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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 19 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

Insulin promotes hepatocarcinoma tumorigenesis by up-regulating PKM2 expression

Highlights: • Insulin induced PKM2 expression. • Insulin enhanced the interaction between PKM2 with TR3 and protected PKM2 from degradation. • Insulin promoted the proliferation of hepatoma cells in vitro and vivo in a PKM2-dependant manner. Insulin, as a growth factor, can increase the risk of certain types of cancer. The present study showed that insulin promoted the proliferation of hepatocellular carcinoma cells in vitro and in vivo through pyruvate kinase M2 (PKM2), which is a rate-limiting enzyme in the process of glycolysis. Moreover, the expression of PKM2 was up-regulated by insulin at the posttranslational level in a nuclear orphan receptor TR3-dependent manner. In addition, insulin could enhance the interaction between PKM2 and TR3 and protect PKM2 from degradation. Our results identified a specific mechanism of insulin affecting cancer metabolism and thus promoting cancer progression, and they contribute to a better understanding of the observation that insulin is linked to an increased cancer risk under hyperinsulinemic conditions.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

HURP regulates Kif18A recruitment and activity to synergistically control microtubule dynamics

Abstract During mitosis, microtubule dynamics are regulated to ensure proper alignment and segregation of chromosomes. The dynamics of kinetochore-attached microtubules are regulated by hepatoma-upregulated protein (HURP) and the mitotic kinesin-8 Kif18A, but the underlying mechanism remains elusive. Using single-molecule imaging in vitro, we demonstrate that Kif18A motility is regulated by HURP. While sparse decoration of HURP activates the motor, higher concentrations hinder processive motility. To shed light on this behavior, we determine the binding mode of HURP to microtubules using cryo-EM. The structure helps rationalize why HURP functions as a microtubule stabilizer. Additionally, HURP partially overlaps with the microtubule-binding site of the Kif18A motor domain, indicating that excess HURP inhibits Kif18A motility by steric exclusion. We also observe that HURP and Kif18A function together to suppress dynamics of the microtubule plus-end, providing a mechanistic basis for how they collectively serve in microtubule length control.

Science & Technology - Other Topics↗
DOE OSTI2021

PNNL DataHub Project: Omics Lethal Human Viruses Project Profiling of the Host Response to Ebola Virus Infection, Processed Experimental Dataset Catalog

Ebola virus (EBOV) is high risk biological agent, classified as a Category A priority pathogen (Flaviviridae) by the National Institute of Allergy and Infectious Diseases (NIAID), known to cause hemorrhagic fever with high mortality rates in humans. Lethal host-pathogen invasion mechanisms and the cellular intricacies behind these fatal infections still remain unclear. The NIAID Modeling Host Responses to Understand Severe Human Virus Infections Research Program project (2013-2018) aimed to develop an improved comprehensive understanding of the host response to a suite of viruses causing lethal infections leveraging a systems biology approach. Herein, PNNL sub-projects provide a never before released comprehensive infectious disease collection of primary and secondary transformation multi-Omics data profiling a series of priority pathogen primary experimental studies for enhanced open-access to viral Omics datasets and project lifecycle metadata. Secondary host-pathogen viral dataset downloads contain one or more statistically processed (normalization data transformation) quantitative dataset collections resulting in qualitative expression analyses of primary host-pathogen experimental study designs. Leveraging unique high-resolution Omics capabilities for proteomics (P), metabolomics (M), lipidomics (L), and transcriptomics (T) dataset downloads each have a direct relationship to a primary sample submission corresponding to a specific Ebola virus [NCBITAXON:186536] (Zaire/Makona or Zaire/Mayinga) experimental infection study. Human host samples types include peripheral blood mononuclear cells isolated from blood plasma ["PBMC", BTO:0001025], human hepatoma carcinoma cells ["HUH", BTO:0001950], human umbilical vein endothelial cells ["HUVEC", BTO:0001949], immortalized human hepatocyte cells ["IHH", BTO:0006147], and human histiocytic lymphoma cells ["U937", BTO:0001412].

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Omics-Lethal Human Viruses, Ebola Experiment EHUH001

The purpose of this experiment was to evaluate the human host response to Zaire Ebola wild-type virus and mutant virus infection. Samples were obtained from human hepatoma carcinoma cells (HUH-7) infected with Zaire Ebola ΔVP30-WT background, in addition to mutant viruses Ebola-ΔsGP (eliminating expression of soluble glycoprotein ssGP) and Ebola-Δmucin (encoding a glycoprotein lacking the mucin domain) for mRNA and miRNA transcriptome expression analysis. Secondary host-associated viral dataset downloads contain one or more statistically processed (normalization data transformation) quantitative dataset collections resulting in qualitative expression analyses of primary host-pathogen experimental study designs. Transcriptomics dataset downloads have a direct relationship to a primary sample submission corresponding to a specific Ebola virus infection.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Omics-Lethal Human Viruses, Ebola Experiment EHUH002

The purpose of this experiment was to evaluate the human host response to Zaire Ebola wild-type virus and mutant virus infection. Samples were obtained from human hepatoma carcinoma cells (HUH-7) infected with Zaire Ebola ΔVP30-WT background for proteome, metabolome, and lipidome expression analysis. Secondary host-associated viral dataset downloads contain one or more statistically processed (normalization data transformation) quantitative dataset collections resulting in qualitative expression analyses of primary host-pathogen experimental study designs. Leveraging unique high-resolution Omics capabilities for proteomics, metabolomics, and lipidomics dataset downloads each have a direct relationship to a primary sample submission corresponding to a specific Ebola virus infection.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Omics-Lethal Human Viruses, Ebola Experiment EHUH003

The purpose of this experiment was to evaluate the human host response to Zaire Ebola wild-type virus infection. Samples were obtained from human hepatoma carcinoma cells (HUH-7) infected with Zaire Ebola ΔVP30-WT background for mRNA and miRNA transcriptome expression analysis. Secondary host-associated viral dataset downloads contain one or more statistically processed (normalization data transformation) quantitative dataset collections resulting in qualitative expression analyses of primary host-pathogen experimental study designs. Transcriptomics dataset downloads have a direct relationship to a primary sample submission corresponding to a specific Ebola virus infection.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Omics-Lethal Human Viruses, Interferon-Stimulated Response Experiment IFNaHUH001

The purpose of this experiment was to evaluate the human host cellular response to treatment with and without interferon alpha/beta (IFNα/β) treatment. Sample time course data was obtained from human hepatoma carcinoma cells (HUH-7) expressing transcriptional activation protein VP30, stably transfected with the Ebola VP30 gene for enabling replication of VP30-deficient Ebola virus for transcriptome expression analysis. Secondary host-associated viral dataset downloads contain one or more statistically processed (normalization data transformation) quantitative dataset collections resulting in qualitative expression analyses of primary host-pathogen experimental study designs. Transcriptomics dataset download have a direct relationship to a primary sample submission corresponding to a specific interferon response to viral infection.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Modeling hepatitis C virus kinetics during liver transplantation highlights the role of the liver in virus clearance

While the liver, specifically hepatocytes, are widely accepted as the main source of hepatitis C virus (HCV) production, the role of the liver/hepatocytes in clearance of circulating HCV remains unknown. Frequent HCV kinetic data were recorded and mathematically modeled from five liver transplant patients throughout the anhepatic (absence of liver) phase and for 4 hr post-reperfusion. During the anhepatic phase, HCV remained at pre-anhepatic levels (n = 3) or declined (n = 2) with t 1/2 ~1 hr. Immediately post-reperfusion, virus declined in a biphasic manner in four patients consisting of a rapid decline (t 1/2 = 5 min) followed by a slower decline (t 1/2 = 67 min). Consistent with the majority of patients in the anhepatic phase, when we monitored HCV clearance at 37°C from culture medium in the absence/presence of chronically infected hepatoma cells that were inhibited from secreting HCV, the HCV t 1/2 in cell culture was longer in the absence of chronically HCV-infected cells. The results suggest that the liver plays a major role in the clearance of circulating HCV and that hepatocytes may be involved.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Individualized Adaptive Radiation Therapy Allows for Safe Treatment of Hepatocellular Carcinoma in Patients With Child-Turcotte-Pugh B Liver Disease

Previous reports of stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC) suggest unacceptably high rates of toxicity in patients with Child-Turcotte-Pugh (CTP) B liver disease. We hypothesized that an individualized adaptive treatment approach based on midtreatment liver function would maintain good local control while limiting toxicity in this population.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

Dose-Response Relationship in Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma: A Pooled Analysis of an Asian Liver Radiation Therapy Group Study

Despite the worldwide implementation of stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC), there is a lack of consensus guideline on prescription dose. Herein, this multinational study aimed to investigate the effects of the prescribed radiation dose on oncologic outcomes of SBRT for HCC.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

CLTRN, Regulated by NRF1/RAN/DLD Protein Complex, Enhances Radiation Sensitivity of Hepatocellular Carcinoma Cells Through Ferroptosis Pathway

Radiation therapy is a viable treatment option for patients with unresectable hepatocellular carcinoma (HCC). However, radiation resistance and adverse effects are issues that needs to be addressed. Herein, for the first time, we investigated the ability of collectrin (CLTRN) to enhance radiosensitivity in patients with HCC.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2021

Antineoplastic activity of Salmonella Typhimurium outer membrane nanovesicles

Highlights: • ST-OMVs is a promising antitumor monotherapy or as an adjuvant to chemotherapies. • ST-OMVs downregulated Ki-67 and upregulated CD49b immune-expression. • ST-OMVs downregulated angiogenesis by inhibiting VEGF gene expression. • ST-OMVs increased tumor cells apoptosis and autophagy (increased caspase-3and Beclin1). Nano-sized Gram-negative bacterial outer membrane vesicles possess unique structural and immunostimulatory effects that could be exploited to regress tumors by alerting the host immune system and reversing the immunosuppressive tumor microenvironment. The current study was conducted to investigate the antitumor activity of the outer membrane vesicles (ST-OMVs) of Salmonella Typhimurium ATCC 14028, in vitro in human colorectal carcinoma (HTC116), breast cancer (MCF-7), and hepatocellular carcinoma (HepG2) cell lines and in vivo in Ehrlich solid carcinoma-bearing mice model either as a mono-immunotherapy or as an adjuvant to a commonly used conventional chemotherapy. In addition, we investigated the safety of ST-OMVs. Adult Swiss albino female mice with transplanted Ehrlich solid carcinoma were treated with either ST-OMVs, paclitaxel or a combination of both. Tumor volume, growth inhibition rate, quantitative RT-PCR of Bax and VEGF genes expression, histopathology and immune-expression of caspase-3, Beclin-1, CD49b and Ki-67 were all analyzed. Our results showed that ST-OMVs significantly decreased tumor volume, significantly increased tumor growth inhibition rate, up-regulated the immunohistochemical expression of caspase-3, Beclin-1, and CD49b (enhanced recruitment of NK cells). Furthermore, ST-OMVs down-regulated the expression of Ki-67, increased Bax gene expression and decreased VEGF gene expression as detected by qRT-PCR analysis. Histologically, ST-OMVs promoted apoptosis, decreased tumor invasion and mitotic activities. Moreover, ST-OMVs showed a remarkable cytotoxic activity in various investigated in vitro cancer cell lines. Our findings demonstrate potential antitumor activity of ST-OMVs that might be used as a promising safe antitumor immunotherapy or an adjuvant to conventional chemotherapeutic drugs, resolving some of their problems.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

RNA binding protein DAZAP1 promotes HCC progression and regulates ferroptosis by interacting with SLC7A11 mRNA

Highlights: • DAZAP1 effectively promotes HCC progression. • DAZAP1 negatively regulates ferroptosis in HCC cells. • DAZAP1 interacts with SLC7A11 mRNA, and positively regulates its stability. RNA-binding proteins (RBPs) closely regulate the whole lifecycle of most RNA molecules, from the very early stage of transcription to RNA decay. Dysregulation of RBPs significantly affects the fate of cancer-related transcripts. Therefore, it is imperative to fully understand the complicated RBP-RNA regulatory networks in malignant diseases and to explore novel therapeutic targets. The RBP DAZAP1 (deleted in azoospermia-associated protein 1), originally identified as an important protein in spermatogenesis, had rarely been studied in the context of carcinogenesis. The role of DAZAP1 in hepatocellular carcinoma (HCC) was unveiled in this study. The relative expression of DAZAP1 was significantly upregulated in HCC and was positively associated with several key malignant characteristics and poor postoperative survival in patients. DAZAP1 knockdown by small interfering RNA markedly inhibited HCC cell proliferation, migration and invasion. Furthermore, DAZAP1 significantly reduced cellular sensitivity to sorafenib (SF), which had been proven to be an inducer of ferroptosis by targeting the system Xc{sup −} (composed of a light chain, xCT/SLC7A11, and a heavy chain, 4F2 heavy chain). At the mechanistic level, DAZAP1 was identified as a potent inhibitor of ferroptosis and an efficient binding partner of SLC7A11 mRNA. Further study revealed that DAZAP1 interacted with the 3′UTR (untranslated region) of SLC7A11 mRNA and positively regulated its stability. In our work, we clarified novel functions of DAZAP1 and preliminarily revealed its underlying mechanism in ferroptosis, which may be conducive to the exploration of biomarkers and therapeutic targets in HCC patients.

60 APPLIED LIFE SCIENCES↗