Toll-like receptor 3 (TLR3) is an endosomal receptor expressed in several immune and epithelial cells. Recent studies have highlighted its expression also in solid tumors, including prostate cancer (PCa), and have described its role primarily in the proinflammatory response and induction of apoptosis. It is up-regulated in some castration-resistant prostate cancers. However, the role of TLR3 in prostate cancer progression remains largely unknown. The current study experimentally demonstrated that exogenous TLR3 activation in PCa cell lines leads to a significant induction of secretion of the cytokines IL-6, IL-8, and interferon-β, depending on the model and chemoresistance status. Transcriptomic analysis of TLR3-overexpressing cells revealed a functional program that is enriched for genes involved in the regulation of cell motility, migration, and tumor invasiveness. Increased motility, migration, and invasion in TLR3-overexpressing cell line were confirmed by several in vitro assays and using an orthotopic prostate xenograft model in vivo. Furthermore, TLR3-ligand induced apoptosis via cleavage of caspase-3/7 and poly (ADP-ribose) polymerase, predominantly in TLR3-overexpressing cells. These results indicate that TLR3 may be involved in prostate cancer progression and metastasis; however, it might also represent an Achilles heel of PCa, which can be exploited for targeted therapy.

• MeSH
• apoptóza MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory prostaty * patologie   MeSH
• poly I-C farmakologie   MeSH
• prostata patologie   MeSH
• toll-like receptor 3 * genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• poly I-C MeSH
• TLR3 protein, human MeSH Prohlížeč
• toll-like receptor 3 * MeSH

Maternal immune activation has been identified as a significant risk factor for schizophrenia. Using rodent models, past work has demonstrated various behavioral and brain impairments in offspring after immune-activating events. We applied 5 mg/kg of poly(I:C) on gestation day 9 to pregnant mouse dams, whose offspring were then stressed during puberty. We show impairments in attentional set-shifting in a T-maze, and a decreased number of parvalbumin-positive interneurons in the hippocampus as a result of peripubertal stress specifically in females.

• Klíčová slova
• Behavioral tests, Cognitive deficit, Immunochallenge, Interneurons, Maternal immune activation, Mouse, Poly(I:C), Prenatal infection, Schizophrenia,
• MeSH
• chování zvířat fyziologie   MeSH
• exekutivní funkce fyziologie   MeSH
• hipokampus cytologie   MeSH
• infekční komplikace v těhotenství * chemicky indukované   imunologie   MeSH
• interneurony cytologie   MeSH
• kognitivní dysfunkce etiologie   patologie   patofyziologie   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• poly I-C aplikace a dávkování   MeSH
• pozornost fyziologie   MeSH
• psychický stres komplikace   patologie   patofyziologie   MeSH
• schizofrenie etiologie   imunologie   patologie   patofyziologie   MeSH
• těhotenství MeSH
• zpožděný efekt prenatální expozice chemicky indukované   patologie   patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• poly I-C MeSH

Pancreatic adenocarcinoma is one of the leading causes of cancer-related deaths, and its therapy remains a challenge. Our proposed therapeutic approach is based on the intratumoral injections of mannan-BAM, toll-like receptor ligands, and anti-CD40 antibody (thus termed MBTA therapy), and has shown promising results in the elimination of subcutaneous murine melanoma, pheochromocytoma, colon carcinoma, and smaller pancreatic adenocarcinoma (Panc02). Here, we tested the short- and long-term effects of MBTA therapy in established subcutaneous Panc02 tumors two times larger than in previous study and bilateral Panc02 models as well as the roles of CD4+ and CD8+ T lymphocytes in this therapy. The MBTA therapy resulted in eradication of 67% of Panc02 tumors with the development of long-term memory as evidenced by the rejection of Panc02 cells after subcutaneous and intracranial transplantations. The initial Panc02 tumor elimination is not dependent on the presence of CD4+ T lymphocytes, although these cells seem to be important in long-term survival and resistance against tumor retransplantation. The resistance was revealed to be antigen-specific due to its inability to reject B16-F10 melanoma cells. In the bilateral Panc02 model, MBTA therapy manifested a lower therapeutic response. Despite numerous combinations of MBTA therapy with other therapeutic approaches, our results show that only simultaneous application of MBTA therapy into both tumors has potential for the treatment of the bilateral Panc02 model.

• Klíčová slova
• Cancer immunotherapy, Checkpoint inhibitors, Mannan, Metastases, Pancreatic adenocarcinoma, TLR ligands,
• MeSH
• adenokarcinom imunologie   patologie   MeSH
• antigeny CD40 antagonisté a inhibitory   MeSH
• imidazoly farmakologie   MeSH
• imunoterapie MeSH
• kyseliny teichoové farmakologie   MeSH
• ligandy MeSH
• lipopolysacharidy farmakologie   MeSH
• mannany farmakologie   MeSH
• myši MeSH
• nádory slinivky břišní imunologie   patologie   MeSH
• poly I-C farmakologie   MeSH
• protokoly antitumorózní kombinované chemoterapie farmakologie   MeSH
• T-lymfocyty účinky léků   imunologie   MeSH
• toll-like receptory MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny CD40 MeSH
• imidazoly MeSH
• kyseliny teichoové MeSH
• ligandy MeSH
• lipopolysacharidy MeSH
• lipoteichoic acid MeSH Prohlížeč
• mannany MeSH
• poly I-C MeSH
• resiquimod MeSH Prohlížeč
• toll-like receptory MeSH

Immunotherapy emerges as a fundamental approach in cancer treatment. Up to date, the efficacy of numerous different immunotherapies has been evaluated. The use of microorganisms or their parts for immune cell activation, referred to as Pathogen-Associated Molecular Patterns (PAMPs), represents highly promising concept. The therapeutic effect of PAMPs can be further amplified by suitable combination of different types of PAMPs such as Toll like receptor (TLR) agonists and phagocytosis activating ligands. Previously, we used the combination of phagocytosis activating ligand (mannan) and mixture of TLR agonists (resiquimod (R-848), poly(I:C), inactivated Listeria monocytogenes) for successful treatment of melanoma in murine B16-F10 model. In the present study, we optimized the composition and timing of previously used mixture. Therapeutic mixture based on well-defined chemical compounds consisted of mannan anchoring to tumor cell surface by biocompatible anchor for membranes (BAM) and TLR agonists resiquimod, poly(I:C), and lipoteichoic acid (LTA). The optimization resulted in (1) eradication of advanced stage progressive melanoma in 83% of mice, (2) acquisition of resistance to tumor re-transplantation, and (3) potential anti-metastatic effect. After further investigation of mechanisms, underlying anti-tumor responses, we concluded that both innate and adaptive immunity are activated and involved in these processes. We tested the efficacy of our treatment in Panc02 murine model of aggressive pancreatic tumor as well. Simultaneous application of agonistic anti-CD40 antibody was necessary to achieve effective therapeutic response (80% recovery) in this model. Our results suggest that herein presented immunotherapeutic approach is a promising cancer treatment strategy with the ability to eradicate not only primary tumors but also metastases.

• Klíčová slova
• Cancer immunotherapy, Melanoma B16-F10, Metastasis, Panc02, Phagocytosis, TLR agonists,
• MeSH
• adenokarcinom imunologie   patologie   terapie   MeSH
• fagocytóza * MeSH
• imidazoly terapeutické užití   MeSH
• imunoterapie MeSH
• kyseliny teichoové terapeutické užití   MeSH
• lipopolysacharidy terapeutické užití   MeSH
• mannany terapeutické užití   MeSH
• melanom experimentální imunologie   patologie   terapie   MeSH
• myši inbrední C57BL MeSH
• nádorové buněčné linie MeSH
• nádory slinivky břišní imunologie   patologie   terapie   MeSH
• neutrofily imunologie   MeSH
• poly I-C terapeutické užití   MeSH
• toll-like receptory agonisté   MeSH
• tumor burden účinky léků   MeSH
• tumor infiltrující lymfocyty imunologie   MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• imidazoly MeSH
• kyseliny teichoové MeSH
• lipopolysacharidy MeSH
• lipoteichoic acid MeSH Prohlížeč
• mannany MeSH
• poly I-C MeSH
• resiquimod MeSH Prohlížeč
• toll-like receptory MeSH

BACKGROUND AND PURPOSE: One of the hallmarks of schizophrenia is altered brain structure, potentially due to antipsychotic treatment, the disorder itself or both. It was proposed that functional changes may precede the structural ones. In order to understand and potentially prevent this unwanted process, brain function assessment should be validated as a diagnostic tool. METHODS: We used Arterial Spin Labelling MRI technique for the evaluation of brain perfusion in several brain regions in a neurodevelopmental poly(I:C) model of schizophrenia (8mg/kg on a gestational day 15) in rats taking into account sex-dependent effects and chronic treatment with aripiprazole (30days), an atypical antipsychotic acting as a partial agonist on dopaminergic receptors. RESULTS: We found the sex of the animal to have a highly significant effect in all regions of interest, with females showing lower blood perfusion than males. However, both males and females treated prenatally with poly(I:C) showed enlargement of the lateral ventricles. Furthermore, we detected increased perfusion in the circle of Willis, hippocampus, and sensorimotor cortex, which was not influenced by chronic atypical antipsychotic aripiprazole treatment in male poly(I:C) rats. CONCLUSION: We hypothesize that perfusion alterations may be caused by the hyperdopaminergic activity in the poly(I:C) model, and the absence of aripiprazole effect on perfusion in brain regions related to schizophrenia may be due to its partial agonistic mechanism.

• Klíčová slova
• Aripiprazole *, Arterial Spin Labelling *, MRI *, Schizophrenia *, Sex *, Wistar rats *,
• MeSH
• antipsychotika farmakologie   MeSH
• aripiprazol farmakologie   MeSH
• magnetická rezonanční tomografie MeSH
• modely nemocí na zvířatech MeSH
• mozek diagnostické zobrazování   účinky léků   patofyziologie   MeSH
• mozkový krevní oběh účinky léků   fyziologie   MeSH
• náhodné rozdělení MeSH
• pohlavní dimorfismus * MeSH
• poly I-C MeSH
• potkani Wistar MeSH
• schizofrenie diagnostické zobrazování   farmakoterapie   patofyziologie   MeSH
• těhotenství MeSH
• zpožděný efekt prenatální expozice MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antipsychotika MeSH
• aripiprazol MeSH
• poly I-C MeSH

Schizophrenia appears to be linked to higher incidence of metabolic syndrome even in the absence of antipsychotic treatment. Atypical antipsychotics substantially differ in their propensity to induce metabolic alterations. Aripiprazole is considered to represent an antipsychotic drug with low risk of metabolic syndrome development. The aim of this study was to evaluate metabolic phenotype of neurodevelopmental polyI:C rat model and assess metabolic effects of chronic aripiprazole treatment with regard to complex neuroendocrine regulations of energy homeostasis. Polyinosinic:polycytidylic acid (polyI:C) was administered subcutaneously at a dose of 8 mg/kg in 10 ml on gestational day 15 to female Wistar rats. For this study 20 polyI:C and 20 control adult male offspring were used, randomly divided into 2 groups per 10 animals for chronic aripiprazole treatment and vehicle. Aripiprazole (5 mg/kg, dissolved tablets, ABILIFY®) was administered once daily via oral gavage for a month. Altered lipid profile in polyI:C model was observed and a trend towards different dynamics of weight gain in polyI:C rats was noted in the absence of significant antipsychotic treatment effect. PolyI:C model was not associated with changes in other parameters i.e. adipokines, gastrointestinal hormones and cytokines levels. Aripiprazole did not influence body weight but it induced alterations in neurohumoral regulations. Leptin and GLP-1 serum levels were significantly reduced, while ghrelin level was elevated. Furthermore aripiprazole decreased serum levels of pro-inflammatory cytokines. Our data indicate dysregulation of adipokines and gastrointestinal hormones present after chronic treatment with aripiprazole which is considered metabolically neutral in the polyI:C model of schizophrenia.

• Klíčová slova
• Adipokine, Aripiprazole, Leptin, Lipid profile, PolyI:C, Schizophrenia, Wistar rats,
• MeSH
• antipsychotika škodlivé účinky   farmakologie   MeSH
• aplikace orální MeSH
• aripiprazol škodlivé účinky   farmakologie   MeSH
• cytokiny krev   MeSH
• ghrelin krev   MeSH
• glukagonu podobný peptid 1 krev   MeSH
• leptin krev   MeSH
• metabolický syndrom krev   chemicky indukované   MeSH
• modely nemocí na zvířatech MeSH
• náhodné rozdělení MeSH
• poly I-C MeSH
• potkani Wistar MeSH
• schizofrenie krev   farmakoterapie   MeSH
• tělesná hmotnost účinky léků   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antipsychotika MeSH
• aripiprazol MeSH
• cytokiny MeSH
• ghrelin MeSH
• glukagonu podobný peptid 1 MeSH
• leptin MeSH
• poly I-C MeSH

BACKGROUND: Using killed microorganisms or their parts to stimulate immunity for cancer treatment dates back to the end of 19th century. Since then, it undergone considerable development. Our novel approach binds ligands to the tumor cell surface, which stimulates tumor phagocytosis. The therapeutic effect is further amplified by simultaneous application of agonists of Toll-like receptors. We searched for ligands that induce both a strong therapeutic effect and are safe for humans. METHODS: B16-F10 murine melanoma model was used. For the stimulation of phagocytosis, mannan or N-formyl-methionyl-leucyl-phenylalanine, was covalently bound to tumor cells or attached using hydrophobic anchor. The following agonists of Toll-like receptors were studied: monophosphoryl lipid A (MPLA), imiquimod (R-837), resiquimod (R-848), poly(I:C), and heat killed Listeria monocytogenes. RESULTS: R-848 proved to be the most suitable Toll-like receptor agonist for our novel immunotherapeutic approach. In combination with covalently bound mannan, R-848 significantly reduced tumor growth. Adding poly(I:C) and L. monocytogenes resulted in complete recovery in 83% of mice and in their protection from the re-transplantation of melanoma cells. CONCLUSION: An efficient cancer treatment results from the combination of Toll-like receptor agonists and phagocytosis stimulating ligands bound to the tumor cells.

• Klíčová slova
• Cancer immunotherapy, Innate immunity, Mannan, Melanoma, Neutrophils, Phagocytosis, Resiquimod,
• MeSH
• cytokiny metabolismus   MeSH
• fagocytóza MeSH
• imidazoly farmakologie   MeSH
• imunoterapie * metody   MeSH
• infiltrace neutrofily imunologie   MeSH
• ligandy MeSH
• mannany imunologie   MeSH
• melanom experimentální MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• nádory imunologie   metabolismus   patologie   terapie   MeSH
• neutrofily imunologie   metabolismus   MeSH
• poly I-C imunologie   MeSH
• přirozená imunita * MeSH
• respirační vzplanutí imunologie   MeSH
• toll-like receptory agonisté   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytokiny MeSH
• imidazoly MeSH
• ligandy MeSH
• mannany MeSH
• poly I-C MeSH
• resiquimod MeSH Prohlížeč
• toll-like receptory MeSH

BACKGROUND: Dendritic cells (DCs) are professional antigen-presenting cells that are capable of inducing immune responses. DC-based vaccines are normally generated using a standard 5- to 7-day protocol. To shorten the DC-based vaccine production for use in cancer immunotherapy, we have developed a fast DC protocol by comparing standard DCs (Day 5 DCs) and fast DCs (Day 3 DCs). METHODS: We tested the generation of Day 5 versus Day 3 DCs using CellGro media and subsequent activation by two activation stimuli: Poly (I:C) and LPS. We evaluated DC morphology, viability, phagocyte activity, cytokine production and ability to stimulate antigen-specific T cells. RESULTS: Day 5 and Day 3 DCs exhibited similar phagocytic capacity. Poly (I:C)-activated Day 5 DCs expressed higher levels of the costimulatory and surface molecules CD80, CD86 and HLA-DR compared to Poly (I:C)-activated Day 3 DCs. Nevertheless, LPS-activated Day 5 and Day 3 DCs were phenotypically similar. Cytokine production was generally stronger when LPS was used as the maturation stimulus, and there were no significant differences between Day 5 and Day 3 DCs. Importantly, Day 5 and Day 3 DCs were able to generate comparable numbers of antigen-specific CD8(+) T cells. The number of Tregs induced by Day 5 and Day 3 DCs was also comparable. CONCLUSION: We identified monocyte-derived DCs generated in CellGro for 3 days and activated using Poly (I:C) similarly potent in most functional aspects as DCs produced by the standard 5 day protocol. These results provide the rationale for the evaluation of faster protocols for DC generation in clinical trials.

• Klíčová slova
• Cancer immunotherapy, Dendritic cell, Fast generation, Monocyte, Vaccine,
• MeSH
• antigen prezentující buňky účinky léků   imunologie   metabolismus   MeSH
• antigenní specifita receptorů T-buněk imunologie   MeSH
• buněčná diferenciace účinky léků   imunologie   MeSH
• buněčné kultury * MeSH
• časové faktory MeSH
• cytokiny biosyntéza   MeSH
• dendritické buňky cytologie   účinky léků   imunologie   metabolismus   MeSH
• fagocytóza imunologie   MeSH
• fenotyp MeSH
• imunofenotypizace MeSH
• imunoterapie MeSH
• lidé MeSH
• nádory imunologie   metabolismus   terapie   MeSH
• poly I-C imunologie   farmakologie   MeSH
• protinádorové vakcíny imunologie   MeSH
• T-lymfocyty - podskupiny imunologie   metabolismus   MeSH
• viabilita buněk MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytokiny MeSH
• poly I-C MeSH
• protinádorové vakcíny MeSH

The expression of the transcription factor encoded by the Wilms tumor gene 1 (WT1) is associated with a variety of human cancers. WT1 protein has been reported to serve as a target antigen for tumor-specific immune responses. We observed that the immunization of mice with peptide vaccines derived from WT1 in a mixture with the CpG adjuvant (ODN 1826) by tattoo administration was superior to subcutaneous delivery of the peptides in combination with CpG formulated with the mineral oil adjuvant or a DNA vaccine or a recombinant vaccinia virus vaccine expressing the truncated WT1 protein. Tattooing with the WT1122-140 and WT1126-134 peptide elicited the response of WT1-specific interferon-γ-producing T cells. Peptide vaccine administered with a tattoo device had an antitumor effect on the growth of the prostate tumor cell line TRAMP-C2, provided that the transforming growth factor-β produced by tumor cells was neutralized by anti-TGFβ monoclonal antibody. The treatment of the tumor-bearing mice with 5-azadeoxycytidine or poly IC did not work in synergy with the peptide vaccine.

• MeSH
• adjuvancia imunologická MeSH
• antitumorózní látky farmakologie   terapeutické užití   MeSH
• azacytidin analogy a deriváty   farmakologie   terapeutické užití   MeSH
• decitabin MeSH
• injekce intradermální MeSH
• monoklonální protilátky imunologie   MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory prostaty terapie   MeSH
• poly I-C farmakologie   terapeutické užití   MeSH
• proteiny WT1 aplikace a dávkování   imunologie   MeSH
• protinádorové vakcíny aplikace a dávkování   MeSH
• subjednotkové vakcíny aplikace a dávkování   MeSH
• tetování MeSH
• transformující růstový faktor beta antagonisté a inhibitory   imunologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adjuvancia imunologická MeSH
• antitumorózní látky MeSH
• azacytidin MeSH
• decitabin MeSH
• monoklonální protilátky MeSH
• poly I-C MeSH
• proteiny WT1 MeSH
• protinádorové vakcíny MeSH
• subjednotkové vakcíny MeSH
• transformující růstový faktor beta MeSH

BACKGROUND: For clinical applications, dendritic cells (DCs) need to be generated using GMP-approved reagents. In this study, we tested the characteristics of DCs generated in two clinical grade culture media and activated by three maturation stimuli, Poly I: C, LPS and the mixture of proinflammatory cytokines in order to identify the optimal combination of culture media and activation stimulus for the clinical use. METHOD: We tested DCs generation using two GMP-certified culture media, CellGro and RPMI+5% human AB serum and evaluated DCs morphology, viability and capapability to mature. We tested three maturation stimuli, PolyI:C, LPS and the mixture of proinflammatory cytokines consisting of IL-1, IL-6, TNF and prostaglandin E2. We evaluated the capacity of activated DCs to induce antigen-specific T cells and regulatory T lymphocytes. RESULTS: Cell culture in CellGro resulted in a higher yield of immature DCs resulting from increased number of adherent monocytes. DCs that were generated in CellGro and activated using Poly I:C were the most efficient in expanding antigen-specific T cells compared to the DCs that were generated in other media and activated using LPS or the cocktail of proinflammatory cytokines. A comparison of all tested combinations revealed that DCs that were generated in CellGro and activated using Poly I:C induced low numbers of regulatory T cells. CONCLUSION: In this study, we identified monocyte-derived DCs that were generated in CellGro and activated using Poly I:C as the most potent clinical-grade DCs for the induction of antigen-specific T cells.

• MeSH
• buněčná diferenciace účinky léků   MeSH
• dendritické buňky cytologie   účinky léků   MeSH
• epitopy imunologie   MeSH
• fenotyp MeSH
• imunoterapie metody   MeSH
• klinické zkoušky jako téma MeSH
• kultivační média farmakologie   MeSH
• lidé MeSH
• nádory imunologie   terapie   MeSH
• poly I-C farmakologie   MeSH
• proliferace buněk účinky léků   MeSH
• regulační T-lymfocyty cytologie   účinky léků   imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• epitopy MeSH
• kultivační média MeSH
• poly I-C MeSH