Publications by authors named "Scott C Beeman"

31 Publications

Analysis Protocol for Dynamic Contrast Enhanced (DCE) MRI of Renal Perfusion and Filtration.

Methods Mol Biol 2021 ;2216:637-653

Washington University School of Medicine, St. Louis, MO, USA.

Here we present an analysis protocol for dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) data of the kidneys. It covers comprehensive steps to facilitate signal to contrast agent concentration mapping via T mapping and the calculation of renal perfusion and filtration parametric maps using model-free approaches, model free analysis using deconvolution, the Toft's model and a Bayesian approach.This chapter is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers. This analysis protocol chapter is complemented by two separate chapters describing the basic concept and experimental procedure.
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http://dx.doi.org/10.1007/978-1-0716-0978-1_38DOI Listing
January 2021

Dynamic Contrast Enhancement (DCE) MRI-Derived Renal Perfusion and Filtration: Basic Concepts.

Methods Mol Biol 2021 ;2216:205-227

Institute of Biostructures and Bioimaging (IBB), Italian National Research Council (CNR), Torino, Italy.

Dynamic contrast-enhanced (DCE) MRI monitors the transit of contrast agents, typically gadolinium chelates, through the intrarenal regions, the renal cortex, the medulla, and the collecting system. In this way, DCE-MRI reveals the renal uptake and excretion of the contrast agent. An optimal DCE-MRI acquisition protocol involves finding a good compromise between whole-kidney coverage (i.e., 3D imaging), spatial and temporal resolution, and contrast resolution. By analyzing the enhancement of the renal tissues as a function of time, one can determine indirect measures of clinically important single-kidney parameters as the renal blood flow, glomerular filtration rate, and intrarenal blood volumes. Gadolinium-containing contrast agents may be nephrotoxic in patients suffering from severe renal dysfunction, but otherwise DCE-MRI is clearly useful for diagnosis of renal functions and for assessing treatment response and posttransplant rejection.Here we introduce the concept of renal DCE-MRI, describe the existing methods, and provide an overview of preclinical DCE-MRI applications to illustrate the utility of this technique to measure renal perfusion and glomerular filtration rate in animal models.This publication is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers. This introduction is complemented by two separate publications describing the experimental procedure and data analysis.
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http://dx.doi.org/10.1007/978-1-0716-0978-1_12DOI Listing
January 2021

Mapping nephron mass in vivo using positron emission tomography.

Am J Physiol Renal Physiol 2021 02 7;320(2):F183-F192. Epub 2020 Dec 7.

Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, Missouri.

Nephron number varies widely in humans. A low nephron endowment at birth or a loss of functioning nephrons is strongly linked to increased susceptibility to chronic kidney disease. In this work, we developed a contrast agent, radiolabeled cationic ferritin (RadioCF), to map functioning glomeruli in vivo in the kidney using positron emission tomography (PET). PET radiotracers can be detected in trace doses (<30 nmol), making them useful for rapid clinical translation. RadioCF is formed from cationic ferritin (CF) and with a radioisotope, Cu-64, incorporated into the ferritin core. We showed that RadioCF binds specifically to kidney glomeruli after intravenous injection in mice, whereas radiolabeled noncationic ferritin (RadioNF) and free Cu-64 do not. We then showed that RadioCF-PET can distinguish kidneys in healthy wild-type (WT) mice from kidneys in mice with oligosyndactylism (Os), a model of congenital hypoplasia and low nephron mass. The average standardized uptake value (SUV) measured by PET 90 min after injection was 21% higher in WT mice than in Os mice, consistent with the higher glomerular density in WT mice. The difference in peak SUV from SUV at 90 min correlated with glomerular density in male mice from both WT and Os cohorts ( = 0.98). Finally, we used RadioCF-PET to map functioning glomeruli in a donated human kidney. SUV within the kidney correlated with glomerular number (= 0.78) measured by CF-enhanced magnetic resonance imaging in the same locations. This work suggests that RadioCF-PET appears to accurately detect nephron mass and has the potential for clinical translation.
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http://dx.doi.org/10.1152/ajprenal.00418.2020DOI Listing
February 2021

Decreased adipose tissue oxygenation associates with insulin resistance in individuals with obesity.

J Clin Invest 2020 12;130(12):6688-6699

Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, and.

BACKGROUNDData from studies conducted in rodent models have shown that decreased adipose tissue (AT) oxygenation is involved in the pathogenesis of obesity-induced insulin resistance. Here, we evaluated the potential influence of AT oxygenation on AT biology and insulin sensitivity in people.METHODSWe evaluated subcutaneous AT oxygen partial pressure (pO2); liver and whole-body insulin sensitivity; AT expression of genes and pathways involved in inflammation, fibrosis, and branched-chain amino acid (BCAA) catabolism; systemic markers of inflammation; and plasma BCAA concentrations, in 3 groups of participants that were rigorously stratified by adiposity and insulin sensitivity: metabolically healthy lean (MHL; n = 11), metabolically healthy obese (MHO; n = 15), and metabolically unhealthy obese (MUO; n = 20).RESULTSAT pO2 progressively declined from the MHL to the MHO to the MUO group, and was positively associated with hepatic and whole-body insulin sensitivity. AT pO2 was positively associated with the expression of genes involved in BCAA catabolism, in conjunction with an inverse relationship between AT pO2 and plasma BCAA concentrations. AT pO2 was negatively associated with AT gene expression of markers of inflammation and fibrosis. Plasma PAI-1 increased from the MHL to the MHO to the MUO group and was negatively correlated with AT pO2, whereas the plasma concentrations of other cytokines and chemokines were not different among the MHL and MUO groups.CONCLUSIONThese results support the notion that reduced AT oxygenation in individuals with obesity contributes to insulin resistance by increasing plasma PAI-1 concentrations and decreasing AT BCAA catabolism and thereby increasing plasma BCAA concentrations.TRIAL REGISTRATIONClinicalTrials.gov NCT02706262.FUNDINGThis study was supported by NIH grants K01DK109119, T32HL130357, K01DK116917, R01ES027595, P42ES010337, DK56341 (Nutrition Obesity Research Center), DK20579 (Diabetes Research Center), DK052574 (Digestive Disease Research Center), and UL1TR002345 (Clinical and Translational Science Award); NIH Shared Instrumentation Grants S10RR0227552, S10OD020025, and S10OD026929; and the Foundation for Barnes-Jewish Hospital.
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http://dx.doi.org/10.1172/JCI141828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685757PMC
December 2020

Toward noninvasive quantification of adipose tissue oxygenation with MRI.

Int J Obes (Lond) 2020 Aug 30;44(8):1776-1783. Epub 2020 Mar 30.

School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, USA.

Background: Molecular oxygen (O) plays a key role in normal and pathological adipose tissue function, yet technologies to measure its role in adipose tissue function are limited. O is paramagnetic and, in principle, directly influences the magnetic resonance (MR) H longitudinal relaxation rate constant of lipids, R; thus, we hypothesize that MR imaging (MRI) can directly measure adipose O via a simple measure of R.

Methods: R was measured in a 4.7T preclinical MRI system at discrete oxygen partial pressure (pO) levels. These measures were made in vitro in an idealized system and in vivo in subcutaneous and visceral white adipose of rodents. pO was determined using an invasive fiber-optic oxygen monitor. From the MRI and fiber optic data we determined the "relaxivity" of O in lipid, a critical parameter in converting the MRI-based R measurement into pO. We used breathing gas challenge to estimate the changes in lipid pO (ΔpO).

Results: The relaxivity of O in lipid was determined to be 1.7·10 ± 4·10 mmHgs at 4.7T and 37 °C, and was consistent between in vitro and in vivo adipose tissue. There was a strong, significant correlation between MRI- and gold standard OxyLite-based measurements of lipid ΔpO for in vivo visceral and subcutaneous fat depots in rodents.

Conclusion: This study lays the foundation for a direct, noninvasive measure of adipose pO using MRI and will allow for noninvasive measurement of O flux in adipose tissue. The proposed approach would be of particular importance in the interrogation of the pathogenesis of type 2 diabetes, where it has been suggested that adipose tissue hypoxia is an independent driver of insulin resistance pathway.
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http://dx.doi.org/10.1038/s41366-020-0567-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719410PMC
August 2020

Knockdown of Reduces Adipocyte Hypoxia And Improves Insulin Resistance in Obesity.

Nat Metab 2019 01 19;1(1):86-97. Epub 2018 Nov 19.

Department of Medicine, Division of Endocrinology and Metabolism, University of California San Diego, La Jolla, CA 92093, USA.

Decreased adipose tissue oxygen tension and increased HIF-1α expression can trigger adipose tissue inflammation and dysfunction in obesity. Our current understanding of obesity-associated decreased adipose tissue oxygen tension is mainly focused on changes in oxygen supply and angiogenesis. Here, we demonstrate that increased adipocyte O demand, mediated by ANT2 activity, is the dominant cause of adipocyte hypoxia. Deletion of adipocyte improves obesity-induced intracellular adipocyte hypoxia by decreasing obesity-induced adipocyte oxygen demand, without effects on mitochondrial number or mass, or oligomycin-sensitive respiration. This led to decreased adipose tissue HIF-1α expression and inflammation with improved glucose tolerance and insulin resistance in both a preventative or therapeutic setting. Our results suggest that ANT2 may be a target for the development of insulin sensitizing drugs and that ANT2 inhibition might have clinical utility.
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http://dx.doi.org/10.1038/s42255-018-0003-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746433PMC
January 2019

Calcium carbonate nanoparticles stimulate tumor metabolic reprogramming and modulate tumor metastasis.

Nanomedicine (Lond) 2019 01 6;14(2):169-182. Epub 2018 Dec 6.

Mallinckrodt Institute of Radiology, Washington University in St Louis School of Medicine, St Louis, MO 63110, USA.

Aim: CaCO nanoparticles (nano-CaCO) can neutralize the acidic pHe of solid tumors, but the lack of intrinsic imaging signal precludes noninvasive monitoring of pH-perturbation in tumor microenvironment. We aim to develop a theranostic version of nano-CaCO to noninvasively monitor pH modulation and subsequent tumor response.

Materials & Methods: We synthesized ferromagnetic core coated with CaCO (magnetite CaCO). Magnetic resonance imaging (MRI) was used to determine the biodistribution and pH modulation using murine fibrosarcoma and breast cancer models.

Results: Magnetite CaCO-MRI imaging showed that nano-CaCO rapidly raised tumor pHe, followed by excessive tumor-associated acid production after its clearance. Continuous nano-CaCO infusion could inhibit metastasis.

Conclusion: Nano-CaCO exposure induces tumor metabolic reprogramming that could account for the failure of previous intermittent pH-modulation strategies to achieve sustainable therapeutic effect.
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http://dx.doi.org/10.2217/nnm-2018-0302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369564PMC
January 2019

Bayesian Modeling of NMR Data: Quantifying Longitudinal Relaxation , and with a Tissue-Water-Relaxation Mimic (Crosslinked Bovine Serum Albumin).

Appl Magn Reson 2018 Jan 4;49(1):3-24. Epub 2017 Dec 4.

Department of Radiology, Washington University, Saint Louis, MO, United States.

Recently, a number of MRI protocols have been reported that seek to exploit the effect of dissolved oxygen (O, paramagnetic) on the longitudinal H relaxation of tissue water, thus providing image contrast related to tissue oxygen content. However, tissue water relaxation is dependent on a number of mechanisms, and this raises the issue of how best to model the relaxation data. This problem, the model selection problem, occurs in many branches of science and is optimally addressed by Bayesian probability theory. High signal-to-noise, densely sampled, longitudinal H relaxation data were acquired from rat brain and from a cross-linked bovine serum albumin (xBSA) phantom, a sample that recapitulates the relaxation characteristics of tissue water . Bayesian-based model selection was applied to a cohort of five competing relaxation models: (i) monoexponential, (ii) stretched-exponential, (iii) biexponential, (iv) Gaussian (normal) R-distribution, and (v) gamma R-distribution. Bayesian joint analysis of multiple replicate datasets revealed that water relaxation of both the xBSA phantom and rat brain was best described by a biexponential model, while xBSA relaxation datasets truncated to remove evidence of the fast relaxation component were best modeled as a stretched exponential. In all cases, estimated model parameters were compared to the commonly used monoexponential model. Reducing the sampling density of the relaxation data and adding Gaussian-distributed noise served to simulate cases in which the data are acquisition-time or signal-to-noise restricted, respectively. As expected, reducing either the number of data points or the signal-to-noise increases the uncertainty in estimated parameters and, ultimately, reduces support for more complex relaxation models.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5918291PMC
http://dx.doi.org/10.1007/s00723-017-0964-zDOI Listing
January 2018

Preclinical MRI: Studies of the irradiated brain.

J Magn Reson 2018 07 26;292:73-81. Epub 2018 Apr 26.

Department of Radiology, Washington University, Saint Louis, MO, United States.

Radiation therapy (RT) plays a central role in the treatment of primary brain tumors. However, despite recent advances in RT treatment, local recurrences following therapy remain common. Radiation necrosis (RN) is a severe, late complication of radiation therapy in the brain. RN is a serious clinical problem often associated with devastating neurologic complications. Therapeutic strategies, including neuroprotectants, have been described, but have not been widely translated in routine clinical use. We have developed a mouse model that recapitulates all of the major pathologic features of late-onset RN for the purposes of characterizing the basic pathogenesis of RN, identifying non-invasive (imaging) biomarkers of RN that might allow for the radiologic discernment of tumor and RN, systematic testing of tumor and RN therapeutics, and exploring the complex interplay between RN pathogenesis and tumor recurrence. Herein, we describe the fundamental clinical challenges associated with RN and the progress made towards addressing these challenges by combining our novel mouse model of late-onset RN and magnetic resonance imaging (MRI). MRI techniques discussed include conventional T1- and T2-weighted imaging, diffusion-weighted imaging, magnetization transfer, and measures of tissue oxygenation. Studies of RN mitigation and neuroprotection are described, including the use of anti-VEGF antibodies, and inhibitors of GSK-3β, HIF-1α, and CXCR4. We conclude with some future perspectives on the irradiated brain and the study and treatment of recurrent tumor growing in an irradiated tumor microenvironment.
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http://dx.doi.org/10.1016/j.jmr.2018.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6029718PMC
July 2018

Effects of an artificial placenta on brain development and injury in premature lambs.

J Pediatr Surg 2018 Jun 8;53(6):1234-1239. Epub 2018 Mar 8.

Extracorporeal Life Support Laboratory, Department of Surgery, Michigan Medicine, Ann Arbor, MI.

Purpose: We evaluated whether brain development continues and brain injury is prevented during Artificial Placenta (AP) support utilizing extracorporeal life support (ECLS).

Methods: Lambs at EGA 118days (term=145; n=4) were placed on AP support (venovenous ECLS with jugular drainage and umbilical vein reinfusion) for 7days and sacrificed. Early (EGA 118; n=4) and late (EGA 127; n=4) mechanical ventilation (MV) lambs underwent conventional MV for up to 48h and were sacrificed, and early (n=5) and late (n=5) tissue control (TC) lambs were sacrificed at delivery. Brains were harvested, formalin-fixed, rehydrated, and studied by magnetic resonance imaging (MRI). The gyrification index (GI), a measure of cerebral folding complexity, was calculated for each brain. Diffusion-weighted imaging was used to determine fractional anisotropy (FA) and apparent diffusion coefficient (ADC) in multiple structures to assess white matter (WM) integrity.

Results: No intracranial hemorrhage was observed. GI was similar between AP and TC groups. ADC and FA did not differ between AP and late TC groups in any structure. Compared to late MV brains, AP brains demonstrated significantly higher ADC (0.45±0.08 vs. 0.27±0.11, p=0.02) and FA (0.61±0.04 vs. 0.44±0.05; p=0.006) in the cerebral peduncles.

Conclusions: After 7days of AP support, WM integrity is preserved relative to mechanical ventilation.

Type Of Study: Research study.
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http://dx.doi.org/10.1016/j.jpedsurg.2018.02.091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994355PMC
June 2018

Minoxidil improves vascular compliance, restores cerebral blood flow, and alters extracellular matrix gene expression in a model of chronic vascular stiffness.

Am J Physiol Heart Circ Physiol 2018 07 2;315(1):H18-H32. Epub 2018 Mar 2.

National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, Maryland.

Increased vascular stiffness correlates with a higher risk of cardiovascular complications in aging adults. Elastin (ELN) insufficiency, as observed in patients with Williams-Beuren syndrome or with familial supravalvular aortic stenosis, also increases vascular stiffness and leads to arterial narrowing. We used Eln mice to test the hypothesis that pathologically increased vascular stiffness with concomitant arterial narrowing leads to decreased blood flow to end organs such as the brain. We also hypothesized that drugs that remodel arteries and increase lumen diameter would improve flow. To test these hypotheses, we compared carotid blood flow using ultrasound and cerebral blood flow using MRI-based arterial spin labeling in wild-type (WT) and Eln mice. We then studied how minoxidil, an ATP-sensitive K channel opener and vasodilator, affects vessel mechanics, blood flow, and gene expression. Both carotid and cerebral blood flows were lower in Eln mice than in WT mice. Treatment of Eln mice with minoxidil lowered blood pressure and reduced functional arterial stiffness to WT levels. Minoxidil also improved arterial diameter and restored carotid and cerebral blood flows in Eln mice. The beneficial effects persisted for weeks after drug removal. RNA-Seq analysis revealed differential expression of 127 extracellular matrix-related genes among the treatment groups. These results indicate that ELN insufficiency impairs end-organ perfusion, which may contribute to the increased cardiovascular risk. Minoxidil, despite lowering blood pressure, improves end-organ perfusion. Changes in matrix gene expression and persistence of treatment effects after drug withdrawal suggest arterial remodeling. Such remodeling may benefit patients with genetic or age-dependent ELN insufficiency. NEW & NOTEWORTHY Our work with a model of chronic vascular stiffness, the elastin ( Eln) mouse, shows reduced brain perfusion as measured by carotid ultrasound and MRI arterial spin labeling. Vessel caliber, functional stiffness, and blood flow improved with minoxidil. The ATP-sensitive K channel opener increased Eln gene expression and altered 126 other matrix-associated genes.
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http://dx.doi.org/10.1152/ajpheart.00683.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087770PMC
July 2018

Inhibitors of HIF-1α and CXCR4 Mitigate the Development of Radiation Necrosis in Mouse Brain.

Int J Radiat Oncol Biol Phys 2018 03 21;100(4):1016-1025. Epub 2017 Dec 21.

Department of Radiology, Washington University, St Louis, Missouri; Alvin J. Siteman Cancer Center, Washington University, St Louis, Missouri. Electronic address:

Purpose: There is mounting evidence that, in addition to angiogenesis, hypoxia-induced inflammation via the hypoxia-inducible factor 1α (HIF-1α)-CXC chemokine receptor 4 (CXCR4) pathway may contribute to the pathogenesis of late-onset, irradiation-induced necrosis. This study investigates the mitigative efficacy of an HIF-1α inhibitor, topotecan, and a CXCR4 antagonist, AMD3100, on the development of radiation necrosis (RN) in an intracranial mouse model.

Methods And Materials: Mice received a single-fraction, 50-Gy dose of hemispheric irradiation from the Leksell Gamma Knife Perfexion and were then treated with either topotecan, an HIF-1α inhibitor, from 1 to 12 weeks after irradiation, or AMD3100, a CXCR4 antagonist, from 4 to 12 weeks after irradiation. The onset and progression of RN were monitored longitudinally via noninvasive, in vivo magnetic resonance imaging (MRI) from 4 to 12 weeks after irradiation. Conventional hematoxylin-eosin staining and immunohistochemistry staining were performed to evaluate the treatment response.

Results: The progression of brain RN was significantly mitigated for mice treated with either topotecan or AMD3100 compared with control animals. MRI-derived lesion volumes were significantly smaller for both of the treated groups, and histologic findings correlated well with the MRI data. By hematoxylin-eosin staining, both treated groups demonstrated reduced irradiation-induced tissue damage compared with controls. Furthermore, immunohistochemistry results revealed that expression levels of vascular endothelial growth factor, CXC chemokine ligand 12, CD68, CD3, and tumor necrosis factor α in the lesion area were significantly lower in treated (topotecan or AMD3100) brains versus control brains, while ionized calcium-binding adapter molecule 1 (Iba1) and HIF-1α expression was similar, though somewhat reduced. CXCR4 expression was reduced only in topotecan-treated mice, while interleukin 6 expression was unaffected by either topotecan or AMD3100.

Conclusions: By reducing inflammation, both topotecan and AMD3100 can, independently, mitigate the development of RN in the mouse brain. When combined with first-line, antiangiogenic treatment, anti-inflammation therapy may provide an adjuvant therapeutic strategy for clinical, postirradiation management of tumors, with additional benefits in the mitigation of RN development.
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http://dx.doi.org/10.1016/j.ijrobp.2017.12.257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389273PMC
March 2018

Non-invasive methods for the assessment of brown adipose tissue in humans.

J Physiol 2018 02 15;596(3):363-378. Epub 2018 Jan 15.

Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, USA.

Brown adipose tissue (BAT) is a recently rediscovered tissue in people that has shown promise as a potential therapeutic target against obesity and its metabolic abnormalities. Reliable non-invasive assessment of BAT volume and activity is critical to allow its importance in metabolic control to be evaluated. Positron emission tomography/computed tomography (PET/CT) in combination with 2-deoxy-2-[ F]fluoroglucose administration is currently the most frequently used and most established method for the detection and quantification of activated BAT in humans. However, it involves radiation exposure and can detect activated (e.g. after cold exposure), but not quiescent, BAT. Several alternative methods that overcome some of these limitations have been developed including different PET approaches, single-photon emission imaging, CT, magnetic resonance based approaches, contrast-enhanced ultrasound, near infrared spectroscopy, and temperature assessment of fat depots containing brown adipocytes. The purpose of this review is to summarize and critically evaluate the currently available methods that non-invasively probe various aspects of BAT biology in order to assess BAT volume and/or metabolism. Although several of these methods show promise for the non-invasive assessment of BAT volume and function, further research is needed to optimize them to enable an accurate, reproducible and practical means for the assessment of human BAT content and its metabolic function.
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http://dx.doi.org/10.1113/JP274255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5792561PMC
February 2018

Measuring rat kidney glomerular number and size in vivo with MRI.

Am J Physiol Renal Physiol 2018 03 1;314(3):F399-F406. Epub 2017 Nov 1.

University of Hawaii at Manoa, Department of Biology , Honolulu, Hawaii.

number is highly variable in humans and is thought to play an important role in renal health. Chronic kidney disease (CKD) is the result of too few nephrons to maintain homeostasis. Currently, nephron number can only be determined invasively or as a terminal assessment. Due to a lack of tools to measure and track nephron number in the living, the early stages of CKD often go unrecognized, preventing early intervention that might halt the progression of CKD. In this work, we present a technique to directly measure glomerular number ( N) and volume in vivo in the rat kidney ( n = 8) using MRI enhanced with the novel contrast agent cationized ferritin (CFE-MRI). Adult male rats were administered intravenous cationized ferritin (CF) and imaged in vivo with MRI. Glomerular number was measured and each glomerulus was spatially mapped in 3D in the image. Mean apparent glomerular volume (a V) and intrarenal distribution of the individual glomerular volume (IGV), were also measured. These metrics were compared between images of the same kidneys scanned in vivo and ex vivo with CFE-MRI. In vivo N and a V correlated to ex vivo metrics within the same kidneys and were within 10% of N and a V previously validated by stereologic methods. This is the first report of direct in vivo measurements of N and a V, introducing an opportunity to investigate mechanisms of renal disease progression and therapeutic response over time.
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http://dx.doi.org/10.1152/ajprenal.00399.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899224PMC
March 2018

Modeling Dynamic Contrast-Enhanced MRI Data with a Constrained Local AIF.

Mol Imaging Biol 2018 02;20(1):150-159

Department of Radiology, Washington University, Saint Louis, MO, USA.

Purpose: This study aims to develop a constrained local arterial input function (cL-AIF) to improve quantitative analysis of dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI) data by accounting for the contrast-agent bolus amplitude error in the voxel-specific AIF.

Procedures: Bayesian probability theory-based parameter estimation and model selection were used to compare tracer kinetic modeling employing either the measured remote-AIF (R-AIF, i.e., the traditional approach) or an inferred cL-AIF against both in silico DCE-MRI data and clinical, cervical cancer DCE-MRI data.

Results: When the data model included the cL-AIF, tracer kinetic parameters were correctly estimated from in silico data under contrast-to-noise conditions typical of clinical DCE-MRI experiments. Considering the clinical cervical cancer data, Bayesian model selection was performed for all tumor voxels of the 16 patients (35,602 voxels in total). Among those voxels, a tracer kinetic model that employed the voxel-specific cL-AIF was preferred (i.e., had a higher posterior probability) in 80 % of the voxels compared to the direct use of a single R-AIF. Maps of spatial variation in voxel-specific AIF bolus amplitude and arrival time for heterogeneous tissues, such as cervical cancer, are accessible with the cL-AIF approach.

Conclusions: The cL-AIF method, which estimates unique local-AIF amplitude and arrival time for each voxel within the tissue of interest, provides better modeling of DCE-MRI data than the use of a single, measured R-AIF. The Bayesian-based data analysis described herein affords estimates of uncertainties for each model parameter, via posterior probability density functions, and voxel-wise comparison across methods/models, via model selection in data modeling.
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http://dx.doi.org/10.1007/s11307-017-1090-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374048PMC
February 2018

Can anti-vascular endothelial growth factor antibody reverse radiation necrosis? A preclinical investigation.

J Neurooncol 2017 05 19;133(1):9-16. Epub 2017 Apr 19.

Department of Radiology, Washington University, Saint Louis, MO, USA.

Anti-vascular endothelial growth factor (anti-VEGF) antibodies are a promising new treatment for late time-to-onset radiation-induced necrosis (RN). We sought to evaluate and validate the response to anti-VEGF antibody in a mouse model of RN. Mice were irradiated with the Leksell Gamma Knife Perfexion™ and then treated with anti-VEGF antibody, beginning at post-irradiation (PIR) week 8. RN progression was monitored via anatomic and diffusion MRI from weeks 4-12 PIR. Standard histology, using haematoxylin and eosin (H&E), and immunohistochemistry staining were used to validate the response to treatment. After treatment, both post-contrast T1-weighted and T2-weighted image-derived lesion volumes decreased (P < 0.001), while the lesion volumes for the control group increased. The abnormally high apparent diffusion coefficient (ADC) for RN also returned to the ADC range for normal brain following treatment (P < 0.001). However, typical RN pathology was still present histologically. Large areas of focal calcification were observed in ~50% of treated mouse brains. Additionally, VEGF and hypoxia-inducible factor 1-alpha (HIF-1α) were continually upregulated in both the anti-VEGF and control groups. Despite improvements observed radiographically following anti-VEGF treatment, lesions were not completely resolved histologically. The subsequent calcification and the continued upregulation of VEGF and HIF-1α merit further preclinical/clinical investigation.
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http://dx.doi.org/10.1007/s11060-017-2410-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548457PMC
May 2017

Biocompatibility of ferritin-based nanoparticles as targeted MRI contrast agents.

Nanomedicine 2016 08 9;12(6):1735-45. Epub 2016 Apr 9.

University of Hawaii at Manoa, Department of Biology, Honolulu, HI. Electronic address:

Ferritin is a naturally occurring iron storage protein, proposed as a clinically relevant nanoparticle with applications as a diagnostic and therapeutic agent. Cationic ferritin is a targeted, injectable contrast agent to measure kidney microstructure with MRI. Here, the toxicity of horse spleen ferritin is assessed as a step to clinical translation. Adult male mice received cationic, native and high dose cationic ferritin (CF, NF, or HDCF) or saline and were monitored for 3weeks. Transient weight loss occurred in the ferritin groups with no difference in renal function parameters. Ferritin-injected mice demonstrated a lower serum iron 3weeks after administration. In ferritin-injected animals pre-treated with hydrocortisone, there were no structural or weight differences in the kidneys, liver, lung, heart, or spleen. This study demonstrates a lack of significant detrimental effects of horse-derived ferritin-based nanoparticles at MRI-detectable doses, allowing further exploration of these agents in basic research and clinical diagnostics.
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http://dx.doi.org/10.1016/j.nano.2016.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4955692PMC
August 2016

Efficient Small Blob Detection Based on Local Convexity, Intensity and Shape Information.

IEEE Trans Med Imaging 2016 Apr 17;35(4):1127-37. Epub 2015 Dec 17.

The identification of small structures (blobs) from medical images to quantify clinically relevant features, such as size and shape, is important in many medical applications. One particular application explored here is the automated detection of kidney glomeruli after targeted contrast enhancement and magnetic resonance imaging. We propose a computationally efficient algorithm, termed the Hessian-based Difference of Gaussians (HDoG), to segment small blobs (e.g., glomeruli from kidney) from 3D medical images based on local convexity, intensity and shape information. The image is first smoothed and pre-segmented into small blob candidate regions based on local convexity. Two novel 3D regional features (regional blobness and regional flatness) are then extracted from the candidate regions. Together with regional intensity, the three features are used in an unsupervised learning algorithm for auto post-pruning. HDoG is first validated in a 2D form and compared with other three blob detectors from literature, which are generally for 2D images only. To test the detectability of blobs from 3D images, 240 sets of simulated images are rendered for scenarios mimicking the renal nephron distribution observed in contrast-enhanced, 3D MRI. The results show a satisfactory performance of HDoG in detecting large numbers of small blobs. Two sets of real kidney 3D MR images (6 rats, 3 human) are then used to validate the applicability of HDoG for glomeruli detection. By comparing MRI to stereological measurements, we verify that HDoG is a robust and efficient unsupervised technique for 3D blobs segmentation.
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http://dx.doi.org/10.1109/TMI.2015.2509463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6991892PMC
April 2016

Use of Cationized Ferritin Nanoparticles to Measure Renal Glomerular Microstructure with MRI.

Methods Mol Biol 2016 ;1397:67-79

Division of Nephrology, Department of Pediatrics, University of Virginia Medical Center, Charlottesville, VA, USA.

Magnetic resonance imaging (MRI) is becoming important for whole-kidney assessment of glomerular morphology, both in vivo and ex vivo. MRI-based renal morphological measurements can be made in intact organs and allow direct measurements of every perfused glomerulus. Cationic ferritin (CF) is used as a superparamagnetic contrast agent for MRI. CF binds to the glomerular basement membrane after intravenous injection, allowing direct, whole-kidney measurements of glomerular number, volume, and volume distribution. Here we describe the production, testing, and use of CF as an MRI contrast agent for quantitative glomerular morphology in intact mouse, rat, and human kidneys.
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http://dx.doi.org/10.1007/978-1-4939-3353-2_7DOI Listing
October 2016

Phenotyping by magnetic resonance imaging nondestructively measures glomerular number and volume distribution in mice with and without nephron reduction.

Kidney Int 2016 Feb;89(2):498-505

Reduced nephron mass is strongly linked to susceptibility to chronic renal and cardiovascular diseases. There are currently no tools to identify nephropenia in clinical or preclinical diagnostics. Such new methods could uncover novel mechanisms and therapies for chronic kidney disease (CKD) and reveal how variation among traits can affect renal function and morphology. Here we used cationized ferritin (CF)–enhanced MRI (CFE-MRI) to investigate the relationship between glomerular number (Nglom) and volume (Vglom) in kidneys of healthy wild-type mice and mice with oligosyndactylism (Os/+), a model of congenital nephron reduction. Mice were injected with CF and perfused, and the resected kidneys were imaged with 7T MRI to detect CF-labeled glomeruli. CFE-MRI was used to measure the intrarenal distribution of individual glomerular volumes and revealed two major populations of glomeruli distinguished by size. Spatial mapping revealed that the largest glomeruli were located in the juxtamedullary region in both wild-type and Os/+ mice and the smallest population located in the cortex. Os/+ mice had about a 50% reduction and 35% increase of Nglom and Vglom, respectively, in both glomerular populations compared with wild type, consistent with glomerular hypertrophy in the Os/+ mice. Thus, we provide a foundation for whole-kidney, MRI-based phenotyping of mouse renal glomerular morphology and provide new potential for quantitative human renal diagnostics.
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http://dx.doi.org/10.1038/ki.2015.316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854807PMC
February 2016

Renal DCE-MRI Model Selection Using Bayesian Probability Theory.

Tomography 2015 Sep;1(1):61-68

Departments of Radiology.

The goal of this work was to demonstrate the utility of Bayesian probability theory-based model selection for choosing the optimal mathematical model from among 4 competing models of renal dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data. DCE-MRI data were collected on 21 mice with high (n = 7), low (n = 7), or normal (n = 7) renal blood flow (RBF). Model parameters and posterior probabilities of 4 renal DCE-MRI models were estimated using Bayesian-based methods. Models investigated included (1) an empirical model that contained a monoexponential decay (washout) term and a constant offset, (2) an empirical model with a biexponential decay term (empirical/biexponential model), (3) the Patlak-Rutland model, and (4) the 2-compartment kidney model. Joint Bayesian model selection/parameter estimation demonstrated that the empirical/biexponential model was strongly favored for all 3 cohorts, the modeled DCE signals that characterized each of the 3 cohorts were distinctly different, and individual empirical/biexponential model parameter values clearly distinguished cohorts of low and high RBF from one another. The Bayesian methods can be readily extended to a variety of model analyses, making it a versatile and valuable tool for model selection and parameter estimation.
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http://dx.doi.org/10.18383/j.tom.2015.00133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6024409PMC
September 2015

O2 -sensitive MRI distinguishes brain tumor versus radiation necrosis in murine models.

Magn Reson Med 2016 06 14;75(6):2442-7. Epub 2015 Jul 14.

Department of Radiology, Washington University, St. Louis, Missouri, USA.

Purpose: The goal of this study was to quantify the relationship between the (1) H longitudinal relaxation rate constant, R1 , and oxygen (O2 ) concentration (relaxivity, r1 ) in tissue and to quantify O2 -driven changes in R1 (ΔR1 ) during a breathing gas challenge in normal brain, radiation-induced lesions, and tumor lesions.

Methods: R1 data were collected in control-state mice (n = 4) during three different breathing gas (and thus tissue O2 ) conditions. In parallel experiments, pO2 was measured in the thalamus of control-state mice (n = 4) under the same breathing gas conditions using an O2 -sensitive microprobe. The relaxivity of tissue O2 was calculated using the R1 and pO2 data. R1 data were collected in control-state (n = 4) mice, a glioma model (n = 7), and a radiation necrosis model (n = 6) during two breathing gas (thus tissue O2 ) conditions. R1 and ΔR1 were calculated for each cohort.

Results: O2 r1 in the brain was 9 × 10(-4)  ± 3 × 10(-4) mm Hg(-1) · s(-1) at 4.7T. R1 and ΔR1 measurements distinguished radiation necrosis from tumor (P< 0.03 and P< 0.01, respectively).

Conclusion: The relaxivity of O2 in the brain is determined. R1 and ΔR1 measurements differentiate tumor lesions from radiation necrosis lesions in the mouse models. These pathologies are difficult to distinguish by traditional imaging techniques; O2 -driven changes in R1 holds promise in this regard. Magn Reson Med 75:2442-2447, 2016. © 2015 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/mrm.25821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854791PMC
June 2016

Disruptive chemical doping in a ferritin-based iron oxide nanoparticle to decrease r2 and enhance detection with T1-weighted MRI.

Contrast Media Mol Imaging 2014 Sep-Oct;9(5):323-32. Epub 2014 Apr 25.

School of Biological and Health Systems Engineering, Arizona State University, Tempe, Arizona, USA.

Inorganic doping was used to create flexible, paramagnetic nanoparticle contrast agents for in vivo molecular magnetic resonance imaging (MRI) with low transverse relaxivity (r2). Most nanoparticle contrast agents formed from superparamagnetic metal oxides are developed with high r2. While sensitive, they can have limited in vivo detection due to a number of constraints with T2 or T2*-weighted imaging. T1-weighted imaging is often preferred for molecular MRI, but most T1-shortening agents are small chelates with low metal payload or are nanoparticles that also shorten T2 and limit the range of concentrations detectable with T1-weighting. Here we used tungsten and iron deposition to form doped iron oxide crystals inside the apoferritin cavity to form a WFe nanoparticle with a disordered crystal and un-coupled atomic magnetic moments. The atomic magnetic moments were thus localized, resulting in a principally paramagnetic nanoparticle. The WFe nanoparticles had no coercivity or saturation magnetization at 5 K and sweeping up to ± 20,000 Oe, while native ferritin had a coercivity of 3000 Oe and saturation at ± 20,000 Oe. This tungsten-iron crystal paramagnetism resulted in an increased WFe particle longitudinal relaxivity (r1) of 4870 mm(-1) s(-1) and a reduced transverse relaxivity (r2) of 9076 mm(-1) s(-1) compared with native ferritin. The accumulation of the particles was detected with T1-weighted MRI in concentrations from 20 to 400 nm in vivo, both injected in the rat brain and targeted to the rat kidney glomerulus. The WFe apoferritin nanoparticles were not cytotoxic up to 700 nm particle concentrations, making them potentially important for targeted molecular MRI.
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http://dx.doi.org/10.1002/cmmi.1578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093841PMC
July 2015

MRI-based glomerular morphology and pathology in whole human kidneys.

Am J Physiol Renal Physiol 2014 Jun 19;306(11):F1381-90. Epub 2014 Mar 19.

Department of Biology, College of Natural Sciences, University of Hawaii at Manoa, Honolulu, Hawaii

Nephron number (N(glom)) and size (V(glom)) are correlated with risk for chronic cardiovascular and kidney disease and may be predictive of renal allograft viability. Unfortunately, there are no techniques to assess N(glom) and V(glom) in intact kidneys. This work demonstrates the use of cationized ferritin (CF) as a magnetic resonance imaging (MRI) contrast agent to measure N(glom) and V(glom) in viable human kidneys donated to science. The kidneys were obtained from patients with varying levels of cardiovascular and renal disease. CF was intravenously injected into three viable human kidneys. A fourth control kidney was perfused with saline. After fixation, immunofluorescence and electron microscopy confirmed binding of CF to the glomerulus. The intact kidneys were imaged with three-dimensional MRI and CF-labeled glomeruli appeared as punctate spots. Custom software identified, counted, and measured the apparent volumes of CF-labeled glomeruli, with an ~6% false positive rate. These measurements were comparable to stereological estimates. The MRI-based technique yielded a novel whole kidney distribution of glomerular volumes. Histopathology demonstrated that the distribution of CF-labeled glomeruli may be predictive of glomerular and vascular disease. Variations in CF distribution were quantified using image texture analyses, which be a useful marker of glomerular sclerosis. This is the first report of direct measurement of glomerular number and volume in intact human kidneys.
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http://dx.doi.org/10.1152/ajprenal.00092.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4042103PMC
June 2014

MRI-detectable nanoparticles: the potential role in the diagnosis of and therapy for chronic kidney disease.

Adv Chronic Kidney Dis 2013 Nov;20(6):479-87

Department of Pediatrics, Division of Nephrology, University of Virginia Medical Center, Charlottesville, VA; Department of Radiology, Washington University School of Medicine, St. Louis, MO; and Department of Biology, College of Natural Sciences, University of Hawaii at Manoa, Honolulu, HI.

Chronic kidney disease (CKD) is a common, deadly, and expensive threat to public health. Patients susceptible to the development of CKD are difficult to identify because there are few noninvasive clinical techniques and markers to assess early kidney dysfunction. Noninvasive imaging techniques are being developed to quantitatively measure kidney morphology and function in preclinical research and in clinical trials. Magnetic resonance imaging (MRI) techniques in particular have the potential to provide structural and functional information in the kidney. Novel molecular imaging techniques, using targeted magnetic nanoparticles that exploit the characteristics of the endogenous protein, ferritin, have been developed in conjunction with MRI to count every perfused glomerulus in the kidney and measure their individual volumes. This technique could open the door to the possibility of prospectively assessing and eventually reducing a patient's risk for progression to CKD. This review highlights the potential clinical benefits of early detection in patients predisposed to CKD and discusses technologic and regulatory hurdles to the translation of these molecular MRI techniques to provide early diagnosis of CKD.
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http://dx.doi.org/10.1053/j.ackd.2013.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6091865PMC
November 2013

Why and how we determine nephron number.

Pediatr Nephrol 2014 Apr;29(4):575-80

The total number of glomeruli (nephrons) in a kidney is an important microanatomical parameter for at least three reasons: it provides an index of the success/extent of nephrogenesis and can thereby provide insights into the roles of specific genes and feto-maternal environmental factors in nephrogenesis; low nephron number has been linked to an increased risk of cardiovascular and renal disease in adulthood; and knowledge of quantitative kidney microanatomy can illuminate our understanding of physiological mechanisms in health and disease. A range of methods has been used to count glomeruli in kidneys over the past 100 years, with design-based stereology (the physical disector/fractionator combination) considered the gold standard. However, this approach is labor-intensive and expensive, and therefore is not utilized by most laboratories. A new method for counting and sizing every glomerulus in the kidney has recently been described. This method involves in vivo labeling of glomeruli with cationic ferritin, and then magnetic resonance imaging (MRI) of the ex vivo kidney. Values are obtained in one sixth of the time of disector-based approaches. This new MRI method holds great promise for studies of glomerular number and size ex vivo and in vivo.
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http://dx.doi.org/10.1007/s00467-013-2600-yDOI Listing
April 2014

The emerging role of MRI in quantitative renal glomerular morphology.

Am J Physiol Renal Physiol 2013 May 20;304(10):F1252-7. Epub 2013 Mar 20.

Department of Biology, College of Natural Sciences, University of Hawaii at Manoa, Honolulu, HI 96822, USA.

Techniques to measure morphological parameters, such as glomerular (and thereby nephron) number, glomerular size, and kidney volume, have been vital to understanding factors contributing to chronic kidney disease (CKD). These techniques have also been important to understanding the associations between CKD and other systemic and cardiovascular diseases and have led to the identification of developmental risk factors for these pathologies. However, existing techniques in quantitative kidney morphology are resource- and time-consuming and are destructive to the organ. This review discusses the emerging generation of techniques to study kidney morphology quantitatively using magnetic resonance imaging (MRI) using the intravenous injection of the superparamagnetic nanoparticle cationic ferritin, which binds to the glomerular basement membrane. A primary advantage of MRI over previously established techniques is the ability to quantify morphology in the intact organ with minimal sample preparation. We highlight areas of research where MRI-based morphological measurements will be helpful in animal models and possibly diagnostic clinical nephrology, discuss technical challenges in light of the progress in MRI techniques to date, and identify novel measurements that may be possible using MRI, both ex vivo and in vivo.
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http://dx.doi.org/10.1152/ajprenal.00714.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3651625PMC
May 2013

Cationized ferritin as a magnetic resonance imaging probe to detect microstructural changes in a rat model of non-alcoholic steatohepatitis.

Magn Reson Med 2013 Dec;70(6):1728-38

Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.

Purpose: The goal of this work was to detect disease-related microstructural changes to the liver using magnetic resonance imaging. Chronic liver disease can cause microstructural changes in the liver that reduce plasma access to the perisinusoidal space--the site of exchange between the blood plasma and the hepatic parenchyma. The reduced plasma access to the perisinusoidal space inhibits hepatic function and contributes to the ∼30,000 chronic liver disease-related deaths per year.

Methods: The extracellular matrix-specific cationized ferritin magnetic resonance imaging probe was injected intravenously into healthy rats and a rat model of the chronic liver disease non-alcoholic steatohepatitis. Rats were subsequently imaged with T2*-weighted magnetic resonance imaging.

Results: This work demonstrates that the binding of cationized ferritin to the perisinusoidal extracellular matrix is reduced by 55% in a rat model of non-alcoholic steatohepatitis compared to healthy controls. This reduced binding is detectable in vivo with magnetic resonance imaging. Immunofluorescence and electron microscopy indicated that the reduced binding is due to inhibited macromolecular access to the perisinusoidal space caused by non-alcoholic steatohepatitis-related microstructural changes.

Conclusions: The reduced accumulation of intravenously injected cationized ferritin may report on changes in macromolecular access to the liver parenchyma in chronic liver disease.
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http://dx.doi.org/10.1002/mrm.24619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4232496PMC
December 2013

Toxicity, biodistribution, and ex vivo MRI detection of intravenously injected cationized ferritin.

Magn Reson Med 2013 Mar 8;69(3):853-61. Epub 2012 May 8.

School of Biological and Health Systems Engineering, Arizona State University, Tempe, Arizona 85287-9709, USA.

The goal of the work was to establish the toxicity and biodistribution of the superparamagnetic protein cationized ferritin (CF) after intravenous injection. Intravenously injected CF has been used to target the extracellular matrix with high specificity in the kidney glomerulus, allowing measurements of individual glomeruli using T2*-weighted MRI. For the routine use of CF as an extracellular matrix-specific tracer, it is important to determine whether CF is toxic. In this work, we investigated the renal and hepatic toxicity, leukocyte count, and clearance of intravenously injected CF. Furthermore, we studied CF labeling in several organs using MRI and immunohistochemistry. Serum measurements of biomarkers suggest that intravenous injection of CF is neither nephrotoxic nor hepatotoxic and does not increase leukocyte counts in healthy rats at a dose of 5.75 mg/100 g. In addition to known glomerular labeling, confocal and MRI suggest that intravenously injected CF labels the extracellular matrix of the hepatic sinusoid, extracellular glycocalyx of alveolar endothelial cells, and macrophages in the spleen. Liver T2* values suggest that CF is cleared by 7 days after injection. These results suggest that CF may serve as a useful contrast agent for detection of a number of structures and functions with minimal toxicity.
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http://dx.doi.org/10.1002/mrm.24301DOI Listing
March 2013

Principles and emerging applications of nanomagnetic materials in medicine.

Wiley Interdiscip Rev Nanomed Nanobiotechnol 2012 Jul-Aug;4(4):345-65. Epub 2012 Apr 9.

School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, USA.

The development of nanometer-scale magnetic materials for biomedical applications spans the interface between the physical sciences and biology. Applications of these materials are rapidly becoming important in medicine and enable targeted therapies and diagnostics. At the same time, specific applications add focus to the development of novel magnetic materials and facilitate a deeper understanding of the physical mechanisms behind their function. This review presents a broad, nontechnical overview of the basis of magnetism in materials at the nanometer scale and describes how these materials are created, characterized, and used. Specific emerging applications in medical diagnostics and therapies are discussed, including cancer cell targeting for thermal ablation, tissue engineering, and three-dimensional noninvasive molecular imaging. Challenges in these fields are discussed, including the toxicity and delivery of magnetic nanomaterials and the sensitivity of imaging and therapeutic techniques. The development of novel nanomagnetic nanomaterials should continue to accelerate as new applications are identified and researchers uncover new mechanisms to increase and modulate magnetism at the nanometer scale.
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http://dx.doi.org/10.1002/wnan.1169DOI Listing
January 2013