A. Geurts-Moespot - Academia.edu (original) (raw)

Papers by A. Geurts-Moespot

Vox sanguinis, Jan 8, 2015

Increased iron and metabolic syndrome (MetS) go hand in hand. Frequent blood donation depletes ir... more Increased iron and metabolic syndrome (MetS) go hand in hand. Frequent blood donation depletes iron stores. This study investigates whether high-intensity blood donation is associated with lower MetS prevalence compared with low-intensity blood donation, and whether iron acts as an intermediary factor. A random sample of 422 male and 211 female active whole-blood donors ≥45 years of age was included in a cross-sectional study. Lipids, glucose and iron parameters were measured after overnight fasting. MetS was defined according to the joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention. Three groups of donation intensity were created by sex-specific tertiles of donation frequency per year and duration of donor career. MetS was present in 22·9% of donors. Prevalence of MetS was 1·46 (95% confidence interval [CI]: 0·93-2·30) times higher in men with high donation intensity, whereas in women MetS prevalence was 2·14 (95% CI: 0·94-4·...

British Journal of Haematology, 2009

The hepatic peptide hormone hepcidin is the key regulator of systemic iron homeostasis. Its quant... more The hepatic peptide hormone hepcidin is the key regulator of systemic iron homeostasis. Its quantification holds promise as a biomarker for diagnosis and monitoring of various iron disorders (Ganz, 2006; Kemna et al, 2008a). Human hepcidin is produced mainly by hepatocytes as an 84-amino-acid (aa) pre-prohepcidin (Pigeon et al, 2001). Subsequent post-translational processing by a signal peptidase and the prohormone convertase furin results in the 60 aa prohepcidin and the biologically active 25 aa form (hepcidin-25) that is secreted in plasma (Krause et al, 2000) and excreted in urine (Park et al, 2001). Additional amino-terminal processing events generate two smaller isoforms (hepcidin-20 and-22) (Park et al, 2001; Kemna et al, 2007). Hepcidin-25 leads to internalisation and degradation of the iron exporter ferroportin, which is present on the cell surface of macrophages and enterocytes (Nemeth et al, 2004a; De Domenico et al, 2008a). Thus, hepcidin inhibits the release of iron by macrophages and attenuates iron uptake in the gut. Increased iron stores and inflammation induce hepcidin production, whereas hypoxia, anaemia, iron deficiency and increased erythropoiesis and erythropoietin administration attenuate hepcidin synthesis (Nicolas et al, 2002a,b; Ganz, 2006; Pak et al, 2006; De Domenico et al, 2008b; Kemna et al, 2008a). Consequently, inflammation decreases the availability of iron, whereas hypoxia or anaemia increase iron release and absorption. Most of these insights have been obtained by molecular in vitro work and mice studies. Despite the importance for systemic iron homeostasis and iron related pathologies, progress in humans has been hampered by the difficulties many researchers face by measuring hepcidin in body fluids. Firstly, until recently, only a few tools were available to quantify hepcidin, in most part because antibodies are hard to raise. Hepcidin has a small and compact structure and antigenic epitopes are scarce. In addition, hepcidin is conserved among a wide range of species, which complicates the induction of antibodies in hosts, such as rabbits. As a result, immunochemical methods based on specific anti-hepcidin antibodies have been largely unavailable. Secondly, quantification of hepcidin is complicated by its tendency to aggregate (Hunter et al, 2002) and stick to laboratory plastics, necessitating implementation of robust laboratory procedures. Current methods can be divided into mass-spectrometrybased and immunochemical assays. We and others have developed methods for the measurements of urine and serum hepcidin-25,-22 and-20 isoforms on novel technology

The American Journal of Medicine, 2009

Blood, 2011

To date, concentrations of the promising biomarker hepcidin have only been assessed in serum of r... more To date, concentrations of the promising biomarker hepcidin have only been assessed in serum of relatively small series of healthy volunteers and patients. We assessed age- and sex-stratified reference ranges of serum hepcidin concentration in a selected reference set and performed regression analyses to study associations between hepcidin and (biochemical) variables in a large, well-phenotyped sample of the general population (n = 2998). All participants filled out a questionnaire on lifestyle, health status, and medical history. Serum measurements of iron parameters, liver enzyme alanine aminotransferase, creatinine and C-reactive protein were available. Serum hepcidin concentrations were lower for premenopausal than for postmenopausal women (median, 4.1nM vs 8.5nM, respectively). Hepcidin concentrations in men were constant over age (median, 7.8nM). Serum hepcidin was strongly associated with serum ferritin in men and women: β-coefficient of log-transformed variables (95% confide...

Oncology reports, 2005

The plasminogen activator (PA) system comprises the 2 serine proteases, urokinase PA (uPA) and ti... more The plasminogen activator (PA) system comprises the 2 serine proteases, urokinase PA (uPA) and tissue PA (tPA), the 2 serpin inhibitors, PAI-1 and PAI-2 and the uPA receptor (uPAR; CD87). High levels of uPA, PAI-1, uPA-PAI-1 complex and uPAR in breast cancer tissue are associated with poor prognosis, while high levels of tPA or PAI-2 correlate with good prognosis. In this study, pre-operative plasma levels of uPA, PAI-1, uPAR, tPA, uPA-PAI-1 complex, and tPA-PAI-1 complex were measured in patients with benign (n=103) and malignant breast disease (n=113) by immunoenzymatic assays (ELISA). While plasma antigen levels of uPA, PAI-1, uPA-PAI-1 complex and uPAR were not significantly different in the 2 groups, antigen levels of tPA and tPA-PAI-1 complex were significantly higher in patients with breast carcinoma compared to the control group. In plasma from the breast cancer patients, uPA levels correlated weakly but significantly with those of tPA (r=0.20, p=0.035) and uPAR (r=0.208, p=...

European Journal of Clinical Nutrition, 2019

Background/Objectives The iron-binding affinity of vaginal lactoferrin (Lf) reduces iron availabl... more Background/Objectives The iron-binding affinity of vaginal lactoferrin (Lf) reduces iron available to genital pathogens. We describe host reproductive, nutritional, infection and iron biomarker profiles affecting vaginal Lf concentration in young nulliparous and primigravid women in Burkina Faso. Subjects/Methods Vaginal eluates from women who had participated in a randomized, controlled periconceptional iron supplementation trial were used to measure Lf using a competitive double-sandwich ELISA. For this analysis samples from both trial arms were combined and pregnant and non-pregnant cohorts compared. Following randomization Lf was measured after 18 months (end assessment) for women remaining non-pregnant, and at two antenatal visits for those becoming pregnant. Associations between log Lf levels and demographic, anthropometric, infection and iron biomarker variables were assessed using linear mixed models. Results Lf samples were available for 712 non-pregnant women at end assessment and for 303 women seen at an antenatal visit. Lf concentrations of pregnant women were comparable to those of non-pregnant, sexually active women. Lf concentration increased with mid-upper-arm circumference, (P = 0.047), body mass index (P = 0.018), Trichomonas vaginalis (P < 0.001) infection, bacterial vaginosis (P < 0.001), serum C-reactive protein (P = 0.048) and microbiota community state types III/IV. Adjusted Lf concentration was positively associated with serum hepcidin (P = 0.047), serum ferritin (P = 0.018) and total body iron stores (P = 0.042). There was evidence that some women maintained persistently high or low Lf concentrations from before, and through, pregnancy. Conclusion Lf concentrations increased with genital infection, higher BMI, MUAC, body iron stores and hepcidin, suggesting nutritional and iron status influence homeostatic mechanisms controlling vaginal Lf responses.

In the present study, we identified and chemically synthesized three cationic and amphipathic pep... more In the present study, we identified and chemically synthesized three cationic and amphipathic peptides (Glycinin-17, BCAS-16, and BCBS-11) from soybean proteins. These peptides had high isoelectric points, high positive net charges, and included multiple hydrophobic amino acids. Subsequently, we identified multiple functions of these peptides, including antimicrobial, lipopolysaccharide-neutralizing, and angiogenic activities, and examined their cytotoxic activities against mammalian red blood cells. Glycinin-17, BCAS-16, and BCBS-11 exhibited antimicrobial activity against Porphyromonas gingivalis and Candida albicans whereas Glycinin-17 did not possess antimicrobial effects on Propionibacterium acnes and Streptococcus mutans. Membrane-depolarization assays and flow cytometric analyses showed that the antimicrobial properties of Glycinin-17, BCAS-16, and BCBS-11 against P. gingivalis, P. acnes, and S. mutans were dependent on membrane-disrupting potential. In contrast, major antimicrobial activities of these peptides against C. albicans were dependent on interactions with targets other than cell membranes. Furthermore, chromogenic Limulus amebocyte lysate assays showed that 50% effective concentrations (EC 50 , 0.12-0.31 µM) of these three peptides neutralize LPS with similar potency (EC 50 : 0.11 µM) to that of polymyxin B. Moreover, tube-formation assays in human umbilical vein endothelial cells showed similar angiogenic activities of the three peptides as that following treatment with LL-37. Although BCAS-16 exhibited hemolytic activity, the rate of hemolysis for Glycinin-17 and BCBS-11 in the presence of 500-µM Glycinin-17 and BCBS-11 was less than 2%. These results demonstrate that cationic and amphipathic peptides from soybean proteins, particularly Glycinin-17 and BCBS-11, have potential as multifunctional ingredients for healthcare applications.

Journal of Receptors and Signal Transduction, 1992

Scintillation Proximity Assay (SPA), which does not require the physical separation of receptor b... more Scintillation Proximity Assay (SPA), which does not require the physical separation of receptor bound and free ligand, was applied to study the interaction of Epidermal Growth Factor (EGF) with its receptor (EGFR) in membrane preparations from human placenta. Fluomicrospheres to which the monoclonal anti-EGFR antibody R1 was coupled, were used. Kinetic binding data of the association of 125I-labeled EGF binding to the receptor at 20 degrees C could be fitted according to a double exponential model, which is consistent with the presence of fast and slow associating EGF binding sites. Dissociation kinetics revealed that perturbation of equilibrium conditions rapidly occurs upon washing. Multiple point Scatchard analysis of equilibrium 125I-labeled EGF binding data revealed curvilinearity, indicating the presence of both high and low affinity EGF binding sites. We conclude that SPA is an interesting new tool in the exploration of the interaction of ligands with their receptors, which allows detailed ligand-receptor studies under precise in situ conditions.

European Journal of Obstetrics & Gynecology and Reproductive Biology, 2006

Background: Haemostasis is a complex balance of activating and inhibitory pathways resulting in c... more Background: Haemostasis is a complex balance of activating and inhibitory pathways resulting in coagulation and lysis. Normal pregnancy is associated with hypercoagulation that is even more profound in complicated pregnancies. Objective: To study the role of the plasminogen-activator system in complicated pregnancy with regard to haemostasis, it is essential to have reference values of components of this system during uneventful pregnancy. In this study we investigated the concentrations of six different components of the plasminogen-activator system preconceptionally, during and after uncomplicated pregnancies. Material and methods: Tissue-type and urokinase-type plasminogen activator (tPA and uPA), plasminogen inhibitor type-1 and-2 (PAI-1 and-2), and the complexes between tPA and PAI-1, and between uPA and PAI-1 (tPA-PAI-1, uPA-PAI-1) were measured by ELISAs in blood obtained preconceptionally, at 6, 10, 20, 32 weeks of gestation, and 6 weeks after delivery in uncomplicated pregnancies (n = 41; all six parameters n = 22). Results: tPA and uPA concentrations decreased in the first 10 weeks of pregnancy and subsequently increased in the third trimester. PAI-1 concentrations increased in the third trimester and PAI-2 concentrations increased throughout pregnancy (preconception versus 32 weeks of gestation; 38.73 versus 102.23 ng/ml, and 0.024 versus 151.06 ng/ml, respectively). tPA-PAI-1 and uPA-PAI-1 complex concentrations decreased in the first trimester, followed by an increase in the third trimester. The concentrations of all components returned to the preconception values 6 weeks after delivery. Conclusion: This study provides longitudinal data on activating and inhibitory components of the plasminogen-activator system during pregnancy. Insight in the longitudinal changes in these concentrations may be of help in the understanding of the thrombotic tendency in pregnancy complications such as preeclampsia.

Clinical Chemistry and Laboratory Medicine (CCLM)

Background Hepcidin concentrations measured by various methods differ considerably, complicating ... more Background Hepcidin concentrations measured by various methods differ considerably, complicating interpretation. Here, a previously identified plasma-based candidate secondary reference material (csRM) was modified into a serum-based two-leveled sRM. We validated its functionality to increase the equivalence between methods for international standardization. Methods We applied technical procedures developed by the International Consortium for Harmonization of Clinical Laboratory Results. The sRM, consisting of lyophilized serum with cryolyoprotectant, appeared commutable among nine different measurement procedures using 16 native human serum samples in a first round robin (RR1). Harmonization potential of the sRM was simulated in RR1 and evaluated in practice in RR2 among 11 measurement procedures using three native human plasma samples. Comprehensive purity analysis of a candidate primary RM (cpRM) was performed by state of the art procedures. The sRM was value assigned with an iso...

European Journal of Immunology

In MS, B cells survive peripheral tolerance checkpoints to mediate local inflammation, but the un... more In MS, B cells survive peripheral tolerance checkpoints to mediate local inflammation, but the underlying molecular mechanisms are relatively underexplored. In mice, the MIF pathway controls B-cell development and the induction of EAE. Here, we found that MIF and MIF receptor CD74 are downregulated, while MIF receptor CXCR4 is upregulated in B cells from early onset MS patients. B cells were identified as the main immune subset in blood expressing MIF. Blocking of MIF and CD74 signaling in B cells triggered CXCR4 expression, and vice versa, with separate effects on their proinflammatory activity, proliferation, and sensitivity to Fas-mediated apoptosis. This study reveals a new reciprocal negative regulation loop between CD74 and CXCR4 in human B cells. The disturbance of this loop during MS onset provides further insights into how pathogenic B cells survive peripheral tolerance checkpoints to mediate disease activity in MS.

Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine, 2018

To date, biomarkers are not routinely used in endometrial cancer diagnosis, prognosis, and follow... more To date, biomarkers are not routinely used in endometrial cancer diagnosis, prognosis, and follow-up. The purpose of this study was to evaluate whether serum HE4 was related to clinicopathological risk factors and outcome. Second, the role of serum HE4 and CA125 was assessed as indicator for recurrent disease during follow-up. A total of 174 patients with endometrial cancer between 1999 and 2009 were selected for this retrospective study. Serum HE4 and CA125 were analyzed at primary diagnosis, during follow-up, and at the time of recurrence. Correlations with clinicopathological factors were studied by univariate and multivariate survival analyses. Lead time was calculated in order to determine which serum marker was elevated prior to clinical detection of recurrent disease. Serum levels of HE4 and CA125 were significantly associated with high tumor grade, myometrial invasion, lymph node involvement, and advanced stage (p < 0.01). HE4 was an independent prognostic factor for redu...

The Journal of infectious diseases, Jan 4, 2018

Safety of iron supplementation for young women is uncertain in malaria endemic settings. Double-b... more Safety of iron supplementation for young women is uncertain in malaria endemic settings. Double-blind randomized controlled non-inferiority trial in rural Burkina Faso. 1959 nulliparae assigned to weekly supplementation (60 mg iron and 2.8 mg folic acid) (n=980) or 2.8 mg folic acid (n=979) until first antenatal visit (ANC1), or 18 months if remaining non-pregnant. 315 women attended ANC1, and 916 remained non-pregnant. There was no difference at ANC1 in parasitemia prevalence (iron 53.4%, 95% CI 45.7:61.0; control 55.3%, 95% CI 47.3:62.9; prevalence ratio 0.97, 95% CI 0.79:1.18; P=0.82); anemia (adjusted effect 0.96, 95% CI 0.83:1.10; P=0.52); iron deficiency (adjusted risk ratio 0.84, 95% CI 0.46:1.54; P= 0.58); or plasma iron biomarkers. Outcomes in non-pregnant women were: parasitemia (iron 42.9%, 95% CI 38.3:47.5; control 39.2% , 95% CI 34.9:43.7, prevalence ratio 1.09, 95% CI 0.93:1.28; P=0.282); anemia (adjusted risk ratio 0.90, 95% CI 0.78:1.05; P= 0.17); iron deficiency (ad...

The Lancet. Haematology, 2017

Current guidelines to treat iron deficiency recommend daily provision of ferrous iron divided thr... more Current guidelines to treat iron deficiency recommend daily provision of ferrous iron divided through the day to increase absorption. However, daily dosing and split dosing might increase serum hepcidin and decrease iron absorption from subsequent doses. Our study aim was to compare iron absorption from oral iron supplements given on consecutive versus alternate days and given as single morning doses versus twice-daily split dosing. We did two prospective, open-label, randomised controlled trials assessing iron absorption using (Fe)-labelled, (Fe)-labelled, or (Fe)-labelled ferrous sulfate in iron-depleted (serum ferritin ≤25 μg/L) women aged 18-40 years recruited from ETH Zurich and the University of Zurich, Switzerland. In study 1, women were randomly assigned (1:1) to two groups. One group was given 60 mg iron at 0800 h (±1 h) on consecutive days for 14 days, and the other group was given the same doses on alternate days for 28 days. In study 2, women were assigned to two groups,...

PloS one, 2016

Serum hepcidin concentration is regulated by iron status, inflammation, erythropoiesis and numero... more Serum hepcidin concentration is regulated by iron status, inflammation, erythropoiesis and numerous other factors, but underlying processes are incompletely understood. We studied the association of common and rare single nucleotide variants (SNVs) with serum hepcidin in one Italian study and two large Dutch population-based studies. We genotyped common SNVs with genome-wide association study (GWAS) arrays and subsequently performed imputation using the 1000 Genomes reference panel. Cohort-specific GWAS were performed for log-transformed serum hepcidin, adjusted for age and gender, and results were combined in a fixed-effects meta-analysis (total N 6,096). Six top SNVs (p<5x10-6) were genotyped in 3,821 additional samples, but associations were not replicated. Furthermore, we meta-analyzed cohort-specific exome array association results of rare SNVs with serum hepcidin that were available for two of the three cohorts (total N 3,226), but no exome-wide significant signal (p<1.4...

Blood, Oct 1, 2016

AMR-mediated hepatic platelet clearance in vivo may represent a physiological mechanism involved ... more AMR-mediated hepatic platelet clearance in vivo may represent a physiological mechanism involved in platelet homeostasis. Platelets desialylate as they circulate, thereby becoming the primary ligand for the AMR, 10 and this interaction regulates hepatocyte thrombopoietin production. 11 Desialylation also occurs when platelets are activated by several physiological stimuli, and AMR clearance may be relevant in attenuating the coagulopathy of sepsis. 12-14 Our results support the indications of international ITP guidelines, 15 which suggest that both PSSs and glycoprotein-specific antibody testing are not mandatory in ITP workup or management. However, if available on a single-center basis, these tests may help to gain insight into the prevalent mechanism underlying thrombocytopenia (increased clearance vs deficient production) in a specific patient who fails first-line therapy with glucocorticoids.

Clinical chemistry, Jul 12, 2016

Absolute plasma hepcidin concentrations measured by various procedures differ substantially, comp... more Absolute plasma hepcidin concentrations measured by various procedures differ substantially, complicating interpretation of results and rendering reference intervals method dependent. We investigated the degree of equivalence achievable by harmonization and the identification of a commutable secondary reference material to accomplish this goal. We applied technical procedures to achieve harmonization developed by the Consortium for Harmonization of Clinical Laboratory Results. Eleven plasma hepcidin measurement procedures (5 mass spectrometry based and 6 immunochemical based) quantified native individual plasma samples (n = 32) and native plasma pools (n = 8) to assess analytical performance and current and achievable equivalence. In addition, 8 types of candidate reference materials (3 concentrations each, n = 24) were assessed for their suitability, most notably in terms of commutability, to serve as secondary reference material. Absolute hepcidin values and reproducibility (intra...

The International journal of biological markers

uPA and PAI-1 are becoming established as amongst the most effective markers of poor prognosis fo... more uPA and PAI-1 are becoming established as amongst the most effective markers of poor prognosis for patients with node-negative breast cancer; tPA is an index of longer survival. This paper describes a sensitive ELISA for the measurement of uPA, tPA and PAI-1 in breast cancer cytosols. The structure of the assay involves coating Ab (sheep alpha-Chicken IgY), catching Ab (chicken alpha-analyte), tagging Ab (rabbit alpha-analyte) and detecting Ab (goat alpha-rabbit IgG) labelled with HRP. The assay has a high degree of accuracy and specificity. Comparison with the American Diagnostic kits shows the results' equivalence for PAI-1 and tPA. For uPA the results of the assay were twice as high. The assay is sensitive and relatively inexpensive. It is the first published assay to yield strictly comparative values for uPA, tPA and PAI-1 in tissue extracts and is readily subject to external quality control.

Cancer Research

Vascular endothelial growth factor (VEGF), a potent angiogenic factor, has been reported to be as... more Vascular endothelial growth factor (VEGF), a potent angiogenic factor, has been reported to be associated with a poor prognosis in primary breast cancer and in several other cancer types. In the present study, we have measured with ELISA the levels of VEGF in cytosolic extracts of 845 primary breast tumors of patients who developed a recurrence during follow-up. All of the patients received tamoxifen (n ‫؍‬ 618) or cyclophosphamide, methotrexate, 5-fluorouracil (CMF) or 5-fluorouracil, Adriamycin, cyclophosphamide (FAC) chemotherapy (n ‫؍‬ 227) as first-line systemic therapy after diagnosis of advanced disease. VEGF levels were not related to age or menopausal status but were negatively related to the cytosolic levels of estrogen receptor and progesterone receptor (P < 0.0001). In patients who relapsed within 1 year after primary surgery, tumor VEGF levels were higher than in patients who showed a longer disease-free interval (P ‫؍‬ 0.0005). In patients with a first relapse in the viscera, VEGF levels were higher compared with those that relapsed to the bone or soft tissue (P ‫؍‬ 0.0004). In univariate analysis for response to first-line tamoxifen therapy, patients with high or intermediate levels showed a poor rate of response, compared with patients with low tumor-VEGF levels (P ‫؍‬ 0.0001). Similarly, in multivariate analysis for response to tamoxifen treatment, corrected for age, site of relapse, disease-free interval, and estrogen receptor and progesterone receptor status, VEGF status was an independent predictive factor (P ‫؍‬ 0.009). In concordance, higher levels of VEGF were associated with a short progression-free survival and postrelapse overall survival (both, P < 0.0001). On first-line chemotherapy, the rate of response decreased with higher tumor levels of VEGF, both in univariate (P ‫؍‬ 0.003) and in multivariate analysis (P ‫؍‬ 0.004). Furthermore, higher VEGF levels were associated with a short progression-free survival (P ‫؍‬ 0.003) and postrelapse overall survival (P ‫؍‬ 0.001). In conclusion, the tumor VEGF level is an important independent marker that predicts a poor efficacy of both tamoxifen and chemotherapy in advanced breast cancer. Knowledge of the tumor level of VEGF might be helpful in selecting individual patients who may benefit from treatments with antiangiogenic agents combined with conventionally used drugs.