P2 purinergic receptor modulation of cytokine production

Cytokines serve important functions in controlling host immunity. Cells involved in the synthesis of these polypeptide mediators have evolved highly regulated processes to ensure that production is carefully balanced. In inflammatory and immune disorders, however, mis-regulation of the production and/or activity of cytokines is recognized as a major contributor to the disease process, and therapeutics that target individual cytokines are providing very effective treatment options in the clinic. Leukocytes are the principle producers of a number of key cytokines, and these cells also express numerous members of the purinergic P2 receptor family. Studies in several cellular systems have provided evidence that P2 receptor modulation can affect cytokine production, and mechanistic features of this regulation have emerged. This review highlights three separate examples corresponding to (1) P2Y6 receptor mediated impact on interleukin (IL)-8 production, (2) P2Y11 receptor-mediated affects on IL-12/23 output, and (3) P2X7 receptor mediated IL-1β posttranslational processing. These examples demonstrate important roles of purinergic receptors in the modulation of cytokine production. Extension of these cellular observations to in vivo situations may lead to new therapeutic strategies for treating cytokine-mediated diseases

Metabolomics on CMOS for personalised medicine

The emergence of personalised and precision healthcare requires detailed knowledge of human molecular pathology. Genomics has been transformed by sequencing technologies that can unravel the human genome in 1 day for less than a thousand dollars. Recently, metabolomics, the quantitative measurement of small molecules, has emerged as a field to study an individual’s molecular profile. This is very important because a genome can only give a prediction of an individual’s propensity to a disease – genotyping, while a metabolome can provide immediate diagnosis of biochemical activity in human body – phenotyping. However, the present approach of measuring metabolites depends on large and expensive equipment such as NMR spectroscopy and mass spectroscopy. More importantly, this equipment does not provide a single analytical platform to measure the entire metabolome. CMOS technology has made a major impact in personal mobile computing, digital imaging and communications as part of everyday life. CMOS provides a single integrated platform for sensing technologies, low-cost manufacturing and miniaturisation of microelectronic systems. CMOS has been used successfully to create an all-electronic sequencing technology. We anticipate that CMOS has the potential to allow multiple biomarkers to be monitored in parallel, thus paving the way for metabolome profiling. This review will provide a background to personalised medicine, in terms of genomics and metabolomics, to show the importance for future healthcare delivery. A theoretical background of enzymes for metabolite quantification will also be discussed. A description of DNA microarray technologies will be provided. A background of CMOS chemical sensor systems will be presented for DNA sequencing and metabolite quantification. Finally, a discussion of future CMOS sensor systems, microelectronics and integration technologies that could lead to new “omics” technologies, will be given

Multiple self-healing squamous epithelioma is caused by a disease-specific spectrum of mutations in TGFBR1

Multiple self-healing squamous epithelioma (MSSE), also known as Ferguson-Smith disease (FSD), is an autosomal-dominant skin cancer condition characterized by multiple squamous-carcinoma-like locally invasive skin tumors that grow rapidly for a few weeks before spontaneously regressing, leaving scars(1,2). High-throughput genomic sequencing of a conservative estimate (24.2 Mb) of the disease locus on chromosome 9 using exon array capture identified independent mutations in TGFBR1 in three unrelated families. Subsequent dideoxy sequencing of TGFBR1 identified 11 distinct monoallelic mutations in 18 affected families, firmly establishing TGFBR1 as the causative gene. The nature of the sequence variants, which include mutations in the extracellular ligand-binding domain and a series of truncating mutations in the kinase domain, indicates a clear genotype-phenotype correlation between loss-of-function TGFBR1 mutations and MSSE. This distinguishes MSSE from the Marfan syndrome-related disorders in which missense mutations in TGFBR1 lead to developmental defects with vascular involvement but no reported predisposition to cance