1. 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 cancerAna 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: 703; Prenosov: 462
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2. Chemokines during anaphylaxis : the importance of CCL2 and CCL2-dependent chemotactic activity for basophilsRomana Vantur, Maruša Rihar, Ana Koren, Matija Rijavec, Peter Kopač, Urška Bidovec, Renato Eržen, Peter Korošec, 2020, izvirni znanstveni članek Povzetek: Background: The role of chemokines in anaphylaxis is unclear. Methods: We prospectively recruited 49 patients presenting to the emergency department with an acute episode of anaphylaxis and 28 healthy subjects. We measured serum levels of the chemokines CCL2, CCL5, CCL7, CCL8, CCL11, CCL13, CCL17, CCL21, CCL22, CCL24, and CCL26, tryptase, the absolute number of circulating basophils, monocytes, lymphocytes, and PMNs, and whole blood FCER1A, CPA3 and HDC gene expression at two time points: during the anaphylactic episode and in convalescent samples collected approximately 3 months later. We then investigated the in vitro chemotactic activity of chemokines induced during anaphylaxis for the in vitro migration of the corresponding cells. Results: Only CCL2 chemokine levels were signifcantly increased in anaphylaxis samples (median 514 pg/ml) compared to convalescent samples (284 pg/ml, P<0.0001) and healthy subjects (279 pg/ml, P<0.0001); there was no signifcant diference in any of the other chemokines. There was a signifcant positive correlation between the rates of increase of serum CCL2 (median [range]: 106.0% [-44.7% to 557.4%]) and tryptase (133.8% [-6.6% to 893.4%]; r=0.68, P<0.0001) and between the acute concentration of serum CCL2 and the acute concentration of serum tryptase (r=0.77, P<0.0001). The number of circulating basophils, but not other blood cells, signifcantly decreased during anaphylaxis (median 5.0 vs. 19.1 cells/[micro]l in convalescent samples; P<0.0001); a decrease in whole-blood gene expression of basophil markers (PKljučne besede: anaphylaxis, chemokines, tryptases, basophils, chemotaxis, CCL2, cell migration
Objavljeno v DiRROS: 18.01.2021; Ogledov: 817; Prenosov: 333
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3. Quantitative, absolute count-based T cell analysis of CD69 upregulation as a new methodology for in vitro diagnosis of delayed-type nickel hypersensitivityAna Koren, Mira Šilar, Helena Rupnik, Mihaela Zidarn, Peter Korošec, 2019, izvirni znanstveni članek Povzetek: Background: T cells play a major role in delayed-type hypersensitivity reactions. Their reactivity can be assessed by measuring the upregulation of the activation marker CD69, followed by proliferation and cytokine production. The aim of our study was to develop a novel, whole blood-based, quantitative, absolute count activation index (AI) analysis of CD69 upregulation on different subsets of T cells in nickel hypersensitive patients and compare it with the previously reported approaches. Methods: Ten patients with nickel allergy and nine healthy controls were included. CD69 expression of CD3+, CD3+CD4+ and CD3+CD8+ T cells in heparinized blood was determined with flow cytometry after incubation with nickel sulfate for 48 h. The absolute cell count of CD69+ cells was determined with microbeads. The production of the cytokines IL-2, IL-5, IL-13, and IFN-[gamma] was determined after nickel sulfate stimulation of PBMNCs for 48 h. Results: We showed that the most sensitive methodology is the absolute AI, which was calculated as the ratio between the absolute count of CD69-positive T cells stimulated with nickel and the absolute count of CD69-positive T cells in non-stimulated blood. This novel quantitative approach was more discriminative than the previously reported approaches in which T cell CD69 percentage AI and cytokine production are measured. Conclusions: Our results demonstrated that measuring the absolute CD69 AI is an accurate new approach to quantify antigen-specific T cells in the blood of patients with hypersensitivity reactions to nickel. This approach may be useful for better in vitro assessment of patients with delayed-type hypersensitivity reactions.
Ključne besede: allergy and immunology, delayed hypresensitivity, nickel, blood, CD antigenes, CD69
Objavljeno v DiRROS: 18.11.2020; Ogledov: 755; Prenosov: 142
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5. CD3+CD4-CD8- mucosal T cells are associated with uncontrolled chronic rhinosinusitis with nasal polypsTanja Soklič, Mira Šilar, Matija Rijavec, Ana Koren, Izidor Kern, Irena Hočevar-Boltežar, Peter Korošec, 2019, kratki znanstveni prispevek Povzetek: Increased mucosal double-negative (DN) CD3+CD4-CD8- T cells were found for the first time in CRS and were much more abundant in uncontrolled CRSwNP than in well-controlled CRSwNP.
Ključne besede: chronic rhinosinusitis, CD3+ T-cells, CD4- T-cells, CD8- T-cells
Objavljeno v DiRROS: 22.10.2020; Ogledov: 1051; Prenosov: 323
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6. Transcription factors gene expression in chronic rhinosinusitis with and without nasal polypsTanja Soklič, Matija Rijavec, Mira Šilar, Ana Koren, Izidor Kern, Irena Hočevar-Boltežar, Peter Korošec, 2019, izvirni znanstveni članek Povzetek: Background. Chronic rhinosinusitis (CRS) current therapeutic approaches still fail in some patients with severe persistent symptoms and recurrences after surgery. We aimed to evaluate the master transcription factors gene expression levels of T cell subtypes in chronic rhinosinusitis with nasal polyps (CRSwNP) and chronic rhinosinusitis without nasal polyps (CRSsNP) that could represent new, up-stream targets for topical DNAzyme treatment. Patients and methods. Twenty-two newly diagnosed CRS patients (14 CRSwNP and 8 CRSsNP) were prospectively biopsied and examined histopathologically. Gene expression levels of T-box transcription factor (T-bet, TBX21), GATA binding protein 3 (GATA3), Retinoic acid-related orphan receptor C (RORC) and Forkhead box P3 (FOXP3) were analyzed by real-time quantitative polymerase chain reaction (RT-qPCR). Results. Eosinophilic CRSwNP was characterized by higher level of GATA3 gene expression compared to noneosinophilic CRSwNP, whereas there was no difference in T-bet, RORC and FOXP3 between eosinophilic and noneosinophilic CRSwNP. In CRSsNP, we found simultaneous upregulation of T-bet, GATA3 and RORC gene expression levels in comparison to CRSwNP; meanwhile, there was no difference in FOXP3 gene expression between CRSwNP and CRSsNP. Conclusions. In eosinophilic CRSwNP, we confirmed the type 2 inflammation by elevated GATA3 gene expression level. In CRSsNP, we unexpectedly found simultaneous upregulation of T-bet and GATA3 that is currently unexplained; however, it might originate from activated CD8+ cells, abundant in nasal mucosa of CRSsNP patients. The elevated RORC in CRSsNP could be part of homeostatic nasal immune response that might be better preserved in CRSsNP patients compared to CRSwNP patients. Further data on transcription factors expression rates in CRS phenotypes are needed.
Ključne besede: sinusitis, nasal polyps, Th1 cells, Th2 cells, Th17 cells, transcription factors, chronic rhinosinusitis
Objavljeno v DiRROS: 09.10.2020; Ogledov: 942; Prenosov: 467
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7. 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: 1055; Prenosov: 237
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