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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 271 records · Page 15

All sources NASA NTRS DOE OSTI

NASA NTRS1994

Production and action of cytokines in space

B6MP102 cells, a continuously cultured murine bone marrow macrophage cell line, were tested for secretion of tumor necrosis factor-alpha and Interleukin-1 during space flight. We found that B6MP102 cells secreted more tumor necrosis factor-alpha and interleukin-1 when stimulated in space with lipopolysaccharide than controls similarly stimulated on earth. This compared to increased secretion of interferon-beta and -gamma by lymphocytes that was measured on the same shuttle flights. Although space flight enhanced B6MP102 secretion of tumor necrosis factor-alpha, an experiment on a subsequent space flight (STS-50) found that cellular cytotoxicity, mediated by tumor necrosis factor-alpha, was inhibited.

Chapes, Stephen K.↗

NASA NTRS1993

Three distinct cell phenotypes of induced-TNF cytotoxicity and their relationship to apoptosis

We have identified three distinct cell phenotypes with respect to the conditions under which cells became susceptible to TNF-mediated lysis. These conditions include: 1) treatment with the protein synthesis inhibitor, cycloheximide; 2) contact with activated macrophages, and 3) infection with vaccinia virus. Whereas vaccinia virus-infected 3T3 cells became sensitive to soluble TNF, F5b cells required contact with activated macrophages. We showed that the "macrophage-resistant" F5m cells did not become sensitive to TNF or to killing by activated macrophages after infection with vaccinia virus. Therefore, vaccinia infection does not sensitize all cells to TNF. We also determined the pathways of lysis for cells after sensitization. Whereas 3T3, LM929, and F5b cells were killed by the process of necrosis, F5m cells lysis was characterized by the release of low mol wt DNA fragments (apoptosis).

Non-NASA Center↗

NASA NTRS1993

Potential health effects of space radiation

Crewmembers on missions to the Moon or Mars will be exposed to radiation belts, galactic cosmic rays, and possibly solar particle events. The potential health hazards due to these space radiations must be considered carefully to ensure the success of space exploration. Because there is no human radioepidemiological data for acute and late effects of high-LET (Linear-Energy-Transfer) radiation, the biological risks of energetic charged particles have to be estimated from experimental results on animals and cultured cells. Experimental data obtained to date indicate that charged particle radiation can be much more effective than photons in causing chromosome aberrations, cell killing, mutation, and tumor induction. The relative biological effectiveness (RBE) varies with biological endpoints and depends on the LET of heavy ions. Most lesions induced by low-LET radiation can be repaired in mammalian cells. Energetic heavy ions, however, can produce large complex DNA damages, which may lead to large deletions and are irreparable. For high-LET radiation, therefore, there are less or no dose rate effects. Physical shielding may not be effective in minimizing the biological effects on energetic heavy ions, since fragments of the primary particles can be effective in causing biological effects. At present the uncertainty of biological effects of heavy particles is still very large. With further understanding of the biological effects of space radiation, the career doses can be kept at acceptable levels so that the space radiation environment need not be a barrier to the exploitation of the promise of space.

Yang, Chui-Hsu↗

DOE OSTI2022

Histopathologic and proteogenomic heterogeneity reveals features of clear cell renal cell carcinoma aggressiveness

Clear cell renal cell carcinomas (ccRCCs) represent ∼75% of RCC cases and account for most RCC-associated deaths. Inter- and intratumoral heterogeneity (ITH) results in varying prognosis and treatment outcomes. To obtain the most comprehensive profile of ccRCC, we perform integrative histopathologic, proteogenomic, and metabolomic analyses on 305 ccRCC tumor segments and 166 paired adjacent normal tissues from 213 cases. Combining histologic and molecular profiles reveals ITH in 90% of ccRCCs, with 50% demonstrating immune signature heterogeneity. High tumor grade, along with BAP1 mutation, genome instability, increased hypermethylation, and a specific protein glycosylation signature define a high-risk disease subset, where UCHL1 expression displays prognostic value. Single-nuclei RNA sequencing of the adverse sarcomatoid and rhabdoid phenotypes uncover gene signatures and potential insights into tumor evolution. In vitro cell line studies confirm the potential of inhibiting identified phosphoproteome targets. This study molecularly stratifies aggressive histopathologic subtypes that may inform more effective treatment strategies.

CPTAC↗

DOE OSTI2024

Mitochondrial ATP generation is more proteome efficient than glycolysis

Metabolic efficiency profoundly influences organismal fitness. Nonphotosynthetic organisms, from yeast to mammals, derive usable energy primarily through glycolysis and respiration. Although respiration is more energy efficient, some cells favor glycolysis even when oxygen is available (aerobic glycolysis, Warburg effect). A leading explanation is that glycolysis is more efficient in terms of ATP production per unit mass of protein (that is, faster). Through quantitative flux analysis and proteomics, we find, however, that mitochondrial respiration is actually more proteome efficient than aerobic glycolysis. This is shown across yeast strains, T cells, cancer cells, and tissues and tumors in vivo. Instead of aerobic glycolysis being valuable for fast ATP production, it correlates with high glycolytic protein expression, which promotes hypoxic growth. Aerobic glycolytic yeasts do not excel at aerobic growth but outgrow respiratory cells during oxygen limitation. Here, we accordingly propose that aerobic glycolysis emerges from cells maintaining a proteome conducive to both aerobic and hypoxic growth.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

NASA NTRS2003

Cell Science and Cell Biology Research at MSFC: Summary

The common theme of these research programs is that they investigate regulation of gene expression in cells, and ultimately gene expression is controlled by the macromolecular interactions between regulatory proteins and DNA. The NASA Critical Path Roadmap identifies Muscle Alterations and Atrophy and Radiation Effects as Very Serious Risks and Severe Risks, respectively, in long term space flights. The specific problem addressed by Dr. Young's research ("Skeletal Muscle Atrophy and Muscle Cell Signaling") is that skeletal muscle loss in space cannot be prevented by vigorous exercise. Aerobic skeletal muscles (i.e., red muscles) undergo the most extensive atrophy during long-term space flight. Of the many different potential avenues for preventing muscle atrophy, Dr. Young has chosen to study the beta-adrenergic receptor (betaAR) pathway. The reason for this choice is that a family of compounds called betaAR agonists will preferentially cause an increase in muscle mass of aerobic muscles (i.e., red muscle) in animals, potentially providing a specific pharmacological solution to muscle loss in microgravity. In addition, muscle atrophy is a widespread medical problem in neuromuscular diseases, spinal cord injury, lack of exercise, aging, and any disease requiring prolonged bedridden status. Skeletal muscle cells in cell culture are utilized as a model system to study this problem. Dr. Richmond's research ("Radiation & Cancer Biology of Mammary Cells in Culture") is directed toward developing a laboratory model for use in risk assessment of cancer caused by space radiation. This research is unique because a human model will be developed utilizing human mammary cells that are highly susceptible to tumor development. This approach is preferential over using animal cells because of problems in comparing radiation-induced cancers between humans and animals.

Source record↗

DOE OSTI2024

yihuishen/metabolic_flux_regulation

Metabolic efficiency profoundly influences organismal fitness. Heterotrophs, from yeast to mammals, derive usable energy primarily through glycolysis and respiration. While respiration is more energy-efficient, some cells favor glycolysis even when oxygen is available (aerobic glycolysis, Warburg effect). A leading explanation is that glycolysis is more efficient in terms of ATP production per unit mass of protein (i.e. faster). Through quantitative flux analysis and proteomics, we find however that mitochondrial respiration is actually more proteome-efficient than aerobic glycolysis. This is shown across yeasts, T cells, cancer cells, and tissues and tumors in vivo. Instead of aerobic glycolysis being valuable for fast ATP production, it correlates with high glycolytic protein expression, which is valuable for hypoxic growth. Aerobic glycolytic yeasts do not excel at aerobic growth, but outgrow respiratory cells in oxygen limitation. Thus, aerobic glycolysis emerges from cells maintaining a proteome conducive to both aerobic and hypoxic growth.

Shen, Yihui↗

DOE OSTI2024

yihuishen/T_cell_MFA

Shen, Yihui↗

DOE OSTI2026

Data for Mitochondrial ATP Generation is More Proteome Efficient than Glycolysis

Metabolomics↗

DOE OSTI2021

IRS4 promotes the progression of non-small cell lung cancer and confers resistance to EGFR-TKI through the activation of PI3K/Akt and Ras-MAPK pathways

IRS4 is a member of the insulin receptor substrate (IRS) protein family. It acts as a cytoplasmic adaptor protein, integrating and transmitting signals from receptor protein tyrosine kinases to the intracellular environment. IRS4 can induce mammary tumorigenesis and is usually overexpressed in non-small cell lung cancer (NSCLC). However, little is known about the role of IRS4 in the development and progression of lung cancer. In this study, we show that IRS4 knockout suppresses the proliferation, colony formation, migration, and invasion of A549 lung cancer cells, as well as tumor growth in a nude mouse xenograft model. In contrast, stable expression of IRS4 showed the opposite effects. As expected, IRS4 was found to activate the PI3K/Akt and Ras-MAPK pathways, and we also showed that IRS4 depletion significantly enhanced the sensitivity of EGFR tyrosine kinase inhibitor (EGFR-TKI)-resistant cells to gefitinib. Taken together, these results show that IRS4 promotes NSCLC progression and may represent a potential therapeutic target for EGFR-TKI-resistant NSCLC.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2021

Current Status of Clinical Trials for Cervical and Uterine Cancer Using Immunotherapy Combined With Radiation

Novel therapies combined with radiation continue to be of significant interest in the developmental treatment paradigm of gynecologic cancers. Clinical implementation of immunotherapy in oncology has rapidly changed the treatment landscape, options, paradigm, and outcomes through clinical trials. Immunotherapy has emerged as a therapeutic pillar in the treatment of solid tumors with demonstrable synergistic activity when combined with radiation therapy and chemoradiotherapy by an alteration or enhancement of the immune system. In solid tumors, radiation therapy induces migration of dendritic cells, T cell activation, and proliferation, and increases in tumor-infiltrating lymphocytes. These immunomodulatory effects in conjunction with immune checkpoint blockade are currently under active investigation in the adjuvant, definitive, and metastatic settings. Results from early phase trials demonstrate promising efficacy and overall tolerable toxicity profiles of combined modality treatment. There is significant interest in optimizing the treatment for patients with locally advanced cervical cancer beyond the standard of care—chemoradiation—which has been in place for the last 30 years. The majority of cervical cancer emerges after persistent infection with a high-risk subtype of the human papillomavirus, where viral oncoproteins lead to cellular changes and immortalization. As a result, immune tolerance can develop, resulting in cancer. Knowledge of the mechanism of human papillomavirus–related oncogenesis suggests that immune therapy or checkpoint blockade can reinvigorate an antitumor immune response. Current clinical trials are exploring the therapeutic potential of these approaches. Uterine cancers have been grouped into 4 molecular subclasses by their driver mutations, mutational burden, and copy-number alterations. Of these subgroups, the polymerase epsilon–mutated and microsatellite-unstable may represent up to 40% of endometrial cancers, and they have been shown to be immunogenic. Because of the inherent immunogenicity of these MSI-high tumors, combined immune modulation strategies, including chemotherapy, radiation, and immunotherapy and immune checkpoint inhibitor therapy, are being explored to improve treatment outcomes. In this review, we explore current immunomodulatory and multimodality therapeutic approaches in the treatment of cervical and uterine cancer through ongoing clinical trials investigating the combination of immunotherapy and radiation therapy.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2021

Cdkn1a transcript variant 2 is a marker of aging and cellular senescence

Cellular senescence is a cell fate response characterized by a permanent cell cycle arrest driven primarily the by cell cycle inhibitor and tumor suppressor proteins p16 Ink4a and p21 Cip1/Waf1 . In mice, the p21 Cip1/Waf1 encoding locus, Cdkn1a , is known to generate two transcripts that produce identical proteins, but one of these transcript variants is poorly characterized. We show that the Cdkn1a transcript variant 2, but not the better-studied variant 1, is selectively elevated during natural aging across multiple mouse tissues. Importantly, mouse cells induced to senescence in culture by genotoxic stress (ionizing radiation or doxorubicin) upregulated both transcripts, but with different temporal dynamics: variant 1 responded nearly immediately to genotoxic stress, whereas variant 2 increased much more slowly as cells acquired senescent characteristics. Upon treating mice systemically with doxorubicin, which induces widespread cellular senescence in vivo , variant 2 increased to a larger extent than variant 1. Variant 2 levels were also more sensitive to the senolytic drug ABT-263 in naturally aged mice. Thus, variant 2 is a novel and more sensitive marker than variant 1 or total p21 Cip1/Waf1 protein for assessing the senescent cell burden and clearance in mice.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2022

Curcumin Nanodiscs Improve Solubility and Serve as Radiological Protectants against Ionizing Radiation Exposures in a Cell-Cycle Dependent Manner

Curcumin, a natural polyphenol derived from the spice turmeric (Curcuma longa), contains antioxidant, anti-inflammatory, and anti-cancer properties. However, curcumin bioavailability is inherently low due to poor water solubility and rapid metabolism. Here, we further refined for use curcumin incorporated into “biomimetic” nanolipoprotein particles (cNLPs) consisting of a phospholipid bilayer surrounded by apolipoprotein A1 and amphipathic polymer scaffolding moieties. Our cNLP formulation improves the water solubility of curcumin over 30-fold and produces nanoparticles with ~350 µg/mL total loading capacity for downstream in vitro and in vivo applications. We found that cNLPs were well tolerated in AG05965/MRC-5 human primary lung fibroblasts compared to cultures treated with curcumin solubilized in DMSO (curDMSO). Pre-treatment with cNLPs of quiescent G0/G1-phase MRC-5 cultures improved cell survival following 137Cs gamma ray irradiations, although this finding was reversed in asynchronously cycling log-phase cell cultures. These findings may be useful for establishing cNLPs as a method to improve curcumin bioavailability for administration as a radioprotective and/or radiomitigative agent against ionizing radiation (IR) exposures in non-cycling cells or as a radiosensitizing agent for actively dividing cell populations, such as tumors.

36 MATERIALS SCIENCE↗

DOE OSTI2022

Patient-Specific Mathematical Model of the Clear Cell Renal Cell Carcinoma Microenvironment

The interactions between cells and molecules in the tumor microenvironment can give insight into the initiation and progression of tumors and their optimal treatment options. In this paper, we developed an ordinary differential equation (ODE) mathematical model of the interaction network of key players in the clear cell renal cell carcinoma (ccRCC) microenvironment. We then performed a global gradient-based sensitivity analysis to investigate the effects of the most sensitive parameters of the model on the number of cancer cells. The results indicate that parameters related to IL-6 have high a impact on cancer cell growth, such that decreasing the level of IL-6 can remarkably slow the tumor’s growth.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2021

YAP/STAT3 promotes the immune escape of larynx carcinoma by activating VEGFR1-TGFβ signaling to facilitate PD-L1 expression in M2-like TAMs

Larynx carcinoma (LC) is the most prevalent head and neck cancer among adults. LC xenograft mouse model was generated to verify the effect of VEGF on macrophage polarization and tumor growth in vivo. EdU assay was performed to measure the cell proliferation. Transwell assay was applied to assess cell migration. The expression of YAP and STAT3 was also significantly increased in LC tumor tissues. Moreover, both YAP and STAT3 overexpression in LC cells promoted the proliferation, migration, as well as the secretion of PD-L1 in M2-like TAMs. Mechanistically, the interaction between YAP and STAT3 facilitated the transcription of VEGF. Moreover, with a co-culture system, VEGF secretion in LC cells enhanced PD-L1 expression in M2-like TAMs via activating VEGFR1-TGFβ signaling pathway. Furthermore, VEGF secreted from LC cells also promoted the tumor growth of LC in vivo. We revealed that dysregulated YAP/STAT3 activity in LC cells could enhance the secretion of VEGF, which then functioned on M2-like TAMs via activating VEGFR1-TGFββ pathway to promote the expression of PD-L1 and immunosuppressive function of M2-like TAMs. Therefore, VEGF and PD-L1 might have a pivotal crosstalk between M2-like TAMs and LC cells, which provided a novel therapeutic target in regulating the metastasis of LC in future.

60 APPLIED LIFE SCIENCES↗

NASA NTRS2001

Optimized shielding for space radiation protection

Future deep space mission and International Space Station exposures will be dominated by the high-charge and -energy (HZE) ions of the Galactic Cosmic Rays (GCR). A few mammalian systems have been extensively tested over a broad range of ion types and energies. For example, C3H10T1/2 cells, V79 cells, and Harderian gland tumors have been described by various track-structure dependent response models. The attenuation of GCR induced biological effects depends strongly on the biological endpoint, response model used, and material composition. Optimization of space shielding is then driven by the nature of the response model and the transmission characteristics of the given material.

NASA Discipline Radiation Health↗

DOE OSTI2021

CD63-mediated cloaking of VEGF in small extracellular vesicles contributes to anti-VEGF therapy resistance

Despite wide use of anti-vascular endothelial growth factor (VEGF) therapy for many solid 30 cancers, most of them become resistant to this therapy and develop into progressive disease. 31 Therefore, new biomarkers and strategies for blocking adaptive resistance of cancer to anti-VEGF therapy are needed. As described herein, we found that cancer-derived small extracellular vesicles (EVs) package increasing quantities of VEGF and other factors in response to anti-VEGF therapy. Notably, small EV-VEGF (eVEGF) is not recognized by bevacizumab and can be transferred to endothelial cells and trigger intracrine signaling and promote angiogenesis. Also, serum eVEGF was present at higher levels in ovarian cancer mouse models with adaptive resistance to bevacizumab than in models sensitive to it. Ovarian cancer cell-derived eVEGF increased tumor growth despite treatment with bevacizumab. Notably, the eVEGF level was elevated in patient serum after bevacizumab-containing therapy. Proteomic data of small EVs from mouse models suggested that several novel biomarkers are promising for drug response prediction. Collectively, these data demonstrated a new mechanism whereby eVEGF evades recognition by therapeutic antibodies and promotes tumor angiogenesis and progression. These findings have clinical implications for biomarkers and new therapeutic strategies for ovarian cancer.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2026

Identification of KLHL12 Ligands Using Fragment-Based Methods

Targeted protein degradation can be induced by recruiting a protein of interest to an E3 ligase, resulting in its ubiquitination and subsequent proteasome-mediated degradation. However, only a small number of E3 ligases have been utilized for degradation. Expansion of the repertoire of useful E3 ligases via the identification of ligands to those ligases could broaden the scope and applicability of the degradation paradigm. We have identified KLHL12 as an E3 ligase with higher expression in cancer over normal tissues. We report here the use of NMR-based screening to identify fragments that bind to KLHL12, and X-ray structures of a fragment hit bound to KLHL12. Using this structural information, we optimized the hits, leading to the first reported small molecules that bind to KLHL12 with submicromolar affinity. Derivatives of these compounds may be useful for the construction of PROTACs to selectively degrade protein targets in tumors while sparing normal cells.

Amines↗