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1.
Artigo em Inglês | MEDLINE | ID: mdl-39009443

RESUMO

Molecular imaging-the mapping of molecular and cellular processes in vivo-has the unique capability to interrogate cancer metabolism in its spatial contexts. This work describes the usage of the two most developed modalities for imaging metabolism in vivo: positron emission tomography (PET) and magnetic resonance (MR). These techniques can be used to probe glycolysis, glutamine metabolism, anabolic metabolism, redox state, hypoxia, and extracellular acidification. This review aims to provide an overview of the strengths and limitations of currently available molecular imaging strategies.

2.
Cell Metab ; 36(6): 1394-1410.e12, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38838644

RESUMO

A vexing problem in mitochondrial medicine is our limited capacity to evaluate the extent of brain disease in vivo. This limitation has hindered our understanding of the mechanisms that underlie the imaging phenotype in the brain of patients with mitochondrial diseases and our capacity to identify new biomarkers and therapeutic targets. Using comprehensive imaging, we analyzed the metabolic network that drives the brain structural and metabolic features of a mouse model of pyruvate dehydrogenase deficiency (PDHD). As the disease progressed in this animal, in vivo brain glucose uptake and glycolysis increased. Propionate served as a major anaplerotic substrate, predominantly metabolized by glial cells. A combination of propionate and a ketogenic diet extended lifespan, improved neuropathology, and ameliorated motor deficits in these animals. Together, intermediary metabolism is quite distinct in the PDHD brain-it plays a key role in the imaging phenotype, and it may uncover new treatments for this condition.


Assuntos
Encéfalo , Glucose , Propionatos , Doença da Deficiência do Complexo de Piruvato Desidrogenase , Animais , Doença da Deficiência do Complexo de Piruvato Desidrogenase/metabolismo , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagem , Glucose/metabolismo , Propionatos/metabolismo , Camundongos , Dieta Cetogênica , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Masculino , Glicólise
3.
Cancer Cell ; 42(7): 1138-1141, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38848719

RESUMO

While cancer research and care have benefited from revolutionary advances in the ability to manipulate and study living systems, the field is limited by a lack of synergy to leverage the power of engineering approaches. Cancer engineering is an emerging subfield of biomedical engineering that unifies engineering and cancer biology to better understand, diagnose, and treat cancer. We highlight cancer engineering's unique challenges, the importance of creating dedicated centers and departments that enable translational collaboration, and educational approaches to arm a new generation of scientists with engineering expertise and a fundamental understanding of cancer biology to transform clinical cancer care.


Assuntos
Neoplasias , Animais , Humanos , Engenharia Biomédica/métodos , Engenharia Biomédica/tendências , Neoplasias/terapia , Neoplasias/genética
5.
bioRxiv ; 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38352450

RESUMO

Hyperpolarized- 13 C magnetic resonance imaging (HP- 13 C MRI) was used to image changes in 13 C-lactate signal during a visual stimulus condition in comparison to an eyes-closed control condition. Whole-brain 13 C-pyruvate, 13 C-lactate and 13 C-bicarbonate production was imaged in healthy volunteers (N=6, ages 24-33) for the two conditions using two separate hyperpolarized 13 C-pyruvate injections. BOLD-fMRI scans were used to delineate regions of functional activation. 13 C-metabolite signal was normalized by 13 C-metabolite signal from the brainstem and the percentage change in 13 C-metabolite signal conditions was calculated. A one-way Wilcoxon signed-rank test showed a significant increase in 13 C-lactate in regions of activation when compared to the remainder of the brain ( p = 0.02, V = 21). No significant increase was observed in 13 C-pyruvate ( p = 0.11, V = 17) or 13 C-bicarbonate ( p = 0.95, V = 3) signal. The results show an increase in 13 C-lactate production in the activated region that is measurable with HP- 13 C MRI.

6.
Magn Reson Med ; 91(5): 2162-2171, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38230992

RESUMO

PURPOSE: To test the hypothesis that lactate oxidation contributes to the 13 $$ {}^{13} $$ C-bicarbonate signal observed in the awake human brain using hyperpolarized 13 $$ {}^{13} $$ C MRI. METHODS: Healthy human volunteers (N = 6) were scanned twice using hyperpolarized 13 $$ {}^{13} $$ C-MRI, with increased radiofrequency saturation of 13 $$ {}^{13} $$ C-lactate on one set of scans. 13 $$ {}^{13} $$ C-lactate, 13 $$ {}^{13} $$ C-bicarbonate, and 13 $$ {}^{13} $$ C-pyruvate signals for 132 brain regions across each set of scans were compared using a clustered Wilcoxon signed-rank test. RESULTS: Increased 13 $$ {}^{13} $$ C-lactate radiofrequency saturation resulted in a significantly lower 13 $$ {}^{13} $$ C-bicarbonate signal (p = 0.04). These changes were observed across the majority of brain regions. CONCLUSION: Radiofrequency saturation of 13 $$ {}^{13} $$ C-lactate leads to a decrease in 13 $$ {}^{13} $$ C-bicarbonate signal, demonstrating that the 13 $$ {}^{13} $$ C-lactate generated from the injected 13 $$ {}^{13} $$ C-pyruvate is being converted back to 13 $$ {}^{13} $$ C-pyruvate and oxidized throughout the human brain.


Assuntos
Bicarbonatos , Imageamento por Ressonância Magnética , Humanos , Imageamento por Ressonância Magnética/métodos , Encéfalo/diagnóstico por imagem , Ácido Pirúvico , Ácido Láctico , Isótopos de Carbono
7.
Magn Reson Med ; 91(6): 2559-2567, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38205934

RESUMO

PURPOSE: To investigate the safety and value of hyperpolarized (HP) MRI of [1-13C]pyruvate in healthy volunteers using deuterium oxide (D2O) as a solvent. METHODS: Healthy volunteers (n = 5), were injected with HP [1-13C]pyruvate dissolved in D2O and imaged with a metabolite-specific 3D dual-echo dynamic EPI sequence at 3T at one site (Site 1). Volunteers were monitored following the procedure to assess safety. Image characteristics, including SNR, were compared to data acquired in a separate cohort using water as a solvent (n = 5) at another site (Site 2). The apparent spin-lattice relaxation time (T1) of [1-13C]pyruvate was determined both in vitro and in vivo from a mono-exponential fit to the image intensity at each time point of our dynamic data. RESULTS: All volunteers completed the study safely and reported no adverse effects. The use of D2O increased the T1 of [1-13C]pyruvate from 66.5 ± 1.6 s to 92.1 ± 5.1 s in vitro, which resulted in an increase in signal by a factor of 1.46 ± 0.03 at the time of injection (90 s after dissolution). The use of D2O also increased the apparent relaxation time of [1-13C]pyruvate by a factor of 1.4 ± 0.2 in vivo. After adjusting for inter-site SNR differences, the use of D2O was shown to increase image SNR by a factor of 2.6 ± 0.2 in humans. CONCLUSIONS: HP [1-13C]pyruvate in D2O is safe for human imaging and provides an increase in T1 and SNR that may improve image quality.


Assuntos
Imageamento por Ressonância Magnética , Ácido Pirúvico , Humanos , Estudos de Viabilidade , Imageamento por Ressonância Magnética/métodos , Encéfalo/diagnóstico por imagem , Isótopos de Carbono , Solventes
8.
Mol Imaging Biol ; 26(2): 222-232, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38147265

RESUMO

Hyperpolarization techniques significantly enhance the sensitivity of magnetic resonance (MR) and thus present fascinating new directions for research and applications with in vivo MR imaging and spectroscopy (MRI/S). Hyperpolarized 13C MRI/S, in particular, enables real-time non-invasive assessment of metabolic processes and holds great promise for a diverse range of clinical applications spanning fields like oncology, neurology, and cardiology, with a potential for improving early diagnosis of disease, patient stratification, and therapy response assessment. Despite its potential, technical challenges remain for achieving clinical translation. This paper provides an overview of the discussions that took place at the international workshop "New Horizons in Hyperpolarized 13C MRI," in March 2023 at the Bavarian Academy of Sciences and Humanities, Munich, Germany. The workshop covered new developments, as well as future directions, in topics including polarization techniques (particularly focusing on parahydrogen-based methods), novel probes, considerations related to data acquisition and analysis, and emerging clinical applications in oncology and other fields.


Assuntos
Imageamento por Ressonância Magnética , Oncologia , Humanos , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/métodos
9.
bioRxiv ; 2023 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-37645894

RESUMO

Despite the success of fructose as a low-cost food additive, recent epidemiological evidence suggests that high fructose consumption by pregnant mothers or during adolescence is associated with disrupted neurodevelopment 1-7 . An essential step in appropriate mammalian neurodevelopment is the synaptic pruning and elimination of newly-formed neurons by microglia, the central nervous system's (CNS) resident professional phagocyte 8-10 . Whether early life high fructose consumption affects microglia function and if this directly impacts neurodevelopment remains unknown. Here, we show that both offspring born to dams fed a high fructose diet and neonates exposed to high fructose exhibit decreased microglial density, increased uncleared apoptotic cells, and decreased synaptic pruning in vivo . Importantly, deletion of the high affinity fructose transporter SLC2A5 (GLUT5) in neonates completely reversed microglia dysfunction, suggesting that high fructose directly affects neonatal development. Mechanistically, we found that high fructose treatment of both mouse and human microglia suppresses synaptic pruning and phagocytosis capacity which is fully reversed in GLUT5-deficient microglia. Using a combination of in vivo and in vitro nuclear magnetic resonance- and mass spectrometry-based fructose tracing, we found that high fructose drives significant GLUT5-dependent fructose uptake and catabolism, rewiring microglia metabolism towards a hypo-phagocytic state. Importantly, mice exposed to high fructose as neonates exhibited cognitive defects and developed anxiety-like behavior which were rescued in GLUT5-deficient animals. Our findings provide a mechanistic explanation for the epidemiological observation that early life high fructose exposure is associated with increased prevalence of adolescent anxiety disorders.

10.
NMR Biomed ; 36(10): e4989, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37336778

RESUMO

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths. Imaging plays a crucial role in the early detection of HCC, although current methods are limited in their ability to characterize liver lesions. Most recently, deuterium metabolic imaging (DMI) has been demonstrated as a powerful technique for the imaging of metabolism in vivo. Here, we assess the metabolic flux of [6,6'-2 H2 ] fructose in cell cultures and in subcutaneous mouse models at 9.4 T. We compare these rates with the most widely used DMI probe, [6,6'-2 H2 ] glucose, exploring the possibility of developing 2 H fructose to overcome the limitations of glucose as a novel DMI probe for detecting liver tumors. Comparison of the in vitro metabolic rates implies their similar glycolytic metabolism in the TCA cycle due to comparable production rates of 2 H glutamate/glutamine (glx) for the two precursors, but overall higher glycolytic metabolism from 2 H glucose because of a higher production rate of 2 H lactate. In vivo kinetic studies suggest that HDO can serve as a robust reporter for the consumption of the precursors in liver tumors. As fructose is predominantly metabolized in the liver, deuterated water (HDO) produced from 2 H fructose is probably less contaminated from whole-body metabolism in comparison with glucose. Moreover, in studies of the normal liver, 2 H fructose is readily converted to 2 H glx, enabling the characterization of 2 H fructose kinetics. This overcomes a major limitation of previous 2 H glucose studies in the liver, which were unable to confidently discern metabolic flux due to overlapped signals of 2 H glucose and its metabolic product, 2 H glycogen. This suggests a unique role for 2 H fructose metabolism in HCC and the normal liver, making it a useful approach for assessing liver-related diseases and the progression to oncogenesis.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Camundongos , Animais , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/metabolismo , Deutério/metabolismo , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/metabolismo , Cinética , Frutose/metabolismo , Glucose/metabolismo , Fígado/diagnóstico por imagem , Fígado/metabolismo , Ácido Láctico/metabolismo
11.
J Magn Reson ; 349: 107407, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36848687

RESUMO

Lattice reduction of K-space acquisition at fractional indices refers to reducing the indices to the smallest nearby integer, thereby generating a Cartesian grid, allowing subsequent inverse Fourier Transformation. For band-limited signals, we show that the error in lattice reduction is equivalent to first order phase shifts, which in the infinite limit approaches W∞=φ(cotφ-i), where φ is a first-order phase shift vector. In general, the inverse corrections can be specified from the binary representation of the fractional part of the K-space indices. For non-uniform sparsity, we show how to incorporate the inverse corrections into compressed sensing reconstructions.

13.
Cell Metab ; 35(2): 316-331.e6, 2023 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-36584675

RESUMO

Apoptotic cell (AC) clearance (efferocytosis) is performed by phagocytes, such as macrophages, that inhabit harsh physiological environments. Here, we find that macrophages display enhanced efferocytosis under prolonged (chronic) physiological hypoxia, characterized by increased internalization and accelerated degradation of ACs. Transcriptional and translational analyses revealed that chronic physiological hypoxia induces two distinct but complimentary states. The first, "primed" state, consists of concomitant transcription and translation of metabolic programs in AC-naive macrophages that persist during efferocytosis. The second, "poised" state, consists of transcription, but not translation, of phagocyte function programs in AC-naive macrophages that are translated during efferocytosis. Mechanistically, macrophages efficiently flux glucose into a noncanonical pentose phosphate pathway (PPP) loop to enhance NADPH production. PPP-derived NADPH directly supports enhanced efferocytosis under physiological hypoxia by ensuring phagolysosomal maturation and redox homeostasis. Thus, macrophages residing under physiological hypoxia adopt states that support cell fitness and ensure performance of essential homeostatic functions rapidly and safely.


Assuntos
Macrófagos , Oxigênio , Humanos , Oxigênio/metabolismo , NADP/metabolismo , Macrófagos/metabolismo , Fagocitose , Hipóxia/metabolismo , Apoptose/fisiologia
14.
Cancer Cell ; 40(12): 1457-1458, 2022 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-36400017

RESUMO

Brain tumors are notoriously difficult to treat. Three recent Cancer Cell articles aim to uncover novel druggable targets in IDH mutant gliomas, diffuse midline gliomas, and medulloblastomas, respectively, and show that these brain tumor types shift their metabolism to become reliant on de novo pyrimidine synthesis.


Assuntos
Neoplasias Encefálicas , Glioma , Humanos , Isocitrato Desidrogenase/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Glioma/patologia , Pirimidinas/farmacologia , Mutação
15.
MAGMA ; 35(6): 895-901, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35876917

RESUMO

OBJECT: Spatial variation in the sensitivity profiles of receive coils in MRI leads to spatially dependent scaling of the signal amplitude across an image. In practice, total sensitivity of the coil array is either calibrated or corrected directly by comparison to a uniform sensitivity image, fitting of coil profiles, or indirectly by constraining the reconstructed image or coil profiles. In the absence of these corrections, popular coil summation strategies are often designed to maximize the signal-to-noise ratio or optimize under-sampled encoding but not necessarily estimate the value of the signal unscaled by the coil spatial sensitivity. MATERIALS AND METHODS: We use ratios of first-order statistics to approach the unscaled value of the signal at any position. Motivated by the assumption that the coil array is a sample from much larger number of possible coils, we present two approaches to scale the mean signal in all coils: (1) an argument for use of the mode of the normalized signals, and (2) using a one-dimensional analog derive an approximate expression for scaling with the ratio of the square-of-the-mean to the mean-of-the-squares. We test these approaches with simulation where idealized coil elements are arrayed around an object, and on directly acquired data with an 8-channel coil array on a uniform 13C phantom, and on Hyperpolarized 13C pyruvate brain MRI. RESULTS: We show improved image uniformity using the ratios of first order statistics compared to a simple homomorphic filter, noting that these approaches are more sensitive to noise. DISCUSSION: We present simple methods for correcting the spatial variation in sensitivity profiles in the context of a coil array. These methods can be used as an initial or adjunct step in data post-processing.


Assuntos
Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Razão Sinal-Ruído , Imagens de Fantasmas , Piruvatos , Encéfalo/diagnóstico por imagem
16.
Cell ; 185(15): 2678-2689, 2022 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-35839759

RESUMO

Metabolic anomalies contribute to tissue dysfunction. Current metabolism research spans from organelles to populations, and new technologies can accommodate investigation across these scales. Here, we review recent advancements in metabolic analysis, including small-scale metabolomics techniques amenable to organelles and rare cell types, functional screening to explore how cells respond to metabolic stress, and imaging approaches to non-invasively assess metabolic perturbations in diseases. We discuss how metabolomics provides an informative phenotypic dimension that complements genomic analysis in Mendelian and non-Mendelian disorders. We also outline pressing challenges and how addressing them may further clarify the biochemical basis of human disease.


Assuntos
Genômica , Metabolômica , Diagnóstico por Imagem , Humanos , Metabolômica/métodos
17.
J Magn Reson ; 341: 107246, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35709570

RESUMO

BRICKD slices refers to shifting the field-of-view by fractional pixel increments between slices; half pixel shifts are analogous to the common brick wall layout. We demonstrate that compressed sensing reconstructions can harness the added information content of this approach and lead to improved performance over a simple stacked slices approach. The method is simple and could be easily implemented on a clinical imaging system.


Assuntos
Algoritmos , Imageamento por Ressonância Magnética , Imageamento por Ressonância Magnética/métodos
18.
Proc Natl Acad Sci U S A ; 119(19): e2120595119, 2022 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-35512101

RESUMO

Glutamine is consumed by rapidly proliferating cells and can provide the carbon and nitrogen required for growth through various metabolic pathways. However, delineating the metabolic fate of glutamine is challenging to interrogate in vivo. Hyperpolarized magnetic resonance, by providing high transient nuclear magnetic resonance signals, provides an approach to measure fast biochemical processes in vivo. Aminohydrolysis of glutamine at carbon-5 plays an important role in providing nitrogen and carbon for multiple pathways. Here, we provide a synthetic strategy for isotope-enriched forms of glutamine that prolongs glutamine-C5 relaxation times and thereby reveals in vivo reactions involving carbon-5. We investigate multiple enrichment states, finding [5-13C,4,4-2H2,5-15N]-L-glutamine to be optimal for hyperpolarized measurement of glutamine conversion to glutamate in vivo. Leveraging this compound, we explore pancreatic cancer glutamine metabolism in vivo. Taken together, this work provides a means for studying glutamine metabolic flux in vivo and demonstrates on-target effects of metabolic enzyme inhibitors.


Assuntos
Glutaminase , Glutamina , Biomarcadores/metabolismo , Ciclo do Ácido Cítrico , Glutaminase/metabolismo , Glutamina/metabolismo , Humanos , Metabolômica
19.
Sci Adv ; 8(14): eabm7985, 2022 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-35385296

RESUMO

The ability to break down fructose is dependent on ketohexokinase (KHK) that phosphorylates fructose to fructose-1-phosphate (F1P). We show that KHK expression is tightly controlled and limited to a small number of organs and is down-regulated in liver and intestinal cancer cells. Loss of fructose metabolism is also apparent in hepatocellular adenoma and carcinoma (HCC) patient samples. KHK overexpression in liver cancer cells results in decreased fructose flux through glycolysis. We then developed a strategy to detect this metabolic switch in vivo using hyperpolarized magnetic resonance spectroscopy. Uniformly deuterating [2-13C]-fructose and dissolving in D2O increased its spin-lattice relaxation time (T1) fivefold, enabling detection of F1P and its loss in models of HCC. In summary, we posit that in the liver, fructolysis to F1P is lost in the development of cancer and can be used as a biomarker of tissue function in the clinic using metabolic imaging.

20.
Methods Mol Biol ; 2393: 561-569, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34837199

RESUMO

Metabolism represents an ensemble of cellular biochemical reactions, and thus metabolic analyses can shed light on the state of cells. Metabolic changes in response to external cues, such as drug treatment, for example, can be rapid and potentially an early indicator of therapeutic response. Unfortunately, conventional techniques to study metabolism, such as optical microscopy or mass spectrometry, have functional limitations in specificity and sensitivity. To address this technical need, we developed a sensitive analytical tool based on nuclear magnetic resonance (NMR) technology, termed hyperpolarized micro-NMR, that enables rapid quantification of multiple metabolic fluxes in a small number of cells, down to 10,000 cells, nondestructively. This analytical capability was achieved by miniaturization of an NMR detection coil along with hyperpolarization of endogenous metabolites. Using this tool, we were able to quantify pyruvate-to-lactate flux in cancer stem cells nondestructively within 2 min, which has not been possible with other techniques. With further optimization, we envision that this novel device could be a powerful analytical platform for sensitive analysis of metabolism in mass-limited samples.


Assuntos
Espectroscopia de Ressonância Magnética , Isótopos de Carbono , Sobrevivência Celular , Imageamento por Ressonância Magnética , Espectrometria de Massas , Células-Tronco Neoplásicas , Ácido Pirúvico
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