Prevalence of the common coding variant rs2241880 of the ATG16L1 gene in Maltese Crohn’s disease patients

In Crohn's disease the ATG16L1 (rs2241880) polymorphism affects Paneth cells and impairs autophagosome formation specifically after activation of nucleotide-binding oligomerisation domain 2 (NOD2). Studies from Europe, Australia and New Zealand have shown an increased frequency of the ATG16L1 rs2241880 SNP allele in Crohn’s disease patients versus controls while studies from Korea, Japan and East Asia revealed no positive association of this gene with Crohn’s disease.peer-reviewe

The potential role of the homeobox gene, Hhex in haematopoietic progenitor expansion

Background: The decision of an erythroid progenitor to proliferate or differentiate is regulated at the level of (i) transcription; (ii) recruitment of transcripts to polysomes for protein synthesis and (iii) signal transduction activating functional effectors. We utilized a factor sensitive erythroid progenitor cell model to study the gene expression profile of cells under proliferative signals. We have shown previously that translation control is an extremely important level of regulation that controls the balance between proliferation and differentiation of erythroid progenitors. This led us to investigate those transcripts that are shifted to polysomes in cells stimulated by erythropoietin (Epo) or stem cell factor (SCF).peer-reviewe

Novel missense mutation in the phosphatase PP2A catalytic subunit characterised in a solid tumour cell line

Introduction: The protein serine/threonine phosphatase type 2A (pp2a) is a heterotrimer complex composed of a catalytic subunit (pp2aC), the scaffolding A subunit (pp2aA), and the variable B regulatory subunit. The pp2a complex attenuates the phosphorylation of various signals involved in cell survival and proliferation. Missense mutations in the coding sequence of the PPP2CA catalytic subunit were previously described, and studies of the pathological effects require further investigation. Of interest low pp2a activity was described as a potential mechanism of Chronic Myeloid Leukaemia blast crisis, hence the use of the CML cell line, K562, as a model of pp2a studies. Increasing evidence show that decreased pp2a activity is implicated in the progression of multiple tumour types and provides a potential therapeutic target.peer-reviewe

Infliximab, osteoporosis and osteopoenia in Crohn’s disease

Introduction: Osteoporosis is common among Crohn’s disease patients. Aims and methods: The aim of our study was to establish which factors are associated with a greater risk of osteoporosis in Crohn’s disease. 83 Crohn’s disease patients were recruited. Informed consent was obtained to gather their phenotypic data in a database and perform a DEXA scan. Results: Mean patient age was 39 years with mean disease duration of 9 years. Mean Z score spine: -0.4, Z score hip: -0.7, T score spine: -0.7, T score hip: -1.3. 30% of the population had osteopoenia and 6% had osteoporosis at the spine. 46% had osteopoenia and 14% had osteoporosis at the hip. Factors which were associated with lower DEXA scores were young age of disease onset (ANOVA p=0.024), patients on Infliximab (p=0.005), long-term steroid use (p=0.032) and low body mass index (BMI, p=0.004). Disease location (ANOVA p=0.851), disease behavior (p=0.911) smoking (p=0.181) and increasing age(>50 years) (p=0.128) were not associated with low DEXA scores. Conclusions: Low BMI, early disease onset and longterm steroid use are risk factors for osteoporosis in Crohn’s disease. An important risk factor for low bone density is Infliximab. Lower Z scores in patients on Infliximab may occur as these patients have more severe inflammation, requiring aggressive treatment. Turk N et al1 have shown that in Crohn’s patients, the proinflammatory cytokine TNF-α is associated with the osteoclastogenic receptor activator of NFKB-ligand, and inversely with bone density. A second explanation might be that low bone densities in patients on Infliximab are a side-effect of the drug. There is no data to suggest this. Studies2-3 show Infliximab to have a beneficial effect on bone turnover markers in Crohn’s patients in the short term. Randomly controlled long-term trials are needed to evaluate the impact of Infliximab on bone density.peer-reviewe

Osteoporosis/osteopenia in Crohn’s disease patients the ATG16L1

Introduction: Osteopenia / osteoporosis are common in Crohn’s patients. Ileal disease in Crohn’s, especially fistulating / stricturing disease, or disease requiring small bowel surgery, can cause malabsorption which can cause osteoporosis. Since ATG16L1 polymorphisms have been shown to give a higher risk of ileal disease, one would expect a higher incidence of osteoporosis in patients with this genotype.peer-reviewe

Mutational analysis of c-KIT and PDGFRA receptors in gastrointestinal stromal tumours

Introduction: The pathogenesis of gastrointestinal stromal tumors (GISTs) is generally associated with activating mutations of the proto-oncogene tyrosine-protein kinase Kit (c-KIT). However, about 15% of GISTs do not harbour c-KIT mutations. It is estimated that 5% of these GISTs have mutations in the platelet-derived growth factor receptor α (PDGFRA). Accurate diagnosis of GIST has become very important since the availability of targeted therapy with tyrosine kinase inhibitors, such as imatinib mesylate. The routine workup for GIST diagnosis includes immunohistochemistry for CD117 (c-KIT polyclonal antibody), as it is estimated that 95% of GIST cases show positive immunoreactivity. However, it can be observed that the routinely used immunohistochemical analysis does not provide complete sensitivity for GIST diagnosis, as there are nearly 5% of GISTs that are negative for c-KIT immunohistochemistry. Mutational analysis for c-KIT and PDGFRA can confirm the diagnosis of GIST, particularly in CD117-negative suspect GIST. Moreover, specific mutations have a prognostic and/or a predictive value for response to therapy.peer-reviewe

NOD2/CARD15 mutations and phenotypic expression of Crohn’s disease in Malta

Background: Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract with variations in localization and behaviour. Mutations in the NOD2/CARD15 gene on chromosome 16q have been implicated in the pathogenesis of the disease and three main sequence variants, all single nucleotide polymorphisms (SNPs), have been identified in North American and European populations. Data from mainland Europe has demonstrated a prevalence of 25-50% within CD patients. The genetic structure of the Maltese population includes Near Eastern Arab, Mediterranean and North African genetic components.peer-reviewe

Serum amyloid A in airway cells

Introduction: Acute-phase serum amyloid A (A-SAA) molecules, encoded for by SAA1 and SAA2 genes, are cytokine-inducible acute phase proteins. Increased A-SAA is implicated in various chronic inflammatory diseases including rheumatoid arthritis, asthma and COPD. Besides its major hepatic secretory source, extrahepatic A-SAA has been identified in bronchoalveolar lavage fluid, and has been claimed to be a potentially useful biomarker for airway inflammation. The cellular origin of airway-released A-SAA, however remains unknown.peer-reviewe