PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer

Combined MAPK/PI3K pathway inhibition represents an attractive, albeit toxic, therapeutic strategy in oncology. Since PTEN lies at the intersection of these two pathways, we investigated whether PTEN status determines the functional response to combined pathway inhibition. PTEN (gene, mRNA, and protein) status was extensively characterized in a panel of cancer cell lines and combined MEK/mTOR inhibition displayed highly synergistic pharmacologic interactions almost exclusively in PTEN-loss models. Genetic manipulation of PTEN status confirmed a mechanistic role for PTEN in determining the functional outcome of combined pathway blockade. Proteomic analysis showed greater phosphoproteomic profile modification(s) in response to combined MEK/mTOR inhibition in PTEN- loss contexts and identified JAK1/STAT3 activation as a potential mediator of synergistic interactions. Overall, our results show that PTEN-loss is a crucial determinant of synergistic interactions between MAPK and PI3K pathway inhibitors, potentially exploitable for the selection of cancer patients at the highest chance of benefit from combined therapeutic strategies

The Effect of a Beta-Adrenoceptor Antagonist on Accommodative Adaption in Hong Kong Children

PURPOSE: Increased susceptibility to nearwork-induced accommodative adaptation has been suggested as a risk factor for myopia development. We investigated whether accommodative adaptation may explain in part the high prevalence of myopia in Hong Kong children and examined the effect of beta-antagonism with topical timolol maleate on accommodative adaptation.Methods: Thirty children (10 emmetropes and 20 myopes) aged between 8 and 12 years were recruited. Tonic accommodation was measured before and after 5 min of video game-playing using an open-field Shin-Nippon autorefractor. Measurements were repeated 30 min after timolol instillation. RESULTS: Children with progressing myopia demonstrated accommodative adaptation following the near task, whereas stable myopes showed counter-adaptive, hyperopic accommodative changes. Timolol increased the magnitude of accommodative adaptation in the stable myopes but had little effect on responses of the progressing myopes or emmetropes. CONCLUSIONS: Neuropharmacological modulation of the accommodative system may have a possible etiological role in the progression of myopia