PI3K-PTEN dysregulation leads to mTOR-driven upregulation of the core clock gene BMAL1 in normal and malignant epithelial cells

Dysfunctional clock signaling is observed in a variety of pathological conditions. Many members of the clock gene family are upregulated in tumor cells. Here, we explored the consequences of a commonly disrupted signaling pathway in head and neck cancer on the regulation of circadian clock genes. PTEN is a key molecular controller of the PI3K signaling, and loss of PTEN function is often observed in a variety of cancers. Our main goal was to determine whether PTEN regulates circadian clock signaling. We found that oxidation-driven loss of PTEN function resulted in the activation of mTOR signaling and activation of the core clock protein BMAL1 (also known as ARNTL). The PTEN-induced BMAL1 upregulation was further confirmed using small interference RNA targeting PTEN, and in vivo conditional depletion of PTEN from the epidermis. We observed that PTEN-driven accumulation of BMAL1 was mTORmediated and that administration of Rapamycin, a specific mTOR inhibitor, resulted in in vivo rescue of normal levels of BMAL1. Accumulation of BMAL1 by deletion of PER2, a Period family gene, was also rescued upon in vivo administration of mTOR inhibitor. Notably, BMAL1 regulation requires mTOR regulatory protein Raptor and Rictor. These findings indicate that mTORC1 and mTORC2 complex plays a critical role in controlling BMAL1, establishing a connection between PI3K signaling and the regulation of circadian rhythm, ultimately resulting in deregulated BMAL1 in tumor cells with disrupted PI3K signaling

Corpos estranhos animados em otorrinolaringologia Strange animated bodies in othorinolaringology

Forma de estudo: Clínico retrospectivo. Material e método: Foram reportados 56 casos de corpos estranhos animados em orelhas (55 insetos e 1 aracnídeo) e 1 caso (inseto) em fossas nasais. O material foi coletado no setor de Emergência do serviço de ORL do Hospital Municipal Souza Aguiar, no centro do Rio de Janeiro, entre os anos de 1998 e 2000, e identificado por zoólogos do Museu Nacional, Rio de Janeiro. A maior parte dos casos ocorreu em Nova Iguaçu e Campo Grande, sendo analisados os quadros clínicos e as complicações ocorridas. Resultado: Os insetos são: 30,35% Blattaria (baratas); 25% Diptera (moscas e mosquitos); 12,5% Lepidoptera (borboletas e mariposas); 10,7% Coleoptera (besouros); 7,15% Hemiptera (percevejos, cigarras, afídeos, etc.), 5,35% Hymenoptera (vespas, abelhas, formigas, marimbondos) e 5,31 % outros.<br>Study design: Clinical retrospective. Material and method: Fufty-six cases of animated foreign bodies collected inside human ears (55 insects and 1 arachnid) and one case collected in nasal fossae (insect) were reported. The material was collected in the Emergency sector of Souza Aguiar Hospital, in Rio de Janeiro, between 1998 and 2000, and was identified by zoologists of Museu Nacional, Rio de Janeiro. Most of the cases had occurred in Nova Iguaçu and Campo Grande, suburbs of Rio de Janeiro. Clinical features and complications were analyzed. Results: The recorded insects are: 30,35% Blattaria (cockroaches); 25% Diptera (flies and mosquitos); 12,5% Lepidoptera (butterflies and moths); 10,7% Coleoptera (beetles); 7,15% Hemiptera (bugs, cicads, aphids, etc.), 5,35% Hymenoptera (wasps, bees, ants, and sawflies) and 5,31 % others