ABSTRACT
While the peripheral nervous system has regenerative ability, restoration of sufficient function remains a challenge. Vimentin has been shown to be localized in axonal growth fronts and associated with nerve regeneration, including myelination, neuroplasticity, kinase signaling in nerve axoplasm, and cell migration; however, the mechanisms regulating its expression within Schwann cell (SC) remain unexplored. The aim of this study was to profile the spatial and temporal expression profile of microRNA (miRNA) in a regenerating rat sciatic nerve after transection, and explore the potential role of miR-138-5p targeting vimentin in SC proliferation and migration. A rat sciatic nerve transection model, utilizing a polyethylene nerve guide, was used to investigate miRNA expression at 7, 14, 30, 60, and 90 days during nerve regeneration. Relative levels of miRNA expression were determined using microarray analysis and subsequently validated with quantitative real-time polymerase chain reaction. In vitro assays were conducted with cultured Schwann cells transfected with miRNA mimics and assessed for migratory and proliferative potential. The top seven dysregulated miRNAs reported in this study have been implicated in cell migration elsewhere, and GO and KEGG analyses predicted activities essential to wound healing. Transfection of one of these, miRNA-138-5p, into SCs reduced cell migration and proliferation. miR-138-5p has been shown to directly target vimentin in cancer cells, and the luciferase assay performed here in rat Schwann cells confirmed it. These results detail a role of miR-138-5p in rat peripheral nerve regeneration and expand on reports of it as an important regulator in the peripheral nervous system.
ABSTRACT
GOALS OF WORK: To assess the efficacy of adding aprepitant to a 5-HT(3) antagonist and dexamethasone as salvage antiemetic therapy for breast cancer patients receiving their initial cycle of an anthracycline and cyclophosphamide (AC) and failing to achieve complete control of emesis. MATERIALS AND METHODS: Eligibility: breast cancer patients receiving their first cycle of AC. TREATMENT: standard dose of a 5-HT(3) antagonist and dexamethasone 8-10 mg IV/PO on day 1 prior to cycle 1 of AC and dexamethasone 4 mg bid on days 2 and 3. Patients without complete control (no emesis, no nausea, or rescue antiemetics) during cycle 1 could proceed to cycle 2. During cycle 2, patients received AC and identical antiemetics (except dexamethasone 4 mg qd on days 2 and 3) plus aprepitant 125 mg PO day 1 and 80 mg PO days 2 and 3. Primary endpoint: complete control, 0-120 h after chemotherapy. RESULTS: Sixty-two patients received cycle 1 of AC. Complete control cycle 1: 13 patients (21%; 95%CI, 12-33%). Of the 49 patients eligible for cycle 2, four elected not to continue on study. Of the 45 patients receiving cycle 2, 44 were evaluable. Complete control and complete response (no emesis, no rescue) for the 5-day study period improved from 0% to 18% (p = 0.14) and 7% to 36% (p = 0.02) on cycles 1 and 2, respectively. CONCLUSIONS: In breast cancer patients receiving AC, the addition of aprepitant to a 5-HT(3) antagonist and dexamethasone during cycle 2 of treatment improved antiemetic outcome. Although the improvement in the primary endpoint of complete control during cycle 2 was not significant, all secondary endpoints such as complete response and no emesis rates were significantly better during cycle 2. The extent of antiemetic control during cycle 2 was numerically inferior to the results achieved in a phase III trial employing aprepitant with cycle 1 of AC chemotherapy, suggesting that the preferred approach is to include aprepitant with the initial cycle of AC chemotherapy.
