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Dive into the research topics where Willem A. Dik is active.

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Featured researches published by Willem A. Dik.


Journal of Experimental Medicine | 2005

New insights on human T cell development by quantitative T cell receptor gene rearrangement studies and gene expression profiling

Willem A. Dik; Karin Pike-Overzet; Floor Weerkamp; Dick de Ridder; Edwin F. E. de Haas; Miranda R. M. Baert; Peter J. van der Spek; Esther E.L. Koster; Marcel J. T. Reinders; Jacques J.M. van Dongen; Anton W. Langerak; Frank J. T. Staal

To gain more insight into initiation and regulation of T cell receptor (TCR) gene rearrangement during human T cell development, we analyzed TCR gene rearrangements by quantitative PCR analysis in nine consecutive T cell developmental stages, including CD34+ lin− cord blood cells as a reference. The same stages were used for gene expression profiling using DNA microarrays. We show that TCR loci rearrange in a highly ordered way (TCRD-TCRG-TCRB-TCRA) and that the initiating Dδ2-Dδ3 rearrangement occurs at the most immature CD34+CD38−CD1a− stage. TCRB rearrangement starts at the CD34+CD38+CD1a− stage and complete in-frame TCRB rearrangements were first detected in the immature single positive stage. TCRB rearrangement data together with the PTCRA (pTα) expression pattern show that human TCRβ-selection occurs at the CD34+CD38+CD1a+ stage. By combining the TCR rearrangement data with gene expression data, we identified candidate factors for the initiation/regulation of TCR recombination. Our data demonstrate that a number of key events occur earlier than assumed previously; therefore, human T cell development is much more similar to murine T cell development than reported before.


Diabetes | 2012

Morbidly Obese Human Subjects Have Increased Peripheral Blood CD4+ T Cells With Skewing Toward a Treg- and Th2-Dominated Phenotype

Kim van der Weerd; Willem A. Dik; Benjamin Schrijver; Dave H. Schweitzer; Anton W. Langerak; Hemmo A. Drexhage; Rosalie M. Kiewiet; Maarten O. van Aken; Astrid van Huisstede; Jacques J.M. van Dongen; Aart-Jan van der Lelij; Frank J. T. Staal; P. Martin van Hagen

Obesity is associated with local T-cell abnormalities in adipose tissue. Systemic obesity-related abnormalities in the peripheral blood T-cell compartment are not well defined. In this study, we investigated the peripheral blood T-cell compartment of morbidly obese and lean subjects. We determined all major T-cell subpopulations via six-color flow cytometry, including CD8+ and CD4+ T cells, CD4+ T-helper (Th) subpopulations, and natural CD4+CD25+FoxP3+ T-regulatory (Treg) cells. Moreover, molecular analyses to assess thymic output, T-cell proliferation (T-cell receptor excision circle analysis), and T-cell receptor-β (TCRB) repertoire (GeneScan analysis) were performed. In addition, we determined plasma levels of proinflammatory cytokines and cytokines associated with Th subpopulations and T-cell proliferation. Morbidly obese subjects had a selective increase in peripheral blood CD4+ naive, memory, natural CD4+CD25+FoxP3+ Treg, and Th2 T cells, whereas CD8+ T cells were normal. CD4+ and CD8+ T-cell proliferation was increased, whereas the TCRB repertoire was not significantly altered. Plasma levels of cytokines CCL5 and IL-7 were elevated. CD4+ T-cell numbers correlated positively with fasting insulin levels. The peripheral blood T-cell compartment of morbidly obese subjects is characterized by increased homeostatic T-cell proliferation to which cytokines IL-7 and CCL5, among others, might contribute. This is associated with increased CD4+ T cells, with skewing toward a Treg- and Th2-dominated phenotype, suggesting a more anti-inflammatory set point.


Arthritis & Rheumatism | 2008

Is imatinib mesylate a promising drug in systemic sclerosis

P. L. A. van Daele; Willem A. Dik; H. B. Thio; P.Th.W. van Hal; J. A. M. van Laar; Herbert Hooijkaas; P. M. van Hagen

A patient with therapy-resistant and progressive systemic sclerosis (SSc) with pulmonary involvement who was treated with imatinib mesylate is described herein. Prior to treatment, pulmonary fibroblasts obtained from the patient were cultured and incubated with imatinib mesylate. Preincubation of the fibroblasts for 16 hours with 2.5 microg/ml imatinib mesylate efficiently abrogated platelet-derived growth factor BB-induced fibroblast proliferation. Furthermore, transforming growth factor beta1-induced type I collagen gene transcription was blocked. During treatment, the patients pulmonary involvement stabilized and her skin tightness improved. To our knowledge, this is the first report of a patient with therapy-refractory SSc responding to treatment with imatinib mesylate.


Blood | 2011

Posttranscriptional deregulation of MYC via PTEN constitutes a major alternative pathway of MYC activation in T-cell acute lymphoblastic leukemia

Mélanie Bonnet; Marie Loosveld; Bertrand Montpellier; Jean-Marc Navarro; Benoît Quilichini; Christophe Picard; Julie Di Cristofaro; Claude Bagnis; Chantal Fossat; Lucie Hernandez; Emilie Mamessier; Sandrine Roulland; Ester Morgado; Christine Formisano-Tréziny; Willem A. Dik; Anton W. Langerak; Thomas Prebet; Norbert Vey; Gérard Michel; Jean Gabert; Jean Soulier; Elizabeth Macintyre; Vahid Asnafi; Dominique Payet-Bornet; Bertrand Nadel

Cumulative evidence indicates that MYC, one of the major downstream effectors of NOTCH1, is a critical component of T-cell acute lymphoblastic leukemia (T-ALL) oncogenesis and a potential candidate for targeted therapy. However, MYC is a complex oncogene, involving both fine protein dosage and cell-context dependency, and detailed understanding of MYC-mediated oncogenesis in T-ALL is still lacking. To better understand how MYC is interspersed in the complex T-ALL oncogenic networks, we performed a thorough molecular and biochemical analysis of MYC activation in a comprehensive collection of primary adult and pediatric patient samples. We find that MYC expression is highly variable, and that high MYC expression levels can be generated in a large number of cases in absence of NOTCH1/FBXW7 mutations, suggesting the occurrence of multiple activation pathways in addition to NOTCH1. Furthermore, we show that posttranscriptional deregulation of MYC constitutes a major alternative pathway of MYC activation in T-ALL, operating partly via the PI3K/AKT axis through down-regulation of PTEN, and that NOTCH1(m) might play a dual transcriptional and posttranscriptional role in this process. Altogether, our data lend further support to the significance of therapeutic targeting of MYC and/or the PTEN/AKT pathways, both in GSI-resistant and identified NOTCH1-independent/MYC-mediated T-ALL patients.


Thorax | 2003

Short course dexamethasone treatment following injury inhibits bleomycin induced fibrosis in rats

Willem A. Dik; Robin J. McAnulty; Marjan A. Versnel; Brigitta A.E. Naber; Luc J. I. Zimmermann; Geoff Laurent; Steven E. Mutsaers

Background: Corticosteroids are routinely used in patients with pulmonary fibrosis. The timing for initiation of treatment is likely to be crucial for corticosteroids to exert an antifibrotic effect. Experimental studies in animals have examined the effect of corticosteroid treatment starting before or at the time of lung injury. However, this is not representative of the human condition as treatment only begins after disease has been established. We examined the effect of a short course corticosteroid treatment starting 3 days after bleomycin induced lung injury on the development of pulmonary fibrosis. Methods: Bleomycin (1.5 mg/kg) was instilled intratracheally into rats to induce pulmonary fibrosis. The effect of a 3-day course of dexamethasone (0.5 mg/kg) initiated 3 days after bleomycin induced lung injury on cell proliferation and collagen deposition was examined by analysing bronchoalveolar lavage (BAL) fluid and lung tissue. Results: Treating bleomycin exposed animals after injury with dexamethasone for 3 days inhibited lung collagen deposition compared with animals exposed to bleomycin without dexamethasone treatment (15.2 (2.2) mg collagen/lung v 22.5 (2.1) mg/lung; p<0.05). Dexamethasone treatment reduced pulmonary parenchymal cell proliferation in bleomycin exposed rats but did not influence BAL fluid mitogenic activity for lung fibroblasts or alter the BAL fluid levels of the fibrogenic mediators transforming growth factor-β1, platelet derived growth factor-AB, and thrombin. Conclusions: A 3 day course of dexamethasone treatment initiated 3 days after bleomycin induced lung injury reduces lung cell proliferation and collagen deposition by mechanisms other than through reduction of transforming growth factor-β1, platelet derived growth factor-AB, and thrombin levels in BAL fluid. We propose that an early short course treatment with dexamethasone may be useful in inhibiting pulmonary fibrosis.


British Journal of Ophthalmology | 2011

The neonatal Fc receptor is expressed by human retinal pigment epithelial cells and is downregulated by tumour necrosis factor-alpha

Kiki van Bilsen; P. Martin van Hagen; Jeroen Bastiaans; Jan C. van Meurs; Tom Missotten; Robert W Kuijpers; Herbert Hooijkaas; Gemma M Dingjan; G. Seerp Baarsma; Willem A. Dik

Background/aims The neonatal Fc receptor (FcRn) protects immunoglobulin G (IgG) from catabolism, controls its transport between cell layers and extends its serum half-life. In the human, vitreous IgG can be found, but how vitreous IgG is processed or transported is currently unknown. The FcRn is a candidate molecule to regulate these processes. The authors examined FcRn expression and regulation in human retinal pigment epithelium (RPE) cells. Methods In three primary RPE cell cultures (from three donor eyes) and in the human RPE cell line ARPE-19, FcRn and beta-2-microglobulin (β2M) mRNA levels were determined by real-time quantitative PCR. FcRn protein expression was analysed by western blot studies. Stimulation experiments were performed with recombinant human tumour necrosis factor (TNF)-α and interferon (IFN)-γ. HT-29, THP-1 and HeLa cell lines were used as FcRn positive and negative non-ocular controls, respectively. Results Expression of FcRn mRNA and protein was demonstrated in all three RPE cultures. After stimulation with TNF-α, FcRn expression is downregulated in RPE cells and upregulated in HT-29 and THP-1 cells. IFN-γ has no effect on FcRn expression in RPE cells. Conclusions Human RPE cells express FcRn. The proinflammatory cytokine TNF-α downregulates FcRn expression. The authors speculate that the FcRn may play a pivotal role in the immune privilege of the human eye.


Neonatology | 2003

Application of the Open-Lung Concept during Positive-Pressure Ventilation Reduces Pulmonary Inflammation in Newborn Piglets

Anton H. van Kaam; Willem A. Dik; Jack J. Haitsma; Anne De Jaegere; Birgitta A. Naber; Wim M. C. van Aalderen; Joke H. Kok; Burkhard Lachmann

It has been shown that application of the open-lung concept (OLC) during high-frequency oscillatory ventilation (HFOV) attenuates pulmonary inflammation. We hypothesized that this attenuation could also be achieved by applying the OLC during positive-pressure ventilation (PPV). After repeated whole-lung lavage, newborn piglets were assigned to one of three ventilation groups: (1) PPVOLC; (2) HFOVOLC, or (3) conventional PPV (PPVCON). After a ventilation period of 5 h, analysis of bronchoalveolar lavage fluid showed a reduced influx of polymorphonuclear neutrophils, interleukin 8, and thrombin activity in both OLC groups as compared with the PPVCON group. There were no differences in tumor necrosis factor alpha levels. We conclude that application of the OLC during PPV reduces pulmonary inflammation as compared with conventional PPV and that the magnitude of this reduction is comparable to that of HFOV.


Neonatology | 2006

Early increased levels of matrix metalloproteinase-9 in neonates recovering from respiratory distress syndrome.

Willem A. Dik; Anton H. van Kaam; Tamara Dekker; Brigitta A.E. Naber; Daphne J. Janssen; A.A. Kroon; Luc J. I. Zimmermann; Marjan A. Versnel; Rene Lutter

Aim: Matrix metalloproteinases (MMPs) play an eminent role in airway injury and remodelling. We explored the hypothesis that pulmonary MMP levels would differ early after birth (2–4 days) between infants with resolving respiratory distress syndrome (RDS) and infants developing chronic lung disease of prematurity (CLD). Methods: Thirty-two prematurely born infants (gestational age ≤30 weeks) diagnosed with RDS were included. In 13 infants RDS resolved while 19 developed CLD. MMP-2 and MMP-9 in bronchoalveolar lavage (BAL) fluids collected on postnatal days 2, 4, 7 and 10 were analyzed by zymography and densitometry. Immunochemistry was performed on BAL cells and lung tissue to identify cellular sources of MMP-9 in RDS and CLD. Results: Median MMP-9 levels increased significantly on day 2 in BAL fluid from patients with resolving RDS (median values MMP-9 = 42.0 arbitrary units (AU)) compared to CLD patients (MMP-9 = 5.4 AU). MMP-9 and neutrophil lipocalin-associated MMP-9 (NGAL) were significantly higher on day 4 in BAL fluid from resolving RDS (MMP-9 = 65.8 AU; NGAL = 16.1 AU) compared to CLD (MMP-9 = 25.4 AU; NGAL = 2.0 AU), Levels of MMP-9 and NGAL increased subsequently on days 7 and 10 in CLD. No differences in MMP-2 levels were detected between RDS and CLD. Neutrophils, macrophages and alveolar type-II epithelial cells were identified as potential sources of MMP-9. Conclusion: Our findings indicate differences in early MMP-9 BAL fluid levels between resolving RDS and developing CLD, which may relate to the ability to raise an early and adequate response to the initial injury.


Shock | 2009

Synthetic oligopeptides related to the β-subunit of human chorionic gonadotropin attenuate inflammation and liver damage after (Trauma) hemorrhagic shock and resuscitation

H. Rogier van den Berg; Nisar Ahmed Khan; Marten van der Zee; Fred Bonthuis; Jan N. M. IJzermans; Willem A. Dik; Ron W. F. de Bruin; Robbert Benner

Severe hemorrhagic shock (HS) followed by resuscitation induces a massive inflammatory response, which may culminate into systemic inflammatory response syndrome, multiple organ dysfunction syndrome, and, finally, death. Treatments that effectively prevent this inflammation are limited so far. In a previous study, we demonstrated that synthetic oligopeptides related to the primary structure of human chorionic gonadotropin (HCG) can inhibit the inflammatory response and mortality that follow high-dose LPS-induced inflammation. Considering this powerful anti-inflammatory effect, we investigated whether administration of similar synthetic HCG-related oligopeptides (LQGV, AQGV, LAGV) during HS were able to attenuate the inflammatory response associated with this condition. Hemorrhagic shock was induced in rats for 60 min by blood withdrawal until a MAP of 40 mmHg was reached. Rats received a single injection with one of the hCG-related oligopeptides (LQGV, AQGV or LAGV) or 0.9% NaCl solution as control 30 min after induction of HS. Treatment with LQGV, AQGV, or LAGV prevented systemic release of TNF-&agr; and IL-6 and was associated with reduced TNF-&agr;, IL-6, and E-selectin mRNA transcript levels in the liver. LQGV treatment prevented neutrophil infiltration into the liver and was associated with reduced liver damage. Our data suggest that HCG-related oligopeptides, in particular LQGV, have therapeutic potential by attenuating the life-threatening inflammation and organ damage that is associated with (trauma) HS and resuscitation.


Leukemia | 2005

Purity for clarity: the need for purification of tumor cells in DNA microarray studies

D de Ridder; C E van der Linden; T Schonewille; Willem A. Dik; Marcel J. T. Reinders; J J M van Dongen; F J T Staal

It is now well established that gene expression profiling using DNA microarrays can provide novel information about various types of hematological malignancies, which may lead to identification of novel diagnostic markers. However, to successfully use microarrays for this purpose, the quality and reproducibility of the procedure need to be guaranteed. The quality of microarray analyses may be severely reduced, if variable frequencies of nontarget cells are present in the starting material. To systematically investigate the influence of different types of impurity, we determined gene expression profiles of leukemic samples containing different percentages of nonleukemic leukocytes. Furthermore, we used computer simulations to study the effect of different kinds of impurity as an alternative to conducting hundreds of microarray experiments on samples with various levels of purity.As expected, the percentage of erroneously identified genes rose with the increase of contaminating nontarget cells in the samples. The simulations demonstrated that a tumor load of less than 75% can lead to up to 25% erroneously identified genes. A tumor load of at least 90% leads to identification of at most 5% false-positive genes. We therefore propose that in order to draw well-founded conclusions, the percentage of target cells in microarray experiment samples should be at least 90%.

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P. Martin van Hagen

Erasmus University Rotterdam

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Herbert Hooijkaas

Erasmus University Rotterdam

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Jeroen Bastiaans

Erasmus University Rotterdam

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P. M. van Hagen

Erasmus University Rotterdam

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Virgil A.S.H. Dalm

Erasmus University Rotterdam

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Marjan A. Versnel

Erasmus University Rotterdam

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Hemmo A. Drexhage

Erasmus University Rotterdam

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