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.

Metabolic reprogramming and cancer progression

Noninvasive human neuroimaging has yielded many discoveries about the brain. Numerous methodological advances have also occurred, though inertia has slowed their adoption. This paper presents an integrated approach to data acquisition, analysis and sharing that builds upon recent advances, particularly from the Human Connectome Project (HCP). The 'HCP-style' paradigm has seven core tenets: (i) collect multimodal imaging data from many subjects; (ii) acquire data at high spatial and temporal resolution; (iii) preprocess data to minimize distortions, blurring and temporal artifacts; (iv) represent data using the natural geometry of cortical and subcortical structures; (v) accurately align corresponding brain areas across subjects and studies; (vi) analyze data using neurobiologically accurate brain parcellations; and (vii) share published data via user-friendly databases. We illustrate the HCP-style paradigm using existing HCP data sets and provide guidance for future research. Widespread adoption of this paradigm should accelerate progress in understanding the brain in health and disease.

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The Human Connectome Project's neuroimaging approach

The sensitivity of magnetic resonance imaging to biochemical and biophysical changes in the extracellular matrix of articular cartilage give it the potential to noninvasively detect the earliest changes of cartilage damage. The transverse relaxation time (T2) of cartilage has been shown to be a sensitive parameter for evaluation of early degeneration in articular cartilage, particularly changes in water and collagen content and tissue anisotropy. Although initial application has been in microimaging of small cartilage explants, in vivo techniques have been developed for cartilage T2 mapping of human joints. In addition to potential application in development of new pharmaceuticals and surgical techniques for preserving cartilage, in vivo cartilage T2 mapping can improve understanding of arthritis, cartilage aging, and response of cartilage to exercise.

Cartilage MRI T2 relaxation time mapping: overview and applications.

Glutamate (Glu) exhibits a pH and concentration dependent chemical exchange saturation transfer effect (CEST) between its -amine group and bulk water, here termed GluCEST. GluCEST asymmetry is observed at ~3 parts per million downfield from bulk water. Following middle cerebral artery occlusion in the rat brain, an approximately 100% elevation of GluCEST in the ipsilateral side compared to the contralateral side was observed, and is predominantly due to pH changes. In a rat brain tumor model with blood brain barrier disruption, intravenous Glu injection resulted in a clear elevation of GluCEST and a comparable increase in the proton magnetic resonance spectroscopy signal of Glu. GluCEST maps from healthy human brain at 7T were also obtained. These results demonstrate the feasibility and potential of GluCEST for mapping relative changes in Glu concentration as well as pH in vivo. Potential contributions from other brain metabolites to the GluCEST effect are also discussed.

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Magnetic resonance imaging of glutamate

An MRI apparatus includes an imaging data acquiring unit and a blood flow information generating unit. The imaging data acquiring unit acquires imaging data from an imaging region including myocardium, without using a contrast medium, by applying a spatial selective excitation pulse to a region including at least a part of an ascending aorta for distinguishably displaying inflowing blood flowing into the imaging region. The blood flow information generating unit generates blood flow image data based on the imaging data.

Magnetic resonance imaging apparatus and magnetic resonance imaging method

Reducing and continuously varying the flip angle of the refocusing RF pulses in a rapid acquisition with relaxation enhancement (RARE; fast/turbo spin echo) sequence is a useful means of addressing high RF power deposition and modulation transfer function (MTF) distortion due to relaxation. This work presents a streamlined technique to generate a sequence of refocusing flip angles on a per-prescription basis that produces relatively high SNR and limits blurring in a wide range of materials encountered in vivo. Since the "effective TE" (traditionally defined as the time at which the center of k-space is sampled) no longer corresponds to the expected amount of spin-echo T2 contrast due to the mixing of stimulated and spin echoes, a "contrast-equivalent" TE is defined and experimentally demonstrated that allows annotation of a more accurate effective TE that matches the contrast produced by 180 degrees refocusing. Furthermore, contrast is shown to be manipulable by the addition of magnetization preparation pulse sequence segments, such as T2-prep, to produce clinically desirable contrast for routine head and body imaging.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/mrm.20863

Fast spin echo sequences with very long echo trains: design of variable refocusing flip angle schedules and generation of clinical T2 contrast.

In vivo mapping of brain myo-inositol.

Purpose

To evaluate sources of error when using a multiecho sequence for quantitative T2 mapping of articular cartilage at 1.5 T.



Materials and Methods

Phantom measurements were used to assess the contribution of stimulated echoes to inaccuracy of T2 measurements in cartilage using a multiecho sequence. Five volunteer studies compared in vivo single-echo spin echo results to multiecho, single-slice and multiecho, multislice acquisitions for assessment of both the stimulated echo and magnetization transfer contrast (MTC) contributions to T2 measurement inaccuracy.



Results

Phantom experiments demonstrated that substantial inaccuracy (10%–13% longer T2 values) is introduced from stimulated echoes with a multiecho sequence with slice-selective refocusing pulses. The in vivo volunteer studies also demonstrated increases in measured T2 by up to 48% with a multiecho sequence. Use of the multiecho sequence in the multislice mode resulted in T2 values closer to the single-echo standards for the volunteer studies. However, this apparent increased accuracy should be regarded as circumstantial, as it only occurs because the error due to MTC has the opposite sign compared to the error due to the stimulated echo contribution.



Conclusion

Use of a multiecho, multislice sequence for cartilage T2 measurements should be undertaken with the caution that substantial inaccuracy is introduced from stimulated echoes and MTC. J. Magn. Reson. Imaging 2003;17:358–364. © 2003 Wiley-Liss, Inc.

/pdf/t2-quantitation-of-articular-cartilage-at-1-5-t-524cvbnovp.pdf

T2 quantitation of articular cartilage at 1.5 T

In general, multiple components such as water direct saturation, magnetization transfer (MT), chemical exchange saturation transfer (CEST) and aliphatic nuclear Overhauser effect (NOE) contribute to the Z-spectrum. The conventional CEST quantification method based on asymmetrical analysis may lead to quantification errors due to the semi-solid MT asymmetry and the aliphatic NOE located on a single side of the Z-spectrum. Fitting individual contributors to the Z-spectrum may improve the quantification of each component. In this study, we aim to characterize the multiple exchangeable components from an intracranial tumor model using a simplified Z-spectral fitting method. In this method, the Z-spectrum acquired at low saturation RF amplitude (50 Hz) was modeled as the summation of five Lorentzian functions that correspond to NOE, MT effect, bulk water, amide proton transfer (APT) effect and a CEST peak located at +2 ppm, called CEST@2ppm. With the pixel-wise fitting, the regional variations of these five components in the brain tumor and the normal brain tissue were quantified and summarized. Increased APT effect, decreased NOE and reduced CEST@2ppm were observed in the brain tumor compared with the normal brain tissue. Additionally, CEST@2ppm decreased with tumor progression. CEST@2ppm was found to correlate with the creatine concentration quantified with proton MRS. Based on the correlation curve, the creatine contribution to CEST@2ppm was quantified. The CEST@2ppm signal could be a novel imaging surrogate for in vivo creatine, the important bioenergetics marker. Given its noninvasive nature, this CEST MRI method may have broad applications in cancer bioenergetics. Copyright © 2014 John Wiley & Sons, Ltd.

Hari Hariharan

Papers

Magnetic resonance imaging of glutamate

Fast spin echo sequences with very long echo trains: design of variable refocusing flip angle schedules and generation of clinical T2 contrast.

In vivo mapping of brain myo-inositol.

T2 quantitation of articular cartilage at 1.5 T

CEST signal at 2ppm (CEST@2ppm) from Z-spectral fitting correlates with creatine distribution in brain tumor.