BACKGROUND: Molecular aberrations occurring in primary ovarian clear cell carcinoma (OCCC) can be of diagnostic, predictive, and prognostic significance. However, a complex molecular study including genomic and transcriptomic analysis of large number of OCCC has been lacking. METHODS: 113 pathologically confirmed primary OCCCs were analyzed using capture DNA NGS (100 cases; 727 solid cancer related genes) and RNA-Seq (105 cases; 147 genes) in order to describe spectra and frequency of genomic and transcriptomic alterations, as well as their prognostic and predictive significance. RESULTS: The most frequent mutations were detected in genes ARID1A, PIK3CA, TERTp, KRAS, TP53, ATM, PPP2R1A, NF1, PTEN, and POLE (51,47,27,18,13,10,7,6,6, and 4%, respectively). TMB-High cases were detected in 9% of cases. Cases with POLEmut and/or MSI-High had better relapse-free survival. RNA-Seq revealed gene fusions in 14/105 (13%) cases, and heterogeneous expression pattern. The majority of gene fusions affected tyrosine kinase receptors (6/14; four of those were MET fusions) or DNA repair genes (2/14). Based on the mRNA expression pattern, a cluster of 12 OCCCs characterized by overexpression of tyrosine kinase receptors (TKRs) AKT3, CTNNB1, DDR2, JAK2, KIT, or PDGFRA (p < 0.00001) was identified. CONCLUSIONS: The current work has elucidated the complex genomic and transcriptomic molecular hallmarks of primary OCCCs. Our results confirmed the favorable outcomes of POLEmut and MSI-High OCCC. Moreover, the molecular landscape of OCCC revealed several potential therapeutical targets. Molecular testing can provide the potential for targeted therapy in patients with recurrent or metastatic tumors.

• MeSH
• adenokarcinom z jasných buněk * genetika   MeSH
• fúze genů MeSH
• genomika MeSH
• lidé MeSH
• lokální recidiva nádoru * MeSH
• stanovení celkové genové exprese MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Anorexia nervosa (AN), a pathological restriction of food intake, leads to metabolic dysregulation. We conducted a metabolomics study to reveal changes caused by AN and the effect of hospital realimentation on metabolism. Both stool and serum from patients with AN and healthy controls were analyzed by NMR and MS. Statistical analysis revealed several altered biochemical and anthropometric parameters and 50 changed metabolites, including phospholipids, acylcarnitines, amino acids, derivatives of nicotinic acid, nucleotides, and energy metabolism intermediates. Biochemical and anthropometric parameters were correlated with metabolomic data. Metabolic changes in patients with AN described in our study imply serious system disruption defects, such as the development of inflammation and oxidative stress, changed free thyroxine (fT4) and thyroid-stimulating hormone (TSH) levels, a deficit of vitamins, muscle mass breakdown, and a decrease in ketone bodies as an important source of energy for the brain and heart. Furthermore, our data indicate only a very slight improvement after treatment. However, correlations of metabolomic results with body weight, interleukin 6, tumor necrosis factor α, fT4, and TSH might entail better prognoses and treatment effectiveness in patients with better system parameter status. Data sets are deposited in MassIVE: MSV000087713, DOI: 10.25345/C57R7X.

• MeSH
• hormony štítné žlázy MeSH
• lidé MeSH
• magnetická rezonanční spektroskopie MeSH
• mentální anorexie * metabolismus   terapie   MeSH
• metabolomika metody   MeSH
• thyreotropin MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The massive production and use of silver nanoparticles (Ag NPs) have led to their increasing release into the environment. Even though the antimicrobial and cytotoxic effects of native nanoparticles have been well studied, the environmental impacts of transformation products such as silver sulfide nanoparticles (Ag2S NPs) have not been elucidated. In the present study, we assessed the toxicity of Ag2S NPs and silver nitrate (AgNO3), as a source of Ag, to the earthworm Eisenia andrei using a nominal concentration of 5 mg Ag kg-1 soil. We used the OECD guidelines to assess effects on weight loss and mortality for 14 days. After exposure, we also extracted the immune effector cells (coelomocytes) and conducted a battery of biomarker tests. To ensure the quality of the toxicological results, the structural changes of NPs during the experiment and the uptake of silver by the earthworms were monitored. During the experiment, mortality effects were not detected, but a weight loss was observed in the earthworms exposed to Ag2S NPs. Altough Ag2S NPs were engulfed by E. andrei cells, neither phenoloxidase activity nor lipid peroxidation differed from the untreated control group. Cells from earthworms treated with Ag2S NPs exerted very broad value range of nitric oxide (NO) generation, suggesting an imbalance in the NO metabolism. Overall, this study suggests minimal risks associated with Ag2S NPs exposure to earthworms. However, further studies are needed to assure no immunotoxicological or chronic effects on a wider range of terrestrial organisms.

• MeSH
• dusičnan stříbrný toxicita   MeSH
• hmotnostní úbytek MeSH
• kovové nanočástice * chemie   toxicita   MeSH
• látky znečišťující půdu * toxicita   MeSH
• Oligochaeta * MeSH
• půda chemie   MeSH
• sloučeniny stříbra MeSH
• stříbro metabolismus   toxicita   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Mucosal surfaces are colonized by highly diverse commensal microbiota. Coating with secretory IgA (SIgA) promotes the survival of commensal bacteria while it inhibits the invasion by pathogens. Bacterial coating could be mediated by antigen-specific SIgA recognition, polyreactivity, and/or by the SIgA-associated glycans. In contrast to many in vitro studies, only a few reported the effect of SIgA glycans in vivo. Here, we used a germ-free antibody-free newborn piglets model to compare the protective effect of SIgA, SIgA with enzymatically removed N-glycans, Fab, and Fc containing the secretory component (Fc-SC) during oral necrotoxigenic E. coli O55 challenge. SIgA, Fab, and Fc-SC were protective, whereas removal of N-glycans from SIgA reduced SIgA-mediated protection as demonstrated by piglets' intestinal histology, clinical status, and survival. In vitro analyses indicated that deglycosylation of SIgA did not reduce agglutination of E. coli O55. These findings highlight the role of SIgA-associated N-glycans in protection. Further structural studies of SIgA-associated glycans would lead to the identification of those involved in the species-specific inhibition of attachment to corresponding epithelial cells.

• MeSH
• aglutinace MeSH
• Escherichia coli fyziologie   MeSH
• glykosylace MeSH
• gnotobiologické modely MeSH
• imunoglobulin A sekreční metabolismus   MeSH
• imunoglobuliny - Fab fragmenty metabolismus   MeSH
• infekce vyvolané Escherichia coli imunologie   MeSH
• jednořetězcové protilátky metabolismus   MeSH
• novorozená zvířata MeSH
• odolnost vůči nemocem MeSH
• polysacharidy metabolismus   MeSH
• prasata MeSH
• těhotenství MeSH
• zvířata MeSH
• Check Tag
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Anorexia nervosa (AN) is a life-threatening psychiatric disorder with not well-described pathogenesis. Besides the genetic and sociological factors, autoimmunity is also considered to take part in AN pathogenesis. We evaluated general serological factors showing the physiological state of 59 patients with AN at hospital admission and their discharge. We detected the altered levels of some general biochemical and immunological parameters. We also detected decreased levels of appetite-regulating alpha-melanocyte stimulating hormone (α-MSH) in patients at hospital admission. Moreover, elevated anti-α-MSH IgM levels and decreased anti-α-MSH IgA levels were observed in patients with AN. Therefore, we analyzed the gut microbiota composition with special focus on α-MSH antigen-mimetic containing microbes from the Enterobacteriaceae family. We correlated gut bacterial composition with anti-α-MSH Ig levels and detected decreasing IgG levels with increasing alpha diversity. The upregulation of pro-inflammatory cytokines IL-6, IL-17, and TNF-α were detected in patients with AN both prior and after hospitalization. We also evaluated the treatment outcome and improvement was observed in the majority of patients with AN. We provide new data about various serum biochemical parameters and their changes during the patients' hospitalization, with emphasis on the immune system, and its possible participation in AN pathogenesis.

• Publikační typ
• časopisecké články MeSH

Cíl: Cílem studie CERES (CzEch REkovelle real life Study) bylo shromáždit první zkušenosti s užíváním zcela nového gonadotropinu, vyhodnotit účinnost folitropinu delta v běžné české klinické praxi a srovnat získané výsledky s výstupy studie ESTHER-1. Metodika: Ovariální stimulací individualizovanou denní dávkou folitropinu delta v mikrogramech na základě hladiny antimüllerického hormonu (AMH) a tělesné hmotnosti pacientky (AMH < 15 pmol/ l: fixní dávka 12 µg/ d; AMH > 15 pmol/ l: 0,10–0,19 µg/ kg/ d; max. 12 µg/ d). Výsledky: Celkem bylo zařazeno 85 pacientek ve věku 24–42 let, průměrný věk 32,9 let, průměrná tělesná hmotnost 67,8 kg, průměrná hodnota AMH 23,2 pmol/ l. Bylo zahájeno 85 kontrolovaných ovariálních stimulací s folitropinem delta a 84 odběrů vajíček. U 40 pacientek (47 %) byl optimální zisk počtu vajíček (8–14), 75 pacientek (88 %) mělo embryotransfer, 10 (12 %) nemělo embryo vhodné k transferu. U 65 pacientek byl proveden single embryo transfer, u 10 byla transferována dvě embrya. Počet klinických gravidit byl 37 (43,5 % cPR – clinical pregnancy rate), počet porodů živého bylo plodů 30 (35,3 % LBR – live birth rate). Byly hlášeny tři (3,5 %) časné ovariální hyperstimulační syndromy (OHSS) mírného typu. Hospitalizace související s léčbou byla 0. Závěr: Individualizace ovariální stimulace vede k optimalizaci ovariální odpovědi a při zachování účinnosti zvyšuje bezpečnost léčby cestou snížení incidence OHSS. Výsledky získané u české populace jsou zcela srovnatelné s výstupy velké mezinárodní randomizované zaslepené klinické zkoušky ESTHER-1.

Objective: The aim of the study CERES (CzEch REkovelle real life Study) was to gather experience with the use of a novel gonadotrophine, to evaluate the efficacy of follitropin delta in Czech clinical settings and to compare our results with the clinical trial ESTHER-1. Methods: Individualized follitropin delta daily dose in µg based on the patient's anti-Müllerian hormone (AMH) level and body weight (AMH < 15 pmol/ L: 12 µg/ d; AMH > 15 pmol/ L: 0.10–0.19 µg/ kg/ d; max. 2 µg/ d). Results: A total of 85 women (aged 24–42 years) was included in the study. The average patient's age was 32.9 years, the average body weight was 67.8 kg, and the mean level of AMH was 23.2 pmol/ L. There were initiated 85 controlled ovarian stimulations with follitropin delta and 84 egg collections. Forty patients (47%) had optimal number of retrieved eggs (8–14), 75 patients (88%) had embryotransfer, 10 patients (12%) had no embryo suitable for transfer, 65 patients had single embryo transfer and 10 patients had 2 embryos for transfer. There were reported 37 clinical pregnancies (43.5% cPR – clinical pregnancy rate), 30 live births (35.3% LBR – live birth rate), 3 (3.5%) early moderate ovarian hyperstimulation syndroms (OHSS) and no hospitalization due to the treatment. Conclusion: Individualized ovarian stimulation optimizes ovarian response, maintains treatment efficacy and improves safety by reducing OHSS incidence. The results of the Czech population study are fully comparable with the international, randomized, assessor-blinded trial ESTHER-1.

• Klíčová slova
• studie CERES,
• MeSH
• antimülleriánský hormon MeSH
• fertilizace in vitro * MeSH
• folikuly stimulující hormon lidský MeSH
• gonadotropiny MeSH
• individualizovaná medicína MeSH
• indukce ovulace * MeSH
• lidé MeSH
• multicentrické studie jako téma MeSH
• ovariální hyperstimulační syndrom MeSH
• prospektivní studie MeSH
• rekombinantní proteiny MeSH
• těhotenství MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH

Continuous activation of the immune system inside a tissue can lead to remodelling of the tissue structure and creation of a specific microenvironment, such as during the tumour development. Chronic inflammation is a central player in stimulating changes that alter the tissue stroma and can lead to fibrotic evolution. In the colon mucosa, regulatory mechanisms, including TGF-β1, avoid damaging inflammation in front of the continuous challenge by the intestinal microbiome. Inducing either DSS colitis or AOM colorectal carcinogenesis in AVN-Wistar rats, we evaluated at one month after the end of each treatment whether immunological changes and remodelling of the collagen scaffold were already in development. At this time point, we found in both models a general downregulation of pro-inflammatory cytokines and even of TGF-β1, but not of IL-6. Moreover, we demonstrated by multi-photon microscopy the simultaneously presence of pro-fibrotic remodelling of the collagen scaffold, with measurable changes in comparison to the control mucosa. The scaffold was significantly modified depending on the type of induced stimulation. These results suggest that at one month after the end of the DSS or AOM inductions, a smouldering inflammation is present in both induced conditions, since the pro-inflammatory cytokines still exceed, in proportion, the local homeostatic regulation of which TGF-β1 is a part (inflammatory threshold). Such an inflammation appears sufficient to sustain remodelling of the collagen scaffold that may be taken as a possible pathological marker for revealing pre-neoplastic inflammation.

• Publikační typ
• časopisecké články MeSH

Germ-free animals (GF) are those without a microbiome since birth. This particular biological model has become one of special interest with the growing evidence of importance of the microbiome in the life, development, adaptation, and immunity of humans and animals in the environments in which they live. Anatomical differences observed in GF compared with conventionally-reared animals (CV) has given rise to the question of the influence of commensal microflora on the development of structure and function (even immunological) of the bowel. Only recently, thanks to achievements in microscopy and associated methods, structural differences can be better evaluated and put in perspective with the immunological characteristics of GF vs. CV animals. This study, using a GF rat model, describes for the first time the possible influence that the presence of commensal microflora, continuously stimulating mucosal immunity, has on the collagen scaffold organization of the colon mucosa. Significant differences were found between CV and GF mucosa structure with higher complexity in the CV rats associated to a more activated immune environment. The immunological data suggest that, in response to the presence of a microbiome, an effective homeostatic regulation in developed by the CV rats in healthy conditions to avoid inflammation and maintain cytokine levels near the spontaneous production found in the GF animals. The results indicated that collagen scaffold adapted to the immune microenvironment; therefore, it is apparent that the microbiome was able to condition the structure of the colon mucosa.

• MeSH
• gnotobiologické modely * MeSH
• kolon MeSH
• krysa rodu rattus MeSH
• mikrobiota * MeSH
• slizniční imunita MeSH
• střevní sliznice MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Brain-gut microbiota interactions are intensively studied in connection with various neurological and psychiatric diseases. While anorexia nervosa (AN) pathophysiology is not entirely clear, it is presumably linked to microbiome dysbiosis. We aimed to elucidate the gut microbiota contribution in AN disease pathophysiology. We analyzed the composition and diversity of the gut microbiome of patients with AN (bacteriome and mycobiome) from stool samples before and after renourishment, and compared them to healthy controls. Further, levels of assorted neurotransmitters and short-chain fatty acids (SCFA) were analyzed in stool samples by MS and NMR, respectively. Biochemical, anthropometric, and psychometric profiles were assessed. The bacterial alpha-diversity parameter analyses revealed only increased Chao 1 index in patients with AN before the realimentation, reflecting their interindividual variation. Subsequently, core microbiota depletion signs were observed in patients with AN. Overrepresented OTUs (operation taxonomic units) in patients with AN taxonomically belonged to Alistipes, Clostridiales, Christensenellaceae, and Ruminococcaceae. Underrepresented OTUs in patients with AN were Faecalibacterium, Agathobacter, Bacteroides, Blautia, and Lachnospira. Patients exhibited greater interindividual variation in the gut bacteriome, as well as in metagenome content compared to controls, suggesting altered bacteriome functions. Patients had decreased levels of serotonin, GABA, dopamine, butyrate, and acetate in their stool samples compared to controls. Mycobiome analysis did not reveal significant differences in alpha diversity and fungal profile composition between patients with AN and healthy controls, nor any correlation of the fungal composition with the bacterial profile. Our results show the changed profile of the gut microbiome and its metabolites in patients with severe AN. Although therapeutic partial renourishment led to increased body mass index and improved psychometric parameters, SCFA, and neurotransmitter profiles, as well as microbial community compositions, did not change substantially during the hospitalization period, which can be potentially caused by only partial weight recovery.

• MeSH
• Archaea klasifikace   růst a vývoj   MeSH
• Bacteria klasifikace   růst a vývoj   metabolismus   MeSH
• dospělí MeSH
• feces mikrobiologie   MeSH
• houby klasifikace   růst a vývoj   metabolismus   MeSH
• index tělesné hmotnosti MeSH
• kyseliny mastné těkavé metabolismus   MeSH
• lidé MeSH
• longitudinální studie MeSH
• mentální anorexie metabolismus   mikrobiologie   MeSH
• metagenom MeSH
• mladý dospělý MeSH
• mykobiom MeSH
• neurotransmiterové látky metabolismus   MeSH
• osa mozek-střevo MeSH
• střevní mikroflóra * MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The equilibrium and reciprocal actions among appetite-stimulating (orexigenic) and appetite-suppressing (anorexigenic) signals synthesized in the gut, brain, microbiome and adipose tissue (AT), seems to play a pivotal role in the regulation of food intake and feeding behavior, anxiety, and depression. A dysregulation of mechanisms controlling the energy balance may result in eating disorders such as anorexia nervosa (AN) and bulimia nervosa (BN). AN is a psychiatric disease defined by chronic self-induced extreme dietary restriction leading to an extremely low body weight and adiposity. BN is defined as out-of-control binge eating, which is compensated by self-induced vomiting, fasting, or excessive exercise. Certain gut microbiota-related compounds, like bacterial chaperone protein Escherichia coli caseinolytic protease B (ClpB) and food-derived antigens were recently described to trigger the production of autoantibodies cross-reacting with appetite-regulating hormones and neurotransmitters. Gut microbiome may be a potential manipulator for AT and energy homeostasis. Thus, the regulation of appetite, emotion, mood, and nutritional status is also under the control of neuroimmunoendocrine mechanisms by secretion of autoantibodies directed against neuropeptides, neuroactive metabolites, and peptides. In AN and BN, altered cholinergic, dopaminergic, adrenergic, and serotonergic relays may lead to abnormal AT, gut, and brain hormone secretion. The present review summarizes updated knowledge regarding the gut dysbiosis, gut-barrier permeability, short-chain fatty acids (SCFA), fecal microbial transplantation (FMT), blood-brain barrier permeability, and autoantibodies within the ghrelin and melanocortin systems in eating disorders. We expect that the new knowledge may be used for the development of a novel preventive and therapeutic approach for treatment of AN and BN.

• MeSH
• autoprotilátky * MeSH
• ghrelin imunologie   MeSH
• inzulin imunologie   MeSH
• leptin imunologie   MeSH
• lidé MeSH
• melanocyty stimulující hormony imunologie   MeSH
• neuropeptid Y imunologie   MeSH
• poruchy příjmu potravy imunologie   mikrobiologie   MeSH
• střevní mikroflóra imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH