Anaplastic large cell lymphoma (ALCL) is an aggressive, CD30+ T cell lymphoma of children and adults. ALK fusion transcripts or mutations in the JAK-STAT pathway are observed in most ALCL tumors, but the mechanisms underlying tumorigenesis are not fully understood. Here, we show that dysregulated STAT3 in ALCL cooccupies enhancers with master transcription factors BATF3, IRF4, and IKZF1 to form a core regulatory circuit that establishes and maintains the malignant cell state in ALCL. Critical downstream targets of this network in ALCL cells include the protooncogene MYC, which requires active STAT3 to facilitate high levels of MYC transcription. The core autoregulatory transcriptional circuitry activity is reinforced by MYC binding to the enhancer regions associated with STAT3 and each of the core regulatory transcription factors. Thus, activation of STAT3 provides the crucial link between aberrant tyrosine kinase signaling and the core transcriptional machinery that drives tumorigenesis and creates therapeutic vulnerabilities in ALCL.

• MeSH
• anaplastická lymfomová kináza genetika   metabolismus   MeSH
• anaplastický velkobuněčný lymfom * genetika   metabolismus   patologie   MeSH
• dítě MeSH
• dospělí MeSH
• Janus kinasy metabolismus   MeSH
• karcinogeneze genetika   MeSH
• lidé MeSH
• nádorová transformace buněk MeSH
• signální transdukce * genetika   MeSH
• transkripční faktor STAT3 genetika   MeSH
• transkripční faktory STAT metabolismus   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Léčba revmatoidní artritidy zaznamenala se zavedením biologických přípravků namířených proti cytokinům a imunitním buňkám významný pokrok. V posledních letech nastal v léčbě revmatoidní artritidy další příznivý posun, ke kterému přispěly léky zasahující do intracelulární signalizace - do dějů katalyzovaných proteinkinázami, konkrétně Janusovými kinázami (JAK). Evropskou lékovou agenturou jsou již pro léčbu revmatoidní artritidy schváleny tři inhibitory JAK - tofacitinib, baricitinib a upadacitinib. Inhibitory JAK mají rychlý nástup účinku, jsou účinné v monoterapii podobně jako v kombinaci s methotrexátem a zejména v monoterapii mají lepší účinnost než inhibitory tumor nekrotizujícího faktoru. Stejně jako při biologické léčbě existuje i při léčbě inhibitory JAK větší riziko závažných infekcí, ve srovnání s biologickou léčbou je častější herpes zoster. V klinické praxi je třeba opatrnosti u pacientů ve zvýšeném riziku tromboembolických příhod. V této souhrnné práci budou na závěr diskutovány zkušenosti z klinické praxe vycházející z národního registru ATTRA.

The treatment of rheumatoid arthritis has made significant progress with the introduction of biologics directed against cytokines and immune cells. In recent years, there has been another beneficial shift in the treatment of rheumatoid arthritis. Drugs interfering with intracellular signaling - in processes catalyzed by protein kinases, specifically Janus kinases (JAK), contributed to this. Three JAK inhibitors - tofacitinib, baricitinib and upadacitinib - have already been approved by the European Medicines Agency for the treatment of rheumatoid arthritis. JAK inhibitors have a rapid onset of action, are effective in monotherapy similar to that in combination with methotrexate and are particularly effective in monotherapy than tumor necrosis factor inhibitors. As with biologic therapy, there is a greater risk of serious infections with JAK inhibitors. Herpes zoster is more common compared with biologic therapy. In clinical practice, caution should be exercised in patients at increased risk of thromboembolic events. In clinical practice, caution should be exercised in patients at increased risk of thromboembolic events. In this final work, the experience of clinical practice based on the national ATTRA registry will be discussed.

• Klíčová slova
• ATTRA,
• MeSH
• biomarkery farmakologické analýza   MeSH
• cytokiny imunologie   metabolismus   MeSH
• infekce chemicky indukované   MeSH
• inhibitory Janus kinas * aplikace a dávkování   klasifikace   škodlivé účinky   MeSH
• Janus kinasy imunologie   metabolismus   MeSH
• lidé MeSH
• registrace statistika a číselné údaje   MeSH
• revmatoidní artritida * farmakoterapie   MeSH
• riziko MeSH
• schvalování léčiv MeSH
• statistika jako téma MeSH
• tromboembolie chemicky indukované   epidemiologie   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH

Mitochondrial dysfunctions belong amongst the most common metabolic diseases but the signalling networks that lead to the manifestation of a disease phenotype are often not well understood. We identified the subunits of respiratory complex I, III and IV as mediators of major signalling changes during Drosophila wing disc development. Their downregulation in larval wing disc leads to robust stimulation of TOR activity, which in turn orchestrates a complex downstream signalling network. Specifically, after downregulation of the complex I subunit ND-49 (mammalian NDUFS2), TOR activates JNK to induce cell death and ROS production essential for the stimulation of compensatory apoptosis-induced proliferation within the tissue. Additionally, TOR upregulates Notch and JAK/STAT signalling and it directs glycolytic switch of the target tissue. Our results highlight the central role of TOR signalling in mediating the complex response to mitochondrial respiratory dysfunction and they provide a rationale why the disease symptoms associated with respiratory dysfunctions are often alleviated by mTOR inhibitors.

• MeSH
• down regulace MeSH
• Drosophila MeSH
• Janus kinasy metabolismus   MeSH
• křídla zvířecí růst a vývoj   metabolismus   MeSH
• proteiny Drosophily genetika   metabolismus   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• receptory Notch metabolismus   MeSH
• respirační komplex I genetika   metabolismus   MeSH
• signální transdukce * MeSH
• transkripční faktory STAT metabolismus   MeSH
• tyrosinkinasové receptory metabolismus   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Honeybee workers undergo metamorphosis in capped cells for approximately 13 days before adult emergence. During the same period, Varroa mites prick the defenseless host many times. We sought to identify proteome differences between emerging Varroa-parasitized and parasite-free honeybees showing the presence or absence of clinical signs of deformed wing virus (DWV) in the capped cells. A label-free proteomic analysis utilizing nanoLC coupled with an Orbitrap Fusion Tribrid mass spectrometer provided a quantitative comparison of 2316 protein hits. Redundancy analysis (RDA) showed that the combination of Varroa parasitism and DWV clinical signs caused proteome changes that occurred in the same direction as those of Varroa alone and were approximately two-fold higher. Furthermore, proteome changes associated with DWV signs alone were positioned above Varroa in the RDA. Multiple markers indicate that Varroa activates TGF-β-induced pathways to suppress wound healing and the immune response and that the collective action of stressors intensifies these effects. Furthermore, we indicate JAK/STAT hyperactivation, p53-BCL-6 feedback loop disruption, Wnt pathway activation, Wnt/Hippo crosstalk disruption, and NF-κB and JAK/STAT signaling conflict in the Varroa-honeybee-DWV interaction. These results illustrate the higher effect of Varroa than of DWV at the time of emergence. Markers for future research are provided.

• MeSH
• biologické markery MeSH
• biologické modely MeSH
• histony metabolismus   MeSH
• Janus kinasy metabolismus   MeSH
• protein-serin-threoninkinasy metabolismus   MeSH
• proteiny Wnt metabolismus   MeSH
• proteom * MeSH
• proteomika * MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• RNA-viry * MeSH
• signální transdukce MeSH
• symbióza * MeSH
• transformující růstový faktor beta * MeSH
• transkripční faktory STAT metabolismus   MeSH
• Varroidae * MeSH
• včely metabolismus   parazitologie   virologie   MeSH
• výpočetní biologie metody   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

This review describes the IL-20 family of cytokines in rheumatoid arthritis (RA) and spondyloartrhitits (SpA) including psoriatic arthritis. The IL-20 receptor (R) cytokines IL-19, IL-20, and IL-24 are produced in both the peripheral blood and the synovial joint and are induced by Toll-like receptor ligands and autoantibody-associated immune complexes in monocytes. IL-19 seems to have anti-inflammatory functions in arthritis. In contrast, IL-20 and IL-24 increase the production of proinflammatory molecules such as monocyte chemoattractant protein 1 and are associated with bone degradation and radiographic progression. IL-22 is also associated with progression of bone erosions. This suggests that the IL-22RA1 subunit shared by IL-20, IL-22, and IL-24 is important for bone homeostasis. In line with this, the IL-22RA1 has been found on preosteoclasts in early RA. IL-26 is produced in high amounts by myofibroblasts and IL-26 stimulation of monocytes is an important inducer of Th17 cells in RA. This indicates a role for IL-26 as an important factor in the interactions between resident synovial cells and infiltrating leukocytes. Clinical trials that investigate inhibitors of IL-20 (fletikumab) and IL-22 (fezakinumab) in psoriasis and RA have been terminated. Instead, it seems that the strategy for modulating the IL-20 cytokine family should take the overlap in cellular sources and effector mechanisms into account. The redundancy encourages inhibition of more than one cytokine or one of the shared receptors. All IL-20 family members utilize the Janus kinase signaling pathway and are therefore potentially inhibited by drugs targeting these enzymes. Effects and adverse effects in ongoing clinical trials with inhibitors of IL-22 and the IL-22RA1 subunit and recombinant IL-22 fusion proteins will possibly provide important information about the IL-20 subfamily of cytokines in the future.

• MeSH
• humanizované monoklonální protilátky MeSH
• interleukiny antagonisté a inhibitory   imunologie   metabolismus   MeSH
• Janus kinasy imunologie   metabolismus   MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• monoklonální protilátky farmakologie   terapeutické užití   MeSH
• neutralizující protilátky farmakologie   terapeutické užití   MeSH
• osteoklasty imunologie   metabolismus   MeSH
• psoriatická artritida farmakoterapie   imunologie   MeSH
• receptory interleukinů antagonisté a inhibitory   imunologie   metabolismus   MeSH
• revmatoidní artritida farmakoterapie   imunologie   MeSH
• signální transdukce imunologie   MeSH
• široce neutralizující protilátky MeSH
• synoviální membrána cytologie   imunologie   metabolismus   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T-cells with an urgent need for rationally designed therapies to address its notoriously chemo-refractory behavior. The median survival of T-PLL patients is <2 years and clinical trials are difficult to execute. Here we systematically explored the diversity of drug responses in T-PLL patient samples using an ex vivo drug sensitivity and resistance testing platform and correlated the findings with somatic mutations and gene expression profiles. Intriguingly, all T-PLL samples were sensitive to the cyclin-dependent kinase inhibitor SNS-032, which overcame stromal-cell-mediated protection and elicited robust p53-activation and apoptosis. Across all patients, the most effective classes of compounds were histone deacetylase, phosphoinositide-3 kinase/AKT/mammalian target of rapamycin, heat-shock protein 90 and BH3-family protein inhibitors as well as p53 activators, indicating previously unexplored, novel targeted approaches for treating T-PLL. Although Janus-activated kinase-signal transducer and activator of transcription factor (JAK-STAT) pathway mutations were common in T-PLL (71% of patients), JAK-STAT inhibitor responses were not directly linked to those or other T-PLL-specific lesions. Overall, we found that genetic markers do not readily translate into novel effective therapeutic vulnerabilities. In conclusion, novel classes of compounds with high efficacy in T-PLL were discovered with the comprehensive ex vivo drug screening platform warranting further studies of synergisms and clinical testing.

• MeSH
• antitumorózní látky farmakologie   terapeutické užití   MeSH
• buněčný cyklus genetika   MeSH
• chemorezistence * MeSH
• chromozomální aberace MeSH
• cílená molekulární terapie MeSH
• exprese genu MeSH
• fenotyp MeSH
• inhibitory proteinkinas farmakologie   MeSH
• Janus kinasy metabolismus   MeSH
• léky antitumorózní - screeningové testy * MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace * MeSH
• nádorové biomarkery * MeSH
• nádorové buněčné linie MeSH
• oxazoly farmakologie   MeSH
• rychlé screeningové testy * MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• stanovení celkové genové exprese MeSH
• T-buněčná prolymfocytární leukemie farmakoterapie   genetika   metabolismus   MeSH
• thiazoly farmakologie   MeSH
• transkripční faktory STAT metabolismus   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

After peripheral nerve injury microglial reactivity change in the spinal cord is associated with an early activation of Janus kinase (JAK)/STAT3 transduction pathway whose blockade attenuates local inflammation and pain hypersensitivity. However, the consequences of microglial JAK/STAT3-mediated signaling on neighboring cells are unknown. Using an in vitro paradigm we assessed the impact of microglial JAK/STAT3 activity on functional characteristics of astrocytes and spinal cord neurons. Purified rat primary microglia was stimulated with JAK/STAT3 classical activator interleukin-6 in the presence or absence of a selective STAT3 inhibitor and rat primary astrocytes or spinal cord neurons were exposed to microglia conditioned media (CM). JAK/STAT3 activity-generated microglial CM modulated both astrocyte and neuron characteristics. Beyond inducing mRNA expression changes in various targets of interest in astrocytes and neurons, microglia CM activated c-Jun N-terminal kinase, STAT3 and NF-κB intracellular pathways in astrocytes and promoted their proliferation. Without modifying neuronal excitability or survival, CM affected the nerve processes morphology and distribution of the post-synaptic density protein 95, a marker of glutamatergic synaptic contacts. These findings show that JAK/STAT3 activity in microglia impacts the functional characteristics of astrocytes and neurons. This suggests its participation in spinal cord tissue plasticity and remodeling occurring after peripheral nerve injury. We show that the activity of JAK/STAT3 pathway in microglial cells confers them a specific signaling modality toward neighboring cells, promoting astrocyte proliferation and changes in neuronal morphology. These in vitro data suggest that the early JAK/STAT3 activation in spinal cord microglia, associated with peripheral nerve injury, participates in functional alteration of various cell populations and in spinal tissue remodeling.

• MeSH
• astrocyty metabolismus   MeSH
• Janus kinasy metabolismus   MeSH
• krysa rodu rattus MeSH
• kultivované buňky MeSH
• mícha cytologie   metabolismus   MeSH
• mikroglie metabolismus   MeSH
• neurony metabolismus   MeSH
• potkani Sprague-Dawley MeSH
• signální transdukce fyziologie   MeSH
• transkripční faktor STAT3 metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

T-2 toxin, a major compound of trichothecenes, inhibits protein synthesis and induces inflammation and cell apoptosis through the activation of MAPK pathway. The JAK/STAT pathway has recently been shown to be downstream targets of trichothecenes. However, whether there is any crosstalk between JNK and JAK/STAT pathways in trichothecene toxicity has not been studied. In the present study, we explored this potential in RAW264.7 cells treated with T-2 toxin. Our results revealed a crosstalk between JNK1 and STAT3 after T-2 toxin treatment, which was mediated by K-Ras. T-2 toxin treatment resulted in rapid phosphorylation, and more importantly, JNK1-STAT3 signaling pathway was shown to maintain the normal function of the mitochondria and to inhibit T-2 toxin-induced apoptosis. Therefore, this pathway was considered to be a potential cell survival pathway. Breakdown and degranulation of ribosomes in the rough endoplasmic reticulum and swelling of mitochondria were clearly visible after the cells had been incubated with T-2 toxin for 12h. Our data suggest that T-2 toxin had a Janus face: it induced both apoptotic and cell survival pathways. These results suggest that the crosstalk and the balance between MAPK and JAK/STAT pathway might be involved in T-2 toxin-induced apoptosis in RAW264.7 cells.

• MeSH
• anthraceny farmakologie   MeSH
• apoptóza účinky léků   MeSH
• biologické modely MeSH
• buněčné linie MeSH
• cytokiny genetika   metabolismus   MeSH
• fluorescenční protilátková technika MeSH
• fosforylace účinky léků   MeSH
• Janus kinasy metabolismus   MeSH
• kinetika MeSH
• makrofágy cytologie   účinky léků   metabolismus   ultrastruktura   MeSH
• mitochondrie účinky léků   metabolismus   ultrastruktura   MeSH
• mitogenem aktivovaná proteinkinasa 8 metabolismus   MeSH
• myši MeSH
• ras proteiny metabolismus   MeSH
• regulace genové exprese účinky léků   MeSH
• ribozomy účinky léků   metabolismus   ultrastruktura   MeSH
• signální transdukce * účinky léků   MeSH
• T-2 toxin farmakologie   MeSH
• transkripční faktor STAT3 metabolismus   MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Tofacitinib je nový lék zasahující na úrovni nitrobuněčné signalizace imunitní a zánětlivé odpovědi. Cíleně ovlivňuje skupinu enzymů známých jako Janusovy kinázy. Ty jsou regulovány několika cytokiny, které podporují aktivitu lymfocytů. Tofacitinib je určen pro perorální podávání a nedávno byl schválen americkým Úřadem pro kontrolu potravin a léčiv pro léčbu středně až vysoce aktivní revmatoidní artritidy s nedostatečným účinkem nebo nesnášenlivostí methotrexátu. Může být podáván v monoterapii nebo v kombinaci s chorobu modifikující antirevmatickou léčbou. Účinnost a bezpečnost tofacitinibu byla prokázána v několika klinických studiích u různých skupin pacientů s revmatoidní artritidou. Otevřené extenze klinických studií mají za úkol zhodnotit dlouhodobou účinnost a bezpečnostní profil tofacitinibu, který se může potenciálně stát lékem pro terapii dalších imunitně zprostředkovaných onemocnění.

Tofacitinib is a new drug exhibiting its action at the level of intracellular signalling and inflammatory response. It targets the group of enzymes known as Janus kinases. These are regulated by several cytokines that support the activity of lymphocytes. Tofacitinib is intended for oral administration and has recently been approved by the FDA for the treatment of moderate to high activity rheumatoid arthritis with insufficient effects or intolerance of methotrexate. It can be administered in monotherapy or in combination with disease-modifying antirheumatic drugs. The efficacy and safety of tofacitinib was shown in several clinical trials in various groups of patients with rheumatoid arthritis. Open extensions of clinical trials serve the purpose to evaluate long-term efficacy and the safety profile of tofacitinib that has the potential to become the drug of choice for the treatment of other immune system mediated diseases.

• MeSH
• aplikace orální MeSH
• biologická terapie MeSH
• inhibitory proteinkinas antagonisté a inhibitory   MeSH
• Janus kinasy * antagonisté a inhibitory   aplikace a dávkování   farmakokinetika   metabolismus   škodlivé účinky   terapeutické užití   MeSH
• klinické zkoušky, fáze II jako téma MeSH
• klinické zkoušky, fáze III jako téma MeSH
• lidé MeSH
• rekonciliace medikace MeSH
• revmatoidní artritida * farmakoterapie   MeSH
• TNF-alfa antagonisté a inhibitory   aplikace a dávkování   farmakokinetika   škodlivé účinky   terapeutické užití   MeSH
• Check Tag
• lidé MeSH

• MeSH
• aktivace transkripce imunologie   MeSH
• biologická terapie metody   MeSH
• cytokiny fyziologie   genetika   chemie   MeSH
• inhibitory enzymů * škodlivé účinky   terapeutické užití   MeSH
• intracelulární signální peptidy a proteiny metabolismus   MeSH
• Janus kinasy * antagonisté a inhibitory   metabolismus   MeSH
• lidé MeSH
• receptory cytokinové chemie   imunologie   MeSH
• regulace genové exprese imunologie   účinky léků   MeSH
• revmatoidní artritida * farmakoterapie   imunologie   metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• klinické zkoušky MeSH