Presenting features and long-term effects of growth hormone treatment of children with optic nerve hypoplasia/septo-optic dysplasia

<p>Abstract</p> <p>Background</p> <p>Optic nerve hypoplasia (ONH) with/or without septo-optic dysplasia (SOD) is a known concomitant of congenital growth hormone deficiency (CGHD).</p> <p>Methods</p> <p>Demographic and longitudinal data from KIGS, the Pfizer International Growth Database, were compared between 395 subjects with ONH/SOD and CGHD and 158 controls with CGHD without midline pathology.</p> <p>Results</p> <p>ONH/SOD subjects had higher birth length/weight, and mid-parental height SDS. At GH start, height, weight, and BMI SDS were higher in the ONH/SOD group. After 1 year of GH, both groups showed similar changes in height SDS, while weight and BMI SDS remained higher in the ONH/SOD group. The initial height responses of the two groups were similar to those predicted using the KIGS-derived prediction model for children with idiopathic GHD. At near-adult height, ONH/SOD and controls had similar height, weight, and BMI SDS.</p> <p>Conclusions</p> <p>Compared to children with CGHD without midline defects, those with ONH/SOD presented with greater height, weight, and BMI SDS. These differences persisted at 1 year of GH therapy, but appeared to be overcome by long-term GH treatment.</p

Antiproliferative Effects and Mechanisms of Liver X Receptor Ligands in Pancreatic Ductal Adenocarcinoma Cells

<div><p>Pancreatic ductal adenocarcinoma (PDAC) is difficult to detect early and is often resistant to standard chemotherapeutic options, contributing to extremely poor disease outcomes. Members of the nuclear receptor superfamily carry out essential biological functions such as hormone signaling and are successfully targeted in the treatment of endocrine-related malignancies. Liver X receptors (LXRs) are nuclear receptors that regulate cholesterol homeostasis, lipid metabolism, and inflammation, and LXR agonists have been developed to regulate LXR function in these processes. Intriguingly, these compounds also exhibit antiproliferative activity in diverse types of cancer cells. In this study, LXR agonist treatments disrupted proliferation, cell-cycle progression, and colony-formation of PDAC cells. At the molecular level, treatments downregulated expression of proteins involved in cell cycle progression and growth factor signaling. Microarray experiments further revealed changes in expression profiles of multiple gene networks involved in biological processes and pathways essential for cell growth and proliferation following LXR activation. These results establish the antiproliferative effects of LXR agonists and potential mechanisms of action in PDAC cells and provide evidence for their potential application in the prevention and treatment of PDAC.</p></div

Microarray analysis of pancreatic cancer cell lines treated with LXR ligands defines common and cell line-specific effects on gene networks.

<p>A, B, Venn diagrams of up-regulated and down-regulated genes (1.1 fold change cutoff) after treatment with GW 3965 for 72 hours. These cell lines show common and cell-line specific transcriptomic responses to ligand treatment. C, Microarray analysis of up-regulated genes show that all cell lines share up-regulation of lipid metabolic, glucose metabolic, and cell proliferation responses. All cell lines down-regulate pathways that regulate response to viral infection, transmembrane support, as well as viral mRNA transcription. Treatments of BxPC-3 and PANC-1 cells down-regulate the expression of genes involved in cell cycle and DNA replication machinery.</p

LXR agonists block cell proliferation and colony-formation in pancreatic cancer cells.

<p>A, B, C, PDAC cells (BxPC-3, Mia-PaCa-2, and PANC-1 cell lines, respectively) show dose-dependent decreases in cell proliferation upon treatment with increasing GW3965 concentrations. EC50 calculations indicate that BxPC-3 and Mia-PaCa-2 cells are more sensitive to ligand treatment than PANC-1 cells. D, Results from MTS assays, a separate measure of overall cell metabolic rate and indirect measurement of cell proliferation, demonstrate a dose-dependent drop in overall metabolism in cells treated with increasing concentrations of GW3965. E, Colony-formation ability in all three cell lines was blocked by GW3965 treatment. F, Colony formation of GW3965 treated cells was quantified relative to vehicle-treated controls. Asterisks indicated statistically significant changes.</p

GW 3965 downregulates oncogenes involved in cancer progression.

<p>A, GW3965 treatment downregulates SKP2 and EGFR protein levels in BxPC-3 and MIA-PaCa-2 cells. Downregulation of EGFR was concomitant with a downregulation of its own phosphorylation in BxPC-3 and MIA-PaCa-2 at 5 uM GW 3965. ERK1/2 and its phosphorylation were not statistically different in any of the cell lines B, C, D Densitometric quantification of SKP2, EGFR, Phospho-EGFR, ERK1/2, and Phospho-ERK1/2 upon treatment with GW3965. Samples were normalized to actin controls. Asterisks indicated statistically significant changes.</p

Knockdown of LXRβ expression block PDAC cell proliferation and response to LXR ligand treatment.

<p>A, Knockdown of LXRα and LXRβ expression was validated by quantitative PCR. Expression data were normalized to 36B4 ribosomal gene transcript levels. B, The effect of LXR knockdown on PDAC cell proliferation was quantified by cell counts following trypan blue exclusion assays. Asterisks indicated statistically significant changes.</p