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A humán DNS hordozza az emberi szervezet felépítéséhez és működéséhez szükséges összes információt, a legtöbb betegség kialakulása azonban elsődlegesen mégsem a genetikai anyagban rögzített információ változásának következménye. A mutációk például csak a daganatok 5–10%-ában közvetlen okai a betegség kialakulásának. A nukleotidszintű genetikai eltérések és strukturális variációk mellett a kromatin térbeli formaváltozása is hozzájárul a fenotípus kialakulásához a génátíródás, illetve a jelátviteli utak módosításán keresztül. Az emberi DNS epigenetikai szabályozás révén folyamatos átrendeződésen megy át. Ilyenkor a DNS nukleotidszekvenciája, információtartalma nem változik, hanem a szabályozó vagy kódoló régió válik aktívvá vagy inaktívvá a mindenkori fiziológiás szükségleteknek, életkori sajátosságoknak megfelelően. A DNS-nek ezt a szabályozott átrendeződését „remodeling”-nek hívjuk. Ennek célja, hogy a sejtekben mindig az aktuális működést biztosító fehérjéknek megfelelő génszakaszok íródjanak át. Ez a működés azonban az életkor előrehaladtával veszít hatékonyságából, és sok betegség kialakulása éppen az epigenetikai szabályozás egyensúlyának megbomlására vezethető vissza. Az epigenetikai változások vizsgálatára és mérésére több olyan régi és új elképzelés, illetve módszer van, melyek diagnosztikus alkalmazása segítséget adhat a betegségek korai előrejelzésében. Összefoglaló cikkünk az epigenetikai szabályozás sokrétűségét kívánja bemutatni, rávilágítva egyes központi molekulák, hormonok szerepére az öregedésben és az azzal összefüggő betegségek létrejöttében. Emellett a legújabb epigenetikai vizsgálómódszerek – úgymint a kromatin-immunprecipitáció (ChIP), a nyitott kromatinrészek feltérképezése, a metiláltsági szint vizsgálata – lényegét is ismerteti, melyek alkalmasak lehetnek a közeljövőben diagnosztikus módszerek kidolgozására is. Orv Hetil. 2022; 163(34): 1334–1344.

In the human environment, the increasing exposure to radiofrequency (RF) radiation, especially that emitted by wireless devices, could be absorbed in the body. Recently, mobile and emerging wireless technologies (UMTS, DECT, LTE, and Wi-Fi) have been using higher frequencies than 2G GSM systems (900/1800 MHz), which means that most of the circulating RF currents are absorbed into the skin and the superficial soft tissue. The harmful genotoxic, cytotoxic, and mutagenic effects of solar ultraviolet (UV) radiation on the skin are well-known. This study aimed at investigating whether 2422 MHz (Wi-Fi) RF exposure combined with UV radiation in different sequences has any effect on the inflammation process in the skin. In vitro experiments examined the inflammation process by cytokines (IL-1α, IL-6, IL-8) and MMP-1 enzyme secretion in a 3D full-thickness human skin model. In the first study, UV exposure was immediately followed by RF exposure to measure the potential additive effects, while in the second study, the possible protective phenomenon (i.e., adaptive response) was investigated when adaptive RF exposure was challenged by UV radiation. Our results suggest that 2422 MHz Wi-Fi exposure slightly, not significantly increased cytokine concentrations of the prior UV exposure. We could not detect the adaptive response phenomenon.

In the last few decades, a substantial body of evidence underlined the pivotal role of bradykinin in certain types of angioedema. The formation and breakdown of bradykinin has been studied thoroughly; however, numerous questions remained open regarding the triggering, course, and termination of angioedema attacks. Recently, it became clear that vascular endothelial cells have an integrative role in the regulation of vessel permeability. Apart from bradykinin, a great number of factors of different origin, structure, and mechanism of action are capable of modifying the integrity of vascular endothelium, and thus, may participate in the regulation of angioedema formation. Our aim in this review is to describe the most important permeability factors and the molecular mechanisms how they act on endothelial cells. Based on endothelial cell function, we also attempt to explain some of the challenging findings regarding bradykinin-mediated angioedema, where the function of bradykinin itself cannot account for the pathophysiology. By deciphering the complex scenario of vascular permeability regulation and edema formation, we may gain better scientific tools to be able to predict and treat not only bradykinin-mediated but other types of angioedema as well.

Most therapeutic agents used for treating brain malignancies face hindered transport through the blood-brain barrier (BBB) and poor tissue penetration. To overcome these problems, we developed peptide conjugates of conventional and experimental anticancer agents. SynB3 cell-penetrating peptide derivatives were applied that can cross the BBB. Tuftsin derivatives were used to target the neuropilin-1 transport system for selectivity and better tumor penetration. Moreover, SynB3-tuftsin tandem compounds were synthesized to combine the beneficial properties of these peptides. Most of the conjugates showed high and selective efficacy against glioblastoma cells. SynB3 and tandem derivatives demonstrated superior cellular internalization. The penetration profile of the conjugates was determined on a lipid monolayer and Transwell co-culture system with noncontact HUVEC-U87 monolayers as simple ex vivo and in vitro BBB models. Importantly, in 3D spheroids, daunomycin-peptide conjugates possessed a better tumor penetration ability than daunomycin. These conjugates are promising tools for the delivery systems with tunable features.

We tested the prognostic relevance of metabolic parameters and their relative changes in patients with metastatic colorectal cancer (mCRC) treated with monoclonal antibody and chemotherapy. SUVmax (standardized uptake volume), SAM (standardized added metabolic activity) and TLG (total lesion glycolysis) are assessed with 18F-fluorodeoxyglucosepositron emission tomography and computed tomography (FDG-PET/CT) to evaluate total metabolic activity of malignant processes. Our purpose was to investigate the change of glucose metabolism in relation to PFS (progression free survival) and OS (overall survival). Fifty-three patients with mCRC with at least one measurable liver metastasis were included in this prospective, multi-center, early exploratory study. All patients were treated with first-line chemotherapy and targeted therapy. Metabolic parameters, like SUVmax, SAM, normalized SAM (NSAM) and TLG were assessed by FDG-PET/CT, carried out at baseline (scan-1) and after two therapeutic cycle (scan-2). Our results suggested neither SUVmax nor TLG have such prognostic value as NSAM in liver metastases of colorectal cancer. The parameters after the two cycles of chemotherapy proved to be better predictors of the clinical outcome. NSAM after two cycles of treatment has a statistically significant predictive value on OS, while SAM was predictive to the PFS. The follow up normalized SAM after 2 cycles of first line oncotherapy was demonstrated to be useful as prognostic biomarkers for OS in metastatic colorectal cancer. We should introduce this measurement in metastatic colorectal cancer if there is at least one metastasis in the liver. Electronic supplementary material The online version of this article (10.1007/s12253-020-00865-5) contains supplementary material, which is available to authorized users.

Endothelial cells play an important role in sensing danger signals and regulating inflammation. Several factors are capable of inducing a proinflammatory response (e.g., LPS, histamine, IFNγ, and bradykinin), and these factors act simultaneously during the natural course of the inflammatory reaction. We have previously shown that the complement protein mannan-binding lectin-associated serine protease-1 (MASP-1) also induces a proinflammatory activation of the endothelial cells. Our aim was to investigate the possible cooperation between MASP-1 and other proinflammatory mediators when they are present in low doses. We used HUVECs and measured Ca2+ mobilization, IL-8, E-selectin, VCAM-1 expression, endothelial permeability, and mRNA levels of specific receptors. LPS pretreatment increased the expression of PAR2, a MASP-1 receptor, and furthermore, MASP-1 and LPS enhanced each other’s effects in regulating IL-8, E-selectin, Ca2+ mobilization, and changes in permeability in a variety of ways. Cotreatment of MASP-1 and IFNγ increased the IL-8 expression of HUVECs. MASP-1 induced bradykinin and histamine receptor expression, and consequently, increased Ca2+ mobilization was found. Pretreatment with IFNγ enhanced MASP-1-induced Ca2+ mobilization. Our findings highlight that well-known proinflammatory mediators and MASP-1, even at low effective doses, can strongly synergize to enhance the inflammatory response of endothelial cells.

All the information, which determine the structure and function of the human body, is carried by the human DNA. However, the development of several human diseases is not primarily originated from the changes of this genetic information, which laid into the DNA. For example, only 5-10% of the developed cancers are caused primarily by mutations. Changes in the three-dimensional structure of the chromatin, beside the genetic alterations in the nu-cleotide level and structural variants of the genome, also take part in the development of phenotype through the modification of transcription and signal transduction. The human DNA is continuously rearranged by epigenetic regulation. In this process, the nucleotide sequence and the coding information are not changing in the DNA, only the active and inactive state of the regulatory and coding regions according to the actual need of the physiological and age-dependent conditions. This regulated rearrangement of the DNA, which is called remodeling, ensures the optimal transcription of the necessary proteins and genes. The effectiveness of this function, however, is decreasing during the aging process and thus resulted in several diseases as a consequence of an unbalanced epigenetic regula-tion. There are several old and new ideas and methods to research and measure the epigenetic changes, which diag-nostic applications could support the early prediction of the development of diseases. The aim of our review article is to summarize the complexity of the epigenetic regulation, highlight the role of some key molecules and hormones in the process of aging, and related diseases as well. Moreover, we describe the newest methods analysing the epige-netic changes, like chromatin immunoprecipitation (ChIP), detection of the open chromatin regions, detection of DNA methylation level, which could be applied as diagnostic methods in the near future.A humán DNS hordozza az emberi szervezet felépítéséhez és működéséhez szükséges összes információt, a legtöbb betegség kialakulása azonban elsődlegesen mégsem a genetikai anyagban rögzített információ változásának következménye. A mutációk például csak a daganatok 5–10%-ában közvetlen okai a betegség kialakulásának. A nukleotidszintű genetikai eltérések és strukturális variációk mellett a kromatin térbeli formaváltozása is hozzájárul a fenotípus kialakulásához a génátíródás, illetve a jelátviteli utak módosításán keresztül. Az emberi DNS epigenetikai szabályozás révén folyamatos átrendeződésen megy át. Ilyenkor a DNS nukleotidszekvenciája, információtartalma nem változik, hanem a szabályozó vagy kódoló régió válik aktívvá vagy inaktívvá a mindenkori fiziológiás szükségleteknek, életkori sajátosságoknak megfelelően. A DNS-nek ezt a szabályozott átrendeződését „remodeling”-nek hívjuk. Ennek célja, hogy a sejtekben mindig az aktuális működést biztosító fehérjéknek megfelelő génszakaszok íródjanak át. Ez a működés azonban az életkor előrehaladtával veszít hatékonyságából, és sok betegség kialakulása éppen az epigenetikai szabályozás egyensúlyának megbomlására vezethető vissza. Az epigenetikai változások vizsgálatára és mérésére több olyan régi és új elképzelés, illetve módszer van, melyek diagnosztikus alkalmazása segítséget adhat a betegségek korai előrejelzésében. Összefoglaló cikkünk az epigenetikai szabályozás sokrétűségét kívánja bemutatni, rávilágítva egyes központi molekulák, hormonok szerepére az öregedésben és az azzal összefüggő betegségek létrejöttében. Emellett a legújabb epigenetikai vizsgálómódszerek – úgymint a kromatin-immunprecipitáció (ChIP), a nyitott kromatinrészek feltérképezése, a metiláltsági szint vizsgálata – lényegét is ismerteti, melyek alkalmasak lehetnek a közeljövőben diagnosztikus módszerek kidolgozására is. Orv Hetil. 2022; 163(34): 1334–1344.

Correction to: Scientific Reports https://doi.org/10.1038/s41598-021-95976-7, published online 18 August 2021

Background Survival after out-of-hospital cardiac arrest (OHCA) is still low. For every minute without resuscitation the likelihood of survival decreases. One critical step is initiation of immediate, high quality cardiopulmonary resuscitation (CPR). The aim of this subgroup analysis of data collected for the European Registry of Cardiac Arrest Study number 2 (EuReCa TWO) was to investigate the association between OHCA survival and two types of bystander CPR namely: chest compression only CPR (CConly) and CPR with chest compressions and ventilations (FullCPR). Method In this subgroup analysis of EuReCa TWO, all patients who received bystander CPR were included. Outcomes were return of spontaneous circulation and survival to 30-days or hospital discharge. A multilevel binary logistic regression analysis with survival as the dependent variable was performed. Results A total of 5884 patients were included in the analysis, varying between countries from 21 to 1444. Survival was 320 (8%) in the CConly group and 174 (13%) in the FullCPR group. After adjustment for age, sex, location, rhythm, cause, time to scene, witnessed collapse and country, patients who received FullCPR had a significantly higher survival rate when compared to those who received CConly (adjusted odds ration 1.46, 95% confidence interval 1.17–1.83). Conclusion In this analysis, FullCPR was associated with higher survival compared to CConly. Guidelines should continue to emphasise the importance of compressions and ventilations during resuscitation for patients who suffer OHCA and CPR courses should continue to teach both.

Biliverdin reductase (BVR)-A is a pleotropic enzyme converting biliverdin to bilirubin and a signaling molecule that has cytoprotective and immunomodulatory effects. We recently showed that biliverdin inhibits the expression of complement activation fragment 5a receptor one (C5aR1) in RAW 264.7 macrophages. In this study, we investigated the role of BVR-A in determining macrophage inflammatory phenotype and function via regulation of C5aR1. We assessed expression of C5aR1, M1-like macrophage markers, including chemokines (RANTES, IP-10), as well as chemotaxis in response to LPS and C5a in bone marrow–derived macrophages from BVRfl/fl and LysM-Cre:BVRfl/fl mice (conditional deletion of BVR-A in myeloid cells). In response to LPS, macrophages isolated from LysM-Cre:BVRfl/fl showed significantly elevated levels of C5aR1 as well as chemokines (RANTES, IP10) but not proinflammatory markers, such as iNOS and TNF. An increase in C5aR1 expression was also observed in peritoneal macrophages and several tissues from LysM-Cre:BVRfl/fl mice in a model of endotoxemia. In addition, knockdown of BVR-A resulted in enhanced macrophage chemotaxis toward C5a. Part of the effects of BVR-A deletion on chemotaxis and RANTES expression were blocked in the presence of a C5aR1 neutralizing Ab, confirming the role of C5a–C5aR1 signaling in mediating the effects of BVR. In summary, BVR-A plays an important role in regulating macrophage chemotaxis in response to C5a via modulation of C5aR1 expression. In addition, macrophages lacking BVR-A are characterized by the expression of M1 polarization–associated chemokines, the levels of which depend in part on C5aR1 signaling.

Dietary methyl-donors play important roles in physiological processes catalyzed by B vitamins as coenzymes, and are used for complementary support in oncotherapy. Our hypothesis was that methyl-donors can not only assist in tolerating cancer treatment but may also directly interfere with tumor growth and proliferation. Therefore, we investigated the proposed cancer inhibitory effects of methyl-donors (in a mixture of L-methionine, choline chloride, folic acid, and vitamin B12) on MCF7 and T47D breast cancer as well as A549 and H1650 lung cancer cell lines. Indeed, methyl-donor treatment significantly reduced the proliferation in all cell lines, possibly through the downregulation of MAPK/ERK and AKT signaling. These were accompanied by the upregulation of the pro-apoptotic Bak and Bax, both in MCF7 and H1650 cells, at reduced anti-apoptotic Mcl-1 and Bcl-2 levels in MCF7 and H1650 cells, respectively. The treatment-induced downregulation of p-p53(Thr55) was likely to contribute to protecting the nuclear localization and apoptosis inducing functions of p53. The presented features are known to improve the sensitivity of cancer therapy. Therefore, these data support the hypothesis, i.e., that methyl-donors may promote apoptotic signaling by protecting p53 functions through downregulating both the MAPK/ERK and the AKT pathways both in breast and lung adenocarcinoma cell lines. Our results can emphasize the importance and benefits of the appropriate dietary supports in cancer treatments. However, further studies are required to confirm these effects without any adverse outcome in clinical settings.

The effective management of patients with sarcomas requires accurate diagnosis and staging. Imaging, such as ultrasonography (US), computed tomography (CT), magnetic resonance imaging (MRI) are the most freqently used methods for the detection of the lesion location, size, morphology and structural changes to adjacent tissues; however, these modalities provide little information about tumour biology. MRI is a robust and useful modality in tumour staging of sarcomas, however metabolic-fluorodeoxyglucose positron emission tomography/ computer tomography (18F-FDG PET/CT) provides greater accuracy to overall staging in combination with MRI [1]. The advantages of 18F-FDG PET/CT method compared with CT and MRI is that it provides a whole body imaging, maps the viability of the tumour or the metabolic activity of the tissue. Additionally, PET detects the most agressive part of the tumour, demonstrates the biological behaviour of the tumour and therefore has a predictive value. Little data ara available on the role of 18F-FDG PET/CT in the management of sarcomas. The present manuscript aims to provide a review of the major indications of 18F-FDG PET/CT for diagnosis, staging, restaging and monitoring response to therapy and to compare its usefulness with the conventional imaging modalities in the management of patients with sarcomas.

Mannan-binding lectin-associated serine protease 1 (MASP-1), the most abundant enzyme of the complement lectin pathway, is able to stimulate human umbilical vein endothelial cells (HUVECs) to alter the expression of several cytokines and adhesion molecules. This study has assessed to what extent MASP-1 is able to modify the transcriptional pattern of inflammation-related (IR) genes in HUVECs. We utilized Agilent microarray to analyse the effects of recombinant MASP-1 (rMASP-1) in HUVECs, on a set of 884 IR genes. Gene Set Enrichment Analysis showed an overall activation of inflammation-related genes in response to rMASP-1. rMASP-1 treatment up- and down-regulated 19 and 11 IR genes, respectively. Most of them were previously unidentified, such as genes of chemokines (CXCL1, CXCL2, CXCL3), inflammatory receptors (TLR2, BDKRB2) and other inflammatory factors (F3, LBP). Expression of IR genes changed early, during the first 2 hours of activation. Both p38-MAPK inhibitor and NFκB inhibitor efficiently suppressed the effect of rMASP-1. We delineated 12 transcriptional factors as possible regulators of rMASP-1-induced IR genes. Our microarray-based data are in line with the hypothesis that complement lectin pathway activation, generating active MASP-1, directly regulates inflammatory processes by shifting the phenotype of endothelial cells towards a more pro-inflammatory type.

Abstract: Introduction: Medical training in the 21st century faces simulation-based education as one of the challenges that efficiently contributes to clinical skills development while moderating the burden on the clinicians and patients alike. Aim: The University of Pécs, Medical School has launched a simulation program in the MediSkillsLab based on history taking with actors to improve patient interviewing communication skills. Method: This new program was inspired by experiences gathered in previous medical language teaching and integrates the method of the “Standardized Patient Program”. The method has been applied in America since the 1960s. Results: This is the first time the program has been introduced in Hungary and implemented in an interdisciplinary design, where medical specialists, linguists, actor-patients and medical students collaborate to improve professional, language and communicative competence of the students. Conclusion: A course like this has its pivotal role in the medical training, and as a result more efficient and patient-oriented communication may take place at the clinical setting. Orv Hetil. 2017; 158(26): 1022–1027.

The absorption of exposure to radiofrequency (RF) emitted by wireless devices leads to a high specific absorption rate in the skin. Ultraviolet (UV) radiation can induce several damages to the skin. The aim of this study was to examine whether combined, consecutive exposure to solar UV radiation and 1950 MHz RF exposure of third generation (3G) mobile system have any effect on inflammation processes in the skin. Under in vitro experiments, the inflammation process was examined by cytokines (IL-1&alpha, IL-6, and IL-8) and MMP-1 enzyme secretion on 3D full thickness human skin model. The RF exposure was applied before or after UV irradiation, in order to study either the possible cooperative or protective effects of exposure to RF and UV. We did not find changes in cytokines due to exposure to RF alone. The RF exposure did not enhance the effects of UV radiation. There was a statistically not-significant decrease in cytokines when the skin tissues were pre-exposed to RF before being exposed to 4 standard erythemal dose (SED) UV compared to UV exposure alone. We found that RF exposure reduced the previously UV-treated MMP-1 enzyme concentration. This study might support the evaluation of the effects on the skin exposed to microwave radiation of 5G mobile technology.

We hypothesized that tumor-associated macrophages (TAMs) are controlled by the diffusible gas carbon monoxide (CO). We demonstrate that induction of apoptosis in lung tumors treated with low doses of CO is associated with increased CD86 expression and activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases (Erk) 1/2 pathway in tumor microenvironment. Presence of CD86-positive cells was required for the anti-tumoral effects of CO in established A549 xenografts. We show that the effects of CO on tumor stroma and reprogramming of macrophages towards the anti-tumoral phenotype is mediated by reactive oxygen species (ROS)-dependent activation of MAPK/Erk1/2-c-myc pathway as well as Notch 1-dependent negative feedback on the metabolic enzyme heme oxygenase-1 (HO-1). We find a similar negative correlation between HO-1 and active MAPK-Erk1/2 levels in human lung cancer specimens.In summary, we describe novel non-cell autonomous mechanisms by which the diffusible gas CO dictates changes in the tumor microenvironment through the modulation of macrophages.

Pathologically increased vascular permeability is an important dysfunction in the pathomechanism of life-threatening conditions, such as sepsis, ischemia/reperfusion, or hereditary angioedema (HAE), diseases accompanied by uncontrolled activation of the complement system. HAE for example is caused by the deficiency of C1-inhibitor (the main regulator of early complement activation), which leads to edematous attacks threatening with circulatory collapse. We have previously reported that endothelial cells become activated during HAE attacks. A natural target of C1-inhibitor is mannan-binding lectin-associated serine protease-1 (MASP-1), a multifunctional serine protease, which plays a key role in the activation of complement lectin pathway. We have previously shown that MASP-1 induces the pro-inflammatory activation of endothelial cells and in this study we investigated whether MASP-1 can directly affect endothelial permeability. All experiments were performed on human umbilical vein endothelial cells (HUVECs). Real-time micro electric sensing revealed that MASP-1 decreases the impedance of HUVEC monolayers and in a recently developed permeability test (XperT), MASP-1 dose-dependently increased endothelial paracellular transport. We show that protease activated receptor-1 mediated intracellular Ca2+-mobilization, Rho-kinase activation dependent myosin light chain (MLC) phosphorylation, cytoskeletal actin rearrangement, and disruption of interendothelial junctions are underlying this phenomenon. Furthermore, in a whole-transcriptome microarray analysis MASP-1 significantly changed the expression of 25 permeability-related genes in HUVECs—for example it up-regulated bradykinin B2 receptor expression. According to our results, MASP-1 has potent permeability increasing effects. During infections or injuries MASP-1 may help eliminate the microbes and/or tissue debris by enhancing the extravasation of soluble and cellular components of the immune system, however, it may also play a role in the pathomechanism of diseases, where edema formation and complement lectin pathway activation are simultaneously present. Our findings also raise the possibility that MASP-1 may be a promising target of anti-edema drug development.

We aim to explore the nature of data analysis in the investigation of talk-in-interaction, concentrating on methodological fuzziness. On the basis of a case study on the phenomenon of repair, we argue that even in a traditionally corpus-based field like conversation analysis, the source of corpus data is of an inherently integrated nature. The actual research practice shows that the methodology of conversation analysis cannot be clearly delimited but has fuzzy boundaries. In order to be able to use occurrences found in corpora as data, corpus as data source should be complemented with further pieces of information from other data sources, for instance, the researcher’s intuition, the results of earlier investigation, the theoretical framework we work in and inferences.

The widespread presence of electromagnetic sources in daily life has initiated several studies on the effects of radiofrequency and power frequency fields. Only few investigations on the genotoxic effects of exposure to intermediate frequency magnetic fields (IF-MF) have been done so far. Therefore, the aim of this study was to evaluate possible genotoxic effects of exposure to 123.90 kHz and 250.80 kHz IF-MF on canine and human blood. Blood was exposed to IF-MF at 630 A/m (0.79 mT) and 80 A/m (0.10 m T) with exposure durations of 1–5 h (hourly), 20 and 24 h. Cylindrically divided Petri dish system was developed for in vitro exposures where different induced current could be achieved in the samples at the same magnetic flux density level. For the assessment of genotoxicity the alkaline comet assay was applied. We detected a statistically significant increase in DNA damage only following 20 h exposure to IF-MF.

International audience; Non-ionizing radiation is the term given to radiation in the part of the electromagnetic spectrum that doesn’t have enough energy to ionize atoms or molecules directly. It includes electric and magnetic fields up to 300 GHz, infrared, visible, and ultraviolet radiation (UV). People are exposed to non-ionizing radiation by several man-made sources every day. This includes microwave ovens, cell phones, baby monitors, cordless phones, garage-door openers, etc. There is a big concern amongst the public and authorities regarding possible adverse health effects from exposure to electromagnetic fields. In 2002 the IARC concluded that extremely low frequency magnetic fields (ELF) are possibly carcinogenic (Group 2B). The same conclusion was reached in 2011 with respect to radiofrequency fields (RF) from mobile phones. UV radiation has been classified by IARC as Group I: carcinogenic to humans. In many cases and studies the link has been established between genotoxicity and the possibility that non-ionizing radiations including EMFs are carcinogenic. In our laboratory we use comet assay for testing genotoxicity of non-ionizing radiation for more than ten years. In experiments we use whole blood samples (human or dog), cell lines (e.g. fibroblast, H295R cell line) or 3 dimensional skin tissue (epidermis) models. In our protocol alkaline Comet assay method is used. On our poster there will be presented brief summary of our experiments with different types of radiation (ELF, RF, intermediate frequency and UV). Part of this work was done in the SKIN-RF project funded by ANSES (France).

Medical training in the 21st century faces simulation-based education as one of the challenges that efficiently contributes to clinical skills development while moderating the burden on the clinicians and patients alike.The University of Pécs, Medical School has launched a simulation program in the MediSkillsLab based on history taking with actors to improve patient interviewing communication skills.This new program was inspired by experiences gathered in previous medical language teaching and integrates the method of the "Standardized Patient Program". The method has been applied in America since the 1960s.This is the first time the program has been introduced in Hungary and implemented in an interdisciplinary design, where medical specialists, linguists, actor-patients and medical students collaborate to improve professional, language and communicative competence of the students.A course like this has its pivotal role in the medical training, and as a result more efficient and patient-oriented communication may take place at the clinical setting. Orv Hetil. 2017; 158(26): 1022-1027.

The effective management of patients with sarcomas requires accurate diagnosis and staging. Imaging, such as ultrasonography (US), computed tomography (CT), magnetic resonance imaging (MRI) are the most freqently used methods for the detection of the lesion location, size, morphology and structural changes to adjacent tissues; however, these modalities provide little information about tumour biology. MRI is a robust and useful modality in tumour staging of sarcomas, however metabolic-fluorodeoxyglucose positron emission tomography/ computer tomography (

Modern imaging techniques have an important role in the diagnostic procedures of malignancies, and assessing response to therapy. The18F-FDG PET/CT revolutionized the evaluation of colorectal cancer in terms of preoperative staging and monitoring of recurrence. Conventional imaging techniques have limitations in early assessment of response to therapy.18F-FDG PET has been shown to allow earlier treatment monitoring, because the metabolic change appears before any anatomic change occurs. The Response Evaluation Criteria in Solid Tumours (RECIST) are widely applied, but they have some limitations. There are new international guidelines for treatment response assessment using PET/CT in solid tumours. The authors review indications and the role of hybrid PET/CT in colorectal cancer. Orv. Hetil., 2013, 154, 1447–1453.

Resistance to radiotherapy due to insufficient cancer cell death is a significant cause of treatment failure in non–small cell lung cancer (NSCLC). The endogenous caspase-8 inhibitor FLIP is a critical regulator of cell death that is frequently overexpressed in NSCLC and is an established inhibitor of apoptotic cell death induced via the extrinsic death receptor pathway. Apoptosis induced by ionizing radiation (IR) has been considered to be mediated predominantly via the intrinsic apoptotic pathway; however, we found that IR-induced apoptosis was significantly attenuated in NSCLC cells when caspase-8 was depleted using RNA interference (RNAi), suggesting involvement of the extrinsic apoptosis pathway. Moreover, overexpression of wild-type FLIP, but not a mutant form that cannot bind the critical death receptor adaptor protein FADD, also attenuated IR-induced apoptosis, confirming the importance of the extrinsic apoptotic pathway as a determinant of response to IR in NSCLC. Importantly, when FLIP protein levels were downregulated by RNAi, IR-induced cell death was significantly enhanced. The clinically relevant histone deacetylase (HDAC) inhibitors vorinostat and entinostat were subsequently found to sensitize a subset of NSCLC cell lines to IR in a manner that was dependent on their ability to suppress FLIP expression and promote activation of caspase-8. Entinostat also enhanced the antitumor activity of IR in vivo. Therefore, FLIP downregulation induced by HDAC inhibitors is a potential clinical strategy to radiosensitize NSCLC and thereby improve response to radiotherapy. Overall, this study provides the first evidence that pharmacological inhibition of FLIP may improve response of NCSLC to IR. Mol Cancer Ther; 15(10); 2432–41. ©2016 AACR.

The aim of this paper is to explore recycling and replacement repairs as self-initiated same-turn self-repair strategies in Hungarian. The study concentrates on four factors: repair operation types, syntactic class and length of the repaired segment, and site of initiation. In accordance with previous works focusing on the relationship between grammar and repair, the analysis shows that the main organizer of the self-repair process is the speaker's interactional aim. This interactional aim is realized in the interactional functions of repair operations: providing the speaker with extra time in the case of recycling repairs, or exchanging an unintended item in the case of replacement repairs. The working of these interactional functions, however, always adapts to the grammatical possibilities of the particular language. I have assumed that the ratio of early and late initiations in recycling repairs depends on the typical orders of function and content words in languages, i.e. the exploitability of the delaying function of function word recycling. While the recycling replacement ratio is likely to be approximately universally constant, within recycling repairs the ratio of early and late initiations depends on the morphosyntactic structures of languages. As in Hungarian function words usually precede their respective content words, recyclings tend to be initiated after recognizable completion.

The elevated expression of claudins (CLDN) and E-cadherin (CDH-1) was found to correlate with poor prognostic features. Our aim was to perform a comprehensive analysis to assess their potential to predict prognosis in breast cancer. The expression of CLDN-1, -3-5, -7, -8, -10, -15, -18, and E-cadherin at the mRNA level was evaluated in correlation with survival in datasets containing expression measurements of 1809 breast cancer patients. The breast cancer tissues of 197 patients were evaluated with tissue microarray technique and immunohistochemical method for CLDN-1-5, -7, and E-cadherin protein expression. An additional validation set of 387 patients was used to test the accuracy of the resulting prognostic score. Based on the bioinformatic screening of publicly-available datasets, the metagene of CLDN-3, -4, -7, and E-cadherin was shown to have the most powerful predictive power in the survival analyses. An immunohistochemical protein profile consisting of CLDN-2, -4, and E-cadherin was able to predict outcome in the most effective manner in the training set. Combining the overlapping members of the above two methods resulted in the claudin-4 and E-cadherin score (CURIO), which was able to accurately predict relapse-free survival in the validation cohort (P = 0.029). The multivariate analysis, including clinicopathological variables and the CURIO, showed that the latter kept its predictive power (P = 0.040). Furthermore, the CURIO was able to further refine prognosis, separating good versus poor prognosis subgroups in luminal A, luminal B, and triple-negative breast cancer intrinsic subtypes. In breast cancer, the CURIO provides additional prognostic information besides the routinely utilized diagnostic approaches and factors.

Claudins, known as major contributors in the formation of the tight junction, are differentially expressed in malignant tumors as compared to the corresponding healthy tissues. Therefore, they are thought to play a role in carcinogenesis and tumor progression. Altered expression of claudin-1 has been reported in several tumor types including endometrial, papillary renal cell and colonic carcinoma, and increased claudin-1 mRNA levels have been observed in papillary thyroid carcinoma (PTC). In this study, we aimed at determining the pattern of claudin-1 expression in various types of thyroid lesions at the protein level and investigating the immunolocalization of beta-catenin reported to regulate claudin-1 expression. Samples included 19 PTCs, ten cases of corresponding regional lymph node metastasis, eight papillary microcarcinomas (PMC), 17 follicular thyroid carcinomas (FTC) and 19 follicular adenomas (FA). All cases were evaluated by quantitative immunohistochemistry. Conspicuous claudin-1 immunostaining was detected in the majority of PTC/PMC primary tumors and lymph node metastases (19/27 and 9/10, respectively). On the other hand, we found weak or no claudin-1 expression in any of the FA and FTC cases or peritumoral non-malignant thyroid tissues. Our data prove that high claudin-1 protein expression is specific for PTC and its regional lymph node metastases, while we failed to verify that claudin-1 is regulated by beta-catenin in thyroid tumors. Based on these results, claudin-1 may be a useful tumor marker for PTC.

The authors report on their first experiences with the UroVysion fluorescence in situ hybridization (FISH) kit developed for the detection of bladder cancer. This new non-invasive diagnostic application of the FISH technique in the field of urology was elaborated to replace cystoscopy. The special urine examination method detects genetic alterations of the urothelial cells found in the urine, using fluorescent directlabeled DNA probes binding to the peri-centromeric regions of chromosomes 3, 7 and 17 as well as on the 9p21 locus. We aimed to evaluate the utility of UroVysion test in the light of the histological diagnosis. Urine samples from 43 bladder cancer patients and 12 patients with no or benign alterations were studied using a new application of FISH technique: the UroVysion reagent kit. The obtained FISH results were compared with the histological findings of the transurethral surgical resection specimens. The study rated the specificity and sensitivity of the technique 100% and 87%, respectively. Therefore, the technique could well fit into the diagnostic process of bladder carcinomas. Statistical analyses showed significant correlation between tumor progression and the severity of the genetic alterations detected by this FISH technique. Furthermore, positive correlation was found between tumor grade and the proportion of tumor cells showing genetic abnormality. The noninvasiveness, the robustness of evaluation and the high specificity/sensitivity are all in favor of this technique. The disadvantages are the higher costs of the technical background and the required future clinical studies to determine whether this technique can replace cystoscopy.

Innate immune cells strongly influence cancer growth and progression via multiple mechanisms including regulation of epithelial to mesenchymal transition (EMT). In this study, we investigated whether expression of the metabolic gene, heme oxygenase-1 (HO-1) in tumor microenvironment imparts significant effects on prostate cancer progression.We showed that HO-1 is expressed in MARCO-positive macrophages in prostate cancer (PCa) xenografts and human prostate cancers. We demonstrated that macrophage specific (LyzM-Cre) conditional deletion of HO-1 suppressed growth of PC3 xenografts in vivo and delayed progression of prostate intraepithelial neoplasia (PIN) in TRAMP mice. However, initiation and progression of cancer xenografts in the presence of macrophages lacking HO-1 resulted in loss of E-cadherin, a known marker of poor prognosis as well as EMT. Application of CO, a product of HO-1 catalysis, increased levels of E-cadherin in the adherens junctions between cancer cells. We further showed that HO-1-driven expression of E-cadherin in cancer cells cultured in the presence of macrophages is dependent on mitochondrial activity of cancer cells.In summary, these data suggest that HO-1-derived CO from tumor-associated macrophages influences, in part, E-cadherin expression and thus tumor initiation and progression.

The aim of the study was to investigate the correlation between claudin (CLDN) protein expression and clinicopathological parameters as well as survival in histological subtypes of non-small cell lung cancer. Archived surgical resection specimens of 137 pathologic stage I primary bronchial cancers including 49 adenocarcinomas of non-lepidic variants (ADC), 46 adenocarcinomas of lepidic variants (L-ADC), and 42 squamous cell carcinomas (SCC) were examined. Immunohistochemistry (IHC) using antibodies against CLDN1,-2,-3,-4,-7 proteins as well as semiquantitative estimation (IHC scores 0–5) were performed. Claudin IHC scores of L-ADC differed significantly from ADC (CLDN1: p = 0.009, CLDN2: p = 0.005, CLDN3: p = 0.004, CLDN4: p = 0.001, CLDN7: p

BACKGROUND: Cells deploy quality control mechanisms to remove damaged or misfolded proteins. Recently, we have reported that a mutation (R43W) in the Frank-ter Haar syndrome protein Tks4 resulted in aberrant intracellular localization.RESULTS: Here we demonstrate that the accumulation of Tks4(R43W) depends on the intact microtubule network. Detergent-insoluble Tks4 mutant colocalizes with the centrosome and its aggregate is encaged by the intermediate filament protein vimentin. Both the microtubule inhibitor nocodazole and the histone deacetylase inhibitor Trichostatin A inhibit markedly the aggresome formation in cells expressing Tks4(R43W). Finally, pretreatment of cells with the proteasome inhibitor MG132 markedly increases the level of aggresomes formed by Tks4(R43W). Furthermore, two additional mutant Tks4 proteins (Tks4(1-48) or Tks4(1-341)) have been investigated. Whereas the shorter Tks4 mutant, Tks4(1-48), shows no expression at all, the longer Tks4 truncation mutant accumulates in the nuclei of the cells.CONCLUSIONS: Our results suggest that misfolded Frank-ter Haar syndrome protein Tks4(R43W) is transported via the microtubule system to the aggresomes. Lack of expression of Tks4(1-48) or aberrant intracellular expressions of Tks4(R43W) and Tks4(1-341) strongly suggest that these mutations result in dysfunctional proteins which are not capable of operating properly, leading to the development of FTHS.

The microtubule-associated proteins 1A (MAP1A) and 1B (MAP1B) are distantly related protein complexes consisting of heavy and light chains and are thought to play a role in regulating the neuronal cytoskeleton, MAP1B during neuritogenesis and MAP1A in mature neurons. To elucidate functional differences between MAP1B and MAP1A and to determine the role of the light chain in the MAP1A protein complex, we chose to investigate the functional properties of the light chain of MAP1A (LC2) and compare them with the light chain of MAP1B (LC1). We found that LC2 binds to microtubulesin vivoandin vitroand induces rapid polymerization of tubulin. A microtubule-binding domain in its NH2terminus was found to be necessary and sufficient for these activities. The analysis of LC1 revealed that it too bound to microtubules and induced tubulin polymerization via a crucial but structurally unrelated NH2-terminal domain. The two light chains differed, however, in their effects on microtubule bundling and stabilityin vivo. Furthermore, we identified actin filament binding domains located at the COOH terminus of LC2 and LC1 and obtained evidence that binding to actin filaments is attributable to direct interaction with actin. Our findings establish LC2 as a crucial determinant of MAP1A function, reveal LC2 as a potential linker of neuronal microtubules and microfilaments, and suggest that the postnatal substitution of MAP1B by MAP1A leads to expression of a protein with an overlapping but distinct set of functions.

We investigated tissue biomarkers in non-small cell lung cancer (NSCLC) to find indicators of brain metastasis and peritumoral brain edema.Fifty-two cases were studied out of which 26 had corresponding brain metastatic tissue. Clinicopathological characteristics of tumors were correlated with biomarkers of cell adhesion, cell growth, cell cycle and apoptosis regulation that were previously immunohistochemically studied but never analyzed separately according to histological subgroups, gender and smoking history.Increased collagen XVII in adenocarcinoma (ADC) and increased caspase-9, CD44v6, and decreased cellular apoptosis susceptibility protein (CAS) and Ki-67 in squamous cell carcinoma (SCC) correlated significantly with brain metastasis. Increased β-catenin, E-cadherin and decreased caspase-9 expression in primary SCC, and decreased CD44v6 expression in brain metastatic SCC tissues showed a significant correlation with the extent of peritumoral brain edema. Positive correlation between smoking and biomarker expression could be observed in metastatic ADCs with p16 and caspase-8, while-negative correlation was found in SCC without brain metastasis with caspase-3, and in SCC with brain metastasis with p27.Our results highlight the importance of separate analysis of biomarker expression in histological subtypes of NSCLC.

Significance: Heme degradation, which was described more than 30 years ago, is still very actively explored with many novel discoveries on its role in various disease models every year. Recent Advances: The heme oxygenases (HO) are metabolic enzymes that utilize NADPH and oxygen to break apart the heme moiety liberating biliverdin (BV), carbon monoxide (CO), and iron. Heme that is derived from hemoproteins can be toxic to the cells and if not removed immediately, it causes cell apoptosis and local inflammation. Elimination of heme from the milieu enables generation of three products that influences numerous metabolic changes in the cell. Critical Issues: CO has profound effects on mitochondria and cellular respiration and other hemoproteins to which it can bind and affect their function, while BV and bilirubin (BR), the substrate and product of BV, reductase, respectively, are potent antioxidants. Sequestration of iron into ferritin and its recycling in the tissues is a part of the homeodynamic processes that control oxidation-reduction in cellular metabolism. Further, heme is an important component of a number of metabolic enzymes, and, therefore, HO-1 plays an important role in the modulation of cellular bioenergetics. Future Directions: In this review, we describe the cross-talk between heme oxygenase-1 (HO-1) and its products with other metabolic pathways. HO-1, which we have labeled Nike, the goddess who personified victory, dictates triumph over pathophysiologic conditions, including diabetes, ischemia, and cancer. Antioxid. Redox Signal. 20, 1709–1722.

Critical functions of the immune system are maintained by the ability of myeloid progenitors to differentiate and mature into macrophages. We hypothesized that the cytoprotective gas molecule carbon monoxide (CO), generated endogenously by heme oxygenases (HO), promotes differentiation of progenitors into functional macrophages. Deletion of HO-1, specifically in the myeloid lineage (Lyz-Cre:Hmox1(flfl)), attenuated the ability of myeloid progenitors to differentiate toward macrophages and decreased the expression of macrophage markers, CD14 and macrophage colony-stimulating factor receptor (MCSFR). We showed that HO-1 and CO induced CD14 expression and efficiently increased expansion and differentiation of myeloid cells into macrophages. Further, CO sensitized myeloid cells to treatment with MCSF at low doses by increasing MCSFR expression, mediated partially through a PI3K-Akt-dependent mechanism. Exposure of mice to CO in a model of marginal bone marrow transplantation significantly improved donor myeloid cell engraftment efficiency, expansion and differentiation, which corresponded to increased serum levels of GM-CSF, IL-1α and MCP-1. Collectively, we conclude that HO-1 and CO in part are critical for myeloid cell differentiation. CO may prove to be a novel therapeutic agent to improve functional recovery of bone marrow cells in patients undergoing irradiation, chemotherapy and/or bone marrow transplantation. NIH grants:( HL-071797, HL-07616, R21CA169904), AHA grant: (10SDG2640091), Julie Henry Fund, Transplant Center of the BIDMC, Eleanor Shore Foundation .