Anti-TNF pharmacogenomics in rheumatoid arthritis: towards personalized therapeutics.

Contains fulltext : 74948.pdf (publisher's version ) (Open Access)RU Radboud Universiteit Nijmegen, 3 maart 2010Promotores : Brunner, H.G., Riel, P.L.C.M. van Co-promotores : Coenen, M.J.H., Franke, B., Barrera Rico, P.229 p

IL-1 Family Cytokine Pathways Underlying NAFLD: Towards New Treatment Strategies

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Pathways responsible for the activation of IL-1 family cytokines are key in the development of NAFLD but underlying mechanisms are not fully understood. Many studies have focused on the inflammasome-caspase-1 pathway and have shown that this pathway is an important inducer of inflammation in NAFLD. However, this pathway is not solely responsible for the activation of proinflammatory cytokines. Also, neutrophil serine proteases (NSPs) are capable of activating cytokines and recent studies reported that these proteases also contribute to NAFLD. These studies provided, for the first time, evidence that this inflammasome-independent pathway is involved in NAFLD. In our opinion, these new insights open up new approaches for therapeutic intervention

The double paradox of elementary economics education

Elementary economics textbooks have become less attractive to students requiring only an introduction to economics, given that their content is pervaded by mathematical diagrams and simple equations. Also they are of relatively little value to those interested in, for example, attempting to gain an understanding of the New Economy, for they rarely emphasise business innovation and its crucial dynamic role. These factors engender something of a double paradox. First, the paradox of the tools and the audience, newcomers are frequently ‘turned off’ by existing economics textbooks, due to the pervasive use of mathematics. Second, the paradox of the content and the relevance, those newcomers who are not initially turned off tend to be disenchanted with economics because they perceive that economics is of little use in understanding the New Economy in which they work, or will come to work. We suggest an integrated solution to both paradoxes. The implementation entails a minor reorientation of the traditional pedagogical strategy for teaching introductory economics

Pharmacogenetics of anti-TNF treatment in patients with rheumatoid arthritis.

TNF-blocking strategies are widely used in the treatment of rheumatoid arthritis (RA). Three anti-TNF agents are registered for use in RA: etanercept, infliximab and adalimumab. Although anti-TNF therapy is very effective in controlling disease activity and slowing down radiological damage, prolonged response is only seen in approximately 70% of the patients. The causes for nonresponse in the remaining patients have not yet been elucidated. Pharmacogenetic studies focusing on genes involved in RA etiology (and/or progression) and in the pharmacokinetics of TNF-blocking agents have identified markers associated with anti-TNF treatment outcome. In the future, more exhaustive, less hypothesis-driven search strategies are expected to discover additional markers. Identification of these markers might be viewed as the first step towards tailored TNF-blocking therapy for patients with RA. Nevertheless, replication and large prospective studies will be needed to demonstrate the validity of the identified genetic markers before implementation into daily clinical practice

Identification of new biomarker candidates for glucocorticoid induced insulin resistance using literature mining

Contains fulltext : 111355.pdf (publisher's version ) (Open Access)BACKGROUND: Glucocorticoids are potent anti-inflammatory agents used for the treatment of diseases such as rheumatoid arthritis, asthma, inflammatory bowel disease and psoriasis. Unfortunately, usage is limited because of metabolic side-effects, e.g. insulin resistance, glucose intolerance and diabetes. To gain more insight into the mechanisms behind glucocorticoid induced insulin resistance, it is important to understand which genes play a role in the development of insulin resistance and which genes are affected by glucocorticoids.Medline abstracts contain many studies about insulin resistance and the molecular effects of glucocorticoids and thus are a good resource to study these effects. RESULTS: We developed CoPubGene a method to automatically identify gene-disease associations in Medline abstracts. We used this method to create a literature network of genes related to insulin resistance and to evaluate the importance of the genes in this network for glucocorticoid induced metabolic side effects and anti-inflammatory processes.With this approach we found several genes that already are considered markers of GC induced IR, such as phosphoenolpyruvate carboxykinase (PCK) and glucose-6-phosphatase, catalytic subunit (G6PC). In addition, we found genes involved in steroid synthesis that have not yet been recognized as mediators of GC induced IR. CONCLUSIONS: With this approach we are able to construct a robust informative literature network of insulin resistance related genes that gave new insights to better understand the mechanisms behind GC induced IR. The method has been set up in a generic way so it can be applied to a wide variety of disease networks

Functional variants of the macrophage migration inhibitory factor do not infer risk of cardiovascular disease in rheumatoid arthritis.

Contains fulltext : 70197.pdf (publisher's version ) (Closed access

Mice deficient in the IL-1β activation genes&nbsp; <em>Prtn3</em>, <em>Elane</em>, and <em>Casp1 </em>are protected against the development of obesity-induced NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. Inflammatory pathways contribute to disease pathogenesis; however, regulation of the underlying mechanism is not completely understood. IL-1β, a pro-inflammatory cytokine, participates in the development and progression of NAFLD. To become bioactive, IL-1β requires enzymatic processing. Mechanisms that activate IL-1β include the classical NLRP3 inflammasome-caspase-1 and the neutrophil serine proteases, neutrophil elastase, and proteinase-3. Several studies have shown that both caspase-1 and the neutrophil serine proteases are important for NAFLD development. However, it is unknown whether these pathways interact and if they have a synergistic effect in promoting NAFLD. In the present study, we developed a novel and unique mouse model by intercrossing caspase-1/11 knockout mice with neutrophil elastase/proteinase-3 double knockout mice. Subsequently, these mice were examined regarding the development of high-fat diet-induced NAFLD. Our results show that mice deficient in caspase-1, neutrophil elastase, and proteinase-3 were protected from developing diet-induced weigh gain, liver steatosis, and adipose tissue inflammation when compared with controls. We conclude that pathways that process pro-IL-1β to bioactive IL-1β play an important role in promoting the development of NAFLD and obesity-induced inflammation. Targeting these pathways could have a therapeutic potential in patients with NAFLD

Multiplex screening of 22 single-nucleotide polymorphisms in 7 Toll-like receptors: an association study in rheumatoid arthritis.

Contains fulltext : 89339.pdf (publisher's version ) (Closed access)OBJECTIVE: Toll-like receptors (TLR) have been implicated in the pathogenesis of arthritis. We investigated the role of functional variants of TLR in the disease phenotype and severity of rheumatoid arthritis (RA). METHODS: All patients from a longterm observational inception cohort (n = 319) were genotyped for 22 single-nucleotide polymorphisms (SNP) in TLR2, 3, 4, 5, 7, 8, and 9 using multiplex assays. Clinical characteristics including sex, age at disease onset, rheumatoid factor (RF), and shared epitope positivity and disease activity score and radiological progression were taken into account. Genotypes were analyzed for association with Disease Activity Scores (DAS28) and joint damage (Rau scores) at 3 and 6 years. Results : After Bonferroni correction, there was a moderate association between RF positivity and TLR8-rs5741883. No other TLR variant was significantly associated with any RA clinical characteristics. CONCLUSION: Using a large inception cohort and strict statistical evaluation, we could not identify an association between functional TLR variants and RA phenotype and disease severity. This suggests the functional TLR variants do not play a major role in RA phenotype and disease severity.1 mei 201

Gene expression profiling in rheumatoid arthritis: current concepts and future directions.

Contains fulltext : 70170.pdf (publisher's version ) (Closed access)Over the last years microarray technologies have generated new perspectives for the high-throughput analysis of biological systems. Nowadays, it is possible to monitor thousands of genes in a single experiment. This molecular profiling technology combined with standardised and validated clinical measurements can allow a more precise characterisation of a patient's phenotype, and may lead to the design of therapeutic protocols and procedures better tailored to an individual patient's needs. In this report we provide an overview of expression profiling studies in rheumatoid arthritis (RA). RA is a chronic inflammatory disease in which both genetic and environmental factors are involved. The precise molecular mechanisms underlying RA are not fully understood. A systematic literature search revealed nine array-based expression profiling studies in patients with RA. Findings from these studies were compared with those of linkage and genome-wide association (GWA) studies. Although we observed many differences in study design, analysis and interpretation of results between the different studies, we extracted two sets of genes: (1) those differentially expressed in more than one study, and (2) genes differentially expressed in at least one of the reviewed studies and present in RA linkage or GWA loci. We suggest that both sets of genes include interesting candidate genes for further study in RA

Complement activation in severely ill patients with sepsis: no relationship with inflammation and disease severity.

BACKGROUND: Sepsis is characterized by a dysregulated immune response to infection. The complement system plays an important role in the host defence to pathogens. However, exaggerated complement activation might contribute to a hyperinflammatory state. The interplay between complement activation and inflammation in relationship with adverse outcomes in sepsis patients is unclear. METHODS: Secondary analysis of complement factors in a prospective study in 209 hospitalized sepsis patients, of whom the majority presented with shock. Concentrations of complement factors C3, C3a, C3c, C5, C5a, and soluble terminal complement complex were assessed in ethylenediaminetetraacetic acid plasma samples collected within 24 h after sepsis diagnosis using enzyme-linked immunosorbent assays. RESULTS: The concentration of complement factors in plasma of severely ill sepsis patients indicated profound activation of the complement system (all P  0.05) in this cohort of patients with high disease severity. CONCLUSIONS: Once an infection progresses to severe sepsis or septic shock, the complement pathway is already profoundly activated and is no longer related to a dysregulated inflammatory response, nor to clinical outcome. This implies that in this patient category with severe disease, the complement system is activated to such an extent that it no longer has predictive value for clinical outcome