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It has recently been shown that the transcription factor Erg, an Ets family member, drives constitutive expression of the intercellular adhesion molecule 2 (ICAM-2) in human umbilical vein endothelial cells (HUVECs) and that its expression is downregulated by the pleiotropic cytokine tumor necrosis factor ␣ (TNF-␣). To identify other Erg target genes and to define its function in the endothelium, a combined approach of antisense oligonucleotides (GeneBloc) and differential gene expression was used. Treatment of HUVECs with Erg-specific GeneBloc for 24, 48, and 72 hours suppressed Erg mRNA and protein levels at all time points. Total RNA extracted from HUVECs treated with Ergspecific or control GeneBloc was analyzed for differences in gene expression using high-density, sequence-verified cDNA arrays containing 482 relevant genes. Inhibition of Erg expression resulted in decreased expression of ICAM-2, as predicted. Four more genes decreased in Erg-deficient HUVECs were the extracellular matrix proteins SPARC and thrombospondin, the adhesive glycoprotein von Willebrand factor, and the small GTPase RhoA. Each of these molecules has been directly or indirectly linked to angiogenesis because of its role in vascular remodeling, adhesion, or shape change. Therefore, the role of Erg in vascular remodeling was tested in an in vitro model, and the results showed that HUVECs treated with Erg GeneBloc had a decreased ability to form tubulelike structures when grown on Matrigel. These results suggest that Erg may be a mediator of the TNF-␣ effects on angiogenesis in vivo. IntroductionThe endothelium plays a key role in a large number of diseases, among them cancer and metastasis, rheumatoid arthritis, atherosclerosis, and thrombosis, by regulating several key processes such as leukocyte recruitment, hemostasis, vascular permeability, and angiogenesis. During inflammation, several mediators can activate the endothelium to promote a proinflammatory, prothrombotic state and to regulate the angiogenic response. Angiogenesis (or new vessel formation) is a tightly regulated process that requires the integration of signals triggered by growth factors and adhesion events, namely modulation of cell-cell contact and interaction with the extracellular matrix. 1 Angiogenesis is a critical aspect of the development, growth, and repair of new tissues; it occurs physiologically in circumstances such as wound healing and the menstrual cycle. It is also a key component of many diseases driven by tissue proliferation, such as cancer and rheumatoid arthritis. 2,3 In such diseases, new vessel formation supports tissue growth and cellular infiltration, and it contributes to the destructive proliferation of the inflammatory tissue. The link between angiogenesis and inflammation has been suggested by various studies that focus on common features such as the cellular infiltrate, proliferation, and overlapping roles of inflammatory mediators and growth factors. [4][5][6] One such mediator is the pleiotropic cytokine tumor necrosis factor ␣ (TNF-␣),...

The SCL gene (also known as TAL-1) encodes a basic helix ± loop ± helix transcription factor that is essential for the development of all haematopoietic lineages, and ectopic expression of which results in T cell leukaemia. SCL is expressed in normal pluripotent haematopoietic stem cells and its expression is maintained during dierentiation along erythroid, mast and megakaryocytic lineages, but is extinguished following commitment to other cell types. The mechanisms responsible for this pattern of expression are poorly understood, but are likely to illuminate the molecular basis for stem cell development and lineage commitment. We have identi®ed multiple lineage-restricted DNase I hypersensitive sites in a 45 kb region spanning the murine SCL locus. Committed erythroid cells and CD34 positive primitive myeloid cells exhibited both shared and unique DNase I hypersensitive sites whereas none were found in T cells. The function of each hypersensitive site was studied using both transient and stable reporter assays in erythroid, primitive myeloid and T cells. Multiple positive and negative regulatory elements were characterised and found to display lineage-speci®city, promoter-speci®city and/or chromatin-dependence. These results represent the ®rst description of key components of a complex network of regulatory elements controlling SCL expression during haematopoiesis.

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In a randomized, double-blind study, cystic fibrosis patients 11-30 years of age with an acute exacerbation of their pulmonary disease were treated with either ticarcillin-tobramycin, azlocillin-tobramycin, or azlocillin-placebo for 10 days. There was significant improvement in Shwachman scores and pulmonary function tests. Concentrations of sputum bacteria were significantly reduced, but after therapy patients had a mean of 10(7) bacteria/ml of sputum. Pseudomonas was transiently eliminated in only one patient. The three regimens had similar impacts on pulmonary function and sputum bacterial concentration. Antibiotic resistance was noted more frequently in the azlocillin-placebo group, but this trend was not statistically significant. Improvement in pulmonary function did not correlate with bacteriological response. Four weeks after discharge, 62% of the improvement in forced expiratory volume in one second and 75% of the improvement in vital capacity remained, but concentrations of sputum bacteria had returned to pretreatment levels, and antibiotic-resistant bacteria persisted.