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1
Dellagiustina, E., L. Mavilla, M. Sintini, and A. Guerra. "Neuroradiologia della sindrome di Alpers." Rivista di Neuroradiologia 5, no. 1_suppl (April 1992): 169–72. http://dx.doi.org/10.1177/19714009920050s135.
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Si segnala la particolare evoluzione neuroradiologica di una piccola paziente, che ha attualmente a.2 e m. 10, e che a seguito di un coma metabolico con stato di male epilettico, iperlattacidemia, epatopatia moderata, anomalie lente sull'EEGramma, ha cominciato all'età di 3 mesi ad eseguire accertamenti neuroradiologici. la TC a quell'età mostrò solo una lievissima atrofia cerebrale con ipodensità irregolare della sostanza bianca. All'età di 6 mesi, allorquando fu posta la diagnosi di sindrome di Alpers, la RM metteva in evidenza un quadro di gravissima atrofia degli emisferi cerebrali, sia corticale che sottocorticale, e, in minor misura, di quelli cerebellari, con relativo risparmio dei nuclei della base e del tronco cerebrale. L'evoluzione atrofica era stata talmente rapida da indurre in tre mesi anche la formazione di due voluminosi ematomi sottodurali. La RM fu decisiva per confermare il sospetto diagnostico. Da allora, la condizione clinica neurologica e metabolica della paziente, in trattamento con dosi elevate di carnitina e vit. Bl, oltre che con anticomiziali, si è stabilizzata. Anche il quadro neuroradiologico si mantiene sostanzialmente invariato, fatta eccezione per il riassorbimento dei due ematomi sottodurali. Le indagini metaboliche approfondite hanno permesso di dimostrare un difetto di attivazione del complesso piruvato-deidrogenasi. La RM si dimostra esame indispensabile per la diagnosi di questa rara malattia, e superiore alla TC. A nostra conoscenza è questo il primo studio neuroradiologico prospettico della sindrome di Alpers.
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van de Weijer, Tineke, Elisabeth H. M. Paiman, and Hildo J. Lamb. "Cardiac metabolic imaging: current imaging modalities and future perspectives." Journal of Applied Physiology 124, no. 1 (January 1, 2018): 168–81. http://dx.doi.org/10.1152/japplphysiol.01051.2016.
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In this review, current imaging techniques and their future perspectives in the field of cardiac metabolic imaging in humans are discussed. This includes a range of noninvasive imaging techniques, allowing a detailed investigation of cardiac metabolism in health and disease. The main imaging modalities discussed are magnetic resonance spectroscopy techniques for determination of metabolite content (triglycerides, glucose, ATP, phosphocreatine, and so on), MRI for myocardial perfusion, and single-photon emission computed tomography and positron emission tomography for quantitation of perfusion and substrate uptake.
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Origgi, D., L. T. Mainardi, A. Falini, G. Calabrese, G. Scotti, S. Cerutti, and G. Tosi. "Quantificazione automatica di spettri 1H ed estrazione di mappe metaboliche da acquisizioni CSI mediante Wavelet Packets." Rivista di Neuroradiologia 13, no. 1 (February 2000): 31–36. http://dx.doi.org/10.1177/197140090001300106.
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La quantificazione dei picchi spettrali del segnale di spettroscopia 1H in risonanza magnetica, utile per un'analisi metabolica dei tessuti in-vivo, richiede un tempo di elaborazione elevato, soprattutto quando si tratta di acquisizioni CSI dove ad essere elaborata è un'intera matrice di dati. Inoltre, la sovrapposizione dei picchi, maggiormente marcata negli spettri con tempo di eco breve (20 ms), rende spesso difficoltosa la separazione dei singoli contributi metabolici. Si propone pertanto un metodo automatico per la quantificazione dei metaboliti, che utilizza l'algoritmo delle Wavelet Packets per scomporre il segnale nel dominio del tempo (FID) in sottobande. La stima dei parametri di ampiezza, fase, frequenza e smorzamento viene quindi eseguita nelle sottobande, dove cadono i picchi di interesse, mediante metodi di predizione lineare basati sulla scomposizione a valori singolari (LPSDV). L'ampiezza stimata dei picchi viene infine utilizzata sia per il calcolo dei rapporti metabolici sia per l'estrazione di mappe metaboliche. Il metodo di quantificazione proposto è stato messo a punto su fantocci e poi applicato alle acquisizioni di volontari sani e infine su alcuni pazienti. L'elaborazione automatica dei dati spettroscopici con il metodo proposto offre la possibilità di studiare in modo efficace ed affidabile i metaboliti cerebrali nonché di rappresentare la loro distribuzione spaziale mediante mappe metaboliche.
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Agudelo, Joao Piraquive, Deepti Upadhyay, Dalin Zhang, Hongjuan Zhao, Rosalie Nolley, Jinny Sun, Shubhangi Agarwal, et al. "Multiparametric Magnetic Resonance Imaging and Metabolic Characterization of Patient-Derived Xenograft Models of Clear Cell Renal Cell Carcinoma." Metabolites 12, no. 11 (November 15, 2022): 1117. http://dx.doi.org/10.3390/metabo12111117.
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Patient-derived xenografts (PDX) are high-fidelity cancer models typically credentialled by genomics, transcriptomics and proteomics. Characterization of metabolic reprogramming, a hallmark of cancer, is less frequent. Dysregulated metabolism is a key feature of clear cell renal cell carcinoma (ccRCC) and authentic preclinical models are needed to evaluate novel imaging and therapeutic approaches targeting metabolism. We characterized 5 PDX from high-grade or metastatic ccRCC by multiparametric magnetic resonance imaging (MRI) and steady state metabolic profiling and flux analysis. Similar to MRI of clinical ccRCC, T2-weighted images of orthotopic tumors of most PDX were homogeneous. The increased hyperintense (cystic) areas observed in one PDX mimicked the cystic phenotype typical of some RCC. The negligible hypointense (necrotic) areas of PDX grown under the highly vascularized renal capsule are beneficial for preclinical studies. Mean apparent diffusion coefficient (ADC) values were equivalent to those of ccRCC in human patients. Hyperpolarized (HP) [1-13C]pyruvate MRI of PDX showed high glycolytic activity typical of high-grade primary and metastatic ccRCC with considerable intra- and inter-tumoral variability, as has been observed in clinical HP MRI of ccRCC. Comparison of steady state metabolite concentrations and metabolic flux in [U-13C]glucose-labeled tumors highlighted the distinctive phenotypes of two PDX with elevated levels of numerous metabolites and increased fractional enrichment of lactate and/or glutamate, capturing the metabolic heterogeneity of glycolysis and the TCA cycle in clinical ccRCC. Culturing PDX cells and reimplanting to generate xenografts (XEN), or passaging PDX in vivo, altered some imaging and metabolic characteristics while transcription remained like that of the original PDX. These findings show that PDX are realistic models of ccRCC for imaging and metabolic studies but that the plasticity of metabolism must be considered when manipulating PDX for preclinical studies.
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Dutta, Prasanta, Travis C. Salzillo, Shivanand Pudakalakatti, Seth T. Gammon, Benny A. Kaipparettu, Florencia McAllister, Shawn Wagner, et al. "Assessing Therapeutic Efficacy in Real-time by Hyperpolarized Magnetic Resonance Metabolic Imaging." Cells 8, no. 4 (April 11, 2019): 340. http://dx.doi.org/10.3390/cells8040340.
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Precisely measuring tumor-associated alterations in metabolism clinically will enable the efficient assessment of therapeutic responses. Advances in imaging technologies can exploit the differences in cancer-associated cell metabolism as compared to normal tissue metabolism, linking changes in target metabolism to therapeutic efficacy. Metabolic imaging by Positron Emission Tomography (PET) employing 2-fluoro-deoxy-glucose ([18F]FDG) has been used as a routine diagnostic tool in the clinic. Recently developed hyperpolarized Magnetic Resonance (HP-MR), which radically increases the sensitivity of conventional MRI, has created a renewed interest in functional and metabolic imaging. The successful translation of this technique to the clinic was achieved recently with measurements of 13C-pyruvate metabolism. Here, we review the potential clinical roles for metabolic imaging with hyperpolarized MRI as applied in assessing therapeutic intervention in different cancer systems.
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Alkire, Michael T., Chris J. D. Pomfrett, Richard J. Haier, Marc V. Gianzero, Candice M. Chan, Bradley P. Jacobsen, and James H. Fallon. "Functional Brain Imaging during Anesthesia in Humans." Anesthesiology 90, no. 3 (March 1, 1999): 701–9. http://dx.doi.org/10.1097/00000542-199903000-00011.
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Background Propofol and isoflurane anesthesia were studied previously with functional brain imaging in humans to begin identifying key brain areas involved with mediating anesthetic-induced unconsciousness. The authors describe an additional positron emission tomography study of halothane's in vivo cerebral metabolic effects. Methods Five male volunteers each underwent two positron emission tomography scans. One scan assessed awake-baseline metabolism, and the other scan assessed metabolism during halothane anesthesia titrated to the point of unresponsiveness (mean +/- SD, expired = 0.7+/-0.2%). Scans were obtained using a GE2048 scanner and the F-18 fluorodeoxyglucose technique. Regions of interest were analyzed for changes in both absolute and relative glucose metabolism. In addition, relative changes in metabolism were evaluated using statistical parametric mapping. Results Awake whole-brain metabolism averaged 6.3+/-1.2 mg x 100 g(-1) x min(-1) (mean +/- SD). Halothane reduced metabolism 40+/-9% to 3.7+/-0.6 mg x 100 g(-1) x min(-1) (P< or =0.005). Regional metabolism did not increase in any brain areas for any volunteer. The statistical parametric mapping analysis revealed significantly less relative metabolism in the basal forebrain, thalamus, limbic system, cerebellum, and occiput during halothane anesthesia. Conclusions Halothane caused a global whole-brain metabolic reduction with significant shifts in regional metabolism. Comparisons with previous studies reveal similar absolute and relative metabolic effects for halothane and isoflurane. Propofol, however, was associated with larger absolute metabolic reductions, suppression of relative cortical metabolism more than either inhalational agent, and significantly less suppression of relative basal ganglia and midbrain metabolism.
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Shim, Hyunsuk, Alfredo Daniel Voloschin, Li Wei, Scott N. Hwang, Andrew H. Miller, Ying Guo, Daniel Brat, et al. "Using proton MRSI to predict response to vorinostat treatment in recurrent GBM." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 3055. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.3055.
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3055 Background: A major impediment to the development of new therapies for glioblastoma (GBM) is a lack of biomarkers indicating response. Epigenetic modifications are now recognized as a frequent occurrence in the early phases of tumorigenesis, playing a central role in tumor development. Epigenetic alterations differ significantly from genetic modifications in that they may be reversed by ‘‘epigenetic drugs’’ such as histone deacetylase inhibitors (HDACis). As a promising new modality for cancer therapy, the first generation of HDACi is currently being tested in phase I/II clinical trials. Methods: GBM alterations from therapy with HDACis, such as vorinostat (SAHA), include tumor redifferentiation/cytostasis rather than tumor size reduction limits the utility of traditional imaging methods such as MRI. Magnetic resonance spectroscopic imaging (MRSI) quantitates various metabolite levels in tumor and normal brain, allowing characterization of metabolic processes in live tissue. Results: In our preclinical model, MRS detected metabolic response to SAHA after only 3 days of treatment: reduced alanine and lactate and elevated myo-inositol, N-acetyl aspartate and creatine; each returning toward normal brain levels. This led to our clinical study of MRSI to evaluate the metabolic response of recurrent GBMs to SAHA + temozolomide. After only 7 days of SAHA treatment, MRSI can distinguish metabolic responders (normalization/restoration of tumor metabolites towards normal brain-like metabolism) from non-responders (no significant change in tumor metabolites). Our initial cohort (n=6) consists of 3 responders and 3 non-responders with highly significant differences in their change in metabolite levels (p < 0.001). Conclusions: Our results provide exciting insights into the mechanisms by which HDACi exerts its effect on GBMs. Tumor cells have increased biosynthetic needs requiring reprogramming of cellular metabolism. This creates increased energy demands, making tumor cells even more vulnerable to interventions targeting their metabolism. HDACi may induce redifferentiation in tumors by targeting tumor metabolism. Thus, MRSI provides a novel modality to predict response to HDACi-containing combination therapy in GBM.
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Zhu, Xiao-Hong, Byeong-Yeul Lee, Paul Tuite, Lisa Coles, Abhishek G. Sathe, Chi Chen, Jim Cloyd, Walter C. Low, Clifford J. Steer, and Wei Chen. "Quantitative Assessment of Occipital Metabolic and Energetic Changes in Parkinson’s Patients, Using In Vivo 31P MRS-Based Metabolic Imaging at 7T." Metabolites 11, no. 3 (March 1, 2021): 145. http://dx.doi.org/10.3390/metabo11030145.
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Abnormal energy metabolism associated with mitochondrial dysfunction is thought to be a major contributor to the progression of neurodegenerative diseases such as Parkinson’s disease (PD). Recent advancements in the field of magnetic resonance (MR) based metabolic imaging provide state-of-the-art technologies for non-invasively probing cerebral energy metabolism under various brain conditions. In this proof-of-principle clinical study, we employed quantitative 31P MR spectroscopy (MRS) imaging techniques to determine a constellation of metabolic and bioenergetic parameters, including cerebral adenosine triphosphate (ATP) and other phosphorous metabolite concentrations, intracellular pH and nicotinamide adenine dinucleotide (NAD) redox ratio, and ATP production rates in the occipital lobe of cognitive-normal PD patients, and then we compared them with age-sex matched healthy controls. Small but statistically significant differences in intracellular pH, NAD and ATP contents and ATPase enzyme activity between the two groups were detected, suggesting that subtle defects in energy metabolism and mitochondrial function are quantifiable before regional neurological deficits or pathogenesis begin to occur in these patients. Pilot data aiming to evaluate the bioenergetic effect of mitochondrial-protective bile acid, ursodeoxycholic acid (UDCA) were also obtained. These results collectively demonstrated that in vivo 31P MRS-based neuroimaging can non-invasively and quantitatively assess key metabolic-energetic metrics in the human brain. This provides an exciting opportunity to better understand neurodegenerative diseases, their progression and response to treatment.
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Moorcraft, J., N. M. Bolas, N. K. Ives, P. Sutton, M. J. Blackledge, B. Rajagopalan, P. L. Hope, and G. K. Radda. "Spatially Localized Magnetic Resonance Spectroscopy of the Brains of Normal and Asphyxiated Newborns." Pediatrics 87, no. 3 (March 1, 1991): 273–82. http://dx.doi.org/10.1542/peds.87.3.273.
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Phase-modulated rotating frame imaging is a modification of magnetic resonance spectroscopy, which uses a linear radiofrequency field gradient to obtain spatially localized biochemical information. Phase-modulated rotating frame imaging was used to study regional cerebral energy metabolism in the brains of 9 normal newborns and 25 newborns after birth asphyxia. Relative concentrations of phosphorus-containing metabolites and intracellular pH were determined for brain tissue at three specified depths below the brain surface for all neonates. Wide variations in metabolite ratios were seen among normal neonates, and considerable metabolic heterogeneity was demonstrated in individual neonates by depth-resolved spectroscopy. Asphyxiated neonates with severe hypoxic-ischemic encephalopathy and a poor neurodevelopmental outcome showed the expected rise in inorganic orthophosphate and fall in phosphocreatine concentrations in both global and spatially localized spectra. Phase-modulated rotating frame imaging showed that metabolic derangement was less in superficial than in deeper brain tissue. The inorganic orthophosphateadenosine triphosphate ratio from 1 to 2 cm below the brain surface was more accurate than any global metabolite ratio for the identification of neonates with a poor short-term outcome. These data are consistent with the known vulnerability of subcortical brain tissue to hypoxic-ischemic injury in the full-term neonate.
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Li, Xianqi, Ovidiu Andronesi, Bernhard Strasser, Kourosh Jafari-Khouzani, Daniel Cahill, Jorg Dietrich, Tracy Batchelor, Martin Bendszus, Ulf Neuberger, and Philipp Vollmuth. "BIMG-22. DEEP LEARNING SUPER-RESOLUTION MR SPECTROSCOPIC IMAGING TO MAP TUMOR METABOLISM IN MUTANT IDH GLIOMA PATIENTS." Neuro-Oncology Advances 3, Supplement_1 (March 1, 2021): i5—i6. http://dx.doi.org/10.1093/noajnl/vdab024.021.
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Abstract Metabolic imaging can map spatially abnormal molecular pathways with higher specificity for cancer compared to anatomical imaging. However, acquiring high resolution metabolic maps similar to anatomical MRI is challenging due to low metabolite concentrations, and alternative approaches that increase resolution by post-acquisition image processing can mitigate this limitation. We developed deep learning super-resolution MR spectroscopic imaging (MRSI) to map tumor metabolism in patients with mutant IDH glioma. We used a generative adversarial network (GAN) architecture comprised of a UNet neural network as the generator network and a discriminator network for adversarial training. For training we simulated a large data set of 9600 images with realistic quality for acquired MRSI to effectively train the deep learning model to upsample by a factor of four. Two types of training were performed: 1) using only the MRSI data, and 2) using MRSI and prior information from anatomical MRI to further enhance structural details. The performance of super-resolution methods was evaluated by peak SNR (PSNR), structure similarity index (SSIM), and feature similarity index (FSIM). After training on simulations, GAN was evaluated on measured MRSI metabolic maps acquired with resolution 5.2×5.2 mm2 and upsampled to 1.3×1.3 mm2. The GAN trained only on MRSI achieved PSNR = 27.94, SSIM = 0.88, FSIM = 0.89. Using prior anatomical MRI improved GAN performance to PSNR = 30.75, SSIM = 0.90, FSIM = 0.92. In the patient measured data, GAN super-resolution metabolic images provided clearer tumor margins and made apparent the tumor metabolic heterogeneity. Compared to conventional image interpolation such as bicubic or total variation, deep learning methods provided sharper edges and less blurring of structural details. Our results indicate that the proposed deep learning method is effective in enhancing the spatial resolution of metabolite maps which may better guide treatment in mutant IDH glioma patients.
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Li, Xianqi, and Ovidiu Andronesi. "NIMG-16. DEEP LEARNING SUPER-RESOLUTION MR SPECTROSCOPIC IMAGING TO MAP TUMOR METABOLISM IN MUTANT IDH GLIOMA PATIENTS." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi131. http://dx.doi.org/10.1093/neuonc/noab196.516.
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Abstract Metabolic imaging can map spatially abnormal molecular pathways with higher specificity for cancer compared to anatomical imaging. However, acquiring high resolution metabolic maps similar to anatomical MRI is challenging in patients due to low metabolite concentrations, and alternative approaches that increase resolution by post-acquisition image processing can mitigate this limitation. We developed deep learning super-resolution MR spectroscopic imaging (MRSI) to map tumor metabolism in patients with mutant IDH glioma. We used a generative adversarial network (GAN) architecture comprised of a UNet neural network as the generator network and a discriminator network for adversarial training. For initial training we simulated a large data set of 9600 images with realistic quality for acquired MRSI to effectively train the deep learning model to upsample by a factor of four. Two types of training were performed: 1) using only the MRSI data, and 2) using MRSI and prior information from anatomical MRI to further enhance structural details. The performance of super-resolution methods was evaluated by peak SNR (PSNR), structure similarity index (SSIM), and feature similarity index (FSIM). After training on simulations, GAN was evaluated on measured MRSI metabolic maps acquired with resolution 5.2×5.2 mm2 and upsampled to 1.3×1.3 mm2. The GAN trained only on MRSI achieved PSNR = 27.94, SSIM = 0.88, FSIM = 0.89. Using prior anatomical MRI improved GAN performance to PSNR = 30.75, SSIM = 0.90, FSIM = 0.92. In the patient measured data, GAN super-resolution metabolic images provided clearer tumor margins and made apparent the tumor metabolic heterogeneity. Compared to conventional image interpolation such as bicubic or total variation, deep learning methods provided sharper edges and less blurring of structural details. Our results indicate that the proposed deep learning method is effective in enhancing the spatial resolution of metabolite maps which may better guide treatment in mutant IDH glioma patients.
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Gómez Damián, Pedro A., Jonathan I. Sperl, Martin A. Janich, Oleksandr Khegai, Florian Wiesinger, Steffen J. Glaser, Axel Haase, Markus Schwaiger, Rolf F. Schulte, and Marion I. Menzel. "Multisite Kinetic Modeling of13C Metabolic MR Using [1-13C]Pyruvate." Radiology Research and Practice 2014 (2014): 1–10. http://dx.doi.org/10.1155/2014/871619.
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Hyperpolarized13C imaging allows real-timein vivomeasurements of metabolite levels. Quantification of metabolite conversion between [1-13C]pyruvate and downstream metabolites [1-13C]alanine, [1-13C]lactate, and [13C]bicarbonate can be achieved through kinetic modeling. Since pyruvate interacts dynamically and simultaneously with its downstream metabolites, the purpose of this work is the determination of parameter values through a multisite, dynamic model involving possible biochemical pathways present in MR spectroscopy. Kinetic modeling parameters were determined by fitting the multisite model to time-domain dynamic metabolite data. The results for different pyruvate doses were compared with those of different two-site models to evaluate the hypothesis that for identical data the uncertainty of a model and the signal-to-noise ratio determine the sensitivity in detecting small physiological differences in the target metabolism. In comparison to the two-site exchange models, the multisite model yielded metabolic conversion rates with smaller bias and smaller standard deviation, as demonstrated in simulations with different signal-to-noise ratio. Pyruvate dose effects observed previously were confirmed and quantified through metabolic conversion rate values. Parameter interdependency allowed an accurate quantification and can therefore be useful for monitoring metabolic activity in different tissues.
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Stopka, Sylwia A., Jiska van der Reest, Walid M. Abdelmoula, Daniela F. Ruiz, Shakchhi Joshi, Alison E. Ringel, Marcia C. Haigis, and Nathalie Y. R. Agar. "Spatially resolved characterization of tissue metabolic compartments in fasted and high-fat diet livers." PLOS ONE 17, no. 9 (September 6, 2022): e0261803. http://dx.doi.org/10.1371/journal.pone.0261803.
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Cells adapt their metabolism to physiological stimuli, and metabolic heterogeneity exists between cell types, within tissues, and subcellular compartments. The liver plays an essential role in maintaining whole-body metabolic homeostasis and is structurally defined by metabolic zones. These zones are well-understood on the transcriptomic level, but have not been comprehensively characterized on the metabolomic level. Mass spectrometry imaging (MSI) can be used to map hundreds of metabolites directly from a tissue section, offering an important advance to investigate metabolic heterogeneity in tissues compared to extraction-based metabolomics methods that analyze tissue metabolite profiles in bulk. We established a workflow for the preparation of tissue specimens for matrix-assisted laser desorption/ionization (MALDI) MSI that can be implemented to achieve broad coverage of central carbon, nucleotide, and lipid metabolism pathways. Herein, we used this approach to visualize the effect of nutrient stress and excess on liver metabolism. Our data revealed a highly organized metabolic tissue compartmentalization in livers, which becomes disrupted under high fat diet. Fasting caused changes in the abundance of several metabolites, including increased levels of fatty acids and TCA intermediates while fatty livers had higher levels of purine and pentose phosphate-related metabolites, which generate reducing equivalents to counteract oxidative stress. This spatially conserved approach allowed the visualization of liver metabolic compartmentalization at 30 μm pixel resolution and can be applied more broadly to yield new insights into metabolic heterogeneity in vivo.
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Bet-Lachin, Anna, Frank Jiang, Lingjing Chen, Keyvan Keshari, David Wilson, John Kurhanewicz, and James L. Rubenstein. "Metabolic Profiling of CNS Lymphoma and Its Microenvironment." Blood 118, no. 21 (November 18, 2011): 588. http://dx.doi.org/10.1182/blood.v118.21.588.588.
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Abstract Abstract 588 Background: Establishing the pathologic basis of focal brain lesions caused by disease processes such as CNS lymphoma is often difficult. Results of standard MRI-based neuro-imaging are non-specific and cytological testing of cerebrospinal fluid (CSF) is highly insensitive. We tested the hypothesis that the metabolic constituents of the CSF reflect pathologic processes within the brain and thus might lead to the identification of novel diagnostic and prognostic biomarkers and provide insight into mechanisms of CNS lymphoma pathogenesis and its impact on cognitive function. We have pursued two novel approaches to define and model the metabolic microenvironment in CNS lymphoma: (1) Differential metabolite profiling of CSF; (2) Metabolic imaging using hyperpolarized 13C probes using preclinical models involving intracranial xenografts of CNS lymphoma. Methods: We are using GC/MS, in collaboration with Metabolon, to profile a broad spectrum of metabolites (> 140) in CSF from CNS lymphoma patients at diagnosis, relapse as well as from control subjects without brain tumors. In parallel, we are using high resolution MRI (14T) to perform anatomic and contrast enhanced imaging plus hyperpolarized metabolic imaging using 13C-metabolic probes such as [1-13C] pyruvate to monitor the production of intratumoral metabolites such as lactate within highly infiltrative xenograft models of CNS lymphoma. Results: Metabolite concentrations in CSF from 15 subjects with active CNS lymphoma were compared to 15 controls without brain tumors. Seventeen metabolites were significantly upregulated in CSF (> two-fold) compared to controls (p<0.05). Notably, despite similar tumor burdens, the CSF concentrations of lactate, malate and succinate were highest in patients with refractory lymphoma compared to chemotherapy-sensitive tumors. Another TCA intermediate, citrate, was detected at similar concentrations in CSF from controls and lymphoma patients. CSF concentrations of N-acetyl-aspartyl-glutamate, a neurotransmitter, were significantly lower in subjects with CNS lymphoma compared to controls. Metabolic imaging of murine CNS lymphoma xenograft (Raji lymphoma) using hyperpolarized [1-13C] pyruvate demonstrated intratumoral Warburg metabolism with a striking elevation of [1-13C] lactate that was apparent beyond the anatomical margins of the contrast enhancing lymphoma, as demonstrated by T1-weighted post-gadolinium images. Conclusions: These preliminary results suggest that 13C imaging may be able to identify regions of metabolic abnormality in CNS lymphoma outside those identified by 1H methods, and thus potentially provide insight into the metabolic features of the lymphoma as well as its stromal microenvironment. Our hypothesis is that MRI-based, non-invasive metabolic imaging will provide insights into the molecular differences between newly-diagnosed and relapsed cases as well as provide novel, non-invasive diagnostic and prognostic biomarkers. Supported by a grant from CFAR and the Sandler Program for Breakthrough Biomedical Research. Disclosures: No relevant conflicts of interest to declare.
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Chen, Minjiang, Siming Lu, Hong Zheng, Min Xu, Jingjing Song, Weibin Yang, Qiaoyou Weng, et al. "Identification of the Potential Metabolic Pathways Involved in the Hepatic Tumorigenesis of Rat Diethylnitrosamine-Induced Hepatocellular Carcinoma via 1H NMR-Based Metabolomic Analysis." BioMed Research International 2019 (January 2, 2019): 1–11. http://dx.doi.org/10.1155/2019/9367082.
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The systemic investigation of the metabolic pathways associated with the hepatic tumorigenesis is important to discover novel biomarkers and identify the potential pathogenesis. Here, the 1H nuclear magnetic resonance- (1H NMR-) based metabolomic analysis was used to monitor the whole process of rat diethylnitrosamine-induced HCC. Intraperitoneal administration of diethylnitrosamine (DEN) was used to induce primary HCCs in male Sprague-Dawley rats. Magnetic resonance imaging (MRI) examinations were performed to follow the tumor formation and growth in the liver and H&E staining was used to confirm MR imaging findings. The rats with DEN treatment and control rats without DEN were euthanized at the time points of 3, 8, and 15 weeks after the start of modeling. 1H NMR-based metabolomic analysis was used to explore hepatic metabolite changes and certify key metabolic pathways in the process of tumor tumorigenesis. Our MRI results depicted the formation of HCC nodules in ten rats 14 weeks after DEN injection which were confirmed by histology. Twenty-four different metabolites were identified and quantified by 1H NMR spectroscopy; OPLS-DA models and corresponding VIP plots analysis further identified ten metabolites associated with the abnormal metabolism. The aberrant glucose, lipid, and glutathione-glutamine-glutamate metabolism could be detected involving in the process of hepatic tumorigenesis, which provides an important evidence for the in-depth study of subsequent molecular mechanisms, especially the glutathione-glutamine-glutamate metabolism.
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Viswanath, Pavithra, Georgios Batsios, Anne Marie Gillespie, Russell O. Pieper, and Sabrina Ronen. "CBMT-41. IMAGING A HALLMARK OF CANCER: HYPERPOLARIZED 13C-MAGNETIC RESONANCE SPECTROSCOPY CAN NON-INVASIVELY MONITOR TERT EXPRESSION IN LOW-GRADE GLIOMAS IN VIVO." Neuro-Oncology 21, Supplement_6 (November 2019): vi42. http://dx.doi.org/10.1093/neuonc/noz175.163.
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Abstract Telomerase reverse transcriptase (TERT) expression is a hallmark of cancer, including in primary glioblastomas and low-grade oligodendrogliomas. Since TERT is essential for glioma proliferation and is an attractive therapeutic target, metabolic imaging of TERT status can inform on tumor progression and response to therapy. To that end, the goal of this study was to identify non-invasive, translational, hyperpolarized 13C-magnetic resonance spectroscopy-detectable metabolic imaging biomarkers of TERT in low-grade oligodendrogliomas. Unbiased metabolomic analysis of immortalized normal human astrocytes without (NHAcontrol) and with TERT (NHAtert) indicated that TERT induced unique metabolic reprogramming. Notably, TERT increased NADPH and NADH levels. Glucose flux through the pentose phosphate pathway (PPP) is a major producer of NADPH. Non-invasive imaging of PPP flux using hyperpolarized [U-13C,U-2H]-glucose indicated that production of the PPP metabolite 6-phosphogluconate (6-PG) was elevated in NHAtert cells relative to NHAcontrol. Importantly, hyperpolarized [U-13C,U-2H]-glucose flux to 6-PG clearly differentiated tumor from normal brain in orthotopic NHAtert tumor xenografts. Next, we exploited the observation that TERT expression increased NADH, which is essential for the metabolism of hyperpolarized [1-13C]-alanine to lactate. Lactate production from hyperpolarized [1-13C]-alanine was higher in NHAtert cells relative to NHAcontrol. Importantly, hyperpolarized [1-13C]-alanine imaging in orthotopic NHAtert tumors revealed pronounced differences in lactate production between tumor tissue and normal brain. Mechanistically, TERT increased expression of glucose-6-phosphate dehydrogenase (G6PDH), the rate-limiting enzyme for 6-PG and NADPH production, and of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme for NADH biosynthesis. Silencing TERT reversed G6PDH and NAMPT expression and normalized hyperpolarized [U-13C,U-2H]-glucose and [1-13C]-alanine metabolism, validating our imaging biomarkers. Finally, hyperpolarized [U-13C,U-2H]-glucose and [1-13C]-alanine could monitor TERT status in the clinically relevant, patient-derived BT54 oligodendroglioma model. In summary, we demonstrate, for the first time, non-invasive in vivo imaging of TERT status in gliomas that can enable longitudinal analysis of tumor burden and treatment response in the clinic.
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Lin, Gigin, and Yuen-Li Chung. "Current Opportunities and Challenges of Magnetic Resonance Spectroscopy, Positron Emission Tomography, and Mass Spectrometry Imaging for Mapping Cancer MetabolismIn Vivo." BioMed Research International 2014 (2014): 1–13. http://dx.doi.org/10.1155/2014/625095.
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Cancer is known to have unique metabolic features such as Warburg effect. Current cancer therapy has moved forward from cytotoxic treatment to personalized, targeted therapies, with some that could lead to specific metabolic changes, potentially monitored by imaging methods. In this paper we addressed the important aspects to study cancer metabolism by using image techniques, focusing on opportunities and challenges of magnetic resonance spectroscopy (MRS), dynamic nuclear polarization (DNP)-MRS, positron emission tomography (PET), and mass spectrometry imaging (MSI) for mapping cancer metabolism. Finally, we highlighted the future possibilities of an integratedin vivoPET/MR imaging systems, together with anin situMSI tissue analytical platform, may become the ultimate technologies for unraveling and understanding the molecular complexities in some aspects of cancer metabolism. Such comprehensive imaging investigations might provide information on pharmacometabolomics, biomarker discovery, and disease diagnosis, prognosis, and treatment response monitoring for clinical medicine.
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Schiepers, Christiaan, Paul Van Hecke, Rik Vandenberghe, Sylvie Van Oostende, Patrick Dupont, Philippe Demaerel, Guy Bormans, and Herwig Carton. "Positron emission tomography, magnetic resonance imaging and proton NMR spectroscopy of white matter in multiple sclerosis." Multiple Sclerosis Journal 3, no. 1 (February 1997): 8–17. http://dx.doi.org/10.1177/135245859700300102.
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Objective: To assess characteristics of MS lesions and normal appearing white matter (NAWM) with various imaging modalities. Glucose metabolism was investigated with FDG - PET, metabolite concentration with proton NMR spectroscopy, and lesion detection with routine brain MRI. Methods: Thirteen patients were studied in a stable phase of their disease, and two during an acute episode. Nine healthy volunteers served as controls. Results: Three patients had a normal brain MRI, 12 had typical lesions. MR images were registered to the PET planes. Lesions and contra-lateral control areas were analyzed, 10/15 lesions showed relative hyper-metabolism and 2 hypo-metabolism. NAA concentration was significantly decreased in both lesions and NAWM. Conclusion: In stable MS, most large lesions have a relatively increased glucose utilization and decreased NAA concentration. NAWM showed a significantly decreased NAA concentration compared to healthy subjects, but no difference in glucose metabolism. Active lesions in acute MS are also hyper-metabolic. This finding opens a new window on the classification of white matter lesions based on glucose utilization.
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Sun, Na, Isis E. Fernandez, Mian Wei, Michael Witting, Michaela Aichler, Annette Feuchtinger, Gerald Burgstaller, et al. "Pharmacometabolic response to pirfenidone in pulmonary fibrosis detected by MALDI-FTICR-MSI." European Respiratory Journal 52, no. 3 (August 2, 2018): 1702314. http://dx.doi.org/10.1183/13993003.02314-2017.
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Idiopathic pulmonary fibrosis (IPF) is a fatal condition that reduces life expectancy and shows a limited response to available therapies. Pirfenidone has been approved for treatment of IPF, but little is known about the distinct metabolic changes that occur in the lung upon pirfenidone administration.Here, we performed a proof-of-concept study using high-resolution quantitative matrix-assisted laser desorption/ionisation Fourier-transform ion cyclotron resonance mass spectrometry imaging (MALDI-FTICR-MSI) to simultaneously detect, visualise and quantify in situ endogenous and exogenous metabolites in lungs of mice subjected to experimental fibrosis and human patients with IPF, and to assess the effect of pirfenidone treatment on metabolite levels.Metabolic pathway analysis and endogenous metabolite quantification revealed that pirfenidone treatment restores redox imbalance and glycolysis in IPF tissues, and downregulates ascorbate and aldarate metabolism, thereby likely contributing to in situ modulation of collagen processing. As such, we detected specific alterations in metabolite pathways in fibrosis and, importantly, metabolic recalibration following pirfenidone treatment.Together, these results highlight the suitability of high-resolution MALDI-FTICR-MSI for deciphering the therapeutic effects of pirfenidone and provide a preliminary analysis of the metabolic changes that occur during pirfenidone treatment in vivo. These data may therefore contribute to improvement of currently available therapies for IPF.
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Tamaki, Nagara, Yuji Kuge, and Keiichiro Yoshinaga. "Myocardial Metabolic Imaging in the Clinical Setting." European Cardiology Review 5, no. 1 (2009): 15. http://dx.doi.org/10.15420/ecr.2012.5.1.15.
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Glucose and free fatty acids are a major energy source in the myocardium. Metabolic imaging with single photon emission tomography (SPECT) and positron emission tomography (PET) have been widely used for the evaluation of the pathophysiology of coronary artery disease (CAD) and heart failure. 18F fluorodeoxyglucose (FDG) is a glucose analogue that is used to measure myocardial glucose utilisation. The myocardial uptake of a modified branched fatty acid, 15-(p-[iodine-123] iodophenyl)-3-(R,S) methylpentadecanoic acid (BMIPP), reflects the activation of fatty-acid metabolism by co-enzyme A (CoA) and indirectly reflects cellular adenosine triphosphate (ATP) production. The turnover rate of the tricarboxylic acid (TCA) cycle reflects the rate of overall myocardial oxidative metabolism. 11C acetate is readily metabolised to CO2 almost exclusively through the TCA cycle. These three major agents have been most commonly used for probing myocardial energy metabolism in vivo. Such metabolic imaging has been used for assessing myocardial viability on the basis of persistent glucose utilisation in ischaemic but viable myocardium. BMIPP and FDG have been identified for locating a recent history of myocardial ischaemia. Furthermore, metabolic imaging is promising for the assessment of the pathophysiology of heart failure and the treatment effect of various drugs, as well as mechanical treatments. In this article we will provide an overview of the application of myocardial metabolic imaging in a clinical setting.
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Butt, Sadia A., Lise V. Søgaard, Peter O. Magnusson, Mette H. Lauritzen, Christoffer Laustsen, Per Åkeson, and Jan H. Ardenkjær-Larsen. "Imaging Cerebral 2-Ketoisocaproate Metabolism with Hyperpolarized 13C Magnetic Resonance Spectroscopic Imaging." Journal of Cerebral Blood Flow & Metabolism 32, no. 8 (March 28, 2012): 1508–14. http://dx.doi.org/10.1038/jcbfm.2012.34.
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The branched chain amino acid transaminase (BCAT) has an important role in nitrogen shuttling and glutamate metabolism in the brain. The purpose of this study was to describe the cerebral distribution and metabolism of hyperpolarized 2-keto[1-13C]isocaproate (KIC) in the normal rat using magnetic resonance modalities. Hyperpolarized KIC is metabolized to [1-13C]leucine (leucine) by BCAT. The results show that KIC and its metabolic product, leucine, are present at imageable quantities 20 seconds after end of KIC administration throughout the brain. Further, significantly higher metabolism was observed in hippocampal regions compared with the muscle tissue. In conclusion, the cerebral metabolism of hyperpolarized KIC is imaged and hyperpolarized KIC may be a promising substrate for evaluation of cerebral BCAT activity in conjunction with neurodegenerative disease.
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Li, Huiling, Zhen Liu, Lujie Yuan, Kevin Fan, Yongxue Zhang, Weibo Cai, and Xiaoli Lan. "Radionuclide-Based Imaging of Breast Cancer: State of the Art." Cancers 13, no. 21 (October 30, 2021): 5459. http://dx.doi.org/10.3390/cancers13215459.
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Breast cancer is a malignant tumor that can affect women worldwide and endanger their health and wellbeing. Early detection of breast cancer can significantly improve the prognosis and survival rate of patients, but with traditional anatomical imagine methods, it is difficult to detect lesions before morphological changes occur. Radionuclide-based molecular imaging based on positron emission tomography (PET) and single-photon emission computed tomography (SPECT) displays its advantages for detecting breast cancer from a functional perspective. Radionuclide labeling of small metabolic compounds can be used for imaging biological processes, while radionuclide labeling of ligands/antibodies can be used for imaging receptors. Noninvasive visualization of biological processes helps elucidate the metabolic state of breast cancer, while receptor-targeted radionuclide molecular imaging is sensitive and specific for visualization of the overexpressed molecular markers in breast cancer, contributing to early diagnosis and better management of cancer patients. The rapid development of radionuclide probes aids the diagnosis of breast cancer in various aspects. These probes target metabolism, amino acid transporters, cell proliferation, hypoxia, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), gastrin-releasing peptide receptor (GRPR) and so on. This article provides an overview of the development of radionuclide molecular imaging techniques present in preclinical or clinical studies, which are used as tools for early breast cancer diagnosis.
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Vergen, Jorge, Clifford Hecht, Lyandysha V. Zholudeva, Meg M. Marquardt, Richard Hallworth, and Michael G. Nichols. "Metabolic Imaging Using Two-Photon Excited NADH Intensity and Fluorescence Lifetime Imaging." Microscopy and Microanalysis 18, no. 4 (July 26, 2012): 761–70. http://dx.doi.org/10.1017/s1431927612000529.
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AbstractMetabolism and mitochondrial dysfunction are known to be involved in many different disease states. We have employed two-photon fluorescence imaging of intrinsic mitochondrial reduced nicotinamide adenine dinucleotide (NADH) to quantify the metabolic state of several cultured cell lines, multicell tumor spheroids, and the intact mouse organ of Corti. Historically, fluorescence intensity has commonly been used as an indicator of the NADH concentration in cells and tissues. More recently, fluorescence lifetime imaging has revealed that changes in metabolism produce not only changes in fluorescence intensity, but also significant changes in the lifetimes and concentrations of free and enzyme-bound pools of NADH. Since NADH binding changes with metabolic state, this approach presents a new opportunity to track the cellular metabolic state.
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Parshina, Yulia P., Anastasia D. Komarova, Leonid N. Bochkarev, Tatyana A. Kovylina, Anton A. Plekhanov, Larisa G. Klapshina, Aleksey N. Konev, et al. "Simultaneous Probing of Metabolism and Oxygenation of Tumors In Vivo Using FLIM of NAD(P)H and PLIM of a New Polymeric Ir(III) Oxygen Sensor." International Journal of Molecular Sciences 23, no. 18 (September 6, 2022): 10263. http://dx.doi.org/10.3390/ijms231810263.
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Tumor cells are well adapted to grow in conditions of variable oxygen supply and hypoxia by switching between different metabolic pathways. However, the regulatory effect of oxygen on metabolism and its contribution to the metabolic heterogeneity of tumors have not been fully explored. In this study, we develop a methodology for the simultaneous analysis of cellular metabolic status, using the fluorescence lifetime imaging microscopy (FLIM) of metabolic cofactor NAD(P)H, and oxygen level, using the phosphorescence lifetime imaging (PLIM) of a new polymeric Ir(III)-based sensor (PIr3) in tumors in vivo. The sensor, derived from a polynorbornene and cyclometalated iridium(III) complex, exhibits the oxygen-dependent quenching of phosphorescence with a 40% longer lifetime in degassed compared to aerated solutions. In vitro, hypoxia resulted in a correlative increase in PIr3 phosphorescence lifetime and free (glycolytic) NAD(P)H fraction in cells. In vivo, mouse tumors demonstrated a high degree of cellular-level heterogeneity of both metabolic and oxygen states, and a lower dependence of metabolism on oxygen than cells in vitro. The small tumors were hypoxic, while the advanced tumors contained areas of normoxia and hypoxia, which was consistent with the pimonidazole assay and angiographic imaging. Dual FLIM/PLIM metabolic/oxygen imaging will be valuable in preclinical investigations into the effects of hypoxia on metabolic aspects of tumor progression and treatment response.
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Yeşildağ, A., A. Ayata, B. Baykal, M. Koroglu, H. Yıldız, B. Oral, F. Oktem, and O. Oyar. "Magnetic resonance imaging and diffusion‐weighted imaging in methylmalonic acidemia." Acta Radiologica 46, no. 1 (February 2005): 101–3. http://dx.doi.org/10.1080/02841850510020888.
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Methylmalonic acidemia (MMA) is an inborn disorder of amino acid metabolism, often presenting with neurological symptoms. We present the results of magnetic resonance imaging (MRI) and diffusion‐weighted imaging (DWI) of the brain in a 16‐month‐old male patient with classic neurological and laboratory findings for MMA. MRI demonstrated the hyperintensity within globi pallidi both on T2‐weighted image and DWI during the acute episode of metabolic acidosis.
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Schrauwen-Hinderling, Vera B., and André C. Carpentier. "Molecular imaging of postprandial metabolism." Journal of Applied Physiology 124, no. 2 (February 1, 2018): 504–11. http://dx.doi.org/10.1152/japplphysiol.00212.2017.
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Disordered postprandial metabolism of energy substrates is one of the main defining features of prediabetes and contributes to the development of several chronic diseases associated with obesity, such as type 2 diabetes and cardiovascular diseases. Postprandial energy metabolism has been studied using classical isotopic tracer approaches that are limited by poor access to splanchnic metabolism and highly dynamic and complex exchanges of energy substrates involving multiple organs and systems. Advances in noninvasive molecular imaging modalities, such as PET and MRI/magnetic resonance spectroscopy (MRS), have recently allowed important advances in our understanding of postprandial energy metabolism in humans. The present review describes some of these recent advances, with particular focus on glucose and fatty acid metabolism in the postprandial state, and discusses current gaps in knowledge and new perspectives of application of PET and MRI/MRS for the investigation and treatment of human metabolic diseases.
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Larion, Mioara, Tyrone Dowdy, Victor Ruiz-Rodado, Matthew Meyer, Hua Song, Wei Zhang, Dionne Davis, Mark Gilbert, and Adrian Lita. "Detection of Metabolic Changes Induced via Drug Treatments in Live Cancer Cells and Tissue Using Raman Imaging Microscopy." Biosensors 9, no. 1 (December 28, 2018): 5. http://dx.doi.org/10.3390/bios9010005.
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Isocitrate dehydrogenase 1 (IDH1) mutations in gliomas, fibrosarcoma, and other cancers leads to a novel metabolite, D-2-hydroxyglutarate, which is proposed to cause tumorigenesis. The production of this metabolite also causes vulnerabilities in cellular metabolism, such as lowering NADPH levels. To exploit this vulnerability, we treated glioma and fibrosarcoma cells that harbor an IDH1 mutation with an inhibitor of nicotinamide adenine dinucleotide (NAD+) salvage pathway, FK866, and observed decreased viability in these cells. To understand the mechanism of action by which the inhibitor FK866 works, we used Raman imaging microscopy and identified that proteins and lipids are decreased upon treatment with the drug. Raman imaging showed a different distribution of lipids throughout the cell in the presence of the drug compared with the untreated cells. We employed nuclear magnetic resonance NMR spectroscopy and mass spectrometry to identify the classes of lipids altered. Our combined analyses point to a decrease in cell division due to loss of lipid content that contributes to membrane formation in the in vitro setting. However, the FK866 drug did not have the same potency in vivo. The use of Raman imaging microscopy indicated an opposite trend of lipid distribution in the tissue collected from treated versus untreated mice when compared with the cells. These results demonstrate the role of Raman imaging microscopy to identify and quantify metabolic changes in cancer cells and tissue.
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Yang, Yi-Fang, Chien-Hsiu Li, Huei-Yu Cai, Bo-Syuan Lin, Cheorl-Ho Kim, and Yu-Chan Chang. "Application of Metabolic Reprogramming to Cancer Imaging and Diagnosis." International Journal of Molecular Sciences 23, no. 24 (December 13, 2022): 15831. http://dx.doi.org/10.3390/ijms232415831.
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Cellular metabolism governs the signaling that supports physiological mechanisms and homeostasis in an individual, including neuronal transmission, wound healing, and circadian clock manipulation. Various factors have been linked to abnormal metabolic reprogramming, including gene mutations, epigenetic modifications, altered protein epitopes, and their involvement in the development of disease, including cancer. The presence of multiple distinct hallmarks and the resulting cellular reprogramming process have gradually revealed that these metabolism-related molecules may be able to be used to track or prevent the progression of cancer. Consequently, translational medicines have been developed using metabolic substrates, precursors, and other products depending on their biochemical mechanism of action. It is important to note that these metabolic analogs can also be used for imaging and therapeutic purposes in addition to competing for metabolic functions. In particular, due to their isotopic labeling, these compounds may also be used to localize and visualize tumor cells after uptake. In this review, the current development status, applicability, and limitations of compounds targeting metabolic reprogramming are described, as well as the imaging platforms that are most suitable for each compound and the types of cancer to which they are most appropriate.
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Venturas, Marta, Jaimin S. Shah, Xingbo Yang, Tim H. Sanchez, William Conway, Denny Sakkas, and Dan J. Needleman. "Metabolic state of human blastocysts measured by fluorescence lifetime imaging microscopy." Human Reproduction 37, no. 3 (January 6, 2022): 411–27. http://dx.doi.org/10.1093/humrep/deab283.
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Abstract STUDY QUESTION Can non-invasive metabolic imaging via fluorescence lifetime imaging microscopy (FLIM) detect variations in metabolic profiles between discarded human blastocysts? SUMMARY ANSWER FLIM revealed extensive variations in the metabolic state of discarded human blastocysts associated with blastocyst development over 36 h, the day after fertilization and blastocyst developmental stage, as well as metabolic heterogeneity within individual blastocysts. WHAT IS KNOWN ALREADY Mammalian embryos undergo large changes in metabolism over the course of preimplantation development. Embryo metabolism has long been linked to embryo viability, suggesting its potential utility in ART to aid in selecting high quality embryos. However, the metabolism of human embryos remains poorly characterized due to a lack of non-invasive methods to measure their metabolic state. STUDY DESIGN, SIZE, DURATION We conducted a prospective observational study. We used 215 morphologically normal human embryos from 137 patients that were discarded and donated for research under an approved institutional review board protocol. These embryos were imaged using metabolic imaging via FLIM to measure the autofluorescence of two central coenzymes, nicotinamide adenine (phosphate) dinucleotide (NAD(P)H) and flavine adenine dinucleotide (FAD+), which are essential for cellular respiration and glycolysis. PARTICIPANTS/MATERIALS, SETTING, METHODS Here, we used non-invasive FLIM to measure the metabolic state of human blastocysts. We first studied spatial patterns in the metabolic state within human blastocysts and the association of the metabolic state of the whole blastocysts with stage of expansion, day of development since fertilization and morphology. We explored the sensitivity of this technique in detecting metabolic variations between blastocysts from the same patient and between patients. Next, we explored whether FLIM can quantitatively measure metabolic changes through human blastocyst expansion and hatching via time-lapse imaging. For all test conditions, the level of significance was set at P < 0.05 after correction for multiple comparisons using Benjamini–Hochberg’s false discovery rate. MAIN RESULTS AND THE ROLE OF CHANCE We found that FLIM is sensitive enough to detect significant metabolic differences between blastocysts. We found that metabolic variations between blastocyst are partially explained by both the time since fertilization and their developmental expansion stage (P < 0.05), but not their morphological grade. Substantial metabolic variations between blastocysts from the same patients remain, even after controlling for these factors. We also observe significant metabolic heterogeneity within individual blastocysts, including between the inner cell mass and the trophectoderm, and between the portions of hatching blastocysts within and without the zona pellucida (P < 0.05). And finally, we observed that the metabolic state of human blastocysts continuously varies over time. LIMITATIONS, REASONS FOR CAUTION Although we observed significant variations in metabolic parameters, our data are taken from human blastocysts that were discarded and donated for research and we do not know their clinical outcome. Moreover, the embryos used in this study are a mixture of aneuploid, euploid and embryos of unknown ploidy. WIDER IMPLICATIONS OF THE FINDINGS This work reveals novel aspects of the metabolism of human blastocysts and suggests that FLIM is a promising approach to assess embryo viability through non-invasive, quantitative measurements of their metabolism. These results further demonstrate that FLIM can provide biologically relevant information that may be valuable for the assessment of embryo quality. STUDY FUNDING/COMPETING INTEREST(S) Supported by the Blavatnik Biomedical Accelerator Grant at Harvard University. Becker and Hickl GmbH and Boston Electronics sponsored research with the loaning of equipment for FLIM. D.J.N. is an inventor on patent US20170039415A1. TRIAL REGISTRATION NUMBER N/A.
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Ding, Hao, Athar Haroon, Simon Wan, Thoralf Niendorf, and Sola Adeleke. "Old Discovery Leading to New Era: Metabolic Imaging of Cancer with Deuterium MRI." Magnetochemistry 9, no. 1 (December 25, 2022): 6. http://dx.doi.org/10.3390/magnetochemistry9010006.
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The understanding of metabolic compartments involved in the survival, growth and invasion of tumours is important for modern cancer research. Deuterium metabolic spectroscopy (DMS) and metabolic imaging (DMI) have been demonstrated as robust, straightforward tools for visualising tumour metabolism in vivo. However, for them to become part of the cancer patient’s management pathway in a clinical setting, there remain many obstacles to overcome. Technological advancement in magnetic resonance imaging hardware and processing is needed. Further justification of DMI’s potential also requires more human study and multidisciplinary collaboration.
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Thiagarajan, Prarthana, Stephen J. Bawden, and Guruprasad P. Aithal. "Metabolic Imaging in Non-Alcoholic Fatty Liver Disease: Applications of Magnetic Resonance Spectroscopy." Journal of Clinical Medicine 10, no. 4 (February 7, 2021): 632. http://dx.doi.org/10.3390/jcm10040632.
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Non-alcoholic fatty liver disease (NAFLD) is poised to dominate the landscape of clinical hepatology in the 21st century. Its complex, interdependent aetiologies, non-linear disease progression and uncertain natural history have presented great challenges to the development of effective therapies. Progress will require an integrated approach to uncover molecular mediators, key pathogenic milestones and response to intervention at the metabolic level. The advent of precision imaging has yielded unprecedented insights into these processes. Quantitative imaging biomarkers such as magnetic resonance imaging (MRI), spectroscopy (MRS) and elastography (MRE) present robust, powerful tools with which to probe NAFLD metabolism and fibrogenesis non-invasively, in real time. Specific advantages of MRS include the ability to quantify static metabolite concentrations as well as dynamic substrate flux in vivo. Thus, a vast range of key metabolic events in the natural history of NAFLD can be explored using MRS. Here, we provide an overview of MRS for the clinician, as well as key pathways exploitable by MRS in vivo. Development, optimisation and validation of multinuclear MRS, in combination with other quantitative imaging techniques, may ultimately provide a robust, non-invasive alternative to liver biopsy for observational and longitudinal studies. Through enabling deeper insight into inflammatory and fibrogenic cascades, MRS may facilitate identification of novel therapeutic targets and clinically meaningful endpoints in NAFLD. Its widespread use in future could conceivably accelerate study design, data acquisition and availability of disease-modifying therapies at a population level.
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Penet, Marie-France, Tariq Shah, Santosh Bharti, Balaji Krishnamachary, Dmitri Artemov, Yelena Mironchik, Flonné Wildes, Anirban Maitra, and Zaver M. Bhujwalla. "Metabolic Imaging of Pancreatic Ductal Adenocarcinoma Detects Altered Choline Metabolism." Clinical Cancer Research 21, no. 2 (November 4, 2014): 386–95. http://dx.doi.org/10.1158/1078-0432.ccr-14-0964.
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Vaziri, Sana, Yaewon Kim, Adam Autry, Hsin-Yu Chen, Jeremy Gordon, Marisa LaFontaine, Jasmine Hu, et al. "NIMG-21. VARIABLE RESOLUTION HYPERPOLARIZED [2-13C]PYRUVATE MRI IN HEALTHY VOLUNTEERS AND PATIENTS WITH IDH-MUTANT GLIOMA." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi132. http://dx.doi.org/10.1093/neuonc/noab196.521.
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Abstract INTRODUCTION Mutations in isocitrate dehydrogenase (IDH) have been investigated as a prognostic biomarker in glioma. The presence of the IDH mutation (IDHm) is associated with 2-hydroxyglutarate (2HG) production and inhibition of glutamate synthesis (McBrayer, Cell 2018). Hyperpolarized carbon-13 (HP-13C) MRI enables dynamic measurements of in-vivo metabolism using a [2-13C]pyruvate labeled probe that undergoes conversion to [2-13C]lactate and [5-13C]glutamate. Here, we present HP [2-13C]pyruvate data from healthy volunteers and patients with IDHm diffuse glioma. Due to its intrinsic low signal-to-noise ratio (SNR), we demonstrate the ability of post-processing denoising to improve its utility and aid in detection of metabolic changes associated with IDHm. METHODS Dynamic HP 13C data were acquired following intravenous injection of [2-13C]pyruvate from five healthy volunteers and one patient with IDHm grade III astrocytoma. A novel multi-resolution frequency specific multislice EPI sequence was used to obtain [2-13C]pyruvate, [5-13C]glutamate, and downfield and upfield [2-13C]lactate signals (3s temporal resolution, pyruvate/lactate/glutamate spatial resolutions = 0.75x0.75cm2/ 2.25x2.25cm2/ 2.25x2.25cm2, 5 slices 3cm thick). Following phase correction, patch-based tensor decomposition denoising was applied to metabolite images. Metabolite differences between normal-appearing white matter (NAWM) and T2 lesion were examined for the patient data. RESULTS HP [2-13C]pyruvate imaging is able to simultaneously probe glycolytic ([2-13C]lactate) and oxidative ([5-13C]glutamate) metabolism. Denoised pyruvate/lactate/glutamate signals achieved a 4-9/3-6/3-7 fold increase in SNR. T2 lesion exhibited decreased glutamate-to-pyruvate and glutamate-to-lactate AUC ratios versus contralateral NAWM (p< 0.018, p < 1.5e-5), consistent with IDH mutant status. CONCLUSION We successfully demonstrated the feasibility of applying variable resolution HP [2-13C]pyruvate metabolic imaging to detect IDHm specific metabolism. This technique addresses a major hurdle in HP 13C MRI by improving SNR while permitting robust metabolism quantification. Future studies will optimize methods for acquiring and processing data to evaluate further data acquired from IDHm glioma patients. Supported by NIH T32 CA151022, P01 CA118816, and NICO.
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Batsios, Georgios, Celine Taglang, Meryssa Tran, Anne Marie Gillepspie, and Pavithra Viswanath. "TMET-20. TERT ACTS VIA FOXO1 TO ALTER REDOX METABOLISM IN BRAIN TUMORS." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii265—vii266. http://dx.doi.org/10.1093/neuonc/noac209.1025.
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Abstract Telomere maintenance is a fundamental hallmark of cancer. Most tumors maintain telomere length via reactivation of telomerase reverse transcriptase (TERT) expression. Identifying imaging biomarkers of TERT can enable non-invasive assessment of tumor proliferation and response to therapy. Deuterium magnetic resonance spectroscopy (DMRS) following administration of 2H-labeled substrates recently emerged as a novel, clinically translatable method of monitoring metabolic activity in vivo. The goal of this study was to delineate metabolic reprogramming associated with TERT expression and to leverage this information for non-invasive imaging of tumor burden and treatment response in gliomas. Our results indicate that TERT expression is associated with elevated levels of the redox metabolite NADH in glioblastomas and oligodendrogliomas. Mechanistically, TERT expression is associated with inhibitory phosphorylation and cytosolic sequestration of FOXO1. FOXO1, in turn, negatively regulates nicotinamide phosphoribosyl transferase (NAMPT), which is the rate-limiting enzyme in NAD+ biosynthesis. As a result, TERT upregulates NAMPT, resulting in elevated steady-state pools of NAD+ and NADH. Concomitantly, FOXO1 negatively regulates the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase, which converts NAD+ to NADH. As a result, TERT upregulates the NADH/NAD+ ratio. Since elevated NADH and NADH/NAD+ ratio drive pyruvate conversion to lactate, we then examined whether DMRS-based imaging of [U-2H]-pyruvate metabolism reports on TERT expression in gliomas. Our results indicate that doxycycline-inducible TERT silencing significantly reduces lactate production from [U-2H]-pyruvate in tumor-bearing mice. Importantly, [U-2H]-pyruvate metabolism to lactate differentiates tumor from normal brain in vivo, including at clinical field strength (3T). Furthermore, [U-2H]-pyruvate reports on early response to treatment with TERT inhibitors or with radiochemotherapy in mice bearing orthotopic patient-derived gliomas at early timepoints before radiographic alterations can be visualized by magnetic resonance imaging. Collectively, our studies integrate a mechanistic understanding of TERT biology with innovative imaging that has the potential to improve assessment of tumor burden and treatment response for glioma patients.
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Lu, Alex Y., Jack L. Turban, Eyiyemisi C. Damisah, Jie Li, Ahmed K. Alomari, Tore Eid, Alexander O. Vortmeyer, and Veronica L. Chiang. "Novel biomarker identification using metabolomic profiling to differentiate radiation necrosis and recurrent tumor following Gamma Knife radiosurgery." Journal of Neurosurgery 127, no. 2 (August 2017): 388–96. http://dx.doi.org/10.3171/2016.8.jns161395.
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OBJECTIVEFollowing an initial response of brain metastases to Gamma Knife radiosurgery, regrowth of the enhancing lesion as detected on MRI may represent either radiation necrosis (a treatment-related inflammatory change) or recurrent tumor. Differentiation of radiation necrosis from tumor is vital for management decision making but remains difficult by imaging alone. In this study, gas chromatography with time-of-flight mass spectrometry (GC-TOF) was used to identify differential metabolite profiles of the 2 tissue types obtained by surgical biopsy to find potential targets for noninvasive imaging.METHODSSpecimens of pure radiation necrosis and pure tumor obtained from patient brain biopsies were flash-frozen and validated histologically. These formalin-free tissue samples were then analyzed using GC-TOF. The metabolite profiles of radiation necrosis and tumor samples were compared using multivariate and univariate statistical analysis. Statistical significance was defined as p ≤ 0.05.RESULTSFor the metabolic profiling, GC-TOF was performed on 7 samples of radiation necrosis and 7 samples of tumor. Of the 141 metabolites identified, 17 (12.1%) were found to be statistically significantly different between comparison groups. Of these metabolites, 6 were increased in tumor, and 11 were increased in radiation necrosis. An unsupervised hierarchical clustering analysis found that tumor had elevated levels of metabolites associated with energy metabolism, whereas radiation necrosis had elevated levels of metabolites that were fatty acids and antioxidants/cofactors.CONCLUSIONSTo the authors' knowledge, this is the first tissue-based metabolomics study of radiation necrosis and tumor. Radiation necrosis and recurrent tumor following Gamma Knife radiosurgery for brain metastases have unique metabolite profiles that may be targeted in the future to develop noninvasive metabolic imaging techniques.
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Cannon, Daniel T., Franklyn A. Howe, Brian J. Whipp, Susan A. Ward, Dominick J. McIntyre, Christophe Ladroue, John R. Griffiths, Graham J. Kemp, and Harry B. Rossiter. "Muscle metabolism and activation heterogeneity by combined31P chemical shift and T2imaging, and pulmonary O2uptake during incremental knee-extensor exercise." Journal of Applied Physiology 115, no. 6 (September 15, 2013): 839–49. http://dx.doi.org/10.1152/japplphysiol.00510.2013.
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The integration of skeletal muscle substrate depletion, metabolite accumulation, and fatigue during large muscle-mass exercise is not well understood. Measurement of intramuscular energy store degradation and metabolite accumulation is confounded by muscle heterogeneity. Therefore, to characterize regional metabolic distribution in the locomotor muscles, we combined31P magnetic resonance spectroscopy, chemical shift imaging, and T2-weighted imaging with pulmonary oxygen uptake during bilateral knee-extension exercise to intolerance. Six men completed incremental tests for the following: 1) unlocalized31P magnetic resonance spectroscopy; and 2) spatial determination of31P metabolism and activation. The relationship of pulmonary oxygen uptake to whole quadriceps phosphocreatine concentration ([PCr]) was inversely linear, and three of four knee-extensor muscles showed activation as assessed by change in T2. The largest changes in [PCr], [inorganic phosphate] ([Pi]) and pH occurred in rectus femoris, but no voxel (72 cm3) showed complete PCr depletion at exercise cessation. The most metabolically active voxel reached 11 ± 9 mM [PCr] (resting, 29 ± 1 mM), 23 ± 11 mM [Pi] (resting, 7 ± 1 mM), and a pH of 6.64 ± 0.29 (resting, 7.08 ± 0.03). However, the distribution of31P metabolites and pH varied widely between voxels, and the intervoxel coefficient of variation increased between rest (∼10%) and exercise intolerance (∼30–60%). Therefore, the limit of tolerance was attained with wide heterogeneity in substrate depletion and fatigue-related metabolite accumulation, with extreme metabolic perturbation isolated to only a small volume of active muscle (<5%). Regional intramuscular disturbances are thus likely an important requisite for exercise intolerance. How these signals integrate to limit muscle power production, while regional “recruitable muscle” energy stores are presumably still available, remains uncertain.
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Meissner, Anja, Alba M. Garcia-Serrano, Lotte Vanherle, Zeinab Rafiee, Nicholas Don-Doncow, Cecilia Skoug, Sara Larsson, Michael Gottschalk, Martin Magnusson, and João M. N. Duarte. "Alterations to Cerebral Perfusion, Metabolite Profiles, and Neuronal Morphology in the Hippocampus and Cortex of Male and Female Mice during Chronic Exposure to a High-Salt Diet." International Journal of Molecular Sciences 24, no. 1 (December 24, 2022): 300. http://dx.doi.org/10.3390/ijms24010300.
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Excess dietary salt reduces resting cerebral blood flow (CBF) and vascular reactivity, which can limit the fueling of neuronal metabolism. It is hitherto unknown whether metabolic derangements induced by high-salt-diet (HSD) exposure during adulthood are reversed by reducing salt intake. In this study, male and female mice were fed an HSD from 9 to 16 months of age, followed by a normal-salt diet (ND) thereafter until 23 months of age. Controls were continuously fed either ND or HSD. CBF and metabolite profiles were determined longitudinally by arterial spin labeling magnetic resonance imaging and magnetic resonance spectroscopy, respectively. HSD reduced cortical and hippocampal CBF, which recovered after dietary salt normalization, and affected hippocampal but not cortical metabolite profiles. Compared to ND, HSD increased hippocampal glutamine and phosphocreatine levels and decreased creatine and choline levels. Dietary reversal only allowed recovery of glutamine levels. Histology analyses revealed that HSD reduced the dendritic arborization and spine density of cortical and hippocampal neurons, which were not recovered after dietary salt normalization. We conclude that sustained HSD exposure throughout adulthood causes permanent structural and metabolic alterations to the mouse brain that are not fully normalized by lowering dietary salt during aging.
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Yang, Minfeng, Arpan Mahanty, Chunjing Jin, Alex Ngai Nick Wong, and Jung Sun Yoo. "Label-free metabolic imaging for sensitive and robust monitoring of anti-CD47 immunotherapy response in triple-negative breast cancer." Journal for ImmunoTherapy of Cancer 10, no. 9 (September 2022): e005199. http://dx.doi.org/10.1136/jitc-2022-005199.
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BackgroundImmunotherapy is revolutionizing cancer treatment from conventional radiotherapies and chemotherapies to immune checkpoint inhibitors which use patients’ immune system to recognize and attack cancer cells. Despite the huge clinical success and vigorous development of immunotherapies, there is a significant unmet need for a robust tool to identify responders to specific immunotherapy. Early and accurate monitoring of immunotherapy response is indispensable for personalized treatment and effective drug development.MethodsWe established a label-free metabolic intravital imaging (LMII) technique to detect two-photon excited autofluorescence signals from two coenzymes, NAD(P)H (reduced nicotinamide adenine dinucleotide (phosphate) hydrogen) and FAD (flavin adenine dinucleotide) as robust imaging markers to monitor metabolic responses to immunotherapy. Murine models of triple-negative breast cancer (TNBC) were established and tested with different therapeutic regimens including anti-cluster of differentiation 47 (CD47) immunotherapy to monitor time-course treatment responses using the developed metabolic imaging technique.ResultsWe first imaged the mechanisms of the CD47-signal regulatory protein alpha pathway in vivo, which unravels macrophage-mediated antibody-dependent cellular phagocytosis and illustrates the metabolism of TNBC cells and macrophages. We further visualized the autofluorescence of NAD(P)H and FAD and found a significant increase during tumor growth. Following anti-CD47 immunotherapy, the imaging signal was dramatically decreased demonstrating the sensitive monitoring capability of NAD(P)H and FAD imaging for therapeutic response. NAD(P)H and FAD intravital imaging also showed a marked decrease after chemotherapy and radiotherapy. A comparative study with conventional whole-body bioluminescence and fluorescent glucose imaging demonstrated superior sensitivity of metabolic imaging. Flow cytometry validated metabolic imaging results. In vivo immunofluorescent staining revealed the targeting ability of NAD(P)H imaging mainly for tumor cells and a small portion of immune-active cells and that of FAD imaging mainly for immunosuppressive cells such as M2-like tumor-associated macrophages.ConclusionsCollectively, this study showcases the potential of the LMII technique as a powerful tool to visualize dynamic changes of heterogeneous cell metabolism of cancer cells and immune infiltrates in response to immunotherapy thus providing sensitive and complete monitoring. Leveraged on ability to differentiate cancer cells and immunosuppressive macrophages, the presented imaging approach provides particularly useful imaging biomarkers for emerged innate immune checkpoint inhibitors such as anti-CD47 therapy.
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Park, Seunggwi, Hashizume Rintaro, Seul Kee Kim, and Ilwoo Park. "Characterization of Distinctive In Vivo Metabolism between Enhancing and Non-Enhancing Gliomas Using Hyperpolarized Carbon-13 MRI." Metabolites 11, no. 8 (July 31, 2021): 504. http://dx.doi.org/10.3390/metabo11080504.
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The development of hyperpolarized carbon-13 (13C) metabolic MRI has enabled the sensitive and noninvasive assessment of real-time in vivo metabolism in tumors. Although several studies have explored the feasibility of using hyperpolarized 13C metabolic imaging for neuro-oncology applications, most of these studies utilized high-grade enhancing tumors, and little is known about hyperpolarized 13C metabolic features of a non-enhancing tumor. In this study, 13C MR spectroscopic imaging with hyperpolarized [1-13C]pyruvate was applied for the differential characterization of metabolic profiles between enhancing and non-enhancing gliomas using rodent models of glioblastoma and a diffuse midline glioma. Distinct metabolic profiles were found between the enhancing and non-enhancing tumors, as well as their contralateral normal-appearing brain tissues. The preliminary results from this study suggest that the characterization of metabolic patterns from hyperpolarized 13C imaging between non-enhancing and enhancing tumors may be beneficial not only for understanding distinct metabolic features between the two lesions, but also for providing a basis for understanding 13C metabolic processes in ongoing clinical trials with neuro-oncology patients using this technology.
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Bermejo, Clara, Jennifer C. Ewald, Viviane Lanquar, Alexander M. Jones, and Wolf B. Frommer. "In vivo biochemistry: quantifying ion and metabolite levels in individual cells or cultures of yeast." Biochemical Journal 438, no. 1 (July 27, 2011): 1–10. http://dx.doi.org/10.1042/bj20110428.
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Over the past decade, we have learned that cellular processes, including signalling and metabolism, are highly compartmentalized, and that relevant changes in metabolic state can occur at sub-second timescales. Moreover, we have learned that individual cells in populations, or as part of a tissue, exist in different states. If we want to understand metabolic processes and signalling better, it will be necessary to measure biochemical and biophysical responses of individual cells with high temporal and spatial resolution. Fluorescence imaging has revolutionized all aspects of biology since it has the potential to provide information on the cellular and subcellular distribution of ions and metabolites with sub-second time resolution. In the present review we summarize recent progress in quantifying ions and metabolites in populations of yeast cells as well as in individual yeast cells with the help of quantitative fluorescent indicators, namely FRET metabolite sensors. We discuss the opportunities and potential pitfalls and the controls that help preclude misinterpretation.
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Zuo, ChuanTao, Yilong Ma, BoMin Sun, Shichun Peng, HuiWei Zhang, David Eidelberg, and YiHui Guan. "Metabolic Imaging of Bilateral Anterior Capsulotomy in Refractory Obsessive Compulsive Disorder: an FDG PET Study." Journal of Cerebral Blood Flow & Metabolism 33, no. 6 (February 27, 2013): 880–87. http://dx.doi.org/10.1038/jcbfm.2013.23.
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The therapeutic benefits of bilateral capsulotomy for the treatment of refractory obsessive compulsive disorder (OCD) are probably attributed to interruption of the cortico-striato-thalamo-cortical circuitry. We evaluated resting brain metabolism and treatment response in OCD patients using positron emission tomography (PET) imaging. [18F]-fluoro-deoxy-glucose PET was performed in eight OCD patients precapsulotomy and postcapsulotomy. We determined metabolic differences between preoperative images in patients and those in eight age-matched healthy volunteers, and postoperative changes and clinical correlations in the patients. The OCD patients showed widespread metabolic increases in normalized glucose metabolism in the bilateral orbitofrontal cortex and inferior frontal gyrus, cingulate gyrus, and bilateral pons/cerebellum, and metabolic decreases bilaterally in the precentral and lingual gyri. Bilateral capsulotomy resulted in significant metabolic decreases bilaterally in the prefrontal cortical regions, especially in the dorsal anterior cingulate cortex (ACC) and in the medial dorsal thalamus and caudate nucleus. In contrast, metabolism increased bilaterally in the precentral and lingual gyri. Clinical improvement in patients correlated with metabolic changes in the bilateral dorsal ACC and in the right middle occipital gyrus after capsulotomy. This study underscores the importance of the internal capsule in modulating ventral prefrontal and dorsal anterior cingulate neuronal activity in the neurosurgical management of OCD patients.
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Zhang, Xin, Yanhua Liu, Shu Yang, Xin Gao, Shuo Wang, Zhaoying Wang, Chen Zhang, et al. "Comparison of Local Metabolic Changes in Diabetic Rodent Kidneys Using Mass Spectrometry Imaging." Metabolites 13, no. 3 (February 22, 2023): 324. http://dx.doi.org/10.3390/metabo13030324.
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Understanding the renal region-specific metabolic alteration in different animal models of diabetic nephropathy (DN) is critical for uncovering the underlying mechanisms and for developing effective treatments. In the present study, spatially resolved metabolomics based on air flow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) was used to compare the local metabolic changes in the kidneys of HFD/STZ-induced diabetic rats and db/db mice. As a result, a total of 67 and 59 discriminating metabolites were identified and visualized in the kidneys of the HFD/STZ-induced diabetic rats and db/db mice, respectively. The result showed that there were significant region-specific changes in the glycolysis, TCA cycle, lipid metabolism, carnitine metabolism, choline metabolism, and purine metabolism in both DN models. However, the regional levels of the ten metabolites, including glucose, AMP, eicosenoic acid, eicosapentaenoic acid, Phosphatidylserine (36:1), Phosphatidylserine (36:4), Phosphatidylethanolamine (34:1), Phosphatidylethanolamine (36:4), Phosphatidylcholine (34:2), Phosphatidylinositol (38:5) were changed in reversed directions, indicating significant differences in the local metabolic phenotypes of these two commonly used DN animal models. This study provides comprehensive and in-depth analysis of the differences in the tissue and molecular pathological features in diabetic kidney injury in HFD/STZ-induced diabetic rats and db/db mice.
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Tran, Meryssa, Georgios Batsios, Céline Taglang, Anne Marie Gillespie, Javad Nazarian, Sabine Mueller, and Pavithra Viswanath. "TAMI-40. PEDIATRIC H3K27M MUTANT GLIOMAS UNDERGO METABOLIC REPROGRAMMING THAT CAN BE LEVERAGED FOR NON-INVASIVE METABOLIC IMAGING." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi206—vi207. http://dx.doi.org/10.1093/neuonc/noab196.824.
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Abstract Diffuse midline gliomas (DMGs) are a universally lethal form of childhood cancer. The infiltrative nature of DMGs makes them difficult to visualize by conventional magnetic resonance imaging. Genomics studies indicate that DMGs are driven by unique histone H3K27M mutations that result in broad epigenetic dysregulation. Many of the resulting changes in gene expression have the potential to induce metabolic reprogramming, which has been identified as a hallmark of cancer. The goal of this study was to dissect metabolic reprogramming in preclinical DMG models in order to identify novel magnetic resonance spectroscopy (MRS)-detectable metabolic biomarkers that can be exploited for non-invasive imaging. First, we used 1H-MRS, which reports on steady-state metabolism, to examine H3K27M mutant SF7761 cells and H3 wild-type normal human astrocytes (NHA). Lactate, glutathione and phosphocholine, which are involved in glycolysis, redox and phospholipid metabolism respectively, were elevated in SF7761 cells relative to NHAs. Mechanistically, these metabolic alterations were associated with upregulation of key enzymes including hexokinase 2, glutamate cysteine ligase and choline kinase a. Importantly, in vivo 1H-MRS showed elevated lactate, glutathione and total choline (combined signal from choline, phosphocholine and glycerophosphocholine) in mice bearing orthotopic SF7761 tumors relative to tumor-free controls. We then examined alterations in dynamic metabolic pathways in our models. Using thermally-polarized 13C-MRS, we identified elevated production of [2-13C]-lactate from [2-13C]-glucose in SF7761 cells relative to NHAs. Hyperpolarized 13C-MRS is a method of enhancing the 13C-MR signal such that metabolic fluxes can be interrogated with high sensitivity. Hyperpolarized [1-13C]-pyruvate flux to [1-13C]-lactate non-invasively monitors glycolysis and is in clinical trials in adult glioma patients. Importantly, hyperpolarized [1-13C]-pyruvate metabolism to lactate was elevated in SF7761 cells relative to NHAs. Collectively, our studies suggest that H3K27M mutant DMGs undergo reprogramming of glucose, redox and phospholipid metabolism that can be leveraged for non-invasive 1H- and hyperpolarized 13C-MRS-based imaging.
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Sun, Chenglong, Tiegang Li, Xiaowei Song, Luojiao Huang, Qingce Zang, Jing Xu, Nan Bi, et al. "Spatially resolved metabolomics to discover tumor-associated metabolic alterations." Proceedings of the National Academy of Sciences 116, no. 1 (December 17, 2018): 52–57. http://dx.doi.org/10.1073/pnas.1808950116.
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Characterization of tumor metabolism with spatial information contributes to our understanding of complex cancer metabolic reprogramming, facilitating the discovery of potential metabolic vulnerabilities that might be targeted for tumor therapy. However, given the metabolic variability and flexibility of tumors, it is still challenging to characterize global metabolic alterations in heterogeneous cancer. Here, we propose a spatially resolved metabolomics approach to discover tumor-associated metabolites and metabolic enzymes directly in their native state. A variety of metabolites localized in different metabolic pathways were mapped by airflow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) in tissues from 256 esophageal cancer patients. In combination with in situ metabolomics analysis, this method provided clues into tumor-associated metabolic pathways, including proline biosynthesis, glutamine metabolism, uridine metabolism, histidine metabolism, fatty acid biosynthesis, and polyamine biosynthesis. Six abnormally expressed metabolic enzymes that are closely associated with the altered metabolic pathways were further discovered in esophageal squamous cell carcinoma (ESCC). Notably, pyrroline-5-carboxylate reductase 2 (PYCR2) and uridine phosphorylase 1 (UPase1) were found to be altered in ESCC. The spatially resolved metabolomics reveal what occurs in cancer at the molecular level, from metabolites to enzymes, and thus provide insights into the understanding of cancer metabolic reprogramming.
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AlMohammad, Abdallah, Murdoch Y. Norton, Andrew E. Welch, Peter F. Sharp, and Stephen Walton. "Gated metabolic myocardial imaging, a surrogate for dual perfusion-metabolism imaging by positron emission tomography." Open Heart 4, no. 2 (July 2017): e000581. http://dx.doi.org/10.1136/openhrt-2016-000581.
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Sun, Jinny, Robert A. Bok, Justin DeLos Santos, Deepti Upadhyay, Romelyn DeLos Santos, Shubhangi Agarwal, Mark Van Criekinge, et al. "Resistance to Androgen Deprivation Leads to Altered Metabolism in Human and Murine Prostate Cancer Cell and Tumor Models." Metabolites 11, no. 3 (February 26, 2021): 139. http://dx.doi.org/10.3390/metabo11030139.
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Currently, no clinical methods reliably predict the development of castration-resistant prostate cancer (CRPC) that occurs almost universally in men undergoing androgen deprivation therapy. Hyperpolarized (HP) 13C magnetic resonance imaging (MRI) could potentially detect the incipient emergence of CRPC based on early metabolic changes. To characterize metabolic shifts occurring upon the transition from androgen-dependent to castration-resistant prostate cancer (PCa), the metabolism of [U-13C]glucose and [U-13C]glutamine was analyzed by nuclear magnetic resonance spectroscopy. Comparison of steady-state metabolite concentrations and fractional enrichment in androgen-dependent LNCaP cells and transgenic adenocarcinoma of the murine prostate (TRAMP) murine tumors versus castration-resistant PC-3 cells and treatment-driven CRPC TRAMP tumors demonstrated that CRPC was associated with upregulation of glycolysis, tricarboxylic acid metabolism of pyruvate; and glutamine, glutaminolysis, and glutathione synthesis. These findings were supported by 13C isotopomer modeling showing increased flux through pyruvate dehydrogenase (PDH) and anaplerosis; enzymatic assays showing increased lactate dehydrogenase, PDH and glutaminase activity; and oxygen consumption measurements demonstrating increased dependence on anaplerotic fuel sources for mitochondrial respiration in CRPC. Consistent with ex vivo metabolomic studies, HP [1-13C]pyruvate distinguished androgen-dependent PCa from CRPC in cell and tumor models based on significantly increased HP [1-13C]lactate.
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Joseph, Josiane, Dong Cho, and Jason Doles. "Metabolomic Analyses Reveal Extensive Progenitor Cell Deficiencies in a Mouse Model of Duchenne Muscular Dystrophy." Metabolites 8, no. 4 (October 3, 2018): 61. http://dx.doi.org/10.3390/metabo8040061.
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Duchenne muscular dystrophy (DMD) is a musculoskeletal disorder that causes severe morbidity and reduced lifespan. Individuals with DMD have an X-linked mutation that impairs their ability to produce functional dystrophin protein in muscle. No cure exists for this disease and the few therapies that are available do not dramatically delay disease progression. Thus, there is a need to better understand the mechanisms underlying DMD which may ultimately lead to improved treatment options. The muscular dystrophy (MDX) mouse model is frequently used to explore DMD disease traits. Though some studies of metabolism in dystrophic mice exist, few have characterized metabolic profiles of supporting cells in the diseased environment. Using nontargeted metabolomics we characterized metabolic alterations in muscle satellite cells (SCs) and serum of MDX mice. Additionally, live-cell imaging revealed MDX-derived adipose progenitor cell (APC) defects. Finally, metabolomic studies revealed a striking elevation of acylcarnitines in MDX APCs, which we show can inhibit APC proliferation. Together, these studies highlight widespread metabolic alterations in multiple progenitor cell types and serum from MDX mice and implicate dystrophy-associated metabolite imbalances in APCs as a potential contributor to adipose tissue disequilibrium in DMD.
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Sanchez, Tim, Marta Venturas, S. Ali Aghvami, Xingbo Yang, Seth Fraden, Denny Sakkas, and Daniel J. Needleman. "Combined noninvasive metabolic and spindle imaging as potential tools for embryo and oocyte assessment." Human Reproduction 34, no. 12 (December 1, 2019): 2349–61. http://dx.doi.org/10.1093/humrep/dez210.
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Abstract STUDY QUESTION Is the combined use of fluorescence lifetime imaging microscopy (FLIM)-based metabolic imaging and second harmonic generation (SHG) spindle imaging a feasible and safe approach for noninvasive embryo assessment? SUMMARY ANSWER Metabolic imaging can sensitively detect meaningful metabolic changes in embryos, SHG produces high-quality images of spindles and the methods do not significantly impair embryo viability. WHAT IS KNOWN ALREADY Proper metabolism is essential for embryo viability. Metabolic imaging is a well-tested method for measuring metabolism of cells and tissues, but it is unclear if it is sensitive enough and safe enough for use in embryo assessment. STUDY DESIGN, SIZE, DURATION This study consisted of time-course experiments and control versus treatment experiments. We monitored the metabolism of 25 mouse oocytes with a noninvasive metabolic imaging system while exposing them to oxamate (cytoplasmic lactate dehydrogenase inhibitor) and rotenone (mitochondrial oxidative phosphorylation inhibitor) in series. Mouse embryos (n = 39) were measured every 2 h from the one-cell stage to blastocyst in order to characterize metabolic changes occurring during pre-implantation development. To assess the safety of FLIM illumination, n = 144 illuminated embryos were implanted into n = 12 mice, and n = 108 nonilluminated embryos were implanted into n = 9 mice. PARTICIPANTS/MATERIALS, SETTING, METHODS Experiments were performed in mouse embryos and oocytes. Samples were monitored with noninvasive, FLIM-based metabolic imaging of nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) autofluorescence. Between NADH cytoplasm, NADH mitochondria and FAD mitochondria, a single metabolic measurement produces up to 12 quantitative parameters for characterizing the metabolic state of an embryo. For safety experiments, live birth rates and pup weights (mean ± SEM) were used as endpoints. For all test conditions, the level of significance was set at P < 0.05. MAIN RESULTS AND THE ROLE OF CHANCE Measured FLIM parameters were highly sensitive to metabolic changes due to both metabolic perturbations and embryo development. For oocytes, metabolic parameter values were compared before and after exposure to oxamate and rotenone. The metabolic measurements provided a basis for complete separation of the data sets. For embryos, metabolic parameter values were compared between the first division and morula stages, morula and blastocyst and first division and blastocyst. The metabolic measurements again completely separated the data sets. Exposure of embryos to excessive illumination dosages (24 measurements) had no significant effect on live birth rate (5.1 ± 0.94 pups/mouse for illuminated group; 5.7 ± 1.74 pups/mouse for control group) or pup weights (1.88 ± 0.10 g for illuminated group; 1.89 ± 0.11 g for control group). LIMITATIONS, REASONS FOR CAUTION The study was performed using a mouse model, so conclusions concerning sensitivity and safety may not generalize to human embryos. A limitation of the live birth data is also that although cages were routinely monitored, we could not preclude that some runt pups may have been eaten. WIDER IMPLICATIONS OF THE FINDINGS Promising proof-of-concept results demonstrate that FLIM with SHG provide detailed biological information that may be valuable for the assessment of embryo and oocyte quality. Live birth experiments support the method’s safety, arguing for further studies of the clinical utility of these techniques. STUDY FUNDING/COMPETING INTEREST(S) Supported by the Blavatnik Biomedical Accelerator Grant at Harvard University and by the Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Institutes of Health Award UL1 TR001102), by NSF grants DMR-0820484 and PFI-TT-1827309 and by NIH grant R01HD092550-01. T.S. was supported by a National Science Foundation Postdoctoral Research Fellowship in Biology grant (1308878). S.F. and S.A. were supported by NSF MRSEC DMR-1420382. Becker and Hickl GmbH sponsored the research with the loaning of equipment for FLIM. T.S. and D.N. are cofounders and shareholders of LuminOva, Inc., and co-hold patents (US20150346100A1 and US20170039415A1) for metabolic imaging methods. D.S. is on the scientific advisory board for Cooper Surgical and has stock options with LuminOva, Inc.
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Nguyen, Don D., Veronika Saharuka, Vitaly Kovalev, Lachlan Stuart, Massimo Del Prete, Kinga Lubowiecka, René De Mot, Vittorio Venturi, and Theodore Alexandrov. "Facilitating Imaging Mass Spectrometry of Microbial Specialized Metabolites with METASPACE." Metabolites 11, no. 8 (July 23, 2021): 477. http://dx.doi.org/10.3390/metabo11080477.
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Metabolite annotation from imaging mass spectrometry (imaging MS) data is a difficult undertaking that is extremely resource intensive. Here, we adapted METASPACE, cloud software for imaging MS metabolite annotation and data interpretation, to quickly annotate microbial specialized metabolites from high-resolution and high-mass accuracy imaging MS data. Compared with manual ion image and MS1 annotation, METASPACE is faster and, with the appropriate database, more accurate. We applied it to data from microbial colonies grown on agar containing 10 diverse bacterial species and showed that METASPACE was able to annotate 53 ions corresponding to 32 different microbial metabolites. This demonstrates METASPACE to be a useful tool to annotate the chemistry and metabolic exchange factors found in microbial interactions, thereby elucidating the functions of these molecules.
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Gilmore, Ian S., Sven Heiles, and Cornelius L. Pieterse. "Metabolic Imaging at the Single-Cell Scale: Recent Advances in Mass Spectrometry Imaging." Annual Review of Analytical Chemistry 12, no. 1 (June 12, 2019): 201–24. http://dx.doi.org/10.1146/annurev-anchem-061318-115516.
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There is an increasing appreciation that every cell, even of the same type, is different. This complexity, when additionally combined with the variety of different cell types in tissue, is driving the need for spatially resolved omics at the single-cell scale. Rapid advances are being made in genomics and transcriptomics, but progress in metabolomics lags. This is partly because amplification and tagging strategies are not suited to dynamically created metabolite molecules. Mass spectrometry imaging has excellent potential for metabolic imaging. This review summarizes the recent advances in two of these techniques: matrix-assisted laser desorption ionization (MALDI) and secondary ion mass spectrometry (SIMS) and their convergence in subcellular spatial resolution and molecular information. The barriers that have held back progress such as lack of sensitivity and the breakthroughs that have been made including laser-postionization are highlighted as well as the future challenges and opportunities for metabolic imaging at the single-cell scale.