The problem of tumor hypoxia has been recognized and studied by the oncology community for over 60 years. From radiation and chemotherapy resistance to the increased risk of metastasis, low oxygen concentrations in tumors have caused patients with many types of tumors to respond poorly to conventional cancer therapies. It is clear that patients with high levels of tumor hypoxia have a poorer overall treatment response and that the magnitude of hypoxia is an important prognostic factor. As a result, the development of methods to measure tumor hypoxia using invasive and noninvasive techniques has become desirable to the clinical oncology community. A variety of imaging modalities have been established to visualize hypoxia in vivo. Positron emission tomography (PET) imaging, in particular, has played a key role for imaging tumor hypoxia because of the development of hypoxia-specific radiolabelled agents. Consequently, this technique is increasingly used in the clinic for a wide variety of cancer types. Following a broad overview of the complexity of tumor hypoxia and measurement techniques to date, this article will focus specifically on the accuracy and reproducibility of PET imaging to quantify tumor hypoxia. Despite numerous advances in the field of PET imaging for hypoxia, we continue to search for the ideal hypoxia tracer to both qualitatively and quantitatively define the tumor hypoxic volume in a clinical setting to optimize treatments and predict response in cancer patients.

The emergence of the threat of radiological terrorism and other radiological incidents has led to the need for development of fast, accurate and noninvasive methods for detection of radiation exposure. The purpose of this study was to extend radiation metabolomic biomarker discovery to humans, as previous studies have focused on mice. Urine was collected from patients undergoing total body irradiation at Memorial Sloan-Kettering Cancer Center prior to hematopoietic stem cell transplantation at 4–6 h postirradiation (a single dose of 1.25 Gy) and 24 h (three fractions of 1.25 Gy each). Global metabolomic profiling was obtained through analysis with ultra performance liquid chromatography coupled to time-of-flight mass spectrometry (TOFMS). Prior to further analyses, each sample was normalized to its respective creatinine level. Statistical analysis was conducted by the nonparametric Kolmogorov-Smirnov test and the Fisher's exact test and markers were validated against pure standards. Seven markers showed distinct differences between pre- and post-exposure samples. Of those, trimethyl-l-lysine and the carnitine conjugates acetylcarnitine, decanoylcarnitine and octanoylcarnitine play an important role in the transportation of fatty acids across mitochondria for subsequent fatty acid β-oxidation. The remaining metabolites, hypoxanthine, xanthine and uric acid are the final products of the purine catabolism pathway, and high levels of excretion have been associated with increased oxidative stress and radiation induced DNA damage. Further analysis revealed sex differences in the patterns of excretion of the markers, demonstrating that generation of a sex-specific metabolomic signature will be informative and can provide a quick and reliable assessment of individuals in a radiological scenario. This is the first radiation metabolomics study in human urine laying the foundation for the use of metabolomics in biodosimetry and providing confidence in biomarker identification based on the overlap between animal models and humans.

The space radiation environment consists of multiple species of high-energy charge particles (HZE), including ⁵⁶Fe and ²⁸Si nuclei, that may impact neuronal cells, but their damaging effects on the central nervous system (CNS) have been poorly defined. Hippocampus-dependent memory functions have been shown to be highly sensitive to ⁵⁶Fe HZE particles, which poses a significant risk to the cognitive performance of astronauts during space missions. While low doses of ⁵⁶Fe radiation do not induce cell death of mature neurons, they affect synaptic plasticity in the CA1 region, the principal neuronal output of the hippocampal formation involved in memory formation. The effects of ²⁸Si on the CNS have not been defined. Compared to behaviorally naïve mice, cognitive testing might affect synaptic plasticity and the effects of ²⁸Si radiation on synaptic plasticity might be modulated by prior cognitive testing. Therefore, in the current study, we quantified the effects of whole-body ²⁸Si radiation (600 MeV/n, 0.25 and 1 Gy) on hippocampus-dependent contextual freezing and synaptic plasticity in the CA1 region of animals not exposed (behaviorally naïve mice) and animals exposed to the contextual freezing test (cognitively tested mice). In behaviorally naïve mice exposed to 0.25 and 1 Gy of ²⁸Si radiation, the magnitude of long-term potentiation (LTP) was enhanced. However, in mice irradiated with 0.25 Gy contextual fear conditioning was enhanced and was associated with a further enhancement of the LTP magnitude. Such increase in synaptic plasticity was not seen in cognitively tested mice irradiated with 1 Gy. Thus, low dose ²⁸Si radiation has effects on synaptic plasticity in the CA1 region of the hippocampus and these effects are modulated by cognitive testing in a contextual fear-conditioning test.

The specific pathways through which radiation produces the lung injuries of pneumonitis (alveolitis) and fibrosis are unknown but may involve an altered immune response. In this study, we investigated the hypothesis that the radiation-induced lung phenotype of Ja18^–/– mice [which lack invariant natural killer T (iNKT) cells] is altered relative to that of C57BL/6J genetic background strain. After 18 Gy whole-thorax irradiation male C57BL/6J mice succumbed to respiratory distress at 28–30 weeks postirradiation and although confirmed by flow cytometric analysis to be deficient in iNKT cells, the postirradiation survival of Ja18^–/– mice was not significantly different from that of C57BL/6J mice (P = 0.87). Histologically, the lungs of both C57BL/6J and Ja18^–/– mice developed fibrosing alveolitis over a similar time course with the same severity (P = 0.15). Analysis of the bronchoalveolar lavage revealed that the C57BL/6J mice and female Ja18^–/– mice succumbed to respiratory distress with neutrophil numbers exceeding those of the Ja18^–/– male mice and untreated control mice. In conclusion, the radiation-induced lung disease of Ja18^–/– mice did not significantly differ from that of C57BL/6J mice.

Although the diverse effects of ionizing radiation on biological and pathological processes at various levels ranging from molecular to whole body are well studied, the effects on adult stem cells by ionizing radiation remain largely unknown. In this study, we characterized the functional modifications of adult Drosophila midgut intestinal stem cells after ionizing radiation treatment. A dose of 10 Gy of radiation decreased the proliferative capacity of intestinal stem cells. Interestingly, after irradiation at 2 Gy, the intestinal stem cells exhibited increased proliferative activity, misdifferentiation and γH2AvD and 8-oxo-dG levels. In addition, the guts irradiated with 2 Gy showed increased JNK and AKT activities. Furthermore, we showed that 2 Gy of ionizing radiation induced centrosome amplification in intestinal stem cells of adult midguts. Our data gives molecular insights into the effects of ionizing radiation on functional modifications of stem cells. The adult Drosophila midgut intestinal stem cells offer a potentially rich new system for the exploration of the biological effects of ionizing radiation.

Because of insufficient clinical data regarding acute radiation damage after single high-dose radiation exposure, acute radiation-induced gastrointestinal (GI) syndrome remains difficult to treat. The goal of this study was to establish an appropriate and efficient minipig model to study high-dose radiation-induced GI syndrome after radiation exposure. For endoscopic access to the ileum, ileocutaneous anastomosis was performed 3 weeks before irradiation in six male Göttingen minipigs. Minipigs were locally irradiated at the abdominal area using a gamma source as follows: 1,000 cGy (n = 3) and 1,500 cGy (n = 3). Endoscopic evaluation for the terminal ileum was periodically performed via the ileocutaneous anastomosis tract. Pieces of tissue were serially taken for histological examination. The irradiated intestine presented characteristic morphological changes over time. The most obvious changes in the ileum were mucosal atrophy and telangiectasia from day 1 to day 17 after abdominal irradiation. Microscopic findings were characterized as architectural disorganization, loss of villi and chronic active inflammation. Increase in cyclooxygenase-2 (COX-2) expression was closely correlated with severity of tissue damage and inflammation. Particularly, the plasma citrulline level (PCL), a potential marker for radiation-induced intestinal damage, was significantly decreased the day after irradiation and recovered when irradiated mucosa was normalized. Our results also showed that PCL changes were positively correlated with microscopic changes and the endoscopic score in radiation-induced mucosal damage. In conclusion, the ileocutaneous anastomosis model using the minipig mimics human GI syndrome and allows the study of sequential changes in the ileum, the main target tissue of abdominal irradiation. In addition, PCL could be a simple biomarker for radiation-induced intestinal damage.

In this article we show the significant tunability of radiation chemistry in supercritical ethane and to a lesser extent in near critical CO₂. The information was obtained by studies of muonium (Mu = μ e^–), which is formed by the thermalization of positive muons in different materials. The studies of the proportions of three fractions of muon polarization, P_Mu, diamagnetic P_D and lost fraction, P_L provided the information on radiolysis processes involved in muon thermalization. Our studies include three different supercritical fluids, water, ethane and carbon dioxide. A combination of mobile electrons and other radiolysis products such as ^•C₂H₅ contribute to interesting behavior at densities ∼40% above the critical point in ethane. In carbon dioxide, an increase in electron mobility contributes to the lost fraction. The hydrated electron in water is responsible for the lost fraction and decreases the muonium fraction.

An unavoidable complication of space travel is exposure to radiation consisting of high-energy charged particles (HZE), such as Fe and Si nuclei. HZE radiation can affect neuronal functions at the level of the synapse or neuronal soma without inducing significant neuronal death. Different radiation species impart distinct patterns of radiation damage depending on their track structure, dose rate and fluence. Moreover, structural differences exist along the dorsoventral axis of the hippocampus that may underlie different radiosensitivities within the same neuronal field (e.g., the CA1 pyramidal cell population of the hippocampus). In this study we tested the functional effects of low doses of ²⁸Si radiation on excitability and synaptic plasticity in hippocampal slices prepared strictly from the ventral hippocampus. We used extracellular electrophysiological techniques to record field excitatory postsynaptic potentials (EPSPs) and population spikes in hippocampal CA1 neurons from C57BL/6J male mice 3 months after exposure to ²⁸Si radiation (600 MeV/n; 0.25 and 1 Gy, whole body). In irradiated mice we found prominent decrements in population spike amplitudes and reduced maximal neuronal output without changes in dendritic field EPSP. Reduced field EPSP vs. population spike ratios indicate radiation-induced impairment of the EPSP-spike (E-S) coupling. This effect was not associated with significant changes in the magnitude of short- and long-term synaptic plasticity [long-term potentiation (LTP)]. These data confirm that irradiation with ²⁸Si particles at relatively low doses alters the properties of the hippocampal network, which can limit its connectivity with other brain centers.

In this study, we investigated the effect of ¹³¹I gelatin microspheres (¹³¹I-GMSs) on human hepatocellular carcinoma cells (HepG2) in nude mice (Balb/c) and the biodistribution of ¹³¹I-GMSs after intratumoral injection. The treatment group and control group animals received intratumoral injections of 1 mCi ¹³¹I-GMSs and GMSs unlabeled ¹³¹I, respectively. The size of the implanted tumor was measured once a week for 8 weeks, and the survival time was calculated from the day of injection to 64 days post-injection. Another 35 animals received intratumoral injections of 0.2 mCi ¹³¹I-GMSs and were subject to single-photon emission computed tomography (SPECT) on days 1, 8, 16, 24 and 32 post-injection. Samples of various organs were collected and used to calculate tissue concentrations on days 1, 4, 8, 16 and 24. Free thyroxine (FT4) in fetal bovine serum was tested to evaluate thyroid function. The tumors were collected for histological examination. ¹³¹I-GMSs produced a pronounced reduction in HepG2 tumor volume, and the overall survival was 73.3% in the treatment group and only 13.3% in the control group (P < 0.001). Tissue radioactivity concentration measurements and SPECT demonstrated that the injected ¹³¹I-GMSs mainly accumulated within the tumors. The concentration of FT4 was stable during the observation period. The microspheres could be observed by histological methods on day 32. ¹³¹I-GMSs suppressed the growth of HepG2 in the nude mice and were retained in the tumor for a long period of time after injection. Direct intratumoral injection of ¹³¹I-GMSs offers a promising modality for the treatment of hepatocellular carcinoma.

Allergic asthma is characterized by chronic airway remodeling, which is associated with the expression of extracellular matrix proteins (ECM) by TGF-β. However, to date there are no reports demonstrating that structural proteins are directly expressed in mast cells. This study aimed to investigate whether ECM proteins are expressed in mast cells activated with antigen/antibody reaction, and whether the resolution effects of irradiation or 8-oxo-dG may contribute to allergic asthma prevention. Bone marrow-derived mast cells (BMMCs) were activated with DNP-HSA/anti-DNP IgE antibody (act-BMMCs). C57BL/6 mice were sensitized and challenged with ovalbumin (OVA) to induce allergic asthma. Mice were treated orally with 8-oxo-dG or exposed to whole body irradiation (using ¹³⁷Cs gamma ray at a dose of 0.5 Gy) for three consecutive days 24 h after OVA challenge. Expression of extracellular matrix (ECM) proteins, TGF-β signaling molecules and NF-κB/AP-1 was determined in the BMMCs, bronchoalveolar lavage (BAL) cells or lung tissues using Western blot, polymerase chain reaction (PCR) and electrophoretic mobility shift assay (EMSA), respectively. Act-BMMCs increased expression of ECM proteins, TGF-β/TGF-β receptor I, TGF-β signaling molecules and cytokines; and increased both NF-κB and AP-1 activity. In addition, the population of mast cells; expression of mast cell markers, TGF-β signaling molecules, ECM proteins/amounts; OVA-specific serum IgE level; numbers of goblet cells; airway hyperresponsiveness; cytokines/chemokines were increased in BAL cells and lung tissues of OVA-challenged mice. All of the above end points were reduced by irradiation or 8-oxo-dG in vitro and in vivo, respectively. The data suggest that mast cells induce expression of ECM proteins through TGF-β produced in inflammatory cells of OVA mice and that post treatment of irradiation or 8-oxo-dG after OVA-challenge may reduce airway remodeling through down-regulating mast cell re-activation by TGF-β/Smad signals.

Advanced glycation end products (AGEs) are an abnormal modification of the collagenous matrix in bone, and their accumulation contributes to alteration of mechanical properties. Using a mouse model of focal external radiotherapy, we quantified the time-dependent changes in the glycation of bone collagen after 4 daily fractions of 5 Gy exposure to unilateral hindlimb. Fluorometric analysis of decalcified femurs demonstrated a significant and transient increase in the quantity of pentosidine, pyridinolines and nonspecific AGEs per unit of collagen at one week postirradiation. These differences did not persist at 4, 8, 12 or 26 weeks postirradiation. Radiation had no effect on bone collagen content. We hypothesize that following the transient increase in glycation products, these crosslinks are then removed as a result of increased postirradiation osteoclast activity and continued mineralization of the bone.