• MeSH
• frekvence genu MeSH
• genetické asociační studie MeSH
• homeodoménové proteiny genetika   MeSH
• lidé MeSH
• molekulární sekvence - údaje MeSH
• mutační analýza DNA MeSH
• nanismus genetika   MeSH
• polymorfismus genetický MeSH
• promotorové oblasti (genetika) MeSH
• sekvence nukleotidů MeSH
• sekvenční delece * MeSH
• studie případů a kontrol MeSH
• vazebná nerovnováha MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Protease-activated receptors (PARs) are transmembrane proteins which rank among G-protein-coupled receptors. So far, four PARs (PAR1-4) have been described. They are activated by a protease cleavage at the N-terminal part of the receptor. Through the cleavage a new N-terminus appears which acts as a ligand activating the receptor. A peptide of the same amino acid sequence as the new N-terminus can activate the receptor without its cleavage. Some non-specific proteases can cleave PAR receptors at different sites, which results in changes in cell signaling. Higher activities of PARs have been observed under various pathological conditions, such as thrombosis, atherosclerosis, inflammations or neurodegeneration. Specific modulators of PAR signaling are a promising class of compounds with a wide therapeutic potential. First PAR inhibitors were based mainly on the amino acid sequence in the activating peptides. Recently, new, low-molecularweight, very specific and effective inhibitors have been developed. One of them, vorapaxar, passed the clinical tests and was introduced to the market.

• MeSH
• kardiovaskulární nemoci farmakoterapie   MeSH
• kinasa 1 receptorů spřažených s G-proteiny * MeSH
• lidé MeSH
• neurodegenerativní nemoci farmakoterapie   MeSH
• peptidy MeSH
• receptor PAR-1 * antagonisté a inhibitory   MeSH
• receptory thrombinu * antagonisté a inhibitory   MeSH
• thrombin MeSH
• trypsin MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH

Purpose Somatic deletions that affect the lymphoid transcription factor-coding gene IKZF1 have previously been reported as independently associated with a poor prognosis in pediatric B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). We have now refined the prognostic strength of IKZF1 deletions by analyzing the effect of co-occurring deletions. Patients and Methods The analysis involved 991 patients with BCP ALL treated in the Associazione Italiana Ematologia ed Oncologia Pediatrica-Berlin-Frankfurt-Muenster (AIEOP-BFM) ALL 2000 trial with complete information for copy number alterations of IKZF1, PAX5, ETV6, RB1, BTG1, EBF1, CDKN2A, CDKN2B, Xp22.33/Yp11.31 (PAR1 region; CRLF2, CSF2RA, and IL3RA), and ERG; replication of findings involved 417 patients from the same trial. Results IKZF1 deletions that co-occurred with deletions in CDKN2A, CDKN2B, PAX5, or PAR1 in the absence of ERG deletion conferred the worst outcome and, consequently, were grouped as IKZF1plus. The IKZF1plus group comprised 6% of patients with BCP ALL, with a 5-year event-free survival of 53 ± 6% compared with 79 ± 5% in patients with IKZF1 deletion who did not fulfill the IKZF1plus definition and 87 ± 1% in patients who lacked an IKZF1 deletion ( P ≤ .001). Respective 5-year cumulative relapse incidence rates were 44 ± 6%, 11 ± 4%, and 10 ± 1% ( P ≤ .001). Results were confirmed in the replication cohort, and multivariable analyses demonstrated independence of IKZF1plus. The IKZF1plus prognostic effect differed dramatically in analyses stratified by minimal residual disease (MRD) levels after induction treatment: 5-year event-free survival for MRD standard-risk IKZF1plus patients was 94 ± 5% versus 40 ± 10% in MRD intermediate- and 30 ± 14% in high-risk IKZF1plus patients ( P ≤ .001). Corresponding 5-year cumulative incidence of relapse rates were 6 ± 6%, 60 ± 10%, and 60 ± 17% ( P ≤ .001). Conclusion IKZF1plus describes a new MRD-dependent very-poor prognostic profile in BCP ALL. Because current AIEOP-BFM treatment is largely ineffective for MRD-positive IKZF1plus patients, new experimental treatment approaches will be evaluated in our upcoming trial AIEOP-BFM ALL 2017.

• MeSH
• aktivátorový protein specifický pro B-buňky genetika   MeSH
• delece genu * MeSH
• dítě MeSH
• inhibitor p15 cyklin-dependentní kinasy genetika   MeSH
• inhibitor p16 cyklin-dependentní kinasy genetika   MeSH
• lidé MeSH
• pre-B-buněčná leukemie genetika   patologie   MeSH
• prognóza MeSH
• receptor PAR-1 genetika   MeSH
• reziduální nádor genetika   patologie   MeSH
• transkripční faktor Ikaros genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Dishevelled (Dvl) is a key component in the Wnt/β-catenin signaling pathway. Dvl can multimerize to form dynamic protein aggregates, which are required for the activation of downstream signaling. Upon pathway activation by Wnts, Dvl becomes phosphorylated to yield phosphorylated and shifted (PS) Dvl. Both activation of Dvl in Wnt/β-catenin signaling and Wnt-induced PS-Dvl formation are dependent on casein kinase 1 (CK1) δ/ε activity. However, the overexpression of CK1 was shown to dissolve Dvl aggregates, and endogenous PS-Dvl forms irrespective of whether or not the activating Wnt triggers the Wnt/β-catenin pathway. Using a combination of gain-of-function, loss-of-function, and domain mapping approaches, we attempted to solve this discrepancy regarding the role of CK1ε in Dvl biology. We analyzed mutual interaction of CK1δ/ε and two other Dvl kinases, CK2 and PAR1, in the Wnt/β-catenin pathway. We show that CK2 acts as a constitutive kinase whose activity is required for the further action of CK1ε. Furthermore, we demonstrate that the two consequences of CK1ε phosphorylation are separated both spatially and functionally; first, CK1ε-mediated induction of TCF/LEF-driven transcription (associated with dynamic recruitment of Axin1) is mediated via a PDZ-proline-rich region of Dvl. Second, CK1ε-mediated formation of PS-Dvl is mediated by the Dvl3 C terminus. Furthermore, we demonstrate with several methods that PS-Dvl has decreased ability to polymerize with other Dvls and could, thus, act as the inactive signaling intermediate. We propose a multistep and multikinase model for Dvl activation in the Wnt/β-catenin pathway that uncovers a built-in de-activation mechanism that is triggered by activating phosphorylation of Dvl by CK1δ/ε.

• MeSH
• adaptorové proteiny signální transdukční genetika   metabolismus   MeSH
• beta-katenin genetika   metabolismus   MeSH
• fosfoproteiny genetika   metabolismus   MeSH
• fosforylace fyziologie   MeSH
• HEK293 buňky MeSH
• kasein kinasa 1 epsilon genetika   metabolismus   MeSH
• kasein kinasa Idelta genetika   metabolismus   MeSH
• kaseinkinasa II genetika   metabolismus   MeSH
• lidé MeSH
• myši MeSH
• peptidové mapování MeSH
• proteiny Wnt genetika   metabolismus   MeSH
• receptor PAR-1 genetika   metabolismus   MeSH
• signální transdukce fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Proteinase-activated receptors (PARs) were discovered more than 25 years ago and since then, their role in cancer has been under investigation. Research has primarily focused on the receptors located on the membrane of cancer cells and their impact on metabolism, intracellular signalling, and proliferation. Regarding the host response to cancer, studies have predominantly examined the relationship of thrombin receptors (PAR-1, PAR-3, and PAR-4) with blood clotting in distant metastatic spread. However, limited studies have examined the role of PARs, especially PAR-2, in the host anti-tumor immunity. This review article provides insights into the role of PAR-2 on cancer cells and immune competent cells involved in cancer development and progression. It also discussed the current knowledge of the importance of PAR-2 activation at various stages of cancer progression and its association with cancer-related pain.

• MeSH
• lidé MeSH
• nádory * metabolismus   MeSH
• receptor PAR-1 metabolismus   MeSH
• receptor PAR-2 * metabolismus   MeSH
• signální transdukce fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The aim of the study was to analyze frequency of SHOX gene defects and selected dysmorphic signs in patients of both idiopathic short stature (ISS) and Léri-Weill dyschondrosteosis (LWD), all derived from the Czech population. Overall, 98 subjects were analyzed in the study. Inclusion criteria were the presence of short stature (-2.0 SD), in combination with at least one of the selected dysmorphic signs for the ISS+ group; and the presence of Madelung deformity, without positive karyotyping for the LWD+ group. Each proband was analyzed by use of P018 MLPA kit, which covers SHOX and its regulatory sequences. Additionally, mutational analysis was done of the coding portions of the SHOX. Both extent and breakpoint localizations in the deletions/duplications found were quite variable. Some PAR1 rearrangements were detected, without obvious phenotypic association. In the ISS+ group, MLPA analysis detected four PAR1 deletions associated with a SHOX gene defect, PAR1 duplication with an ambiguous effect, and two SHOX mutations (13.7%). In the LWD+ group, MLPA analysis detected nine deletions in PAR1 region, with a deleterious effect on SHOX, first reported case of isolated SHOX enhancer duplication, and SHOX mutation (68.8%). In both ISS+ and LWD+ groups were positivity associated with a disproportionately short stature; in the ISS+ group, in combination with muscular hypertrophy. It seems that small PAR1 rearrangements might be quite frequent in the population. Our study suggests disproportionateness, especially in combination with muscular hypertrophy, as relevant indicators of ISS to be the effect of SHOX defect.

• MeSH
• dítě MeSH
• dospělí MeSH
• homeodoménové proteiny genetika   MeSH
• lidé MeSH
• mladiství MeSH
• mutace MeSH
• osteochondrodysplazie diagnóza   genetika   MeSH
• poruchy růstu diagnóza   genetika   MeSH
• předškolní dítě MeSH
• svalová atrofie genetika   MeSH
• variabilita počtu kopií segmentů DNA MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Cílem protidestičkové léčby je primární či sekundární prevence aterotrombózy, která je příčinou vážných chorob (akutní koronární syndrom, ischemický iktus, kritické ischemie končetin), jež jsou nejčastějšími příčinami úmrtí ve vyspělých zemích. Kyselina acetylsalicylová a klopidogrel jsou považovány za zlatý standard současné protidestičkové léčby s prokázaným klinickým přínosem. Jejich stinnými stránkami jsou nedostatečný efekt, rezistence k terapii u části populace, lékové interakce a zvýšené riziko krvácení. Nedostatečný účinek stávající protidestičkové léčby je pozorován rovněž u specifických skupin pacientů, jakými jsou např. diabetici 2. typu či pacienti s ischemickou chorobou dolních končetin. V současné době je již k dispozici celá řada nových protidestičkových léků inhibujících různé fáze tvorby destičkového trombu. Preparáty typu blokátorů ADP receptorů P2Y12, antagonistů destičkových trombinových receptorů PAR-1, blokátorů syntézy tromboxanu A2 či antagonisté jeho receptorů a antagonisté povrchových destičkových glykoproteinů (GP IIb/IIIa) prošly celou řadou klinických studií a některé již mají místo v klinické praxi. Lepší účinnost nových léků oproti standardům byla dosud prokázána pouze v některých specifických situacích. Protidestičková terapie je vždy spojena se zvýšeným výskytem krvácivých komplikací.

The aim of antiplatelet therapy is the primary and secondary prevention of atherothrombosis which causes serious diseases (acute coronary syndrome, ischemic stroke, peripheral artery disease) that are among the leading causes of mortality in developed countries. Acetylsalicylic acid and klopidogrel are considered as the gold standard of antiplatelet therapy with verified benefit. The main drawbacks of them are treatment failure, individual resistance to the therapy, drug interactions and increased risk of bleeding. A limited efficacy of classic antiplatelet drugs is observed in some specific groups of patients, for example in patients with type 2 diabetes mellitus or those with peripheral artery disease. Currently, numerous new antiplatelet drugs are available which inhibit different phases of platelet thrombus formation. Antiplatelet drugs targeting ADP receptors P2Y, thrombin receptors PAR-1, thromboxane A2 synthesis and IIb/IIIa glycoprotein receptors have been tested in a large number of clinical trials and some of them are used in clinical practice. But only some of the new drugs in some specific situations have been shown to be superior to aspirin or klopidogrel. Antiplatelet therapy is always associated with an increased incidence of bleeding complications. thromboxane A2 synthesis, IIb/IIIa glycoprotein inhibitors.

• MeSH
• ateroskleróza farmakoterapie   MeSH
• financování organizované MeSH
• inhibitory agregace trombocytů terapeutické užití   MeSH
• lidé MeSH
• prostaglandiny MeSH
• receptor PAR-1 antagonisté a inhibitory   MeSH
• receptory thromboxanů antagonisté a inhibitory   MeSH
• trombocytový glykoproteinový komplex IIb-IIIa MeSH
• tromboembolie MeSH
• trombolytická terapie MeSH
• Check Tag
• lidé MeSH

The present study aimed to investigate the roles of fibrin deposition and protease activated receptor-1 (PAR-1) in renal cytokine/chemokine production and inflammatory cell infiltration in rats of different ages. Acute inflammation was induced by lipopolysaccharide (LPS) in rats which were then treated with tranexamic acid (TA), TA+urokinase (UK) or TA+low-molecular-weight heparin (HP). Fibrin deposition, inflammatory cells and expressions of PAR-1, monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule 1 (ICAM-1) were detected. A reduction in fibrin deposition and PAR-1 expression in the LPS+TA+HP group was associated with decreased infiltration of inflammatory cells and down-regulated expressions of MCP-1 and ICAM-1. In the LPS+TA+UK group, the fibrin deposition, but not the PAR-1 expression, was reduced, However, the infiltration of inflammatory cells decreased and the expressions of MCP-1 and ICAM-1 down-regulated. There were significant differences in the fibrin deposition, infiltration of inflammatory cells and expression of PAR-1, MCP-1 and ICAM-1 between young and old rats undergoing the same treatment. These findings demonstrated that fibrin deposition plays more important roles than PAR-1 dose in cytokine/chemokine production and inflammatory cell infiltration in vivo, and ageing may deteriorate the fibrin deposition-induced production of cytokines/chemokines and infiltration of inflammatory cells.

• MeSH
• barvení a značení metody   využití   MeSH
• chemokiny chemie   izolace a purifikace   účinky léků   MeSH
• cytokiny chemie   účinky léků   MeSH
• experimenty na zvířatech MeSH
• fibrin chemie   účinky léků   MeSH
• financování organizované MeSH
• hemokoagulace genetika   imunologie   MeSH
• ledviny cytologie   enzymologie   účinky léků   MeSH
• northern blotting metody   využití   MeSH
• potkani Wistar MeSH
• receptor PAR-1 genetika   imunologie   účinky léků   MeSH
• stárnutí MeSH
• statistika jako téma MeSH
• western blotting metody   využití   MeSH
• zánět MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH

Heterozygous aberrations of SHOX gene have been reported to be responsible for Léri-Weill dyschondrosteosis (LWD) and small portion of idiopathic short stature. The study was established to assess effectiveness of using phenotype 'scoring form' in patients indicated for SHOX gene defect analysis. The submitted study is based on a retrospective group of 352 unrelated patients enrolled as a part of the routine diagnostic practice and analyzed for aberrations affecting the SHOX gene. All participants were scanned for deletion/duplication within the main pseudoautosomal region (PAR1) using the multiplex ligation-dependent probe amplification (MLPA) method. The phenotype 'scoring form' is used in our laboratory practice to preselect patients for subsequent mutation analysis of SHOX gene-coding sequences. The overall detection rate was 11.1% but there was a significant increase in frequency of SHOX gene defect positive with increasing achieved score (P<0.0001). The most frequent aberration was a causal deletion within PAR1. In three probands, MLPA analysis indicated a more complex rearrangement. Madelung deformity or co-occurrence of disproportionate short stature, short forearm and muscular hypertrophy had represented the most potent markers to determine the likelihood of SHOX gene defect detection. We conclude that appliance of phenotype 'scoring form' had saved excessive sample analysis and enabled effective routine diagnostic testing.

• MeSH
• duplikace genu genetika   MeSH
• fenotyp MeSH
• genetické testování MeSH
• homeodoménové proteiny genetika   MeSH
• lidé MeSH
• multiplexová polymerázová řetězová reakce MeSH
• mutační analýza DNA metody   MeSH
• nanismus genetika   MeSH
• osteochondrodysplazie diagnóza   genetika   MeSH
• poruchy růstu diagnóza   genetika   MeSH
• retrospektivní studie MeSH
• sekvenční delece genetika   MeSH
• techniky amplifikace nukleových kyselin MeSH
• tělesná výška genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Despite recent developments in revascularisation, anti-platelet and anti-thrombotic therapies, patients with acute coronary syndromes (ACS) remain at increased risk of recurrent atherothrombotic events. Dual anti-platelet therapy comprising aspirin and platelet P2Y12 receptor inhibition has become the cornerstone of therapy in ACS. However, thrombin-mediated pathways, which contribute to platelet activation and are responsible for the formation of fibrin clot, remain active following initial plaque rupture. Recently, orally administered drugs which directly target thrombin, factor Xa or thrombin-mediated platelet activation have been developed. Efficacy outcomes in trials of these novel anti-thrombotic agents in ACS have yielded mixed results and their adoption in clinical practice is currently hampered due to a penalty of increased bleeding. To date, the direct Xa inhibitor rivaroxaban and the protease-activated receptor-1 antagonist atopaxar have shown most promise and require further evaluation to determine their role in ACS management.

• MeSH
• akutní koronární syndrom * farmakoterapie   MeSH
• antikoagulancia farmakologie   terapeutické užití   MeSH
• faktor Xa MeSH
• farmakoterapie metody   MeSH
• hodnocení léčiv MeSH
• inhibitory agregace trombocytů * farmakologie   terapeutické užití   MeSH
• inhibitory faktoru Xa MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• receptor PAR-1 antagonisté a inhibitory   MeSH
• thrombin antagonisté a inhibitory   MeSH
• trombóza farmakoterapie   prevence a kontrola   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH