Vaccinia virus (VACV) is an enveloped DNA virus from the Orthopoxvirus family, various strains of which were used in the successful eradication campaign against smallpox. Both original and newer VACV-based replicating vaccines reveal a risk of serious complications in atopic individuals. VACV encodes various factors interfering with host immune responses at multiple levels. In atopic skin, the production of type I interferon is compromised, while VACV specifically inhibits the phosphorylation of the Interferon Regulatory Factor 3 (IRF-3) and expression of interferons. To overcome this block, we generated a recombinant VACV-expressing murine IRF-3 (WR-IRF3) and characterized its effects on virus growth, cytokine expression and apoptosis in tissue cultures and in spontaneously atopic Nc/Nga and control Balb/c mice. Further, we explored the induction of protective immune responses against a lethal dose of wild-type WR, the surrogate of smallpox. We demonstrate that the overexpression of IRF-3 by WR-IRF3 increases the expression of type I interferon, modulates the expression of several cytokines and induces superior protective immune responses against a lethal poxvirus challenge in both Nc/Nga and Balb/c mice. Additionally, the results may be informative for design of other virus-based vaccines or for therapy of different viral infections.

• Klíčová slova
• IRF-3, Nc/Nga mice, atopic dermatitis, cytokines, eczema vaccinatum, immunization, interferon beta, interleukin-1 beta, smallpox, vaccinia virus,
• MeSH
• exprese genu genetika   MeSH
• imunita imunologie   MeSH
• infekce vyvolané poxviry imunologie   prevence a kontrola   MeSH
• interferon typ I metabolismus   MeSH
• interferonový regulační faktor 3 genetika   imunologie   MeSH
• interleukin-1beta imunologie   MeSH
• kůže imunologie   MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• Poxviridae patogenita   MeSH
• regulace exprese virových genů genetika   MeSH
• replikace viru imunologie   MeSH
• vakcínie virologie   MeSH
• virové vakcíny imunologie   MeSH
• virus vakcinie genetika   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• interferon typ I MeSH
• interferonový regulační faktor 3 MeSH
• interleukin-1beta MeSH
• virové vakcíny MeSH

Type I interferon (IFN), mainly produced by dendritic cells (DCs), is critical in the host defence against tick-transmitted pathogens. Here, we report that salivary cysteine protease inhibitor from the hard tick Ixodes scapularis, sialostatin L2, affects IFN-β mediated immune reactions in mouse dendritic cells. Following IFN receptor ligation, the Janus activated kinases/signal transducer and activator of transcription (JAK/STAT) pathway is activated. We show that sialostatin L2 attenuates phosphorylation of STATs in spleen dendritic cells upon addition of recombinant IFN-β. LPS-stimulated dendritic cells release IFN-β which in turn leads to the induction of IFN-stimulated genes (ISG) through JAK/STAT pathway activation. The induction of two ISG, interferon regulatory factor 7 (IRF-7) and IP-10, was suppressed by sialostatin L2 in LPS-stimulated dendritic cells. Finally, the interference of sialostatin L2 with IFN action led to the enhanced replication of tick-borne encephalitis virus in DC. In summary, we present here that tick salivary cystatin negatively affects IFN-β responses which may consequently increase the pathogen load after transmission via tick saliva.

• Klíčová slova
• cystatin, dendritic cell, interferon, tick,
• MeSH
• Borrelia burgdorferi fyziologie   MeSH
• cystatiny imunologie   MeSH
• dendritické buňky imunologie   MeSH
• fosforylace MeSH
• interferon beta imunologie   MeSH
• interferonový regulační faktor 7 imunologie   MeSH
• klíště imunologie   mikrobiologie   MeSH
• lipopolysacharidy imunologie   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• receptory cytokinové imunologie   MeSH
• receptory interferonů metabolismus   MeSH
• slinné cystatiny imunologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cystatiny MeSH
• interferon beta MeSH
• interferonový regulační faktor 7 MeSH
• IP10-Mig receptor MeSH Prohlížeč
• Irf7 protein, mouse MeSH Prohlížeč
• lipopolysacharidy MeSH
• receptory cytokinové MeSH
• receptory interferonů MeSH
• sialostatin L, Ixodes scapularis MeSH Prohlížeč
• slinné cystatiny MeSH

Kaposi sarcoma-associated herpesvirus is associated with two lymphoproliferative disorders, primary effusion lymphoma (PEL) and Castleman disease. In PEL, Kaposi sarcoma-associated herpesvirus is present in a latent form expressing only few viral genes. Among them is a viral homologue of cellular interferon regulatory factors, vIRF-3. To study the role of vIRF-3 in PEL lymphomagenesis, we analyzed the interaction of vIRF-3 with cellular proteins. Using yeast two-hybrid screen, we detected the association between vIRF-3 and c-Myc suppressor, MM-1alpha. The vIRF-3 and MM-1alpha interaction was also demonstrated by glutathione S-transferase pulldown assay and coimmunoprecipitation of endogenous vIRF-3 and MM-1alpha in PEL-derived cell lines. Overexpression of vIRF-3 enhanced the c-Myc-dependent transcription of the gene cdk4. Addressing the molecular mechanism of the vIRF-3-mediated stimulation, we demonstrated that the association between MM-1alpha and c-Myc was inhibited by vIRF-3. Furthermore, the recruitment of vIRF-3 to the cdk4 promoter and the elevated levels of the histone H3 acetylation suggest the direct involvement of vIRF-3 in the activation of c-Myc-mediated transcription. These findings indicate that vIRF-3 can effectively stimulate c-Myc function in PEL cells and consequently contribute to de-regulation of B-cell growth and differentiation.

• MeSH
• genová knihovna MeSH
• interferonové regulační faktory metabolismus   MeSH
• interferonový regulační faktor 3 metabolismus   MeSH
• lidé MeSH
• lidský herpesvirus 8 metabolismus   MeSH
• nádorové buněčné linie MeSH
• primární efuzivní lymfom metabolismus   MeSH
• protoonkogenní proteiny c-myc metabolismus   MeSH
• techniky dvojhybridového systému MeSH
• virové proteiny metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• interferonové regulační faktory MeSH
• interferonový regulační faktor 3 MeSH
• protoonkogenní proteiny c-myc MeSH
• viral interferon regulatory factors MeSH Prohlížeč
• virové proteiny MeSH

Coevolution of ticks and the vertebrate immune system has led to the development of immunosuppressive molecules that prevent immediate response of skin-resident immune cells to quickly fend off the parasite. In this article, we demonstrate that the tick-derived immunosuppressor sialostatin L restrains IL-9 production by mast cells, whereas degranulation and IL-6 expression are both unaffected. In addition, the expression of IL-1β and IRF4 is strongly reduced in the presence of sialostatin L. Correspondingly, IRF4- or IL-1R-deficient mast cells exhibit a strong impairment in IL-9 production, demonstrating the importance of IRF4 and IL-1 in the regulation of the Il9 locus in mast cells. Furthermore, IRF4 binds to the promoters of Il1b and Il9, suggesting that sialostatin L suppresses mast cell-derived IL-9 preferentially by inhibiting IRF4. In an experimental asthma model, mast cell-specific deficiency in IRF4 or administration of sialostatin L results in a strong reduction in asthma symptoms, demonstrating the immunosuppressive potency of tick-derived molecules.

• MeSH
• bronchiální astma genetika   imunologie   patologie   MeSH
• cystatiny imunologie   farmakologie   MeSH
• degranulace buněk imunologie   MeSH
• genetická transkripce MeSH
• imunosupresiva farmakologie   MeSH
• interakce hostitele a parazita imunologie   MeSH
• interferonové regulační faktory nedostatek   genetika   imunologie   MeSH
• interleukin-1beta genetika   imunologie   MeSH
• interleukin-6 genetika   imunologie   MeSH
• interleukin-9 antagonisté a inhibitory   genetika   imunologie   MeSH
• mastocyty účinky léků   imunologie   patologie   MeSH
• myši inbrední BALB C MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• přirozená imunita účinky léků   MeSH
• promotorové oblasti (genetika) MeSH
• receptory interleukinu-1 genetika   imunologie   MeSH
• regulace genové exprese MeSH
• signální transdukce MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Intramural MeSH
• Názvy látek
• cystatiny MeSH
• imunosupresiva MeSH
• interferon regulatory factor-4 MeSH Prohlížeč
• interferonové regulační faktory MeSH
• interleukin-1beta MeSH
• interleukin-6 MeSH
• interleukin-9 MeSH
• receptory interleukinu-1 MeSH
• sialostatin L, Ixodes scapularis MeSH Prohlížeč

PURPOSE: The aim of the study was to compare the effect of three initial doses of the anti-VEGF ranibizumab and aflibercept medication on serous pigment epithelial detachment (PED), subretinal fluid (SRF) and intraretinal fluid (IRF) in the macula of treatment naive neovascular AMD (nvAMD) patients. MATERIAL AND METHODS: The cohort consists of 148 patients, of which 74 patients were treated with ranibizumab (51 females and 23 males) and 74 with aflibercept (46 females and 28 males). The data was recorded prospectively from the moment of diagnosis and start of treatment for a period of 3 months. At the moment of diagnosis and 3 months later, an OCT examination (Spectralis OCT, Heidelberg Engineering, Heidelberg, Germany) was performed. The OCT examination included a macular scan with 25 scans. Using the OCT instrument software, we measured the maximum anterior-posterior elevation of serous PED, the highest thickness of SRF and the largest diameter of the intraretinal cystic space. The statistical significance of differences between groups was evaluated using the t-test for continuous data and the Fisher exact test for categorical data. Changes in values of continuous variables over time were evaluated using the Wilcoxon paired test. Paired comparisons of binary parameters were determined by the McNemar test. RESULTS: Full regression of PED, SRF and IRF occurred in 3 (4.1%), 25 (39%) and 20 (51%) patients treated with ranibizumab, and in 5 (7.9%, p = 0.470), 28 (47%, p = 0.470) and 25 (57%, p = 0.827) patients treated with aflibercept, respectively. The average regression of PED, SRF and IRF was -60.4 μm (median -37.5 μm), -84.3 μm (median -85 μm) and -109.3 μm (median -81 μm) in patients treated with ranibizumab, and -46.3 μm (median -30 μm, p = 0.389), -127.7 μm (median -104 μm, p = 0.096) and -204.4 μm (median -163 μm, p = 0.005) in patients treated with aflibercept, respectively. We did not show a statistically significant difference in the regression rates of PED, SRF and IRF between the ranibizumab and aflibercept groups. (in patients with IRF after adjustment of the higher baseline IRF volumes in patients treated with aflibercept, p = 0.891). CONCLUSION: We are convinced that ranibizumab and aflibercept have the same effect on serous PED, SRF and IRF in the macula in patients with treatment naive nvAMD during the initial loading phase.

• Klíčová slova
• aflibercept, age related macular degeneration, age-related macular degeneration, intraretinal fluid, pigment epithelium detachment, ranibizumab, subretinal fluid,
• MeSH
• inhibitory angiogeneze farmakologie   terapeutické užití   MeSH
• injekce intravitreální MeSH
• lidé MeSH
• odchlípení sítnice * diagnóza   MeSH
• optická koherentní tomografie MeSH
• ranibizumab terapeutické užití   MeSH
• receptory vaskulárního endoteliálního růstového faktoru MeSH
• rekombinantní fúzní proteiny terapeutické užití   MeSH
• retinální pigmenty terapeutické užití   MeSH
• retrospektivní studie MeSH
• vaskulární endoteliální růstový faktor A MeSH
• vlhká makulární degenerace * diagnóza   farmakoterapie   MeSH
• zraková ostrost MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• aflibercept MeSH Prohlížeč
• inhibitory angiogeneze MeSH
• ranibizumab MeSH
• receptory vaskulárního endoteliálního růstového faktoru MeSH
• rekombinantní fúzní proteiny MeSH
• retinální pigmenty MeSH
• vaskulární endoteliální růstový faktor A MeSH

Some patients with relapsed/refractory Hodgkin lymphoma (HL) are not considered suitable for stem cell transplant (SCT) and have a poor prognosis. This phase IV study (NCT01990534) evaluated brentuximab vedotin (1·8 mg/kg intravenously once every 3 weeks) in 60 patients (aged ≥18 years) with CD30-positive relapsed/refractory HL, a history of ≥1 prior systemic chemotherapy regimen, who were considered unsuitable for SCT/multi-agent chemotherapy. Primary endpoint was overall response rate (ORR) per independent review facility (IRF). Secondary endpoints included duration of response (DOR), progression-free survival (PFS) per IRF, overall survival (OS), proportion proceeding to SCT and safety. The ORR was 50%, with 12% CR; 47% proceeded to SCT. Median DOR was 4·6 months and median duration of CR was 6·1 months. After a median follow-up of 6·9 and 16·6 months, median PFS and OS were 4·8 months (95% confidence interval, 3·0-5·3) and not reached, respectively; estimated OS rate was 86% at 12 months. Most common adverse events (≥10%) were peripheral neuropathy (35%), pyrexia (18%), diarrhoea and neutropenia (each 10%). Brentuximab vedotin showed notable activity with a safety profile consistent with known toxicities, and may act as a bridge to SCT, enabling high-risk patients who achieve suboptimal response to frontline/salvage chemotherapy/radiotherapy to receive potentially curative SCT.

• Klíčová slova
• Hodgkin lymphoma, brentuximab vedotin, novel anti-tumour agents, phase IV, relapsed/refractory,
• MeSH
• brentuximab vedotin MeSH
• dospělí MeSH
• Hodgkinova nemoc farmakoterapie   mortalita   MeSH
• imunokonjugáty aplikace a dávkování   škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• míra přežití MeSH
• mladiství MeSH
• následné studie MeSH
• přežití bez známek nemoci MeSH
• prospektivní studie MeSH
• protokoly protinádorové kombinované chemoterapie MeSH
• rizikové faktory MeSH
• senioři MeSH
• transplantace kmenových buněk MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze IV MeSH
• multicentrická studie MeSH
• Názvy látek
• brentuximab vedotin MeSH
• imunokonjugáty MeSH

Despite currently used intravesical therapies in non-muscle-invasive bladder cancer (NMIBC), the rate of intravesical recurrence remains very high. We aimed to evaluate the effectiveness of adding nonintravesical interventions to standard intravesical therapies to prevent intravesical recurrence. In April 2024, 3 databases were queried for prospective studies evaluating nonintravesical interventions in addition to standard intravesical therapies for NMIBC (CRD42024490988). The primary outcome was intravesical recurrence-free survival (iRFS). Standard pairwise meta-analyses were performed using hazard ratios (HR) and 95% confidence intervals (95% CI) with a random-effects model. We identified 18 eligible studies (14 RCTs and 4 prospective trials) comprising 4,593 NMIBC patients, which investigated pharmacological interventions (eg, selenium, vitamins, Lactobacillus casei, celecoxib, metformin, mistletoe lectin) and lifestyle modifications (diet). The addition of Lactobacillus casei significantly improved iRFS (HR: 0.50; 95% CI: 0.34-0.73; P < .001). A high western diet pattern significantly worsened iRFS (HR:1.48, 95%CI:1.06-2.06, P = .03). The other nonintravesical interventions were not associated with iRFS. Our comprehensive review of the published literature highlights the need for further research into the efficacy of nonvesical interventions for NMIBC. While Lactobacillus was shown to improve iRFS in 2 RCTs, additional high-quality randomized studies are required to evaluate the effectiveness of other interventions.

• Klíčová slova
• Celecoxib, Diet, Lactobacillus casei, Non-muscle-invasive bladder cancer, Vitamins,
• MeSH
• aplikace intravezikální MeSH
• Lactobacillus casei MeSH
• lidé MeSH
• lokální recidiva nádoru * prevence a kontrola   MeSH
• nádory močového měchýře * terapie   patologie   prevence a kontrola   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• přehledy MeSH
• systematický přehled MeSH