The isocitrate dehydrogenase (IDH)1 mutation is associated with accumulation of 2-hydroxyglutarate (2-HG), but the metabolic fluxes associated with 2-HG production and cellular reprogramming of mutant IDH1 cells are not fully understood. The objective of this study was to use 13C magnetic resonance spectroscopy (MRS) to probe the fate of 13C-labeled metabolites (at thermal polarization and hyperpolarized by dynamic nuclear polarization) and to monitor the glycolytic pathway, the TCA cycle, and glutamine metabolism in wild-type and mutant IDH1 glioma cells. To achieve this goal, U87 cells expressing mutant IDH1 and wild-type IDH1 were generated by transduction with a lentiviral vector coding for mutant or wild-type IDH1 respectively. MRS studies were performed using a cell perfusion (bioreactor) system. Live cells were exposed to hyperpolarized 1-13C or 2-13C-labeled pyruvic acid, 1-13C glucose or 3-13C glutamine and cell metabolism was probed using 13C MRS. We found that in mutant IDH1 cells pyruvate flux to lactate was increased relative to wild-type cells, and pyruvate flux to glutamate and 2-HG was decreased compared to pyruvate flux to glutamate in wild-type IDH1 cell. Glutamine flux to glutamate in wild-type cells, or to glutamate and 2-HG in mutant IDH1 cells was comparable. Accordingly, the total intracellular glutamate pool was reduced in mutant IDH1 cells. The drop in pyruvate flux to the TCA cycle was mediated by a significant drop in pyruvate dehydrogenase (PDH) activity, which was due to significantly increased inhibitory PDH phosphorylation. When considering 2-HG synthesis, our data also indicate that, consistent with previous work, the majority of 2-HG is produced from glutamine (82%). However in our cells a significant portion (18%) was also derived from glucose. Our findings thus point to metabolic reprogramming in IDH1 mutant cells beyond 2-HG production and highlight the value of MRS for characterizing the metabolic changes associated with the IDH1 mutation.

Adult living donor liver transplantation (LDLT) is increasingly used for the treatment of end-stage liver disease. The three most commonly harvested grafts for LDLT are left lateral segment, left lobe, and right lobe grafts. The left lateral segment graft, which includes Couinaud's segments II and III, is usually used for pediatric recipients or small size recipients. Most of the adult recipients need either a left or a right lobe graft. Whether a left or right lobe graft should be harvested from the donors depends on estimated graft and donor remnant liver volume, as well as biliary and vascular anatomy. Detailed preoperative assessment of the potential donor liver volumetrics, biliary and vascular anatomy, and liver parenchyma is vital to minimize risks to the donors and maximize benefits to the recipients. Computed tomography (CT) and magnetic resonance imaging (MRI) are currently the imaging modalities of choice in the preoperative evaluation of potential donors. This review provides an overview of key surgical considerations in LDLT that the radiologists must be aware of, and imaging findings on CT and MRI that the radiologists must convey to the surgeons when evaluating potential donors for LDLT.

Mutations of the isocitrate dehydrogenase 1 (IDH1) gene are among the most prevalent in low-grade glioma and secondary glioblastoma, represent an early pathogenic event, and are associated with epigenetically driven modulations of metabolism. Of particular interest is the recently uncovered relationship between the IDH1 mutation and decreased activity of the branched-chain amino acid transaminase 1 (BCAT1) enzyme. Noninvasive imaging methods that can assess BCAT1 activity could therefore improve detection of mutant IDH1 tumors and aid in developing and monitoring new targeted therapies. BCAT1 catalyzes the transamination of branched-chain amino acids while converting α-ketoglutarate (α-KG) to glutamate. Our goal was to use (13)C magnetic resonance spectroscopy to probe the conversion of hyperpolarized [1-(13)C] α-KG to hyperpolarized [1-(13)C] glutamate as a readout of BCAT1 activity. We investigated two isogenic glioblastoma lines that differed only in their IDH1 status and performed experiments in live cells and in vivo in rat orthotopic tumors. Following injection of hyperpolarized [1-(13)C] α-KG, hyperpolarized [1-(13)C] glutamate production was detected both in cells and in vivo, and the level of hyperpolarized [1-(13)C] glutamate was significantly lower in mutant IDH1 cells and tumors compared with their IDH1-wild-type counterparts. Importantly however, in our cells the observed drop in hyperpolarized [1-(13)C] glutamate was likely mediated not only by a drop in BCAT1 activity, but also by reductions in aspartate transaminase and glutamate dehydrogenase activities, suggesting additional metabolic reprogramming at least in our model. Hyperpolarized [1-(13)C] glutamate could thus inform on multiple mutant IDH1-associated metabolic events that mediate reduced glutamate production.

Mutant isocitrate dehydrogenase 1 (IDH1) catalyzes the production of 2-hydroxyglutarate but also elicits additional metabolic changes. Levels of both glutamate and pyruvate dehydrogenase (PDH) activity have been shown to be affected in U87 glioblastoma cells or normal human astrocyte (NHA) cells expressing mutant IDH1, as compared with cells expressing wild-type IDH1. In this study, we show how these phenomena are linked through the effects of IDH1 mutation, which also reprograms pyruvate metabolism. Reduced PDH activity in U87 glioblastoma and NHA IDH1 mutant cells was associated with relative increases in PDH inhibitory phosphorylation, expression of pyruvate dehydrogenase kinase-3, and levels of hypoxia inducible factor-1α. PDH activity was monitored in these cells by hyperpolarized (13)C-magnetic resonance spectroscopy ((13)C-MRS), which revealed a reduction in metabolism of hyperpolarized 2-(13)C-pyruvate to 5-(13)C-glutamate, relative to cells expressing wild-type IDH1. (13)C-MRS also revealed a reduction in glucose flux to glutamate in IDH1 mutant cells. Notably, pharmacological activation of PDH by cell exposure to dichloroacetate (DCA) increased production of hyperpolarized 5-(13)C-glutamate in IDH1 mutant cells. Furthermore, DCA treatment also abrogated the clonogenic advantage conferred by IDH1 mutation. Using patient-derived mutant IDH1 neurosphere models, we showed that PDH activity was essential for cell proliferation. Taken together, our results established that the IDH1 mutation induces an MRS-detectable reprogramming of pyruvate metabolism, which is essential for cell proliferation and clonogenicity, with immediate therapeutic implications.