Gastrointestinálne stromálne tumory (GISTy) predstavujú najčastejšie mezenchýmové nádory tráviaceho traktu. Ich súčasná liečba dnes, v závislosti od viacerých parametrov ochorenia, zahŕňa najmä chirurgickú resekciu a biologickú liečbu inhibítormi tyrozínových kináz (TKIs). Tu prezentujeme raritný prípad 53-ročného pacienta s mutáciou p.W557_558Kdel exónu 11 c-KIT génu v primárnom GISTe žalúdka diagnostikovanom v gastroskopickej biopsii, ktorý bol liečený neoadjuvantnou cielenou liečbou imatinibom. Po počiatočnej fáze stabilizácie ochorenia vznikla u pacienta rezistencia na túto terapiu. Napriek liečbe TKI inhibítormi druhej a tretej línie a totálnej chirurgickej extirpácii v ďalšom priebehu dochádzalo k opakovaným remisiám a relapsom. V resekčnom materiáli sme identifikovali viacpočetné mutácie v rôznych exónoch c-KIT génu, kde pri perzistencii primárnej delečnej mutácie v exóne 11 vznikli ďalšie sekundárne zriedkavé mutácie v exónoch 13 (p.V654A) a 17 (p.Y823D). Opakované úseky remisií a relapsov tak po liečbe TKIs, ako aj po chirurgickej resekcii tumoru, poukazujú na nepriaznivý vplyv týchto genetických zmien a otvárajú otázku potreby modifikácie terapeutického prístupu imatinib-rezistentných GISTov striedaním jednotlivých TKIs namiesto doteraz zaužívanej monoterapie.

Gastrointestinal stromal tumours (GISTs) represent the most common mesenchymal tumours of the digestive tract. Based on various parameters, the recent GIST treatment includes surgical and/or targeted therapy using tyrosine kinase inhibitors (TKIs). In this paper we present a case of 53-year-old patient with c-KIT exon 11 (p.W557_558Kdel) mutated primary GIST of stomach diagnosed by a gastroscopic biopsy and treated by neoadjuvant TKI therapy using imatinib. After incipient disease stabilization, the patient developed therapy resistance. In spite of the second and third-line TKI treatment and radical surgery, the following disease course consisted of repeated remissions and relapses. The resection material showed multiple c-KIT mutations in various exons, including persisting primary exon 11 deletion mutation and two secondary infrequent c-KIT mutations in exon 13 (p.V654A) and exon 17 (p.Y823D). Repeating cycles of remissions and relapses after TKI treatments and surgical resection show the adverse effects of these genetic mutations on GIST behaviour and might advocate therapy management modification allowing therapeutic combinations of TKIs instead of conventional monotherapies in imatinib resistent GISTs.

• MeSH
• axony patologie   MeSH
• biologická terapie metody   MeSH
• chemorezistence MeSH
• cílená molekulární terapie metody   MeSH
• gastrointestinální stromální tumory * chirurgie   farmakoterapie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mezenchymom chirurgie   farmakoterapie   MeSH
• mutace MeSH
• neoadjuvantní terapie metody   MeSH
• protinádorové látky terapeutické užití   MeSH
• protoonkogenní proteiny c-kit * genetika   MeSH
• stomatochirurgické výkony MeSH
• tyrosinkinasy antagonisté a inhibitory   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

BACKGROUND: Single nucleotide polymorphisms can create a genetic microenvironment in some tumors that affects the course of treatment, resistance, etc. Whether single nucleotide polymorphisms have an impact on gastrointestinal stromal tumor (GIST) development and disease progression is not yet accurately verified. KIT SNPM541L in exon 10 correlates with a worse prognosis of many cancers. The impact of KIT SNPM541L in GISTs is relatively unknown and, therefore, its analyses could have potential in patient therapy and could provide more detailed information on tumor character, clinical presentation, or tumor behavior in treatment. AIM: The aim of the study was the analysis of the biological and clinical significance of the KIT SNPM541L polymorphism in exon 10. MATERIALS AND METHODS: Paraffin sample tissues were obtained from the National GIST Register in Martin. Retrospective samples from 177 GIST patients were divided into several groups. Detection of SNPM541L was performed by Sanger sequencing. Statisitical analyses were performed to determine the prevalence of KIT SNPM541L in the Slovak GIST cohort, to search for correlation between c-KIT status and clinicopathological, molecular and biological data. RESULTS: Overall, 29 samples out of 177 showed KIT SNPM541L polymorphism. CONCLUSION: Our results do not support the association between KIT SNPM541L and increased risk of relapse in localized primary GISTs. Additionally, we found a positive correlation between KIT SNPM541L occurrence and earlier onset of relapse in PDGFRa and WT subgroup of GISTs.

• MeSH
• dospělí MeSH
• gastrointestinální nádory epidemiologie   genetika   patologie   MeSH
• gastrointestinální stromální tumory epidemiologie   genetika   patologie   MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé středního věku MeSH
• lidé MeSH
• míra přežití MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádorové biomarkery genetika   MeSH
• následné studie MeSH
• prognóza MeSH
• protoonkogenní proteiny c-kit genetika   MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Evropa MeSH

Several sequences forming G-quadruplex are highly conserved in regulatory regions of genomes of different organisms and affect various biological processes like gene expression. Diverse G-quadruplex properties can be modulated via their interaction with small polyaromatic molecules such as pyrene. To investigate how pyrene interacts with G-rich DNAs, we incorporated deoxyuridine nucleotide(s) with a covalently attached pyrene moiety (Upy) into a model system that forms parallel G-quadruplex structures. We individually substituted terminal positions and positions in the pentaloop of the c-kit2 sequence originating from the KIT proto-oncogene with Upy and performed a detailed NMR structural study accompanied with molecular dynamic simulations. Our results showed that incorporation into the pentaloop leads to structural polymorphism and in some cases also thermal destabilization. In contrast, terminal positions were found to cause a substantial thermodynamic stabilization while preserving topology of the parent c-kit2 G-quadruplex. Thermodynamic stabilization results from π-π stacking between the polyaromatic core of the pyrene moiety and guanine nucleotides of outer G-quartets. Thanks to the prevalent overall conformation, our structures mimic the G-quadruplex found in human KIT proto-oncogene and could potentially have antiproliferative effects on cancer cells.

• MeSH
• deoxyuridin chemie   MeSH
• G-kvadruplexy * MeSH
• lidé MeSH
• molekulární modely MeSH
• nukleární magnetická rezonance biomolekulární MeSH
• promotorové oblasti (genetika) MeSH
• protoonkogenní proteiny c-kit genetika   MeSH
• pyreny chemie   MeSH
• termodynamika MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Duchenne muscular dystrophy (DMD) is a devastating condition shortening the lifespan of young men. DMD patients suffer from age-related dilated cardiomyopathy (DCM) that leads to heart failure. Several molecular mechanisms leading to cardiomyocyte death in DMD have been described. However, the pathological progression of DMD-associated DCM remains unclear. In skeletal muscle, a dramatic decrease in stem cells, so-called satellite cells, has been shown in DMD patients. Whether similar dysfunction occurs with cardiac muscle cardiovascular progenitor cells (CVPCs) in DMD remains to be explored. We hypothesized that the number of CVPCs decreases in the dystrophin-deficient heart with age and disease state, contributing to DCM progression. We used the dystrophin-deficient mouse model (mdx) to investigate age-dependent CVPC properties. Using quantitative PCR, flow cytometry, speckle tracking echocardiography, and immunofluorescence, we revealed that young mdx mice exhibit elevated CVPCs. We observed a rapid age-related CVPC depletion, coinciding with the progressive onset of cardiac dysfunction. Moreover, mdx CVPCs displayed increased DNA damage, suggesting impaired cardiac muscle homeostasis. Overall, our results identify the early recruitment of CVPCs in dystrophic hearts and their fast depletion with ageing. This latter depletion may participate in the fibrosis development and the acceleration onset of the cardiomyopathy.

• MeSH
• dilatační kardiomyopatie genetika   metabolismus   patologie   MeSH
• Duchennova muskulární dystrofie genetika   metabolismus   patologie   MeSH
• dystrofin nedostatek   genetika   MeSH
• kardiomyocyty metabolismus   patologie   MeSH
• kardiovaskulární systém metabolismus   patologie   MeSH
• kmenové buňky metabolismus   patologie   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myokard metabolismus   patologie   MeSH
• myši inbrední mdx genetika   MeSH
• myši MeSH
• poškození DNA genetika   MeSH
• protoonkogenní proteiny c-kit genetika   MeSH
• regulace genové exprese genetika   MeSH
• stárnutí genetika   patologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

In systemic mastocytosis (SM), the clinical features and survival vary greatly. Patient-related factors determining the outcome in SM are largely unknown. Methods: We examined the impact of sex on the clinical features, progression-free survival (PFS), and overall survival (OS) in 3403 patients with mastocytosis collected in the registry of the European Competence Network on Mastocytosis (ECNM). The impact of cytogenetic and molecular genetic aberrations on sex differences was analyzed in a subset of patients. Results: Of all patients enrolled, 55.3% were females. However, a male predominance was found in a subset of advanced SM (AdvSM) patients, namely SM with an associated hematologic neoplasm (SM-AHN, 70%; p < 0.001). Correspondingly, organomegaly (male: 23% vs. female: 13%, p = 0.007) was more, whereas skin involvement (male: 71% vs. female: 86%, p = 0.001) was less frequent in males. In all patients together, OS (p < 0.0001) was significantly inferior in males, and also within the WHO sub-categories indolent SM, aggressive SM (ASM) and SM-AHN. PFS was significantly (p = 0.0002) worse in males when all patients were grouped together; due to low numbers of events, this significance persisted only in the subcategory smoldering SM. Finally, prognostically relevant cytogenetic abnormalities (10% vs. 5%, p = 0.006) or molecular aberrations (SRSF2/ASXL1/RUNX1 profile; 63% vs. 40%, p = 0.003) were more frequently present in males. Conclusions: Male sex has a major impact on clinical features, disease progression, and survival in mastocytosis. Male patients have an inferior survival, which seems related to the fact that they more frequently develop a multi-mutated AdvSM associated with a high-risk molecular background.

• MeSH
• akutní myeloidní leukemie komplikace   MeSH
• chromozomální aberace * MeSH
• dítě MeSH
• doba přežití bez progrese choroby MeSH
• dospělí MeSH
• gastrointestinální nemoci patofyziologie   MeSH
• hematologické nádory komplikace   MeSH
• hepatomegalie patofyziologie   MeSH
• kojenec MeSH
• kožní nemoci patofyziologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mastocytární leukemie patofyziologie   MeSH
• míra přežití MeSH
• mladiství MeSH
• mladý dospělý MeSH
• myelodysplastické syndromy komplikace   MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• prognóza MeSH
• protein PEBP2A2 genetika   MeSH
• protoonkogenní proteiny c-kit genetika   MeSH
• represorové proteiny genetika   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• serin-arginin sestřihové faktory genetika   MeSH
• sexuální faktory * MeSH
• splenomegalie patofyziologie   MeSH
• systémová mastocytóza komplikace   genetika   mortalita   patofyziologie   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• Klíčová slova
• pazopanib,
• MeSH
• klinické zkoušky, fáze III jako téma MeSH
• lidé MeSH
• multicentrické studie jako téma MeSH
• přežívající onkologičtí pacienti MeSH
• protinádorové látky terapeutické užití   MeSH
• protoonkogenní proteiny c-kit MeSH
• randomizované kontrolované studie jako téma MeSH
• receptory růstového faktoru odvozeného z trombocytů MeSH
• receptory vaskulárního endoteliálního růstového faktoru MeSH
• retrospektivní studie MeSH
• sarkom * farmakoterapie   MeSH
• tyrosinkinasy antagonisté a inhibitory   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH

Cutaneous and subcutaneous mast cell tumours (MCTs) are counted among the most frequent cancers in dogs. However, the genetic aetiology of their development is still mostly unknown, with the exception of KIT and tumor protein p53 (TP53 ) mutations reported in less than a half of cutaneous MCTs. In subcutaneous MCTs, no gene alterations were previously detected. We analysed KIT and TP53 mutations in cutaneous and subcutaneous MCTs, and identified methylated CpG sites in KIT and TP53 promoters and adjacent exon 1 regions. The mutation analysis focused on KIT exons 8, 9 and 11, and TP53 exons 5-8, and revealed mutations in 26% and 7% cutaneous MCT cases, respectively. Moreover, we report a first case of KIT mutation ever detected in subcutaneous MCTs. KIT exon 11 mutations and high Kiupel and Patnaik grades were associated with reduced survival in this study. Both KIT and TP53 gene were generally unmethylated in canine cutaneous MCTs. A sporadic methylation of the CpG positions in KIT promoter and adjacent exon 1 was detected in 70.4% of cutaneous and 82% of subcutaneous MCTs. A sporadic methylation of the CpG positions in the TP53 promoter and exon 1 was observed in 36.8% of the analysed cutaneous MCT samples. Only in two subcutaneous MCTs, we observed more than 30% of clones showing KIT methylation at the CpG positions 13 or 14. The CpG position 14 is involved in a predicted binding site for Sp1 transcription factor. However, the significance of KIT promoter methylation at this specific position needs further evaluation.

• MeSH
• kožní mastocytóza genetika   chirurgie   veterinární   MeSH
• mutace MeSH
• nádorový supresorový protein p53 genetika   MeSH
• nádory kůže genetika   chirurgie   veterinární   MeSH
• nemoci psů genetika   chirurgie   MeSH
• pilotní projekty MeSH
• přežití MeSH
• protoonkogenní proteiny c-kit genetika   MeSH
• psi MeSH
• subkutánní tkáň MeSH
• zvířata MeSH
• Check Tag
• psi MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: At first sight, the issue of terminology in morphological sciences may seem as "closed and changeless chapter", as many of the structures within the human body have been known for centuries. However, the exact opposite is true. Terminologia Histologica: International Terms for Human Cytology and Histology published under the Federative International Programme on Anatomical Terminology in 2008 is a new standard in human cell and tissue terminology. The list of items in the first and still valid official nomenclature of cellular and tissue structures, the Terminologia Histologica (TH), is the best and most extensive of all the histological nomenclatures ever issued. MATERIALS AND METHODS: The aim of this article is a systematic and in-depth analysis of the current internationally accepted nomenclature TH, with focus on important histological structures which are missing in this first edition. Some should be incorporated just for the sake of completeness and consistence, others are purely absent terms for individual structures or some are recently described new tissue structures. RESULTS: We also discuss about a question, how to deal with the issue of eponyms. Eponyms reflect medicine's rich and colourful history. Although they have not been considered official terms in the anatomical nomenclature since 1955, they are still widely used in clinical practice. CONCLUSIONS: We hope that this opinion article will develop a wide scientific discussion before the publication of the second edition, so perhaps the mentioned minor flaws will be corrected, so the new edition of the TH will become truly an internationally accepted communication tool for all histologists, histopathologists and anatomists.

• MeSH
• bazální membrána metabolismus   MeSH
• lidé MeSH
• orgánová specificita * MeSH
• protoonkogenní proteiny c-kit metabolismus   MeSH
• terminologie jako téma * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• gastrointestinální nádory farmakoterapie   genetika   patologie   farmakoterapie   genetika   imunologie   MeSH
• hepatocelulární karcinom chirurgie   farmakoterapie   genetika   MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• lidé MeSH
• nádorové biomarkery genetika   MeSH
• nivolumab terapeutické užití   MeSH
• protinádorové látky imunologicky aktivní farmakologie   terapeutické užití   MeSH
• protoonkogenní proteiny c-kit účinky léků   MeSH
• tekutá biopsie metody   MeSH
• tyrosinkinasové receptory účinky léků   MeSH
• Check Tag
• lidé MeSH

Genetic causes of canine mast cell tumours (MCTs), except for mutations in the KIT gene detected in some MCTs, are generally unknown. We used whole exome sequencing to reveal mutation spectra in canine MCTs. We detected somatic mutations in 87 genes including 10 genes recognized as human cancer drivers. Besides KIT, 14 other genes were recurrently mutated. Subsequently, we performed next generation sequencing of a panel of 50 selected genes in additional MCT samples. In this group, the most frequently altered gene was GNB1 showing a recurrent dinucleotide substitution at position of Gly116 in 30% of the MCT samples (n = 6/20) and Ile80 substitution accompanied by a splice region mutation in one case. We extended the study by analysis of the above mentioned GNB1 regions in additional MCT samples by Sanger sequencing, and assessed the overall prevalence of GNB1 mutations to 17.3% (n = 14/81), which is similar to the prevalence of KIT alterations. Our results indicate that GNB1 mutations are probably involved in canine MCT pathogenesis in both cutaneous and subcutaneous MCT cases. As opposed to KIT alterations, the presence of GNB1 mutations did not negatively affect survival times, and our data even showed a trend towards positive prognosis. If our results are confirmed in a larger number of MCTs, an extension of molecular testing of canine MCTs by GNB1 analysis would help to refine the molecular stratification of MCTs, and become useful for targeted treatment strategies.

• MeSH
• mastocytární sarkom genetika   patologie   veterinární   MeSH
• mastocyty patologie   MeSH
• mutace MeSH
• nemoci psů genetika   patologie   MeSH
• proteiny vázající GTP - beta-podjednotky genetika   MeSH
• protoonkogenní proteiny c-kit genetika   MeSH
• psi MeSH
• vysoce účinné nukleotidové sekvenování veterinární   MeSH
• zvířata MeSH
• Check Tag
• psi MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH