Introduction: Radiation therapy increases the risk of secondary malignancy and morbidity in cancer survivors. The role of obesity and exercise training in modulating this risk is not well understood. As such, we used a preclinical model of radiation-induced malignancy to investigate whether diet-induced obesity and/or endurance exercise training altered lifelong survival, cancer incidence, and morbidity. Methods: Male CBA mice were randomly divided into control diet/sedentary group (CTRL/SED), high-fat diet (45% fat)/sedentary group (HFD/SED), control diet/exercise group (2-3 d•wk −1 ; CTRL/EX), or high-fat diet/exercise group (HFD/EX) groups then exposed to whole-body radiation (3 Gy). End point monitoring and pathology determined mortality and cancer incidence, respectively. Health span index, a measure of morbidity, was determined by a composite measure of 10 anthropometric, metabolic, performance, and behavioral measures. Results: Overall survival was higher in HFD/SED compared with CTRL/SED (P < 0.05). The risk of cancer-related mortality by 18 months postradiation was 1.99 and 1.63 in HFD/SED compared with CTRL/EX (RR = 1.99, 95% confidence interval = 1.20-3.31, P = 0.0081) and CTRL/SED (RR = 1.63, 95% confidence interval = 1.06-2.49, P = 0.0250), respectively. The number of mice at end point with cancer was higher in HFD/SED compared with CTRL/EX and CTRL/SED (P < 0.05). Health span index was highest in CTRL/EX (score = +2.5), followed by HFD/EX (score = +1), and HFD/SED (score = −1) relative to CTRL/SED. Conclusion: This work provides the basis for future preclinical studies investigating the dose-response relationship between exercise training and late effects of radiation therapy as well as the mechanisms responsible for these effects.

Purpose: Overexpression and activation of matrix metalloproteinase-13 (MMP-13) within atheroma increases susceptibility to plaque rupture, a major cause of severe cardiovascular complications. In comparison to pan-MMP targeting [ 18 F]BR-351, we evaluated the potential for [ 18 F]FMBP, a selective PET radiotracer for MMP-13, to detect extracellular matrix (ECM) remodeling in vascular plaques possessing markers of inflammation.Procedures: [ 18 F]FMBP and [ 18 F]BR-351 were initially assessed in vitro by incubation with en face aortae from 8 month-old atherogenic ApoE -/mice. Ex vivo biodistributions, plasma metabolite analyses, and ex vivo autoradiography were analogously performed 30 minutes after intravenous radiotracer administration in age-matched C57Bl/6 and ApoE -/mice under baseline or homologous blocking conditions. En face aortae were subsequently stained with Oil Red O (ORO), sectioned, and subject to immunofluorescence staining for Mac-2 and MMP-13.Results: High-resolution autoradiographic image analysis demonstrated target specificity and regional concordance to lipid-rich lesions. Biodistribution studies revealed hepatobiliary excretion, low accumulation of radioactivity in non-excretory organs, and few differences between strains and conditions in non-target organs. Plasma metabolite analyses uncovered that [ 18 F]FMBP exhibited excellent in vivo stability (≥74% intact) while [ 18 F]BR-351 was extensively metabolized (≤37% intact). Ex vivo autoradiography and histology of en face aortae revealed that [ 18 F]FMBP, relative to [ 18 F]BR-351, exhibited 2.9-fold greater lesion uptake, substantial specific binding (68%), and improved sensitivity to atherosclerotic tissue (2.9-fold vs 2.1-fold). Immunofluorescent staining of aortic en face cross-sections demonstrated elevated Mac-2 and MMP-13 positive areas within atherosclerotic lesions identified by [ 18 F]FMBP ex vivo autoradiography.Conclusions: While both radiotracers successfully identified atherosclerotic plaques, [ 18 F]FMBP showed superior specificity and sensitivity for lesions possessing features of destructive plaque 3 remodeling. The detection of ECM remodeling by selective targeting of MMP-13 may enable characterization of high-risk atherosclerosis featuring elevated collagenase activity.

Dysfunction of the cardiac sympathetic nervous system contributes to the development of cardiovascular diseases including ischemia, heart failure, and arrhythmias. Molecular imaging probes such as meta-[ 123 I]iodobenzylguanidine have demonstrated the utility of assessing neuronal integrity by targeting norepinephrine transporter (NET, uptake-1). However, current radiotracers can report only on innervation due to suboptimal kinetics and lack sensitivity to NET in rodents, precluding mechanistic studies in these species. The objective of this work was to characterize myocardial sympathetic neuronal uptake mechanisms and kinetics of the positron emission tomography (PET) radiotracer meta-[ 18 F]fluorobenzylguanidine ([ 18 F]mFBG) in rats. Automated synthesis using spirocyclic iodonium(III) ylide radiofluorination produces [ 18 F]mFBG in 24 ± 1% isolated radiochemical yield and 30−95 GBq/μmol molar activity. PET imaging in healthy rats delineated the left ventricle, with monoexponential washout kinetics (k mono = 0.027 ± 0.0026 min −1 , A mono = 3.08 ± 0.33 SUV). Ex vivo biodistribution studies revealed tracer retention in the myocardium, while pharmacological treatment with selective NET inhibitor desipramine, nonselective neuronal and extraneuronal uptake-2 inhibitor phenoxybenzamine, and neuronal ablation with neurotoxin 6hydroxydopamine reduced myocardial retention by 33, 76, and 36%, respectively. Clearance of [ 18 F]mFBG from the myocardium was unaffected by treatment with uptake-1 and uptake-2 inhibitors following peak myocardial activity. These results suggest that myocardial distribution of [ 18 F]mFBG in rats is dependent on both NET and extraneuronal transporters and that limited reuptake to the myocardium occurs. [ 18 F]mFBG may therefore prove useful for imaging intraneuronal dysfunction in small animals.

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There are nearly 16 million cancer survivors living in the United States today, with two‐thirds of them having received radiation therapy as part of their treatment. Furthermore, there is a concurrent increase in obesity and physical inactivity among this population. Combined with the effects of ionizing radiation (IR), these host factors are increasing the risk of secondary, treatment‐induced cancers and may contribute to poor healthspan outcomes in cancer survivors. As such, a critical need exists to develop a better understanding of how these host factors interact with radiation exposure, such that we can provide cancer survivors with better lifestyle recommendations to enhance their overall quality of life and decrease their secondary cancer risk. Male CBA mice were randomly divided into a control diet group (CTRL) or a 45% high fat diet group (HFD) to induce obesity. At nine weeks of age, half of the mice in each dietary group began a treadmill exercise training intervention (EX), or remained sedentary (SED), and were then all exposed to ionizing radiation (3 Gy) at 13 weeks of age. Healthspan was measured in each group at 17 months of age by assessing: endurance performance, metabolic and locomotor activity, depression‐like behaviour, forelimb grip strength and plasma clinical chemistry. Endurance performance was significantly greater in CTRL/EX compared to both HFD groups 5 days pre‐IR and compared to both SED groups 5 months post‐IR (both p<0.05). Metabolic analysis revealed a significant increase in the respiratory exchange ratio in CTRL compared to HFD mice (p<0.05), but there were no significant differences in O2 consumption, CO2, or heat production (p>0.05). There was also a trend for an increase in locomotor activity in the CTRL/EX compared to CTRL/SED group during their light and dark cycle (p = 0.06 and p = 0.108, respectively). Further, there was a significant decrease in depression‐like behaviour among HFD compared to CTRL mice, and EX compared to SED mice (p<0.05), as well as a significant decrease in forelimb grip strength normalized to body weight among HFD compared to CTRL mice (p<0.05). Additionally, there was a significant increase in total cholesterol levels among HFD compared to CTRL mice (p<0.05). Interestingly, the CTRL/EX and HFD/EX groups had a 20% decrease in cancer incidence compared to the HFD/SED group, and EX mice had a 17.5% decrease in cancer incidence compared to SED mice, independent of diet (both p>0.05). Our current findings suggest that long‐term exercise and dietary interventions should be implemented in cancer survivors exposed to radiation therapy in order to improve healthspan and potentially protect against secondary cancer incidence. Support or Funding Information The American Institute of Cancer Research (AICR), The Natural Sciences and Engineering Research Council of Canada (NSERC), and The Canadian Institutes of Health Research (CIHR)