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All sourcesNASA NTRSDOE OSTI
NASA NTRS2016

3D Printing in Zero G Technology Demonstration Mission: Summary of On-Orbit Operations, Material Testing, and Future Work

Human space exploration to date has been limited to low Earth orbit and the moon. The International Space Station (ISS), an orbiting laboratory 200 miles above the earth, provides a unique and incredible opportunity for researchers to prove out the technologies that will enable humans to safely live and work in space for longer periods of time and venture farther into the solar system. The ability to manufacture parts in-space rather than launch them from earth represents a fundamental shift in the current risk and logistics paradigm for human spaceflight. In particularly, additive manufacturing (or 3D printing) techniques can potentially be deployed in the space environment to enhance crew safety (by providing an on-demand part replacement capability) and decrease launch mass by reducing the number of spare components that must be launched for missions where cargo resupply is not a near-term option. In September 2014, NASA launched the 3D Printing in Zero G technology demonstration mission to the ISS to explore the potential of additive manufacturing for in-space applications and demonstrate the capability to manufacture parts and tools on-orbit. The printer for this mission was designed and operated by the company Made In Space under a NASA SBIR (Small Business Innovation Research) phase III contract. The overarching objectives of the 3D print mission were to use ISS as a testbed to further maturation of enhancing technologies needed for long duration human exploration missions, introduce new materials and methods to fabricate structure in space, enable cost-effective manufacturing for structures and mechanisms made in low-unit production, and enable physical components to be manufactured in space on long duration missions if necessary. The 3D print unit for fused deposition modeling (FDM) of acrylonitrile butadiene styrene (ABS) was integrated into the ISS Microgravity Science Glovebox (MSG) in November 2014 and phase I printing operations took place from November through December of that year. Phase I flight operations yielded 14 unique parts (21 total specimens) that could be directly compared against ground-based prints of identical geometry manufactured using the printer prior to its launch to ISS. The 3DP unit functioned safely and produced specimens necessary to advance the understanding of the critical design and operational parameters for the FDM process as affected by the microgravity environment. From the standpoint of operations, 3DP demonstrated the ability to remove parts from the build-tray on-orbit, teleoperate the printer from the ground, perform critical maintenance functions within defined human factors limits, produce a functional tool that could be evaluated for form/fit/function, and uplink a new part file from the ground and produce it on the printer. The flight parts arrived at NASA Marshall Space Flight Center in Huntsville, Alabama in April 2015, where they underwent months of testing in the materials and processes laboratory. Ground and flight prints completed the following phases of testing: photographic/visual inspection, mass and density evaluation, structured light scanning, XRay and CT, mechanical testing, optical microscopy, scanning electron microscopy, and chemical analysis. This presentation will discuss the results of this testing as well as phase II operations for the printer, which took place in June and July of 2016. Lessons learned from the tech demo and their impacts on the design and development of the second generation 3D printer for ISS, the Additive Manufacturing Facility (AMF) by Made In Space will also be presented. In addition, progress in other elements of NASA's In Space Manufacturing (ISM) initiative such as the on-demand ISM utilization catalog, in-space Recycler ISS Technology Demonstration development, launch packaging recycling, in-space printable electronics, development of higher strength polymeric materials for 3D printing and Additive Construction by Mobile Emplacement (ACME) will also be addressed.

Prater, Tracie↗
NASA NTRS2018

Multidisciplinary Design Optimization and Cruise Mach Number Study of Truss-Braced Wing Aircraft

The Subsonic Ultra Green Aircraft Research (SUGAR) Phase III was led by Dr. Rakesh K. Kapania and Dr. Joseph A. Schetz at the Multidisciplinary Analysis and Design Center for Advanced Vehicles, Department of Aerospace and Ocean Engineering, Virginia Tech, Blacksburg VA. The research was performed from December 2014 to December 2015. Three major areas were investigated: Multidisciplinary Design Optimization (MDO) studies of truss braced wing (TBW) and strut braced wing (SBW) vehicles at cruise Mach numbers of 0.7 and 0.8 for a flight mission similar to current market single aisle configurations. The performance and the characteristics of the optimized vehicles were compared to the SUGAR Phase II TBW vehicle. These results were obtained without applying any of the extended transonic aerodynamic and aeroelastic tools that will be discussed later. It was found that the cruise Mach number has a large effect on the best “truss” configuration. At Mach 0.7, an SBW has a better fuel consumption and better take-off gross weight (TOGW). However, at Mach 0.8, the TBW is superior because the jury strut aids in satisfying the flutter constraint; Two-dimensional, steady, transonic aerodynamic analysis of the Boeing Airfoil J (BACJ) airfoil was performed for a range of thickness ratios, Mach numbers and lift coefficients. Reynolds-averaged Navier-Stokes (RANS) equations were solved to obtain the lift-curve slope, wave drag coefficient, the location of the center of pressure and to predict the separation at the trailing edge, which may lead to buffeting. One of the goals was to develop a database of lift-curve slope and the location of center of pressure, which could be used in a transonic aeroelastic analysis. Another goal was to compare the wave drag coefficients to those predicted by Lock’s fourth-power law and also to compare the transonic effects obtained from RANS simulations to those predicted by the Korn equations. A third goal was to develop a buffet boundary, which can be integrated into the MDO framework to prevent the optimized designs from probable buffeting; A state-space transonic aeroelastic analysis tool was developed, which can incorporate the nonlinear transonic effects in the unsteady aerodynamics but is yet computationally cheap when used within the VT MDO framework. The aeroelastic analysis uses Leishman- Beddoes (LB) indicial functions, which generated a state-space representation of the aeroelastic system. The indicial functions allow the incorporation of data for steady lift-curve slope and location of the center of pressure. Thus, the steady transonic effects are included, and the unsteady aerodynamic responses are a linearization about the steady results. The aeroelastic approach discretizes the wing into numerous strips, which results in a large eigenvalue problem as each strip has eight augmented aerodynamic states as per the LB theory. Thus, to reduce the computation expense, a reduced order model (ROM) was developed. The approach was validated using a few examples.

Kapania, Rakesh K.↗
NASA NTRS2005

KSC SBIR/STTR 2004 Program Year Report

The Kennedy Space Center Level III SBIR/STTR management staff is under the Technology Transfer Office within the Spaceport Engineering and Technology Directorate. The SBIR and STTR programs provide an opportunity for small high technology companies and research institutions to participate in Government-sponsored research and development (R&D) programs in key technology areas. The SBIR program was established by Congress in 1982 to provide increased opportunities for small businesses to participate in R&D programs, increase employment, and improve U.S. competitiveness. The program's specific objectives are to stimulate U.S. technological innovation, use small businesses to meet Federal research and development needs, increase private sector commercialization of innovations, and foster and encourage participation by socially disadvantaged businesses. Legislation enacted in December 2000 reauthorized the program and strengthened emphasis on pursuing commercial applications of SBIR projects. An SBIR Phase I contract is the opportunity to establish the feasibility and technical merit of a proposed innovation. Selected competitively, the Phase I contract lasts for 6 months and is funded up to $70,000. SBIR Phase II contracts continue the most promising Phase I projects based on scientific! technical merit, expected value to NASA, company capability, and commercial potential. Phase II contracts are usually for a period of 24 months and may not exceed $600,000. NASA usually selects approximately 40 percent of Phase I projects to continue to the Phase II level. Phase III is the process of furthering the development of a product to make it commercially available. The STTR program awards contracts to small business concerns for cooperative R&D with a nonprofit research institution. Research institutions include nonprofit research organizations, Federal laboratories, or universities. The goal of the program established by Congress is to facilitate the transfer of technology developed by a research institution through the entrepreneurship of a small business. The STIR program is smaller in funding than the SBIR program. While the proposal is submitted by the small business concern, at least 30 percent of the funding and work must originate with the research institution. STTR Phase I projects receive up to $100K for a one-year effort, and a Phase II contract receives up to $600K for two years.

Source record↗
DOE OSTI2021

Cloud microphysical structure analysis based on high-resolution insitu measurements

This study investigates the microphysical parameters and shapes of droplet size distributions (DSDs) along three aircraft traverses of developing convective clouds during Cloud Aerosol Interactions and Precipitation Enhancement Experiment (CAIPEEX) Phase III 2015 at a sampling frequency of 25 Hz. The droplet number concentration (Nc, cm -3 ), and liquid water content (LWC, g m -3 ) present steep gradients within zones of a few tens of meters near the cloud edges and relatively gentle gradients in the strong updraft zones. Sometimes, the horizontal LWC distribution resembles a trapezoidal shape with steep LWC and Nc gradients near the cloud edges. The LWC maximums (LWC max ) are lower than the adiabatic LWCs, but the high adiabatic fractions in the cloud core indicate low dilution. High LWC/LWC max , largest droplets, and narrow and similarly shaped DSDs are found in the regions of high updrafts. Zones of low LWC/LWC max are found close to the cloud edges, where DSDs are highly diverse, containing both large and small droplets. Finally, we analyze the mixing diagrams. Significant in-phase turbulent fluctuations in LWC and N c were found. The effective radii change slightly across cloud updraft zones but decrease at the zone of low LWC/LWC max ratio close to cloud edges. The spectra of LWC and N c obey Kolmogorov -5/3 turbulence law. The radii of the correlation of LWC and N c in updraft zones are of several tens of meters. Filaments up to 120–175 m in size are also noticed.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2015

New Generator Technology

New generator technology project is driven by the need to be able to remotely deploy generator technology where it is needed, when it is needed. Both the military and aid programs that provide assistance after disasters could use the ability to deploy energy generation that fits the needs of the situation. Currently, pre-specified generators are deployed, sometime more than half way around the world to provide electricity. Through our Phase-I to Phase III DARPA grant, we will provide a mechanism where a 3d print station and raw materials could be shipped to a deployment site and remotely deployed personnel. These remote personnel can collaborate with engineers at a home location where 3d print plans can be optimized for the remote purpose. The plans can then be sent electronically to the remote location for printing, much like NASA sent the plans for a socket wrench to the International Space Station for printing in . If multiple generators need to be deployed at different remote locations, within miles of each other the printer rig can be moved to print the generators where they are needed. 3d printing is growing in the field of manufacturing. 3d printing has matured to the point where many types of materials are now available for many types of manufacturing. Both magnetic and electrically conductive material materials have recently been developed which can now lead to 3d printing of engines and generators. Our project will provide a successful printer rig that can be remotely deployed, to print a generator design in the field as well as provide a process for deploying the printed generator as well. This Systems Engineering Management Plan(SEMP) will provide the planning required for a Phase I DARPA grant that may also include goals for Phase II and Phase II grants. The SEMP provides a proposed project schedule, references, system engineering processes, specialty engineering system deployment and product support sections. Each section will state how our company will provide the necessary services to make this project succeed.

3D printing, manufacturing, generator technology, ↗
DOE OSTI2022

Liquid Salt Combined-Cycle Pilot Plant Design

The work described in this report is responsive to the Office of Fossil Energy program ‘Energy Storage for Fossil Power Generation.’ This Phase I report has been prepared by Pintail Power LLC, with support from Nexant ECA, Electric Power Research Institute (EPRI) and Southern Company Services as a deliverable for the U.S. Department of Energy for NETL Award DE-FE-00320016. The Liquid Salt Combined Cycle™ (LSCC™) technology provides large-scale energy storage integrated with Fossil Electric Generating Units (FEGUs) to meet critical needs in the energy transition by providing: • the lowest cost large-scale storage for time-shifting of renewable energy, • superior fuel efficiency to reduce GHGs from dispatchable resources, • flexible capacity and ramping to balance variability of wind and solar resources, • essential grid stability services to assure reliability of a low-carbon grid. The LSCC approach: • employs equipment that has already been proven in utility service, • uses safe, non-toxic, non-degrading, perpetual-life storage medium, • leverages and repurposes existing FEGU assets, • expands the value stack of energy storage to reduce market, financing, and commodity risks. Pintail Power has developed the LSCC technology to meet the need for reliable, efficient, and cost-effective integration of Variable Renewable Energy (VRE) into a low-carbon electric grid by coupling proven thermal energy storage with proven gas turbines, steam turbines, and heat transfer equipment. This novel approach is intended to address the key issues facing the grid and operators of renewable and fossil generating units including: • Overgeneration and curtailment of renewables, • Need for fast ramping dispatchable resources, • Improved efficiency and flexibility of fossil units, • Additional peaking capacity to support electrification of transportation and heating, • Provision of reliability services to support high penetration of VRE, especially synchronous inertia and fast frequency response. A Technology Readiness assessment by EPRI confirmed that LSCC technology consists of commercially proven hardware used in industrial and utility applications. Although the novel LSCC approach has not yet been demonstrated as a complete system, interfaces between major components have been conservatively specified. A Phase III pilot is planned to demonstrate equipment integration and operation. The patented innovation is removal of the evaporator section from the exhaust heat recovery system, with the evaporation performed by stored energy in a separate steam generator. This arrangement couples renewable and fossil power generation via long-duration energy storage to deliver cost, performance, and operational synergies, including superior charging and discharging flexibility, reduced fuel consumption and lower CO 2 emissions compared to conventional Combined Cycle Power Plants, and low-cost, large-scale energy storage. The LSCC technology is composed of proven equipment integrated with gas turbine exhaust heat in a novel system. During charging, electric heaters raise the salt temperature as it flows from the Cold Salt Tank to the Hot Salt Tank. During discharging, hot salt produces steam from feedwater that is heated with gas turbine exhaust, which also superheats steam to drive a steam turbine. LSCC technology can be added to any combustion-turbine to integrate renewable energy, provide needed grid services, and increase the value of fossil electric generating units based on the technology’s following attributes: • Long-duration storage enables time-shifting of VRE to avoid curtailment and impairment of renewable assets. • Long storage duration combined with fast-charging capability increases arbitrage opportunities by storing more energy when the price is low and discharging more hours when the price is high. • Long storage duration allows resource adequacy to be supplied across multiple days to increase reliability and reduce risk. • The stored energy reduces fuel heat rate and GHG emissions, and increases merit, so the LSCC dispatches earlier and longer to increase the plant’s capacity factor and asset value. • The stored energy enables pre-heating and startup of the steam cycle, without operating the gas turbine, to enable fast startup and ramping when dispatched for discharge. • The steam turbine can operate without the gas turbine so it can provide valuable synchronous inertia during charging without consuming fuel. • Fast frequency response and regulation services can be provided during charging using solid-state heater and pump controls to vary the charge power input in response to grid signals. • The LSCC system can be configured for resilience including black start, islanded/micro-grid operation, and even self-recharging of storage using either gas turbine power or gas turbine exhaust heat. The commercialization plan is to add LSCC technology to existing simple cycle gas turbine power plants with the 50MW GE LM6000 aero-derivative gas turbine as the reference design basis. A Techno-economic assessment of the reference design evaluated the benefits (Levelized Avoided Cost of Energy) and costs (Levelized Cost of Energy). The plant definition included all major systems and budgetary vendor quotes. Pintail Power and NexantECA developed the overall cost estimate for the LSCC plant up to the total plant cost level, following the DOE-NETL cost estimate guidelines at AACE Class 3 (-20%/+30%). This includes the equipment cost, bulk material, direct and indirect labor costs to arrive at the bare erected cost. Engineering costs are factored from the BEC and added to it to arrive at the EPC cost. Process and project contingencies were then factored from the EPC cost and rolled-up to yield the total plant cost of $\$$184 million for 1746 MWh of discharge electricity. • At $\$$105/kWh, the reference plant costs less than any of the Energy Storage Systems evaluated by PNNL in 2020 for the Energy Storage Grand Challenge. Operations and Maintenance cost estimates were scaled from combined cycle practice, assuming that the LSCC unit was co-located with and sharing some labor expense with other units, to arrive at $\$$2.2 million per year. Plant economics were evaluated using prices from the ERCOT Day-Ahead Market for calendar year 2019 (excluding the market disruptions from the COVID pandemic and the February 2020 deep freeze event). Assuming economic dispatch in the ERCOT Day-Ahead market, the reference plant capacity factor would have discharged for 2777 hours at 91.9 MW, a 31.66% capacity factor, with a marginal cost of $\$$25.59/MWh, and a LACE of $\$$82.41/MWh. Fixed charges were calculated according to EIA guidelines to arrive at an LCOE of $\$$83.48. The benefit-to-cost ratio of 0.99 suggests that the reference plant would have been cost-effective and competitive in the market. EPRI interviewed selected utilities to gauge the need for, applicability of and interest in the LSCC system. Several utilities are currently managing increased load growth along with the inclusion of increasing levels of renewable generation, putting pressure on conventional generation by requiring increased turndown requirements and ultimately lower capacity factors. All of the utilities interviewed have CO 2 reduction targets in the 2030-2050 timeframe that will severely limit the participation of fossil generation and require better utilization of carbon free generation. While there is limited opportunity for storage in the current markets, the utilities interviewed stated that there will be a substantial need for long duration energy storage in the future given the expected trends. Utilizing an energy storage system will generally be preferred over new gas capacity in some cases, with the capabilities of the LSCC system being a potential option for retrofit to existing simple cycle gas turbine units, allowing them to deliver greater participation in the market with lower carbon intensity. A technology gap assessment and technology maturation plan identified a pilot-scale demonstration as the final step before commercialization. Key gaps to be addressed during the Phase II FEED (Front-End Engineering Design) are component selection and design, commissioning procedures, and operational procedures and the control system for LSCC charging and discharging. The project team has been expanded to include Wood Group PLC as EPC. The proposed Phase II work leads to a pilot-scale engineering demonstration (TRL 6) to be conducted at Southern Company’s Plant Rowan, where the prototype system will perform “all the functions that will be required of the operational system.” The proposed pilot will facilitate commercialization (TRL-9) by scale-up to utility-scale systems integrated with peaking GTs or directly to facility scale systems using industrial GTs. The conceptual design for the pilot plant focuses on the novel integration aspects of LSCC technology. A slipstream of gas turbine exhaust will feed a waste heat recovery unit coupled to a molten salt steam generator heated by stored energy. The pilot is intended to demonstrate all key operating modes of the LSCC technology during charging, discharging and standby. The pilot equipment will be approximately one-seventh scale of the LM6000 commercial target and is expected to have commercial off-ramp potential for facility-scale applications.

01 COAL, LIGNITE, AND PEAT↗
DOE OSTI2015

Quantifying uncertainty in stable isotope mixing models

Mixing models are powerful tools for identifying biogeochemical sources and determining mixing fractions in a sample. However, identification of actual source contributors is often not simple, and source compositions typically vary or even overlap, significantly increasing model uncertainty in calculated mixing fractions. This study compares three probabilistic methods, SIAR [ Parnell et al ., 2010] a pure Monte Carlo technique (PMC), and Stable Isotope Reference Source (SIRS) mixing model, a new technique that estimates mixing in systems with more than three sources and/or uncertain source compositions. In this paper, we use nitrate stable isotope examples (δ 15 N and δ 18 O) but all methods tested are applicable to other tracers. In Phase I of a three-phase blind test, we compared methods for a set of six-source nitrate problems. PMC was unable to find solutions for two of the target water samples. The Bayesian method, SIAR, experienced anchoring problems, and SIRS calculated mixing fractions that most closely approximated the known mixing fractions. For that reason, SIRS was the only approach used in the next phase of testing. In Phase II, the problem was broadened where any subset of the six sources could be a possible solution to the mixing problem. Results showed a high rate of Type I errors where solutions included sources that were not contributing to the sample. In Phase III some sources were eliminated based on assumed site knowledge and assumed nitrate concentrations, substantially reduced mixing fraction uncertainties and lowered the Type I error rate. These results demonstrate that valuable insights into stable isotope mixing problems result from probabilistic mixing model approaches like SIRS. The results also emphasize the importance of identifying a minimal set of potential sources and quantifying uncertainties in source isotopic composition as well as demonstrating the value of additional information in reducing the uncertainty in calculated mixing fractions.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2019

Radioablation by Image-Guided (HDR) Brachytherapy and Transarterial Chemoembolization in Hepatocellular Carcinoma: A Randomized Phase II Trial

Background and Aims: The aim of this single-center, open-label phase II study was to assess the efficacy of image-guided high-dose-rate (HDR) brachytherapy (iBT) compared with conventional transarterial embolization (cTACE) in unresectable hepatocellular carcinoma. Methods: Seventy-seven patients were treated after randomization to iBT or cTACE, as single or repeated interventions. Crossover was allowed if clinically indicated. The primary endpoint was time to untreatable progression (TTUP). Eligibility criteria included a Child–Pugh score of ≤ 8 points, absence of portal vein thrombosis (PVT) at the affected liver lobe, and ≤ 4 lesions. Survival was analyzed by using the Cox proportional hazard model with stratification for Barcelona Clinic Liver Cancer (BCLC) stages. Results: Twenty patients were classified as BCLC-A (iBT/cTACE 8/12), 35 as BCLC-B (16/19), and 22 as BCLC-C (13/9). The 1-, 2-, and 3-year TTUP probabilities for iBT compared with cTACE were 67.5% versus 55.2%, 56.0% versus 27.4%, and 29.5% versus 11.0%, respectively, with an adjusted hazard ratio (HR) of 0.49 (95% confidence interval 0.27–0.89; p = 0.019). The 1-, 2-, and 3-year TTPs for iBT versus cTACE were 56.0% versus 28.2%, 23.9% versus 6.3%, and 15.9% versus 6.3%, respectively, with an adjusted HR of 0.49 (0.29–0.85; p = 0.011). The 1-, 2-, and 3-year OS rates were 78.4% versus 67.7%, 62.0% versus 47.3%, and 36.7% versus 27.0%, respectively, with an adjusted HR of 0.62 (0.33–1.16; p = 0.136). Conclusions: This explorative phase II trial showed a superior outcome of iBT compared with cTACE in hepatocellular carcinoma and supports proceeding to a phase III trial.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

Challenging problems of quality assurance and quality control (QA/QC) of meteorological time series data

Abstract Representativeness and quality of collected meteorological data impact accuracy and precision of climate, hydrological, and biogeochemical analyses and predictions. We developed a comprehensive Quality Assurance (QA) and Quality Control (QC) statistical framework, consisting of three major phases: Phase I—Preliminary data exploration, i.e., processing of raw datasets, with the challenging problems of time formatting and combining datasets of different lengths and different time intervals; Phase II—QA of the datasets, including detecting and flagging of duplicates, outliers, and extreme data; and Phase III—the development of time series of a desired frequency, imputation of missing values, visualization and a final statistical summary. The paper includes two use cases based on the time series data collected at the Billy Barr meteorological station (East River Watershed, Colorado), and the Barro Colorado Island (BCI, Panama) meteorological station. The developed statistical framework is suitable for both real-time and post-data-collection QA/QC analysis of meteorological datasets.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Electrosynthesis of Ti{sub 5}Si{sub 3}, Ti{sub 5}Si{sub 3}/TiC, and Ti{sub 5}Si{sub 3}/Ti{sub 3}SiC{sub 2} from Ti-Bearing Blast Furnace Slag in Molten CaCl{sub 2}

Ti{sub 5}Si{sub 3}, Ti{sub 5}Si{sub 3}/TiC, and Ti{sub 5}Si{sub 3}/Ti{sub 3}SiC{sub 2} have been electrochemically synthesized from the Ti-bearing blast furnace slag/TiO{sub 2} and/or C mixture precursors at a cell voltage of 3.8 V and 1223 K to 1273 K (950 °C to 1000 °C) in molten CaCl{sub 2}. The pressed porous mixture pellets were used as the cathode, and a solid oxide oxygen-ion-conducting membrane (SOM)-based anode was used as the anode. The phase composition and morphologies of the cathodic products were systematically characterized. The final products possess a porous nodular microstructure due to the interconnection of particles. The variations of impurity elements, i.e., Ca, Mg, and Al, have been analyzed, and the result shows that Ca and Mg can be almost completely removed; however, Al cannot be easily removed from the pellet due to the formation of Ti-Al alloys during the electroreduction process. The electroreduction process has also been investigated by the layer-depended phase composition analysis of the dipped/partially reduced pellets to understand the detailed reaction process. The results indicate that the electroreduction process of the Ti-bearing blast furnace slag/TiO{sub 2} and/or C mixture precursors can be typically divided into four periods, i.e., (i) the decomposition of initial Ca(Mg,Al)(Si,Al){sub 2}O{sub 6}, (ii) the reduction of Ti/Si-containing intermediate phases, (iii) the removal of impurity elements, and (iv) the formation of Ti{sub 5}Si{sub 3}, TiC, and Ti{sub 3}SiC{sub 2}. It is suggested that the SOM-based anode process has great potential to be used for the direct and facile preparation of Ti alloys and composites from cheap Ti-containing ores.

36 MATERIALS SCIENCE↗
DOE OSTI2023

Structure-based mechanism and inhibition of cholesteryl ester transfer protein

Purpose of Review: Cholesteryl ester transfer proteins (CETP) regulate plasma cholesterol levels by transferring cholesteryl esters (CEs) among lipoproteins. Lipoprotein cholesterol levels correlate with the risk factors for atherosclerotic cardiovascular disease (ASCVD). This article reviews recent research on CETP structure, lipid transfer mechanism, and its inhibition. Recent Findings: Genetic deficiency in CETP is associated with a low plasma level of low-density lipoprotein cholesterol (LDL-C) and a profoundly elevated plasma level of high-density lipoprotein cholesterol (HDL-C), which correlates with a lower risk of atherosclerotic cardiovascular disease (ASCVD). However, a very high concentration of HDL-C also correlates with increased ASCVD mortality. Considering that the elevated CETP activity is a major determinant of the atherogenic dyslipidemia, i.e., pro-atherogenic reductions in HDL and LDL particle size, inhibition of CETP emerged as a promising pharmacological target during the past two decades. CETP inhibitors, including torcetrapib, dalcetrapib, evacetrapib, anacetrapib and obicetrapib, were designed and evaluated in phase III clinical trials for the treatment of ASCVD or dyslipidemia. Although these inhibitors increase in plasma HDL-C levels and/or reduce LDL-C levels, the poor efficacy against ASCVD ended interest in CETP as an anti-ASCVD target. Nevertheless, interest in CETP and the molecular mechanism by which it inhibits CE transfer among lipoproteins persisted. Insights into the structural-based CETP-lipoprotein interactions can unravel CETP inhibition machinery, which can hopefully guide the design of more effective CETP inhibitors that combat ASCVD. Summary: Individual-molecule 3D structures of CETP bound to lipoproteins provide a model for understanding the mechanism by which CETP mediates lipid transfer and which in turn, guide the rational design of new anti-ASCVD therapeutics.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2016

RVX-297- a novel BD2 selective inhibitor of BET bromodomains

Bromodomains are epigenetic readers that specifically bind to the acetyl lysine residues of histones and transcription factors. Small molecule BET bromodomain inhibitors can disrupt this interaction which leads to potential modulation of several disease states. Here we describe the binding properties of a novel BET inhibitor RVX-297 that is structurally related to the clinical compound RVX-208, currently undergoing phase III clinical trials for the treatment of cardiovascular diseases, but is distinctly different in its biological and pharmacokinetic profiles. We report that RVX-297 preferentially binds to the BD2 domains of the BET bromodomain and Extra Terminal (BET) family of protein. We demonstrate the differential binding modes of RVX-297 in BD1 and BD2 domains of BRD4 and BRD2 using X-ray crystallography, and describe the structural differences driving the BD2 selective binding of RVX-297. The isothermal titration calorimetry (ITC) data illustrate the related differential thermodynamics of binding of RVX-297 to single as well as dual BET bromodomains. - Highlights: • A novel inhibitor of BET bromodomains, RVX-297 is described. • The differential binding modes of RVX-297 in BD1 and BD2 domains of BRD4 and BRD2 using X-ray crystallography are described. • RVX-297 preferentially binds to the BD2 domains of the BET bromodomains. • The structural and thermodynamic properties of the BD2 selective binding of RVX-297 are characterized.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Inhibitory effect of fasiglifam on hepatitis B virus infections through suppression of the sodium taurocholate cotransporting polypeptide

Highlights: • Fasiglifam decreased extracellular HBV DNA in NTCP expressed HepG2 cells. • Fasiglifam also decreased extracellular HBV DNA in PXB cells. • Fasiglifam only affect on HBV infection via NTCP inhibition. Fasiglifam is a selective partial agonist of G-protein–coupled receptor 40 (GPR40), which was developed for the treatment of type 2 diabetes mellitus. However, the clinical development of fasiglifam was voluntarily terminated during phase III clinical trials due to adverse liver effects. Fasiglifam showed an inhibitory effect on sodium taurocholate cotransporting polypeptide (NTCP) in human and rat hepatocytes. Recently, NTCP was reported to be a functional receptor for human hepatitis B virus (HBV) infections. Therefore, in this study, we hypothesised that fasiglifam would be a good candidate for a novel HBV entry inhibitor, and its effects were evaluated by using NTCP-overexpressing HepG2 cells, human hepatocyte cell lines and human hepatocytes (PXB cells) obtained from PXB mice. Pre-treatment with fasiglifam at a concentration of 30 μM prior to HBV infection significantly suppressed supernatant HBV DNA levels after HBV infection in NTCP-overexpressing HepG2 cells, human hepatocyte cell lines and PXB cells. Fasiglifam did not suppress supernatant HBV DNA levels up to 50 μM in HepG2.2.15.7 cells, which are stably transfected with a complete HBV genome without HBV infection. These results indicated that fasiglifam only affect on HBV infection via NTCP inhibition. For HBV treatment of fasiglifam, further investigation including additional non clinical research in addition to the evaluation of safety and efficacy in humans would be needed in the future study.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Extended (5-year) Outcomes of Accelerated Partial Breast Irradiation Using MammoSite Balloon Brachytherapy: Patterns of Failure, Patient Selection, and Dosimetric Correlates for Late Toxicity

Purpose: Accelerated partial breast irradiation (APBI) with balloon and catheter-based brachytherapy has gained increasing popularity in recent years and is the subject of ongoing phase III trials. Initial data suggest promising local control and cosmetic results in appropriately selected patients. Long-term data continue to evolve but are limited outside of the context of the American Society of Breast Surgeons Registry Trial. Methods and Materials: A retrospective review of 157 patients completing APBI after breast-conserving surgery and axillary staging via high-dose-rate {sup 192}Ir brachytherapy from June 2002 to December 2007 was made. APBI was delivered with a single-lumen MammoSite balloon-based applicator to a median dose of 34 Gy in 10 fractions over a 5-day period. Tumor coverage and critical organ dosimetry were retrospectively collected on the basis of computed tomography completed for conformance and symmetry. Results: At a median follow-up time of 5.5 years (range, 0-10.0 years), the 5-year and 7-year actuarial incidences of ipsilateral breast control were 98%/98%, of nodal control 99%/98%, and of distant control 99%/99%, respectively. The crude rate of ipsilateral breast recurrence was 2.5% (n=4); of nodal failure, 1.9% (n=3); and of distant failure, 0.6% (n=1). The 5-year and 7-year actuarial overall survival rates were 89%/86%, with breast cancer–specific survival of 100%/99%, respectively. Good to excellent cosmetic outcomes were achieved in 93.4% of patients. Telangiectasia developed in 27% of patients, with 1-year, 3-year, and 5-year actuarial incidence of 7%/24%/33%; skin dose >100% significantly predicted for the development of telangiectasia (50% vs 14%, P<.0001). Conclusions: Long-term single-institution outcomes suggest excellent tumor control, breast cosmesis, and minimal late toxicity. Skin toxicity is a function of skin dose, which may be ameliorated with dosimetric optimization afforded by newer multicatheter brachytherapy applicators and a more rigorous skin dose constraint of ≤100%.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2013

Use of EORTC Target Definition Guidelines for Dose-Intensified Salvage Radiation Therapy for Recurrent Prostate Cancer: Results of the Quality Assurance Program of the Randomized Trial SAKK 09/10

Purpose: Different international target volume delineation guidelines exist and different treatment techniques are available for salvage radiation therapy (RT) for recurrent prostate cancer, but less is known regarding their respective applicability in clinical practice. Methods and Materials: A randomized phase III trial testing 64 Gy vs 70 Gy salvage RT was accompanied by an intense quality assurance program including a site-specific and study-specific questionnaire and a dummy run (DR). Target volume delineation was performed according to the European Organisation for the Research and Treatment of Cancer guidelines, and a DR-based treatment plan was established for 70 Gy. Major and minor protocol deviations were noted, interobserver agreement of delineated target contours was assessed, and dose-volume histogram (DVH) parameters of different treatment techniques were compared. Results: Thirty European centers participated, 43% of which were using 3-dimensional conformal RT (3D-CRT), with the remaining centers using intensity modulated RT (IMRT) or volumetric modulated arc technique (VMAT). The first submitted version of the DR contained major deviations in 21 of 30 (70%) centers, mostly caused by inappropriately defined or lack of prostate bed (PB). All but 5 centers completed the DR successfully with their second submitted version. The interobserver agreement of the PB was moderate and was improved by the DR review, as indicated by an increased κ value (0.59 vs 0.55), mean sensitivity (0.64 vs 0.58), volume of total agreement (3.9 vs 3.3 cm{sup 3}), and decrease in the union volume (79.3 vs 84.2 cm{sup 3}). Rectal and bladder wall DVH parameters of IMRT and VMAT vs 3D-CRT plans were not significantly different. Conclusions: The interobserver agreement of PB delineation was moderate but was improved by the DR. Major deviations could be identified for the majority of centers. The DR has improved the acquaintance of the participating centers with the trial protocol.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2015

Cost-Effectiveness Analysis of Single Fraction of Stereotactic Body Radiation Therapy Compared With Single Fraction of External Beam Radiation Therapy for Palliation of Vertebral Bone Metastases

Purpose: Stereotactic body radiation therapy (SBRT) has been proposed for the palliation of painful vertebral bone metastases because higher radiation doses may result in superior and more durable pain control. A phase III clinical trial (Radiation Therapy Oncology Group 0631) comparing single fraction SBRT with single fraction external beam radiation therapy (EBRT) in palliative treatment of painful vertebral bone metastases is now ongoing. We performed a cost-effectiveness analysis to compare these strategies. Methods and Materials: A Markov model, using a 1-month cycle over a lifetime horizon, was developed to compare the cost-effectiveness of SBRT (16 or 18 Gy in 1 fraction) with that of 8 Gy in 1 fraction of EBRT. Transition probabilities, quality of life utilities, and costs associated with SBRT and EBRT were captured in the model. Costs were based on Medicare reimbursement in 2014. Strategies were compared using the incremental cost-effectiveness ratio (ICER), and effectiveness was measured in quality-adjusted life years (QALYs). To account for uncertainty, 1-way, 2-way and probabilistic sensitivity analyses were performed. Strategies were evaluated with a willingness-to-pay (WTP) threshold of $100,000 per QALY gained. Results: Base case pain relief after the treatment was assumed as 20% higher in SBRT. Base case treatment costs for SBRT and EBRT were $9000 and $1087, respectively. In the base case analysis, SBRT resulted in an ICER of $124,552 per QALY gained. In 1-way sensitivity analyses, results were most sensitive to variation of the utility of unrelieved pain; the utility of relieved pain after initial treatment and median survival were also sensitive to variation. If median survival is ≥11 months, SBRT cost <$100,000 per QALY gained. Conclusion: SBRT for palliation of vertebral bone metastases is not cost-effective compared with EBRT at a $100,000 per QALY gained WTP threshold. However, if median survival is ≥11 months, SBRT costs ≤$100,000 per QALY gained, suggesting that selective SBRT use in patients with longer expected survival may be the most cost-effective approach.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2020

Iodine Immobilization by Materials through Sorption and Redox-Driven Processes: A Literature Review

Radioiodine-129 (129I) in the subsurface is mobile and limited information is available on treatment technologies. Scientific literature was reviewed to compile information on materials that could potentially be used to immobilize 129I through sorption and redox-driven processes, with an emphasis on ex-situ processes. Candidate materials to immobilize 129I include iron minerals, sulfur-based materials, silver-based materials, bismuth-based materials, ion exchange resins, activated carbon, modified clays, and tailored materials (metal organic frameworks (MOFS), layered double hydroxides (LDHs) and aerogels). Where available, compiled information includes material performance in terms of (i) capacity for 129I uptake; (ii) long-term performance (i.e., solubility of a precipitated phase); (iii) technology maturity; (iv) cost; (v) available quantity; (vi) environmental impact; (vii) ability to emplace the technology for in situ use at the field-scale; and (viii) ex situ treatment (for media extracted from the subsurface or secondary waste streams). Because it can be difficult to compare materials due to differences in experimental conditions applied in the literature, Part II of this review describes results of laboratory studies for selected materials using a standardized batch loading test.

Moore, Robert C.↗
DOE OSTI2022

Machine-learning from Pseudomonas putida KT2440 transcriptomes reveals its transcriptional regulatory network

Bacterial gene expression is orchestrated by numerous transcription factors (TFs). Elucidating how gene expression is regulated is fundamental to understanding bacterial physiology and engineering it for practical use. In this study, a machine-learning approach was applied to uncover the genome-scale transcriptional regulatory network (TRN) in Pseudomonas putida KT2440, an important organism for bioproduction. We performed independent component analysis of a compendium of 321 high-quality gene expression profiles, which were previously published or newly generated in this study. We identified 84 groups of independently modulated genes (iModulons) that explain 75.7% of the total variance in the compendium. With these iModulons, we (i) expand our understanding of the regulatory functions of 39 iModulon associated TFs (e.g., HexR, Zur) by systematic comparison with 1993 previously reported TF-gene interactions; (ii) outline transcriptional changes after the transition from the exponential growth to stationary phases; (iii) capture group of genes required for utilizing diverse carbon sources and increased stationary response with slower growth rates; (iv) unveil multiple evolutionary strategies of transcriptome reallocation to achieve fast growth rates; and (v) define an osmotic stimulon, which includes the Type VI secretion system, as coordination of multiple iModulon activity changes. Taken together, this study provides the first quantitative genome-scale TRN for P. putida KT2440 and a basis for a comprehensive understanding of its complex transcriptome changes in a variety of physiological states.

09 BIOMASS FUELS↗