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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 1,603 records · Page 89
All sourcesNASA NTRSDOE OSTI
DOE OSTI2019

Deep latency: A new insight into a functional HIV cure

Latent HIV reservoir is the main obstacle that prevents a cure for HIV-1 (HIV). While antiretroviral therapy is effective in controlling viral replication, it cannot eliminate latent HIV reservoirs in patients. Several strategies have been proposed to combat HIV latency, including bone marrow transplantation to replace blood cells with CCR5-mutated stem cells, gene editing to disrupt the HIV genome, and “Shock and Kill” to reactivate latent HIV followed by an immune clearance. However, high risks and limitations to scale-up in clinics, off-target effects in human genomes or failure to reduce reservoir sizes in patients hampered our current efforts to achieve an HIV cure. This necessitates alternative strategies to control the latent HIV reservoirs. This review will discuss an emerging strategy aimed to deeply silence HIV reservoirs, the development of this concept, its potential and caveats for HIV remission/cure, and prospective directions for silencing the latent HIV, thereby preventing viruses from rebound.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Structure-based design of SARS-CoV-2 papain-like protease inhibitors

The COVID-19 pandemic is caused by SARS-CoV-2, an RNA virus with high transmissibility and mutation rate. Given the paucity of orally bioavailable antiviral drugs to combat SARS-CoV-2 infection, there is a critical need for additional antivirals with alternative mechanisms of action. Papain-like protease (PL pro ) is one of the two SARS-CoV-2 encoded viral cysteine proteases essential for viral replication. PL pro cleaves at three sites of the viral polyproteins. In addition, PLpro antagonizes the host immune response upon viral infection by cleaving ISG15 and ubiquitin from host proteins. Therefore, PL pro is a validated antiviral drug target. In this study, we report the X-ray crystal structures of papain-like protease (PL pro ) with two potent inhibitors, Jun9722 and Jun9843 . Subsequently, we designed and synthesized several series of analogs to explore the structure-activity relationship, which led to the discovery of PL pro inhibitors with potent enzymatic inhibitory activity and antiviral activity against SARS-CoV-2. Together, the lead compounds are promising drug candidates for further development.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Basophil mediated pro-allergic inflammation in vehicle-emitted particles exposure

Despite of the fact that engine manufacturers develop a new technology to reduce exhaust emissions, insufficient attention given to particulate emissions. However, diesel exhaust particles are a major source of air-borne pollution, contain vast amount of polycyclic aromatic hydrocarbons (PAHs) and may have deleterious effects on the immune system, resulting in the induction and enhancement of pro-allergic processes. In the current study, vehicle emitted particles (VEP) from 2 different types of cars (diesel - D and gasoline - G) and locomotive (L) were collected. Overall, 129 four-week-old, male SPF-class Kunming mice were subcutaneously instilled with either low dose 100, 250 or high dose, 500 mg/kg VEP and 15 mice were assigned as control group. The systemic toxicity was evaluated and alterations in the percentages of the CD3, CD4, CD8, CD16, CD25 expressing cells, basophils, eosinophils and neutrophils were determined. Basophil percentages were inversely associated with the PAH content of the VEPs, however basophil sensitization was more important than cell count in VEP exposure. Thus, the effects of VEP-PAHs emerge with the activation of basophils in an allergen independent fashion. Despite the increased percentage of CD4+ T cells, a sharp decrease in basophil counts at 500 mg/kg of VEP indicates a decreased inhibitory effect of CD16+ monocytes on the proliferation of CD4+ T cell and suppressed polarization into a Th2 phenotype. Therefore, although the restrictions for vehicles emissions differ between countries, follow up studies and strict regulations are needed. - Highlights: • Basophil sensitization is more important than cell count in VEP exposure. • CD16+ cells are more effective than basophils on CD4+ T cell proliferation. • CD16+ and CD16- monocytes respond to VEP exposure in opposite directions. • CD8+ T cell proliferation is inhibited by all doses of VEPs. • Globally, more stringent standards are needed for vehicle particle emissions.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2017

Pregnancy outcome and ultraviolet radiation; A systematic review

Background: Season and vitamin D are indirect and direct correlates of ultraviolet (UV) radiation and are associated with pregnancy outcomes. Further to producing vitamin D, UV has positive effects on cardiovascular and immune health that may support a role for UV directly benefitting pregnancy. Objectives: To investigate the effects of UV exposure on pregnancy; specifically fetal growth, preterm birth and hypertensive complications. Methods: We conducted a systematic review of Medline, EMBASE, DoPHER, Global Health, ProQuest Public Health, AustHealth Informit, SCOPUS and Google Scholar to identify 537 citations, 8 of which are included in this review. This review was registered on PROSPERO and a. narrative synthesis is presented following PRISMA guidance. Results: All studies were observational and assessed at high risk of bias. Higher first trimester UV was associated with and improved fetal growth and increased hypertension in pregnancy. Interpretation is limited by study design and quality. Meta-analysis was precluded by the variety of outcomes and methods. Discussion: The low number of studies and risk of bias limit the validity of any conclusions. Environmental health methodological issues are discussed with consideration given to design and analytical improvements to further address this reproductive environmental health question. Conclusions: The evidence for UV having benefits for pregnancy hypertension and fetal growth is limited by the methodological approaches utilized. Future epidemiological efforts should focus on improving the methods of modeling and linking widely available environmental data to reproductive health outcomes. - Highlights: • Biologically plausible pathways support an association between ultraviolet radiation (UV) and pregnancy outcomes. • This study is the first systematic review of prevailing literature on the relationship between UV and singleton pregnancy outcomes. • It focuses on both substantive findings and the methodologies that were used. • Only seven studies met the search criteria and these were methodologically heterogeneous demonstrating a paucity of evidence. • Given the plausibility of the UV pathway, more studies examining this hypothesis are needed.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Ambient ultrafine particles activate human monocytes: Effect of dose, differentiation state and age of donors

Highlights: • UFP causes TNF-α secretion independently of ROS formation. • Differentiated THP-1 cells are more responsive to UFP exposure. • Age of donor does not contribute to the proinflammatory effect of UFP. Exposure to ambient particulate matter (PM) has been linked to adverse pulmonary and cardiovascular health effects. Activation of both inflammatory and oxidative stress pathways has been observed and may be a probable cause of these outcomes. We tested the hypothesis that in human monocytes, PM-induced oxidative and inflammatory responses are interrelated. A human monocytic cell line (THP-1) was used to determine if dose and differentiation state plays a role in the cellular response after a 24hr exposure to particles. Primary human monocytes derived from eight female, non-smoker donors (aged: 21, 24, 27, 28, 48, 49, 54 & 60yo) were used to determine if the age of donors modulates the response. Cells were treated with aqueous suspensions of ambient ultrafine particles (UFP, defined as smaller than 0.2 µm in size) or a media control for 24hr. After exposure, reactive oxygen species (ROS) formation was increased irrespective of dose or differentiation state of THP-1 cells. In the primary human monocytes, ROS formation was not significantly changed. The release of the proinflammatory cytokine, tumor necrosis factor alpha (TNF-α), was dose-dependent and greatest in differentiated compared to undifferentiated THP-1 cells exposed to UFP. In the Primary human monocytes, TNF-α secretion was increased irrespective of the age of the donor. Our results suggest that after a 24hr exposure to particles, general reactive oxygen species formation was nonspecific and uncorrelated to cytokine secretion which was consistently enhanced. Cytokines play an important role in orchestrating many immune responses and thus the ability of ambient particles to enhance robust secretion of a proinflammatory cytokine from primary human monocytes, and how this may influence the response to pathogens and alter disease states, needs to be further evaluated.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Modulation of oxidative phosphorylation (OXPHOS) by radiation- induced biophotons

Highlights: • This paper provides evidence that the biophoton signals known to be emitted by irradiated cells, interfere with the processes of oxidative phosphorylation (OXPHOS) in cells receiving the signals. • The paper demonstrates that Complex 1 activity is completely supressed by these biophotons resulting in downstream compromise of ATP production. • The mechanism may help explain fatigue and immune compromise effects of low dose exposure to ionising radiation. Radiation-induced biophotons are an electromagnetic form of bystander signalling. In human cells, biophoton signalling is capable of eliciting effects in non-irradiated bystander cells. However, the mechanisms by which the biophotons interact and act upon the bystander cells are not clearly understood. Mitochondrial energy production and ROS are known to be involved but the precise interactions are not known. To address this question, we have investigated the effect of biophoton emission upon the function of the complexes of oxidative phosphorylation (OXPHOS). The exposure of bystander HCT116 p53 +/+ cells to biophoton signals emitted from β-irradiated HCT116 p53 +/+ cells induced significant modifications in the activity of Complex I (NADH dehydrogenase or NADH:ubiquinone oxidoreductase) such that the activity was severely diminished compared to non-irradiated controls. The enzymatic assay showed that the efficiency of NADH oxidation to NAD+ was severely compromised. It is suspected that this impairment may be linked to the photoabsorption of biophotons in the blue wavelength range (492–455 nm). The photobiomodulation to Complex I was suspected to contribute greatly to the inefficiency of ATP synthase function since it resulted in a lower quantity of H{sup +} ions to be available for use in the process of chemiosmosis. Other reactions of the ETC were not significantly impacted. Overall, these results provide evidence for a link between biophoton emission and biomodulation of the mitochondrial ATP synthesis process. However, there are many aspects of biological modulation by radiation-induced biophotons which will require further elucidation.

63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTAN↗
DOE OSTI2018

The influence of microplastics and halogenated contaminants in feed on toxicokinetics and gene expression in European seabass (Dicentrarchus labrax)

Highlights: • Microplastics in feed influenced the toxicokinetics and affected the liver. • k{sub el} of PCBs and BFRs lower for diet with contaminants sorbed to microplastics compared to other contaminated diets. • The assimilation efficiencies lower for the contaminated diet with clean microplastics, likely due to higher eliminations. • Seabass quickly metabolised PBDE99 to PBDE47 unaffected by the presence of microplastics. • Significant gene expression of livers (cyp1a, il1β, gstα) indicate that contaminants sorbed to microplastics increase the toxicity of some contaminants. When microplastics pollute fish habitats, it may be ingested by fish, thereby contaminating fish with sorbed contaminants. The present study investigates how combinations of halogenated contaminants and microplastics associated with feed are able to alter toxicokinetics in European seabass and affect the fish. Microplastic particles (2%) were added to the feed either with sorbed contaminants or as a mixture of clean microplastics and chemical contaminants, and compared to feed containing contaminants without microplastics. For the contaminated microplastic diet, the accumulation of polychlorinated biphenyls (PCBs) and brominated flame retardants (BFRs) in fish was significantly higher, increasing up to 40 days of accumulation and then reversing to values comparable to the other diets at the end of accumulation. The significant gene expression results of liver (cyp1a, il1β, gstα) after 40 days of exposure indicate that microplastics might indeed exacerbate the toxic effects (liver metabolism, immune system, oxidative stress) of some chemical contaminants sorbed to microplastics. Seabass quickly metabolised BDE99 to BDE47 by debromination, probably mediated by deiodinase enzymes, and unlike other contaminants, this metabolism was unaffected by the presence of microplastics. For the other PCBs and BFRs, the elimination coefficients were significantly lower in fish fed the diet with contaminants sorbed to microplastic compared to the other diets. The results indicate that microplastics affects liver detoxification and lipid distribution, both of which affect the concentration of contaminants.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Ambient ozone exposure and mental health: A systematic review of epidemiological studies

Highlights: • 31 studies concerned about ozone and mental health outcomes were reviewed. • Inconclusive evidence on ozone and autism, cognitive decline, depression and suicide. • Currently evidence is inconclusive and more high quality studies are needed. An increasing number of studies have suggested adverse effects of air pollution on mental health. Given the potentially negative impacts of ozone exposure on the immune and nervous system driven from animal experiments, ozone might also affect mental health. However, no systematic synthesis of the relevant literature has been conducted yet. This paper reviews the studies that assessed the link between ozone exposure and mental health thus far.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

PM10 exposure is associated with increased hospitalizations for respiratory syncytial virus bronchiolitis among infants in Lombardy, Italy

Highlights: • Respiratory syncytial virus bronchiolitis (RSV-B) might be influenced by air pollution. • PM10 was associated with RSV-B hospitalizations among infants in Lombardy, Italy. • The most relevant exposure windows were the 2 weeks preceding hospitalization. Respiratory syncytial virus (RSV) is the primary cause of acute lower respiratory infections in children, bronchiolitis in particular. Airborne particulate matter (PM) may influence the children's immune system and foster the spread of RSV infection. We aimed to verify whether PM10 exposure is associated with hospitalization due to RSV bronchiolitis. We selected hospital discharge records (HRD) with ICD-9-CM code 466.11 of infants < 1 year of age, occurring in the epidemic seasons of two years (2012–2013) in Lombardy, Italy. Cases were assigned daily PM10 and apparent temperature levels of the capital city of their residential province. Different exposure windows were considered: single days preceding hospitalization (lag 0 to 30), their average estimates (lag 0–1 to 0–30), and the four weeks preceding hospitalization (week 1 to 4). Negative binomial regression models adjusted for apparent temperature and season were applied to the daily counts of hospitalizations in each province. Results were expressed as incidence rate ratios (IRR) and 95% confidence intervals (95%CI) per 10 µg/m{sup 3} increase in PM10 concentration. Random effects meta-analyses of province-specific IRR were performed to obtain regional estimates. 2814 HRD met our inclusion criteria; males represented about 55% of the cases. A 6% increased risk of hospitalization (95%CI: 1.03–1.10) was found at lag 0 and an almost overlapping 7% increase at lag 1. IRR ranged from 1.03 to 1.05 between lags 2 and 11. No increased risk was observed from lag 12. When considering averaged daily lags, risk estimates gradually increased in the two weeks preceding hospitalization from 1.08 (1.04–1.12) at lag 0–1 to 1.15 (1.08–1.23) between lags 0–11 and 0–13. Analyses on weekly lags showed a risk increase of 6% (1.01–1.12) during week 1 and of 7% (1.02–1.13) during week 2. Our study found a clear association between short- and medium-term PM10 exposures and increased risk of hospitalization due to RSV bronchiolitis among infants.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Effects of polychlorinated biphenyls (PCB) on California sea lion (Zalophus californianus) lymphocyte functions upon in vitro exposure

Highlights: • PCBs induce immunomodulation of California sea lion lymphocytes. • Non dioxin-like PCBs stimulate sea lion lymphocyte proliferation at low concentrations. • Sea lion NK activity can increase under high levels of some non-dioxin PCB congeners. • PCB-induced modulation of sea lion lymphocytes can influence tumor progression. • Frozen lymph node mononuclear cells are viable for ecotoxicological analyses. Polychorinated biphenyl (PCB) congeners are a cause for concern due to their persistence in the environment, their lipophilic properties that cause them to bio-accumulate in top predators, and their adverse effects on mammalian health. For example, the common urogenital carcinoma reported in California sea lions (Zalophus californianus) (CSL) is associated with high tissue levels of PCBs, but the mechanisms responsible for this association are unknown. This study investigated the effect of exposure to six PCB congeners and a congener mix at low and environmentally relevant concentrations on NK cell-like and T cell activity using in vitro assays on cryopreserved lymph node mononuclear cells isolated from dead CSL. Non dioxin-like congeners 153 and 180 increased lymphocyte proliferation at 5 and 10 ppm, while congener 138 decreased proliferation by up to 43% at 15 ppm. Dioxin-like PCBs 118 and 169 did not affect lymphocyte proliferation, while the effects of congener 105 depended on the mitogen concentration; these did not correlate with their predicted toxic equivalent factors. NK cell-like activity was affected only by the highest concentration of PCBs tested; it was increased by non-dioxin-like congeners 138 and 153, and decreased by dioxin-like congener 169. The PCB congener mix suggested that the effects of PCB congeners were not simply additive. Our results concur with effects of PCBs reported for other pinniped's lymphocytes and add further experimental support to the observation that dioxin-like PCBs are not the most toxic congeners for marine mammals, contrary to effects in other species. This is the first evidence of in vitro suppression of NK cell-like cytotoxicity by a dioxin-like congener in a pinniped. More importantly, the observed results suggest that PCBs can modulate the CSL immune system, increasing exposed individuals’ susceptibility to viral and oncogenic challenges.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2022

A deep redox proteome profiling workflow and its application to skeletal muscle of a Duchenne Muscular Dystrophy model

Perturbation to the redox state accompanies many diseases and its effects are viewed through oxidation of biomolecules, including proteins, lipids, and nucleic acids. The thiol groups of protein cysteine residues undergo an array of redox post-translational modifications (PTMs) that are important for regulation of protein and pathway function. To better understand what proteins are redox regulated following a perturbation, it is important to be able to comprehensively profile protein thiol oxidation at the proteome level. Herein, we report a deep redox proteome profiling workflow and demonstrate its application in measuring the changes in thiol oxidation along with global protein expression in skeletal muscle from mdx mice, a model of Duchenne Muscular Dystrophy (DMD). In depth coverage of the thiol proteome was achieved with >18,000 Cys sites from 5608 proteins in muscle being quantified. Compared to the control group, mdx mice exhibit markedly increased thiol oxidation, where ~2% shift in the median oxidation occupancy was observed. Further, pathway analysis for the redox data revealed that coagulation system and immune-related pathways were among the most susceptible to increased thiol oxidation in mdx mice, whereas protein abundance changes were more enriched in pathways associated with bioenergetics. This study illustrates the importance of deep redox profiling in gaining greater insight into oxidative stress regulation and pathways/processes that are perturbed in an oxidizing environment.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Using geographic information science to evaluate legal restrictions on freight transportation routing in disruptive scenarios

Disasters have consequences and freight transportation is not immune from the effects of such disruptions. In the aftermath of disasters, planners and policymakers have to utilize scarce resources and work within legal frameworks to provide recovery for affected citizens and business. As seen with Hurricane Sandy, various observers noted the challenge with freight rerouting due to inoperable infrastructure and legal barriers involved with intermodal freight transportation. This paper focuses on how Geographic Information Systems (GIS); specifically WebTRAGIS (Transportation Routing Analysis GIS), a transportation routing platform developed at Oak Ridge National Laboratory, can be used to evaluate different routing options for freight transportation. In the case of freight transportation, the Merchant Marine Act of 1920 (also known as the Jones Act) restricts Short Sea Shipping (SSS) between coastwise points within U.S. territorial waters. This restriction leads to reliance on land-side modes for handling increased freight resulting from cargo diversion. Using Hurricane Sandy and the closure of the Port of New York/New Jersey as a case study, different modal studies were conducted; ultimately highlighting the various routes and provides insight into potential review of modal restrictions such as the Jones Act.

99 GENERAL AND MISCELLANEOUS↗
DOE OSTI2015

Definitive Management of Oligometastatic Melanoma in a Murine Model Using Combined Ablative Radiation Therapy and Viral Immunotherapy

Purpose: The oligometastatic state is an intermediate state between a malignancy that can be completely eradicated with conventional modalities and one in which a palliative approach is undertaken. Clinically, high rates of local tumor control are possible with stereotactic ablative radiation therapy (SABR), using precisely targeted, high-dose, low-fraction radiation therapy. However, in oligometastatic melanoma, virtually all patients develop progression systemically at sites not initially treated with ablative radiation therapy that cannot be managed with conventional chemotherapy and immunotherapy. We have demonstrated in mice that intravenous administration of vesicular stomatitis virus (VSV) expressing defined tumor-associated antigens (TAAs) generates systemic immune responses capable of clearing established tumors. Therefore, in the present preclinical study, we tested whether the combination of systemic VSV-mediated antigen delivery and SABR would be effective against oligometastatic disease. Methods and Materials: We generated a model of oligometastatic melanoma in C57BL/6 immunocompetent mice and then used a combination of SABR and systemically administered VSV-TAA viral immunotherapy to treat both local and systemic disease. Results: Our data showed that SABR generates excellent control or cure of local, clinically detectable, and accessible tumor through direct cell ablation. Also, the immunotherapeutic activity of systemically administered VSV-TAA generated T-cell responses that cleared subclinical metastatic tumors. We also showed that SABR induced weak T-cell-mediated tumor responses, which, particularly if boosted by VSV-TAA, might contribute to control of local and systemic disease. In addition, VSV-TAA therapy alone had significant effects on control of both local and metastatic tumors. Conclusions: We have shown in the present preliminary murine study using a single tumor model that this approach represents an effective, complementary combination therapy model that addresses the need for both systemic and local control in oligometastatic melanoma.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

Proton Minibeam Radiation Therapy Reduces Side Effects in an In Vivo Mouse Ear Model

Purpose: Proton minibeam radiation therapy is a novel approach to minimize normal tissue damage in the entrance channel by spatial fractionation while keeping tumor control through a homogeneous tumor dose using beam widening with an increasing track length. In the present study, the dose distributions for homogeneous broad beam and minibeam irradiation sessions were simulated. Also, in an animal study, acute normal tissue side effects of proton minibeam irradiation were compared with homogeneous irradiation in a tumor-free mouse ear model to account for the complex effects on the immune system and vasculature in an in vivo normal tissue model. Methods and Materials: At the ion microprobe SNAKE, 20-MeV protons were administered to the central part (7.2 × 7.2 mm{sup 2}) of the ear of BALB/c mice, using either a homogeneous field with a dose of 60 Gy or 16 minibeams with a nominal 6000 Gy (4 × 4 minibeams, size 0.18 × 0.18 mm{sup 2}, with a distance of 1.8 mm). The same average dose was used over the irradiated area. Results: No ear swelling or other skin reactions were observed at any point after minibeam irradiation. In contrast, significant ear swelling (up to fourfold), erythema, and desquamation developed in homogeneously irradiated ears 3 to 4 weeks after irradiation. Hair loss and the disappearance of sebaceous glands were only detected in the homogeneously irradiated fields. Conclusions: These results show that proton minibeam radiation therapy results in reduced adverse effects compared with conventional homogeneous broad-beam irradiation and, therefore, might have the potential to decrease the incidence of side effects resulting from clinical proton and/or heavy ion therapy.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

Lymphocyte-Sparing Effect of Stereotactic Body Radiation Therapy in Patients With Unresectable Pancreatic Cancer

Purpose: Radiation-induced lymphopenia (RIL) is associated with inferior survival in patients with glioblastoma, lung cancer, and pancreatic cancer. We asked whether stereotactic body radiation therapy (SBRT) decreases severity of RIL compared to conventional chemoradiation therapy (CRT) in locally advanced pancreatic cancer (LAPC). Methods and Materials: Serial total lymphocyte counts (TLCs) from patients enrolled in a prospective trial of SBRT for LAPC were compared to TLCs from an existing database of LAPC patients undergoing definitive CRT. SBRT patients received 33 Gy (6.6 Gy × 5 fractions). CRT patients received a median dose of 50.4 Gy (1.8 Gy × 28 fractions) with concurrent 5-fluorouracil (77%) or gemcitabine (23%) therapy. Univariate and multivariate analyses (MVA) were used to identify associations between clinical factors and post-treatment TLC and between TLC and survival. Results: Thirty-two patients received SBRT and 101 received CRT. Median planning target volume (PTV) was smaller in SBRT (88.7 cm{sup 3}) than in CRT (344.6 cm{sup 3}; P<.001); median tumor diameter was larger for SBRT (4.6 cm) than for CRT (3.6 cm; P=.01). SBRT and CRT groups had similar median baseline TLCs. One month after starting radiation, 71.7% of CRT patients had severe lymphopenia (ie, TLC <500 cells/mm{sup 3} vs 13.8% of SBRT patients; P<.001). At 2 months, 46.0% of CRT patients remained severely lymphopenic compared with 13.6% of SBRT patients (P=.007). MVA demonstrated that treatment technique and baseline TLCs were significantly associated with post-treatment TLC at 1 but not 2 months after treatment. Higher post-treatment TLC was associated with improved survival regardless of treatment technique (hazard ratio [HR] for death: 2.059; 95% confidence interval: 1.310-3.237; P=.002). Conclusions: SBRT is associated with significantly less severe RIL than CRT at 1 month in LAPC, suggesting that radiation technique affects RIL and supporting previous modeling studies. Given the association of severe RIL with survival in LAPC, further study of the effect of radiation technique on immune status is warranted.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

Stereotactic Radiosurgery: Treatment of Brain Metastasis Without Interruption of Systemic Therapy

Purpose: To evaluate the prevalence, outcomes, and toxicities of concurrent delivery of systemic therapy with stereotactic radiosurgery (SRS) for treatment of brain metastases. Methods and Materials: We conducted a retrospective review of 193 patients treated at our institution with SRS without prior whole-brain radiation therapy (WBRT) for brain metastases between 2009 and 2014. Outcome metrics included administration of concurrent systemic therapy, myelosuppression, neurotoxicity, and survival. Results: One hundred ninety-three patients with a median age of 61 years underwent a total of 291 SRS treatments. Thirty-seven percent of SRS treatments were delivered concurrently with systemic therapy, of which 46% were with conventional myelosuppressive chemotherapy, and 54% with targeted and immune therapy agents. Myelosuppression was minimal after treatment with both systemic therapy and SRS, with 14% grade 3-4 toxicity for lymphopenia and 4-9% for leukopenia, neutropenia, anemia, and thrombocytopenia. Neurotoxicity was also minimal after combined therapy, with no grade 4 and <5% grade 3 toxicity, 34% dexamethasone requirement, and 4% radiation necrosis, all similar to treatments with SRS alone. Median overall survival was similar after SRS alone (14.4 months) versus SRS with systemic therapy (12.9 months). In patients with a new diagnosis of primary cancer with brain metastasis, early treatment with concurrent systemic therapy and SRS correlated with improved survival versus SRS alone (41.6 vs 21.5 months, P<.05). Conclusions: Systemic therapy can be safely given concurrently with SRS for brain metastases: our results suggest minimal myelosuppression and neurotoxicity. Concurrent therapy is an attractive option for patients who have both intracranial and extracranial metastatic disease and may be particularly beneficial in patients with a new diagnosis of primary cancer with brain metastasis.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2016

Radiation-Induced Esophagitis In Vivo and In Vitro Reveals That Epidermal Growth Factor Is a Potential Candidate for Therapeutic Intervention Strategy

Purpose: To establish and characterize radiation-induced esophagitis (RIE) in vivo and in vitro. Methods and Materials: Fractionated thoracic irradiation at 0, 8, 12, or 15 Gy was given daily for 5 days to Balb/c or C57Bl/6 mice. Changes in body weight gain and daily food intake were assessed. At the end of the study, we removed the esophagus and examined histology by hematoxylin and eosin staining, immune cell infiltration and apoptosis by fluorescence-activated cell sorting, and gene expression changes by quantitative real-time polymerase chain reaction. Het-1A human esophageal epithelial cells were irradiated at 6 Gy, treated with recombinant human growth factors, and examined for gene expression changes, apoptosis, proliferation, and signal transduction pathways. Results: We observed that irradiation at 12 Gy or 15 Gy per fraction produced significant reduction in body weight and decreased food intake in Balb/c mice but not as much in C57Bl/6 mice. Further analyses of Balb/c mice irradiated at 12 Gy/fraction revealed attenuated epithelium, inflamed mucosa, and increased numbers of infiltrating CD4+ helper T cells and apoptotic cells. Moreover, we found that expression of tissue inhibitor for metalloproteinase-1, plasminogen activator inhibitor-1, granulocyte macrophage-colony stimulating factor, vascular endothelial growth factor, and stromal-derived factor-1 were increased, whereas epidermal growth factor (EGF) was decreased. Irradiated Het-1A cells similarly showed a significant decrease in expression of EGF and connective tissue growth factor (CTGF). Treatment of EGF but not CTGF partially protected Het-1A cells from radiation-induced apoptosis and revealed phosphorylation of EGFR, AKT, and ERK signaling pathways. Conclusions: We established a mouse model of RIE in Balb/c mice with 12 Gy × 5 fractions, which showed reduced body weight gain, food intake, and histopathologic features similar to those of human esophagitis. Decreased EGF expression in the irradiated esophagus suggests that EGF may be a potential therapeutic intervention strategy to treat RIE.

62 RADIOLOGY AND NUCLEAR MEDICINE↗