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Varga K.,Hungarian Academy of Sciences | Paszty K.,Hungarian Academy of Sciences | Padanyi R.,Hungarian National Blood Transfusion Service | Hegedu;s L.,Hungarian Academy of Sciences | And 4 more authors.
Cell Calcium | Year: 2014

The expression of the plasma membrane Ca2+ ATPase (PMCA) isoforms is altered in several types of cancer cells suggesting that they are involved in cancer progression. In this study we induced differentiation of MCF-7 breast cancer cells by histone deacetylase inhibitors (HDACis) such as short chain fatty acids (SCFAs) or suberoylanilide hydroxamic acid (SAHA), and by phorbol 12-myristate 13-acetate (PMA) and found strong upregulation of PMCA4b protein expression in response to these treatments. Furthermore, combination of HDACis with PMA augmented cell differentiation and further enhanced PMCA4b expression both at mRNA and protein levels. Immunocytochemical analysis revealed that the upregulated protein was located mostly in the plasma membrane. To examine the functional consequences of elevated PMCA4b expression, the characteristics of intracellular Ca2+ signals were investigated before and after differentiation inducing treatments, and also in cells overexpressing PMCA4b. The increased PMCA4b expression - either by treatment or overexpression - led to enhanced Ca2+ clearance from the stimulated cells. We found pronounced PMCA4 protein expression in normal breast tissue samples highlighting the importance of this pump for the maintenance of mammary epithelial Ca2+ homeostasis. These results suggest that modulation of Ca2+ signaling by enhanced PMCA4b expression may contribute to normal development of breast epithelium and may be lost in cancer. © 2014 Elsevier Ltd. Source

Bors A.,National Diagnostics | Andrikovics H.,National Diagnostics | Illes Z.,National Diagnostics | Jager R.,Hungarian National Blood Transfusion Service | And 4 more authors.
Blood Coagulation and Fibrinolysis | Year: 2015

Deficiencies of blood coagulation factors VIII and IX (haemophilia A and haemophilia B) represent the most common inherited bleeding disorders with a wide range of causative mutations. Carrier and prenatal diagnostics are preferably performed by direct mutation detection; however, in certain situations, indirect family studies may also be useful. We aimed to utilize a combination of direct and indirect techniques for carrier and prenatal diagnostics in both haemophilias in a single national centre. Two hundred and eleven haemophilia A families were investigated by screening for inversions of introns 1 and 22, and by family studies using polymorphic markers. Twenty-eight haemophilia A and 39 haemophilia B families were investigated by Sanger-sequencing of the coding regions. Among severe haemophilia A families, frequencies of intron 22 and 1 inversions were 82 out of 145 (57%) and two out of 145 (1.4%). Sequencing of the entire coding region of the respective factor gene was performed and 12 (haemophilia A) and 5 (haemophilia B) previously unpublished disease-causing mutations were identified. For genetic markers used for haemophilia A indirect family testing, heterozygosity rates varied between 137 out of 327 [42% intragenic BclI restriction fragment length polymorphism (RFLP], 168 out of 254 (66% intragenic F8Civs13CA) and 202 out of 261 (77% extragenic DXS15CA) with a combined rate of 92% (intragenic markers) and 97% (all three markers). For male fetuses, prenatal diagnostics was provided to 43 haemophilia A families (n=22 with direct mutation detection and n=21 by indirect family testing) and to three haemophilia B families. The combination of direct and indirect molecular genetics approaches is a successful and cost-effective approach to provide carrier and prenatal diagnostics and risk assessment for inhibitor formation. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Source

Smudla A.,Semmelweis University | Hegedus K.,Semmelweis University | Mihaly S.,Hungarian National Blood Transfusion Service | Szabo G.,Semmelweis University | Fazakas J.,Semmelweis University
Annals of Transplantation | Year: 2012

Background: Adequate communication with donors' relatives in the intensive care unit can crucially increase the number of donations and can influence the relatives' grief reaction and depression. The aim of this quantitative investigation was to explore how communication in the ICU about brain death and consent to donation affected family members' psychological condition.Material/Methods: The self-completed questionnaire, which the donors' relatives filled in 3-6 months after donation consisted of demographic data, participants' knowledge, opinions about and attitudes toward donation, communication in the ICU regarding brain death and donation, and 2 psychometric inventories: the Hungarian-translated version of the Revised Grief Experience Inventory and the Hungarian adaptation of the Shortened Version of the Beck Depression Inventory. Results: Before organ recovery, 100% of the 29 participants supported donation, but 24.1% considered donation for transplantation to be unhelpful, and 41.4% doubted that the diagnosis was reliable after donation. Bereavement and depression did not correlate with age, marital status or degree of religiousness. Females had higher "physical distress" and more severe depression. The psychological reaction was lower amongst relatives with higher education. Depressive symptoms occurred in 72.4% of participants. Individuals who did not have confidence in the brain death diagnosis had more intense grief reaction (p=0.020) and more serious depressive symptoms (p=0.002). Conclusions: To decrease the negative psychological impact of donation, relatives need the Help Earlier in parallel with the Loss of Loved Person. The first step of the "HELLP" concept is to establish adequate communication; consequently, the physicians' education about communication is essential. © Ann Transplant, 2012. Source

Penniston J.T.,Hungarian Academy of Sciences | Penniston J.T.,Massachusetts General Hospital | Padanyi R.,Hungarian National Blood Transfusion Service | Paszty K.,Hungarian Academy of Sciences | And 2 more authors.
Journal of Cell Science | Year: 2014

Plasma membrane Ca2+ ATPases (PMCAs, also known as ATP2B1-ATP2B4) are known targets of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2], but if and how they control the PtdIns(4,5)P2 pool has not been considered. We demonstrate here that PMCAs protect PtdIns(4,5)P2 in the plasma membrane from hydrolysis by phospholipase C (PLC). Comparison of active and inactive PMCAs indicates that the protection operates by two mechanisms; one requiring active PMCAs, the other not. It appears that the mechanism requiring activity is the removal of the Ca2+ required for sustained PLC activity, whereas the mechanism not requiring activity is PtdIns(4,5)P2 binding. We show that in PMCA overexpressing cells, PtdIns(4,5)P2 binding can lead to less inositol 1,4,5-triphosphate (InsP3) and diminished Ca2+ release from intracellular Ca2+ pools. Inspection of a homology model of PMCA suggests that PMCAs have a conserved cluster of basic residues forming a 'blue collar' at the interface between the membrane core and the cytoplasmic domains. By molecular dynamics simulation, we found that the blue collar forms four binding pockets for the phosphorylated inositol head group of PtdIns(4,5)P2; these pockets bind PtdIns(4,5)P2 strongly and frequently. Our studies suggest that by having the ability to bind PtdIns(4,5)P2, PMCAs can control the accessibility of PtdIns(4,5)P2 for PLC and other PtdIns(4,5)P2-mediated processes. © 2014. Published by The Company of Biologists Ltd. Source

Kasza I.,Hungarian Academy of Sciences | Kasza I.,CellPharma Kft | Varady G.,Hungarian Academy of Sciences | Varady G.,CellPharma Kft | And 7 more authors.
PLoS ONE | Year: 2012

We have developed a rapid, simple and reliable, antibody-based flow cytometry assay for the quantitative determination of membrane proteins in human erythrocytes. Our method reveals significant differences between the expression levels of the wild-type ABCG2 protein and the heterozygous Q141K polymorphic variant. Moreover, we find that nonsense mutations on one allele result in a 50% reduction in the erythrocyte expression of this protein. Since ABCG2 polymorphisms are known to modify essential pharmacokinetic parameters, uric acid metabolism and cancer drug resistance, a direct determination of the erythrocyte membrane ABCG2 protein expression may provide valuable information for assessing these conditions or for devising drug treatments. Our findings suggest that erythrocyte membrane protein levels may reflect genotype-dependent tissue expression patterns. Extension of this methodology to other disease-related or pharmacologically important membrane proteins may yield new protein biomarkers for personalized diagnostics. © 2012 Kasza et al. Source

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