Background & Aims-There is controversy over the outcomes of esophageal adenocarcinoma with superficial submucosal invasion. We evaluated the impact of depth of submucosal invasion on the presence of metastatic lymphadenopathy and survival in patients with esophageal adenocarcinoma.

Macrophage cyclooxygenase-2 (COX-2) plays an important role in prostaglandin E2 and thromboxane A2 production. Statins are inhibitors of HMG CoA (3-Hydroxy-3-methylglutaryl coenzyme A) reductases and cholesterol synthesis, which block the expression of several inflammatory proteins independent of their capacity to lower endogenous cholesterol. In the present study, we investigated the effect of simvastatin and mevastatin on COX-2 induction in human monocytic cell line U937 and analyzed the underlying mechanisms. Pretreatment of U937 cells with simvastatin or mevastatin for 24 h resulted in a significant reduction in the lipopolysaccharide (LPS)-dependent induction of prostaglandin E2, thromboxane A2 synthesis, and COX-2 expression. Mevalonate, the direct metabolite of HMG CoA reductase, and farnesyl pyrophosphate and geranylgeranyl-pyrophosphate, intermediates of the mevalonate pathway, significantly reversed the inhibitory effect of statins on COX-2. An inhibitor of geranylgeranyl transferases, GGTI-286 mimicked the effect of statins on COX-2 expression. Cytonecrotic factor-1 increased LPS-dependent expression of COX-2. Treatment of cells with NSC 23766, an inhibitor of Rac, which we demonstrated to block Rac 2 activation, resulted in an inhibition of the LPS-dependent expression of COX-2. Whereas no effect was obtained with RhoA/C blocker, C3 exoenzyme. Gel retardation experiments and NFkappaB-p65 transcription factor assay showed that simvastatin and NSC 23766 decrease significantly NF-kappaB complex formation. In macrophages, the antiinflammatory effects of statins are mediated in part through the inhibition of COX-2 and prostanoids. Rac GTPase protein is identified as one of the targets of statins in this regulation.

Background-The incidence and risk factors for recurrence of dysplasia after ablation of Barrett's esophagus (BE) have not been well defined.

The role of the sphingolipid ceramide in modulating the immune response has been controversial, in part because of conflicting data regarding its ability to regulate the transcription factor NF-κB. To help clarify this role, we investigated the effects of ceramide on IL-2, a central NF-κB target. We found that ceramide inhibited protein kinase C (PKC)-mediated activation of NF-κB. Ceramide was found to significantly reduce the kinase activity of PKCθ as well as PKCα, the critical PKC isozymes involved in TCR-induced NF-κB activation. This was followed by strong inhibition of IL-2 production in both Jurkat T leukemia and primary T cells. Exogenous sphingomyelinase, which generates ceramide at the cell membrane, also inhibited IL-2 production. As expected, the repression of NF-κB activation by ceramide led to the reduction of transcription of the IL-2 gene in a dose-dependent manner. Inhibition of IL-2 production by ceramide was partially overcome when NF-κB nuclear translocation was reconstituted with activation of a PKC-independent pathway by TNF-α or when PKCθ was overexpressed. Importantly, neither the conversion of ceramide to complex glycosphingolipids, which are known to have immunosuppressive effects, nor its hydrolysis to sphingosine, a known inhibitor of PKC, was necessary for its inhibitory activity. These results indicate that ceramide plays a negative regulatory role in the activation of NF-κB and its targets as a result of inhibition of PKC.

Many developments have been made in the field of Barrett esophagus that have tremendous clinical implications. There are new definitions of Barrett esophagus that have had an immediate clinical impact on cancer risk and screening. Of interest is the definition by the British Society of Gastroenterology, which does not require the presence of intestinal metaplasia for a diagnosis of Barrett esophagus. Imaging techniques that allow improved visualization of intestinal metaplasia at the cellular level are now being used in clinical practice. New hypotheses elucidating the progression from squamous epithelium to intestinal metaplasia have been proposed. Indeed, the crucial role that transcription factors have in the pathogenesis of Barrett esophagus has been clarified. Improved characterization of the molecular mechanisms underlying Barrett esophagus is an incentive to undertake more basic science research in this field. Such research could also help with the development of chemoprevention strategies for this precancerous condition. This Review discusses the advances in understanding of the pathogenesis, diagnosis and treatment of Barrett esophagus.