The role of fetal fibronectin and plasminogen activator inhibitor 1 biomarkers in antenatal prediction of placenta accreta spectrum.

In this study, we aimed to assess the determining role of foetal fibronectin (FFN) and plasminogen activator inhibitor type (PAI-1) levels in the antenatal prediction of placenta accreta spectrum in cases with risk factors for placenta accreta spectrum. Singleton live pregnancies with placenta previa or low-lying placenta within 32-34 weeks of gestation were included in the study. The cases were divided into two groups after delivery as those with PAS and those with normal placentation. 54 cases diagnosed with placenta previa or low-lying placenta were included in the study. 17 of the cases underwent peripartum hysterectomy due to placenta accreta spectrum. 37 cases with normal placentation underwent caesarean delivery. Foetal fibronectin (p:.03) and PAI-1 (p:.02) levels were determined to be significantly different between cases with placenta accreta spectrum and cases with normal placentation. AUC for foetal FFN was calculated to be 0.69, while the AUC for, PAI-1was 0.66. Results for both FFN and PAI-1 were not found useful enough for the diagnosis of PAS. IMPACT STATEMENTWhat is already known on this subject? We lack biomarkers which can identify placenta accreta spectrum.What do the results of this study add? Maternal plasma levels of FFN and PAI-1 significantly altered in PASWhat are the implications of these findings for clinical practice and/or future research? If multiple of median values of FFN and PAI-1 levels in maternal blood are determined in future studies, it can be used in the antenatal diagnosis of PAS cases.

Time course of endothelial dysfunction and atherothrombosis markers in patients with acute myocardial infarction with st segment elevation and type 2 diabetes mellitus depending on reperfusion therapy approach.

OBJECTIVE: The aim: To evaluate the levels of plasminogen activator type 1 inhibitor, asymmetric dimethylarginine and endothelial nitric oxide synthase on day 10-14 in patients, depending on the presence or absence of concomitant type 2 diabetes and the type of reperfusion therapy. PATIENTS AND METHODS: Materials and methods: The study involved 130 patients with acute myocardial infarction, divided into 2 groups: Group 1 consisted of patients with acute myocardial infarction with type 2 diabetes mellitus (n = 73), Group 2 comprised patients with acute type 2 diabetes mellitus (n = 57). The quantitative content of IAP-1 was determined by enzymelinked immunosorbent assay using a commercial test system manufactured by Technoclone PAI-1 ELISA Kit (Austria), NOS - Enzyme-Linked Immunosorbent Assay (ELISA) Kit for Nitric Oxide Synthase Endothelial (NOS) ADMA ELISA Kit (Austria). RESULTS: Results and conclusions: Percutaneous coronary intervention contributes to a significant reduction in the content of ADMA, which is a marker of endothelial dysfunction and increase NOS on the 10-14th day of acute myocardial infarction compared with standard therapy. During PCI, the level of IAP-1 did not significantly change in the time course of treatment due to post-inflammatory and post-traumatic activation of platelets in the vascular wall.

Thrombin and plasmin generation in patients with plasminogen or plasminogen activator inhibitor type 1 deficiency.

INTRODUCTION: Deficiencies of plasminogen and plasminogen activator inhibitor type 1 (PAI-1) are rare disorders of fibrinolysis. Current laboratory assays for analysis of activity of plasminogen and PAI-1 do not provide an accurate correlation with clinical phenotype. METHODS: The Nijmegen Hemostasis Assay (NHA) was used to simultaneously measure thrombin and plasmin generation in 5 patients with plasminogen deficiency (PLGD) and 10 patients with complete PAI-1 deficiency. Parameters analysed included: lag time ratio, thrombin peak time ratio, thrombin peak height, thrombin potential (AUC), fibrin lysis time, plasmin peak height and plasmin potential. Parameters were expressed as a percentage compared to a reference value of 53 healthy normal controls. RESULTS: Patients with PLGD demonstrated a short lag time and thrombin peak time, with normal thrombin peak height but an increased AUC. Plasmin generation was able to be detected in only one (23% plasminogen activity) of the five PLGD patients. All ten PAI-1 deficient patients demonstrated a short lag and thrombin peak time, low thrombin peak height with normal AUC. Plasmin generation revealed an increased plasmin peak and plasmin potential; interestingly, there was a large variation between individual patients despite all patients having the same homozygous defect. CONCLUSION: Patients with either PLGD or PAI-1 deficiency show distinct abnormalities in plasmin and thrombin generation in the NHA. The differences observed in the propagation phase of thrombin generation may be explained by plasmin generation. These results suggest that disorders of fibrinolysis also influence coagulation and a global assay measuring both activities may better correlate with clinical outcome.

Role of Plasminogen Activator Inhibitor Type 1 in Pathologies of Female Reproductive Diseases.

Normal pregnancy is a state of hypercoagulability with diminishing fibrinolytic activity, which is mainly caused by an increase of plasminogen activator inhibitor type 1 (PAI-1). PAI-1 is the main inhibitor of plasminogen activators, including tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). In human placentas, PAI-1 is expressed in extravillous interstitial trophoblasts and vascular trophoblasts. During implantation and placentation, PAI-1 is responsible for inhibiting extra cellular matrix (ECM) degradation, thereby causing an inhibition of trophoblasts invasion. In the present study, we have reviewed the literature of various reproductive diseases where PAI-1 plays a role. PAI-1 levels are increased in patients with recurrent pregnancy losses (RPL), preeclampsia, intrauterine growth restriction (IUGR), gestational diabetes mellitus (GDM) in the previous pregnancy, endometriosis and polycystic ovary syndrome (PCOS). In general, an increased expression of PAI-1 in the blood is associated with an increased risk for infertility and a worse pregnancy outcome. GDM and PCOS are related to the genetic role of the 4G/5G polymorphism of PAI-1. This review provides an overview of the current knowledge of the role of PAI-1 in reproductive diseases. PAI-1 represents a promising monitoring biomarker for reproductive diseases and may be a treatment target in the near future.

Bleeding related to disturbed fibrinolysis.

The components and reactions of the fibrinolysis system are well understood. The pathway has fewer reactants and interactions than coagulation, but the generation of a complete quantitative model is complicated by the need to work at the solid-liquid interface of fibrin. Diagnostic tools to detect disease states due to malfunctions in the fibrinolysis pathway are also not so well developed as is the case with coagulation. However, there are clearly a number of inherited or acquired pathologies where hyperfibrinolysis is a serious, potentially life-threatening problem and a number of antifibrinolytc drugs are available to treat hyperfibrinolysis. These topics will be covered in the following review.

Podocyte injury-driven intracapillary plasminogen activator inhibitor type 1 accelerates podocyte loss via uPAR-mediated ß1-integrin endocytosis.

Podocyte-endothelial cell cross-talk is paramount for maintaining the filtration barrier. The present study investigated the endothelial response to podocyte injury and its subsequent role in glomerulosclerosis using the podocyte-specific injury model of NEP25/LMB2 mice. NEP25/LMB2 mice showed proteinuria and local podocyte loss accompanied by thrombotic microangiopathy on day 8. Mice showed an increase of glomerular plasminogen activator inhibitor type 1 (PAI-1) mRNA and aberrant endothelial PAI-1 protein already on day 1, before thrombosis and proteinuria. A PAI-1-specific inhibitor reduced proteinuria and thrombosis and preserved podocyte numbers in NEP25/LMB2 mice by stabilization of ß1-integrin translocation. Heparin loading significantly reduced thrombotic formation, whereas proteinuria and podocyte numbers were unchanged. Immortalized podocytes treated with PAI-1 and the urokinase plasminogen activator (uPA) complex caused significant cell detachment, whereas podocytes treated with PAI-1 or uPA alone or with the PAI-1/uPA complex pretreated with an anti-uPA receptor (uPAR) antibody failed to cause detachment. Confocal microscopy and cell surface biotinylation experiments showed that internalized ß1-integrin was found together with uPAR in endocytotic vesicles. The administration of PAI-1 inhibitor or uPAR-blocking antibody protected cultured podocytes from cell detachment. In conclusion, PAI-1/uPA complex-mediated uPAR-dependent podocyte ß1-integrin endocytosis represents a novel mechanism of glomerular injury leading to progressive podocytopenia. This aberrant cross-talk between podocytes and endothelial cells represents a feedforward injury response driving podocyte loss and progressive glomerulosclerosis.

Changes in blood coagulation-fibrinolysis markers by pneumatic tourniquet during total knee joint arthroplasty with venous thromboembolism.

This study investigated changes in blood coagulation-fibrinolysis markers during total knee arthroplasty (TKA). Preoperative 16-row multidetector row computed tomography (MDCT) revealed no asymptomatic venous thromboembolism (VTE) in the 42 patients recruited. Using MDCT postoperatively, patients were divided into thrombus (asymptomatic VTE, 19 patients) and no-thrombus (23 patients) groups. Blood taken at intervals before and after pneumatic tourniquet release revealed increased plasminogen activator inhibitor type-1 (PAI-1) at 30s for both groups and at 90s (both P=0.01) in the thrombus group. D-dimer levels were highest at 30 and 90s for both groups (P = 0.01). PAI-1 and D-dimer levels were strongly correlated at both time points in the thrombus group. Inactivating fibrinolysis due to PAI-1 may lead to asymptomatic VTE after TKA.

Qigui-Yishen decoction delays renal fibrosis in mice with chronic kidney disease by regulating TM and PAI-1.

OBJECTIVE: To explore the mechanism of Qigui-Yishen decoction in delaying renal fibrosis in mice by regulating thrombin regulatory protein (Thrombomodulin, TM) and plasminogen activator inhibitor-1 (PAI-1) based on network pharmacology. METHODS: The active ingredients of Qigui Yishen decoction and their target molecules associated with chronic kidney disease (CKD) were retrieved from websites and databases, sorted out, and screened, and the possible targets of Qigui Yishen decoction for reducing CKD renal fibrosis were predicted and analyzed. Forty Institute of Cancer research (ICR) rats were used to establish a unilateral ureteral obstruction (UUO) model, and divided into several groups: sham operation group, model group, high concentration decoction group (1 g/mL), low concentration decoction group (0.46 g/mL), and benazepril group (0.1 g/mL). At the end of the experiment, the levels of serum creatinine (Scr) and blood urea nitrogen (BUN) were detected. Masson staining was used to observe changes in the renal interstitial fibrosis index. Immunohistochemistry and western blot were used to detect the expressions of TM, PAI-1, transforming growth factor-ß1 (TGF-ß1) and collagen I (Col I) in kidney tissues, and the differences between groups were compared. RESULTS: Qigui Yishen decoction contains 42 effective ingredients such as sitosterol, mannitol, and quercetin, with 662 drug targets and 16154 disease targets. Analysis revealed 570 potential targets, including TM4SF19, PAIP1, TGF-ß1, and Col I-AI. Compared to the sham operation group, all treatment groups exhibited increased Scr and BUN levels (P<0.05) and enhanced renal interstitial fibrosis (P<0.05) after UUO model establishment. Moreover, immunohistochemical results showed significant increases in PAI-1, TGF-ß1, and Col I (all P<0.05), and a significant decrease in TM expression (P<0.05). Compared to the model group, the high concentration decoction group, low concentration decoction group and benazepril group had no significant difference in Scr and BUN values (P>0.05), but the renal interstitial fibrosis index was lower (P<0.05). Also, the relative expressions of PAI-1, TGF-ß1 and Col I in the kidney tissue of mice were decreased, while the relative expression of TM was increased (P<0.05). CONCLUSION: Qigi Yishen decoction has the characteristics of multiple components and multiple targets, and can play a role in delaying renal fibrosis by regulating the expression of PAI-1, TGF-ß1, Col I, and TM.

Metabolic Changes Induced by Bariatric Surgery May be Mediated by PAI-1 and PCSK9 Crosstalk.

BACKGROUND: Adiposity favors several metabolic disorders with an exacerbated chronic pro-inflammatory status and tissue damage, with high levels of plasminogen activator inhibitor type 1 (PAI-1) and proprotein convertase subtilisin/kexin type 9 (PCSK9). OBJECTIVE: To demonstrate the influence of bariatric surgery on the crosstalk between PAI-1 and PCSK9 to regulate metabolic markers. METHODS: Observational and longitudinal study of 190 patients with obesity and obesity-related comorbidities who underwent bariatric surgery. We measured, before and after bariatric surgery, the anthropometric variables and we performed biochemical analysis by standard methods (glucose, insulin, triglycerides [TG], total cholesterol, high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C] and TG/HDL-C ratio, PAI-1 and PCSK9 were measured by ELISA). RESULTS: PAI-1 levels decreased significantly after bariatric surgery, and were positively correlated with lipids, glucose, and TG, with significance on PCSK9 and TG/HDL-C alleviating the insulin resistance (IR) and inducing a state reversal of type 2 diabetes (T2D) with a significant decrease in body weight and BMI (p <0.0001). Multivariate regression analysis predicted a functional model in which PAI-1 acts as a regulator of PCSK9 (p <0.002), TG (p <0.05), and BMI; at the same time, PCSK9 modulates LDL-C HDL-C and PAI-1. CONCLUSIONS: After bariatric surgery, we found a positive association and crosstalk between PAI-1 and PCSK9, which modulates the delicate balance of cholesterol, favoring the decrease of circulating lipids, TG, and PAI-1, which influences the glucose levels with amelioration of IR and T2D, demonstrating the crosstalk between fibrinolysis and lipid metabolism, the two main factors involved in atherosclerosis and cardiovascular disease in human obesity.

Enhanced Expression of Plasminogen Activators and Inhibitor in the Healing of Tympanic Membrane Perforation in Rats.

The significance of plasminogen activation during the tympanic membrane (TM) healing is known mainly from studies performed on knock-out mice. In the previous study, we reported activation of genes coding proteins of plasminogen activation and inhibition system in rat's TM perforation healing. The aim of the present study was the evaluation of protein products expressed by these genes and their tissue distribution using Western blotting and immunofluorescent method, respectively, during 10-day observation period after injury. Otomicroscopical and histological evaluation were employed to assess the healing process. The expression of urokinase plasminogen activator (uPA) and its receptor (uPAR) were significantly upregulated in the proliferation phase, with subsequent gradual attenuation during remodeling phase of healing process, when keratinocyte migration was weakening. The expression of plasminogen activator inhibitor type 1 (PAI-1) also showed the highest levels during the proliferation phase. The increase of tissue plasminogen activator (tPA) expression was observed during the whole observation period, with the highest activity during the remodeling phase. Immunofluorescence of these proteins was present mainly in migrating epithelium. Our study found that plasminogen activation (uPA, uPAR, tPA) and inhibitory (PAI-1) molecules form a well-structured regulatory system of the epithelial migration that is critical to the healing of TM after its perforation.

Circadian Rhythm and Risk of Hemorrhagic Transformation after Acute Ischemic Stroke Treated with Intravenous Thrombolysis - A Systematic Review.

BACKGROUND: A circadian pattern for the onset of acute ischemic stroke (AIS) has been described, with a higher risk in the early morning and a lower risk during nighttime. However, data assessing the circadian distribution of hemorrhagic transformation after intravenous thrombolysis (ivT) are still incongruent. OBJECTIVES: This review aimed to evaluate whether the time interval based on AIS onset or ivT time could influence the occurrence of intracranial hemorrhage (ICH) related to ivT and if the circadian rhythm of endogenous production of tissue plasminogen activator (t-PA) favors ICH occurrence. METHODS: We conducted a systematic review following the PRISMA guidelines, searching PubMed and Embase for articles in English using the keywords: 'stroke', 'thrombolysis', and 'circadian'. Articles investigating the AIS onset or ivT time effects on circadian variations of ICH in AIS adult patients treated with ivT were included. Based on ICH's incidence and odds ratio, time intervals associated with higher risk and time intervals associated with lower risk were defined. The Newcastle-Ottawa Scale was used to assess the risk of bias. The resulting data were reported in a qualitative narrative synthesis. RESULTS: From the 70 abstracts returned by electronic literature search, six studies with 33,365 patients fulfilled the inclusion criteria, out of which three were retrospective analysis studies, one case-control study, one prospective study, and one post hoc analysis of a multicentre trial. Some studies assessed the relationship between ICH occurrence and circadian rhythm depending on AIS onset time (n = 2), treatment time (n = 2), or both (n = 4). All studies investigated the patients' comorbidities as confounding variables for the circadian pattern of symptomatic ICH (sICH). Two studies found no association between AIS onset or ivT time and patient risk factors, but the other four found several differences and used multivariate logistic regression models to balance these covariates. The overall score of the Newcastle- Ottawa scale was 83.3%, which might be interpreted as overall high quality. CONCLUSION: ICH occurred after ivT seems to follow a circadian pattern; the 18:00-00:00 time frame was the safest one, and patients with AIS onset or ivT time between these hours had the lowest incidence of any ICH, including sICH. The 06:00-12:00 block was associated with the highest incidence of ICH and sICH. However, the analysis is limited by the small number of included studies and the heterogeneous findings reported. Further homogenized studies using comparable time frames and sICH definitions are needed to demonstrate this circadian pattern. The review protocol was registered in the OSF database under reference UHNF, doi:10.17605/OSF.IO/UHNF6.

Lung-borne systemic inflammation in mechanically ventilated infant rats due to high PEEP, oxygen, and hypocapnia.

BACKGROUND: Intensive care practice calls for ventilator adjustments due to fast-changing clinical conditions in ventilated critically ill children. These adaptations include positive end-expiratory pressure (PEEP), fraction of inspired oxygen (FiO2), and respiratory rate (RR). It is unclear which alterations in ventilator settings trigger a significant systemic inflammatory response. METHODS: Fourteen-day old Wistar rat pups were randomized to the following groups: (a) "control" with tidal volume ~8 mL/kg, PEEP 5 cmH2O, FiO2 0.4, RR 90 min-1, (b) "PEEP 1", (c) "PEEP 9" (d) "FiO2 0.21", (e) "FiO2 1.0", (f) "hypocapnia" with RR of 180 min-1, and (g) "hypercapnia" with RR of 60 min-1. Following 120 min of mechanical ventilation, plasma for inflammatory biomarker analyses was obtained by direct cardiac puncture at the end of the experiment. RESULTS: Interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were driven by FiO2 0.4 and 1.0 (P=0.02, P<0.01, respectively), tissue plasminogen activator inhibitor type-1 (tPAI-1) was increased by high PEEP (9 cmH2O, P<0.05) and hypocapnia (P<0.05), and TNF-α was significantly lower in hypercapnia (P<0.01). Tissue inhibitor of metalloproteinase-1 (TIMP-1), cytokine-induced neutrophil chemoattractant 1 (CINC-1), connective tissue growth factor (CTGF), and monocyte chemoattractant protein-1 (MCP-1) remained unaffected. CONCLUSION: Alterations of PEEP, FiO2, and respiratory frequency induced a significant systemic inflammatory response in plasma of infant rats. These findings underscore the importance of lung-protective ventilation strategies. However, future studies are needed to clarify whether ventilation induced systemic inflammation in animal models is pathophysiologically relevant to human infants.

Diurnal Oscillations of Fibrinolytic Parameters in Patients with Acute Myocardial Infarction and Their Relation to Platelet Reactivity: Preliminary Insights.

There is limited information about diurnal changes in fibrinolysis parameters after acute myocardial infarction (AMI) and their relationship with on-treatment platelet reactivity. The aim of this study was to assess tissue plasminogen activator (t-PA), plasminogen activator inhibitor type-1 (PAI-1), α2-antiplasmin (α2-AP) activity, and plasmin-antiplasmin (PAP) complexes in 30 AMI patients taking dual antiplatelet therapy (DAPT), i.e., acetylsalicylic acid and clopidogrel. Fibrinolytic parameters were assessed at four time points (6 a.m., 10 a.m., 2 p.m., and 7 p.m.) on the third day after AMI using immunoenzymatic methods. Moreover, platelet reactivity was measured using multiple-electrode aggregometry, to assess potential differences in fibrinolytic parameters in low/high on-aspirin platelet reactivity and low/high on-clopidogrel platelet reactivity subgroups of patients. We detected significant diurnal oscillations in t-PA and PAI-1 levels in the whole study group. However, PAP complexes and α2-AP activity were similar at the analyzed time points. Our study reveals a potential impact of DAPT on the time course of fibrinolytic parameters, especially regarding clopidogrel. We suggest the presence of diurnal variations in t-PA and PAI-1 concentrations in AMI patients, with the highest levels midmorning, regardless of platelet reactivity. Significantly elevated levels of PAI-1 during the evening hours in clopidogrel-resistant patients may increase the risk of thrombosis.

Anti-fibrotic effect of 6-bromo-indirubin-3'-oxime (6-BIO) via regulation of activator protein-1 (AP-1) and specificity protein-1 (SP-1) transcription factors in kidney cells.

PAI-1 and CTGF are overexpressed in kidney diseases and cause fibrosis of the lungs, liver, and kidneys. We used a rat model of unilateral ureteral obstruction (UUO) to investigate whether 6-BIO, a glycogen synthase kinase-3ß inhibitor, attenuated fibrosis by inhibiting PAI-1 and CTGF in vivo. Additionally, TGFß-induced cellular fibrosis was observed in vitro using the human kidney proximal tubular epithelial cells (HK-2), and rat interstitial fibroblasts (NRK49F). Expression of fibrosis-related proteins and signaling molecules such as PAI-1, CTGF, TGFß, αSMA, SMAD, and MAPK were determined in HK-2 and NRK49F cells using immunoblotting. To identify the transcription factors that regulate the expression of PAI-1 and CTGF the promoter activities of AP-1 and SP-1 were analyzed using luciferase assays. Confocal microscopy was used to observe the co-localization of AP-1 and SP-1 to PAI-1 and CTGF. Expression of PAI-1, CTGF, TGFß, and α-SMA increased in UUO model as well as in TGFß-treated HK-2 and NRK49F cells. Furthermore, UUO and TGFß treatment induced the activation of P-SMAD2/3, SMAD4, P-ERK 1/2, P-P38, and P-JNK MAPK signaling pathways. PAI-1, CTGF, AP-1 and SP-1 promoter activity increased in response to TGFß treatment. However, treatment with 6-BIO decreased the expression of proteins and signaling pathways associated with fibrosis in UUO model as well as in TGFß-treated HK-2 and NRK49F cells. Moreover, 6-BIO treatment attenuated the expression of PAI-1 and CTGF as well as the promoter activities of AP-1 and SP-1, thereby regulating the SMAD and MAPK signaling pathways, and subsequently exerting anti-fibrotic effects on kidney cells.

Quantile-specific heritability of plasminogen activator inhibitor type-1 (PAI-1, aka SERPINE1) and other hemostatic factors.

BACKGROUND: Plasminogen activator inhibitor type-1 (PAI-1, aka SERPINE1) is a moderately heritable glycoprotein that regulates fibrin clot dissolution (fibrinolysis). OBJECTIVES: Test whether the heritabilities (h2 ) of PAI-1 and other hemostatic factors are constant throughout their distribution or whether they are quantile-specific (i.e., a larger or smaller h2 depending on whether their concentrations are high or low). METHODS: Quantile regression was applied to 5606 parent-offspring pairs and 5310 full siblings of the Framingham Heart Study. Quantile-specific heritability was estimated from the parent-offspring regression slope (ßPO , h2  = 2ßPO /(1+rspouse )) and the full-sib regression slope (ßFS , h2  = {(1+8rspouse ßFS )0.5 -1}/(2rspouse )). RESULTS: Heritability (h2  ± SE) increased significantly with increasing percentiles of the offspring's age- and sex-adjusted PAI-1 distribution when estimated from ßPO (plinear trend  = 0.0001): 0.09 ± 0.02 at the 10th, 0.09 ± 0.02 at the 25th, 0.16 ± 0.02 at the 50th, 0.29 ± 0.04 at the 75th, and 0.26 ± 0.08 at the 90th percentile of the PAI-1 distribution, and when estimated from ßFS (plinear trend  = 6.5x10-7 ). There was no significant evidence for quantile-specific heritability for factor VII (plinear trend  = 0.35), D-dimer (plinear trend  = 0.08), tPA (plinear trend  = 0.74), or von Willebrand factor (plinear trend  = 0.79). CONCLUSION: Higher mean plasma PAI-1 antigen concentrations tend to accentuate genetic effects (quantile-dependent expressivity), which is consistent with the greater reported differences in PAI-1 concentrations between rs1799889 SERPINE1 (4G/5G) genotypes in patients with osteonecrosis, meningococcal sepsis, obesity, prior myocardial infarction, deep vein thrombosis, and polycystic ovarian syndrome than in healthy controls. It is also consistent with the greater increases in PAI-1 concentrations in 4G-allele carriers than 5G/5G homozygotes following fibrinolytic treatment, low-salt intake, and high saturated fat intake.

Experimental and Clinical Evidence Supports the Use of Urokinase Plasminogen Activation System Components as Clinically Relevant Biomarkers in Gastroesophageal Adenocarcinoma.

Gastric and oesophageal cancers (GOCs) are lethal cancers which metastasise early and recur frequently, even after definitive surgery. The urokinase plasminogen activator system (uPAS) is strongly implicated in the invasion and metastasis of many aggressive tumours including GOCs. Urokinase plasminogen activator (uPA) interaction with its receptor, urokinase plasminogen activator receptor (uPAR), leads to proteolytic activation of plasminogen to plasmin, a broad-spectrum protease which enables tumour cell invasion and dissemination to distant sites. uPA, uPAR and the plasminogen activator inhibitor type 1 (PAI-1) are overexpressed in some GOCs. Accumulating evidence points to a causal role of activated receptor tyrosine kinase pathways enhancing uPAS expression in GOCs. Expression of these components are associated with poorer clinicopathological features and patient survival. Stromal cells, including tumour-associated macrophages and myofibroblasts, also express the key uPAS proteins, supporting the argument of stromal involvement in GOC progression and adverse effect on patient survival. uPAS proteins can be detected on circulating leucocytes, circulating tumour cells and within the serum; all have the potential to be developed into circulating biomarkers of GOC. Herein, we review the experimental and clinical evidence supporting uPAS expression as clinical biomarker in GOC, with the goal of developing targeted therapeutics against the uPAS.

Cerebral vasculopathy and strokes in a child with COVID-19 antibodies: illustrative case.

BACKGROUND: The ability of coronavirus disease 2019 (COVID-19) to cause neurological insults in afflicted adults is becoming increasingly understood by way of an ever-growing amount of international data. By contrast, the pandemic illness's neurological effects in the pediatric population are both poorly understood and sparsely reported. OBSERVATIONS: In this case, the authors reported their experience with a preschool-age child with hydrocephalus who suffered multiterritory strokes presumed secondary to immune-mediated cerebral vasculopathy as a result of asymptomatic COVID-19 infection. LESSONS: Growing evidence indicates that COVID-19 can cause neurological sequelae such as encephalitis and strokes. In this case report, the authors discussed a case of cerebral vasculopathy and strokes in a pediatric patient who was positive for COVID-19.

Cell adhesion molecules, plasminogen activator inhibitor type 1, and metabolic syndrome in patients with psoriasis.

The objective of this study is to delineate the cellular adhesion molecule (CAM) profile and plasminogen activator inhibitor type 1 (PAI-1), and their association with metabolic syndrome (MetS) and carbohydrate metabolism biomarkers in psoriasis patients with mild and moderate severity. Sixty-seven patients with psoriasis as well as 102 healthy subjects were recruited. Insulin and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), but not glucose, were significantly higher in psoriasis than in controls. Psoriasis was characterized by increased plasma levels of platelet endothelial cell adhesion molecule 1 (PECAM-1), vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), E-selectin, and PAI-1 as compared with controls. Psoriasis diagnosis could explain 59.0% of CAM and PAI-1 variance, with a particularly strong impact on E-selectin (45.6%), VCAM-1 (32.7%), and PAI-1 (24.8%). Subjects with MetS showed significantly higher E-selectin and PAI-1 than those without MetS. Using VCAM-1, E-selectin, PAI-1 (all positively), and P-selectin (inversely) in a binary regression equation, it was found that 87.6% of all patients were correctly classified with a sensitivity of 92.5% and a specificity of 84.3%. CAM and PAI-1 were correlated with carbohydrate metabolism biomarkers (glucose, insulin, and HOMA-IR). In conclusion, CAM levels are associated with psoriasis diagnosis and MetS may influence E-selectin and PAI-1 concentrations. More studies are needed to verify the causality among these factors, as well as their relation to the different degrees of disease severity.

Impact of Polytrauma and Acute Respiratory Distress Syndrome on Markers of Fibrinolysis: A Prospective Pilot Study.

Acute respiratory distress syndrome (ARDS), which is associated with major morbidity and high mortality, is commonly developed by polytraumatized patients. Its pathogenesis is complex, and its development is difficult to anticipate, as candidate biomarkers for the prediction of ARDS were found not to be reliable for clinical use. In this prospective study, we assessed the serum antigen levels of tissue plasminogen activator (tPA) and plasminogen activator inhibitor type-1 (PAI-1) of 28 survivors of blunt polytrauma (age ≥18 years; injury severity score ≥16) at admission and on days 1, 3, 5, 7, 10, 14, and 21 of hospitalization. Our results show that these patients presented high mean tPA and PAI-1 antigen levels at admission; despite their decline, these parameters remained elevated for 3 weeks. Over this period, the mean tPA antigen level was higher in polytrauma victims suffering from ARDS than in those without ARDS, whereas the mean PAI-1 level was higher in polytrauma victims sustaining pneumonia than in those without pneumonia. Moreover, in each individual developing ARDS, the polytrauma-related elevated tPA antigen level either continued to rise after admission or suffered a second increase up to the onset of ARDS, declining immediately thereafter. Therefore, our findings support the assessment of serum tPA antigen levels after the initial treatment of polytraumatized patients, as this parameter shows potential as a biomarker for the development of ARDS and for the consequent identification of high-risk individuals.

Prostaglandin E2 receptor 3 (EP3) signaling promotes migration of cervical cancer via urokinase-type plasminogen activator receptor (uPAR).

PURPOSE: Cervical cancer metastasis results in poor prognosis and increased mortality, which is not separated from inflammatory reactions accumulated by prostaglandin E2 (PGE2). As a specific G-protein coupled PGE2 receptor, EP3 is demonstrated as a negative prognosticator of cervical malignancy. Now, we aimed to investigate the pathological mechanism of EP3 in modulating cervical cancer carcinogenesis. METHODS: Bioinformatics analysis was used to identify PAI-1 and uPAR correlations with EP3 expression, as well as the prognosis of cervical cancer patients. In vitro analyses were carried out to investigate the role of EP3 on cervical cancer proliferation and migration. RESULTS: In vitro studies showed that sulprostone (an EP3 agonist) enhanced the proliferation and migration of cervical cancer cells, whereas silencing of EP3 inhibited their proliferation and migration. Furthermore, EP3 knockdown increased the expression of plasminogen activator inhibitor type 1 (PAI-1), urokinase-type plasminogen activator receptor (uPAR), and phosphorylated extracellular signal-regulated kinases 1/2 (p-ERK1/2), but decreased p53 expression. Bioinformatics analysis showed that both PAI-1 and uPAR were correlated with EP3 expression, as well as the prognosis of cervical cancer patients. The survival analysis further showed that uPAR overexpression (IRS≥2) was correlated with a lower overall survival rate of cervical cancer patients with advanced stages (FIGO III-IV). CONCLUSION: These results indicated that EP3 signaling pathway might facilitate the migration of cervical cancer cells through modulating uPAR expression. Therefore, EP3 and uPAR could represent novel therapeutic targets in the treatment of cervical cancer in advantaged stages.