The tumorigenic potential of mouse polyomavirus (MPyV) has been studied for decades in cell culture models and has been mainly attributed to nonstructural middle T antigen (MT), which acts as a scaffold signal adaptor, activates Src tyrosine kinases, and possesses transforming ability. We hypothesized that MPyV could also transform mouse cells independent of MT via a Toll-like receptor 4 (TLR4)-mediated inflammatory mechanism. To this end, we investigated the interaction of MPyV with TLR4 in mouse embryonic fibroblasts (MEFs) and 3T6 cells, resulting in secretion of interleukin 6 (IL-6), independent of active viral replication. TLR4 colocalized with MPyV capsid protein VP1 in MEFs. Neither TLR4 activation nor recombinant IL-6 inhibited MPyV replication in MEFs and 3T6 cells. MPyV induced STAT3 phosphorylation through both direct and MT-dependent and indirect and TLR4/IL-6-dependent mechanisms. We demonstrate that uninfected mouse fibroblasts exposed to the cytokine environment from MPyV-infected fibroblasts upregulated the expressions of MCP-1, CCL-5, and α-SMA. Moreover, the cytokine microenvironment increased the invasiveness of MEFs and CT26 carcinoma cells. Collectively, TLR4 recognition of MPyV induces a cytokine environment that promotes the cancer-associated fibroblast (CAF)-like phenotype in noninfected fibroblasts and increases cell invasiveness.

• Publication type
• Journal Article MeSH

A hallmark of cancer, including pancreatic ductal adenocarcinoma (PDA), is a massive stromal and inflammatory reaction. Many efforts have been made to identify the anti- or protumoral role of cytokines and immune subpopulations within the stroma. Here, we investigated the role of interleukin-17A (IL17A) and its effect on tumor fibroblasts and the tumor microenvironment. We used a spontaneous PDA mouse model (KPC) crossed to IL17A knockout mice to show an extensive desmoplastic reaction, without impaired immune infiltration. Macrophages, especially CD80+ and T cells, were more abundant at the earlier time point. In T cells, a decrease in FoxP3+ cells and an increase in CD8+ T cells were observed in KPC/IL17A-/- mice. Fibroblasts isolated from IL17A+/+ and IL17A-/- KPC mice revealed very different messenger RNA (mRNA) and protein profiles. IL17A-/- fibroblasts displayed the ability to restrain tumor cell invasion by producing factors involved in extracellular matrix remodeling, increasing T cell recruitment, and producing higher levels of cytokines and chemokines favoring T helper 1 cell recruitment and activation and lower levels of those recruiting myeloid/granulocytic immune cells. Single-cell quantitative PCR on isolated fibroblasts confirmed a very divergent profile of IL17A-proficient and -deficient cells. All these features can be ascribed to increased levels of IL17F observed in the sera of IL17A-/- mice, and to the higher expression of its cognate receptor (IL17RC) specifically in IL17A-/- cancer-associated fibroblasts (CAFs). In addition to the known effects on neoplastic cell transformation, the IL17 cytokine family uniquely affects fibroblasts, representing a suitable candidate target for combinatorial immune-based therapies in PDA.

• MeSH
• Adenocarcinoma genetics   pathology   MeSH
• CD8-Positive T-Lymphocytes metabolism   pathology   MeSH
• Carcinoma, Pancreatic Ductal genetics   pathology   MeSH
• Cancer-Associated Fibroblasts metabolism   pathology   MeSH
• Forkhead Transcription Factors genetics   MeSH
• Interleukin-17 genetics   MeSH
• Carcinogenesis genetics   MeSH
• Humans MeSH
• Disease Models, Animal MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Tumor Microenvironment genetics   MeSH
• Receptors, Interleukin genetics   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

BACKGROUND/AIM: Pancreatic ductal adenocarcinoma (PDAC) still represents one of the most aggressive cancers. Understanding of the epithelial-mesenchymal crosstalk as a crucial part of the tumor microenvironment should pave the way for therapies to improve patient survival rates. Well-established cell lines present a useful and reproducible model to study PDAC biology. However, the tumor-stromal interactions between cancer cells and cancer-associated fibroblasts (CAFs) are still poorly understood. MATERIALS AND METHODS: We studied interactions between four PDAC cell lines (Panc-1, CAPAN-2, MIAPaCa-2, and PaTu-8902) and conditioned media derived from primary cultures of normal fibroblasts/PDAC-derived CAFs (PANFs). RESULTS: When the tested PDAC cell lines were stimulated by PANF-derived conditioned media, the most aggressive behavior was acquired by the Panc-1 cell line (increased number and size of colonies, remaining expression of vimentin and keratin 8 as well as increase of epithelial-to-mesenchymal polarization markers), whereas PaTu-8902 cells were rather inhibited. Of note, administration of the conditioned media to MIAPaCa-2 cells resulted in an inverse effect on the size and number of colonies, whereas CAPAN-2 cells were rather stimulated. To explain the heterogeneous pattern of the observed PDAC crosstalk at the in vitro level, we further compared the phenotype of primary cultures of cells derived from ascitic fluid with that of the tested PDAC cell lines, analyzed tumor samples of PDAC patients, and performed gene expression profiling of PANFs. Immuno-cyto/histo-chemical analysis found specific phenotype differences within the group of examined patients and tested PDAC cell lines, whereas the genomic approach in PANFs found the key molecules (IL6, IL8, MFGE8 and periostin) that may contribute to the cancer aggressive behavior. CONCLUSION: The desmoplastic patient-specific regulation of cancer cells by CAFs (also demonstrated by the heterogeneous response of PDAC cell lines to fibroblasts) precludes simple targeting and development of an effective treatment strategy and rather requires establishment of an individualized tumor-specific treatment protocol.

• MeSH
• Carcinoma, Pancreatic Ductal metabolism   pathology   MeSH
• Epithelial-Mesenchymal Transition MeSH
• Cancer-Associated Fibroblasts metabolism   pathology   MeSH
• Fibroblasts metabolism   pathology   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Tumor Microenvironment MeSH
• Pancreatic Neoplasms metabolism   pathology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Sborník se zaměřuje na řízení sociálních služeb, zajištění jejich kvality, a na sociální pracovníky. Určeno odborné veřejnosti.; Kniha kolektivu autorů je pomocníkem a průvodcem všech manažerů v sociálních službách s ambicí obsáhnout podstatné oblasti a otázky, se kterými se právě manažeři potýkají. Zároveň se publikace věnuje kvalitě sociálních služeb, a to ze všech různých úhlů pohledu – určena je nejen pro manažery, ale i odborné pracovníky, kteří se kvalitou zabývají. Hlavním cílem autorů je zvýšit a zvyšovat kvalitu sociálních služeb v ČR a být oporou, ale i podporou manažerům v sociálních službách.

• MeSH
• Quality of Health Care MeSH
• Practice Management MeSH
• Social Work MeSH
• Social Workers MeSH

• Conspectus
• Druhy sociální pomoci a služeb
• NML Fields
• sociologie
• NML Publication type
• kolektivní monografie

Publikace se zaměřuje na syndromy s „café au lait“ makulami a na neurofibromatózu. Určeno odborné i široké veřejnosti.; Odborná monografie se zabývá tématem neurofibromatóz a dalších syndromů spojených s hyperpigmentací.

• MeSH
• Diagnosis, Differential MeSH
• Genetic Predisposition to Disease MeSH
• Hyperpigmentation MeSH
• Neoplasms complications   MeSH
• Neurofibromatoses MeSH
• Cafe-au-Lait Spots MeSH

• Conspectus
• Patologie. Klinická medicína
• NML Fields
• dermatovenerologie
• neurologie
• onkologie
• NML Publication type
• kolektivní monografie

BACKGROUND: Androgen receptor targeted therapies have emerged as an effective tool to manage advanced prostate cancer (PCa). Nevertheless, frequent occurrence of therapy resistance represents a major challenge in the clinical management of patients, also because the molecular mechanisms behind therapy resistance are not yet fully understood. In the present study, we therefore aimed to identify novel targets to intervene with therapy resistance using gene expression analysis of PCa co-culture spheroids where PCa cells are grown in the presence of cancer-associated fibroblasts (CAFs) and which have been previously shown to be a reliable model for antiandrogen resistance. METHODS: Gene expression changes of co-culture spheroids (LNCaP and DuCaP seeded together with CAFs) were identified by Illumina microarray profiling. Real-time PCR, Western blotting, immunohistochemistry and cell viability assays in 2D and 3D culture were performed to validate the expression of selected targets in vitro and in vivo. Cytokine profiling was conducted to analyze CAF-conditioned medium. RESULTS: Gene expression analysis of co-culture spheroids revealed that CAFs induced a significant upregulation of cholesterol and steroid biosynthesis pathways in PCa cells. Cytokine profiling revealed high amounts of pro-inflammatory, pro-migratory and pro-angiogenic factors in the CAF supernatant. In particular, two genes, 3-hydroxy-3-methylglutaryl-Coenzyme A synthase 2 (HMGCS2) and aldo-keto reductase family 1 member C3 (AKR1C3), were significantly upregulated in PCa cells upon co-culture with CAFs. Both enzymes were also significantly increased in human PCa compared to benign tissue with AKR1C3 expression even being associated with Gleason score and metastatic status. Inhibiting HMGCS2 and AKR1C3 resulted in significant growth retardation of co-culture spheroids as well as of various castration and enzalutamide resistant cell lines in 2D and 3D culture, underscoring their putative role in PCa. Importantly, dual targeting of cholesterol and steroid biosynthesis with simvastatin, a commonly prescribed cholesterol synthesis inhibitor, and an inhibitor against AKR1C3 had the strongest growth inhibitory effect. CONCLUSIONS: From our results we conclude that CAFs induce an upregulation of cholesterol and steroid biosynthesis in PCa cells, driving them into AR targeted therapy resistance. Blocking both pathways with simvastatin and an AKR1C3 inhibitor may therefore be a promising approach to overcome resistances to AR targeted therapies in PCa. Video abstract.

• MeSH
• Receptors, Androgen metabolism   MeSH
• Molecular Sequence Annotation MeSH
• Benzamides pharmacology   MeSH
• Models, Biological MeSH
• Biosynthetic Pathways genetics   MeSH
• Spheroids, Cellular metabolism   pathology   MeSH
• Cell Cycle genetics   MeSH
• Drug Resistance, Neoplasm drug effects   genetics   MeSH
• Cholesterol biosynthesis   MeSH
• Extracellular Matrix metabolism   MeSH
• Phenotype MeSH
• Phenylthiohydantoin pharmacology   MeSH
• Cancer-Associated Fibroblasts metabolism   pathology   MeSH
• Culture Media, Conditioned pharmacology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Prostatic Neoplasms, Castration-Resistant genetics   pathology   MeSH
• Prostatic Neoplasms genetics   metabolism   pathology   MeSH
• Nitriles pharmacology   MeSH
• Disease Progression * MeSH
• Cell Proliferation genetics   MeSH
• Gene Expression Regulation, Neoplastic drug effects   MeSH
• Aged MeSH
• Simvastatin pharmacology   MeSH
• Gene Expression Profiling MeSH
• Up-Regulation * MeSH
• Cell Survival drug effects   genetics   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Průvodce správným fungováním v managementu kvality. Publikace je na českém trhu unikátní: obsahuje souhrnné informace o systémech řízení, příklady ze skutečných firem i návrhy správných řešení. Na jednom místě čtenář najde nejběžněji používané, v praxi vyzkoušené metody a aktuální požadavky pro systémové normy. Dozví se, jak metody kvalitně aplikovat, jak zvýšit efektivitu a snížit nákladovost vybudovaného systému. Příručka se hodí pro širokou veřejnost, poslouží v podnikové praxi i v rámci vysokoškolského studia. Autor v ní zúročil více než dvacet let zkušeností v oboru – působí jako lektor, konzultant a auditor systému řízení. O řízení kvality a podnikovém řízení také přednáší na akademické půdě.

• Keywords
• lidské zdroje, ISO - systém managementu kvality,
• MeSH
• Total Quality Management MeSH
• Quality Control MeSH
• Risk Management MeSH
• Publication type
• Handbook MeSH

• Conspectus
• Management. Řízení
• 37.016
• NML Publication type
• učebnice vysokých škol

Román o lásce a psaní ve věku digitálního smutku; Vlastně už anotace nedokážu číst. Potkává se v nich příliš mnoho zájmů. Takže úplně jednoduše: Tohle je román o lásce a o psaní ve věku digitálního smutku. Zkoumám v něm víc než pět let jednoho milostného vztahu a další dva roky, kdy jsem o něm psal. Je v něm dost vášně, slz a také několik zjevení. Je to román o tom, proč vlastně jsme jeden s druhým, co na sobě milujeme, a proč se i přesto opouštíme. Jsem v něm sám za sebe, tak jako je člověk sám za sebe v lásce a ve všem, co stojí za řeč. Asi je to román pro ty, kdo dávají přednost sdílení před sděleními. A katarzi před happy endem. –––– Těžko říct, zda tento román autorovi pomohl vyznat se v životě. Vznikla však výjimečná kniha o lásce a o psaní „v době digitálního smutku“, kniha, která svou otevřeností a stylistickou vybroušeností může změnit čtenáře a posunout českou literaturu dál.

Reflexivní román o historii jednoho milostného vztahu je zároveň i "románem o románu o lásce" a o literární tvorbě.; Vlastně už anotace nedokážu číst. Potkává se v nich příliš mnoho zájmů. Takže úplně jednoduše: Tohle je román o lásce a o psaní ve věku digitálního smutku. Zkoumám v něm víc než pět let jednoho milostného vztahu a další dva roky, kdy jsem o něm psal. Je v něm dost vášně, slz a také několik zjevení. Je to román o tom, proč vlastně jsme jeden s druhým, co na sobě milujeme, a proč se i přesto opouštíme. Jsem v něm sám za sebe, tak jako je člověk sám za sebe v lásce a ve všem, co stojí za řeč. Asi je to román pro ty, kdo dávají přednost sdílení před sděleními. A katarzi před happy endem. –––– Těžko říct, zda tento román autorovi pomohl vyznat se v životě. Vznikla však výjimečná kniha o lásce a o psaní „v době digitálního smutku“, kniha, která svou otevřeností a stylistickou vybroušeností může změnit čtenáře a posunout českou literaturu dál.

• Publication type
• Fictional Work MeSH

• Conspectus
• Česká próza
• Biografie

• About
• Němec, Jan, 1981- Authority

Plasma profiles of acylcarnitines (ACs) and amino acids (AAs) may have interest as potential biomarkers. Here we analyzed plasma AC and AA profiles in 2 rat models with different metabolic programming outcomes: offspring of dams fed a cafeteria diet during lactation (O-CAF, with a thin-outside-fat-inside phenotype) and the offspring of dams with diet-induced obesity subjected to dietary normalization before gestation [offspring of postcafeteria dams (O-PCaf), nonaltered phenotype]. The purpose was to identify early variables that might indicate a propensity for a dysmetabolic state. O-CAF rats presented higher circulating levels of most of the lipid-derived ACs and higher hepatic expression of genes related to fatty acid oxidation ( Ppara and Cpt1a) than controls [offspring of control dams (O-C)]. They also exhibited an altered plasma AA profile. These differences were not observed in O-PCaf animals. A partial least squares-discriminant analysis score plot of the metabolomics data showed a clear separation between O-CAF and O-C animals. The long-chain ACs (C18, C18:1, C18:2, C16:1, and C16DC) and the AAs glycine, alanine, isoleucine, serine, and proline are the variables mainly influencing this separation. In summary, we have identified a cluster of ACs and AAs whose alterations may indicate poor nutrition during lactation due to maternal unbalanced diet intake and predict the later dysmetabolic phenotype observed in the offspring.-Pomar, C. A., Kuda, O., Kopecky, J., Rombaldova, M., Castro, H., Picó, C., Sánchez, J., Palou, A. Alterations in plasma acylcarnitine and amino acid profiles may indicate poor nutrition during the suckling period due to maternal intake of an unbalanced diet and may predict later metabolic dysfunction.

• MeSH
• Amino Acids blood   MeSH
• Diet * MeSH
• Maternal Nutritional Physiological Phenomena * MeSH
• Liver metabolism   MeSH
• Carnitine analogs & derivatives   blood   MeSH
• Animals, Suckling * MeSH
• Rats MeSH
• Lactation MeSH
• Metabolic Diseases etiology   MeSH
• Lipid Metabolism MeSH
• Models, Animal MeSH
• Multivariate Analysis MeSH
• Nutritional Status * MeSH
• Pregnancy MeSH
• Prenatal Exposure Delayed Effects metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Pregnancy MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH