- Annexin A2 (ANX A2): An Emerging Biomarker and Potential Therapeutic Target for Aggressive Cancers. [Review]
- IJInt J Cancer 2018 Aug 19
- ANX A2 is an important member of annexin family of proteins expressed on surface of endothelial cells (ECs), macrophages, mononuclear cells and various types of cancer cells. It exhibits high affinit...
ANX A2 is an important member of annexin family of proteins expressed on surface of endothelial cells (ECs), macrophages, mononuclear cells and various types of cancer cells. It exhibits high affinity binding for calcium (Ca++ ) and phospholipids. ANX A2 plays an important role in many biological processes such as endocytosis, exocytosis, autophagy, cell-cell communications and biochemical activation of plasminogen. On the cell surface ANX A2 organizes the assembly of plasminogen (PLG) and tissue plasminogen activator (tPA) for efficient conversion of PLG to plasmin, a serine protease. Proteolytic activity of plasmin is required for activation of inactive pro-metalloproteases (pro-MMPs) and latent growth factors for their biological actions. These activation steps are critical for degradation of extracellular matrix (ECM) and basement proteins (BM) for cancer cell invasion and metastasis. Increased expression of ANX A2 protein/gene has been correlated with invasion and metastasis in a variety of human cancers. Moreover, clinical studies have positively correlated ANX A2 protein expression with aggressive cancers and with resistance to anti-cancer drugs, shorter disease-free survival (DFS), and worse overall survival (OS). The mechanism(s) by which ANX A2 regulates cancer invasion and metastasis are beginning to emerge. Investigators used various technologies to target ANX A2 in preclinical model of human cancers and demonstrated exciting results. In this review paper, we analyzed existing literature concurrent with our own findings and provided a critical overview of ANX A2-dependent mechanism(s) of cancer invasion and metastasis. This article is protected by copyright. All rights reserved.
- Nebulization of Single-Chain Tissue-Type and Single-Chain Urokinase Plasminogen Activator for Treatment of Inhalational Smoke-Induced Acute Lung Injury. [Journal Article]
- JDJ Drug Deliv Sci Technol 2018; 48:19-27
- Single-chain tissue-type plasminogen activator (sctPA) and single-chain urokinase plasminogen activator (scuPA) have attracted interest as enzymes for the treatment of inhalational smoke-induced acut...
Single-chain tissue-type plasminogen activator (sctPA) and single-chain urokinase plasminogen activator (scuPA) have attracted interest as enzymes for the treatment of inhalational smoke-induced acute lung injury (ISALI). In this study, the pulmonary delivery of commercial human sctPA and lyophilized scuPA and their reconstituted solution forms were demonstrated using vibrating mesh nebulizers (Aeroneb® Pro (active) and EZ Breathe® (passive)). Both the Aeroneb® Pro and EZ Breathe® vibrating mesh nebulizers produced atomized droplets of protein solution of similar size of less than about 5 μm, which is appropriate for pulmonary delivery. Enzymatic activities of scuPA and of sctPA were determined after nebulization and both remained stable (88.0% and 93.9%). Additionally, the enzymatic activities of sctPA and tcuPA were not significantly affected by excipients, lyophilization or reconstitution conditions. The results of these studies support further development of inhaled formulations of fibrinolysins for delivery to the lungs following smoke-induced acute pulmonary injury.
- Rectus Sheath Hematoma Following Intravenous Thrombolysis With Recombinant Tissue Plasminogen Activator for Cerebral Infarction: A Case Report. [Journal Article]
- JSJ Stroke Cerebrovasc Dis 2018 Aug 16
- A 76-year-old Japanese man was admitted to our department because of aphasia and right hemiparesis. Brain magnetic resonance imaging showed cerebral infarction caused by occlusion of the left middle ...
A 76-year-old Japanese man was admitted to our department because of aphasia and right hemiparesis. Brain magnetic resonance imaging showed cerebral infarction caused by occlusion of the left middle cerebral artery, and alteplase therapy was started. Thrombectomy was subsequently performed, resulting in recanalization. On day 4 after admission, he complained of epigastric pain when coughing. On day 8, contrast-enhanced computed tomography showed a left abdominal rectus sheath hematoma without extravasation. We carefully followed up the patient with conservative therapy, and the rectus sheath hematoma was ameliorated. Rectus sheath hematomas present as acute abdominal pain and are often misdiagnosed. Although several predisposing factors for rectus sheath hematomas have been identified, whether recombinant tissue-type plasminogen activator causes rectus sheath hematomas, remains unclear. This case highlights the need to consider a rectus sheath hematoma as a differential diagnosis of abdominal pain following treatment with recombinant tissue-type plasminogen activator.
- Acute Blood Pressure Management in Acute Ischemic Stroke and Spontaneous Cerebral Hemorrhage. [Review]
- CTCurr Treat Options Neurol 2018 Aug 18; 20(9):39
- We discuss the evidence and guidelines for acute blood pressure (BP) management for patients presenting with acute ischemic stroke or spontaneous cerebral hemorrhage.
We discuss the evidence and guidelines for acute blood pressure (BP) management for patients presenting with acute ischemic stroke or spontaneous cerebral hemorrhage.
- Role of PKB/SGK-dependent phosphorylation of GSK-3α/β in vascular calcification during cholecalciferol overload in mice. [Journal Article]
- BBBiochem Biophys Res Commun 2018 Aug 10
- Medial vascular calcification is a highly regulated process involving osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells. Both, protein kinase B (PKB) and serum- and glucocortic...
Medial vascular calcification is a highly regulated process involving osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells. Both, protein kinase B (PKB) and serum- and glucocorticoid-inducible kinase 1 (SGK1) are involved in the intracellular signaling of vascular calcification and both phosphorylate and inactivate glycogen synthase kinase 3 (GSK-3). The present study explored whether PKB/SGK-dependent phosphorylation of GSK-3α/β is involved in vascular calcification. Experiments were performed in Gsk-3α/β double knockin mice lacking functional PKB/SGK phosphorylation sites (gsk-3KI) and corresponding wild-type mice (gsk-3WT) following high-dosed cholecalciferol treatment as well as ex vivo in aortic ring explants from gsk-3KI and gsk-3WT mice treated without and with phosphate. In gsk-3WT mice, high-dosed cholecalciferol induced vascular calcification and aortic osteo-/chondrogenic signaling, shown by increased expression of osteogenic markers Msx2, Cbfa1 and tissue-nonspecific alkaline phosphatase (Alpl). All these effects were suppressed in aortic tissue from gsk-3KI mice. Cholecalciferol decreased aortic Gsk-3α/β phosphorylation (Ser21/9) in gsk-3WT mice, while no phosphorylation was observed in gsk-3KI mice. Moreover, the mRNA expression of type III sodium-dependent phosphate transporter (Pit1) and plasminogen activator inhibitor 1 (Pai1) was increased following cholecalciferol treatment in aortic tissue of gsk-3WT mice, effects again blunted in gsk-3KI mice. In addition, phosphate treatment induced mineral deposition and osteogenic markers expression in aortic ring explants from gsk-3WT mice, effects reduced in aortic ring explants from gsk-3KI mice. In conclusion, vascular PKB/SGK-dependent phosphorylation of GSK-3α/β contributes to the osteoinductive signaling leading to vascular calcification.
- Surgical management of submacular hemorrhage: experience at an academic Canadian centre. [Journal Article]
- CJCan J Ophthalmol 2018; 53(4):408-414
- CONCLUSIONS: Vitrectomy with subretinal t-PA and pneumatic displacement seems to be an effective treatment for SMH in terms of blood displacement and visual outcomes.
- Tenecteplase versus alteplase for management of acute ischemic stroke: a pairwise and network meta-analysis of randomized clinical trials. [Journal Article]
- JTJ Thromb Thrombolysis 2018 Aug 16
- Tenecteplase is a genetically mutated variant of alteplase with superior pharmacodynamic and pharmacokinetic properties. However, its efficacy and safety in acute ischemic strokes are limited. Hence,...
Tenecteplase is a genetically mutated variant of alteplase with superior pharmacodynamic and pharmacokinetic properties. However, its efficacy and safety in acute ischemic strokes are limited. Hence, we conducted a study to evaluate the efficacy and safety of tenecteplase compared with alteplase in acute ischemic stroke. Electronic databases were searched for randomized clinical trials (RCTs) comparing tenecteplase with alteplase in acute ischemic stroke patients eligible for thrombolysis. We evaluated various efficacy and safety outcomes using random-effects models for both pairwise and Bayesian network meta-analyses along with meta-regression analyses. We included 5 RCTs with a total of 1585 patients. Compared with alteplase, tenecteplase treatment was associated with significantly greater complete recanalization (odd ratio [OR] 2.01; 95% confidence interval [CI] 1.04-3.87; p = 0.04) and early neurological improvement (OR 1.43; 95% CI 1.01-2.03; p = 0.05). There were no differences between the two thrombolytics in terms of excellent recovery (modified Rankin Scale [mRS] 0-1; OR 1.17; 95% CI 0.95-1.44; p = 0.13), functional independence (mRS 0-2; OR 1.24; 95% CI 0.78-1.98), poor recovery (mRS 4-6; OR 0.78; 95% CI 0.49-1.25; p = 0.31), complete/partial recanalization (OR 1.51; 95% CI 0.70-3.26; p = 0.30), any intracerebral hemorrhage (OR 0.81; 95% CI 0.56-1.17; p = 0.26), symptomatic intracerebral hemorrhage (OR 0.98; 95% CI 0.52-1.83; p = 0.94), or mortality (OR 0.83; 95% CI 0.54-1.26; p = 0.38). In network meta-analysis, there were better efficacy and imaging-based outcomes with tenecteplase 0.25 mg/kg without increased risk of safety outcomes. Our results demonstrate that in acute ischemic stroke, thrombolysis with tenecteplase is at least as effective and safe as alteplase.
- Successful Treatment of Massive Pulmonary Thromboembolism with Reteplase: Case Series. [Journal Article]
- TTanaffos 2018; 17(1):53-56
- Massive pulmonary thromboembolism (PTE) has an increased risk of mortality. Thrombolytic therapy is the accepted treatment. Reteplase, a variant of tissue plasminogen activator, has been used in acut...
Massive pulmonary thromboembolism (PTE) has an increased risk of mortality. Thrombolytic therapy is the accepted treatment. Reteplase, a variant of tissue plasminogen activator, has been used in acute myocardial infarction with acceptable safety and efficacy, but studies in massive PTE are rare. In this study we report five cases of successful treatment of massive PTE with reteplase.
- Rosuvastatin Reduces Neuroinflammation in the Hemorrhagic Transformation After rt-PA Treatment in a Mouse Model of Experimental Stroke. [Journal Article]
- FCFront Cell Neurosci 2018; 12:225
- Hemorrhagic transformation (HT) is a serious complication that stimulates inflammation during reperfusion therapy after acute ischemic stroke. Rosuvastatin, a 3-hydroxymethyl-3-methylglutaryl coenzym...
Hemorrhagic transformation (HT) is a serious complication that stimulates inflammation during reperfusion therapy after acute ischemic stroke. Rosuvastatin, a 3-hydroxymethyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, might improve the outcome of HT by inhibiting neuroinflammation. This study aimed to explore the protective effects of rosuvastatin against HT after recombinant tissue plasminogen activator (rt-PA) treatment in mice with experimental stroke via the attenuation of inflammation. A total of one hundred sixty-nine male BALB/c mice were used in the experiment. HT was successfully established in 70 mice that were subjected to 3 h of middle cerebral artery occlusion (MCAO) followed by a 10 mg/kg rt-PA injection over 10 min and reperfusion for 24 h. The mice were then administered rosuvastatin (1 mg/kg, 5 mg/kg) or saline (vehicle). The brain water content and neurological deficits (wire hang and adhesive removal somatosensory tests) were assessed at 24 h after rt-PA reperfusion following MCAO surgery. The morphology, blood-brain barrier (BBB) permeability and number of astrocytes and microglia were assessed by immunohistochemistry, electron microscopy and western blotting at 24 h after rt-PA reperfusion following MCAO surgery. Rosuvastatin protected against impaired neurological function and reversed the BBB leakage observed in the HT group. The increased activation of astrocytes and microglia and secretion of inflammatory factors caused by HT damage were significantly attenuated by high-dose rosuvastatin treatment vs. normal-dose rosuvastatin treatment. Related inflammatory pathways, such as the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, were downregulated in the rosuvastatin-treated groups compared with the HT group. In conclusion, our results indicate that rosuvastatin is a promising therapeutic agent for HT after rt-PA reperfusion following MCAO surgery in mice, as it attenuates neuroinflammation. Additionally, high-dose rosuvastatin treatment could have a greater anti-inflammatory effect on HT than normal-dose rosuvastatin treatment.
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- Plasminogen activator inhibitor-1 and tissue plasminogen activator and incident AF: Data from the PREVEND study. [Journal Article]
- IJInt J Cardiol 2018 Aug 10