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Dubois L.,Uppsala University Hospital | Stridsberg M.,Uppsala University Hospital | Kharaziha P.,Karolinska Institutet | Chioureas D.,Karolinska Institutet | And 3 more authors.
Prostate | Year: 2015

BACKGROUND. Prostasomes are nanosized extracellular vesicles exocytosed by prostate epithelial cells. They have been assigned many roles propitious to sperm in favor of fertilization. Prostatic cancer cells can also produce and secrete extracellular vesicles. METHODS. We assessed using ELISA, the surface expression of chromogranin proproteins on prostasomes and malignant extracellular vesicles of four different prostate cancer cell-lines, two hormone sensitive and two hormone refractory. We used a panel of chromogranin A and chromogranin B antibodies against peptides in-between hypothetical cleavage sites along the proproteins. RESULTS. A diverging pattern of chromogranin peptides was apparent when comparing prostasomes and malignant extracellular vesicles indicating a phenotypical change. We also compared western blot patterns (prostasomes and malignant extracellular vesicles) for selected antibodies that displayed high absorbances in the ELISA. Western blot analyses revealed various cleavage patterns of those proproteins that were analyzed in prostasomes and extracellular vesicles. CONCLUSION. Chromogranins are constituents of not only prostasomes but also of malignant prostate cell-derived extracellular vesicles with different amino acid sequences exposed at the membrane surface giving rise to a mosaic pattern. These findings may be of relevance for designing new assays for detection or even possible treatment of prostate cancers. © 2015 Wiley Periodicals, Inc. Source


Thompson M.L.,University of Washington | Ananth C.V.,Columbia University | Jaddoe V.W.V.,Erasmus | Miller R.S.,Swedish Medical Center | Williams M.A.,Harvard University
Paediatric and Perinatal Epidemiology | Year: 2014

Background Preeclampsia (PE) and gestational diabetes mellitus (GDM) adversely affect pregnancy outcomes and the subsequent health of both mother and infant. It is known that elevated pre-pregnancy body mass index (BMI) is associated with increased risk of these obstetrical complications. However, little is known about the role of adult weight patterns prior to pregnancy. Methods Self-reported weight at ages prior to the current pregnancy was recorded in a prospective cohort study of 3567 pregnant women, allowing assessment of longitudinal pre-pregnancy weight trajectories and their association with subsequent PE and GDM in the study pregnancy. Results Women who would subsequently experience PE or GDM in the study pregnancy experienced on average almost double the rate of adult weight gain than other women [PE: additional 0.30 kg/year, 95% confidence interval (CI) 0.09, 0.51 and GDM: additional 0.34 kg/year, 95% CI 0.21, 0.48]. Women with mean adult annual weight gain above the 90th percentile (1.4 kg/year) had elevated risk of subsequent PE and GDM independent of their BMI at age 18 and of their obesity status at the time of the study pregnancy. Finite mixture trajectory modelling identified four monotonely ordered, increasing mean weight trajectories. Relative to the second lowest (most common) weight trajectory, women in the highest trajectory were at greater risk of PE [odds ratio (OR) 5.0, 95% CI 2.9, 8.8] and GDM (OR 2.8, 95% CI 1.7, 4.5). Conclusions These results indicate that higher adult weight gain trajectories prior to pregnancy may play a role in predisposing women to PE or GDM. © 2014 John Wiley & Sons Ltd. Source


Heijnen B.F.J.,Maastricht University | Pelkmans L.P.J.,Maastricht University | Danser A.H.J.,Erasmus | Garrelds I.M.,Erasmus | And 4 more authors.
JRAAS - Journal of the Renin-Angiotensin-Aldosterone System | Year: 2014

This study investigated renin-angiotensin system (RAS)-induced cardiac remodeling and its reversibility in the presence and absence of high blood pressure (BP) in Cyp1a1-Ren2 transgenic inducible hypertensive rats (IHR). In IHR (pro)renin levels and BP can be dose-dependently titrated by oral administration of indole-3-carbinol (I3C). Young (four-weeks old) and adult (30-weeks old) IHR were fed I3C for four weeks (leading to systolic BP >200 mmHg). RAS-stimulation was stopped and animals were followed-up for a consecutive period. Cardiac function and geometry was determined echocardiographically and the hearts were excised for molecular and immunohistochemical analyses. Echocardiographic studies revealed that four weeks of RAS-stimulation incited a cardiac remodeling process characterized by increased left ventricular (LV) wall thickness, decreased LV volumes, and shortening of the left ventricle. Hypertrophic genes were highly upregulated, whereas in substantial activation a fibrotic response was absent. Four weeks after withdrawal of I3C, (pro)renin levels were normalized in all IHR. While in adult IHR BP returned to normal, hypertension was sustained in young IHR. Despite the latter, myocardial hypertrophy was fully regressed in both young and adult IHR. We conclude that (pro)renin-induced severe hypertension in IHR causes an age-independent fully reversible myocardial concentric hypertrophic remodeling, despite a continued elevated BP in young IHR. © The Author(s) 2014. Source


Perry J.R.B.,University of Exeter | Perry J.R.B.,University of Oxford | Perry J.R.B.,Kings College London | Corre T.,University of Lausanne | And 79 more authors.
Human Molecular Genetics | Year: 2013

Early menopause (EM) affects up to 10% of the female population, reducing reproductive lifespan considerably. Currently, it constitutes the leading cause of infertility in the western world, affecting mainly those women who postpone their first pregnancy beyond the age of 30 years. The genetic aetiology of EM is largely unknown in the majority of cases. We have undertaken a meta-analysis of genome-wide association studies (GWASs) in 3493 EM cases and 13 598 controls from 10 independent studies. No novel genetic variants were discovered, but the 17 variants previously associated with normal age at natural menopause as a quantitative trait (QT) were also associated with EM and primary ovarian insufficiency (POI). Thus, EM has a genetic aetiology which overlaps variation in normal age at menopause and is at least partly explained by the additive effects of the same polygenic variants. The combined effect of the common variants captured by the single nucleotide polymorphism arrays was estimated to account for ~30% of the variance in EM. The association between the combined 17 variants and the risk of EM was greater than the best validated non-genetic risk factor, smoking. © The Author 2013. Published by Oxford University Press. Source


De Graaf M.,Erasmus | Fouchier R.A.M.,Erasmus
EMBO Journal | Year: 2014

The recent emergence of a novel avian A/H7N9 influenza virus in poultry and humans in China, as well as laboratory studies on adaptation and transmission of avian A/H5N1 influenza viruses, has shed new light on influenza virus adaptation to mammals. One of the biological traits required for animal influenza viruses to cross the species barrier that received considerable attention in animal model studies, in vitro assays, and structural analyses is receptor binding specificity. Sialylated glycans present on the apical surface of host cells can function as receptors for the influenza virus hemagglutinin (HA) protein. Avian and human influenza viruses typically have a different sialic acid (SA)-binding preference and only few amino acid changes in the HA protein can cause a switch from avian to human receptor specificity. Recent experiments using glycan arrays, virus histochemistry, animal models, and structural analyses of HA have added a wealth of knowledge on receptor binding specificity. Here, we review recent data on the interaction between influenza virus HA and SA receptors of the host, and the impact on virus host range, pathogenesis, and transmission. Remaining challenges and future research priorities are also discussed. Recent cases of humans carrying avian Influenza strains highlight the importance of unraveling the role of virus-receptor interactions in cross-species adaptation. de Graaf and Fouchier review how virus hemagglutinin binding to host receptors governs virus pathogenesis, transmission and host spectrum. © 2014 The Authors. Source

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