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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 109 records · Page 6
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

MLL1 is regulated by KSHV LANA and is important for virus latency

Abstract Mixed lineage leukemia 1 (MLL1) is a histone methyltransferase. Kaposi's sarcoma-associated herpesvirus (KSHV) is a leading cause of malignancy in AIDS. KSHV latently infects tumor cells and its genome is decorated with epigenetic marks. Here, we show that KSHV latency-associated nuclear antigen (LANA) recruits MLL1 to viral DNA where it establishes H3K4me3 modifications at the extensive KSHV terminal repeat elements during primary infection. LANA interacts with MLL1 complex members, including WDR5, integrates into the MLL1 complex, and regulates MLL1 activity. We describe the 1.5-Å crystal structure of N-terminal LANA peptide complexed with MLL1 complex member WDR5, which reveals a potential regulatory mechanism. Disruption of MLL1 expression rendered KSHV latency establishment highly deficient. This deficiency was rescued by MLL1 but not by catalytically inactive MLL1. Therefore, MLL1 is LANA regulable and exerts a central role in virus infection. These results suggest broad potential for MLL1 regulation, including by non-host factors.

Tan, Min↗
DOE OSTI2023

Transformative Technology for FLASH Radiation Therapy

The general concept of radiation therapy used in conventional cancer treatment is to increase the therapeutic index by creating a physical dose differential between tumors and normal tissues through precision dose targeting, image guidance, and radiation beams that deliver a radiation dose with high conformality, e.g., protons and ions. However, the treatment and cure are still limited by normal tissue radiation toxicity, with the corresponding side effects. A fundamentally different paradigm for increasing the therapeutic index of radiation therapy has emerged recently, supported by preclinical research, and based on the FLASH radiation effect. FLASH radiation therapy (FLASH-RT) is an ultra-high-dose-rate delivery of a therapeutic radiation dose within a fraction of a second. Experimental studies have shown that normal tissues seem to be universally spared at these high dose rates, whereas tumors are not. While dose delivery conditions to achieve a FLASH effect are not yet fully characterized, it is currently estimated that doses delivered in less than 200 ms produce normal-tissue-sparing effects, yet effectively kill tumor cells. Despite a great opportunity, there are many technical challenges for the accelerator community to create the required dose rates with novel compact accelerators to ensure the safe delivery of FLASH radiation beams.

43 PARTICLE ACCELERATORS↗
DOE OSTI2024

Mechanistic Insights into the Successful Development of Combination Therapy of Enfortumab Vedotin and Pembrolizumab for the Treatment of Locally Advanced or Metastatic Urothelial Cancer

Antibody–drug conjugates (ADCs) consist of an antibody backbone that recognizes and binds to a target antigen expressed on tumor cells and a small molecule chemotherapy payload that is conjugated to the antibody via a linker. ADCs are one of the most promising therapeutic modalities for the treatment of various cancers. However, many patients have developed resistance to this form of therapy. Extensive efforts have been dedicated to identifying an effective combination of ADCs with other types of anticancer therapies to potentially overcome this resistance. A recent clinical study demonstrated that a combination of the ADC enfortumab vedotin (EV) with the immune checkpoint inhibitor (ICI) pembrolizumab can achieve remarkable clinical efficacy as the first-line therapy for the treatment of locally advanced or metastatic urothelial carcinoma (la/mUC)—leading to the first approval of a combination therapy of an ADC with an ICI for the treatment of cancer patients. In this review, we highlight knowledge and understanding gained from the successful development of EV and the combination therapy of EV with ICI for the treatment of la/mUC. Using urothelial carcinoma as an example, we will focus on dissecting the underlying mechanisms necessary for the development of this type of combination therapy for a variety of cancers.

Oncology↗
NASA NTRS1975

Electrophoresis of biological materials

The selection of biological products was studied for electrophoresis in space. Free flow electrophoresis, isoelectric focusing, and isotachophoresis are described. The candidates discussed include: immunoglobulins and gamma globulins; isolated islet of langerhans from pancreas; bone marrow; tumor cells; kidney cells, cryoprecipitate; and column separated cultures.

Source record↗
NASA NTRS1977

Depth-dose relations for heavy ion beams

Radiation transport of heavy ions in matter is of interest to radiological protection in space and high-altitude aircraft. In addition, heavy ion beams are expected to be of advantage in radiotherapy since their characteristic Bragg curve allows a relative reduction of the dose in reaching a tumor site and the near elimination of exposure beyond the tumor region as the beam exits the body. Furthermore, the radioresistance of tumorous cells due to their hypoxic state may be reduced or eliminated by the high specific ionization of heavy ion beams. The depth-dose distribution of heavy ion beams consists of energy deposited by the attenuated primary beam with its characteristic Bragg curve and a relatively unstructured background due to secondary radiations produced in nuclear reactions. As the ion mass increases, the secondary contribution becomes more structured and may add significantly to the Bragg peak of the primary ions. The result for heavy ions (z greater than 20) is a greatly broadened Bragg peak region, especially in comparison to straggling effects, which may prove to be of importance in radiotherapy and biomedical research.

Wilson, J. W.↗
NASA NTRS1993

Immunoconjugates: Magic Bullets for Cancer Therapy?

Conjugating cytotoxic agents to antibodies allows for site-specific delivery of the agent to tumor cells and should provide increased efficacy and reduced non-specific toxicity. These site-specific cytotoxic agents are known as immunoconjugates or 'magic bullets' and have demonstrated great promise as therapeutic agents for cancer and other diseases. The historical developments and future potential of this new approach to cancer therapy are reviewed.

Passeri, Daniel R.↗
NASA NTRS1994

Microcapsules and Methods for Making

This invention relates to methods for forming multi-lamellar microcapsules of both hydrophilic and hydrophobic immiscible liquid phases using several polymer/solvent systems. Liquid-Liquid diffusion and spontaneous emulsification are controlled by properly timed sequence exposures of immiscible phases in aqueous vehicles dispersed in hydrocarbon solvents containing small quantities of oil, co-surfactants, and glycerides. Water-in-oil and oil-in-water microcapsules are formed containing selected combinations of several types of drugs, co-encapsulated within fluid compartments inside the microcapsule. Commercial applications of the process and the resultant product relate to drug therapy for treating medical conditions such as cancer, circulatory conditions, and other conditions in which pharmaceuticals are advantageously targeted to specific organs, or delivered in combination with other pharmaceuticals. Small microcapsules may be delivered intravenously to diseased organs or clotted vessels. The use of multiple drugs within the same microcapsule structure provides advantages for applications such as chemoembolization treatments and may be used to deliver both chemotherapeutic drugs, against tumor cells, and an immuno-adjuvant or immunological stimulant to enhance the patient's immune response. Active forms of urokinase and other enzymes may be delivered without dilution to the local site of an embolism for dissolving the embolism. Thus, the invention has several potentially valuable commercial applications related to pharmaceutical and medical applications.

Morrison, Dennis R.↗
NASA NTRS1991

Structural investigation of protein kinase C inhibitors

The phospholipid and Ca2+ dependent protein kinase (PKC) plays an essential role in a variety of cellular events. Inhibition of PKC was shown to arrest growth in tumor cell cultures making it a target for possible antitumor therapy. Calphostins are potent inhibitors of PKC with high affinity for the enzyme regulatory site. Structural characteristics of calphostins, which confer the inhibitory activity, are investigated by comparing their optimized structures with the existing models for PKC activation. The resulting model of inhibitory activity assumes interaction with two out of the three electrostatic interaction sites postulated for activators. The model shows two sites of hydrophobic interaction and enables the inhibitory activity of gossypol to be accounted for.

NASA Discipline Exobiology↗
NASA NTRS2001

TP53-dependent chromosome instability is associated with transient reductions in telomere length in immortal telomerase-positive cell lines

Telomere shortening in telomerase-negative somatic cells leads to the activation of the TP53 protein and the elimination of potentially unstable cells. We examined the effect of TP53 gene expression on both telomere metabolism and chromosome stability in immortal, telomerase-positive cell lines. Telomere length, telomerase activity, and chromosome instability were measured in multiple clones isolated from three related human B-lymphoblast cell lines that vary in TP53 expression; TK6 cells express wild-type TP53, WTK1 cells overexpress a mutant form of TP53, and NH32 cells express no TP53 protein. Clonal variations in both telomere length and chromosome stability were observed, and shorter telomeres were associated with higher levels of chromosome instability. The shortest telomeres were found in WTK1- and NH32-derived cells, and these cells had 5- to 10-fold higher levels of chromosome instability. The primary marker of instability was the presence of dicentric chromosomes. Aneuploidy and other stable chromosome alterations were also found in clones showing high levels of dicentrics. Polyploidy was found only in WTK1-derived cells. Both telomere length and chromosome instability fluctuated in the different cell populations with time in culture, presumably as unstable cells and cells with short telomeres were eliminated from the growing population. Our results suggest that transient reductions in telomere lengths may be common in immortal cell lines and that these alterations in telomere metabolism can have a profound effect on chromosome stability. Copyright 2000 Wiley-Liss, Inc.

Non-NASA Center↗
NASA NTRSDate not supplied

Radiocatalyst for Radiation Protection and Microbial Control

Radiocatalysts are materials that reduce the activation energy required to split water into hydrogen and reactive oxygen species (ROS). They are activated by radiation and can be used to improve the ability of water to act as a radiation barrier. This paper reports the results of an experimental evaluation of a gold radiocatalyst. This work provides a preliminary evaluation of the ability of these types of catalysts to increase the efficiency of water hydrolysis when exposed to different types of radiation (GCR). Although the radiation exposure devices used in this testing were not capable of generating radiation as diverse as is commonly found in space, the testing is useful in evaluating the function of these radiocatalytic nanoparticles when exposed to a a subset of the types of radiation that are found in GCR. The results are relevant to evaluating the use of this material for both space radiation protection and the production of useful byproducts, such as ROS, which can be used to maintain the sterility of stored water supplies. Radiocatalysts are materials typically used in radiation cancer therapy to improve the kill rate of tumors. These nanoparticles can be directly injected into tumors or functionalized to enter tumor cells via the blood stream. When they are exposed to radiation, they produce ROS. ROS are water hydrolysis products such as OH¯, O¯, O3, H2O2. This study used radiocatalytic 1.8 nm gold nanoparticles functionalized with citrate. These nanoparticles were tested through exposure to Xrays, 56Fe particles and gamma rays to demonstrate activity to a variety of radiation sources. The results demonstrate that radiocatalysts can improve the radiation absorption of water by a factor of 3 to 8 and can effectively kill bacteria at radiation levels above 1 Gy.

radiocatalyst radiation protection biocide↗
DOE OSTI2022

Transformative Technology for FLASH Radiation Therapy: A Snowmass 2021 White Paper

Conventional cancer therapies include surgery, radiation therapy, chemotherapy, and, more recently, immunotherapy. These modalities are often combined to improve the therapeutic index. The general concept of radiation therapy is to increase the therapeutic index by creating a physical dose differential between tumors and normal tissues through precision dose targeting, image guidance, and high radiation beams that deliver radiation dose with high conformality, e.g., protons and ions. However, treatment and cure are still limited by normal tissue radiation toxicity, with many patients experiencing acute and long-term side effects. Recently, however, a fundamentally different paradigm for increasing the therapeutic index of radiation therapy has emerged, supported by preclinical research, and based on the FLASH radiation effect. FLASH radiation therapy (FLASH-RT) is an ultra-high dose-rate delivery of a therapeutic radiation dose within a fraction of a second. Experimental studies have shown that normal tissues seem to be universally spared at these high dose rates, whereas tumors are not. The dose delivery conditions are not yet fully characterized. Still, it is currently estimated that large doses of 10 Gy or more delivered in 200 ms or less produce normal tissue sparing effects yet effectively kill tumor cells. There is a great opportunity, but also many technical challenges, for the accelerator community to create the required dose rates with novel and compact accelerators to ensure the safe delivery of FLASH radiation beams.

43 PARTICLE ACCELERATORS↗
DOE OSTI2022

Machine learning-assisted elucidation of CD81–CD44 interactions in promoting cancer stemness and extracellular vesicle integrity

Tumor-initiating cells with reprogramming plasticity or stem-progenitor cell properties (stemness) are thought to be essential for cancer development and metastatic regeneration in many cancers; however, elucidation of the underlying molecular network and pathways remains demanding. Combining machine learning and experimental investigation, here we report CD81, a tetraspanin transmembrane protein known to be enriched in extracellular vesicles (EVs), as a newly identified driver of breast cancer stemness and metastasis. Using protein structure modeling and interface prediction-guided mutagenesis, we demonstrate that membrane CD81 interacts with CD44 through their extracellular regions in promoting tumor cell cluster formation and lung metastasis of triple negative breast cancer (TNBC) in human and mouse models. In-depth global and phosphoproteomic analyses of tumor cells deficient with CD81 or CD44 unveils endocytosis-related pathway alterations, leading to further identification of a quality-keeping role of CD44 and CD81 in EV secretion as well as in EV-associated stemness-promoting function. CD81 is coexpressed along with CD44 in human circulating tumor cells (CTCs) and enriched in clustered CTCs that promote cancer stemness and metastasis, supporting the clinical significance of CD81 in association with patient outcomes. Our study highlights machine learning as a powerful tool in facilitating the molecular understanding of new molecular targets in regulating stemness and metastasis of TNBC.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

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

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

62 RADIOLOGY AND NUCLEAR MEDICINE↗
NASA NTRS2001

Gene amplification and microsatellite instability induced in tumorigenic human bronchial epithelial cells by alpha particles and heavy ions

Gene amplification and microsatellite alteration are useful markers of genomic instability in tumor and transformed cell lines. It has been suggested that genomic instability contributes to the progression of tumorigenesis by accumulating genetic changes. In this study, amplification of the carbamyl-P-synthetase, aspartate transcarbamylase, dihydro-orotase (CAD) gene in transformed and tumorigenic human bronchial epithelial (BEP2D) cells induced by either alpha particles or (56)Fe ions was assessed by measuring resistance to N-(phosphonacetyl)-l-aspartate (PALA). In addition, alterations of microsatellite loci located on chromosomes 3p and 18q were analyzed in a series of primary and secondary tumor cell lines generated in nude mice. The frequency of PALA-resistant colonies was 1-3 x 10(-3) in tumor cell lines, 5-8 x 10(-5) in transformed cells prior to inoculation into nude mice, and less than 10(-7) in control BEP2D cells. Microsatellite alterations were detected in all 11 tumor cell lines examined at the following loci: D18S34, D18S363, D18S877, D3S1038 and D3S1607. No significant difference in either PALA resistance or microsatellite instability was found in tumor cell lines that were induced by alpha particles compared to those induced by (56)Fe ions.

Non-NASA Center↗
DOE OSTI2022

Pathophysiological Integration of Metabolic Reprogramming in Breast Cancer

Metabolic changes that facilitate tumor growth are one of the hallmarks of cancer. The triggers of these metabolic changes are located in the tumor parenchymal cells, where oncogenic mutations induce an imperative need to proliferate and cause tumor initiation and progression. Cancer cells undergo significant metabolic reorganization during disease progression that is tailored to their energy demands and fluctuating environmental conditions. Oxidative stress plays an essential role as a trigger under such conditions. These metabolic changes are the consequence of the interaction between tumor cells and stromal myofibroblasts. The metabolic changes in tumor cells include protein anabolism and the synthesis of cell membranes and nucleic acids, which all facilitate cell proliferation. They are linked to catabolism and autophagy in stromal myofibroblasts, causing the release of nutrients for the cells of the tumor parenchyma. Metabolic changes lead to an interstitium deficient in nutrients, such as glucose and amino acids, and acidification by lactic acid. Together with hypoxia, they produce functional changes in other cells of the tumor stroma, such as many immune subpopulations and endothelial cells, which lead to tumor growth. Thus, immune cells favor tissue growth through changes in immunosuppression. This review considers some of the metabolic changes described in breast cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Non-small cell lung cancer cell–derived exosomal miR-17-5p promotes osteoclast differentiation by targeting PTEN

Highlights: • exosomes of SPC-A-1BM cell line prompt osteoclastogenesis. • miR-17-5p increased in exosomes of SPC-A-1BM cell line. • miR-17-5p prompt osteoclastogenesis. • miR-17-5p function through PTEN/PI3K/AKT pathway in osteoclastogenesis in NSCLC. Aberrant activity of bone resorbing osteoclasts plays a key role in the development of osteoporosis and cancer bone metastasis. The identification of novel and specific targets will be helpful for the development of new therapeutic strategies for bone metastasis in lung cancer. Herein, we examined microRNAs in tumor cell-derived exosomes to investigate the communication between the bone environment and tumor cells. TCGA database analysis showed that the level of miR-17-5p increased in non-small cell lung cancer tissues compared with non-tumor tissues. To investigate the function of exosomes in inducing osteoclastogenesis, osteoclast precursors were incubated with exosomes isolated from non-small cell lung cancer cell line, as well as receptor activator of NF-KB ligand and M-CSF to induce osteoclastogenesis. We found that exosomal miR-17-5p is upregulated in a non-small cell lung cancer cell line with bone metastasis compared with the original cell line. Overexpression of miR-17-5p enhanced the osteoclastogenesis of RAW264.7 cells. PTEN was identified as a direct target of miR-17-5p and showed negative effects on osteoclastogenesis. Importantly, treatment of LY294002 (an inhibitor of the PI3K/Akt pathway) attenuated miR-17-5p-mediated osteoclastogenesis effects. Taken together, our findings demonstrated that miR-17-5p promotes osteoclastogenesis through the PI3K/Akt pathway via targeting PTEN in lung cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

IL-17A Increases Doxorubicin Efficacy in Triple Negative Breast Cancer

Due to lack of targetable receptors and intertumoral heterogeneity, triple negative breast cancer (TNBC) remains particularly difficult to treat. Doxorubicin (DOX) is typically used as nonselective neoadjuvant chemotherapy, but the diversity of treatment efficacy remains unclear. Comparable to variability in clinical response, an experimental model of TNBC using a 4T1 syngeneic mouse model was found to elicit a differential response to a seven-day treatment regimen of DOX. Single-cell RNA sequencing identified an increase in T cells in tumors that responded to DOX treatment compared to tumors that continued to grow uninhibited. Additionally, compared to resistant tumors, DOX sensitive tumors contained significantly more CD4 T helper cells (339%), γδ T cells (727%), Naïve T cells (278%), and activated CD8 T cells (130%). Furthermore, transcriptional profiles of tumor infiltrated T cells in DOX responsive tumors revealed decreased exhaustion, increased chemokine/cytokine expression, and increased activation and cytotoxic activity. γδ T cell derived IL-17A was identified to be highly abundant in the sensitive tumor microenvironment. IL-17A was also found to directly increase sensitivity of TNBC cells in combination with DOX treatment. In TNBC tumors sensitive to DOX, increased IL-17A levels lead to a direct effect on cancer cell responsiveness and chronic stimulation of tumor infiltrated T cells leading to improved chemotherapeutic efficacy. IL-17A’s role as a chemosensitive cytokine in TNBC may offer new opportunities for treating chemoresistant breast tumors and other cancer types.

4T1↗
DOE OSTI2021

Disruption of adenosine 2A receptor improves the anti-tumor function of anti-mesothelin CAR T cells both in vitro and in vivo

Chimeric antigen receptor (CAR) T cells have been successfully used for the treatment of hematological malignancies including acute and chronic lymphoblastic leukemia. However, results of CAR T cell projects in solid tumors have been less impressive to date, partly because of immunosuppressive tumor microenvironment (TME). It is widely known that high adenosine production is an important factor causing tumor-induced immunosuppression in TME, and adenosine mediates the suppression of anti-tumor T cell responses via binding and signaling through adenosine 2a receptor (A2aR). Previous studies have shown that adenosine generated by cancer cells significantly inhibits T cell anti-tumor activity through binding and then activating adenosine 2A receptors (A2aRs) of T cells. Based on the previous work, in our study, we evaluated whether A2aR disruption by shRNA could enhance the anti-tumor function of anti-mesothelin (MSLN) CAR T cells both in vitro and in vivo. For this goal above, we used MSLN-positive human ovarian serous carcinoma cells (SKOV3) and human colon cancer cells (HCT116) as target cancer cells while MSLN-negative human ovarian cancer cells (ES2) as non-target cancer cells. We observed that targeting cell-intrinsic A2aR through shRNA overexpression caused significant A2aR disruption in CAR T cells and profoundly increased CAR T cell efficacy in both CAR T cell cytokine production and cytotoxicity towards MSLN-positive cancer cells in vitro. More importantly, in SKOV3 xenograft mouse models, anti-MSLN CAR-T cells significantly reduced the tumor burden compared with non-transduced T cells, and the anti-tumor activity of A2aR-disrupted anti-MSLN CAR-T cells was stronger than that of wild-type anti-MSLN CAR-T cells. Altogether, our study showed enhanced anti-tumor efficacy caused by shRNA-mediated A2aR disruption in anti-MSLN CAR T cells both in vitro and in vivo, which proved that shRNA-mediated modification of gene expression might be an excellent strategy for improving CAR T cell function in immunosuppressive tumor microenvironment (TME) and could potentially improve the outcome of treatment in clinical trials.

60 APPLIED LIFE SCIENCES↗