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Yick C.Y.,University of Amsterdam | Zwinderman A.H.,University of Amsterdam | Kunst P.W.,Admiraal de Ruyter Hospital | Grunberg K.,Medical Center | And 6 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2013

Rationale: Glucocorticoids are the mainstay of asthma therapy. However, it is unclear whether the benefits of glucocorticoids in asthma are merely based on antiinflammatory properties. Glucocorticoids may also alter gene expression of airway smooth muscle (ASM). We hypothesized that the gene expression profile of the ASM layer in endobronchial biopsies of patients with asthma is altered by oral glucocorticoid therapy as compared with placebo. Objectives: First, we investigated the change in ASM transcriptomic profile in endobronchial biopsies after 14 days of oral glucocorticoid therapy. Second, we investigated the association between changes in ASM transcriptomic profile and lung function. Methods: Twelve steroid-free patients with atopic asthma were included in this double-blind intervention study. Endobronchial biopsies were taken before and after 14 days of oral prednisolone (n = 6) or placebo (n = 6).RNAof laser-dissectedASMwas sequenced (RNA-Seq) using GS FLX+ (454/Roche). Gene networks were identified by Ingenuity Pathway Analysis. RNA-Seq reads were assumed to follow a negative binomial distribution. At the current sample size the estimated false discovery rate was approximately 3%. Measurements and Main Results : Fifteen genes were significantly changed by 14 days of oral prednisolone. Two of these genes (FAM129A, SYNPO2) were associated with airway hyperresponsiveness (provocative concentration of methacholine causing a 20% drop in FEV1: r = -0.740, P < 0.01; r = -0.746, P < 0.01). Pathway analysis revealed three gene networks that were associated with cellular functions including cellular growth, proliferation, and development. Conclusions: Oral prednisolone changes the transcriptomic profile of the ASM layer in asthma. This indicates that in parallel to antiinflammatory properties, glucocorticoids also exert effects on gene expression of ASM, which is correlated with improved airway function. Copyright © 2013 by the American Thoracic Society.


Heimans L.,Leiden University | Wevers-de Boer K.V.C.,Leiden University | Visser K.,Leiden University | Goekoop R.J.,Haga Hospital | And 9 more authors.
Annals of the Rheumatic Diseases | Year: 2014

Objectives To assess which treatment strategy is most effective in inducing remission in early (rheumatoid) arthritis. Methods 610 patients with early rheumatoid arthritis (RA 2010 criteria) or undifferentiated arthritis (UA) started treatment with methotrexate (MTX) and a tapered high dose of prednisone. Patients in early remission (Disease Activity Score <1.6 after 4 months) tapered prednisone to zero and those with persistent remission after 8 months, tapered and stopped MTX. Patients not in early remission were randomised to receive either MTX plus hydroxychloroquine plus sulfasalazine plus low-dose prednisone (arm 1) or to MTX plus adalimumab (ADA) (arm 2). If remission was present after 8 months both arms tapered to MTX monotherapy; if not, arm 1 changed to MTX plus ADA and arm 2 increased the dose of ADA. Remission rates and functional and radiological outcomes were compared between arms and between patients with RA and those with UA. Results 375/610 (61%) patients achieved early remission. After 1 year 68% of those were in remission and 32% in drug-free remission. Of the randomised patients, 25% in arm 1 and 41% in arm 2 achieved remission at year 1 (p<0.01). Outcomes were comparable between patients with RA and those with UA. Conclusions Initial MTX and prednisone resulted in early remission in 61% of patients with early (rheumatoid) arthritis. Of those, 68% were in remission and 32% were in drug-free remission after 1 year. In patients not in early remission, earlier introduction of ADA resulted in more remission at year 1 than first treating with disease-modifying antirheumatic drug combination therapy plus prednisone.


Kunst P.W.,Admiraal de Ruyter Hospital | Grunberg K.,Medical Center | Mauad T.,University of Sao Paulo
European Respiratory Journal | Year: 2013

The cellular and molecular pathways in asthma are highly complex. Increased understanding can be obtained by unbiased transcriptomic analysis (RNA-Seq). We hypothesised that the transcriptomic profile of whole human endobronchial biopsies differs between asthma patients and controls. First, we investigated the feasibility of obtaining RNA from whole endobronchial biopsies suitable for RNA-Seq. Secondly, we examined the difference in transcriptomic profiles between asthma and controls. This cross-sectional study compared four steroid-free atopic asthma patients and five healthy nonatopic controls. Total RNA from four biopsies per subject was prepared for RNA-Seq. Comparison of the numbers of reads per gene in asthma and controls was based on the Poisson distribution. 46 genes were differentially expressed between asthma and controls, including pendrin, periostin and BCL2. 10 gene networks were found to be involved in cellular morphology, movement and development. RNA isolated from whole human endobronchial biopsies is suitable for RNA-Seq, showing different transcriptomic profiles between asthma and controls. Novel and confirmative genes were found to be linked to asthma. These results indicate that biological processes in the airways of asthma patients are regulated differently when compared to controls, which may be relevant for the pathogenesis and treatment of the disease. Copyright ©ERS 2013.


Bilgin Y.M.,Admiraal de Ruyter Hospital | De Greef G.E.,Erasmus Medical Center
Current Opinion in Hematology | Year: 2016

Purpose of review Nowadays, plerixafor is approved for patients who fail to mobilize sufficient CD34+ cells for an autologous stem cell transplantation. Plerixafor is effective in the majority of these patients, who otherwise could not be treated adequately. We discussed in this review the current status of the optimal use of plerixafor in different clinical diagnoses and settings. Recent findings Plerixafor seems to be more effective in patients with multiple myeloma than in lymphoma. Even patients who had very low circulating CD34+ cells before administration of plerixafor have an important benefit. Several strategies in different clinical settings showed an effective response after administration of plerixafor, without the superiority of one strategy. Plerixafor is well tolerated with acceptable toxicity; however, it is an expensive drug. Summary Plerixafor is an effective drug in patients who fail to mobilize with conventional strategy. No strategy seems superior for the optimal use of plerixafor. More studies focusing on the kinetics and cost-effectiveness are needed. Copyright © 2015 Wolters Kluwer Health, Inc.


Kerkhofs L.,Admiraal de Ruyter Hospital | Lugini A.,Ospedale San Camillo de Lellis | Stanculeanu D.-L.,Bucharest Institute of Oncology | Palomo A.G.,Hospital de Leon
Future Oncology | Year: 2012

Aim: To evaluate the effectiveness of a biosimilar erythropoiesis- stimulating agent (Binocrit®) for the treatment of patients with cancer and chemotherapy-induced anemia in real-life clinical practice. Materials & methods: Data were collected retrospectively from patients at five European centers (in France, Italy, The Netherlands, Romania and Spain) who received treatment with Binocrit. Hemoglobin (Hb) levels were recorded at regular intervals during Binocrit therapy for up to 26 weeks. Hb response (an increase of ≥1 g/dl in 4 weeks or a Hb level in the range 10-12 g/dl during the study) was assessed in patients with a Hb level ≥8.5 g/dl at the start of therapy who received treatment for at least 6 weeks. Hb response rates in patients who did and did not receive intravenous (iv.) iron were also assessed, and data on any serious unexpected adverse events were collected. Results: Among evaluable patients (n = 113), 79% achieved a Hb response. Response rates were similar among evaluable patients who received an initial Binocrit dose of 30,000 or 40,000 IU/week (81 vs 78%; p = not significant). The Hb response rate was significantly greater in patients who received iv. iron than in patients who did not receive iv. iron (93 vs 77%; p < 0.05). No serious unexpected adverse events were reported. Conclusion: Use of the biosimilar erythropoiesis- stimulating agent Binocrit is effective and safe for the treatment of patients with cancer and chemotherapy-induced anemia. Supplementation with iv. iron increases the response rate compared with oral or no iron supplementation. © 2012 Future Medicine Ltd.

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