BACKGROUND: The PLAUR gene encodes the urokinase-like plasminogen activator receptor (uPAR) and may undergo alternative splicing. Excluding cassette exons 3, 5 and 6 from the transcript results in truncated protein variants whose precise functions have not been elucidated yet. The PLAUR gene is one of several expressed in myeloid cells, where uPAR participates in different cellular processes, including the contact activation system and kallikrein-kinin system, which play an important role in hereditary angioedema (HAE) pathogenesis. A hypothesis about the PLAUR splicing pattern impact on HAE severity was tested. METHODS AND RESULTS: The RT-PCR quantified by capillary electrophoresis was used. Although no significant difference in alternative transcript frequency was observed between healthy volunteers and HAE patients, a significant increase in all cassette exon inclusion variants was revealed during monocyte-to-macrophage differentiation. CONCLUSIONS: PLAUR alternative splicing in monocytes and macrophages neither was different between HAE patients and healthy controls, nor reflected disease severity. However, the results showed an PLAUR splicing pattern was changing during monocyte-to-macrophage differentiation, but the significance of these changes is unknown and awaits future clarification.

• MeSH
• alternativní sestřih genetika   MeSH
• hereditární angioedémy * genetika   patologie   MeSH
• leukocyty MeSH
• lidé MeSH
• makrofágy patologie   MeSH
• monocyty * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

PURPOSE: Our goal was to compare cancer-specific mortality (CSM) rates between radical prostatectomy (RP) vs external beam radiotherapy (EBRT) in National Comprehensive Cancer Network© (NCCN©) high risk (HR) patients, as well as in Johns Hopkins University (JH) HR and very high risk (VHR) subgroups. MATERIALS AND METHODS: Within the Surveillance, Epidemiology, and End Results database (2010-2016), we identified 24,407 NCCN HR patients, of whom 10,300 (42%) vs 14,107 (58%) patients qualified for JH HR vs VHR, respectively. Overall, 9,823 (40%) underwent RP vs 14,584 (60%) EBRT. Cumulative incidence plots and competing-risks regression addressed CSM after 1:1 propensity score matching (according to age, prostate specific antigen, clinical T and N stages, and biopsy Gleason score) between RP and EBRT patients. All analyses addressed the combined NCCN HR cohort, as well as in JH HR and JH VHR subgroups. RESULTS: In the combined NCCN HR cohort 5-year CSM rates were 2.3% for RP vs 4.1% for EBRT and yielded a multivariate hazard ratio of 0.68 (95% CI 0.54-0.86, p <0.001) favoring RP. In VHR patients 5-year CSM rates were 3.5% for RP vs 6.0% for EBRT, yielding a multivariate hazard ratio of 0.58 (95% CI 0.44-0.77, p <0.001) favoring RP. Conversely, in HR patients no significant difference was recorded between RP vs EBRT (HR 0.7, 95% CI 0.39-1.25, p=0.2). CONCLUSIONS: Our data suggest that RP holds a CSM advantage over EBRT in the combined NCCN HR cohort, and in its subgroup of JH VHR patients.

• MeSH
• analýza přežití MeSH
• brachyterapie statistika a číselné údaje   MeSH
• hodnocení rizik statistika a číselné údaje   MeSH
• kalikreiny krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory prostaty krev   diagnóza   mortalita   terapie   MeSH
• program SEER MeSH
• prostata patologie   účinky záření   chirurgie   MeSH
• prostatektomie statistika a číselné údaje   MeSH
• prostatický specifický antigen krev   MeSH
• retrospektivní studie MeSH
• rizikové faktory MeSH
• senioři MeSH
• staging nádorů MeSH
• stupeň nádoru MeSH
• tendenční skóre MeSH
• věkové faktory MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH

Hereditary angioedema with C1 Inhibitor deficiency (C1-INH-HAE) is caused by a constellation of variants of the SERPING1 gene (n = 809; 1,494 pedigrees), accounting for 86.8% of HAE families, showing a pronounced mutagenic liability of SERPING1 and pertaining to 5.6% de novo variants. C1-INH is the major control serpin of the kallikrein-kinin system (KKS). In addition, C1-INH controls complement C1 and plasminogen activation, both systems contributing to inflammation. Recognizing the failed control of C1s protease or KKS provides the diagnosis of C1-INH-HAE. SERPING1 variants usually behave in an autosomal-dominant character with an incomplete penetrance and a low prevalence. A great majority of variants (809/893; 90.5%) that were introduced into online database have been considered as pathogenic/likely pathogenic. Haploinsufficiency is a common feature in C1-INH-HAE where a dominant-negative variant product impacts the wild-type allele and renders it inactive. Small (36.2%) and large (8.3%) deletions/duplications are common, with exon 4 as the most affected one. Point substitutions with missense variants (32.2%) are of interest for the serpin structure-function relationship. Canonical splice sites can be affected by variants within introns and exons also (14.3%). For noncanonical sequences, exon skipping has been confirmed by splicing analyses of patients' blood-derived RNAs (n = 25). Exonic variants (n = 6) can affect exon splicing. Rare deep-intron variants (n = 6), putatively acting as pseudo-exon activating mutations, have been characterized as pathogenic. Some variants have been characterized as benign/likely benign/of uncertain significance (n = 74). This category includes some homozygous (n = 10) or compound heterozygous variants (n = 11). They are presenting with minor allele frequency (MAF) below 0.00002 (i.e., lower than C1-INH-HAE frequency), and may be quantitatively unable to cause haploinsufficiency. Rare benign variants could contribute as disease modifiers. Gonadal mosaicism in C1-INH-HAE is rare and must be distinguished from a de novo variant. Situations with paternal or maternal disomy have been recorded (n = 3). Genotypes must be interpreted with biological investigation fitting with C1-INH expression and typing. Any SERPING1 variant reminiscent of the dysfunctional phenotype of serpin with multimerization or latency should be identified as serpinopathy.

• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

PURPOSE: Although the Prostate Imaging-Reporting and Data System™ version 2 (PI-RADS™ v2) is a reliable diagnostic tool for significant prostate cancer, less is known about the prognostic significance of the structured reporting scheme for estimating oncologic outcomes after treatment. We aimed to synthesize the available evidence regarding the association of PI-RADS v2 score and risk of biochemical recurrence (BCR) among patients undergoing primary definitive treatment for prostate cancer. MATERIALS AND METHODS: We systematically queried the PubMed® and Web of Science™ databases to identify studies addressing the association between the PI-RADS v2 and treatment outcomes. We included studies through November 2020 that assessed the independent prognostic significance of PI-RADS v2. After assessing risk of bias and quality, we conducted a formal meta-analysis to estimate the pooled effects of prostate magnetic resonance imaging (MRI) classification on the risk of BCR. RESULTS: We identified 9 and 7 eligible studies including 2,274 and 1,215 patients for the systematic review and meta-analysis, respectively. Eight were conducted in the context of radical prostatectomy and 1 post-radiation. Among patients treated with radical prostatectomy, higher PI-RADS v2 scores were significantly associated with risk of BCR (pooled HR 3.06, 95% CI 2.16-4.33; p <0.01). There was no significant heterogeneity among studies. For all studies, PI-RADS v2 score remained significantly associated with BCR (pooled HR 3.19, 95% CI 2.28-4.45; p <0.01). CONCLUSIONS: Prostate MRI findings assessed with the PI-RADS v2 classification were independently associated with risk of BCR after definitive local therapy, primarily based on data from radical prostatectomy. These findings support the prognostic significance of MRI, in addition to its role in prostate cancer diagnosis.

• MeSH
• brachyterapie MeSH
• hodnocení rizik metody   MeSH
• kalikreiny krev   MeSH
• lidé MeSH
• lokální recidiva nádoru krev   diagnóza   epidemiologie   prevence a kontrola   MeSH
• magnetická rezonanční tomografie * MeSH
• nádory prostaty krev   diagnóza   epidemiologie   terapie   MeSH
• prognóza MeSH
• prostata diagnostické zobrazování   účinky záření   chirurgie   MeSH
• prostatektomie MeSH
• prostatický specifický antigen krev   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• systematický přehled MeSH

Purpose: Prostate-specific antigen (PSA) is a sensitive but unspecific marker for prostate cancer (PC) detection, which may result in harms including overdiagnosis and overtreatment. Therefore, the development of new markers is of absolute value. The urinary level of engrailed-2 (EN2) protein has been recently suggested as a promising PC biomarker, correlating with tumour volume and stage. This study evaluated EN2 and its potential use in clinical practice.Materials and methods: Urinary EN2 was assessed by different commercially available enzyme-linked immunosorbent assay kits. The study sample included 90 patients with clinically localized PC compared to 30 healthy controls, and a group of 40 patients indicated for prostate biopsy due to an elevated PSA level where both pre- and post-digital rectal examination urine samples were collected.Results: No statistical difference between the patient group and the control group was obtained in all measured variables. There was no significant correlation between urinary EN2 and serum PSA, tumour staging and grading. Attentive DRE did not lead to significant changes of urinary EN2 or impact on its predictive power.Conclusions: Our results show that EN2 as a PC biomarker brings no additional value to the current use of PSA in clinical practice.

• MeSH
• analýza moči MeSH
• biopsie MeSH
• dospělí MeSH
• ELISA MeSH
• homeodoménové proteiny moč   MeSH
• kalikreiny krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové biomarkery krev   moč   MeSH
• nádory prostaty krev   diagnóza   patologie   moč   MeSH
• prediktivní hodnota testů MeSH
• prostatický specifický antigen krev   MeSH
• proteiny nervové tkáně moč   MeSH
• senioři MeSH
• staging nádorů MeSH
• studie případů a kontrol MeSH
• stupeň nádoru MeSH
• tumor burden MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH

Serine peptidases are involved in many physiological processes including digestion, haemostasis and complement cascade. Parasites regulate activities of host serine peptidases to their own benefit, employing various inhibitors, many of which belong to the Kunitz-type protein family. In this study, we confirmed the presence of potential anticoagulants in protein extracts of the haematophagous monogenean Eudiplozoon nipponicum which parasitizes the common carp. We then focused on a Kunitz protein (EnKT1) discovered in the E. nipponicum transcriptome, which structurally resembles textilinin-1, an antihemorrhagic snake venom factor from Pseudonaja textilis. The protein was recombinantly expressed, purified and biochemically characterised. The recombinant EnKT1 did inhibit in vitro activity of Factor Xa of the coagulation cascade, but exhibited a higher activity against plasmin and plasma kallikrein, which participate in fibrinolysis, production of kinins, and complement activation. Anti-coagulation properties of EnKT1 based on the inhibition of Factor Xa were confirmed by thromboelastography, but no effect on fibrinolysis was observed. Moreover, we discovered that EnKT1 significantly impairs the function of fish complement, possibly by inhibiting plasmin or Factor Xa which can act as a C3 and C5 convertase. We localised Enkt1 transcripts and protein within haematin digestive cells of the parasite by RNA in situ hybridisation and immunohistochemistry, respectively. Based on these results, we suggest that the secretory Kunitz protein of E. nipponicum has a dual function. In particular, it impairs both haemostasis and complement activation in vitro, and thus might facilitate digestion of a host's blood and protect a parasite's gastrodermis from damage by the complement. This study presents, to our knowledge, the first characterisation of a Kunitz protein from monogeneans and the first example of a parasite Kunitz inhibitor that impairs the function of the complement.

• MeSH
• antifibrinolytika chemie   imunologie   MeSH
• antikoagulancia chemie   imunologie   MeSH
• faktor Xa imunologie   MeSH
• hemostáza * MeSH
• infekce červy třídy Trematoda krev   imunologie   parazitologie   veterinární   MeSH
• inhibitory enzymů chemie   imunologie   MeSH
• inhibitory faktoru Xa chemie   imunologie   MeSH
• interakce hostitele a parazita MeSH
• kapři krev   imunologie   parazitologie   MeSH
• komplement imunologie   MeSH
• nemoci ryb krev   imunologie   parazitologie   MeSH
• plasmin imunologie   MeSH
• plazmatický kalikrein antagonisté a inhibitory   imunologie   MeSH
• proteiny červů chemie   genetika   imunologie   MeSH
• sekvence aminokyselin MeSH
• sekvenční seřazení MeSH
• Trematoda chemie   genetika   imunologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Kallikrein-related proteases (KLKs) play a critical role in epidermis physiology and have been implicated in skin pathologies such as Netherton syndrome. The contribution of individual KLKs to skin proteolysis is poorly understood. Monitoring of their activities in skin proteome is hampered by overlapping substrate specificities, and there is a need for novel assays. Here, we present a platform of selective and sensitive fluorogenic substrates and inhibitors for profiling KLK5, KLK7 and KLK14. These chemical tools were evaluated using recombinant KLKs and tissue from a unique set of mice deficient in eight combinations of KLKs and their natural regulator LEKTI.

• MeSH
• kalikreiny nedostatek   genetika   metabolismus   MeSH
• kůže metabolismus   MeSH
• lidé MeSH
• modely nemocí na zvířatech * MeSH
• myši knockoutované MeSH
• myši MeSH
• proteolýza * MeSH
• stanovení celkové genové exprese MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Rozacea patří mezi nejčastější obličejové dermatózy. Rozlišovány jsou čtyři základní formy tohoto onemocnění projevující se nejčastěji přechodnými a trvalými erytémy obličeje, teleangiektaziemi, papulami a pustulami, případně zbytněním měkkých tkání obličeje. Etiopatogeneze rozacey není doposud plně objasněna, předpokládají se multifaktoriální vlivy zahrnující poruchy regulace vrozeného imunitního systému, roli kožních komensálů a neurovaskulárních poruch. V přehledu je uvedena současná klasifikace a přístupy k léčbě tohoto onemocnění zahrnující léčebná opatření, terapii lokální a systémovou, nemoci.

Rosacea is one of the most common facial dermatoses. There are four basic clinical subtypes of this disease, most often characterized by transient and persistent erythema of the face, telangiectasias, papules and pustules, or by hyperplasia of soft tissues of the face. Etiopathogenesis of rosacea is not fully understood yet, it is supposed to be multifactorial, including dysregulation of the innate immune system, role of skin commensals and neurovascular dysregulation. The review presents the current classification and approaches to the treatment of this disease, including therapeutic measures, local and systemic therapy.

• MeSH
• antibakteriální látky terapeutické užití   MeSH
• antiparazitární látky MeSH
• fotochemoterapie MeSH
• ivermektin terapeutické užití   MeSH
• kalikreiny fyziologie   MeSH
• lidé MeSH
• obličejové dermatózy MeSH
• rosacea * dietoterapie   klasifikace   terapie   MeSH
• tetracykliny aplikace a dávkování   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

BACKGROUND: Additional urinary biomarkers for diabetic nephropathy (DN) are needed, providing early and reliable diagnosis and new insights into its mechanisms. Rigorous selection criteria and homogeneous study population may improve reproducibility of the proteomic approach. METHODS: Long-term type 1 diabetes patients without metabolic comorbidities were included, 11 with sustained microalbuminuria (MA) and 14 without MA (nMA). Morning urine proteins were precipitated and resolved by 2D electrophoresis. Principal component analysis (PCA) and Projection to latent structures discriminatory analysis (PLS-DA) were adopted to assess general data validity, to pick protein fractions for identification with mass spectrometry (MS), and to test predictive value of the resulting model. RESULTS: Proteins (n = 113) detected in more than 90% patients were considered representative. Unsupervised PCA showed excellent natural data clustering without outliers. Protein spots reaching Variable Importance in Projection score above 1 in PLS (n = 42) were subjected to MS, yielding 33 positive identifications. The PLS model rebuilt with these proteins achieved accurate classification of all patients (R2X = 0.553, R2Y = 0.953, Q2 = 0.947). Thus, multiple earlier recognized biomarkers of DN were confirmed and several putative new biomarkers suggested. Among them, the highest significance was met in kininogen-1. Its activation products detected in nMA patients exceeded by an order of magnitude the amount found in MA patients. CONCLUSIONS: Reducing metabolic complexity of the diseased and control groups by meticulous patients' selection allows to focus the biomarker search in DN. Suggested new biomarkers, particularly kininogen fragments, exhibit the highest degree of correlation with MA and substantiate validation in larger and more varied cohorts.

• MeSH
• albuminurie diagnóza   moč   MeSH
• biologické markery moč   MeSH
• časná diagnóza MeSH
• diabetické nefropatie diagnóza   moč   MeSH
• dospělí MeSH
• kalikrein-kininový systém * MeSH
• lidé MeSH
• nefrony metabolismus   MeSH
• proteiny metabolismus   MeSH
• reprodukovatelnost výsledků MeSH
• senzitivita a specificita MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH

Kalikrein-kininový systém (KKS) je zařazován mezi důležité systémy řídící cévní tonus, hemodynamiku a tubulární funkce ledvin. Tato integrativní úloha spojuje KKS s jinými systémy řídících funkci orgánů jako je renin-angiotenzinový systém (RAS) a systém oxidu dusnatého (NO). Nicméně, přesnou úlohu KKS v těchto řídících mechanismech je třeba více objasnit. Proto jsou v tomto projektu navrženy studie těchto mechanismů na unikátním modelu transgenních myší kde je využita technika Cre/lox rekombinace pro funkční analýzu genu in vivo, v našem případě touto technikou bude inaktivován gen pro bradykininový B2 receptor v distálním tubulu. Tento myší kmen bude testován za podmínek zvýšeného příjmu soli nebo mu bude experimentálně navozena hypertenze. Tímto navrhovaný projekt přinese nové poznatky zaměřené na mezisystémové funkční interakce mezi KKS, RAS a NO, které se mohou výrazně uplatnit v patofyziologii hypertenze a přidruženého poškození ledvin.; The kallikrein–kinin system (KKS) has been considered to play a physiological role in controlling vascular tone, renal henodynamics and tubular function. An integrative role in cross-talk between KKS and other systems such as the renin-angiotensin system (RAS) and nitric oxide (NO) has been suggested. However, the exact role of KKS in these physiological mechanisms needs to be addressed more conclusively. In this project, we propose to study these mechanisms in unique transgenic mouse model with the Cre/lox recombination system, in our case, the gene for bradykinin B2 receptor is inactivated only in the distal tubule. This mouse strain will be tested under various salt conditions or experimental hypertension will be induced. Thus our proposal should provide the novel evidence related to the functional interactions between KKS, RAS and NO system that might be involved in the regulation of renal function and blood pressure, and thus could contribute in pathophysiology of hypertension and renal injury.

• MeSH
• distální tubuly ledvin MeSH
• hypertenze MeSH
• kalikrein-kininový systém MeSH
• myši transgenní MeSH
• oxid dusnatý MeSH
• receptor bradykininu B2 MeSH
• renin-angiotensin systém MeSH

• Konspekt
• Patologie. Klinická medicína
• Experimentální medicína
• NLK Obory
• kardiologie
• experimentální medicína
• genetika, lékařská genetika
• NLK Publikační typ
• závěrečné zprávy o řešení grantu IGA MZ ČR