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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 55 records · Page 3
All sourcesNASA NTRSDOE OSTI
DOE OSTI2022

A Novel EGFRvIII T-Cell Bispecific Antibody for the Treatment of Glioblastoma

Abstract T-cell bispecific antibodies (TCB) are engineered molecules that bind both the T-cell receptor and tumor-specific antigens. Epidermal growth factor receptor variant III (EGFRvIII) mutation is a common event in glioblastoma (GBM) and is characterized by the deletion of exons 2–7, resulting in a constitutively active receptor that promotes cell proliferation, angiogenesis, and invasion. EGFRvIII is expressed on the surface of tumor cells and is not expressed in normal tissues, making EGFRvIII an ideal neoantigen target for TCBs. We designed and developed a novel 2+1 EGFRvIII-TCB with optimal pharmacologic characteristics and potent antitumor activity. EGFRvIII-TCB showed specificity for EGFRvIII and promoted tumor cell killing as well as T-cell activation and cytokine secretion only in patient-derived models expressing EGFRvIII. Moreover, EGFRvIII-TCB promoted T-cell recruitment into intracranial tumors. EGFRvIII-TCB induced tumor regression in GBM animal models, including humanized orthotopic GBM patient-derived xenograft models. Our results warrant the clinical testing of EGFRvIII-TCB for the treatment of EGFRvIII-expressing GBMs.

Oncology↗
DOE OSTI2022

Training Ultrasound Image Classification Deep-Learning Algorithms for Pneumothorax Detection Using a Synthetic Tissue Phantom Apparatus

Ultrasound (US) imaging is a critical tool in emergency and military medicine because of its portability and immediate nature. However, proper image interpretation requires skill, limiting its utility in remote applications for conditions such as pneumothorax (PTX) which requires rapid intervention. Artificial intelligence has the potential to automate ultrasound image analysis for various pathophysiological conditions. Training models require large data sets and a means of troubleshooting in real-time for ultrasound integration deployment, and they also require large animal models or clinical testing. Here, we detail the development of a dynamic synthetic tissue phantom model for PTX and its use in training image classification algorithms. The model comprises a synthetic gelatin phantom cast in a custom 3D-printed rib mold and a lung mimicking phantom. When compared to PTX images acquired in swine, images from the phantom were similar in both PTX negative and positive mimicking scenarios. We then used a deep learning image classification algorithm, which we previously developed for shrapnel detection, to accurately predict the presence of PTX in swine images by only training on phantom image sets, highlighting the utility for a tissue phantom for AI applications.

Boice, Emily N. (ORCID:0000000171802842)↗
DOE OSTI2021

Effects of Single-Dose Versus Hypofractionated Focused Radiation on Vertebral Body Structure and Biomechanical Integrity: Development of a Rabbit Radiation-Induced Vertebral Compression Fracture Model

Vertebral compression fracture is a common complication of spinal stereotactic body radiation therapy. Development of an in vivo model is crucial to fully understand how focal radiation treatment affects vertebral integrity and biology at various dose fractionation regimens. We present a clinically relevant animal model to analyze the effects of localized, high-dose radiation on vertebral microstructure and mechanical integrity. Using this model, we test the hypothesis that fractionation of radiation dosing can reduce focused radiation therapy's harmful effects on the spine.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

Synchrotron Microbeam Radiation Therapy for the Treatment of Lung Carcinoma: A Preclinical Study

In the past 3 decades, synchrotron microbeam radiation therapy (S-MRT) has been shown to achieve both good tumor control and normal tissue sparing in a range of preclinical animal models. However, the use of S-MRT for the treatment of lung tumors has not yet been investigated. This study is the first to evaluate the therapeutic efficacy of S-MRT for the treatment of lung carcinoma, using a new syngeneic and orthotopic mouse model.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2024

Characterization of Histophilus somni sialic acid uptake mutant (Δ nanP -Δ nanU ) using a mouse septicemia and mortality model

Histophilus somni is an important pathogen of the bovine respiratory disease complex, yet the mechanisms underlying its virulence remain poorly understood. It is known that H. somni can incorporate sialic acid into lipooligosaccharide (LOS), and sialylated H. somni is more resistant to phagocytosis and complement-mediated killing by serum compared to non-sialylated bacteria in vitro. However, the virulence of non-sialylated H. somni has not been evaluated in vivo using an animal model. In this study, we investigated the contribution of sialic acid to virulence by constructing an H. somni sialic acid uptake mutant (ΔnanP-ΔnanU) and comparing the parent and mutant strains in a mouse septicemia and mortality model. Intraperitoneal challenge of mice with wildtype H. somni (1 × 10 8 colony forming units/mouse, CFU) was lethal to all animals. Mice challenged with three different doses (1, 2, or 5 × 108 CFU/mouse) of an H. somni ΔnanP-ΔnanU sialic acid uptake mutant exhibited survival rates of 90 %, 60 %, and 0 % respectively. High-performance anion exchange chromatography analyses revealed that LOS prepared from both parent and the ΔnanP-ΔnanU mutant strains of H. somni were sialylated. These findings suggest the presence of de novo sialic acid synthesis pathway, although the genes associated with de novo sialic acid synthesis (neuB and neuC) were not identified by genomic analysis. The lower attenuation in mice is most likely attributed to the sialylated LOS of H. somni nanPU mutant.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Effect of Interleukin-7 on Radiation-Induced Lymphopenia and Its Antitumor Effects in a Mouse Model

Local ionizing radiation (IR) can lead to systemic lymphocyte depletion, which is associated with poor survival outcomes in patients with cancer. Interleukin-7 (IL-7) plays an important role in lymphocyte homeostasis; however, its role in alleviating radiation-induced lymphopenia remains unclear. Hence, we established a radiation-induced lymphopenia animal model and evaluated the effect of exogenous IL-7 administration.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

Cellular, molecular, and therapeutic characterization of pilocarpine-induced temporal lobe epilepsy

Animal models have expanded our understanding of temporal lobe epilepsy (TLE). However, translating these to cell-specific druggable hypotheses is not explored. Herein, we conducted an integrative insilico-analysis of an available transcriptomics dataset obtained from animals with pilocarpine-induced-TLE. A set of 119 genes with subtle-to-moderate impact predicted most forms of epilepsy with ~ 97% accuracy and characteristically mapped to upregulated homeostatic and downregulated synaptic pathways. The deconvolution of cellular proportions revealed opposing changes in diverse cell types. The proportion of nonneuronal cells increased whereas that of interneurons, except for those expressing vasoactive intestinal peptide (Vip), decreased, and pyramidal neurons of the cornu-ammonis (CA) subfields showed the highest variation in proportion. A probabilistic Bayesian-network demonstrated an aberrant and oscillating physiological interaction between nonneuronal cells involved in the blood–brain-barrier and Vip interneurons in driving seizures, and their role was evaluated insilico using transcriptomic changes induced by valproic-acid, which showed opposing effects in the two cell-types. Additionally, we revealed novel epileptic and antiepileptic mechanisms and predicted drugs using causal inference, outperforming the present drug repurposing approaches. These well-powered findings not only expand the understanding of TLE and seizure oscillation, but also provide predictive biomarkers of epilepsy, cellular and causal micro-circuitry changes associated with it, and a drug-discovery method focusing on these events.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Quantifying the contribution of Fc-mediated effector functions to the antiviral activity of anti–HIV-1 IgG1 antibodies in vivo

In combating viral infections, the Fab portion of an antibody could mediate virus neutralization, whereas Fc engagement of Fc-γ receptors (FcγRs) could mediate an array of effector functions. Evidence abounds that effector functions are important in controlling infections by influenza, Ebola, or HIV-1 in animal models. However, the relative contribution of virus neutralization versus effector functions to the overall antiviral activity of an antibody remains unknown. To address this fundamental question in immunology, here we utilized our knowledge of HIV-1 dynamics to compare the kinetics of the viral load decline (ΔVL) in infected animals given a wild-type (WT) anti–HIV-1 immunoglobulin G1 (IgG1) versus those given a Fc-Null variant of the same antibody. In three independent experiments in HIV-1–infected humanized mice and one pivotal experiment in simian–human immunodeficiency virus (SHIV)-infected rhesus macaques, an earlier and sharper decline in viral load was consistently detected for the WT antibody. Quantifications of the observed differences indicate that Fc-mediated effector functions accounted for 25–45% of the total antiviral activity in these separate experiments. In this study, Fc-mediated effector functions have been quantified in vivo relative to the contribution of virus neutralization mediated by the Fab.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Vascular dysfunction in hemorrhagic viral fevers: opportunities for organotypic modeling

The hemorrhagic fever viruses (HFVs) cause severe or fatal infections in humans. Named after their common symptom hemorrhage, these viruses induce significant vascular dysfunction by affecting endothelial cells, altering immunity, and disrupting the clotting system. Despite advances in treatments, such as cytokine blocking therapies, disease modifying treatment for this class of pathogen remains elusive. Improved understanding of the pathogenesis of these infections could provide new avenues to treatment. While animal models and traditional 2D cell cultures have contributed insight into the mechanisms by which these pathogens affect the vasculature, these models fall short in replicating in vivo human vascular dynamics. The emergence of microphysiological systems (MPSs) offers promising avenues for modeling these complex interactions. These MPS or ‘organ-on-chip’ models present opportunities to better mimic human vascular responses and thus aid in treatment development. In this review, we explore the impact of HFV on the vasculature by causing endothelial dysfunction, blood clotting irregularities, and immune dysregulation. We highlight how existing MPS have elucidated features of HFV pathogenesis as well as discuss existing knowledge gaps and the challenges in modeling these interactions using MPS. Understanding the intricate mechanisms of vascular dysfunction caused by HFV is crucial in developing therapies not only for these infections, but also for other vasculotropic conditions like sepsis.

42 ENGINEERING↗
DOE OSTI2021

CD47 blockade enhances therapeutic efficacy of cisplatin against lung carcinoma in a murine model

Cisplatin (CDDP) is the first generation of platinum-based drug and is widely used to treat many cancers due to its potency. The present study aims to explore the effects of CDDP on lung carcinoma and its relationship with macrophage phagocytosis. In in vitro study, murine and human lung cancer cell lines were applied and treated with CDDP, CD47 antibody (aCD47), or CDDP plus aCD47. In in vivo study, a tumor xenograft animal model was treated with CDDP, aCD47, or CDDP plus aCD47. Real-time PCR was applied to determine the mRNA expressions. Enzyme-linked immunosorbent assay (ELISA), Western blotting, and Immunofluorescent staining were applied to determine the protein expressions. Flow cytometry was applied to analyze cell apoptosis, phagocytosis, and specific cell populations. CDDP enhanced the expressions of CD47 in lung cancer cells. Interestingly, the blockage of CD47 enhanced the macrophages' phagocytic activity on the CDDP-treated tumor cells. The treatment of CDDP and aCD47 exhibited anti-tumor effects and prolonged the LLC tumor-bearing mice survival time. Mechanistic studies revealed that the treatment of CDDP and aCD47 regulated the phagocytic activity of macrophage, percentage of CD8{sup +} T cells, and cytokines (tumor growth factor (TGF)-β, interleukin (IL)12p70, and interferon (IFN)-γ) in the tumor-bearing model. CD47 blockade enhanced therapeutic efficacy of cisplatin against lung carcinoma in vivo and in vitro.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

A Foundational Study for Normal F8 -Containing Mouse Models for the miRNA Regulation of Hemophilia A: Identification and Analysis of Mouse miRNAs that Downregulate the Murine F8 Gene

Hemophilia A (HA) is associated with defects in the F8 gene, encoding coagulation factor VIII (FVIII). Our previous studies show that F8-targeting micro RNAs (miRNAs), a group of small RNAs involved in gene regulation, can downregulate F8 expression causing HA in individuals with normal F8-genotypes and increased HA severity in patients with mutations in F8. Understanding the mechanistic underpinnings of human genetic diseases caused or modulated by miRNAs require a small animal model, such as a mouse model. Here, we report a foundational study to develop such a model system. We identified the mouse 3'untranslated region (3'UTR) on murine F8-mRNA (muF8-mRNA) that can bind to murine miRNAs. We then selected three miRNAs for evaluation: miR-208a, miR-351 and miR-125a. We first demonstrate that these three miRNAs directly target the 3'UTR of muF8-mRNA and reduce the expression of a reporter gene (luciferase) mRNA fused to the muF8-3' UTR in mammalian cells. Furthermore, in mouse cells that endogenously express the F8 gene and produce FVIII protein, the ectopic expression of these miRNAs downregulated F8-mRNA and FVIII protein. These results provide proof-of-concept and reagents as a foundation for using a normal F8-containing mouse as a model for the miRNA regulation of normal F8 in causing or aggravating the genetic disease HA.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Mouse models of Ebola virus tolerance and lethality: characterization of CD-1 mice infected with wild-type, guinea pig-adapted, or mouse-adapted virus

Development of lethal models of Ebola virus disease has been achieved by the serial passage of virus isolates from human cases in mice and guinea pigs. Use of mice infected with non-adapted virus has been limited due to the absence of overt clinical disease. In recent years, newly recognized sequelae identified in human cases has highlighted the importance of continued investigations of non-lethal infection both in humans and animal models. Here, we revisit the use of rodent-adapted and non-adapted Ebola virus (EBOV) in mice to investigate infection tolerance and future utility of these models in pathogenesis and therapeutic intervention studies. We found that like non-adapted wild-type EBOV, guinea pig-adapted EBOV resulted in widespread tissue infection, variably associated with tissue pathology, and alterations in clinical and immunological analytes in the absence of overt disease. Notably, infection with either non-lethal variant did not greatly differ from lethal mouse-adapted EBOV until near the time end-point criteria are reached in these mice. Furthermore, these data support future investigations of pathogenesis, convalescence, and sequelae in mouse models of virus tolerance.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Physical Models from Physical Templates Using Biocompatible Liquid Crystal Elastomers as Morphologically Programmable Inks For 3D Printing

Advanced manufacturing has received considerable attention as a tool for the fabrication of cell scaffolds however, finding ideal biocompatible and biodegradable materials that fit the correct parameters for 3D printing and guide cells to align remain a challenge. Herein, a photocrosslinkable smectic-A (Sm-A) liquid crystal elastomer (LCE) designed for 3D printing is presented, that promotes cell proliferation but most importantly induces cell anisotropy. The LCE-based bio-ink allows the 3D duplication of a highly complex brain structure generated from an animal model. Vascular tissue models are generated from fluorescently stained mouse tissue spatially imaged using confocal microscopy and subsequently processed to create a digital 3D model suitable for printing. The 3D structure is reproduced using a Digital Light Processing (DLP) stereolithography (SLA) desktop 3D printer. Synchrotron Small-Angle X-ray Diffraction (SAXD) data reveal a strong alignment of the LCE layering within the struts of the printed 3D scaffold. The resultant anisotropy of the LCE struts is then shown to direct cell growth. This study offers a simple approach to produce model tissues built within hours that promote cellular alignment.

3D cell culture↗
DOE OSTI2021

Integration of evidence across human and model organism studies: A meeting report

The National Institute on Drug Abuse and Joint Institute for Biological Sciences at the Oak Ridge National Laboratory hosted a meeting attended by a diverse group of scientists with expertise in substance use disorders (SUDs), computational biology, and FAIR (Findability, Accessibility, Interoperability, and Reusability) data sharing. The meeting's objective was to discuss and evaluate better strategies to integrate genetic, epigenetic, and 'omics data across human and model organisms to achieve deeper mechanistic insight into SUDs. Specific topics were to (a) evaluate the current state of substance use genetics and genomics research and fundamental gaps, (b) identify opportunities and challenges of integration and sharing across species and data types, (c) identify current tools and resources for integration of genetic, epigenetic, and phenotypic data, (d) discuss steps and impediment related to data integration, and (e) outline future steps to support more effective collaboration—particularly between animal model research communities and human genetics and clinical research teams. This review summarizes key facets of this catalytic discussion with a focus on new opportunities and gaps in resources and knowledge on SUDs.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

The cardiac molecular setting of metabolic syndrome in pigs reveals disease susceptibility and suggests mechanisms that exacerbate COVID-19 outcomes in patients

Abstract Although metabolic syndrome (MetS) is linked to an elevated risk of cardiovascular disease (CVD), the cardiac-specific risk mechanism is unknown. Obesity, hypertension, and diabetes (all MetS components) are the most common form of CVD and represent risk factors for worse COVID-19 outcomes compared to their non MetS peers. Here, we use obese Yorkshire pigs as a highly relevant animal model of human MetS, where pigs develop the hallmarks of human MetS and reproducibly mimics the myocardial pathophysiology in patients. Myocardium-specific mass spectroscopy-derived metabolomics, proteomics, and transcriptomics enabled the identity and quality of proteins and metabolites to be investigated in the myocardium to greater depth. Myocardium-specific deregulation of pro-inflammatory markers, propensity for arterial thrombosis, and platelet aggregation was revealed by computational analysis of differentially enriched pathways between MetS and control animals. While key components of the complement pathway and the immune response to viruses are under expressed, key N6-methyladenosin RNA methylation enzymes are largely overexpressed in MetS. Blood tests do not capture the entirety of metabolic changes that the myocardium undergoes, making this analysis of greater value than blood component analysis alone. Our findings create data associations to further characterize the MetS myocardium and disease vulnerability, emphasize the need for a multimodal therapeutic approach, and suggests a mechanism for observed worse outcomes in MetS patients with COVID-19 comorbidity.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

A bioactive supramolecular and covalent polymer scaffold for cartilage repair in a sheep model

Regeneration of hyaline cartilage in human-sized joints remains a clinical challenge, and it is a critical unmet need that would contribute to longer healthspans. Injectable scaffolds for cartilage repair that integrate both bioactivity and sufficiently robust physical properties to withstand joint stresses offer a promising strategy. We report here on a hybrid biomaterial that combines a bioactive peptide amphiphile supramolecular polymer that specifically binds the chondrogenic cytokine transforming growth factor β-1 (TGFβ-1) and crosslinked hyaluronic acid microgels that drive formation of filament bundles, a hierarchical motif common in natural musculoskeletal tissues. The scaffold is an injectable slurry that generates a porous rubbery material when exposed to calcium ions once placed in cartilage defects. The hybrid material was found to support in vitro chondrogenic differentiation of encapsulated stem cells in response to sustained delivery of TGFβ-1. Using a sheep model, we implanted the scaffold in shallow osteochondral defects and found it can remain localized in mechanically active joints. Evaluation of resected joints showed significantly improved repair of hyaline cartilage in osteochondral defects injected with the scaffold relative to defects injected with the growth factor alone, including implantation in the load-bearing femoral condyle. These results demonstrate the potential of the hybrid biomimetic scaffold as a niche to favor cartilage repair in mechanically active joints using a clinically relevant large-animal model.

Science & Technology - Other Topics↗
DOE OSTI2022

Comparative genomic and transcriptomic analyses of trans-kingdom pathogen Fusarium solani species complex reveal degrees of compartmentalization

Background: The Fusarium solani species complex (FSSC) comprises fungal pathogens responsible for mortality in a diverse range of animals and plants, but their genome diversity and transcriptome responses in animal pathogenicity remain to be elucidated. We sequenced, assembled and annotated six chromosome-level FSSC clade 3 genomes of aquatic animal and plant host origins. We established a pathosystem and investigated the expression data of F. falciforme and F. keratoplasticum in Chinese softshell turtle (Pelodiscus sinensis) host. Results: Comparative analyses between the FSSC genomes revealed a spectrum of conservation patterns in chromosomes categorised into three compartments: core, fast-core (FC), and lineage-specific (LS). LS chromosomes contribute to variations in genomes size, with up to 42.2% of variations between F. vanettenii strains. Each chromosome compartment varied in structural architectures, with FC and LS chromosomes contain higher proportions of repetitive elements with genes enriched in functions related to pathogenicity and niche expansion. We identified differences in both selection in the coding sequences and DNA methylation levels between genome features and chromosome compartments which suggest a multi-speed evolution that can be traced back to the last common ancestor of Fusarium. We further demonstrated that F. falciforme and F. keratoplasticum are opportunistic pathogens by inoculating P. sinensis eggs and identified differentially expressed genes also associated with plant pathogenicity. These included the most upregulated genes encoding the CFEM (Common in Fungal Extracellular Membrane) domain. Conclusions: The high-quality genome assemblies provided new insights into the evolution of FSSC chromosomes, which also serve as a resource for studies of fungal genome evolution and pathogenesis. This study also establishes an animal model for fungal pathogens of trans-kingdom hosts.

59 BASIC BIOLOGICAL SCIENCES↗