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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 235 records · Page 13
All sourcesNASA NTRSDOE OSTI
DOE OSTI2019

Management of Pulmonary Arterial Hypertension in the Pediatric Patient

Purpose of Review: Pediatric pulmonary arterial hypertension (PAH) is associated with significant morbidity and mortality. Herein we review the diagnosis and classification for pediatric PAH and detail the current therapeutic options available for use in the pediatric PAH population. Recent Findings: Classification and treatment of pediatric PAH is guided by adult criteria and treatment algorithms, yet the distribution of factors contributing to PAH in children differs significantly from that seen in adults. It is necessary to understand these differences in order to appropriately tailor therapy to the needs of the child or adolescent. An expanding array of targeted PAH drugs are now approved for use in adults, and many of these drugs are used “off-label” to treat children and adolescents with PAH. Use of these novel therapies has coincided with marked improvement in outcomes, suggesting significant benefit. However, because most of these drugs have not been studied in rigorous randomized, controlled trials in children, it is critical that physicians understand their mechanisms of action, potential benefits, and safety profiles. Summary: Pediatric PAH outcomes have improved substantially in the modern era, coinciding with the “off-label” use of targeted PAH drugs in children and adolescents. Ideally, care should be provided at centers with specialized expertise in the diagnosis and treatment of pediatric PAH by providers who understand the appropriate diagnostic algorithms, classification schemes, and treatment approaches.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2025

Trithiol ligand provides tumor-targeting 191 Pt-complexes with high molar activity and promising in vivo properties

The Auger electron-emitting radionuclide 191 Pt is a promising candidate for radiopharmaceutical therapy. Herein, we explored novel labeling methods for 191 Pt using thiol-containing ligands to improve the in vivo stability and targeting ability of 191 Pt-labeled complexes. We synthesized dithiol-containing N 2 S 2 and NS 2 ligands, and a trithiol ligand, and then compared their radiochemical reactivity with 191 Pt. [ 191 Pt]Pt-trithiol was synthesized and its biodistribution was evaluated in mice and compared with free 191 Pt. Finally, a 191 Pt-trithiol complex targeting prostate-specific membrane antigen (PSMA): [ 191 Pt]Pt-trithiol-PSMA was developed and evaluated in mice bearing tumor xenografts and compared with a 191 Pt-complex labeled via monothiol-containing Cys ([ 191 Pt]Pt-Cys-PSMA). A comparison of N 2 S 2 , NS 2 , and trithiol showed that the trithiol ligand is the best for producing 191 Pt-labeled compounds in high yield and as a single peak in preparative HPLC. Notably, the trithiol ligand made 191 Pt-labeled compounds and precursors separatable, achieving 191 Pt-labeled products with a high molar activity: 200–400 mCi/μmol (7.4–14.8 GBq/μmol) at EOS. Additionally, [ 191 Pt]Pt-trithiol and [ 191 Pt]Pt-trithiol-PSMA were stable in vivo with rapid clearance compared with free 191 Pt and [ 191 Pt]Pt-Cys-PSMA. [ 191 Pt]Pt-trithiol-PSMA resulted in a low uptake in most normal organs and a high uptake in the kidneys and prostate cancer with PSMA expression. Furthermore, this study demonstrated that a labeling method with trithiol for Pt radionuclides achieves 191 Pt-labeled products with high molar activity. 191 Pt-trithiol-PSMA showed promising in vivo stability and tumor-targeting specificity, which should facilitate the pharmaceutical development of Pt radionuclides for radiopharmaceutical therapy, especially Auger electron cancer therapy.

Auger emitters↗
DOE OSTI2021

Attention Guided Lymph Node Malignancy Prediction in Head and Neck Cancer

Accurate lymph node (LN) malignancy classification is essential for treatment target identification in head and neck cancer (HNC) radiation therapy. Given the constraints imposed by relatively small sample sizes in real-world medical applications, to classify LN malignancy status accurately, we proposed an attention-guided classification (AGC) scheme that (1) incorporates human knowledge (ie, LN contours) into model training to guide model’s “learning” direction, alleviating the critical requirement of large training samples by deep learning approaches; and (2) does not require accurate delineation of LNs in the inference stage but can highlight the discriminative region nearby the LN, which is important for malignancy determination.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

A transcriptional relationship with a natural product disrupts mitochondrial biogenesis

Discovery of new compound leads and oncology targets to treat cancer will require overcoming resistance to traditional therapies such as BRAF and mitogen-activated protein kinase inhibitors (MAPKi). In addition, potent new therapies will benefit from selective localization at the cancer site rather than general cell toxicity which can lead to undesired side effects. This selectivity can be gained by identifying new compound leads that are “prodrugs”, that is they are activated by mechanisms selective to cancer cells leading to strong pharmacological activity (Zhang, 2017). Continuing discovery of anticancer agents that overcome resistance and take advantage of cancer cell mechanisms will be greatly augmented by returning to the potent well of natural products; in fact, an analysis of a 70-year period ending in 2014 showed that nearly 50% of approved anticancer drugs are or are derived from natural products (Newman, 2016). Discovery of new agents with high potency and selectivity will require natural product research focused on discovering biologically active compounds with unique structures and mechanisms of action that utilize target cell functions.

Wright, Aaron T.↗
DOE OSTI2021

Targeted polyelectrolyte complex micelles treat vascular complications in vivo

Vascular disease is a leading cause of morbidity and mortality in the United States and globally. Pathological vascular remodeling, such as atherosclerosis and stenosis, largely develop at arterial sites of curvature, branching, and bifurcation, where disturbed blood flow activates vascular endothelium. Current pharmacological treatments of vascular complications principally target systemic risk factors. Improvements are needed. We previously devised a targeted polyelectrolyte complex micelle to deliver therapeutic nucleotides to inflamed endothelium in vitro by displaying the peptide VHPKQHR targeting vascular cell adhesion molecule 1 (VCAM-1) on the periphery of the micelle. This paper explores whether this targeted nanomedicine strategy effectively treats vascular complications in vivo. Disturbed flow-induced microRNA-92a (miR-92a) has been linked to endothelial dysfunction. We have engineered a transgenic line (miR-92a EC-TG /Apoe –/– ) establishing that selective miR-92a overexpression in adult vascular endothelium causally promotes atherosclerosis in Apoe –/– mice. We tested the therapeutic effectiveness of the VCAM-1–targeting polyelectrolyte complex micelles to deliver miR-92a inhibitors and treat pathological vascular remodeling in vivo. VCAM-1–targeting micelles preferentially delivered miRNA inhibitors to inflamed endothelial cells in vitro and in vivo. The therapeutic effectiveness of anti–miR-92a therapy in treating atherosclerosis and stenosis in Apoe –/– mice is markedly enhanced by the VCAM-1–targeting polyelectrolyte complex micelles. These results demonstrate a proof of concept to devise polyelectrolyte complex micelle-based targeted nanomedicine approaches treating vascular complications in vivo.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Integrating HPC simulations and physical experiments to characterize the effects of gamma radiation on seismic protective devices

Seismic protective systems, composed of seismic isolators and dampers, can substantially reduce the effects of earthquake shaking on nuclear power plants and components therein. To enable the use of these devices to protect equipment inside a plant and close to a source of radiation, the U.S. Department of Energy (DOE) funded a project at the Idaho National Laboratory (INL) and the University at Buffalo to characterize the effects of absorbed gamma dose on their mechanical properties. An early task in the project was to determine the exposure time required in the INL Foss Therapy Services (FTS) 60 Co gamma irradiator to achieve a target absorbed dose in the materials used to construct isolators and dampers, including fluids, polymers, composites, and metals. This task required the novel integration of high-performance computing (HPC), Monte Carlo N-Particle (MCNP) simulations, and irradiation experiments using Fricke dosimetry. An MCNP model of the FTS irradiator at INL was developed and validated using Fricke dosimetry. Simulations of three experiments in the irradiator, two with Fricke vials only and one with Fricke vials and a large-size isolator, predicted the Fricke-measured absorbed dose rate to within 15% in all three cases, providing high confidence in the calculation of the gamma dose absorbed in the materials comprising the seismic protective devices. The simulations demonstrated that the effects of photon scattering on absorbed dose rate in the FTS irradiator are negligible for test articles installed close to the cobalt sources and near the rear of the irradiator. The validated MCNP model of the FTS irradiator is being used to support ongoing DOE-funded experiments on seismic protective devices and could be applied to future, non-seismic-related experiments. In conclusion, the novel validation process successfully deployed for the FTS irradiator at INL could be applied to other irradiators, requiring new MCNP models and simulations, and irradiation experiments using dosimeters.

42 - ENGINEERING↗
DOE OSTI2025

Gestational exposure to HIV drugs alters intestinal mucosa-associated microbial diversity in adult rat offspring

The antiretroviral (ARV) drug combination of abacavir sulfate, dolutegravir, and lamivudine [ABC/DTG/3TC; Tri combination Anti-retroviral therapy (TC-ART)] has revolutionized HIV treatment by effectively targeting different stages of viral replication. Despite its therapeutic efficiency for maintaining low viremia in the mother during pregnancy, there are concerns for long-term liabilities in offspring that are indirectly exposed during vulnerable periods of development. The commensal microbiota plays a crucial role in maintaining overall gut health, and disruption of the microbiome is often linked to various extraintestinal effects such as immune dysregulation and inflammation. We recently reported the effects of this drug combination in altering fecal microbiome composition of aged rats perinatally exposed to ABC/DTG/3TC-ART. The fecal microbiome can provide only a snapshot of the composition of microbial community at the end of the digestive tract, which may not reflect the microbial population interacting with ileal mucosa. Thus, the current work reports the effects of this drug combination in the gut mucosa-associated microbiome of the same animals, which showed significant microbial diversity and species richness in high dose exposed female adult offspring, along with dose-dependent changes in Firmicutes/Bacteroidetes ratio. The high dose exposure also showed an increase in opportunistic bacterial species in male animals. Overall, we found that, similar to the fecal microbiome, perinatal exposure to TC-ART led to sex- and dose-dependent alterations in the gut mucosa-associated microbial population in aged rats, suggesting that early life exposure to these drugs may influence gut mucosa-associated immune responses and intestinal permeability.

Research & Experimental Medicine↗
DOE OSTI2021

Structural engineering of chimeric antigen receptors targeting HLA-restricted neoantigens

Chimeric antigen receptor (CAR) T cells have emerged as a promising class of therapeutic agents, generating remarkable responses in the clinic for a subset of human cancers. One major challenge precluding the wider implementation of CAR therapy is the paucity of tumor-specific antigens. Here, we describe the development of a CAR targeting the tumor-specific isocitrate dehydrogenase 2 (IDH2) with R140Q mutation presented on the cell surface in complex with a common human leukocyte antigen allele, HLA-B*07:02. Engineering of the hinge domain of the CAR, as well as crystal structure-guided optimization of the IDH2 R140Q- HLA-B*07:02-targeting moiety, enhances the sensitivity and specificity of CARs to enable targeting of this HLA-restricted neoantigen. This approach thus holds promise for the development and optimization of immunotherapies specific to other cancer driver mutations that are difficult to target by conventional means.

99 GENERAL AND MISCELLANEOUS↗
DOE OSTI2020

Knocking out barriers to engineered cell activity

Engineered T cell therapies are revolutionizing cancer treatment by achieving long-lasting remission in blood-related cancers, such as leukemia and lymphoma. These therapies involve removal of patient T cells, “reprogramming” them to attack cancer cells, and then transferring them back into the patient. Targeted gene inactivation (knockout) using CRISPR-Cas9 can enhance T cell activity (1, 2) and has the potential to expand cell therapy applications. Until now, it has been unknown whether CRISPR-Cas9–edited T cells would be tolerated and thrive once reinfused into a human. On page 1001 of this issue, Stadtmauer et al. (3) present data from a phase 1 clinical trial (designed to test safety and feasibility) on the first cancer patients treated with CRISPR-Cas9–modified T cells. The findings represent an important advance in the therapeutic application of gene editing and highlight the potential to accelerate development of cell-based therapies.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Gold leaf phantom development for the assessment of proton radiographic sensitivity limits simulating gold nanoparticle tagged tumors

Proton radiography may guide proton therapy cancer treatments with beam’s-eye-view anatomical images and a proton-based estimation of proton stopping power. However, without contrast enhancement, proton radiography will not be able to distinguish tumor from tissue. To provide this contrast, functionalized, high-Z nanoparticles that specifically target a tumor could be injected into a patient before imaging. We conducted this study to understand the ability of gold, as a high-Z, biologically compatible tracer, to differentiate tumors from surrounding tissue. We indicate that AuNP-enhanced proton radiography might be a feasible technology to provide image-guidance to proton therapy, potentially reducing off-target effects and sparing nearby tissue. These data can be used to develop treatment plans and clinical applications can be derived from the simulations.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2025

Ticking off Lyme disease: OspA mRNA vaccine halts infection in mouse model

Lyme disease, a condition caused by Borrelia burgdorferi sensu lato and transmitted to humans via ticks, affects approximately 676,000 individuals annually in the United States and Western Europe.1 Currently, there is no approved Lyme vaccine available for human use. A promising study by Tahir et al., published in Molecular Therapy Nucleic Acids, investigated the efficacy of mRNA and subunit vaccines targeting Lyme disease.2 This research demonstrated complete protection from infection in a tick-fed mouse model using an outer surface protein A (OspA) mRNA vaccine. Although mRNA vaccines have shown success against viral pathogens, their clinical application against bacterial diseases has been limited.3 Thus, this study represents an important step toward developing an effective mRNA vaccine against Lyme disease.

He, Wei↗
DOE OSTI2021

NPRL2 reduces the niraparib sensitivity of castration-resistant prostate cancer via interacting with UBE2M and enhancing neddylation

In this study, we explored the regulatory effects of nitrogen permease regulator 2-like (NPRL2) on niraparib sensitivity, a PARP inhibitor (PARPi) in castrate-resistant prostate cancer (CRPC). Data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) program were retrospectively examined. Gene-set enrichment analysis (GSEA) was conducted between high and low NRPL2 expression prostate adenocarcinoma (PRAD) cases in TCGA. CCK-8 assay, Western blot analysis of apoptotic proteins, and flow cytometric analysis of apoptosis were applied to test niraparib sensitivity. Immunofluorescent (IF) staining and co-immunoprecipitation (co-IP) were conducted to explore the proteins interacting with NPRL2. Results showed that the upregulation of a canonical protein-coding transcript of NPRL2 (ENST00000232501.7) is associated with an unfavorable prognosis. Bioinformatic analysis predicts a physical interaction between NPRL2 and UBE2M, which is validated by a following Co-IP assay. This interaction increases NPRL2 stability by reducing polyubiquitination and proteasomal degradation. Depletion of NPRL2 or UBE2M significantly increases the niraparib sensitivity of CRPC cells and enhances niraparib-induced tumor growth inhibition in vivo. NPRL2 cooperatively enhances UBE2M-mediated neddylation and facilitates the degradation of multiple substrates of Cullin-RING E3 ubiquitin ligases (CRLs). In conclusion, this study identified a novel NPRL2-UBE2M complex in modulating neddylation and niraparib sensitivity of CRPC cells. Therefore, targeting NPRL2 might be considered as an adjuvant strategy for PARPi therapy.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Supervised learning with word embeddings derived from PubMed captures latent knowledge about protein kinases and cancer

Abstract Inhibiting protein kinases (PKs) that cause cancers has been an important topic in cancer therapy for years. So far, almost 8% of >530 PKs have been targeted by FDA-approved medications, and around 150 protein kinase inhibitors (PKIs) have been tested in clinical trials. We present an approach based on natural language processing and machine learning to investigate the relations between PKs and cancers, predicting PKs whose inhibition would be efficacious to treat a certain cancer. Our approach represents PKs and cancers as semantically meaningful 100-dimensional vectors based on word and concept neighborhoods in PubMed abstracts. We use information about phase I-IV trials in ClinicalTrials.gov to construct a training set for random forest classification. Our results with historical data show that associations between PKs and specific cancers can be predicted years in advance with good accuracy. Our tool can be used to predict the relevance of inhibiting PKs for specific cancers and to support the design of well-focused clinical trials to discover novel PKIs for cancer therapy.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Drosophila models to study causative genes for human rare intractable neurological diseases

Highlights: • Drosophila models targeting some ALS-causing genes are described. • Drosophila models targeting some CMT-causing genes are described. • Drosophila models targeting some Sotos syndrome-causing genes are described. • Genes and pathways that commonly interact with ALS- and/or CMT-causing genes are described. Drosophila is emerging as a convenient model for investigating human diseases. Functional homologues of almost 75% of human disease-related genes are found in Drosophila. Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease that causes defects in motoneurons. Charcot-Marie-Tooth disease (CMT) is one of the most commonly found inherited neuropathies affecting both motor and sensory neurons. No effective therapy has been established for either of these diseases. In this review, after overviewing ALS, Drosophila models targeting several ALS-causing genes, including TDP-43, FUS and Ubiquilin2, are described with their genetic interactants. Then, after overviewing CMT, examples of Drosophila models targeting several CMT-causing genes, including mitochondria-related genes and FIG 4, are also described with their genetic interactants. In addition, we introduce Sotos syndrome caused by mutations in the epigenetic regulator gene NSD1. Lastly, several genes and pathways that commonly interact with ALS- and/or CMT-causing genes are described. In the case of ALS and CMT that have many causative genes, it may be not practical to perform gene therapy for each of the many disease-causing genes. The possible uses of the common genes and pathways as novel diagnosis markers and effective therapeutic targets are discussed.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Adaptive Radiation Therapy (ART) Strategies and Technical Considerations: A State of the ART Review From NRG Oncology

The integration of adaptive radiation therapy (ART), or modifying the treatment plan during the treatment course, is becoming more widely available in clinical practice. ART offers strong potential for minimizing treatment-related toxicity while escalating or de-escalating target doses based on the dose to organs at risk. Yet, ART workflows add complexity into the radiation therapy planning and delivery process that may introduce additional uncertainties. This work sought to review presently available ART workflows and technological considerations such as image quality, deformable image registration, and dose accumulation. Quality assurance considerations for ART components and minimum recommendations are described. Personnel and workflow efficiency recommendations are provided, as is a summary of currently available clinical evidence supporting the implementation of ART. Finally, to guide future clinical trial protocols, an example ART physician directive and a physics template following standard NRG Oncology protocol is provided.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

Method and Atlas to Enable Targeting for Cardiac Radioablation Employing the American Heart Association Segmented Model

Cardiac radioablation using stereotactic body radiation therapy is gaining popularity as a noninvasive treatment for otherwise refractory ventricular arrhythmias. As radiation oncologists might be unaccustomed to the lexicon used by cardiologists to describe the location of arrhythmogenic foci, a preliminary guide to cardiac-specific anatomy and orientation is needed to foster effective communication between the radiation oncologist and cardiology team.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2023

Use of Longitudinal Serum Analysis and Machine Learning to Develop a Classifier for Cancer Early Detection

Early detection of solid tumors through a simple screening process, such as the proteomic analysis of biofluids, has the potential to significantly alter the management and outcomes of cancers. The application of advanced targeted proteomics measurements and data analysis strategies to uniformly collected serum or plasma samples would enable longitudinal studies of cancer risk, progression, and response to therapy that have the potential to significantly reduce cancer burden in general. In this article, we describe a generalizable workflow combining robust, multiplexed targeted proteomics measurements applied to longitudinal samples from the Department of Defense Serum Repository with a Random Forest machine learning method for developing and initially evaluating the performance of candidate biomarker panels for early detection of cancers. The effectiveness of this approach was demonstrated in a cohort of 175 head and neck squamous cell carcinoma patients. The outlined protocols include methods for sample preparation, instrument analysis, and data analysis and interpretation using this workflow.

Longitudinal analysis, machine learning, cancer, e↗
DOE OSTI2023

Microelectrode Arrays Measure Blocking of Voltage-Gated Calcium Ion Channels on Supported Lipid Bilayers Derived from Primary Neurons

Drug studies targeting neuronal ion channels are crucial to understand neuronal function and develop therapies for neurological diseases. The traditional method to study neuronal ion-channel activities heavily relies on the whole-cell patch clamp as the industry standard. However, this technique is both technically challenging and labour-intensive, while involving the complexity of keeping cells alive with low throughput. Therefore, the shortcomings are limiting the efficiency of ion-channel-related neuroscience research and drug testing. Here, this work reports a new system of integrating neuron membranes with organic microelectrode arrays (OMEAs) for ion-channel-related drug studies. This work demonstrates that the supported lipid bilayers (SLBs) derived from both neuron-like (neuroblastoma) cells and primary neurons are integrated with OMEAs for the first time. The increased expression of voltage-gated calcium (CaV) ion channels on differentiated SH-SY5Y SLBs compared to non-differentiated ones is sensed electrically. Also, dose-response of the CaV ion-channel blocking effect on primary cortical neuronal SLBs from rats is monitored. The dose range causing ion channel blocking is comparable to literature. This system overcomes the major challenges from traditional methods (e.g., patch clamp) and showcases an easy-to-test, rapid, ultra-sensitive, cell-free, and high-throughput platform to monitor dose-dependent ion-channel blocking effects on native neuronal membranes.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗