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1.
Exp Dermatol ; 24(2): 157-9, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25393687

RESUMO

Colorimetric staining techniques such as immunohistochemistry (IHC), immunofluorescence (IF) and histochemistry (HC) provide useful information regarding the localization and relative amount of a molecule/substance in skin. We have developed a novel, straightforward method to assess colorimetric staining by combining features from two open-source software programs. As a proof of principle, we demonstrate the utility of this approach by analysing changes in skin melanin deposition during the radiation-induced tanning response of Yucatan mini-pigs. This method includes a visualization step to validate the accuracy of colour selection before quantitation to ensure accuracy. The data show that this method is robust and will provide a means to obtain accurate comparative analyses of staining in IHC/IF/HC samples.


Assuntos
Colorimetria/métodos , Melaninas/química , Pele/metabolismo , Software , Animais , Biópsia , Epiderme/metabolismo , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Microscopia de Fluorescência , Suínos , Porco Miniatura
2.
Adv Space Res ; 49(2): 237-248, 2012 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-23766550

RESUMO

Animal models are frequently used to assist in the determination of the long- and short-term effects of space flight. The space environment, including microgravity, can impact many physiological and immunological system parameters. It has been found that ground based models of microgravity produce changes in white blood cell counts, which negatively affects immunologic function. As part of the Center of Acute Radiation Research (CARR), we compared the acute effects on white blood cell parameters induced by the more traditionally used animal model of hindlimb unloading (HU) with a recently developed reduced weightbearing analog known as partial weight suspension (PWS). Female ICR mice were either hindlimb unloaded or placed in the PWS system at 16% quadrupedal weightbearing for 4 h, 1, 2, 7 or 10 days, at which point complete blood counts were obtained. Control animals (jacketed and non-jacketed) were exposed to identical conditions without reduced weightbearing. Results indicate that significant changes in total white blood cell (WBC), neutrophil, lymphocyte, monocyte and eosinophil counts were observed within the first 2 days of exposure to each system. These differences in blood cell counts normalized by day 7 in both systems. The results of these studies indicate that there are some statistically significant changes observed in the blood cell counts for animals exposed to both the PWS and HU simulated microgravity systems.

3.
JTO Clin Res Rep ; 3(5): 100315, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35516726

RESUMO

Introduction: Given the emergence of combination of programmed cell death protein-1 and CTLA4 pathway blockade as effective treatment options in malignant pleural mesothelioma (MPM), there is interest in the extent to which programmed death-ligand 1 (PD-L1) expression may be prognostic of clinical outcomes and predictive of response to anti-programmed death (ligand) 1 (PD-[L]1) therapies. Methods: MEDLINE and EMBASE electronic databases were searched until November 4, 2020. English-language randomized trials and observational studies that reported clinical outcomes and PD-L1 expression in adult patients (>18 or >20 y) with MPM were included. Forest plots were used to descriptively summarize clinical outcome data across studies. Results: A total of 29 publications were identified providing data on the research question. Among the studies in which anti-PD-(L)1 therapies were not specified to have been used, 63% (10 of 16) found patients with tumors expressing PD-L1 (typically >1%) to have poorer survival than those with tumors expressing lower levels of PD-L1. Among the studies in which anti-PD-(L)1 therapies were used, 83% (five of six) did not reveal an association between survival and PD-L1 tumor expression. The single study directly comparing outcomes between those treated and untreated with anti-PD-(L)1 therapies across different PD-L1 cutoffs did not identify any differences between the groups. Conclusions: The quality and consistency of the existing evidence base are currently insufficient to draw conclusions regarding a prognostic or predictive role of PD-L1 in MPM. Furthermore, high-quality studies on this topic are required to support the use of PD-L1 as a biomarker in MPM.

4.
JCO Precis Oncol ; 5: 953-973, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34136742

RESUMO

Four programmed death ligand 1 (PD-L1) immunohistochemistry assays (28-8, 22C3, SP263, and SP142) have been approved for use by the US Food and Drug Administration (FDA). Analytical concordance between these assays has been evaluated in multiple studies. This systematic review included studies that investigated the analytical concordance of immunohistochemistry assays utilizing two or more PD-L1 antibodies from FDA-approved diagnostics for evaluation of PD-L1 expression on tumor or immune cells across a range of tumor types and algorithms. METHODS: Literature searches were conducted in MEDLINE (via PubMed) and EMBASE to identify studies published between January 1, 2010, and March 31, 2019, that evaluated analytical concordance between two or more assays based on antibodies from FDA-approved assays. Proceedings of key oncology and pathology congresses that took place between January 2016 and March 2019 were searched for abstracts of studies evaluating PD-L1 assay concordance. RESULTS: A total of 42 studies across a range of tumor types met the selection criteria. Concordance between 28-8-, 22C3-, and SP263-based assays in lung cancer, urothelial carcinoma, and squamous cell carcinoma of the head and neck was high when used to assess PD-L1 expression on tumor cells (TCs). SP142-based assays had overall low concordance with other approved assays when used to assess PD-L1 expression on TCs. Analytical concordance for assessment of PD-L1 expression on immune cells was variable and generally lower than for PD-L1 expression on TCs. CONCLUSION: A large body of evidence supports the potential interchangeability of 28-8-, 22C3-, and SP263-based assays for the assessment of PD-L1 expression on TCs in lung cancer. Further studies are required in tumor types for which less evidence is available.


Assuntos
Anticorpos/análise , Antígeno B7-H1/imunologia , Neoplasias/diagnóstico , Neoplasias/imunologia , Humanos , Imuno-Histoquímica , Estadiamento de Neoplasias , Estados Unidos , United States Food and Drug Administration
5.
Radiat Res ; 172(4): 437-43, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19772464

RESUMO

Gene expression profiles were examined using cDNA microarray technology in human thyroid epithelial (Htori-3) cells exposed to a low, non-toxic dose (10 cGy) of radiation from HZE particles in the form of iron ions in the absence or presence of selenomethionine (SeM). A total of 215 genes were differentially regulated 2 h after exposure to a 10-cGy dose of iron-ion radiation. In the microarray analysis, SeM had profound effects on the radiation-induced expression of several specific genes, which includes PLAU, IGFBP3, FOLR1, B4GALT1 and COL1A1. Of particular interest to us was a gene cluster, "secreted proteins", that was up-regulated after radiation exposure. Seven up-regulated genes of this gene cluster fall within the chemokine/cytokine gene cluster, namely, CXCL1, CXCL2, IL6, IL11, IL8, IL24 and TGFbeta2. In microarray studies, the radiation-induced up-regulated expression of some these genes encoding cytokine/chemokine proteins was significantly decreased by SeM treatment. For IL8, TGFbeta2, CXCL1 and CXCL2, these observations were validated by qPCR techniques. It is concluded that SeM can regulate ionizing radiation-induced gene expression and may serve as an effective countermeasure for some of the acute inflammatory/immune responses induced by low-dose HZE-particle radiation.


Assuntos
Citocinas/genética , Células Epiteliais/metabolismo , Células Epiteliais/efeitos da radiação , Ferro/farmacologia , Glândula Tireoide/citologia , Ativação Transcricional/efeitos da radiação , Astronautas , Linhagem Celular , Células Epiteliais/efeitos dos fármacos , Meio Ambiente Extraterreno , Perfilação da Expressão Gênica , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Doses de Radiação , Reprodutibilidade dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Selenometionina/farmacologia , Ativação Transcricional/efeitos dos fármacos
6.
Radiat Res ; 172(2): 175-86, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19630522

RESUMO

Abstract Dietary antioxidants have radioprotective effects after gamma-radiation exposure that limit hematopoietic cell depletion and improve animal survival. The purpose of this study was to determine whether a dietary supplement consisting of l-selenomethionine, vitamin C, vitamin E succinate, alpha-lipoic acid and N-acetyl cysteine could improve survival of mice after proton total-body irradiation (TBI). Antioxidants significantly increased 30-day survival of mice only when given after irradiation at a dose less than the calculated LD(50/30); for these data, the dose-modifying factor (DMF) was 1.6. Pretreatment of animals with antioxidants resulted in significantly higher serum total white blood cell, polymorphonuclear cell and lymphocyte cell counts at 4 h after 1 Gy but not 7.2 Gy proton TBI. Antioxidants significantly modulated plasma levels of the hematopoietic cytokines Flt-3L and TGFbeta1 and increased bone marrow cell counts and spleen mass after TBI. Maintenance of the antioxidant diet resulted in improved recovery of peripheral leukocytes and platelets after sublethal and potentially lethal TBI. Taken together, oral supplementation with antioxidants appears to be an effective approach for radioprotection of hematopoietic cells and improvement of animal survival after proton TBI.


Assuntos
Antioxidantes/administração & dosagem , Sobrevivência Celular/efeitos da radiação , Suplementos Nutricionais , Células-Tronco Hematopoéticas/efeitos da radiação , Lesões por Radiação/mortalidade , Irradiação Corporal Total/efeitos adversos , Administração Oral , Animais , Células-Tronco Hematopoéticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Prótons/efeitos adversos , Lesões por Radiação/dietoterapia , Lesões por Radiação/prevenção & controle , Lesões por Radiação/veterinária , Tolerância a Radiação/efeitos dos fármacos , Tolerância a Radiação/efeitos da radiação , Protetores contra Radiação/administração & dosagem , Análise de Sobrevida , Taxa de Sobrevida
7.
PLoS One ; 14(2): e0207503, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30742630

RESUMO

The cardiovascular biology of proton radiotherapy is not well understood. We aimed to compare the genomic dose-response to proton and gamma radiation of the mouse aorta to assess whether their vascular effects may diverge. We performed comparative RNA sequencing of the aorta following (4 hrs) total-body proton and gamma irradiation (0.5-200 cGy whole body dose, 10 dose levels) of conscious mice. A trend analysis identified genes that showed a dose response. While fewer genes were dose-responsive to proton than gamma radiation (29 vs. 194 genes; q-value ≤ 0.1), the magnitude of the effect was greater. Highly responsive genes were enriched for radiation response pathways (DNA damage, apoptosis, cellular stress and inflammation; p-value ≤ 0.01). Gamma, but not proton radiation induced additionally genes in vasculature specific pathways. Genes responsive to both radiation types showed almost perfectly superimposable dose-response relationships. Despite the activation of canonical radiation response pathways by both radiation types, we detected marked differences in the genomic response of the murine aorta. Models of cardiovascular risk based on photon radiation may not accurately predict the risk associated with proton radiation.


Assuntos
Aorta/efeitos da radiação , Genoma/genética , Genoma/efeitos da radiação , Animais , Apoptose/genética , Apoptose/efeitos da radiação , Dano ao DNA/genética , Dano ao DNA/efeitos da radiação , Relação Dose-Resposta à Radiação , Raios gama , Genômica/métodos , Inflamação/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Projetos Piloto , Prótons , Radiação Ionizante
8.
Radiat Res ; 186(2): 121-40, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27459701

RESUMO

Results from our recent studies have led to the novel hypothesis that radiation-induced coagulopathy (RIC) and associated hemorrhage occurring as part of the acute radiation syndrome (ARS) is a major cause of death resulting from radiation exposure in large mammals, including humans. This article contains information related to RIC, as well as potential strategies for the prevention and treatment of RIC. In addition, new findings are reported here on the occurrence of RIC biomarkers in humans exposed to radiation. To determine whether irradiated humans have RIC biomarkers, blood samples were obtained from radiotherapy patients who received treatment for different types of malignancies. Blood samples from allogeneic hematopoietic cell transplantation (allo-HCT) patients obtained before, during and after irradiation indicated that exposure led to prolonged clot formation times, increased levels of thrombin-antithrombin III (TAT) complex and increased circulating nucleosome/histone (cNH) levels, which suggest potential coagulopathies in the allo-HCT patients. Since these allo-HCT patients received chemotherapy prior to radiotherapy, it is possible that the chemical agents could have influenced the observed results. Frozen plasma samples from radiotherapy patients with prostate, lung and breast cancer were also obtained for analyses of cNH levels. The results indicated that some of these patients had very high cNH blood levels. Analysis of cNH levels in plasma samples from irradiated ferrets also indicated increased cNH levels compared to preirradiation baseline levels. The results from irradiated animals and some radiotherapy patients suggest the possibility that anti-histone antibodies, which block the toxic effects of elevated cNH levels in the blood, might be useful as therapeutic agents for adverse biological radiation-induced effects. The detection of increased levels of cNH in some radiotherapy patient blood samples demonstrates its potential as a biomarker for diagnosing and/or predicting the propensity for developing coagulopathies/hemorrhage, offering possible treatment options with personalized medicine therapies for cancer patients.


Assuntos
Transtornos da Coagulação Sanguínea/prevenção & controle , Transtornos da Coagulação Sanguínea/terapia , Lesões por Radiação/prevenção & controle , Lesões por Radiação/terapia , Animais , Biomarcadores/sangue , Transtornos da Coagulação Sanguínea/sangue , Transtornos da Coagulação Sanguínea/patologia , Furões , Histonas/sangue , Humanos , Nucleossomos/metabolismo , Nucleossomos/efeitos da radiação , Lesões por Radiação/sangue , Lesões por Radiação/patologia
9.
Life Sci Space Res (Amst) ; 4: 11-6, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25774341

RESUMO

During a major solar particle event (SPE), astronauts in space are at risk of exposure to an increased dose of proton radiation. The whole body distribution of the absorbed SPE proton dose is inhomogeneous, and such an inhomogeneous SPE proton dose can be simulated by electron radiation. Using Yucatan minipigs as an animal model, we compared the time courses of leukocyte count changes after exposure to proton simulated SPE (pSPE) radiation or electron simulated SPE (eSPE) radiation. The results demonstrated that the time required after irradiation to reach the lowest leukocyte counts was generally comparable between the pSPE and eSPE radiation exposures. However, the leukocyte count often recovered faster after electron irradiation compared to proton irradiation at the corresponding doses. In addition, the radiation dose required to achieve comparable magnitudes of leukocyte count decrease was higher in the eSPE animals than for the pSPE animals. In conclusion, based on the magnitude of the decrease and the time required to reach the lowest leukocyte counts after irradiation, the pSPE radiation was more effective than the eSPE radiation in reducing the peripheral leukocyte counts. Lymphocytes appeared to be the most sensitive type of leukocytes in response to either type of SPE radiation. It is particularly noteworthy that following exposure to pSPE radiation at the skin doses >5 Gy, the neutrophils do not recover from the radiation damage at times up to 30 days, and the neutrophils have not recovered to their baseline levels even at 90 days post-irradiation. These results suggest a marked difference in the ability of the neutrophils to recover from pSPE radiation compared with the results observed for eSPE radiation.


Assuntos
Elétrons/efeitos adversos , Leucócitos/efeitos da radiação , Neutrófilos/efeitos da radiação , Prótons/efeitos adversos , Atividade Solar , Animais , Relação Dose-Resposta à Radiação , Meio Ambiente Extraterreno , Contagem de Leucócitos , Modelos Animais , Doses de Radiação , Radiação Ionizante , Suínos , Porco Miniatura
10.
Life Sci Space Res (Amst) ; 6: 21-8, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26256624

RESUMO

The space environment exposes astronauts to risks of acute and chronic exposure to ionizing radiation. Of particular concern is possible exposure to ionizing radiation from a solar particle event (SPE). During an SPE, magnetic disturbances in specific regions of the Sun result in the release of intense bursts of ionizing radiation, primarily consisting of protons that have a highly variable energy spectrum. Thus, SPE events can lead to significant total body radiation exposures to astronauts in space vehicles and especially while performing extravehicular activities. Simulated energy profiles suggest that SPE radiation exposures are likely to be highest in the skin. In the current report, we have used our established miniature pig model system to evaluate the skin toxicity of simulated SPE radiation exposures that closely resemble the energy and fluence profile of the September, 1989 SPE using either conventional radiation (electrons) or proton simulated SPE radiation. Exposure of animals to electron or proton radiation led to dose-dependent increases in epidermal pigmentation, the presence of necrotic keratinocytes at the dermal-epidermal boundary and pigment incontinence, manifested by the presence of melanophages in the derm is upon histological examination. We also observed epidermal hyperplasia and a reduction in vascular density at 30 days following exposure to electron or proton simulated SPE radiation. These results suggest that the doses of electron or proton simulated SPE radiation results in significant skin toxicity that is quantitatively and qualitatively similar. Radiation-induced skin damage is often one of the first clinical signs of both acute and non-acute radiation injury where infection may occur, if not treated. In this report, histopathology analyses of acute radiation-induced skin injury are discussed.


Assuntos
Meio Ambiente Extraterreno , Prótons/efeitos adversos , Exposição à Radiação/efeitos adversos , Radiação Ionizante , Pele/lesões , Pele/efeitos da radiação , Animais , Astronautas , Relação Dose-Resposta à Radiação , Exposição Ambiental/efeitos adversos , Modelos Animais , Doses de Radiação , Pigmentação da Pele/efeitos da radiação , Atividade Solar , Sistema Solar , Suínos , Porco Miniatura , Irradiação Corporal Total/efeitos adversos
11.
Life Sci Space Res (Amst) ; 4: 6-10, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26072960

RESUMO

The left anterior descending (LAD, interventricular) coronary artery provides the blood supply to the mid-region of the heart and is a major site of vessel stenosis. Changes in LAD function can have major effects on heart function. In this report, we examined the effect of electron simulated solar particle event (eSPE) radiation on LAD function in a porcine animal model. Vasodilatory responses to adenosine diphosphate (ADP; 10(−9)­10(−4) M), bradykinin (BK; 10(−11)­10(−6) M), and sodium nitroprusside (SNP; 10(−10)­10(−4) M) were assessed. The LAD arteries from Control (non-irradiated) and the eSPE (irradiated) animals were isolated and exhibited a similar relaxation response following treatment with either ADP or SNP. In contrast, a significantly reduced relaxation response to BK treatment was observed in the eSPE irradiated group, compared to the control group. These data demonstrate that simulated SPE radiation exposure alters LAD function.


Assuntos
Difosfato de Adenosina/farmacologia , Bradicinina/farmacologia , Fenômenos Fisiológicos Cardiovasculares/efeitos dos fármacos , Vasos Coronários/efeitos da radiação , Coração/efeitos da radiação , Nitroprussiato/farmacologia , Vasodilatadores/farmacologia , Animais , Elétrons/efeitos adversos , Masculino , Suínos , Porco Miniatura
12.
PLoS One ; 10(3): e0120126, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25793272

RESUMO

A major risk for astronauts during prolonged space flight is infection as a result of the combined effects of microgravity, situational and confinement stress, alterations in food intake, altered circadian rhythm, and radiation that can significantly impair the immune system and the body's defense systems. We previously reported a massive increase in morbidity with a decrease in the ability to control a bacterial challenge when mice were maintained under hindlimb suspension (HS) conditions and exposed to solar particle event (SPE)-like radiation. HS and SPE-like radiation treatment alone resulted in a borderline significant increase in morbidity. Therefore, development and testing of countermeasures that can be used during extended space missions in the setting of exposure to SPE radiation becomes a serious need. In the present study, we investigated the efficacy of enrofloxacin (an orally bioavailable antibiotic) and Granulocyte colony stimulating factor (G-CSF) (Neulasta) on enhancing resistance to Pseudomonas aeruginosa infection in mice subjected to HS and SPE-like radiation. The results revealed that treatment with enrofloxacin or G-CSF enhanced bacterial clearance and significantly decreased morbidity and mortality in challenged mice exposed to suspension and radiation. These results establish that antibiotics, such as enrofloxacin, and G-CSF could be effective countermeasures to decrease the risk of bacterial infections after exposure to SPE radiation during extended space flight, thereby reducing both the risk to the crew and the danger of mission failure.


Assuntos
Antibacterianos/farmacologia , Infecções Bacterianas/prevenção & controle , Fator Estimulador de Colônias de Granulócitos/farmacologia , Atividade Solar , Voo Espacial , Animais , Enrofloxacina , Feminino , Fluoroquinolonas/farmacologia , Camundongos
13.
Life Sci Space Res (Amst) ; 5: 13-20, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25909052

RESUMO

Astronauts could be exposed to solar particle event (SPE) radiation, which is comprised mostly of proton radiation. Proton radiation is also a treatment option for certain cancers. Both astronauts and clinical patients exposed to ionizing radiation are at risk for loss of white blood cells (WBCs), which are the body's main defense against infection. In this report, the effect of Neulasta treatment, a granulocyte colony stimulating factor, after proton radiation exposure is discussed. Mini pigs exposed to total body proton irradiation at a dose of 2 Gy received 4 treatments of either Neulasta or saline injections. Peripheral blood cell counts and thromboelastography parameters were recorded up to 30 days post-irradiation. Neulasta significantly improved WBC loss, specifically neutrophils, in irradiated animals by approximately 60% three days after the first injection, compared to the saline treated, irradiated animals. Blood cell counts quickly decreased after the last Neulasta injection, suggesting a transient effect on WBC stimulation. Statistically significant changes in hemostasis parameters were observed after proton radiation exposure in both the saline and Neulasta treated irradiated groups, as well as internal organ complications such as pulmonary changes. In conclusion, Neulasta treatment temporarily alleviates proton radiation-induced WBC loss, but has no effect on altered hemostatic responses.


Assuntos
Eritrócitos/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/farmacologia , Neutrófilos/efeitos dos fármacos , Tromboelastografia/efeitos dos fármacos , Irradiação Corporal Total/efeitos adversos , Animais , Contagem de Eritrócitos , Filgrastim , Contagem de Leucócitos , Polietilenoglicóis , Prótons/efeitos adversos , Radiação Ionizante , Proteínas Recombinantes/farmacologia , Atividade Solar , Suínos , Porco Miniatura
14.
J Radiat Res ; 55(2): 364-72, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24309720

RESUMO

The space radiation environment imposes increased dangers of exposure to ionizing radiation, particularly during a solar particle event (SPE). These events consist primarily of low energy protons that produce a highly inhomogeneous dose distribution. Due to this inherent dose heterogeneity, experiments designed to investigate the radiobiological effects of SPE radiation present difficulties in evaluating and interpreting dose to sensitive organs. To address this challenge, we used the Geant4 Monte Carlo simulation framework to develop dosimetry software that uses computed tomography (CT) images and provides radiation transport simulations incorporating all relevant physical interaction processes. We found that this simulation accurately predicts measured data in phantoms and can be applied to model dose in radiobiological experiments with animal models exposed to charged particle (electron and proton) beams. This study clearly demonstrates the value of Monte Carlo radiation transport methods for two critically interrelated uses: (i) determining the overall dose distribution and dose levels to specific organ systems for animal experiments with SPE-like radiation, and (ii) interpreting the effect of random and systematic variations in experimental variables (e.g. animal movement during long exposures) on the dose distributions and consequent biological effects from SPE-like radiation exposure. The software developed and validated in this study represents a critically important new tool that allows integration of computational and biological modeling for evaluating the biological outcomes of exposures to inhomogeneous SPE-like radiation dose distributions, and has potential applications for other environmental and therapeutic exposure simulations.


Assuntos
Modelos Biológicos , Modelos Estatísticos , Método de Monte Carlo , Radiometria/métodos , Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia de Alta Energia/métodos , Tomografia Computadorizada por Raios X/métodos , Simulação por Computador , Humanos , Aceleradores de Partículas , Dosagem Radioterapêutica
15.
Life Sci Space Res (Amst) ; 2: 86-91, 2014 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-25202654

RESUMO

NASA has funded several projects that have provided evidence for the radiation risk in space. One radiation concern arises from solar particle event (SPE) radiation, which is composed of energetic electrons, protons, alpha particles and heavier particles. SPEs are unpredictable and the accompanying SPE radiation can place astronauts at risk of blood cell death, contributing to a weakened immune system and increased susceptibility to infection. The doses, dose rates, and energies of the proton radiation expected to occur during a SPE have been simulated at the NASA Space Radiation Laboratory, Brookhaven National Laboratory, delivering total body doses to mice. Hematological values were evaluated at acute time points, up to 24 hrs. post-radiation exposure.

16.
PLoS One ; 9(1): e85665, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24454913

RESUMO

A major risk of extended space travel is the combined effects of weightlessness and radiation exposure on the immune system. In this study, we used the hindlimb suspension model of microgravity that includes the other space stressors, situational and confinement stress and alterations in food intake, and solar particle event (SPE)-like radiation to measure the combined effects on the ability to control bacterial infections. A massive increase in morbidity and decrease in the ability to control bacterial growth was observed using 2 different types of bacteria delivered by systemic and pulmonary routes in 3 different strains of mice. These data suggest that an astronaut exposed to a strong SPE during extended space travel is at increased risk for the development of infections that could potentially be severe and interfere with mission success and astronaut health.


Assuntos
Infecções por Klebsiella/imunologia , Infecções por Pseudomonas/imunologia , Lesões Experimentais por Radiação/imunologia , Infecções Respiratórias/imunologia , Estresse Psicológico/imunologia , Animais , Bacteriemia/sangue , Bacteriemia/imunologia , Corticosterona/sangue , Feminino , Elevação dos Membros Posteriores , Humanos , Imunidade Inata/efeitos da radiação , Infecções por Klebsiella/sangue , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos ICR , Peritonite/sangue , Peritonite/imunologia , Infecções por Pseudomonas/sangue , Lesões Experimentais por Radiação/sangue , Infecções Respiratórias/sangue , Atividade Solar , Voo Espacial , Estresse Psicológico/sangue
17.
J Radiat Res ; 55(2): 228-44, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24027300

RESUMO

The present study was undertaken to determine relative biological effectiveness (RBE) values for simulated solar particle event (SPE) radiation on peripheral blood cells using Yucatan minipigs and electron-simulated SPE as the reference radiation. The results demonstrated a generally downward trend in the RBE values with increasing doses of simulated SPE radiation for leukocytes in the irradiated animals. The fitted RBE values for white blood cells (WBCs), lymphocytes, neutrophils, monocytes and eosinophils were above 1.0 in all three radiation dose groups at all time-points evaluated, and the lower limits of the 95% confidence intervals were > 1.0 in the majority of the dose groups at different time-points, which together suggest that proton-simulated SPE radiation is more effective than electron-simulated SPE radiation in reducing the number of peripheral WBCs, lymphocytes, neutrophils, monocytes and eosinophils, especially at the low end of the 5-10 Gy dose range evaluated. Other than the RBE values, the responses of leukocytes to electron-simulated SPE radiation and proton-simulated SPE radiation exposure are highly similar with respect to the time-course, the most radiosensitive cell type (the lymphocytes), and the shape of the dose-response curves, which is generally log-linear. These findings provide additional evidence that electron-simulated SPE radiation is an appropriate reference radiation for determination of RBE values for the simulated SPE radiations, and the RBE estimations using electron-simulated SPE radiation as the reference radiation are not complicated by other characteristics of the leukocyte response to radiation exposure.


Assuntos
Leucócitos Mononucleares/fisiologia , Leucócitos Mononucleares/efeitos da radiação , Prótons , Tolerância a Radiação/fisiologia , Energia Solar , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas , Relação Dose-Resposta à Radiação , Leucócitos Mononucleares/citologia , Doses de Radiação , Eficiência Biológica Relativa , Suínos , Porco Miniatura
18.
PLoS One ; 9(6): e100800, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24959865

RESUMO

The skin serves multiple functions that are critical for life. The protection from pathogens is achieved by a complicated interaction between aggressive effectors and controlling functions that limit damage. Inhomogeneous radiation with limited penetration is used in certain types of therapeutics and is experienced with exposure to solar particle events outside the protection of the Earth's magnetic field. This study explores the effect of ionizing radiation on skin immune function. We demonstrate that radiation, both homogeneous and inhomogeneous, induces inflammation with resultant specific loss of regulatory T cells from the skin. This results in a hyper-responsive state with increased delayed type hypersensitivity in vivo and CD4+ T cell proliferation in vitro. The effects of inhomogeneous radiation to the skin of astronauts or as part of a therapeutic approach could result in an unexpected enhancement in skin immune function. The effects of this need to be considered in the design of radiation therapy protocols and in the development of countermeasures for extended space travel.


Assuntos
Lesões Experimentais por Radiação/imunologia , Pele/efeitos da radiação , Linfócitos T Reguladores/efeitos da radiação , Animais , Linfócitos T CD4-Positivos/patologia , Proliferação de Células/efeitos da radiação , Feminino , Masculino , Camundongos Endogâmicos ICR , Radiação Ionizante , Suínos
19.
J Radiat Res ; 55(5): 855-61, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24855043

RESUMO

The space radiation environment imposes increased dangers of exposure to ionizing radiation, particularly during a solar particle event. These events consist primarily of low-energy protons that produce a highly inhomogeneous depth-dose distribution. Here we describe a novel technique that uses pencil beam scanning at extended source-to-surface distances and range shifter (RS) to provide robust but easily modifiable delivery of simulated solar particle event radiation to large animals. Thorough characterization of spot profiles as a function of energy, distance and RS position is critical to accurate treatment planning. At 105 MeV, the spot sigma is 234 mm at 4800 mm from the isocentre when the RS is installed at the nozzle. With the energy increased to 220 MeV, the spot sigma is 66 mm. At a distance of 1200 mm from the isocentre, the Gaussian sigma is 68 mm and 23 mm at 105 MeV and 220 MeV, respectively, when the RS is located on the nozzle. At lower energies, the spot sigma exhibits large differences as a function of distance and RS position. Scan areas of 1400 mm (superior-inferior) by 940 mm (anterior-posterior) and 580 mm by 320 mm are achieved at the extended distances of 4800 mm and 1200 mm, respectively, with dose inhomogeneity <2%. To treat large animals with a more sophisticated dose distribution, spot size can be reduced by placing the RS closer than 70 mm to the surface of the animals, producing spot sigmas below 6 mm.


Assuntos
Radiação Cósmica , Radiometria/instrumentação , Radiometria/veterinária , Energia Solar , Irradiação Corporal Total/instrumentação , Irradiação Corporal Total/veterinária , Elétrons , Desenho de Equipamento , Análise de Falha de Equipamento , Humanos , Prótons , Doses de Radiação , Reprodutibilidade dos Testes , Espalhamento de Radiação , Sensibilidade e Especificidade
20.
Int J Radiat Biol ; 89(10): 823-31, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23651328

RESUMO

PURPOSE: To determine the mechanism of proton radiation- induced coagulopathy. MATERIAL AND METHODS: Ferrets were exposed to either solar particle event (SPE)-like proton radiation at a predetermined dose rate of 0.5 Gray (Gy) per hour (h) for a total dose of 0 or 1 Gy. Blood was collected pre- and post-irradiation for a complete blood cell count or a soluble fibrin concentration analysis, to determine whether coagulation activation had occurred. Tissue was stained with an anti-fibrinogen antibody to confirm the presence of fibrin in blood vessels. RESULTS: SPE-like proton radiation exposure resulted in coagulation cascade activation, as determined by increased soluble fibrin concentration in blood from 0.7-2.4 at 3 h, and 9.9 soluble fibrin units (p < 0.05) at 24 h post-irradiation and fibrin clots in blood vessels of livers, lungs and kidneys from irradiated ferrets. In combination with this increase in fibrin clots, ferrets had increased prothrombin time and partial thromboplastin time values post-irradiation, which are representative of the extrinsic/intrinsic coagulation pathways. Platelet counts remained at pre-irradiation values over the course of 7 days, indicating that the observed effects were not platelet-related, but instead likely to be due to radiation-induced effects on secondary hemostasis. White blood cell (WBC) counts were reduced in a statistically significant manner from 24 h through the course of the seven-day experiment. CONCLUSIONS: SPE-like proton radiation results in significant decreases in all WBC counts as well as activates secondary hemostasis; together, these data suggest severe risks to astronaut health from exposure to SPE radiation.


Assuntos
Coagulação Sanguínea/efeitos da radiação , Furões , Prótons/efeitos adversos , Animais , Contagem de Células Sanguíneas , Coagulação Sanguínea/efeitos dos fármacos , Fator IX/farmacologia , Fibrina/química , Fibrina/metabolismo , Atividade Solar , Solubilidade , Vitamina K 1/farmacologia
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