Despite great enthusiasm towards immunotherapy, reliable biomarkers are still lacking. The importance of subsets based on human papillomavirus (HPV) status is supported by a growing body of evidence. However, role of other possible subgroups such as anatomic localization of primary tumor remains controversial. Our objective was to investigate immune cell infiltrate and checkpoint inhibitor proteins in above-mentioned head and neck cancer subsets. Archival tumor samples of 106 laryngeal, oropharyngeal, and hypopharyngeal cancer patients were stained with PD-L1, PD-L2, PD-1, and CTLA-4 antibodies. Proportion of tumor-infiltrating lymphocytes was assessed as well. In HPV-negative tumors, PD-L1 immune cell positivity was associated with better disease-specific survival. PD-L1 expression on immune cells correlated with improved disease-specific survival in laryngeal tumors. Furthermore, PD-L1 immune cell positivity correlated with CTLA-4 expression on immune cells and it was accompanied by high tumor-infiltrating lymphocyte rate. PD-L1 expression on tumor cells and PD-1 status showed strong correlation in all patients and in oropharyngeal and laryngeal localization, but not in hypopharynx. HPV-negative oropharyngeal cancers showed negative PD-L1 status on tumor cells. CTLA-4 positivity was observed in 49.5% and 20.6% on immune cells and on tumor cells, respectively. We concluded that PD-L1 expression on immune cells indicates better prognosis in laryngeal squamous cell carcinoma and in HPV-negative head and neck squamous cell carcinoma. We have not found any essential differences between anatomic subgroups. A possibly distinct role of hypopharyngeal localization regarding immune activity requires further clarification.

Stimulation of mammalian cells by epidermal growth factor (EGF) elicits complex signaling events, including an increase in hydrogen peroxide (H 2 O 2 ) production. Understanding the significance of this response is limited by the fact that the source of EGF-induced H 2 O 2 production is unknown. Here we show that EGF-induced H 2 O 2 production in epidermal cell lines is dependent on the agonist-induced calcium signal. We analyzed the expression of NADPH oxidase isoforms and found both A431 and HaCaT cells to express the calcium-sensitive NADPH oxidase, Dual oxidase 1 (Duox1) and its protein partner Duox activator 1 (DuoxA1).Inhibition of Duox1 expression by small interfering RNAs eliminated EGF-induced H 2 O 2 production in both cell lines. We also demonstrate that H 2 O 2 production by Duox1 leads to the oxidation of thioredoxin-1 and the cytosolic peroxiredoxins. Our observations provide evidence for a new signaling paradigm in which changes of intracellular calcium concentration are transformed into redox signals through the calcium-dependent activation of Duox1.

Autophagy is a catabolic process that enables cells to degrade obsolete content and refuel energy depots. In colorectal cancer (CRC) autophagy has been shown to promote tumorigenesis through energy delivery in the condition of uncontrolled proliferation. With this study, we aimed at evaluating whether autophagy sustains CRC cell viability and if it impacts therapy resistance. Initially, a colorectal cancer tissue micro array, containing mucosa (n = 10), adenoma (n = 18) and adenocarcinoma (n = 49) spots, was stained for expression of essential autophagy proteins LC3b, Atg7, p62 and Beclin-1. Subsequently, central autophagy proteins were downregulated in CRC cells using siRNA technology. Viability assays, flow cytometry and immunoblotting were performed and three-dimensional cell culture was utilized to study autophagy in a tissue mimicking environment. In our study we found an upregulation of Atg7 in CRC. Furthermore, we identified Atg7 as crucial factor within the autophagy network for CRC cell viability. Its disruption induced cell death via triggering apoptosis and in combination with conventional chemotherapy it exerted synergistic effects in inducing CRC cell death. Cell death was strictly dependent on nuclear LC3b, since simultaneous knockdown of Atg7 and LC3b completely restored viability. This study unravels a novel cell death preventing function of Atg7 in interaction with LC3b, thereby unmasking a promising therapeutic target in CRC.

Gap juctions are transmembrane communication channels known to be involved in the control of cell proliferation by mediating the exchange of ions and small molecules between cells. Gap junctions are composed of connexon hemichannels made up of 6 connexin proteins, which abnormal expression and functions have been linked to tumor progression and poorer prognosis. Here, we studied the prognostic impact of the most prevalent connexin isotype, connexin 43 (Cx43) in head and neck squamous cell carcinomas (HNSCC). Tissue microarrays made from tumor samples of 90 HNSCC patients were immunostained for Cx43 and cell cycle regulation-related biomarkers including p53, Ki67, p16, aurora A, geminin, and p21 proteins. Scoring and histopathologic evaluation were performed in digital slides. A 4-tier scoring distinguishing the percentage of positively stained tumor cells was used including score 1: <5%, score 2: 6% to 20%, score 3: 21% to 60%, and score 4: >60%. For statistics, Kaplan-Meier curves with log-rank tests, Cox-regression, and Pearson χ/Fisher exact tests were used.A significant positive correlation was found between Cx43 expression and disease-specific survival of patients (P=0.004). The rate of p21 protein-positive tumor cells also proved to be a significant positive prognostic marker (P=0.014). Cx43 levels also showed a significant positive correlation with p53 expression (P=0.036). However, there was no statistical association between Cx43 levels and the rest of the markers tested neither with T, N, or M stage.In conclusion, our data suggest that reduced Cx43 expression and low p21 protein levels may have a significant negative impact on HNSCC prognosis.

No abstract

Az artériás pulzusnyomás (PP) értéke, bár nehezebben értelmezhető, mint más vérnyomásértékeké, mégis felvilágosítást adhat a cardiovascularis rendszer működéséről. Ilyen a nagy artériás erek szélkazánfunkciója (stiffness) és a perifériás ellenállás mértéke. Mindkettő változhat az életkorral és fizikai aktivitás hatására. Fontossága ellenére a legújabb, 2018-as ESC/ESH hypertoniaajánlás nem foglalkozik részletesen a PP értékével, illetve annak jelentőségével. Korábbi vizsgálataink alapján feltételeztük, hogy fizikailag aktív fiatalokban a pulzusnyomás szélsőséges értékeket és nemi különbségeket is mutathat. Módszerek: A vizsgálatokat egyetemi hallgatókon végeztük (N=64; 51,6% férfi). Átlagéletkoruk 23,2±2,7 év, a legfiatalabb 18, a legidősebb 28 éves volt. A vérnyomás és a szívfrekvencia (HR) mérésére automata vérnyomásmérőt (Omron MIT5) használtunk az egyének felkarjára helyezve. A méréseket nyugodt környezetben, ülő helyzetben végeztük és háromszor megismételtük egyperces időközönként. Eredmények: Testtömegindex (BMI, kg/m2): nők 22,1±2,7; férfiak 24,1±2,9. Vérnyomás (Hgmm): szisztolés 118,7±13,4; diasztolés 73,7±9,3; nyugalmi szívfrekvencia (HR, 1/perc): 74,3±12,7 és a PP 44,9±12,6 volt. A nők szisztolés nyomása alacsonyabb volt (110,6±10,9; minimum–maximum: 92–130 Hgmm), mint a férfiaké (126,2±10,9; minimum–maximum: 97–146,5 Hgmm, p<0,001), a diasztolés értékben nemek között nem volt szignifikáns különbség. A nők HR-ja magasabb volt (78,2±13,4; minimum–maximum: 54–116,5 ütés/min), mint a férfiaké (70,6±10,9; minimum–maximum: 46–90,5; 1/min, p=0,017). A nők PP-je kisebb volt (37,1±9,4), mint a férfiaké (52,3±10,6; p<0,001). Nőkben a legalacsonyabb PP 20 Hgmm, míg a legmagasabb 62 Hgmm volt. Férfiakban a legalacsonyabb PP 24,5 Hgmm, míg a legmagasabb 74,5 Hgmm volt. Következtetések: Vizsgálatunkban fiatal felnőttkorra (~25 év) és nemekre specifikus artériás pulzusnyomás értékeket állapítottunk meg, ami azért fontos, mert az ESC/ESH hypertoniaajánlás nem közöl ”normál” referenciaértéket. Figyelemre méltó, hogy a PP értéke jelentős szórást mutatott a vizsgált mintában és sok fiatal férfinál mutatott 40 Hgmm-nél magasabb értéket, ami cardiovascularis rizikót jelenthet, ezért követése indokolt lehet még fiatal korban is.

in experimental composite tissue allotransplantation and evaluation of important immunological aspects: rejection dynamics, immunosuppression protocol testing and induction of immunologic tolerance. The surgical procedures performed in cadaveric models shown the feasibility of the abdominal wall allotransplantation procedure which may be translated to future clinical practice in association with organ transplantation. It may be possible to develop an alternative approach for iliac crest microsurgical transplant as tolerogenic strategy in solid organs or vascularized composite allotransplantation. Conclusion:Preclinical experience represents a mandatory step in developing a vascularized composite allotransplantation program, translating the knowledge obtained from experimental animal research and cadaveric studies to further clinical practice, ensuring optimal results for patients with complex tissue defects.

No abstract