Organophosphorus nerve agents (OPNAs) are irreversible inhibitors of acetylcholinesterase that pose a serious threat to public health because of their use as chemical weapons. Exposure to high doses of OPNAs can dramatically potentiate cholinergic synaptic activity and cause status epilepticus (SE). Current standard of care for OPNA exposure involves treatment with cholinergic antagonists, oxime cholinesterase reactivators, and benzodiazepines. However, data from pre-clinical models suggest that OPNA-induced SE rapidly becomes refractory to benzodiazepines. Neuroactive steroids (NAS), such as allopregnanolone, retain anticonvulsant activity in rodent models of benzodiazepine-resistant SE, perhaps because they modulate a broader variety of GABA receptor subtypes. SGE-516 is a novel, next generation NAS and a potent and selective GABA receptor positive allosteric modulator (PAM). The present study first established that SGE-516 reduced electrographic seizures in the rat lithium-pilocarpine model of pharmacoresistant SE. Then the anticonvulsant activity of SGE-516 was investigated in the soman-intoxication model of OPNA-induced SE. SGE-516 (5.6, 7.5, and 10mg/kg, IP) significantly reduced electrographic seizure activity compared to control when administered 20min after SE onset. When 10mg/kg SGE-516 was administered 40min after SE onset, seizure activity was still significantly reduced compared to control. In addition, all cohorts of rats treated with SGE-516 exhibited significantly reduced neuronal cell death as measured by FluoroJade B immunohistochemistry. These data suggest synthetic NASs that positively modulate both synaptic and extrasynaptic GABA receptors may be candidates for further study in the treatment of OPNA-induced SE.

OXA can induce notable multi-faceted biological effects in glioma cells and BMDMs at relatively low drug concentrations. These findings may have significant therapeutic relevance against GBM and warrant further investigation.

The objectives of this study are to assess perioperative opioid use in patients undergoing knee surgery and to examine the relationship between preoperative opioid use and 2-year postoperative patient-reported outcomes (PROs). We hypothesized that preoperative opioid use and, more specifically, higher quantities of preoperative opioid use would be associated with worse PROs in knee surgery patients. We studied 192 patients undergoing knee surgery at a single urban institution. Patients completed multiple PRO measures preoperatively and 2-year postoperatively, including six patient-reported outcomes measurement information system (PROMIS) domains; the International Knee Documentation Committee (IKDC) questionnaire, numeric pain scale (NPS) scores for the operative knee and the rest of the body, Marx's knee activity rating scale, Tegner's activity scale, International Physical Activity Questionnaire, as well as measures of met expectations, overall improvement, and overall satisfaction. Total morphine equivalents (TMEs) were calculated from a regional prescription monitoring program. Eighty patients (41.7%) filled an opioid prescription preoperatively, and refill TMEs were significantly higher in this subpopulation. Opioid use was associated with unemployment, government insurance, smoking, depression, history of prior surgery, higher body mass index, greater comorbidities, and lower treatment expectations. Preoperative opioid use was associated with significantly worse 2-year scores on most PROs, including PROMIS physical function, pain interference, fatigue, social satisfaction, IKDC, NPS for the knee and rest of the body, and Marx's and Tegner's scales. There was a significant dose-dependent association between greater preoperative TMEs and worse scores for PROMIS physical function, pain interference, fatigue, social satisfaction, NPS body, and Marx's and Tegner's scales. Multivariable analysis confirmed that any preoperative opioid use, but not quantity of TMEs, was an independent predictor of worse 2-year scores for function, activity, and knee pain. Preoperative opioid use and TMEs were neither independent predictors of met expectations, satisfaction, patient-perceived improvement, nor improvement on any PROs. Our findings demonstrate that preoperative opioid use is associated with clinically relevant worse patient-reported knee function and pain after knee surgery.

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Prostate cancer has well-characterized changes that take place metabolically in the citric acid cycle (CAC) such as increased lactate formation, reversal of physiologic buildup of citrate and breakdown into downstream CAC products. Metabolic MR spectroscopy utilizing 13C-labeled pyruvate now allows for clinical characterization of metabolic pathways in tissue. However, the traditionally utilized substrate of [1-13C]pyruvate has limitations because as the pyruvate is broken down, the labeled carbon does not enter the CAC and instead is lost as CO2. We propose that [2-13C]pyruvate, is better to characterize changes in the CAC. Specifically, [2-13]C-pyruvate can be converted to 13C-labeled acetyl CoA and subsequently metabolized in the CAC as 13C-labeled intermediate compounds (such as glutamate which rapidly pools alpha-ketogluterate). Alternatively in altered bioenergetic states, [2-13C]pyruvate is reduced to 13C-labeled lactate (Warburg effect) or transaminated to 13C-labeled alanine. By exposing prostate cancer cells to [2-13C]pyruvate and determining the relative labeling of lactate, glutamate, and alanine, we can elucidate which metabolic pathways (CAC, Warburg, transamination) are utilized in prostate cancer metabolism. The aim of this study was to determine how the metabolism of [2-13C]pyruvate via the CAC, reduction to lactate, and transamination differed in high and low malignancy prostate cancer cells.Methods: Tumorigenic prostate cells LNCaP and PC3 were exposed a medium containing [2-13C]pyruvate for 4 hours. PCA extraction was then performed to obtain the metabolites. 13C labeled compounds formed intracellularly and those released into the medium were analyzed using NMR chemical shifts with focus on peaks associated with pyruvate, lactate, alanine, glutamate, and other compounds related to the CAC. Dioxane was used as an internal standard for NMR characterization. Results: The labeled carbon from the [2-13C]pyruvate can be identified in the downstream metabolites of the citric acid cycle, after reduction to lactate, and/or transamination by determining labeled metabolites by 13C-NMR analysis. This allows for the ability to calculate the relative metabolism of pyruvate via the three pathways; transamination (74%), lactate formation (16%), and CAC (10%). Conclusions: [2-13C]pyruvate can be successfully utilized as a tool to explore the alterations in pathways of metabolism, including the citric acid cycle, in prostate cancer cells. Citation Format: Aymen Alqazzaz, Dexue Fu, Arman Karimi, Gustavo Ferreira, Mary McKenna, Mohummad M. Siddiqui. Utilizing metabolic pathways to improve diagnosis and risk stratification of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 371.