Ultrasound combined with urokinase under key-shaped bone window enhances blood clot lysis in an in vitro model of spontaneous intracerebral hemorrhage.

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.

PLAU, transcriptionally negatively regulated by GATA6, promotes lung squamous carcinoma cell proliferation and migration.

BACKGROUND: Lung squamous cell carcinoma (LUSC) is associated with high mortality and has limited therapeutic treatment options. Plasminogen activator urokinase (PLAU) plays important roles in tumor cell malignancy. However, the oncogenic role of PLAU in the progression of LUSC remains unknown. GATA-binding factor 6 (GATA6), a key regulator of lung development, inhibits LUSC cell proliferation and migration, but the underlying regulatory mechanism remains to be further explored. Moreover, the regulatory effect of GATA6 on PLAU expression has not been reported. The aim of this study was to identify the role of PLAU and the transcriptional inhibition mechanism of GATA6 on PLAU expression in LUSC. METHODS: To identify the potential target genes regulated by GATA6, differentially expressed genes (DEGs) obtained from GEO datasets analysis and RNA-seq experiment were subjected to Venn analysis and correlation heatmap analysis. The transcriptional regulatory effects of GATA6 on PLAU expression were detected by real-time PCR, immunoblotting, and dual-luciferase reporter assays. The oncogenic effects of PLAU on LUSC cell proliferation and migration were evaluated by EdU incorporation, Matrigel 3D culture and Transwell assays. PLAU expression was detected in tissue microarray of LUSC via immunohistochemistry (IHC) assay. To determine prognostic factors for prognosis of LUSC patients, the clinicopathological characteristics and PLAU expression were subjected to univariate Cox regression analysis. RESULTS: PLAU overexpression promoted LUSC cell proliferation and migration. PLAU is overexpressed in LUSC tissues compared with normal tissues. Consistently, high PLAU expression, which acts as an independent risk factor, is associated with poor prognosis of LUSC patients. Furthermore, the expression of PLAU is transcriptionally regulated by GATA6. CONCLUSION: In this work, it was revealed that PLAU is a novel oncogene for LUSC and a new molecular regulatory mechanism of GATA6 in LUSC was unveiled. Targeting the GATA6/PLAU pathway might help in the development of novel therapeutic treatment strategies for LUSC.

The Light Chain Allosterically Enhances the Protease Activity of Murine Urokinase-Type Plasminogen Activator.

The active form of the murine urokinase-type plasminogen activator (muPA) is formed by a 27-residue disordered light chain connecting the amino-terminal fragment (ATF) with the serine protease domain. The two chains are tethered by a disulfide bond between C1CT in the disordered light chain and C122CT in the protease domain. Previous work showed that the presence of the disordered light chain affected the inhibition of the protease domain by antibodies. Here we show that the disordered light chain induced a 3.7-fold increase in kcat of the protease domain of muPA. In addition, hydrogen-deuterium exchange mass spectrometry (HDX-MS) and accelerated molecular dynamics (AMD) were performed to identify the interactions between the disordered light chain and the protease domain. HDX-MS revealed that the light chain is contacting the 110s, the turn between the ß10- and ß11-strand, and the ß7-strand. A reduction in deuterium uptake was also observed in the activation loop, the 140s loop and the 220s loop, which forms the S1-specificty pocket where the substrate binds. These loops are further away from where the light chain seems to be interacting with the protease domain. Our results suggest that the light chain most likely increases the activity of muPA by allosterically favoring conformations in which the specificity pocket is formed. We propose a model by which the allostery would be transmitted through the ß-strands of the ß-barrels to the loops on the other side of the protease domain.

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.

Gene Association Study of the Urokinase Plasminogen Activator and Its Receptor Gene in Alzheimer's Disease.

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.

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.

The Roles of Fibrinolytic Factors in Bone Destruction Caused by Inflammation.

Chronic inflammatory diseases, such as rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, Crohn's disease, periodontitis, and carcinoma metastasis frequently result in bone destruction. Pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), IL-6, and IL-17 are known to influence bone loss by promoting the differentiation and activation of osteoclasts. Fibrinolytic factors, such as plasminogen (Plg), plasmin, urokinase-type plasminogen activator (uPA), its receptor (uPAR), tissue-type plasminogen activator (tPA), α2-antiplasmin (α2AP), and plasminogen activator inhibitor-1 (PAI-1) are expressed in osteoclasts and osteoblasts and are considered essential in maintaining bone homeostasis by regulating the functions of both osteoclasts and osteoblasts. Additionally, fibrinolytic factors are associated with the regulation of inflammation and the immune system. This review explores the roles of fibrinolytic factors in bone destruction caused by inflammation.

Plasminogen activator urokinase interacts with the fusion protein and antagonizes the growth of Peste des petits ruminants virus.

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 dose-dependent 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.IMPORTANCEThe 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.

Dysregulated fibrinolysis and plasmin activation promote the pathogenesis of osteoarthritis.

Joint injury is associated with risk for development of osteoarthritis (OA). Increasing evidence suggests that activation of fibrinolysis is involved in OA pathogenesis. However, the role of the fibrinolytic pathway is not well understood. Here, we showed that the fibrinolytic pathway, which includes plasminogen/plasmin, tissue plasminogen activator, urokinase plasminogen activator (uPA), and the uPA receptor (uPAR), was dysregulated in human OA joints. Pharmacological inhibition of plasmin attenuated OA progression after a destabilization of the medial meniscus in a mouse model whereas genetic deficiency of plasmin activator inhibitor, or injection of plasmin, exacerbated OA. We detected increased uptake of uPA/uPAR in mouse OA joints by microPET/CT imaging. In vitro studies identified that plasmin promotes OA development through multiple mechanisms, including the degradation of lubricin and cartilage proteoglycans and induction of inflammatory and degradative mediators. We showed that uPA and uPAR produced inflammatory and degradative mediators by activating the PI3K, 3'-phosphoinositide-dependent kinase-1, AKT, and ERK signaling cascades and activated matrix metalloproteinases to degrade proteoglycan. Together, we demonstrated that fibrinolysis contributes to the development of OA through multiple mechanisms and suggested that therapeutic targeting of the fibrinolysis pathway can prevent or slow development of OA.

Thrombotic microenvironment responsive crosslinking cyclodextrin metal-organic framework nanocarriers for precise targeting and thrombolysis.

Global public health is seriously threatened by thrombotic disorders because of their high rates of mortality and disability. Most thrombolytic agents, especially protein-based pharmaceuticals, have a short half-life in circulation, reducing their effectiveness in thrombolysis. The creation of an intelligent drug delivery system that delivers medication precisely and releases it under regulated conditions at nearby thrombus sites is essential for effective thrombolysis. In this article, we present a unique medication delivery system (MCRUA) that selectively targets platelets and releases drugs by stimulation from the thrombus' microenvironment. The thrombolytic enzyme urokinase-type plasminogen-activator (uPA) and the anti-inflammatory medication Aspirin (acetylsalicylic acid, ASA) are both loaded onto pH-sensitive CaCO3/cyclodextrin crosslinking metal-organic frameworks (MC) that make up the MCRUA system. c(RGD) is functionalized on the surface of MC, which is functionalized by RGD to an esterification reaction. Additionally, the thrombus site's acidic microenvironment causes MCRUA to disintegrate to release uPA for thrombolysis and aiding in vessel recanalization. Moreover, cyclodextrin-encapsulated ASA enables the treatment of the inflammatory environment within the thrombus, enhancing the antiplatelet aggregation effects and promoting cooperative thrombolysis therapy. When used for thrombotic disorders, our drug delivery system (MCRUA) promotes thrombolysis, suppresses rethrombosis, and enhances biosafety with fewer hemorrhagic side effects.

A versatile engineered extracellular vesicle platform simultaneously targeting and eliminating senescent stromal cells and tumor cells to promote tumor regression.

Chemotherapy is an important therapeutic approach for malignant tumors for it triggers apoptosis of cancer cells. However, chemotherapy also induces senescence of stromal cells in the tumor microenvironment to promote tumor progression. Strategies aimed at killing tumor cells while simultaneously eliminating senescent stromal cells represent an effective approach to cancer treatment. Here, we developed an engineered Src-siRNA delivery system based on small extracellular vesicles (sEVs) to simultaneously eliminate senescent stromal cells and tumor cells for cancer therapy. The DSPE-PEG-modified urokinase plasminogen activator (uPA) peptide was anchored to the membranes of induced mesenchymal stem cell-derived sEVs (uPA-sEVs), and Src siRNA was loaded into the uPA-sEVs by electroporation (uPA-sEVs-siSrc). The engineered uPA-sEVs-siSrc retained the basic sEVs properties and protected against siSrc degradation. uPA peptide modification enhanced the sEVs with the ability to simultaneously target doxorubicin-induced senescent stromal cells and tumor cells. Src silencing by uPA-sEVs-siSrc induced apoptosis of both senescent stromal cells and tumor cells. The uPA-sEVs-siSrc displayed preferential tumor accumulation and effectively inhibited tumor growth in a tumor xenograft model. Furthermore, uPA-sEVs-siSrc in combination with doxorubicin significantly reduced the senescence burden and enhanced the therapeutic efficacy of chemotherapy. Taken together, uPA-sEVs-siSrc may serve as a promising therapy to kill two birds with one stone, not only killing tumor cells to achieve remarkable antitumor effect, but also eliminating senescent cells to enhance the efficacy of chemotherapeutic agent in tumor regression.

[Effect of plasminogen activator urokinase receptor gene on the activation and apoptosis of neutrophil].

Objective: To investigate the effect of plasminogen activator urokinase receptor (PLAUR) gene on neutrophil activation and apoptosis in neutrophil-like cell model. Methods: Human acute myeloid leukemia cell line HL60 was cultured in vitro and induced to differentiate into neutrophil-like cells by all-trans retinoic acid (ATRA). Lentiviral vectors interfering with human PLAUR gene was constructed and transfected into neutrophil-like cells (siRNA group). The phosphate buffer saline (PBS) group (untransfected neutrophil-like cells) and normal blank control group (NC group) (neutrophil-like cells transfected with blank plasmid) were used as controls (n=3). After starvation culture and addition of interleukin-17 afterwards in these 3 groups, the expression of CD11b on the cell membrane was detected by flow cytometry, and the levels of myeloperoxide (MPO) and extracellular neutrophil traps (NETs) in the supernatant were detected by enzyme-linked immunosorbent assay (ELISA) to investigate the activation of neutrophil-like cells. The apoptosis was detected by flow cytometry with annexin V/propidium iodide (PI) double staining and the expressions of apoptosis-related proteins caspase-3, bax and bcl-2 were detected by Western blotting. Results: The expression of CD11b in siRNA group (32.37±8.17) was lower than that in PBS group (46.27±1.54) and NC group (53.07±8.14) (P<0.05) by flow cytometry. The levels of MPO and NETs (33.37±1.11, 57.69±3.03) in the supernatant of siRNA group were significantly lower than those in PBS group (41.64±2.20, 77.60±4.33) and NC group (40.84±5.11, 76.15±2.10) (P<0.05). Flow cytometry with annexin V/PI showed that the expression of apoptosis in siRNA group (20.42%±2.45%) was significantly higher than that in PBS group (11.91%±2.23%) and NC group (11.13%±2.56%) (P<0.05). The relative expression of caspase-3 protein and bax protein (0.84±0.05, 0.83±0.04) in siRNA group was significantly higher than that in PBS group (0.68±0.02, 0.63±0.08) and NC group (0.71±0.01, 0.66±0.10) (P<0.05), and the relative expression of anti-apoptosis protein bcl-2 decreased in siRNA group (0.38±0.02) than in PBS group (0.73±0.05) and NC group (0.69±0.06) (P<0.05). Conclusion: PLAUR promotes the activation of neutrophil-like cells and inhibits the apoptosis.

A microthrombus-driven fixed-point cleaved nanosystem for preventing post-thrombolysis recurrence via inhibiting ferroptosis.

Thrombus-induced cardiovascular diseases threaten human health. Current treatment strategies often rely on urokinase plasminogen activator (uPA) for its efficacy, yet it has such limiting factors as short half-life, lack of thrombus targeting, and systemic side effects leading to unintended bleeding. In addition, thrombolytic interventions can trigger inflammation-induced damage at thrombus sites, which affects endothelial function. To address these challenges, Fer-1/uPA@pep-CREKA-Lipo (Fu@pep-CLipo) has been developed. This system achieves precise and efficient thrombolysis while enhancing the thrombus microenvironment and mitigating ischemia-reperfusion injury, with exceptional thrombus targeting ability via the strong affinity of the Cys-Arg-Glu-Lys-Ala (CREKA) peptide for fibrin. The Cys-Nle-TPRSFL-DSPE (pep) could respond to the thrombus microenvironment and fixed-point cleavage. The uPA component linked to the liposome surface is strategically cleaved upon exposure to abundant thrombin at thrombus sites. Importantly, the inclusion of Fer-1 within Fu@pep-CLipo contributes to reactive oxygen species (ROS) scavenging and significantly improves the thrombus microenvironment. This innovative approach not only achieves highly efficient and precise thrombolysis but also positively influences the expression of eNOS protein while suppressing inflammatory factors like TNF-α and IL-6. This dual action contributes to improved thrombus inflammatory microenvironment and mitigated ischemia-reperfusion injury.

Ligand-Based Design of Selective Peptidomimetic uPA and TMPRSS2 Inhibitors with Arg Bioisosteres.

Trypsin-like serine proteases are involved in many important physiological processes like blood coagulation and remodeling of the extracellular matrix. On the other hand, they are also associated with pathological conditions. The urokinase-pwlasminogen activator (uPA), which is involved in tissue remodeling, can increase the metastatic behavior of various cancer types when overexpressed and dysregulated. Another member of this protease class that received attention during the SARS-CoV 2 pandemic is TMPRSS2. It is a transmembrane serine protease, which enables cell entry of the coronavirus by processing its spike protein. A variety of different inhibitors have been published against both proteases. However, the selectivity over other trypsin-like serine proteases remains a major challenge. In the current study, we replaced the arginine moiety at the P1 site of peptidomimetic inhibitors with different bioisosteres. Enzyme inhibition studies revealed that the phenylguanidine moiety in the P1 site led to strong affinity for TMPRSS2, whereas the cyclohexylguanidine derivate potently inhibited uPA. Both inhibitors exhibited high selectivity over other structurally similar and physiologically important proteases.

In silico study of combination thrombolytic therapy with alteplase and mutant pro-urokinase for fibrinolysis in ischemic stroke.

The synergistic advantage of combining tissue plasminogen activator (tPA) with pro-urokinase (proUK) for thrombolysis has been demonstrated in several in vitro experiments, and a single site proUK mutant (m-proUK) has been developed for better stability in plasma. Based on these studies, combination thrombolytic therapy with intravenous tPA and m-proUK has been suggested as a promising treatment for patients with ischemic stroke. This paper evaluates the efficacy and safety of the dual therapy by computational simulations of pharmacokinetics and pharmacodynamics coupled with a local fibrinolysis model. Seven dose regimens are simulated and compared with the standard intravenous tPA monotherapy. Our simulation results provide more insights into the complementary reaction mechanisms of tPA and m-proUK during clot lysis and demonstrate that the dual therapy can achieve a similar recanalization time (about 50 min) to tPA monotherapy, while keeping the circulating fibrinogen level within a normal range. Specifically, our results show that for all dual therapies with a 5 mg tPA bolus, the plasma concentration of fibrinogen remains stable at around 7.5 µM after a slow depletion over 50 min, whereas a rapid depletion of circulating fibrinogen (to 5 µM) is observed with the standard tPA therapy, indicating the potential advantage of dual therapy in reducing the risk of intracranial hemorrhage. Through simulations of varying dose combinations, it has been found that increasing tPA bolus can significantly affect fibrinogen level but only moderately improves recanalization time. Conversely, m-proUK doses and infusion duration exhibit a mild impact on fibrinogen level but significantly affect recanalization time. Therefore, future optimization of dose regimen should focus on limiting the tPA bolus while adjusting m-proUK dosage and infusion rate. Such adjustments could potentially maximize the therapeutic advantages of this combination therapy for ischemic stroke treatment.

Urokinase prophylactic anticoagulation in children with nephrotic syndrome: a multicenter retrospective cohort study.

OBJECTIVE: To analyze the clinical effect of urokinase on the prevention of thrombosis in children with primary nephrotic syndrome. METHODS: A total of 370 children diagnosed with primary nephrotic syndrome (PNS) in the Children's Hospital of Soochow University and Zibo Maternal and Child Health Hospital from January 2018 to December 2022 were selected as the research objects. The patients were divided into a urokinase adjuvant therapy group and non-urokinase adjuvant therapy group according to the application of drugs. The clinical data of the children were collected, including sex, age, drug application, bleeding during treatment, and telephone follow-up, to record whether thromboembolism occurred in the acute stage and remission stage. The clinical pattern of PNS, renal biopsy, histopathological type, and related laboratory indexes before and after treatment were recorded. RESULTS: A total of 313 patients were treated with urokinase and 57 patients were not. More thrombotic events was observed in non-urokinase group compared to the urokinase group(2 versus 0 episodes, p = 0.02). The thrombotic events observed included one patient had pulmonary embolism combined with right ventricular thrombosis, and another had intracranial venous thrombosis. More minor bleeding events occurred in urokinase group compared to the non-urokinase group(7 versus 1 episodes, p = 1.0). No major bleeding events occurred in either group. CONCLUSION: The rational prophylactic use of urokinase anticoagulation in children with PNS can prevent the formation of thromboembolism and has good safety.

Soluble urokinase plasminogen activator receptor (suPAR) as a prognostic marker in COVID-19 patients: a systematic review.

OBJECTIVE: The aim of this study was to perform a systematic review of the usefulness of suPAR as a prognostic marker in non-critical COVID-19 patients. MATERIALS AND METHODS: We carried out a literature search in MEDLINE, Embase, and Web of Science using the following keywords: ("soluble urokinase receptor" OR "urokinase plasminogen activator receptor" OR "suPAR" OR "soluble uPAR" OR "soluble uPA receptor") AND ("COVID-19" OR "SARS-CoV-2"). We included observational studies (descriptive or analytic) that measured plasma suPAR on COVID-19 patients 18 years old or older, with non-critical disease at the beginning of the study. RESULTS: After screening and eligibility assessment, a total of 16 articles were included in the review. Most studies that measured mean differences found that suPAR levels were higher in patients with worse outcomes. The studies that measured diagnostic accuracy concluded that suPAR was highly sensitive and moderately specific to predicting bad outcomes. Studies that performed a survival analysis found that patients with high suPAR levels were more at risk of bad outcomes. Most of the studies included in this review were performed before extensive vaccination and omicron wave. CONCLUSIONS: COVID-19 patients with moderate initial disease and elevated suPAR levels are more at risk of poor outcomes. Larger prospective clinical trials are needed to confirm the results obtained in this review.

Urokinase in the treatment of tuberculous pleurisy: a systematic review and meta-analysis.

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.

Robotic stereotactic radiosurgery with CyberKnife - brain metastases and fibrinolysis.

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 (Tab. 2, Ref. 18).