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Budapest, Hungary

Minarovits J.,Microbiological Research Group | Niller H.H.,University of Regensburg
Patho-Epigenetics of Disease | Year: 2012

In multicellular organisms the establishment, maintenance, and programmed alterations of cell-type specific gene expression patterns are regulated by epigenetic mechanisms. Thus, epigenetic alterations (DNA methylation, DNA associated Polycomb-Trithorax protein complexes, histone modifications) ensure the unique transcriptional activity and phenotypic diversity of diploid cells that carry identical or nearly identical DNA sequences.Because DNA methyltransferase I (DNMT1) associates with replication foci during S phase and prefers hemimethylated DNA as a substrate, DNMT1 ensures the clonal propagation of cytosine methylation patterns (maintenance methylation). Thus, DNA methylation may provide a memory function by helping progeny cells to "remember" their proper cellular identity.An alternative system of epigenetic memory, the Polycomb and Trithorax groups of protein complexes, that may operate both independently from and in concert with DNA methylation, ensures the heritable regulation of gene expression viamodification of histone tails.The complex interplay of epigenetic regulatory mechanisms permits both the dynamic modulation of gene expression and the faithful transmission of gene expression patterns to each progeny cell upon division. These carefully orchestrated processes can go wrong, however, resulting in epigenetic reprogramming of the cells that may manifest in pathological changes, as it was first realized during the studies of epigenetic alterations in malignant tumors. By now it became a well established fact that not only genetic changes, but also the disruption of epigenetic regulation can result in carcinogenesis and tumor progression. Scientists working in other fields soon followed the pioneering work of cancer researchers, and revealed that epigenetic dysregulation forms the basis of a wide spectrum of human diseases. © 2012 Springer Science+Business Media New York. All rights are reserved. Source

Ay E.,Microbiological Research Group | Banati F.,Microbiological Research Group | Mezei M.,Microbiological Research Group | Bakos A.,Microbiological Research Group | And 5 more authors.
AIDS Reviews | Year: 2013

We surveyed current trends in epigenetics in general and epigenetics of HIV infection and AIDS in particular to pinpoint promising areas for translational research. Epigenetic mechanisms mark and affect the structure of chromatin, thereby controlling the activity of promoters. Because epigenetic changes are reversible, epigenetic drugs can be used to modulate gene activity. At present, silenced HIV genomes, the latent HIV reservoir, is a major obstacle for a curative treatment of AIDS patients. Epigenetic therapy aims at the purging of the latent reservoir by switching on transcription of silent HIV genomes. The basic idea is that the cytopathic effect of the replicating virus and the immune system may eliminate the reactivated cells, whereas HAART may block the infection of new target cells. Although current efforts concentrate on long-lived resting memory CD4+ T-cells, dormant HIV proviruses also reside in other cell types. Thus, epigenetic characterization of the various HIV-infected host cells and host cell-dependent HIV latency mechanisms is a promising research area and may facilitate the development of cell type-specific epigenetic drugs. HAART itself affects the epigenotype of host cells. This may contribute to the development of drug resistance and unwanted side effects. A pharmacoepigenetic approach may help to elucidate and revert such phenomena. In addition to latent reservoir purging, epigenetic research offers alternative therapeutic tools as well; although not aimed at the elimination of the virus, targeted silencing of HIV transcription by epigenetic regulators may help HAART to minimize virus replication. © Permanyer Publications 2013. Source

Kovacs G.G.,Medical University of Vienna | Sanchez-Juan P.,Institute For Formation And Research Of The Fundacion Marques Of Valdecilla | Sanchez-Juan P.,Research Center Biomedica en Red sobre Enfermedades Neurodegenerativas | Strobel T.,Medical University of Vienna | And 18 more authors.
Alzheimer Disease and Associated Disorders | Year: 2010

Accumulation of cathepsin D immunoreactive lysosomes correlates with tissue pathology in sporadic Creutzfeldt-Jakob disease (CJD) brains. The C-to-T transition within exon 2 of the cathepsin D (CTSD) gene is associated with altered enzymatic activity. Possession of the TT genotype is a risk factor for variant CJD. To verify the association between the CTSD position 224T allele and the risk for and survival in sporadic and genetic CJD, we genotyped 540 sporadic, 101 genetic CJD, and 723 control individuals. Genotype data and duration of illness were compared using multiple logistic regression and Kruskal-Wallis test. Multivariate survival analysis was performed using Cox's regression model. The distribution of CTSD position 224 alleles was approximately the same in all groups. We observed a trend for shorter survival in sporadic CJD patients harboring the T allele at position 224 of the CTSD gene in particular in sporadic CJD patients with the prion protein gene position 129 MM genotype. We conclude that the CTSD position 224 polymorphism alone is not a significant risk or disease-modifying factor in sporadic or genetic CJD. © 2010 by Lippincott Williams & Wilkins. Source

Stanojevic M.,University of Belgrade | Gokengin D.,Ege University | Mezei M.,Microbiological Research Group | Minarovits J.,Microbiological Research Group | And 5 more authors.
AIDS Reviews | Year: 2012

The Balkans is a gateway between Europe, Asia, and the African continent, a fact with potential important consequences on the epidemiology of HIV-1 infection in the region. The duration of the HIV-1 epidemics in many countries of the Balkans is similar to the one in the Western European countries. However, striking differences exist in several countries of the region in both the epidemic situation and, even more so, in our knowledge about it. In particular, the molecular epidemiology of HIV in the Balkans is largely unknown. In order to gain some preliminary insight into HIV-1 diversity in the region, we reviewed the available molecular epidemiology data about HIV-1 diversity in 10 countries of the region: Albania, Bulgaria, Croatia, Greece, Montenegro, Romania, Slovenia, Serbia, Turkey, and Hungary, a neighboring country to four Balkan countries. The data were obtained either from published studies or in direct communication with the participating members. The existing molecular epidemiology data revealed a broad diversity in subtype distribution among Balkan countries. In several countries, subtype B is predominant (e.g. Serbia, Slovenia, and Hungary), while in others the proportion of non-B subtypes is much larger (Albania subtype A, Romania subtype F). In some areas, HIV-1 subtype distribution is marked by divergence between different risk groups or transmission routes (e.g. Croatia). Recently, HIV-1/AIDS epidemics in Eastern Europe have been among the fastest growing in the world. Many major contributing factors for the breakout and spread of these epidemics are present in many of the Balkan countries, as reflected through the process of social transition, wars, unemployment, extensive drug use, high sexual risk behavior, as well as other factors. Yet, in the Balkan countries the prevalence rate of HIV-1 infection is low, under 0.1 percent. Concomitantly, the molecular epidemiology of HIV-1 in the Balkans has not been thoroughly studied so far. The review and analysis of the available data indicate a broad diversity of circulating HIV-1 subtypes in the region, with the predominance of non-B clades in some countries, underscoring the need for an ongoing surveillance of HIV-1 diversity. The setup of a collaborative network might provide important information for the better management and control of the HIV-1 epidemic in the area. Source

Rasul E.,Karolinska Institutet | Salamon D.,Karolinska Institutet | Nagy N.,Karolinska Institutet | Leveau B.,Karolinska Institutet | And 7 more authors.
PLoS ONE | Year: 2014

The EBV carrying lines MEC1 and MEC2 were established earlier from explants of blood derived cells of a chronic lymphocytic leukemia (CLL) patient at different stages of progression to prolymphocytoid transformation (PLL). This pair of lines is unique in several respects. Their common clonal origin was proven by the rearrangement of the immunoglobulin genes. The cells were driven to proliferation in vitro by the same indigenous EBV strain. They are phenotypically different and represent subsequent subclones emerging in the CLL population. Furthermore they reflect the clinical progression of the disease. We emphasize that the support for the expression of the EBV encoded growth program is an important differentiation marker of the CLL cells of origin that was shared by the two subclones. It can be surmised that proliferation of EBV carrying cells in vitro, but not in vivo, reflects the efficient surveillance that functions even in the severe leukemic condition. The MEC1 line arose before the aggressive clinical stage from an EBV carrying cell within the subclone that was in the early prolymphocytic transformation stage while the MEC2 line originated one year later, from the subsequent subclone with overt PLL characteristics. At this time the disease was disseminated and the blood lymphocyte count was considerably elevated. The EBV induced proliferation of the MEC cells belonging to the subclones with markers of PLL agrees with earlier reports in which cells of PLL disease were infected in vitro and immortalized to LCL. They prove also that the expression of EBV encoded set of proteins can be determined at the event of infection. This pair of lines is particularly important as they provide in vitro cells that represent the subclonal evolution of the CLL disease. Furthermore, the phenotype of the MEC1 cells shares several characteristics of ex vivo CLL cells. © 2014 Rasul et al. Source

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