A genome scale RNAi screen identifies GLI1 as a novel gene regulating vorinostat sensitivity.

Vorinostat is an FDA-approved histone deacetylase inhibitor (HDACi) that has proven clinical success in some patients; however, it remains unclear why certain patients remain unresponsive to this agent and other HDACis. Constitutive STAT (signal transducer and activator of transcription) activation, overexpression of prosurvival Bcl-2 proteins and loss of HR23B have been identified as potential biomarkers of HDACi resistance; however, none have yet been used to aid the clinical utility of HDACi. Herein, we aimed to further elucidate vorinostat-resistance mechanisms through a functional genomics screen to identify novel genes that when knocked down by RNA interference (RNAi) sensitized cells to vorinostat-induced apoptosis. A synthetic lethal functional screen using a whole-genome protein-coding RNAi library was used to identify genes that when knocked down cooperated with vorinostat to induce tumor cell apoptosis in otherwise resistant cells. Through iterative screening, we identified 10 vorinostat-resistance candidate genes that sensitized specifically to vorinostat. One of these vorinostat-resistance genes was GLI1, an oncogene not previously known to regulate the activity of HDACi. Treatment of vorinostat-resistant cells with the GLI1 small-molecule inhibitor, GANT61, phenocopied the effect of GLI1 knockdown. The mechanism by which GLI1 loss of function sensitized tumor cells to vorinostat-induced apoptosis is at least in part through interactions with vorinostat to alter gene expression in a manner that favored apoptosis. Upon GLI1 knockdown and vorinostat treatment, BCL2L1 expression was repressed and overexpression of BCL2L1 inhibited GLI1-knockdown-mediated vorinostat sensitization. Taken together, we present the identification and characterization of GLI1 as a new HDACi resistance gene, providing a strong rationale for development of GLI1 inhibitors for clinical use in combination with HDACi therapy.

Inverted papilloma in a 10-year-old boy.

Inverted nasal papillomas are rare tumors in children. Four large series include only a single patient (of a total of 269) younger than 20 years. We report the occurrence of an inverted nasal papilloma in a 10-year-old boy; this tumor exhibited clinical and histopathologic features identical to those of similar neoplasms in adults. Inverted papillomas in children should be treated by wide local excision, usually using a lateral rhinotomy approach. The rationale for such aggressive surgery is based on the high rate of recurrence (25% to 75%) and a propensity for the development of carcinomas (5% to 15%) as associated lesions.

Adult epiglottitis, cellulitis, and Streptococcus pneumoniae bacteremia.

Described is an adult with acute epiglottitis, cellulitis of the neck and chest, and Streptococcus pneumoniae bacteremia. Although this syndrome is usually associated with Haemophilus influenzae type b, this case illustrates that in adults a similar syndrome can be produced by S. pneumoniae. The failure to determine an etiologic agent in approximately two thirds of reported adult cases of epiglottitis raises the question as to whether S. pneumoniae, a common adult respiratory pathogen, might fill this etiological void. To establish such an association between S. pneumoniae and acute epiglottitis would be further impetus to immunize patients against S. pneumoniae.