computed tomography. The remaining 24 of the surgical neck clipping group, without UK infusion, were assigned to group A. Symptomatic vasospasm occurred in 7 (29.2%) patients in group A, 2 (6.3%) in group B, and none in group C (group A vs. group B [ P = 0.02]; group B vs. group C [ P = 0.14]). Excellent clinical outcomes (modified Rankin score, 0 or 1) were observed in 37.5%, 59.4%, and 76.5% of patients in group A, B, and C, respectively (group A vs. group B [ P = 0.11]). Clearance of SAH via intrathecal UK infusion significantly reduced symptomatic vasospasm in patients in both UK groups, resulting in better clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: Empyema caused by Streptococcus constellatus (S. constellatus) is rare in patients with HIV. To analyze the clinical data of a patient living with HIV (PLHIV), who got empyema caused by S. constellatus, investigating the diagnosis and treatment of this disease through literature review to improve the clinical understanding of this disease. Case presentation: We have reported here a 58-year-old male PLHIV with cough, wheezing, and fever for 20 days. He has a history type 2 diabetes, alcohol abuse, and a teeth extracted. Chest computed tomography revealed multiple encapsulated pleural effusions, pneumatosis, and partial compressive atelectasis in the right lung. Submission of pleural efusions timely, and then cultures revealed S. constellatus. After comprehensive treatment, including antibiotics, closed pleural drainage, and intrapleural injection of urokinase, the pleural efusion was absorbed, and chest computed tomography also confirmed the improvement. Conclusions: S. constellatus should not be neglected as a pus pathogen in patients with HIV. comprehensive treatment is important for empyema of S. constellatus. [ABSTRACT FROM AUTHOR]

Occupational and environmental exposure of various toxins or cigarette smoke causes non-small cell lung carcinoma (NSCLC); a devastating disease with a very low survival rate after metastasis. Increased activity of plasmin is a hallmark in NSCLC metastasis. It is accepted that metastatic cells exhibit higher plasmin activity than cells from primary tumors. Mechanisms behind this elevation, however, are barely understood. We compared plasmin activity and cell migration of A549 cells derived from a primary lung tumor with metastatic H1299 lung cells isolated from lymph nodes. Surprisingly, we found higher plasmin activity and migration for A549 cells. mRNA levels of the plasminogen activator inhibitor-1 (PAI-1) were higher in H1299 cells and activity of extracellular-regulated kinases-1/2 (ERK-1/2) was increased. An inhibitor of ERK-1/2 decreased PAI-1 mRNA levels and increased plasmin activity or cell migration in H1299 cells. Transforming growth factor-β (TGF-β) decreased plasmin activity and migration in A549 cells but enhanced both in H1299 cells. The cytokine massively increased PAI-1 and decreased urokinase plasminogen activator (uPA) levels in A549 cells but strongly induced uPA and only weakly PAI- 1 expression in H1299 cells. Consequently, TGF-β enhanced plasmin activity and cell migration in H1299. Additionally, TGF-β activated ERK-1/2 stronger in H1299 than in A549 cells. Accordingly, an ERK-1/2 inhibitor completely reversed the effects of TGF-β on uPA expression, plasmin activity and migration in H1299 cells. Hence, we provide first data indicating TGF-β-promoted increased plasmin activity and suggest that blocking TGF-β-promoted ERK-1/2 activity might be a straightforward approach to inhibit NSCLC metastasis. [ABSTRACT FROM AUTHOR]

Nephrotic syndrome (NS) consists of the clinical triad of hypoalbuminaemia, high levels of proteinuria and oedema, and describes a heterogeneous group of disease processes with different underlying drivers. The existence of circulating factor disease (CFD) as a driver of NS has been epitomised by a subset of patients who exhibit disease recurrence after transplantation, alongside laboratory work. Several circulating factors have been proposed and studied, broadly grouped into protease components such as soluble urokinase-type plasminogen activator (suPAR), hemopexin (Hx) and calcium/calmodulin-serine protease kinase (CASK), and other circulating proteases, and immune components such as TNF-α, CD40 and cardiotrophin-like cytokine-1 (CLC-1). While currently there is no definitive way of assessing risk of CFD pre-transplantation, promising work is emerging through the study of 'multi-omic' bioinformatic data from large national cohorts and biobanks. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the effect of four different drug classes on soluble urokinase plasminogen activator receptor (suPAR), a biomarker active in multiple inflammatory processes and a risk factor for complications, in people with type 1 and type 2 diabetes. Methods: We conducted post hoc analyses of a randomized, open‐label, crossover trial including 26 adults with type 1 and 40 with type 2 diabetes with urinary albumin‐creatinine ratio ≥30 and ≤500 mg/g assigned to 4‐week treatments with telmisartan 80 mg, empagliflozin 10 mg, linagliptin 5 mg and baricitinib 2 mg, separated by 4‐week washouts. Plasma suPAR was measured before and after each treatment. SuPAR change after each treatment was calculated and, for each individual, the best suPAR‐reducing drug was identified. Subsequently, the effect of the best individual drug was compared against the mean of the other three drugs. Repeated‐measures linear mixed‐effects models were employed. Results: The baseline median (interquartile range) plasma suPAR was 3.5 (2.9, 4.3) ng/mL. No overall effect on suPAR levels was observed for any one drug. The individual best‐performing drug varied, with baricitinib being selected for 20 participants (30%), followed by empagliflozin for 19 (29%), linagliptin for 16 (24%) and telmisartan for 11 (17%). The individual best‐performing drug reduced suPAR by 13.3% (95% confidence interval [CI] 3.7, 22.8; P = 0.007). The difference in suPAR response between the individual best‐performing drug and the other three was −19.7% (95% CI −23.1, −16.3; P < 0.001). Conclusions: We demonstrated no overall effect of 4‐week treatment with telmisartan, empagliflozin, linagliptin or baricitinib on suPAR. However, individualization of treatment might significantly reduce suPAR levels. [ABSTRACT FROM AUTHOR]

During tumorigenesis, urokinase (uPA) and uPA receptor (uPAR) play essential roles in mediating pathological progression in many cancers. To understand the crosstalk between the uPA/uPAR signaling and cancer, as well as to decipher their cellular pathways, we proposed to use cancer driver genes to map out the uPAR signaling. In the study, an integrated pharmaceutical bioinformatics approach that combined modulator identification, driver gene ontology networking, protein targets prediction and networking, pathway analysis and uPAR modulator screening platform construction was employed to uncover druggable targets in uPAR signaling for developing a novel anti-cancer modality. Through these works, we found that uPAR signaling interacted with 10 of 21 KEGG cancer pathways, indicating the important role of uPAR in mediating intracellular cancerous signaling. Furthermore, we verified that receptor tyrosine kinases (RTKs) and ribosomal S6 kinases (RSKs) could serve as signal hubs to relay uPAR-mediated cellular functions on cancer hallmarks such as angiogenesis, proliferation, migration and metastasis. Moreover, we established an in silico virtual screening platform and a uPAR–driver gene pair rule for identifying potential uPAR modulators to combat cancer. Altogether, our results not only elucidated the complex networking between uPAR modulation and cancer but also provided a paved way for developing new chemical entities and/or re-positioning clinically used drugs against cancer. [ABSTRACT FROM AUTHOR]

Objective To investigate the temporal trend of intravenous thrombolysis in patients with acute ischemic stroke (AIS) who arrived within 6 hours after onset from 2016 to 2022 in China, and compare the risks of in-hospital outcomes between rt-PA and urokinase thrombolysis. Methods A total of 555 991 AIS patients who arrived within 6 hours after onset were enrolled in the Chinese Stroke Center Alliance (CSCA) from January 2016 to December 2022. The rates of rt-PA and urokinase intravenous thrombolysis in AIS patients within 6 hours after onset were calculated respectively of each year. Multivariate logistic regression was used to analyze the risks of hemorrhagic transformation, in-hospital death and good functional outcome at discharge (mRS score 0-1) of urokinase thrombolysis group compared with rt-PA group. Results 113 521 and 30 950 patients were treated with rt-PA and urokinase intravenous thrombolytic therapy respectively. The thrombolysis rates of rt-PA and urokinase were 20.42% and 5.57% respectively. From 2016 to 2022, the rt-PA intravenous thrombolysis rate increased from 11.26% to 30.19%, while the urokinase thrombolysis rate fluctuated at a low level. Multivariate logistic regression analysis showed that compared with rt-PA intravenous thrombolytic therapy, patients with urokinase intravenous thrombolytic therapy had a lower risk of hemorrhagic transformation (OR 0.740, 95%CI 0.662-0.827, P<0.01) and in-hospital death (OR 0.820, 95%CI 0.764-0.881, P<0.01). There was no significant difference in the rate of good functional outcome at discharge between the two groups (OR 0.989, 95%CI 0.951-1.028, P=0.57). Conclusions The rate of rt-PA intravenous thrombolysis in AIS patients who arrived within 6 hours after onset increased year by year from 2016 to 2022. The risk of hemorrhagic transformation and in-hospital death after urokinase thrombolysis may be lower than that of rt-PA intravenous thrombolysis. [ABSTRACT FROM AUTHOR]

Background: The intraoperative use of thrombolytic agents, such as urokinase, is an established adjunct technique in free flap salvage. However, choice of agent, technique of administration and dosage varies across reconstructive units, with no consensus on optimal protocol. Methods: A retrospective review was performed of free flaps requiring operative exploration and salvage at our institution between July 2016 and June 2022. Flaps with persistent poor venous outflow despite standard salvage measures received urokinase thrombolytic therapy. A literature review was also performed to identify existing urokinase administration protocols, including indication and technique of administration. A search of PubMed and Embase databases was performed to identify relevant articles published between 1982 and 2022. Results: 28 flaps required takeback to theatre for exploration and attempted salvage, with an overall salvage success rate of 71%. Urokinase was used in 8 cases when the flap did not respond intraoperatively to standard salvage procedures, with salvage success of 38%. For the literature review, 155 articles met our search criteria. 10 articles were suitable to be reviewed. Due to study heterogeneity and small case numbers, statistical analysis was not possible. A summative review of findings and outcomes was instead performed to compare with our own experience. Conclusions: There is lack of uniformity in urokinase administration protocols across reconstructive units. We present a step-by step protocol for the use of intraoperative urokinase in free flap salvage that is easy to understand and follow. Standardisation of administration protocol and larger case series are required to determine the true efficacy and utility of urokinase. Level of evidence: Level IV, Therapeutic. [ABSTRACT FROM AUTHOR]

A2-macroglobulin (A2M) is an antiproteinase that plays different roles in hemostasis. A2M is a homo-tetrameric glycoprotein of high molecular weight highly conserved throughout evolution. Proteinase inhibitor activity of A2M is possible via a unique cage structure able to trap proteinase without having any direct inhibition regarding enzymatic activity. Clearance of trapped proteinase is achieved through A2M binding to the low-density lipoprotein receptor-related protein 1: LRP1. A2M synthesis is controlled by pro-inflammatory cytokines and increases in several chronic or acute inflammatory diseases and also varies with age. A2M can trap several proteinases involved in both coagulation and fibrinolysis, thus acting as a trigger and inhibitor of hemostasis. A2M is able to inhibit thrombin, factor Xa, activated protein C, plasmin, tissue-plasminogen activator and urokinase. A2M is usually put apart in hemostasis balanced regulation. A2M plasma concentration are differently regulated during inflammatory-related diseases. It can also neutralize cytokines that are known to modify hemostasis as well. In this review, we propose to summarize known functions of A2M focusing on the roles of this antiproteinase in hemostasis and thrombosis. [ABSTRACT FROM AUTHOR]

The microenvironment plays an essential role in multiple myeloma (MM) development, progression, cell proliferation, survival, immunological escape, and drug resistance. Mesenchymal stromal cells and macrophages release tolerogenic cytokines and favor anti-apoptotic signaling pathway activation, while the urokinase plasminogen activator receptor (uPAR) system contributes to migration through an extracellular matrix. Here, we first summarized the role of macrophages and the uPAR system in MM pathogenesis, and then we reported the potential therapeutic effects of uPAR inhibitors in a case series of primary MM-derived adherent cells. Our preliminary results showed that after uPAR inhibitor treatments, interleukein-6 (mean ± SD, 8734.95 ± 4169.2 pg/mL vs. 359.26 ± 393.8 pg/mL, pre- vs. post-treatment; p = 0.0012) and DKK-1 levels (mean ± SD, 7005.41 ± 6393.4 pg/mL vs. 61.74 ± 55.2 pg/mL, pre- vs. post-treatment; p = 0.0043) in culture medium were almost completely abolished, supporting further investigation of uPAR blockade as a therapeutic strategy for MM treatment. Therefore, uPAR inhibitors could exert both anti-inflammatory and pro-immunosurveillance activity. However, our preliminary results need further validation in additional in vitro and in vivo studies. [ABSTRACT FROM AUTHOR]

Background: During catheter-directed thrombolysis (CDT), D-dimer (D-D) are generated in large quantities and fibrinogen (FIB) is continuously consumed. Reduction of FIB increases the risk of bleeding. However, there are currently few studies on the relationship between D-D and FIB concentrations during CDT. Objectives: To evaluate the relationship of D-D and FIB concentrations during CDT with urokinase for deep venous thrombosis (DVT). Method: 17 patients with lower limb DVT were enrolled and treated with CDT. The concentrations of plasma D-D and FIB were measured every 8 h during thrombolysis. The degree of thrombolysis was evaluated, the change rules of D-D and FIB concentrations were analyzed, and the change curve graphs were drawn. The "thrombus volume," "thrombolysis time," "thrombolysis ratio," "D-D peak," "D-D rising speed," "FIB falling speed," and "duration of D-D elevation" were calculated in each patient. The mixed model was used to simulate the time change trend of the plasma D-D and FIB concentrations. Pearson method and linear regression were used to analyze the correlation and linear relationship, respectively. Results: The D-D concentration first increased rapidly and then decreased gradually, and the FIB concentration continued to decrease during thrombolysis. The rate of the decline of FIB varies with the urokinase dose. The thrombus volume is positively correlated with D-D rising speed, duration of D-D elevation, D-D peak, and FIB falling speed; the D-D rising speed is positively correlated with the D-D peak and FIB falling speed; and the D-D peak is positively correlated with the FIB falling speed. The correlation coefficients were all statistically significant (p < 0.05). Efficacy reached level I–II in 76.5% patients. No major bleeding occurred in any of the patients. Conclusion: During CDT with urokinase for DVT, the concentrations of D-D and FIB show specific changes, and there are some specific relationships between each other. Understanding these changes and relationships may be helpful to adjust the thrombolysis time and urokinase dose more rationally. [ABSTRACT FROM AUTHOR]

γ-bungarotoxin (γ-BGT) is an RGD motif-containing protein, derived from the venom of Bungarus multicinctus , leading to acute death in mice. These RGD motif-containing proteins from snake venom belonging to the disintegrin family can interfere with vascular endothelial homeostasis by directly binding cell surface integrins. Targeting integrins that generate vascular endothelial dysfunction may contribute to γ-BGT poisoning, however, the underlying mechanisms have not been investigated in detail. In this study, the results showed that γ-BGT played a role in -promoting the permeability of the vascular endothelial barrier. Depending on its selective binding to integrin α5 in vascular endothelium (VE), γ-BGT initiated downstream events, including focal adhesion kinase dephosphorylation and cytoskeleton remodeling, resulting in the intercellular junction interruption. Those alternations facilitated paracellular permeability of VE and barrier dysfunction. Proteomics profiling identified that as a downstream effector of the integrin α5 / FAK signaling pathway cyclin D1 partially mediated the cellular structural changes and barrier dysfunction. Furthermore, VE-released plasminogen activator urokinase and platelet-derived growth factor D could serve as potential diagnostic biomarkers for γ-BGT-induced vascular endothelial dysfunction. Our results indicate the mechanisms through which γ-BGT as a novel disintegrin directly interacts with the VE, with consequences for barrier dysfunction. • γ-BGT increases the permeability of the vascular endothelial barrier. • γ-BGT suppresses integrin α5 and contributes to intercellular junctions and cytoskeleton remodeling. • Integrin α5/FAK/CCND1 pathway is partly involved in γ-BGT-induced barrier disruption. • PLAU and PDGFD could serve as potential diagnostic biomarkers for γ-BGT poisoning [ABSTRACT FROM AUTHOR]

Purpose: To investigate the predictive role of pre-thrombolytic high sensitivity C-reactive protein (hs-CRP) on the safety and efficacy of intravenous thrombolysis in patients with acute ischemic stroke (AIS). Methods: Patients with AIS who underwent intravenous thrombolysis with recombinant plasminogen activator (rtPA) or urokinase without endovascular therapy from June 2019 to June 2022 were retrospectively analysed. All patients were grouped into two groups (high or low hs-CRP group) according to the median value of hs-CRP before intravenous thrombolysis. The baseline NIHSS, NIHSS changes before and after thrombolysis (ΔNIHSS), the rate of good thrombolysis response (NIHSS decreased ≥ 2 points from baseline), the rate of any intracranial hemorrhage, age, sex, hypertension, diabetes, uric acid and platelet count were compared between the two groups. Logistic regression analysis was performed to identify possible prognostic factors for a good thrombolysis response. Results: A total of 212 patients were included in the analysis, with a mean age of 66.3 ± 12.5 years. In total, 145 patients received rtPA, and 67 patients received urokinase. Patients were divided into a high hs-CRP group (> 1.60 mg/L) and a low hs-CRP group (≤ 1.60 mg/L) according to the median hs-CRP level (1.60 mg/L). The ΔNIHSS of the high hs-CRP group was significantly smaller than that of the low hs-CRP group (0 [-1 ~ 0] vs. -1 [-2 ~ 0], P < 0.05). The good rate of thrombolysis response in the high hs-CRP group was significantly lower than that in the low hs-CRP group (21.9% vs. 36.5%, P < 0.05). Similar results were shown in the rtPA subgroup between the high and low hs-CRP groups but not in the urokinase subgroup. Logistic regression analysis showed that hs-CRP > 1.60 mg/L was negatively correlated with a good thrombolysis response rate (OR = 0.496, 95% CI = 0.266–0.927, P = 0.028). Conclusion: hs-CRP > 1.6 mg/L may serve as a poor prognosis predictive factor for patients with AIS receiving intravenous thrombolysis. However, due to the small sample size of this study, further studies are needed to verify our results. [ABSTRACT FROM AUTHOR]

Background. Ultrasound-accelerated thrombolysis (USAT) is a safe and effective treatment for patients with intermediate–high-risk pulmonary embolism (PE). In all studies investigating USAT in the setting of PE, the recombinant tissue-plasminogen activator (rt-PA) alteplase or actilyse was used. Currently, there is a shortage of alteplase (Alteplase, Boehringer Ingelheim) in Europe. It is unknown whether the efficacy of urokinase (UK) is comparable with alteplase for USAT in patients with PE. Methods. Patients with intermediate–high-risk PE undergoing USAT with urokinase and alteplase were included in this study. One-to-one nearest neighbour matching was performed to account for baseline differences. We identified one patient treated with USAT and UK (n = 9) for each patient treated with USAT and alteplase (n = 9). Results. A total of 56 patients underwent USAT. The treatment was successful in all patients. The propensity score matched the identified nine pairs of patients. There were no statistically significant differences in the change in right ventricle-to-left ventricle (RV/LV) ratio (0.4 ± 0.3 versus 0.5 ± 0.4, p = 0.54), systolic pulmonary artery pressure (17.3 ± 8.0 versus 18.1 ± 8.1, p = 0.17), or improvement of RV function (5.8 ± 3.8 versus 5.1 ± 2.6, p = 1.0). The complication rates were comparable (11% in both groups, p = 0.55). There were no deaths in hospital or during 90 days in either group. Conclusions. In this case-matched comparison, the short-term clinical and echocardiographic outcomes showed comparable results between USAT–UK and USAT–rt-PA. [ABSTRACT FROM AUTHOR]

Objective: To compare the safety and efficacy of catheter-directed thrombolysis (CDT) and pharmacomechanical thrombolysis (PMT) in the treatment of acute deep venous thrombosis of lower extremities (DVT). Methods: The clinical data of 98 patients with unilateral DVT in Department of Vascular Surgery Banan Hospital affiliated to Chongqing Medical University from January 2018 to December 2021 were retrospectively analyzed. According to different therapeutic modalities, the patients were divided into PMT group (n=48) and CDT group (n=50). The perioperative indicators, the swelling reduction rates of affected thigh and calf, the thrombus clearance rate, the perioperative complications rate and the incidence of PTS in one year after operation were compared and analyzed. Results: The dosage of urokinase and length of hospital stay in PMT group were significantly fewer than CDT group (P<0.05), but the mean blood loss was significantly more than that in CDT group (P<0.05). The swelling elimination rate and thrombus clearance rate of affected limbs in PMT group were significantly better than that of CDT group(P<0.05). There was no significant difference between these two groups on the incidence of perioperative complications and PTS in one year after operation (P>0.05). Conclusion: PMT possesses a higher thrombus clearance rate than CDT, PMT can significantly shorten the length of hospital stay and reduce the dosage of urokinase, but the incidence of perioperative complications and PTS in one year after operation are similar between these two groups. [ABSTRACT FROM AUTHOR]

The involvement of tumor-derived extracellular vesicles (EVs) in macrophage polarization has been reported. In our present study, we tried to discuss the regulatory role of LINC00511 encapsulated in pancreatic cancer (PCa) cell-derived EVs in the development and progression of PCa. EVs from PCa cell line BxPC-3 culture medium were collected and subsequently identified by electron microscopy and nanoparticle tracking analysis. The expression pattern of LINC00511 in PCa cell-derived EVs was determined. The interaction among LINC00511, microRNA-193a-3p, and plasminogen activator urokinase (PLAU) was explored. After co-culture of PCa cell-derived EVs with macrophages, the regulatory roles of LINC00511 in macrophage polarization, PCa cell functions, glucose consumption, lactate production, glycolysis, and mitochondrial oxidative phosphorylation were investigated. PCa cell line BxPC-3 had highly expressed LINC00511 and LINC00511 could be internalized by macrophages. LINC00511 affected macrophage polarization through miR-193a-3p-dependent regulation of PLAU expression. Besides, EV-derived LINC00511 accelerated glycolysis and promoted mitochondrial oxidative phosphorylation of PCa cells through macrophage polarization, thus inducing invasion and migration of PCa cells. LINC00511 encapsulated in PCa cell-derived EVs facilitates glycolysis of PCa cells through regulation of macrophage polarization in the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Objectives: Reliable biomarkers in the early stages of idiopathic arthritis (JIA) are scarce and the disease heterogeneity makes it clinically challenging to predict the risk of joint damage. Biomarkers with prognostic potential are warranted in order to individualize treatment and follow-up in JIA. The soluble urokinase plasminogen activator receptor (suPAR) has been reported as an easily measurable biomarker for prognosis and severity in several rheumatic diseases but it has never been studied in JIA. Methods: Sera from 51 well-characterized patients with JIA and 50 age- and sex-matched control subjects were collected and stored for later analysis of suPAR. Patients were carefully followed clinically over 3 years and analysis of erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor (RF) and antibodies against cyclic citrullinated peptides (anti-CCP) were analyzed as part of clinical routine. Signs of joint erosions were evaluated by radiography. Results: Overall, the levels of suPAR did not differ significantly between JIA patients and controls but those with polyarticular involvement showed higher suPAR (p = 0.013). In addition, elevated suPAR were associated with joint erosions (p = 0.026). Two RF/anti-CCP negative individuals with erosions showed high levels of suPAR. Conclusions: We present new data on the biomarker suPAR in JIA. Our results indicate that, apart from RF and anti-CCP, analysis of suPAR could be of additional value in assessing the risk of erosions. Analysis of suPAR early could potentially guide treatment decision-making in JIA, but our observations should be confirmed in prospective studies. [ABSTRACT FROM AUTHOR]

Background: The study investigated the prognostic value of soluble urokinase plasminogen activator receptor (suPAR) in patients undergoing cardiac surgery and calculated a simplified biomarker score comprising suPAR, N‐terminal pro B‐type natriuretic peptide (NT‐proBNP) and age. Methods and Results: Biomarkers were assessed in a cohort of 478 patients undergoing elective cardiac surgery. After a median follow‐up of 4.2 years, a total of 72 (15.1%) patients died. SuPAR, NT‐proBNP and age were independent prognosticators of mortality in a multivariable Cox regression model after adjustment for EuroScoreII. We then calculated a simplified biomarker score comprising age, suPAR and NT‐proBNP, which had a superior prognostic value compared to EuroScoreII (Harrel's C of 0.76 vs. 0.72; P for difference = 0.02). Besides long‐term mortality, the biomarker score had an excellent performance predicting one‐year mortality and hospitalization due to heart failure. Conclusion: The biomarker suPAR and NT‐proBNP were strongly and independently associated with mortality in patients undergoing cardiac surgery. A simplified biomarker score comprising only three variables (age, suPAR and NT‐proBNP) performed better than the established EuroScoreII with respect to intermediate and long‐term outcome as well as hospitalization due to heart failure. As such, integration of established and upcoming biomarkers in clinical practice may provide improved decision support in cardiac surgery. [ABSTRACT FROM AUTHOR]

Intraventricular hemorrhage (IVH) is a severe and devastating stroke. Research on existing treatment options has been controversial. Therefore, we aimed to evaluate the safety and efficacy of minimally implanted stereotactic puncture combined with urokinase (uPA) in the treatment of IVH. The clinical data of 122 IVH patients admitted to our department from 2018 to 2022 were retrospectively analyzed. According to the modified RanKin score (mRS) after 30 days, the patients were divided into good prognosis (mRS 0-3) and poor prognosis (mRS 4-6), and the factors affecting the prognosis were screened by univariate and multivariate analysis, and then the tendency Score matching and paired patient screening were performed for comparative analysis between uPA and non-uPA groups. Patients' age, uPA usage, initial Glasgow Coma Scale and primary blood volume all could affect the mRS score of patients. One hundred patients were finally included, including 50 cases in the uPA group and 50 cases in the non-uPA group. The analysis showed that at follow-up after 30 days, 46.0% of the patients in the uPA group and 28.0% in the non-uPA group had an mRS score of 0–3; however, they were not statistically significantly different. The postoperative hematoma clearance rate in the uPA group was significantly higher than that in the non-uPA group (P < 0.001), and the incidence of postoperative complications was not increased (P > 0.05). uPA treatment can improve the treatment efficiency. However, its effect in improving patient outcomes does not appear to be significant. [ABSTRACT FROM AUTHOR]

Urokinase receptors regulate the interplay between inflammation, immunity, and blood clotting. The soluble urokinase plasminogen activator system is an immunologic regulator affecting endothelial function and its related receptor; the soluble urokinase plasminogen activator receptor (suPAR) has been reported to impact kidney injury. This work aims to measure serum levels of suPAR in COVID-19 patients and correlate the measurements with variable clinicolaboratory parameters and patient outcomes. In this prospective cohort study, 150 COVID-19 patients and 50 controls were included. The circulating suPAR levels were quantified by Enzyme-linked immunosorbent assay (ELISA). Routine COVID-19 laboratory assessments, including CBC, CRP, LDH, serum creatinine, and estimated glomerular filtration rates, were performed. The need for oxygen therapy, CO-RAD score, and survival rates was assessed. Bioinformatic analysis and molecular docking were run to explore the urokinase receptor structure/function and to characterize molecules as potential anti-suPAR therapeutic targets, respectively. We found higher circulating suPAR levels in COVID-19 patients vs. controls (p < 0.001). Circulating suPAR levels positively correlated with COVID-19 severity, the need for O2 therapy, the total leukocytes count, and the neutrophils to lymphocyte ratio, while they were negatively correlated with the O2 saturation level, albumin, blood calcium, lymphocytic count, and GFR. In addition, the suPAR levels were associated with poor prognostic outcomes such as a high incidence of acute kidney injury (AKI) and mortality rate. Kaplan–Meier curves showed a lower survival rate with higher suPAR levels. The logistic regression analysis confirmed the significant association of suPAR levels with the occurrence of AKI related to COVID-19 and with increased mortality probability within three months of COVID-19 follow-up. Some compounds that can act similarly to uPAR were discovered and tested by molecular docking to identify the possible ligand–protein interactions. In conclusion, higher circulating suPAR levels were associated with COVID-19 severity and could be considered a putative predictor of AKI development and mortality. [ABSTRACT FROM AUTHOR]

Background: In patients with COVID-19 and baseline soluble urokinase plasminogen receptor plasma (suPAR) levels ≥ 6ng/mL, early administration of anakinra, a recombinant interleukin-1 receptor antagonist, may prevent disease progression and death. In case of suPAR testing unavailability, the Severe COvid Prediction Estimate (SCOPE) score may be used as an alternative in guiding treatment decisions. Methods: We conducted a monocenter, retrospective cohort study, including patients with SARS-CoV2 infection and respiratory failure. Patients treated with anakinra (anakinra group, AG) were compared to two control groups of patients who did not receive anakinra, respectively with ≥ 6 ng/mL (CG1) and < 6 ng/mL (CG2) baseline suPAR levels. Controls were manually paired by age, sex, date of admission and vaccination status and, for patients with high baseline suPAR, propensity score weighting for receiving anakinra was applied. Primary endpoint of the study was disease progression at day 14 from admission, as defined by patient distribution on a simplified version of the 11-point World Health Organization Clinical Progression Scale (WHO-CPS). Results: Between July, 2021 and January, 2022, 153 patients were included, among which 56 were treated with off-label anakinra, 49 retrospectively fulfilled prescriptive criteria for anakinra and were assigned to CG1, and 48 presented with suPAR levels < 6ng/mL and were assigned to CG2. At day 14, when comparing to CG1, patients who received anakinra had significantly reduced odds of progressing towards worse clinical outcome both in ordinal regression analysis (OR 0.25, 95% CI 0.11–0.54, p<0.001) and in propensity-adjusted multiple logistic regression analysis (OR 0.32, 95% CI 0.12–0.82, p = 0.021) thus controlling for a wide number of covariates. Sensitivities of baseline suPAR and SCOPE score in predicting progression towards severe disease or death at day 14 were similar (83% vs 100%, p = 0.59). Conclusion: This real-word, retrospective cohort study confirmed the safety and the efficacy of suPAR-guided, early use of anakinra in hospitalized COVID-19 patients with respiratory failure. [ABSTRACT FROM AUTHOR]

Introduction: The inflammatory response after laparoscopy and laparotomy has been compared in studies in adults, but only a few studies have compared the immune response between laparoscopy and laparotomy in children. Aim: To compare open and laparoscopic appendectomies regarding a new biomarker, suPAR, to evaluate the inflammatory response. Material and methods: Patients between 3 and 17 years of age who were admitted to the pediatric surgery department and scheduled for appendectomy due to appendicitis were enrolled in the investigation. The patients were randomized to receive either laparoscopic (n = 20) or conventional open appendectomy (n = 20). The primary outcome was a change in preoperative and postoperative suPAR levels. The secondary outcomes were the white blood cell count, lymphocytes, neutrophils, platelets, C-reactive protein level, appendix diameter, symptoms, symptom duration, surgical complications, operative time, rescue analgesics, hospital stay, and family satisfaction. Results: The mean age of the patients undergoing laparoscopic appendectomy was 10.55 ±2.743 (3-17) years. The mean age of the patients undergoing open appendectomy was 11.40 ±3.515 (3-17) years. A statistically significant difference was found when the postoperative suPAR values between the two groups were compared (p = 0.048). The operative time and hospital stay in the laparoscopic group were significantly shorter than those in the open group (p = 0.001, p = 0.047). Conclusions: Laparoscopic appendectomy is associated with a shorter operative time, a shorter hospital stay, and a smaller inflammatory response caused by surgical stress than open appendectomy. suPAR is an effective marker for comparing postoperative inflammatory stress between open and closed appendectomies. [ABSTRACT FROM AUTHOR]

Increases of soluble urokinase plasminogen activator receptor (suPAR) were measured in both urine and plasma of a Chlorocebus aethiops (African green monkey; AGM) mucosal infected with SARS‐CoV‐2. The data indicate that elevated suPAR may be associated with renal dysfunction and pathology in the context of COVID‐19. [ABSTRACT FROM AUTHOR]

The soluble urokinase plasminogen activator receptor (suPAR) is the bioactive form of uPAR, a membrane-bound glycoprotein, and it is primarily expressed on the surface of immunologically active cells. Mirroring local inflammation and immune activation, suPAR has gained interest as a potential prognostic biomarker in several inflammatory diseases. Indeed, in many diseases, including cancer, diabetes, cardiovascular diseases, kidney diseases, and inflammatory disorders, higher suPAR concentrations have been associated with disease severity, disease relapse, and mortality. Our review describes and discusses the supporting literature concerning the promising role of suPAR as a biomarker in different autoimmune rheumatic and non-rheumatic diseases. [ABSTRACT FROM AUTHOR]

The most concerning adverse effects of thrombolytic agents are major bleeding and intracranial hemorrhage due to their short half-life, low fibrin specificity, and high dosage. To alleviate bleeding side effects during thrombolytic therapy which would bring about the risk of aggravation, we try to find a novel biodegradable delivery nanosystem to carry drugs to target the thrombus, reduce the dosage of the drug, and system side effects. A novel urokinase/poly-α, β-d, l-aspartyl-Arg-Gly-Asp-Ser complex (UK/PD-RGDS) was synthesized and simply prepared. Its thrombolytic potency was assayed by the bubble-rising method and in vitro thrombolytic activity by the thrombus clot lysis assay separately. The in vivo thrombolytic activity and bleeding complication were evaluated by a rat model of carotid arteriovenous bypass thrombolysis. The thrombolytic potency (1288.19 ± 155.20 U/mg) of the UK/PD-RGDS complex nano-globule (18–130 nm) was 1.3 times that of commercial UK (966.77 ± 148.08 U/mg). In vivo, the UK/PD-RGDS complex (2000 IU/kg) could reduce the dose of UK by 90% while achieving the equivalent thrombolysis effect as the free UK (20,000 IU/kg). Additionally, the UK/PD-RGDS complex decreased the tail bleeding time compared with UK. The organ distribution of the FITC-UK/PD-RGDS complex was explored in the rat model. The UK/PD-RGDS complex could provide a promising platform to enhance thrombolytic efficacy significantly and reduce the major bleeding degree. [ABSTRACT FROM AUTHOR]

Alteplase is the only FDA-approved drug for thrombolysis in acute ischemic stroke (AIS). Meanwhile, several thrombolytic drugs are deemed to be promising candidates to substitute alteplase. This paper evaluates the efficacy and safety of urokinase, ateplase, tenecteplase, and reteplase for intravenous AIS therapy by computational simulations of the pharmacokinetics and pharmacodynamics combined with a local fibrinolysis model. The performances of the drugs are evaluated by comparing clot lysis time, plasminogen activator inhibitor (PAI) inhibition resistance, intracranial hemorrhage (ICH) risk, and activation time from drug administration to clot lysis. Our results reveal that urokinase has the quickest lysis completion but the highest ICH risk due to excess fibrinogen depletion in systemic plasma. While tenecteplase and alteplase have very similar thrombolysis efficacy, tenecteplase has a lower risk of ICH and better resistance to PAI-1. Among the four simulated drugs, reteplase has the slowest fibrinolysis rate, but fibrinogen concentration in systemic plasma is unaffected during thrombolysis. [ABSTRACT FROM AUTHOR]

Background: Thrombolytic agents and anticoagulants are the two classes of medication used in the treatment of acute pulmonary embolism (PE). There is continuous renewal and iteration of thrombolytic agents, and the efficacy and adverse effects of different agents have different effects on PE due to their different mechanisms of action. Objectives: The aim of the study was to evaluate the efficacy and safety of different thrombolytic agents in the treatment of all types of acute PE: hemodynamically unstable PE (massive PE) and hemodynamically stable PE (submassive PE and low-risk PE), using a network meta-analysis. Methods: A search was conducted of the following databases: PubMed, The Cochrane Library, Embase, and Web of Science to collect randomized controlled trials (RCTs) comparing thrombolytic agents with heparin or other thrombolytic agents in patients with acute PE; the clinical outcomes included patient mortality, recurrent PE, pulmonary artery systolic pressure (PASP) after treatment, and major and minor bleeding. The measurement duration of outcome indicators was the longest follow-up period. Thereafter, a network meta-analysis was performed using a Bayesian network framework. Results: A total of 29 RCTs (3,067 patients) were included, of which 6 studies (304 patients) were massive PE, 14 studies (2,173 patients) were submassive PE, 1 study (83 patients) included massive and submassive PE, and 8 studies (507 patients) were PE of unknown type. The treatment regimens included thrombolytic therapy (alteplase, reteplase, tenecteplase, streptokinase, and urokinase) and anticoagulant therapy alone. The results showed that the mortality using thrombolytic agents (except tenecteplase) was significantly lower compared with heparin. The recurrence of PE with alteplase was significantly lower compared with heparin (RR = 0.23, 95% CI, 0.04, 0.65). The PASP after using alteplase was significantly lower compared with heparin (mean difference = −11.36, 95% CI, −21.45, −1.56). Compared with heparin, the incidence of minor bleeding associated with tenecteplase was higher (RR = 3.27, 95% CI, 1.36, 7.39); compared with streptokinase, the incidence of minor bleeding associated with tenecteplase was higher (RR = 3.22, 95% CI, 1.01, 11.10). Conclusion: For patients with acute PE, four thrombolytic agents (alteplase, reteplase, streptokinase, and urokinase) appeared to be superior in efficacy compared with anticoagulants alone due to a reduction in mortality and no increase in bleeding risk. Alteplase may be a better choice because it not only reduced mortality but also reduced PE recurrence rate and treated PASP. Tenecteplase did not reduce mortality compared with anticoagulants alone and may not be a good choice of thrombolytic agent due to an increase in minor bleeding compared with streptokinase and anticoagulants alone. Thrombolytic drugs should be rationally selected to optimize the thrombolytic regimen and achieve as good a balance as possible between thrombolysis and bleeding. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic ductal adenocarcinomas (PDACs) with gene amplification or overexpression of urokinase-type plasminogen activator receptor (uPAR) have a particularly dismal prognosis. We show here that uPAR reinforces the MEK/ERK signaling pathway in tumor cells with a KRAS mutation with the suppression of FAK and CDC42 signaling. This synergy keeps tumor cells in a mesenchymal state that favors cell migration and proliferation, but also sensitizes them towards gemcitabine. These observations highlight a potential therapeutic dilemma that applies to KRAS and uPAR as emerging targets. Treatments targeting either KRAS or uPAR could induce cellular dormancy and render the tumor more resistant to chemotherapy (such as gemcitabine). The clinical benefit of adding autophagy inhibitors such as chloroquine in this situation remains to be shown. Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers. Given the currently limited therapeutic options, the definition of molecular subgroups with the development of tailored therapies remains the most promising strategy. Patients with high-level gene amplification of urokinase plasminogen activator receptor (uPAR/PLAUR) have an inferior prognosis. We analyzed the uPAR function in PDAC to understand this understudied PDAC subgroup's biology better. Methods: A total of 67 PDAC samples with clinical follow-up and TCGA gene expression data from 316 patients were used for prognostic correlations. Gene silencing by CRISPR/Cas9, as well as transfection of uPAR and mutated KRAS, were used in PDAC cell lines (AsPC-1, PANC-1, BxPC3) treated with gemcitabine to study the impact of these two molecules on cellular function and chemoresponse. HNF1A and KRT81 were surrogate markers for the exocrine-like and quasi-mesenchymal subgroup of PDAC, respectively. Results: High levels of uPAR were correlated with significantly shorter survival in PDAC, especially in the subgroup of HNF1A-positive exocrine-like tumors. uPAR knockout by CRISPR/Cas9 resulted in activation of FAK, CDC42, and p38, upregulation of epithelial makers, decreased cell growth and motility, and resistance against gemcitabine that could be reversed by re-expression of uPAR. Silencing of KRAS in AsPC1 using siRNAs reduced uPAR levels significantly, and transfection of mutated KRAS in BxPC-3 cells rendered the cell more mesenchymal and increased sensitivity towards gemcitabine. Conclusions: Activation of uPAR is a potent negative prognostic factor in PDAC. uPAR and KRAS cooperate in switching the tumor from a dormant epithelial to an active mesenchymal state, which likely explains the poor prognosis of PDAC with high uPAR. At the same time, the active mesenchymal state is more vulnerable to gemcitabine. Strategies targeting either KRAS or uPAR should consider this potential tumor-escape mechanism. [ABSTRACT FROM AUTHOR]

A new fluorescent imaging probe indocyanine green‐VC (ICG‐VC) in the second near‐infrared window (NIR‐II) was fabricated based on the urokinase‐type plasminogen activator receptor (uPAR) targeted polypeptide VC (VSNKYFSNIHWGC). The relative quantum yield (ΦF)was 0.34 %. The tail of its fluorescence emission wavelength exceeded 1000 nm with excellent photostability. In vitro cell analysis, MTT results indicated the high biocompatibility of ICG‐VC with U87MG cells. ICG‐VC showed good photothermal conversion behavior and photothermal stability.In vivo NIR‐II fluorescence imaging, ICG‐VC exhibited high spatiotemporal resolution in the lymphatic vessels with a high resolution of 717 μm and signal‐to‐noise ratio of 4.36, and displayed an excellent U87MG tumor uptake within 4 h, which reached the maximum at 8 h with a signal‐to‐noise ratio of 5.32. [ABSTRACT FROM AUTHOR]

Patients with kidney failure have a high risk for cardiovascular events. We aimed to evaluate the prognostic importance of selected biomarkers related to haemostasis, endothelial function, and vascular regulation in patients with acute coronary syndrome (ACS), and to study whether this association differed in patients with renal dysfunction. Plasma was collected in 1370 ACS patients included between 2008 and 2015. Biomarkers were analysed using a Proximity Extension Assay and a Multiple Reaction Monitoring mass spectrometry assay. To reduce multiplicity, biomarkers correlating with eGFR were selected a priori among 36 plasma biomarkers reflecting endothelial and vascular function, and haemostasis. Adjusted Cox regression were used to study their association with the composite outcome of myocardial infarction, ischemic stroke, heart failure or death. Interaction with eGFR strata above or below 60 ml/min/1.73 m2 was tested. Tissue factor, proteinase-activated receptor, soluble urokinase plasminogen activator surface receptor (suPAR), thrombomodulin, adrenomedullin, renin, and angiotensinogen correlated inversely with eGFR and were selected for the Cox regression. Mean follow-up was 5.2 years during which 428 events occurred. Adrenomedullin, suPAR, and renin were independently associated with the composite outcome. Adrenomedullin showed interaction with eGFR strata (p = 0.010) and was associated with increased risk (HR 1.88; CI 1.44–2.45) only in patients with eGFR ≥60 ml/min/ 1.73 m2. Adrenomedullin, suPAR, and renin were associated with the composite outcome in all. Adrenomedullin, involved in endothelial protection, showed a significant interaction with renal function and outcome, and was associated with the composite outcome only in patients with preserved kidney function. • After acute coronary syndrome, patients with kidney failure have worse outcome. • Proteomic biomarkers reflecting endothelial and vascular function was analysed. • Cohort consisted of 1370 patients with acute coronary syndrome. • Adrenomedullin was associated with outcome only in preserved kidney function patients. • Adrenomedullin differ in prognostic value in relation to kidney function. [ABSTRACT FROM AUTHOR]

Background Current malaria diagnostic tests do not reliably identify children at risk of severe and fatal infection. Host immune and endothelial activation contribute to malaria pathogenesis. Soluble urokinase-type plasminogen activator receptor (suPAR) is a marker of these pathways. We hypothesized that measuring suPAR at presentation could risk-stratify children with malaria. Methods Plasma suPAR levels were determined in consecutive febrile children with malaria at presentation to hospital in Jinja, Uganda. We evaluated the accuracy of suPAR in predicting in-hospital mortality, and whether suPAR could improve a validated clinical scoring system (Lambaréné Organ Dysfunction Score [LODS]). Results Of the 1226 children with malaria, 39 (3.2%) died. suPAR concentrations at presentation were significantly higher in children who went on to die than in those who survived (P <.0001). suPAR levels were associated with disease severity (LODS: 0 vs 1, P =.001; 1 vs 2, P <.001; 2 vs 3, 0 vs 2, 1 vs 3, and 0 vs 3, P <.0001). suPAR concentrations were excellent predictors of in-hospital mortality (area under the receiver operating characteristic curve [AUROC], 0.92 [95% confidence interval {CI},.91–.94]). The prognostic accuracy of LODS (AUROC, 0.93 [95% CI,.91–.94]) was improved when suPAR was added (AUROC, 0.97 [95% CI,.96–.98]; P <.0001). Conclusions Measuring suPAR at presentation can identify children at risk of severe and fatal malaria. Adding suPAR to clinical scores could improve the recognition and triage of children at risk of death. suPAR can be detected with a point-of-care test and can now be evaluated in prospective trials. [ABSTRACT FROM AUTHOR]

Background: Achieving rapid and complete reperfusion is the ultimate purpose for ischemic stroke with large vessel occlusion (LVO). Although mechanical thrombectomy (MT) had been a proverbially important procedure, medium vessel occlusion (MeVO) with thrombus migration can sporadically occur after MT. Moreover, the safe and effective approach for such had been unknown. We reported thrombolysis with intraarterial urokinase for MeVO with thrombus migration after MT. Methods: We included 122 patients who were treated by MT with LVO stroke at our institution between April 2019 and March 2021. Of 26 patients (21.3%) who developed MeVO with thrombus migration after MT, 11 (9.0%) underwent additional MT (MT group) and 15 (12.3%) received intraarterial urokinase (UK group). The procedure time; angiographically modified Treatment in Cerebral Ischemia Scale (mTICI); functional independence, which was defined as modified Rankin Scale 0–2, on day 30 or upon discharge; and symptomatic and asymptomatic intracerebral hemorrhage (ICH) were compared between the UK and MT groups. Results: The procedure time, mTICI, and asymptomatic ICH did not significantly differ between the groups. In the UK group, 8 of 15 (53.3%) patients obtained functional independence, and the functional independence rate was significantly higher in the UK group than in the MT group (p < 0.05). Symptomatic ICH did not occur in the UK group, and its incidence was significantly smaller than that in the MT group (p < 0.05). Conclusion: The results of this study suggest that intraarterial urokinase for MeVO with thrombus migration after MT may safely improve angiographic reperfusion. [ABSTRACT FROM AUTHOR]

Introduction: Vaginal hematoma is commonly treated by traditional incision and sutures. In this report, we describe the treatment of a spontaneous vaginal hematoma after vaginal delivery by ultrasound-guided urokinase injection. Case Presentation: A 32-year-old multipara developed a spontaneous vaginal hematoma after vaginal delivery. The hematoma diagnosed via ultrasound examination of the postpartum pelvic basin was located in the posterior vaginal wall, and measured to be 8.92 × 5.71 cm from transvaginal ultrasonography. After considering the size and position of the hematoma, treatment by urokinase injection under ultrasound guidance was selected and performed three times. Forty-two days after the last treatment, the hematoma had disappeared. Discussion and Conclusion: For patients in stable condition, when incision and sutures of vaginal hematoma after natural delivery is difficult to perform, urokinase injection under ultrasound guidance can be an effective treatment method that helps in the absorption of the hematoma. [ABSTRACT FROM AUTHOR]

Acute thrombosis is a leading cause of mortality and morbidity worldwide. Pharmacological thrombolysis relies on plasminogen activators (PAs), which are associated with major side effects including potentially fatal bleeding. Alternative therapeutic options that do not rely on PAs are urgently required. Here, the efficacy of targeted photothermal therapy is evaluated for thrombolysis using liposomes loaded with IR780 dye, which release heat upon near‐infrared (NIR) irradiation. Liposomes targeted to activated platelets—one of the main components of thrombi—accumulate preferentially in thrombi both in vitro and in vivo compared to non‐targeted controls. In a mouse model of thrombosis, targeted IR780 immunoliposomes (Tar‐IR‐L) produce ≈12 °C average local temperature increase upon NIR irradiation (5 min, 1 W cm−2). This causes a significant reduction in clot area compared to controls treated with non‐targeted liposomes or phosphate‐buffered saline, which only increase local temperature slightly (6 and 3 °C) when irradiated. Co‐loading a low‐dose single chain urokinase plasminogen activator (scuPA) to targeted IR780 liposomes (Tar‐scuPA‐IR‐L) does not result in a superior thrombolytic effect, which indicates that photothermal therapy alone may allow thrombolysis without the need for fibrinolytic drugs. This approach may prevent potential bleeding complications, promising a safer alternative to current pharmacological approaches. [ABSTRACT FROM AUTHOR]

The urokinase-type plasminogen activator (uPA) system consists of the proteinase uPA, its receptor (PLAUR/uPAR). Under physiological conditions, uPA and PLAUR are predominantly expressed by blood cells, including neutrophils, monocytes, and macrophages, and play important roles in cell activation, adhesion, migration, and extravasation. Here, we report that PLAUR, which is highly expressed in macrophages and dendritic cells (DCs) but hardly expressed in CD4+ T cells, inhibits the release of HIV-1 progeny virions from the cell membrane. Silencing PLAUR markedly enhanced the transmission of HIV-1 in macrophages and DCs. We further demonstrated that PLAUR is localized at the cell membrane to block the release of HIV-1 virions. Interestingly, we found that uPA compromises the PLAUR-mediated inhibition to slightly enhance HIV-1 production in primary macrophages and DCs. In the absence of PLAUR, this enhanced effect induced by uPA is abrogated. In conclusion, PLAUR is a new anti-HIV-1 protein produced in both macrophages and DCs where it inhibits HIV-1 transmission. This discovery may provide a novel therapeutic target for combating HIV. [ABSTRACT FROM AUTHOR]