Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain1-4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage5-8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES+KI67+ unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.

• MeSH
• antigen Ki-67 metabolismus   MeSH
• buněčná diferenciace * genetika   MeSH
• buněčný rodokmen MeSH
• histondemethylasy MeSH
• lidé MeSH
• meduloblastom * klasifikace   genetika   patologie   MeSH
• metencephalon * embryologie   patologie   MeSH
• mozeček embryologie   patologie   MeSH
• mutace MeSH
• nádory mozečku * klasifikace   genetika   patologie   MeSH
• proteiny hedgehog metabolismus   MeSH
• proteiny T-boxu metabolismus   MeSH
• represorové proteiny MeSH
• svalové proteiny MeSH
• transkripční faktory Otx nedostatek   genetika   MeSH
• transkripční faktory PEBP2A genetika   MeSH
• transkripční faktory MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

PURPOSE: This study evaluated the ability of 18F-Fluorodeoxyglucose (FDG) and 18F-Fluorothymidine (FLT) imaging with positron emission tomography (PET) to measure early response to endocrine therapy from baseline to just prior to surgical resection in estrogen receptor positive (ER+) breast tumors. METHODS: In two separate studies, women with early stage ER+ breast cancer underwent either paired FDG-PET (n = 22) or FLT-PET (n = 27) scans prior to endocrine therapy and again in the pre-operative setting. Tissue samples for Ki-67 were taken for all patients both prior to treatment and at the time of surgery. RESULTS: FDG maximum standardized uptake value (SUVmax) declined in 19 of 22 lesions (mean 17% (range -45 to 28%)). FLT SUVmax declined in 24 of 27 lesions (mean 26% (range -77 to 7%)). The Ki-67 index declined in both studies, from pre-therapy (mean 23% (range 1 to 73%)) to surgery [mean 8% (range < 1 to 41%)]. Pre- and post-therapy PET measures showed strong rank-order agreement with Ki-67 percentages for both tracers; however, the percent change in FDG or FLT SUVmax did not demonstrate a strong correlation with Ki-67 index change or Ki-67 at time of surgery. CONCLUSIONS: A window-of-opportunity approach using PET imaging to assess early response of breast cancer therapy is feasible. FDG and FLT-PET imaging following a short course of neoadjuvant endocrine therapy demonstrated measurable changes in SUVmax in early stage ER+ positive breast cancers. The percentage change in FDG and FLT-PET uptake did not correlate with changes in Ki-67; post-therapy SUVmax for both tracers was significantly associated with post-therapy Ki-67, an established predictor of endocrine therapy response.

• MeSH
• antigen Ki-67 metabolismus   MeSH
• dideoxynukleosidy terapeutické užití   MeSH
• dospělí MeSH
• fluorodeoxyglukosa F18 terapeutické užití   MeSH
• inhibitory aromatasy terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mastektomie MeSH
• nádorové biomarkery metabolismus   MeSH
• nádory prsu diagnostické zobrazování   farmakoterapie   metabolismus   chirurgie   MeSH
• neoadjuvantní terapie MeSH
• pozitronová emisní tomografie MeSH
• radiofarmaka terapeutické užití   MeSH
• receptory pro estrogeny metabolismus   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• výsledek terapie 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
• Research Support, N.I.H., Extramural MeSH

Fibrates belong to a group of ligands of peroxisome proliferator-activated receptor alpha (PPARα), which play a role in the regulation of CYP epoxygenases and soluble epoxide hydrolase (sEH), key enzymes in the metabolism of biologically highly active epoxyeicosatrienoic acids (EETs). We demonstrated that low doses of fibrates stimulate proliferation of the MCF7 cell line, while high doses suppress it. The increase in cell proliferation was accompanied by an increase in CYP epoxygenases and decrease in sEH levels. The overall level of PPARα remained same after low-dose fibrate stimulation; however, there was a significant shift of the receptor to the cell nucleus. PPARα expression was further demonstrated by immunohistochemistry in both carcinoma and healthy breast tissue samples both in the cytoplasm and in the nuclei. We have also observed higher nuclear PPARα positivity in tumor tissues. Although our results obtained for MCF7 cells suggest the potential role of PPARα in cell proliferation, we did not find an association between nuclear localization of PPARα and the expression of proliferation marker Ki-67 in tumor tissues. The exact role of PPARα in carcinogenesis still remains unclear.

• MeSH
• antigen Ki-67 metabolismus   MeSH
• deriváty kyseliny fibrové farmakologie   MeSH
• epoxid hydrolasy metabolismus   MeSH
• geny erbB-2 * MeSH
• inhibiční koncentrace 50 MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• nádory prsu metabolismus   patologie   MeSH
• PPAR alfa metabolismus   MeSH
• proliferace buněk účinky léků   MeSH
• pyrimidiny farmakologie   MeSH
• receptory pro estrogeny metabolismus   MeSH
• receptory progesteronu metabolismus   MeSH
• rozpustnost MeSH
• subcelulární frakce metabolismus   MeSH
• systém (enzymů) cytochromů P-450 metabolismus   MeSH
• transport proteinů účinky léků   MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

INTRODUCTION: Many widely used international histological textbooks claim that the epithelium of the human uterine tube consists of two, three, and, eventually, four types of cells. Most discrepancies among these textbooks relate to debates regarding the presence or absence of basal cells, whether the peg/intercalary cells and secretory cells are the same or distinct cell populations, and if the epithelium contains a population of immunologically active cells (T- and B-lymphocytes, NK cells, macrophages and dendritic cells) or dispersed endocrine cells. METHODS: Uterine tubes were obtained from 22 women (average age: 46.73 y) undergoing gynecological surgery. The women were in fertile age, mostly in the middle of the menstrual cycle (ovulation phase). Tissue samples were processed for immunohistochemistry using primary antibodies against proliferation markers (Ki67 and PCNA), immune system cells (CD1a, CD3, CD4, CD8, CD20, CD45RO, CD56, CD68, granzyme B and S100) and disperse endocrine cells (chromogranin A and synaptophysin). RESULTS: Most of the mature tubal epithelial cells, ciliated cells, and secretory cells were mitotically active (PCNA+), a population of basal undifferentiated cells was not identified. The dividing cells had a narrow-shaped nucleus (Ki67 positive). These cells were morphologically identical to - by the terminology mentioned - intercalary cells, assuming they represented actually dividing cells (epitheliocytus tubarius mitoticus). The tubal "basal cells" displayed small, hyperchromatic nuclei and very pale cytoplasm (clear cytoplasmic halo). They were located in the epithelium adjacent to the basement membrane, were non-mitotically active and their immunophenotype corresponded to intraepithelial regulatory T-lymphocytes (CD3+, CD8+, CD45RO+, CD4-, CD20-, CD56- and granzyme B-). Intraepithelial B-lymphocytes were only rarely identified. Intraepithelial NK cells, dendritic cells, macrophages and dispersed endocrine cells were not identified. CONCLUSIONS: We recommend replacing the term "epitheliocytus tubarius basalis" in the Terminologia Histologica with the term "lymphocytus T intraepithelialis tubarius", which represents intraepithelial regulatory T-cells (CD8+, CD45RO+) of the uterine tube. Additionally, we propose that intercalary/peg cells are actively dividing cells, instead of effete or degenerating cells. Finally, the histological nomenclature should be corrected in a way that peg/intercalary cells are not considered synonymous terms for secretory cells.

• MeSH
• antigen Ki-67 metabolismus   MeSH
• CD antigeny analýza   MeSH
• dospělí MeSH
• epitelové buňky klasifikace   imunologie   MeSH
• imunohistochemie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mitóza MeSH
• proliferace buněk MeSH
• proliferační antigen buněčného jádra metabolismus   MeSH
• vejcovody anatomie a histologie   cytologie   imunologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

AIMS: Immunohistochemical analysis of retraction pocket pars tensa of tympanic membrane in children. Identification of signs typical for cholesteatoma and support of retraction theory of cholesteatoma. STUDY DESIGN: a prospective study analysing 31 surgically removed retraction pockets. DEPARTMENT: University Hospital, Children's Medical Centre Methods: Retraction pockets processed by a standard process for immunohistochemical analysis. The observed findings were specified using antibodies CD45 LCA (leukocyte common antigen), CD31 (platelet endothelial cell adhesion molecule), D2-40 (marker of lymphatic endothelium), MMP9 (marker of degradation of connective tissue extracellular matrix) and Ki67 (cellular marker of proliferation). RESULTS: All observed parameters except for MMP9 had a significantly higher incidence in retraction pocket stage III compared to stage II according to Charachon. CONCLUSION: We described immunohistochemical signs of retraction pocket pars tensa of tympanic membrane in children resulting in cholesteatoma. All the observed signs occur in the structure of matrix and perimatrix of cholesteatoma. A significantly higher incidence of all observed parameters except from MMP9 was proved in retraction pocket stage III, unlike in stage II. This observation proves the fact that retraction pocket is a progressive disease and is a procholesteatoma stage.

• MeSH
• antigen Ki-67 metabolismus   MeSH
• antigeny CD31 metabolismus   MeSH
• antigeny CD45 metabolismus   MeSH
• biologické markery metabolismus   MeSH
• cholesteatom středního ucha metabolismus   MeSH
• dítě MeSH
• imunohistochemie MeSH
• lidé MeSH
• matrixová metaloproteinasa 9 metabolismus   MeSH
• membrana tympani metabolismus   MeSH
• prospektivní studie MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The fetus is thought to be protected from exposure to foreign antigens, yet CD45RO+ T cells reside in the fetal intestine. Here we combined functional assays with mass cytometry, single-cell RNA sequencing and high-throughput T cell antigen receptor (TCR) sequencing to characterize the CD4+ T cell compartment in the human fetal intestine. We identified 22 CD4+ T cell clusters, including naive-like, regulatory-like and memory-like subpopulations, which were confirmed and further characterized at the transcriptional level. Memory-like CD4+ T cells had high expression of Ki-67, indicative of cell division, and CD5, a surrogate marker of TCR avidity, and produced the cytokines IFN-γ and IL-2. Pathway analysis revealed a differentiation trajectory associated with cellular activation and proinflammatory effector functions, and TCR repertoire analysis indicated clonal expansions, distinct repertoire characteristics and interconnections between subpopulations of memory-like CD4+ T cells. Imaging mass cytometry indicated that memory-like CD4+ T cells colocalized with antigen-presenting cells. Collectively, these results provide evidence for the generation of memory-like CD4+ T cells in the human fetal intestine that is consistent with exposure to foreign antigens.

• MeSH
• antigen Ki-67 genetika   imunologie   metabolismus   MeSH
• antigen prezentující buňky cytologie   imunologie   metabolismus   MeSH
• antigeny CD5 genetika   imunologie   metabolismus   MeSH
• CD4-pozitivní T-lymfocyty cytologie   imunologie   metabolismus   MeSH
• imunofenotypizace MeSH
• imunologická paměť genetika   imunologie   MeSH
• kultivované buňky MeSH
• lidé MeSH
• plod cytologie   imunologie   metabolismus   MeSH
• průtoková cytometrie MeSH
• stanovení celkové genové exprese metody   MeSH
• střeva cytologie   embryologie   imunologie   MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• vývojová regulace genové exprese imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Oncogenic microRNAs (oncomiRs) accumulate in serum due to their increased stability and thus serve as biomarkers in breast cancer (BC) pathogenesis. Four oncogenic microRNAs (miR-155, miR-19a, miR-181b, and miR-24) and one tumor suppressor microRNA (let-7a) were shown to differentiate between high- and low-risk early breast cancer (EBC) and reflect the surgical tumor removal and adjuvant therapy. Here we applied the longitudinal multivariate data analyses to stochastically model the serum levels of each of the oncomiRs using the RT-PCR measurements in the EBC patients (N = 133) that were followed up 4 years after diagnosis. This study identifies that two of the studied oncomiRs, miR-155 and miR-24, are highly predictive of EBC relapse. Furthermore, combining the oncomiR level with Ki-67 expression further specifies the relapse probability. Our data move further the notion that oncomiRs in serum enable not only monitoring of EBC but also are a very useful tool for predicting relapse independently of any other currently analyzed characteristics in EBC patients. Our approach can be translated into medical practice to estimate individual relapse risk of EBC patients.

• MeSH
• antigen Ki-67 metabolismus   MeSH
• časové faktory MeSH
• dospělí MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokální recidiva nádoru diagnóza   genetika   MeSH
• longitudinální studie MeSH
• mikro RNA krev   genetika   MeSH
• multivariační analýza MeSH
• nádorové biomarkery krev   genetika   MeSH
• nádory prsu genetika   MeSH
• senioři nad 80 let MeSH
• senioři 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

• MeSH
• antigen Ki-67 metabolismus   MeSH
• dítě MeSH
• dospělí MeSH
• ependymom metabolismus   patologie   MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• messenger RNA metabolismus   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádory centrálního nervového systému metabolismus   patologie   MeSH
• předškolní dítě MeSH
• ROC křivka MeSH
• senioři MeSH
• transkripční faktory SOXE genetika   metabolismus   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• úvodníky MeSH

It is supposed that plant functional foods, rich in phytochemicals, may potentially have preventive effects in carcinogenesis. In this study, the anticancer effects of cloves in the in vivo and in vitro mammary carcinoma model were assessed. Dried flower buds of cloves (CLOs) were used at two concentrations of 0.1% and 1% through diet during 13 weeks after the application of chemocarcinogen. After autopsy, histopathological and immunohistochemical analyses of rat mammary carcinomas were performed. Moreover, in vitro evaluation using MCF-7 cells was carried out. Dietary administered CLO caused the dose-dependent decrease in tumour frequency by 47.5% and 58.5% when compared to control. Analysis of carcinoma cells in animals showed bcl-2, Ki67, VEGFA, CD24 and CD44 expression decrease and Bax, caspase-3 and ALDH1 expression increase after high-dose CLO administration. MDA levels were substantially decreased in rat carcinomas in both CLO groups. The evaluation of histone modifications revealed increase in lysine trimethylations and acetylations (H4K20me3, H4K16ac) in carcinomas after CLO administration. TIMP3 promoter methylation levels of CpG3, CpG4, CpG5 islands were altered in treated cancer cells. An increase in total RASSF1A promoter methylation (three CpG sites) in CLO 1 group was found. In vitro studies showed antiproliferative and pro-apoptotic effects of CLO extract in MCF-7 cells (analyses of cytotoxicity, Brdu, cell cycle, annexin V/PI, caspase-7, Bcl-2 and mitochondrial membrane potential). This study showed a significant anticancer effect of clove buds in the mammary carcinoma model in vivo and in vitro.

• MeSH
• adenokarcinom dietoterapie   genetika   metabolismus   patologie   MeSH
• antigen Ki-67 genetika   metabolismus   MeSH
• antitumorózní látky fytogenní izolace a purifikace   farmakologie   MeSH
• epigeneze genetická účinky léků   MeSH
• experimentální nádory mléčných žláz dietoterapie   genetika   metabolismus   patologie   MeSH
• histony genetika   metabolismus   MeSH
• kaspasa 3 genetika   metabolismus   MeSH
• krysa rodu rattus MeSH
• květy chemie   MeSH
• lidé MeSH
• membránový potenciál mitochondrií účinky léků   MeSH
• metylace DNA účinky léků   MeSH
• MFC-7 buňky MeSH
• nádorové supresorové proteiny genetika   metabolismus   MeSH
• nádory prsu dietoterapie   genetika   metabolismus   patologie   MeSH
• potkani Sprague-Dawley MeSH
• protein X asociovaný s bcl-2 genetika   metabolismus   MeSH
• protoonkogenní proteiny c-bcl-2 genetika   metabolismus   MeSH
• retinaldehydrogenasa genetika   metabolismus   MeSH
• rostlinné extrakty chemie   MeSH
• signální transdukce MeSH
• Syzygium chemie   MeSH
• tumor burden účinky léků   MeSH
• vaskulární endoteliální růstový faktor A genetika   metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The capability of lymphocytes to respond to antigenic or mitogenic stimulation is an important feature in the diagnosis of various immunodeficiencies and immune disorders. We used large cohorts of both immune compromised patients and healthy controls to measure lymphocyte proliferations by means of three methods: CFSE staining, Ki-67 expression and (3)H-thymidine incorporation. The advantages and disadvantages of each method was then evaluated for use in routine clinical diagnostic. The statistical analysis was performed between the outcomes and the correlation between all three methods was computed. CFSE and Ki-67 assay correlated well with the r=0.767, correlation between Ki-67 expression and (3)H-thymidine incorporation was 0.546 and correlation between CFSE staining and (3)H-thymidine incorporation was 0.337. The differences between these three methods concerning complexity, sensitivity and reliability as well as the financial aspects are discussed hereafter. CFSE and its analogues provide the cheapest and reasonable choice for measuring lymphocyte proliferation, while Ki-67 represents a more expensive, but more sensitive and robust method. The original (3)H-thymidine assay does not bring any advantages and cannot compare to the competition presented by modern flow cytometric methods available today.

• MeSH
• aktivace lymfocytů MeSH
• antigen Ki-67 metabolismus   MeSH
• fluoresceiny MeSH
• hostitel s imunodeficiencí * MeSH
• imunoanalýza metody   MeSH
• kohortové studie MeSH
• kultivované buňky MeSH
• lidé MeSH
• lymfocyty imunologie   MeSH
• monitorování imunologické MeSH
• proliferace buněk MeSH
• průtoková cytometrie MeSH
• reprodukovatelnost výsledků MeSH
• senzitivita a specificita MeSH
• sukcinimidy MeSH
• thymidin MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH