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All sourcesNASA NTRSDOE OSTI
DOE OSTI2017

Large-Eddy Simulation of Shallow Cumulus over Land: A Composite Case Based on ARM Long-Term Observations at Its Southern Great Plains Site

Based on long-term observations by the Atmospheric Radiation Measurement program at its Southern Great Plains site, a new composite case of continental shallow cumulus (ShCu) convection is constructed for large-eddy simulations (LES) and single-column models. The case represents a typical daytime nonprecipitating ShCu whose formation and dissipation are driven by the local atmospheric conditions and land surface forcing and are not influenced by synoptic weather events. The case includes early morning initial profiles of temperature and moisture with a residual layer; diurnally varying sensible and latent heat fluxes, which represent a domain average over different land surface types; simplified large-scale horizontal advective tendencies and subsidence; and horizontal winds with prevailing direction and average speed. Observed composite cloud statistics are provided for model evaluation. The observed diurnal cycle is well reproduced by LES; however, the cloud amount, liquid water path, and shortwave radiative effect are generally underestimated. LES are compared between simulations with an all-or-nothing bulk microphysics and a spectral bin microphysics. The latter shows improved agreement with observations in the total cloud cover and the amount of clouds with depths greater than 300 m. When compared with radar retrievals of in-cloud air motion, LES produce comparable downdraft vertical velocities, but a larger updraft area, velocity, and updraft mass flux. Both observations and LES show a significantly larger in-cloud downdraft fraction and downdraft mass flux than marine ShCu.

58 GEOSCIENCES↗
DOE OSTI2023

Radiative cooling effects on reverse shocks formed by magnetized supersonic plasma flows

We study the structure of reverse shocks formed by the collision of supersonic, magnetized plasma flows driven by an inverse (or exploding) wire array with a planar conducting obstacle. We observe that the structure of these reverse shocks varies dramatically with wire material, despite the similar upstream flow velocities and mass densities. For aluminum wire arrays, the shock is sharp and well-defined, consistent with magneto-hydrodynamic theory. In contrast, we do not observe a well-defined shock using tungsten wires, and instead we see a broad region dominated by density fluctuations on a wide range of spatial scales. We diagnose these two very different interactions using interferometry, Thomson scattering, shadowgraphy, and a newly developed imaging refractometer that is sensitive to small deflections of the probing laser corresponding to small-scale density perturbations. We conclude that the differences in shock structure are most likely due to radiative cooling instabilities, which create small-scale density perturbations elongated along magnetic field lines in the tungsten plasma. These instabilities grow more slowly and are smoothed by thermal conduction in the aluminum plasma.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗
NASA NTRS2017

Atmospheric Collapse on Early Mars: The Role of CO2 Clouds

The abundance of evidence that liquid water flowed on the surface early in Mars' history strongly implies that the early Martian atmosphere was significantly more massive than it is today. While it seems clear that the total CO2 inventory was likely substantially larger in the past, the fundamental question about the physical state of that CO2 is not completely understood. Because the temperature at which CO2 condenses increases with surface pressure, surface CO2 ice is more likely to form and persist as the atmospheric mass increases. For the atmosphere to remain stable against collapse, there must be enough energy, distributed planet wide, to stave off the formation of permanent CO2 caps that leads to atmospheric collapse. The presence of a "faint young sun" that was likely about 25 percent less luminous 3.8 billion years ago than the sun today makes this even more difficult. Several physical processes play a role in the ultimate stability of a CO2 atmosphere. The system is regulated by the energy balance between solar insolation, the radiative effects of the atmosphere and its constituents, atmospheric heat transport, heat exchange between the surface and the atmosphere, and latent heating/cooling. Specific considerations in this balance for a given orbital obliquity/eccentricity and atmospheric mass are the albedo of the caps, the dust content of the atmosphere, and the presence of water and/or CO2 clouds. Forget et al. show that, for Mars' current obliquity (in a circular orbit), CO2 atmospheres ranging in surface pressure from 500 hectopascals to 3000 hectopascals would have been stable against collapsing into permanent surface ice reservoirs. Soto et al. examined a similar range in initial surface pressure to investigate atmospheric collapse and to compute collapse rates. CO2 clouds and their radiative effects were included in Forget et al. but they were not included in Soto et al. Here we focus on how CO2 clouds affect the stability of the atmosphere against collapse.

Kahre, M. A.↗
NASA NTRS1972

Geomagnetic field distortions and their effects on radiation belt particles.

One of the quadrupole terms in the main geomagnetic field is found to contribute to a north-south 'shear distortion' of the particle-drift shells, whereas one of the octupole components causes a longitude-dependent radial deformation and associated 'drift-shell splitting.' The collective action of all higher multipoles on trapped-particle motion is then used to analyze the 'true' anomalies or distortions of the internal geomagnetic field that are independent of the quadrupole-related eccentricity of the main dipole. These 'true' anomalies must originate in upper-mantle or crustal perturbations that lie relatively near the earth's surface on both sides of the mid-Atlantic ridge; they influence trapped-particle drift shells only where the latter have their closest approach to the earth (South Atlantic and South African areas). The quadrupole and octupole perturbations, on the other hand, obviously originate deep in the earth's core. In the final part of this review, we discuss the effects of external magnetospheric currents. A time-dependent symmetric ring current causes drift shells to be displaced radially, with associated particle acceleration; magnetopause currents introduce a day-night asymmetry, causing shell splitting.

Roederer, J. G.↗
NASA NTRS1963

Metal whiskers

Metal whiskers - induced growth, growth mechanism, energy sources for growth, magnetic properties, and radiation effects

WHISKER↗
NASA NTRS2018

Aerosol-Radiation-Cloud Interactions in the South-East Atlantic: Model-Relevant Observations and the Beneficiary Modeling Efforts in the Realm of the EVS-2 Project ORACLES

Globally, aerosols remain a major contributor to uncertainties in assessments of anthropogenically-induced changes to the Earth climate system, despite concerted efforts using satellite and suborbital observations and increasingly sophisticated models. The quantification of direct and indirect aerosol radiative effects, as well as cloud adjustments thereto, even at regional scales, continues to elude our capabilities. Some of our limitations are due to insufficient sampling and accuracy of the relevant observables, under an appropriate range of conditions to provide useful constraints for modeling efforts at various climate scales. In this talk, I will describe (1) the efforts of our group at NASA Ames to develop new airborne instrumentation to address some of the data insufficiencies mentioned above; (2) the efforts by the EVS-2 ORACLES project to address aerosol-cloud-climate interactions in the SE Atlantic and (3) time permitting, recent results from a synergistic use of A-Train aerosol data to test climate model simulations of present-day direct radiative effects in some of the AEROCOM phase II global climate models.

Redemann, Jens↗
NASA NTRS2018

Results from ORACLES-2016: Observed Biomass Burning Aerosol Properties over the Southeast Atlantic Ocean and the Relationship to Meteorology

The Southeast Atlantic Ocean (SEA), with seasonal biomass burning (BB) smoke plumes overlying persistent stratocumulus cloud deck, offers an excellent natural laboratory to make the observations necessary to understand the complexities of aerosol-cloud-radiation interactions. The first field deployment of the NASA ORACLES (ObseRvations of Aerosols above CLouds and their intEractionS) campaign was conducted in September of 2016 out of Walvis Bay, Namibia. During this deployment, two NASA aircraft (a P-3 and an ER-2) were flown with a suite of aerosol, cloud, radiation, and meteorological instruments for remote-sensing and in-situ observations. In this talk, I will first present results from an intercomparison of the different instrument retrievals for the 2016 flights, with a specific focus on the measures of aerosol absorption. In ORACLES, data collected by eight different instrument teams are used to derive aerosol properties over this region by independent methods. We focus on the single scattering albedo (SSA), a measure of the relative absorption versus total extinction by aerosols, as the main comparable property between all methods. I will also discuss comparisons of the retrieved aerosol absorption parameters, as well as the agreement and the variability seen between different instruments, and spatially over the study region. Another important factor in understanding aerosol radiative effects is how the magnitude of these effects may be modified by meteorological conditions. I will next describe observations collected from the P-3 aircraft (from near-surface up to 6-7 kilometers) which show a strong correlation between the in-situ pollution indicators (carbon monoxide and aerosol properties) and atmospheric water vapor content, seen at all altitudes above the boundary layer. This condition is seen to persist over all flights, with minimal detrainment during advection from the continental source. In exploring the potential causal factors behind and implications of this relationship, we see indications that convective dynamics over the continent likely contribute to this elevated signal, but neither meteorological reanalysis nor trajectory analysis fully capture the magnitude and vertical structure of the observed elevated signal. Finally, I will discuss the radiative implications of the observed correlations, a topic of ongoing analysis in ORACLES: understanding the mechanisms which cause water vapor to covary with plume strength is important to quantifying the radiative effects (direct and semi-direct) of biomass burning aerosol in the region.

Pistone, Kristina↗
NASA NTRS2017

Studying the Effect of Radiation in the Context of Deep Space Travel

While it has been shown that decades of astronauts and cosmonauts can suffer from illnesses both during and after spaceflight, the underlying causes are still poorly understood, due in part to the fact that there are so many variables to consider when investigating the human immune system in a complex environment. Invertebrates have become popular models for studying human disease because they are cheap, highly amenable to experimental manipulation, and have innate immune systems with a high genetic similarity to humans. Fruit flies (Drosophila melanogaster) have been shown to experience a dramatic shift in immune gene expression following spaceflight, but are still able to fight off infections when exposed to bacteria. However, the common bacterial pathogen Serratia marcescens was shown to become more lethal to fruit flies after being cultured in space, suggesting that not only do we need to consider host changes in susceptibility, but also changes in the pathogen itself after spaceflight conditions. Being able to simulate spaceflight conditions in a controlled environment on the ground gives us the ability to not only evaluate the effects of microgravity on the host immune system, but also how the microorganisms that cause immune disorders are being affected by these drastic environmental shifts. In this study, I use a ground-based simulated microgravity environment to examine the genetic changes associated with increased S. marcescens virulence in order to understand how microgravity is affecting this pathogen, as well as how these genetic changes influence and interact with the host immune system. This study will provide us with more directed approaches to studying the effects of spaceflight on human beings, with the ultimate goal of being able to counteract immune dysfunction in future space exploration.

Bhattacharya, Sharmila↗
DOE OSTI2023

Characterization of radiation damage effects in high-energy neutrino target graphite using low-energy ions

Exposure of graphite targets to high intensity proton beams at neutrino production facilities causes changes in the target material that can result in a shortened operation lifetime. The dominant factors in this process are currently thought to be mechanical in nature resulting primarily from microstructural effects that lead to thermal and structural changes in bulk material properties. As currently planned beam facilities with increased proton energy and intensity begin to come online it will be important to thoroughly understand these processes, and ideally to be able to predict the effects of new beam designs on target properties. Direct analysis of targets exposed to existing high-energy proton beams is complicated by several factors, such as very limited access to proton beam facilities, high associated costs, irradiation times on the order of months, and the resulting radioactivity of irradiated samples that requires special facilities for post-irradiation examination. Much of the existing literature concerning irradiation damage in graphite has been focused on the needs of the nuclear engineering community, however high-energy proton targets operate in a much different environment. In comparison to graphite irradiated in a nuclear reactor, graphite used in proton beam targets receives a higher dose rate, have greater gas production, and experience short irradiation pulses as opposed to continuous irradiation. Low-energy ion irradiation offers a method of inducing similar levels of radiation damage to high-energy protons while avoiding many of the difficulties and limitations associated with high-energy proton beams and the corresponding activated specimen testing. My research described in this thesis focused on investigating how low-energy ion irradiation could be used to induce the same or similar types of microstructural alteration and mechanical property degradation as that seen in high-energy neutrino production target graphites by varying damage le vels and irradiation temperatures prior to post-irradiation characterisation.

43 PARTICLE ACCELERATORS↗
NASA NTRSDate not supplied

Chimeric Mouse Models for Space Radiation Risk Investigations

Assessment of human health risks associated with space radiation exposure is based largely on the knowledge learned from studies in which animals, mostly rodents, are exposed to high-LET radiation on the ground. It has been recognized that translation of animal results to meaningful implications for human disease can be challenging, particularly for certain risk categories such as the high-LET radiation effects in the central nervous system (CNS). Considering limitations in utilizing non-human primates and clinical studies in humans, chimeric animals can potentially bridge the knowledge gap between rodents and humans. In a chimeric animal, a specific organ or a cell type is replaced with respective human cells that are functional. A number of chimeric mouse models have been developed in the medical research community to study human diseases, and some of the models can potentially be used for NASA applications. For instance, mice engrafted with human hepatocytes, which have been used in studies of genotoxicity from carcinogen exposures, can be used for quantification of space radiation damage. A chimeric brain model, which was shown to perform superiorly in memory and cognitive tests, can also be a candidate for studying the CNS effects of radiation. It has also been reported that mice engrafted with human hematopoietic progenitor cells were exposed to X-rays and high-LET Si ions to investigate the radiation effects in the immune system. In a pilot study, we use PXB mice whose livers contain >90% human cells. These mice are exposed to gamma rays for investigations of DNA damage and transcriptomics changes in the humanized livers. Results obtained from PXB mice will be compared non-engrafted control animals from the same background strain that are exposed to identical conditions. The aim of the study is to determine whether chimeric mouse models are suitable for investigations of space radiation risks.

Honglu Wu↗
NASA NTRSDate not supplied

Chimeric Mouse Models for Space Radiation Risk Investigations

Assessment of human health risks associated with space radiation exposure is based largely on the knowledge learned from studies in which animals, mostly rodents, are exposed to high-LET radiation on the ground. It has been recognized that translation of animal results to meaningful implications for human disease can be challenging, particularly for certain risk categories such as the high-LET radiation effects in the central nervous system (CNS). Considering limitations in utilizing non-human primates and clinical studies in humans, chimeric animals can potentially bridge the knowledge gap between rodents and humans. In a chimeric animal, a specific organ or a cell type is replaced with respective human cells that are functional. A number of chimeric mouse models have been developed in the medical research community to study human diseases, and some of the models can potentially be used for NASA applications. For instance, mice engrafted with human hepatocytes, which have been used in studies of genotoxicity from carcinogen exposures, can be used for quantification of space radiation damage. A chimeric brain model, which was shown to perform superiorly in memory and cognitive tests, can also be a candidate for studying the CNS effects of radiation. It has also been reported that mice engrafted with human hematopoietic progenitor cells were exposed to X-rays and high-LET Si ions to investigate the radiation effects in the immune system. In a pilot study, we use PXB mice whose livers contain >90% human cells. These mice are exposed to gamma rays for investigations of DNA damage and transcriptomics changes in the humanized livers. Results obtained from PXB mice will be compared non-engrafted control animals from the same background strain that are exposed to identical conditions. The aim of the study is to determine whether chimeric mouse models are suitable for investigations of space radiation risks.

Honglu Wu↗
DOE OSTI2018

Using spectral methods to obtain particle size information from optical data: applications to measurements from CARES 2010

Abstract. Multi-wavelength in situ aerosol extinction, absorption and scattering measurements made at two ground sites during the 2010 Carbonaceous Aerosols and Radiative Effects Study (CARES) are analyzed using a spectral deconvolution method that allows extraction of particle-size-related information, including the fraction of extinction produced by the fine-mode particles and the effective radius of the fine mode. The spectral deconvolution method is typically applied to analysis of remote sensing measurements. Here, its application to in situ measurements allows for comparison with more direct measurement methods and validation of the retrieval approach. Overall, the retrieved fine-mode fraction and effective radius compare well with other in situ measurements, including size distribution measurements and scattering and absorption measurements made separately for PM1 and PM10, although there were some periods during which the different methods yielded different results. One key contributor to differences between the results obtained is the alternative, spectrally based definitions of fine and coarse modes from the optical methods, relative to instruments that use a physically defined cut point. These results indicate that for campaigns where size, composition and multi-wavelength optical property measurements are made, comparison of the results can result in closure or can identify unusual circumstances. The comparison here also demonstrates that in situ multi-wavelength optical property measurements can be used to determine information about particle size distributions in situations where direct size distribution measurements are not available.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗
NASA NTRS2011

An Assessment of Differences Between Cloud Effective Particle Radius Retrievals for Marine Water Clouds from Three MODIS Spectral Bands

The Moderate Resolution Imaging Spectroradiometer (MODIS) cloud product provides three separate 1 km resolution retrievals of cloud particle effective radii (r (sub e)), derived from 1.6, 2.1 and 3.7 micron band observations. In this study, differences among the three size retrievals for maritime water clouds (designated as r (sub e), 1.6 r (sub e), 2.1 and r (sub e),3.7) were systematically investigated through a series of case studies and global analyses. Substantial differences are found between r (sub e),3.7 and r (sub e),2.1 retrievals (delta r (sub e),3.7-2.l), with a strong dependence on cloud regime. The differences are typically small, within +/- 2 micron, over relatively spatially homogeneous coastal stratocumulus cloud regions. However, for trade wind cumulus regimes, r (sub e),3.7 was found to be substantially smaller than r (sub e),2.1, sometimes by more than 10 micron. The correlation of delta r(sub e),3.7-2.1 with key cloud parameters, including the cloud optical thickness (tau), r (sub e) and a cloud horizontal heterogeneity index (H-sigma) derived from 250 m resolution MODIS 0.86 micron band observations, were investigated using one month of MODIS Terra data. It was found that differences among the three r (sub e) retrievals for optically thin clouds (tau <5) are highly variable, ranging from - 15 micron to 10 micron, likely due to the large MODIS retrieval uncertainties when the cloud is thin. The delta r (sub e),3.7-2.1 exhibited a threshold-like dependence on both r (sub e),2.l and H-sigma. The re,3.7 is found to agree reasonably well with re,2.! when re,2.l is smaller than about 15J-Lm, but becomes increasingly smaller than re,2.1 once re,2.! exceeds this size. All three re retrievals showed little dependence when H-sigma < 0.3 (defined as standard deviation divided by the mean for the 250 m pixels within a 1 km pixel retrieval). However, for H-=sigma >0.3, both r (sub e),1.6 and r (sub e),2.1 were seen to increase quickly with H-sigma. On the other hand, r (sub e),3.7 statistics showed little dependence on H-sigma and remained relatively stable over the whole range of H-sigma values. Potential contributing causes to the substantial r (sub e),3.7 and r (sub e),2.1 differences are discussed. In particular, based on both 1-D and 3-D radiative transfer simulations, we have elucidated mechanisms by which cloud heterogeneity and 3-D radiative effects can cause large differences between r (sub e),3.7 and r (sub e),2.l retrievals for highly inhomogeneous clouds. Our results suggest that the contrast in observed delta r (sub e)3.7-2.1 between cloud regimes is correlated with increases in both cloud r (sub e) and H-sigma. We also speculate that in some highly inhomogeneous drizzling clouds, vertical structure induced by drizzle and 3-D radiative effects might operate together to cause dramatic differences between r (sub e),3.7 and r (sub e),2.1 retrievals.

Platnick, Steven↗
DOE OSTI2018

Exploring the observational constraints on the simulation of brown carbon

Organic aerosols (OA) that strongly absorb solar radiation in the near-UV are referred to as brown carbon (BrC). The sources, evolution, and optical properties of BrC remain highly uncertain and contribute significantly to uncertainty in the estimate of the global direct radiative effect (DRE) of aerosols. Previous modeling studies of BrC optical properties and DRE have been unable to fully evaluate model performance due to the lack of direct measurements of BrC absorption. In this study, we develop a global model simulation (GEOS-Chem) of BrC and test it against BrC absorption measurements from two aircraft campaigns in the continental US (SEAC 4 RS and DC3). To the best of our knowledge, this is the first study to compare simulated BrC absorption with direct aircraft measurements. We show that BrC absorption properties estimated based on previous laboratory measurements agree with the aircraft measurements of freshly emitted BrC absorption but overestimate aged BrC absorption. In addition, applying a photochemical scheme to simulate bleaching/degradation of BrC improves model skill. The airborne observations are therefore consistent with a mass absorption coefficient (MAC) of freshly emitted biomass burning OA of 1.33 m 2 g -1 at 365 nm coupled with a 1-day whitening e-folding time. Using the GEOS-Chem chemical transport model integrated with the RRTMG radiative transfer model, we estimate that the top-of-the-atmosphere all-sky direct radiative effect (DRE) of OA is -0.344 Wm -2 , 10 % higher than that without consideration of BrC absorption. Therefore, our best estimate of the absorption DRE of BrC is +0.048 Wm -2 . We suggest that the DRE of BrC has been overestimated previously due to the lack of observational constraints from direct measurements and omission of the effects of photochemical whitening.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2012

Measuring Sparticles with the Matrix Element

We apply the Matrix Element Method (MEM) to mass determination of squark pair production with direct decay to quarks and LSP at the LHC, showing that simultaneous mass determination of squarks and LSP is possible. We furthermore propose methods for inclusion of QCD radiation effects in the MEM. The goal of the LHC at CERN, scheduled to start this year, is to discover new physics through deviations from the Standard Model (SM) predictions. After discovery of deviations from the SM, the next step will be classification of the new physics. An important first goal in this process will be establishing a mass spectrum of the new particles. One of the most challenging scenarios is pair-production of new particles which decay to invisible massive particles, giving missing energy signals. Many methods have been proposed for mass determination in such scenarios (for a recent list of references, see e.g. [1]). In this proceeding, we report the first steps in applying the Matrix Element Method (MEM) in the context of supersymmetric scenarios giving missing energy signals. After a quick review of the MEM, we will focus on squark pair production, a process where other mass determination techniques have difficulties to simultaneously determine the LSP and squark masses. Finally, we will introduce methods to extend the range of validity of the MEM, by taking into account initial state radiation (ISR) in the method.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗
DOE OSTI2012

Advanced Test Reactor National Scientific User Facility Progress

The Advanced Test Reactor (ATR) at the Idaho National Laboratory (INL) is one of the world’s premier test reactors for studying the effects of intense neutron radiation on reactor materials and fuels. The ATR began operation in 1967, and has operated continuously since then, averaging approximately 250 operating days per year. The combination of high flux, large test volumes, and multiple experiment configuration options provide unique testing opportunities for nuclear fuels and material researchers. The ATR is a pressurized, light-water moderated and cooled, beryllium-reflected highly-enriched uranium fueled, reactor with a maximum operating power of 250 MWth. The ATR peak thermal flux can reach 1.0 x1015 n/cm2-sec, and the core configuration creates five main reactor power lobes (regions) that can be operated at different powers during the same operating cycle. In addition to these nine flux traps there are 68 irradiation positions in the reactor core reflector tank. The test positions range from 0.5” to 5.0” in diameter and are all 48” in length, the active length of the fuel. The INL also has several hot cells and other laboratories in which irradiated material can be examined to study material radiation effects. In 2007 the US Department of Energy (DOE) designated the ATR as a National Scientific User Facility (NSUF) to facilitate greater access to the ATR and the associated INL laboratories for material testing research by a broader user community. Goals of the ATR NSUF are to define the cutting edge of nuclear technology research in high temperature and radiation environments, contribute to improved industry performance of current and future light water reactors, and stimulate cooperative research between user groups conducting basic and applied research. The ATR NSUF has developed partnerships with other universities and national laboratories to enable ATR NSUF researchers to perform research at these other facilities, when the research objectives cannot be met using the INL facilities. The ATR NSUF program includes a robust education program enabling students to participate in their research at INL and the partner facilities, attend the ATR NSUF annual User Week, and compete for prizes at sponsored conferences. Development of additional research capabilities is also a key component of the ATR NSUF Program; researchers are encouraged to propose research projects leading to these enhanced capabilities. Some ATR irradiation experiment projects irradiate more specimens than are tested, resulting in irradiated materials available for post irradiation examination by other researchers. These “extra” specimens comprise the ATR NSUF Sample Library. This presentation will highlight the ATR NSUF Sample Library and the process open to researchers who want to access these materials and how to propose research projects using them. This presentation will provide the current status of all the ATR NSUF Program elements. Many of these were not envisioned in 2007, when DOE established the ATR NSUF.

22 GENERAL STUDIES OF NUCLEAR REACTORS↗
DOE OSTI2015

Inhibition of Vascular Endothelial Growth Factor A and Hypoxia-Inducible Factor 1α Maximizes the Effects of Radiation in Sarcoma Mouse Models Through Destruction of Tumor Vasculature

Purpose: To examine the addition of genetic or pharmacologic inhibition of hypoxia-inducible factor 1α (HIF-1α) to radiation therapy (RT) and vascular endothelial growth factor A (VEGF-A) inhibition (ie trimodality therapy) for soft-tissue sarcoma. Methods and Materials: Hypoxia-inducible factor 1α was inhibited using short hairpin RNA or low metronomic doses of doxorubicin, which blocks HIF-1α binding to DNA. Trimodality therapy was examined in a mouse xenograft model and a genetically engineered mouse model of sarcoma, as well as in vitro in tumor endothelial cells (ECs) and 4 sarcoma cell lines. Results: In both mouse models, any monotherapy or bimodality therapy resulted in tumor growth beyond 250 mm{sup 3} within the 12-day treatment period, but trimodality therapy with RT, VEGF-A inhibition, and HIF-1α inhibition kept tumors at <250 mm{sup 3} for up to 30 days. Trimodality therapy on tumors reduced HIF-1α activity as measured by expression of nuclear HIF-1α by 87% to 95% compared with RT alone, and cytoplasmic carbonic anhydrase 9 by 79% to 82%. Trimodality therapy also increased EC-specific apoptosis 2- to 4-fold more than RT alone and reduced microvessel density by 75% to 82%. When tumor ECs were treated in vitro with trimodality therapy under hypoxia, there were significant decreases in proliferation and colony formation and increases in DNA damage (as measured by Comet assay and γH2AX expression) and apoptosis (as measured by cleaved caspase 3 expression). Trimodality therapy had much less pronounced effects when 4 sarcoma cell lines were examined in these same assays. Conclusions: Inhibition of HIF-1α is highly effective when combined with RT and VEGF-A inhibition in blocking sarcoma growth by maximizing DNA damage and apoptosis in tumor ECs, leading to loss of tumor vasculature.

62 RADIOLOGY AND NUCLEAR MEDICINE↗