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It is well understood that the level of molecular oxygen (O2) in tissue is a very important factor impacting both physiology and pathological processes as well as responsiveness to some treatments. Data on O2 in tissue could be effectively utilized to enhance precision medicine. However, the nature of the data that can be obtained using existing clinically applicable techniques is often misunderstood, and this can confound the effective use of the information. Attempts to make clinical measurements of O2 in tissues will inevitably provide data that are aggregated over time and space and therefore will not fully represent the inherent heterogeneity of O2 in tissues. Additionally, the nature of existing techniques to measure O2 may result in uneven sampling of the volume of interest and therefore may not provide accurate information on the “average” O2 in the measured volume. By recognizing the potential limitations of the O2 measurements, one can focus on the important and useful information that can be obtained from these techniques. The most valuable clinical characterizations of oxygen are likely to be derived from a series of measurements that provide data about factors that can change levels of O2, which then can be exploited both diagnostically and therapeutically. The clinical utility of such data ultimately needs to be verified by careful studies of outcomes related to the measured changes in levels of O2.

L-band electron paramagnetic resonance (EPR) in vivo dosimetry has the potential advantage of being able to accurately and sensitively measure the absorbed dose of ionizing radiation by measurements of teeth in situ. The equipment is transportable to the site where a radiation incident occurred and can be operated without specialized facilities. It, therefore, is very suitable for medical triage of victims in a large-scale radiation incident to quickly determine whether the dose was large enough to require urgent care. The measurements are made on the outer surfaces of the two upper incisor teeth. However, some in vitro studies of extracted teeth using higher frequency EPR have suggested that exposure to ultraviolet rays (UV) from sunlight might confound estimates of the dose of ionizing radiation made with EPR. Because the outer surfaces of incisors are likely to be exposed to UV/sunlight, it, therefore, is essential to determine the potential quantitative impact of UV on L-band EPR dosimetry measurements based on incisors. We, therefore, investigated the quantitative effect of UV on the EPR signal from ionizing irradiation of human teeth using the L-band spectrometer developed for field dosimetry. The UV-generated EPR signal was very small relative to the signals resulting from doses of ionizing radiation that are used for triage. For example, using our estimates of the effects of UV, for a lifetime of 50 years of exposure of these teeth (assuming an average exposure to sunlight of two hours/day), the expected average lifetime effect of UV-induced signal would be equivalent to 0.33 Gy; in contrast, triage criteria for accidental exposure to ionizing irradiation generally start at 2.0 Gy.

During a first-in-humans clinical trial investigating electron paramagnetic resonance tumor oximetry, a patient injected with the particulate oxygen sensor Printex ink was found to have unexpected fluorodeoxyglucose (FDG) uptake in a dermal nodule via positron emission tomography (PET). This nodule co-localized with the Printex ink injection; biopsy of the area, due to concern for malignancy, revealed findings consistent with ink and an associated inflammatory reaction. Investigations were subsequently performed to assess the impact of oxygen sensors on FDG-PET/CT imaging. A retrospective analysis of three clinical tumor oximetry trials involving two oxygen sensors (charcoal particulates and LiNc-BuO microcrystals) in 22 patients was performed to evaluate FDG imaging characteristics. The impact of clinically used oxygen sensors (carbon black, charcoal particulates, LiNc-BuO microcrystals) on FDG-PET/CT imaging after implantation in rat muscle (n = 12) was investigated. The retrospective review revealed no other patients with FDG avidity associated with particulate sensors. The preclinical investigation found no injected oxygen sensor whose mean standard uptake values differed significantly from sham injections. The risk of a false-positive FDG-PET/CT scan due to oxygen sensors appears low. However, in the right clinical context the potential exists that an associated inflammatory reaction may confound interpretation.

The management of radiation injuries following a catastrophic event where large numbers of people may have been exposed to life-threatening doses of ionizing radiation will rely critically on the availability and use of suitable biodosimetry methods. In vivo electron paramagnetic resonance (EPR) tooth dosimetry has a number of valuable and unique characteristics and capabilities that may help enable effective triage. We have produced a prototype of a deployable EPR tooth dosimeter and tested it in several in vitro and in vivo studies to characterize the performance and utility at the state of the art. This report focuses on recent advances in the technology, which strengthen the evidence that in vivo EPR tooth dosimetry can provide practical, accurate, and rapid measurements in the context of its intended use to help triage victims in the event of an improvised nuclear device. These advances provide evidence that the signal is stable, accurate to within 0.5 Gy, and can be successfully carried out in vivo. The stability over time of the radiation-induced EPR signal from whole teeth was measured to confirm its long-term stability and better characterize signal behavior in the hours following irradiation. Dosimetry measurements were taken for five pairs of natural human upper central incisors mounted within a simple anatomic mouth model that demonstrates the ability to achieve 0.5 Gy standard error of inverse dose prediction. An assessment of the use of intact upper incisors for dose estimation and screening was performed with volunteer subjects who have not been exposed to significant levels of ionizing radiation and patients who have undergone total body irradiation as part of bone marrow transplant procedures. Based on these and previous evaluations of the performance and use of the in vivo tooth dosimetry system, it is concluded that this system could be a very valuable resource to aid in the management of a massive radiological event.

The cells of the intestinal epithelium provide a selectively permeable barrier between the external environment and internal tissues. The integrity of this barrier is maintained by tight junctions, specialised cell-cell contacts that permit the absorption of water and nutrients while excluding microbes, toxins and dietary antigens. Impairment of intestinal barrier function contributes to multiple gastrointestinal disorders, including food hypersensitivity, inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Glycoprotein A33 (GPA33) is an intestinal epithelium-specific cell surface marker and member of the CTX group of transmembrane proteins. Roles in cell-cell adhesion have been demonstrated for multiple CTX family members, suggesting a similar function for GPA33 within the gastrointestinal tract. To test a potential requirement for GPA33 in intestinal barrier function, we generated Gpa33(-/-) mice and subjected them to experimental regimens designed to produce food hypersensitivity, colitis and CAC. Gpa33(-/-) mice exhibited impaired intestinal barrier function. This was shown by elevated steady-state immunosurveillance in the colonic mucosa and leakiness to oral TRITC-labelled dextran after short-term exposure to dextran sodium sulphate (DSS) to injure the intestinal epithelium. Gpa33(-/-) mice also exhibited rapid onset and reduced resolution of DSS-induced colitis, and a striking increase in the number of colitis-associated tumours produced by treatment with the colon-specific mutagen azoxymethane (AOM) followed by two cycles of DSS. In contrast, Gpa33(-/-) mice treated with AOM alone showed no increase in sporadic tumour formation, indicating that their increased tumour susceptibility is dependent on inflammatory stimuli. Finally, Gpa33(-/-) mice displayed hypersensitivity to food allergens, a common co-morbidity in humans with IBD. We propose that Gpa33(-/-) mice provide a valuable model to study the mechanisms linking intestinal permeability and multiple inflammatory pathologies. Moreover, this model could facilitate preclinical studies aimed at identifying drugs that restore barrier function.

The principle of biodosimetry is to utilize changes induced in the individual by ionizing radiation to estimate the dose and, if possible, to predict or reflect the clinically relevant response, i.e., the biological consequences of the dose. Ideally, the changes should be specific for ionizing radiation, and the response should be unaffected by prior medical or physiological variations among subjects, including changes that might be caused by the stress and trauma from a radiation event. There are two basic types of biodosimetry with different and often complementary characteristics: those based on changes in biological parameters such as gene activation or chromosomal abnormalities and those based on physical changes in tissues (detected by techniques such as EPR). In this paper, we consider the applicability of the various techniques for different scenarios: small- and large-scale exposures to levels of radiation that could lead to the acute radiation syndrome and exposures with lower doses that do not need immediate care, but should be followed for evidence of long-term consequences. The development of biodosimetry has been especially stimulated by the needs after a large-scale event where it is essential to have a means to identify those individuals who would benefit from being brought into the medical care system. Analyses of the conventional methods officially recommended for responding to such events indicate that these methods are unlikely to achieve the results needed for timely triage of thousands of victims. Emerging biodosimetric methods can fill this critically important gap.

The objective of this study is to describe the oxygen profile obtained by electron paramagnetic resonance (EPR) oximetry of tissue after radiation, surgery, and hyperbaric oxygen therapy (HBOT) and its relationship to wound healing in a rodent model. The study design is rodent model for wound healing. A rodent model for wound healing was used for oxygen measurements before and after various treatments. EPR measurements and biopsies of normal vs irradiated and flap vs non-flap tissues were taken at 1–3-week intervals for 12 weeks. Wound healing was evaluated by gross photos, histology, and immunostaining. Student’s t test and a linear mixed model were used to compare oxygen levels and gross healing with radiation exposure. A Proportional Odds model was also used to calculate odds ratio toward better wound-healing rate with radiation exposure. In the rodent model, at 1–3 weeks after irradiation, the mean tissue oxygen measurement was significantly lower in irradiated versus non-irradiated leg tissue. There was a significant difference in oxygenation between flap and non-flap tissue in an irradiated bed at 1 and 3 weeks after surgery. On gross evaluation, wound healing from z -plasty flap was significantly worse in irradiated tissue compared to non-irradiated tissue. A rodent model for wound healing showed that radiation resulted in decreased tissue oxygenation at 1–3 weeks after irradiation. Wound healing was compromised in irradiated tissue at earlier time points when tissue oxygenation was lower. Oxygen profiling with EPR oximetry can be used to identify timing of oxygen interventions to improve wound healing. Level of evidence is NA, animal studies.

EPR spectrometers (and various sub-systems) have been designed and constructed to facilitate in vivo measurements with human subjects for dosimetry and oximetry. Most applications are primarily focused on surface tissue measurements; however, oximetric measurements utilizing implantable devices are also discussed. Given various specifications and considerations across these two primary applications, several embodiments and configurations of the associated sub-systems to the spectrometer have been realized and implemented. These embodiments and configurations have been developed and tested with a focus on the end-use and the end-users. This includes acknowledgement of the challenges and needs for making measurements in unanesthetized human patients, the nature of the data that are most likely to be useful for clinical decision-making, and the person who will be making the actual measurements. Significant developments in spectrometer automation and features to ensure the quality of recorded data are featured.

There is a strong need to enable accurate and convenient oxygen measurements in vivo for human subjects to improve treatments for cancer, peripheral vascular disease, and other diseases where tissue oxygen levels have a significant impact. While EPR spectroscopy has the potential to do this effectively, the full exploitation of these capabilities requires optimization of resonators for use with human subjects. Patient motion, and its effects on resonator coupling and positioning relative to the implanted oximetry probe, is a major source of noise and artifacts. Additionally, optimization of detection sensitivity to enable measurements from tissues at depths of several centimeters with clinically practical acquisition times is needed. To meet these needs, surface resonators with high sensitivity and flexible cables that allow the detection loop to be conveniently attached to the skin surface were developed for use with low frequency (L-Band, 1.15 GHz) continuous wave EPR. These resonators include a multi-segment sensing loop with a common capacitance. The light-weight segmented sensing loops, with diameters of 10–20 mm, can be connected to a commercial topical fixation applicator to conveniently and securely position them on patients’ skin surfaces. It was shown that a resonator of 20 mm in diameter makes it possible to obtain adequate EPR signals in tissue phantoms up to a depth of 20 mm with ~ 2 min of signal averaging. This novel lightweight resonator design, with sensitive multi-segment design and flexible cable with skin surface attachment, significantly reduced the impacts of subject motion enabling reliable EPR oximetry measurements in human subjects.

Previous work has shown that capturing optical emission from plastic discs attached directly to the skin can be a viable means to accurately measure surface dose during total skin electron therapy. This method can provide accurate dosimetric information rapidly and remotely without the need for postprocessing. The objective of this study was to: (1) improve the robustness and usability of the scintillators and (2) enhance sensitivity of the optical imaging system to improve scintillator emission detection as related to tissue surface dose. Baseline measurements of scintillator optical output were obtained by attaching the plastic discs to a flat tissue phantom and simultaneously irradiating and imaging them. Impact on underlying surface dose was evaluated by placing the discs on-top of the active element of an ionization chamber. A protective coating and adhesive backing were added to allow easier logistical use, and they were also subjected to disinfection procedures, while verifying that these changes did not affect the linearity of response with dose. The camera was modified such that the peak of detector quantum efficiency better overlapped with the emission spectra of the scintillating discs. Patient imaging was carried out and surface dose measurements were captured by the updated camera and compared to those produced by optically stimulated luminescence detectors (OSLD). The updated camera was able to measure surface dose with <3  %   difference compared to OSLD–Cherenkov emission from the patient was suppressed and scintillation detection was enhanced by 25  ×   and 7  ×  , respectively. Improved scintillators increase underlying surface dose on average by 5.2  ±  0.1  %   and light output decreased by 2.6  ±  0.3  %  . Disinfection had <0.02  %   change on scintillator light output. The enhanced sensitivity of the imaging system to scintillator optical emission spectrum can now enable a reduction in physical dimensions of the dosimeters without loss in ability to detect light output.