Nitrosylcobalamin Potentiates the Anti-Neoplastic Effects of Chemotherapeutic Agents via Suppression of Survival Signaling

Nitrosylcobalamin (NO-Cbl) is a chemotherapeutic pro-drug derived from vitamin B12 that preferentially delivers nitric oxide (NO) to tumor cells, based upon increased receptor expression. NO-Cbl induces Apo2L/TRAIL-mediated apoptosis and inhibits survival signaling in a variety of malignant cell lines. Chemotherapeutic agents often simultaneously induce an apoptotic signal and activation of NF-kappaB, which has the undesired effect of promoting cell survival. The specific aims of this study were to 1) measure the anti-tumor effects of NO-Cbl alone and in combination with conventional chemotherapeutic agents, and to 2) examine the mechanism of action of NO-Cbl as a single agent and in combination therapy.Using anti-proliferative assays, electrophoretic mobility shift assay (EMSA), immunoblot analysis and kinase assays, we demonstrate an increase in the effectiveness of chemotherapeutic agents in combination with NO-Cbl as a result of suppressed NF-kappaB activation.Eighteen chemotherapeutic agents were tested in combination with NO-Cbl, in thirteen malignant cell lines, resulting in a synergistic anti-proliferative effect in 78% of the combinations tested. NO-Cbl pre-treatment resulted in decreased NF-kappaB DNA binding activity, inhibition of IkappaB kinase (IKK) enzymatic activity, decreased AKT activation, increased caspase-8 and PARP cleavage, and decreased cellular XIAP protein levels.The use of NO-Cbl to inhibit survival signaling may enhance drug efficacy by preventing concomitant activation of NF-kappaB or AKT

A novel endoscopic hydro-mastoidectomy technique for transcanal endoscopic ear surgery

AbstractBackgroundIn order to remove a cholesteatoma in the mastoid under transcanal endoscopic ear surgery, it is necessary to perform transcanal endoscopic mastoidectomy. Bone dust and blood, however, obscure the surgical field. A novel endoscopic hydro-mastoidectomy technique was developed, in which the operator performs the mastoidectomy ‘underwater’ using a lens cleaning system that provides saline perfusion in the surgical space.MethodsA curved round coarse diamond bur is attached to an otological drill. A lens cleaning sheath is fitted to the endoscope. The surgeon controls the infusion of saline solution by stepping on a footswitch of the power console.ResultsEndoscopic hydro-mastoidectomy washes out bone dust and blood from the surgical field, improving the surgical view during mastoidectomy. Additionally, the operator can easily control the flow of saline perfusion.ConclusionThis technique provides a clear surgical view by washing out bone dust and blood from the surgical area. The setup for endoscopic hydro-mastoidectomy technique is easy and the operator needs only to buy sheaths if they already own the power console, as many otological and rhinological surgeons do.</jats:sec