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JAMA Network Open Apr 2023There is a paucity of high-quality prospective randomized clinical trials comparing intrapleural fibrinolytic therapy (IPFT) with surgical decortication in patients with... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
There is a paucity of high-quality prospective randomized clinical trials comparing intrapleural fibrinolytic therapy (IPFT) with surgical decortication in patients with complicated pleural infections.
OBJECTIVE
To assess the feasibility, safety, and efficacy of an algorithm comparing tissue plasminogen activator plus deoxyribonuclease therapy with surgical decortication in patients with complicated pleural infections.
DESIGN, SETTING, AND PARTICIPANTS
This parallel pilot randomized clinical trial was performed at a single urban community-based center from March 1, 2019, to December 31, 2021, with follow-up for 90 days. Seventy-four individuals were screened and 48 were excluded. Twenty-six patients 18 years or older with clinical pleural infection and positive findings of pleural fluid analysis were included. Of these, 20 patients underwent randomized selection (10 in each group), and 6 were observed.
INTERVENTIONS
Intrapleural tissue plasminogen activator plus deoxyribonuclease therapy vs surgical decortication.
MAIN OUTCOMES AND MEASURES
Primary outcomes were the percentage of patients enrolled to study completion and multidisciplinary adherence. Secondary outcomes included the number of patients with and the reason for inadequate screening, screening to enrollment failures, time to accrual of 20 patients or the number accrued at 1 year, and clinical data.
RESULTS
Twenty-six patients were enrolled, 10 were randomized to each group, and 6 were observed. There was 100% enrollment to study completion in each treatment group, no protocol deviations, 2 minor protocol amendments, and no screening to enrollment failures. It took 32 months to enroll 26 patients. The 20 randomized patients had a median age of 57 (IQR, 46-65) years, were predominantly men (15 [75%]), and had a median RAPID (Renal, Age, Purulence, Infection Source, and Dietary Factors) score of 2 (IQR, 1-3). Treatment failure occurred in 1 patient and 2 crossover treatments occurred, all of which were in the IPFT group. Intraprocedure and postprocedure complications were similar between the groups. There were no reoperations or in-hospital deaths. Median duration of chest tube use was comparable in the IPFT (5 [IQR, 4-8] days) and surgery (4 [IQR, 3-5] days) groups (P = .21). Median hospital stay tended to be longer in the IPFT (11 [IQR, 4-18] days) vs surgery (5 [IQR, 4-6] days) groups, although the difference as not significantly different (P = .08). There were no 30-day readmissions or 30- or 90-day deaths.
CONCLUSIONS AND RELEVANCE
In this pilot randomized clinical trial, the study algorithm was feasible, safe, and efficacious. This provides evidence to move forward with a multicenter randomized clinical trial.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03873766.
Topics: Male; Humans; Middle Aged; Aged; Female; Tissue Plasminogen Activator; Fibrinolytic Agents; Prospective Studies; Thrombolytic Therapy; Communicable Diseases; Deoxyribonucleases
PubMed: 37043201
DOI: 10.1001/jamanetworkopen.2023.7799 -
Cellular and Molecular Life Sciences :... Mar 2022Neuroserpin is an axonally secreted serpin that is involved in regulating plasminogen and its enzyme activators, such as tissue plasminogen activator (tPA). The protein... (Review)
Review
Neuroserpin is an axonally secreted serpin that is involved in regulating plasminogen and its enzyme activators, such as tissue plasminogen activator (tPA). The protein has been increasingly shown to play key roles in neuronal development, plasticity, maturation and synaptic refinement. The proteinase inhibitor may function both independently and through tPA-dependent mechanisms. Herein, we discuss the recent evidence regarding the role of neuroserpin in healthy and diseased conditions and highlight the participation of the serpin in various cellular signalling pathways. Several polymorphisms and mutations have also been identified in the protein that may affect the serpin conformation, leading to polymer formation and its intracellular accumulation. The current understanding of the involvement of neuroserpin in Alzheimer's disease, cancer, glaucoma, stroke, neuropsychiatric disorders and familial encephalopathy with neuroserpin inclusion bodies (FENIB) is presented. To truly understand the detrimental consequences of neuroserpin dysfunction and the effective therapeutic targeting of this molecule in pathological conditions, a cross-disciplinary understanding of neuroserpin alterations and its cellular signaling networks is essential.
Topics: Axons; Cell Communication; Humans; Neoplasms; Nervous System Diseases; Neuronal Plasticity; Neuropeptides; Plasminogen; Serpins; Signal Transduction; Tissue Plasminogen Activator; Neuroserpin
PubMed: 35244780
DOI: 10.1007/s00018-022-04185-6 -
International Journal of Molecular... Apr 2022Urokinase-type plasminogen activator is widely discussed as a marker for cancer prognosis and diagnosis and as a target for cancer therapies. Together with its receptor,...
Inhibition of Human Urokinase-Type Plasminogen Activator (uPA) Enzyme Activity and Receptor Binding by DNA Aptamers as Potential Therapeutics through Binding to the Different Forms of uPA.
Urokinase-type plasminogen activator is widely discussed as a marker for cancer prognosis and diagnosis and as a target for cancer therapies. Together with its receptor, uPA plays an important role in tumorigenesis, tumor progression and metastasis. In the present study, systematic evolution of ligands by exponential enrichment (SELEX) was used to select single-stranded DNA aptamers targeting different forms of human uPA. Selected aptamers allowed the distinction between HMW-uPA and LMW-uPA, and therefore, presumably, have different binding regions. Here, uPAapt-02-FR showed highly affine binding with a K of 0.7 nM for HMW-uPA and 21 nM for LMW-uPA and was also able to bind to pro-uPA with a K of 14 nM. Furthermore, no cross-reactivity to mouse uPA or tissue-type plasminogen activator (tPA) was measured, demonstrating high specificity. Suppression of the catalytic activity of uPA and inhibition of uPAR-binding could be demonstrated through binding with different aptamers and several of their truncated variants. Since RNA aptamers are already known to inhibit uPA-uPAR binding and other pathological functions of the uPA system, these aptamers represent a novel, promising tool not only for detection of uPA but also for interfering with the pathological functions of the uPA system by additionally inhibiting uPA activity.
Topics: Animals; Aptamers, Nucleotide; Humans; Ligands; Mice; Neoplasms; Protein Binding; Urokinase-Type Plasminogen Activator
PubMed: 35563278
DOI: 10.3390/ijms23094890 -
Clinical Rheumatology Sep 2020The pathogenesis of Coronavirus disease 2019 (COVID-19) is gradually being comprehended. A high number of thrombotic episodes are reported, along with the mortality... (Review)
Review
The pathogenesis of Coronavirus disease 2019 (COVID-19) is gradually being comprehended. A high number of thrombotic episodes are reported, along with the mortality benefits of heparin. COVID-19 can be viewed as a prothrombotic disease. We overviewed the available evidence to explore this possibility. We identified various histopathology reports and clinical case series reporting thromboses in COVID-19. Also, multiple coagulation markers support this. COVID-19 can be regarded as a risk factor for thrombosis. Applying the principles of Virchow's triad, we described abnormalities in the vascular endothelium, altered blood flow, and platelet function abnormalities that lead to venous and arterial thromboses in COVID-19. Endothelial dysfunction, activation of the renin-angiotensin-aldosterone system (RAAS) with the release of procoagulant plasminogen activator inhibitor (PAI-1), and hyperimmune response with activated platelets seem to be significant contributors to thrombogenesis in COVID-19. Stratifying risk of COVID-19 thromboses should be based on age, presence of comorbidities, D-dimer, CT scoring, and various blood cell ratios. Isolated heparin therapy may not be sufficient to combat thrombosis in this disease. There is an urgent need to explore newer avenues like activated protein C, PAI-1 antagonists, and tissue plasminogen activators (tPA). These should be augmented with therapies targeting RAAS, antiplatelet drugs, repurposed antiinflammatory, and antirheumatic drugs. Key Points • Venous and arterial thromboses in COVID-19 can be viewed through the prism of Virchow's triad. • Endothelial dysfunction, platelet activation, hyperviscosity, and blood flow abnormalities due to hypoxia, immune reactions, and hypercoagulability lead to thrombogenesis in COVID-19. • There is an urgent need to stratify COVID-19 patients at risk for thrombosis using age, comorbidities, D-dimer, and CT scoring. • Patients with COVID-19 at high risk for thrombosis should be put on high dose heparin therapy.
Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Anticoagulants; Betacoronavirus; Blood Platelets; Blood Viscosity; COVID-19; Coronavirus Infections; Endothelium, Vascular; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinolytic Agents; Heparin; Humans; Pandemics; Peptidyl-Dipeptidase A; Plasminogen Activator Inhibitor 1; Platelet Activation; Platelet Aggregation Inhibitors; Pneumonia, Viral; SARS-CoV-2; Severity of Illness Index; Thrombophilia; Thrombosis; Tissue Plasminogen Activator
PubMed: 32654082
DOI: 10.1007/s10067-020-05275-1 -
International Journal of Molecular... Sep 2023Myocardial infarction (MI) with obstructive coronary artery disease (MI-CAD) and MI in the absence of obstructive coronary artery disease (MINOCA) affect different...
Myocardial infarction (MI) with obstructive coronary artery disease (MI-CAD) and MI in the absence of obstructive coronary artery disease (MINOCA) affect different populations and may have separate pathophysiological mechanisms, with greater inflammatory activity in MINOCA compared to MI-CAD. (Hp) can cause systemic inflammation and has been associated with cardiovascular disease (CVD). We aimed to investigate whether Hp infection is associated with concentrations of protein biomarkers of inflammation and CVD. In a case-control study, patients with MINOCA ( = 99) in Sweden were included, complemented by matched subjects with MI-CAD ( = 99) and controls ( = 100). Protein biomarkers were measured with a proximity extension assay in plasma samples collected 3 months after MI. The seroprevalence of Hp and cytotoxin-associated gene A (CagA) was determined using ELISA. The associations between protein levels and Hp status were studied with linear regression. The prevalence of Hp was 20.2%, 19.2%, and 16.0% for MINOCA, MI-CAD, and controls, respectively ( = 0.73). Seven proteins were associated with Hp in an adjusted model: tissue plasminogen activator (tPA), interleukin-6 (IL-6), myeloperoxidase (MPO), TNF-related activation-induced cytokine (TRANCE), pappalysin-1 (PAPPA), soluble urokinase plasminogen activator receptor (suPAR), and P-selectin glycoprotein ligand 1 (PSGL-1). Hp infection was present in one in five patients with MI, irrespective of the presence of obstructive CAD. Inflammatory proteins were elevated in Hp-positive subjects, thus not ruling out that Hp may promote an inflammatory response and potentially contribute to the development of CVD.
Topics: Humans; Coronary Artery Disease; Tissue Plasminogen Activator; Helicobacter pylori; MINOCA; Case-Control Studies; Seroepidemiologic Studies; Myocardial Infarction; Biomarkers
PubMed: 37762446
DOI: 10.3390/ijms241814143 -
International Journal of Molecular... Jan 2023Pulmonary fibrosis is a common and threatening post-COVID-19 complication with poorly resolved molecular mechanisms and no established treatment. The plasminogen...
Pulmonary fibrosis is a common and threatening post-COVID-19 complication with poorly resolved molecular mechanisms and no established treatment. The plasminogen activator system, including urokinase (uPA) and urokinase receptor (uPAR), is involved in the pathogenesis of COVID-19 and contributes to the development of lung injury and post-COVID-19 pulmonary fibrosis, although their cellular and molecular underpinnings still remain obscure. The aim of the current study was to assess the role of uPA and uPAR in the pathogenesis of pulmonary fibrosis. We analyzed uPA and uPAR expression in human lung tissues from COVID-19 patients with pulmonary fibrosis using single-cell RNA-seq and immunohistochemistry. We modeled lung fibrosis in -/- and -/- mice upon bleomycin instillation and explored the effect of uPAR downregulation in A549 and BEAS-2B lung epithelial cells. We found that uPAR expression drastically decreased in the epithelial airway basal cells and monocyte/macrophage cells, whereas uPA accumulation significantly increased in tissue samples of COVID-19 patients. Lung injury and fibrosis in -/- vs. WT mice upon bleomycin instillation revealed that uPAR deficiency resulted in pro-fibrogenic uPA accumulation, IL-6 and ACE2 upregulation in lung tissues and was associated with severe fibrosis, weight loss and poor survival. uPAR downregulation in A549 and BEAS-2B was linked to an increased N-cadherin expression, indicating the onset of epithelial-mesenchymal transition and potentially contributing to pulmonary fibrosis. Here for the first time, we demonstrate that plasminogen treatment reversed lung fibrosis in -/- mice: the intravenous injection of 1 mg of plasminogen on the 21st day of bleomycin-induced fibrosis resulted in a more than a two-fold decrease in the area of lung fibrosis as compared to non-treated mice as evaluated by the 42nd day. The expression and function of the plasminogen activator system are dysregulated upon COVID-19 infection, leading to excessive pulmonary fibrosis and worsening the prognosis. The potential of plasminogen as a life-saving treatment for non-resolving post-COVID-19 pulmonary fibrosis warrants further investigation.
Topics: Humans; Mice; Animals; Pulmonary Fibrosis; Urokinase-Type Plasminogen Activator; Lung Injury; COVID-19; Fibrosis; Plasminogen; Bleomycin
PubMed: 36674896
DOI: 10.3390/ijms24021382 -
European Stroke Journal Sep 2023Alteplase is widely used as an intravenous thrombolytic drug in acute ischemic stroke (AIS). Recently however, tenecteplase, a modified form of tissue plasminogen...
INTRODUCTION
Alteplase is widely used as an intravenous thrombolytic drug in acute ischemic stroke (AIS). Recently however, tenecteplase, a modified form of tissue plasminogen activator, has been shown to increase early recanalization rate and has proven to be non-inferior with a similar safety profile compared to alteplase. This study aims to evaluate the cost-effectiveness of 0.25 mg/kg tenecteplase versus 0.9 mg/kg alteplase for intravenous thrombolysis in AIS patients from the Dutch healthcare payer perspective.
METHODS
A Markov decision-analytic model was constructed to assess total costs, total quality-adjusted life year (QALY), an incremental cost-effectiveness ratio, and incremental net monetary benefit (INMB) of two treatments at willingness-to-pay (WTP) thresholds of €50,000/QALY and €80,000/QALY over a 10-year time horizon. One-way sensitivity analysis, probabilistic sensitivity analysis, and scenario analysis were conducted to test the robustness of results. Clinical data were obtained from large randomized controlled trials and real-world data.
RESULTS
Treatment with tenecteplase saved €21 per patient while gaining 0.05 QALYs, resulting in INMB of €2381, clearly rendering tenecteplase cost-effective compared to alteplase. Importantly, tenecteplase remained the cost-effective alternative in all scenarios, including AIS patients due to large vessel occlusion (LVO). Probabilistic sensitivity analysis proved tenecteplase to be cost-effective with a 71.0% probability at a WTP threshold of €50,000/QALY.
CONCLUSIONS
Tenecteplase treatment was cost-effective for all AIS patients (including AIS patients with LVO) compared to alteplase. The finding supports the broader use of tenecteplase in acute stroke care, as health outcomes improve at acceptable costs while having practical advantages, and a similar safety profile.
Topics: Humans; Tissue Plasminogen Activator; Tenecteplase; Cost-Benefit Analysis; Ischemic Stroke; Stroke
PubMed: 37641549
DOI: 10.1177/23969873231174943 -
Biomaterials Dec 2023Systemic injection of thrombolytic drugs is the gold standard treatment for non-invasive blood clot resolution. The most serious risks associated with the intravenous...
Systemic injection of thrombolytic drugs is the gold standard treatment for non-invasive blood clot resolution. The most serious risks associated with the intravenous injection of tissue plasminogen activator-like proteins are the bleeding complication and the dose related neurotoxicity. Indeed, the drug has to be injected in high concentrations due to its short half-life, the presence of its natural blood inhibitor (PAI-1) and the fast hepatic clearance (0.9 mg/kg in humans, 10 mg/kg in mouse models). Overall, there is a serious need for a dose-reduced targeted treatment to overcome these issues. We present in this article a new acoustic cavitation-based method for polymer MBs synthesis, three times faster than current hydrodynamic-cavitation method. The generated MBs are ultrasound responsive, stable and biocompatible. Their functionalization enabled the efficient and targeted treatment of stroke, without side effects. The stabilizing shell of the MBs is composed of Poly-Isobutyl Cyanoacrylate (PIBCA), copolymerized with fucoidan. Widely studied for its targeting properties, fucoidan exhibit a nanomolar affinity for activated endothelium and activated platelets (P-selectins). Secondly, the thrombolytic agent (rtPA) was loaded onto microbubbles (MBs) with a simple adsorption protocol. Hence, the present study validated the in vivo efficiency of rtPA-loaded Fuco MBs to be over 50 % more efficient than regular free rtPA injection for stroke resolution. In addition, the relative injected rtPA grafted onto targeting MBs was 1/10th of the standard effective dose (1 mg/kg in mouse). As a result, no hemorrhagic event, BBB leakage nor unexpected tissue distribution were observed.
Topics: Humans; Animals; Mice; Tissue Plasminogen Activator; Microbubbles; Polymers; Fibrinolytic Agents; Stroke
PubMed: 37952499
DOI: 10.1016/j.biomaterials.2023.122385 -
Scientific Reports Jul 2022The extracellular activity of Plasminogen activator inhibitor-1 (PAI-1) is well described, acting as an inhibitor of tissue plasminogen activator and urokinase-type...
The extracellular activity of Plasminogen activator inhibitor-1 (PAI-1) is well described, acting as an inhibitor of tissue plasminogen activator and urokinase-type plasminogen activator, impacting fibrinolysis. Recent studies have revealed a pro-tumorigenic role of PAI-1 in human cancers, via the regulation of angiogenesis and tumor cell survival. In this study, immunohistochemical staining of 939 human bladder cancer specimens showed that PAI-1 expression levels correlated with tumor grade, tumor stage and overall survival. The typical subcellular localization of PAI-1 is cytoplasmic, but in approximately a quarter of the cases, PAI-1 was observed to be localized to both the tumor cell cytoplasm and the nucleus. To investigate the potential function of nuclear PAI-1 in tumor biology we applied chromatin immunoprecipitation (ChIP)-sequencing, gene expression profiling, and rapid immunoprecipitation mass spectrometry to a pair of bladder cancer cell lines. ChIP-sequencing revealed that PAI-1 can bind DNA at distal intergenic regions, suggesting a role as a transcriptional coregulator. The downregulation of PAI-1 in bladder cancer cell lines caused the upregulation of numerous genes, and the integration of ChIP-sequence and RNA-sequence data identified 57 candidate genes subject to PAI-1 regulation. Taken together, the data suggest that nuclear PAI-1 can influence gene expression programs and support malignancy.
Topics: Humans; Neovascularization, Pathologic; Plasminogen Activator Inhibitor 1; Plasminogen Activator Inhibitor 2; Tissue Plasminogen Activator; Urinary Bladder Neoplasms; Urokinase-Type Plasminogen Activator
PubMed: 35842542
DOI: 10.1038/s41598-022-16518-3 -
FEBS Letters Aug 2020Pathogens that colonize deep tissues and spread systemically encounter the innate host resistance mechanism of complement-mediated lysis and complement opsonization... (Review)
Review
Pathogens that colonize deep tissues and spread systemically encounter the innate host resistance mechanism of complement-mediated lysis and complement opsonization leading to engulfment and degradation by phagocytic cells. Yersinia and Salmonella species have developed numerous strategies to block the antimicrobial effects of complement. These include recruitment of complement regulatory proteins factor H, C4BP, and vitronectin (Vn) as well as interference in late maturation events such as assembly of C9 into the membrane attack complex that leads to bacterial lysis. This review will discuss the contributions of various surface structures (proteins, lipopolysaccharide, and capsules) to evasion of complement-mediated immune clearance of the systemic pathogens Yersiniae and Salmonellae. Bacterial proteins required for recruitment of complement regulatory proteins will be described, including the details of their interaction with host regulatory proteins, where known. The potential role of the surface proteases Pla (Yersinia pestis) and PgtE (Salmonella species) on the activity of complement regulatory proteins will also be addressed. Finally, the implications of complement inactivation on host cell interactions and host cell targeting for type 3 secretion will be discussed.
Topics: Animals; Bacterial Proteins; Complement System Proteins; Humans; Immune Evasion; Plasminogen Activators; Salmonella; Type III Secretion Systems; Yersinia pestis
PubMed: 32170725
DOI: 10.1002/1873-3468.13771