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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 109 records · Page 6
All sourcesNASA NTRSDOE OSTI
DOE OSTI2023

Divide and conquer: broadly neutralizing antibody combinations for improved HIV-1 viral coverage

Successful HIV-1 prevention and therapy will require broad and potent coverage of within-host and global viral diversity. Broadly neutralizing antibody (bNAb) combination and multispecific therapeutics provide an opportunity to meet this challenge due to the complementary activity of individual antibody components. Here, we review the principles and applications of this concept. The Antibody Mediated Prevention (AMP) trials have demonstrated the high bar for neutralization potency and breadth that bNAb-mediated prevention modalities will need to achieve to have a meaningful impact on the HIV-1 epidemic. Additional clinical studies have recently shown that an even higher bar may be required for therapeutic inhibition of the diverse within-host quasispecies present in viremic and aviremic people with HIV-1 (PWH). We discuss how the complementarity of bNAbs in terms of neutralization profiles, resistance mutations and coverage of within-host quasispecies may overcome these stringent requirements and lead to effective bNAb combination or multispecific antibody based prophylactic and therapeutic strategies. The design of next-generation bNAb-based combination or multispecific therapeutics for the prevention and/or treatment of HIV-1 infection will need to leverage the complementarity of component bNAbs to maximize the potency and breadth that will be required for clinical success.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

A quantitative model used to compare within-host SARS-CoV-2, MERS-CoV, and SARS-CoV dynamics provides insights into the pathogenesis and treatment of SARS-CoV-2

The scientific community is focused on developing antiviral therapies to mitigate the impacts of the ongoing novel coronavirus disease 2019 (COVID-19) outbreak. This will be facilitated by improved understanding of viral dynamics within infected hosts. Here, using a mathematical model in combination with published viral load data, we compare within-host viral dynamics of SARS-CoV-2 with analogous dynamics of MERS-CoV and SARS-CoV. Our quantitative analyses using a mathematical model revealed that the within-host reproduction number at symptom onset of SARS-CoV-2 was statistically significantly larger than that of MERS-CoV and similar to that of SARS-CoV. In addition, the time from symptom onset to the viral load peak for SARS-CoV-2 infection was shorter than those of MERS-CoV and SARS-CoV. These findings suggest the difficulty of controlling SARS-CoV-2 infection by antivirals. We further used the viral dynamics model to predict the efficacy of potential antiviral drugs that have different modes of action. The efficacy was measured by the reduction in the viral load area under the curve (AUC). Our results indicate that therapies that block de novo infection or virus production are likely to be effective if and only if initiated before the viral load peak (which appears 2–3 days after symptom onset), but therapies that promote cytotoxicity of infected cells are likely to have effects with less sensitivity to the timing of treatment initiation. Furthermore, combining a therapy that promotes cytotoxicity and one that blocks de novo infection or virus production synergistically reduces the AUC with early treatment. Our unique modeling approach provides insights into the pathogenesis of SARS-CoV-2 and may be useful for development of antiviral therapies.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Modern Radiation Therapy for Extranodal Nasal-Type NK/T-cell Lymphoma: Risk-Adapted Therapy, Target Volume, and Dose Guidelines from the International Lymphoma Radiation Oncology Group

In the multidisciplinary management of early-stage extranodal natural killer/T-cell lymphoma, nasal type (ENKTCL), with curative intent, radiation therapy is the most efficacious modality and is an essential component of a combined-modality regimen. In the past decade, utilization of upfront radiation therapy and non–anthracycline-based chemotherapy has improved treatment and prognosis. This guideline mainly addresses the heterogeneity of clinical features, principles of risk-adapted therapy, and the role and appropriate design of radiation therapy. Radiation therapy methods (including target volume definition, dose and delivery methods) are crucial for optimizing cure for patients with early-stage ENKTCL. The application of the principles of involved site radiation therapy in this lymphoma entity often leads to a more extended clinical target volume (CTV) than in other lymphoma types because it usually presents with primary tumor invasion, multifocal lesions, or extensive submucosal infiltration beyond the macroscopic disease. The CTV varies across different primary sites and is classified mainly into nasal, nonnasal upper aerodigestive tract (UADT), and extra-UADT entities. This review is a consensus of the International Lymphoma Radiation Oncology Group regarding the approach to radiation therapy, target-volume definition, optimal dose, and dose constraints in ENKTCL treatment.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

Fractionated Radiation Severely Reduces the Number of CD8+ T Cells and Mature Antigen Presenting Cells Within Lung Tumors

The combination of standard-of-care radiation therapy (RT) with immunotherapy is moving to the mainstream of non-small cell lung cancer treatment. Multiple preclinical studies reported on the CD8{sup +} T cell stimulating properties of RT, resulting in abscopal therapeutic effects. A literature search demonstrates that most preclinical lung cancer studies applied subcutaneous lung tumor models. Hence, in-depth immunologic evaluation of clinically relevant RT in orthotopic lung cancer models is lacking.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2022

Spatiotemporal mapping of microscopic strains and defects to reveal Li-dendrite-induced failure in all-solid-state batteries

Solid-state electrolytes (SSEs) are key to the success and reliability of all-solid-state lithium batteries, potentially enabling improvements in terms of safety and energy density over state-of-the-art lithium-ion batteries. However, there are several critical challenges to their implementation, including the interfacial instability stemming from the dynamic interaction of as-formed dendritic lithium during cycling. Here, we emphasize the importance of studying the spatial distribution and temporal evolution of strains and defects in crystalline solid-state electrolytes at the micro-scale, and how this affects dendrite growth. A proof-of-principle study is demonstrated using the synchrotron radiation based micro Laue X-ray diffraction method, and a custom-developed in-situ cycling device. Defects and residual strains are mapped, and the evolution of intragranular misorientation is observed. The feasibility of using this technique is discussed, and recommendations for micro-strain engineering to address the Li/SSEs interfacial issues are given. Additionally, work directions are pointed out with the consideration of combining multi-techniques for “poly-therapy”.

36 MATERIALS SCIENCE↗
DOE OSTI2020

Development of a New Chelation Model: Bioassay Data Interpretation and Dose Assessment after Plutonium Intake via Wound and Treatment with DTPA

The administration of chelation therapy to treat significant intakes of actinides, such as plutonium, affects the actinide’s normal biokinetics. In particular, it enhances the actinide’s rate of excretion, such that the standard biokinetic models cannot be applied directly to the chelation-affected bioassay data in order to estimate the intake and assess the radiation dose. Here we propose a new chelation model that can be applied to the chelation-affected bioassay data after plutonium intake via wound and treatment with DTPA. In the proposed model, chelation is assumed to occur in the blood, liver, and parts of the skeleton. Ten datasets, consisting of measurements of 14 C-DTPA, 238 Pu, and 239 Pu involving humans given radiolabeled DTPA and humans occupationally exposed to plutonium via wound and treated with chelation therapy, were used for model development. The combined dataset consisted of daily and cumulative excretion (urine and feces), wound counts, measurements of excised tissue, blood, and post-mortem tissue analyses of liver and skeleton. The combined data were simultaneously fit using the chelation model linked with a plutonium systemic model, which was linked to an ad hoc wound model. The proposed chelation model was used for dose assessment of the wound cases used in this study.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Improving Dose-Optimization Processes Used in Oncology Drug Development to Minimize Toxicity and Maximize Benefit to Patients

This review highlights strategies to integrate dose optimization into premarketing drug development and discusses the underlying statistical principles. Poor dose optimization can have negative consequences for patients, most commonly because of toxicity, including poor quality of life, reduced effectiveness because of inability of patients to stay on current therapy or receive subsequent therapy because of toxicities, and difficulty in developing combination regimens. We reviewed US Food and Drug Administration initial approvals (2019-2021) of small molecules and antibody-drug conjugates for oncologic indications to determine the proportion with a recommended dosage at the maximum tolerated dose or the maximal administered dose, to characterize the use of randomized evaluations of multiple dosages in dose selection, to describe the frequency of dose modifications at the recommended dosage, and to identify case examples that highlight key principles for premarket dose optimization during drug development. Herein, we highlight major principles for dose optimization and review examples of recent US Food and Drug Administration approvals that illustrate how investigation of dose- and exposure-response relationships and use of randomized dose trials can support dose optimization. Although there has been some progress, dose optimization through randomized dose evaluation in oncology trials is not routinely conducted. Dose optimization is essential to ensure that patients receive therapies which maximize efficacy while minimizing toxicity.

Oncology↗
DOE OSTI2022

Targeted Alpha Particle Therapy Remodels the Tumor Microenvironment and Improves Efficacy of Immunotherapy

The tumor microenvironment (TME) can severely impair immunotherapy efficacy by repressing the immune system. In a multiple myeloma (MM) murine model, we investigated the impact of targeted alpha particle therapy (TAT) on the immune TME. TAT was combined with an adoptive cell transfer of CD8 T cells (ACT), and the mechanisms of action of this combination were assessed at the tumor site.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

Hybrid magnetic nanoparticles as efficient nanoheaters in biomedical applications

Heating at the nanoscale is the basis of several biomedical applications, including magnetic hyperthermia therapies and heat-triggered drug delivery. The combination of multiple inorganic materials in hybrid magnetic nanoparticles provides versatile platforms to achieve an efficient heat delivery upon different external stimuli or to get an optical feedback during the process. However, the successful design and application of these nanomaterials usually require intricate synthesis routes and their magnetic response is still not fully understood. In this review we give an overview of the novel systems reported in the last few years, which have been mostly obtained by organic phase-based synthesis and epitaxial growth processes. Since the heating efficiency of hybrid magnetic nanoparticles often relies on the exchange-interaction between their components, we discuss various interface-phenomena that are responsible for their magnetic properties. Finally, followed by a brief comment on future directions in the field, we outline recent advances on multifunctional nanoparticles that can boost the heating power with light and combine heating and temperature sensing in a single nanomaterial.

36 MATERIALS SCIENCE↗
DOE OSTI2021

Strategies for Motion Robust Proton Therapy With Pencil Beam Scanning for Esophageal Cancer

Proton therapy of esophageal cancer is superior to photon radiation therapy in terms of normal tissue sparing. However, respiratory motion and anatomical changes may compromise target dose coverage owing to density changes, geometric misses, and interplay effects. Here we investigate the combined effect on clinical target volume (CTV) coverage and compare proton therapy with intensity modulated radiation therapy (IMRT).

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2026

Single-particle detection of enhanced polarizability in Au-decorated semiconducting nanorods via scanning dielectric microscopy

Hybrid nanostructures that combine semiconducting and metallic components offer great potential for photothermal therapy, optoelectronics, and sensing, by integrating tunable optical properties with enhanced light absorption and charge transport. Boosting the integrated performance of these hybrid systems demands techniques capable of probing local variations of the physical properties inaccessible to bulk analysis. Here, we report the single-particle dielectric characterization of hybrid, semiconducting bismuth sulfide (Bi 2 S 3 ) nanorods (NR) decorated with metallic Au nanoparticles (NP), employing scanning dielectric microscopy, which uses electrostatic force microscopy in combination with finite-element numerical simulations. We reveal a pronounced enhancement in the local dielectric response of Bi2S3 upon Au decoration, attributed to interfacial polarization and electron transfer from Au to the Bi 2 S 3 matrix, thus suggesting a enhanced metallic-like polarizability at the single-particle level. Numerical simulations show that the response is dominated by the vertical component of the permittivity and that the decorating metallic Au NP produce only moderate shielding of the semiconductor Bi 2 S 3 NR core, indicating that the large increase in the dielectric response originates primarily from intrinsic modifications within the NR. Overall, these findings provide direct insight into structure–property relationships at the single-particle level, supporting the rational design of advanced hybrid nanostructures with tailored electronic functionalities.

36 MATERIALS SCIENCE↗
DOE OSTI2021

Systematic Screening of COVID-19 Disease Based on Chest CT and RT-PCR for Cancer Patients Undergoing Radiation Therapy in a Coronavirus French Hotspot

Patients with cancer are presumed to be more vulnerable to COVID-19. We evaluated a screening strategy combining chest computed tomography (CT) and reverse-transcription polymerase chain reaction (RT-PCR) for patients treated with radiation therapy at our cancer center located in a COVID-19 French hotspot during the first wave of the pandemic.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2023

Applying Multimodal Mass Spectrometry to Image Tumors Undergoing Ferroptosis Following In Vivo Treatment with a Ferroptosis Inducer

Epithelial ovarian cancer (EOC) is the most common form of ovarian cancer. The poor prognosis generally associated with this disease has led to the search for improved therapies such as ferroptosis-inducing agents. Ferroptosis is a form of regulated cell death that is dependent on iron and is characterized by lipid peroxidation. Precise mapping of lipids and iron within tumors exposed to ferroptosis-inducing agents may provide insight into processes of ferroptosis in vivo and ultimately assist in the optimal deployment of ferroptosis inducers in cancer therapy. In this work, we present a method for combining matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) with secondary ion mass spectrometry (SIMS) to analyze changes in spatial lipidomics and metal composition, respectively, in ovarian tumors following exposure to a ferroptosis inducer. Tumors were obtained by injecting human ovarian cancer tumor-initiating cells into mice, followed by treatment with the ferroptosis inducer erastin. SIMS imaging detected iron accumulation in the tumor tissue, and sequential MALDI-MS imaging of the same tissue section displayed two chemically distinct regions of lipids. Additionally, one region was associated with the iron-rich area detected with SIMS, and the other region encompassed the remainder of the tissue section. Bulk lipidomics confirmed the lipid assignments putatively assigned from the MALDI-MS data. Overall, we demonstrate the ability of multimodal MSI to identify the spatial locations of iron and lipids in the same tissue section and associate these regions with clinical pathology.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Potentiating antibiotic efficacy via perturbation of non-essential gene expression

Proliferation of multidrug-resistant (MDR) bacteria poses a threat to human health, requiring new strategies. Here we propose using fitness neutral gene expression perturbations to potentiate antibiotics. We systematically explored 270 gene knockout-antibiotic combinations in Escherichia coli, identifying 90 synergistic interactions. Identified gene targets were subsequently tested for antibiotic synergy on the transcriptomic level via multiplexed CRISPR-dCas9 and showed successful sensitization of E. coli without a separate fitness cost. These fitness neutral gene perturbations worked as co-therapies in reducing a Salmonella enterica intracellular infection in HeLa. Finally, these results informed the design of four antisense peptide nucleic acid (PNA) co-therapies, csgD, fnr, recA and acrA, against four MDR, clinically isolated bacteria. PNA combined with sub-minimal inhibitory concentrations of trimethoprim against two isolates of Klebsiella pneumoniae and E. coli showed three cases of re-sensitization with minimal fitness impacts. Our results highlight a promising approach for extending the utility of current antibiotics.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Radiation Therapy Enhanced by NBTXR3 Nanoparticles Overcomes Anti-PD1 Resistance and Evokes Abscopal Effects

Radiation combined with PD1 blockade offers significant treatment benefits in several tumor types; however, anti-PD1 resistance precludes such benefits in many cases. Here we attempted to overcome anti-PD1 resistance by combining localized radiation with a radioenhancing nanoparticle (NBTXR3) and systemic anti-PD1 treatment to achieve abscopal effects in an anti-PD1–resistant mouse model of lung cancer.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2023

Case report: Fatal Legionella infection diagnosed via by metagenomic next-generation sequencing in a patient with chronic myeloid leukemia

Legionella is an aerobic, gram-negative, intracellular pathogen and is an important cause of community-acquired pneumonia. Legionella pneumophila is the most common causative agent of Legionella pneumonia. Clinical diagnosis of Legionella pneumonia is challenging due to the lack of specific clinical manifestations and the low positive rates of conventional pathogen detection methods. In this study, we report a case of a patient with chronic myeloid leukemia who developed rigors and high fever after chemotherapy and immunotherapy. Chest computed tomography revealed consolidation in the left lower lobe of the lung and ground-glass opacities in both lower lobes. Multiple blood cultures showed Escherichia coli , Staphylococcus aureus , Bacillus licheniformis , and positive results in the β-D-glucan test (G test). The patient was treated with various sensitive antimicrobial agents, including meropenem plus fluconazole, meropenem plus carpofungin, and vancomycin. Unfortunately, the patient’s condition gradually worsened and eventually resulted in death. On the following day of death, metagenomic next-generation sequencing (mNGS) of 1whole blood revealed L. pneumophila pneumonia with concurrent bloodstream infection (blood mNGS reads 114,302). These findings suggest that when conventional empirical antimicrobial therapy proves ineffective for critically ill patients with pneumonia, the possibility of combined Legionella infection must be considered, and mNGS can provide a diagnostic tool in such cases.

Bu, Chunhong↗
DOE OSTI2020

Thermoeconomic cost optimization of superconducting magnets for proton therapy gantries

A compact gantry delivering 70-220 MeV protons with fixed field in the superconducting magnets could reduce the cost and improve the adoption of proton therapy. While a number of magnet and cryogenics designs have been proposed, the combined capital and operating costs of state-of-the-art superconducting materials have not been analyzed. In response, we develop a thermoeconomic model of a multi-stage, conduction cooled gantry lattice and analyze the cryocooler operating cost, cryocooler capital cost and conductor capital cost for Nb-Ti, Nb 3 Sn, REBCO and Bi-2223 over a continuous range of magnet temperatures, and a differential evolution algorithm is used to identify the optimal combination of thermal intercept temperatures. Although Nb3Sn yields the lowest Net Present Value (NPV) of $111.7k at a magnet temperature of 9.4 K, the optimized Bi-2223 design at 12.8 K approaches the realm of commercial feasibility by offering improved thermal stability and forgoing the need for costly conductor heat treatment and magnet quench training. Furthermore, it was found that Nb3Sn was more cost effective than Nb-Ti and that REBCO was not economically viable for the parameters of this investigation. Overall, the thermoeconomic model developed herein can optimize conductor choices, magnet temperatures and thermal staging which has value for any conduction-cooled superconducting magnet.

BSCCO↗
DOE OSTI2020

State and Regional Variation in Prescription- and Payment-Related Promoters of Adherence to Blood Pressure Medication

Introduction: Medication adherence can improve hypertension management. How blood pressure medications are prescribed and purchased can promote or impede adherence. Methods: We used comprehensive dispensing data on prescription blood pressure medication from Symphony Health’s 2017 Integrated Dataverse to assess how prescription- and payment-related factors that promote medication adherence (ie, fixed-dose combinations, generic formulations, mail order, low-cost or no-copay medications) vary across US states and census regions and across the market segments (grouped by patient age, prescriber type, and payer type) responsible for the greatest number of blood pressure medication fills. Results: In 2017, 706.5 million prescriptions for blood pressure medication were filled, accounting for $29.0 billion in total spending (17.0% incurred by patients). As a proportion of all fills, factors that promoted adherence varied by state: fixed-dose combinations (from 5.8% in Maine to 17.9% in Mississippi); generic formulations (from 95.2% in New Jersey to 98.4% in Minnesota); mail order (from 4.7% in Rhode Island to 14.5% in Delaware); and lower or no copayment (from 56.6% in Utah to 72.8% in California). Furthermore, mean days’ supply per fill (from 43.1 in Arkansas to 63.8 in Maine) and patient spending per therapy year (from $38 in Hawaii to $76 in Georgia) varied. Concentration of adherence factors differed by market segment. Patients aged 18 to 64 with a primary care physician prescriber and Medicaid coverage had the lowest concentration of fixed-dose combination fills, mean days’ supply per fill, and patient spending per therapy year. Patients aged 65 years or older with a primary care physician prescriber and commercial insurance had the highest concentration of fixeddose combinations fills and mail order fills. Conclusion: Addressing regional and market segment variation in factors promoting blood pressure medication adherence may increase adherence and improve hypertension management.

60 APPLIED LIFE SCIENCES↗