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

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At least 55 records · Page 3
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

Pharmacological Inhibition of HSP90 Radiosensitizes Head and Neck Squamous Cell Carcinoma Xenograft by Inhibition of DNA Damage Repair, Nucleotide Metabolism, and Radiation-Induced Tumor Vasculogenesis

Recent preclinical studies suggest combining the HSP90 inhibitor AT13387 (Onalespib) with radiation (IR) against colon cancer and head and neck squamous cell carcinoma (HNSCC). These studies emphasized that AT13387 downregulates HSP90 client proteins involved in oncogenic signaling and DNA repair mechanisms as major drivers of enhanced radiosensitivity. Given the large array of client proteins HSP90 directs, we hypothesized that other key proteins or signaling pathways may be inhibited by AT13387 and contribute to enhanced radiosensitivity. Metabolomic analysis of HSP90 inhibition by AT13387 was conducted to identify metabolic biomarkers of radiosensitization and whether modulations of key proteins were involved in IR-induced tumor vasculogenesis, a process involved in tumor recurrence.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2017

XYLEM NAC DOMAIN1, an angiosperm NAC transcription factor, inhibits xylem differentiation through conserved motifs that interact with RETINOBLASTOMA‐RELATED

Summary The Arabidopsis thaliana gene XYLEM NAC DOMAIN1 ( XND1 ) is upregulated in xylem tracheary elements. Yet overexpression of XND1 blocks differentiation of tracheary elements. The molecular mechanism of XND1 action was investigated. Phylogenetic and motif analyses indicated that XND1 and its homologs are present only in angiosperms and possess a highly conserved C‐terminal region containing linear motifs (CKII‐acidic, LXCXE, E2F TD ‐like and LXCXE‐mimic) predicted to interact with the cell cycle and differentiation regulator RETINOBLASTOMA‐RELATED (RBR). Protein–protein interaction and functional analyses of XND1 deletion mutants were used to test the importance of RBR‐interaction motifs. Deletion of either the LXCXE or the LXCXE‐mimic motif reduced both the XND1–RBR interaction and XND1 efficacy as a repressor of differentiation, with loss of the LXCXE motif having the strongest negative impacts. The function of the XND1 C‐terminal domain could be partially replaced by RBR fused to the N‐terminal domain of XND1. XND1 also transactivated gene expression in yeast and plants. The properties of XND1, a transactivator that depends on multiple linear RBR‐interaction motifs to inhibit differentiation, have not previously been described for a plant protein. XND1 harbors an apparently angiosperm‐specific combination of interaction motifs potentially linking the general differentiation regulator RBR with a xylem‐specific pathway for inhibition of differentiation.

Zhao, Chengsong↗
NASA NTRS1998

Inhibition of auxin movement from the shoot into the root inhibits lateral root development in Arabidopsis

In roots two distinct polar movements of auxin have been reported that may control different developmental and growth events. To test the hypothesis that auxin derived from the shoot and transported toward the root controls lateral root development, the two polarities of auxin transport were uncoupled in Arabidopsis. Local application of the auxin-transport inhibitor naphthylphthalamic acid (NPA) at the root-shoot junction decreased the number and density of lateral roots and reduced the free indoleacetic acid (IAA) levels in the root and [3H]IAA transport into the root. Application of NPA to the basal half of or at several positions along the root only reduced lateral root density in regions that were in contact with NPA or in regions apical to the site of application. Lateral root development was restored by application of IAA apical to NPA application. Lateral root development in Arabidopsis roots was also inhibited by excision of the shoot or dark growth and this inhibition was reversible by IAA. Together, these results are consistent with auxin transport from the shoot into the root controlling lateral root development.

NASA Discipline Plant Biology↗
DOE OSTI2016

Wnt inhibition is dysregulated in gliomas and its re-establishment inhibits proliferation and tumor sphere formation

Evidence indicates that the growth of glioblastoma (GBM), the most common and malignant primary brain cancer, is driven by glioma stem cells (GSCs) resistant to current treatment. As Wnt-signaling is pivotal in stem cell maintenance, we wanted to explore its role in GSCs with the objective of finding distinct signaling mechanisms that could serve as potential therapeutic targets. We compared gene expression in GSCs (n=9) and neural stem cells from the adult human brain (ahNSC; n=3) to identify dysregulated genes in the Wnt signaling pathway. This identified a six-gene Wnt signature present in all nine primary GSC cultures, and the combined expression of three of these genes (SFRP1, SFRP4 and FZD7) reduced median survival of glioma patients from 38 to 17 months. Treatment with recombinant SFRP1 protein in primary cell cultures downregulated nuclear β-catenin and decreased in vitro proliferation and sphere formation in a dose-dependent manner. Furthermore, expressional and functional analysis of SFRP1-treated GSCs revealed that SFRP1 halts cell cycling and induces apoptosis. These observations demonstrate that Wnt signaling is dysregulated in GSC, and that inhibition of the Wnt pathway could serve as a therapeutic strategy in the treatment of GBM. - Highlights: • A comparison of GSCs to ahNSCs reveals Wnt-pathway dysregulation. • A signature of six Wnt-genes is present in all nine primary tumors. • The expression of three Wnt-genes reduces median survival from 38 to 17 months. • Treatment with SFRP1 decreases in vitro proliferation and sphere formation. • SFRP1 regulates GSC tumorigenicity through regulation of cell cycle and apoptosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Structural analysis and unique molecular recognition properties of a Bauhinia forficata lectin that inhibits cancer cell growth

Lectins have been used at length for basic research and clinical applications. New insights into the molecular recognition properties enhance our basic understanding of carbohydrate–protein interactions and aid in the design/development of new lectins. In this study, we used a combination of cell‐based assays, glycan microarrays, and X‐ray crystallography to evaluate the structure and function of the recombinant Bauhinia forficata lectin (BfL). The lectin was shown to be cytostatic for several cancer cell lines included in the NCI ‐60 panel; in particular, it inhibited growth of melanoma cancer cells ( LOX IMVI ) by over 95%. BfL is dimeric in solution and highly specific for binding of oligosaccharides and glycopeptides with terminal N ‐acetylgalactosamine (Gal NA c). BfL was found to have especially strong binding (apparent K d = 0.5–1.0 n m ) to the tumor‐associated Tn antigen. High‐resolution crystal structures were determined for the ligand‐free lectin, as well as for its complexes with three Tn glycopeptides, globotetraose, and the blood group A antigen. Extensive analysis of the eight crystal structures and comparison to structures of related lectins revealed several unique features of Gal NA c recognition. Of special note, the carboxylate group of Glu126, lining the glycan‐binding pocket, forms H‐bonds with both the N ‐acetyl of Gal NA c and the peptide amido group of Tn antigens. Stabilization provided by Glu126 is described here for the first time for any Gal NA c‐specific lectin. Taken together, the results provide new insights into the molecular recognition of carbohydrates and provide a structural understanding that will enable rational engineering of BfL for a variety of applications. Database Structural data are available in the PDB under the accession numbers 5T50 , 5T52 , 5T55 , 5T54 , 5T5L , 5T5J , 5T5P , and 5T5O .

Lubkowski, Jacek↗
DOE OSTI2017

Vesicular stomatitis virus N protein‐specific single‐domain antibody fragments inhibit replication

Abstract The transcription and replication machinery of negative‐stranded RNA viruses presents a possible target for interference in the viral life cycle. We demonstrate the validity of this concept through the use of cytosolically expressed single‐domain antibody fragments ( VHH s) that protect cells from a lytic infection with vesicular stomatitis virus ( VSV ) by targeting the viral nucleoprotein N. We define the binding sites for two such VHH s, 1004 and 1307, by X‐ray crystallography to better understand their inhibitory properties. We found that VHH 1307 competes with the polymerase cofactor P for binding and thus inhibits replication and mRNA transcription, while binding of VHH 1004 likely only affects genome replication. The functional relevance of these epitopes is confirmed by the isolation of escape mutants able to replicate in the presence of the inhibitory VHH s. The escape mutations allow identification of the binding site of a third VHH that presumably competes with P for binding at another site than 1307. Collectively, these binding sites uncover different features on the N protein surface that may be suitable for antiviral intervention.

Hanke, Leo↗