- Publikační typ
- abstrakt z konference MeSH
Radiotherapy (RT) plays an important role in the management of cancer patients. RT is used in more than 50% of patients during the course of their disease in a curative or palliative setting. In the past decades it became apparent that the abscopal effect induced by RT might be dependent on the activation of immune system, and that the induction of immunogenic cancer cell death and production of danger-associated molecular patterns from dying cells play a major role in the radiotherapy-mediated anti-tumor efficacy. Therefore, the combination of RT and immunotherapy is of a particular interest that is reflected in designing clinical trials to treat patients with various malignancies. The use of cytokines as immunoadjuvants in combination with RT has been explored over the last decades as one of the immunotherapeutic combinations to enhance the clinical response to anti-cancer treatment. Here we review mainly the data on the efficacy of IFN-α, IL-2, IL-2-based immunocytokines, GM-CSF, and TNF-α used in combinations with various radiotherapeutic techniques in clinical trials. Moreover, we discuss the potential of IL-15 and its analogs and IL-12 cytokines in combination with RT based on the efficacy in preclinical mouse tumor models.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Cíl: Určit účinnost antiagregační léčby kyselinou acetylsalicylovou v sekundární prevenci v přísně selektovaném souboru pacientů po ischemické CMP. Soubor a metody: Do souboru bylo zahrnuto 106 pacientů s minimalizací možných faktorů, které by mohly ovlivnit efekt kyseliny acetylsalicylové. Compliance byla potvrzena laboratorním vyšetřením kyseliny salicylové v plazmě, embolizační příhody minimalizovány pečlivým vyšetřením srdce a karotických tepen. U všech pacientů užívajících 100 mg kyseliny acetylsalicylové denně jsme vyšetřili sérové koncentrace 11-dehydrotromboxanu B2. Výsledky: I v tomto přísně selektovaném souboru k účinné supresi tromboxanu (95 % a více) došlo jen u 76 pacientů, ale u dalších 24 suprese dosahovala 80-94,9 % a pouze u šesti pacientů byla ještě nižší. Pacienti s neúčinnou supresí tromboxanu měli statisticky významně vyšší body mass index, cholesterol a LDL cholesterol a kyselinu močovou. Závěr: Kyselina acetylsalicylová vedla k výrazné supresi tromboxanu u všech pacientů, požadovaný stupeň suprese nedosáhla více než čtvrtina souboru pacientů. V souladu s nejnovějšími poznatky je pravděpodobné, že zdánlivě nedostatečná suprese tromboxanu je způsobena produkcí tromboxanu z mimodestičkových zdrojů.
Aim: To assess the efficacy of antiplatelet therapy with acetylsalicylic acid (ASA) in secondary prevention in a strictly selected group of patients after ischemic stroke. Patients and methods: The group included 106 patients with a minimum of factors potentially affecting the effect of ASA. While compliance was verified by laboratory determination of ASA levels in plasma, presence of previous embolic events was minimized by thorough examination of the heart and carotid arteries. All patients taking 100 mg of ASA daily had their serum 11-dehydrotromboxane B2 levels determined. Results: Even in this strictly selected set of patients, effective thromboxane suppression (95% and higher) was only achieved in 76 patients, with suppression levels of 80-94.9% determined in 24 patients, and lower in another six patients. Patients with inadequate thromboxane suppression had statistically higher body mass index, cholesterol and LDL cholesterol, and uric acid levels. Conclusion: While ASA use led to marked thromboxane suppression in all patients, the required level of suppression was not achieved in over a fourth of our patients. Consistent with latest reports, it is likely that the seemingly inadequate suppression of thromboxane is due to its production from sources other than platelets.
- Klíčová slova
- 11-dehydrotromboxan,
- MeSH
- Aspirin * terapeutické užití MeSH
- cévní mozková příhoda * prevence a kontrola MeSH
- lidé středního věku MeSH
- lidé MeSH
- prospektivní studie MeSH
- sekundární prevence * MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
High hydrostatic pressure (HHP) has been known to affect biological systems for >100 years. In this review, we describe the technology of HHP and its effect macromolecules and physiology of eukaryotic cells. We discuss the use of HHP in cancer immunotherapy to kill tumor cells for generation of whole cell and dendritic cell-based vaccines. We further summarize the current use and perspectives of HHP application in biomedicine, specifically in orthopedic surgery and for the viral, microbial and protozoan inactivation to develop vaccines against infectious diseases.
- MeSH
- biotechnologie přístrojové vybavení metody MeSH
- dendritické buňky imunologie MeSH
- eukaryotické buňky MeSH
- hydrostatický tlak * MeSH
- imunoterapie metody MeSH
- inaktivace viru MeSH
- lidé MeSH
- nádory patologie terapie MeSH
- ortopedické výkony metody MeSH
- vakcíny imunologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
High hydrostatic pressure (HHP) can be used to generate dendritic cell (DC)-based active immunotherapy for prostate, lung and ovarian cancer. We showed here that HHP treatment of selected human cancer cell lines leads to a degradation of tumor antigens which depends on the magnitude of HHP applied and on the cancer cell line origin. Whereas prostate or ovarian cell lines displayed little protein antigen degradation with HHP treatment up to 300MPa after 2h, tumor antigens are hardly detected in lung cancer cell line after treatment with HHP 250MPa at the same time. On the other hand, quick reduction of tumor antigen-coding mRNA was observed at HHP 200MPa immediately after treatment in all cell lines tested. To optimize the DC-based active cellular therapy protocol for HHP-sensitive cell lines the immunogenicity of HHP-treated lung cancer cells at 150, 200 and 250MPa was compared. Lung cancer cells treated with HHP 150MPa display characteristics of immunogenic cell death, however cells are not efficiently phagocytosed by DC. Despite induction of the highest number of antigen-specific CD8+T cells, 150 MPa-treated lung cancer cells survive in high numbers. This excludes their use in DC vaccine manufacturing. HHP of 200MPa treatment of lung cancer cells ensures the optimal ratio of efficient immunogenic killing and delivery of protein antigens in DC. These results represent an important pre-clinical data for generation of immunogenic killed lung cancer cells in ongoing NSCLC Phase I/II clinical trial using DC-based active cellular immunotherapy (DCVAC/LuCa).
High hydrostatic pressure (HHP) induces immunogenic death of tumor cells which confer protective anti-tumor immunity in vivo. Moreover, DC pulsed with HHP-treated tumor cells induced therapeutic effect in mouse cancer model. In this study, we tested the immunogenicity, stability and T cell stimulatory activity of human monocyte-derived dendritic cell (DC)-based HHP lung cancer vaccine generated in GMP compliant serum free medium using HHP 250 MPa. DC pulsed with HHP-killed lung cancer cells and poly(I:C) enhanced DC maturation, chemotactic migration and production of pro-inflammatory cytokines after 24h. Moreover, DC-based HHP lung cancer vaccine showed functional plasticity after transfer into serum-containing media and stimulation with LPS or CD40L after additional 24h. LPS and CD40L stimulation further differentially enhanced the expression of costimulatory molecules and production of IL-12p70. DC-based HHP lung cancer vaccine decreased the number of CD4+CD25+Foxp3+ T regulatory cells and stimulated IFN-γ-producing tumor antigen-specific CD4+ and CD8+ T cells from non-small cell lung cancer (NSCLC) patients. Tumor antigen specific CD8+ and CD4+ T cell responses were detected in NSCLC patient's against a selected tumor antigens expressed by lung cancer cell lines used for the vaccine generation. We also showed for the first time that protein antigen from HHP-killed lung cancer cells is processed and presented by DC to CD8+ T cells. Our results represent important preclinical data for ongoing NSCLC Phase I/II clinical trial using DC-based active cellular immunotherapy (DCVAC/LuCa) in combination with chemotherapy and immune enhancers.
- MeSH
- CD4-pozitivní T-lymfocyty imunologie MeSH
- CD8-pozitivní T-lymfocyty imunologie MeSH
- dendritické buňky imunologie MeSH
- hydrostatický tlak MeSH
- imunoterapie metody MeSH
- interferon gama metabolismus MeSH
- kultivované buňky MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádory plic terapie MeSH
- nemalobuněčný karcinom plic terapie MeSH
- protinádorové vakcíny imunologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Citalopram, a selective serotonin reuptake inhibitor (SSRi), is widely used to treat major depression. Patients treated with SSRIs suffer more frequently from bleeding disorders caused by the antiplatelet effect of SSRIs. METHODS: To investigate the potential suppressive effect of citalopram treatment on plasma thromboxane B2 levels and its possible correlation with actual plasma concentration of citalopram. Plasma concentrations of thromboxane B2 and citalopram were examined in a cohort of 77 aspirin-treated geriatric patients before and in the third week of citalopram therapy. RESULTS: Citalopram therapy led to a significant decrease of plasma concentrations of thromboxane B2 compared to its levels before initiation of the therapy. Furthermore, we have shown negative correlation in thromboxane B2 levels and actual plasma concentration of citalopram. Actual plasma concentrations of citalopram were significantly higher compared to younger adult patients treated with similar dose. CONCLUSIONS: In this study we have shown that even short-term citalopram therapy led to a suppression of thromboxane B2 production in aspirin-treated patients. This suppressive effect correlates with actual plasma concentration of citalopram.
- MeSH
- Aspirin farmakologie MeSH
- citalopram krev farmakologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- selektivní inhibitory zpětného vychytávání serotoninu krev farmakologie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- thromboxan B2 krev MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Bordetella adenylate cyclase toxin-hemolysin (CyaA) penetrates the cytoplasmic membrane of phagocytes and employs two distinct conformers to exert its multiple activities. One conformer forms cation-selective pores that permeabilize phagocyte membrane for efflux of cytosolic potassium. The other conformer conducts extracellular calcium ions across cytoplasmic membrane of cells, relocates into lipid rafts, translocates the adenylate cyclase enzyme (AC) domain into cells and converts cytosolic ATP to cAMP. We show that the calcium-conducting activity of CyaA controls the path and kinetics of endocytic removal of toxin pores from phagocyte membrane. The enzymatically inactive but calcium-conducting CyaA-AC⁻ toxoid was endocytosed via a clathrin-dependent pathway. In contrast, a doubly mutated (E570K+E581P) toxoid, unable to conduct Ca²⁺ into cells, was rapidly internalized by membrane macropinocytosis, unless rescued by Ca²⁺ influx promoted in trans by ionomycin or intact toxoid. Moreover, a fully pore-forming CyaA-ΔAC hemolysin failed to permeabilize phagocytes, unless endocytic removal of its pores from cell membrane was decelerated through Ca²⁺ influx promoted by molecules locked in a Ca²⁺-conducting conformation by the 3D1 antibody. Inhibition of endocytosis also enabled the native B. pertussis-produced CyaA to induce lysis of J774A.1 macrophages at concentrations starting from 100 ng/ml. Hence, by mediating calcium influx into cells, the translocating conformer of CyaA controls the removal of bystander toxin pores from phagocyte membrane. This triggers a positive feedback loop of exacerbated cell permeabilization, where the efflux of cellular potassium yields further decreased toxin pore removal from cell membrane and this further enhances cell permeabilization and potassium efflux.
- MeSH
- adenylátcyklasový toxin farmakologie MeSH
- buněčné linie MeSH
- draslík metabolismus MeSH
- endocytóza účinky léků MeSH
- iontový transport účinky léků MeSH
- klathrin metabolismus MeSH
- makrofágy cytologie metabolismus MeSH
- membránové mikrodomény metabolismus MeSH
- myši MeSH
- permeabilita buněčné membrány účinky léků MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: Thromboxane B2 (TxB2) and particularly 11-dehydrothromboxane B2 (11-dTxB2) are widely used as prognostic risk markers of platelet activation in cardiovascular diseases. The main errors in TxB2 and 11-dTxB2 determination include either low concentrations of circulating TxB2 (1 - 2 pg/mL) and 11-dTxB2 (0.9 - 4.3 pg/mL) or rather high transiency (mean TxB2 half-life is approximately 5 minutes) as well as an incorrect pre-analytical phase set up. The aim of this study was to investigate the impact of a widely used purification step on the results of enzyme immunosorbent assay (EIA)--based measurement of the two selected thromboxanes. METHODS: For the purpose of this study, 20 plasma samples (10 healthy donors, 10 patients under treatment with acetylsalicylic acid) were screened for TxB2 and 11-dTxB2 concentrations using commercial competitive EIA kits (Cayman Chemicals, Tallinn, Estonia; Neogen, Lexington, KY, USA) with or without the introduction of the purification procedure. RESULTS: The purification step does not significantly affect the results of EIA measurements of the two of TxA2 metabolites (TxB2, 11-dTxB2) in human plasma. The levels of TxB2 and 11-dTxB2 determined in the plasma samples were not significantly changed (p < 0.05) when the purification step was omitted compared to the purified samples. CONCLUSIONS: This study establishes a protocol allowing for reliable and reproducible plasma TxB2 and 11-dTxB2 EIA measurement for routine basic screening of platelet function.
- MeSH
- aktivace trombocytů účinky léků MeSH
- antiflogistika nesteroidní farmakologie MeSH
- Aspirin farmakologie MeSH
- extrakce na pevné fázi metody MeSH
- imunoenzymatické techniky metody MeSH
- kardiovaskulární nemoci krev diagnóza MeSH
- lidé MeSH
- prognóza MeSH
- reagenční diagnostické soupravy MeSH
- reprodukovatelnost výsledků MeSH
- thromboxan B2 analogy a deriváty krev MeSH
- trombocyty účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
