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MicroRNAs (miRNAs) are evolutionarily conserved small non-coding RNAs, that are involved in the multistep process of carcinogenesis, contributing to all established hallmarks of cancer. In this review, implications of miRNAs in hematological malignancies and their clinical utilization fields are discussed. As components of the complex regulatory network of gene expression, influenced by the tissue microenvironment and epigenetic modifiers, miRNAs are "micromanagers" of all physiological processes including the regulation of hematopoiesis and metabolic pathways. Dysregulated miRNA expression levels contribute to both the initiation and progression of acute leukemias, the metabolic reprogramming of malignantly transformed hematopoietic precursors, and to the development of chemoresistance. Since they are highly stable and can be easily quantified in body fluids and tissue specimens, miRNAs are promising biomarkers for the early detection of hematological malignancies. Besides novel opportunities for differential diagnosis, miRNAs can contribute to advanced chemoresistance prediction and prognostic stratification of acute leukemias. Synthetic oligonucleotides and delivery vehicles aim the therapeutic modulation of miRNA expression levels. However, major challenges such as efficient delivery to specific locations, differences of miRNA expression patterns between pediatric and adult hematological malignancies, and potential side effects of miRNA-based therapies should be considered.

Over the past two decades, novel hallmarks of cancer have been described, including the altered epigenetic landscape of malignant diseases. In addition to the methylation and hyd-roxymethylation of DNA, numerous novel forms of histone modifications and nucleosome remodeling have been discovered, giving rise to a wide variety of targeted therapeutic interventions. DNA hypomethylating drugs, histone deacetylase inhibitors and agents targeting histone methylation machinery are of distinguished clinical significance. The major focus of this review is placed on targeted epigenetic interventions in the most common pediatric malignancies, including acute leukemias, brain and kidney tumors, neuroblastoma and soft tissue sarcomas. Upcoming novel challenges include specificity and potential undesirable side effects. Different epigenetic patterns of pediatric and adult cancers should be noted. Biological significance of epigenetic alterations highly depends on the tissue microenvironment and widespread interactions. An individualized treatment approach requires detailed genetic, epigenetic and metabolomic evaluation of cancer. Advances in molecular technologies and clinical translation may contribute to the development of novel pediatric anticancer treatment strategies, aiming for improved survival and better patient quality of life.

Making benefit from the epigenetic effects of environmental factors such as physical activity may result in a considerable improvement in the prevention of chronic civilization diseases. In our chronic swimming rat model, the expression levels of such microRNAs were characterized, that are involved in skeletal muscle differentiation, hypertrophy and fine-tuning of metabolism, which processes are influenced by chronic endurance training, contributing to the metabolic adaptation of skeletal muscle during physical activity. After chronic swimming, the level of miR-128a increased significantly in EDL muscles, which may influence metabolic adaptation and stress response as well. In SOL, the expression level of miR-15b and miR-451 decreased significantly after chronic swimming, which changes are opposite to their previously described increment in insulin resistant skeletal muscle. MiR-451 also targets PGC-1α mRNA, whiches expression level significantly increased in SOL muscles, resulting in enhanced biogenesis and oxidative capacity of mitochondria. In summary, the microRNA expression changes that were observed during our experiments suggest that chronic swim training contributes to a beneficial metabolic profile of skeletal muscle.

Abstract: Although very early onset inflammatory bowel disease that develops in early childhood (before the age of 6 years) has a different etiology from Crohn’s disease and ulcerative colitis, it is also characterized by chronic inflammation of the gastrointestinal tract. Basically, very early onset inflammatory bowel disease should be considered as an immunodeficiency with monogenic origin where both gastrointestinal manifestations and symptoms of immunodeficiencies may develop in variable combinations. However, in the future, the evaluation of genetic alterations in the background of the disease will probably be performed by next-generation sequencing technology; one should also consider that the sequence of the DNA stands in continuous interaction with a wide variety of environmental effects, among which nutrition should be emphasized by all means. Epigenetic alterations that are induced by environmental factors, could contribute to the pathogenesis of inflammatory bowel diseases that develop during childhood, therefore, they should also be identified during further research. It has a key significance to establish the diagnosis of very early onset inflammatory bowel disease as early as possible, because this could give the opportunity to start the adequate treatment which is bone marrow transplantation in the case of monogenic immunodeficiencies. Orv Hetil. 2018; 159(49): 2050–2056.

In den achtziger und neunziger Jahren wurde bei der Entwicklung und Umsetzung des kommunikativ-interkulturellen Ansatzes im Fremdsprachenunterricht eine totale Umorientierung erforderlich. „In den letzten Jahrzehnten hat das Konzept der sogenannten Kompetenzorientierung im Fremdsprachenunterricht zunehmend an Bedeutung gewonnen“, wie es von Wicke (2017: 5) formuliert wurde. Eine der vielen Kompetenzen ist die Projektkompetenz, der Gegenstand meiner Untersuchungen

Although very early onset inflammatory bowel disease that develops in early childhood (before the age of 6 years) has a different etiology from Crohn's disease and ulcerative colitis, it is also characterized by chronic inflammation of the gastrointestinal tract. Basically, very early onset inflammatory bowel disease should be considered as an immunodeficiency with monogenic origin where both gastrointestinal manifestations and symptoms of immunodeficiencies may develop in variable combinations. However, in the future, the evaluation of genetic alterations in the background of the disease will probably be performed by next-generation sequencing technology; one should also consider that the sequence of the DNA stands in continuous interaction with a wide variety of environmental effects, among which nutrition should be emphasized by all means. Epigenetic alterations that are induced by environmental factors, could contribute to the pathogenesis of inflammatory bowel diseases that develop during childhood, therefore, they should also be identified during further research. It has a key significance to establish the diagnosis of very early onset inflammatory bowel disease as early as possible, because this could give the opportunity to start the adequate treatment which is bone marrow transplantation in the case of monogenic immunodeficiencies. Orv Hetil. 2018; 159(49): 2050-2056.Absztrakt: A 6 éves életkor előtt kialakuló, úgynevezett nagyon korai kezdetű gyulladásos bélbetegség a Crohn-betegségtől és a colitis ulcerosától eltérő etiológiájú, de szintén krónikus bélrendszeri gyulladással járó kórkép. Döntően monogénes eredetű immundefektusnak kell tartanunk, amelyben a bélrendszeri tünetek mellett az immundeficientiákra jellemző tünetek változatos formában jelentkezhetnek. A háttérben álló géndefektusok meghatározásának jövője várhatóan az új generációs szekvenálási technológia, azonban a genetikai meghatározottság mellett szem előtt kell tartanunk azt is, hogy a génállomány a környezeti hatásokkal folyamatos kölcsönhatásban áll. Az utóbbiak közül a táplálkozás feltétlenül kiemelendő. A jövőben a gyermekkorban manifesztálódó gyulladásos bélbetegségekre jellemző, környezeti tényezők által indukált epigenetikai változások azonosítására szintén törekednünk kell. A betegség lehető legkorábbi felismerése kulcsfontosságú, hiszen ez teszi lehetővé az adekvát kezelés megkezdését, monogénes immundefektusban a csontvelő-transzplantáció mielőbbi elvégzését. Orv Hetil. 2018; 159(49): 2050–2056.

Disruption of epigenetic regulation and characteristic metabolic alterations (known as the Warburg-effect) are well-known hallmarks of cancer. In our study we investigated the expression levels of microRNAs and histone deacetylase enzymes via RT-qPCR in bone marrow specimens of adult patients suffering from hematological malignancies (total cohort n = 40), especially acute myeloid leukemia (n = 27). The levels of the three examined Warburg-effect related microRNAs (miR-378*, miR-23b, miR-26a) positively correlated with each other and the oncogenic miR-155 and miR-125b, while negatively with the level of the tumorsuppressor miR-124. Significant relationships have been confirmed between the levels of SIRT6, HDAC4 and the microRNAs listed above. In NPM1-mutated AML (n = 6), the level of miR-125b was significantly lower than in the group of AML patients not carrying this mutation (n = 13) (p

Myalgia and muscle weakness may appreciably contribute to the poor adherence to statin therapy. Although the pathomechanism of statin-induced myopathy is not completely understood, changes in calcium homeostasis and reduced coenzyme Q10 levels are hypothesized to play important roles. In our experiments, fluvastatin and/or coenzyme Q10 was administered chronically to normocholesterolaemic or hypercholaestherolaemic rats, and the modifications of the calcium homeostasis and the strength of their muscles were investigated. While hypercholesterolaemia did not change the frequency of sparks, fluvastatin increased it on muscles both from normocholesterolaemic and from hypercholesterolaemic rats. This effect, however, was not mediated by a chronic modification of the ryanodine receptor as shown by the unchanged ryanodine binding in the latter group. While coenzyme Q10 supplementation significantly reduced the frequency of the spontaneous calcium release events, it did not affect their amplitude and spatial spread in muscles from fluvastatin-treated rats. This indicates that coenzyme Q10 supplementation prevented the spark frequency increasing effect of fluvastatin without having a major effect on the amount of calcium released during individual sparks. In conclusion, we have found that fluvastatin, independently of the cholesterol level in the blood, consistently and specifically increased the frequency of calcium sparks in skeletal muscle cells, an effect which could be prevented by the addition of coenzyme Q10 to the diet. These results support theories favouring the role of calcium handling in the pathophysiology of statin-induced myopathy and provide a possible pathway for the protective effect of coenzyme Q10 in statin treated patients symptomatic of this condition.

Hairy cell leukemia is a chronic, clonal disease of the hemopoetic stem cell. Although our knowledge on its pathogenesis has increased a lot during the previous years, further details are needed to provide a more personalized, and therefore more successful treatment for patients. New advancements in the growing field of epigenetics may contribute to the finding of novel therapeutic target molecules. Similarly to acute leukemia, hairy cell leukemia also possesses a unique microRNA expression pattern. Decreased levels of tumor suppressor microRNAs lead to the elevation of the expression levels of their oncogenic targets. During our investigations on the level of let-7b and miR-124 in the bone marrow sample of a patient suffering from hairy cell leukemia, decreased expression levels have been found in the case of both microRNAs. These alterations also influence the activity of the MAPK signaling pathway, resulting from the regulation of its members by microRNAs including those mentioned above. Our results support new details about the connection between altered microRNA expression levels and signal transduction pathways in hairy cell leukemia.

The term epigenetics includes regulatory mechanisms that influence gene expression without any changes in the sequence of the DNA, namely DNA methylation, histone modification and small, non-coding RNAs. Methylation of the DNA leads to the repression of gene expression, while histone modification can result in both activation and inhibition of the transcription depending on the type and site of modification. These mechanisms are confirmed to have important pathogenetic role during the process of leukemogenesis. In distinct subtypes of leukemia specific alterations of the DNA methylation profile, histone code and typical changes of the microRNA expression levels have been observed. The importance of them is inhered in their promising potential clinical applications. In order to achieve further improvement in the therapeutic results of leukemia, prognostic classification has to be further improved. With the help of the epigenetic alterations, subgroups could be differentiated within the known prognostic groups. Changes in the DNA methylation pattern, histone code and microRNA expression levels correlate with the success of the treatment in many cases, moreover they could provide help to predict chemoresistance or detect the minimal residual disease following chemotherapy. Enzymes influencing the structure of chromatin form a wide variety of new potential therapeutic targets. Based on preliminary results, sorts of epigenetic therapy may be combined successfully either with each other or with conventional chemotherapeutic drugs in the treatment of leukemia.Az epigenetika a génexpressziót a DNS szekvenciájának megváltozása nélkül szabályozó mechanizmusokkal foglalkozik. Tárgykörébe tartozik a DNS-metiláció, a hisztonmodifikáció és a kis, nem kódoló RNS-ek csoportja. A DNS-metiláció a génexpresszió repressziójához vezet. A hisztonmodifikáció a módosítás típusától és az érintett oldallánctól függõen a transzkripció aktivációját és gátlását egyaránt eredményezheti. E szabályozó mechanizmusok zavarai igazoltan szerepet játszanak a leukémia kialakulásában. A leukémia különbözõ altípusaiban a DNS-metilációs mintázat, a hisztonkód és a mikro-RNS expressziós szintek jellegzetes eltéréseit figyelték meg, melyek jelentõsége lehetséges klinikai alkalmazásukban rejlik. A terápiás eredmények javításához a prognosztikai klasszifikációs rendszer pontosítása szükséges. Az epigenetikai eltérések segítségével egy adott prognosztikai csoporton belül további alcsoportok elkülönítése válhat lehetségessé. A DNS metilációs mintázatában, a hisztonkódban, illetve a mikro-RNS-ek expressziós szintjében bekövetkezõ változások sok esetben korrelálnak az alkalmazott terápia eredményességével, bizonyos esetekben pedig segítséget nyújthatnak a kemorezisztencia elõrejelzésében vagy a kemoterápiát követõen a minimális reziduális betegség felismerésében. A kromatin szerkezetét befolyásoló, az epigenetikai módosításokért felelõs enzimek potenciális terápiás célpontokként szolgálhatnak. Elõzetes eredmények szerint az epigenetikai terápia különbözõ típusai egymással és a konvencionális kemoterápiával egyaránt sikeresen kombinálhatók lehetnek a jövõben a leukémia terápiájában.

MicroRNAs are a class of small non-coding RNAs regulating gene expression at posttranscriptional level. Their target genes include numerous regulators of cell cycle, cell proliferation as well as apoptosis. Therefore, they are implicated in the initiation and progression of cancer, tissue invasion and metastasis formation as well. MicroRNA profiles supply much information about both the origin and the differentiation state of tumours. MicroRNAs also have a key role during haemopoiesis. An altered expression level of those have often been observed in different types of leukemia. There are successful attempts to apply microRNAs in the diagnosis and prognosis of acute lymphoblastic leukemia and acute myeloid leukemia. Measurement of the expression levels may help to predict the success of treatment with different kinds of chemotherapeutic drugs. MicroRNAs are also regarded as promising therapeutic targets, and can contribute to a more personalized therapeutic approach in haemato-oncologic patients.