No abstract

The current study supports the hypothesis that microRNA expression has an impact on chemotherapy resistance in esophageal cancer.

Vitamin D (vit D) status has been linked to the occurrence and severity of auto-immune and inflammatory diseases. This study evaluates the effects of vit D status on adoptive transfer of adjuvant-induced arthritis (ATA). Rats maintained on diets replete or deficient in vit D3 received arthritogenic thoracic duct cells and were monitored for severity of arthritis. CD45 + cells obtained by collagenase digestion of hind-paw synovium-rich tissues (SRTs) were analysed to observe the effects of dietary vit D3 on the inflammatory process. Arthritis was more severe in vitamin D-deficient (vit-D À ) rats compared with vitamin D-replete (vit-D + ) rats. Resolution was delayed in vit-D À rats compared with vit-D + rats, or rats fed standard chow. During the acute phase of ATA, numbers of CD45 + cells were significantly increased in the SRTs of vit-D À rats compared with vit-D + rats. This increase involved T-cells, polymorphonuclear leukocytes, macrophages, dendritic cells (DCs) and MHC II hi cells that resemble activated monocytes. A major difference between the dietary groups was that most DCs at the peak of inflammation in vit-D À rats were CD4 -, whereas in convalescent vit-D + rats most expressed CD4. Multiple categories of genes expressed by DCs differed between deficient and replete rats, with deficiency being associated with relative upregulation of certain pro-inflammatory genes and replete status being associated with upregulation of genes associated with resolution of inflammation. The findings indicate that ATA is more severe and prolonged in vit-D deficiency, that vit-D deficiency promotes accumulation of CD4 À DCs in synovium during ATA and that a gene-expression profile is likely to contribute to the observed increased severity and duration of arthritis. The role of vitamin D (vit D) in calcium homeostasis and maintenance of skeletal health has long been recognised. 1 The vit D receptor has been found on more than 35 cell types 2 and more recently the immuno-regulatory effects of vit D have been appreciated. The latter properties have been observed in experimentally induced animal models of autoimmune diseases, including experimental autoimmune encephalomyelitis, 3 collagen-induced arthritis, 4 autoimmune type 1 diabetes, 5 T-cell-mediated colitis 6 and murine lupus. 7 Epidemiological studies have linked vit D insufficiency with frequency of a number of autoimmune diseases, including multiple sclerosis, 8 rheumatoid arthritis (RA), 9 type 1 diabetes, 10 Bechet's syndrome 11 and inflammatory bowel disease. 12 Epidemiological evidence has also associated higher dietary intake of vit D with protection from autoimmune diseases. 13,14 The present study was undertaken to explore the effects of vit D status in a well-characterised model of immune-mediated arthritis. Adjuvant-induced arthritis (AIA) is a T-cell-mediated disease 15 that has similarities to rheumatoid arthritis in distribution (predominantly peripheral and symmetrical) and in histopathology. 16 We have shown that ATA, induced using thoracic duct (TD)...

Sphingosine kinase 1 (SK1) is a lipid kinase that catalyses the formation of sphingosine-1-phosphate (S1P). Considerable evidence has implicated elevated cellular SK1 in tumour development, progression and disease severity. In particular, SK1 has been shown to enhance cell survival and proliferation and induce neoplastic transformation. Although S1P has been found to have both cell-surface G-protein-coupled receptors and intracellular targets, the specific downstream pathways mediating oncogenic signalling by SK1 remain poorly defined. Here, using a gene expression array approach, we have demonstrated a novel mechanism whereby SK1 regulates cell survival, proliferation and neoplastic transformation through enhancing expression of transferrin receptor 1 (TFR1). We showed that elevated levels of SK1 enhanced total as well as cell-surface TFR1 expression, resulting in increased transferrin uptake into cells. Notably, we also found that SK1 activation and localization to the plasma membrane, which are critical for its oncogenic effects, are necessary for regulation of TFR1 expression specifically through engagement of the S1P G-protein coupled receptor, S1P2. Furthermore, we showed that blocking TFR1 function with a neutralizing antibody inhibits SK1-induced cell proliferation, survival and neoplastic transformation of NIH3T3 fibroblasts. Similar effects were observed following antagonism of S1P2. Together these findings suggest that TFR1 has an important role in SK1-mediated oncogenesis.