This study deals with detecting the associations of atopic dermatitis' (AD) phenotypes in children: alone or combined with seasonal allergic rhino-conjunctivitis (SARC) and/or perennial allergic rhinitis (PAR), and/or with bronchial asthma (BA) with single nucleotide polymorphisms (SNP) of filaggrin (FLG), thymic stromal lymphopoietin (TSLP) and orsomucoid-like-1 protein 3 (ORMDL3) genes. Male and female pediatric patients aged from 3 to 18 years old were recruited into the main (AD in different combinations with SARC, PAR, BA) and control groups (disorders of digestives system, neither clinical nor laboratory signs of atopy). Patients were genotyped for SNP of rs_7927894 FLG, rs_11466749 TSLP, rs_7216389 ORMDL3 variants. Statistically significant associations of the increased risk were detected of AD combined with SARC and/or PAR and AD combined with BA (possibly, SARC and/or PAR) with C/T rs_7927894 FLG and T/T rs_7216389 ORMDL3 genotypes. Genotype C/C rs_7927894 FLG significantly decreases the risk of AD combined with SARC and/or PAR by 2.56 fold. Several genotypes' associations had a trend to significance: C/C rs_7216389 ORMDL3 decreases and C/T rs_7216389 ORMDL3 increases the risk for developing AD alone phenotype; A/G rs_11466749 TSLP decreases the risk of AD combined with BA (possibly, SARC and/or PAR) phenotype development.

• MeSH
• atopická dermatitida genetika   MeSH
• celoroční alergická rýma genetika   MeSH
• cytokiny genetika   MeSH
• dítě MeSH
• fenotyp MeSH
• genetická predispozice k nemoci MeSH
• genotyp MeSH
• jednonukleotidový polymorfismus * MeSH
• kojenec MeSH
• konjunktivitida genetika   MeSH
• lidé MeSH
• membránové proteiny genetika   MeSH
• mladiství MeSH
• předškolní dítě MeSH
• proteiny S100 genetika   MeSH
• rinitida genetika   MeSH
• riziko MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

S100 proteins are involved in the pathogenesis of sporadic colorectal carcinoma through different mechanisms. The aim of our study was to assess tissue mRNA encoding S100 proteins in patients with non-advanced and advanced colorectal adenoma. Mucosal biopsies were taken from the caecum, transverse colon and rectum during diagnostic and/or therapeutic colonoscopy. Another biopsy was obtained from adenomatous tissue in the advanced adenoma group. The tissue mRNA for each S100 protein (S100A4, S100A6, S100A8, S100A9, S100A11 and S100P) was investigated. Eighteen biopsies were obtained from the healthy mucosa in controls and the non-advanced adenoma group (six individuals in each group) and thirty biopsies in the advanced adenoma group (ten patients). Nine biopsies were obtained from advanced adenoma tissue (9/10 patients). Significant differences in mRNA investigated in the healthy mucosa were identified between (1) controls and the advanced adenoma group for S100A6 (p = 0.012), (2) controls and the non-advanced adenoma group for S100A8 (p = 0.033) and (3) controls and the advanced adenoma group for S100A11 (p = 0.005). In the advanced adenoma group, differences between the healthy mucosa and adenomatous tissue were found in S100A6 (p = 0.002), S100A8 (p = 0.002), S100A9 (p = 0.021) and S100A11 (p = 0.029). Abnormal mRNA expression for different S100 proteins was identified in the pathological adenomatous tissue as well as in the morphologically normal large intestinal mucosa.

• MeSH
• adenom genetika   metabolismus   patologie   MeSH
• kalgranulin A genetika   metabolismus   MeSH
• kalgranulin B genetika   metabolismus   MeSH
• kolorektální nádory genetika   metabolismus   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• messenger RNA genetika   metabolismus   MeSH
• nádorové biomarkery genetika   metabolismus   MeSH
• nádorové proteiny genetika   metabolismus   MeSH
• následné studie MeSH
• pilotní projekty MeSH
• prognóza MeSH
• protein S100A6 genetika   metabolismus   MeSH
• proteiny buněčného cyklu genetika   metabolismus   MeSH
• proteiny S100 genetika   metabolismus   MeSH
• proteiny vázající vápník genetika   metabolismus   MeSH
• S100 kalcium vázající protein A4 genetika   metabolismus   MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

S100 proteins are involved in biological events related to colorectal carcinogenesis. Aim of this prospective study was to assess serum concentration of S100A6, A8, A9 and A11 proteins in patients with colorectal neoplasia. Eighty-four subjects were enrolled: 20 controls (average risk population with normal findings on colonoscopy; 7 men, 13 women, age 23-74, mean 55 ± 14), 20 patients with non-advanced colorectal adenoma (non-AA, 10 men, 10 women, age 41-82, mean 62 ± 11), 22 with advanced colorectal adenoma (AA, 15 men, 7 women, age 49-80, mean 64 ± 8) and 22 with colorectal cancer (CRC, 12 men, 10 women, age 49-86, mean 69 ± 10). Peripheral venous blood was obtained. Serum S100 proteins were investigated by enzyme immunoassay technique. Serum S100A6 was significantly lower in CRC (mean 8530 ± 4743 ng/L), p = .035 compared to controls (mean 11308 ± 2968 ng/L). Serum S100A8 was significantly higher in AA (median 11955 ng/L, IQR 2681-34756 ng/L), p = .009 and in CRC (median 27532 ng/L, IQR 6794-35092 ng/L), p < .001 compared to controls (median 2513 ng/L, IQR 2111-4881 ng/L). Serum S100A9 concentrations did not differ between any tested group and controls, p > .05. Serum concentration of S100A11 was significantly lower in non-AA (mean 3.5 ± 2.4 μg/L), p = .004 and in CRC (mean 3.4 ± 2.4 μg/L), p = .002 compared to controls (mean 5.9 ± 2.5 μg/L). Sensitivity and specificity for S100A8 protein in patients with CRC were 94% and 73%; positive predictive value 68% and negative predictive value 95%. Patients with colorectal neoplasia have significantly lower serum S100A6 and S100A11 levels, significantly higher S100A8 and unaltered serum S100A9 levels.

• MeSH
• adenom krev   diagnóza   genetika   patologie   MeSH
• dospělí MeSH
• ELISA MeSH
• exprese genu MeSH
• kalgranulin A krev   genetika   MeSH
• kalgranulin B krev   genetika   MeSH
• karcinogeneze genetika   metabolismus   patologie   MeSH
• kolorektální nádory krev   diagnóza   genetika   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové biomarkery krev   genetika   MeSH
• prospektivní studie MeSH
• protein S100A6 krev   genetika   MeSH
• proteiny buněčného cyklu krev   genetika   MeSH
• proteiny S100 krev   genetika   MeSH
• senioři MeSH
• senzitivita a specificita MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Mutation spectra of 250 cancer driver, druggable, and actionable genes were analyzed in surgically resected pancreatic ductal adenocarcinoma (PDAC) patients who developed metachronous pulmonary metastases. Targeted sequencing was performed in DNA from blood and archival samples of 15 primary tumors and three paired metastases. Results were complemented with the determination of G12V mutation in KRAS by droplet digital PCR. The median number of protein-changing mutations was 52 per patient. KRAS and TP53 were significantly enriched in fractions of mutations in hotspots. Individual gene mutation frequencies or mutational loads accounting separately for drivers, druggable, or clinically actionable genes, did not significantly associate with patients' survival. LRP1B was markedly mutated in primaries of patients who generalized (71%) compared to those developing solitary pulmonary metastases (0%). FLG2 was mutated exclusively in primary tumors compared to paired metastases. In conclusion, signatures of prognostically differing subgroups of PDAC patients were generated for further utilization in precision medicine.

• MeSH
• adenokarcinom genetika   patologie   MeSH
• frekvence genu genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace genetika   MeSH
• nádorový supresorový protein p53 genetika   MeSH
• nádory plic genetika   patologie   MeSH
• nádory slinivky břišní genetika   patologie   MeSH
• proteiny S100 genetika   MeSH
• protoonkogenní proteiny p21(ras) genetika   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

We report a case of a 35-year old male patient with a tumor located in the deep dermis on his forearm. The lesion was completely excised but recurred 4 years later. The patient showed no signs of neurofibromatosis type 1. The morphology and immunophenotype of the tumor corresponded to the recently characterized group of soft tissue spindle cell lesions defined by a relatively uniform cytomorphology, patternless architecture, conspicuous stromal and perivascular hyalinization, S100 and CD34 coexpression and recurrent fusions involving RAF1, BRAF, and NTRK1/2 genes. Using a 592-gene panel and massively parallel next-generation sequencing platform, we initially detected only NF1 gene mutation in our case. However, further molecular testing with Archer fusion assay revealed a novel NCOA4-RET gene fusion, adding it to the list of multiple kinase fusions originally reported in these tumors. Although break-apart FISH showed false negative result due to the presence of intrachromosomal rearrangement, RT-PCR confirmed the fusion transcript. Knowing the exact fusion is of great clinical importance especially for patients within the aggressive subset of these neoplasms that could be treated with selective kinase inhibitors. The presented case underscores the benefits of massively parallel sequencing as the types and number of gene fusions these tumors can potentially harbor render single-gene assays such as FISH impractical, and in this particular case, also insensitive.

• MeSH
• antigeny CD34 genetika   metabolismus   MeSH
• dospělí MeSH
• hyalin metabolismus   MeSH
• koaktivátory jaderných receptorů genetika   metabolismus   MeSH
• lidé MeSH
• mutace MeSH
• nádory měkkých tkání genetika   patologie   MeSH
• neurofibromin 1 genetika   MeSH
• onkogenní fúze * MeSH
• proteiny S100 genetika   metabolismus   MeSH
• protoonkogenní proteiny c-ret genetika   metabolismus   MeSH
• škára metabolismus   patologie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH

The transient receptor potential channel of melastatin 4 (TRPM4) belongs to a group of large ion receptors that are involved in countless cell signalling cascades. This unique member is ubiquitously expressed in many human tissues, especially in cardiomyocytes, where it plays an important role in cardiovascular processes. Transient receptor potential channels (TRPs) are usually constituted by intracellular N- and C- termini, which serve as mediators affecting allosteric modulation of channels, resulting in the regulation of the channel function. The TRPs tails contain a number of conserved epitopes that specifically bind the intracellular modulators. Here, we identify new binding sites for the calmodulin (CaM) and S100 calcium-binding protein A1 (S100A1), located in the very distal part of the TRPM4 N terminus. We have used chemically synthesized peptides of the TRPM4, mimicking the binding epitopes, along with fluorescence methods to determine and specify CaM- and S100A1-binding sites. We have found that the ligands binding epitopes at the TRPM4 N terminus overlap, but the interacting mechanism of both complexes is probably different. The molecular models supported by data from the fluorescence method confirmed that the complexes formations are mediated by the positively charged (R139, R140, R144) and hydrophobic (L134, L138, V143) residues present at the TRPM4 N terminus-binding epitopes. The data suggest that the molecular complexes of TRPM4/CaM and TRPM4/S100A1 would lead to the modulation of the channel functions.

• MeSH
• databáze proteinů MeSH
• epitopy MeSH
• expertní systémy MeSH
• fluorescenční polarizace MeSH
• interakční proteinové domény a motivy MeSH
• kalmodulin chemie   genetika   metabolismus   MeSH
• kationtové kanály TRPM chemie   genetika   metabolismus   MeSH
• kinetika MeSH
• konformace proteinů MeSH
• konzervovaná sekvence MeSH
• lidé MeSH
• ligandy MeSH
• molekulární modely * MeSH
• mutace MeSH
• peptidové fragmenty chemická syntéza   chemie   genetika   metabolismus   MeSH
• proteiny S100 chemie   genetika   metabolismus   MeSH
• rekombinantní proteiny chemie   metabolismus   MeSH
• sekvence aminokyselin MeSH
• simulace molekulového dockingu MeSH
• substituce aminokyselin MeSH
• vazebná místa MeSH
• výpočetní biologie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH

Úvod: Systémová sklerodermie (SSc) je generalizované onemocnění pojivové tkáně postihující kůži a vnitřní orgány. V patogenezi SSc se uplatňuje zánět, vaskulopatie a fibróza. Žádný z dosud zkoušených léku zatím neprokázal přesvědčivou účinnost v léčbě SSc. S100A4 se účastní regulace buněčné motility, proliferace, apoptózy, angiogeneze a remodelace extracelulární matrix. Původně byl popsán jako promotor metastazování u nádorů, avšak nedávno byly dokumentovány i jeho prozánětlivé vlastnosti u zánětlivých revmatických onemocnění. Cílem této práce bylo prozkoumat roli S100A4 při patologické aktivaci fibroblastů u SSc a v modelech experimentální kožní fibrózy. Výsledky: Exprese S100A4 byla zvýšená v kůži pacientů se SSc, v SSc fibroblastech i v myších modelech experimentální kožní fibrózy způsobem závislým na TGF-ß / Smad signální kaskádě. Zvýšení exprese S100A4 anebo stimulace pomocí rekombinantního S100A4 proteinu indukovaly v klidových normálních fibroblastech aktivovaný fenotyp. Snížení exprese S100A4 nebo jeho kompletní deficit naopak utlumily profibrotické účinky TGF-ß a potlačili tvorbu kolagenu. S100A4 knock-out myši (S100A4-/-) byly uchráněny před rozvojem experimentální kožní fibrózy indukované bleomycinem a měly redukované ztluštění dermis, snížený obsah hydroxyprolinu a menší počet aktivovaných fibroblastů, tzv. myofibroblastů. Deficit S100A4 podobně utlumil rozvoj kožní fibrózy u Tight skin-1 (Tsk-1) myšího modelu. Antifibrotické účinky inaktivace S100A4 v obou experimentálních modelech kožní fibrózy byly zprostředkované inhibicí TGF-ß / Smad signální kaskády. Závěr: Naše výsledky ukazují, že S100A4 je pozitivním regulátorem stimulačních účinků TGF-ß na fibroblasty u SSc. Exprese S100A4 je indukovaná pomocí TGF-ß a S100A4 zpětně potencuje stimulační účinky TGF-ß / Smad signální kaskády na tvorbu kolagenu SSc fibroblasty a indukci fibrózy. Jelikož je S100A4 důležitým mediátorem profibrotických účinků TGF-ß a efekt protilátek neutralizujících S100A4 je momentálně zkoumán u nádorových onemocnění, mohl by se S100A4 protein stát kandidátní molekulou nové antifibrotické terapie.

Introduction: Systemic sclerosis (SSc) is a generalized connective tissue disease affecting the skin and internal organs. The pathogenesis of SSc is characterized by inflammation, vasculopathy and fibrosis. To date, none of the tested drugs have demonstrated convincing efficacy in the treatment of SSc. S100A4 is involved in the regulation of cell motility, proliferation, apoptosis, angiogenesis and remodeling of the extracellular matrix. It was originally described as a promoter of metastasis in tumors, however, its pro-inflammatory properties have recently been demonstrated in inflammatory rheumatic diseases. The aim of this study was to assess the role of S100A4 in pathological activation of fibroblasts in SSc and in experimental models of dermal fibrosis. Results: The expression of S100A4 was increased in the skin of SSc patients, in SSc fibroblasts and in experimental fibrosis in a TGF-ß / Smad dependent manner. Overexpression of S100A4 or stimulation with recombinant S100A4 induced an activated phenotype in resting normal fibroblasts. In contrast, inhibition of S100A4 or its complete deficit abrogated the pro-fibrotic effects of TGF-ß and decreased the release of collagen. S100A4 knock-out mice (S100A4-/-) were protected from bleomycin-induced skin fibrosis with reduced dermal thickening, decreased hydroxyproline content and lower counts of activated fibroblasts, so called myofibroblasts. Similarly, deficiency of S100A4 also ameliorated fibrosis in the Tight skin-1 (Tsk-1) mouse model. Anti-fibrotic effects of the inactivation of S100A4 in both experimental models of dermal fibrosis were mediated by inhibition of TGF-ß / Smad signaling. Conclusion: Our results characterize S100A4 as a positive regulator of the stimmulatory effects of TGF-ß on fibroblasts in SSc. S100A4 is induced by TGF-ß and in turn amplifies the stimulatory effects of canonical TGF-ß / Smad signaling on collagen synthesis by SSc fibroblasts and on induction of fibrosis. Since S100A4 is essentially required for the pro-fibrotic effects of TGF-ß and neutralizing antibodies against S100A4 are currently evaluated in tumors, S100A4 might become a candidate molecule for novel anti-fibrotic therapies.

• Klíčová slova
• in vivo,
• MeSH
• exprese genu MeSH
• extracelulární matrix * MeSH
• fibroblasty * fyziologie   patologie   MeSH
• fibróza * genetika   patofyziologie   MeSH
• klonování DNA MeSH
• kolagen biosyntéza   MeSH
• kůže patologie   MeSH
• lidé MeSH
• malá interferující RNA * fyziologie   MeSH
• modely u zvířat MeSH
• myši MeSH
• pojivová tkáň * patologie   účinky léků   MeSH
• proteiny S100 * fyziologie   genetika   MeSH
• signální transdukce * MeSH
• systémová sklerodermie * etiologie   patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH

Calcium cycling is a major determinant of cardiac function. S100A1 is the most abundant member of the calcium-binding S100 protein family in myocardial tissue. S100A1 interacts with a variety of calcium regulatory proteins such as SERCA2a, ryanodine receptors, L-type calcium channels and Na(+)/Ca(2+) exchangers, thus enhancing calcium cycling. Aside from this major function, S100A1 has an important role in energy balance, myofilament sliding, myofilament calcium sensibility, titin-actin interaction, apoptosis and cardiac remodeling. Apart from its properties regarding cardiomyocytes, S100A1 is also important in vessel relaxation and angiogenesis. S100A1 potentiates cardiac function thus increasing the cardiomyocytes' functional reserve; this is an important feature in heart failure. In fact, S100A1 seems to normalize cardiac function after myocardial infarction. Also, S100A1 is essential in the acute response to adrenergic stimulation. Gene therapy experiments show promising results, although further studies are still needed to reach clinical practice. In this review, we aim to describe the molecular basis and regulatory function of S100A1, exploring its interactions with a myriad of target proteins. We also explore its functional effects on systolic and diastolic function as well as its acute actions. Finally, we discuss S100A1 gene therapy and its progression so far.

• MeSH
• genetická terapie MeSH
• homeostáza MeSH
• kardiovaskulární fyziologické jevy * MeSH
• kontrakce myokardu MeSH
• lidé MeSH
• proteiny S100 genetika   metabolismus   fyziologie   MeSH
• srdeční selhání patofyziologie   terapie   MeSH
• vápník metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Transient receptor potential melastatin 3 ion channel (TRPM3) belongs to the TRP family of cation-permeable ion channels involved in many important biological functions such as pain transduction, thermosensation, and mechanoregulation. The channel was reported to play an important role in Ca(2+) homeostasis, but its gating mechanisms, functions, and regulation are still under research. Utilizing biophysical and biochemical methods, we characterized two independent domains, Ala-35-Lys-124 and His-291-Gly-382, on the TRPM3 N terminus, responsible for interactions with the Ca(2+)-binding proteins calmodulin (CaM) and S100A1. We identified several positively charged residues within these domains as having a crucial impact on CaM/S100A1 binding. The data also suggest that the interaction is calcium-dependent. We also performed competition assays, which suggested that CaM and S100A1 are able to compete for the same binding sites within the TRPM3 N terminus. This is the first time that such an interaction has been shown for TRP family members.

• MeSH
• kalmodulin chemie   genetika   metabolismus   MeSH
• kationtové kanály TRPM chemie   genetika   metabolismus   MeSH
• lidé MeSH
• missense mutace MeSH
• proteiny S100 chemie   genetika   metabolismus   MeSH
• substituce aminokyselin MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

OBJECTIVES: The S100A4 protein is known as a metastasis promoting factor; however, its involvement in non-malignant diseases such as RA and psoriasis has been recently described. The aim of this study was to investigate the expression and possible role of S100A4 in idiopathic inflammatory myopathies. METHODS: S100A4 protein expression was detected by immunohistochemistry in muscle tissue from control individuals (n = 11) and patients with PM and DM (n = 8/6). IF staining was used to co-localize S100A4 with selected cells. Cytokine expression and protein synthesis in S100A4-treated cells were analysed by RT-PCR and ELISA. RESULTS: S100A4 protein was significantly up-regulated in muscle tissue of patients with inflammatory myopathies compared with control individuals and was associated particularly with the presence of mononuclear infiltrates. Only few regenerating muscle fibres in PM/DM expressed S100A4. Then we analysed the effect of S100A4 on human myocytes and peripheral blood mononuclear cells (PBMCs). Although S100A4 did not affect myocytes, stimulation of PBMCs with S100A4 significantly induced the expression and synthesis of TNF-α, IL-1β and IL-6, but not of IFN-α. We showed that S100A4 is not directly involved in perforin/granzyme B-induced apoptosis and that it does not modulate the expression of Bax and Bcl2 mRNA in myocytes and PBMCs. CONCLUSION: Increased expression of S100A4 in inflamed muscle tissue highlights its potential role in the pathogenesis of inflammatory myopathies. S100A4 may act as a cytokine-like factor indirectly promoting muscle fibre damage by stimulating mononuclear cells to increase the synthesis of pro-inflammatory cytokines.

• MeSH
• biologické markery metabolismus   MeSH
• cytokiny genetika   metabolismus   MeSH
• dermatomyozitida genetika   metabolismus   patologie   MeSH
• dospělí MeSH
• exprese genu MeSH
• kosterní svalová vlákna účinky léků   metabolismus   patologie   MeSH
• kosterní svaly metabolismus   patologie   MeSH
• leukocyty mononukleární účinky léků   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lipopolysacharidy farmakologie   MeSH
• messenger RNA metabolismus   MeSH
• polymyozitida genetika   metabolismus   patologie   MeSH
• proteiny S100 genetika   metabolismus   farmakologie   MeSH
• rekombinantní proteiny farmakologie   MeSH
• senioři MeSH
• upregulace účinky léků   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH