Harold M. Swartz

Melanin is one the most common biological pigments. In humans, specialized cells called melanocytes synthesize the pigment from tyrosine and 3,4-dihydroxyphenylalanine via enzyme-catalyzed reactions and spontaneous processes. The formed melanin granule consists of nanoaggregates of oligomers containing different monomers. Although the main biological function of melanin is protection against damage from solar radiation, melanin may also be involved in protection against oxidative stress. In the latter function, sequestration of redox-active metal ions and scavenging of reactive oxygen species are of importance. The paper reviews basic physicochemical properties of melanin responsible for binding of metal ions and discusses specific conditions that may induce cytotoxicity of metal ions such as iron and copper by facilitating their redox activation and release from melanin. While the value of EPR spectroscopy and other EPR-related techniques for the study of melanin is emphasized, the concomitant use of other physicochemical methods is the most efficient approach.

We applied a non-destructive tooth dosimetry technique using L-band electron paramagnetic resonance (EPR) to assess radiation doses in cattle due to the Fukushima Daiichi Nuclear Power Station (FDNPS) accident, which occurred 10 years ago. The radiation exposure of cattle in the area affected by the FDNPS accident was estimated retrospectively with X-band and L-band EPR devices. Characteristic radiation-induced EPR signals were obtained from the teeth of the cattle in Fukushima, confirming their exposure. The estimated doses to the teeth were found to be consistent with the dose trends estimated for individual cows, while considerable uncertainties were seen in the doses of some tooth samples. This variation might be due to errors in the accuracy of the method but also might reflect the actual exposure because the cattle may have been exposed to higher areas of radioactivity in their quest for food and/or due to irradiation from absorption of the isotopes with localization in or near the teeth. However, at a minimum, these results confirm that L-band EPR can be used for non-destructive qualitative assessment of radiation exposure to animals using their teeth, which could be very valuable. Possible causes of the uncertainties should be investigated to enhance the value of the use of this technique.

An effective medical response to a large-scale radiation event requires prompt and effective initial triage so that appropriate care can be provided to individuals with significant risk for severe acute radiation injury. Arguably, it would be advantageous to use injury rather than radiation dose for the initial assessment; i.e., use bioassays of biological damage. Such assays would be based on changes in intrinsic biological response elements; e.g., up- or down-regulation of genes, proteins, metabolites, blood cell counts, chromosomal aberrations, micronuclei, micro-RNA, cytokines, or transcriptomes. Using a framework to evaluate the feasibility of biodosimetry for triaging up to a million people in less than a week following a major radiation event, Part 1 analyzes the logistical feasibility and clinical needs for ensuring that biomarkers of organ-specific injury could be effectively used in this context. We conclude that the decision to use biomarkers of organ-specific injury would greatly benefit by first having independent knowledge of whether the person’s exposure was heterogeneous and, if so, what was the dose distribution (to determine which organs were exposed to high doses). In Part 2, we describe how these two essential needs for prior information (heterogeneity and dose distribution) could be obtained by using in vivo nail dosimetry. This novel physical biodosimetry method can also meet the needs for initial triage, providing non-invasive, point-of-care measurements made by non-experts with immediate dose estimates for four separate anatomical sites. Additionally, it uniquely provides immediate information as to whether the exposure was homogeneous and, if not, it can estimate the dose distribution. We conclude that combining the capability of methods such as in vivo EPR nail dosimetry with bioassays to predict organ-specific damage would allow effective use of medical resources to save lives.

While it is well-established that hypoxia is a major factor that affects clinical outcomes in cervical cancer, widespread usage of clinically available methods to detect and evaluate hypoxia during the course of treatment have not been established. This review compares these methods, summarizes their strengths and weaknesses, and assesses the pathways for their useful employment to alter clinical practice. We conducted a search on PubMed for literature pertaining to imaging hypoxic cervical cancer, and implemented keywords related to oxygen measurement tools to improve the relevance of the search results. Oxygenation level-dependent applications of MRI have demonstrated hypoxia-induced radioresistance, and changes in cervix tumor oxygenation from hyperoxic therapy. The hypoxic areas within tumors can be indirectly identified in dynamic contrast-enhanced images, where they generally display low signal enhancement, and diffusion-weighted images, which demonstrates areas of restricted diffusion (which correlates with hypoxia). Positron emmision tomography, used independently and with other imaging modalities, has demonstrated utility in imaging hypoxia through tracers specific for low oxygen levels, like Cu-ATSM tracers and nitroimidazoles. Detecting hypoxia in the tumors of patients diagnosed with cervical cancer via medical imaging and non-imaging tools like electron paramagnetic resonance oximetry can be utilized clinically, such as for guiding radiation and post-treatment surveillance, for a more personalized approach to treatment. The merits of these methods warrant further investigation via comparative effectiveness research and large clinical trials into their clinical applications.

The aim of the paper is to discuss what currently is feasible clinically to measure the level of oxygen and how that measurement can be clinically useful. Because oxygen in tissues is quite heterogeneous and all methods of measurement can only provide an average across heterogeneities at some spatial and temporal resolution, the values that are obtained may have limitations on their clinical utility. However, even if such limitations are significant, if one utilizes repeated measurements and focuses on changes in the measured levels, rather than ‘absolute levels’, it may be possible to obtain very useful clinical information. While these considerations are especially pertinent in cancer, they also pertain to most other types of pathology.

A new resonator for X-band in vivo EPR nail dosimetry, the dielectric-backed aperture resonator (DAR), is developed based on rectangular TE₁₀₂ geometry. This novel geometry for surface spectroscopy improves at least a factor of 20 compared to a traditional non-backed aperture resonator. Such an increase in EPR sensitivity is achieved by using a non-resonant dielectric slab, placed on the aperture inside the cavity. The dielectric slab provides an increased magnetic field at the aperture and sample, while minimizing sensitive aperture resonance conditions. This work also introduces a DAR semi-spherical (SS)-TE₀₁₁ geometry. The SS-TE₀₁₁ geometry is attractive due to having twice the incident magnetic field at the aperture for a fixed input power. It has been shown that DAR provides sufficient sensitivity to make biologically relevant measurements both in vitro and in vivo. Although in vivo tests have shown some effects of physiological motions that suggest the necessity of a more robust finger holder, equivalent dosimetry sensitivity of approximately 1.4 Gy has been demonstrated.

EPR oximetry, which enables reliable, accurate, and repeated measurements of the partial pressure of oxygen in tissues, provides a unique opportunity to investigate the role of oxygen in the pathogenesis and treatment of several diseases including cancer, stroke, and heart failure. Building on significant advances in the in vivo application of EPR oximetry for small animal models of disease, we are developing suitable probes and instrumentation required for use in human subjects. Our laboratory has established the feasibility of clinical EPR oximetry in cancer patients using India ink, the only material presently approved for clinical use. We now are developing the next generation of probes, which are both superior in terms of oxygen sensitivity and biocompatibility including an excellent safety profile for use in humans. Further advances include the development of implantable oxygen sensors linked to an external coupling loop for measurements of deep-tissue oxygenations at any depth, overcoming the current limitation of 10 mm. This paper presents an overview of recent developments in our ability to make meaningful measurements of oxygen partial pressures in human subjects under clinical settings.

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.