The knowledge of mechanisms of regulation of IL-10 production by B cells remains still very limited. We show here that highly purified mouse B cells stimulated with LPS produce significant levels of IL-10, but Bregs in our model do not express detectable level of either Foxp3 or GATA-3. Nevertheless, IL-10 production by B cells is regulated by cytokines. In activated B cells, IL-10 production was significantly enhanced by IFN-γ and decreased in the presence of IL-4 or TGF-β. These findings are in sharp contrast with the observations in T cells, where IL-10 production correlates with GATA-3 or FoxP3 expression, and the cytokines regulate IL-10 production in a reverse manner than in activated B cells. These results thus show that the production of IL-10 by Bregs is regulated by cytokines independently of the expression of GATA-3 and FoxP3, which is clearly different from GATA-3-dependent IL-10 production by activated Th2 cells and FoxP3 expression in IL-10-producing Tregs.

• MeSH
• aktivace lymfocytů imunologie   MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa imunologie   MeSH
• forkhead transkripční faktory metabolismus   MeSH
• interferon gama imunologie   MeSH
• interleukin-10 biosyntéza   MeSH
• interleukin-4 imunologie   MeSH
• kultivované buňky MeSH
• lipopolysacharidy imunologie   MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• regulační B-lymfocyty imunologie   MeSH
• regulační T-lymfocyty imunologie   MeSH
• Th2 buňky imunologie   MeSH
• transformující růstový faktor beta imunologie   MeSH
• transkripční faktor GATA3 metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• Publikační typ
• souhrny MeSH

• Publikační typ
• abstrakt z konference MeSH

• MeSH
• hodnocení rizik MeSH
• jídelníček * MeSH
• kolorektální nádory * diagnóza   genetika   imunologie   MeSH
• lidé MeSH
• masné výrobky * škodlivé účinky   MeSH
• maso škodlivé účinky   MeSH
• potraviny škodlivé účinky   MeSH
• stravovací zvyklosti MeSH
• transkripční faktor GATA3 imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• novinové články MeSH

Germline GATA2 mutations cause cellular deficiencies with high propensity for myeloid disease. We investigated 426 children and adolescents with primary myelodysplastic syndrome (MDS) and 82 cases with secondary MDS enrolled in 2 consecutive prospective studies of the European Working Group of MDS in Childhood (EWOG-MDS) conducted in Germany over a period of 15 years. Germline GATA2 mutations accounted for 15% of advanced and 7% of all primary MDS cases, but were absent in children with MDS secondary to therapy or acquired aplastic anemia. Mutation carriers were older at diagnosis and more likely to present with monosomy 7 and advanced disease compared with wild-type cases. For stratified analysis according to karyotype, 108 additional primary MDS patients registered with EWOG-MDS were studied. Overall, we identified 57 MDS patients with germline GATA2 mutations. GATA2 mutations were highly prevalent among patients with monosomy 7 (37%, all ages) reaching its peak in adolescence (72% of adolescents with monosomy 7). Unexpectedly, monocytosis was more frequent in GATA2-mutated patients. However, when adjusted for the selection bias from monosomy 7, mutational status had no effect on the hematologic phenotype. Finally, overall survival and outcome of hematopoietic stem cell transplantation (HSCT) were not influenced by mutational status. This study identifies GATA2 mutations as the most common germline defect predisposing to pediatric MDS with a very high prevalence in adolescents with monosomy 7. GATA2 mutations do not confer poor prognosis in childhood MDS. However, the high risk for progression to advanced disease must guide decision-making toward timely HSCT.

• MeSH
• chromozomální aberace MeSH
• dítě MeSH
• fenotyp MeSH
• genetická predispozice k nemoci MeSH
• hluchota genetika   MeSH
• Kaplanův-Meierův odhad MeSH
• klinické zkoušky, fáze III jako téma MeSH
• lidé MeSH
• lidské chromozomy, pár 1 genetika   MeSH
• lidské chromozomy, pár 7 genetika   MeSH
• lidské chromozomy, pár 8 genetika   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mutační analýza DNA MeSH
• myelodysplastické syndromy epidemiologie   etiologie   genetika   patologie   MeSH
• předškolní dítě MeSH
• prevalence MeSH
• prognóza MeSH
• prospektivní studie MeSH
• syndromy imunologické nedostatečnosti genetika   MeSH
• transkripční faktor GATA2 nedostatek   genetika   MeSH
• věk při počátku nemoci MeSH
• výběrový bias MeSH
• zárodečné mutace MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Barakatov syndróm, tiež známy aj ako HDR syndróm, je klinicky heterogénne, extrémne zriedkavé, autozómovo dominantne dedičné ochorenie, ktorého frekvencia výskytu nie je známa. Primárne je spôsobený deléciou chromozómu 10p14 alebo mutáciou GATA3 génu, ktorý je umiestnený na 10. chromozóme. Hoci fenotypovo je definovaný triádou HDR: hypoparatyreóza (H), hluchota (deafness; D), postihnutie obličiek (renal involvement; R), v dostupnej literatúre boli identifikované aj prípady pozostávajúce z jeho jednotlivých komponentov HD, DR, HR (1). Syndróm bol prvýkrát opísaný Amin J. Barakatom v r. 1977 u súrodencov s hypokalciémiou a proteinúriou (2). Podľa dostupných údajov bolo doposiaľ v medicínskej literatúre publikovaných okolo 180 prípadov tohto ochorenia celosvetovo (3). V tomto článku prezentuje- me vlastnú kazuistiku pacienta s Barakatovým syndrómom s hypoparatyreózou, unilaterálnou hluchotou a obličkovým postihnutím.

Barakat syndrome, also known as HDR syndrome, is a clinically heterogenous, autosomal dominant rare genetic disease, which frequency is unknown. It is primarily caused by deletion of chromosome 10p14 or mutation of GATA3 gene, located on chromosome 10. Although this syndrome is phenotypically defined by its triad of HDR: hypoparathyroidism (H), deafness (D), renal disease (R), the literature identifies cases with different components, consisting of HD, DR, HR (1). The syndrome was first described by Amin J. Barakat et al. in 1977 in siblings with hypocalcemia and proteinuria (2). So far, about 180 cases have been reported in the worldwide medical literature (3). In this report we present our own case report of patient with Barakat syndrome with hypoparathyrodism, unilateral deafness and renal impairment.

• Klíčová slova
• Barakatův syndrom,
• MeSH
• dospělí MeSH
• genetické nemoci vrozené * diagnóza   genetika   MeSH
• hluchota diagnóza   etiologie   MeSH
• hypoparatyreóza diagnóza   etiologie   terapie   MeSH
• lidé MeSH
• nemoci ledvin diagnóza   etiologie   genetika   MeSH
• percepční nedoslýchavost diagnóza   etiologie   genetika   MeSH
• transkripční faktor GATA3 MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

Low-grade oncocytic tumour (LOT) of the kidney has recently emerged as a potential novel tumour type. Despite similarity to oncocytoma or eosinophilic chromophobe renal cell carcinoma, it shows diffuse keratin 7 immunohistochemistry (IHC) and negative KIT (CD117), which differs from both. We aimed to identify the molecular characteristics of these tumours. Seventeen tumours (one male, 16 female, nine previously published) fitting the original description of this entity (solid eosinophilic cell morphology, often with areas of tumour cells loosely stretched in oedematous stroma, and the above IHC features) were analysed with a next-generation sequencing panel of 324 cancer-associated genes from formalin-fixed, paraffin-embedded tissue. All tumours harboured at least one alteration in either TSC1 (n = 7, 41%), TSC2 (n = 2, 12%), MTOR (n = 5, 29%) or PIK3CA (n = 4, 24%). Four tumours harboured a second alteration, including two NF2, one each in conjunction with MTOR and TSC2 alterations, one PTEN with TSC1 alteration and one tumour with both MTOR and TSC1 alterations. No other renal cancer-related or recurring gene alterations were identified. In addition to the previously described IHC findings, 16 of 16 were positive for GATA3. Eleven patients with follow-up had no metastases or recurrent tumours. Recurrent tuberous sclerosis/MTOR pathway gene alterations in LOT support its consideration as a distinct morphological, immunohistochemical and genetic entity. PIK3CA is another pathway member that may be altered in these tumours. Further study will be necessary to determine whether tumour behaviour or syndromic associations differ from those of oncocytoma and chromophobe carcinoma, warranting different clinical consideration.

• MeSH
• fosfatidylinositol-3-kinasy třídy I genetika   MeSH
• karcinom z renálních buněk * genetika   MeSH
• ledviny MeSH
• lidé MeSH
• lokální recidiva nádoru MeSH
• mutace MeSH
• nádory ledvin * genetika   MeSH
• oxyfilní adenom * genetika   MeSH
• TOR serin-threoninkinasy genetika   MeSH
• transkripční faktor GATA3 genetika   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Ageing constitutes the most important risk factor for all major chronic ailments, including malignant, cardiovascular and neurodegenerative diseases. However, behavioural and pharmacological interventions with feasible potential to promote health upon ageing remain rare. Here we report the identification of the flavonoid 4,4'-dimethoxychalcone (DMC) as a natural compound with anti-ageing properties. External DMC administration extends the lifespan of yeast, worms and flies, decelerates senescence of human cell cultures, and protects mice from prolonged myocardial ischaemia. Concomitantly, DMC induces autophagy, which is essential for its cytoprotective effects from yeast to mice. This pro-autophagic response induces a conserved systemic change in metabolism, operates independently of TORC1 signalling and depends on specific GATA transcription factors. Notably, we identify DMC in the plant Angelica keiskei koidzumi, to which longevity- and health-promoting effects are ascribed in Asian traditional medicine. In summary, we have identified and mechanistically characterised the conserved longevity-promoting effects of a natural anti-ageing drug.

• MeSH
• Angelica chemie   MeSH
• autofagie účinky léků   MeSH
• buněčná smrt účinky léků   MeSH
• buněčné linie účinky léků   MeSH
• Caenorhabditis elegans účinky léků   MeSH
• dlouhověkost účinky léků   fyziologie   MeSH
• Drosophila melanogaster účinky léků   MeSH
• flavonoidy aplikace a dávkování   farmakologie   MeSH
• ischemická choroba srdeční farmakoterapie   MeSH
• lidé MeSH
• mechanistické cílové místo rapamycinového komplexu 1 metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• proteiny přenášející kationty genetika   MeSH
• regulace genové exprese účinky léků   MeSH
• rostlinné extrakty farmakologie   MeSH
• Saccharomyces cerevisiae - proteiny genetika   MeSH
• Saccharomyces cerevisiae účinky léků   metabolismus   MeSH
• signální transdukce MeSH
• sirolimus farmakologie   MeSH
• stárnutí účinky léků   fyziologie   MeSH
• tradiční orientální medicína MeSH
• transkripční faktory GATA účinky léků   MeSH
• transkripční faktory účinky léků   genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

IKAROS family zinc finger 1/IKZF1 is a transcription factor important in lymphoid differentiation, and a known tumor suppressor in acute lymphoid leukemia. Recent studies suggest that IKZF1 is also involved in myeloid differentiation. To investigate whether IKZF1 deletions also play a role in pediatric acute myeloid leukemia, we screened a panel of pediatric acute myeloid leukemia samples for deletions of the IKZF1 locus using multiplex ligation-dependent probe amplification and for mutations using direct sequencing. Three patients were identified with a single amino acid variant without change of IKZF1 length. No frame-shift mutations were found. Out of 11 patients with an IKZF1 deletion, 8 samples revealed a complete loss of chromosome 7, and 3 cases a focal deletion of 0.1-0.9Mb. These deletions included the complete IKZF1 gene (n=2) or exons 1-4 (n=1), all leading to a loss of IKZF1 function. Interestingly, differentially expressed genes in monosomy 7 cases (n=8) when compared to non-deleted samples (n=247) significantly correlated with gene expression changes in focal IKZF1-deleted cases (n=3). Genes with increased expression included genes involved in myeloid cell self-renewal and cell cycle, and a significant portion of GATA target genes and GATA factors. Together, these results suggest that loss of IKZF1 is recurrent in pediatric acute myeloid leukemia and might be a determinant of oncogenesis in acute myeloid leukemia with monosomy 7.

• MeSH
• akutní myeloidní leukemie genetika   mortalita   MeSH
• chromozomální delece MeSH
• delece genu * MeSH
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• lidské chromozomy, pár 7 genetika   MeSH
• míra přežití MeSH
• mladiství MeSH
• nádorové proteiny genetika   MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• přežití po terapii bez příznaků nemoci MeSH
• transkripční faktor Ikaros genetika   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH

AIMS: The large nested variant of urothelial carcinoma (LNUC) has been added to the World Health Organization (WHO) 2016 classification. Scant data exist, and little is known about its clinical behaviour. MATERIAL AND RESULTS: Cases fulfilling the morphological criteria of LNUC were collected. Pure and mixed cases (i.e. with other patterns of invasive UC) were studied. Immunohistochemical staining with cytokeratin (CK)7, p63, GATA-3, CK20, p53 and Ki-67 was performed. Included were 26 cystectomies (RC) and 10 resections (TURB) belonging to 36 patients with an average age of 66.7 years. Fourteen (39%) were pure LNUCs, and 22 (61%) displayed mixed features. Seventy per cent of the TURBs had pT2 tumours, while 58% of RCs had extravesical disease (≥pT3 and/or ≥pN1), with the rate of advanced disease being higher in mixed (69%) in comparison to pure cases (40%). Similarly, 38% of mixed cases had nodal metastases in comparison to 20% of pure cases. Overall, eight patients (24%) died of disease at a mean interval time of 21.7 months and seven patients (21%) showed recurrence or metastases. Disease progression was significantly higher in mixed cases (55 and 31% in mixed and pure cases, respectively). Positive staining was: CK7 = 87.5%, CK20 = 72%, GATA-3 = 91%, P63 = 100%, p53 = 56% and Ki-67 = mean of 16%. CONCLUSION: Despite the bland cytological appearance and deceptive pattern of invasion of the LNUC, our study validates its fully malignant potential with metastatic spread and tumour-related deaths. Distinguishing mixed from pure LNUCs seems to be of value. LNUCs show comparable immunophenotype to both conventional urothelial carcinoma and the nested variant of urothelial carcinoma.

• MeSH
• dospělí MeSH
• karcinom z přechodných buněk patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové biomarkery analýza   MeSH
• nádory močového měchýře patologie   MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH