Hyperpolarized (HP) MRI using [1-13C] pyruvate is a novel method that can characterize energy metabolism in the human brain and brain tumors. Here, we present the first dynamically acquired human brain HP 13C metabolic spectra and spatial metabolite maps in cases of both untreated and recurrent tumors. production of HP lactate from HP pyruvate by tumors was indicative of altered cancer metabolism, whereas production of HP lactate in the entire brain was likely due to baseline metabolism. We correlated our results with standard clinical brain MRI, MRI DCE perfusion, and in one case FDG PET/CT. Our results suggest that HP 13C pyruvate-to-lactate conversion may be a viable metabolic biomarker for assessing tumor response. Hyperpolarized pyruvate MRI enables metabolic imaging in the brain and can be a quantitative biomarker for active tumors. http://cancerres.aacrjournals.org/content/canres/78/14/3755/F1.large.jpg .

MRI utilizing the hepatobiliary agent gadoxetate has the highest overall sensitivity and PPV, and may be the single optimal method for diagnosis of HCC. Non-contrast-enhanced US has the lowest sensitivity and PPV. More rigorous reference standards are needed to compare the performance of contrast-enhanced US with CT and MRI. Differences in sensitivity and PPV between CT and conventional gadolinium-enhanced MRI are not statistically significant overall.

Summary Cadherin-mediated cell adhesion is achieved through dimerization of cadherin N-terminal extracellular (EC1) domains presented from apposed cells. The dimer state is formed by exchange of N-terminal β-strands and insertion of conserved tryptophan indole side chains from one monomer into hydrophobic acceptor pockets of the partner molecule. The present work characterizes individual monomer and dimer states and the monomer-dimer equilibrium of the mouse Type II cadherin-8 EC1 domain using NMR spectroscopy. Limited picosecond-to-nanosecond timescale dynamics of the tryptophan indole moieties for both monomer and dimer states are consistent with well-ordered packing of the N-terminal β-strands intramolecularly and intermolecularly, respectively. However, pronounced microsecond-to-millisecond timescale dynamics of the side chains are observed for the monomer, but not the dimer, state, suggesting that monomers transiently sample configurations in which the indole moieties are exposed. Dimer formation is favored at low pH and by the presence of calcium, indicating a role for calcium in the strand swapping mechanism. The results are discussed in terms of possible kinetic mechanisms for EC1 dimerization.

Summary The oncometabolite 2-hydroxyglutarate (2-HG) is a signature biomarker in various cancers where it accumulates as a result of mutations in isocitrate dehydrogenase (IDH). The metabolic source of 2-HG, in a wide variety of cancers, dictates both its generation and also potential therapeutic strategies, but this remains difficult to access in vivo. Here, utilizing patient-derived chondrosarcoma cells harboring endogenous mutations in IDH1 and 2, we report that 2-HG can be rapidly generated from glutamine in vitro. Then, using hyperpolarized magnetic resonance imaging (HP-MRI), we demonstrate that in vivo HP [1-13C] glutamine can be used to non-invasively measure glutamine-derived HP 2-HG production. This can be readily modulated utilizing a selective IDH1 inhibitor, opening the door to targeting glutamine-derived 2-HG therapeutically. Rapid rates of HP 2-HG generation in vivo further demonstrate that, in a context dependent manner, glutamine can be a primary carbon source for 2-HG production in mutant IDH tumors.

BACKGROUND AND PURPOSE:A limitation in postoperative monitoring of patients with glioblastoma is the lack of objective measures to quantify residual and recurrent disease. Automated computer-assisted volumetric analysis of contrast-enhancing tissue represents a potential tool to aid the radiologist in following these patients. In this study, we hypothesize that computer-assisted volumetry will show increased precision and speed over conventional 1D and 2D techniques in assessing residual and/or recurrent tumor.

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Voltage-gated sodium channels initiate the rapid upstroke of action potentials in many excitable tissues. Mutations within intracellular C-terminal sequences of specific channels underlie a diverse set of channelopathies, including cardiac arrhythmias and epilepsy syndromes. The three-dimensional structure of the C-terminal residues 1777-1882 of the human Na V 1.2 voltagegated sodium channel has been determined in solution by NMR spectroscopy at pH 7.4 and 290.5 K. The ordered structure extends from residues Leu-1790 to Glu-1868 and is composed of four ␣-helices separated by two short anti-parallel ␤-strands; a less well defined helical region extends from residue Ser-1869 to Arg-1882, and a disordered N-terminal region encompasses residues 1777-1789. Although the structure has the overall architecture of a paired EF-hand domain, the Na V 1. 2؉ titration also were performed for the Na V 1.5 (1773-1878) isoform, demonstrating similar secondary structure architecture and the absence of Ca 2؉ binding by the EFhand loops. Clinically significant mutations identified in the C-terminal region of Na V 1 sodium channels cluster in the helix I-IV interface and the helix II-III interhelical segment or in helices III and IV of the Na V 1.2 (1777-1882) structure.Voltage-gated sodium channels (VGSCs) 5 are molecular assemblies that span the plasma membrane of excitable cells and conduct sodium current selectively in response to depolarizing stimuli. Mutations in VGSCs underlie a variety of diseases, including the cardiac arrhythmogenic Long-QT3 and Brugada syndromes (1, 2) and neurological syndromes, such as epilepsy (3, 4).Known components of VGSCs include a pore-forming ␣ subunit, auxiliary ␤ subunits, and associated modulating proteins, such as calmodulin (5, 6). The ␣ subunit is composed of four homologous six-transmembrane helical domains connected by inter-domain linkers and N-terminal and C-terminal cytoplasmic regions. Specific ␣ subunit isoforms are expressed differentially in skeletal muscle (Na V 1.4), cardiac muscle (Na V 1.5) and the nervous system (Na V 1.1, Na V 1.2, Na V 1.3, splice variants of Na V 1.5, and Na V 1.6-Na V 1.9) and control the rapid upstroke of action potentials (7). VGSC activity is characterized by two open states and several inactivated states (8). Kinetics of channel inactivation occur on timescales ranging from milliseconds to seconds and determine multiple aspects of action potentials (9, 10). The molecular mechanisms of VGSC inactivation are complex and involve the ␣ subunit, the ␤ subunits, and calmodulin (11-13). Specific contributions to ␣ subunit inactivation have been localized to interhelical intra-domain regions (14 -16), the linker region between domains III-IV, which forms the pore occluding inactivation gate (17,18), and the C-terminal cytoplasmic domain (CTD) (19 -21).Specific disease-causing mutations within the CTD affect channel function by altering kinetics of channel inactivation (22). The CTD is predicted by sequence analysis (23, 24) and homology modeling (25-27) to c...

The ever-changing tumor-microenvironment constantly challenges individual cancer cells to balance supply and demand, presenting tumor vulnerabilities and therapeutic opportunities. Everolimus and temsirolimus are inhibitors of mTOR (mTORi) approved for treating metastatic renal cell carcinoma (mRCC). However, treatment outcome varies greatly among patients. Accordingly, administration of mTORi in mRCC is diminishing, which could potentially result in missing timely delivery of effective treatment for select patients. Here we implemented a clinically applicable, integrated platform encompassing a single dose of [1-13C] pyruvate to visualize the in vivo effect of mTORi on the conversion of pyruvate to lactate using hyperpolarized MRI. A striking difference that predicts treatment benefit was demonstrated using two preclinical models derived from clear cell RCC (ccRCC) patients who exhibited primary resistance to VEGFRi and quickly succumbed to their diseases within 6 months after the diagnosis of metastasis without receiving mTORi. Our findings suggest that hyperpolarized MRI could be further developed to personalize kidney cancer treatment.