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Huff, Janice L.

Publications and source records attributed to Huff, Janice L..

At least 19 records
All sourcesNASA NTRSDOE OSTI
NASA NTRS2019

Mitigation Strategies for Space Radiation Health Risks

Astronauts embarking on missions beyond low Earth orbit (LEO) will be exposed to a radiation field that may increase the risks of developing cancer, cardiovascular diseases, central nervous system disorders, and immune decrements. Operational parameters will be the primary determinants of crew radiation exposure. NASA uses integrated design tools and risk models to optimize these parameters to minimize radiation exposure. NASA is also considering medical countermeasures (MCMs) to reduce radiation-associated health risks. MCMs for potential use in space-based applications can be developed from a variety of sources, including: a) population-based chemoprevention trials against targeted diseases b) drug development efforts focused on treating acute effects from accidental radiation exposures c) drug development to mitigate side effects of radiotherapy d) mechanistic studies of distinct damage caused by high charge (Z) and energy (HZE) radiation. Use of agents developed for other applications, or repurposed, is advantageous because long-term safety in humans is already established.

Huff, Janice L.↗
NASA NTRS2017

Cancer Risk in Astronauts: A Constellation of Uncommon Consequences

Excess cancers resulting from external radiation exposures have been noted since the early 1950s, when a rise in leukemia rates was first reported in young atomic bomb survivors [1]. Further studies in atomic bomb survivors, cancer patients treated with radiotherapy, and nuclear power plant workers have confirmed that radiation exposure increases the risk of not only leukemia, but also a wide array of solid cancers [2,3]. NASA has long been aware of this risk and limits astronauts' risk of exposure-induced death (REID) from cancer by specifying permissible mission durations (PMD) for astronauts on an individual basis. While cancer is present among astronauts, current data does not suggest any excess of known radiation-induced cancers relative to a comparable population of U.S. adults; however, very uncommon cancers have been diagnosed in astronauts including nasopharyngeal cancer, lymphoma of the brain, and acral myxoinflammatory fibroblastic sarcoma. In order to study cancer risk in astronauts, a number of obstacles must be overcome. Firstly, several factors make the astronaut cohort considerably different from the cohorts that have previously been studied for effects resulting from radiation exposure. The high rate of accidents and the much healthier lifestyle of astronauts compared to the U.S. population make finding a suitable comparison population a problematic task. Space radiation differs substantially from terrestrial radiation exposures studied in the past; therefore, analyses of galactic cosmic radiation (GCR) in animal models must be conducted and correctly applied to the human experience. Secondly, a large enough population of exposed astronauts must exist in order to obtain the data necessary to see any potential statistically significant differences between the astronauts and the control population. Thirdly, confounders and effect modifiers, such as smoking, diet, and other space stressors, must be correctly identified and controlled for in those analyses. In order to begin work assessing the astronaut population, the earliest groups of astronauts (selection groups 1-7) provide a unique model. These astronauts were relatively homogenous, white males whose lifestyle characteristics were similar to an average U.S. citizen of the same birth cohort. This work reviews radiation exposure levels, age, and causes of mortality among these early NASA astronauts and discusses the benefits and limitations of assessing such a cohort for radiation-induced cancer risk.

Milder, Caitlin M.↗
NASA NTRS2016

Evidence Report: Risk of Acute and Late Central Nervous System Effects from Radiation Exposure

Possible acute and late risks to the central nervous system (CNS) from galactic cosmic rays (GCR) and solar particle events (SPE) are concerns for human exploration of space. Acute CNS risks may include: altered cognitive function, reduced motor function, and behavioral changes, all of which may affect performance and human health. Late CNS risks may include neurological disorders such as Alzheimer's disease (AD), dementia and premature aging. Although detrimental CNS changes are observed in humans treated with high-dose radiation (e.g., gamma rays and 9 protons) for cancer and are supported by experimental evidence showing neurocognitive and behavioral effects in animal models, the significance of these results on the morbidity to astronauts has not been elucidated. There is a lack of human epidemiology data on which to base CNS risk estimates; therefore, risk projection based on scaling to human data, as done for cancer risk, is not possible for CNS risks. Research specific to the spaceflight environment using animal and cell models must be compiled to quantify the magnitude of CNS changes in order to estimate this risk and to establish validity of the current permissible exposure limits (PELs). In addition, the impact of radiation exposure in combination with individual sensitivity or other space flight factors, as well as assessment of the need for biological/pharmaceutical countermeasures, will be considered after further definition of CNS risk occurs.

Nelson, Gregory A.↗
NASA NTRS2015

An Overview of NASA's Risk of Cardiovascular Disease from Radiation Exposure

The association between high doses of radiation exposure and cardiovascular damage is well established. Patients that have undergone radiotherapy for primary cancers of the head and neck and mediastinal regions have shown increased risk of heart and vascular damage and long-term development of radiation-induced heart disease [1]. In addition, recent meta-analyses of epidemiological data from atomic bomb survivors and nuclear industry workers has also shown that acute and chronic radiation exposures is strongly correlated with an increased risk of circulatory disease at doses above 0.5 Sv [2]. However, these analyses are confounded for lower doses by lifestyle factors, such as drinking, smoking, and obesity. The types of radiation found in the space environment are significantly more damaging than those found on Earth and include galactic cosmic radiation (GCR), solar particle events (SPEs), and trapped protons and electrons. In addition to the low-LET data, only a few studies have examined the effects of heavy ion radiation on atherosclerosis, and at lower, space-relevant doses, the association between exposure and cardiovascular pathology is more varied and unclear. Understanding the qualitative differences in biological responses produced by GCR compared to Earth-based radiation is a major focus of space radiation research and is imperative for accurate risk assessment for long duration space missions. Other knowledge gaps for the risk of radiation-induced cardiovascular disease include the existence of a dose threshold, low dose rate effects, and potential synergies with other spaceflight stressors. The Space Radiation Program Element within NASA's Human Research Program (HRP) is managing the research and risk mitigation strategies for these knowledge gaps. In this presentation, we will review the evidence and present an overview of the HRP Risk of Cardiovascular Disease and Other Degenerative Tissue Effects from Radiation Exposure.

Patel, Zarana S.↗
NASA NTRS2015

Evidence Report: Risk of Acute and Late Central Nervous System Effects from Radiation Exposure

Possible acute and late risks to the central nervous system (CNS) from galactic cosmic rays (GCR) and solar particle events (SPE) are a documented concern for human exploration of space. Acute CNS risks include: altered cognitive function, reduced motor function, and behavioral changes, all of which may affect performance and human health. Late CNS risks include neurological disorders such as Alzheimer's disease (AD), dementia and premature aging. Although detrimental CNS changes are observed in humans treated with high-dose radiation (e.g., gamma rays and protons) for cancer and are supported by experimental evidence showing neurocognitive and behavioral effects in animal models, the significance of these results on the morbidity to astronauts has not been elucidated. There is a lack of human epidemiology data on which to base CNS risk estimates; therefore, risk projection based on scaling to human data, as done for cancer risk, is not possible for CNS risks. Research specific to the spaceflight environment using animal and cell models must be compiled to quantify the magnitude of CNS changes in order to estimate this risk and to establish validity of the current permissible exposure limits (PELs). In addition, the impact of radiation exposure in combination with individual sensitivity or other space flight factors, as well as assessment of the need for biological/pharmaceutical countermeasures, will be considered after further definition of CNS risk occurs.

Nelson, Gregory A.↗
NASA NTRS2014

Development of an Autonomous, Dual Chamber Bioreactor for the Growth of 3-Dimensional Epithelial-Stromal Tissues in Microgravity

We are developing a novel, autonomous bioreactor that can provide for the growth and maintenance in microgravity of 3‐D organotypic epithelial‐stromal cultures that require an air‐liquid interface. These complex 3‐D tissue models accurately represent the morphological features, differentiation markers, and growth characteristics observed in normal human epithelial tissues, including the skin, esophagus, lung, breast, pancreas, and colon. However, because of their precise and complex culture requirements, including that of an air‐liquid interface, these 3‐D models have yet to be utilized for life sciences research aboard the International Space Station. The development of a bioreactor for these cultures will provide the capability to perform biological research on the ISS using these realistic, tissue‐like human epithelial‐stromal cell models and will contribute significantly to advances in fundamental space biology research on questions regarding microgravity effects on normal tissue development, aging, cancer, and other disease processes. It will also allow for the study of how combined stressors, such as microgravity with radiation and nutritional deficiencies, affect multiple biological processes and will provide a platform for conducting countermeasure investigations on the ISS without the use of animal models. The technology will be autonomous and consist of a cell culture chamber that provides for air‐liquid, liquid‐liquid, and liquid‐air exchanges within the chambers while maintaining the growth and development of the biological samples. The bioreactor will support multiple tissue types and its modular design will provide for incorporation of add‐on capabilities such as microfluidics drug delivery, media sampling, and in situ biomarker analysis. Preliminary flight testing of the hardware will be conducted on a parabolic platform through NASA's Flight Opportunities Program.

Patel, Zarana S.↗
NASA NTRS2014

Space Radiation and Risks to Human Health

The radiation environment in space poses significant challenges to human health and is a major concern for long duration manned space missions. Outside the Earth's protective magnetosphere, astronauts are exposed to higher levels of galactic cosmic rays, whose physical characteristics are distinct from terrestrial sources of radiation such as x‐rays and gamma‐rays. Galactic cosmic rays consist of high energy and high mass nuclei as well as high energy protons; they impart unique biological damage as they traverse through tissue with impacts on human health that are largely unknown. The major health issues of concern are the risks of radiation carcinogenesis, acute and late decrements to the central nervous system, degenerative tissue effects such as cardiovascular disease, as well as possible acute radiation syndromes due to an unshielded exposure to a large solar particle event. The NASA Human Research Program's Space Radiation Program Element is focused on characterization and mitigation of these space radiation health risks along with understanding these risks in context of the other biological stressors found in the space environment. In this overview, we will provide a description of these health risks and the Element's research strategies to understand and mitigate these risks.

Huff, Janice L.↗
NASA NTRS2014

Radiation Quality Effects on Transcriptome Profiles in 3-D Cultures After Charged Particle Irradiation

In this work, we evaluated the differential effects of low- and high-LET radiation on 3-D organotypic cultures in order to investigate radiation quality impacts on gene expression and cellular responses. Current risk models for assessment of space radiation-induced cancer have large uncertainties because the models for adverse health effects following radiation exposure are founded on epidemiological analyses of human populations exposed to low-LET radiation. Reducing these uncertainties requires new knowledge on the fundamental differences in biological responses (the so-called radiation quality effects) triggered by heavy ion particle radiation versus low-LET radiation associated with Earth-based exposures. In order to better quantify these radiation quality effects in biological systems, we are utilizing novel 3-D organotypic human tissue models for space radiation research. These models hold promise for risk assessment as they provide a format for study of human cells within a realistic tissue framework, thereby bridging the gap between 2-D monolayer culture and animal models for risk extrapolation to humans. To identify biological pathway signatures unique to heavy ion particle exposure, functional gene set enrichment analysis (GSEA) was used with whole transcriptome profiling. GSEA has been used extensively as a method to garner biological information in a variety of model systems but has not been commonly used to analyze radiation effects. It is a powerful approach for assessing the functional significance of radiation quality-dependent changes from datasets where the changes are subtle but broad, and where single gene based analysis using rankings of fold-change may not reveal important biological information.

Patel, Zarana S.↗
NASA NTRS2014

Space Radiation and Risks to Human Health

The radiation environment in space poses significant challenges to human health and is a major concern for long duration manned space missions. Outside the Earth's protective magnetosphere, astronauts are exposed to higher levels of galactic cosmic rays, whose physical characteristics are distinct from terrestrial sources of radiation such as x‐rays and gamma‐rays. Galactic cosmic rays consist of high energy and high mass nuclei as well as high energy protons; they impart unique biological damage as they traverse through tissue with impacts on human health that are largely unknown. The major health issues of concern are the risks of radiation carcinogenesis, acute and late decrements to the central nervous system, degenerative tissue effects such as cardiovascular disease, as well as possible acute radiation syndromes due to an unshielded exposure to a large solar particle event. The NASA Human Research Program's Space Radiation Program Element is focused on characterization and mitigation of these space radiation health risks along with understanding these risks in context of the other biological stressors found in the space environment. In this overview, we will provide a description of these health risks and the Element's research strategies to understand and mitigate these risks.

Huff, Janice L.↗
NASA NTRS2010

Influence of Ionizing Radiation on Stromal-Epithelial Intercellular Communication in Esophageal Carcinogenesis

Esophageal cancer is the 6th leading cause of cancer death worldwide. Its development is associated with a variety of risk factors including tobacco use, heavy alcohol consumption, human papilloma virus infection, and certain dietary factors such as trace mineral and vitamin deficiencies. An association with ionizing radiation exposure is revealed by the high excess relative risk for squamous cell carcinoma of the esophagus observed in the survivors of the atomic bomb detonations in Japan. It is also seen as a secondary malignancy in patients who received radiotherapy for breast and thoracic cancers; additionally, patients with head/neck and oral squamous cell cancers are at increased risk for metachronous esophageal squamous cell cancers. This malignancy is rapidly fatal, mainly because it remains asymptomatic until late, advanced stages when the disease is rarely curable. The stromal microenvironment plays an essential role in the maintenance and modulation of normal epithelial cell growth and differentiation and cross talk between the epithelial and stromal compartments can influence many aspects of malignant progression, including tumor cell proliferation, migration, invasion and recruitment of new blood vessels. To test the hypothesis that radiation exposure plays a role in esophageal carcinogenesis via non-targeted mechanisms involving stromal-epithelial cell communication, we are studying radiation effects on hTERT-immortalized human esophageal epithelial cells and genetic variants grown in co-culture with human esophageal stromal fibroblasts (Okawa et al., Genes & Dev. 2007. 21: 2788-2803). We examined how radiation treatment of stromal fibroblasts affected epithelial migration and invasion, behaviors associated with cancer promotion and progression. Chemotactic and haptotactic migration of epithelial cells stimulated by conditioned media from irradiated fibroblasts was measured using assays conducted in Transwell cell culture chambers. Our results using low LET radiation showed a dose-dependent increase in migration of epithelial cells when exposed to conditioned media from irradiated vs. non-irradiated fibroblasts. We also observed enhanced invasion through a basement membrane simulant. To identify chemotactic proteins secreted by irradiated stromal fibroblasts, we used antibody capture cytokine arrays and have identified several proteins as candidates. Increased secretion of these factors by irradiated fibroblasts was confirmed using ELISA. We are currently analyzing the contribution of these individual factors on epithelial migration and invasion, as well as their influence on cell survival and DNA repair. Studies using high-LET radiation will help determine radiation quality effects on these processes. These results should further our understanding of the mechanisms by which radiation impacts the tissue microenvironment and how it influences cancer development processes.

Patel, Zarana S.↗
NASA NTRS2010

Pathway Model of the Kinetics of the TGFbeta Antagonist Smad7 and Cross-Talk with the ATM and WNT Pathways

Signal transduction controls cellular and tissue responses to radiation. Transforming growth factor beta (TGFbeta) is an important regulator of cell growth and differentiation and tissue homeostasis, and is often dis-regulated in tumor formation. Mathematical models of signal transduction pathways can be used to elucidate how signal transduction varies with radiation quality, and dose and dose-rate. Furthermore, modeling of tissue specific responses can be considered through mechanistic based modeling. We developed a mathematical model of the negative feedback regulation by Smad7 in TGFbeta-Smad signaling and are exploring possible connections to the WNT/beta -catenin, and ATM/ATF2 signaling pathways. A pathway model of TGFbeta-Smad signaling that includes Smad7 kinetics based on data in the scientific literature is described. Kinetic terms included are TGFbeta/Smad transcriptional regulation of Smad7 through the Smad3-Smad4 complex, Smad7-Smurf1 translocation from nucleus to cytoplasm, and Smad7 negative feedback regulation of the TGFO receptor through direct binding to the TGFO receptor complex. The negative feedback controls operating in this pathway suggests non-linear responses in signal transduction, which are described mathematically. We then explored possibilities for cross-talk mediated by Smad7 between DNA damage responses mediated by ATM, and with the WNT pathway and consider the design of experiments to test model driven hypothesis. Numerical comparisons of the mathematical model to experiments and representative predictions are described.

Carra, Claudio↗
NASA NTRS2008

A Human Espophageal Epithelial Cell Model for Study of Radiation Induced Cancer and DNA Damage Repair

For cancer risk assessment in astronauts and for countermeasure development, it is essential to understand the molecular mechanisms of radiation carcinogenesis and how these mechanisms are influenced by exposure to the types of radiation found in space. We are developing an in vitro model system for the study of radiation-induced initiation and progression of esophageal carcinoma, a type of cancer found to have a significant enhancement in incidence in the survivors of the atomic bomb detonations in Japan. Here we present the results of our preliminary characterization of both normal and hTERT immortalized esophageal epithelial cells grown in 2-dimensional culture. We analyzed DNA repair capacity by measuring the kinetics of formation and loss of - H2AX foci following radiation exposure. Additionally, we analyzed induction of chromosomal aberrations using 3-color fluorescence in situ hybridization (FISH). Data were generated using both low LET (gamma rays) and high LET ions (1000 MeV/nucleon iron).

Huff, Janice L.↗
NASA NTRS2007

High-LET Patterns of DSBs in DNA Loops, the HPRT Gene and Phosphorylation Foci

We present new results obtained with our model based on the track structure and chromatin geometry that predicts the DSB spatial and genomic distributions in a cell nucleus with the full genome represented. The model generates stochastic patterns of DSBs in the physical space of the nucleus filled with the realistic configuration of human chromosomes. The model was re-used to find the distribution of DSBs in a physical volume corresponding to a visible phosphorylation focus believed to be associated with a DSB. The data shows whether there must more than one DSB per foci due to finite size of the visible focus, even if a single DSB is radiochemically responsible for the phosphorylation of DNA in its vicinity. The same model can predict patterns of closely located DSBs in a given gene, or in a DNA loop, one of the large-scale chromatin structures. We demonstrated for the example of the HPRT gene, how different sorts of radiation lead to proximity effect in DSB locations, which is important for modeling gene deletions. The spectrum of intron deletions and total gene deletions was simulated for the HPRT gene. The same proximity effect of DSBs in a loop can hinder DSB restitutions, as parts of the loop between DSBs is deleted with a higher likelihood. The distributions of DSBs and deletions of DNA in a loop are presented.

Ponomarev, Artem L.↗
NASA NTRS2007

Three-dimensional Model of Tissue and Heavy Ions Effects

A three-dimensional tissue model was incorporated into a new Monte Carlo algorithm that simulates passage of heavy ions in a tissue box . The tissue box was given as a realistic model of tissue based on confocal microscopy images. The action of heavy ions on the cellular matrix for 2- or 3-dimensional cases was simulated. Cells were modeled as a cell culture monolayer in one example, where the data were taken directly from microscopy (2-d cell matrix), and as a multi-layer obtained from confocal microscopy (3-d case). Image segmentation was used to identify cells with precise areas/volumes in an irradiated cell culture monolayer, and slices of tissue with many cell layers. The cells were then inserted into the model box of the simulated physical space pixel by pixel. In the case of modeled tissues (3-d), the tissue box had periodic boundary conditions imposed, which extrapolates the technique to macroscopic volumes of tissue. For the real tissue (3-d), specific spatial patterns for cell apoptosis and necrosis are expected. The cell patterns were modeled based on action cross sections for apoptosis and necrosis estimated from current experimental data. A spatial correlation function indicating a higher spatial concentration of damaged cells from heavy ions relative to the low-LET radiation cell damage pattern is presented. The spatial correlation effects among necrotic cells can help studying microlesions in organs, and probable effects of directionality of heavy ion radiation on epithelium and endothelium.

Ponomarev, Artem L.↗