No abstract

Organophosphate pesticides irreversibly and semi‐permanently inhibit acetylcholinesterase, the enzyme responsible for the degradation of the neurotransmitter acetylcholine. Therefore, inhibition of acetylcholinesterase by organophosphate pesticides causes hyperstimulation of the cholinergic nervous system affecting the development and function of neurons in the CNS and PNS. This study seeks to understand the acute effects of organophosphate pesticides, including chlorpyrifos, on differentiating PC‐12 cells, and the effects of long‐term exposure on differentiated PC‐12 cell viability and susceptibility to neurotoxic agents. A dose‐dependent increase in cell death was observed for PC‐12 cells exposed to chlorpyrifos during differentiation. Additionally, results indicated that differentiating PC‐12 cells were most sensitive to chlorpyrifos at mid to late stages of differentiation when the neurons were beginning to form synapses. At earlier stages, chlorpyrifos had little effect on cell survival. Long‐term exposure to a sub‐lethal concentration of chlorpyrifos caused a decrease in neuronal viability, and influenced their susceptibility to H2O2‐induced oxidative damage and Aβ42‐induced damage. Together these data demonstrate that organophosphate exposure adversely affects PC‐12 cell survival and long‐term exposure alters their susceptibility to agents involved in neurodegenerative disease.

Introduction: High-dose total body irradiation (TBI) is often part of myeloablative conditioning in acute leukemia. Modern volumetric modulated arc therapy (VMAT)-based plans employ arcs to the inferior-most portion of the body that can be simulated in a head-first position and use 2D planning for the inferior body which can result in heterogeneous doses. Here, we describe our institution's unique protocol for delivering high-dose TBI entirely with VMAT and retrospectively compare dosimetric outcomes with helical tomotherapy (HT) plans. Additionally, we describe our method of oropharyngeal mucosal sparing that was implemented after fatal mucositis occurred in two patients. Methods: Thirty-one patients were simulated and treated in head-first (HFS) and feet-first (FFS) orientations. Patients were treated with VMAT (n = 26) or HT (n = 5). In VMAT plans, to synchronize doses between the orientations, images were deformably registered and the HFS dose was transferred to the FFS plan and used as a background dose when optimizing plans. Six to eight isocenters with two arcs per isocenter were generated. HT was delivered with an established technique. Patients were treated to 13.2 Gy over eight twice daily fractions. Dosimetric outcomes and toxicities were retrospectively compared. Results: Prescription dose and organ at risk (OAR) constraints were met for all patients. Lower lung doses were achieved with VMAT relative to HT plans (7.4 vs 7.7 Gy, P = .009). Statistically significant improvement in mucositis was not achieved after adopting a mucosal-sparing technique, however lower doses to the oropharyngeal mucosal were achieved (6.9 vs 14.1 Gy, P = .009), and no further mucositis-related deaths occurred. Conclusions: This full-body VMAT method of TBI achieves dose goals, eliminates risk of heterogenous doses within the femur, and demonstrates that selective OAR sparing with the purpose of reducing TBI-related morbidity and mortality is possible at any institution with a VMAT-capable linear accelerator.