The Effects of Radiation and Dose-Fractionation on Cancer and Non-Tumor Disease Development

Liu, William; Haley, Benjamin; Kwasny, Mary; Li, Jian Jian; Grdina, David J.; Paunesku, Tatjana; Woloschak, Gayle E.

doi:10.3390/ijerph9124688

Cited by 11 publications

(12 citation statements)

References 24 publications

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“…A study using a subset of animals from the Janus series of experiments compared acute or fractionated exposures of gamma or neutron radiation on the hazards associated with the development of cancer and non-cancer diseases of the liver, lung, kidney or vascular system [22]. Fractionation played a significant role in both cancer and non-cancer disease related risk in both gamma and neutron irradiated animals; fractionation was significantly associated with a longer survival across multiple non-cancer diseases.…”

Section: Introductionmentioning

confidence: 99%

The PI3K/Akt/mTOR Pathway Is Implicated in the Premature Senescence of Primary Human Endothelial Cells Exposed to Chronic Radiation

et al. 2013

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The etiology of radiation-induced cardiovascular disease (CVD) after chronic exposure to low doses of ionizing radiation is only marginally understood. We have previously shown that a chronic low-dose rate exposure (4.1 mGy/h) causes human umbilical vein endothelial cells (HUVECs) to prematurely senesce. We now show that a dose rate of 2.4 mGy/h is also able to trigger premature senescence in HUVECs, primarily indicated by a loss of growth potential and the appearance of the senescence-associated markers ß-galactosidase (SA-ß-gal) and p21. In contrast, a lower dose rate of 1.4 mGy/h was not sufficient to inhibit cellular growth or increase SA-ß-gal-staining despite an increased expression of p21. We used reverse phase protein arrays and triplex Isotope Coded Protein Labeling with LC-ESI-MS/MS to study the proteomic changes associated with chronic radiation-induced senescence. Both technologies identified inactivation of the PI3K/Akt/mTOR pathway accompanying premature senescence. In addition, expression of proteins involved in cytoskeletal structure and EIF2 signaling was reduced. Age-related diseases such as CVD have been previously associated with increased endothelial cell senescence. We postulate that a similar endothelial aging may contribute to the increased rate of CVD seen in populations chronically exposed to low-dose-rate radiation.

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Section: Introductionmentioning

confidence: 99%

The PI3K/Akt/mTOR Pathway Is Implicated in the Premature Senescence of Primary Human Endothelial Cells Exposed to Chronic Radiation

et al. 2013

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“…Janus experiments were analyzed in many different ways over the years (14, 17, 20, 30, 31, 39, 42–47) and each new approach for analysis of these data brought novel information about the effects of dose fractionation. By analyzing control mice in a way that allowed us to pool Janus experiments together, we gained statistical power to run tests on the importance of fractionation for specific causes of death.…”

Section: Discussionmentioning

confidence: 99%

“…To make the data more robust for analyses, we grouped CODs into lymphomas, tumors other than lymphomas – referred to as tumors (sometimes separating them into lung tumors and tumors (no lung tumors)), non-tumors, or causes of death unknown (CDU). Specific analyses of diseases affecting the liver, lung, kidney, and vascular system for a subset of these data were previously conducted (39).…”

Section: Methodsmentioning

confidence: 99%

Analyses of cancer incidence and other morbidities in gamma irradiated B6CF1 mice

Woloschak¹,

Zander²,

Paunesku³

2020

Preprint

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26With increasing medical radiation exposures, it is important to understand how 27 different modes of delivery of ionizing radiation as well as total doses of exposure impact 28 health outcomes. Our lab studied the risks associated with ionizing radiation by analyzing the 29 Northwestern University Radiation Archive for animals (NURA). NURA contains detailed data 30 from a series of 10 individual neutron and gamma irradiation experiments conducted on over 31 50,000 mice. Rigorous statistical testing on control mice from all Janus experiments enabled us 32 to select studies that could be compared to one another and uncover unexpected differences 33 among the controls as well as experimental animals. For controls, mice sham irradiated with 34 300 fractions died significantly earlier than those with fewer sham fractions. Using the 35 integrated dataset of gamma irradiated and control mice, we found that fractionation 36 significantly decreased the death hazard for animals dying of lymphomas, tumors, non-tumors, 37 and unknown causes. Gender differences in frequencies of causes of death were identified 38 irrespective of irradiation and dose fractionation, with female mice being at a greater risk for all 39 causes of death, except for lung tumors. Irradiated and control male mice were at a significantly 40 greater risk for lung tumors, the opposite from observations noted in humans. Additionally, we 41 discovered that lymphoma deaths can occur quickly after exposures to high doses of gamma 42 rays. This study systematically cross-compared outcomes of different modes of fractionation 43 across a wide span of total doses to demonstrate that protraction modulated survival and 44 disease status differently based on the total dose, cause of death, and sex of an animal. This 45 novel method for analyzing the Janus datasets will lead to insightful new mechanistic 46 hypotheses and research in the fields of radiation biology and protection.49 impacts is important for setting radiation protection standards. Approximately half of 50 humankind's cumulative annual radiation exposure comes from natural sources, such as cosmic 51 radiation and soil; the other half is derived from human-made sources including medical 52 procedures and nuclear medicine (1). Most of the general population receives low dose chronic 53 ionizing radiation exposures, accumulating to a few hundred mSv over a lifetime (2). 54Calculating the risks associated with these chronic exposures is challenging because of 55 the high background levels for the same diseases ionizing radiation can induce and the low 56 overall effect of these lower dose/dose-rate exposures. There are several helpful data sources 57 that researchers have utilized to help quantify these risks including radiation therapy studies, 58 atomic bomb survivor data, and other epidemiological studies from workers in the field and 59 nuclear disasters. The radiation doses given to patients for radiation therapy are much larger 60 than standard exposure and are only used on a small segmen...

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“…Comparisons between the two qualities of radiation are beneficial for determining the underlying biological factors leading to differential health outcomes. Numerous in vivo studies comparing x-rays or gamma rays with neutrons evaluated life shortening or focused on genetic changes to establish a suitable relative biological effectiveness factor (RBE) (6–9, 14–20). Work with radioprotectors and neutron irradiation in vivo and in vitro also found profound differences between the high and low LET ionizing radiation (21–24).…”

Section: Introductionmentioning

confidence: 99%

Analyses of cancer incidence and other morbidities in neutron irradiated B6CF1 mice

Zander

Paunesku

Woloschak

2020

Preprint

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24 The Department of Energy conduced ten large-scale neutron irradiation experiments at 25 Argonne National Laboratory between 1972 and 1989. Using a new approach to utilize 26 experimental controls to determine whether a cross comparison between experiments was 27 appropriate, we amalgamated data on neutron exposures to discover that fractionation 28 significantly improved overall survival. A more detailed investigation showed that fractionation 29 only had a significant impact on the death hazard for animals that died from solid tumors, but 30 did not significantly impact any other causes of death. Additionally, we compared the effects of 31 sex, age first irradiated, and radiation fractionation on neutron irradiated mice versus cobalt 60 32 gamma irradiated mice and found that solid tumors were the most common cause of death in 33 neutron irradiated mice, while lymphomas were the dominant cause of death in gamma 34 irradiated mice. Most animals in this study were irradiated before 150 days of age but a subset 35 of mice was first exposed to gamma or neutron irradiation over 500 days of age. Advanced age 36 played a significant role in decreasing the death hazard for neutron irradiated mice, but not for 37 gamma irradiated mice. Mice that were 500 days old before their first exposures to neutrons 38 began dying later than both sham irradiated or gamma irradiated mice. 40 INTRODUCTION 41Ionizing radiation can be classified by its linear energy transfer (LET) to better 42 understand how quickly radiation is attenuated and the concentration of energy deposited near 43 the particle track. Experiments evaluating the biological effects of low and high LET ionizing 44 radiation found that high LET radiation is more damaging to biological material in part because 3 45 sites of DNA double strand damage and other types of damage are in closer proximity to one 46 another than occurs with low LET radiation. These clusters of damage make DNA repair more 47 difficult and lead to increased cell death (1). Neutrons are the smallest and the most 48 penetrating of all particles included in the category of high LET ionizing radiation. Neutrons are 49 further classified by the amount of kinetic energy in a free neutron and this energy ranges from 50 less than 0.02eV for cold neutrons to over 20MeV for ultrafast neutrons. While numerous 51 animal studies were conducted in the USA, Europe and Asia using low LET radiation such as x-52 rays and gamma rays (2-5), extensive neutron irradiation experiments were less common. 53Between 1972 and 1989, Argonne National Laboratory (ANL) housed one of the few 54 neutron irradiators called the JANUS reactor suitable for large-scale whole-body animal 55 irradiations with fission spectrum neutrons with an energy range peak at 1 MeV (6-10). During 56 this time, ANL performed ten independent experiments investigating the effects of gamma and 57 neutron irradiations on mice. (11). These animals were irradiated under different conditions 58 and allowed to live out their entire lifespan. Ionizing radi...

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The Effects of Radiation and Dose-Fractionation on Cancer and Non-Tumor Disease Development

Cited by 11 publications

References 24 publications

The PI3K/Akt/mTOR Pathway Is Implicated in the Premature Senescence of Primary Human Endothelial Cells Exposed to Chronic Radiation

The PI3K/Akt/mTOR Pathway Is Implicated in the Premature Senescence of Primary Human Endothelial Cells Exposed to Chronic Radiation

Analyses of cancer incidence and other morbidities in gamma irradiated B6CF1 mice

Analyses of cancer incidence and other morbidities in neutron irradiated B6CF1 mice

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