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DOE OSTI2020

Glycolate Analysis in Tank 22: Developing and Testing Analytical Methods for the Savannah River Site Liquid Waste System

Researchers developed and tested a range of techniques to support a low mg/L Limit of Quantitation (LOQ) of glycolate in radioactive Tank 22 waste solution by Ion Chromatography (IC) and by proton NMR. For the IC method, Dionex OnGuard II cartridges were tested as a means of removing alkali earth and transition metals that can interfere during ion chromatography applications especially when analyzing for low-concentration, chelating analytes. Additionally, concentrations of nitrate in the raw Tank 22 sample (5,000 to 10,000 mg/L) were managed by using reasonable levels of sample dilution. The resulting IC performance quality was enhanced by improving the baseline, increasing sensitivity [Limit of Quantitation (LOQ) of 12 mg/L and Limit of Detection (LOD) of 4.0 mg/L], and resolving analytes into well-defined Gaussian peaks when using the Dionex OnGuard II H⁺ cartridges to remove matrix interferences. High concentrations of nitrate limited the performance of the IC method. To achieve an acceptable baseline, samples with high nitrate content require more dilution, resulting in higher detection limits. Tests on samples with higher concentrations of nitrate (Tank 30 and 32 supernate with approximately 150000 mg/L nitrate) suggested that IC detection limits for glycolate in these samples would be > 500 mg/L. Thus, an LOQ of 12 mg/L is not feasible by this IC method on evaporator feed samples. An alternative method of glycolate analysis, using proton nuclear magnetic resonance (H NMR), was developed by the research team. In initial tests, the H NMR technique provided reasonable quantitation of glycolate in Tank 22 conditions by direct observation of the liquid. The H NMR method may provide improved detection limits for solutions with higher nitrate concentrations. We recommend further development of this analysis for high nitrate LWS samples such as evaporator feed and evaporator drop tank content. A method for pretreatment of samples using crystalline silicotitanate (CST) was developed and tested. The objective of the pretreatment was to facilitate analysis of samples with higher levels of radioactivity. The pretreatment did not influence the glycolate concentration in solution, and the pretreatment is projected to reduce Cs 137 activity in a sample by a factor of 16,200. The double strike CST pretreatment was demonstrated and would allow milliliters of higher activity samples to be transferred from the Shielded Cells and handled in a containment unit for glycolate analysis. The various studies validated IC and H NMR methods for glycolate analysis, defined the range of applicability, and demonstrated key supporting analytical protocols. Based on the results, high quality glycolate analysis of Tank 22 is feasible down to approximately 12 mg/L, with the potential for broader applicability of the methods to other conditions in the Savannah River Site Liquid Waste System (LWS).

12 MANAGEMENT OF RADIOACTIVE AND NON-RADIOACTIVE W↗

DOE OSTI2018

Biocompatible Water Soluble Polyacrylic Acid Coated CdSe/Cu Quantum Dot Conjugates for Biomolecule Detection

Biocompatible polyacrylic acid functionalized CdSe/Cu quantum dot conjugates were synthesized to be used for biomolecules detection. The study results demonstrate the conjugation of the 2.5-3 nm QD with gram negative bacteria with a low detection limit of 28 cfu/ml. The photoluminescence (PL) intensity was correlated to bacterial count, cellular proteins and exopolysaccharides in the tested samples. Confocal Scanning Laser Microscopy (CSLM) images showed significant QD uptake within the cells, both cytoplasm and DNA were the predominant targeted biomolecules, higher fluorescent uptake was shown in gram negative bacteria than that observed for gram positive bacteria. Moreover, PL showed that there was a distinction between live and dead cells as well as gram negative and gram positive cells. Cell viability was not affected even after 6 days (100% viability) rendering it a non-toxic QD. The method is simple and is performed in a single step within approximately 10 min as compared to multi-step protocols for classical microbial count or fluorescent dye staining. All the above results indicate that the CdSe/Cu-PAA QDs are suitable for biomolecule detection, bio-labeling and bioimaging applications.

77 NANOSCIENCE AND NANOTECHNOLOGY↗

DOE OSTI2016

SU-G-JeP1-05: Clinical Impact of MLC Tracking for Lung SABR

Purpose: The objective of this study was to investigate the dosimetric benefits of multi-leaf collimator (MLC) tracking for lung SABR treatments in end-to-end clinically realistic planning and delivery scenarios. Methods: The clinical benefits of MLC tracking were assessed using previously delivered treatment plans and physical experiments. The 10 most recent single lesion lung SABR patients were re-planned following a 4D-GTV-based real-time adaptive protocol (PTV defined as the end-of-exhalation GTV plus 5.0 mm margins). The plans were delivered on a Trilogy Varian linac. Electromagnetic transponders (Calypso, Varian Medical Systems, USA) were embedded into a programmable moving phantom (HexaMotion platform) tracked with the Varian Calypso system. For each physical experiment, the MLC positions were collected and used as input for dose reconstruction. For both planned and physical experiments, the OAR dose metrics from the conventional and real-time adaptive SABR plans (Mean Lung Dose (MLD), V20 for lung, and near-maximum dose (D2%) for spine and heart) were statistically compared. The Wilcoxon test was used to compare plan and physical experiment dose metrics. Results: While maintaining target coverage, percentage reductions in dose metrics to the OARs were observed for both planned and physical experiments. Comparing the two plans showed MLD percentage reduction (MLDr) of 25.4% (absolute differences of 1.41 Gy) and 28.9% (1.29%) for the V20r. D2% percentage reduction for spine and heart were respectively 27.9% (0.3 Gy) and 20.2% (0.3 Gy). For the physical experiments, MLDr was 23.9% (1.3 Gy), and V20r 37.4% (1.6%). D2% reduction for spine and heart were respectively 27.3% (0.3 Gy) and 19.6% (0.3 Gy). For both plans and physical experiments, significant OAR dose differences (p<0.05) were found between the conventional SABR and real-time adaptive plans. Conclusion: Application of MLC tracking for lung SABR patients has the potential to reduce the dose to OARs during radiation therapy.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

SU-E-I-04: Improving CT Quality for Radiation Therapy of Patients with High Body Mass Index Using Iterative Reconstruction Algorithms

Purpose: Iterative reconstruction (IR) algorithms are developed to improve CT image quality (IQ) by reducing noise without diminishing spatial resolution or contrast. The CT IQ for patients with a high Body Mass Index (BMI) can suffer from increased noise due to photon starvation. The purpose of this study is to investigate and to quantify the IQ enhancement for high BMI patients through the application of IR algorithms. Methods: CT raw data collected for 6 radiotherapy (RT) patients with BMI, greater than or equal to 30 were retrospectively analyzed. All CT data were acquired using a CT scanner (Somaton Definition AS Open, Siemens) installed in a linac room (CT-on-rails) using standard imaging protocols. The CT data were reconstructed using the Sinogram Affirmed Iterative Reconstruction (SAFIRE) and Filtered Back Projection (FBP) methods. IQ metrics of the obtained CTs were compared and correlated with patient depth and BMI. The patient depth was defined as the largest distance from anterior to posterior along the bilateral symmetry axis. Results: IR techniques are demonstrated to preserve contrast and reduce noise in comparison to traditional FBP. Driven by the reduction in noise, the contrast to noise ratio is roughly doubled by adopting the highest SAFIRE strength. A significant correlation was observed between patient depth and IR noise reduction through Pearson’s correlation test (R = 0.9429/P = 0.0167). The mean patient depth was 30.4 cm and the average relative noise reduction for the strongest iterative reconstruction was 55%. Conclusion: The IR techniques produce a measureable enhancement to CT IQ by reducing the noise. Dramatic noise reduction is evident for the high BMI patients. The improved CT IQ enables more accurate delineation of tumors and organs at risk and more accuarte dose calculations for RT planning and delivery guidance. Supported by Siemens.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2024

Assessment of Condition Monitoring Methods and Technologies for Inservice Inspection and Testing of Nuclear Power Plant Components

This report was prepared for the U.S. Nuclear Regulatory Commission (NRC) to explore the application of advanced technologies toward meeting the current and future regulatory requirements for maintenance and condition monitoring of structures, systems, and components. The advanced technologies considered in this work are advanced sensors and instrumentation, data analytics, machine learning and artificial intelligence (ML/AI), physics-based models, and digital twins (DT). The interest in the application of advanced technologies for condition monitoring in nuclear power plants continues to grow, and current and future licensees are expected to implement advanced technologies as part of their inservice inspection (ISI) and inservice testing (IST) programs. This report delineates the outcomes of an exploratory investigation into the implementation of advanced condition monitoring technologies to address ISI and IST requirements. A thorough review was conducted of the existing regulatory requirements for ISI and IST, along with an analysis of associated industry practices. Additionally, a state-of-the-art assessment was performed on advanced condition monitoring technologies frequently employed in non-nuclear sectors. This research incorporated two nuclear-specific case studies to illustrate the application of these technologies within the current nuclear fleet. The report provides an exhaustive discussion on the technical challenges, considerations, and opportunities associated with the deployment of advanced condition monitoring technologies. The following are key considerations in the application of advanced technologies for the ISI and IST of nuclear power plant components: • Developing adequate verification and validation procedures to confirm the functional and non-functional requirements, • Developing technical capabilities to conduct real-time asset condition monitoring, • Establishing guidance and protocol for modeling and simulation tools to continuously meet regulatory requirements, • Addressing trustworthiness, explainability, and interpretability of ML/AI methods, • Evaluating maintenance activities to maintain an adequate safety margin and avoid undesirable conditions, • Establishing cybersecure condition monitoring programs associated with a computer-based software system, and • Establishing standardized evaluation metrics for advanced condition monitoring programs. Interest in the use of advanced technologies for condition monitoring in ISI and IST programs continues to grow, and the technology is expected to experience rapid and wide industry adoption in the near future. Adoption of advanced technologies for condition monitoring could have novel and unique impacts on regulatory activities associated with ISI and IST programs. The NRC is continuing to explore the regulatory aspects of advanced technologies as part of ISI and IST programs by pursuing additional research in this technical area.

22 - GENERAL STUDIES OF NUCLEAR REACTORS↗

DOE OSTI2015

YARNsim: Simulating Hadoop YARN

Despite the popularity of the Apache Hadoop system, its success has been limited by issues such as single points of failure, centralized job/task management, and lack of support for programming models other than MapReduce. The next generation of Hadoop, Apache Hadoop YARN, is designed to address these issues. In this paper, we propose YARNsim, a simulation system for Hadoop YARN. YARNsim is based on parallel discrete event simulation and provides protocol-level accuracy in simulating key components of YARN. YARNsim provides a virtual platform on which system architects can evaluate the design and implementation of Hadoop YARN systems. Also, application developers can tune job performance and understand the tradeoffs between different configurations, and Hadoop YARN system vendors can evaluate system efficiency under limited budgets. To demonstrate the validity of YARNsim, we use it to model two real systems and compare the experimental results from YARNsim and the real systems. The experiments include standard Hadoop benchmarks, synthetic workloads, and a bioinformatics application. The results show that the error rate is within 10% for the majority of test cases. The experiments prove that YARNsim can provide what-if analysis for system designers in a timely manner and at minimal cost compared with testing and evaluating on a real system.

Hadoop↗

DOE OSTI2016

SU-C-204-05: Magnetic Resonance-Induced Adaptive Response to Orthovoltage Radiation Therapy in FSa and SA-NH Mouse Tumor Cell Lines

Purpose: To assess the effect of pre-treatment Magnetic Resonance Imaging (MRI) on cell survival following orthovoltage radiation therapy. Methods: This in vitro study examined the survival of FSa cells (extracted from methylcholanthrene-induced fibrosarcoma in the flank of a C3H female mouse) and SA-NH cells (derived from a spontaneously arising murine sarcoma tumor) having undergone an MRI scan prior to radiation exposure. Cell cultures were kept at 37 C, in a humidified environment with 5% CO2, and were grown to confluence prior to the start of the experiment. Each cell culture underwent two, 25 minute MRIs spaced 24 hours apart using a standard brain imaging protocol. The cultures were exposed to a 2 Gy dose of radiation beginning 15 minutes after the end of each MRI scan. Irradiations were performed by a Philips RT250 X-ray generator at 250 kVp and 15 mA. All MR imaging was performed on a 1.5 T Philips Achieva scanner using a head and neck vasculature coil. Results: Cells given an MRI scan prior to radiation exhibited an increase in mean surviving fraction of 10.8% and 9.6% in FSa and SA-NH cells, respectively. The difference was found to be statistically significant in both cell types by a student two-tailed t test with P = 0.011 and P < 0.001 for FSa and SA-NH, respectively. Conclusion: MRI may cause an increase in radio-resistance in FSa and SA-NH cells. If this biological effect is found to be consistent across other cell types and voltage ranges, these results could help inform treatment planning by improving our understanding of the joint effects of MRI and ionizing radiation. This work was supported in part under NIH grant numbers T32 EB002103, NCI R01-CA 132998, DOE Low Dose Program/Project Grant DE-413 SC0001271. DJ Grdina is a paid consultant to Pinnacle Biologics. DJ Grdina and JS Murley are minority equity partners in Pinnacle Oncology LLC.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2020

Distributed Ledger Technology Preliminary Performance Assessment for Applications in Utilities Operational Technology

This paper provides descriptions of the key components of different distributed ledger technology platforms. Distributed ledger technology (DLT) allows for distribution of databases among different organizations and devices. The platforms use cryptographically linked “blocks” to store and verify transactional information between these organizations. DLT increases data security, data integrity, trust among its participants. Different organizations are looking to deploy this distributed and decentralized approach to avoid the single-point-of-failure vulnerabilities associated with centralized data repositories. In this study we examine twelve different DLT platforms. There is agreement within the community that of all the platforms considered here, Hyperledger and Ethereum are the most mature when it comes to privacy and permissions. These DLT platforms are being used for applications such as transactive energy, health care, and the food and goods supply chain. However, further development is required to realize the full promise of DLT. Our assessment includes a general description of each DLT and its key characteristics. Such characteristics include consensus protocol and cryptography used, public vs. private, and permissioned or permissionless. The selection and implementation of a DLT architecture depends heavily on the use case and performance requirements. During this research we found key parameters to measure performance and existing tools for assessment. Four different parameters were identified 1) consensus, 2) throughput, 3) latency, and 4) scalability. The architectures of Hyperledger Caliper and Blockbench are described as different performance assessment frameworks. From this preliminary study it is evident that there are dissimilarities on the performance assessments methods developers and users are characterizing DLT architectures. The purpose of this paper is to identify key parameters to test performance, tools that are being used and provide information on results from previous studies.

97 MATHEMATICS AND COMPUTING↗

DOE OSTI2019

Computational modeling of continuum scale constitutive equations to improve biomass feedstock material handling and conveying systems

Existing design practices for common feedstock handling equipment such as hoppers and screw feeders have not been successful in many situations. The lack of an appropriate toolset to characterize and model biomass flow behavior is deemed the root cause of plugging, stalls, and flow-related issues in biomass handling systems design and operations. New standardized characterization protocols in conjunction with appropriate constitutive models will lead to successful biomass handling system design and operations. This study investigates constitutive models for bulk solid flow based on the first principles to overcome issues in biomass handling. The focus is on two major issues in biomass handling, i.e., initiating and sustaining of flow in the hopper that is widely used in biomass conveying operation. Accordingly, this article focuses on analytical models of biomass hopper flow. Mohr-Coulomb, Drucker-Prager, and modified Cam-clay models are investigated as constitutive bulk solid flow models. Parameters of those models are determined using a set of triaxial tests. Triaxial tests are conducted using the cubical triaxial tester (CTT) in the Food and Biomaterials Lab of the Pennsylvania State University. Milled 1mm corn stover and 2mm wood chip biomass materials having different flow characteristics are examined, and their respective flow behavior out of a hopper are simulated using the Finite Element method implementing identified constitutive models and determined fundamental mechanical properties. It is found that, with the same hopper geometry, ground corn stover 1mm tends to exhibit funnel flow whereas ground Douglas fir 2 mm tends to exhibit mass flow. These simulation results are validated with hopper flow experiments. This study demonstrates how biomass flow problems can be predicted and mitigated by numerically modeled fundamental constitutive equations.

09 BIOMASS FUELS↗

DOE OSTI2021

Screening Ionic Liquids Based on Ionic Volume and Electrostatic Potential Analyses

Ionic liquids are known to have tunable solvation properties, based on the pairing of different anions and cations, but the compositional landscape is vast and challenging to navigate efficiently. Some computational screening protocols are available, but they can be either time-consuming or difficult to implement. Herein, we perform a detailed investigation of the fundamental role of electrostatic interactions in these systems. We effectively develop a bridge between the previous volume-based approach (VBA) with a quantum structure–property relationship (QSPR) approach to create fast, simple screening guidelines. We propose a new parameter that is applicable to both monovalent and multivalent ions, the ionic polarity index (IPI), which is defined as the ratio of the average electrostatic surface potential ($\bar{V}$) of the ion to the net charge of the ion (q). The IPI correlation has been tested on a diverse dataset of 121 ions and reliable predictions can be obtained within a homologous series of ionic liquid compounds.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

DOE OSTI2020

HIDES: Hybrid Intrusion Detector for Energy Systems

The establishment of a resilient electric grid accompanied by a secure communications network is an ongoing battle as advanced persistent threats continue to exploit existing vulnerabilities in legacy supervisory control and data acquisition system (SCADA) infrastructure. Traditional intrusion detection systems (IDSs) lack consistent performance because of the continuously evolving attack surface of SCADA systems. These shortcomings can be overcome by integrating logical system behavior, protocol-specific knowledge, and data-based learning to develop a comprehensive IDS solution. In this paper, we present a Hybrid Intrusion Detector for Energy Systems by integrating a network-based IDS, state-of-the-art machine learning-based IDS, and model-based IDS to detect unknown and stealthy cyberattacks targeting the SCADA networks. The proposed IDS uses synchrophasor measurements and cyber logs to learn patterns of different scenarios based on spatiotemporal behaviors of power systems. As a proof of concept, we implement and validate the proposed IDS by leveraging resources available at the National Renewable Energy Laboratory's Energy Systems Integration Facility test bed. Experimental results show promising performance in detecting cyberattacks while providing realtime visualization of power system measurements and cyber logs.

machine-learning intrusion detection system↗

DOE OSTI2020

A Benthic Habitat Monitoring Approach for Marine and Hydrokinetic Sites (Final Technical Report)

This final technical report summarizes the work completed as part of the Standardized and Cost-Effective Benthic Habitat Mapping and Monitoring Tools for MHK Environmental Assessments project funded by U.S. Department of Energy (DOE) under contract DE-EE007826 to Integral Consulting Inc. The overall goal of this project was to demonstrate a consistent, repeatable, and semi-automated seafloor and sediment mapping approach for rapidly characterizing benthic physical and biological/habitat conditions to support marine environmental assessments for marine and hydrokinetic energy sites. The approach evaluated combines sediment profile imaging and plan view (SPI/PV) technology with multibeam echosounder surveys as an effective and low-cost benthic habitat mapping protocol. A key innovation was the development of a semi-automated computer vision system that standardizes the extraction of data from the SPI/PV images. Other elements of the project were SPI camera hardware modifications, including the design and fabrication of a prototype “power” SPI camera to improve camera prism penetration in firm substrates, and outreach to agency regulators and other stakeholders on this habitat mapping approach. This technical report consists of five main subsections that summarize: 1) the benthic mapping approach; 2) benthic mapping results from the three areas’ surveys; 3) the development and performance of the image processing algorithms; 4) SPI camera hardware improvements and prototype testing; and 5) the regulatory outreach efforts.

16 TIDAL AND WAVE POWER↗

DOE OSTI2024

Interlaced Characterization and Calibration (ICC) for Improved Computational Simulation Credibility

Accurate material characterization and model calibration are pivotal for simulations used for high-consequence engineering decisions. Current characterization and calibration methods (1) use simplified test specimen geometries and global data, (2) cannot guarantee that sufficient characterization data is collected for a specific model of interest, (3) provide only mean parameter values with no uncertainty quantification, and (4) are sequential, inflexible, and time-consuming. This work developed a new paradigm—coined Interlaced Characterization and Calibration (ICC)—which drives forward the state-of-the-art in model calibration by bringing together recent advancements into one improved workflow. The ICC paradigm (1) employs tools to efficiently use full-field data to calibrate high-fidelity material models, (2) aligns the data needed with the data collected by adopting an optimal experimental design protocol, (3) provides uncertainty metrics on the calibrated model parameters, and (4) incorporates these advances into a quasi real-time feedback loop. The ICC framework was validated synthetically with both low-fidelity and high-fidelity simulations paired with several different elastoplastic material models, and was also demonstrated experimentally with an aluminum 6061 cruciform exemplar specimen. Results showed that the ICC framework—in which Bayesian optimal experimental design actively guided the experiment— resulted in calibrations with similar or better accuracy than predetermined experiments based on subject matter expertise. Moreover, the ICC framework produced a complete model calibration— with quantified uncertainties on model parameters—in 1 week, a 5 - 10× increase in efficiency over traditional approaches. Thus, the ICC paradigm improves both the calibration process and quality, by (1) improving efficiency, which increases agility of solid mechanics modeling and enables utilization of computational simulation (CompSim) at earlier stages of the design cycle and (2) providing quantified, and in some cases reduced, parameter uncertainties, which increases confidence in model predictions and supports credible decision making.

97 MATHEMATICS AND COMPUTING↗

DOE OSTI2023

Critical Contribution of Imbalanced Charge Loss to Performance Deterioration of Si-Based Lithium-Ion Cells during Calendar Aging

Increasing the energy density of lithium-ion batteries, and thereby reducing costs, is a major target for industry and academic research. One of the best opportunities is to replace the traditional graphite anode with a high-capacity anode material, such as silicon. However, Si-based lithium-ion batteries have been widely reported to suffer from a limited calendar life for automobile applications. Heretofore, there lacks a fundamental understanding of calendar aging for rationally developing mitigation strategies. Both open-circuit voltage and voltage-hold aging protocols were utilized to characterize the aging behavior of Si-based cells. Particularly, a high-precision leakage current measurement was applied to quantitatively measure the rate of parasitic reactions at the electrode/electrolyte interface. The rate of parasitic reactions at the Si anode was found 5 times and 15 times faster than those of LiNi 0.8 Mn 0.1 Co 0.1 O 2 and LiFePO 4 cathodes, respectively. Here, the imbalanced charge loss from parasitic reactions plays a critical role in exacerbating performance deterioration. In addition, a linear relationship between capacity loss and charge consumption from parasitic reactions provides fundamental support to assess calendar life through voltage-hold tests. These new findings imply that longer calendar life can be achieved by suppressing parasitic reactions at the Si anode to balance charge consumption during calendar aging.

25 ENERGY STORAGE↗

DOE OSTI2025

Advancements in Constitutive Model Calibration: Leveraging the Power of Full‐Field DIC Measurements and In Situ Load Path Selection for Reliable Parameter Inference

Accurate material characterization and model calibration are essential for computationally supported high-consequence engineering decisions. Historically, characterization and calibration methods (1) use simplified test specimen geometries and global data, (2) cannot guarantee that sufficient characterization data are collected for a specific model of interest, (3) use deterministic methods that provide best-fit parameter values with no uncertainty quantification, and (4) are sequential, inflexible, and time-consuming. This work brings together several recent advancements into an improved workflow called interlaced characterization and calibration (ICC) that advances the state-of-the-art in constitutive model calibration. The ICC paradigm (1) employs tools to efficiently use full-field data to calibrate high-fidelity material models, (2) aligns the data needed with the data collected by adopting an optimal experimental design protocol, (3) quantifies parameter uncertainty through Bayesian inference and (4) incorporates these advancements into a quasi real-time feedback loop. The ICC framework is demonstrated here on the calibration of a material model using simulated full-field data for an aluminium cruciform specimen being deformed biaxially. The cruciform is actively driven through the myopically preferred load path using Bayesian optimal experimental design, which selects load steps that yield the maximum expected information gain (EIG). Principal component analysis (PCA) is performed on the model predictions of full-field displacements, and fast surrogate models are built to approximate the input-output relationships of the expensive finite element model. Furthermore, the tools developed and demonstrated here show that high-fidelity constitutive models can be efficiently and reliably calibrated with quantified uncertainty, thus supporting credible decision-making and potentially increasing the agility of solid mechanics modelling by enabling utilization of computational simulations at earlier stages of the design cycle.

Bayesian optimal experimental design↗

DOE OSTI2019

Combined Effects of Three High-Energy Charged Particle Beams Important for Space Flight on Brain, Behavioral and Cognitive Endpoints in B6D2F1 Female and Male Mice

The radiation environment in deep space includes the galactic cosmic radiation with different proportions of all naturally occurring ions from protons to uranium. Most experimental animal studies for assessing the biological effects of charged particles have involved acute dose delivery for single ions and/or fractionated exposure protocols. Here, we assessed the behavioral and cognitive performance of female and male C 57 BL/6J × DBA2/J F1 (B6D2F1) mice 2 months following rapidly delivered, sequential irradiation with protons (1 GeV, 60%), 16 O (250 MeV/n, 20%), and 28 Si (263 MeV/n, 20%) at 0, 25, 50, or 200 cGy at 4-6 months of age. Cortical BDNF, CD68, and MAP-2 levels were analyzed 3 months after irradiation or sham irradiation. During the dark period, male mice irradiated with 50 cGy showed higher activity levels in the home cage than sham-irradiated mice. Mice irradiated with 50 cGy also showed increased depressive behavior in the forced swim test. When cognitive performance was assessed, sham-irradiated mice of both sexes and mice irradiated with 25 cGy showed normal responses to object recognition and novel object exploration. However, object recognition was impaired in female and male mice irradiated with 50 or 200 cGy. For cortical levels of the neurotrophic factor BDNF and the marker of microglial activation CD68, there were sex × radiation interactions. In females, but not males, there were increased CD68 levels following irradiation. In males, but not females, there were reduced BDNF levels following irradiation. A significant positive correlation between BDNF and CD68 levels was observed, suggesting a role for activated microglia in the alterations in BDNF levels. Finally, sequential beam irradiation impacted the diversity and composition of the gut microbiome. These included dose-dependent impacts and alterations to the relative abundance of several gut genera, such as Butyricicoccus and Lachnospiraceae . Thus, exposure to rapidly delivered sequential proton, 16 O ion, and 28 Si ion irradiation significantly affects behavioral and cognitive performance, cortical levels of CD68 and BDNF in a sex-dependent fashion, and the gut microbiome.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2018

Dose-limiting Urinary Toxicity With Pembrolizumab Combined With Weekly Hypofractionated Radiation Therapy in Bladder Cancer

There is currently significant interest in the potential benefits of combining radiation and immune checkpoint blockade (ICB) to stimulate both regional and distant abscopal immune responses. In melanoma and lung cancer, patients who have received radiation therapy during ICB appear to have prolonged survival. The PLUMMB trial (Pembrolizumab in Muscle-invasive/Metastatic Bladder cancer) (NCT02560636) is a phase I study to test the tolerability of a combination of weekly radiation therapy with pembrolizumab in patients with metastatic or locally advanced urothelial cancer of the bladder. In the first dose-cohort, patients received pembrolizumab 100 mg 3-weekly, starting 2 weeks before commencing weekly adaptive bladder radiation therapy to a dose of 36 Gy in 6 fractions. The first dose-cohort was stopped after 5 patients, having met the predefined definition of dose-limiting toxicity. Three patients experienced grade 3 urinary toxicities, 2 of which were attributable to therapy. One patient experienced a grade 4 rectal perforation. In view of these findings, the trial has been paused and the protocol will be amended to reduce radiation therapy dose per fraction. The authors advise caution to those combining radiation therapy and ICB, particularly when radiation therapy is given at high dose per fraction for pelvic tumours. The PLUMMB trial met the protocol-defined definition of dose-limiting toxicity and will be amended to reduce radiation therapy dose.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2018

Part 1: Tracing Russian VX to its synthetic routes by multivariate statistics of chemical attribution signatures

Chemical attribution signatures (CAS) associated with different synthetic routes used for the production of Russian VX (VR) were identified here. The goal of the study was to retrospectively determine the production method employed for an unknown VR sample. Six different production methods were evaluated, carefully chosen to include established synthetic routes used in the past for large scale production of the agent, routes involving general phosphorus-sulfur chemistry pathways leading to the agent, and routes whose main characteristic is their innate simplicity in execution. Two laboratories worked in parallel and synthesized a total of 37 batches of VR via the six synthetic routes following predefined synthesis protocols. The chemical composition of impurities and byproducts in each route was analyzed by GC/MS-EI and 49 potential CAS were recognized as important markers in distinguishing these routes using Principal Component Analysis (PCA). The 49 potential CAS included expected species based on knowledge of reaction conditions and pathways but also several novel compounds that were fully identified and characterized by a combined analysis that included MS-CI, MS-EI and HR-MS. The CAS profiles of the calibration set were then analyzed using partial least squares discriminant analysis (PLS-DA) and a cross validated model was constructed. The model allowed the correct classification of an external test set without any misclassifications, demonstrating the utility of this methodology for attributing VR samples to a particular production method. This work is part one of a three-part series in this Forensic VSI issue of a Sweden-United States collaborative effort towards the understanding of the CAS of VR in diverse batches and matrices. This part focuses on the CAS in synthesized batches of crude VR and in the following two parts of the series the influence of food matrices on the CAS profiles are investigated.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗