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Imaging tumor microenvironments such as hypoxia, oxygenation, redox status, and/or glycolytic metabolism in tissues/cells is useful for diagnostic and prognostic purposes. New imaging modalities are under development for imaging various aspects of tumor microenvironments. Electron Paramagnetic Resonance Imaging (EPRI) though similar to NMR/MRI is unique in its ability to provide quantitative images of pO2 in vivo. The short electron spin relaxation times have been posing formidable challenge to the technology development for clinical application. With the availability of the narrow line width trityl compounds, pulsed EPR imaging techniques were developed for pO2 imaging. EPRI visualizes the exogenously administered spin probes/contrast agents and hence lacks the complementary morphological information. Dynamic nuclear polarization (DNP), a phenomenon that transfers the high electron spin polarization to the surrounding nuclear spins (1H and 13C) opened new capabilities in molecular imaging. DNP of 13C nuclei is utilized in metabolic imaging of 13C-labeled compounds by imaging specific enzyme kinetics. In this article, imaging strategies mapping physiologic and metabolic aspects in vivo are reviewed within the framework of their application in cancer research, highlighting the potential and challenges of each of them. [ABSTRACT FROM AUTHOR]

Reoxygenation has a significant impact on the tumor response to radiotherapy. With developments in radiotherapy technology, the relevance of the reoxygenation phenomenon in treatment efficacy has been a topic of interest. Evaluating the reoxygenation in the tumor microenvironment throughout the course of radiation therapy is important in developing effective treatment strategies. In the current study, we used electron paramagnetic resonance imaging (EPRI) to directly map and quantify the partial oxygen pressure (pO2) in tumor tissues. Human colorectal cancer cell lines, HT29 and HCT116, were used to induce tumor growth in female athymic nude mice. Tumors were irradiated with 3, 10, or 20 Gy using an x‐ray irradiator. Prior to each EPRI scan, magnetic resonance imaging (MRI) was performed to obtain T2‐weighted anatomical images for reference. The differences in the mean pO2 were determined through two‐tailed Student's t‐test and one‐way analysis of variance. The median pO2 60 min after irradiation was found to be lower in HCT116 than in HT29 (9.1 ± 1.5 vs. 14.0 ± 1.0 mmHg, p = 0.045). There was a tendency for delayed and incomplete recovery of pO2 in the HT29 tumor when a higher dose of irradiation (10 and 20 Gy) was applied. Moreover, there was a dose‐dependent increase in the hypoxic areas (pO2 < 10 mmHg) 2 and 24 h after irradiation in all groups. In addition, an area that showed pO2 fluctuation between hypoxia and normoxia (pO2 > 10 mmHg) was also identified surrounding the region with stable hypoxia, and it slightly enlarged after recovery from acute hypoxia. In conclusion, we demonstrated the reoxygenation phenomenon in an in vivo xenograft model study using EPRI. These findings may lead to new knowledge regarding the reoxygenation process and possibilities of a new radiation therapy concept, namely, reoxygenation‐based radiation therapy. [ABSTRACT FROM AUTHOR]

• Propose PU-CDM to suppress streak artifacts and yield high-quality EPRI images. • Propose PUNet as the Gaussian noise prediction network in PU-CDM. • Extensive experiments have proven the superior performance of PU-CDM. Sparse-view reconstruction in electron paramagnetic resonance imaging (EPRI) aims to reduce scanning times, which is critical for tumor oxygen imaging, yet is often plagued by streak artifacts in filtered back-projection (FBP) reconstructions. To address this, we propose a pyramid UNet based conditional diffusion model (PU-CDM) to suppress these streak artifacts in EPRI images. PU-CDM uniquely introduces pyramid pooling and aggregation into the UNet architecture of the conditional diffusion model, while incorporating two advanced mechanisms—dense convolutions and self-attention—into the input module. By significantly improving the accuracy of the Gaussian noise prediction network in the conditional diffusion model, PU-CDM achieves superior performance in sparse-view reconstruction, generating high-quality images with only 5 sampling steps. Experimental results, both qualitative and quantitative, show that the images reconstructed by PU-CDM outperform those reconstructed by some existing representative deep learning models in terms of artifact removal and structural fidelity. PU-CDM can achieve accurate sparse-view reconstruction in EPRI, thus promoting EPRI towards fast scanning. In addition, PU-CDM can also be used for fast magnetic resonance imaging (MRI), low-dose computed tomography (LDCT) reconstruction, and natural image processing. [ABSTRACT FROM AUTHOR]

The paramagnetic defects in the magnesium-oxide (MgO) thin-film grown on a silicon (Si) substrate (MgO|Si) by a molecular beam epitaxy method are reported. These thin films have been used as an MgO tunnel barrier material for the spin-injection to Si from Fe. According to the crystallinity evaluation, the MgO film possessed a (001) oriented structure. We investigated the paramagnetic defects and impurities of several MgO|Si samples by electron paramagnetic resonance (EPR). The EPR spectra showed a strong isotropic signal with a g-value of 2.002 and six weak satellite peaks which were assigned to oxygen vacancies of highly oriented MgO(001) (F+ center) coupled with 25Mg nuclei (I=5/2). The spin area density of MgO (thickness=1.6 nm), which can be used as a tunnel barrier for spin injection, was determined to be 7×1013 cm-2. This value corresponds to 1% of O atoms replaced with vacancies. The identification of the paramagnetic centers and the quantitative estimation of their concentration in MgO films is important and may pave the way for highly efficient spin injection from Fe to Si via an MgO tunnel barrier. [ABSTRACT FROM AUTHOR]

Imaging tumor microenvironments such as hypoxia, oxygenation, redox status, and/or glycolytic metabolism in tissues/cells is useful for diagnostic and prognostic purposes. New imaging modalities are under development for imaging various aspects of tumor microenvironments. Electron Paramagnetic Resonance Imaging (EPRI) though similar to NMR/MRI is unique in its ability to provide quantitative images of pO2 in vivo. The short electron spin relaxation times have been posing formidable challenge to the technology development for clinical application. With the availability of the narrow line width trityl compounds, pulsed EPR imaging techniques were developed for pO2 imaging. EPRI visualizes the exogenously administered spin probes/contrast agents and hence lacks the complementary morphological information. Dynamic nuclear polarization (DNP), a phenomenon that transfers the high electron spin polarization to the surrounding nuclear spins (1H and 13C) opened new capabilities in molecular imaging. DNP of 13C nuclei is utilized in metabolic imaging of 13C-labeled compounds by imaging specific enzyme kinetics. In this article, imaging strategies mapping physiologic and metabolic aspects in vivo are reviewed within the framework of their application in cancer research, highlighting the potential and challenges of each of them.

Purpose: To develop a novel resonator for high‐quality fast scan electron paramagnetic resonance (EPR) and EPR/NMR co‐imaging of the head and brain of mice at 1.25 GHz. Methods: Resonator dimensions were scaled to fit the mouse head with maximum filling factor. A single‐loop 6‐gap resonator of 20 mm diameter and 20 mm length was constructed. High resonator stability was achieved utilizing a fixed position double coupling loop. Symmetrical mutually inverted connections rendered it insensitive to field modulation and fast scan. Coupling adjustment was provided by a parallel‐connected variable capacitor located at the feeding line at λ/4 distance. To minimize radiation loss, the shield around the resonator was supplemented with a planar conductive disc that focuses return magnetic flux. Results: Coupling of the resonator loaded with the mouse head was efficient and easy. This resonator enabled high‐quality in vivo 3D EPR imaging of the mouse head following intravenous infusion of nitroxide probes. With this resonator and rapid scan EPR system, 4 ms scans were acquired in forward and reverse directions so that images with 2‐scan 3,136 projections were acquired in 25 s. Head images were achieved with resolutions of 0.4 mm, enabling visualization of probe localization and uptake across the blood–brain barrier. Conclusions: This resonator design provides good sensitivity, high stability, and B1 field homogeneity for in vivo fast scan EPR of the mouse head and brain, enabling faster measurements and higher resolution imaging of probe uptake, localization, and metabolism than previously possible. [ABSTRACT FROM AUTHOR]

Precise radiation guided by oxygen images has demonstrated superiority over the traditional radiation methods. Electron paramagnetic resonance (EPR) imaging has proven to be the most advanced oxygen imaging modality. However, the main drawback of EPR imaging is the long scan time. For each projection, we usually need to collect the projection many times and then average them to achieve high signal-to-noise ratio (SNR). One approach to fast scan is to reduce the repeating time for each projection. While the projections would be noisy and thus the traditional commonly-use filtered backprojection (FBP) algorithm would not be capable of accurately reconstructing images. Optimization-based iterative algorithms may accurately reconstruct images from noisy projections for they may incorporate prior information into optimization models. Based on the total variation (TV) algorithms for EPR imaging, in this work, we propose a directional TV (DTV) algorithm to further improve the reconstruction accuracy. We construct the DTV constrained, data divergence minimization (DTVcDM) model, derive its Chambolle–Pock (CP) solving algorithm, validate the correctness of the whole algorithm, and perform evaluations via simulated and real data. The experimental results show that the DTV algorithm outperforms the existing TV and FBP algorithms in fast EPR imaging. Compared to the standard FBP algorithm, the proposed algorithm may achieve 10 times of acceleration. [Display omitted] • We propose a DTV algorithm for fast EPR imaging to speed up the scan process 10 times. • This is the first extension and application of DTV algorithm in 3D pulsed EPRI. • We first give a simple but effective model-parameters selection method. • We accelerate the convergence rate by introducing two balanced parameters. [ABSTRACT FROM AUTHOR]

The multi-modal imaging contrast agent has been attracted an increased interest to the tumor detecting and diagnosis in these recent years since the multi-modal imaging technology combines the advantages of several medical imaging modalities. A water-soluble fullerenol probe containing glypican-3 monoclonal antibody (GPC3-mAb) group mAb-GPC3-C60(OH)10-(TMIO)3-(NI)3 was synthesized by the incorporation of 5-formyl-1,1,3,3-tetramethylisoindolin-2-yloxyl (FTMIO), naphthalimide (NI) and GPC3-mAb as a tumor-targeting group into fullerenol C60(OH)11. This nanomaterial was further characterized by FTIR, UV, MS, fluorescence, etc., and then its properties including electron paramagnetic resonance (EPR), particle size, electrophoresis, electrochemical assay, cell cytotoxicity, cell uptake and fluorescent imaging of HeLa tumor cells in vitro were also evaluated. Experiment results indicated that mAb-GPC3-C60(OH)10-(TMIO)3-(NI)3 had similar fluorescent properties as NI and similar electrochemical and redox properties as 5-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl (CTMIO). Moreover, mAb-GPC3-C60(OH)10-(TMIO)3-(NI)3 possessed low cell cytotoxicity, good fluorescence and good tumor-targeting property. Meanwhile, mAb-GPC3-C60(OH)10-(TMIO)3-(NI)3 can be taken up highly by HeLa tumor cells, achieve good green fluorescent imaging in tumor cells and highly enhance the contrast of fluorescent images. Therefore, mAb-GPC3-C60(OH)10-(TMIO)3-(NI)3 can disperse homogeneously in aqueous solution and be used as a potential tumor-targeting dual-modal contrast agent for EPR imaging/fluorescence imaging (EPRI/FI). [ABSTRACT FROM AUTHOR]

Objective. Electron paramagnetic resonance (EPR) imaging is an advanced in vivo oxygen imaging modality. The main drawback of EPR imaging is the long scanning time. Sparse-view projections collection is an effective fast scanning pattern. However, the commonly-used filtered back projection (FBP) algorithm is not competent to accurately reconstruct images from sparse-view projections because of the severe streak artifacts. The aim of this work is to develop an advanced algorithm for sparse reconstruction of 3D EPR imaging. Methods. The optimization based algorithms including the total variation (TV) algorithm have proven to be effective in sparse reconstruction in EPR imaging. To further improve the reconstruction accuracy, we propose the directional TV (DTV) model and derive its Chambolle-Pock solving algorithm. Results. After the algorithm correctness validation on simulation data, we explore the sparse reconstruction capability of the DTV algorithm via a simulated six-sphere phantom and two real bottle phantoms filled with OX063 trityl solution and scanned by an EPR imager with a magnetic field strength of 250 G. Conclusion. Both the simulated and real data experiments show that the DTV algorithm is superior to the existing FBP and TV-type algorithms and a deep learning based method according to visual inspection and quantitative evaluations in sparse reconstruction of EPR imaging. Significance. These insights gained in this work may be used in the development of fast EPR imaging workflow of practical significance., (© 2024 Institute of Physics and Engineering in Medicine.)

• Propose an edge-preserving total nuclear variation for sparse reconstruction. • Propose a method to dynamically adjust the intensity of gradient diffusion. • Extensive experiments have demonstrated the effectiveness of the proposed method. Currently, slow scanning speed has become a technical bottleneck limiting the development of electron paramagnetic resonance imaging (EPRI), a novel oxygen imaging modality. Image reconstruction from sparse-view projections is an important imaging configuration to achieve fast scanning in EPRI. However, EPR images reconstructed from sparse-view projections using traditional analytic algorithms suffer from sparse artifacts, causing severe image degradation. In this work, we aim to use an optimization-based approach to achieve high-precision sparse reconstruction for EPRI. Methods. Inspired by the success of total nuclear variation (TV N) for denoising multi-channel spectral CT images and adaptive-weighted total variation (awTV) for improving the edge-preserving performance of TV, we proposed an edge-preserving total nuclear variation (EPTV N) minimization algorithm for sparse reconstruction in EPRI. The EPTV N combines the advantage of TV N in modelling structural similarity and low-rank prior between multi-channel images for denoising with the advantage of awTV for edge-preserving, which can better protect the edge structure of images while suppressing sparse artifacts. Results. We designed two numerical phantoms with different properties, a piecewise-constant phantom and a gradient phantom, and a physical phantom, and then performed inverse crime, simulation study and real-data study. Experimental results show that the EPTV N minimization algorithm can reconstruct more accurate EPR images from sparse-view projections for both the numerical and physical phantoms. Significance. The proposed method can effectively suppress sparse artifacts and protect edge structures of reconstructed images, thus achieving high-precision sparse-view reconstruction for EPRI. The insights of this work can also be applied to multi-channel image denoising tasks. [ABSTRACT FROM AUTHOR]

Performing nanoscale scanning electron paramagnetic resonance (EPR) requires three essential ingredients: First, a static magnetic field together with field gradients to Zeeman split the electronic energy levels with spatial resolution; second, a radio frequency (rf) magnetic field capable of inducing spin transitions; finally, a sensitive detection method to quantify the energy absorbed by spins. This is usually achieved by combining externally applied magnetic fields with inductive coils or cavities, fluorescent defects, or scanning probes. Here, we theoretically propose the realization of an EPR scanning sensor merging all three characteristics into a single device: the vortex core stabilized in ferromagnetic thin-film discs. On one hand, the vortex ground state generates a significant static magnetic field and field gradients. On the other hand, the precessional motion of the vortex core around its equilibrium position produces a circularly polarized oscillating magnetic field, which is enough to produce spin transitions. Finally, the spin-magnon coupling broadens the vortex gyrotropic frequency, suggesting a direct measure of the presence of unpaired electrons. Moreover, the vortex core can be displaced by simply using external magnetic fields of a few mT, enabling EPR scanning microscopy with large spatial resolution. Our numerical simulations show that, by using low damping magnets, it is theoretically possible to detect single spins located on the disc's surface. Vortex nanocavities could also attain strong coupling to individual spin molecular qubits with potential applications to mediate qubit-qubit interactions or to implement qubit readout protocols.

Mesenchymal stem cells (MSC) are increasingly being studied as a source of cell therapy for neurodegenerative diseases, and several groups have reported their beneficial effects on Alzheimer's disease (AD). In this study using AD model mice (APdE9), we found that transplantation of MSC via the tail vein improved spatial memory in the Morris water maze test. Using electron paramagnetic resonance imaging to evaluate the in vivo redox state of the brain, we found that MSC transplantation suppressed oxidative stress in AD model mice. To elucidate how MSC treatment ameliorates oxidative stress, we focused on amyloid-β (Aβ) pathology and microglial function. MSC transplantation reduced Aβ deposition in the cortex and hippocampus. Transplantation of MSC also decreased Iba1-positive area in the cortex and reduced activated ameboid shaped microglia. On the other hand, MSC transplantation accelerated accumulation of microglia around Aβ deposits and prompted microglial Aβ uptake and clearance as shown by higher frequency of Aβ-containing microglia. MSC transplantation also increased CD14-positive microglia in vivo, which play a critical role in Aβ uptake. To confirm the effects of MSC on microglia, we co-cultured the mouse microglial cell line MG6 with MSC. Co-culture with MSC enhanced Aβ uptake by MG6 cells accompanied by upregulation of CD14 expression. Additionally, co-culture of MG6 cells with MSC induced microglial phenotype switching from M1 to M2 and suppressed production of proinflammatory cytokines. These data indicate that MSC treatment has the potential to ameliorate oxidative stress through modification of microglial functions, thereby improving Aβ pathology in AD model mice. [ABSTRACT FROM AUTHOR]

Purpose: In continuous wave EPR imaging, the acquisition of high‐quality images was previously limited by the requisite long acquisition times of each image projection that was typically greater than 1 second. To accelerate the process of image acquisition facilitating greater numbers of projections and higher image resolution, instrumentation was developed to greatly accelerate the magnetic field scan that is used to obtain each EPR image projection. Methods: A low‐inductance solenoidal coil for field scanning was used along with a spherical solenoid air core magnet, and scans were driven by triangular symmetric waves, allowing forward and reverse spectrum acquisition as rapid as 3.8 ms. The uniform distribution of projections was used to optimize the contribution of projections for 3D image reconstruction. Results: Using this fast‐scan EPR system, high‐quality EPR images of phantoms and perfused rat hearts were performed using trityl or nanoparticulate LiNcBuO (lithium octa‐n‐butoxy‐substituted naphthalocyanine) probes with fast‐scan EPR imaging at L‐band, achieving spatial resolutions of up to 250 micrometers in 1 minute. Conclusion: Fast‐scan EPR imaging can greatly facilitate the efficient and precise mapping of the spatial distribution of free radical and other paramagnetic probes in living systems. [ABSTRACT FROM AUTHOR]

Abstract We present the concept of image registration using ultrasound (US) and electron paramagnetic resonance (EPR) imaging and discuss the benefits of this solution, as well as its limitations. Both phantoms and murine tumors were used to test US and EPR image co-registration. Comparison of dental molding cast immobilization and predesigned cradle revealed that the latter approach is more effective in stabilizing the fiducial position. In vivo imaging of mouse tumors, image registration and comparison of fiducials system for 3D spatial as well as 4D spatial-spectral EPR imaging supported by 3D US were demonstrated. Ultrasound may provide a convenient alternative to other anatomical imaging methods for image registration in preclinical research. Of particular interest is a fusion of US tissue structure, doppler vascular function and EPR oxygen or redox imaging. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Stochastic RF excitation and resulting data correlation before image reconstruction. • Use of stochastic sequences can result in reduced RF power during EPR imaging. • Reduced RF power brings the SAR of EPR imaging near levels of some MRI imaging. • SAR levels are low enough to explore possible clinical applications. Abstract An excessive RF power requirement is one of the main obstacles in the clinical translation of EPR imaging. The radio frequency (RF) pulses used in EPR imaging to excite electron spins must be very short to match their fast relaxation. With traditional pulse schemes and ninety degree flip angles, this can lead to either unsafe specific absorption rate (SAR) levels or unfeasibly long repetition times. In spectroscopy experiments, it has been shown that stochastic excitation and correlation detection can reduce the power while maintaining sensitivity but have yet to be applied to imaging experiments. Stochastic excitation is implemented using a pseudo-random phase modulation of the input stimulus. Using a crossed coil resonator assembly comprised of an outer saddle coil and an inner surface coil, it was possible to obtain a minimum isolation of ∼50 dB across a 12 MHz bandwidth. An incident peak RF power of 5 mW was used to excite the system. The low background signal obtained from this resonator allowed us to generate images with 32 dB (>1000:1) signal-to-noise ratio (SNR) while exciting with a traditional pulse sequence in a phantom containing the solid paramagnetic probe NMP-TCNQ (N-methyl pyridinium tetracyanoquinodimethane). Using two different stochastic excitation schemes, we were able to achieve a greater than 4-fold increase in SNR at the same peak power and number of averages, compared to single pulse excitation. This procedure allowed imaging at significantly lower RF power levels than used in conventional EPR imaging system configurations. Similar techniques may enable clinical applications for EPR imaging by facilitating the use of larger RF coils while maintaining a safe SAR level. [ABSTRACT FROM AUTHOR]

In rapid scan EPR the rapidly-changing magnetic field induces a background signal that may be larger than the EPR signal. A method has been developed to correct for that background signal by acquiring two sets of data, denoted as scan 1 and scan 2. In scan 2 the external field B 0 is reversed and the data acquisition trigger is offset by one half cycle of the scan field relative to the settings used in scan 1. For data acquired with a cross-loop resonator subtraction of scan 2 from scan 1 cancels the background and enhances the EPR signal. Experiments were performed at an EPR frequency of about 258 MHz, which is in the range that is commonly used for in vivo imaging. Samples include nitroxide radicals, a trityl radical, a dinitroxide, and a nitroxide in the presence of a magnetic field gradient. This method has the advantage that no assumption is made about the shape of the background signal, and it provides an approach to automating the background correction. [ABSTRACT FROM AUTHOR]

Two novel RuII complexes, having 2,2′‐bipyridyl and a pincer‐type methylene‐bridged N‐heterocyclic carbene (NHC) ligand, were synthesized and characterized to evaluate the effects of structural features of the complexes on their redox and photochemical properties. The methylene‐bridged NHC ligand coordinated in a meridional manner and the isopropyl groups on the NHC rings exhibited intramolecular CH/π interaction with the 2,2′‐bipyridyl ligand, which played a role to strongly maintain the distorted ligand structure. In addition, the two Ru complexes exhibited reversible redox waves in the cyclic voltammograms and they were oxidized by an electron‐transfer oxidant to afford RuIII complexes, which were characterized by EPR spectroscopy and theoretical analyses. [ABSTRACT FROM AUTHOR]

Significance: Electron paramagnetic resonance imaging (EPRI) is capable of generating images of tissue oxygenation using exogenous paramagnetic probes such as trityl radicals or nitroxyl radicals. The spatial distribution of the paramagnetic probe can be generated using magnetic field gradients as in magnetic resonance imaging and, from its spectral features, spatial maps of oxygen can be obtained from live objects. In this review, two methods of signal acquisition and image formation/reconstruction are described. The probes used and its application to study tumor physiology and monitor treatment response with chemotherapy drugs in mouse models of human cancer are summarized. Recent Advances: By implementing phase encoding/Fourier reconstruction in EPRI in time domain mode, the frequency contribution to the spatial resolution was avoided and images with improved spatial resolution were obtained. The EPRI-generated pO2 maps in tumor were useful to detect and evaluate the effects of various antitumor therapies on tumor physiology. Coregistration with other imaging modalities provided a better understanding of hypoxia-related alteration in physiology. Critical Issues: The high radiofrequency (RF) power of EPR irradiation and toxicity profile of radical probes are the main obstacles for clinical application. The improvement of RF low power pulse sequences may allow for clinical translation. Future Directions: Pulsed EPR oximetry can be a powerful tool to research various diseases involving hypoxia such as cancer, ischemic heart diseases, stroke, and diabetes. With appropriate paramagnetic probes, it can also be applied for various other purposes such as detecting local acid–base balance or oxidative stress. Antioxid. Redox Signal. 28, 1378–1393. [ABSTRACT FROM AUTHOR]

Electron paramagnetic resonance (EPR)-based spectroscopic and imaging techniques allow for the study of free radicals—molecules with one or more unpaired electrons. Biological EPR applications include detection of endogenous biologically relevant free radicals as well as use of specially designed exogenous radicals to probe local microenvironments. This Forum focuses on recent advances in the field of in vivo EPR applications discussed at the International Conference on Electron Paramagnetic Resonance Spectroscopy and Imaging of Biological Systems (EPR-2017). Although direct EPR detection of endogenous free radicals such as reactive oxygen species (ROS) in vivo remains unlikely in most cases, alternative approaches based on applications of advanced spin traps and probes for detection of paramagnetic products of ROS reactions often allow for specific assessment of free radical production in living subjects. In recent decades, significant progress has been achieved in the development and in vivo application of specially designed paramagnetic probes as “molecular spies” to assess and map physiologically relevant functional information such as tissue oxygenation, redox status, pH, and concentrations of interstitial inorganic phosphate and intracellular glutathione. Recent progress in clinical EPR instrumentation and development of biocompatible paramagnetic probes for in vivo multifunctional tissue profiling will eventually make translation of the EPR techniques into clinical settings possible. Antioxid. Redox Signal. 28, 1341–1344. [ABSTRACT FROM AUTHOR]

Significance: Proton-electron double-resonance imaging (PEDRI) employs electron paramagnetic resonance irradiation with low-field magnetic resonance imaging so that the electron spin polarization is transferred to nearby protons, resulting in higher signals. PEDRI provides information about free radical distribution and, indirectly, about the local microenvironment such as partial pressure of oxygen (pO2), tissue permeability, redox status, and acid-base balance. Recent Advances: Local acid-base balance can be imaged by exploiting the different resonance frequency of radical probes between R and RH+ forms. Redox status can also be imaged by using the loss of radical-related signal after reduction. These methods require optimized radical probes and pulse sequences. Critical Issues: High-power radio frequency irradiation is needed for optimum signal enhancement, which may be harmful to living tissue by unwanted heat deposition. Free radical probes differ depending on the purpose of PEDRI. Some probes are less effective for enhancing signal than others, which can reduce image quality. It is so far not possible to image endogenous radicals by PEDRI because low concentrations and broad line widths of the radicals lead to negligible signal enhancement. Future Directions: PEDRI has similarities with electron paramagnetic resonance imaging (EPRI) because both techniques observe the EPR signal, directly in the case of EPRI and indirectly with PEDRI. PEDRI provides information that is vital to research on homeostasis, development of diseases, or treatment responses in vivo. It is expected that the development of new EPR techniques will give insights into novel PEDRI applications and vice versa. Antioxid. Redox Signal. 28, 1345–1364. [ABSTRACT FROM AUTHOR]

OBJECTIVES: This work aims to explore more accurate pixel-driven projection methods for iterative image reconstructions in order to reduce high-frequency artifacts in the generated projection image. METHODS: Three new pixel-driven projection methods namely, small-pixel-large-detector (SPLD), linear interpolation based (LIB) and distance anterpolation based (DAB), were proposed and applied to reconstruct images. The performance of these methods was evaluated in both two-dimensional (2D) computed tomography (CT) images via the modified FORBILD phantom and three-dimensional (3D) electron paramagnetic resonance (EPR) images via the 6-spheres phantom. Specifically, two evaluations based on projection generation and image reconstruction were performed. For projection generation, evaluation was using a 2D disc phantom, the modified FORBILD phantom and the 6-spheres phantom. For image reconstruction, evaluations were performed using the FORBILD and 6-spheres phantom. During evaluation, 2 quantitative indices of root-mean-square-error (RMSE) and contrast-to-noise-ratio (CNR) were used. RESULTS: Comparing to the use of ordinary pixel-driven projection method, RMSE of the SPLD based least-square algorithm was reduced from 0.0701 to 0.0384 and CNR was increased from 5.6 to 19.47 for 2D FORBILD phantom reconstruction. For 3D EPRI, RMSE of SPLD was also reduced from 0.0594 to 0.0498 and CNR was increased from 3.88 to 11.58. In addition, visual evaluation showed that images reconstructed in both 2D and 3D images suffered from high-frequency line-shape artifacts when using the ordinary pixel-driven projection method. However, using 3 new methods all suppressed the artifacts significantly and yielded more accurate reconstructions. CONCLUSIONS: Three proposed pixel-driven projection methods achieved more accurate iterative image reconstruction results. These new and more accurate methods can also be easily extended to other imaging modalities. Among them, SPLD method should be recommended to 3D and four dimensional (4D) EPR imaging. [ABSTRACT FROM AUTHOR]

Radiation treatment success and high tumor oxygenation and success have been known to be highly correlated. This suggests that radiation therapy guided by images of tumor regions with low oxygenation, oxygen-guided radiation therapy (OGRT) may be a promising enhancement of cancer radiation treatment. Before applying the technique to human subjects, OGRT needs to be tested in animals, most easily in rodents. Electron paramagnetic resonance imaging provides quantitative maps of tissue and tumor oxygen in rodents with 1 mm spatial resolution and 1 torr pO resolution at low oxygen levels. The difficulty of using mouse models is their small size and that of their tumors. To overcome this we used XRAD225Cx micro-CT/ therapy system and 3D printed conformal blocks. Radiation is delivered first to a uniform 15% tumor control dose for the whole tumor and then a boost dose to either hypoxic tumor regions or equal volumes of well oxygenated tumor. Delivery of the booster dose used a multiple beam angles to deliver radiation beams whose shape conforms to that of all hypoxic regions or fully avoids those regions. To treat/avoid all hypoxic regions we used individual radiation blocks 3D-printed from acrylonitrile butadiene styrene polymer infused with tungsten particles fabricated immediately after imaging to determine regions with pO less than 10 torr. Preliminary results demonstrate the efficacy of the radiation treatment with hypoxic boosts with syngeneic FSa fibrosarcoma tumors in the legs of C3H mice. [ABSTRACT FROM AUTHOR]

Hypoxia is considered one of the microenvironmental factors associated with the malignant nature of glioblastoma. Thus, evaluating intratumoural distribution of hypoxia would be useful for therapeutic planning as well as assessment of its effectiveness during the therapy. Electron paramagnetic resonance imaging (EPRI) is an imaging technique which can generate quantitative maps of oxygen in vivo using the exogenous paramagnetic compound, triarylmethyl and monitoring its line broadening caused by oxygen. In this study, the feasibility of EPRI for assessment of oxygen distribution in the glioblastoma using orthotopic U87 and U251 xenograft model is examined. Heterogeneous distribution of pO2 between 0 and 50 mmHg was observed throughout the tumours except for the normal brain tissue. U251 glioblastoma was more likely to exhibit hypoxia than U87 for comparable tumour size (median pO2; 29.7 and 18.2 mmHg, p =.028, in U87 and U251, respectively). The area with pO2 under 10 mmHg on the EPR oximetry (HF10) showed a good correlation with pimonidazole staining among tumours with evaluated size. In subcutaneous xenograft model, irradiation was relatively less effective for U251 compared with U87. In conclusion, EPRI is a feasible method to evaluate oxygen distribution in the brain tumour. [ABSTRACT FROM AUTHOR]

In rapid-scan EPR the magnetic field or frequency is repeatedly scanned through the spectrum at rates that are much faster than in conventional continuous wave EPR. The signal is directly-detected with a mixer at the source frequency. Rapid-scan EPR is particularly advantageous when the scan rate through resonance is fast relative to electron spin relaxation rates. In such scans, there may be oscillations on the trailing edge of the spectrum. These oscillations can be removed by mathematical deconvolution to recover the slow-scan absorption spectrum. In cases of inhomogeneous broadening, the oscillations may interfere destructively to the extent that they are not visible. The deconvolution can be used even when it is not required, so spectra can be obtained in which some portions of the spectrum are in the rapid-scan regime and some are not. The technology developed for rapid-scan EPR can be applied generally so long as spectra are obtained in the linear response region. The detection of the full spectrum in each scan, the ability to use higher microwave power without saturation, and the noise filtering inherent in coherent averaging results in substantial improvement in signal-to-noise relative to conventional continuous wave spectroscopy, which is particularly advantageous for low-frequency EPR imaging. This overview describes the principles of rapid-scan EPR and the hardware used to generate the spectra. Examples are provided of its application to imaging of nitroxide radicals, diradicals, and spin-trapped radicals at a Larmor frequency of ca. 250 MHz. [ABSTRACT FROM AUTHOR]

The value of any measurement and a fortiori any measurement technology is defined by the reproducibility and the accuracy of the measurements. This implies a relative freedom of the measurement from factors confounding its accuracy. In the past, one of the reasons for the loss of focus on the importance of imaging oxygen in vivo was the difficulty in obtaining reproducible oxygen or pO 2 images free from confounding variation. This review will briefly consider principles of electron paramagnetic oxygen imaging and describe how it achieves absolute oxygen measurements. We will provide a summary review of the progress in biomedical EPR imaging, predominantly in cancer biology research, discuss EPR oxygen imaging for cancer treatment and tissue graft assessment for regenerative medicine applications. [ABSTRACT FROM AUTHOR]

We report the observations of electron paramagnetic resonance and impedance measurements of graphene oxide and reduced graphene oxide performed in the wide temperature range in order to get insight into the electronic properties of graphene-based materials and the role of oxygen functionalities in the charge carrier transport phenomena. In such systems the strong spin localization, hopping charge carrier transport as well as the formation of adsorption layers are observed, all the phenomena changing significantly after the heavily oxidized graphene is reduced. [ABSTRACT FROM AUTHOR]

Purpose Electron paramagnetic resonance (EPR) imaging has evolved as a promising tool to provide non-invasive assessment of tissue oxygenation levels. Due to the extremely short T 2 relaxation time of electrons, single point imaging (SPI) is used in EPRI, limiting achievable spatial and temporal resolution. This presents a problem when attempting to measure changes in hypoxic state. In order to capture oxygen variation in hypoxic tissues and localize cycling hypoxia regions, an accelerated EPRI imaging method with minimal loss of information is needed. Methods We present an image acceleration technique, partial Fourier compressed sensing (PFCS), that combines compressed sensing (CS) and partial Fourier reconstruction. PFCS augments the original CS equation using conjugate symmetry information for missing measurements. To further improve image quality in order to reconstruct low-resolution EPRI images, a projection onto convex sets (POCS)-based phase map and a spherical-sampling mask are used in the reconstruction process. The PFCS technique was used in phantoms and in vivo SCC7 tumor mice to evaluate image quality and accuracy in estimating O 2 concentration. Results In both phantom and in vivo experiments, PFCS demonstrated the ability to reconstruct images more accurately with at least a 4-fold acceleration compared to traditional CS. Meanwhile, PFCS is able to better preserve the distinct spatial pattern in a phantom with a spatial resolution of 0.6 mm. On phantoms containing Oxo63 solution with different oxygen concentrations, PFCS reconstructed linewidth maps that were discriminative of different O 2 concentrations. Moreover, PFCS reconstruction of partially sampled data provided a better discrimination of hypoxic and oxygenated regions in a leg tumor compared to traditional CS reconstructed images. Conclusions EPR images with an acceleration factor of four are feasible using PFCS with reasonable assessment of tissue oxygenation. The technique can greatly enhance EPR applications and improve our understanding cycling hypoxia. Moreover this technique can be easily extended to various MRI applications. [ABSTRACT FROM AUTHOR]

Dynamic alteration in the levels of cellular hydrogen peroxide (H2O2) is closely related to a variety of human diseases, as well as signal transduction pathways that regulate cell survival and death. Although qualitative or quantitative methods are available for measuring either intra- or extra-cellular H2O2 levels, accurate and comprehensive in situ detection of the real-time H2O2 dynamics of living cells remains a significant challenge. To solve this problem, a novel multi-dimensional in situ cell assay platform combining electrochemistry, electron spin resonance (ESR) and optical imaging is designed. In this platform, the real-time concentration of extracellular H2O2 released from stimulated cells can be accurately detected by ESR assisted chronoamperometry, while the level of intracellular H2O2 is simultaneously monitored via the incorporated fluorescence imaging. Accurately and simultaneously analyzing the level variations of extra- and intra-cellular reactive oxygen species based on our assay platform can complement each other for further precise and in-depth investigation of their membrane transport and related cellular signaling, which will benefit disease diagnosis and treatment. [ABSTRACT FROM AUTHOR]

We report herein a method for the recovery, purification, and application of OX063, a costly, commercially available nontoxic spin probe widely used for electron paramagnetic resonance (EPR) imaging, as well as its corresponding quinone methide (QM) form. This precious probe can be successfully recovered after use in animal model experiments (25-47% recovery from crude lyophilizate with 98.5% purity), even from samples that are <2 years old. Significantly, the recovered trityl can be reused in further animal model EPR imaging experiments. The work also describes support for the observed formation of an air-sensitive radical derived from the QM under reducing conditions. [ABSTRACT FROM AUTHOR]

In vivo electron paramagnetic resonance (EPR) imaging and spectroscopy are non-invasive technologies used to specifically detect and quantify paramagnetic species. However, the relative instability of spin probes such as triarylmethyl radicals limits their application to conduct oxygen quantification and mapping. In this study we encapsulated tetrathiatriarylmethyl radical (TAM; known as “Finland” probe) in Pluronic F-127 hydrogel (PF-127) in order to limit its degradation and evaluate its in vitro and in vivo EPR properties as a function of oxygen. Our results show that the EPR signal of encapsulated TAM in PF-127 hydrogel is similar to the one in solution. Although it is less sensitive to oxygen, it is suitable for oximetry. We also demonstrated that the incorporation of TAM in PF-127 hydrogel leads to an improved in vivo EPR stability of the radical under anesthesia. This new formulation enables high quality EPR imaging and oximetry and paves the way for the application of TAM radical-based probes in various biomedical fields. [ABSTRACT FROM AUTHOR]

Hypoxic tumors are resistant to radiotherapy, motivating the development of tools to image local oxygen concentrations. It is generally believed that stable or chronic hypoxia is the source of resistance, but more recent work suggests a role for transient hypoxia. Conventional EPR imaging (EPRI) is capable of imaging tissue pO 2 in vivo , with high pO 2 resolution and 1 mm spatial resolution but low imaging speed (10 min temporal resolution for T 1 -based pO 2 mapping), which makes it difficult to investigate the oxygen changes, e.g., transient hypoxia. Here we describe a new imaging method which accelerates dynamic EPR oxygen imaging, allowing 3D imaging at 2 frames per minute, fast enough to image transient hypoxia at the “speed limit” of observed pO 2 change. The method centers on a low-rank tensor model that decouples the tradeoff between imaging speed, spatial coverage/resolution, and number of inversion times (pO 2 accuracy). We present a specialized sparse sampling strategy and image reconstruction algorithm for use with this model. The quality and utility of the method is demonstrated in simulations and in vivo experiments in tumor bearing mice. [ABSTRACT FROM AUTHOR]

While linguistic theory posits an arbitrary relation between signifiers and the signified (de Saussure, 1916), our analysis of a large-scale German database containing affective ratings of words revealed that certain phoneme clusters occur more often in words denoting concepts with negative and arousing meaning. Here, we investigate how such phoneme clusters that potentially serve as sublexical markers of affect can influence language processing. We registered the EEG signal during a lexical decision task with a novel manipulation of the words' putative sublexical affective potential: the means of valence and arousal values for single phoneme clusters, each computed as a function of respective values of words from the database these phoneme clusters occur in. Our experimental manipulations also investigate potential contributions of formal salience to the sublexical affective potential: Typically, negative high-arousing phonological segments--based on our calculations--tend to be less frequent and more structurally complex than neutral ones. We thus constructed two experimental sets, one involving this natural confound, while controlling for it in the other. A negative high-arousing sublexical affective potential in the strictly controlled stimulus set yielded an early posterior negativity (EPN), in similar ways as an independent manipulation of lexical affective content did. When other potentially salient formal features at the sublexical level were not controlled for, the effect of the sublexical affective potential was strengthened and prolonged (250-650 ms), presumably because formal salience helps making specific phoneme clusters efficient sublexical markers of negative high-arousing affective meaning. These neurophysiological data support the assumption that the organization of a language's vocabulary involves systematic sound-to-meaning correspondences at the phonemic level that influence the way we process language. [ABSTRACT FROM AUTHOR]

EPR (Electron Paramagnetic Resonance) imaging is particularly useful in monitoring hypoxic zones in tumors which are highly resistant to radiation and chemotherapeutic treatment. This first part of the article covers aspects of CW (continuous wave) imaging with details of FT (pulsed Fourier Transform)-EPR imaging covered in Part 2, to be published in the next issue of Resonance. [ABSTRACT FROM AUTHOR]

Since its introduction the importance of complementary k || -space (LEED) and real space (LEEM) information in the investigation of surface science phenomena has been widely demonstrated over the last five decades. In this paper we report the application of a novel kind of electron spectromicroscope Dual Emission Electron spectroMicroscope (DEEM) with two independent electron optical channels for reciprocal and real space quasi-simultaneous imaging in investigation of a Cs covered Mo(110) single crystal by using the 800 eV electron beam from an “in-lens” electron gun system developed for the sample illumination. With the DEEM spectromicroscope it is possible to observe dynamic, irreversible processes at surfaces in the energy-filtered real space and in the corresponding energy-filtered k ǁ -space quasi-simultaneously in two independent imaging columns. The novel concept of the high energy electron beam sample illumination in the cathode lens based microscopes allows chemically selective imaging and analysis under laboratory conditions. [ABSTRACT FROM AUTHOR]

A study concerning the image quality in electron paramagnetic resonance imaging in two-dimensional spatial experiments is presented. The aim of the measurements was to improve the signal-to-noise ratio (SNR) of the projections and the reconstructed image by applying modulation amplitude higher than the radical electron paramagnetic resonance linewidth. Data were gathered by applying four constant modulation amplitudes, where one was below 1/3 (Amod = 0.04mT) of the radical linewidth (◢Bpp= 0.14mT). Three other modulation amplitude values were used in this experiment, leading to undermodulated (Amod<1/3 ◢Bpp), partially overmodulated (Amod∼1/3 ◢Bpp) and fully overmodulated (Amod>>1/3 ◢Bpp) projections. The advantages of an applied overmodulation condition were demonstrated in the study performed on a phantom containing four shapes of 1.25mM water solution of 2, 2, 6, 6-tetramethyl-1-piperidinyloxyl. It was shown that even when the overmodulated reference spectrum was used in the deconvolution procedure, as well as the projection itself, the phantom shapes reconstructed as images directly correspond to those obtained in undermodulation conditions. It was shown that the best SNR of the reconstructed images is expected for the modulation amplitude close to 1/3 of the projection linewidth, which is defined as the distance from the first maximum to the last minimum of the gradient-broadened spectrum. For higher modulation amplitude, the SNR of the reconstructed image is decreased, even if the SNR of the measured projection is increased. [ABSTRACT FROM AUTHOR]

The major light harvesting complex II (LHCII) of green plants plays a key role in the absorption of sunlight, the regulation of photosynthesis, and in preventing photodamage by excess light. The latter two functions are thought to involve the lumenal loop and the N-terminal domain. Their structure and mobility in an aqueous environment are only partially known. Electron paramagnetic resonance (EPR) has been used to measure the structure of these hydrophilic protein domains in detergent-solubilized LHCII. A new technique is introduced to prepare LHCII trimers in which only one monomer is spin-labeled. These heterogeneous trimers allow to measure intra-molecular distances within one LHCII monomer in the context of a trimer by using double electron-electron resonance (DEER). These data together with data from electron spin echo envelope modulation (ESEEM) allowed to model the N-terminal protein section, which has not been resolved in current crystal structures, and the lumenal loop domain. The N-terminal domain covers only a restricted area above the superhelix in LHCII, which is consistent with the "Velcro" hypothesis to explain thylakoid grana stacking (Standfuss, J., van Terwisscha Scheltinga, A. C., Lamborghini, M., and Kühlbrandt, W. (2005)EMBOJ. 24, 919'928). The conformation of the lumenal loop domain is surprisingly different between LHCII monomers and trimers but not between complexes with and without neoxanthin bound. [ABSTRACT FROM AUTHOR]