Early detection of radiation therapy response in non-Hodgkin's lymphoma xenografts by in vivo (1)H magnetic resonance spectroscopy and imaging.

NMR Biomed. 2010 Jul;23(6):624-32

Authors: Lee SC, Poptani H, Pickup S, Jenkins WT, Kim S, Koch CJ, Delikatny EJ, Glickson JD

The purpose of the study was to investigate the capability of (1)H MRS and MRI methods for detecting early response to radiation therapy in non-Hodgkin's lymphoma (NHL). Studies were performed on the WSU-DLCL2 xenograft model in nude mice of human diffuse large B-cell lymphoma, the most common form of NHL. Radiation treatment was applied as a single 15 Gy dose to the tumor. Tumor lactate, lipids, total choline, T(2) and apparent diffusion coefficients (ADC) were measured before treatment and at 24 h and 72 h after radiation. A Hadamard-encoded slice-selective multiple quantum coherence spectroscopy sequence was used for detecting lactate (Lac) while a stimulated echo acquisition mode sequence was used for detection of total choline (tCho) and lipids. T(2)- and diffusion-weighted imaging sequences were used for measuring T(2) and ADC. Within 24 h after radiation, significant changes were observed in the normalized integrated resonance intensities of Lac and the methylenes of lipids. Lac/H(2)O decreased by 38 +/- 15% (p = 0.03), and lipid (1.3 ppm, CH(2))/H(2)O increased by 57 +/- 14% (p = 0.01). At 72 h after radiation, tCho/H(2)O decreased by 45 +/- 14% (p = 0.01), and lipid (2.8 ppm, polyunsaturated fatty acid)/H(2)O increased by 970 +/- 36% (p = 0.001). ADC increased by 14 +/- 2% (p = 0.003), and T(2) did not change significantly. Tumor growth delay and regression were observed thereafter. This study enabled comparison of the relative sensitivities of various (1)H MRS and MRI indices to radiation and suggests that (1)H MRS/MRI measurements detect early responses to radiation that precede tumor volume changes. Copyright (c) 2010 John Wiley & Sons, Ltd.

PMID: 20661875 [PubMed - in process]

A comparative study of age-related hearing loss in wild type and insulin-like growth factor I deficient mice.

Front Neuroanat. 2010;4:27

Authors: Riquelme R, Cediel R, Contreras J, la Rosa Lourdes RD, Murillo-Cuesta S, Hernandez-Sanchez C, Zubeldia JM, Cerdan S, Varela-Nieto I

Insulin-like growth factor-I (IGF-I) belongs to the family of insulin-related peptides that fulfils a key role during the late development of the nervous system. Human IGF1 mutations cause profound deafness, poor growth and mental retardation. Accordingly, Igf1(-/-) null mice are dwarfs that have low survival rates, cochlear alterations and severe sensorineural deafness. Presbycusis (age-related hearing loss) is a common disorder associated with aging that causes social and cognitive problems. Aging is also associated with a decrease in circulating IGF-I levels and this reduction has been related to cognitive and brain alterations, although there is no information as yet regarding the relationship between presbycusis and IGF-I biodisponibility. Here we present a longitudinal study of wild type Igf1(+/+) and null Igf1(-/-) mice from 2 to 12 months of age comparing the temporal progression of several parameters: hearing, brain morphology, cochlear cytoarchitecture, insulin-related factors and IGF gene expression and IGF-I serum levels. Complementary invasive and non-invasive techniques were used, including auditory brainstem-evoked response (ABR) recordings and in vivo MRI brain imaging. Igf1(-/-) null mice presented profound deafness at all the ages studied, without any obvious worsening of hearing parameters with aging. Igf1(+/+) wild type mice suffered significant age-related hearing loss, their auditory thresholds and peak I latencies augmenting as they aged, in parallel with a decrease in the circulating levels of IGF-I. Accordingly, there was an age-related spiral ganglion degeneration in wild type mice that was not evident in the Igf1 null mice. However, the Igf1(-/-) null mice in turn developed a prematurely aged stria vascularis reminiscent of the diabetic strial phenotype. Our data indicate that IGF-I is required for the correct development and maintenance of hearing, supporting the idea that IGF-I-based therapies could contribute to prevent or ameliorate age-related hearing loss.

PMID: 20661454 [PubMed - in process]

In vivo angiogenesis imaging of solid tumors by {alpha}v{beta}3-targeted, dual-modality micellar nanoprobes.

Exp Biol Med (Maywood). 2010 Aug 1;235(8):957-65

Authors: Kessinger CW, Khemtong C, Togao O, Takahashi M, Sumer BD, Gao J

The objective of this study was to develop and evaluate an alpha(v)beta(3)-specific nanoprobe consisting of fluorescent superparamagnetic polymeric micelles (FSPPM) for in vivo imaging of tumor angiogenesis. Spherical micelles were produced using poly(ethylene glycol)-b-poly(d,l-lactide) co-polymers conjugated with tetramethylrhodamine, a fluorescent dye, and loaded with superparamagnetic iron oxide nanoparticles. The resulting micelle diameter was 50-70 nm by dynamic light scattering and transmission electron microscopy measurements. Micelles were encoded with an alpha(v)beta(3)-specific peptide, cyclic RGDfK, and optimized for maximum fluorescence and targeting in alpha(v)beta(3)-overexpressing cells in vitro. In mice, cRGD-FSPPM-treated animals showed alpha(v)beta(3)-specific FSPPM accumulation in human lung cancer subcutaneous tumor xenografts. Together with the histological validation, the three-dimensional gradient echo magnetic resonance imaging (MRI) data provide high spatial resolution mapping and quantification of angiogenic vasculature in an animal tumor model using targeted, ultrasensitive MRI nanoprobes.

PMID: 20660096 [PubMed - in process]

Mapping of CBV changes in 5-HT(1A) terminal fields by functional MRI in the mouse brain.

Eur Neuropsychopharmacol. 2010 Jul 23;

Authors: Mueggler T, Razoux F, Russig H, Buehler A, Franklin TB, Baltes C, Mansuy IM, Rudin M

Visualization of brain activity in humans and animals using functional magnetic resonance imaging (fMRI) is an established method for translational neuropsychopharmacology. It is useful to study the activity of defined brain structures, however it requires further refinement to allow more specific cellular analyses, like for instance, the activity of selected pools of brain cells. Here, we investigated brain activity in serotonergic pathways in the adult mouse brain by using acute pharmacological challenge of 5-hydroxytryptamine (5-HT) 1A receptors. We show that administration of the 5-HT(1A) receptor agonist 8-OH-DPAT prompts a dose-dependent reduction in local cerebral blood volume (CBV) in brain areas rich in neurons expressing post-synaptic 5-HT(1A) receptor, including the prefrontal cortex, hippocampus and amygdalar nuclei. Region-specific inhibition of the response by co-injection of 8-OH-DPAT with the selective 5-HT(1A) receptor antagonist WAY-100635, or in 5-HT(1A) knock-out mice, suggests that 5-HT(1A) receptors are the primary targets of the agonist. Overall, the data demonstrate the feasibility of mapping region-specific serotonergic transmission in the adult mouse brain in vivo by non-invasive fMRI. The method opens novel perspectives for investigating 5-HT(1A) receptor functions in mouse models of human pathologies resulting from a dysfunction of the 5-HT(1A) receptor or the serotonergic system, including depression and anxiety.

PMID: 20656461 [PubMed - as supplied by publisher]

An MRI-based atlas and database of the developing mouse brain.

Neuroimage. 2010 Jul 22;

Authors: Chuang N, Mori S, Yamamoto A, Jiang H, Ye X, Xu X, Richards LJ, Nathans J, Miller MI, W Toga A, Sidman RL, Zhang J

The advent of mammalian gene engineering and genetically modified mouse models has led to renewed interest in developing resources for referencing and quantitative analysis of mouse brain anatomy. In this study, we used diffusion tensor imaging (DTI) for quantitative characterization of anatomical phenotypes in the developing mouse brain. As an anatomical reference for neuroscience research using mouse models, this paper presents DTI based atlases of ex vivo C57BL/6 mouse brains at several developmental stages. The atlas complements existing histology and MRI-based atlases by providing users access to three-dimensional, high-resolution images of the developing mouse brain, with distinct tissue contrasts and segmentations of major gray matter and white matter structures. The usefulness of the atlas and database was demonstrated by quantitative measurements of the development of major gray matter and white matter structures. Population average images of the mouse brain at several postnatal stages were created using large deformation diffeomorphic metric mapping and their anatomical variations were quantitatively characterized. The atlas and database enhance our ability to examine the neuroanatomy in normal or genetically engineered mouse strains and mouse models of neurological diseases.

PMID: 20656042 [PubMed - as supplied by publisher]

26 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

MRI imaging AND vivo AND mouse

These pubmed results were generated on 2010/07/22

PubMed, a service of the National Library of Medicine, includes over 15 million citations for biomedical articles back to the 1950's. These citations are from MEDLINE and additional life science journals. PubMed includes links to many sites providing full text articles and other related resources.

Quantitative Magnetic Resonance Imaging Of Enzyme Activity On The Cell Surface: In Vitro And In Vivo Monitoring Of Adp-ribosyltransferase 2 On T Cells.

Mol Imaging. 2010 Aug;9(4):211-22

Authors: Bannas P, Graumann O, Balcerak P, Peldschus K, Kaul MG, Hohenberg H, Haag F, Adam G, Ittrich H, Koch-Nolte F

AbstractThe objective of this study was to quantify enzymatic activity on the surface of T cells by magnetic resonance imaging (MRI) using R2 and R2* relaxometry. Lymphoma cells expressing adenosine diphosphate (ADP)-ribosyltransferase 2 (ART2) were incubated with increasing doses of its substrate etheno-nicotinamide adenine dinucleotide (NAD), resulting in increasing amounts of surface protein ADP-ribosylation. Etheno-ADP-ribosylated proteins were detected with monoclonal antibody 1G4 and superparamagnetic iron oxide conjugated secondary antibodies (Ab-SPIO). Labeling efficiency was determined with R2 and R2* relaxometry on a clinical 3.0 T scanner. Parallel aliquots of cells were analyzed by flow cytometry. Cell-bound SPIO conjugates were detected by immunofluorescence and electron microscopy and quantified by atomic absorption spectroscopy. To mimic an inflammatory site in vivo, Ab-SPIO-labeled cells were injected subcutaneously in mice and analyzed by MRI. Immunofluorescence and electron microscopy confirmed cell-surface localization of Ab-SPIO. MRI of Ab-SPIO-labeled cells showed a corresponding signal reduction. Increases in R2 and R2* determined by magnetic resonance relaxometry correlated linearly with the expression level of ART2 and the concentration of the ART2 substrate etheno-NAD. R2 and R2* increases correlated linearly with the results from flow cytometry and atomic absorption spectroscopy analyses. Quantitative R2 and R2* mapping enable noninvasive determination of enzymatic activity on T cells and holds promise for characterization of inflammatory sites in vivo by MRI.

PMID: 20643024 [PubMed - in process]

Ferritin Overexpression For Noninvasive Magnetic Resonance Imaging-based Tracking Of Stem Cells Transplanted Into The Heart.

Mol Imaging. 2010 Aug;9(4):201-10

Authors: Naumova AV, Reinecke H, Yarnykh V, Deem J, Yuan C, Charles E M

An unmet need in cardiac cell therapy is a noninvasive imaging technique capable of tracking changes in graft size over time and monitoring cell dynamics such as replication and death, factors to which commonly used superparamagnetic nanoparticles are insensitive. Our goal was to explore if overexpression of ferritin, a nontoxic iron-binding protein, can be used for noninvasive magnetic resonance imaging (MRI) of cells transplanted into the infarcted heart. Mouse skeletal myoblasts (C2C12 cells) were engineered to overexpress ferritin. Ferritin overexpression did not interfere with cell viability, proliferation, or differentiation into multinucleated myotubes. Ferritin overexpression caused a 25% decrease in T2 relaxation time in vitro compared to wild-type cells. Transgenic grafts were detected in vivo 3 weeks after transplantation into infarcted hearts of syngeneic mice as areas of hypointensity caused by iron accumulation in overexpressed ferritin complexes. Graft size evaluation by MRI correlated tighly with histologic measurements (R2 = .8). Our studies demonstrated the feasibility of ferritin overexpression in mouse skeletal myoblasts and the successful detection of transgenic cells by MRI in vitro and in vivo after transplantation into the infarcted mouse heart. These experiments lay the groundwork for using the MRI gene reporter ferritin to track stem cells transplanted to the heart.

PMID: 20643023 [PubMed - in process]

Gadolinium toxicity: epidermis thickness measurement by magnetic resonance imaging at 500 MHz.

Skin Res Technol. 2010 Aug 1;16(3):339-53

Authors: Sharma R

Purpose: Regional epidermal thickening and hair follicle width measurement by delayed gadolinium contrast magnetic resonance imaging (MRI) may assess the contrast agent gadolinium toxicity on mice skin. Materials and methods: Delayed contrast in vivo MRI was performed in mice. Six mice skin samples were removed and exposed to a gadolinium contrast agent at different times after 2, 4, 6 and 8 h. The relaxation constants of each skin structure were measured. The thickness of the epidermis and hair follicle on follow-up ex vivo delayed-contrast MRI served as an index of gadolinium toxicity on the skin. Results: In vivo MRI by fast low-angle shot imaging technique showed distinct skin layers. High-resolution gradient echo T1-weighted and multislice multiecho proton density-weighted MRI intensities in the epidermis and hair follicle showed a positive correlation with delayed gadolinium-enhanced MRI hyperintensities (Pearson's correlation coefficient r(2)=0.81, P<0.0001) in the excised mice skin tissues. Delayed contrast-enhanced mice skin MRI after 2-4 h showed epidermis swelling and hair follicle regions with a size measurement accuracy of 65%, a sensitivity of 95%, a specificity of 25%, a positive predictive value of 65% and a negative predictive value of 65%. Areas under the receiver operating characteristic curves by MRI were 0.92-0.94 for hair and epidermis as good discriminators. MRI visualized distinct relaxation constants of the epidermis, sebaceous gland, skin papillary and reticular dermis layers and hair follicle. Conclusion: Gadolinium contrast-enhanced MRI may visualize the thickening of the epidermis wall and hair follicle as an index of viable mice skin. Gadolinium enhanced the MRI visibility of skin structures. Gadolinium treatment showed skin toxicity as epidermis thickening the first time due to the undesirable use of high concentrations of gadolinium in microimaging.

PMID: 20637004 [PubMed - in process]

Rapid T(1) mapping of mouse myocardium with saturation recovery look-locker method.

Magn Reson Med. 2010 Jul 14;

Authors: Li W, Griswold M, Yu X

Dynamic contrast-enhanced MRI using gadolinium or manganese provides unique characterization of myocardium and its pathology. In this study, an electrocardiography (ECG) triggered saturation recovery Look-Locker method was developed and validated for fast cardiac T(1) mapping in small animal models. By sampling the initial portion of the longitudinal magnetization recovery curve, high temporal resolution ( approximately 3 min) can be achieved at a high spatial resolution (195 x 390 mum2) in mouse heart without the aid of parallel imaging or echo-planar imaging. Validation studies were performed both in vitro on a phantom and in vivo on C57BL/6 mice (n = 6). Our results showed a strong agreement between T(1) measured by saturation recovery Look-Locker and by the standard saturation recovery method in vitro or inversion recovery Look-Locker in vivo. The utility of saturation recovery Look-Locker in dynamic contrast-enhanced MRI studies was demonstrated in manganese-enhanced MRI experiments in mice. Our results suggest that saturation recovery Look-Locker can provide rapid and accurate cardiac T(1) mapping for studies using small animal models. Magn Reson Med, 2010. (c) 2010 Wiley-Liss, Inc.

PMID: 20632410 [PubMed - as supplied by publisher]

Molecular basis for barbed end uncapping by the carmil homology (CAH) domain 3 of mouse carmil-1.

J Biol Chem. 2010 Jul 13;

Authors: Zwolak A, Uruno T, Piszczek G, Hammer JA, Tjandra N

Capping Protein (CP) is a ubiquitously-expressed, 62 kDa heterodimer that binds the barbed end of the actin filament with ~0.1 nM affinity to prevent further monomer addition. CARMIL is a multi-domain protein, present from protozoa to mammals, that binds CP and is important for normal actin dynamics in vivo. CARMIL's CP binding site resides in its CAH3 domain located at or near the protein's C-terminus. CAH3 binds CP with ~1 nM affinity, resulting in a complex with weak capping activity (30-200 nM). Solution assays and single-molecule imaging show that CAH3 binds CP already present on the barbed end, causing a 300-fold increase in CP's dissociation rate from the end i.e. uncapping. Here we used nuclear magnetic resonance (NMR) to define the molecular interaction between the minimal CAH3 domain (CAH3a/b) of mouse CARMIL-1 (mCARMIL-1) and CP. Specifically, we show that the highly basic CAH3a sub-domain is required for CAH3's high affinity interaction with a complementary ''acidic groove'' on CP opposite its actin-binding surface. This CAH3a: CP interaction orients the CAH3b sub-domain, which we show is also required for potent anti-CP activity, directly adjacent to CP's basic patch, shown previously to be required for CP's association to and high affinity interaction with the barbed end. The importance of specific residue interactions between CP and CAH3a/b were confirmed by site-directed mutagenesis of both proteins. Together, these results offer a mechanistic explanation for the barbed end uncapping activity of CARMIL, and they identify the basic patch on CP as a crucial regulatory site.

PMID: 20630878 [PubMed - as supplied by publisher]

Development of an inductively coupled MR coil system for imaging and spectroscopic analysis of an implantable bioartificial construct at 11.1 T.

Magn Reson Med. 2010 Apr;63(4):998-1006

Authors: Volland NA, Mareci TH, Constantinidis I, Simpson NE

Developing a method to noninvasively monitor tissue-engineered constructs is critical for the optimization of construct design and for assessing therapeutic efficacy. For this purpose, NMR is a powerful technique that can be used to obtain both images and spectroscopic data. But the inherent sensitivity of NMR limits the observation of a bioartificial construct with current NMR surface coil technology. In this study, we address this limitation through the development of an inductively coupled, implantable coil system, demonstrate its use at high field (11.1 T), and investigate the use of this coil system for monitoring a bioartificial construct in vitro and in vivo. The results establish that large gains in signal to noise can be obtained with this coil system over that obtainable with a surface coil. This coil system provides a means to quantitatively analyze the structure and function of implanted bioartificial organs.

PMID: 20373400 [PubMed - indexed for MEDLINE]

Tumor blood volume determination by using susceptibility-corrected DeltaR2* multiecho MR.

Radiology. 2010 Jun;255(3):781-9

Authors: Persigehl T, Wall A, Kellert J, Ring J, Remmele S, Heindel W, Dahnke H, Bremer C

PURPOSE: To evaluate a susceptibility-corrected multiecho magnetic resonance (MR) relaxometry technique for an accurate and robust determination of DeltaR2* as a noninvasive surrogate parameter of the perfused tumor blood volume. MATERIALS AND METHODS: All experiments were approved by the institutional animal care committee. In a glass tube phantom with different superparamagnetic iron oxide (SPIO) particle concentrations and at tumor mice xenografts with DU-4475, HT-1080, and MDA-MB-435 tumors (n = 15 total, n = 5 per model) with different degrees of neovascularization after injection of different ultrasmall SPIO (USPIO) doses changes of the transverse relaxation rate (DeltaR2*) were determined by using a fixed echo time (TE) of 22 msec and a susceptibility-corrected multigradient-echo technique. The mean DeltaR2* value and the vascular volume fraction (VVF) of each tumor was determined and compared with independent in vivo fluorescent tumor perfusion measurements and histologic analysis helped determine microvessel density (MVD). Statistical differences were tested by using analysis of variance and linear correlations. RESULTS: For the phantom study, DeltaR2* maps calculated with a fixed TE of 22 msec showed a higher standard deviation of the noise index compared with the susceptibility-corrected multiecho technique. For the xenograft model, mean tumor DeltaR2* values (+/- standard error of the mean) showed significant differences between the various tumors (eg, DU-4475: 12.3 sec(-1) +/- 2.67, HT-1080: 36.47 sec(-1) +/- 5.84, and MDA-MB-435: 64.01 sec(-1) +/- 8.87 at 80 mumol of iron per kilogram; P < .05). DeltaR2* values increased dose dependently and in a linear fashion, resulting in reproducibly stable VVF measurements. Fluorescent tumor perfusion measurements and MVD counts corroborated the MR results. CONCLUSION: Susceptibility-corrected multiecho MR relaxometry allows a highly accurate and robust determination of DeltaR2* and VVF with an excellent dynamic range for tumor characterization at clinically relevant doses of USPIO.

PMID: 20501715 [PubMed - indexed for MEDLINE]

Cardiovascular phenotyping of the mouse heart using a 4D radial acquisition and liposomal Gd-DTPA-BMA.

Magn Reson Med. 2010 Apr;63(4):979-87

Authors: Bucholz E, Ghaghada K, Qi Y, Mukundan S, Rockman HA, Johnson GA

MR microscopy has enormous potential for small-animal cardiac imaging because it is capable of producing volumetric images at multiple time points to accurately measure cardiac function. MR has not been used as frequently as ultrasound to measure cardiac function in the small animal because the MR methods required relatively long scan times, limiting throughput. Here, we demonstrate four-dimensional radial acquisition in conjunction with a liposomal blood pool agent to explore functional differences in three populations of mice: six C57BL/6J mice, six DBA/2J mice, and six DBA/2J CSQ+ mice, all with the same gestational age and approximately the same weight. Cardiovascular function was determined by measuring both left ventricular and right ventricular end diastolic volume, end systolic volume, stroke volume, and ejection fraction. Statistical significance was observed in end diastolic volume, end systolic volume, and ejection fraction for left ventricular measurements between all three populations of mice. No statistically significant difference was observed in stroke volume in either the left or right ventricle for any of the three populations of mice. This study shows that MRI is capable of efficient, high-throughput, four-dimensional cardiovascular phenotyping of the mouse.

PMID: 20373399 [PubMed - indexed for MEDLINE]

High field BOLD response to forepaw stimulation in the mouse.

Neuroimage. 2010 Jun;51(2):704-12

Authors: Adamczak JM, Farr TD, Seehafer JU, Kalthoff D, Hoehn M

We have established a robust protocol for longitudinal fMRI in mice at high field MRI using a medetomidine anesthesia. Electrical forepaw stimulation in anesthetized animals is widely used to produce BOLD contrast in the primary somatosensory cortex. To preserve neuronal activity, most fMRI experiments used alpha-chloralose to produce sedation, but severe side effects make this procedure unsuitable for survival experiments. As advantageous alternative, the alpha(2)-adrenergic receptor agonist medetomidine has been applied successfully to permit longitudinal fMRI studies in rats. With the advent of transgenic technology, mouse models have become increasingly attractive raising the demand for implementation of a suitable fMRI protocol for mice. Therefore, we investigated the use of medetomidine for repetitive fMRI experiments in C57BL/6 mice. We evaluated the optimal medetomidine dose for subcutaneous application. Somatosensory evoked potentials (SSEPs) in the contralateral somatosensory cortex were recorded to assess brain activity under medetominidine following forepaw stimulation. Repetitive administration of medetomidine, the requirement for longitudinal brain activation studies, was well tolerated. Using the forepaw stimulation paradigm, we observed BOLD contrast in the contralateral somatosensory cortex in approximately 50% of the performed scans using gradient echo-echo planar imaging (GE-EPI). However, imaging the small mouse brain at high field strength is challenging and we observed strong susceptibility artifacts in GE-EPI images in the cortex. We have developed an agar gel cap for successful compensation of these artifacts as prerequisite for successful mouse fMRI at 11.7T. The established protocol will be suitable for brain activation studies in transgenic animals and for studies of functional deficit and recovery after brain injury in mice.

PMID: 20211267 [PubMed - indexed for MEDLINE]

MicroCT-Based Virtual Histology Evaluation of Preclinical Medulloblastoma.

Mol Imaging Biol. 2010 Jul 9;

Authors: Prajapati SI, Kilcoyne A, Samano AK, Green DP, McCarthy SD, Blackman BA, Brady MM, Zarzabal LA, Tatiparthy AK, Sledz TJ, Duong T, Ohshima-Hosoyama S, Giles FJ, Michalek JE, Rubin BP, Keller C

PURPOSE: The purpose of this paper is to validate a rapid and cost-effective ex vivo technique, microCT-based virtual histology, as an alternative to MRI imaging for assessing the therapeutic response in genetically engineered mouse models of cancer. PROCEDURES: All animal procedures were conducted in accordance with the Guidelines for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Texas Health Science Center at San Antonio. MRI imaging was performed on 6-week-old, bortezomib-treated genetically engineered Patched1, p53 mice that recapitulate the characteristics of human medulloblastoma. After MRI scans, the same mice were euthanized to collect brain or spine samples for virtual histology staining followed by microCT scanning. RESULTS: Nine-micrometer resolution ex vivo micro X-ray computed tomography (microCT)-based virtual histology images were qualitatively reflective of high-field live animal images obtained with magnetic resonance imaging (MRI) and histopathology. Cerebellar volumes on microCT-based virtual histology correlated closely with MRI cerebellar volumes (R = 0.998). MRI and microCT-based virtual histology both indicated a significant difference between cerebellar volumes of untreated and treated mice (p = 0.02 and p = 0.04, respectively). The ex vivo microCT method also allowed a 7,430-fold improvement in voxel resolution (voxel volume of 729 mum(3) for 9-mum isometric resolution microCT vs. 5,416,800 mum(3) for 400 x 111 x 122 mum resolution MRI) at a 28% cost savings ($400 vs. $555 per animal). CONCLUSION: The ex vivo, en bloc technique of microCT-based virtual histology matched MRI in reflecting histopathology. MicroCT-based virtual histology proved to be a more cost-effective technique and less labor-intensive. On the other hand, MRI provides ability to perform in vivo imaging, faster scanning and lower radiation dose by sacrificing the spatial resolution. Thus, both in vivo MRI and ex vivo microCT-based virtual histology are effective means of quantitatively evaluating therapeutic response in preclinical models of cerebellar tumors including the childhood cancer, medulloblastoma.

PMID: 20617390 [PubMed - as supplied by publisher]

Functional hyperbranched polymers: toward targeted in vivo 19F magnetic resonance imaging using designed macromolecules.

J Am Chem Soc. 2010 Apr 21;132(15):5336-7

Authors: Thurecht KJ, Blakey I, Peng H, Squires O, Hsu S, Alexander C, Whittaker AK

We have demonstrated the design and synthesis of hyperbranched molecules that can be successfully imaged in vivo using (19)F MRI in under 10 min. These polymers are cytocompatible following chain extension with PEGMA. In addition, functionalization of these macromolecules can be achieved in a facile manner and with accessible and correct ligand presentation. Such hyperbranched polymers hold promise as new generation tracking and targeting MRI contrast agents.

PMID: 20345132 [PubMed - indexed for MEDLINE]

In vivo MRI and ex vivo quantification of iron and Kupffer cells demonstrate residual phagocytic activity in mouse liver after a gadolinium chloride injection.

Biochimie. 2010 Jul 2;

Authors: Fabre M, Leroy-Willig A, Denis CV, Ba N, Schoëvaërt D, Guettier C, Geldwerth-Feniger D

Kupffer cells (KCs), the resident macrophages of the liver, display a phagocytic activity that is not well quantified in animal models. Its experimental invalidation in rodents has been carried out by various means, among which the gadolinium chloride (GdCl(3)) injection has been widely used, and has been generally monitored by ex vivo techniques. The aim of our study was to determine the KC phagocytic activity induced in mouse liver following a single GdCl(3) injection, through Magnetic Resonance Imaging (MRI) measurement of liver uptake of Ferumoxide in vivo, and through ex vivo quantification of Perls positive and F4/80 labeled macrophages. In this study, we showed that 24 hours after an IV injection at a dose of 50 mg/kg body weight, GdCl(3) did not induce any hepatocellular damage, nor did it strongly suppress liver phagocytic activity, as demonstrated by the persistent hepatic uptake of the iron-based MRI contrast agent Ferumoxide. In the GdCl(3)-treated mice, the injection of Ferumoxide produced an increase in the liver proton transverse relaxation rate R2 which averaged 71 +/- 24% of that of the control animals. The ex vivo iron and immune phenotypic quantification, performed after the Ferumoxide injection and MRI, confirmed the presence of activated phagocytes in the liver of the GdCl(3)-treated animals, with a global iron score and F4/80 positive cell count respectively averaging 85 +/- 26% and 46 +/- 13% of their values in the untreated mice. In vivo MRI evaluation of the liver phagocytic activity using Ferumoxide may further prove useful in the follow up of both experimental and human pathologies.

PMID: 20600563 [PubMed - as supplied by publisher]

Imaging of branched chain amino acid metabolism in tumors with hyperpolarized 13C ketoisocaproate.

Int J Cancer. 2010 Aug 1;127(3):729-36

Authors: Karlsson M, Jensen PR, in 't Zandt R, Gisselsson A, Hansson G, Duus JØ, Meier S, Lerche MH

Powerful analytical tools are vital for characterizing the complex molecular changes underlying oncogenesis and cancer treatment. This is particularly true, if information is to be collected in vivo by noninvasive approaches. In the recent past, hyperpolarized (13)C magnetic resonance (MR) spectroscopy has been employed to quickly collect detailed spectral information on the chemical fate of tracer molecules in different tissues at high sensitivity. Here, we report a preclinical study showing that alpha-ketoisocaproic acid (KIC) can be used to assess molecular signatures of tumors with hyperpolarized MR spectroscopy. KIC is metabolized to leucine by the enzyme branched chain amino acid transferase (BCAT), which is found upregulated in some tumors. BCAT is a putative marker for metastasis and a target of the proto-oncogene c-myc. Very different fluxes through the BCAT-catalyzed reaction can be detected for murine lymphoma (EL4) and rat mammary adenocarcinoma (R3230AC) tumors in vivo. EL4 tumors show a more than 7-fold higher hyperpolarized (13)C leucine signal relative to the surrounding healthy tissue. In R3230AC tumor on the other hand branched chain amino acid metabolism is not enhanced relative to surrounding tissues. The distinct molecular signatures of branched chain amino acid metabolism in EL4 and R3230AC tumors correlate well with ex vivo assays of BCAT activity.

PMID: 19960440 [PubMed - indexed for MEDLINE]

Retinal channelrhodopsin-2-mediated activity in vivo evaluated with manganese-enhanced magnetic resonance imaging.

Mol Vis. 2010;16:1059-1067

Authors: Ivanova E, Roberts R, Bissig D, Pan ZH, Berkowitz BA

PURPOSE: Ectopic expression of light-sensitive proteins, such as channelrhodopsin-2, represent a novel approach for restoring light-detection capabilities to degenerated retina. A noninvasive method that can detect light-mediated activities of such light-sensitive proteins in the retina in vivo would be important for correlating expression patterns and retinal function. In this study, we tested the hypothesis that retinal uptake of manganese, measured noninvasively with manganese-enhanced magnetic resonance imaging (MEMRI), is a biomarker of channelrhodopsin-2-mediated activity in vivo. METHODS: The eyes of 3-month-old rd1/rd1 mice were either untreated ("uninjected," negative control) or injected intravitreally with either saline ("saline," negative control) or adeno-associated virus carrying a fusion construct of channelopsin-2 (Chop2) and green fluorescent protein (GFP; "Chop2-GFP"). MEMRI examination was performed 2 months later on either dark or continuous bright blue light-exposed mice to assess the distribution and extent of manganese uptake in the retina and optic nerve. In separate experiments, MEMRI was used to map laminar accumulation of manganese vertically through the retina. For comparison, Chop2-GFP expression was evaluated in whole mounts and vertical sections of virus-infected retinas and optic nerve. RESULTS: In the two control groups (regardless of lighting exposure) and between the control groups and the dark-exposed virus-treated eyes, retinal and optic nerve uptake of manganese did not differ. In light-exposed virus-treated eyes, manganese uptake in the retina and optic nerve was significantly greater relative to the other groups. In a retinal cross-section, manganese accumulation in light-exposed virus-treated eyes was spatially matched with Chop2-GFP expression in the optic nerve and all remaining retinal layers except the inner nuclear layer. CONCLUSIONS: First-time evidence is presented indicating the usefulness of measuring intraretinal manganese accumulation as a noninvasive biomarker of channelrhodopsin-2-mediated activity in vivo.

PMID: 20596255 [PubMed - as supplied by publisher]