Inhibition of de novo ceramide biosynthesis affects aging phenotype in an in vitro model of neuronal senescence.

Although aging is considered to be an unavoidable event, recent experimental evidence suggests that the process can be counteracted. Intracellular calcium (Ca2+i) dyshomeostasis, mitochondrial dysfunction, oxidative stress, and lipid dysregulation are critical factors that contribute to senescence-related processes. Ceramides, a pleiotropic class of sphingolipids, are important mediators of cellular senescence, but their role in neuronal aging is still largely unexplored. In this study, we investigated the effects of L-cycloserine (L-CS), an inhibitor of thede novoceramide biosynthesis, on the aging phenotype of cortical neurons cultured for 22 days, a setting employed as anin vitromodel of senescence. Our findings indicate that, compared to control cultures, 'aged' neurons display dysregulation of [Ca2+]ilevels, mitochondrial dysfunction, increased generation of reactive oxygen species (ROS), altered synaptic activity as well as the activation of neuronal death-related molecules. Treatment with L-CS positively affected the senescent phenotype, a result associated with recovery of neuronal [Ca2+]isignaling and reduction of mitochondrial dysfunction and ROS generation. The results suggest that thede novoceramide biosynthesis represents a critical intermediate in the molecular and functional cascade leading to neuronal senescence and identify ceramide biosynthesis inhibitors as promising pharmacological tools to decrease age-related neuronal dysfunctions

The pharmacological perturbation of brain zinc impairs BDNF-related signaling and the cognitive performances of young mice.

Zinc (Zn2+) is a pleiotropic modulator of the neuronal and brain activity. The disruption of intraneuronal Zn2+ levels triggers neurotoxic processes and affects neuronal functioning. In this study, we investigated how the pharmacological modulation of brain Zn2+ affects synaptic plasticity and cognition in wild-type mice. To manipulate brain Zn2+ levels, we employed the Zn2+ (and copper) chelator 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol, CQ). CQ was administered for two weeks to 2.5-month-old (m.o.) mice, and effects studied on BDNF-related signaling, metalloproteinase activity as well as learning and memory performances. CQ treatment was found to negatively affect short- and long-term memory performances. The CQ-driven perturbation of brain Zn2+ was found to reduce levels of BDNF, synaptic plasticity-related proteins and dendritic spine density in vivo. Our study highlights the importance of choosing "when", "where", and "how much" in the modulation of brain Zn2+ levels. Our findings confirm the importance of targeting Zn2+ as a therapeutic approach against neurodegenerative conditions but, at the same time, underscore the potential drawbacks of reducing brain Zn2+ availability upon the early stages of development

A Machine Learning-Based Holistic Approach to Predict the Clinical Course of Patients within the Alzheimer’s Disease Spectrum

Background: Alzheimer’s disease (AD) is a neurodegenerative condition driven by multifactorial etiology. Mild cognitive impairment (MCI) is a transitional condition between healthy aging and dementia. No reliable biomarkers are available to predict the conversion from MCI to AD. Objective: To evaluate the use of machine learning (ML) on a wealth of data offered by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and Alzheimer’s Disease Metabolomics Consortium (ADMC) database in the prediction of the MCI to AD conversion. Methods: We implemented an ML-based Random Forest (RF) algorithm to predict conversion from MCI to AD. Data related to the study population (587 MCI subjects) were analyzed by RF as separate or combined features and assessed for classification power. Four classes of variables were considered: neuropsychological test scores, AD-related cerebrospinal fluid (CSF) biomarkers, peripheral biomarkers, and structural magnetic resonance imaging (MRI) variables. Results: The ML-based algorithm exhibited 86% accuracy in predicting the AD conversion of MCI subjects. When assessing the features that helped the most, neuropsychological test scores, MRI data, and CSF biomarkers were the most relevant in the MCI to AD prediction. Peripheral parameters were effective when employed in association with neuropsychological test scores. Age and sex differences modulated the prediction accuracy. AD conversion was more effectively predicted in females and younger subjects. Conclusion: Our findings support the notion that AD-related neurodegenerative processes result from the concerted activity of multiple pathological mechanisms and factors that act inside and outside the brain and are dynamically affected by age and sex

EPMA-World Congress 2015: Bonn, Germany. 3-5 September 2015

Table of contents A1 Predictive and prognostic biomarker panel for targeted application of radioembolisation improving individual outcomes in hepatocellular carcinoma Jella-Andrea Abraham, Olga Golubnitschaja A2 Integrated market access approach amplifying value of “Rx-CDx” Ildar Akhmetov A3 Disaster response: an opportunity to improve global healthcare Russell J. Andrews, Leonidas Quintana A4 USA PPPM: proscriptive, profligate, profiteering medicine-good for 1 % wealthy, not for 99 % unhealthy Russell J. Andrews A5 The role of IDO in a murine model of gingivitis: predictive and therapeutic potentials Babak Baban, Jun Yao Liu, Xu Qin, Tailing Wang, Mahmood S. Mozaffari A6 Specific diets for personalised treatment of diabetes type 2 Viktoriia V. Bati, Tamara V. Meleshko, Olga B. Levchuk, Nadiya V. Boyko A7 Towards personalized physiotherapeutic approach Joanna Bauer, Ewa Boerner, Halina Podbielska A8 Cells, animal, SHIME and in silico models for detection and verification of specific biomarkers of non-communicable chronic diseases Alojz Bomba, Viktor O. Petrov, Volodymyr G. Drobnych, Rostyslav V. Bubnov, Oksana M. Bykova, Nadiya V. Boyko A9 INTERACT-chronic care model: Self-treatment by patients with decision support e-Health solution Hans-Peter Brunner-La Rocca, Lutz Fleischhacker, Olga Golubnitschaja, Frank Heemskerk, Thomas Helms, Tiny Jaarsma, Judita Kinkorova, Jan Ramaekers, Peter Ruff, Ivana Schnur, Emilio Vanoli, Jose Verdu A10 PPPM in cardiovascular medicine in 2015 Hans-Peter Brunner-La Rocca A11 Magnetic resonance imaging of nanoparticles in mice, potential for theranostic and contrast media development – pilot results Rostyslav V. Bubnov, Sergiy A. Grabovetskyi, Olena M. Mykhalchenko, Natalia O. Tymoshok, Oleksandr B. Shcherbakov, Igor P. Semeniv, Mykola Y. Spivak A12 Ultrasound diagnosis for diabetic neuropathy - comparative study Rostyslav V. Bubnov, Tetyana V. Ostapenko A13 Ultrasound for stratification patients with diabetic foot ulcers for prevention and personalized treatment - pilot results Rostyslav V. Bubnov, Nazarii M. Kobyliak, Nadiya M. Zholobak, Mykola Ya. Spivak A14 Project ImaGenX – designing and executing a questionnaire on environment and lifestyle risk of breast cancer John Paul Cauchi A15 Genomics – a new structural brand of predictive, preventive and personalized medicine or the new driver as well? Dmitrii Cherepakhin, Marina Bakay, Artem Borovikov, Sergey Suchkov A16 Survey of questionnaires for evaluation of the quality of life in various medical fields Barbara Cieślik, Agnieszka Migasiewicz, Maria-Luiza Podbielska, Markus Pelleter, Agnieszka Giemza, Halina Podbielska A17 Personalized molecular treatment for muscular dystrophies Sebahattin Cirak A18 Secondary mutations in circulating tumour DNA for acquired drug resistance in patients with advanced ALK + NSCLC Marzia Del Re, Paola Bordi, Valentina Citi, Marta Palombi, Carmine Pinto, Marcello Tiseo, Romano Danesi A19 Recombinant species-specific FcεRI alpha proteins for diagnosis of IgE-mediated allergies in dogs, cats and horses Lukas Einhorn, Judit Fazekas, Martina Muhr, Alexandra Schoos, Lucia Panakova, Ina Herrmann, Krisztina Manzano-Szalai, Kumiko Oida, Edda Fiebiger, Josef Singer, Erika Jensen-Jarolim A20 Global methodology for developmental neurotoxicity testing in humans and animals early and chronically exposed to chemical contaminants Arpiné A. Elnar, Nadia Ouamara, Nadiya Boyko, Xavier Coumoul, Jean-Philippe Antignac, Bruno Le Bizec, Gauthier Eppe, Jenny Renaut, Torsten Bonn, Cédric Guignard, Margherita Ferrante, Maria Liusa Chiusano, Salvatore Cuzzocrea, Gerard O'Keeffe, John Cryan, Michelle Bisson, Amina Barakat, Ihsane Hmamouchi, Nasser Zawia, Anumantha Kanthasamy, Glen E. Kisby, Rui Alves, Oscar Villacañas Pérez, Kim Burgard, Peter Spencer, Norbert Bomba, Martin Haranta, Nina Zaitseva, Irina May, Stéphanie Grojean, Mathilde Body-Malapel, Florencia Harari, Raul Harari, Kristina Yeghiazaryan, Olga Golubnitschaja, Vittorio Calabrese, Christophe Nemos, Rachid Soulimani A21 Mental indicators at young people with attributes hypertension and pre-hypertension Maria E. Evsevyeva, Elena A. Mishenko, Zurida V. Kumukova, Evgeniy V. Chudnovsky, Tatyana A. Smirnova A22 On the approaches to the early diagnosis of stress-induced hypertension in young employees of State law enforcement agencies Maria E. Evsevyeva, Ludmila V. Ivanova, Michail V. Eremin, Maria V. Rostovtseva A23 Сentral aortic pressure and indexes of augmentation in young persons in view of risk factors Maria E. Evsevyeva, Michail V. Eremin, Vladimir I. Koshel, Oksana V. Sergeeva, Nadesgda M. Konovalova A24 Breast cancer prediction and prevention: Are reliable biomarkers in horizon? Shantanu Girotra, Olga Golubnitschaja A25 Flammer Syndrome and potential formation of pre-metastatic niches: A multi-centred study on phenotyping, patient stratification, prediction and potential prevention of aggressive breast cancer and metastatic disease Olga Golubnitschaja, Manuel Debald, Walther Kuhn, Kristina Yeghiazaryan, Rostyslav V. Bubnov, Vadym M. Goncharenko, Ulyana Lushchyk, Godfrey Grech, Katarzyna Konieczka A26 Innovative tools for prenatal diagnostics and monitoring: improving individual pregnancy outcomes and health-economy in EU Olga Golubnitschaja, Jan Jaap Erwich, Vincenzo Costigliola, Kristina Yeghiazaryan, Ulrich Gembruch A27 Immunohistochemical assessment of APUD cells in endometriosis Vadym M. Goncharenko, Vasyl O. Beniuk, Olga V. Kalenska, Rostyslav V. Bubnov A28 Updating personalized management algorithm of endometrial hyperplasia in pre-menopause women Vadym M. Goncharenko, Vasyl O. Beniuk, Rostyslav V. Bubnov, Olga Melnychuk A29 The personified treatment approach of polimorbid patients with periodontal inflammatory diseases Irina A. Gorbacheva, Lyudmila Y. Orekhova, Vadim V. Tachalov A30 Ukrainian experience in hybrid war – the challenge to update algorithms for personalized care and early prevention of different military injuries Olena I. Grechanyk, Rizvan Ya. Abdullaiev, Rostyslav V. Bubnov A31 Tear fluid biomarkers: a comparison of tear fluid sampling and storage protocols Suzanne Hagan, Eilidh Martin, Ian Pearce, Katherine Oliver A32 The correlation of dietary habits with gingival problems during menstruation Cenk Haytac, Fariz Salimov, Servin Yoksul, Anatoly A. Kunin, Natalia S. Moiseeva A33 Genomic medicine in a contemporary Spanish population of prostate cancer: our experience Bernardo Herrera-Imbroda, Sergio del Río-González, Maria Fernanda Lara, Antonia Angulo, Francisco Javier Machuca Santa-Cruz A34 Challenges, opportunities and collaborations for personalized medicine applicability in uro-oncological disease Bernardo Herrera-Imbroda, Sergio del Río-González, Maria Fernanda Lara A35 Metabolic hallmarks of cancer as targets for a personalized therapy John Ionescu A36 Influence of genetic polymorphism as a predictor of the development of periodontal disease in patients with gastric ulcer and 12 duodenal ulcer Alfiya Z. Isamulaeva, Anatoly A. Kunin, Shamil Sh. Magomedov, Aida I. Isamulaeva A37 Challenges in diabetic macular edema Tatjana Josifova A38 Overview of the EPMA strategies in laboratory medicine relevant for PPPM Marko Kapalla, Juraj Kubáň, Olga Golubnitschaja, Vincenzo Costigliola A39 EPMA initiative for effective organization of medical travel: European concepts and criteria Vincenzo Costigliola, Marko Kapalla, Juraj Kubáň, Olga Golubnitschaja A40 Design and innovation in e-textiles: implications for PPPM Anthony Kent, Tom Fisher, Tilak Dias A41 Biobank in Pilsen as a member of national node BBMRI_CZ Judita Kinkorová, Ondřej Topolčan A42 Big data in personalized medicine: hype and hope Matthias Kohl A43 The 3P approach as the platform of the European Dentistry Department (DPPPD) Anatoly A. Kunin, Natalia S. Moiseeva A44 The endometrium cytokine patterns for predictive diagnosis of proliferation severity and cancer prevention Andrii I. Kurchenko, Vasyl A. Beniuk, Vadym M. Goncharenko, Rostyslav V. Bubnov, Nadiya V. Boyko, Andriy M. Strokan A45 A monocyte-based in-vitro system for testing individual responses to the implanted material: future for personalized implant construction Julia Kzhyshkowska, Alexandru Gudima, Ksenia S. Stankevich, Victor D. Filimonov4, Harald Klüter, Evgeniya M. Mamontova, Sergei I. Tverdokhlebov A46 Prediction and prevention of adverse health effects by meteorological factors: Biomarker patterns and creation of a device for self-monitoring and integrated care Ulyana B. Lushchyk, Viktor V. Novytskyy, Igor P. Babii, Nadiya G. Lushchyk, Lyudmyla S. Riabets, Ivanna I. Legka A47 Targeting "disease signatures" towards personalized healthcare Mira Marcus-Kalish, Alexis Mitelpunkt, Tal Galili, Neta Shachar, Yoav Benjamini A48 Influence of the skin imperfection on the personal quality of life and possible tools for objective diagnosis Agnieszka Migasiewicz, Markus Pelleter, Joanna Bauer, Ewelina Dereń, Halina Podbielska A49 The new direction in caries prevention based on the ultrastructure of dental hard tissues and filling materials Natalia S. Moiseeva, Anatoly A. Kunin, Dmitry A. Kunin A50 The use of LED radiation in prevention of dental diseases Natalia S. Moiseeva, Yury A. Ippolitov, Dmitry A. Kunin, Alexei N. Morozov, Natalia V. Chirkova, Nakhid T. Aliev A51 Status of endothelial progenitor cells in diabetic nephropathy: predictive and preventive potentials Mahmood S. Mozaffari, Jun Yao Liu, Babak Baban A52 The status of glucocorticoid-induced leucine zipper protein in salivary gland in Sjögren’s syndrome: predictive and personalized treatment potentials Mahmood S. Mozaffari, Jun Yao Liu, Rafik Abdelsayed, Xing-Ming Shi, Babak Baban A53 Maximal aerobic capacity - important quality marker of health Jaroslav Novák, Milan Štork, Václav Zeman A54 The EMPOWER project: laboratory medicine and Horizon 2020 Wytze P. Oosterhuis, Elvar Theodorsson A55 Personality profile manifestations in patient’s attitude to oral care and adherence to doctor’s prescriptions Lyudmila Y. Orekhova, Tatyana V. Kudryavtseva, Elena R. Isaeva, Vadim V. Tachalov, Ekaterina S. Loboda A56 Results of an European survey on personalized medicine addressed to directions of laboratory medicine Mario Pazzagli, Francesca Malentacchi, Irene Mancini, Ivan Brandslund, Pieter Vermeersch, Matthias Schwab, Janja Marc, Ron H.N. van Schaik, Gerard Siest, Elvar Theodorsson, Chiara Di Resta A57 MCI or early dementia predictive speech based diagnosis techniques Matus Pleva, Jozef Juhar A58 Personalized speech based mobile application for eHealth Matus Pleva, Jozef Juhar A59 Circulating tumor cell-free DNA as the biomarker in the management of cancer patients Jiří Polívka jr., Filip Janků, Martin Pešta, Jan Doležal, Milena Králíčková, Jiří Polívka A60 Complex stroke care – educational programme in Stroke Centre University Hospital Plzen Jiří Polívka, Alena Lukešová, Nina Müllerová, Petr Ševčík, Vladimír Rohan A61 Sleep apnea and sleep fragmentation contribute to brain aging Kneginja Richter, Lence Miloseva, Günter Niklewski A62 Personalised approach for sleep disturbances in shift workers Kneginja Richter, Jens Acker, Guenter Niklewski A63 Medical travel and innovative PPPM clusters: new concept of integration Olga Safonicheva, Vincenzo Costigliola A64 Medical travel and women health Olga Safonicheva A65 Continuity of generations in the training of specialists in the field of reconstructive microsurgery Maxim Sautin, Janna Sinelnikova, Sergey Suchkov A66 Telemonitoring of stroke patients – empirical evidence of individual risk management results from an observational study in Germany Songül Secer, Stephan von Bandemer A67 Women’s increasing breast cancer risk with n-6 fatty acid intake explained by estrogen-fatty acid interactive effect on DNA damage: implications for gender-specific nutrition within personalized medicine Niva Shapira A68 Cytobacterioscopy of the gingival crevicular fluid as a method for preventive diagnosis of periodontal diseases Aleksandr Shcherbakov, Anatoly A. Kunin, Natalia S. Moiseeva A69 Use of specially treated composites in dentistry to avoid violations of aesthetics Bogdan R. Shumilovich, Zhanna Lipkind, Yulia Vorobieva, Dmitry A. Kunin, Anastasiia V. Sudareva A70 National eHealth system – platform for preventive, predictive and personalized diabetes care Ivica Smokovski, Tatjana Milenkovic A72 The common energy levels of Prof. Szent-Györgyi, the intrinsic chemistry of melanin, and the muscle physiopathology. Implications in the context of Preventive, Predictive, and Personalized Medicine Arturo Solís-Herrera, María del Carmen Arias-Esparza, Sergey Suchkov A73 Plurality and individuality of hepatocellular carcinoma: PPPM perspectives Krishna Chander Sridhar, Olga Golubnitschaja A74 Strategic aspects of higher medical education reforms to secure newer educational platforms for getting biopharma professionals matures Maria Studneva, Sihong Song, James Creeden, Мark Мandrik, Sergey Suchkov A75 Overview of the strategies and activities of the European Federation of Clinical Chemistry and Laboratory Medicine, (EFLM) Elvar Theodorsson, EFLM A76 New spectroscopic techniques for point of care label free diagnostics Syed A. M. Tofail A77 Tumor markers for personalized medicine and oncology - the role of Laboratory Medicine Ondřej Topolčan, Judita Kinkorová, Ondřej Fiala, Marie Karlíková, Šárka Svobodová, Radek Kučera, Radka Fuchsová, Vladislav Třeška, Václav Šimánek, Ladislav Pecen, Jan Šoupal, Štěpán Svačina2 A78 Modern medical terminology (MMT) as a driver of the global educational reforms Evgeniya Tretyak, Maria Studneva, Sergey Suchkov A79 Juvenile hypertension; the relevance of novel predictive, preventive and personalized assessment of its determinants Francesca M. Trovato, G. Fabio Martines, Daniela Brischetto, Daniela Catalano, Giuseppe Musumeci, Guglielmo M. Trovato A80 Proteomarkers Biotech George Th. Tsangaris, Athanasios K. Anagnostopoulos A81 Proteomics and mass spectrometry based non-invasive prenatal testing of fetal health and pregnancy complications George Th. Tsangaris, Athanasios K. Anagnostopoulos A82 Integrated Ecosystem for an Integrated Care model for Heart Failure (HF) patients including related comorbidities (ZENITH) José Verdú, German Gutiérrez, Jordi Rovira, Marta Martinez, Lutz Fleischhacker, Donna Green, Arthur Garson, Elena Tamburini, Stefano Cuomo, Juan Martinez-Leon, Teresa Abrisqueta, Hans-Peter Brunner-La Rocca, Tiny Jaarsma, Teresa Arredondo, Cecilia Vera, Giuseppe Fico, Olga Golubnitschaja, Fernando Arribas, Martina Onderco, Isabel Vara, on behalf of ZENITH consortium A83 Predictive, preventive and personalized medicine in diabetes onset and complication (MOSAIC project) José Verdú, Francesco Sambo, Barbara Di Camillo, Claudio Cobelli, Andrea Facchinetti, Giuseppe Fico, Riccardo Bellazzi, Lucia Sacchi, Arianna Dagliati, Daniele Segnani, Valentina Tibollo, Manuel Ottaviano, Rafael Gabriel, Leif Groop, Jacqueline Postma, Antonio Martinez, Liisa Hakaste, Tiinamaija Tuomi, Konstantia Zarkogianni, on behalf of MOSAIC consortium A84 Possibilities for personalized therapy of diabetes using in vitro screening of insulin and oral hypoglycemic agents Igor Volchek, Nina Pototskaya, Andrey Petrov A85 The innovative technology for personalized therapy of human diseases based on in vitro drug screening Igor Volchek, Nadezhda Pototskaya, Andrey Petrov A86 Bone destruction and temporomandibular joint: predictive markers, pathogenetic aspects and quality of life Ülle Voog-Oras, Oksana Jagur, Edvitar Leibur, Priit Niibo, Triin Jagomägi, Minh Son Nguyen, Chris Pruunsild, Dagmar Piikov, Mare Saag A87 Sub-optimal health management – global vision for concepts in medical travel Wei Wang A88 Sub-optimal health management: synergic PPPM-TCAM approach Wei Wang A89 Innovative technologies for minimal invasive diagnostics Andreas Weinhäusel, Walter Pulverer, Matthias Wielscher, Manuela Hofner, Christa Noehammer, Regina Soldo, Peter Hettegger, Istvan Gyurjan, Ronald Kulovics, Silvia Schönthaler, Gabriel Beikircher, Albert Kriegner, Stephan Pabinger, Klemens Vierlinger A90 Rare disease diobanks for personalized medicine Ayşe Yüzbaşıoğlu, Meral Özgüç, Member of EuroBioBank - European Network of DNA, Cell and Tissue Banks for Rare Disease

Long-Term Dynamic Changes of NMDA Receptors Following an Excitotoxic Challenge

Excitotoxicity is a form of neuronal death characterized by the sustained activation of N-methyl-D-aspartate receptors (NMDARs) triggered by the excitatory neurotransmitter glutamate. NADPH-diaphorase neurons (also known as nNOS (+) neurons) are a subpopulation of aspiny interneurons, largely spared following excitotoxic challenges. Unlike nNOS (−) cells, nNOS (+) neurons fail to generate reactive oxygen species in response to NMDAR activation, a critical divergent step in the excitotoxic cascade. However, additional mechanisms underlying the reduced vulnerability of nNOS (+) neurons to NMDAR-driven neuronal death have not been explored. Using functional, genetic, and molecular analysis in striatal cultures, we indicate that nNOS (+) neurons possess distinct NMDAR properties. These specific features are primarily driven by the peculiar redox milieu of this subpopulation. In addition, we found that nNOS (+) neurons exposed to a pharmacological maneuver set to mimic chronic excitotoxicity alter their responses to NMDAR-mediated challenges. These findings suggest the presence of mechanisms providing long-term dynamic regulation of NMDARs that can have critical implications in neurotoxic settings

The pharmacological perturbation of brain zinc impairs BDNF-related signaling and the cognitive performances of young mice.

Zinc (Zn2+) is a pleiotropic modulator of the neuronal and brain activity. The disruption of intraneuronal Zn2+ levels triggers neurotoxic processes and affects neuronal functioning. In this study, we investigated how the pharmacological modulation of brain Zn2+ affects synaptic plasticity and cognition in wild-type mice. To manipulate brain Zn2+ levels, we employed the Zn2+ (and copper) chelator 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol, CQ). CQ was administered for two weeks to 2.5-month-old (m.o.) mice, and effects studied on BDNF-related signaling, metalloproteinase activity as well as learning and memory performances. CQ treatment was found to negatively affect short- and long-term memory performances. The CQ-driven perturbation of brain Zn2+ was found to reduce levels of BDNF, synaptic plasticity-related proteins and dendritic spine density in vivo. Our study highlights the importance of choosing "when", "where", and "how much" in the modulation of brain Zn2+ levels. Our findings confirm the importance of targeting Zn2+ as a therapeutic approach against neurodegenerative conditions but, at the same time, underscore the potential drawbacks of reducing brain Zn2+ availability upon the early stages of development

New gene functions in megakaryopoiesis and platelet formation

Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function

Maps of open chromatin highlight cell type-restricted patterns of regulatory sequence variation at hematological trait loci

<p>Nearly three-quarters of the 143 genetic signals associated with platelet and erythrocyte phenotypes identified by meta-analyses of genome-wide association (GWA) studies are located at non-protein-coding regions. Here, we assessed the role of candidate regulatory variants associated with cell type-restricted, closely related hematological quantitative traits in biologically relevant hematopoietic cell types. We used formaldehyde-assisted isolation of regulatory elements followed by next-generation sequencing (FAIRE-seq) to map regions of open chromatin in three primary human blood cells of the myeloid lineage. In the precursors of platelets and erythrocytes, as well as in monocytes, we found that open chromatin signatures reflect the corresponding hematopoietic lineages of the studied cell types and associate with the cell type-specific gene expression patterns. Dependent on their signal strength, open chromatin regions showed correlation with promoter and enhancer histone marks, distance to the transcription start site, and ontology classes of nearby genes. Cell type-restricted regions of open chromatin were enriched in sequence variants associated with hematological indices. The majority (63.6%) of such candidate functional variants at platelet quantitative trait loci (QTLs) coincided with binding sites of five transcription factors key in regulating megakaryopoiesis. We experimentally tested 13 candidate regulatory variants at 10 platelet QTLs and found that 10 (76.9%) affected protein binding, suggesting that this is a frequent mechanism by which regulatory variants influence quantitative trait levels. Our findings demonstrate that combining large-scale GWA data with open chromatin profiles of relevant cell types can be a powerful means of dissecting the genetic architecture of closely related quantitative traits.</p>

Epma-World Congress 2015

A1 Predictive and prognostic biomarker panel for targeted application of radioembolisation improving individual outcomes in hepatocellular carcinoma, Jella-Andrea Abraham, Olga Golubnitschaja, A2 Integrated market access approach amplifying value of “Rx-CDx”, Ildar Akhmetov, A3 Disaster response: an opportunity to improve global healthcare, Russell J. Andrews, Leonidas Quintana, A4 USA PPPM: proscriptive, profligate, profiteering medicine-good for 1 % wealthy, not for 99 % unhealthy, Russell J. Andrews, A5 The role of IDO in a murine model of gingivitis: predictive and therapeutic potentials, Babak Baban, Jun Yao Liu, Xu Qin, Tailing Wang, Mahmood S. Mozaffari, A6 Specific diets for personalised treatment of diabetes type 2, Viktoriia V. Bati, Tamara V. Meleshko, Olga B. Levchuk, Nadiya V. Boyko, A7 Towards personalized physiotherapeutic approach, Joanna Bauer, Ewa Boerner, Halina Podbielska, A8 Cells, animal, SHIME and in silico models for detection and verification of specific biomarkers of non-communicable chronic diseases, Alojz Bomba, Viktor O. Petrov, Volodymyr G. Drobnych, Rostyslav V. Bubnov, Oksana M. Bykova, Nadiya V. Boyko, A9 INTERACT-chronic care model: Self-treatment by patients with decision support e-Health solution, Hans-Peter Brunner-La Rocca, Lutz Fleischhacker, Olga Golubnitschaja, Frank Heemskerk, Thomas Helms, Tiny Jaarsma, Judita Kinkorova, Jan Ramaekers, Peter Ruff, Ivana Schnur, Emilio Vanoli, Jose Verdu, A10 PPPM in cardiovascular medicine in 2015, Hans-Peter Brunner-La Rocca, A11 Magnetic resonance imaging of nanoparticles in mice, potential for theranostic and contrast media development – pilot results, Rostyslav V. Bubnov, Sergiy A. Grabovetskyi, Olena M. Mykhalchenko, Natalia O. Tymoshok, Oleksandr B. Shcherbakov, Igor P. Semeniv, Mykola Y. Spivak, A12 Ultrasound diagnosis for diabetic neuropathy - comparative study, Rostyslav V. Bubnov, Tetyana V. Ostapenko, A13 Ultrasound for stratification patients with diabetic foot ulcers for prevention and personalized treatment - pilot results, Rostyslav V. Bubnov, Nazarii M. Kobyliak, Nadiya M. Zholobak, Mykola Ya. Spivak, A14 Project ImaGenX – designing and executing a questionnaire on environment and lifestyle risk of breast cancer, John Paul Cauchi, A15 Genomics – a new structural brand of predictive, preventive and personalized medicine or the new driver as well?, Dmitrii Cherepakhin, Marina Bakay, Artem Borovikov, Sergey Suchkov, A16 Survey of questionnaires for evaluation of the quality of life in various medical fields, Barbara Cieślik, Agnieszka Migasiewicz, Maria-Luiza Podbielska, Markus Pelleter, Agnieszka Giemza, Halina Podbielska, A17 Personalized molecular treatment for muscular dystrophies, Sebahattin Cirak, A18 Secondary mutations in circulating tumour DNA for acquired drug resistance in patients with advanced ALK + NSCLC, Marzia Del Re, Paola Bordi, Valentina Citi, Marta Palombi, Carmine Pinto, Marcello Tiseo, Romano Danesi, A19 Recombinant species-specific FcεRI alpha proteins for diagnosis of IgE-mediated allergies in dogs, cats and horses, Lukas Einhorn, Judit Fazekas, Martina Muhr, Alexandra Schoos, Lucia Panakova, Ina Herrmann, Krisztina Manzano-Szalai, Kumiko Oida, Edda Fiebiger, Josef Singer, Erika Jensen-Jarolim, A20 Global methodology for developmental neurotoxicity testing in humans and animals early and chronically exposed to chemical contaminants, Arpiné A. Elnar, Nadia Ouamara, Nadiya Boyko, Xavier Coumoul, Jean-Philippe Antignac, Bruno Le Bizec, Gauthier Eppe, Jenny Renaut, Torsten Bonn, Cédric Guignard, Margherita Ferrante, Maria Liusa Chiusano, Salvatore Cuzzocrea, Gerard O'Keeffe, John Cryan, Michelle Bisson, Amina Barakat, Ihsane Hmamouchi, Nasser Zawia, Anumantha Kanthasamy, Glen E. Kisby, Rui Alves, Oscar Villacañas Pérez, Kim Burgard, Peter Spencer, Norbert Bomba, Martin Haranta, Nina Zaitseva, Irina May, Stéphanie Grojean, Mathilde Body-Malapel, Florencia Harari, Raul Harari, Kristina Yeghiazaryan, Olga Golubnitschaja, Vittorio Calabrese, Christophe Nemos, Rachid Soulimani, A21 Mental indicators at young people with attributes hypertension and pre-hypertension, Maria E. Evsevyeva, Elena A. Mishenko, Zurida V. Kumukova, Evgeniy V. Chudnovsky, Tatyana A. Smirnova, A22 On the approaches to the early diagnosis of stress-induced hypertension in young employees of State law enforcement agencies, Maria E. Evsevyeva, Ludmila V. Ivanova, Michail V. Eremin, Maria V. Rostovtseva, A23 Сentral aortic pressure and indexes of augmentation in young persons in view of risk factors, Maria E. Evsevyeva, Michail V. Eremin, Vladimir I. Koshel, Oksana V. Sergeeva, Nadesgda M. Konovalova, A24 Breast cancer prediction and prevention: Are reliable biomarkers in horizon?, Shantanu Girotra, Olga Golubnitschaja, A25 Flammer Syndrome and potential formation of pre-metastatic niches: A multi-centred study on phenotyping, patient stratification, prediction and potential prevention of aggressive breast cancer and metastatic disease, Olga Golubnitschaja, Manuel Debald, Walther Kuhn, Kristina Yeghiazaryan, Rostyslav V. Bubnov, Vadym M. Goncharenko, Ulyana Lushchyk, Godfrey Grech, Katarzyna Konieczka, A26 Innovative tools for prenatal diagnostics and monitoring: improving individual pregnancy outcomes and health-economy in EU, Olga Golubnitschaja, Jan Jaap Erwich, Vincenzo Costigliola, Kristina Yeghiazaryan, Ulrich Gembruch, A27 Immunohistochemical assessment of APUD cells in endometriosis, Vadym M. Goncharenko, Vasyl O. Beniuk, Olga V. Kalenska, Rostyslav V. Bubnov, A28 Updating personalized management algorithm of endometrial hyperplasia in pre-menopause women, Vadym M. Goncharenko, Vasyl O. Beniuk, Rostyslav V. Bubnov, Olga Melnychuk, A29 The personified treatment approach of polimorbid patients with periodontal inflammatory diseases, Irina A. Gorbacheva, Lyudmila Y. Orekhova, Vadim V. Tachalov, A30 Ukrainian experience in hybrid war – the challenge to update algorithms for personalized care and early prevention of different military injuries, Olena I. Grechanyk, Rizvan Ya. Abdullaiev, Rostyslav V. Bubnov, A31 Tear fluid biomarkers: a comparison of tear fluid sampling and storage protocols, Suzanne Hagan, Eilidh Martin, Ian Pearce, Katherine Oliver, A32 The correlation of dietary habits with gingival problems during menstruation, Cenk Haytac, Fariz Salimov, Servin Yoksul, Anatoly A. Kunin, Natalia S. Moiseeva, A33 Genomic medicine in a contemporary Spanish population of prostate cancer: our experience, Bernardo Herrera-Imbroda, Sergio del Río-González, Maria Fernanda Lara, Antonia Angulo, Francisco Javier Machuca Santa-Cruz, A34 Challenges, opportunities and collaborations for personalized medicine applicability in uro-oncological disease, Bernardo Herrera-Imbroda, Sergio del Río-González, Maria Fernanda Lara, A35 Metabolic hallmarks of cancer as targets for a personalized therapy, John Ionescu, A36 Influence of genetic polymorphism as a predictor of the development of periodontal disease in patients with gastric ulcer and 12 duodenal ulcer, Alfiya Z. Isamulaeva, Anatoly A. Kunin, Shamil Sh. Magomedov, Aida I. Isamulaeva, A37 Challenges in diabetic macular edema, Tatjana Josifova, A38 Overview of the EPMA strategies in laboratory medicine relevant for PPPM, Marko Kapalla, Juraj Kubáň, Olga Golubnitschaja, Vincenzo Costigliola, A39 EPMA initiative for effective organization of medical travel: European concepts and criteria, Vincenzo Costigliola, Marko Kapalla, Juraj Kubáň, Olga Golubnitschaja, A40 Design and innovation in e-textiles: implications for PPPM, Anthony Kent, Tom Fisher, Tilak Dias, A41 Biobank in Pilsen as a member of national node BBMRI_CZ, Judita Kinkorová, Ondřej Topolčan, A42 Big data in personalized medicine: hype and hope, Matthias Kohl, A43 The 3P approach as the platform of the European Dentistry Department (DPPPD), Anatoly A. Kunin, Natalia S. Moiseeva, A44 The endometrium cytokine patterns for predictive diagnosis of proliferation severity and cancer prevention, Andrii I. Kurchenko, Vasyl A. Beniuk, Vadym M. Goncharenko, Rostyslav V. Bubnov, Nadiya V. Boyko, Andriy M. Strokan, A45 A monocyte-based in-vitro system for testing individual responses to the implanted material: future for personalized implant construction, Julia Kzhyshkowska, Alexandru Gudima, Ksenia S. Stankevich, Victor D. Filimonov4, Harald Klüter, Evgeniya M. Mamontova, Sergei I. Tverdokhlebov, A46 Prediction and prevention of adverse health effects by meteorological factors: Biomarker patterns and creation of a device for self-monitoring and integrated care, Ulyana B. Lushchyk, Viktor V. Novytskyy, Igor P. Babii, Nadiya G. Lushchyk, Lyudmyla S. Riabets, Ivanna I. Legka, A47 Targeting "disease signatures" towards personalized healthcare, Mira Marcus-Kalish, Alexis Mitelpunkt, Tal Galili, Neta Shachar, Yoav Benjamini, A48 Influence of the skin imperfection on the personal quality of life and possible tools for objective diagnosis, Agnieszka Migasiewicz, Markus Pelleter, Joanna Bauer, Ewelina Dereń, Halina Podbielska, A49 The new direction in caries prevention based on the ultrastructure of dental hard tissues and filling materials, Natalia S. Moiseeva, Anatoly A. Kunin, Dmitry A. Kunin, A50 The use of LED radiation in prevention of dental diseases, Natalia S. Moiseeva, Yury A. Ippolitov, Dmitry A. Kunin, Alexei N. Morozov, Natalia V. Chirkova, Nakhid T. Aliev, A51 Status of endothelial progenitor cells in diabetic nephropathy: predictive and preventive potentials, Mahmood S. Mozaffari, Jun Yao Liu, Babak Baban, A52 The status of glucocorticoid-induced leucine zipper protein in salivary gland in Sjögren’s syndrome: predictive and personalized treatment potentials, Mahmood S. Mozaffari, Jun Yao Liu, Rafik Abdelsayed, Xing-Ming Shi, Babak Baban, A53 Maximal aerobic capacity - important quality marker of health, Jaroslav Novák, Milan Štork, Václav Zeman, A54 The EMPOWER project: laboratory medicine and Horizon 2020, Wytze P. Oosterhuis, Elvar Theodorsson, A55 Personality profile manifestations in patient’s attitude to oral care and adherence to doctor’s prescriptions, Lyudmila Y. Orekhova, Tatyana V. Kudryavtseva, Elena R. Isaeva, Vadim V. Tachalov, Ekaterina S. Loboda, A56 Results of an European survey on personalized medicine addressed to directions of laboratory medicine, Mario Pazzagli, Francesca Malentacchi, Irene Mancini, Ivan Brandslund, Pieter Vermeersch, Matthias Schwab, Janja Marc, Ron H.N. van Schaik, Gerard Siest, Elvar Theodorsson, Chiara Di Resta, A57 MCI or early dementia predictive speech based diagnosis techniques, Matus Pleva, Jozef Juhar, A58 Personalized speech based mobile application for eHealth, Matus Pleva, Jozef Juhar, A59 Circulating tumor cell-free DNA as the biomarker in the management of cancer patients, Jiří Polívka jr., Filip Janků, Martin Pešta, Jan Doležal, Milena Králíčková, Jiří Polívka, A60 Complex stroke care – educational programme in Stroke Centre University Hospital Plzen, Jiří Polívka, Alena Lukešová, Nina Müllerová, Petr Ševčík, Vladimír Rohan, A61 Sleep apnea and sleep fragmentation contribute to brain aging, Kneginja Richter, Lence Miloseva, Günter Niklewski, A62 Personalised approach for sleep disturbances in shift workers, Kneginja Richter, Jens Acker, Guenter Niklewski, A63 Medical travel and innovative PPPM clusters: new concept of integration, Olga Safonicheva, Vincenzo Costigliola, A64 Medical travel and women health, Olga Safonicheva, A65 Continuity of generations in the training of specialists in the field of reconstructive microsurgery, Maxim Sautin, Janna Sinelnikova, Sergey Suchkov, A66 Telemonitoring of stroke patients – empirical evidence of individual risk management results from an observational study in Germany, Songül Secer, Stephan von Bandemer, A67 Women’s increasing breast cancer risk with n-6 fatty acid intake explained by estrogen-fatty acid interactive effect on DNA damage: implications for gender-specific nutrition within personalized medicine, Niva Shapira, A68 Cytobacterioscopy of the gingival crevicular fluid as a method for preventive diagnosis of periodontal diseases, Aleksandr Shcherbakov, Anatoly A. Kunin, Natalia S. Moiseeva, A69 Use of specially treated composites in dentistry to avoid violations of aesthetics, Bogdan R. Shumilovich, Zhanna Lipkind, Yulia Vorobieva, Dmitry A. Kunin, Anastasiia V. Sudareva, A70 National eHealth system – platform for preventive, predictive and personalized diabetes care, Ivica Smokovski, Tatjana Milenkovic, A72 The common energy levels of Prof. Szent-Györgyi, the intrinsic chemistry of melanin, and the muscle physiopathology. Implications in the context of Preventive, Predictive, and Personalized Medicine, Arturo Solís-Herrera, María del Carmen Arias-Esparza, Sergey Suchkov, A73 Plurality and individuality of hepatocellular carcinoma: PPPM perspectives, Krishna Chander Sridhar, Olga Golubnitschaja, A74 Strategic aspects of higher medical education reforms to secure newer educational platforms for getting biopharma professionals matures, Maria Studneva, Sihong Song, James Creeden, Мark Мandrik, Sergey Suchkov, A75 Overview of the strategies and activities of the European Federation of Clinical Chemistry and Laboratory Medicine, (EFLM), Elvar Theodorsson, EFLM, A76 New spectroscopic techniques for point of care label free diagnostics, Syed A. M. Tofail, A77 Tumor markers for personalized medicine and oncology - the role of Laboratory Medicine, Ondřej Topolčan, Judita Kinkorová, Ondřej Fiala, Marie Karlíková, Šárka Svobodová, Radek Kučera, Radka Fuchsová, Vladislav Třeška, Václav Šimánek, Ladislav Pecen, Jan Šoupal, Štěpán Svačina2, A78 Modern medical terminology (MMT) as a driver of the global educational reforms, Evgeniya Tretyak, Maria Studneva, Sergey Suchkov, A79 Juvenile hypertension; the relevance of novel predictive, preventive and personalized assessment of its determinants, Francesca M. Trovato, G. Fabio Martines, Daniela Brischetto, Daniela Catalano, Giuseppe Musumeci, Guglielmo M. Trovato, A80 Proteomarkers Biotech, George Th. Tsangaris, Athanasios K. Anagnostopoulos, A81 Proteomics and mass spectrometry based non-invasive prenatal testing of fetal health and pregnancy complications, George Th. Tsangaris, Athanasios K. Anagnostopoulos, A82 Integrated Ecosystem for an Integrated Care model for Heart Failure (HF) patients including related comorbidities (ZENITH), José Verdú, German Gutiérrez, Jordi Rovira, Marta Martinez, Lutz Fleischhacker, Donna Green, Arthur Garson, Elena Tamburini, Stefano Cuomo, Juan Martinez-Leon, Teresa Abrisqueta, Hans-Peter Brunner-La Rocca, Tiny Jaarsma, Teresa Arredondo, Cecilia Vera, Giuseppe Fico, Olga Golubnitschaja, Fernando Arribas, Martina Onderco, Isabel Vara, on behalf of ZENITH consortium, A83 Predictive, preventive and personalized medicine in diabetes onset and complication (MOSAIC project), José Verdú, Francesco Sambo, Barbara Di Camillo, Claudio Cobelli, Andrea Facchinetti, Giuseppe Fico, Riccardo Bellazzi, Lucia Sacchi, Arianna Dagliati, Daniele Segnani, Valentina Tibollo, Manuel Ottaviano, Rafael Gabriel, Leif Groop, Jacqueline Postma, Antonio Martinez, Liisa Hakaste, Tiinamaija Tuomi, Konstantia Zarkogianni, on behalf of MOSAIC consortium, A84 Possibilities for personalized therapy of diabetes using in vitro screening of insulin and oral hypoglycemic agents, Igor Volchek, Nina Pototskaya, Andrey Petrov, A85 The innovative technology for personalized therapy of human diseases based on in vitro drug screening, Igor Volchek, Nadezhda Pototskaya, Andrey Petrov, A86 Bone destruction and temporomandibular joint: predictive markers, pathogenetic aspects and quality of life, Ülle Voog-Oras, Oksana Jagur, Edvitar Leibur, Priit Niibo, Triin Jagomägi, Minh Son Nguyen, Chris Pruunsild, Dagmar Piikov, Mare Saag, A87 Sub-optimal health management – global vision for concepts in medical travel, Wei Wang, A88 Sub-optimal health management: synergic PPPM-TCAM approach, Wei Wang, A89 Innovative technologies for minimal invasive diagnostics, Andreas Weinhäusel, Walter Pulverer, Matthias Wielscher, Manuela Hofner, Christa Noehammer, Regina Soldo, Peter Hettegger, Istvan Gyurjan, Ronald Kulovics, Silvia Schönthaler, Gabriel Beikircher, Albert Kriegner, Stephan Pabinger, Klemens Vierlinger, A90 Rare disease diobanks for personalized medicine, Ayşe Yüzbaşıoğlu, Meral Özgüç, Member of EuroBioBank - European Network of DNA, Cell and Tissue Banks for Rare DiseasesPubMe