Cytokines in tear fluid of patients with ocular graft-versus-host disease after allogeneic stem cell transplantation

Purpose: To investigate the profile of cytokines in tear fluid of patients after allogeneic stem cell transplantation (allo-SCT) and determine their relation to the presence and manifestations of ocular graft-versus-host disease (GvHD). Methods: In this cross sectional study tear fluid was collected in 34 consecutive adult patients that previously underwent allo-SCT (16 with ocular GvHD and 18 without) and 16 age- and gender-matched healthy controls using the Schirmer test under local anesthesia. Tear fluid was analyzed by multiplex immunoassay for the presence of interleukin (IL)-2, IL-4, IL-6, IL-10, IL-17, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma. Levels of measured cytokines were correlated with the find Results: The levels of IL-6 and IFN-gamma in tear fluid in ocular GvHD patients were significantly elevated in comparison to patients without ocular GvHD and healthy controls (p<0.005 for each) The levels of IFN-gamma correlated with the Schirmer score (r=-0.48, p<0.0001) and tear break up time (TBUT; r=-0.38, p=0.03). Tear IL-6 levels correlated with complaints of dry eyes (r=0.39, p=0.02), tear production (r=-0.59, p<0.0001), fluorescent staining of the cornea (r=0.42, p=0.01), and with the OS Conclusions: IL-6 and IFN-gamma were elevated in tear fluid of patients with ocular GvHD and correlated with different symptoms of dry eye disease, suggesting that IFN-gamma is elevated during the early stages and IL-6 is involved in later stages of ocular GVHD and exhibits moreover an association with its severity

Senųjų raštų morfologijos duomenų bazės taikymas semantikos tyrimams: veiksmažodžių semantika

[full article and abstract in Lithuanian; abstract in English] The Old Writings’ Morphology Database, created by Dalia Jakulytė, is adopted for semantics research by adding a semantics module. This module is created as a table of semantic features of every word form (the main entity of the database). The places for such semantic features are reserved: Meaning, Meaning Explanation, Section / Class / Type / Group, Semantic Field and Semantic Group. To verify the semantics module, the semantics of the infixed and sta stem verbs from Knyga nobažnystės (1653) was analysed on a DB basis. The semantic functions of the verbs were established. &nbsp; &nbsp;[straipsnis ir santrauka lietuvių kalba; santrauka anglų kalba] Straipsnyje pristatomos senųjų raštų morfologijos duomenų bazės taikymo semantikos tyrimams galimybės ir bandomasis Knygos nobažnystės intarpinių ir sta kamieno veiksmažodžių semantikos tyrimas. Detalizuotas duomenų bazės semantikos modelis leido greitai ir tiksliai surinkti bei suklasifikuoti empirinę medžiagą Knygos nobažnystės veiksmažodžių semantinių vaidmenų tyrimui, atskleidusiam analizuojamos predikatinės struktūros ypatumus

Association of Risk Variants in the <i>CFH </i>Gene With Elevated Levels of Coagulation and Complement Factors in Idiopathic Multifocal Choroiditis

Importance: Idiopathic multifocal choroiditis (MFC) is poorly understood, thereby hindering optimal treatment and monitoring of patients. Objective: To identify the genes and pathways associated with idiopathic MFC. Design, Setting, and Participants: This was a case-control genome-wide association study (GWAS) and protein study of blood plasma samples conducted from March 2006 to February 2022. This was a multicenter study involving 6 Dutch universities. Participants were grouped into 2 cohorts: cohort 1 consisted of Dutch patients with idiopathic MFC and controls, and cohort 2 consisted of patients with MFC and controls. Plasma samples from patients with idiopathic MFC who had not received treatment were subjected to targeted proteomics. Idiopathic MFC was diagnosed according to the Standardization of Uveitis Nomenclature (SUN) Working Group guidelines for punctate inner choroidopathy and multifocal choroiditis with panuveitis. Data were analyzed from July 2021 to October 2022. Main outcomes and measures: Genetic variants associated with idiopathic MFC and risk variants associated with plasma protein concentrations in patients. Results: This study included a total of 4437 participants in cohort 1 (170 [3.8%] Dutch patients with idiopathic MFC and 4267 [96.2%] controls; mean [SD] age, 55 [18] years; 2443 female [55%]) and 1344 participants in cohort 2 (52 [3.9%] patients with MFC and 1292 [96.1%] controls; 737 male [55%]). The primary GWAS association mapped to the CFH gene with genome-wide significance (lead variant the A allele of rs7535263; odds ratio [OR], 0.52; 95% CI, 0.41-0.64; P = 9.3 × 10-9). There was no genome-wide significant association with classical human leukocyte antigen (HLA) alleles (lead classical allele, HLA-A*31:01; P = .002). The association with rs7535263 showed consistent direction of effect in an independent cohort of 52 cases and 1292 control samples (combined meta-analysis OR, 0.58; 95% CI, 0.38-0.77; P = 3.0 × 10-8). In proteomic analysis of 87 patients, the risk allele G of rs7535263 in the CFH gene was strongly associated with increased plasma concentrations of factor H-related (FHR) proteins (eg, FHR-2, likelihood ratio test, adjusted P = 1.1 × 10-3) and proteins involved in platelet activation and the complement cascade. Conclusions and relevance: Results suggest that CFH gene variants increase systemic concentrations of key factors of the complement and coagulation cascades, thereby conferring susceptibility to idiopathic MFC. These findings suggest that the complement and coagulation pathways may be key targets for the treatment of idiopathic MFC.</p

New insights into the genetic component of non-infectious uveitis through an Immunochip strategy

Background: Large-scale genetic studies have reported several loci associated with specific disorders involving uveitis. Our aim was to identify genetic risk factors that might predispose to uveitis per se, independent of the clinical diagnosis, by performing a dense genotyping of immune-related loci. Methods: 613 cases and 3693 unaffected controls from three European case/control sets were genotyped using the Immunochip array. Only patients with non-infectious non-anterior uveitis and without systemic features were selected. To perform a more comprehensive analysis of the human leucocyte antigen (HLA) region, SNPs, classical alleles and polymorphic amino acid variants were obtained via imputation. A meta-analysis combining the three case/control sets was conducted by the inverse variance method. Results: The highest peak belonged to the HLA region. A more detailed analysis of this signal evidenced a strong association between the classical allele HLA-A*2902 and birdshot chorioretinopathy (p=3.21E-35, OR=50.95). An omnibus test yielded HLA-A 62 and 63 as relevant amino acid positions for this disease. In patients with intermediate and posterior uveitis, the strongest associations belonged to the rs7197 polymorphism, within HLA-DRA (p=2.07E-11, OR=1.99), and the HLA-DR15 haplotype (DRB1*1501: p=1.16E-10, OR=2.08; DQA1*0102: p=4.37E-09, OR=1.77; DQB1*0602: p=7.26E-10, OR=2.02). Outside the HLA region, the MAP4K4/IL1R2 locus reached statistical significance (rs7608679: p=8.38E-07, OR=1.42). Suggestive associations were found at five other loci. Conclusions: We have further interrogated the association between the HLA region and non-infectious non-anterior uveitis. In addition, we have identified a new non-HLA susceptibility factor and proposed additional risk loci with putative roles in this complex condition

Significance Analysis of Tourist Sports Events

Import 04/11/2015Cílem této bakalářské práce je popsání významu sportovních akcí v cestovním ruchu. Práce je rozdělena do dvou částí. První část představuje teoretická východiska zaměřená na cestovní ruch, sportovní událost, sportovní marketing a metody použité v práci. Druhá část práce obsahuje analýzu mezinárodních sportovních událostí v podobě olympijských her, Mistrovství světa ve fotbale. Podrobněji analyzuji sportovní události v České republice v roce 2015, Mistrovství Evropy ve fotbale do 21 let, Světový pohár v Biatlonu, Halové Mistrovství Evropy v Atletice a nejdůkladněji zkoumám Mistrovství světa v ledním hokeji 2015. Dotazník směřovaný pro návštěvníky hokejové sportovní události zkoumá dopady na turismus a cestovní ruch.The aim of this bachelor thesis is to describe significance analysis of tourist sports events. This thesis is divided in two parts. The first part presents the theoretical basis of tourist, sports events and sports marketing and methods used in work. The second part contains an analysis of international sporting events as the Olympic games and FIFA World Cup. I explain the influence of significant sport events in Czech republic in 2015, European Football Championship under 21 years, Biathlon World Cup and European Athletic Indoor Championships. I analyze in detail IIHF Hockey World Championship 2015. Questionnaire was made with questions focused on impact of tourism destinations and tourism.115 - Katedra managementuvýborn

A Disease-Associated MicroRNA Cluster Links Inflammatory Pathways and an Altered Composition of Leukocyte Subsets to Noninfectious Uveitis

PURPOSE. The cause of noninfectious uveitis (NIU) is poorly understood but is considered to be mediated by a complex interplay between genetic, environmental, and-relatively unexplored-epigenetic factors. MicroRNAs (miRNAs) are noncoding small RNAs that are important epigenetic regulators implicated in pathologic signaling. Therefore, we mapped the circulating miRNA-ome of NIU patients and studied miRNA perturbations within the broader context of the immune system.METHODS. We designed a strategy to robustly identify changes in the miRNA profiles of two independent cohorts totaling 54 untreated patients with active and eye-restricted disease and 26 age-matched controls. High-resolution miRNA-ome data were obtained by TaqMan OpenArray technology and subsequent RT-qPCR. Flow cytometry data, and proteomic data spanning the cellular immune system, were used to map the uveitis-miRNA signature to changes in the composition of specific leukocyte subsets in blood.RESULTS. Using stringent selection criteria, we identified and independently validated an miRNA cluster that is associated with NIU. Pathway enrichment analysis for genes targeted by this cluster revealed significant enrichment for the PI3K/Akt, MAPK, FOXO, and VEGF signaling pathways, and photoreceptor development. In addition, unsupervised multidomain analyses linked the presence of the uveitis-associated miRNA cluster to a different composition of leukocyte subsets, more specifically, CD16(+)CD11c(+)HLA-DR- cells.CONCLUSIONS. Together, this study identified a unique miRNA cluster associated with NIU that was related to changes in leukocyte subsets demonstrating systemic changes in epigenetic regulation underlying NIU

Rearranged EML4-ALK fusion transcripts sequester in circulating blood platelets and enable blood-based crizotinib response monitoring in non-small-cell lung cancer

Purpose: Non-small-cell lung cancers harboring EML4-ALK rearrangements are sensitive to crizotinib. However, despite initial response, most patients will eventually relapse, and monitoring EML4-ALK rearrangements over the course of treatment may help identify these patients. However, challenges associated with serial tumor biopsies have highlighted the need for blood-based assays for the monitoring of biomarkers. Platelets can sequester RNA released by tumor cells and are thus an attractive source for the non-invasive assessment of biomarkers. Methods: EML4-ALK rearrangements were analyzed by RT-PCR in platelets and plasma isolated from blood obtained from 77 patients with non-small-cell lung cancer, 38 of whom had EML4-ALK-rearranged tumors. In a subset of 29 patients with EML4-ALK-rearranged tumors who were treated with crizotinib, EML4-ALK rearrangements in platelets were correlated with progression-free and overall survival. Results: RT-PCR demonstrated 65% sensitivity and 100% specificity for the detection of EML4-ALK rearrangements in platelets. In the subset of 29 patients treated with crizotinib, progression-free survival was 3.7 months for patients with EML4-ALK+ platelets and 16 months for those with EML4-ALK− platelets (hazard ratio, 3.5; P = 0.02). Monitoring of EML4-ALK rearrangements in the platelets of one patient over a period of 30 months revealed crizotinib resistance two months prior to radiographic disease progression. Conclusions: Platelets are a valuable source for the non-invasive detection of EML4-ALK rearrangements and may prove useful for predicting and monitoring outcome to crizotinib, thereby improving clinical decisions based on radiographic imaging alone