- 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
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
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
Type 1 diabetes (T1D) is an autoimmune disease caused by T-cell mediated destruction of pancreatic beta cells. Recently, small cationic α-defensin molecules have been implicated in the pathogenesis of certain inflammatory and autoimmune diseases. The purpose of this study was to assess the α-defensin expression in patients with T1D and elucidate the cellular source of their production. Our results show that 30% of patients exhibit increased levels of α-defensin mRNAs in their capillary blood. Quantitative RT-PCR performed on FACS-sorted granulocytes identified CD15(dull)/CD14(weak) population as the cellular source of α-defensins. Surprisingly, this granulocyte subpopulation displayed augmentation of α-defensin expression in all T1D patients tested. The determination of cell surface markers, expression of cell-specific genes and confocal microscopy identified CD15(dull)/CD14(weak) cells as eosinophils. The presence of transcriptionally active eosinophils in diabetic patients suggests that eosinophils could be a part of an intricate innate immune cellular network involved in the development of diabetes.
- MeSH
- alfa-defensiny krev genetika imunologie MeSH
- antigen Lewis X imunologie MeSH
- antigeny CD14 imunologie MeSH
- autoimunita MeSH
- beta-buňky imunologie metabolismus patologie MeSH
- diabetes mellitus 1. typu krev genetika imunologie MeSH
- dítě MeSH
- dospělí MeSH
- eozinofily imunologie metabolismus patologie MeSH
- exprese genu MeSH
- imunologická tolerance MeSH
- lidé MeSH
- messenger RNA biosyntéza MeSH
- mladiství MeSH
- peroxidasa krev genetika imunologie MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- předškolní dítě MeSH
- přirozená imunita MeSH
- průtoková cytometrie MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- předškolní dítě MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Tato pilotní studie se zabývá problematikou možného terapeutického využití konceptu proprioceptivní neuromuskulární facilitace (PNF) u pacientů s Desaultovou fixací ramenního kloubu. Na sledované skupině 7 zdravých osob byla pomocí povrchové elektromyografie snímána elektrická aktivita musculus trapezius pars descendens, pars transversa et pars ascendens, musculus deltoideus pars acromialis, musculus infraspinatus a musculus pectoralis major pars sternocostalis levé, imobilizované končetiny, při provedení PNF vzorců na periferii imobilizované končetiny a na kontralaterální končetině. V průběhu jednotlivých vzorců byl vyhodnocen 5s úsek ustálené izometrické kontrakce. Následně byla data normalizována a vzájemně porovnávána. S ohledem na literaturu jsme definovali hodnotu nad 20 % maximální volní kontrakce (MVC) příslušného svalu za dostačující k zajištění funkční kapacity motorických jednotek daného svalu, a tím zabránění rozvoje svalových atrofií imobilizované končetiny. S výjimkou m. trapezius pars transversa dosahuje elektrická aktivita měřených svalů vyšších hodnot prováděním PNF vzorců na periferii fixované končetiny.
This pilot study deals with the problems of possible therapeutic application of the concept of proprioceptive neuromuscular facilitation (PNF) in patients with Desault fixation of shoulder joint. In the observed group of 7 healthy subjects the authors scanned electric activity of musculus trapezius pars descendens, pars transversa et pars ascendens, musculus deltoideus pars acromialis, musculus infraspinatus and musculus pectoralis major pars sternocostalis of the left immobilized extremity, in performing PNF formulae on the periphery of the immobilized extremity and on the contralateral extremity. In the course of the individual formulae the authors evaluated 5s segment of stabilized isometric contraction. The data were subsequently normalized and mutually compared. In view of the results in literature we defined the value above 20% of maximal intentional contraction (MVC) of the relevant muscle as sufficient for securing functional capacity of motoric units of the given muscle and therefore to prevent muscular atrophies of the immobilized extremity. With the exception of m. trapezius pars transversa the electric activity of the measured muscles reached higher values while performing PNF formulae on the periphery of the fixed extremity.
- Klíčová slova
- PNF, povrchová elektromyografie,
- MeSH
- elektromyografie MeSH
- financování organizované MeSH
- horní končetina zranění MeSH
- interpretace statistických dat MeSH
- klouby zranění MeSH
- lidé MeSH
- metody MeSH
- nemoci kloubů rehabilitace MeSH
- nestabilita kloubu rehabilitace MeSH
- obvazy využití MeSH
- poranění ramene MeSH
- rameno MeSH
- statistika jako téma MeSH
- svalová kontrakce MeSH
- výsledek terapie MeSH
- výsledky a postupy - zhodnocení (zdravotní péče) MeSH
- Check Tag
- lidé MeSH
