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Jelen tanulmányban a nyelvi jogok elismerése mellett szóló három fő érvet vizsgálom. Ezek egyike szerint a nyelvi sokféleség fontos és megőrzendő érték, a nyelv identitásformáló tényező. Egy másik megközelítés rámutat, hogy a nyelvi különbözőség konfliktushoz vezet, amennyiben az egyes nyelvi közösségek eltérő jogokkal rendelkeznek nyelvük használatára. A harmadik érvelési irány szerint a nyelvi jogok a többi emberi joghoz való hozzáférés, a demokratikus részvétel eszközei, de önmagukban is emberi jogoknak tekinthetők. Akár egy védendő érték biztosítékának, akár hasznos konfliktuskezelési eszköznek, akár emberi jogoknak tekintjük a nyelvi jogokat, a nyelvi kérdés szabályozását nem lehet az egyes államok szabad belátására bízni: szükség van a nemzetközi közösség eddigieknél hathatósabb szerepvállalására is.

This article provides an overview of the implementation of the rights of European national, ethnic or linguistic minorities and indigenous peoples in 2020, in the fields of administration of justice, public administration, participation, citizenship and tranfrontier exchanges. Relevant legal developments are presented in the activities of the United Nations, the Organization for Security and Co-operation in Europe, the European Union, and the Council of Europe. Special attention is paid to the application of the European Charter for Regional or Minority Languages and the Framework Convention for the Protection of National Minorities, which are the most important international treaties on the rights of minorities in Europe.

BackgroundPlasmodium falciparumparasites cause malaria and co-exist in humans together with B-cells for long periods of time. Immunity is only achieved after repeated exposure. There has been a lack of methods to mimic the in vivo co-occurrence, where cells and parasites can be grown together for many days, and it has been difficult with long time in vitro studies.Methods and resultsA new method for growingP. falciparumin 5% CO2with a specially formulated culture medium is described. This knowledge was used to establish the co-culture of liveP. falciparumtogether with human B-cells in vitro for 10 days. The presence of B-cells clearly enhanced parasite growth, but less so when Transwell inserts were used (not allowing passage of cells or merozoites), showing that direct contact is advantageous. B-cells also proliferated more in presence of parasites. Symbiotic parasitic growth was verified using CESS cell-line and it showed similar results, indicating that B-cells are indeed the cells responsible for the effect. In malaria endemic areas, people often have increased levels of atypical memory B-cells in the blood, and in this assay it was demonstrated that when parasites were present there was an increase in the proportion of CD19 + CD20 + CD27 − FCRL4 + B-cells, and a contraction of classical memory B-cells. This effect was most clearly seen when direct contact between B-cells and parasites was allowed.ConclusionsThese results demonstrate thatP. falciparumand B-cells undoubtedly can affect each other when allowed to multiply together, which is valuable information for future vaccine studies.

Összefoglaló. A hajas sejtes leukémia (HCL) egy indolens lefolyású ritka B-sejtes lymphoma. Diagnosztikájában jellegzetes morfológiai képén túlmenően a sejtek felszínén megtalálható markerek azonosítása áramlási citometriával, valamint a betegségben előforduló specifikus fehérjék immunhisztokémiai detektálása jelenti a rutineljárást. Kiemelt szerepet tölt be a differenciáldiagnosztikában a BRAF V600E mutációjának a kimutatása, melyre ma már számos módszer áll rendelkezésre, mint például az immunhisztokémia, pyroszekvenálás, allélspecifikus PCR vagy a droplet digitalis PCR. A tumorsejtek jelátviteli rendszerében és szabályozásában azonban a BRAF mutációjának következtében kialakuló folyamatos aktivitása mellett egyéb mechanizmusok is szerepet játszhatnak, többek között növekedési faktorok, interleukinek, adhéziós fehérjék vagy éppen mikro-RNS-ek. A patomechanizmus egyre részletesebb megismerése érdekében egyéb daganatokhoz hasonlóan a HCL-ben is aktív kutatások folynak a genetikai háttér feltérképezésére új generációs szekvenálás segítségével. Leírtak már nagy százalékban előforduló mutációkat a CDKN1B-, KLF2- és KMT2C-gének esetében, továbbá egyéb génekben is alacsonyabb előfordulási aránnyal. Genetikailag, sőt klinikai manifesztáció és terápiás válasz alapján is jelentős eltérések láthatóak a klasszikus és variáns HCL-es betegek között, elkülönítésük épp ezért rendkívül fontos. Míg a klasszikus esetben első vonalban alkalmazott purin nukleozid analógok kiemelkedő válaszreakciót képesek kiváltani, a variáns HCL-es betegek gyakran refrakterek a kezelésre, és esetükben a célzott BRAF-gátlók szintén hatástalanok. Számos klinikai kutatás zajlik a jelenleg is alkalmazott terápiás szerek optimalizálása, kombinációban történő alkalmazása, valamint egyéb lymphoid daganatokban alkalmazott gyógyszerek és új támadáspontok ellen tervezett molekuláknak a HCL kezelésébe történő bevonása céljából. Summary. Hairy cell leukemia (HCL) is a rare indolent B-cell malignancy. In addition to characteristic morphology of HCL cells, the identification of the cellular surface markers and the expression of specific proteins by flow cytometry and immunohistochemistry are routine procedure in HCL diagnosis. Detection of BRAF V600E mutation plays key role in differential diagnosis of HCL which can be detected by several novel methods, such as immunohistochemistry, pyrosequencing, allele specific PCR or droplet digital PCR. Beside the BRAF mutation there can be other mechanisms causing constitutive activity in the signaling pathway and regulating the tumor cells such as growth factors, interleukins, adhesion proteins and micro-RNAs as well. Like in other malignancies, in order to clarify the pathomechanism, the genetic background of HCL is also actively investigated by next-generation sequencing. Frequent mutations were described in CDKN1B, KLF2 and KMT2C genes, moreover in other genes with lower incidence rate, as well. Genetically, and even in clinical manifestation and therapeutic response, significant differences can be found between patients with classical and variant HCL. While classical type has outstanding response for the first-line treatment with purine analogues, patients with variant HCL are often refractory to the treatment, and the BRAF inhibitors prove to be ineffective. Therefore, it is really important to distinguish these two entities. Several clinical studies are still in progress for the optimization and application of combining the currently applied therapeutic agents, furthermore other drugs that used in lymphoid malignancies are under investigation. New target molecules are also designed as novel therapeutic opportunity in HCL treatment.

The global behaviour of the compact pairwise approximation of SIS epidemic propagation on networks is studied. It is shown that the system can be reduced to two equations enabling us to carry out a detailed study of the dynamic properties of the solutions. It is proved that transcritical bifurcation occurs in the system at \begin{document}$ \tau = \tau _c = \frac{\gamma n}{\langle n^{2}\rangle-n} $\end{document} , where \begin{document}$ \tau $\end{document} and \begin{document}$ \gamma $\end{document} are infection and recovery rates, respectively, \begin{document}$ n $\end{document} is the average degree of the network and \begin{document}$ \langle n^{2}\rangle $\end{document} is the second moment of the degree distribution. For subcritical values of \begin{document}$ \tau $\end{document} the disease-free steady state is stable, while for supercritical values a unique stable endemic equilibrium appears. We also prove that for subcritical values of \begin{document}$ \tau $\end{document} the disease-free steady state is globally stable under certain assumptions on the graph that cover a wide class of networks.

The Bcl-2 inhibitor venetoclax has been recently introduced into the treatment of chronic lymphocytic leukemia. Venetoclax is a highly effective drug, however acquired resistance may make long-term treatment challenging. In our study, we present potential novel resistance mechanisms and prognostic markers that are potentially able to predict the early appearance of the resistance.Repeated complete blood counts, flow cytometric measurements, and physical examinations were performed during the patient follow-up. Clinical and laboratory parameters showed that the patient developed clinical resistance to venetoclax on day 450 of therapy. Resistance mutation analysis (D103Y) and apoptosis arrays from samples at the time of resistance were done.We were able to identify the resistance mutations just a very low variant allele frequency level from the resistant samples. Furthermore we detected increased Bcl-2 expression in peripheral blood (PB), and XIAP overexpression in bone marrow (BM) that could lead to venetoclax resistance. We examined the immunophenotype of CLL cells and recognized that while the expression of CD86 did not change until day 270 of the treatment, since then its expression steadily increased. Moreover, we compared the expression of CD86 in the resistant PB and BM samples and did not find a notable difference between the compartments.Our results imply that CLL cells may try to avoid the apoptotic effect of venetoclax through increased CD86 expression by activating antiapoptotic mechanisms. Confirmatory experiments are still required to unequivocally prove that CD86 is a prognostic marker, however, its predictive property during the venetoclax treatment is promising.

Tyrosine kinase inhibitor (TKI) treatment has dramatically improved the survival of chronic myeloid leukemia (CML) patients, but measurable residual disease typically persists. To more effectively eradicate leukemia cells, simultaneous targeting of BCR-ABL1 and additional CML-related survival proteins has been proposed. Notably, several highly specific myeloid cell leukemia 1 (MCL1) inhibitors have recently entered clinical trials for various hematologic malignancies, although not for CML, reflecting the insensitivity of CML cell lines to single MCL1 inhibition. Here, we show that combining TKI (imatinib, nilotinib, dasatinib, or asciminib) treatment with the small-molecule MCL1 inhibitor S63845 exerted strong synergistic antiviability and proapoptotic effects on CML lines and CD34+ stem/progenitor cells isolated from untreated CML patients in chronic phase. Using wild-type BCR-ABL1-harboring CML lines and their T315I-mutated sublines (generated by CRISPR/Cas9-mediated homologous recombination), we prove that the synergistic proapoptotic effect of the drug combination depended on TKI-mediated BCR-ABL1 inhibition, but not on TKI-related off-target mechanisms. Moreover, we demonstrate that colony formation of CML but not normal hematopoietic stem/progenitor cells became markedly reduced upon combination treatment compared to imatinib monotherapy. Our results suggest that dual targeting of MCL1 and BCR-ABL1 activity may efficiently eradicate residual CML cells without affecting normal hematopoietic stem/progenitors. Funding Agencies|Cancer Research Funds of Radiumhemmet [174283]; Thorsmans Stiftelse for Pre-leukemi Forskning; Gunnar Grimfors Gavofond for Hematologisk Forskning; Cathrine Everts Research Foundation; Lars Hierta Memorial Foundation; Emil Anderson Fund for Medical Research; Swedish Research CouncilSwedish Research CouncilEuropean Commission [2013-08807]; Karolinska Institute Foundation and Funds; Karolinska InstituteKarolinska Institutet

Topoisomerases are essential for the replication of herpesviruses but the mechanisms by which the viruses hijack the cellular enzymes are largely unknown. We found that topoisomerase-II (TOP2) is a substrate of the Epstein-Barr virus (EBV) ubiquitin deconjugase BPLF1. BPLF1 co-immunoprecipitated and deubiquitinated TOP2, and stabilized SUMOylated TOP2 trapped in cleavage complexes (TOP2ccs), which halted the DNA damage response to TOP2-induced double strand DNA breaks and promoted cell survival. Induction of the productive virus cycle in epithelial and lymphoid cell lines carrying recombinant EBV encoding the active enzyme was accompanied by TOP2 deubiquitination, accumulation of TOP2ccs and resistance to Etoposide toxicity. The protective effect of BPLF1 was dependent on the expression of tyrosyl-DNA phosphodiesterase 2 (TDP2) that releases DNA-trapped TOP2 and promotes error-free DNA repair. These findings highlight a previously unrecognized function of BPLF1 in supporting a non-proteolytic pathway for TOP2ccs debulking that favors cell survival and virus production., Author summary The N-terminal domains of the herpesvirus large tegument proteins encode a conserved cysteine protease with ubiquitin- and NEDD8-specific deconjugase activity. Members of the viral enzyme family regulate different aspects of the virus life cycle including virus replication, the assembly of infectious virus particles and the host innate anti-viral response. However, only few substrates have been validated under physiological conditions of expression and very little is known on the mechanisms by which the enzymes contribute to the reprograming of cellular functions that are required for efficient infection and virus production. Cellular type I and type II topoisomerases (TOP1 and TOP2) resolve topological problems that arise during DNA replication and transcription and are therefore essential for herpesvirus replication. We report that the Epstein-Barr virus (EBV) ubiquitin deconjugase BPLF1 selectively regulates the activity of TOP2 in cells treated with the TOP2 poison Etoposide and during productive infection. Using transiently transfected and stable cell lines that express catalytically active or inactive BPLF1, we found that BPLF1 interacts with both TOP2α and TOP2β in co-immunoprecipitation and in vitro pull-down assays and the active enzyme stabilizes TOP2 trapped in TOP2ccs, promoting a shift towards TOP2 SUMOylation. This hinders the activation of DNA-damage responses and reduces the toxicity of Etoposide. The physiological relevance of this finding was validated using pairs of EBV carrying HEK-293T cells and EBV immortalized lymphoblastoid cell lines (LCLs) expressing the wild type or catalytic mutant enzyme. Using knockout LCLs we found that the capacity of BPLF1 to rescue of Etoposide toxicity is dependent on the expression of tyrosyl-DNA phosphodiesterase 2 (TDP2) that releases DNA-trapped TOP2 and promotes error-free DNA repair.

Water is one of the most significant and vulnerable natural resources. The aim of our study presented here was to assess the sediment and water quality of Újpest backwater and its main influencing factors. The study area is located in the north side of Budapest, a backwater of the Danube river. An industrial region of the city, also serving as recreational area for nearby residents. The average water depth is 4,5 meters and the length of the backwater is 2200 meters. The most significant economic activity is the ship-building and maintenance. In order to assess water and sediment quality, a number of physical, chemical and the microbiological measurements were carried out on both water and sediment samples. The water samples were collected at two dates, while sediments samples were taken at one date in 2015. Sediment analysis included heavy metals (Cu, Zn, Pb, Cd), TPH and PAH measurements. Water quality analysis included chemical (NH3, NH4+, NO3-, Fe, pH value, conductivity, dissolved oxygen) and microbiological parameters. The results of the study showed that the sediment contained different types of heavy metals and hydrocarbons due to the industrial activities and transportation. During the analyses, we measured high Pb, Cd, Cu, Zn, TPH and PAH concentration in the northern part of the backwater. Possible reasons of the high values include ship maintenance and repairing, ship traffic and road traffic. Measured high Pb, Cd, TPH and PAH concentrations in the sediment might carry environmental risks. Among the general water quality parameters, we found high Fe concentrations mist likely connected to railway traffic in the northern part of the sampling area, while microbial analysis showed only acceptable or lower counts.

Weakly and tightly sorbed phosphate species on chernozem and humus sand are investigated by radioactive tracer method using 32P. The comparison of the heterogeneous isotope exchange of 32P-labeled phosphate of non-radioactively incubated soils and desorption of 32P-labeled phosphate of radioactively incubated soils shows the transformation of weakly sorbed species to tightly sorbed ones. The quantity of weakly sorbed phosphorus and the steady state phosphorus exchange rate between soil and soil solution, transformation half-life of weakly to tightly sorbed phosphate are calculated.

This section overviews the 2017 situation of the language rights of European minorities in the fields of education, the administration of justice and public administration. The author presents the relevant legal developments in the activities of the major international organizations, i.e. the United Nations, the Organization for Security and Cooperation in Europe, the European Union, and the Council of Europe including the case law of the European Court of Human Rights, and the implementation of the European Charter for Regional and Minority Languages as well as the Framework Convention for the Protection of National Minorities. In the concluding remarks, tendencies and common patterns are emphasized.

Purpose More than half of the familial cutaneous melanomas have unknown genetic predisposition. This study aims at characterizing a novel melanoma susceptibility gene. Methods We performed exome and targeted sequencing in melanoma-prone families without any known melanoma susceptibility genes. We analyzed the expression of candidate gene DENND5A in melanoma samples in relation to pigmentation and UV signature. Functional studies were carried out using microscopic approaches and zebrafish model. Results We identified a novel DENND5A truncating variant that segregated with melanoma in a Swedish family and 2 additional rare DENND5A variants, 1 of which segregated with the disease in an American family. We found that DENND5A is significantly enriched in pigmented melanoma tissue. Our functional studies show that loss of DENND5A function leads to decrease in melanin content in vitro and pigmentation defects in vivo. Mechanistically, harboring the truncating variant or being suppressed leads to DENND5A losing its interaction with SNX1 and its ability to transport the SNX1-associated vesicles from melanosomes. Consequently, untethered SNX1-premelanosome protein and redundant tyrosinase are redirected to lysosomal degradation by default, causing decrease in melanin content. Conclusion Our findings provide evidence of a physiological role of DENND5A in the skin context and link its variants to melanoma susceptibility.

Topoisomerases are essential for the replication of herpesviruses but the mechanisms by which the viruses hijack the cellular enzymes are largely unknown. We found that topoisomerase-II (TOP2) is a substrate of the Epstein-Barr virus (EBV) ubiquitin deconjugase BPLF1. BPLF1 selectively inhibited the ubiquitination of TOP2 following treatment with topoisomerase poisons, interacted with TOP2α and TOP2β in co-immunoprecipitation and in vitro pull-down, stabilized Etoposide-trapped TOP2 cleavage complexes (TOP2cc) and promoted TOP2 SUMOylation, which halted the DNA-damage response and reduced Etoposide toxicity. Induction of the productive virus cycle promoted the accumulation of TOP2βcc, enhanced TOP2β SUMOylation, and reduced Etoposide toxicity in lymphoblastoid cell lines carrying recombinant EBV encoding the active enzyme. Attenuation of this phenotype upon expression of a catalytic mutant BPLF1-C61A impaired viral DNA synthesis and virus release. These findings highlight a previously unrecognized function of BPLF1 in promoting non-proteolytic pathways for TOP2cc debulking that favor cell survival and virus production.

Funder: Kjell och Märta Beijers Stiftelse (SE), Funder: Hjärnfonden; doi: http://dx.doi.org/10.13039/501100003792, Funder: Cancerfonden; doi: http://dx.doi.org/10.13039/501100002794, Funder: Vetenskapsrådet; doi: http://dx.doi.org/10.13039/501100004359, Funder: Alzheimerfonden; doi: http://dx.doi.org/10.13039/501100008599, Funder: Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse (SE), Funder: Science for Life Laboratory (SE), Funder: Fundacja na rzecz Nauki Polskiej (PL), Funder: Uppsala University, Epidemiological investigations show that mosaic loss of chromosome Y (LOY) in leukocytes is associated with earlier mortality and morbidity from many diseases in men. LOY is the most common acquired mutation and is associated with aberrant clonal expansion of cells, yet it remains unclear whether this mosaicism exerts a direct physiological effect. We studied DNA and RNA from leukocytes in sorted- and single-cells in vivo and in vitro. DNA analyses of sorted cells showed that men diagnosed with Alzheimer’s disease was primarily affected with LOY in NK cells whereas prostate cancer patients more frequently displayed LOY in CD4 + T cells and granulocytes. Moreover, bulk and single-cell RNA sequencing in leukocytes allowed scoring of LOY from mRNA data and confirmed considerable variation in the rate of LOY across individuals and cell types. LOY-associated transcriptional effect (LATE) was observed in ~ 500 autosomal genes showing dysregulation in leukocytes with LOY. The fraction of LATE genes within specific cell types was substantially larger than the fraction of LATE genes shared between different subsets of leukocytes, suggesting that LOY might have pleiotropic effects. LATE genes are involved in immune functions but also encode proteins with roles in other diverse biological processes. Our findings highlight a surprisingly broad role for chromosome Y, challenging the view of it as a “genetic wasteland”, and support the hypothesis that altered immune function in leukocytes could be a mechanism linking LOY to increased risk for disease.

mTOR activation has been observed in rhabdomyosarcoma (RMS), however, mTOR complex (mTORC) 1 inhibition has had limited success thus far. mTOR activation alters the metabolic pathways, which is linked to survival and metastasis. These pathways have not been thoroughly analyzed in RMSs. We performed immunohistochemistry on 65 samples to analyze the expression of mTOR complexes (pmTOR, pS6, Rictor), and several metabolic enzymes (phosphofructokinase, lactate dehydrogenase-A, &beta, F1-ATPase, glucose-6-phosphate dehydrogenase, glutaminase). RICTOR amplification, as a potential mechanism of Rictor overexpression, was analyzed by FISH and digital droplet PCR. In total, 64% of the studied primary samples showed mTOR activity with an mTORC2 dominance (82%). Chemotherapy did not cause any relevant change in mTOR activity. Elevated mTOR activity was associated with a worse prognosis in relapsed cases. RICTOR amplification was not confirmed in any of the cases. Our findings suggest the importance of the Warburg effect and the pentose-phosphate pathway beside a glutamine demand in RMS cells. The expression pattern of the studied mTOR markers can explain the inefficacy of mTORC1 inhibitor therapy. Therefore, we suggest performing a detailed investigation of the mTOR profile before administering mTORC1 inhibitor therapy. Furthermore, our findings highlight that targeting the metabolic plasticity could be an alternative therapeutic approach.

Recent advances in molecular technologies enable sensitive and quantitative assessment of circulating tumor DNA, offering a noninvasive disease monitoring tool for patients with malignant disorders. Here, we demonstrated on four follicular lymphoma cases that circulating tumor DNA based EZH2 mutation analysis performed by a highly sensitive droplet digital PCR method may be a valuable treatment monitoring approach in EZH2 mutant follicular lymphoma. EZH2 variant allele frequencies changed in parallel with the volume of metabolically active tumor sites observed on 18F-fluorodeoxyglucose positron emission tomography combined with computer tomography (PET-CT) scans. Variant allele frequencies of EZH2 mutations decreased or were eliminated rapidly upon successful treatment, with treatment failure being associated with elevated EZH2 variant allele frequencies. We also demonstrated spatial heterogeneity in a patient with two different EZH2 mutations in distinct anatomical sites, with both mutations simultaneously detected in the liquid biopsy specimen. In summary, circulating tumor DNA based EZH2 mutation analysis offers a rapid, real-time, radiation-free monitoring tool for sensitive detection of EZH2 mutations deriving from different anatomical sites in follicular lymphoma patients receiving immunochemotherapy.

The microbiological quality of milk is important not only for food safety, but it can also influence the quality of dairy products. In this study, our aim was to assess the microbiological status of the bulk milk of a milk-producing farm, and some natural and flavored (garlic, dill, onion) gomolya cheeses made from pasteurized milk produced by their own processing plant. We determined the number of coliform bacteria, Escherichia coli, Staphylococcus aureus, and molds of three milk and eight cheese samples. The tests were conducted between July and September, 2017. In bulk milk, the mean coliform count was 3.83±0.17 log10 CFU/ml; the mean E. coli count was 1.38±0.14 log10 CFU/ml; the mean mold count was 3.74±1.30 log10 CFU/ml; and the S. aureus count was

We have addressed the role of bacterial co-infection in viral oncogenesis using as model Epstein-Barr virus (EBV), a human herpesvirus that causes lymphoid malignancies and epithelial cancers. Infection of EBV carrying epithelial cells with the common oral pathogenic Gram-negative bacterium Aggregatibacter actinomycetemcomitans (Aa) triggered reactivation of the productive virus cycle. Using isogenic Aa strains that differ in the production of the cytolethal distending toxin (CDT) and purified catalytically active or inactive toxin, we found that the CDT acts via induction of DNA double strand breaks and activation of the Ataxia Telangectasia Mutated (ATM) kinase. Exposure of EBV-negative epithelial cells to the virus in the presence of sub-lethal doses of CDT was accompanied by the accumulation of latently infected cells exhibiting multiple signs of genomic instability. These findings illustrate a scenario where co-infection with certain bacterial species may favor the establishment of a microenvironment conducive to the EBV-induced malignant transformation of epithelial cells.

The sorption of phosphate on soils is studied by radioisotopic tracer method. Two consecutive processes with rather different rates were differentiated: namely the heterogeneous isotope exchange between the phosphate in the soil solution and the weakly sorbed phosphate (fast reaction), and the transformation of weakly sorbed phosphate to tightly sorbed phosphate (slow reaction). In this paper, it is shown how the rate constants of these two processes can be determined by a radiotracer with a relatively short half-life.

Four modified bentonites (La(III), Ce(III), Y(III), Fe(III)) were prepared by ion exchange process to remove arsenite (III) ions from water. The modified bentonites were examined with X-ray fluorescence spectroscopy (XRF) and X-ray diffraction (XRD). The rare earth (REE) and Fe(III) ion content in bentonite was higher than the CEC values obtained by ammonium acetate method related to trivalent ions (2.7 x 10-4 mol g-1). The kinetics, equilibrium time, sorption isotherms and desorption experiments were examined. Lanthanum, yttrium and cerium bentonite can bind similar amount of arsenite(III) ions. Iron-bentonite cannot bind significant amounts of arsenite ions. The active sites and the solubilities of the sorption complex were determined. Arsenite (III) ions sorb in the interlayer space as REEAsO3. The solubility of the arsenite complex was two orders of magnitude smaller than that of the phosphate complex. After desorption the eluted amount of arsenite (III) was 55 % related to the sorbed amount of arsenite. The d(001) basal spacing of modified bentonites and that of after sorption and desorption was measured. After the sorption of arsenite ion on lanthanum bentonite, the d(001) basal spacing of montmorillonite was decreased and after desorption an increase in d(001) basal spacing was observed again. Modified bentonites can be used for removing arsenic ions from water.

Several monoclonal antibodies and inhibitors targeting signalling pathways are being used in personalised medicine. Anti-EGFR antibodies seem to be effective, however, therapy resistance often occurs in colon carcinoma cases. mTOR inhibitors (mTORIs) could have a potential role in the breakthrough of therapy resistance. The mTOR activity related protein expression patterns and the in vitro effects of EGFR inhibitors (EGFRIs), mTORIs and their combinations were studied in different colon carcinoma cell lines (with different genetic backgrounds). Alamar Blue test and flow cytometry were used to analyse the in vitro proliferation and apoptotic effects of cetuximab, gefitinib, cisplatin, rapamycin, PP242 and NVP-BEZ235. The expressions of mTOR activity related proteins (p-70S6K, p-S6, Rictor, p-mTOR, Raptor) were studied by Western blot, immunocytochemistry and Duolink staining. The EGFRI resistance of the studied colon carcinoma cell lines related to their known mutations were confirmed, neither gefitinib nor cetuximab inhibited the proliferation or induced apoptosis in vitro. Individual differences in Rictor and Raptor expressions were detected by Western blot and immunocytochemistry beside elevated mTOR activity of these different colon carcinoma cell lines. These expression patterns correlated to the mTORIs sensitivity differences, moreover, mTORIs could enhance the effects of EGFRIs and other in vitro treatments. Our results suggest that mTORI combinations could be helpful in both EGFRI and platinum-based therapy of colon carcinomas. Moreover, we suggest determining both mTOR complex activity and mutations in Akt/mTOR signalling pathways for selecting the appropriate mTORIs and patients in potential future combination treatments.

Absztrakt: A follicularis lymphoma terapiajaban a rituximab alkalmazasanak koszonhetően a betegek varhato elettartama szamottevően megnőtt, azonban a betegseg jelenlegi tudasunk szerint tovabbra is...

Absztrakt: A kronikus limfocitas leukemia klinikailag heterogen megjelenese genetikai diverzitassal parosul. Hazankban fluoreszcens in situ hibridizacio terjedt el a betegekben előfordulo, prognosz...

Background Philadelphia negative myeloproliferative neoplasms (MPNs) are characterized by frequent mutations of driver genes including JAK2, CALR and MPL. While the influence of JAK2 V617F mutant allele burden on the clinical phenotype of MPN patients is well-described, the impact of CALR mutant allele burden on clinical features needs further investigation. Patients and methods Quantitative assessment of JAK2 and CALR mutations was performed on diagnostic DNA samples from 425 essential thrombocythemia (ET) and 227 primary myelofibrosis patients using real-time quantitative PCR and fragment length analysis. Characterization of CALR mutations and detection of MPL mutations were performed by Sanger sequencing. Results Twelve novel CALR mutations have been identified. ET patients with CALRmut load exceeding the median value exhibited lower hemoglobin values (12.0 vs. 13.6 g/dL), higher LDH levels (510 vs. 351 IU/L) and higher rate of myelofibrotic transformation (19% vs. 5%). The CALRmut load was higher among ET patients presenting with splenomegaly compared to those without splenomegaly (50.0% vs. 43.5%). Conclusion Our study confirms the clinical significance of driver mutational status and JAK2mut load in MPNs; in addition, unravels a novel clinical association between high CALRmut load and a more proliferative phenotype in ET.

The primary aim of this study was to determine mTOR-pathway activity in primary central nervous system lymphoma (PCNSL), which could be a potential target for therapy. After demonstrating that p-S6 positivity largely exceeded mTOR activity, we aimed to identify other pathways that may lead to S6 phosphorylation. We measured mTOR activity with immunohistochemistry for p-mTOR and its downstream effectors p(T389)-p70S6K1, p-S6, and p-4E-BP1 in 31 cases of PCNSL and 51 cases of systemic diffuse large B-cell lymphoma (DLBCL) and evaluated alternative S6 phosphorylation pathways with p-RSK, p(T229)-p70S6K1, and PASK antibodies. Finally, we examined the impact of PASK inhibition on S6 phosphorylation on BHD1 cell line. mTOR-pathway activity was significantly less frequent in PCNSL compared with DLBCL. p-S6 positivity was related to mTOR-pathway in DLBCL, but not in PCNSL. Among the other kinases potentially responsible for S6 phosphorylation, PASK proved to be positive in all cases of PCNSL and DLBCL. Inhibition of PASK resulted in reduced expression of p-S6 in BHD1-cells. This is the first study demonstrating an mTOR independent p-S6 activity in PCNSL and that PASK may contribute to the phosphorylation of S6. Our findings also suggest a potential role of PASK in the pathomechanism of PCNSL and in DLBCL.