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Iskalni niz: "avtor" (Peter Korošec) .

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Art v 1 IgE epitopes of patients and humanized mice are conformational
Maja Zabel, Milena Weber, Bernhard Kratzer, Cordula Köhler, Beatrice Jahn-Schmid, Gabriele Gadermaier, Pia Gattinger, Urška Bidovec, Peter Korošec, Ursula Smole, Rudolf Valenta, Winfried F. Pickl, 2022, izvirni znanstveni članek

Povzetek: Background: Worldwide, pollen of the weed mugwort (Artemisia vulgaris) is a major cause of severe respiratory allergy, with its major allergen, Art v 1, being the key pathogenic molecule for millions of patients. Humanized mice transgenic for a human T-cell receptor specific for the major Art v 1 T-cell epitope and the corresponding HLA have been made. Objective: We sought to characterize IgE epitopes of Art v 1–sensitized patients and humanized mice for molecular immunotherapy of mugwort allergy. Methods: Four overlapping peptides incorporating surface-exposed amino acids representing the full-length Art v 1 sequence were synthesized and used to search for IgE reactivity to sequential epitopes. For indirect mapping, peptide-specific rabbit antibodies were raised to block IgE against surface-exposed epitopes on folded Art v 1. IgE reactivity and basophil activation studies were performed in clinically defined mugwort-allergic patients. Secondary structure of recombinant (r) Art v 1 and peptides was determined by circular dichroism spectroscopy. Results: Mugwort-allergic patients and humanized mice sensitized by allergen inhalation showed IgE reactivity and/or basophil activation mainly to folded, complete Art v 1 but not to unfolded, sequential peptide epitopes. Blocking of allergic patients’ IgE with peptide-specific rabbit antisera identified a hitherto unknown major conformational IgE binding site in the C-terminal Art v 1 domain. Conclusions: Identification of the new major conformational IgE binding site on Art v 1, which can be blocked with IgG raised against non-IgE reactive Art v 1 peptides, is an important basis for the development of a hypoallergenic peptide vaccine for mugwort allergy.
Ključne besede: mugwort pollen allergy, IgE epitope, allergen-specific immunotherapy
Objavljeno v DiRROS: 31.08.2022; Ogledov: 86; Prenosov: 19
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Solid cancer patients achieve adequate immunogenicity and low rate of severe adverse events after SARS-CoV-2 vaccination
Urška Janžič, Urška Bidovec, Katja Mohorčič, Loredana Mrak, Nina Fokter Dovnik, Marija Ivanović, Maja Ravnik, Marina Čakš, Erik Škof, Jerneja Debeljak, Peter Korošec, Matija Rijavec, 2022, izvirni znanstveni članek

Povzetek: Background: SARS-CoV-2 vaccination in cancer patients is crucial to prevent severe COVID-19 disease course. Methods: This study assessed immunogenicity of cancer patients on active treatment receiving mRNA-based SARS-CoV-2 vaccine by detection of anti-SARS-CoV-2 S1 IgG antibodies in serum, before, after the first and second doses and 3 months after a complete primary course of vaccination. Results were compared with healthy controls. Results: Of 112 patients, the seroconversion rate was 96%. A significant reduction in antibody levels was observed 3 months after vaccination in patients receiving immune checkpoint inhibitors versus control participants (p < 0.001). Adverse events were mostly mild. Conclusion: Immunogenicity after mRNA-based vaccine in cancer patients is adequate but influenced by the type of anticancer therapy. Antibody levels decline after 3 months, and thus a third vaccination is warranted.
Ključne besede: onkološko zdravljenje, imunogenost, osnovno cepljenje mRNA, čvrsti tumorji, anticancer treatment, immunogenicity, mRNA-based vaccination, solid cancer
Objavljeno v DiRROS: 24.06.2022; Ogledov: 213; Prenosov: 76
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Dynamic contrast-enhanced MRI in malignant pleural mesothelioma : prediction of outcome based on DCE-MRI measurements in patients undergoing cytotoxic chemotherapy
Martina Vivoda Tomšič, Peter Korošec, Viljem Kovač, Sotirios Bisdas, Katarina Šurlan Popović, 2022, izvirni znanstveni članek

Povzetek: The malignant pleural mesothelioma (MPM) response rate to chemotherapy is low. The identification of imaging biomarkers that could help guide the most effective therapy approach for individual patients is highly desirable. Our aim was to investigate the dynamic contrast-enhanced (DCE) MR parameters as predictors for progression-free (PFS) and overall survival (OS) in patients with MPM treated with cisplatin-based chemotherapy. Methods: Thirty-two consecutive patients with MPM were enrolled in this prospective study. Pretreatment and intratreatment DCE-MRI were scheduled in each patient. The DCE parameters were analyzed using the extended Tofts (ET) and the adiabatic approximation tissue homogeneity (AATH) model. Comparison analysis, logistic regression and ROC analysis were used to identify the predictors for the patient's outcome. Results: Patients with higher pretreatment ET and AATH-calculated Ktrans and ve values had longer OS (P≤.006). Patients with a more prominent reduction in ET-calculated Ktrans and kep values during the early phase of chemotherapy had longer PFS (P =.008). No parameter was identified to predict PFS. Pre-treatment ET-calculated Ktrans was found to be an independent predictive marker for longer OS (P=.02) demonstrating the most favourable discrimination performance compared to other DCE parameters with an estimated sensitivity of 89% and specificity of 78% (AUC 0.9, 95% CI 0.74-0.98, cut off > 0.08 min-1). Conclusions: In the present study, higher pre-treatment ET-calculated Ktrans values were associated with longer OS. The results suggest that DCE-MRI might provide additional information for identifying MPM patients that may respond to chemotherapy.
Ključne besede: cisplatin, magnetic resonance imaging, mesothelioma
Objavljeno v DiRROS: 06.04.2022; Ogledov: 367; Prenosov: 183
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Utility of telomerase gene mutation testing in patients with idiopathic pulmonary fibrosis in routine practice
Julij Šelb, Katarina Osolnik, Izidor Kern, Peter Korošec, Matija Rijavec, 2022, izvirni znanstveni članek

Povzetek: Recent studies have suggested that causative variants in telomerase complex genes (TCGs) are present in around 10% of individuals with idiopathic pulmonary fibrosis (IPF) regardless of family history of the disease. However, the studies used a case-control rare variant enrichment study design which is not directly translatable to routine practice. To validate the prevalence results and to establish the individual level, routine clinical practice, and utility of those results we performed next generation sequencing of TCGs on a cohort of well-characterized consecutive individuals with IPF (diagnosis established according to ATS/ERS/JRS/ALAT guidelines). Of 27 IPF patients, three had a family history of idiopathic interstitial pneumonia (familial IPF) and 24 did not (sporadic IPF). Pathogenic/likely-pathogenic variants (according to American College of Medical Genetics criteria) in TCG were found in three individuals (11.1%) of the whole cohort; specifically, they were present in 2 out of 24 (8.3%) of the sporadic and in 1 out of 3 (33.3%) of the patients with familial IPF. Our results, which were established on an individual-patient level study design and in routine clinical practice (as opposed to the case-control study design), are roughly in line with the around 10% prevalence of causative TCG variants in patients with IPF.
Ključne besede: telomerase, idiopathic pulmonary fibrosis, genetic variation, telomerase complex
Objavljeno v DiRROS: 07.02.2022; Ogledov: 317; Prenosov: 124
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Heterogeneous response of airway eosinophilia to anti-IL-5 biologics in severe asthma patients
Maruša Kopač, Matija Rijavec, Peter Korošec, Urška Bidovec, Izidor Kern, Romana Vantur, Sabina Škrgat, 2022, izvirni znanstveni članek

Povzetek: Many questions concerning responders (R) and nonresponders (NR) in severe eosinophilic asthma (SEA) after blocking the IL-5 (interleukin 5) pathway are still not clear, especially regarding the early parameters of response to biologics in personalized treatment strategies. We evaluated 17 SEA patients treated with anti-IL-5 biologics (16 patients mepolizumab, one patient benralizumab) before the introduction of biologics, and at a week 16 follow-up. Clinical, cellular and immunological parameters in peripheral blood were measured in R and NR. Sputum induction with the measurement of cellular and immunological parameters was performed at 16 weeks only. There were 12 R and 5 NR to biologics. After 16 weeks, there was a significant improvement in percentages of FEV1 (p = 0.001), and asthma control test (ACT) (p = 0.001) in the R group, but not in NR. After 16 weeks, the eosinophils in induced sputum were 27.0% in NR and 4.5% in R (p = 0.05), with no difference in IL-5 concentrations (p = 0.743). Peripheral eosinophilia decreased significantly in NR (p = 0.032) and R (p = 0.002). In patients with SEA on anti-IL-5 therapy, there was a marked difference in airway eosinophilic inflammation between R and NR already at 16 weeks, after anti-IL-5 introduction.
Objavljeno v DiRROS: 13.01.2022; Ogledov: 388; Prenosov: 229
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Treatment outcome clustering patterns correspond to discrete asthma phenotypes in children
Ivana Banić, Mario Lovrić, Gerald Cuder, Roman Kern, Matija Rijavec, Peter Korošec, Mirjana Kljajić-Turkalj, 2021, izvirni znanstveni članek

Povzetek: Despite widely and regularly used therapy asthma in children is not fully controlled. Recognizing the complexity of asthma phenotypes and endotypes imposed the concept of precision medicine in asthma treatment. By applying machine learning algorithms assessed with respect to their accuracy in predicting treatment outcome, we have successfully identified 4 distinct clusters in a pediatric asthma cohort with specific treatment outcome patterns according to changes in lung function (FEV1 and MEF50), airway inflammation (FENO) and disease control likely affected by discrete phenotypes at initial disease presentation, differing in the type and level of inflammation, age of onset, comorbidities, certain genetic and other physiologic traits. The smallest and the largest of the 4 clusters- 1 (N = 58) and 3 (N = 138) had better treatment outcomes compared to clusters 2 and 4 and were characterized by more prominent atopic markers and a predominant allelic (A allele) effect for rs37973 in the GLCCI1 gene previously associated with positive treatment outcomes in asthmatics. These patients also had a relatively later onset of disease (6 + yrs). Clusters 2 (N = 87) and 4 (N = 64) had poorer treatment success, but varied in the type of inflammation (predominantly neutrophilic for cluster 4 and likely mixed-type for cluster 2), comorbidities (obesity for cluster 2), level of systemic inflammation (highest hsCRP for cluster 2) and platelet count (lowest for cluster 4). The results of this study emphasize the issues in asthma management due to the overgeneralized approach to the disease, not taking into account specific disease phenotypes.
Ključne besede: asthma, allergy and immunology, pediatrics, machine learning, treatment outcome, phenotypes, childhood asthma, clustering
Objavljeno v DiRROS: 16.08.2021; Ogledov: 500; Prenosov: 313
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Hymenoptera venom immunotherapy : immune mechanisms of induced protection and tolerance
Ajda Demšar, Peter Korošec, Mitja Košnik, Mihaela Zidarn, Matija Rijavec, 2021, pregledni znanstveni članek

Povzetek: Hymenoptera venom allergy is one of the most severe allergic diseases, with a considerable prevalence of anaphylactic reaction, making it potentially lethal. In this review, we provide an overview of the current knowledge and recent findings in understanding induced immune mechanisms during different phases of venom immunotherapy. We focus on protection mechanisms that occur early, during the build-up phase, and on the immune tolerance, which occurs later, during and after Hymenoptera venom immunotherapy. The short-term protection seems to be established by the early desensitization of mast cells and basophils, which plays a crucial role in preventing anaphylaxis during the build-up phase of treatment. The early generation of blocking IgG antibodies seems to be one of the main reasons for the lower activation of effector cells. Long-term tolerance is reached after at least three years of venom immunotherapy. A decrease in basophil responsiveness correlates with tolerated sting challenge. Furthermore, the persistent decline in IgE levels and, by monitoring the cytokine profiles, a shift from a Th2 to Th1 immune response, can be observed. In addition, the generation of regulatory T and B cells has proven to be essential for inducing allergen tolerance. Most studies on the mechanisms and effectiveness data have been obtained during venom immunotherapy (VIT). Despite the high success rate of VIT, allergen tolerance may not persist for a prolonged time. There is not much known about immune mechanisms that assure longterm tolerance post-therapy.
Ključne besede: allergy and immunology, hypersensitivity, immunotherapy, immune tolerance, venoms, Hymenoptera, Hymenoptera venom, short-term protection, long-term tolerance
Objavljeno v DiRROS: 16.08.2021; Ogledov: 397; Prenosov: 120
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Gene expression levels of the prolyl hydroxylase domain proteins PHD1 and PHD2 but not PHD3 are decreased in primary tumours and correlate with poor prognosis of patients with surgically resected non-small-cell lung cancer
Ana Koren, Matija Rijavec, Tomaž Krumpestar, Izidor Kern, Aleksander Sadikov, Tanja Čufer, Peter Korošec, 2021, izvirni znanstveni članek

Povzetek: Background: Hypoxia correlates with poor prognosis in several cancer types, including lung cancer. Prolyl hydroxylase domain proteins (PHDs) play a role in cell oxygen sensing, negatively regulating the hypoxia-inducible factor (HIF) pathway. Our study aim was to evaluate PHD1, PHD2 and PHD3 mRNA expression levels in primary tumours and normal lungs of non-small-cell lung cancer (NSCLC) patients and to correlate it with selected regulators of HIF signalling, with clinicopathological characteristics and overall survival (OS). Methods: Tumour tissue samples were obtained from 60 patients with surgically resected NSCLC who were treated with radical surgery. In 22 out of 60 cases, matching morphologically normal lung tissue was obtained. PHD1, PHD2 and PHD3 mRNA expressions were measured using RT-qPCR. Results: The PHD1 and PHD2 mRNA levels in primary tumours were significantly decreased compared to those in normal lungs (both p < 0.0001). PHD1 and PHD2 expression in tumours was positively correlated (rs = 0.82; p < 0.0001) and correlated well with HIF pathway downstream genes HIF1A, PKM2 and PDK1. Decreased PHD1 and PHD2 were associated with larger tumour size, higher tumour stage (PHD1 only) and squamous cell carcinoma. Patients with low PHD1 and patients with low PHD2 expression had shorter OS than patients with high PHD1 (p = 0.02) and PHD2 expression (p = 0.01). PHD1 showed borderline independent prognostic values in multivariate analysis (p = 0.06). In contrast, we found no associations between PHD3 expression and any of the observed parameters. Conclusions: Our results show that reduced expression of PHD1 and PHD2 is associated with the development and progression of NSCLC. PHD1 could be further assessed as a prognostic marker in NSCLC.
Ključne besede: non-small-cell lung carcinoma, prognosis, non-small cell lung cancer, mRNA expression, prolyl hydroxylase domain proteins
Objavljeno v DiRROS: 21.05.2021; Ogledov: 745; Prenosov: 526
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T2-high asthma, classified by sputum mRNA expression of IL4, IL5, and IL13, is characterized by eosinophilia and severe phenotype
Matija Rijavec, Tomaž Krumpestar, Sabina Škrgat, Izidor Kern, Peter Korošec, 2021, izvirni znanstveni članek

Povzetek: Asthma is a common chronic disease, with different underlying inflammatory mechanisms. Identification of asthma endotypes, which reflect a variable response to different treatments, is important for more precise asthma management. T2 asthma is characterized by airway inflammation driven by T2 cytokines including interleukins IL-4, IL-5, and IL-13. This study aimed to determine whether induced sputum samples can be used for gene expression profiling of T2-high asthma classified by IL4, IL5, and IL13 expression. Induced sputum samples were obtained from 44 subjects, among them 36 asthmatic patients and eight controls, and mRNA expression levels of IL4, IL5, and IL13 were quantified by RT-qPCR. Overall, gene expression levels of IL4, IL5, and IL13 were significantly increased in asthmatic patients' samples compared to controls and there was a high positive correlation between expressions of all three genes. T2 gene mean was calculated by combining the expression levels of all three genes (IL4, IL5, and IL13) and according to T2 gene mean expression in controls, we set a T2-high/T2-low cutoff value. Twenty-four (67%) asthmatic patients had T2-high endotype and those patients had significantly higher eosinophil blood and sputum counts. Furthermore, T2-high endotype was characterized as a more severe, difficult-to-treat asthma, and often uncontrolled despite the use of inhaled and/or oral corticosteroids. Therefore, the majority of those patients (15 [63%] of 24) needed adjunct biological therapy to control their asthma symptoms/exacerbations. In conclusion, we found that interleukins IL4, IL5, and IL13 transcripts could be effectively detected in sputum from asthmatic patients. Implementation of T2 gene mean can be used as sputum molecular biomarker to categorize patients into T2-high endotype, characterized by eosinophilia and severe, difficult-to-treat asthma, and often with a need for biological treatment.
Ključne besede: asthma, gene expression, interleukin-4, interleukin-5, interleukin-13, severe asthma, endotype, IL-4, IL-5, IL-13, biologic treatment
Objavljeno v DiRROS: 02.02.2021; Ogledov: 787; Prenosov: 428
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