PURPOSE: To investigate the prognostic role of expression of urokinase-type plasminogen activator system members, such as urokinase-type activator (uPA), uPA-receptor (uPAR), and plasminogen activator inhibitor-1 (PAI-1), in patients treated with radical prostatectomy (RP) for prostate cancer (PCa). METHODS: Immunohistochemical staining for uPA system was performed on a tissue microarray of specimens from 3121 patients who underwent RP. Cox regression analyses were performed to investigate the association of overexpression of these markers alone or in combination with biochemical recurrence (BCR). Decision curve analysis was used to assess the clinical impact of these markers. RESULTS: uPA, uPAR, and PAI-1 were overexpressed in 1012 (32.4%), 1271 (40.7%), and 1311 (42%) patients, respectively. uPA overexpression was associated with all clinicopathologic characteristics of biologically aggressive PCa. On multivariable analysis, uPA, uPAR, and PAI-1 overexpression were all three associated with BCR (HR: 1.75, p < 0.01, HR: 1.22, p = 0.01 and HR: 1.20, p = 0.03, respectively). Moreover, the probability of BCR increased incrementally with increasing cumulative number of overexpressed markers. Decision curve analysis showed that addition of uPA, uPAR, and PAI-1 resulted in a net benefit compared to a base model comparing standard clinicopathologic features across the entire threshold probability range. In subgroup analyses, overexpression of all three markers remained associated with BCR in patients with favorable pathologic characteristics. CONCLUSION: Overexpression of uPA, uPAR, and PAI-1 in PCa tissue were each associated with worse BCR. Additionally, overexpression of all three markers is informative even in patients with favorable pathologic characteristics potentially helping clinical decision-making regarding adjuvant therapy and/or intensified follow-up.

• MeSH
• aktivátor plasminogenu urokinasového typu biosyntéza   fyziologie   MeSH
• inhibitor aktivátoru plazminogenu 1 biosyntéza   fyziologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokální recidiva nádoru epidemiologie   etiologie   MeSH
• nádorové biomarkery biosyntéza   fyziologie   MeSH
• nádory prostaty epidemiologie   etiologie   metabolismus   chirurgie   MeSH
• prognóza MeSH
• prostatektomie * MeSH
• receptory urokinázového aktivátoru plazminogenu biosyntéza   fyziologie   MeSH
• retrospektivní studie MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH

PURPOSE: Urokinase-plasminogen activator (uPA), its receptor (uPAR), and the plasmin-activator inhibitor type 1 (PAI-1) have been associated with oncologic outcomes in various malignancies and could help identify bladder cancer (BC) patients treated with radical cystectomy (RC) who are likely to benefit from intensification of therapy to prevent disease progression. Our aim was to assess the value of uPA, uPAR, and PAI-1 for prognosticating survival outcomes of patients treated with RC for BC. MATERIALS AND METHODS: Tumor specimens from 272 consecutive patients treated with RC for advanced BC were assessed with immunohistochemical staining for uPA, uPAR, and PAI-1. Overexpression was assessed by pathological image analysis. Kaplan-Meier estimates and multivariable Cox-regression were used to analyze survival. Harrell's C-index was used to assess for clinical impact of the uPA system. RESULTS: uPA, uPAR, and PAI-1 were overexpressed in 48.2%, 51.1%, and 52.2% of patients, respectively. uPA overexpression was associated with lymphovascular invasion (P = 0.034) and nodal status (P = 0.013); PAI-1 overexpression was associated with primary muscle-invasive BC (P = 0.015) and lymphovascular invasion (P = 0.024). uPA, uPAR, and the number of overexpressed markers were all 3 significantly associated with shorter overall recurrence-free-, distant recurrence-free-, and cancer-specific survival. In multivariable analyses, uPA overexpression remained associated with shorter recurrence-free survival (hazard ratio [HR] = 1.79; P = 0.036) in the entire cohort, in patients without lymph node metastasis (HR = 1.98; P = 0.018) and those with nonorgan-confined disease (HR = 1.98; P = 0.022). uPAR overexpression was associated with shorter recurrence-free survival in patients without lymph node metastasis (HR = 2.01; P = 0.021) and those with organ-confined disease (HR = 4.11; P = 0.037). CONCLUSION: Members of the uPA system are associated with features of biologically aggressive BC and oncologic outcomes. However, their value beyond currently available information remains limited.

• MeSH
• aktivátor plasminogenu urokinasového typu analýza   fyziologie   MeSH
• cystektomie * metody   MeSH
• inhibitor aktivátoru plazminogenu 1 analýza   fyziologie   MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• míra přežití MeSH
• nádory močového měchýře chemie   mortalita   chirurgie   MeSH
• prognóza MeSH
• receptory urokinázového aktivátoru plazminogenu analýza   fyziologie   MeSH
• retrospektivní studie MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• aktivace neutrofilů * fyziologie   MeSH
• aktivátor plasminogenu urokinasového typu metabolismus   MeSH
• buněčná adheze fyziologie   MeSH
• chemotaxe * fyziologie   MeSH
• extracelulární pasti metabolismus   MeSH
• faktor XII * metabolismus   MeSH
• hojení ran * fyziologie   MeSH
• lidé MeSH
• neutrofily * metabolismus   MeSH
• signální transdukce * fyziologie   MeSH
• zánět metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

The urokinase-type plasminogen activator (uPA) and PA inhibitor 1 (PAI-1) play important roles in breast cancer metastasis through cell migration and invasion. They are clinically applicable prognostic and predictive markers. High levels of uPA and PAI-1 are associated with high risk of recurrence and adjuvant chemotherapy provides substantial benefit for this breast cancer population. The current sole validated method for quantifying uPA level in breast tumour tissue is ELISA assay. It requires 50–300 mg of fresh or frozen tissue, which is the main limitation for routine use. In this study, we evaluated the performances of customized antibody microarray to quantify uPA concentration from reduced extraction solution of breast tumour tissue and compared it with standard ELISA kit. We firstly optimized the elaboration of customized antibody microarray in order to sensitively detect and quantify uPA standard solutions. In the best conditions, we analysed uPA concentration in 16 cytosolic extracts from breast tumour tissue. Results showed that our customized antibody microarray could correctly quantify uPA concentration while consuming 100 times less volume of tumour tissue extraction solution than ELISA. Our antibody microarray is a powerful and promising tool for the miniaturization of the immunoassay quantification of uPA from breast tumour tissue extracts.

• MeSH
• aktivátor plasminogenu urokinasového typu * analýza   imunologie   škodlivé účinky   MeSH
• biologické markery MeSH
• čipová analýza tkání * metody   přístrojové vybavení   MeSH
• ELISA MeSH
• imunoanalýza metody   MeSH
• lidé MeSH
• metastázy nádorů MeSH
• nádory prsu * diagnóza   imunologie   MeSH
• prognóza MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• srovnávací studie MeSH

Several plasminogen activators (PAs) have been found effective in treating different thromboembolic diseases. However, administration of conventional thrombolytic therapy is limited by a low efficacy of present formulations of PAs. Conventional treatments using these therapeutic proteins are associated with several limitations including rapid inactivation and clearance, short half-life, bleeding complications or non-specific tissue targeting. Liposome-based formulations of PAs such as streptokinase, tissue-plasminogen activator and urokinase have been developed to improve the therapeutic efficacy of these proteins. Resulting liposomal formulations were found to preserve the original activity of PAs, promote their selective delivery and improve thrombus targeting. Therapeutic potential of these liposome-based PAs has been demonstrated successfully in various pre-clinical models in vivo. Reductions in unwanted side effects (e.g., hemorrhage or immunogenicity) as well as enhancements of efficacy and safety were achieved in comparison to currently existing treatment options based on conventional formulations of PAs. This review summarizes present achievements in: (i) preparation of liposome-based formulations of various PAs, (ii) development of PEGylated and targeted liposomal PAs, (iii) physico-chemical characterization of these developed systems, and (iv) testing of their thrombolytic efficacy. We also look to the future and the imminent arrival of theranostic liposomal formulations to move this field forward.

• MeSH
• aktivátor plasminogenu urokinasového typu aplikace a dávkování   terapeutické užití   MeSH
• fibrinolytika aplikace a dávkování   terapeutické užití   MeSH
• lidé MeSH
• liposomy chemie   ultrastruktura   MeSH
• metaloendopeptidasy aplikace a dávkování   terapeutické užití   MeSH
• nanostruktury chemie   ultrastruktura   MeSH
• plasmin aplikace a dávkování   terapeutické užití   MeSH
• streptokinasa aplikace a dávkování   terapeutické užití   MeSH
• tkáňový aktivátor plazminogenu aplikace a dávkování   terapeutické užití   MeSH
• tromboembolie farmakoterapie   MeSH
• trombolytická terapie metody   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Fibrinolýza pomáhá regulovat hemostázu, a zabraňuje tak vytvoření neadekvátně velkého trombu, který by mohl omezit průtok krve cévním řečištěm. Hlavním enzymem podílejícím se na fibrinolýze je plazmin. Tkáňový aktivátor plazminogenu (tPA) a urokináza (uPA) jsou agens konvertující plazminogen na aktivní plazmin, tvoří společně s receptorem pro urokinázu (uPAR) a inhibitory urokinázy (PAI 1, PAI 2, PAI 3 a protease nexin) plazminogen aktivátor systém (PAS), který je mimo jiné součástí metastatické kaskády a významnou měrou se podílí na invazivním růstu a angiogenezi maligních nádorů. Pro samotnou fibrinolýzu má zásadní význam tPA, uPA se pak podílí na degradaci tkání jak při fyziologických, tak i patologických pochodech. Receptor pro uPA – uPAR je navázán na buněčnou membránu prostřednictvím glykosylfosfatidylinositolu. Navázáním uPA na uPAR dochází k aktivaci proteintyrosinkináz, proteinkinázy C a MAP-kinázy. Současně byla popsána i přímá signální cesta Jak/STAT kaskádou s využitím signální transdukce Scr-like proteintyrosinkinázy. Exprese uPAR je regulována řadou růstových faktorů, např. EGF, bFGF a HGF. Zdá se, že jednotlivé faktory PAS se podílí na procesu malignizace nádorových onemocnění. Na otázku, do jaké míry je jejich vliv zásadní u konkrétních malignit, by měl odpovědět další výzkum. V článku autoři předkládají souhrn poznatků o interakci fibrinolýzy a nádorového procesu, speciálně o vlivu urokinázy a dalších aktivátorů a jejich inhibitorů na metastazování maligních tumorů. Text obsahuje informace o faktorech, jejichž zavedení do praxe je zatím předmětem četných diskuzí, nicméně do budoucna by jednotlivé faktory PAS mohly hrát významnou úlohu při plánování strategie léčby a zároveň by se mohly stát i terčem cílené terapie.

Fibrinolysis is process, which leads to the degradation of fibrin to fibrin monomers. Fibrinolysis helps to regulate hemostasis and prevents the creation of inappropriately large thrombus, which could reduce blood flow to the bloodstream. The main enzyme involved in fibrinolysis is plasmin. Tissue plasminogen activator (tPA) and urokinase (uPA) are agents converting plasminogen into active plasmin, together with urokinase receptor (uPAR) and urokinase inhibitors (PAI 1, PAI 2, PAI 3 and protease nexin) form plasminogen activator system (PAS) which is among others also part of the metastatic cascade and significantly contributes to invasive growth and angiogenesis of malignant tumours. In contrast to tPA that is fundamental in fibrinolysis, uPA plays an essential role in tissue degradation as part of physiological and pathological processes. uPAR is a GPI (glycosylphosphatidylinositol)-anchored protein. The binding of uPA to uPAR results in activation of protein tyrosine kinase, protein kinase C and MAP kinase. At the same time, direct signalling pathway via Jak/STAT cascade utilising signalling transduction of Scr-like protein tyrosine kinase have also been described. uPAR expression is regulated by many growth factors, e.g. EGF, FGF-2 and HGF. It seems that individual PAS factors are involved in the process of rendering malignant tumors invasive. To what degree this influence is essential to specific malignancies, should be answered by further research. In the article the authors present a summary of findings about the interaction of fibrinolysis and tumor process, especially on the effects of urokinase and other activators and their inhibitors in metastasis of malignant tumors. The text contains information on the factors theirs introduction into practice is still the subject of numerous discussions, but in the future, individual PAS factors could play an important role in planning treatment strategies and also could become targets of targeted therapy.

• Klíčová slova
• plazminogen aktivátor systém, uPA, uPAR, PAI 1, PAI 2,
• MeSH
• aktivátor plasminogenu urokinasového typu fyziologie   metabolismus   MeSH
• aktivátory plazminogenu fyziologie   metabolismus   terapeutické užití   MeSH
• fibrinolýza fyziologie   MeSH
• financování organizované MeSH
• inhibitor aktivátoru plazminogenu 1 metabolismus   MeSH
• inhibitor aktivátoru plazminogenu 2 metabolismus   MeSH
• invazivní růst nádoru MeSH
• lidé MeSH
• metastázy nádorů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

• MeSH
• aktivátor plasminogenu urokinasového typu diagnostické užití   MeSH
• analýza přežití * MeSH
• diagnostické techniky molekulární * metody   MeSH
• hodnocení rizik * MeSH
• invazivní růst nádoru genetika   patofyziologie   patologie   MeSH
• lidé MeSH
• nádorové biomarkery analýza   metabolismus   MeSH
• nádory prsu * diagnóza   genetika   patologie   MeSH
• prediktivní hodnota testů MeSH
• receptor erbB-2 diagnostické užití   účinky léků   MeSH
• receptory pro estrogeny analýza   účinky léků   MeSH
• receptory progesteronu analýza   účinky léků   MeSH
• rizikové faktory * MeSH
• rozsev nádorových buněk MeSH
• staging nádorů využití   MeSH
• věk při počátku nemoci MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH

The UVB-irradiated cornea is damaged by oxidative stress. Toxic oxygen products induced by UVB radiation in the cornea are insufficiently removed by antioxidants, whose numbers decrease with increasing UVB irradiation. In addition, the UVB-irradiated cornea suffers from hypoxic conditions because damaged corneal cells cannot utilize oxygen normally, although the supply of oxygen to the cornea is unchanged (normal). This contributes to attenuated re-epithelialization, corneal neovascularization and apoptotic cell death. Our previous publications reported that trehalose applied on the corneal surface during irradiation significantly suppressed UVB-induced corneal oxidative damage. The results of this study provide for the first time important evidence that trehalose applied on the surface of corneas for two weeks following repeated UVB irradiation (312 nm, daily dose 0.5 J/cm2) accelerated corneal healing, restored corneal transparency and suppressed corneal neovascularization. Compared to buffered saline treatment, following which caspase-3, nitrotyrosine, malondialdehyde and urokinase-type plasminogen activator were still strongly expressed in the corneal epithelium two weeks after irradiation and corneal neovascularization was evident, apoptotic cell death was already significantly reduced after one week of trehalose application. The expression of other markers of injury returned to normal levels during two weeks of trehalose treatment. In conclusion, our results show that trehalose accelerated healing of the UVB irradiated cornea, very probably via suppression of hypoxia-response injury. In addition, immunohistochemical results on corneal cryostat sections corresponded with those obtained using corneal impression cytologies, thus confirming that corneal impression cytologies are useful for diagnostic purposes.

• MeSH
• aktivátor plasminogenu urokinasového typu metabolismus   MeSH
• apoptóza účinky léků   MeSH
• biologické markery metabolismus   MeSH
• cytodiagnostika metody   MeSH
• experimentální radiační poranění farmakoterapie   metabolismus   patologie   MeSH
• hojení ran účinky léků   MeSH
• imunohistochemie metody   MeSH
• injekce nitrooční MeSH
• kaspasa 3 metabolismus   MeSH
• králíci MeSH
• malondialdehyd metabolismus   MeSH
• nemoci rohovky farmakoterapie   metabolismus   patologie   MeSH
• oxidační stres MeSH
• patologická angiogeneze farmakoterapie   MeSH
• rohovkový epitel účinky záření   MeSH
• trehalosa aplikace a dávkování   terapeutické užití   MeSH
• tyrosin analogy a deriváty   metabolismus   MeSH
• ultrafialové záření MeSH
• zmrazené řezy metody   MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Urokinase (uPA) plays an essential role in the activation of plasminogen to plasmin, and together with its receptor (uPAR), tissue activator (tPA) and urokinase inhibitors (PAI 1, PAI 2, PAI 3 and protease nexin) forms the plasminogen activator system (PAS), a component of metastatic cascade importantly contributing to the invasive growth and angiogenesis of malignant tumours. In our project we examined the expression of uPA, uPAR, PAI 1 and PAI 2 in tumor tissue and we also studied the plasma levels of PAI 1 before and after the initiation of therapy in patients with colorectal carcinoma in relationship to grade of tumor and the treatment response. In our prospective evaluation we included 80 patients treated for adenocarcinoma of the colon and rectum. Analysis of collected data revealed statistically significant evidence of a relationship between the level of PAI 1 in plasma before treatment and grade of the tumor, which increases with tumor grade (p=0.025). We demonstrated that there exists a statistically significant relationship between the expression of PAI 2 (p<0.001) and uPAR (p=0.031) and grade of tumor. We also confirmed a statistically significant relationship between soluble levels of PAI 1 before treatment and therapeutic response (p=0.021). In our group of patients the expression of uPA, uPAR, PAI 1 and 2 in tumor tissue in relation to response to treatment was also assessed. Our results suggest that the greater expression of these parameters in tumor tissue is linked to a worse response to therapy. In conclusion, PAS factors help as a prognostic indicators and could also act as a predictive factor in colorectal carcinoma.

• MeSH
• adenokarcinom metabolismus   sekundární   terapie   MeSH
• aktivátor plasminogenu urokinasového typu metabolismus   MeSH
• dospělí MeSH
• imunoenzymatické techniky MeSH
• inhibitor aktivátoru plazminogenu 1 metabolismus   MeSH
• inhibitor aktivátoru plazminogenu 2 metabolismus   MeSH
• kolektomie MeSH
• kolorektální nádory metabolismus   patologie   terapie   MeSH
• kombinovaná terapie MeSH
• lidé středního věku MeSH
• lidé MeSH
• míra přežití MeSH
• prospektivní studie MeSH
• protokoly antitumorózní kombinované chemoterapie terapeutické užití   MeSH
• receptory urokinázového aktivátoru plazminogenu metabolismus   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• staging nádorů MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND/AIMS: Urokinase (uPA) is a serine protease, which together with uPAR, tPA, PAI 1 and PAI 2 forms the plasminogen activator system, a component of metastatic cascade contributing to the invasive growth and angiogenesis of malignant tumours. METHODOLOGY: Both preceding therapy and after 6-8 weeks of the treatment, plasma PAI 1 levels (photometric microplate method on the ELISA) and uPA, uPAR, PAI 1 and PAI 2 tissue expression (immunohistochemical reaction) were analysed from 80 colorectal carcinoma patients. RESULTS: Analysis showed higher pre-treatment plasma levels of PAI 1 in patients with advanced tumours, which decreased after surgery or the start of therapy (p=0.004); Patients with higher plasma level PAI 1 before (0.013) and after therapy (0.004) had significantly shorter survival. There was a higher expression of uPA (p<0.001), uPAR (p<0.001), PAI 1 (p=0.042) and PAI 2 (p<0.001) in advanced colorectal carcinoma. A relationship between PAI 2 (p=0.010) and uPAR (p=0.019) expression and survival was demonstrated. There is a correlation between pre-treatment plasma PAI 1 levels and PAI 2 (p=0.028) and uPAR (p=0.043) expression. CONCLUSIONS: Immunohistochemical analysis of PAS in tumour tissue and plasma PAI 1 levels was found to be a useful prognostic factor in colorectal carcinoma patients. Plasma PAI 1 could be advantageous in evaluating the effectiveness of a mode of treatment.

• MeSH
• aktivátor plasminogenu urokinasového typu analýza   MeSH
• dospělí MeSH
• imunohistochemie MeSH
• inhibitor aktivátoru plazminogenu 1 analýza   krev   MeSH
• inhibitor aktivátoru plazminogenu 2 analýza   MeSH
• kolorektální nádory metabolismus   mortalita   MeSH
• lidé středního věku MeSH
• lidé MeSH
• receptory urokinázového aktivátoru plazminogenu analýza   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH