Immunohistochemistry was performed on the tissue microarray using monoclonal antibodies which we have developed to the retinoic acid metabolising enzymes CYP26A1, CYP26B1, CYP26C1 and lecithin retinol acyl transferase (LRAT) using a semi-quantitative scoring scheme to assess expression. Moderate or strong expression of CYP26A1 was observed in 32.5% of cancers compared to 10% of normal colonic epithelium samples (p smaller than 0.001). CYP26B1 was moderately or strongly expressed in 25.2% of tumours and was significantly less expressed in normal colonic epithelium (p smaller than 0.001). CYP26C1 was not expressed in any sample. LRAT also showed significantly increased expression

in primary colorectal cancers compared with normal colonic epithelium (p smaller than 0.001). Strong CYP26B1 expression was significantly associated with poor prognosis (HR =1.239, 95%CI =1.104-1.390, selleck chi(2) = 15.063, p =0.002). Strong Dinaciclib nmr LRAT was also associated with poorer outcome (HR= 1.321, 95%CI = 1.034-1.688, chi(2) = 5.039, p =0.025). In mismatch repair proficient tumours strong

CYP26B1 (HR 1.330, 95%CI =1.173-1.509, chi(2) 21.493, p smaller than 0.001) and strong LRAT (HR =1.464, 950/0CI=1.110-1.930, chi(2) = 7.425, p= 0.006) were also associated with poorer prognosis. This study has shown that the retinoic acid metabolising enzymes CYP26A1, CYP26B1 and LRAT are significantly overexpressed in colorectal cancer and that CYP26B1 and LRAT are significantly associated with prognosis both in the total cohort and in those tumours which are mismatch repair proficient. CYP26B1 was independently prognostic in a multivariate model both in the whole patient cohort (HR =1.177, 95%CI =1.020-1.216, p=0.026) and in mismatch repair proficient tumours (HR = 1.255, 950/0CI = 1.073 – 1.467, PI3K inhibitor p =0.004).”
“The peripheral nervous

system is critically involved in bone metabolism, osteogenesis, and bone remodeling. Nerve fibers of sympathetic and sensory origin innervate synovial tissue and subchondral bone of diathrodial joints. They modulate vascularization and matrix differentiation during endochondral ossification in embryonic limb development, indicating a distinct role in skeletal growth and limb regeneration processes. In pathophysiological situations, the innervation pattern of sympathetic and sensory nerve fibers is altered in adult joint tissues and bone. Various resident cell types of the musculoskeletal system express receptors for sensory and sympathetic neurotransmitters. Osteoblasts, osteoclasts, mesenchymal stem cells, synovial fibroblasts, and different types of chondrocytes produce distinct subtypes of adrenoceptors, receptors for vasointestinal peptide, for substance P and calcitonin gene-related peptide. Many of these cells even synthesize neuropeptides such as substance P and calcitonin gene-related peptide and are positive for tyrosine-hydroxylase, the rate-limiting enzyme for biosynthesis of catecholamines.