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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 73 records · Page 4
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

Novel small molecule inhibitor of Kpnβ1 induces cell cycle arrest and apoptosis in cancer cells

Karyopherin beta 1 (Kpnβ1) is a major nuclear import receptor that mediates the import of cellular cargoes into the nucleus. Recently it has been shown that Kpnβ1 is highly expressed in several cancers, and its inhibition by siRNA induces apoptotic cancer cell death, while having little effect on non-cancer cells. This study investigated the effect of a novel small molecule, Inhibitor of Nuclear Import-60 (INI-60), on cancer cell biology, as well as nuclear import activities associated with Kpnβ1, and cancer progression in vivo using cervical and oesophageal cancer cell lines. INI-60 treatment resulted in the inhibition of cancer cell proliferation, colony formation, migration and invasion, and induced a G1/S cell cycle arrest, followed by cancer cell death via apoptosis. Non-cancer cells were minimally affected by INI-60 at concentrations that inhibited cancer cells. INI-60 treatment altered the localisation of Kpnβ1 and its cargoes, NFκB/p65, NFAT and AP-1, and the overexpression of Kpnβ1 reduced INI-60 cytotoxicity. INI-60 also inhibited KYSE 30 oesophageal cancer cell line growth in vivo. Taken together, these results show that INI-60 inhibits the nuclear import of Kpnβ1 cargoes and interferes with cancer cell biology. INI-60 presents as a potential therapeutic approach for cancers of different tissue origins and warrants further investigation as a novel anti-cancer agent.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Proof of principle study: synchrotron X-ray fluorescence microscopy for identification of previously radioactive microparticles and elemental mapping of FFPE tissues

Biobanks containing formalin-fixed, paraffin-embedded (FFPE) tissues from animals and human atomic-bomb survivors exposed to radioactive particulates remain a vital resource for understanding the molecular effects of radiation exposure. These samples are often decades old and prepared using harsh fixation processes which limit sample imaging options. Optical imaging of hematoxylin and eosin (H&E) stained tissues may be the only feasible processing option, however, H&E images provide no information about radioactive microparticles or radioactive history. Synchrotron X-ray fluorescence microscopy (XFM) is a robust, non-destructive, semi-quantitative technique for elemental mapping and identifying candidate chemical element biomarkers in FFPE tissues. Still, XFM has never been used to uncover distribution of formerly radioactive micro-particulates in FFPE canine specimens collected more than 30 years ago. In this work, we demonstrate the first use of low-, medium-, and high-resolution XFM to generate 2D elemental maps of ~ 35-year-old, canine FFPE lung and lymph node specimens stored in the Northwestern University Radiobiology Archive documenting distribution of formerly radioactive micro-particulates. Additionally, we use XFM to identify individual microparticles and detect daughter products of radioactive decay. The results of this proof-of-principle study support the use of XFM to map chemical element composition in historic FFPE specimens and conduct radioactive micro-particulate forensics.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

The CAM assay in the study of the metastatic process

Among the in vivo experimental models, the chick embryo chorioallantoic membrane (CAM) has been routinely used to implant several malignant cell lines or tumor tissues to study their angiogenic and metastatic capability. Since the chick embryo is naturally immunodeficient, the CAM can support the engraftment of tumor cells, and their growth therein can faithfully recapitulate most of the characteristics of the carcinogenic process including: growth, invasion, angiogenesis and colonization of distant tissues. This review article is focused on the discussion of the more recent literature data concerning the use of the CAM to investigate the metastatic process.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

DYNC1H1 regulates NSCLC cell growth and metastasis by IFN-γ-JAK-STAT signaling and is associated with an aberrant immune response

Highlights: • DYNC1H1 is upregulated and its high expression predicted poor outcomes in NSCLC. • Loss of function of DYNC1H1 inhibits cell growth and metastasis of NSCLC cells in vitro. • DYNC1H1 knockdown inhibited metastasis of NSCLC cells in vivo. • DYNC1H1 loss of function suppresses IFN-γ-JAK-STAT signaling pathway in NSCLC. • DYNC1H1 expression is correlated with aberrant immune response in NSCLC indicated by analysis of TCGA immune data. It is urgent to identify new biomarkers and therapeutic targets to ameliorate the clinical prognosis of patients with lung cancer. The functional significance and molecular mechanism of dynein cytoplasmic 1 heavy chain 1 (DYNC1H1) in nonsmall cell lung cancer (NSCLC) progression is still elusive. In our current study, publicly available data and Western blotting experiments confirmed that DYNC1H1 expression was upregulated in lung cancer samples compared with noncancerous samples. Quantitative real-time PCR (qPCR) results indicated that high DYNC1H1 expression in lung cancer tissues was significantly associated with clinical tumor stage and distal metastasis; moreover, its high expression was negatively correlated with prognosis. Functional experiments demonstrated that DYNC1H1 loss of function caused a significant decrease in cell viability and cell proliferative ability, inhibition of the cell cycle, and promotion of both migration potential and invasion potential in vitro. Animal experiments by tail vein injection of lung cancer cells showed that DYNC1H1 knockdown significantly decreased lung cancer metastasis. Mechanistically, the results from a human protein array showed changes in the IFN-γ-JAK-STAT signaling pathway, and analysis of The Cancer Genome Atlas (TCGA) immune data demonstrated that disturbance of the immune microenvironment might be involved in the impaired growth and metastatic ability mediated by DYNC1H1 loss in NSCLC. DYNC1H1 might serve as a promising biological marker of prognosis and a potential clinical therapeutic target for patients with NSCLC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

A dehydrated, aseptically-processed human amnion/chorion allograft accelerates healing in a delayed murine excisional wound model

Since chronic, non-healing wounds represent an increasing source of economic and temporal burden for patients who suffer from them and healthcare professionals that treat them, therapeutic modalities that promote closure of delayed and non-healing wounds are of utmost importance. Recent clinical results of allografts derived from amnion and chorion placental layers encourage further investigation of the mechanisms underlying clinical efficacy of these products for treatment of wounds. Here, we utilized a diabetic murine splinted excisional wound model to investigate the effects of a dehydrated human amnion/chorion-derived allograft (dHACA) on delayed wound healing, as well as the effects of dehydrated allograft derived solely from amnion tissue of the same donor. We examined wound healing by histological endpoint analysis, and we assessed other parameters relevant to functional wound healing in the wound bed including angiogenesis, macrophage phenotypes, proliferative activity, and gene expression. Herein we demonstrate that application of dHACA to a murine diabetic model of delayed wound progression results in better macroscale wound resolution outcomes, including rate of closure, compared to unaided wound progression, while dehydrated human amnion allograft (dHAA) fails to improve outcomes. Improved gross wound resolution observed with dHACA was accompanied by increased granulation tissue formation, proliferation and vascular ingrowth observed in the wound bed, early macrophage polarization towards anti-inflammatory phenotypes, and downregulation of pro-fibrotic gene expression. Overall, our data suggest that improvements in the rates of delayed wound closure observed from combined amnion/chorion allografts are associated with modulation of critical cellular and tissue processes commonly found to be dysregulated in delayed healing wounds, including proliferation, vascularization, inflammation, and re-epithelialization.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Maternal undernutrition modulates hepatic MicroRNAs expression in the early life of offspring

Emerging studies revealed that a poor intrauterine environment elicited by maternal nutrient restriction (MNR) is associated with an increased risk of metabolic diseases in adulthood. Previous research has shown that microRNAs (miRNAs) exert pivotal roles in modulating molecular pathways involved in disease pathogenesis and progression. In this respect, we herein examined miRNA profiles in samples of liver from offspring whose mothers were fed either with a 50% food-restricted diet or standard laboratory chow during pregnancy. Our findings enumerated that miR-181a, involved in lipid metabolism, was found to be downregulated in the liver of MNR offspring at 1 day of age when compared to that of control offspring. We also noted that overexpression of miR-181a reduced the lipid droplets after treatment with oleic acid for 48 h, which suppressed the expressions levels of SIRT1, FOXO1, KLF6 and PPARγ in BRL-3A cells, while the opposite results were observed with decreased expression of miR-181a. Furthermore, the luciferase reporter assay confirmed the direct interactions between miR-181a with KLF6 and SIRT1. In adults, the MNR offspring elucidated increased TG content, decreased expression of miR-181a, and increased expressions levels of SIRT1, FOXO1, KLF6, and PPARγ in liver tissues. Collectively, these findings provided novel evidence that MNR could regulate miRNAs expression, which might be related to lipid metabolism in MNR offspring.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Organotypic platform for studying cancer cell metastasis

Highlights: • Liver and brain slices can be stable, realistic in vitro 3D models. • Cell stiffness and adhesion to the tissue play determinant roles in cellular invasion in 3D. • MEK inhibitors can lead to increased cell stiffness and adhesion forces, and consequently reduced cancer cell invasion. • MDA-MB-231 breast cancer cells migrate faster and deeper into brain tissue compared to liver tissue. Metastasis is the leading cause of mortality in cancer patients. To migrate to distant sites, cancer cells would need to adapt their behaviour in response to different tissue environments. Thus, it is essential to study this process in models that can closely replicate the tumour microenvironment. Here, we evaluate the use of organotypic liver and brain slices to study cancer metastasis. Morphological and viability parameters of the slices were monitored daily over 3 days in culture to assess their stability as a realistic 3D tissue platform for in vitro metastatic assays. Using these slices, we evaluated the invasion of MDA-MB-231 breast cancer cells and of a subpopulation that was selected for increased motility. We show that the more aggressive invasion of the selected cells likely resulted not only from their lower stiffness, but also from their lower adhesion to the surrounding tissue. Different invasion patterns in the brain and liver slices were observed for both subpopulations. Cells migrated faster in the brain slices (with an amoeboid-like mode) compared to in the liver slices (where they migrated with mesenchymal or collective migration-like modes). Inhibition of the Ras/MAPK/ERK pathway increased cell stiffness and adhesion forces, which resulted in reduced invasiveness. These results illustrate the potential for organotypic tissue slices to more closely mimic in vivo conditions during cancer cell metastasis than most in vitro models.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

High-resolution deep view microscopy of cells and tissues

Methods, experimental setups and perspectives of three-dimensional deep view imaging microscopy of cell or tissue samples are reported. Preliminary biophysical and clinically relevant examples are presented. (paper)

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗
DOE OSTI2021

Estimates of Alpha/Beta (α/β) Ratios for Individual Late Rectal Toxicity Endpoints: An Analysis of the CHHiP Trial

Changes in fraction size of external beam radiation therapy exert nonlinear effects on subsequent toxicity. Commonly described by the linear-quadratic model, fraction size sensitivity of normal tissues is expressed by the α/β ratio. We sought to study individual α/β ratios for different late rectal effects after prostate external beam radiation therapy.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

Normal Tissue Injury Induced by Photon and Proton Therapies: Gaps and Opportunities

Despite technological advances in radiation therapy (RT) and cancer treatment, patients still experience adverse effects. Proton therapy (PT) has emerged as a valuable RT modality that can improve treatment outcomes. Normal tissue injury is an important determinant of the outcome; therefore, for this review, we analyzed 2 databases: (1) clinical trials registered with ClinicalTrials.gov and (2) the literature on PT in PubMed, which shows a steady increase in the number of publications. Most studies in PT registered with ClinicalTrials.gov with results available are nonrandomized early phase studies with a relatively small number of patients enrolled. From the larger database of nonrandomized trials, we listed adverse events in specific organs/sites among patients with cancer who are treated with photons and protons to identify critical issues. The present data demonstrate dosimetric advantages of PT with favorable toxicity profiles and form the basis for comparative randomized prospective trials. A comparative analysis of 3 recently completed randomized trials for normal tissue toxicities suggests that for early stage non-small cell lung cancer, no meaningful comparison could be made between stereotactic body RT and stereotactic body PT due to low accrual (NCT01511081). In addition, for locally advanced non-small cell lung cancer, a comparison of intensity modulated RT with passive scattering PT (now largely replaced by spot-scanned intensity modulated PT), PT did not provide any benefit in normal tissue toxicity or locoregional failure over photon therapy. Finally, for locally advanced esophageal cancer, proton beam therapy provided a lower total toxicity burden but did not improve progression-free survival and quality of life (NCT01512589). The purpose of this review is to inform the limitations of current trials looking at protons and photons, considering that advances in technology, physics, and biology are a continuum, and to advocate for future trials geared toward accurate precision RT that need to be viewed as an iterative process in a defined path toward delivering optimal radiation treatment. A foundational understanding of the radiobiologic differences between protons and photons in tumor and normal tissue responses is fundamental to, and necessary for, determining the suitability of a given type of biologically optimized RT to a patient or cohort.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

Dual role of Fam208a during zygotic cleavage and early embryonic development

Maintenance of genome stability is essential for every living cell as genetic information is repeatedly challenged during DNA replication in each cell division event. Errors, defects, delays, and mistakes that arise during mitosis or meiosis lead to an activation of DNA repair processes and in case of their failure, programmed cell death, i.e. apoptosis, could be initiated. Fam208a is a protein whose importance in heterochromatin maintenance has been described recently. In this work, we describe the crucial role of Fam208a in sustaining genome stability during cellular division. }The targeted depletion of Fam208a in mice using CRISPR/Cas9 led to embryonic lethality before E12.5. We also used the siRNA approach to downregulate Fam208a in zygotes to avoid the influence of maternal RNA in the early stages of development. This early downregulation increased arresting of the embryonal development at the two-cell stage and the occurrence of multipolar spindles formation. To investigate this further, we used the yeast two-hybrid (Y2H) system and identified new putative interaction partners Gpsm2, Svil, and Itgb3bp. Their co-expression with Fam208a was assessed by RT-qPCR profiling and in situ hybridization [1] in multiple murine tissues. Based on these results we proposed that Fam208a functions within the HUSH complex by interaction with Mphosph8 as these proteins are not only able to physically interact but also co-localise. We are bringing new evidence that Fam208a is a multi-interacting protein affecting genome stability on the cell division level at the earliest stages of development and by interaction with methylation complex in adult tissues. }In addition to its epigenetic functions, Fam208a appears to have an important role in the zygotic division, possibly via interaction with newly identified putative partners Gpsm2, Svil, and Itgb3bp.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

KIF18b-dependent hypomethylation of PARPBP gene promoter enhances oxaliplatin resistance in colorectal cancer

Highlights: • High expression of PARPBP promotes oxaliplatin resistance of CRC. • KIF18b induces PARPBP expression by suppressing promoter methylation. • SP1 recruits DNMT3b to methylate PARPBP promoter. • KIF18b disturbs the recruitment of DNMT3b to PARPBP promoter. As the new platinum drug oxaliplatin has been widely used in clinical treatment of colorectal cancer (CRC), oxaliplatin resistance has become a burning problem. In this study, higher expression of PARP-1 binding protein (PARPBP) was detected in oxaliplatin-resistant CRC (OR-CRC) cells than in non-resistant cells. Further research showed that kinesin family member 18 b (KIF18b) induced the overexpression of PARPBP, sustaining oxaliplatin resistance in OR-CRC cells. Through exploring the PARPBP gene promoter, we found that SP1-recruited DNMT3b methylated PARPBP promoter to suppress transcription in CRC cells, and increased KIF18b attenuated the recruitment of DNMT3b to PARPBP promoter by directly interacting with SP1 in OR-CRC cells. Clinical analysis suggested a positive relationship between KIF18b and PARPBP in CRC tissues and indicated poor prognosis in CRC patients with high level of KIF18b or PARPBP. In summary, KIF18b-induced PARPBP contributes to the resistant phenotype of OR-CRC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Salivary and Dental Complications in Childhood Cancer Survivors Treated With Radiation Therapy to the Head and Neck: A Pediatric Normal Tissue Effects in the Clinic (PENTEC) Comprehensive Review

Radiation therapy (RT) to the head and neck (H&N) region is critical in the management of various pediatric malignancies; however, it may result in late toxicity. This comprehensive review from the Pediatric Normal Tissue Effects in the Clinic (PENTEC) initiative focused on salivary dysfunction and dental abnormalities in survivors who received RT to the H&N region as children.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

Substrate stiffness modulates endothelial cell function via the YAP-Dll4-Notch1 pathway

Highlights: • Soft stiffness increases Dll4 expression in endothelial cells via YAP suppression. • Soft substrate-induced Dll4-Notch1 signaling is facilitated by VEGF stimulation. • Elevated Dll4-Notch1 signaling contributes to the regulation of VEGFRs expression. • Substrate stiffness modulates gene expression linked to endothelial cell function. Endothelial cells adapt their functions as a consequence of sensing extracellular substrate stiffness; these alterations allow them to maintain their vascular structure and function. Substrate stiffness-mediated yes-associated protein 1 (YAP) activation plays an important role in mechano-transduction and pro-angiogenic phenotype of endothelial cells, and Delta-like ligand 4 (Dll4)-Notch1 signaling is closely related to angiogenesis; however, the impact of substrate stiffness-mediated interrelation of these pathways on endothelial cell functions remains elusive. We confirmed that endothelial cells on softer substrates not only elongate cellular aspects but also attenuate YAP activation compared to cells on stiffer substrates. Endothelial cells on softer substrates also upregulate the vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR2 mRNA expression that is enhanced by VEGF stimulation. We determined that endothelial cells on softer substrates increased Dll4 expression, but not Notch1 expression, via YAP signaling. Moreover, endothelial cells on soft substrates induced not only VEGFRs upregulation but also suppression of pro-inflammatory interleukin-6 and plasminogen activator inhibitor-1 mRNA expression and the facilitation of anti-coagulant thrombomodulin and pro-coagulant tissue factor mRNA expression. Our results suggest that endothelial cells activate the YAP-Dll4-Notch signaling pathway in response to substrate stiffness and dictate cellular function.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Normal Tissue Response of Combined Temporal and Spatial Fractionation in Proton Minibeam Radiation Therapy

Proton minibeam radiation therapy, a spatial fractionation concept, widens the therapeutic window. By reducing normal tissue toxicities, it allows a temporally fractionated regime with high daily doses. However, an array shift between daily fractions can affect the tissue-sparing effect by decreasing the total peak-to-valley dose ratio. Therefore, combining temporal fractions with spatial fractionation raises questions about the impact of daily applied dose modulations, reirradiation accuracies, and total dose modulations.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

Involvement of TFAP2A in the activation of GSDMD gene promoter in hyperoxia-induced ALI

Highlights: • Hyperoxia exposure increases GSDMD expression in rat lung tissue and A549 cells. • The core promoter region of GSDMD located in −98/-12 bp relative to TSS. • E2F4 and TFAP2A positively regulate the basal transcriptional activity of GSDMD by directly binding to its promoter. • TFAP2A directly drives the expression of GSDMD in hyperoxia-inducedA549 cells. • TFAP2A expression is increased in lung tissues of rats with hyperoxia-induced ALI and linearly correlated with GSDMD. Oxygen therapy is a common treatment in neonatal intensive care units, but long-term continuous hyperoxia ventilation may induce acute lung injury (ALI). Gasdermin D (GSDMD)-mediated pyroptosis participates in various diseases including ALI, but the role of GSDMD in hyperoxia-induced ALI is yet understood. Here, we showed a significant increase in GSDMD after exposure to high oxygen. To elucidate the molecular mechanisms involved in GSDMD regulation, we identified the core promoter of GSDMD, −98 ~ −12 bp relative to the transcriptional start site (TSS). The results of mutational analysis, overexpression or siRNA interference, EMSA and ChIP demonstrated that E2F4 and TFAP2A positively regulate the transcriptional activity of the GSDMD by binding to its promoter. However, only TFAP2A showed a regulatory effect on the expression of GSDMD. Moreover, TFAP2A was increased in the lung tissues of rats exposed to hyperoxia and showed a strong linear correlation with GSDMD. Our results indicated that TFAP2A positively regulates the GSDMD expression via binding to the promoter region of GSDMD.

60 APPLIED LIFE SCIENCES↗