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Early increase of soluble urokinase plasminogen activator receptor (suPAR) serum levels is indicative of increased risk of progression of coronavirus disease 2019 (COVID-19) to respiratory failure. The SAVE-MORE double-blind, randomized controlled trial evaluated the efficacy and safety of anakinra, an IL-1α/β inhibitor, in 594 patients with COVID-19 at risk of progressing to respiratory failure as identified by plasma suPAR ≥6 ng ml −1 , 85.9% ( n  = 510) of whom were receiving dexamethasone. At day 28, the adjusted proportional odds of having a worse clinical status (assessed by the 11-point World Health Organization Clinical Progression Scale (WHO-CPS)) with anakinra, as compared to placebo, was 0.36 (95% confidence interval 0.26–0.50). The median WHO-CPS decrease on day 28 from baseline in the placebo and anakinra groups was 3 and 4 points, respectively (odds ratio (OR) = 0.40, P  < 0.0001); the respective median decrease of Sequential Organ Failure Assessment (SOFA) score on day 7 from baseline was 0 and 1 points (OR = 0.63, P = 0.004). Twenty-eight-day mortality decreased (hazard ratio = 0.45, P = 0.045), and hospital stay was shorter. The SAVE-MORE phase 3 study demonstrates the efficacy of anakinra, an IL-1α/β inhibitor, in patients with COVID-19 and high serum levels of soluble plasminogen activator receptor.

Cellular senescence is characterized by stable cell-cycle arrest and a secretory program that modulates the tissue microenvironment 1 , 2 . Physiologically, senescence serves as a tumour-suppressive mechanism that prevents the expansion of premalignant cells 3 , 4 and has a beneficial role in wound-healing responses 5 , 6 . Pathologically, the aberrant accumulation of senescent cells generates an inflammatory milieu that leads to chronic tissue damage and contributes to diseases such as liver and lung fibrosis, atherosclerosis, diabetes and osteoarthritis 1 , 7 . Accordingly, eliminating senescent cells from damaged tissues in mice ameliorates the symptoms of these pathologies and even promotes longevity 1 , 2 , 8 – 10 . Here we test the therapeutic concept that chimeric antigen receptor (CAR) T cells that target senescent cells can be effective senolytic agents. We identify the urokinase-type plasminogen activator receptor (uPAR) 11 as a cell-surface protein that is broadly induced during senescence and show that uPAR-specific CAR T cells efficiently ablate senescent cells in vitro and in vivo. CAR T cells that target uPAR extend the survival of mice with lung adenocarcinoma that are treated with a senescence-inducing combination of drugs, and restore tissue homeostasis in mice in which liver fibrosis is induced chemically or by diet. These results establish the therapeutic potential of senolytic CAR T cells for senescence-associated diseases. Chimeric antigen receptor (CAR) T cells targeting uPAR, a cell-surface protein that is upregulated on senescent cells, eliminate senescent cells in vitro and in vivo and reduce liver fibrosis in mice.

Systemic chronic inflammation (SCI) is persistent, health-damaging, low-grade inflammation that plays a major role in immunosenescence and in development and progression of many diseases. But currently, there are no recognized standard biomarkers to assess SCI levels alone, and SCI is typically measured by combining biomarkers of acute inflammation and infection, e.g., CRP, IL-6, and TNFα. In this review, we highlight 10 properties and characteristics that are shared by the blood protein soluble urokinase plasminogen activator receptor (suPAR) and SCI, supporting the argument that suPAR is a biomarker of SCI: (1) Expression and release of suPAR is upregulated by immune activation; (2) uPAR and suPAR exert pro-inflammatory functions; (3) suPAR is associated with the amount of circulating immune cells; (4) Blood suPAR levels correlate with the levels of established inflammatory biomarkers; (5) suPAR is minimally affected by acute changes and short-term influences, in contrast to many currently used markers of systemic inflammation; (6) Like SCI, suPAR is non-specifically associated with multiple diseases; (7) suPAR and SCI both predict morbidity and mortality; (8) suPAR and SCI share the same risk factors; (9) suPAR is associated with risk factors and outcomes of inflammation above and beyond other inflammatory biomarkers; (10) The suPAR level can be reduced by anti-inflammatory interventions and treatment of disease. Assessing SCI has the potential to inform risk for morbidity and mortality. Blood suPAR is a newer biomarker which may, in fact, be a biomarker of SCI since it is stably associated with inflammation and immune activation; shares the same risk factors as many age-related diseases; is both elevated by and predicts age-related diseases. There is strong evidence that suPAR is a prognostic marker of adverse events, morbidity, and mortality. It is associated with immune activity and prognosis across diverse conditions, including kidney disease, cardiovascular disease, cancer, diabetes, and inflammatory disorders. Thus, we think it likely represents a common underlying disease-process shared by many diseases; that is, SCI. We review the supporting literature and propose a research agenda that can help test the hypothesis that suPAR indexes SCI, with the potential of becoming the new gold standard for measuring SCI.

Soluble urokinase plasminogen activator receptor was measured in three patient cohorts at risk for acute kidney injury. Experimental models were used to assess suPAR as a therapeutic target. High suPAR levels were associated with acute kidney injury in both clinical and experimental settings.

The paradoxical pro-tumorigenic function of plasminogen activator inhibitor 1 (PAI-1, aka Serpin E1) in cancer progression and metastasis has been the subject of an abundant scientific literature that has pointed to a pro-angiogenic role, a growth and migration stimulatory function, and an anti-apoptotic activity, all directed toward promoting tumor growth, cancer cell survival, and metastasis. With uPA, PAI-1 is among the most reliable biomarkers and prognosticators in many cancer types. More recently, a novel pro-tumorigenic function of PAI-1 in cancer-related inflammation has been demonstrated. These multifaceted activities of PAI-1 in cancer progression are explained by the complex structure of PAI-1 and its multiple functions that go beyond its anti-fibrinolytic and anti-plasminogen activation activities. However, despite the multiple evidences supporting a pro-tumorigenic role of PAI-1 in cancer, and the development of several inhibitors, targeting PAI-1, has remained elusive. In this article, the various mechanisms responsible for the pro-tumorigenic functions of PAI-1 are reviewed with emphasis on its more recently described contribution to cancer inflammation. The challenges of targeting PAI-1 in cancer therapy are then discussed.

This study examined plasma levels of soluble urokinase-type plasminogen activator receptor (suPAR) and the estimated glomerular filtration rate at baseline and incident CKD. Higher suPAR levels predicted incident CKD and an accelerated decline in the eGFR. Chronic kidney disease and progressive loss of kidney function constitute a major public health problem affecting 11% of the U.S. population. 1 Patients with chronic kidney disease are at high risk for cardiovascular disease and death. 2 It is thus important to identify patients at high risk for chronic kidney disease and to treat underlying disease processes that drive kidney injury. 3 In clinical practice, methods of screening for kidney disease are limited to measurement of urinary protein excretion and calculation of the estimated glomerular filtration rate (eGFR). Proteinuria and a decline in the eGFR are relatively insensitive indexes of early injury and . . .

People with kidney disease are disproportionately affected by atherosclerosis for unclear reasons. Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived mediator of kidney disease, levels of which are strongly associated with cardiovascular outcomes. We assessed suPAR's pathogenic involvement in atherosclerosis using epidemiologic, genetic, and experimental approaches. We found serum suPAR levels to be predictive of coronary artery calcification and cardiovascular events in 5,406 participants without known coronary disease. In a genome-wide association meta-analysis including over 25,000 individuals, we identified a missense variant in the plasminogen activator, urokinase receptor (PLAUR) gene (rs4760), confirmed experimentally to lead to higher suPAR levels. Mendelian randomization analysis in the UK Biobank using rs4760 indicated a causal association between genetically predicted suPAR levels and atherosclerotic phenotypes. In an experimental model of atherosclerosis, proprotein convertase subtilisin/kexin-9 (Pcsk9) transfection in mice overexpressing suPAR (suPARTg) led to substantially increased atherosclerotic plaques with necrotic cores and macrophage infiltration compared with those in WT mice, despite similar cholesterol levels. Prior to induction of atherosclerosis, aortas of suPARTg mice excreted higher levels of CCL2 and had higher monocyte counts compared with WT aortas. Aortic and circulating suPARTg monocytes exhibited a proinflammatory profile and enhanced chemotaxis. These findings characterize suPAR as a pathogenic factor for atherosclerosis acting at least partially through modulation of monocyte function.

Why did you do this work?Empyema thoracis is a recognised complication of pneumonia. While there are guidelines by the British Thoracic Society (BTS) for the management of pleural infection in children, there is still a varied approach to practice across centres.What did you do?This study is a service evaluation audit detailing patients with empyema and care received at our centre.We reviewed the medical records of admissions with empyema over a period of 16 months (January 2023 – May 2024). We have excluded uncomplicated pleural effusions in this study. We aimed to outline the demographic, compare reproducibility of clinical management and identify aggravating factors. Data was analysed using Microsoft Excel.What did you find?A total of 9 children were admitted for empyema in the period with male:female was (3:6), and more ≤5-year-old (6:3). All were healthy children with immunisation history confirmed in 6 of the children as up to date.All blood cultures had no growth. Pleural fluid culture was positive for only 2 cases (Streptococcus pneumoniae, Streptococcus milleri). Pleural fluid PCR yielded 4 Streptococcus pneumoniae, 1 Streptococcus pyogenes, 2 negative PCRs and 2 unrequested.There were 4 negative throat swabs, positive swabs had mixed growth with Rhinovirus (3), RSV, Streptococcus A, Mycoplasma (2), COVID and Human Metapneumovirus (HMPV) (1) with associated prolonged defervescence (7.8 vs 6).All had a chest ultrasound, and a chest drain placement at averagely 2 days post admission (1–6) with post placement X-rays and mean drain duration 4.2 days (1–7). Only 2 children required a Video Assisted Thoracoscopy surgery (VATS). 5 children completed 6 doses of Urokinase therapy. Asides discomfort while in-situ, there were no documented complications of the drain.Initial antibiotic therapy was varied with Co-Amoxiclav, Cefuroxime, Cefotaxime and Amoxicillin used initially. Clindamycin was added in all. Further changes were microbiology guided. Intravenous medication administration averaged 12.8 days (7–18), and fever defervescence from admission was average of 7 days (2–16).Oral antibiotic at discharge was for an average period of 24.9 days (14–28) with Co-Amoxiclav: Amoxicillin (6:3). Average discharge CRP was 34.7 (7–72) versus 284.8 at admission (92–510). The average in-hospital stay was 13 days (8–17).Vaccine response was requested for only 3 of the 9 children.All children were scheduled for respiratory clinic follow up within 8–12 weeks.What does it mean?The striking finding is the varied choice of IV antibiotics. While all the choices were appropriate, having a local standard approach will be helpful. Patients who had multiple organisms in their throat swab took longer to be afebrile.ReferenceBalfour-Lynn IM, et al. BTS guidelines for the management of pleural infection in children. Thorax 2005;60(Suppl I):i1–i21. doi: 10.1136/thx.2004.030676

The tumor microenvironment (TME) is now being widely accepted as the key contributor to a range of processes involved in cancer progression from tumor growth to metastasis and chemoresistance. The extracellular matrix (ECM) and the proteases that mediate the remodeling of the ECM form an integral part of the TME. Plasmin is a broad-spectrum, highly potent, serine protease whose activation from its precursor plasminogen is tightly regulated by the activators (uPA, uPAR, and tPA), the inhibitors (PAI-1, PAI-2), and plasminogen receptors. Collectively, this system is called the plasminogen activation system. The expression of the components of the plasminogen activation system by malignant cells and the surrounding stromal cells modulates the TME resulting in sustained cancer progression signals. In this review, we provide a detailed discussion of the roles of plasminogen activation system in tumor growth, invasion, metastasis, and chemoresistance with specific emphasis on their role in the TME. We particularly review the recent highlights of the plasminogen receptor S100A10 (p11), which is a pivotal component of the plasminogen activation system.

Coagulation factor XII (FXII) deficiency is associated with decreased neutrophil migration, but the mechanisms remain uncharacterized. Here, we examine how FXII contributes to the inflammatory response. In 2 models of sterile inflammation, FXII-deficient mice (F12-/-) had fewer neutrophils recruited than WT mice. We discovered that neutrophils produced a pool of FXII that is functionally distinct from hepatic-derived FXII and contributes to neutrophil trafficking at sites of inflammation. FXII signals in neutrophils through urokinase plasminogen activator receptor-mediated (uPAR-mediated) Akt2 phosphorylation at S474 (pAktS474). Downstream of pAkt2S474, FXII stimulation of neutrophils upregulated surface expression of αMβ2 integrin, increased intracellular calcium, and promoted extracellular DNA release. The sum of these activities contributed to neutrophil cell adhesion, migration, and release of neutrophil extracellular traps in a process called NETosis. Decreased neutrophil signaling in F12-/- mice resulted in less inflammation and faster wound healing. Targeting hepatic F12 with siRNA did not affect neutrophil migration, whereas WT BM transplanted into F12-/- hosts was sufficient to correct the neutrophil migration defect in F12-/- mice and restore wound inflammation. Importantly, these activities were a zymogen FXII function and independent of FXIIa and contact activation, highlighting that FXII has a sophisticated role in vivo that has not been previously appreciated.