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Timothy M. Thomson Emily Toscano-Guerra Ernesto Casis Rosanna Paciucci 《British journal of haematology》2020,190(4):520-524
Coronavirus disease 2019 (COVID-19) is frequently associated with severe systemic consequences, including vasculitis, a hyperinflammatory state and hypercoagulation. The mechanisms leading to these life-threatening abnormalities are multifactorial. Based on the analysis of publicly available interactomes, we propose that severe acute respiratory syndrome coronavirus-2 infection directly causes a deficiency in C1 esterase inhibitor, a pathogen-specific mechanism that may help explain significant systemic abnormalities in patients with COVID-19. 相似文献
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Jasti S. Rao Alan Rayford Masaaki Yamamoto K. Kian Ang Philip Tofilon Raymond Sawaya 《Journal of neuro-oncology》1994,22(2):161-171
Summary Radiation-induced damage to the central nervous system is believed to be targeted to glial or endothelial cells or both, although the pathophysiology of this process is still poorly understood. A series of experiments were, therefore, conducted, including irradiation to primary rat astrocytes (in vitro) and rat spinal cords (in vivo). The levels of plasminogen activators (uPA and tPA) and their inhibitors (PNI and PAI-1) were determined by fibrin zymography, ELISA, amidolytic activity assay, complex formation, and Western blot analysis. Fibrin zymography revealed the presence of Mr 48,000 (uPA) and Mr 68,000 (tPA) lytic bands that were increased in irradiated samples. Three- to four-fold higher levels of tPA and 8- to 10-fold higher levels of uPA were detected in irradiated samples. Western blot analysis confirmed the presence of a 51-kDa band (PAI-1) in irradiated samples. PAI-1 is undetectable in nonirradiated spinal cord. Serum-free medium and cell and spinal cord extracts of nonirradiated samples showed a 43-kDa band (PNI), the intensity of which is decreased in irradiated samples. Four- to five-fold decreased levels of PNI were detected in irradiated serum-free media and cell extracts, but no levels of PNI were detected in irradiated spinal cord extracts. This study provides additional information regarding the proposed roles of plasminogen activators and their inhibitors in the development of CNS damage after irradiation. 相似文献
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Maria Guarino Giovan G. Di Costanzo Andrea Gallotta Raffaella Tortora Laura Paneghetti Francesco Auriemma 《Scandinavian journal of clinical and laboratory investigation》2017,77(6):448-453
Introduction: Hepatocellular carcinoma (HCC) develops in about 3–4% of cirrhotic patients every year. The squamous cell carcinoma antigen (SCCA) has been found elevated in liver cancer specimens by immunohistochemistry, and detected in complex with IgM (SCCA-IgM) in the serum of patients with HCC. The aim of this study was to evaluate the ability of serological SCCA-IgM levels to predict the efficacy of HCC therapy.Materials and methods: From April 2012 to April 2014, 131 patients with a new diagnosis of HCC were enrolled. The HCC diagnosis was made according to the EASL guidelines. The patients were staged and treated according to the BCLC Staging System: BCLC stages A and B were treated with locoregional therapy, and BCLC stage C was treated with Sorafenib. Response to therapy was evaluated according to the mRECIST criteria. Serum SCCA-IgM levels were determined by a commercially available ELISA kit at basal time (T0) and after one month of treatment (T1).Results: At baseline and one month into therapy, SCCA-IgM levels were significantly lower (p value <.05) in patients who responded to therapy compared to those who did not respond (median SCCA-IgM level [25th?+?75th percentile] at T0:115.1?AU/mL [50.0?+?174.4] vs. 149.1?AU/mL [111.3?+?198.8]; median SCCA-IgM level [25th?+?75th percentile] at T1: 113.4?AU/mL [50.0?+?194.2] vs. 170.6?AU/mL [111.7?+?344.2]).Conclusion: Our study suggests that the SCCA-IgM determination could be helpful in predicting the response to therapy in patients with HCC. 相似文献
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Jasti S. Rao Peter A. Steck Philip Tofilon Douglas Boyd Francis Ali-Osman William G. Stetler-Stevenson Lance A. Liotta Raymond Sawaya 《Journal of neuro-oncology》1993,18(2):129-138
Summary The invasive nature of human gliomas represents a major factor in preventing their total resection. The exact nature of the underlying mechanisms of tumor cell invasion are still unclear. In this study, we have quantitatively assayed a glioblastoma cell line for its ability to migrate through a polycarbonate filter coated with matrigel which contains a complex of multiple basement membrane components. At 48 h the glioblastoma cell line (U251) showed a rate of invasiveness of 42% and also dependent on the concentration of matrigel. The U251 cell line produced a urokinase type plasminogen activator and a 92-KDa type IV collagenase. Both enzymes were inhibited by the addition of uPA and 92-KDa type IV collagenase antibodies. Those same antibodies reduced the invasion rate of U251 cells from 42% to 12 and 21%, respectively. Similarly, the addition of -aminocaproic acid (a plasmin inhibitor) or tissue inhibitor of metalloprotease (TIMP2, a collagenase inhibitor) reduced the invasiveness of U251 cells from 42% to 14% and 10%, respectively. Additionally, the other two glioblastoma cell lines (LG11, UWR1) and astrocytes showed a rate of invasiveness at 41%, 61% and 12%, respectively. Finally, the addition of hyaluronic acid to the matrigel, a constituent of brain extracellular matrix, enhanced the rate of invasion. These findings provide evidence for the role of serine proteases and metalloproteases in facilitating the invasion of extracellular matrix components by glioblastoma cell line and suggest a therapeutic role for protease inhibitors in attempting to minimize the invasive propensity of gliomas. 相似文献
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Y. M. FORTENBERRY H. C. WHINNA† S. T. COOPER‡ T. MYLES§ L. L. K. LEUNG§ F. C. CHURCH†¶ 《Journal of thrombosis and haemostasis》2007,5(7):1486-1492
Background: Protein C inhibitor (PCI) and antithrombin (AT) are serine protease inhibitors (serpins) that inhibit a wide array of blood coagulation serine proteases including thrombin. OBJECTIVE: Fifty-five Ala-scanned recombinant thrombin mutants were used to determine thrombin residues important for inhibition by PCI with and without the cofactors heparin and thrombomodulin (TM) and compared with the prototypical serpin, AT. RESULTS: Residues around the active site (Tyr50 and Glu202) and the sodium-binding site (Glu229 and Arg233) were required for thrombin inhibition by PCI with and without cofactors. Exosite-2 residues (Arg89, Arg93, Glu94, Arg98, Arg245, Arg248, and Gln251) were critical for heparin-accelerated inhibition of thrombin by PCI. Exosite-1 residues (especially Lys65 and Tyr71) were required for enhanced PCI inhibition of thrombin-TM. Interestingly, we also found that the TM chondroitin sulfate moiety is not required for the approximately 150-fold enhanced rate of thrombin inhibition by PCI. Using the aforementioned thrombin exosite-2 mutants that were essential for heparin-catalyzed PCI-thrombin inhibition reactions we found no change in PCI inhibition rates for thrombin-TM. CONCLUSIONS: Collectively, these results show that (i) similar thrombin exosite-2 residues are critical for the heparin-catalyzed inhibition by PCI and AT, (ii) PCI and AT are different in their thrombin-TM inhibition properties, and (iii) PCI has a distinct advantage over AT in the regulation of the activity of thrombin-TM. 相似文献
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The occurrence of type-1 plasminogen activator inhibitor (PAI-1) in human cerebrospinal fluid (CSF) has not previously been reported. As a member of the serpin superfamily of serine protease inhibitors and an acute phase response component, PAI-1 has powerful potential roles in nervous system homeostasis. We have detected this serpin antigen using a polyclonal anti-PAI-1 antibody in normal human CSF. In Western blotting, PAI-1 in several CSF samples appears as a two-band antigen of Mr = 54 and 35 kDa, presumably the intact and proteolytic fragment, respectively. In vitro complex formation studies confirm that the 54 kDa form of PAI-1 interacts with 125I-urokinase after activation with SDS, but the 35 kDa form does not. Quantification of total PAI-1 antigen in 18 normal human CSF samples by ELISA reveals a mean value of 1.0 ± 0.07 (SEM) μg/dL, indicating that a relatively low concentration of the inhibitor occurs in normal human CSF. This information should now allow comparison of PAI-1 levels and activity in various neurologic disorders. © 1993 Wiley-Liss, Inc. 相似文献
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Corral J González-Conejero R Hernández-Espinosa D Vicente V 《British journal of haematology》2007,137(2):99-108
A new anticoagulant system involving a serpin has been recently characterised. The protein Z/Z-dependent protease inhibitor (PZ/ZPI) system inhibits activated factors X, XI and IX by different mechanisms. By homology with other anticoagulant systems (antithrombin or the protein C/protein S), deficiency of the serpin (ZPI) or its cofactor (PZ) might imbalance the haemostatic system with thrombotic consequences. Evidence supports the in vivo anticoagulant role of this complex and the thrombotic consequences of its deficiency. Non-sense variations of the ZPI (W303X and R67X) have been associated with increased risk of venous thrombosis. Moreover, PZ deficient mice carrying the FV Leiden have a thrombotic phenotype. Finally, some reports suggest that PZ deficiency might increase the risk of thrombosis. However, other studies question the thrombotic relevance of both ZPI and PZ deficiencies. This system could play a redundant role in haemostasis that explains the conflicting results on its thrombotic potential, which might be exacerbated in combination with other prothrombotic factors. 相似文献