James Tropp

Bio: James Tropp is an academic researcher from GE Healthcare. The author has contributed to research in topics: Imaging phantom & Pyruvic acid. The author has an hindex of 18, co-authored 30 publications receiving 2441 citations.

Metabolic Imaging of Patients with Prostate Cancer Using Hyperpolarized [1-13C]Pyruvate

Abstract: This first-in-man imaging study evaluated the safety and feasibility of hyperpolarized [1-13C]pyruvate as an agent for noninvasively characterizing alterations in tumor metabolism for patients with prostate cancer. Imaging living systems with hyperpolarized agents can result in more than 10,000-fold enhancement in signal relative to conventional magnetic resonance (MR) imaging. When combined with the rapid acquisition of in vivo 13C MR data, it is possible to evaluate the distribution of agents such as [1-13C]pyruvate and its metabolic products lactate, alanine, and bicarbonate in a matter of seconds. Preclinical studies in cancer models have detected elevated levels of hyperpolarized [1-13C]lactate in tumor, with the ratio of [1-13C]lactate/[1-13C]pyruvate being increased in high-grade tumors and decreased after successful treatment. Translation of this technology into humans was achieved by modifying the instrument that generates the hyperpolarized agent, constructing specialized radio frequency coils to detect 13C nuclei, and developing new pulse sequences to efficiently capture the signal. The study population comprised patients with biopsy-proven prostate cancer, with 31 subjects being injected with hyperpolarized [1-13C]pyruvate. The median time to deliver the agent was 66 s, and uptake was observed about 20 s after injection. No dose-limiting toxicities were observed, and the highest dose (0.43 ml/kg of 230 mM agent) gave the best signal-to-noise ratio for hyperpolarized [1-13C]pyruvate. The results were extremely promising in not only confirming the safety of the agent but also showing elevated [1-13C]lactate/[1-13C]pyruvate in regions of biopsy-proven cancer. These findings will be valuable for noninvasive cancer diagnosis and treatment monitoring in future clinical trials.

Dipolar relaxation and nuclear Overhauser effects in nonrigid molecules: The effect of fluctuating internuclear distances

Abstract: A simple treatment of the dipolar contribution to nuclear magnetic relaxation is developed for molecules in which conformational fluctuations modulate the relevant internuclear distances. Expressions are given for AX system spectral densities using a general model in which conformational fluctuations occur as random jumps among discrete conformations, while the molecule as a whole undergoes rotational diffusion as either a spherical or a symmetric top. Approximations valid for proton spin systems are given for cases in which the jumping rates are either fast or slow compared to rotational diffusion; the results are independent of the jumping rates. Similar results are obtained for cross‐correlation spectral densities. For complex spin systems, e.g., An1Mn2Xn3..., the cross‐relaxation constants σij which couple pairs of magnetizations, depend only upon autocorrelation, spectral densities and are thus easily obtained from the AX system results. Measurement of σij by time resolved Overhauser effect experimen...

Hyperpolarized C-13 spectroscopic imaging of the TRAMP mouse at 3T—Initial experience

Abstract: The transgenic adenocarcinoma of mouse prostate (TRAMP) mouse is a well-studied murine model of prostate cancer with histopathology and disease progression that mimic the human disease. To investigate differences in cellular bioenergetics between normal prostate epithelial cells and prostate tumor cells, in vivo MR spectroscopic (MRS) studies with non-proton nuclei, such as 13C, in the TRAMP model would be extremely useful. The recent development of a method for retaining dynamic nuclear polarization (DNP) in solution permits high signal-to-noise ratio (SNR) 13C MRI or MRSI data to be obtained following injection of a hyperpolarized 13C agent. In this transgenic mouse study, this method was applied using a double spin-echo (DSE) pulse sequence with a small-tip-angle excitation RF pulse, hyperbolic-secant refocusing pulses, and a flyback echo-planar readout trajectory for fast (10–14 s) MRSI of 13C pyruvate (pyr) and its metabolic products at 0.135 cm3 nominal spatial resolution. Elevated 13C lactate (lac) was observed in both primary and metastatic tumors, demonstrating the feasibility of studying cellular bioenergetics in vivo with DNP hyperpolarized 13C MRSI. Magn Reson Med, 2007. © 2007 Wiley-Liss, Inc.

Metabolic Imaging of the Human Brain with Hyperpolarized 13C Pyruvate Demonstrates 13C Lactate Production in Brain Tumor Patients.

Abstract: Hyperpolarized (HP) MRI using [1-13C] pyruvate is a novel method that can characterize energy metabolism in the human brain and brain tumors. Here, we present the first dynamically acquired human brain HP 13C metabolic spectra and spatial metabolite maps in cases of both untreated and recurrent tumors. In vivo production of HP lactate from HP pyruvate by tumors was indicative of altered cancer metabolism, whereas production of HP lactate in the entire brain was likely due to baseline metabolism. We correlated our results with standard clinical brain MRI, MRI DCE perfusion, and in one case FDG PET/CT. Our results suggest that HP 13C pyruvate-to-lactate conversion may be a viable metabolic biomarker for assessing tumor response.Significance: Hyperpolarized pyruvate MRI enables metabolic imaging in the brain and can be a quantitative biomarker for active tumors.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/14/3755/F1.large.jpg Cancer Res; 78(14); 3755-60. ©2018 AACR.

Metabolic Imaging in the Anesthetized Rat Brain Using Hyperpolarized [1-13C] Pyruvate and [1-13C] Ethyl Pyruvate

Abstract: Formulation, polarization, and dissolution conditions were developed to obtain a stablehyperpolarized solution of [1- 13 C]-ethyl pyruvate. A maximum tolerated concentration andinjection rate were determined, and 13 C spectroscopic imaging was used to compare the uptake ofhyperpolarized [1- 13 C]-ethyl pyruvate relative to hyperpolarized [1- 13 C]-pyruvate intoanesthetized rat brain. Hyperpolarized [1- 13 C]-ethyl pyruvate and [1- 13 C]-pyruvate metabolicimaging in normal brain is demonstrated and quantified in this feasibility and range-finding study. Keywords hyperpolarized; carbon-13; ethyl-pyruvate; brain; pyruvate; lactateMR metabolic imaging of hyperpolarized [1- 13 C]-pyruvate has proven to be useful,especially in oncology and cardiology (1,2). Dynamic and tissue level changes in [1- 13 C]-pyruvate and its metabolic products, [1- 13 C]-lactate, [1- 13 C]-alanine, and [ 13 C] bicarbonate,have been shown to correlate with metabolic states of interest, including disease progression(3,4) and response to therapy (5,6). However, for potential neurologic applications, theblood-brain transport of pyruvate may be a limiting factor. Age, anesthesia, and dietary statecan all impact transport rates (7–9), and under some conditions, the 1- to 2-min window ofuseful hyperpolarized [1-

Metabolic Imaging of Patients with Prostate Cancer Using Hyperpolarized [1-13C]Pyruvate

Abstract: This first-in-man imaging study evaluated the safety and feasibility of hyperpolarized [1-13C]pyruvate as an agent for noninvasively characterizing alterations in tumor metabolism for patients with prostate cancer. Imaging living systems with hyperpolarized agents can result in more than 10,000-fold enhancement in signal relative to conventional magnetic resonance (MR) imaging. When combined with the rapid acquisition of in vivo 13C MR data, it is possible to evaluate the distribution of agents such as [1-13C]pyruvate and its metabolic products lactate, alanine, and bicarbonate in a matter of seconds. Preclinical studies in cancer models have detected elevated levels of hyperpolarized [1-13C]lactate in tumor, with the ratio of [1-13C]lactate/[1-13C]pyruvate being increased in high-grade tumors and decreased after successful treatment. Translation of this technology into humans was achieved by modifying the instrument that generates the hyperpolarized agent, constructing specialized radio frequency coils to detect 13C nuclei, and developing new pulse sequences to efficiently capture the signal. The study population comprised patients with biopsy-proven prostate cancer, with 31 subjects being injected with hyperpolarized [1-13C]pyruvate. The median time to deliver the agent was 66 s, and uptake was observed about 20 s after injection. No dose-limiting toxicities were observed, and the highest dose (0.43 ml/kg of 230 mM agent) gave the best signal-to-noise ratio for hyperpolarized [1-13C]pyruvate. The results were extremely promising in not only confirming the safety of the agent but also showing elevated [1-13C]lactate/[1-13C]pyruvate in regions of biopsy-proven cancer. These findings will be valuable for noninvasive cancer diagnosis and treatment monitoring in future clinical trials.

Chemistry of MRI Contrast Agents: Current Challenges and New Frontiers

Abstract: Tens of millions of contrast-enhanced magnetic resonance imaging (MRI) exams are performed annually around the world. The contrast agents, which improve diagnostic accuracy, are almost exclusively small, hydrophilic gadolinium(III) based chelates. In recent years concerns have arisen surrounding the long-term safety of these compounds, and this has spurred research into alternatives. There has also been a push to develop new molecularly targeted contrast agents or agents that can sense pathological changes in the local environment. This comprehensive review describes the state of the art of clinically approved contrast agents, their mechanism of action, and factors influencing their safety. From there we describe different mechanisms of generating MR image contrast such as relaxation, chemical exchange saturation transfer, and direct detection and the types of molecules that are effective for these purposes. Next we describe efforts to make safer contrast agents either by increasing relaxivity, increasing resistance to metal ion release, or by moving to gadolinium(III)-free alternatives. Finally we survey approaches to make contrast agents more specific for pathology either by direct biochemical targeting or by the design of responsive or activatable contrast agents.

The return of metabolism: biochemistry and physiology of the pentose phosphate pathway

Abstract: The pentose phosphate pathway (PPP) is a fundamental component of cellular metabolism. The PPP is important to maintain carbon homoeostasis, to provide precursors for nucleotide and amino acid biosynthesis, to provide reducing molecules for anabolism, and to defeat oxidative stress. The PPP shares reactions with the Entner-Doudoroff pathway and Calvin cycle and divides into an oxidative and non-oxidative branch. The oxidative branch is highly active in most eukaryotes and converts glucose 6-phosphate into carbon dioxide, ribulose 5-phosphate and NADPH. The latter function is critical to maintain redox balance under stress situations, when cells proliferate rapidly, in ageing, and for the 'Warburg effect' of cancer cells. The non-oxidative branch instead is virtually ubiquitous, and metabolizes the glycolytic intermediates fructose 6-phosphate and glyceraldehyde 3-phosphate as well as sedoheptulose sugars, yielding ribose 5-phosphate for the synthesis of nucleic acids and sugar phosphate precursors for the synthesis of amino acids. Whereas the oxidative PPP is considered unidirectional, the non-oxidative branch can supply glycolysis with intermediates derived from ribose 5-phosphate and vice versa, depending on the biochemical demand. These functions require dynamic regulation of the PPP pathway that is achieved through hierarchical interactions between transcriptome, proteome and metabolome. Consequently, the biochemistry and regulation of this pathway, while still unresolved in many cases, are archetypal for the dynamics of the metabolic network of the cell. In this comprehensive article we review seminal work that led to the discovery and description of the pathway that date back now for 80 years, and address recent results about genetic and metabolic mechanisms that regulate its activity. These biochemical principles are discussed in the context of PPP deficiencies causing metabolic disease and the role of this pathway in biotechnology, bacterial and parasite infections, neurons, stem cell potency and cancer metabolism.

Metabolic reprogramming and cancer progression

Abstract: Metabolic reprogramming is a hallmark of malignancy. As our understanding of the complexity of tumor biology increases, so does our appreciation of the complexity of tumor metabolism. Metabolic heterogeneity among human tumors poses a challenge to developing therapies that exploit metabolic vulnerabilities. Recent work also demonstrates that the metabolic properties and preferences of a tumor change during cancer progression. This produces distinct sets of vulnerabilities between primary tumors and metastatic cancer, even in the same patient or experimental model. We review emerging concepts about metabolic reprogramming in cancer, with particular attention on why metabolic properties evolve during cancer progression and how this information might be used to develop better therapeutic strategies.