Activation of Hsp90 Enzymatic Activity and Conformational Dynamics through Rationally Designed Allosteric Ligands.

Hsp90 is a molecular chaperone of pivotal importance for multiple cell pathways. ATP-regulated internal dynamics are critical for its function and current pharmacological approaches block the chaperone with ATP-competitive inhibitors. Herein, a general approach to perturb Hsp90 through design of new allosteric ligands aimed at modulating its functional dynamics is proposed. Based on the characterization of a first set of 2-phenylbenzofurans showing stimulatory effects on Hsp90 ATPase and conformational dynamics, new ligands were developed that activate Hsp90 by targeting an allosteric site, located 65 Šfrom the active site. Specifically, analysis of protein responses to first-generation activators was exploited to guide the design of novel derivatives with improved ability to stimulate ATP hydrolysis. The molecules' effects on Hsp90 enzymatic, conformational, co-chaperone and client-binding properties were characterized through biochemical, biophysical and cellular approaches. These designed probes act as allosteric activators of the chaperone and affect the viability of cancer cell lines for which proper functioning of Hsp90 is necessary.

The management of midline frontonasal dermoids: a review of 55 cases at a tertiary referral center and a protocol for treatment.

BACKGROUND: The incidence of midline frontonasal dermoid cysts is one in 20,000 to one in 40,000. These lesions may have intracranial extension. This is explained by the anatomy and embryology of nasofrontal development. Skin involvement may also be extensive. Incomplete excision frequently leads to recurrence. The authors report their experience and pathway for management of midline dermoids. METHODS: Databases were searched to identify patients who had undergone surgery for removal of a dermoid cyst. Preoperative imaging and indications for surgery were reviewed. Cases were grouped according to surgical approach, and outcomes and complications were identified. RESULTS: Fifty-five patients were treated. Magnetic resonance imaging or computed tomography was used to delineate the anatomy, and surgical excision was expedited if there was a history of infection, especially if imaging suggested intracranial extension. Twelve patients were treated endoscopically (one was converted to open). Eleven required transcranial approaches for intracranial extension (20 percent). Of these, one lesion breached the dura. The remaining 32 patients had dermoids excised with an open approach (direct, bicoronal, or rhinoplasty). There were no recurrences in the open group and there was one recurrence in the transcranial group. This was treated by reexcision. CONCLUSION: Midline dermoid cysts are relatively uncommon. However, knowledge of the pathogenesis of these lesions together with the authors' experience over 15 years has allowed them to develop a protocol-driven approach, with a low incidence of complications. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.