31. Heritable risk for severe anaphylaxis associated with increased [alpha]-tryptase-encoding germline copy number at TPSAB1Jonathan J. Lyons, Jack Chovanec, Michael P. O'Connell, Yihui Liu, Julij Šelb, Roberta Zanotti, Yun Bai, Jiwon Kim, Quang T. Le, Tom DiMaggio, Matija Rijavec, Peter Korošec, 2020, izvirni znanstveni članek Povzetek: Background: An elevated basal serum tryptase level is associated with severe systemic anaphylaxis, most notably caused by Hymenoptera envenomation. Although clonal mast cell disease is the culprit in some individuals, it does not fully explain this clinical association. Objective: Our aim was to determine the prevalence and associated impact of tryptase genotypes on anaphylaxis in humans. Methods: Cohorts with systemic mastocytosis (SM) and venom as well as idiopathic anaphylaxis from referral centers in Italy, Slovenia, and the United States, underwent tryptase genotyping by droplet digital PCR. Associated anaphylaxis severity (Mueller scale) was subsequently examined. Healthy volunteers and controls with nonatopic disease were recruited and tryptase was genotyped by droplet digital PCR and in silico analysis of genome sequence, respectively. The effects of pooled and recombinant human tryptases, protease activated receptor 2 agonist and antagonist peptides, and a tryptase-neutralizing mAb on human umbilical vein endothelial cell permeability were assayed using a Transwell system. Results: Hereditary [alpha]-tryptasemia (H[alpha]T)--a genetic trait caused by increased [alpha]-tryptase-encoding Tryptase-[alpha]/[beta]1 (TPSAB1) copy number resulting in elevated BST level--was common in healthy individuals (5.6% [n = 7 of 125]) and controls with nonatopic disease (5.3% [n = 21 of 398]). H[alpha]T was associated with grade IV venom anaphylaxis (relative risk = 2.0; P < .05) and more prevalent in both idiopathic anaphylaxis (n = 8 of 47; [17%; P = .006]) and SM (n = 10 of 82 [12.2%; P = .03]) relative to the controls. Among patients with SM, concomitant H[alpha]T was associated with increased risk for systemic anaphylaxis (relative risk = 9.5; P = .007). In vitro, protease-activated receptor-2-dependent vascular permeability was induced by pooled mature tryptases but not [alpha]- or [beta]-tryptase homotetramers. Conclusions: Risk for severe anaphylaxis in humans is associated with inherited differences in [alpha]-tryptase-encoding copies at TPSAB1.
Ključne besede: mastocytosis, venoms, hypersensitivity, anaphylaxis - diagnosis, mast cells, idiopathic anaphylaxis, mast cell activation, hereditary alpha-tryptasemia
Objavljeno v DiRROS: 11.09.2020; Ogledov: 2007; Prenosov: 371
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32. Correlations between vitreous cytokine levels and inflammatory cells in fibrovascular membranes of patients with proliferative diabetic retinopathyMojca Urbančič, Danijel Petrovič, Aleksandra Milutinović Živin, Peter Korošec, Matjaž Fležar, Mojca Globočnik Petrovič, 2020, izvirni znanstveni članek Povzetek: Purpose: The purpose of this study was to investigate the levels of cytokines in the vitreous, and their correlation with the density of inflammatory cells in fibrovascular membranes (FVMs) in patients with proliferative diabetic retinopathy (PDR) to evaluate intraocular inflammatory conditions with regard to disease activity.Methods: Thirty-three patients (33 eyes) with PDR requiring vitreoretinal surgery because of FVMs and tractional detachment were enrolled in the study, and compared with 20 patients (20 eyes) with macular hole (MH; control group). All patients underwent complete ophthalmological examinations before surgery. The activity of the disease was noted in patients with PDR. Samples of vitreous and blood were taken, and cytokine (MCP-1, IL-8, IL-6, VEGF, IL-1%, TNF-%, MIP-1%, MIP-1%, IL-10, and IL-12) levels were measured using cytometric bead array (CBA). Samples of FVMs were analyzed with immunohistochemical methods for the presence of inflammatory cells (CD45+, CD14+, CD3+, CD4+, CD8+, and CD19+ cells), and the numerical areal density was calculated (NA). Spearman%s correlation was used to as-sess the association between variables. The Mann%Whitney test was used to assess the differences between independent groups. The Wilcoxon signed-rank test was used for assessing differences between two related groups. A p value of less than 0.05 was considered statistically significant.Results: Patients with active PDR had statistically significantly higher levels of MCP-1 (p = 0.003), VEGF (p = 0.009), and IL-8 (p = 0.02) in the vitreous in comparison with those with inactive PDR. CD45+, CD14+, CD3+, CD4+, CD8+, and CD19+ cells were identified in FVMs for patients with PDR. Statistically significantly higher numerical areal density of T lymphocytes (CD3+, CD4+, and CD8+) was demonstrated in patients with active PDR in comparison with patients with inactive PDR. Moderate to strong correlations were found between either MCP-1 or IL-8 in the vitreous, and the numerical areal density of cells (CD45+, CD3+, CD4+, and CD8+) in the FVMs, and weaker between either MCP-1 or IL-8 in the vitreous and the numerical areal density of CD14+ cells in the FVMs.Conclusions: The correlation of cytokine (MCP-1 and IL-8) vitreous levels with the density of inflammatory cells in FVMs, and differences in cytokine levels in the vitreous between patients with active and inactive PDR, and between the vitreous and serum in PDR indicate the importance of local intraocular inflammation in patients with PDR.
Ključne besede: diabetic retinopathy, fibrovascular membranes, inflammatory cells
Objavljeno v DiRROS: 09.09.2020; Ogledov: 1459; Prenosov: 693
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33. Unsuccessful desensitization to paclitaxel in a patient with high basophil sensitivityPeter Kopač, Ana Koren, Maja Jošt, Dushan Mangaroski, Mitja Lainščak, Peter Korošec, 2020, kratki znanstveni prispevek Ključne besede: basophil activation test, drug hypersensitivity, immunologic desensitization, paclitaxel
Objavljeno v DiRROS: 07.08.2020; Ogledov: 1648; Prenosov: 466
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34. Heat shock protein 27 as a predictor of prognosis in patients admitted to hospital with acute COPD exacerbationMatthias Zimmermann, Denise Traxler, Christine Bekos, Elisabeth Simader, Thomas Mueller, Alexandra Graf, Mitja Lainščak, Robert Marčun, Mitja Košnik, Matjaž Fležar, Aleš Rozman, Peter Korošec, 2020, izvirni znanstveni članek Povzetek: Episodes of acute exacerbations are major drivers of hospitalisation and death from COPD. To date, there are no objective biomarkers of disease activity or biomarkers to predict patient outcome. In this study, 211 patients hospitalised for an acute exacerbation of COPD have been included. At the time of admission,routine blood tests have been performed including complete blood count, C-reactive protein, cardiac troponin T and NT-proBNP. Heat shock protein 27 (HSP27) serum concentrations were determined at time of admission, discharge and 180 days after discharge by ELISA. We were able to demonstrate significantly increased HSP27 serum concentrations in COPD patients at time of admission to hospital as compared to HSP27 concentrations obtained 180 days after discharge. In univariable Cox regression analyses, a HSP27 serum concentration >/= 3098 pg/mL determined at admission was a predictor of all-cause mortality at 90 days, 180 days, 1 year and 3 years. In multivariable analyses, an increased HSP27 serum concentration at admission retained its prognostic ability with respect to all-cause mortality for up to 1year follow-up. However, an increased HSP27 serum concentration at admission was not an independent predictor of long-term all-cause mortality at 3 years. Elevated serum HSP27 concentrations significantly predicted short-term mortality in patients admitted to hospital with acute exacerbation of COPD and could help to improve outcomes by identifying high-risk patients.
Ključne besede: COPD, acute exacerbation, disease activity
Objavljeno v DiRROS: 29.07.2020; Ogledov: 1701; Prenosov: 1054
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36. Pomen hipoksije pri obsevanjuPeter Korošec, Mitja Anžič, Monika Češnjevar, Gaber Plavc, Irena Oblak, 2015, izvirni znanstveni članek Povzetek: Uspešnost zdravljenja z radioterapijo (RT) je odvisna od številnih dejavnikov, med katerimi je tudi oksigenacija tumorskih celic. Tumorske celice, ki so dobro preskrbljene s kisikom, so namreč na obsevanje tudi do 3-krat bolj občutljive kot hipoksične tumorske celice. Poleg tega deluje hipoksija v tumorjih kot selekcijski pritisk, zaradi katerega preživijo le bolj maligne celice, z manjšim apoptotskim potencialom. V prisotnosti hipoksije se povečata genomska nestabilnost in metastatski potencial tumorskih celic, zveča pa se tudi odpornost celic na kemoterapijo, kar vse vpliva na uspešnost zdravljenja z RT. Hipoksija je posledica neskladja med celičnim dihanjem, koncentracijo kisika v krvi in perfuzijo tumorja, pri čemer so najpogostejši patogenetski mehanizmi neustrezna ožiljenost, motena difuzija kisika ter anemija, ki je lahko posledica rakave bolezni ali zdravljenja. Z uporabo invazivnih in novejših neinvazivnih diagnostičnih metod lahko ocenimo delež hipoksičnih celic v tumorju in temu prilagodimo terapevtski pristop. Boljši učinek obsevanja slabše oksigeniranih tumorjev lahko dosežemo z uporabo radiosenzibilizatorjev, z izboljšanjem tumorske oksigenacije, s selektivnim uničenjem hipoksičnih celic s citotoksini ter z obsevanjem hipoksičnih predelov z višjimi obsevalnimi odmerki ob pomoči radioprotektorjev in z uporabo sodobnih obsevalnih tehnik.
Ključne besede: hipoksija, oksigenacija tumorskih celic, radioterapija, obsevanje
Objavljeno v DiRROS: 19.03.2018; Ogledov: 3779; Prenosov: 939
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