Faculty Bibliography

OPINION STATEMENT/UNASSIGNED:Endoscopic surveillance is an important method to identify colorectal neoplasia in patients with inflammatory bowel disease. Advances in endoscopic techniques using pancolonic chromoendoscopy have improved the detection of dysplasia compared to white-light endoscopy, which has the potential to decrease the risk of colorectal cancer. Currently, pancolonic chromoendoscopy is readily available for use, and in the future, it will likely become the standard of care for endoscopic surveillance. Pancolonic chromoendoscopy followed by confocal laser endomicroscopy may further increase the yield on surveillance endoscopy, although confocal laser endomicroscopy is not readily available outside of a limited number of institutions. Other endoscopic tools such as narrow band imaging have not been shown to be beneficial over white-light endoscopy. Emerging tools such as stool DNA testing show promise as an adjunct to colonoscopy but are still in the early stages of development. For management, patients with well-demarcated circumscribed dysplastic lesions should be resected endoscopically, followed by a continued endoscopic surveillance program. Patients with lesions that cannot be resected completely or that have features suggestive of invasive carcinoma on either endoscopy or histology should undergo colectomy. Patients with flat high-grade dysplasia should undergo colectomy. Patients with flat low-grade dysplasia should have a discussion about the risks and benefits of undergoing colectomy versus continuing in an endoscopic surveillance program. If they opt for surveillance, these patients should have more frequent follow-up surveillance examinations (every 3 to 6 months) with pancolonic chromoendoscopy.

Granulocyte-macrophage colony stimulating factor (GM-CSF) activity has been linked to pro-inflammatory effects in autoimmune syndromes, such as rheumatoid arthritis. Thus GM-CSF mimetics with antagonist activity might play a therapeutic role in these diseases. The human GM-CSF core structure consists of a four alpha-helix bundle, and GM-CSF activity is controlled by its binding to a two-subunit receptor. A number of residues located on the B and C helices of GM-CSF are postulated to interact with the alpha chain of the GM-CSF receptor (GM-CSFR). Several approaches have been successfully utilized to develop peptide mimetics of this site, including peptides from the native sequence, a peptide derived from a recombinant antibody (rAb) light chain which mimicked GM-CSF receptor binding activity, and structurally guided de novo design. Analysis of the rAb light chain had suggested mimicry of GM-CSF with residues mostly contributed by the CDR I region. Key residues involved in CDR I peptide/GM-CSFR binding were identified by truncation and alteration of individual residues, while the structural elements required to antagonize the biological action of GM-CSF were separately tested in binding and inhibitory activity assays of multiple cyclic analogues. A peptide designed to retain the loop conformation of the CDR I region of the rAb light chain competed with GM-CSF for both antibody and receptor binding, but the role of specific residues in antibody versus receptor binding differed markedly. These studies suggest that structural analysis of peptide mimetics can reveal differences in receptor and antibody binding, perhaps including key interactions that impact binding kinetics. Peptide mimetics of other four-helix bundle cytokines are reviewed, including helical and reverse turn mimetics of helical structures. Use of peptide mimetics coupled with structural and kinetic analysis provides a powerful approach to identifying important receptor-ligand interactions, which implications for rational design of novel therapeutics.