The aim of the study was to estimate genetic alterations detected in ovarian and cervical cancer cells, in correlation with other available parameters of a histopathological and clinical character and to find the important associations and differences of both these tumor sites with diverse impacts on the cancer's prognosis. Sixty patients presenting with ovarian cancer and twenty patients manifesting cervical cancer were included in the study. The histological type and grade, MIB-1 and p53 were estimated. For genetic testing, both conventional and molecular methods were applied. The results were subjected to statistical evaluation, using analysis of variances and I2 test. Ovarian cancer patients with extensive chromosomal rearrangements were assessed to be significantly younger. The typical findings, different in ovarian and cervical cancer cells have been found, including some less frequent findings (deletion of 22q in 36% of all ovarian cancer samples, as well as amplifications of chromosome 2 and deletions of chromosome 10, 11p and 21q in cervical cancer cells). The expression of proliferation marker MIB-1 was observed to be significantly higher in women with a high p53 HSCORE. The significant importance of genetic alterations and the activity of proliferative markers, including common correlations with an unfavorable outcome with respect to ovarian tumors in younger women were found. Key words: chromosomal rearrangements, genetic alterations, ovarian cancer, cervical cancer, prognostic significance.

• MeSH
• chromozomální aberace * MeSH
• dospělí MeSH
• karyotypizace MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace MeSH
• nádorové biomarkery analýza   MeSH
• nádory děložního čípku genetika   MeSH
• nádory vaječníků genetika   MeSH
• prognóza MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• věkové faktory MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• nádorové biomarkery MeSH

The CHEK2 gene mutations I157T (c.470T>C) and IVS2+1G>A affecting the forkhead-associated domain (FHA) have been shown to increase the risk of breast cancer development in several populations. We analyzed the CHEK2 gene segment coding for FHA domain in 673 unselected breast cancer patients and 683 controls from the Czech Republic using the denaturant high-performance liquid chromatography. The found frequency of predominant FHA alteration I157T did not differ between breast cancer patients (19/673; 2.82%) and controls (17/683; 2.49%; P=0.71). Besides this mutation we characterized another nine alterations-six located within FHA coding sequence and three occurring in introns 1 or 2). Eight variants occurred once each in patients with breast cancer and two were present in controls. Three alterations found in breast cancer patients were novel missense variants (Y159H, T172A, and L174F) affecting highly conservative residues in FHA domain. Despite the lack of association of I157T mutation with breast cancer development in our population we deduced that the FHA domain is the subject of rare population-specific alterations that might modify risk of various cancers.

• MeSH
• checkpoint kinasa 2 MeSH
• duktální karcinom prsu epidemiologie   genetika   patologie   MeSH
• genetická predispozice k nemoci * MeSH
• incidence MeSH
• intraduktální neinfiltrující karcinom epidemiologie   genetika   patologie   MeSH
• lidé MeSH
• lobulární karcinom genetika   patologie   MeSH
• missense mutace genetika   MeSH
• nádory prsu genetika   patologie   MeSH
• prognóza MeSH
• protein-serin-threoninkinasy genetika   MeSH
• studie případů a kontrol MeSH
• terciární struktura proteinů MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• checkpoint kinasa 2 MeSH
• CHEK2 protein, human MeSH Prohlížeč
• protein-serin-threoninkinasy MeSH

♦ BACKGROUND: Permanent stimulation of the peritoneum during peritoneal dialysis (PD) is likely to result in increased expression of genes encoding proteins involved in inflammation and tissue remodeling. Peritoneal fibrosis and neoangiogenesis may develop. ♦ OBJECTIVE: To assess highly expressed genes potentially in volved in peritoneal alterations during PD treatment using an animal model. ♦ METHODS: A PD catheter was implanted in 36 male Wistar rats after 70% nephrectomy. The rats were divided into 3 groups, exposed to dialysis solution for 8 weeks, and sacrificed 2 weeks later. Group B was exposed to a buffer, group D was exposed to a 3.86% glucose-based dialysis solution, and in group D+H, a second hit of intraperitoneal blood on top of the dialysis solution was given to induce the development of peritoneal sclerosis. Before sacrifice, peritoneal function was assessed. Omental tissue was obtained for analysis of gene expression using RT-qPCR. ♦ RESULTS: Fibrosis scores, vessel counts, and peritoneal function parameters were not different between the groups. Genes involved in the transforming growth factor beta signaling pathway, cell proliferation, angiogenesis, and inflammation were more expressed (p < 0.05) in the D+H group. Almost no differences were found between the control groups. We identified 4 genes that were related to peritoneal transport. ♦ CONCLUSION: Already a mid-term peritoneal exposure, when no microscopical and functional alterations are present, provokes activation of gene pathways of cell proliferation, fibrosis, neoangiogenesis, and inflammation.

• Klíčová slova
• Peritoneal dialysis, angiogenesis, fibrosis, gene expression, inflammation, peritoneal membrane alterations, peritoneal transport,
• MeSH
• chronické selhání ledvin terapie   MeSH
• dialyzační roztoky farmakologie   MeSH
• genetická transkripce * MeSH
• imunohistochemie MeSH
• interval spolehlivosti MeSH
• jehlová biopsie MeSH
• krysa rodu Rattus MeSH
• kvantitativní polymerázová řetězová reakce MeSH
• modely nemocí na zvířatech MeSH
• náhodné rozdělení MeSH
• nefrektomie metody   MeSH
• patologická angiogeneze genetika   MeSH
• peritoneální dialýza škodlivé účinky   metody   MeSH
• peritoneální fibróza genetika   patologie   MeSH
• potkani Wistar MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• dialyzační roztoky MeSH

Alzheimer's disease (AD) is a disabling neurodegenerative disorder that leads to long-term functional and cognitive impairment and greatly reduces life expectancy. Early genetic studies focused on tracking variations in genome-wide DNA sequences discovered several polymorphisms and novel susceptibility genes associated with AD. However, despite the numerous risk factors already identified, there is still no fully satisfactory explanation for the mechanisms underlying the onset of the disease. Also, as with other complex human diseases, the causes of low heritability are unclear. Epigenetic mechanisms, in which changes in gene expression do not depend on changes in genotype, have attracted considerable attention in recent years and are key to understanding the processes that influence age-related changes and various neurological diseases. With the recent use of massive sequencing techniques, methods for studying epigenome variations in AD have also evolved tremendously, allowing the discovery of differentially expressed disease traits under different conditions and experimental settings. This is important for understanding disease development and for unlocking new potential AD therapies. In this work, we outline the genomic and epigenomic components involved in the initiation and development of AD and identify potentially effective therapeutic targets for disease control.

• Klíčová slova
• Alzheimer’s disease, dementia, epigenetic mechanisms, genetic risk factors, genome-wide association study (GWAS), missing heritability, older adults,
• MeSH
• Alzheimerova nemoc genetika   patologie   MeSH
• epigeneze genetická * MeSH
• genetická predispozice k nemoci * MeSH
• genomika metody   MeSH
• lidé MeSH
• metylace DNA * MeSH
• regulace genové exprese * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Glioblastoma is currently considered the most common and, unfortunately, also the most aggressive primary brain tumor, with the highest morbidity and mortality rates. The average survival of patients diagnosed with glioblastoma is 14 months, and only 2% of patients survive 3 years after surgery. Based on our clinical experience and knowledge from extensive clinical studies, survival is mainly related to the molecular biological properties of glioblastoma, which are of interest to the general medical community. Our study examined a total of 71 retrospective studies published from 2016 through 2022 and available on PubMed that deal with mutations of selected genes in the pathophysiology of GBM. In conclusion, we can find other mutations within a given gene group that have different effects on the prognosis and quality of survival of a patient with glioblastoma. These mutations, together with the associated mutations of other genes, as well as intratumoral heterogeneity itself, offer enormous potential for further clinical research and possible application in therapeutic practice.

• Klíčová slova
• gene mutations, glioblastoma, overall survival, prognosis,
• MeSH
• glioblastom * genetika   diagnóza   patologie   mortalita   MeSH
• klinická relevance MeSH
• lidé MeSH
• mutace * MeSH
• nádorové biomarkery genetika   MeSH
• nádory mozku * genetika   diagnóza   patologie   MeSH
• prognóza MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• nádorové biomarkery MeSH

There is a rise in the incidence of thyroid nodules in pediatric patients. Most of them are benign tissues, but part of them can cause papillary thyroid cancer (PTC). The aim of this study was to detect the mutations in commonly investigated genes as well as in novel PTC-causing genes in thyroid nodules and to correlate the found mutations with clinical and pathological data. The cohort of 113 pediatric samples consisted of 30 benign lesions and 83 PTCs. DNA from samples was used for next-generation sequencing to identify mutations in the following genes: HRAS, KRAS, NRAS, BRAF, IDH1, CHEK2, PPM1D, EIF1AX, EZH1 and for capillary sequencing in case of the TERT promoter. RNA was used for real-time PCR to detect RET/PTC1 and RET/PTC3 rearrangements. Total detection rate of mutations was 5/30 in benign tissues and 35/83 in PTCs. Mutations in RAS genes (HRAS G13R, KRAS G12D, KRAS Q61R, NRAS Q61R) were detected in benign lesions and HRAS Q61R and NRAS Q61K mutations in PTCs. The RET/PTC rearrangement was identified in 18/83 of PTCs and was significantly associated with higher frequency of local and distant metastases. The BRAF V600E mutation was identified in 15/83 of PTCs and significantly correlated with higher age of patients and classical variant of PTC. Germline variants in the genes IDH1, CHEK2 and PPM1D were found. In conclusion, RET/PTC rearrangements and BRAF mutations were associated with different clinical and histopathological features of pediatric PTC. RAS mutations were detected with high frequency in patients with benign nodules; thus, our results suggest that these patients should be followed up intensively.

• Klíčová slova
• benign, mutations, next-generation sequencing, papillary thyroid cancer, pediatric,
• Publikační typ
• časopisecké články MeSH

In pathogenic fungi and oomycetes, interspecific hybridization may lead to the formation of new species having a greater impact on natural ecosystems than the parental species. From the early 1990s, a severe alder (Alnus spp.) decline due to an unknown Phytophthora species was observed in several European countries. Genetic analyses revealed that the disease was caused by the triploid hybrid P. × alni, which originated in Europe from the hybridization of P. uniformis and P. × multiformis. Here, we investigated the population structure of P. × alni (158 isolates) and P. uniformis (85 isolates) in several European countries using microsatellite markers. Our analyses confirmed the genetic structure previously observed in other European populations, with P. uniformis populations consisting of at most two multilocus genotypes (MLGs) and P. × alni populations dominated by MLG Pxa-1. The genetic structure of P. × alni populations in the Czech Republic, Hungary and Sweden seemed to reflect the physical isolation of river systems. Most rare P. × alni MLGs showed a loss of heterozygosity (LOH) at one or a few microsatellite loci compared with other MLGs. This LOH may allow a stabilization within the P. × alni genome or a rapid adaptation to stress situations. Alternatively, alleles may be lost because of random genetic drift in small, isolated populations, with no effect on fitness of P. × alni. Additional studies would be necessary to confirm these patterns of population diversification and to better understand the factors driving it.

• Klíčová slova
• biological invasion, ecology and epidemiology, genome alterations, population biology, population diversity, simple sequence repeats, subgenome,
• MeSH
• ekosystém MeSH
• genetická variace MeSH
• genotyp MeSH
• mikrosatelitní repetice genetika   MeSH
• nemoci rostlin MeSH
• Phytophthora * genetika   MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Evropa MeSH
• Švédsko MeSH

Autosomal dominant hyperuricemia, gout, renal cysts, and progressive renal insufficiency are hallmarks of a disease complex comprising familial juvenile hyperuricemic nephropathy and medullary cystic kidney diseases type 1 and type 2. In some families the disease is associated with mutations of the gene coding for uromodulin, but the link between the genetic heterogeneity and mechanism(s) leading to the common phenotype symptoms is not clear. In 19 families, we investigated relevant biochemical parameters, performed linkage analysis to known disease loci, sequenced uromodulin gene, expressed and characterized mutant uromodulin proteins, and performed immunohistochemical and electronoptical investigation in kidney tissues. We proved genetic heterogeneity of the disease. Uromodulin mutations were identified in six families. Expressed, mutant proteins showed distinct glycosylation patterns, impaired intracellular trafficking, and decreased ability to be exposed on the plasma membrane, which corresponded with the observations in the patient's kidney tissue. We found a reduction in urinary uromodulin excretion as a common feature shared by almost all of the families. This was associated with case-specific differences in the uromodulin immunohistochemical staining patterns in kidney. Our results suggest that various genetic defects interfere with uromodulin biology, which could lead to the development of the common disease phenotype. 'Uromodulin-associated kidney diseases' may be thus a more appropriate term for this syndrome.

• MeSH
• bazální membrána patologie   ultrastruktura   MeSH
• biopsie MeSH
• dítě MeSH
• dna (nemoc) MeSH
• dospělí MeSH
• genetická heterogenita * MeSH
• genetická vazba MeSH
• hyperurikemie genetika   metabolismus   MeSH
• hypofýza cytologie   MeSH
• imunohistochemie MeSH
• kultivované buňky MeSH
• ledvinové kanálky patologie   ultrastruktura   MeSH
• ledviny metabolismus   patologie   chirurgie   ultrastruktura   MeSH
• lidé MeSH
• lidské chromozomy, pár 1 MeSH
• lidské chromozomy, pár 16 MeSH
• missense mutace MeSH
• mladiství MeSH
• mukoproteiny genetika   metabolismus   moč   MeSH
• mutační analýza DNA MeSH
• polycystické ledviny autozomálně dominantní genetika   MeSH
• polymorfismus délky restrikčních fragmentů MeSH
• rodokmen MeSH
• sekvence nukleotidů MeSH
• syndrom MeSH
• transfekce MeSH
• uromodulin MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• mukoproteiny MeSH
• UMOD protein, human MeSH Prohlížeč
• uromodulin MeSH

Both brain and peripheral nitric oxide (NO) play a role in the control of blood pressure and circulatory homeostasis. Central NO production seems to counteract angiotensin II-induced enhancement of sympathetic tone. The aim of our study was to evaluate NO synthase (NOS) activity and protein expression of its three isoforms--neuronal (nNOS), endothelial NOS (eNOS) and inducible (iNOS)--in two brain regions involved in blood pressure control (diencephalon and brainstem) as well as in the kidney of young adult rats with either genetic (12-week-old SHR) or salt-induced hypertension (8-week-old Dahl rats). We have demonstrated reduced nNOS and iNOS expression in brainstem of both hypertensive models. In SHR this abnormality was accompanied by attenuated NOS activity and was corrected by chronic captopril treatment which prevented the development of genetic hypertension. In salt hypertensive Dahl rats nNOS and iNOS expression was also decreased in the diencephalon where neural structures important for salt hypertension development are located. As far as peripheral NOS activity and expression is concerned, renal eNOS expression was considerably reduced in both genetic and salt-induced hypertension. In conclusions, we disclosed similar changes of NO system in the brainstem (but not in the diencephalon) of rats with genetic and salt-induced hypertension. Decreased nNOS expression was associated with increased blood pressure due to enhanced sympathetic tone.

• MeSH
• hypertenze enzymologie   etiologie   genetika   MeSH
• izoenzymy genetika   metabolismus   MeSH
• krysa rodu Rattus MeSH
• kuchyňská sůl toxicita   MeSH
• ledviny enzymologie   metabolismus   MeSH
• mozek enzymologie   metabolismus   MeSH
• oxid dusnatý metabolismus   MeSH
• potkani inbrední Dahl MeSH
• synthasa oxidu dusnatého genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• izoenzymy MeSH
• kuchyňská sůl MeSH
• oxid dusnatý MeSH
• synthasa oxidu dusnatého MeSH

BACKGROUND: The principal aim of this report was to study second primary malignant neoplasms (SMNs) in long-term survivors of pancreatic ductal adenocarcinoma (PDAC) with regard to the germline genetic background. PATIENTS AND METHODS: A total of 118 PDAC patients after a curative-intent surgery who were treated between 2006 and 2011 were analyzed. Of the 22 patients surviving for >5 years, six went on to develop SMNs. A genetic analysis of 219 hereditary cancer-predisposition and candidate genes was performed by targeted next-generation sequencing in germline DNA from 20 of these patients. RESULTS: Of all the radically resected PDAC patients, six patients went on to subsequently develop SMNs, which accounted for 27% of the long-term survivors. The median time to diagnosis of SMNs, which included two cases of rectal cancer, and one case each of prostate cancer, malignant melanoma, breast cancer, and urinary bladder cancer, was 52.5 months. At the time of analysis, none of these patients had died as a result of PDAC progression. We identified four carriers of germline pathogenic mutations in 20 analyzed long-term survivors. One carrier of the CHEK2 mutation was found among four analyzed patients who developed SMNs. Of the remaining 16 long-term PDAC survivors, 3 patients (19%) carried germline mutation(s) in the MLH1+ ATM, CHEK2, and RAD51D gene, respectively. CONCLUSION: This retrospective analysis indicates that SMNs in PDAC survivors are an important clinical problem and may be more common than has been acknowledged to be the case. In patients with good performance status, surgical therapy should be considered, as the SMNs often have a favorable prognosis.

• Klíčová slova
• hereditary cancer genes, long-term survivors, pancreatic ductal adenocarcinoma, second primary neoplasms, subsequent malignant neoplasm, surgical treatment,
• Publikační typ
• časopisecké články MeSH