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Purpose: Hyperpolarized imaging experiments have conflicting requirements of high spatial, temporal, and spectral resolution. Spectral‐spatial RF excitation has been shown to form an attractive magnetization‐efficient method for hyperpolarized imaging, but the optimum readout strategy is not yet known. Methods: In this work, we propose a novel 3D hybrid‐shot spiral sequence which features two constant density regions that permit the retrospective reconstruction of either high spatial or high temporal resolution images post hoc, (adaptive spatiotemporal imaging) allowing greater flexibility in acquisition and reconstruction. Results: We have implemented this sequence, both via simulation and on a preclinical scanner, to demonstrate its feasibility, in both a 1H phantom and with hyperpolarized 13C pyruvate in vivo. Conclusions: This sequence forms an attractive method for acquiring hyperpolarized imaging datasets, providing adaptive spatiotemporal imaging to ameliorate the conflict of spatial and temporal resolution, with significant potential for clinical translation. [ABSTRACT FROM AUTHOR]

Rapid cancer cell proliferation promotes the production of reducing equivalents, which counteract the effects of relatively high levels of reactive oxygen species. Reactive oxygen species levels increase in response to chemotherapy and cell death, whereas an increase in antioxidant capacity can confer resistance to chemotherapy and is associated with an aggressive tumor phenotype. The pentose phosphate pathway is a major site of NADPH production in the cell, which is used to maintain the main intracellular antioxidant, glutathione, in its reduced state. Previous studies have shown that the rate of hyperpolarized [1-13C]dehydroascorbic acid (DHA) reduction, which can be measured in vivo using non-invasive 13C magnetic resonance spectroscopic imaging, is increased in tumors and that this is correlated with the levels of reduced glutathione. We show here that the rate of hyperpolarized [1-13C]DHA reduction is increased in tumors that have been oxidatively prestressed by depleting the glutathione pool by buthionine sulfoximine treatment. This increase was associated with a corresponding increase in pentose phosphate pathway flux, assessed using 13C-labeled glucose, and an increase in glutaredoxin activity, which catalyzes the glutathione-dependent reduction of DHA. These results show that the rate of DHA reduction depends not only on the level of reduced glutathione, but also on the rate of NADPH production, contradicting the conclusions of some previous studies. Hyperpolarized [1-13C]DHA can be used, therefore, to assess the capacity of tumor cells to resist oxidative stress in vivo. However, DHA administration resulted in transient respiratory arrest and cardiac depression, which may prevent translation to the clinic. [ABSTRACT FROM AUTHOR]

Purpose Dissolution dynamic nuclear polarization can increase the sensitivity of the 13C magnetic resonance spectroscopy experiment by at least four orders of magnitude and offers a novel approach to the development of MRI gene reporters based on enzymes that metabolize 13C-labeled tracers. We describe here a gene reporter based on the enzyme pyruvate decarboxylase (EC 4.1.1.1), which catalyzes the decarboxylation of pyruvate to produce acetaldehyde and carbon dioxide. Methods Pyruvate decarboxylase from Zymomonas mobilis ( zmPDC) and a mutant that lacked enzyme activity were expressed using an inducible promoter in human embryonic kidney (HEK293T) cells. Enzyme activity was measured in the cells and in xenografts derived from the cells using 13C MRS measurements of the conversion of hyperpolarized [1-13C] pyruvate to H13 [ABSTRACT FROM AUTHOR]

Purpose: A resonance at ~181 ppm in the 13C spectra of tumors injected with hyperpolarized [U-2H, U-13C]glucose was assigned to 6-phosphogluconate (6PG), as in previous studies in yeast, whereas in breast cancer cells in vitro this resonance was assigned to 3-phosphoglycerate (3PG). These peak assignments were investigated here using measurements of 6PG and 3PG 13C-labeling using liquid chromatography tandem mass spectrometry (LC-MS/MS) Methods: Tumor-bearing mice were injected with 13C6 glucose and the 13C-labeled and total 6PG and 3PG concentrations measured. 13C MR spectra of glucose-6-phosphate dehydrogenase deficient (zwf1D) and wild-type yeast were acquired following addition of hyperpolarized [U-2H, U-13C]glucose and again 13Clabeled and total 6PGand 3PGwere measured by LC-MS/MS Results: Tumor 13C-6PG was more abundant than 13C-2PG/ 3PG and the resonance at ~181 ppm matched more closely that of 6PG. 13C MR spectra of wild-type and zwf1D yeast cells showed a resonance at ~181 ppm after labeling with hyperpolarized [U-2H, U-13C]glucose, however, there was no 6PG in zwf1D cells. In the wild-type cells 3PG was approximately four-fold more abundant than 6PG Conclusion: The resonance at ~181 ppm in 13C MR spectra following injection of hyperpolarized [U-2H, U-13C]glucose originates predominantly from 6PG in EL4 tumors and 3PG in yeast cells. [ABSTRACT FROM AUTHOR]

Purpose Aldehyde dehydrogenase (ALDH2) is an emerging drug target for the treatment of heart disease, cocaine and alcohol dependence, and conditions caused by genetic polymorphisms in ALDH2. Noninvasive measurement of ALDH2 activity in vivo could inform the development of these drugs and accelerate their translation to the clinic. Methods [1-13C, U-2H5] ethanol was hyperpolarized using dynamic nuclear polarization, injected into mice and its oxidation in the liver monitored using 13C MR spectroscopy and spectroscopic imaging. Results Oxidation of [1-13C, U-2H5] ethanol to [1-13C] acetate was observed. Saturation of the acetaldehyde resonance, which was below the level of detection in vivo, demonstrated that acetate was produced via acetaldehyde. Irreversible inhibition of ALDH2 activity with disulfiram resulted in a proportional decrease in the amplitude of the acetate resonance. Conclusion 13C magnetic resonance spectroscopy measurements of hyperpolarized [1-13C, U-2H5] ethanol oxidation allow real-time assessment of ALDH2 activity in liver in vivo. Magn Reson Med, 2014. © The Authors. Magnetic Resonance in Medicine Published by Wiley Periodicals, Inc. on behalf of International Society of Medicine in Resonance. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited. Magn Reson Med 73:1733-1740, 2015. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Purpose To assess the potential of a gene reporter system, based on a urea transporter (UTB) and hyperpolarized [13C]urea. Methods Mice were implanted subcutaneously with either unmodified control cells or otherwise identical cells expressing UTB. After injection of hyperpolarized [13C]urea, a spin echo sequence was used to measure urea concentration, T1, and diffusion in control and UTB-expressing tissue. Results The apparent diffusion coefficient of hyperpolarized urea was 21% lower in tissue expressing UTB, in comparison with control tissue ( P < 0.05, 1-tailed t-test, n = 6 in each group). No difference in water apparent diffusion coefficient or cellularity between these tissues was found, indicating that they were otherwise similar in composition. Conclusion Expression of UTB, by mediating cell uptake of urea, lowers the apparent diffusion coefficient of hyperpolarized 13C urea in tissue and thus the transporter has the potential to be used as a magnetic resonance-based gene reporter in vivo. Magn Reson Med 73:1401-1406, 2015. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Long-term cardiovascular complications of cancer therapy are becoming ever more prevalent due to increased numbers of cancer survivors. Cancer therapy-induced cardiotoxicity (CTIC) is an incompletely understood consequence of various chemotherapies, targeted anti-cancer agents and radiation therapy. It is typically detected clinically by a reduction in cardiac left ventricular ejection fraction, assessed by echocardiography. However, once cardiac functional decline is apparent, this indicates irreversible cardiac damage, highlighting a need for the development of diagnostics which can detect CTIC prior to the onset of functional decline. There is increasing evidence to suggest that pathological alterations to cardiac metabolism play a crucial role in the development of CTIC. This review discusses the metabolic alterations and mechanisms which occur in the development of CTIC, with a focus on doxorubicin, trastuzumab, imatinib, ponatinib, sunitinib and radiotherapy. Potential methods to diagnose and predict CTIC prior to functional cardiac decline in the clinic are evaluated, with a view to both biomarker and imaging-based approaches. Finally, the therapeutic potential of therapies which manipulate cardiac metabolism in the context of adjuvant cardioprotection against CTIC is examined. Together, an integrated view of the role of metabolism in pathogenesis, diagnosis and treatment is presented. [ABSTRACT FROM AUTHOR]

Purpose: Phosphorus saturation-transfer experiments can quantify metabolic fluxes noninvasively. Typically, the forward flux through the creatine kinase reaction is investigated by observing the decrease in phosphocreatine (PCr) after saturation of γ-ATP. The quantification of total ATP utilization is currently underexplored, as it requires simultaneous saturation of inorganic phosphate ( P i ) and PCr. This is challenging, as currently available saturation pulses reduce the already-low γ-ATP signal present., Methods: Using a hybrid optimal-control and Shinnar-Le Roux method, a quasi-adiabatic RF pulse was designed for the dual saturation of PCr and P i to enable determination of total ATP utilization. The pulses were evaluated in Bloch equation simulations, compared with a conventional hard-cosine DANTE saturation sequence, before being applied to perfused rat hearts at 11.7 T., Results: The quasi-adiabatic pulse was insensitive to a >2.5-fold variation in B 1 , producing equivalent saturation with a 53% reduction in delivered pulse power and a 33-fold reduction in spillover at the minimum effective B 1 . This enabled the complete quantification of the synthesis and degradation fluxes for ATP in 30-45 minutes in the perfused rat heart. While the net synthesis flux (4.24 ± 0.8 mM/s, SEM) was not significantly different from degradation flux (6.88 ± 2 mM/s, P = .06) and both measures are consistent with prior work, nonlinear error analysis highlights uncertainties in the P i -to-ATP measurement that may explain a trend suggesting a possible imbalance., Conclusions: This work demonstrates a novel quasi-adiabatic dual-saturation RF pulse with significantly improved performance that can be used to measure ATP turnover in the heart in vivo., (© 2021 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: Hyperpolarized imaging experiments have conflicting requirements of high spatial, temporal, and spectral resolution. Spectral-spatial RF excitation has been shown to form an attractive magnetization-efficient method for hyperpolarized imaging, but the optimum readout strategy is not yet known., Methods: In this work, we propose a novel 3D hybrid-shot spiral sequence which features two constant density regions that permit the retrospective reconstruction of either high spatial or high temporal resolution images post hoc, (adaptive spatiotemporal imaging) allowing greater flexibility in acquisition and reconstruction., Results: We have implemented this sequence, both via simulation and on a preclinical scanner, to demonstrate its feasibility, in both a 1 H phantom and with hyperpolarized 13 C pyruvate in vivo., Conclusions: This sequence forms an attractive method for acquiring hyperpolarized imaging datasets, providing adaptive spatiotemporal imaging to ameliorate the conflict of spatial and temporal resolution, with significant potential for clinical translation., (© 2020 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: Dissolution dynamic nuclear polarization can increase the sensitivity of the (13) C magnetic resonance spectroscopy experiment by at least four orders of magnitude and offers a novel approach to the development of MRI gene reporters based on enzymes that metabolize (13) C-labeled tracers. We describe here a gene reporter based on the enzyme pyruvate decarboxylase (EC 4.1.1.1), which catalyzes the decarboxylation of pyruvate to produce acetaldehyde and carbon dioxide., Methods: Pyruvate decarboxylase from Zymomonas mobilis (zmPDC) and a mutant that lacked enzyme activity were expressed using an inducible promoter in human embryonic kidney (HEK293T) cells. Enzyme activity was measured in the cells and in xenografts derived from the cells using (13) C MRS measurements of the conversion of hyperpolarized [1-(13) C] pyruvate to H(13) CO3-., Results: Induction of zmPDC expression in the cells and in the xenografts derived from them resulted in an approximately two-fold increase in the H(13) CO3-/[1-(13) C] pyruvate signal ratio following intravenous injection of hyperpolarized [1-(13) C] pyruvate., Conclusion: We have demonstrated the feasibility of using zmPDC as an in vivo reporter gene for use with hyperpolarized (13) C MRS. Magn Reson Med 76:391-401, 2016. © 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited., (© 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: A resonance at ∼181 ppm in the (13) C spectra of tumors injected with hyperpolarized [U-(2) H, U-(13) C]glucose was assigned to 6-phosphogluconate (6PG), as in previous studies in yeast, whereas in breast cancer cells in vitro this resonance was assigned to 3-phosphoglycerate (3PG). These peak assignments were investigated here using measurements of 6PG and 3PG (13) C-labeling using liquid chromatography tandem mass spectrometry (LC-MS/MS) METHODS: Tumor-bearing mice were injected with (13) C6 glucose and the (13) C-labeled and total 6PG and 3PG concentrations measured. (13) C MR spectra of glucose-6-phosphate dehydrogenase deficient (zwf1Δ) and wild-type yeast were acquired following addition of hyperpolarized [U-(2) H, U-(13) C]glucose and again (13) C-labeled and total 6PG and 3PG were measured by LC-MS/MS RESULTS: Tumor (13) C-6PG was more abundant than (13) C-2PG/3PG and the resonance at ∼181 ppm matched more closely that of 6PG. (13) C MR spectra of wild-type and zwf1Δ yeast cells showed a resonance at ∼181 ppm after labeling with hyperpolarized [U-(2) H, U-(13) C]glucose, however, there was no 6PG in zwf1Δ cells. In the wild-type cells 3PG was approximately four-fold more abundant than 6PG CONCLUSION: The resonance at ∼181 ppm in (13) C MR spectra following injection of hyperpolarized [U-(2) H, U-(13) C]glucose originates predominantly from 6PG in EL4 tumors and 3PG in yeast cells., (© 2014 Wiley Periodicals, Inc.)

Purpose: Aldehyde dehydrogenase (ALDH2) is an emerging drug target for the treatment of heart disease, cocaine and alcohol dependence, and conditions caused by genetic polymorphisms in ALDH2. Noninvasive measurement of ALDH2 activity in vivo could inform the development of these drugs and accelerate their translation to the clinic., Methods: [1-(13) C, U-(2) H5 ] ethanol was hyperpolarized using dynamic nuclear polarization, injected into mice and its oxidation in the liver monitored using (13) C MR spectroscopy and spectroscopic imaging., Results: Oxidation of [1-(13) C, U-(2) H5 ] ethanol to [1-(13) C] acetate was observed. Saturation of the acetaldehyde resonance, which was below the level of detection in vivo, demonstrated that acetate was produced via acetaldehyde. Irreversible inhibition of ALDH2 activity with disulfiram resulted in a proportional decrease in the amplitude of the acetate resonance., Conclusion: (13) C magnetic resonance spectroscopy measurements of hyperpolarized [1-(13) C, U-(2) H5 ] ethanol oxidation allow real-time assessment of ALDH2 activity in liver in vivo., (© 2014 The Authors. Magnetic Resonance in Medicine Published by Wiley Periodicals, Inc. on behalf of International Society of Medicine in Resonance.)