Conclusion: Inhibition of MicroRNA-494 by a gene silencing oligonucleotide results in smaller atherosclerotic plaques and increased plaque stability.Summary: MicroRNAs (miRs) are short non-coding RNAs approximately 20 nucleotides long that are capable of down regulating target gene expressions on a post-transcriptional level (Chen, K et al, Nat Rev Genet 2007;8:93-103). A single miR on average has 20 predicted target genes (Rajewsky N, Nat Genet 2006;38:S8-S13). Based on their ability to fine tune multiple expressions of multiple genes miRs may be excellent drug targets for complex diseases such as atherosclerosis. The authors selected 164 genes involved in atherosclerosis using www.targetscan.org and determined which miRs potentially regulated expression of these genes. They identified multiple miRs from the 14q32 miR cluster, a cluster of genes highly involved in vascular remodeling. In human plaques collected during carotid endarterectomy they found the miR 14q32 (miR-494) was abundantly expressed in unstable lesions. They then induced atherosclerotic plaque formation in hypercholesterolemic ApoE À/À mice by placing semiconstrictive collars around the carotid arteries. They then injected "gene silencing oligonucleotides" against miR-494 (GSO-494) with negative controls (GSO-control) using fluorescently labeled GSOs. They then confirmed uptake of GSOs in affected areas of the carotids but not elsewhere in the vasculature. GSO-494 significantly down regulated miR-494 expression in the carotid arteries although miR-494 target genes themselves were upregulated. Further analysis revealed a 65% decrease in plaque size after GSO-494 treatment. Plaque stability was increased in GSO-494-treated mice determined by an 80% decrease in the necrotic core size and a 50% increase in plaque collagen content. In addition, miR-494 also resulted in decreased cholesterol levels and decreased very low density lipo-protein (VLDL) fractions.Comment: The study indicates it may be possible to specifically target genes involved in the atherosclerotic process and doing so can reduce atherosclerosis formation and potentially increase plaque stability. Because single miRs may have multiple effects, inhibiting miRs as a treatment for atherosclerosis can be considered, but the off-target effects of miR inhibition with GSOs will need to be investigated closely.
An esophageal fistula is a pathological connection between the esophagus and another structure. The most common treatment for an esophageal fistula is airway stenting. However, several case series have demonstrated the superiority of the over-the-scope clip (OTSC) system for fistula closure. We report a case requiring multiple stent/OTSC placements in an esophageal-pleural fistula (EPF) due to underlying malignancy.
A 57-year-old male with stage IV esophageal cancer with an esophageal stent presented with three days of back pain and shortness of breath. A gastrografin was performed and showed a fistula at the proximal aspect of the pre-existing esophageal stent. A self-expandable metallic stent (SEMS) was utilized to bridge the fistula to the pre-existing esophageal stent. An esophagram two days later revealed extravasation and continuous esophageal leak. OTSC was then deployed at the fistula. A SEMS was also implanted through the patient’s pre-existing stent. Endoscopy showed persistent esophageal perforation. The initial OTSC and SEMS combination was removed. After removal, a second OTSC was placed over the fistula, allowing for complete suction of the fistula into the OTSC clip cap. We followed this by deploying another SEMS through the pre-existing stent and clipping them together. The proximal end of this new stent fully covered the fistula, creating a complete seal.
This case is notable in that successful EPF closure secondary to existing esophageal stent erosion was achieved by utilizing a properly positioned OTSC with stent-within-stent combination management.
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