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  • 1
    Language: English
    In: Radiation research, April 2011, Vol.175(4), pp.510-18
    Description: The human lung is among the most sensitive and critical tissues of concern in localized and systemic radiation exposures, and it is a subject of active preclinical research for evaluating mitigating therapies within the radiation countermeasures program. Our previous study comparing C57BL/6, CBA and C57L mice after whole-thorax irradiation pointed to the problems of late pleural effusions that prevented the full development of lung injury in C57BL/6 mice and suggested that the CBA and C57L strains are more favorable for modeling lung injury in humans (Jackson et al., Radiat. Res. 173, 10-20, 2010). We extended these comparisons to include three other mouse strains (BALB/c, C57BR/J and A/J mice) irradiated with 10, 12.5 or 15 Gy. Most of these mice were unable to survive the first 6 months and presented with a mixture of lung injury and pleural effusions as determined from gross pathology, histology and micro-CT. The independent and varying development of compressive pleural effusions of ill-defined etiology represents a concern for these strains in that they may not satisfy the preclinical requirements for approval of medical countermeasures (e.g. radiation mitigators) for human use. Thus, among the various different mouse strains studied so far for these pathologies, only three (CBA, C3H and C57L) appear to be desirable in exhibiting an early wave of pulmonary dysfunction attributed exclusively to radiation pneumonitis and for further assessment of radioprotective and mitigating therapies. C57L mice are particularly relevant in that they show significant lung damage at lower radiation doses that are closer to what is predicted for humans.
    Keywords: Disease Models, Animal ; Species Specificity ; Lung Diseases -- Physiopathology ; Radiation Injuries -- Physiopathology ; Thorax -- Radiation Effects
    ISSN: 00337587
    E-ISSN: 1938-5404
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  • 2
    Language: English
    In: International Journal of Radiation Oncology, Biology, Physics, 01 June 2012, Vol.83(2), pp.740-748
    Description: Apoptosis in irradiated normal lung tissue has been observed several weeks after radiation. However, the signaling pathway propagating cell death after radiation remains unknown. C57BL/6J mice were irradiated with 15 Gy to the whole thorax. Pro-apoptotic signaling was evaluated 6 weeks after radiation with or without administration of AEOL10150, a potent catalytic scavenger of reactive oxygen and nitrogen species. Apoptosis was observed primarily in type I and type II pneumocytes and endothelium. Apoptosis correlated with increased PTEN expression, inhibition of downstream PI3K/AKT signaling, and increased p53 and Bax protein levels. Transforming growth factor-β1, Nox4, and oxidative stress were also increased 6 weeks after radiation. Therapeutic administration of AEOL10150 suppressed pro-apoptotic signaling and dramatically reduced the number of apoptotic cells. Increased PTEN signaling after radiation results in apoptosis of lung parenchymal cells. We hypothesize that upregulation of PTEN is influenced by Nox4-derived oxidative stress. To our knowledge, this is the first study to highlight the role of PTEN in radiation-induced pulmonary toxicity.
    Keywords: Radiation ; Apoptosis ; Reactive Oxygen Species ; Pten ; Nox4 ; Medicine
    ISSN: 0360-3016
    E-ISSN: 1879-355X
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  • 3
    Language: English
    In: Urology, May 2015, Vol.85(5), pp.1214.e1-1214.e6
    Description: To establish a feasible rat model of radiation-induced erectile dysfunction after targeted prostate irradiation using an image-guided irradiation unit specially designed for small-animal radiation research. The X-RAD 225Cx research platform was used in the present study. We first performed quality assurance testing using a rat cadaver. After confirming dosimetry, 24 age-matched, young, adult, male rats were assigned to sham radiation or radiation to the prostate with doses of 15, 20, or 25 Gy. To confirm appropriate prostate irradiation, physiological erectile function was evaluated using intracavernous pressure (ICP) measurements with cavernous nerve electrical stimulation at 9 weeks after radiotherapy. Each animal was weighed at the time of ICP measurement. In addition, we investigated the cyclic guanosine monophosphate level in the penile cavernosa using a commercial enzyme-linked immunosorbent assay kit. Quality assurance results confirmed the accuracy of the irradiation technique. Dose-dependent decreases in ICP in irradiated rats were observed without major toxicity. No difference in body weight was noted among the experimental groups. Cyclic guanosine monophosphate levels were significantly decreased in the group that received 25 Gy compared with the age-matched sham-irradiated group. High-precision imaging and targeting capabilities provided by the micro-IGRT platform enable us to develop a reproducible animal model of radiation-induced erectile dysfunction in prostate cancer research.
    Keywords: Medicine
    ISSN: 0090-4295
    E-ISSN: 1527-9995
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  • 4
    Language: English
    In: Pharmaceutical Research, 2017, Vol.34(12), pp.2698-2709
    Description: To access, purchase, authenticate, or subscribe to the full-text of this article, please visit this link: http://dx.doi.org/10.1007/s11095-017-2200-9 Byline: Jace W. Jones (1), Isabel L. Jackson (2), Zeljko Vujaskovic (2), Michael D. Kaytor (3), Maureen A. Kane (1) Keywords: biomarkers; genistein; lung injury; metabolomics; radiation Abstract: Purpose Biomarkers serve a number of purposes during drug development including defining the natural history of injury/disease, serving as a secondary endpoint or trigger for intervention, and/or aiding in the selection of an effective dose in humans. BIO 300 is a patent-protected pharmaceutical formulation of nanoparticles of synthetic genistein being developed by Humanetics Corporation. The primary goal of this metabolomic discovery experiment was to identify biomarkers that correlate with radiation-induced lung injury and BIO 300 efficacy for mitigating tissue damage based upon the primary endpoint of survival. Methods High-throughput targeted metabolomics of lung tissue from male C57L/J mice exposed to 12.5 Gy whole thorax lung irradiation, treated daily with 400 mg/kg BIO 300 for either 2 weeks or 6 weeks starting 24 h post radiation exposure, were assayed at 180 d post-radiation to identify potential biomarkers. Results A panel of lung metabolites that are responsive to radiation and able to distinguish an efficacious treatment schedule of BIO 300 from a non-efficacious treatment schedule in terms of 180 d survival were identified. Conclusions These metabolites represent potential biomarkers that could be further validated for use in drug development of BIO 300 and in the translation of dose from animal to human. Author Affiliation: (1) School of Pharmacy, Department of Pharmaceutical Sciences, University of Maryland, 20 N. Pine Street, Baltimore, Maryland, 21201, USA (2) School of Medicine, Division of Translational Radiation Sciences Department of Radiation Oncology, University of Maryland, Baltimore, 21201, Maryland, USA (3) Humanetics Corporation, Edina, 55435, Minnesota, USA Article History: Registration Date: 30/05/2017 Received Date: 17/03/2017 Accepted Date: 30/05/2017 Online Date: 02/10/2017 Article note: Electronic supplementary material The online version of this article (doi: 10.1007/s11095-017-2200-9) contains supplementary material, which is available to authorized users.
    Keywords: biomarkers ; genistein ; lung injury ; metabolomics ; radiation
    ISSN: 0724-8741
    E-ISSN: 1573-904X
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  • 5
    Language: English
    In: Radiation research, January 2010, Vol.173(1), pp.10-20
    Description: The mouse has been used extensively to model radiation injury to the lung, a major dose-limiting organ for radiotherapy. Substantial differences in the timing and sensitivity of this tissue between mouse strains have been reported, with some strains, including C57BL/6, being designated as "fibrosis-prone". Pleural effusions have also been reported to be a prominent problem in many mouse strains, but it remains unclear how this affects the lung function and survival of the standard C57BL/6 mouse. The purpose of this investigation was to re-evaluate this strain in comparison with C57L and CBA mice after whole-thorax irradiation at doses ranging from 10 to 15 Gy. Breathing rate measurements, micro-computerized tomography, lung tissue weight, pleural fluid weight and histopathology showed that the most prominent features were an early phase of pneumonitis (C57L and CBA) followed by a late incidence of massive pleural effusions (CBA and C57BL/6). A remarkable difference was seen between the C57 strains: The C57L mice were exquisitely sensitive to early pneumonitis at 3 to 4 months while C57BL/6 mice showed a delayed response, with most mice presenting with large accumulations of pleural fluid at 6 to 9 months. These results therefore caution against the routine use of C57BL/6 mice in radiation lung experiments because pleural effusions are rarely observed in patients as a consequence of radiotherapy. Future experiments designed to investigate genetic determinants of radiation lung damage should focus on the high sensitivity of the C57L strain (in comparison with CBA or C3H mice) and the possibility that they are more susceptible to pulmonary fibrosis as well as pneumonitis.
    Keywords: Disease Models, Animal ; Pleural Effusion ; Radiation Tolerance ; Lung -- Radiation Effects
    ISSN: 00337587
    E-ISSN: 1938-5404
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  • 6
    Language: English
    In: Radiation research, August 2013, Vol.180(2), pp.216-21
    Description: The role of mast cell infiltrates in the pathology of radiation damage to the lung has been a subject of continuing investigation over the past four decades. This has been accompanied by a number of proposals as to how mast cells and the secretory products thereof participate in the generation of acute inflammation (pneumonitis) and the chronic process of collagen deposition (fibrosis). An additional pathophysiology examines the possible connection between mast cell hyperplasia and pulmonary hypertension through the release of vasoactive mediators. The timing and magnitude of pneumonitis and fibrosis are known to vary tremendously among different genetic mouse strains and animal species. Therefore, we have systematically compared mast cell numbers in lung sections from nine mouse strains, two rat strains and nonhuman primates (NHP) after whole thorax irradiation (WTI) at doses ranging from 10-15 Gy and at the time of entering respiratory distress. Mice of the BALB/c strain had a dramatic increase in interstitial mast cell numbers, similar to WAG/Rij and August rats, while relatively low levels of mast cell infiltrate were observed in other mouse strains (CBA, C3H, B6, C57L, WHT and TO mice). Enumeration of mast cell number in five NHPs (rhesus macaque), exhibiting severe pneumonitis at 17 weeks after 10 Gy WTI, also indicated a low response shared by the majority of mouse strains. There appeared to be no relationship between the mast cell response and the strain-dependent susceptibility towards pneumonitis or fibrosis. Further investigations are required to explore the possible participation of mast cells in mediating specific vascular responses and whether a genetically diverse mast cell response occurs in humans.
    Keywords: Macaca Mulatta -- Physiology ; Mast Cells -- Physiology ; Mice, Inbred Strains -- Physiology ; Radiation Pneumonitis -- Pathology ; Rats, Inbred Strains -- Physiology
    ISSN: 00337587
    E-ISSN: 1938-5404
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  • 7
    In: Health Physics, 2012, Vol.103(4), pp.454-462
    Description: ABSTRACT: Advances in large scale screening of medical countermeasures for radiation-induced normal tissue toxicity are currently hampered by animal irradiation paradigms that are both inefficient and highly variable among institutions. Here, a novel high-throughput small animal irradiation platform is introduced for use in orthovoltage small animal irradiators. Radiochromic film and metal oxide semiconductor field effect transistor detectors were used to examine several parameters, including 2D field uniformity, dose rate consistency, and shielding transmission. The authors posit that this setup will improve efficiency of drug screens by allowing for simultaneous targeted irradiation of multiple animals to improve efficiency within a single institution. Additionally, they suggest that measurement of the described parameters in all centers conducting countermeasure studies will improve the translatability of findings among institutions. The use of tissue equivalent phantoms in performing dosimetry measurements for small animal irradiation experiments was also investigated. Though these phantoms are commonly used in dosimetry, the authors recorded a significant difference in both the entrance and target tissue dose rates between euthanized rats and mice with implanted detectors and the corresponding phantom measurement. This suggests that measurements using these phantoms may not provide accurate dosimetry for in vivo experiments. Based on these measurements, the authors propose that this small animal irradiation platform can increase the capacity of animal studies by allowing for more efficient animal irradiation. They also suggest that researchers fully characterize the parameters of whatever radiation setup is in use in order to facilitate better comparison among institutions.
    Keywords: Medicine ; Biology;
    ISSN: 0017-9078
    E-ISSN: 15385159
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  • 8
    Language: English
    In: International Journal of Radiation Oncology, Biology, Physics, 01 November 2017, Vol.99(3), pp.680-688
    Description: Radiation-induced erectile-dysfunction (RiED) is one of the most common side effects of radiation therapy (RT) and significantly reduces the quality of life (QoL) of cancer patients. Approximately 50% of prostate cancer patients experience RiED within 3 to 5 years after completion of RT. A series of vascular, muscular, and neurogenic injuries after prostate RT lead to RiED; however, the precise role of RT-induced neurogenic injury in RiED has not been fully established. The cavernous nerves (CN) are postganglionic parasympathetic nerves located beside the prostate gland that assist in penile erection. This study was designed to investigate the role of CN injury, tissue damage, and altered signaling pathways in an RiED rat model. Male rats were exposed to a single dose of 25 Gy prostate-confined RT. Erectile function was evaluated by intracavernous pressure (ICP) measurements conducted both 9 and 14 weeks after RT. Neuronal injury was evaluated in the CN using quantitative polymerase chain reaction, conduction studies, transmission electron microscopy, and immunoblotting. Masson trichrome staining was performed to elucidate fibrosis level in penile tissues. There were significant alterations in the ICP ( 〈.0001) of RT rats versus non-RT rats. TEM analysis showed decreased myelination, increased microvascular damage, and progressive axonal atrophy of the CN fibers after RT. Electrophysiologic analysis showed significant impairment of the CN conduction velocity after RT. RT also significantly increased RhoA/Rho-associated protein kinase 1 (ROCK1) mRNA and protein expression. In addition, penile tissue showed increased apoptosis and fibrosis 14 weeks after RT. RT-induced CN injury may contribute to RiED; this is therefore a rationale for developing novel therapeutic strategies to mitigate CN and tissue damage. Moreover, further investigation of the RhoA/ROCK pathway's role in mitigating RiED is necessary.
    Keywords: Medicine
    ISSN: 0360-3016
    E-ISSN: 1879-355X
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  • 9
    In: Radiation Research, 2012, Vol.177(5), p.e0025-e0039
    Description: Since 9/11, there have been concerns that terrorists may detonate a radiological or nuclear device in an American city. Aside from several decorporation and blocking agents for use against internal radionuclide contamination, there are currently no medications within the Strategic National Stockpile that are approved to treat the immediate or delayed complications resulting from accidental exposure to radiation. Although the majority of research attention has focused on developing countermeasures that target the bone marrow and gastrointestinal tract, since they represent the most acutely radiosensitive organs, individuals who survive early radiation syndromes will likely suffer late effects in the months that follow. Of particular concern are the delayed effects seen in the lung that play a major role in late mortality seen in radiation-exposed patients and accident victims. To address these concerns, the National Institute of Allergy and Infectious Diseases convened a workshop to discuss pulmonary model development, mechanisms of radiation-induced lung injury, targets for medical countermeasures development, and end points to evaluate treatment efficacy. Other topics covered included guidance on the challenges of developing and licensing drugs and treatments specific to a radiation lung damage indication. This report reviews the data presented, as well as key points from the ensuing discussion.
    Keywords: Engineering ; Biology ; Physics;
    ISSN: 0033-7587
    ISSN: 19385404
    E-ISSN: 19385404
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  • 10
    Language: English
    In: Radiation research, May 2012, Vol.177(5), pp.717-21
    Description: Due to the ever-present threat of a radiological or nuclear accident or attack, the National Institute of Allergy and Infectious Diseases, Radiation Medical Countermeasures Program was initiated in 2004. Since that time, the Program has funded research to establish small and large animal models for radiation damage, as well as the development of approaches to mitigate/treat normal tissue damage following radiation exposure. Because some of these exposures may be high-dose, and yet heterogeneous, the expectation is that some victims will survive initial acute radiation syndromes (e.g. hematopoietic and gastrointestinal), but then suffer from potentially lethal lung complications. For this reason, efforts have concentrated on the development of animal models of lung irradiation damage that mimic expected exposure scenarios, as well as drugs to treat radiation-induced late lung sequelae including pneumonitis and fibrosis. Approaches targeting several pathways are under study, with the eventual goal of licensure by the United States Food and Drug Administration for government stockpiling. This Commentary outlines the status of countermeasure development in this area and provides information on the specifics of licensure requirements, as well as guidance and a discussion of challenges involved in developing and licensing drugs and treatments specific to a radiation lung damage indication.
    Keywords: Nuclear Warfare ; Radioactive Hazard Release ; Lung -- Radiation Effects ; Lung Diseases -- Prevention & Control ; Radiation-Protective Agents -- Therapeutic Use
    ISSN: 00337587
    E-ISSN: 1938-5404
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