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Papanikolopoulou A.,National and Kapodistrian University of Athens | Landt O.,TIB MOLBIOL | Reczko M.,Biomedical science Research Center | Drakoulis N.,National and Kapodistrian University of Athens
Review of Clinical Pharmacology and Pharmacokinetics, International Edition | Year: 2010

Recently, common variants on human chromosome 8q24 were found to be associated with prostate cancer risk. While conducting an association study at the Greek population to investigate the frequency and the susceptibility of one SNP, rs6983267, located at the region 3 of chromosome 8q24, to the prostate cancer, we found highly significant correlation (Odds ratio=2.83 and p-value=0.002). Comparing the findings to other studies, conducted in northern Europeans, the population attributable risk (PAR%) and the frequency of the at risk allele (G vs T) were higher at the Greek population with an independent risk for the carriers to develop the disease. ©PHARMAKON-Press.

Dimas A.S.,University of Oxford | Dimas A.S.,Biomedical science Research Center | Lagou V.,University of Oxford | Barker A.,Institute of Metabolic Science | And 81 more authors.
Diabetes | Year: 2014

Patients with established type 2 diabetes display both b-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci, and indices of proinsulin processing, insulin secretion, and insulin sensitivity. We included data from up to 58,614 nondiabetic subjects with basal measures and 17,327 with dynamic measures. We used additive genetic models with adjustment for sex, age, and BMI, followed by fixed-effects, inverse-variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second cluster (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without a detectable change in fasting glucose levels. The final group contained 20 risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition. © 2014 by the American Diabetes Association.

Alexandratos A.,Hellenic Pasteur Institute | Alexandratos A.,University of Ioannina | Clos J.,Bernhard Nocht Institute for Tropical Medicine | Samiotaki M.,Biomedical science Research Center | And 4 more authors.
Molecular Microbiology | Year: 2013

Overexpression of Leishmania histone H1 (LeishH1) was previously found to cause a promastigote-to-amastigote differentiation handicap, deregulation of cell-cycle progression, and loss of parasite infectivity. The aim of this study was to identify changes in the proteome of LeishH1 overexpressing parasites associated with the avirulent phenotype observed. 2D-gel electrophoresis analysis revealed only a small protein subset of differentially expressed proteins in the LeishH1 overexpressing promastigotes. Among these was the chaperone HSP83, known for its protective role in Leishmania drug-induced apoptosis, which displayed lower translational rates. To investigate if the lower expression levels of HSP83 are associated with the differentiation handicap, we assayed the thermostability of parasites by subjecting them to heat-shock (25°C→37°C), a natural stress-factor occurring during stage differentiation. Heat-shock promoted apoptosis to a greater extent in the LeishH1 overexpressing parasites. Interestingly, these parasites were not only more sensitive to heat-shock but also to drug-induced [Sb(III)] cell-death. In addition, the restoration of HSP83 levels re-established drug resistance, and restored infectivity to LeishH1 overexpressing parasites in the murine J774 macrophage model. Overall, this study suggests that LeishH1 levels are critical for the parasite's stress-induced adaptation within the mammalian host, and highlights the cross-talk between pathways involved in drug resistance, apoptosis and virulence. © 2013 John Wiley & Sons Ltd.

Van Den Abbeele J.,Antwerp Institute of Tropical Medicine | Bourtzis K.,University of Western Greece | Bourtzis K.,Biomedical science Research Center | Weiss B.,Yale University | And 4 more authors.
Journal of Invertebrate Pathology | Year: 2013

To date, IAEA-supported Sterile Insect Technique (SIT) projects for tsetse and trypanosomiasis control have been in areas without human sleeping sickness, but future projects could include areas of actual or potential human disease transmission. In this context it would be imperative that released sterile tsetse flies are incompetent to transmit the disease-causing trypanosome parasite. Therefore, development of tsetse fly strains refractory to trypanosome infection is highly desirable as a simple and effective method of ensuring vector incompetence of the released flies. This new IAEA Coordinated Research Project (CRP) focuses on gaining a deeper knowledge of the tripartite interactions between the tsetse fly vectors, their symbionts and trypanosome parasites. The objective of this CRP is to acquire a better understanding of mechanisms that limit the development of trypanosome infections in tsetse and how these may be enhanced. © 2012 International Atomic Energy Agency.

Stenbeck G.,Brunel University | Lawrence K.M.,Biomedical science Research Center | Albert A.P.,Biomedical science Research Center
Frontiers in Endocrinology | Year: 2012

A precise control of vesicular trafficking is crucial not only for osteoclastic bone resorption, but also for the crosstalk between osteoclasts and osteoblasts, which regulates bone homeostasis. In addition to the release of growth factors and modulators, such as gluta-mate, flux through the intracellular trafficking routes could also provide the osteoclast with a monitoring function of its resorption activity. To establish the signaling pathways regulating trafficking events in resorbing osteoclasts, we used the bone conserving hormone calcitonin, which has the unique property of inducing osteoclast quiescence. Calcitonin acts through the calcitonin receptor and activates multiple signaling pathways. By monitoring trafficking of a fluorescent low molecular weight probe in mature, bone resorbing osteoclasts we show for the first time that calcitonin blocks endocytosis from the ruffled border by phospholipase C (PLC) activation. Furthermore, we identify a requirement for polyunsaturated fatty acids in endocytic trafficking in osteoclasts. Inhibition of PLC prior to calcitonin treatment restores endocytosis to 75% of untreated rates. This effect is independent of protein kinase C activation and can be mimicked by an increase in intracellular calcium. We thus define an essential role for intracellular calcium levels in the maintenance of endocytosis in osteoclasts. © 2012 Stenbeck, Lawrence and Albert.

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