Redic, Kimberly

Abstract The brain avidly consumes glucose to fuel neurophysiology. Cancers of the brain, such as glioblastoma (GBM), relinquish physiological integrity and gain the ability to proliferate and invade healthy tissue. How brain cancers rewire glucose utilization to drive aggressive growth remains elusive. Here, we infused 13C-labeled glucose into patients and mice with brain cancer, coupled with quantitative metabolic flux analysis, to map the fates of glucose-derived carbon in tumor vs. cortex. Through the first direct and comprehensive measurements of carbon and nitrogen labeling in both cortex and glioma tissues, we uncover profound metabolic transformations. In human cortex, glucose carbons fuel essential physiologic processes including TCA cycle oxidation and neurotransmitter synthesis. Conversely, gliomas downregulate these processes and scavenge alternative carbon sources such as amino acids from the environment, repurposing glucose-derived carbons to generate molecules needed for proliferation and invasion. Targeting this metabolic rewiring in mice through dietary amino acid modulation selectively alters GBM metabolism, slows tumor growth, and augments the efficacy of standard-of-care treatments. These findings illuminate how aggressive brain tumors exploit glucose to suppress normal physiological activity in favor of malignant expansion and offer potential therapeutic strategies to enhance treatment outcomes.

Purpose The primary aim was to determine if dispensing of cyclophosphamide tablets resulted in accumulated residue on pharmacy counting tools during a simulated outpatient dispensing process. Secondary objectives included determining if cyclophosphamide contamination exceeded a defined threshold level of 1 ng/cm 2 and if a larger number of prescriptions dispensed resulted in increased contamination. Methods Mock prescriptions of 40 cyclophosphamide 50 mg tablets were counted on clean trays in three scenarios using a simulated outpatient pharmacy after assaying five cleaned trays as controls. The three scenarios consisted of five simulated dispensings of one, three, or six prescriptions dispensed per scenario. Wipe samples of trays and spatulas were collected and assayed for all trays, including the five clean trays used as controls. Contamination was defined as an assayed cyclophosphamide level at or above 0.001 ng/cm 2 and levels above 1 ng/cm 2 were considered sufficient to cause risk of human uptake. Mean contamination for each scenario was calculated and compared using one-way analysis of variance. P-values of < 0.05 implied significance. Results Mean cyclophosphamide contamination on trays used to count one, three, and six cyclophosphamide prescriptions was 0.51 ± 0.10 (p=0.0003), 1.02 ± 0.10 (p < 0.0001), and 1.82 ± 0.10 ng/cm 2 (p < 0.0001), respectively. Control trays did not show detectable cyclophosphamide contamination. Increasing the number of prescriptions dispensed from 1 to 3, 1 to 6, and 3 to 6 counts increased contamination by 0.51 ± 0.15 (p = 0.0140), 1.31 + 0.15 (p < 0.0001), and 0.80 ± 0.15 ng/cm 2 (p = 0.0004), respectively. Conclusion Dispensing one or more prescriptions of 40 cyclophosphamide 50 mg tablets contaminates pharmacy counting tools, and an increased number of prescriptions dispensed correlates with increased level of contamination. Counting out three or more prescriptions leads to trays having contamination that surpasses the threshold at which worker exposure may be increased. Pharmacies should consider devoting a separate tray to cyclophosphamide tablets, as cross-contamination could occur with other drugs and the efficacy of decontamination methods is unclear. Employee exposure could be minimized with the use of personal protective equipment, environmental controls, and cleaning trays between uses. Future investigation should assess the extent of drug powder dispersion, the effects of various cleaning methods, and the potential extent of contamination with different oral cytotoxic drugs.