• MeSH
• antitumorózní látky terapeutické užití   MeSH
• lidé MeSH
• metastázy nádorů MeSH
• nádory prostaty * farmakoterapie   MeSH
• radiofarmaka * terapeutické užití   MeSH
• vyvíjení léků trendy   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• rozhovory MeSH

Publikace se zaměřuje na zdravý spánkový režim a na různé spánkové poruchy. Určeno široké veřejnosti.

• MeSH
• poruchy spánku a bdění MeSH
• spánek MeSH
• zdraví MeSH
• životní styl MeSH
• Publikační typ
• monografie MeSH
• populární práce MeSH

• Konspekt
• Zdraví a hygiena volného času, rekreace a spánku
• NLK Obory
• psychologie, klinická psychologie

In recent years, a number of drugs targeting the prostate-specific membrane antigen (PSMA) have become important tools in the diagnosis and treatment of prostate cancer. In the present work, we report on the synthesis and preclinical evaluation of a series of 18F-labeled PSMA ligands for diagnostic application based on the theragnostic ligand PSMA-617. By applying modifications to the linker structure, insight into the structure-activity relationship could be gained, highlighting the importance of hydrophilicity and stereoselectivity on interaction with PSMA and hence the biodistribution. Selected compounds were co-crystallized with the PSMA protein and analyzed by X-rays with mixed results. Among these, PSMA-1007 (compound 5) showed the best interaction with the PSMA protein. The respective radiotracer [18F]PSMA-1007 was translated into the clinic and is, in the meantime, subject of advanced clinical trials.

• MeSH
• antigeny povrchové MeSH
• glutamátkarboxypeptidasa II antagonisté a inhibitory   MeSH
• lidé MeSH
• ligandy MeSH
• nádory prostaty diagnostické zobrazování   MeSH
• niacinamid analogy a deriváty   chemie   farmakologie   MeSH
• oligopeptidy chemie   farmakologie   MeSH
• pozitronová emisní tomografie MeSH
• radiofarmaka farmakologie   MeSH
• radioizotopy fluoru chemie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

In recent years, several radioligands targeting prostate-specific membrane antigen (PSMA) have been clinically introduced as a new class of theranostic radiopharmaceuticals for the treatment of prostate cancer (PC). In the second decade of the 21(st) century, a new era in nuclear medicine was initiated by the clinical introduction of small-molecule PSMA inhibitor radioligands, 40 y after the clinical introduction of (18)F-FDG. Because of the high incidence and mortality of PC, the new PSMA radioligands have already had a remarkable impact on the clinical management of PC. For the continuing clinical development and long-term success of theranostic agents, designing modern prospective clinical trials in theranostic nuclear medicine is essential. First-in-human studies with PSMA radioligands derived from small-molecule PSMA inhibitors showed highly sensitive imaging of PSMA-positive PC by means of PET and SPECT as well as a dramatic response of metastatic castration-resistant PC after PSMA radioligand therapy. This tremendous success logically led to the initiation of prospective clinical trials with several PSMA radioligands. Meanwhile, MIP-1404, PSMA-11, 2-(3-{1-carboxy-5-[(6-fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (DCFPyL), PSMA-617, PSMA-1007, and others have entered or will enter prospective clinical trials soon in several countries. The significance becomes apparent by, for example, the considerable increase in the number of publications about PSMA-targeted PET imaging from 2013 to 2016 (e.g., a search of the Web of Science for "PSMA" AND "PET" found only 19 publications in 2013 but 218 in 2016). Closer examination of the initial success of PC treatment with PSMA inhibitor radiotracers leads to several questions from the basic research perspective as well as from the perspective of clinical demands: What lessons have been learned regarding the design of PSMA radioligands that have already been developed? Has an acceptable compromise between optimal PSMA radioligand design and a broad range of clinical demands been reached? Can the lessons learned from multiple successes within the PSMA experience be transferred to further theranostic approaches?

• MeSH
• antigeny povrchové MeSH
• diagnóza * MeSH
• glutamátkarboxypeptidasa II antagonisté a inhibitory   MeSH
• lidé MeSH
• močovina chemie   farmakologie   terapeutické užití   MeSH
• molekulová hmotnost MeSH
• objevování léků metody   MeSH
• radioaktivní indikátory MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Germ cell tumors and particularly seminomas reflect the epigenomic features of their parental primordial germ cells (PGCs), including genomic DNA hypomethylation and expression of pluripotent cell markers. Because the DNA hypomethylation might be a result of TET dioxygenase activity, we examined expression of TET1-3 enzymes and the level of their product, 5-hydroxymethylcytosine (5hmC), in a panel of histologically characterized seminomas and non-seminomatous germ cell tumors. Expression of TET dioxygenase mRNAs was quantified by real-time PCR. TET1 expression and the level of 5hmC were examined immunohistochemically. Quantitative assessment of 5-methylcytosine (5mC) and 5hmC levels was done by the liquid chromatography-mass spectroscopy technique. We found highly increased expression of TET1 dioxygenase in most seminomas and strong TET1 staining in seminoma cells. Isocitrate dehydrogenase 1 and 2 mutations were not detected, suggesting the enzymatic activity of TET1. The levels of 5mC and 5hmC in seminomas were found decreased in comparison to non-seminomatous germ cell tumors and healthy testicular tissue. We propose that TET1 expression should be studied as a potential marker of seminomas and mixed germ cell tumors and we suggest that elevated expression of TET dioxygenase enzymes is associated with the maintenance of low DNA methylation levels in seminomas. This "anti-methylator" phenotype of seminomas is in contrast to the CpG island methylator phenotype (CIMP) observed in a fraction of tumors of various types.

• MeSH
• 5-methylcytosin analogy a deriváty   analýza   MeSH
• dioxygenasy analýza   genetika   MeSH
• DNA vazebné proteiny analýza   genetika   MeSH
• dospělí MeSH
• lidé MeSH
• metylace DNA * MeSH
• oxygenasy se smíšenou funkcí analýza   genetika   MeSH
• protoonkogenní proteiny analýza   genetika   MeSH
• regulace genové exprese u nádorů MeSH
• seminom genetika   patologie   MeSH
• testikulární nádory genetika   patologie   MeSH
• testis metabolismus   patologie   MeSH
• upregulace MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Syncytin-1 and 2, human fusogenic glycoproteins encoded by the env genes of the endogenous retroviral loci ERVWE1 and ERVFRDE1, respectively, contribute to the differentiation of multinucleated syncytiotrophoblast in chorionic villi. In non-trophoblastic cells, however, the expression of syncytins has to be suppressed to avoid potential pathogenic effects. Previously, we have shown that the transcriptional suppression of ERVWE1 promoter is controlled epigenetically by DNA methylation and chromatin modifications. In this study, we describe the aberrant expression of syncytin-1 in biopsies of testicular germ cell tumors. RESULTS: We found efficient expression and splicing of syncytin-1 in seminomas and mixed germ cell tumors with seminoma component. Although another fusogenic gene, syncytin-2 was also derepressed in seminomas, its expression was significantly lower than that of syncytin-1. Neither the transcription factor GCM1 nor the increased copy number of ERVWE1 were sufficient for this aberrant expression of syncytin-1 in seminomas. In accordance with our recent finding of the highly increased expression of TET1 dioxygenase in most seminomas, the ERVWE1 promoter was significantly hypomethylated in comparison with the matched controls. In contrast, 5-hydroxymethylcytosine levels were not detectable at the ERVWE1 promoter. We further describe that another endogenous retroviral element adjacent to ERVWE1 remains transcriptionally suppressed and two additional HERV-W family members are only slightly upregulated in seminomas. CONCLUSIONS: We conclude that DNA demethylation of the ERVWE1 promoter in seminomas is a prerequisite for syncytin-1 derepression. We propose the spliced syncytin-1 expression as a marker of seminoma and suggest that aberrant expression of endogenous retroviruses might be a correlate of the hypomethylated genome of seminomas.

• MeSH
• DNA virů metabolismus   MeSH
• endogenní retroviry genetika   MeSH
• epigeneze genetická MeSH
• genové produkty env biosyntéza   MeSH
• lidé MeSH
• metylace DNA MeSH
• regulace genové exprese * MeSH
• seminom patologie   virologie   MeSH
• těhotenské proteiny biosyntéza   MeSH
• testikulární nádory patologie   virologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

We will examine the gene expression of syncytin-1 and 2 at the level of mRNA in tumors of the male germ line, particularly seminomas, mixed germinal carcinomas, and choriocarcinomas. This will be correlated with the tumor histology, mainly with the representation of of multinuclear giant cells. Expression of syncytins will be assessed as to their predictive and diagnostic value for the clinics. Furthermore, we will follow the splicing of syncytin mRNAs using the PCR with splice-specific primers localized in exons and introns. Using the bisulfite technique, we will describe the patterns of CpG methylation of syncytin promoters and LTRs in aforementioned tumors. In the cell lines derived from respective germ line tumors, we will examine histone modifications and other epigenomic features of syncytin loci using the chromatin immunoprecipitation.

Bude stanovena genová exprese syncytinu-1 a 2 na úrovni mRNA v nádorech mužské germinální linie, zejména seminomech, smíšených germinálních karcinomech a choriokarcinomech. Bude sledována korelace s histologickým obrazem nádorů, hlavně s přítomností mnohojaderných obřích buněk. Exprese syncytinů bude posouzena co do prediktivního a diagnostického významu pro klinickou praxi. Dále budeme sledovat sestřih syncytinové mRNA pomocí PCR se specifickými primery umístěnými v intronech nebo exonech. Pomocí bisulfitové reakce popíšeme rovněž pattern CpG methylace syncytinového promotoru a LTR. Na buněčných liniích odvozených od příslušných nádorů germinální linie budeme sledovat pomocí chromatinové imunoprecipitace histonové modifikace a další epigentické parametry syncytinových lokusů.

• MeSH
• choriokarcinom MeSH
• chromatinová imunoprecipitace MeSH
• exony MeSH
• exprese genu MeSH
• genové produkty env MeSH
• germinální a embryonální nádory MeSH
• histony MeSH
• mikro RNA analýza   MeSH
• polymerázová řetězová reakce MeSH
• Retroviridae - proteiny onkogenní MeSH
• seminom MeSH

• Konspekt
• Biochemie. Molekulární biologie. Biofyzika
• NLK Obory
• molekulární biologie, molekulární medicína
• andrologie
• onkologie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu IGA MZ ČR

Mammalian TLRs in adult animals serve indispensable functions in establishing innate and adaptive immunity and contributing to the homeostasis of surrounding tissues. However, the expression and function of TLRs during mammalian embryonic development has not been studied so far. Here, we show that CD45(+) CD11b(+) F4/80(+) macrophages from 10.5-day embryo (E10.5) co-express TLRs and CD14. These macrophages, which have the capability to engulf both apoptotic cells and bacteria, secrete a broad spectrum of proinflammatory cytokines and chemokines upon TLR stimulation, demonstrating that their TLRs are functional. Comparative microarray analysis revealed an additional set of genes that were significantly upregulated in E10.5 TLR2(+) CD11b(+) macrophages. This analysis, together with our genetic, microscopic, and biochemical evidence, showed that embryonic phagocytes express protein machinery that is essential for the recycling of cellular iron and that this expression can be regulated by TLR engagement in a MyD88-dependent manner, leading to typical inflammatory M1 responses. These results characterize the utility of TLRs as suitable markers for early embryonic phagocytes as well as molecular triggers of cellular responses, the latter being demonstrated by the involvement of TLRs in an inflammation-mediated regulation of embryonic homeostasis via iron metabolism.

• MeSH
• diferenciační antigeny genetika   imunologie   metabolismus   MeSH
• embryo savčí cytologie   imunologie   metabolismus   MeSH
• makrofágy cytologie   imunologie   metabolismus   MeSH
• myši knockoutované MeSH
• myši MeSH
• protein MyD88 genetika   imunologie   metabolismus   MeSH
• signální transdukce fyziologie   MeSH
• toll-like receptor 2 genetika   imunologie   metabolismus   MeSH
• vývojová regulace genové exprese genetika   imunologie   MeSH
• zánět genetika   imunologie   MeSH
• železo imunologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Francisella tularensis is a highly infectious intracellular pathogen that has evolved an efficient strategy to subvert host defense response to survive inside the host. The molecular mechanisms regulating these host-pathogen interactions and especially those that are initiated at the time of the bacterial entry via its attachment to the host plasma membrane likely predetermine the intracellular fate of pathogen. Here, we provide the evidence that infection of macrophages with F. tularensis leads to changes in protein composition of macrophage-derived lipid rafts, isolated as detergent-resistant membranes (DRMs). Using SILAC-based quantitative proteomic approach, we observed the accumulation of autophagic adaptor protein p62 at the early stages of microbe-host cell interaction. We confirmed the colocalization of the p62 with ubiquitinated and LC3-decorated intracellular F. tularensis microbes with its maximum at 1 h postinfection. Furthermore, the infection of p62-knockdown host cells led to the transient increase in the intracellular number of microbes up to 4 h after in vitro infection. Together, these data suggest that the activation of the autophagy pathway in F. tularensis infected macrophages, which impacts the early phase of microbial proliferation, is subsequently circumvented by ongoing infection.

• MeSH
• autofagie * MeSH
• buněčné linie MeSH
• membránové mikrodomény chemie   metabolismus   MeSH
• molekulární sekvence - údaje MeSH
• myši MeSH
• proteomika * MeSH
• sekvence aminokyselin MeSH
• tularemie metabolismus   MeSH
• western blotting MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• Publikační typ
• abstrakt z konference MeSH