Project description:Fibroblast growth factor receptors (FGFRs) can act as driving oncoproteins in certain cancers due to mutation, over-expression or activating gene fusions and are therefore attractive drug targets. Here we have characterized tumour cell responses to three new inhibitors of FGFR1-3, AZ12576089, AZ12908010 and the clinical candidate AZD4547, making comparisons with the well-characterized FGFR inhibitor PD173074. Using a panel of 16 human tumour cell lines we show that the anti-proliferative activity of AZ12908010 and AZD4547 is strongly linked to the presence of de-regulated FGFR signalling. In contrast, AZ12576089 was also able to inhibit proliferation of cells lacking de-regulated FGFR, suggesting off-target effects. Acquired resistance to targeted tyrosine kinase inhibitors (TKIs) is a growing problem in the clinic. To assess how FGFR-dependent tumour cells may adapt to long-term exposure to FGFR inhibitors we generated a derivative of the KMS-11 myeloma cell line (FGFRY373C) with acquired resistance to AZ12908010 (KMS-11R cells). Basal P-FGFR3, P-FRS2 and P-ERK1/2 and D-type cyclins were all inhibited by AZ12908010 in parental KMS-11 cells whereas these markers were constitutively elevated and refractory to drug in KMS-11R cells. Sequencing of FGFR3 in KMS-11R cells revealed the presence of a heterozygous mutation at the gatekeeper residue, encoding FGFR3V555M. Consistent with this KMS-11R cells were cross-resistant to AZD4547 and PD173074 but remained fully sensitive to AZ12576089, confirming that the anti-proliferative effects of AZ12576089 are not related to FGFR inhibition. These results define the selectivity and efficacy of two new FGFR inhibitors and identify a secondary gatekeeper mutation as a mechanism of acquired resistance to FGFR inhibitors that should be anticipated as clinical evaluation proceeds.
Project description:We found a candidate region (with 55 known or predicted genes) that was found to linkage to the MACS syndrome. Because it is transmitted in an autosomal recessive fashion, and given the fact most recessive disorders are caused by loss-of-function mutations often resulting in decreased mRNA levels, we hypothesized that screening the expression of the various genes located within the disease interval may point to candidate genes of interest. We therefore established fibroblast cell lines from punch skin biopsies obtained from 2 patients and 4 ethnically matched healthy controls. We then compared global gene expression using microarrays in the 6 cell lines (all genes contained within the disease interval were represented on the array).
Project description:Time course data from thapsigargin-stimulated ER stress for 8 and 24 hours, in order to elucidate factors that influence T cell priming.
Project description:To gain insights into the genetic program activated within the distinct vascular and inflammatory transplant microenvironments in Id1/Id3 deficient and WT mice, we performed a series of gene screening experiments using RNA from total graft tissue as well as from myeloid and endothelial (i.e., CD31+ and ISB4+) cells isolated from the grafts at 1 week post-transplantation.
Project description:Short- and long-interval response of JY cells treated with Trichostatin A (TSA), used in gene pathway analysis. <br><br>Please note that the "Target IDs" used in the user submitted data files have been mapped to Illumina Probe_Ids (as recommended by Illumina) and this mapping is not 1 to 1. Original user submitted files have been included in the .mageml.tar.gz archive on the FTP site for this experiment.
Project description:Analysis of microarray data from livers 4 hr after DEN administration revealed changes in the expression of several genes relevant to regulation of reactive oxygen species (ROS) accumulation, cell death, and cell cycle control.
Project description:Gene expression profiles were generated with Illumina arrays for untreated human mesenchymal stem cells and also Argonaute1 bound mRNAs in the same cells. In addition gene expression profiles were generated for the human embryo cell line H1 before and after differentiation along the neural lineage. NOTE: assays for human embryonic stem cells before and after differentiation were added in July 2014 and data files for the mesenchymal stem cells were updated.