Abstract:
:There is an ongoing and significant need for radiation countermeasures to reduce morbidities and mortalities associated with exposure of the heart and lungs from a radiological or nuclear incidents. Radiation-induced late effects occur months to years after exposure, stemming from significant tissue damage and remodeling, resulting in fibrosis and loss of function. TGF-β is reported to play a role in both pulmonary and cardiac fibrosis. We investigated the ability of a small molecule TGF-β receptor 1 inhibitor, IPW-5371, to mitigate the effects of thoracic irradiation in C57L/J mice, a murine model that most closely resembles that observed in humans in the induction of fibrosis and dose response. To simulate a radiological event, radiation was administered in two doses: 5 Gy total-body irradiation (eliciting a whole-body response) and immediately after that, a thoracic "top-up" of 6.5 Gy irradiation, for a total dose of 11.5 Gy to the thorax. IPW-5371 was administered once daily, orally, starting 24 h postirradiation for 6 or 20 weeks at a dose of 10 mg/kg or 30 mg/kg. Animals were monitored for a period of 180 days for survival, and cardiopulmonary injury was assessed by echocardiography, breathing rate and arterial oxygen saturation. Exposure of the thorax (11.5 Gy) induced both pulmonary and cardiac injury, resulting in a reduced life span with median survival of 135 days. IPW-5371 treatment for 6 weeks, at both 10 mg/kg and 30 mg/kg, delayed disease onset and mortality, with median survival of 165 days. Twenty weeks of IPW-5371 treatment at 30 mg/kg preserved arterial O2 saturation and cardiac contractile reserve and resulted in significant decreases in breathing frequency and cardiac and pulmonary fibrosis. This led to dramatic improvement in survival compared to the irradiated, vehicle-treated group (P < 0.001), and was statistically insignificant from the nonirradiated group. We observed that IPW-5371 treatment resulted in decreased pSmad3 tissue levels, confirming the effect of IPW-5371 on TGF-β signaling. These results demonstrate that IPW-5371 represents a potentially promising radiation countermeasure for the treatment of radiation-induced late effects.
journal_name
Radiat Resjournal_title
Radiation researchauthors
Rabender C,Mezzaroma E,Mauro AG,Mullangi R,Abbate A,Anscher M,Hart B,Mikkelsen Rdoi
10.1667/RR14403.2subject
Has Abstractpub_date
2016-11-01 00:00:00pages
478-488issue
5eissn
0033-7587issn
1938-5404journal_volume
186pub_type
杂志文章abstract::To understand the biophysical mechanism(s) underlying the induction of cell death by the decay of the Auger electron emitter iodine-125 in DNA, Chinese hamster V79 lung fibroblasts were labeled with 5-[(125)I]iodo-2'-deoxyuridine ((125)IdU) for two doubling times and frozen and stored at -135 degrees C in the presence...
journal_title:Radiation research
pub_type: 杂志文章
doi:10.1667/0033-7587(2000)154[0326:todiiq]2.0.co;2
更新日期:2000-09-01 00:00:00
abstract::Although conclusive evidence has been obtained for the presence of radiation-induced bystander effects, the mechanisms that trigger and regulate these processes are still largely unknown. The bystander effect may play a critical role in determining the biological effectiveness of low-dose exposures, but questions on h...
journal_title:Radiation research
pub_type: 杂志文章
doi:10.1667/rr3319
更新日期:2005-03-01 00:00:00
abstract::The possibility of a large-scale acute radiation exposure necessitates the development of new methods that could provide rapid individual dose estimates with high sample throughput. The focus of the study was an intercomparison of laboratories' dose-assessment performances using gene expression assays. Lithium-heparin...
journal_title:Radiation research
pub_type: 杂志文章
doi:10.1667/RR3236.1
更新日期:2013-08-01 00:00:00
abstract::While nontargeted and low-dose effects such as the bystander effect are now accepted, the mechanisms underlying the response have yet to be elucidated. It has been shown that the transfer of irradiated cell conditioned medium (ICCM) can kill cells that are not directly irradiated; however, to date the effect of ICCM c...
journal_title:Radiation research
pub_type: 杂志文章
doi:10.1667/RR1141.1
更新日期:2008-02-01 00:00:00
abstract::To examine the role of radiation energy deposition in DNA on cellular effects, we investigated the ability of 125IdUrd and 131IdUrd to kill cells and induce mutations at the hprt locus. We employed human lymphoblastoid cells proficient (TK6) or deficient (SE30) in the ability to incorporate a thymidine analog into DNA...
journal_title:Radiation research
pub_type: 杂志文章
doi:
更新日期:1990-07-01 00:00:00
abstract::Little computational or experimental information is available on site-specific hydroxyl attack probabilities to DNA. In this study, an atomistic stochastic model of OH radical reactions with DNA was developed to compute relative OH attack probabilities at individual deoxyribose hydrogen atoms. A model of the self-comp...
journal_title:Radiation research
pub_type: 杂志文章
doi:10.1667/0033-7587(2002)157[0038:ssoatt]2.0.co;2
更新日期:2002-01-01 00:00:00
abstract::The major limitation to reaching a curative radiation dose in radioresistant tumors such as malignant gliomas is the high sensitivity to radiation and subsequent damage of the surrounding normal tissues. Novel dose delivery methods such as minibeam radiation therapy (MBRT) may help to overcome this limitation. MBRT ut...
journal_title:Radiation research
pub_type: 杂志文章
doi:10.1667/RR14018.1
更新日期:2015-09-01 00:00:00
abstract::These studies examined the effects of X radiation and interleukin 3 (IL-3), which is an effective cytokine for the generation of megakaryocytopoiesis from X-irradiated hematopoietic stem/progenitor cells, on the terminal process of human megakaryocytopoiesis and thrombopoiesis. Mature megakaryocytes were induced by cu...
journal_title:Radiation research
pub_type: 杂志文章
doi:10.1667/RR1519.1
更新日期:2009-09-01 00:00:00
abstract::Very low doses of ionizing radiation, 5 to 100 mGy, can induce adaptive responses characterized by elevation in cell survival and reduction in micronuclei formation. Utilizing these end points, RKO human colon carcinoma and transformed mouse embryo fibroblasts (MEF), wild-type or knockout cells missing TNF receptors 1...
journal_title:Radiation research
pub_type: 杂志文章
doi:10.1667/RR3126.2
更新日期:2013-02-01 00:00:00
abstract::The natural survival, relative to properly chosen controls, of 26 beagle dogs injected once intravenously with an average of 0.58 +/- 0.04 kBq 239Pu/kg, 23 dogs injected with 2.31 +/- 0.43 kBq 226Ra/kg, 13 dogs injected with 1.84 +/- 0.26 kBq 228Ra/kg, 12 dogs injected with 0.56 +/- 0.030 kBq 228Th/kg, and 12 dogs inj...
journal_title:Radiation research
pub_type: 杂志文章
doi:
更新日期:1991-06-01 00:00:00
abstract::The mortality experience between 1956 and 1985 of 8977 males employed by Atomic Energy of Canada Limited is reported. A total of 4260 men, 47% of the cohort, were exposed to low doses of external ionizing radiation at low dose rates, with a mean cumulative equivalent dose of 52.1 mSv. For cancers as a whole the excess...
journal_title:Radiation research
pub_type: 杂志文章
doi:
更新日期:1993-03-01 00:00:00
abstract::The concentrations of uranium isotopes and their decay products 226Ra, 222Rn, 210Pb and 210po have been analyzed in the mineral spring waters of a highly radioactive region of Brazil: Aguas da Prata. This region is located in the Poços de Caldas Plateau, one of the largest weathered alkaline intrusions in the world. D...
journal_title:Radiation research
pub_type: 杂志文章
doi:
更新日期:1998-08-01 00:00:00
abstract::Domestic radon risk estimates are typically based either on data for uranium miners or on data derived from A-bomb survivors; comparison of domestic radon risk estimates derived from these two disparate sources represents an important test of their reliability. There is currently a significant discrepancy of about a f...
journal_title:Radiation research
pub_type: 杂志文章
doi:
更新日期:1995-04-01 00:00:00
abstract::Whether inner-shell ionizations of DNA atoms, called core ionizations, are critical events for cell inactivation by ionizing radiations such as 100 keV electrons and gamma rays has been investigated. The number of core ionizations in DNA atoms per gray of the two types of radiations is calculated from various Monte Ca...
journal_title:Radiation research
pub_type: 杂志文章
doi:10.1667/RR0451.1
更新日期:2007-04-01 00:00:00
abstract::Ionization generates a large number of secondary low-energy electrons (LEEs) with a most probable energy of approximately 10 eV, which can break DNA bonds by dissociative electron attachment (DEA) and lead to DNA damage. In this study, we investigated radiation damage to dry DNA induced by X rays (1.5 keV) alone on a ...
journal_title:Radiation research
pub_type: 杂志文章
doi:10.1667/RR14476.1
更新日期:2016-11-01 00:00:00
abstract::In boron neutron capture therapy, the absorbed dose from the (10)B(n,alpha)(7)Li reaction depends on the (10)B concentration and (10)B distribution in the irradiated volume. Thus compounds used in BNCT should have tumor-specific uptake and low accumulation in normal tissues. This study compares in a mouse model the (1...
journal_title:Radiation research
pub_type: 杂志文章
doi:10.1667/RR1700.1
更新日期:2009-10-01 00:00:00
abstract::Beagle dogs had signs of restrictive lung disease 1 to 5 years after exposure by inhalation to 239PuO2 aerosols. The 239PuO2 aerosols were monodisperse with activity median aerodynamic diameters of 0.75, 1.5, or 3.0 microns. The plutonium particles produced protracted alpha irradiation of the lungs. Ten dogs had speci...
journal_title:Radiation research
pub_type: 杂志文章
doi:
更新日期:1988-08-01 00:00:00
abstract::Numerous studies have shown that histone deacetylase inhibitors (HDACis) improve cellular acetylation while also enhancing the radiation sensitivity. In this work, however, we confirmed that low-dose trichostatin A (TSA) as a typical HDACi could reduce rather than increase the radiosensitivity of cancer cells, while t...
journal_title:Radiation research
pub_type: 杂志文章
doi:10.1667/RADE-20-00145.1
更新日期:2021-01-29 00:00:00
abstract::Nonhuman organisms are being exposed to ionizing radiations at radionuclide-contaminated sites around the world. Direct methods are seldom available for measuring biologically relevant doses received by these organisms. Here we extend biological dosimetry techniques, which are much better developed for humans and a fe...
journal_title:Radiation research
pub_type: 杂志文章
doi:10.1667/0033-7587(2000)153[0752:ctitab]2.0.co;2
更新日期:2000-06-01 00:00:00
abstract::The photodynamic properties of a second-generation photodynamic sensitizer, meta-tetra(hydroxyphenyl)chlorin (mTHPC) were studied by dye-sensitized photoinactivation (650 nm) of HT29 human adenocarcinoma cells in culture. The photocytotoxicity of mTHPC in vitro depended on the presence of molecular oxygen. A strong in...
journal_title:Radiation research
pub_type: 杂志文章
doi:
更新日期:1999-10-01 00:00:00
abstract::As part of a long-term study of the effects of irradiation during development, prenatal and early neonatal mortality were evaluated for beagles exposed in utero at 8 days postcoitus (dpc), 28 dpc, 55 dpc, or 2 days postpartum. Mean doses used were 0,0.16, or 0.83 Gy. A decrease in whelping rates was observed for femal...
journal_title:Radiation research
pub_type: 杂志文章
doi:
更新日期:1988-07-01 00:00:00
abstract::Previous surveys of radiation therapy among the Life Span Study (LSS) population at the Radiation Effects Research Foundation (RERF) revealed that 1,670 (1.4%) of the LSS participants received radiation treatments before 1984. The data on therapeutic radiation doses are indispensable for studying the relationship betw...
journal_title:Radiation research
pub_type: 杂志文章
doi:10.1667/0033-7587(2001)155[0785:odfrti]2.0.co;2
更新日期:2001-06-01 00:00:00
abstract::To clarify the information in the Radiation Effects Research Foundation data regarding cancer risks of low radiation doses, we focus on survivors with doses less than 0.5 Sv. For reasons indicated, we also restrict attention mainly to survivors within 3, 000 m of the hypocenter of the bombs. Analysis is of solid cance...
journal_title:Radiation research
pub_type: 杂志文章
doi:10.1667/0033-7587(2000)154[0178:rrcral]2.0.co;2
更新日期:2000-08-01 00:00:00
abstract::There is a need for minimally invasive biomarkers that can accurately and quickly quantify radiation exposure. Radiation-responsive proteins have applications in clinical medicine and for mass population screenings after a nuclear or radiological incident where the level of radiation exposure and exposure pattern comp...
journal_title:Radiation research
pub_type: 杂志文章
doi:10.1667/RR13927.1
更新日期:2015-07-01 00:00:00
abstract::The effect of exposure of human epidermal keratinocytes to ionizing radiation, both in vivo and in vitro, on the expression of the epidermal growth factor receptor (EGF-R) was studied on the protein, mRNA, and functional levels. Quantitative fluorometry of short-term organ cultures incubated with a monoclonal antibody...
journal_title:Radiation research
pub_type: 杂志文章
doi:
更新日期:1993-10-01 00:00:00
abstract::In an attempt to elucidate mechanisms underlying the variation in radiosensitivity during the cell cycle, mutations in the HPRT gene were selected with 6-thioguanine, quantified and characterized in synchronous human bladder carcinoma cells (EJ30-15) that were irradiated in G1 or S phase with 3 or 6 Gy. Synchronous ce...
journal_title:Radiation research
pub_type: 杂志文章
doi:
更新日期:1997-12-01 00:00:00
abstract::To compare the effects of exposure to a near-resonant frequency of microwaves at two orientations with a higher frequency exposure, five rhesus monkeys were exposed for 4 hr to 225 MHz, electric field oriented parallel to the long axis of the body (225 MHz-E), and to 225 MHz, magnetic field orientation (225 MHz-H), or...
journal_title:Radiation research
pub_type: 杂志文章
doi:
更新日期:1985-04-01 00:00:00
abstract::While lifespan studies provide basic information for estimating the risk of ionizing radiation, findings on the effect of low-dose/low-dose-rate irradiation on the lifespan of mammals are controversial. Here we evaluate the effect of continuous exposure to low-dose-rate γ radiation on the lifespan of mice with acceler...
journal_title:Radiation research
pub_type: 杂志文章
doi:10.1667/RR2977.1
更新日期:2013-06-01 00:00:00
abstract::An understanding of proton radiobiology is critical for optimization of both proton radiotherapy and assessment of carcinogenesis risk from space radiation. Although the physical aspects of proton beam radiobiology is well understood, the biological aspects, particularly the complex biological end points, have been un...
journal_title:Radiation research
pub_type: 杂志文章,评审
doi:10.1667/RR2839.1
更新日期:2013-03-01 00:00:00
abstract::Vascular injury after radiation exposure contributes to multiple types of tissue injury through a cascade of events. Some of the earliest consequences of radiation damage include increased vascular permeability and promotion of inflammation, which is partially manifested by increased leukocyte-endothelial (L/E) intera...
journal_title:Radiation research
pub_type: 杂志文章
doi:10.1667/RR14896.1
更新日期:2018-07-01 00:00:00