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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 181 records · Page 10
All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

A framework of computer vision-enhanced microfluidic approach for automated assessment of the transient sickling kinetics in sickle red blood cells

The occurrence of vaso-occlusive crisis greatly depends on the competition between the sickling delay time and the transit time of individual sickle cells, i.e., red blood cells from sickle cell disease (SCD) patients, while they are traversing the circulatory system. Many drugs for treating SCD work by inhibiting the polymerization of sickle hemoglobin (HbS), effectively delaying the sickling process in sickle cells (SS RBCs). Most previous studies on screening anti-sickling drugs, such as voxelotor, rely on in vitro testing of sickling characteristics, often conducted under prolonged deoxygenation for up to 1 hour. However, since the microcirculation of RBCs typically takes less than 1 minute, the results of these studies may be less accurate and less relevant for in vitro-in vivo correlation. In our current study, we introduce a computer vision-enhanced microfluidic framework designed to automatically capture the transient sickling kinetics of SS RBCs within a 1-min timeframe. Our study has successfully detected differences in the transient sickling kinetics between vehicle control and voxelotor-treated SS RBCs. This approach has the potential for broader applications in screening anti-sickling therapies.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

CD46 targeted 212 Pb alpha particle radioimmunotherapy for prostate cancer treatment

We recently identified CD46 as a novel prostate cancer cell surface antigen that shows lineage independent expression in both adenocarcinoma and small cell neuroendocrine subtypes of metastatic castration resistant prostate cancer (mCRPC), discovered an internalizing human monoclonal antibody YS5 that binds to a tumor selective CD46 epitope, and developed a microtubule inhibitor-based antibody drug conjugate that is in a multi-center phase I trial for mCRPC (NCT03575819). Here we report the development of a novel CD46-targeted alpha therapy based on YS5. We conjugated 212 Pb, an in vivo generator of alpha-emitting 212 Bi and 212 Po, to YS5 through the chelator TCMC to create the radioimmunoconjugate, 212 Pb-TCMC-YS5. We characterized 212 Pb-TCMC-YS5 in vitro and established a safe dose in vivo. We next studied therapeutic efficacy of a single dose of 212 Pb-TCMC-YS5 using three prostate cancer small animal models: a subcutaneous mCRPC cell line-derived xenograft (CDX) model (subcu-CDX), an orthotopically grafted mCRPC CDX model (ortho-CDX), and a prostate cancer patient-derived xenograft model (PDX). In all three models, a single dose of 0.74 MBq (20 µCi) 212 Pb-TCMC-YS5 was well tolerated and caused potent and sustained inhibition of established tumors, with significant increases of survival in treated animals. A lower dose (0.37 MBq or 10 µCi 212 Pb-TCMC-YS5) was also studied on the PDX model, which also showed a significant effect on tumor growth inhibition and prolongation of animal survival. These results demonstrate that 212 Pb-TCMC-YS5 has an excellent therapeutic window in preclinical models including PDXs, opening a direct path for clinical translation of this novel CD46-targeted alpha radioimmunotherapy for mCRPC treatment.

212Pb↗
DOE OSTI2025

Engineered IL-18 variants with half-life extension and improved stability for cancer immunotherapy

Background The pro-inflammatory cytokine, interleukin-18 (IL-18), plays an instrumental role in bolstering anti-tumor immunity. However, the therapeutic application of IL-18 has been limited due to its susceptibility to neutralization by IL-18 binding protein (IL-18BP), short in vivo half-life, and unfavorable physicochemical properties. Methods In order to overcome the poor drug-like properties of IL-18, we installed an artificial disulfide bond, removed the native, unpaired cysteines, and fused the stabilized cytokine to an IgG Fc domain. The stability, potency, pharmacokinetic and pharmacodynamic properties as well as efficacy of disulfide-stabilized IL-18 Fc-fusion (dsIL-18-Fc) were assessed via in vitro and in vivo studies. Results The stability and mammalian host cell production yields of dsIL-18-Fc were improved, compared to the wild-type (WT) cytokine, while maintaining its biological potency and interactions with IL-18 receptor α (IL-18Rα) and IL-18BP. Recombinant fusion of the cytokine to an IgG Fc domain provided extended half-life. Notably, despite maintaining sensitivity to IL-18BP, dsIL-18-Fc was effective at activating both T and natural killer (NK) cells, and elicited a strong anti-tumor response, either as a single agent, or in conjunction with anti-programmed cell death-ligand 1 (anti-PD-L1) therapy. Conclusions We engineered IL-18 for reinforced stability, extended half-life, and improved manufacturability. The therapeutic benefit of dsIL-18-Fc, coupled with a more favorable manufacturability profile and enhanced drug-like properties, underscores the potential utility of this engineered cytokine in cancer immunotherapy.

Immunology↗
DOE OSTI2021

Screening and Validation of Molecular Targeted Radiosensitizers

The development of molecular targeted drugs with radiation and chemotherapy is critically important for improving the outcomes of patients with hard-to-treat, potentially curable cancers. However, too many preclinical studies have not translated into successful radiation oncology trials. Major contributing factors to this insufficiency include poor reproducibility of preclinical data, inadequate preclinical modeling of intertumoral genomic heterogeneity that influences treatment sensitivity in the clinic, and a reliance on tumor growth delay instead of local control (TCD50) endpoints. There exists an urgent need to overcome these barriers to facilitate successful clinical translation of targeted radiosensitizers. To this end, we have used 3-dimensional (3D) cell culture assays to better model tumor behavior in vivo. Examples of successful prediction of in vivo effects with these 3D assays include radiosensitization of head and neck cancers by inhibiting epidermal growth factor receptor or focal adhesion kinase signaling, and radioresistance associated with oncogenic mutation of KRAS. To address the issue of tumor heterogeneity, we leveraged institutional resources that allow high-throughput 3D screening of radiation combinations with small-molecule inhibitors across genomically characterized cell lines from lung, head and neck, and pancreatic cancers. This high-throughput screen is expected to uncover genomic biomarkers that will inform the successful clinical translation of targeted agents from the National Cancer Institute Cancer Therapy Evaluation Program portfolio and other sources. Screening “hits” need to be subjected to refinement studies that include clonogenic assays, addition of disease-specific chemotherapeutics, target/biomarker validation, and integration of patient-derived tumor models. The chemoradiosensitizing activities of the most promising drugs should be confirmed in TCD50 assays in xenograft models with or without relevant biomarker and using clinically relevant radiation fractionation. We predict that appropriately validated and biomarker-directed targeted therapies will have a higher likelihood than past efforts of being successfully incorporated into the standard management of hard-to-treat tumors.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2022

In vivo stabilization of a less toxic asparaginase variant leads to a durable antitumor response in acute leukemia

Asparagine is a non-essential amino acid since it can either be taken up via the diet or synthesized by asparagine synthetase. Acute lymphoblastic leukemia (ALL) cells do not express asparagine synthetase or express it only minimally, which makes them completely dependent on extracellular asparagine for their growth and survival. This dependency makes ALL cells vulnerable to treatment with L-asparaginase, an enzyme that hydrolyzes asparagine. To date, all clinically approved L-asparaginases have significant L-glutaminase co-activity, associated with non-immune related toxic side effects observed during therapy. Therefore, reduction of L-glutaminase co-activity with concomitant maintenance of its anticancer L-asparaginase effect may effectively improve the tolerability of this unique drug. Previously, we designed a new alternative variant of Erwinia chrysanthemi (ErA; Erwinaze) with decreased L-glutaminase co-activity, while maintaining its L-asparaginase activity, by the introduction of three key mutations around the active site (ErA-TM). However, Erwinaze and our ErA-TM variant have very short half-lives in vivo. Here, we show that the fusion of ErA-TM with an albumin binding domain (ABD)-tag significantly increases its in vivo persistence. In addition, we evaluated the in vivo therapeutic efficacy of ABD-ErA-TM in a B-ALL xenograft model of SUP-B15. Our results show a comparable long-lasting durable antileukemic effect between the standard-of-care pegylated-asparaginase and ABD-ErA-TM L-asparaginase, but with fewer co-glutaminase-related acute side effects. Since the toxic side effects of current L-asparaginases often result in treatment discontinuation in ALL patients, this novel ErA-TM variant with ultra-low L-glutaminase co-activity and long in vivo persistence may have great clinical potential.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

The Cancer Microbiome: Distinguishing Direct and Indirect Effects Requires a Systemic View

The collection of microbes that live in and on the human body – the human microbiome – can impact on cancer initiation, progression, and response to therapy, including cancer immunotherapy. The mechanisms by which microbiomes impact on cancers can yield new diagnostics and treatments, but much remains unknown. The interactions between microbes, diet, host factors, drugs, and cell–cell interactions within the cancer itself likely involve intricate feedbacks, and no single component can explain all the behavior of the system. Understanding the role of host-associated microbial communities in cancer systems will require a multidisciplinary approach combining microbial ecology, immunology, cancer cell biology, and computational biology – a systems biology approach.

Xavier, Joao B.↗
DOE OSTI2024

A Semi‐Automated, High‐Throughput Approach for the Synthesis and Identification of Highly Photo‐Cytotoxic Iridium Complexes

Abstract The discovery of new compounds with pharmacological properties is usually a lengthy, laborious and expensive process. Thus, there is increasing interest in developing workflows that allow for the rapid synthesis and evaluation of libraries of compounds with the aim of identifying leads for further drug development. Herein, we apply combinatorial synthesis to build a library of 90 iridium(III) complexes (81 of which are new) over two synthesise‐and‐test cycles, with the aim of identifying potential agents for photodynamic therapy. We demonstrate the power of this approach by identifying highly active complexes that are well‐tolerated in the dark but display very low nM phototoxicity against cancer cells. To build a detailed structure–activity relationship for this class of compounds we have used density functional theory (DFT) calculations to determine some key electronic parameters and study correlations with the experimental data. Finally, we present an optimised semi‐automated synthesise‐and‐test protocol to obtain multiplex data within 72 hours.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2023

HIV-1 protease inhibitors with a P1 phosphonate modification maintain potency against drug-resistant variants by increased interactions with flap residues

Protease inhibitors are the most potent antivirals against HIV-1, but they still lose efficacy against resistant variants. Improving the resistance profile is key to developing more robust inhibitors, which may be promising candidates for simplified next-generation antiretroviral therapies. Here, in this study, we explored analogs of darunavir with a P1 phosphonate modification in combination with increasing size of the P1′ hydrophobic group and various P2′ moieties to improve potency against resistant variants. The phosphonate moiety substantially improved potency against highly mutated and resistant HIV-1 protease variants, but only when combined with more hydrophobic moieties at the P1′ and P2′ positions. Phosphonate analogs with a larger hydrophobic P1′ moiety maintained excellent antiviral potency against a panel of highly resistant HIV-1 variants, with significantly improved resistance profiles. The cocrystal structures indicate that the phosphonate moiety makes extensive hydrophobic interactions with the protease, especially with the flap residues. Many residues involved in these protease-inhibitor interactions are conserved, enabling the inhibitors to maintain potency against highly resistant variants. These results highlight the need to balance inhibitor physicochemical properties by simultaneous modification of chemical groups to further improve resistance profiles.

60 APPLIED LIFE SCIENCES↗
NASA NTRS1979

Space motion sickness

Research on the etiology, prediction, treatment and prevention of space motion sickness, designed to minimize the impact of this syndrome which was experienced frequently and with severity by individuals on the Skylab missions, on Space Shuttle crews is reviewed. Theories of the cause of space motion sickness currently under investigation by NASA include sensory conflict, which argues that motion sickness symptoms result from a mismatch between the total pattern of information from the spatial senses and that stored from previous experiences, and fluid shift, based upon the redistribution of bodily fluids that occurs upon continued exposure to weightlessness. Attempts are underway to correlate space motion sickness susceptibility to different provocative environments, vestibular and nonvestibular responses, and the rate of acquisition and length of retention of sensory adaptation. Space motion sickness countermeasures under investigation include various drug combinations, of which the equal combination of promethazine and ephedrine has been found to be as effective as the scopolomine and dexedrine combination, and vestibular adaptation and biofeedback training and autogenic therapy.

Homick, J. L.↗
DOE OSTI2019

Cancer Treatment-Associated Pericardial Disease: Epidemiology, Clinical Presentation, Diagnosis, and Management

Purpose of Review: Cancer therapeutics have seen tremendous growth in the last decade and have been effective in the treatment of several cancer types. However, with advanced therapies like kinase inhibitors and immunotherapies, there have been unintended consequences of cardiotoxicities. While traditional chemotherapy and radiation-induced cardiotoxicity have been well studied, further research is needed to understand the adverse effects of newer regimens. Recent Findings: Both immune-mediated and non-immune-medicated cytotoxicity have been noted with targeted therapies such as tyrosine kinase inhibitors and immune checkpoint inhibitors. In this manuscript, we describe the pericardial syndromes associated with cancer therapies and propose management strategies. Pericardial effusion and pericarditis are common presentations in cancer patients and often difficult to diagnose. Concomitant myocarditis may also present with pericardial toxicity, especially with immunotherapies. In addition to proper history and physical, additional testing such as cardiovascular imaging and tissue histology need to be obtained as appropriate. Holding the offending oncology drug, and institution of anti-inflammatory medications, and immunosuppressants such as steroids are indicated. Summary: A high index of suspicion, use of standardized definitions, and comprehensive evaluation are needed for early identification, appropriate treatment, and better outcomes for patients with cancer treatment-associated pericardial disease. Further research is needed to understand the pathophysiology and to evaluate how the management of pericardial conditions in these patients differ from traditional management and also evaluate new therapies.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

Artificial intelligence in cancer research, diagnosis and therapy

Artificial intelligence and machine learning techniques are breaking into biomedical research and health care, which importantly includes cancer research and oncology, where the potential applications are vast. These include detection and diagnosis of cancer, subtype classification, optimization of cancer treatment and identification of new therapeutic targets in drug discovery. While big data used to train machine learning models may already exist, leveraging this opportunity to realize the full promise of artificial intelligence in both the cancer research space and the clinical space will first require significant obstacles to be surmounted. In this Viewpoint article, we asked four experts for their opinions on how we can begin to implement artificial intelligence while ensuring standards are maintained so as transform cancer diagnosis and the prognosis and treatment of patients with cancer and to drive biological discovery.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

In-vivo neuronal dysfunction by Aβ and tau overlaps with brain-wide inflammatory mechanisms in Alzheimer’s disease

The molecular mechanisms underlying neuronal dysfunction in Alzheimer’s disease (AD) remain uncharacterized. Here, we identify genes, molecular pathways and cellular components associated with whole-brain dysregulation caused by amyloid-beta (Aβ) and tau deposits in the living human brain. We obtained in-vivo resting-state functional MRI (rs-fMRI), Aβ- and tau-PET for 47 cognitively unimpaired and 16 AD participants from the Translational Biomarkers in Aging and Dementia cohort. Adverse neuronal activity impacts by Aβ and tau were quantified with personalized dynamical models by fitting pathology-mediated computational signals to the participant’s real rs-fMRIs. Then, we detected robust brain-wide associations between the spatial profiles of Aβ-tau impacts and gene expression in the neurotypical transcriptome (Allen Human Brain Atlas). Within the obtained distinctive signature of in-vivo neuronal dysfunction, several genes have prominent roles in microglial activation and in interactions with Aβ and tau. Moreover, cellular vulnerability estimations revealed strong association of microglial expression patterns with Aβ and tau’s synergistic impact on neuronal activity (q < 0.001). These results further support the central role of the immune system and neuroinflammatory pathways in AD pathogenesis. Neuronal dysregulation by AD pathologies also associated with neurotypical synaptic and developmental processes. In addition, we identified drug candidates from the vast LINCS library to halt or reduce the observed Aβ-tau effects on neuronal activity. Top-ranked pharmacological interventions target inflammatory, cancer and cardiovascular pathways, including specific medications undergoing clinical evaluation in AD. Our findings, based on the examination of molecular-pathological-functional interactions in humans, may accelerate the process of bringing effective therapies into clinical practice.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

A Semi‐Automated, High‐Throughput Approach for the Synthesis and Identification of Highly Photo‐Cytotoxic Iridium Complexes

Abstract The discovery of new compounds with pharmacological properties is usually a lengthy, laborious and expensive process. Thus, there is increasing interest in developing workflows that allow for the rapid synthesis and evaluation of libraries of compounds with the aim of identifying leads for further drug development. Herein, we apply combinatorial synthesis to build a library of 90 iridium(III) complexes (81 of which are new) over two synthesise‐and‐test cycles, with the aim of identifying potential agents for photodynamic therapy. We demonstrate the power of this approach by identifying highly active complexes that are well‐tolerated in the dark but display very low nM phototoxicity against cancer cells. To build a detailed structure–activity relationship for this class of compounds we have used density functional theory (DFT) calculations to determine some key electronic parameters and study correlations with the experimental data. Finally, we present an optimised semi‐automated synthesise‐and‐test protocol to obtain multiplex data within 72 hours.

Kench, Timothy↗
DOE OSTI2021

Localized Delivery of Cisplatin to Cervical Cancer Improves Its Therapeutic Efficacy and Minimizes Its Side Effect Profile

Cervical cancer represents the fourth most frequent malignancy in the world among women, and mortality has remained stable for the past 4 decades. Intravenous cisplatin with concurrent radiation therapy is the standard-of-care for patients with local and regional cervical cancer. However, cisplatin induces serious dose-limiting systemic toxicities and recurrence frequently occurs. In this study, we aimed to develop an intracervical drug delivery system that allows cisplatin release directly into the tumor and minimize systemic side effects.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2024

Peptide-mimetic treatment of Pseudomonas aeruginosa in a mouse model of respiratory infection

The rise of drug resistance has become a global crisis, with >1 million deaths due to resistant bacterial infections each year. Pseudomonas aeruginosa, in particular, remains a serious problem with limited solutions due to complex resistance mechanisms that now lead to more than 32,000 multidrug-resistant (MDR) infections and over 2000 deaths in the U.S. annually. While the emergence of resistant bacteria has become ominously common, identification of useful new drug classes has been limited over the past over 40 years. We found that a potential novel therapeutic, the peptide-mimetic TM5, is effective at killing P. aeruginosa and displays sufficiently low toxicity in mammalian cells to allow for use in treatment of infections. Interestingly, TM5 kills P. aeruginosa more rapidly than traditional antibiotics, within 30–60 min in vitro, and is effective against a range of clinical isolates, including extensively drug resistant strains. In vivo, TM5 significantly reduced bacterial load in the lungs within 24 h compared to untreated mice and demonstrated few adverse effects. Taken together, these observations suggest that TM5 shows promise as an alternative therapy for MDR P. aeruginosa respiratory infections.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

PpIX‐enabled fluorescence‐based detection and photodynamic priming of platinum‐resistant ovarian cancer cells under fluid shear stress

Over 75% percent of ovarian cancer patients are diagnosed with advanced-stage disease characterized by unresectable intraperitoneal dissemination and the presence of ascites, or excessive fluid build-up within the abdomen. Conventional treatments include cytoreductive surgery followed by multi-line platinum and taxane chemotherapy regimens. Despite an initial response to treatment, over 75% of patients with advanced-stage ovarian cancer will relapse and succumb to platinum-resistant disease. Recent evidence suggests that fluid shear stress (FSS), which results from the movement of fluid such as ascites, induces epithelial-to-mesenchymal transition and confers resistance to carboplatin in ovarian cancer cells. This study demonstrates, for the first time, that FSS-induced platinum resistance correlates with increased cellular protoporphyrin IX (PpIX), the penultimate downstream product of heme biosynthesis, the production of which can be enhanced using the clinically approved pro-drug aminolevulinic acid (ALA). These data suggest that, with further investigation, PpIX could serve as a fluorescence-based biomarker of FSS-induced platinum resistance. Additionally, this study investigates the efficacy of PpIX-enabled photodynamic therapy (PDT) and the secretion of extracellular vesicles under static and FSS conditions in Caov-3 and NIH:OVCAR-3 cells, two representative cell lines for high-grade serous ovarian carcinoma (HGSOC), the most lethal form of the disease. FSS induces resistance to ALA-PpIX-mediated PDT, along with a significant increase in the number of EVs. Finally, the ability of PpIX-mediated photodynamic priming (PDP) to enhance carboplatin efficacy under FSS conditions is quantified. These preliminary findings in monolayer cultures necessitate additional studies to determine the feasibility of PpIX as a fluorescence-based indicator, and mediator of PDP, to target chemoresistance in the context of FSS.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Effect of in utero and lactational exposure to antiretroviral therapy on the gut microbial composition and metabolic function in aged rat offspring

Despite the highly effective impact of antiretroviral therapy (ART) in reducing mother-to-child transmission of human immunodeficiency virus (HIV), there are concerns of long-term impacts of ART on the health of the offspring. The implications of perinatal exposure to antiviral drugs on the gut bacterial population and metabolic function in the offspring is unclear but may influence health outcomes given the various reported effects of the microbiome in human health. This study aims to gain insight into the potential effect ofin uteroand lactational exposure to ART on gut microbiota populations and short‐chain fatty acids (SCFAs) production in aged rat offspring. Pregnant rats were administered a combination of antiretroviral drugs (abacavir/dolutegravir/lamivudine) at two different dose levels during gestation and throughout lactation, and the fecal bacterial abundance and SCFA levels of the offspring were analyzed when they reached 12 months of age. Our results showed dose-dependent and sex-based differences in fecal microbial abundance at various taxonomic levels. Specifically, we found a decline inFirmicutesin males, and an increase inActinobacteriaamong males and females. Furthermore, a sex-specific distribution reorganization ofLactobacillus,Bifidobacterium, andAkkermansiawas identified. No significant difference in the concentration of prominent SCFAs and IgA levels were identified. These findings provide preliminary information indicating the need to evaluate perinatal effects of ART more comprehensively on the gut bacterial and metabolic function in future studies, and their potential role in offspring health outcomes.

Research & Experimental Medicine↗