A mulasztásról

In the field of criminal law, we can interpret omission as a type of conduct of the perpetrator. However, it cannot be defined in the same way as its counterpart, the action. According to the criminal law doctrine, the concept of omission has three several elements: the legal duty, the possibility to act, and the ability to act. This complex contexture follows a concept according to which some types of the crimes – which are committed by omission – are questionable from the aspect of criminal law literature and in some cases it brings up constitutional issues, too. The national legislation, the practice of law and surprisingly the law literature have not responded yet to the connected problems, they are still waiting for the solutions to these problems. My study is a reaction to this neglected issue in such a way that it shows the particularity of the crimes which are committed by omission based on a systematization aspect which has been unknown in Hungarian legal literature. I standardize these crimes with a formal aspect used in German and Swiss legal literature where jurisprudence makes distinction between ‘real’ and ‘not real’ crimes which are committed by omission. With the help of this classification, the types of legal duties can be linked to another dogmatic matter in this way, to the characteristic of construct of the statutory definition of the crime and the scope of offenders, too. ‘Not real omission’ can be identified as a variation of criminal offence which is regulated in ‘opened’ statutory definitions. According to the hypothesis of this paper, this kind of legislative solution has constitutional issues. The solution for these problems stands in the centre of my study. In order to make the analysis more illustrative, I use an original method of systematization, and in the comparative parts, I also use the solutions from the German and the Swiss criminal law. As a conclusion of my study, I have the aim to prove the above-mentioned hypothesis. Also, I present my de lege ferenda suggestion which is based on the conclusion of the foreign regulations and of various legal literature

Studies on a widely-recognized snail model species (Lymnaea stagnalis) provide further evidence that vertebrate steroids do not have a hormonal role in the reproduction of mollusks

Experiments were carried out to determine whether, as with other mollusks that have been studied, the snail, Lymnaea stagnalis , can absorb, esterify and store vertebrate steroids that are present in the water. We also carried out experiments to determine whether neural tissues of the snail could be immunohistochemically stained with an antibody to human aromatase (a key enzyme that catalyzes the conversion of testosterone [T] to 17β-estradiol [E 2 ]); and, if so, to determine the significance of such staining. Previous studies on other mollusks have reported such staining and have proposed this as decisive evidence that mollusks have the same steroid synthesis pathway as vertebrates. We found that snails absorb, esterify and retain esterified T, E 2 , progesterone and ethinyl-estradiol (albeit with an absorption rate about four times slower, on a weight basis, than the mussel, Mytilus edulis ). We also found that not only anti-human aromatase, but also anti-human nuclear progesterone receptor (nPR) and anti-human gonadotropin-releasing hormone antibodies immunohistochemically stained snail neural cells. However, further experiments, involving gel electrophoretic separation, followed by immunostaining, of proteins extracted from the neural tissue, found at least two positively-stained bands for each antibody, none of which had masses matching the human proteins to which the antibodies had been raised. The anti-aromatase antibody even stained the 140 kDA ladder protein used as a molecular weight marker on the gels. Mass spectrometric analysis of the bands did not find any peptide sequences that corresponded to the human proteins. Our findings confirm that the presence of vertebrate-like sex steroids in molluscan tissues is not necessarily evidence of endogenous origin. The results also show that immunohistochemical studies using antibodies against human proteins are grossly non-specific and likely to have little or no value in studying steroid synthesis or activity in mollusks. Our conclusions are consistent with the fact that genes for aromatase and nPR have not been found in the genome of the snail or of any other mollusk. Our overarching conclusion, from this and our previous studies, is that the endocrinology of mollusks is not the same as that of humans or any other vertebrates and that continuing to carry out physiological and ecotoxicological studies on mollusks on the basis of this false assumption, is an unconscionable waste of resources

PARP inhibition induces Akt-mediated cytoprotective effects through the formation of a mitochondria-targeted phospho-ATM-NEMO-Akt-mTOR signalosome

The cytoprotective effect of poly(ADP-ribose) polymerase 1 (PARP1) inhibition is well documented in various cell types subjected to oxidative stress. Previously, we have demonstrated that PARP1 inhibition activates Akt, and showed that this response plays a critical role in the maintenance of mitochondrial integrity and in cell survival. However, it has not yet been defined how nuclear PARP1 signals to cytoplasmic Akt.Methods: WRL 68, HeLa and MCF7 cells were grown in culture. Oxidative stress was induced with hydrogen peroxide. PARP was inhibited with the PARP inhibitor PJ34. ATM, mTOR- and NEMO were silenced using specific siRNAs. Cell viability assays were based on the MTT assay. PARP-ATM pulldown experiments were conducted; each protein was visualized by Western blotting. Immunoprecipitation of ATM, phospho-ATM and NEMO was performed from cytoplasmic and mitochondrial cell fractions and proteins were detected by Western blotting. In some experiments, a continually active Akt construct was introduced. Nuclear to cytoplasmic and mitochondrial translocation of phospho-Akt was visualized by confocal microscopy.Results: Here we present evidence for a PARP1 mediated, PARylation- dependent interaction between ATM and NEMO, which is responsible for the cytoplasmic transport of phosphorylated (thus, activated) ATM kinase. In turn, the cytoplasmic p-ATM and NEMO forms complex with mTOR and Akt, yielding the phospho-ATM-NEMO-Akt-mTOR signalosome, which is responsible for the PARP- inhibition induced Akt activation. The phospho-ATM-NEMO-Akt-mTOR signalosome localizes to the mitochondria and is essential for the PARP-inhibition-mediated cytoprotective effects in oxidatively stressed cells. When the formation of the signalosome is prevented, the cytoprotective effects diminish, but cells can be rescued by constantly active Akt1, further confirming the critical role of Akt activation in cytoprotection.Conclusions: Taken together, the data presented in the current paper are consistent with the hypothesis that PARP inhibition suppresses the PARylation of ATM, which, in turn, forms an ATM-NEMO complex, which exits the nucleus, and combines in the cytosol with mTOR and Act, resulting in Act phosphorylation (i.e. activation), which, in turn, produces the cytoprotective action via the induction of Akt- mediated survival pathways. This mechanism can be important in the protective effect of PARP inhibitor in various diseases associated with oxidative stress. Moreover, disruption of the formation or action of the phospho-ATM-NEMO-Akt-mTOR signalosome may offer potential future experimental therapeutic checkpoints

Fémkomplexek mint enzimmodellek és biológiailag aktív vegyületek = Metal Complexes as Enzyme Models and Biologically Active Materials

A szerves vegyületek reakciói dioxigénnel mind biológiai mind pedig ipari szempotból fontos területe a kémiának. A biológiai rendszerek enyhe reakciókörülmények mellett működnek és működésük részletes megismerése és esetleges ipari alkalmazása állandó érdeklődésre tart számot. Kutatási projektünk metalloenzimek működési és szerkezeti modelljeinek a tanulmányozására irányult. Meg kívántuk ismerni, ki akartuk deríteni, hogy a triplet dioxigén milyen módokon aktiválható, és oxidázok, monooxigenázok, dioxigenázok, katalázok és szuperoxid dizmutázok hogyan működnek és mi az enzimreakciók feltételezett mechanizmusa. Nagy kihívás volt a C?H és C?C kötések aktiválása enyhe reakciókörülmények mellett, ahol jó részeredményeket értünk el. Megállapítottuk továbbá, hogy az u.n. reaktív oxigén molekulák (ROS) hogyan eliminálhatók a kémiai sztressz redukálása céljából, és tisztáztuk alapvető kémiájukat. Eredményeket értünk el un. ?bioinspirált? reakciók megvalósításában is és néhány mesterséges metalloenzim mint pl. kataláz és szuperoxid dizmutáz kidlgozásában. Eredményeinkről eddig 32 közlemény jelent meg nemzetközi szakfolyóiratokban. | The reaction of organic molecules with triplet dioxygen is very important both in biological and in industrial area. Biological systems work at much milder condition and there is a permanent interest to know how biological catalysts (enzymes) really work and how we can use them in chemistry. Our project focused on metalloenzyme models having either structural or functional similarities to the enzymes in order to find out the ways dioxygen can be activated, how oxidases, monooxygenases, dioxygenases, catalases, and superoxide dismutases really work and what is their possible mechanisms. Real challenges are the activation of C?H and C?C bonds under mild condition where we could find some progress. We obtained knowledge how ROS (Reactive Oxygen Species) formed during these processes can be eliminated to avoid oxidative stress and what is their basic chemistry. On the other hand we also had some progress in terms of ?bioinspired reactions? and also to find some artificial metalloenzymes such as catalase and superoxide dismutase. We published our results in 32 peer-reviewed international journals

Involvement of Mitochondrial Mechanisms and Cyclooxygenase‐2 Activation in the Effect of Desethylamiodarone on 4T1 Triple‐Negative Breast Cancer Line

Novel compounds significantly interfering with the mitochondrial energy production may have therapeutic value in triple-negative breast cancer (TNBC). This criterion is clearly fulfilled by desethylamiodarone (DEA), which is a major metabolite of amiodarone, a widely used antiarrhythmic drug, since the DEA previously demonstrated anti-neoplastic, anti-metastasizing, and direct mitochondrial effects in B16F10 melanoma cells. Additionally, the more than fifty years of clinical experience with amiodarone should answer most of the safety concerns about DEA. Accordingly, in the present study, we investigated DEA’s potential in TNBC by using a TN and a hormone receptor positive (HR+) BC cell line. DEA reduced the viability, colony formation, and invasive growth of the 4T1 cell line and led to a higher extent of the MCF-7 cell line. It lowered mitochondrial transmembrane potential and induced mitochondrial fragmentation. On the other hand, DEA failed to significantly affect various parameters of the cellular energy metabolism as determined by a Seahorse live cell respirometer. Cyclooxygenase 2 (COX-2), which was upregulated by DEA in the TNBC cell line only, accounted for most of 4T1’s DEA resistance, which was counteracted by the selective COX-2 inhibitor celecoxib. All these data indicate that DEA may have potentiality in the therapy of TNBC

Correlation between the progressive cytoplasmic expression of a novel small heat shock protein (Hsp16.2) and malignancy in brain tumors

<p>Abstract</p> <p>Background</p> <p>Small heat shock proteins are molecular chaperones that protect proteins against stress-induced aggregation. They have also been found to have anti-apoptotic activity and to play a part in the development of tumors. Recently, we identified a new small heat shock protein, Hsp16.2 which displayed increased expression in neuroectodermal tumors. Our aim was to investigate the expression of Hsp16.2 in different types of brain tumors and to correlate its expression with the histological grade of the tumor.</p> <p>Methods</p> <p>Immunohistochemistry with a polyclonal antibody to Hsp16.2 was carried out on formalin-fixed, paraffin-wax-embedded sections using the streptavidin-biotin method. 91 samples were examined and their histological grade was defined. According to the intensity of Hsp16.2 immunoreactivity, low (+), moderate (++), high (+++) or none (-) scores were given.</p> <p>Immunoblotting was carried out on 30 samples of brain tumors using SDS-polyacrylamide gel electrophoresis and Western-blotting.</p> <p>Results</p> <p>Low grade (grades 1–2) brain tumors displayed low cytoplasmic Hsp16.2 immunoreactivity, grade 3 tumors showed moderate cytoplasmic staining, while high grade (grade 4) tumors exhibited intensive cytoplasmic Hsp16.2 staining. Immunoblotting supported the above mentioned results. Normal brain tissue acted as a negative control for the experiment, since the cytoplasm did not stain for Hsp16.2. There was a positive correlation between the level of Hsp16.2 expression and the level of anaplasia in different malignant tissue samples.</p> <p>Conclusion</p> <p>Hsp16.2 expression was directly correlated with the histological grade of brain tumors, therefore Hsp16.2 may have relevance as becoming a possible tumor marker.</p

PARP Inhibitor PJ34 Protects Mitochondria and Induces DNA-Damage Mediated Apoptosis in Combination With Cisplatin or Temozolomide in B16F10 Melanoma Cells

<p>PARP-1 inhibition has recently been employed in both mono- and combination therapies in various malignancies including melanoma with both promising and contradicting results reported. Although deeper understanding of the underlying molecular mechanisms may help improving clinical modalities, the complex cellular effects of PARP inhibitors make disentangling of the mechanisms involved in combination therapies difficult. Here, we used two cytostatic agents used in melanoma therapies in combination with PARP inhibition to have an insight into cellular events using the B16F10 melanoma model. We found that, when used in combination with cisplatin or temozolomide, pharmacologic blockade of PARP-1 by PJ34 augmented the DNA-damaging and cytotoxic effects of both alkylating compounds. Interestingly, however, this synergism unfolds relatively slowly and is preceded by molecular events that are traditionally believed to support cell survival including the stabilization of mitochondrial membrane potential and morphology. Our data indicate that the PARP inhibitor PJ34 has, apparently, opposing effects on the mitochondrial structure and cell survival. While, initially, it stimulates mitochondrial fusion and hyperpolarization, hallmarks of mitochondrial protection, it enhances the cytotoxic effects of alkylating agents at later stages. These findings may contribute to the optimization of PARP inhibitor-based antineoplastic modalities.</p