[Show abstract][Hide abstract] ABSTRACT: Kidney size adaptively increases as mammals grow and in response to the loss of 1 kidney. It is not clear how kidneys size themselves or if the processes that adapt kidney mass to lean body mass also mediate renal hypertrophy following unilateral nephrectomy (UNX). Here, we demonstrated that mice harboring a proximal tubule-specific deletion of Pten (PtenptKO) have greatly enlarged kidneys as the result of persistent activation of the class I PI3K/mTORC2/AKT pathway and an increase of the antiproliferative signals p21Cip1/WAF and p27Kip1. Administration of rapamycin to PtenptKO mice diminished hypertrophy. Proximal tubule-specific deletion of Egfr in PtenptKO mice also attenuated class I PI3K/mTORC2/AKT signaling and reduced the size of enlarged kidneys. In PtenptKO mice, UNX further increased mTORC1 activation and hypertrophy in the remaining kidney; however, mTORC2-dependent AKT phosphorylation did not increase further in the remaining kidney of PtenptKO mice, nor was it induced in the remaining kidney of WT mice. After UNX, renal blood flow and amino acid delivery to the remaining kidney rose abruptly, followed by increased amino acid content and activation of a class III PI3K/mTORC1/S6K1 pathway. Thus, our findings demonstrate context-dependent roles for EGFR-modulated class I PI3K/mTORC2/AKT signaling in the normal adaptation of kidney size and PTEN-independent, nutrient-dependent class III PI3K/mTORC1/S6K1 signaling in the compensatory enlargement of the remaining kidney following UNX.
The Journal of clinical investigation 05/2015; 125(6). DOI:10.1172/JCI78945 · 13.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Perfusion-based changes in MR signal intensity can occur in response to the introduction of exogenous contrast agents and endogenous tissue properties (e.g. blood oxygenation). MR measurements aimed at capturing these changes often implement single-shot echo planar imaging (ssEPI). In recent years ssEPI readouts have been combined with parallel imaging (PI) to allow fast dynamic multi-slice imaging as well as the incorporation of multiple echoes. A multiple spin- and gradient-echo (SAGE) EPI acquisition has recently been developed to allow measurement of transverse relaxation rate (R2 and R2⁎) changes in dynamic susceptibility contrast (DSC)-MRI experiments in the brain. With SAGE EPI, the use of PI can influence image quality, temporal resolution, and achievable echo times. The effect of PI on dynamic SAGE measurements, however, has not been evaluated. In this work, a SAGE EPI acquisition utilizing SENSE PI and partial Fourier (PF) acceleration was developed and evaluated. Voxel-wise measures of R2 and R2⁎ in healthy brain were compared using SAGE EPI and conventional non-EPI multiple echo acquisitions with varying SENSE and PF acceleration. A conservative SENSE factor of 2 with PF factor of 0.73 was found to provide accurate measures of R2 and R2⁎ in white (WM) (rR2 = [0.55-0.79], rR2⁎ = [0.47-0.71]) and gray (GM) matter (rR2 = [0.26-0.59], rR2⁎ = [0.39-0.74]) across subjects. The combined use of SENSE and PF allowed the first dynamic SAGE EPI measurements in muscle, with a SENSE factor of 3 and PF factor of 0.6 providing reliable relaxation rate estimates when compared to multi-echo methods. Application of the optimized SAGE protocol in DSC-MRI of high-grade glioma patients provided T1 leakage-corrected estimates of CBV and CBF as well as mean vessel diameter (mVD) and simultaneous measures of DCE-MRI parameters Ktrans and ve. Likewise, application of SAGE in a muscle reperfusion model allowed dynamic measures of R2’, a parameter that has been shown to correlate with muscle oxy-hemoglobin saturation.
Magnetic Resonance Imaging 12/2014; 32(10). DOI:10.1016/j.mri.2014.08.032 · 2.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Quantitative dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) provides estimates of physiologically relevant parameters related to tissue blood flow, vascular permeability, and tissue volume fractions which can then be used for prognostic and diagnostic reasons. However, standard techniques for DCE-MRI analysis ignore intra-voxel diffusion, which may play an important role in contrast agent distribution and voxel signal intensity and, thus, will affect quantification of the aforementioned parameters. To investigate the effect of intra-voxel diffusion on quantitative DCE-MRI, we developed a finite element model of contrast enhancement at the voxel level. For diffusion in the range of that expected for gadolinium chelates in tissue (i.e., 1×10-4 to 4×10-4 mm2/s), parameterization errors range from -58% to 12% for Ktrans, -9% to 8% for ve, and -60% to 213% for vp over the range of Ktrans, ve, vp, and temporal resolutions investigated. Thus the results show that diffusion has a significant effect on parameterization using standard techniques.
PLoS ONE 10/2014; 9(10):e108726. DOI:10.1371/journal.pone.0108726 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The goal of this study was to optimize and validate a combined spin- and gradient-echo (SAGE) sequence for dynamic susceptibility contrast (DSC)-MRI to obtain hemodynamic parameters in a preclinical setting. The SAGE EPI sequence was applied in phantoms and in vivo rat brain (normal, tumor, and stroke tissue). Partial and full Fourier encoding schemes were implemented and characterized. Maps of cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time (MTT), vessel size index (VSI), volume transfer constant (K(trans)), and volume fraction of the extravascular extracellular space (ve) were obtained. Partial Fourier encoding provided shortened echo times with acceptable SNR and temporal stability, thus enabling reliable characterization of T2, T2(⁎) and T1 in both phantoms and rat brain. The hemodynamic parameters CBV, CBF, and MTT for gradient-echo and spin-echo contrast were determined in tumor and stroke; VSI, K(trans), and ve were also computed in tumor tissue. The SAGE EPI sequence allows the acquisition of multiple gradient- and spin-echoes, from which measures of perfusion, permeability, and vessel size can be obtained in a preclinical setting. Partial Fourier encoding can be used to minimize SAGE echo times and reliably quantify dynamic T2 and T2(⁎) changes. This acquisition provides a more comprehensive assessment of hemodynamic status in brain tissue with vascular and perfusion abnormalities.
Magnetic Resonance Imaging 08/2014; 32(10). DOI:10.1016/j.mri.2014.08.027 · 2.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Advances in hardware and software have enabled the realization of clinically feasible, quantitative multimodality imaging of tissue pathophysiology. Earlier efforts relating to multimodality imaging of cancer have focused on the integration of anatomical and functional characteristics, such as PET-CT and single-photon emission CT (SPECT-CT), whereas more-recent advances and applications have involved the integration of multiple quantitative, functional measurements (for example, multiple PET tracers, varied MRI contrast mechanisms, and PET-MRI), thereby providing a more-comprehensive characterization of the tumour phenotype. The enormous amount of complementary quantitative data generated by such studies is beginning to offer unique insights into opportunities to optimize care for individual patients. Although important technical optimization and improved biological interpretation of multimodality imaging findings are needed, this approach can already be applied informatively in clinical trials of cancer therapeutics using existing tools. These concepts are discussed herein.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study is to evaluate the utility of high-resolution non-invasive endogenous high-field
MRI methods for the longitudinal structural and quantitative assessments of mouse kidney disease using
the model of unilateral ureter obstruction (UUO). T1-weighted, T2-weighted and magnetization transfer
(MT) imaging protocols were optimized to improve the regional contrast in mouse kidney. Conventional T1
and T2 weighted images were collected in UUO mice on day 0 (~3 h), day 1, day 3 and day 6 after injury, on
a 7 T small animal MRI system. Cortical and medullary thickness, corticomedullary contrast and
Magnetization Transfer Ratio (MTR) were assessed longitudinally. Masson trichrome staining was used
to histologically assess changes in tissue microstructure. Over the course of UUO progression there were
significant (p b 0.05) changes in thickness of cortex and outer medulla, and regional changes in T2 signal
intensity and MTR values. Histological changes included tubular cell death, tubular dilation, urine
retention, and interstitial fibrosis, assessed by histology. The MRI measures of renal cortical and medullary
atrophy, cortical–medullary differentiation and MTR changes provide an endogenous, non-invasive and
quantitative evaluation of renal morphology and tissue composition during UUO progression.
Magnetic Resonance Imaging 08/2014; 32(9):1125-1132. DOI:10.1016/j.mri.2014.07.012 · 2.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The systematic investigation of susceptibility-induced contrast in MRI is important to better interpret the influence of microvascular and microcellular morphology on DSC-MRI derived perfusion data. Recently, a novel computational approach called the Finite Perturber Method (FPM), which enables the study of susceptibility-induced contrast in MRI arising from arbitrary microvascular morphologies in 3D has been developed. However, the FPM has lower efficiency in simulating water diffusion especially for complex tissues. In this work, an improved computational approach that combines the FPM with a matrix-based finite difference method (FDM), which we call the Finite Perturber the Finite Difference Method (FPFDM), has been developed in order to efficiently investigate the influence of vascular and extravascular morphological features on susceptibility-induced transverse relaxation. The current work provides a framework for better interpreting how DSC-MRI data depend on various phenomena, including contrast agent leakage in cancerous tissues and water diffusion rates. In addition, we illustrate using simulated and micro-CT extracted tissue structures the improved FPFDM along with its potential applications and limitations.
PLoS ONE 01/2014; 9(1):e84764. DOI:10.1371/journal.pone.0084764 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Classic signal processing theory dictates that, in order to faithfully reconstruct a band-limited signal (e.g., an image), the sampling rate must be at least twice the maximum frequency contained within the signal, i.e., the Nyquist frequency. Recent developments in applied mathematics, however, have shown that it is often possible to reconstruct signals sampled below the Nyquist rate. This new method of compressed sensing (CS) requires that the signal have a concise and extremely dense representation in some mathematical basis. Magnetic resonance imaging (MRI) is particularly well suited for CS approaches, owing to the flexibility of data collection in the spatial frequency (Fourier) domain available in most MRI protocols. With custom CS acquisition and reconstruction strategies, one can quickly obtain a small subset of the full data and then iteratively reconstruct images that are consistent with the acquired data and sparse by some measure. Successful use of CS results in a substantial decrease in the time required to collect an individual image. This extra time can then be harnessed to increase spatial resolution, temporal resolution, signal-to-noise, or any combination of the three. In this article, we first review the salient features of CS theory and then discuss the specific barriers confronting CS before it can be readily incorporated into clinical quantitative MRI studies of cancer. We finally illustrate applications of the technique by describing examples of CS in dynamic contrast-enhanced MRI and dynamic susceptibility contrast MRI.
Cancer Imaging 12/2013; 13(4):633-44. DOI:10.1102/1470-7330.2013.0041 · 2.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The application of dynamic susceptibility contrast (DSC) MRI methods to assess brain tumors is often confounded by the extravasation of contrast agent (CA). Disruption of the blood-brain barrier allows CA to leak out of the vasculature leading to additional T(1), T(2) and T(2) relaxation effects in the extravascular space, thereby affecting the signal intensity time course in a complex manner. The goal of this study was to validate a dual-echo DSC-MRI approach that separates and quantifies the T(1) and T(2) contributions to the acquired signal and enables the estimation of the volume transfer constant, K(trans), and the volume fraction of the extravascular extracellular space, v(e). To test the validity of this approach, DSC-MRI- and dynamic contrast enhanced (DCE) MRI-derived K(trans) and v(e) estimates were spatially compared in both 9L and C6 rat brain tumor models. A high degree of correlation (concordance correlation coefficients >0.83, Pearson's r>0.84) and agreement was found between the DSC-MRI- and DCE-MRI-derived measurements. These results indicate that dual-echo DSC-MRI can be used to simultaneously extract reliable DCE-MRI kinetic parameters in brain tumors in addition to conventional blood volume and blood flow metrics.
Magnetic Resonance Imaging 05/2012; 30(7):944-53. DOI:10.1016/j.mri.2012.03.008 · 2.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Compressive sensing (CS) in Cartesian magnetic resonance imaging (MRI) involves random partial Fourier acquisitions. The random nature of these acquisitions can lead to variance in reconstruction errors. In quantitative MRI, variance in the reconstructed images translates to an uncertainty in the derived quantitative maps. We show that for a spatially regularized 2 ×-accelerated human breast CS DCE-MRI acquisition with a 192 (2) matrix size, the coefficients of variation (CoVs) in voxel-level parameters due to the random acquisition are 1.1%, 0.96%, and 1.5% for the tissue parameters K(trans), v(e), and v(p), with an average error in the mean of -2.5%, -2.0%, and -3.7%, respectively. Only 5% of the acquisition schemes had a systematic underestimation larger than than 4.2%, 3.7%, and 6.1%, respectively. For a 2 × -accelerated rat brain CS DSC-MRI study with a 64(2) matrix size, the CoVs due to the random acquisition were 19%, 9.5%, and 15% for the cerebral blood flow and blood volume and mean transit time, respectively, and the average errors in the tumor mean were 9.2%, 0.49%, and -7.0%, respectively. Across 11 000 different CS reconstructions, we saw no outliers in the distribution of parameters, suggesting that, despite the random undersampling schemes, CS accelerated quantitative MRI may have a predictable level of performance.
[Show abstract][Hide abstract] ABSTRACT: Magnetic resonance imaging (MRI) has played an important role in the diagnosis and management of cancer since it was first developed, but other modalities also continue to advance and provide complementary information on the status of tumors. In the future, there will be a major continuing role for noninvasive imaging in order to obtain information on the location and extent of cancer, as well as assessments of tissue characteristics that can monitor and predict treatment response and guide patient management. Developments are currently being undertaken that aim to provide improved imaging methods for the detection and evaluation of tumors, for identifying important characteristics of tumors such as the expression levels of cell surface receptors that may dictate what types of therapy will be effective and for evaluating their response to treatments. Molecular imaging techniques based mainly on radionuclide imaging can depict numerous, specific, cellular and molecular markers of disease and have unique potential to address important clinical and research challenges. In this review, we consider what continuing and evolving roles will be played by MRI in this era of molecular imaging. We discuss some of the challenges for MRI of detecting imaging agents that report on molecular events, but highlight also the ability of MRI to assess other features such as cell density, blood flow and metabolism which are not specific hallmarks of cancer but which reflect molecular changes. We discuss the future role of MRI in cancer and describe the use of selected quantitative imaging techniques for characterizing tumors that can be translated to clinical applications, particularly in the context of evaluating novel treatments.
Magnetic Resonance Imaging 06/2011; 29(5):587-600. DOI:10.1016/j.mri.2011.02.003 · 2.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dark lumen MRI colonography detects colonic polyps by minimization of the intestinal lumen signal intensity. Here we validate the use of perfluorinated oil as an intestinal-filling agent for dark lumen MRI studies in mice, enabling the physiological characterization of colonic polyps by dynamic contrast-enhanced MRI. In control and Min (multiple intestinal neoplasia) mice with and without pretreatment with oral dextran sodium sulfate (DSS), polyps as small as 0.94 mm diameter were consistently identified using standard 2D gradient echo imaging (voxel size, 0.23 x 0.16 x 0.5 mm). In serial studies, polyp growth rates were heterogeneous with an average approximately 5% increase in polyp volume per day. In DSS-treated control mice the colon wall contrast agent extravasation rate constant, K(trans), and extravascular extracellular space volume fraction, v(e), values were measured for the first time and found to be 0.10 +/- 0.03 min(-1) and 0.23 +/- 0.09, respectively. In DSS-treated Min mice, polyp K(trans) values (0.09 +/- 0.04 min(-1)) were similar to those in the colon wall but the v(e) values were substantially lower (0.16 +/- 0.03), suggesting increased cellular density. The functional dark-lumen colonography approach described herein provides new opportunities for the noninvasive assessment of gastrointestinal disease pathology and treatment response in mouse models.
Magnetic Resonance in Medicine 09/2008; 60(3):718-26. DOI:10.1002/mrm.21724 · 3.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Magnetic resonance images (MRI) that depict rates of water diffusion in tissues can be used to characterize the cellularity of tumors and are valuable in assessing their early response to treatment. Water diffusion rates are sensitive to the cellular and molecular content of tissues and are affected by local microstructural changes associated with tumor development. However, conventional maps of water diffusion reflect the integrated effects of restrictions to free diffusion at multiple scales up to a specific limiting spatial dimension, typically several micrometers. Such measurements cannot distinguish effects caused by structural variations at a smaller scale. Variations in diffusion rates then largely reflect variations in the density of cells, and no information is available about changes on a subcellular scale. We report here our experiences using a new approach based on Oscillating Gradient Spin-Echo (OGSE) MRI methods that can differentiate the influence on water diffusion of structural changes on scales much smaller than the diameter of a single cell. MRIs of glioblastomas in rat brain in vivo show an increased contrast and spatial heterogeneity when diffusion measurements are selectively sensitized to shorter distance scales. These results show the benefit of OGSE methods for revealing microscopic variations in tumors in vivo and confirm that diffusion measurements depend on factors other than cellularity.
Cancer Research 07/2008; 68(14):5941-7. DOI:10.1158/0008-5472.CAN-08-0832 · 9.33 Impact Factor