Diffusion Phantom Michal Komlosh 1, Evren Ozarslan 1, Martin Lizak 1, Ferenc Horkay 1, Peter Bass... more Diffusion Phantom Michal Komlosh 1, Evren Ozarslan 1, Martin Lizak 1, Ferenc Horkay 1, Peter Basser 1 1 National Institute of Health Introduction: Diffusion MRI methods can provide valuable microstructural in formation about tissues and porous media within an imaging volume [1-3], how ever, calibrating them is problematic owing to the lack of suitable anisotropic diffusion MRI phantoms. Here we constructed an anisotropic diffusion MRI phantom to calibrate diffusion MRI sequences and validate models that relate the diffusion MRI signal to the MRI pulse sequences and material microstruc ture. We then use this phantom to calibrate a d-PFG filtered MRI experiment to measure and map mean pore size [4]. Materials and Methods: This new phantom consists of four 2 mm thick waterfilled glass capillary arrays (GCA) (Photonis USA). The nominal pore diameter of two wafers is 10 μm; that of the other two is 25 μm. D-PFG filtered NMR sequences were acquired by applying two wave vectors sequenti...
Hematopoietic stem cell transplantation (HSCT) offers a cure for cancers that are refractory to c... more Hematopoietic stem cell transplantation (HSCT) offers a cure for cancers that are refractory to chemotherapy and radiation. Most HSCT recipients develop chronic graft-versus-host disease (cGVHD), a systemic alloimmune attack on host organs. Diagnosis is based on clinical signs and symptoms, as biopsies are risky. T cells are central to the biology of cGVHD. We found that a low Treg/CD4+ T effector memory (Tem) ratio in circulation, lymphoid, and target organs identified early and established mouse cGVHD. Using deuterated water labeling to measure multicompartment in vivo kinetics of these subsets, we show robust Tem and Treg proliferation in lymphoid and target organs, while Tregs undergo apoptosis in target organs. Since deuterium enrichment into DNA serves as a proxy for cell proliferation, we developed a whole-body clinically relevant deuterium MRI approach to nonradioactively detect cGVHD and potentially allow imaging of other diseases characterized by rapidly proliferating cells.
months; P = .22). ATG exposed patients had significantly better GVHD-Free Relapse-Free Survival (... more months; P = .22). ATG exposed patients had significantly better GVHD-Free Relapse-Free Survival (GRFS), with a two-year GRFS of 23% v 3% (P = .003; Figure 1). There were no differences in ICU admission rates or in incidence or type of infections. In multivariate analysis ATG exposure was not associated with relapse or survival outcomes, but was independently associated with decreased incidence of chronic GVHD (HR .33, 95% CI .14-.78; P = .012). Conclusions: Here we report significantly lower chronic GVHD rates and improved GRFS in an ATG exposed MUD HSCT cohort compared to an unexposed MRD counterpart. Our findings suggest that low dose ATG may be effective at preventing GVHD without compromising relapse or survival, and that broader exploration of its optimal dosing is warranted.
Lung adenocarcinoma patients harboring kinase domain mutations in Epidermal growth factor recepto... more Lung adenocarcinoma patients harboring kinase domain mutations in Epidermal growth factor receptor (EGFR) have significant clinical benefit from EGFR-targeted tyrosine kinase inhibitors (TKIs). Although a majority of patients experience clinical symptomatic benefit immediately, an objective response can only be demonstrated after 6-8 weeks of treatment. Evaluation of patient response by imaging shows that 30-40% of patients do not respond due to intrinsic resistance to these TKIs. We investigated immediate-early effects of EGFR-TKI treatment in mutant EGFR-driven transgenic mouse models by FDG-PET and MRI and correlated the effects on the tumor and the tumor microenvironment. Within 24 hours of erlotinib treatment we saw approximately 65% tumor regression in mice with TKI-sensitive EGFRL858R lung adenocarcinoma. However, mice with EGFRL858R/T790M-driven tumors did not respond to either erlotinib or afatinib monotherapy, but did show a significant tumor response to afatinib-cetuximab...
This work proposes the ISMRM Raw Data format as a common MR raw data format, which promotes algor... more This work proposes the ISMRM Raw Data format as a common MR raw data format, which promotes algorithm and data sharing. A file format consisting of a flexible header and tagged frames of k-space data was designed. Application Programming Interfaces were implemented in C/C++, MATLAB, and Python. Converters for Bruker, General Electric, Philips, and Siemens proprietary file formats were implemented in C++. Raw data were collected using magnetic resonance imaging scanners from four vendors, converted to ISMRM Raw Data format, and reconstructed using software implemented in three programming languages (C++, MATLAB, Python). Images were obtained by reconstructing the raw data from all vendors. The source code, raw data, and images comprising this work are shared online, serving as an example of an image reconstruction project following a paradigm of reproducible research. The proposed raw data format solves a practical problem for the magnetic resonance imaging community. It may serve as...
Inductive coupling and tuning of NMR probes is ideally suited for certain applications because no... more Inductive coupling and tuning of NMR probes is ideally suited for certain applications because no direct electrical connections to the resonant circuit are required. The relatively transparent case of series-tuned link coupling is analyzed. It is shown that tuning and coupling adjustments are orthogonal and that most of the RF field comes from the main circuit, not the link. Applications of inductive tuning and coupling are suggested, including low-temperature NMR where Dewar space is restricted. An experimental comparison of conventional, link-coupled, and link-coupled and tuned circuits at 85 MHz is reported. Some novel VHF self-contained resonators are discussed and their performance is experimentally compared to conventional coils. 0 1988 Academic PTess. Inc.
Page 1. 992 J. Phys. Chem. 1990, 94, 992-994 Rotation and Pseudorotation in Solid Cyclooctane Mar... more Page 1. 992 J. Phys. Chem. 1990, 94, 992-994 Rotation and Pseudorotation in Solid Cyclooctane Martin J. Lizak, Robert C. Keller, Matthew S. Coffey, Mark S. Conradi,* Department of Physics, Washington Uniuersity, St. Louis, Missouri 631 30 ...
The orientationally disordered (plastic, rotor) phase 1/11 of solid cyclooctane is found to readi... more The orientationally disordered (plastic, rotor) phase 1/11 of solid cyclooctane is found to readily supercool through the I/II-111 (rotor-nonrotor) transition at-104 "C. We present both NMR and thermal evidence that supercooled 1/11 transforms to a hidden, nonrotor phase 111' at-140 "C. The stable nonrotor phase I11 can be obtained by warming 111' above-140 "C, whereupon phase 1/11 appears briefly and transforms irreversibly to 111. Measurements of the relaxation times T I , T,, and T,, are used to characterize molecular rotation and diffusion. 2H NMR is used to demonstrate that rotor phases I and I1 involve molecules with restricted rotation, in qualitative agreement with the suggested Pm3n structure.
Review of Progress in Quantitative Nondestructive Evaluation, 1992
Ceramic materials offer low weight, high temperature stability, good wear resistance and good har... more Ceramic materials offer low weight, high temperature stability, good wear resistance and good hardness, and are thus becoming increasingly important materials in high temperature applications such as heat engines, heat shields and aerospace leading edge structural components. Ceramic materials tend to be brittle in nature, however, and their mechanical properties are sensitive to many types of flaws which can be produced in manufacturing. These flaws are currently difficult to detect with nondestructive techniques, and have thus remained poorly characterized. 1 ,2 For this reason, new NDE methods are needed to help enable the large-scale implementation of ceramics, and overcome the poor reliability and reproducibility common to current ceramic manufacturing processes.
MRI using hyperpolarized 13 C-labeled pyruvate is a promising tool to biochemically profile tumor... more MRI using hyperpolarized 13 C-labeled pyruvate is a promising tool to biochemically profile tumors and monitor their response to therapy. This technique requires injection of pyruvate into tumor-bearing animals. Pyruvate is an endogenous entity but the influence of exogenously injected bolus doses of pyruvate on tumor microenvironment is not well understood. In this study, the effect of injecting a bolus of pyruvate on tumor oxygen status was investigated. EPR oxygen imaging revealed that the partial pressure of oxygen (pO 2) in squamous cell carcinoma (SCC) implanted in mice decreased significantly 30 min after [1-13 C]pyruvate injection, but recovered to pre-injection levels after 5 hours. DCE-MRI studies showed that, at the dose of pyruvate used, no changes in tumor perfusion were noticed. Immunohistochemical analysis of hypoxic marker pimonidazole independently verified that the SCC tumor transiently became more hypoxic by pyruvate injection. Efficacy of radiotherapy was suppressed when X-irradiation was delivered during the period of pyruvate-induced transient hypoxia. These results suggest importance of taking into account the transient decrease in tumor pO 2 after pyruvate injection in hyperpolarized 13 C MRI, since tumor oxygen status is an important factor in determining outcomes of therapies.
The temperature dependence of the proton NMR line width of polycarbonate and of the phenoxy resin... more The temperature dependence of the proton NMR line width of polycarbonate and of the phenoxy resin formed from bisphenol A and epichlorohydrin have been measured as a function of hydrostatic pressure. These measurements lead to the conclusion that for both polymers, ring motions are suppressed by the denser chain packing resulting from hydrostatic pressure. The magnitude of the NMR pressure dependence is comparable to the pressure variation of the y mechanical loss peak in polycarbonate. The 'H NMR results, together with those from a variety of cross-polarization magic-angle spinning 13C NMR experiments performed at room temperature and atmospheric pressure, are interpreted in terms of a bundle model of chain packing in the glassy matrix. From the observed activation volumes, activation energies, and main-chain reorientation rates, the bundles are inferred to involve the correlated motions of just a few chains.
Imaging techniques allow for the conduct of noninvasive, in vivo longitudinal small-animal studie... more Imaging techniques allow for the conduct of noninvasive, in vivo longitudinal small-animal studies, but also require access to expensive and complex equipment, and personnel who are properly trained in their use. The authors describe their planning and staffing of the NIH Mouse Imaging Facility, and highlight important issues to consider when designing a similar facility.
BACKGROUND Currently available noninvasive techniques for measuring blood flow velocities are con... more BACKGROUND Currently available noninvasive techniques for measuring blood flow velocities are constrained by limited view orientations (Doppler ultrasound) or limited time resolution (magnetic resonance imaging, MRI). We describe an MRI technique for measuring flow velocities in real time at arbitrary orientations within a cylindrical volume or "beam": V-mode nuclear magnetic resonance (NMR). METHODS AND RESULTS The technique was implemented on a standard 1.5-T clinical NMR imager with no special hardware and was tested on phantoms and human volunteers. The beam can be fired at rates up to 60 times per second, allowing measurements on a time scale that is appropriate for ungated cardiac studies. In phantoms, steady flow velocities were measured with the beam aligned along the direction of flow, and the measured velocities correlated well with the actual velocities (r > 0.99). The radial distribution of velocities in phantoms under constant flow conditions was also deter...
Aims: The tumor microenvironment is characterized by a highly reducing redox status, a low pH, an... more Aims: The tumor microenvironment is characterized by a highly reducing redox status, a low pH, and hypoxia. Anti-angiogenic therapies for solid tumors frequently function in two steps: the transient normalization of structurally and functionally aberrant tumor blood vessels with increased blood perfusion, followed by the pruning of tumor blood vessels and the resultant cessation of nutrients and oxygen delivery required for tumor growth. Conventional anatomic or vascular imaging is impractical or insufficient to distinguish between the two steps of tumor response to anti-angiogenic therapies. Here, we investigated whether the noninvasive imaging of the tumor redox state and energy metabolism could be used to characterize anti-angiogenic drug-induced transient vascular normalization. Results: Daily treatment of squamous cell carcinoma (SCCVII) tumor-bearing mice with the multityrosine kinase inhibitor sunitinib resulted in a rapid decrease in tumor microvessel density and the suppression of tumor growth. Tumor pO 2 imaging by electron paramagnetic resonance imaging showed a transient increase in tumor oxygenation after 2-4 days of sunitinib treatment, implying improved tumor perfusion. During this window of vascular normalization, magnetic resonance imaging of the redox status using an exogenously administered nitroxide probe and hyperpolarized 13 C MRI of the metabolic flux of pyruvate/lactate couple revealed an oxidative shift in tumor redox status. Innovation: Redox-sensitive metabolic couples can serve as noninvasive surrogate markers to identify the vascular normalization window in tumors with imaging techniques. Conclusion: A multimodal imaging approach to characterize physiological, metabolic, and redox changes in tumors is useful to distinguish between the different stages of anti-angiogenic treatment.
Imaging results are presented for C,F, gas imbibed into a porous ceramic matrix-ceramic fiber com... more Imaging results are presented for C,F, gas imbibed into a porous ceramic matrix-ceramic fiber composite. The images display delaminations and voids and reveal the layered nature of the material. Thus, NMR of imbibed gas is a potential nondestructive technique for advanced ceramics. The role of the gas molecules is more complicated and more rich than simply providing an NMR signal with long T2. The combination of surface adsorption and the small feature sizes causes order of magnitude changes in the spin density, T, , and the diffusion rate from those of the bulk gas. We suggest that these effects may be used to distinguish features of specified size ranges or, equivalently, specified local surface-tovolume ratios.
Disseminated candidiasis primarily targets the kidneys and brain in mice and humans. Damage to th... more Disseminated candidiasis primarily targets the kidneys and brain in mice and humans. Damage to these critical organs leads to the high mortality associated with such infections, and invasion across the blood-brain barrier can result in fungal meningoencephalitis. Candida albicans can penetrate a brain endothelial cell barrier in vitro through transcellular migration, but this mechanism has not been confirmed in vivo. MRI using the extracellular vascular contrast agent gadolinium diethylenetriaminepentaacetic acid demonstrated that integrity of the blood-brain barrier is lost during C. albicans invasion. Intravital two-photon laser scanning microscopy was used to provide the first real-time demonstration of C. albicans colonizing the living brain, where both yeast and filamentous forms of the pathogen were found. Furthermore, we adapted a previously described method utilizing MRI to monitor inflammatory cell recruitment into infected tissues in mice. Macrophages and other phagocytes were visualized in kidney and brain by the administration of ultrasmall iron oxide particles. In addition to obtaining new insights into the passage of C. albicans across the brain microvasculature, these imaging methods provide useful tools to study further the pathogenesis of C. albicans infections, to define the roles of Candida virulence genes in kidney versus brain infection and to assess new therapeutic measures for drug development. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.
The intracellular enzyme urea amidolyase (Dur1,2p) enables C. albicans to utilize urea as a sole ... more The intracellular enzyme urea amidolyase (Dur1,2p) enables C. albicans to utilize urea as a sole nitrogen source. Because deletion of the DUR1,2 gene reduces survival of C. albicans co-cultured with a murine macrophage cell line, we investigated the role of Dur1,2p in pathogenesis using a mouse model of disseminated candidiasis. A dur1,2D/dur1,2D strain was significantly less virulent than the wild-type strain, showing significantly higher survival rate, better renal function, and decreased and less sustained fungal colonization in kidney and brain. Complementation of the mutant restored virulence. DUR1,2 deletion resulted in a milder host inflammatory reaction. Immunohistochemistry, flow cytometry, and magnetic resonance imaging showed decreased phagocytic infiltration into infected kidneys. Systemic cytokine levels of wild-type mice infected with the dur1,2 mutant showed a more balanced systemic pro-inflammatory cytokine response. Host gene expression and protein analysis in infected kidneys revealed parallel changes in the local immune response. Significant differences were observed in the kidney IL-1 inflammatory pathway, IL-15 signaling, MAP kinase signaling, and the alternative complement pathway. We conclude that Dur1,2p is important for kidney colonization during disseminated candidiasis and contributes to an unbalanced host inflammatory response and subsequent renal failure. Therefore, this Candida-specific enzyme may represent a useful drug target to protect the host from kidney damage associated with disseminated candidiasis.
Disseminated fungal infections caused by Candida species are associated with homing of the pathog... more Disseminated fungal infections caused by Candida species are associated with homing of the pathogen to specific organs in human and murine hosts. Kidneys are a primary target organ of Candida albicans, and invasion into the kidney medulla can lead to loss of renal function and death. Therefore, development of noninvasive methods to assess kidney infections could aid in the management of disseminated candidemia. We describe a magnetic resonance imaging method utilizing iron oxide-based contrast agents to noninvasively assess recruitment of phagocytes and kidney inflammation. C. albicans also colonizes the brain and can cause meningoencephalitis. We describe additional imaging methods to assess loss of the blood-brain barrier function that initiates brain infections.
Purpose. Magnetic resonance imaging (MRI) is becoming increasingly important for the diagnosis an... more Purpose. Magnetic resonance imaging (MRI) is becoming increasingly important for the diagnosis and characterization of ocular pathologies. A drawback to this technique is that image contrast between different regions of tissue can be obscured because of the similarity of their nuclear magnetic resonance relaxation parameters. This problem is addressed by magnetization transfer contrast (MTC) enhancement, a MRI technique that generates high-contrast images based on characteristic tissue differences resulting from the interaction of water and macromolecules. The purpose of this study was to investigate the feasibility of using MTCenhanced imaging to monitor quantitatively the lens changes associated with sugar cataract formation in galactose-fed dogs.
Diffusion Phantom Michal Komlosh 1, Evren Ozarslan 1, Martin Lizak 1, Ferenc Horkay 1, Peter Bass... more Diffusion Phantom Michal Komlosh 1, Evren Ozarslan 1, Martin Lizak 1, Ferenc Horkay 1, Peter Basser 1 1 National Institute of Health Introduction: Diffusion MRI methods can provide valuable microstructural in formation about tissues and porous media within an imaging volume [1-3], how ever, calibrating them is problematic owing to the lack of suitable anisotropic diffusion MRI phantoms. Here we constructed an anisotropic diffusion MRI phantom to calibrate diffusion MRI sequences and validate models that relate the diffusion MRI signal to the MRI pulse sequences and material microstruc ture. We then use this phantom to calibrate a d-PFG filtered MRI experiment to measure and map mean pore size [4]. Materials and Methods: This new phantom consists of four 2 mm thick waterfilled glass capillary arrays (GCA) (Photonis USA). The nominal pore diameter of two wafers is 10 μm; that of the other two is 25 μm. D-PFG filtered NMR sequences were acquired by applying two wave vectors sequenti...
Hematopoietic stem cell transplantation (HSCT) offers a cure for cancers that are refractory to c... more Hematopoietic stem cell transplantation (HSCT) offers a cure for cancers that are refractory to chemotherapy and radiation. Most HSCT recipients develop chronic graft-versus-host disease (cGVHD), a systemic alloimmune attack on host organs. Diagnosis is based on clinical signs and symptoms, as biopsies are risky. T cells are central to the biology of cGVHD. We found that a low Treg/CD4+ T effector memory (Tem) ratio in circulation, lymphoid, and target organs identified early and established mouse cGVHD. Using deuterated water labeling to measure multicompartment in vivo kinetics of these subsets, we show robust Tem and Treg proliferation in lymphoid and target organs, while Tregs undergo apoptosis in target organs. Since deuterium enrichment into DNA serves as a proxy for cell proliferation, we developed a whole-body clinically relevant deuterium MRI approach to nonradioactively detect cGVHD and potentially allow imaging of other diseases characterized by rapidly proliferating cells.
months; P = .22). ATG exposed patients had significantly better GVHD-Free Relapse-Free Survival (... more months; P = .22). ATG exposed patients had significantly better GVHD-Free Relapse-Free Survival (GRFS), with a two-year GRFS of 23% v 3% (P = .003; Figure 1). There were no differences in ICU admission rates or in incidence or type of infections. In multivariate analysis ATG exposure was not associated with relapse or survival outcomes, but was independently associated with decreased incidence of chronic GVHD (HR .33, 95% CI .14-.78; P = .012). Conclusions: Here we report significantly lower chronic GVHD rates and improved GRFS in an ATG exposed MUD HSCT cohort compared to an unexposed MRD counterpart. Our findings suggest that low dose ATG may be effective at preventing GVHD without compromising relapse or survival, and that broader exploration of its optimal dosing is warranted.
Lung adenocarcinoma patients harboring kinase domain mutations in Epidermal growth factor recepto... more Lung adenocarcinoma patients harboring kinase domain mutations in Epidermal growth factor receptor (EGFR) have significant clinical benefit from EGFR-targeted tyrosine kinase inhibitors (TKIs). Although a majority of patients experience clinical symptomatic benefit immediately, an objective response can only be demonstrated after 6-8 weeks of treatment. Evaluation of patient response by imaging shows that 30-40% of patients do not respond due to intrinsic resistance to these TKIs. We investigated immediate-early effects of EGFR-TKI treatment in mutant EGFR-driven transgenic mouse models by FDG-PET and MRI and correlated the effects on the tumor and the tumor microenvironment. Within 24 hours of erlotinib treatment we saw approximately 65% tumor regression in mice with TKI-sensitive EGFRL858R lung adenocarcinoma. However, mice with EGFRL858R/T790M-driven tumors did not respond to either erlotinib or afatinib monotherapy, but did show a significant tumor response to afatinib-cetuximab...
This work proposes the ISMRM Raw Data format as a common MR raw data format, which promotes algor... more This work proposes the ISMRM Raw Data format as a common MR raw data format, which promotes algorithm and data sharing. A file format consisting of a flexible header and tagged frames of k-space data was designed. Application Programming Interfaces were implemented in C/C++, MATLAB, and Python. Converters for Bruker, General Electric, Philips, and Siemens proprietary file formats were implemented in C++. Raw data were collected using magnetic resonance imaging scanners from four vendors, converted to ISMRM Raw Data format, and reconstructed using software implemented in three programming languages (C++, MATLAB, Python). Images were obtained by reconstructing the raw data from all vendors. The source code, raw data, and images comprising this work are shared online, serving as an example of an image reconstruction project following a paradigm of reproducible research. The proposed raw data format solves a practical problem for the magnetic resonance imaging community. It may serve as...
Inductive coupling and tuning of NMR probes is ideally suited for certain applications because no... more Inductive coupling and tuning of NMR probes is ideally suited for certain applications because no direct electrical connections to the resonant circuit are required. The relatively transparent case of series-tuned link coupling is analyzed. It is shown that tuning and coupling adjustments are orthogonal and that most of the RF field comes from the main circuit, not the link. Applications of inductive tuning and coupling are suggested, including low-temperature NMR where Dewar space is restricted. An experimental comparison of conventional, link-coupled, and link-coupled and tuned circuits at 85 MHz is reported. Some novel VHF self-contained resonators are discussed and their performance is experimentally compared to conventional coils. 0 1988 Academic PTess. Inc.
Page 1. 992 J. Phys. Chem. 1990, 94, 992-994 Rotation and Pseudorotation in Solid Cyclooctane Mar... more Page 1. 992 J. Phys. Chem. 1990, 94, 992-994 Rotation and Pseudorotation in Solid Cyclooctane Martin J. Lizak, Robert C. Keller, Matthew S. Coffey, Mark S. Conradi,* Department of Physics, Washington Uniuersity, St. Louis, Missouri 631 30 ...
The orientationally disordered (plastic, rotor) phase 1/11 of solid cyclooctane is found to readi... more The orientationally disordered (plastic, rotor) phase 1/11 of solid cyclooctane is found to readily supercool through the I/II-111 (rotor-nonrotor) transition at-104 "C. We present both NMR and thermal evidence that supercooled 1/11 transforms to a hidden, nonrotor phase 111' at-140 "C. The stable nonrotor phase I11 can be obtained by warming 111' above-140 "C, whereupon phase 1/11 appears briefly and transforms irreversibly to 111. Measurements of the relaxation times T I , T,, and T,, are used to characterize molecular rotation and diffusion. 2H NMR is used to demonstrate that rotor phases I and I1 involve molecules with restricted rotation, in qualitative agreement with the suggested Pm3n structure.
Review of Progress in Quantitative Nondestructive Evaluation, 1992
Ceramic materials offer low weight, high temperature stability, good wear resistance and good har... more Ceramic materials offer low weight, high temperature stability, good wear resistance and good hardness, and are thus becoming increasingly important materials in high temperature applications such as heat engines, heat shields and aerospace leading edge structural components. Ceramic materials tend to be brittle in nature, however, and their mechanical properties are sensitive to many types of flaws which can be produced in manufacturing. These flaws are currently difficult to detect with nondestructive techniques, and have thus remained poorly characterized. 1 ,2 For this reason, new NDE methods are needed to help enable the large-scale implementation of ceramics, and overcome the poor reliability and reproducibility common to current ceramic manufacturing processes.
MRI using hyperpolarized 13 C-labeled pyruvate is a promising tool to biochemically profile tumor... more MRI using hyperpolarized 13 C-labeled pyruvate is a promising tool to biochemically profile tumors and monitor their response to therapy. This technique requires injection of pyruvate into tumor-bearing animals. Pyruvate is an endogenous entity but the influence of exogenously injected bolus doses of pyruvate on tumor microenvironment is not well understood. In this study, the effect of injecting a bolus of pyruvate on tumor oxygen status was investigated. EPR oxygen imaging revealed that the partial pressure of oxygen (pO 2) in squamous cell carcinoma (SCC) implanted in mice decreased significantly 30 min after [1-13 C]pyruvate injection, but recovered to pre-injection levels after 5 hours. DCE-MRI studies showed that, at the dose of pyruvate used, no changes in tumor perfusion were noticed. Immunohistochemical analysis of hypoxic marker pimonidazole independently verified that the SCC tumor transiently became more hypoxic by pyruvate injection. Efficacy of radiotherapy was suppressed when X-irradiation was delivered during the period of pyruvate-induced transient hypoxia. These results suggest importance of taking into account the transient decrease in tumor pO 2 after pyruvate injection in hyperpolarized 13 C MRI, since tumor oxygen status is an important factor in determining outcomes of therapies.
The temperature dependence of the proton NMR line width of polycarbonate and of the phenoxy resin... more The temperature dependence of the proton NMR line width of polycarbonate and of the phenoxy resin formed from bisphenol A and epichlorohydrin have been measured as a function of hydrostatic pressure. These measurements lead to the conclusion that for both polymers, ring motions are suppressed by the denser chain packing resulting from hydrostatic pressure. The magnitude of the NMR pressure dependence is comparable to the pressure variation of the y mechanical loss peak in polycarbonate. The 'H NMR results, together with those from a variety of cross-polarization magic-angle spinning 13C NMR experiments performed at room temperature and atmospheric pressure, are interpreted in terms of a bundle model of chain packing in the glassy matrix. From the observed activation volumes, activation energies, and main-chain reorientation rates, the bundles are inferred to involve the correlated motions of just a few chains.
Imaging techniques allow for the conduct of noninvasive, in vivo longitudinal small-animal studie... more Imaging techniques allow for the conduct of noninvasive, in vivo longitudinal small-animal studies, but also require access to expensive and complex equipment, and personnel who are properly trained in their use. The authors describe their planning and staffing of the NIH Mouse Imaging Facility, and highlight important issues to consider when designing a similar facility.
BACKGROUND Currently available noninvasive techniques for measuring blood flow velocities are con... more BACKGROUND Currently available noninvasive techniques for measuring blood flow velocities are constrained by limited view orientations (Doppler ultrasound) or limited time resolution (magnetic resonance imaging, MRI). We describe an MRI technique for measuring flow velocities in real time at arbitrary orientations within a cylindrical volume or "beam": V-mode nuclear magnetic resonance (NMR). METHODS AND RESULTS The technique was implemented on a standard 1.5-T clinical NMR imager with no special hardware and was tested on phantoms and human volunteers. The beam can be fired at rates up to 60 times per second, allowing measurements on a time scale that is appropriate for ungated cardiac studies. In phantoms, steady flow velocities were measured with the beam aligned along the direction of flow, and the measured velocities correlated well with the actual velocities (r > 0.99). The radial distribution of velocities in phantoms under constant flow conditions was also deter...
Aims: The tumor microenvironment is characterized by a highly reducing redox status, a low pH, an... more Aims: The tumor microenvironment is characterized by a highly reducing redox status, a low pH, and hypoxia. Anti-angiogenic therapies for solid tumors frequently function in two steps: the transient normalization of structurally and functionally aberrant tumor blood vessels with increased blood perfusion, followed by the pruning of tumor blood vessels and the resultant cessation of nutrients and oxygen delivery required for tumor growth. Conventional anatomic or vascular imaging is impractical or insufficient to distinguish between the two steps of tumor response to anti-angiogenic therapies. Here, we investigated whether the noninvasive imaging of the tumor redox state and energy metabolism could be used to characterize anti-angiogenic drug-induced transient vascular normalization. Results: Daily treatment of squamous cell carcinoma (SCCVII) tumor-bearing mice with the multityrosine kinase inhibitor sunitinib resulted in a rapid decrease in tumor microvessel density and the suppression of tumor growth. Tumor pO 2 imaging by electron paramagnetic resonance imaging showed a transient increase in tumor oxygenation after 2-4 days of sunitinib treatment, implying improved tumor perfusion. During this window of vascular normalization, magnetic resonance imaging of the redox status using an exogenously administered nitroxide probe and hyperpolarized 13 C MRI of the metabolic flux of pyruvate/lactate couple revealed an oxidative shift in tumor redox status. Innovation: Redox-sensitive metabolic couples can serve as noninvasive surrogate markers to identify the vascular normalization window in tumors with imaging techniques. Conclusion: A multimodal imaging approach to characterize physiological, metabolic, and redox changes in tumors is useful to distinguish between the different stages of anti-angiogenic treatment.
Imaging results are presented for C,F, gas imbibed into a porous ceramic matrix-ceramic fiber com... more Imaging results are presented for C,F, gas imbibed into a porous ceramic matrix-ceramic fiber composite. The images display delaminations and voids and reveal the layered nature of the material. Thus, NMR of imbibed gas is a potential nondestructive technique for advanced ceramics. The role of the gas molecules is more complicated and more rich than simply providing an NMR signal with long T2. The combination of surface adsorption and the small feature sizes causes order of magnitude changes in the spin density, T, , and the diffusion rate from those of the bulk gas. We suggest that these effects may be used to distinguish features of specified size ranges or, equivalently, specified local surface-tovolume ratios.
Disseminated candidiasis primarily targets the kidneys and brain in mice and humans. Damage to th... more Disseminated candidiasis primarily targets the kidneys and brain in mice and humans. Damage to these critical organs leads to the high mortality associated with such infections, and invasion across the blood-brain barrier can result in fungal meningoencephalitis. Candida albicans can penetrate a brain endothelial cell barrier in vitro through transcellular migration, but this mechanism has not been confirmed in vivo. MRI using the extracellular vascular contrast agent gadolinium diethylenetriaminepentaacetic acid demonstrated that integrity of the blood-brain barrier is lost during C. albicans invasion. Intravital two-photon laser scanning microscopy was used to provide the first real-time demonstration of C. albicans colonizing the living brain, where both yeast and filamentous forms of the pathogen were found. Furthermore, we adapted a previously described method utilizing MRI to monitor inflammatory cell recruitment into infected tissues in mice. Macrophages and other phagocytes were visualized in kidney and brain by the administration of ultrasmall iron oxide particles. In addition to obtaining new insights into the passage of C. albicans across the brain microvasculature, these imaging methods provide useful tools to study further the pathogenesis of C. albicans infections, to define the roles of Candida virulence genes in kidney versus brain infection and to assess new therapeutic measures for drug development. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.
The intracellular enzyme urea amidolyase (Dur1,2p) enables C. albicans to utilize urea as a sole ... more The intracellular enzyme urea amidolyase (Dur1,2p) enables C. albicans to utilize urea as a sole nitrogen source. Because deletion of the DUR1,2 gene reduces survival of C. albicans co-cultured with a murine macrophage cell line, we investigated the role of Dur1,2p in pathogenesis using a mouse model of disseminated candidiasis. A dur1,2D/dur1,2D strain was significantly less virulent than the wild-type strain, showing significantly higher survival rate, better renal function, and decreased and less sustained fungal colonization in kidney and brain. Complementation of the mutant restored virulence. DUR1,2 deletion resulted in a milder host inflammatory reaction. Immunohistochemistry, flow cytometry, and magnetic resonance imaging showed decreased phagocytic infiltration into infected kidneys. Systemic cytokine levels of wild-type mice infected with the dur1,2 mutant showed a more balanced systemic pro-inflammatory cytokine response. Host gene expression and protein analysis in infected kidneys revealed parallel changes in the local immune response. Significant differences were observed in the kidney IL-1 inflammatory pathway, IL-15 signaling, MAP kinase signaling, and the alternative complement pathway. We conclude that Dur1,2p is important for kidney colonization during disseminated candidiasis and contributes to an unbalanced host inflammatory response and subsequent renal failure. Therefore, this Candida-specific enzyme may represent a useful drug target to protect the host from kidney damage associated with disseminated candidiasis.
Disseminated fungal infections caused by Candida species are associated with homing of the pathog... more Disseminated fungal infections caused by Candida species are associated with homing of the pathogen to specific organs in human and murine hosts. Kidneys are a primary target organ of Candida albicans, and invasion into the kidney medulla can lead to loss of renal function and death. Therefore, development of noninvasive methods to assess kidney infections could aid in the management of disseminated candidemia. We describe a magnetic resonance imaging method utilizing iron oxide-based contrast agents to noninvasively assess recruitment of phagocytes and kidney inflammation. C. albicans also colonizes the brain and can cause meningoencephalitis. We describe additional imaging methods to assess loss of the blood-brain barrier function that initiates brain infections.
Purpose. Magnetic resonance imaging (MRI) is becoming increasingly important for the diagnosis an... more Purpose. Magnetic resonance imaging (MRI) is becoming increasingly important for the diagnosis and characterization of ocular pathologies. A drawback to this technique is that image contrast between different regions of tissue can be obscured because of the similarity of their nuclear magnetic resonance relaxation parameters. This problem is addressed by magnetization transfer contrast (MTC) enhancement, a MRI technique that generates high-contrast images based on characteristic tissue differences resulting from the interaction of water and macromolecules. The purpose of this study was to investigate the feasibility of using MTCenhanced imaging to monitor quantitatively the lens changes associated with sugar cataract formation in galactose-fed dogs.
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Papers by Martin Lizak