RESUMEN
BACKGROUND: Studies demonstrating the potential utility of reflectance confocal microscopy (RCM) have been performed under experimental conditions. OBJECTIVE: To provide an overview of RCM practice in real-life. METHODS: A multicenter, prospective study carried out in 10 university dermatology departments in France. RESULTS: Overall, 410 patients were enrolled. One-half of the patients (48%) were referred by private practice dermatologists. They were referred for diagnosis (84.9%) or presurgical mapping (13%). For diagnosis, the lesions were located on the face (62%), arms and legs (14.9%), and trunk (13.6%), and presurgical mapping was almost exclusively on the face (90.9%). Among those referred for diagnosis, the main indication was suspicion of a skin tumor (92.8%). Of these, 50.6% were spared biopsies after RCM. When RCM indicated surgery, histology revealed malignant lesions in 72.7% of cases. The correlation between RCM and histopathology was high, with a correlation rate of 82.76% and a kappa coefficient of 0.73 (0.63; 0.82). LIMITATIONS: This study was performed in the settings of French tertiary referral hospitals. CONCLUSION: This study shows that in real-life RCM can be integrated into the workflow of a public private network, which enables a less invasive diagnostic procedure for patients.
RESUMEN
Cathepsin D (CD) is overexpressed in several types of cancer and constitutes an important biological target. Pepstatin A, a pentapeptide incorporating two non-proteinogenic statin residues, is among the most potent inhibitor of CD but lacks selectivity and suffers from poor bioavailability. Eight analogues of Pepstatin A, were synthesized, replacing residues in P3 or P1 position by non-canonical (S)- and (R)-α-Trifluoromethyl Alanine (TfmAla), (S)- and (R)-Trifluoromethionine (TFM) or non-natural d-Valine. The biological activities of those analogues were quantified on isolated CD and Pepsin by fluorescence-based assay (FRET) and cytotoxicity of the best fluorinated inhibitors was evaluated on SKOV3 ovarian cancer cell line. (R)-TFM based analog of Pepstatin A (compound 6) returned a sub-nanomolar IC50 against CD and an increased selectivity. Molecular Docking experiments could partially rationalize these results. Stabilized inhibitor 6 in the catalytic pocket of CD showed strong hydrophobic interactions of the long and flexible TFM side chain with lipophilic residues of S1 and S3 sub-pockets of the catalytic pocket. The newly synthesized inhibitors returned no cytotoxicity at IC50 concentrations on SKOV3 cancer cells, however the compounds derived from (S)-TfmAla and (R)-TFM led to modifications of cells morphologies, associated with altered organization of F-actin and extracellular Fibronectin.
