A bidirectional competitive interaction between circHomer1 and Homer1b within the orbitofrontal cortex regulates reversal learning.

Although circular RNAs (circRNAs) are enriched in the brain, their relevance for brain function and psychiatric disorders is poorly understood. Here, we show that circHomer1 is inversely associated with relative HOMER1B mRNA isoform levels in both the orbitofrontal cortex (OFC) and stem-cell-derived neuronal cultures of subjects with psychiatric disorders. We further demonstrate that in vivo circHomer1 knockdown (KD) within the OFC can inhibit the synaptic expression of Homer1b mRNA. Furthermore, we show that circHomer1 directly binds to Homer1b mRNA and that Homer1b-specific KD increases synaptic circHomer1 levels and improves OFC-mediated behavioral flexibility. Importantly, double circHomer1 and Homer1b in vivo co-KD results in a complete rescue in circHomer1-associated alterations in both chance reversal learning and synaptic gene expression. Lastly, we uncover an RNA-binding protein that can directly bind to circHomer1 and promote its biogenesis. Taken together, our data provide mechanistic insights into the importance of circRNAs in brain function and disease.

Combined treatment with cisplatin and sirolimus to enhance cell death in human mesothelioma.

OBJECTIVE: Although platinum-based chemotherapy is widely used in malignant pleural mesothelioma, its modest therapeutic effect warrants identification of enhancing agents. As with many cancers, the phosphatidylinositol 3-kinase/Akt pathway is often activated in malignant pleural mesothelioma and has been implicated in the tumor's aggressiveness. Sirolimus is a well-established inhibitor of the mammalian target of rapamycin. We sought to determine whether combination treatment with sirolimus and cisplatin would enhance cell death in malignant pleural mesothelioma. METHODS: Human malignant pleural mesothelioma cell lines were incubated with sirolimus or cisplatin alone or in combination and assayed for cell viability. To characterize phosphorylation status after treatment, Akt and downstream proteins of mammalian target of rapamycin pathway, p70 S6 kinase and 4E-BP1, were analyzed by Western blot. Effect of combination treatment was also analyzed with extreme drug resistance assay in 12 human malignant pleural mesothelioma tumors with varying resistance to cisplatin. RESULTS: Individual malignant pleural mesothelioma cell lines exhibited a range of sensitivities to each drug without correlation with subtype. Sirolimus and cisplatin significantly (P = .029) increased cell death versus either drug alone in 4 cell lines. Combined treatment caused dephosphorylation of Akt, 4E-BP1, and p70 S6 kinase. Cell proliferation was significantly decreased in tumors subjected to sirolimus and cisplatin versus cisplatin or sirolimus alone. CONCLUSIONS: Sirolimus appears to enhance the cytotoxicity of cisplatin in malignant pleural mesothelioma cell lines through the mammalian target of rapamycin pathway. These results provide a basis for the clinical evaluation of combined sirolimus and cisplatin chemotherapy in malignant pleural mesothelioma.