Gas Chromatography/Mass Spectrometry Metabolomics of Urine and Serum from Nonhuman Primates Exposed to Ionizing Radiation: Impacts on the Tricarboxylic Acid Cycle and Protein Metabolism

Pannkuk, Evan L.; Laiakis, Evagelia C.; Authier, Simon; Wong, Kwan-Yiu; Fornace, Albert J.

doi:10.1021/acs.jproteome.7b00064

Cited by 36 publications

(48 citation statements)

References 48 publications

(118 reference statements)

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“…In the recent past, radiation biologists have redirected their efforts to investigate chemical alternatives in biological fluid metabolome, biological alternatives in the gut microbiome, and other molecules of interest. There are several studies identifying proteins [129,130], metabolites as biomarkers for radiation exposure in blood [131–133], urine [131,134,135], and the gut using NHP models [135–139]. In addition, there are ample studies with lipidomics [132], microbiome [140], and mRNA [141].…”

Section: Biomarkers For Radiation Injury and Efficacy Of Radiationmentioning

confidence: 99%

Nonhuman primates as models for the discovery and development of radiation countermeasures

Singh

Olabisi

2017

Expert Opinion on Drug Discovery

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Introduction Despite significant scientific advances over the past six decades toward the development of safe and effective radiation countermeasures for humans using animal models, only two pharmaceutical agents have been approved by United States Food and Drug Administration (US FDA) for hematopoietic acute radiation syndrome (H-ARS). Additional research efforts are needed to further develop large animal models for improving the prediction of clinical safety and effectiveness of radiation countermeasures for ARS and delayed effects of acute radiation exposure (DEARE) in humans. Area covered The authors review the suitability of animal models for the development of radiation countermeasures for ARS following the FDA Animal Rule with a special focus on nonhuman primate (NHP) models of ARS. There are seven centers in the United States currently conducting studies with irradiated NHPs, with the majority of studies being conducted with rhesus monkeys. Expert opinion The NHP model is considered the gold standard animal model for drug development and approval by the FDA. The lack of suitable substitutes to NHP models for predicting response in humans serves as a bottleneck for the development of radiation countermeasures. Additional large animal models need to be characterized to support the development and FDA-approval of new radiation countermeasures.

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Section: Biomarkers For Radiation Injury and Efficacy Of Radiationmentioning

confidence: 99%

Nonhuman primates as models for the discovery and development of radiation countermeasures

Singh

Olabisi

2017

Expert Opinion on Drug Discovery

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“…The temperature of the inlet, transfer line, and ion source was set to 150, 270, and 230 °C, respectively. The GC temperature programming was set to 0.2 min of isothermal heating at 70 °C, followed by 10 °C/min ramp to 270 °C, a 4.0 min isothermal heating of 270 °C, 20 °C/min ramp to 320 °C, and a 2.0 min isothermal heating of 320 °C as previously described 52 . Electron impact ionization (70 eV) at full scan mode ( m/z 40–600) was used, with an acquisition rate of 30 spectra/sec.…”

Section: Methodsmentioning

confidence: 99%

“…Fatty acid methyl esters (C 4 –C 24 FAMEs; Sigma-Aldrich), alkanes (alkane standard mix [C 10 –C 40 ]; Sigma-Aldrich), and quality control standards (oxalic acid, malonic acid, malic acid, citric acid, methionine, and 2-butenedioic acid) were run to ensure reproducibility of retention indices and derivatization. Data was processed, aligned, and analyzed using ChromaTOF v. 4.51.6.0 with the statistical compare function (Leco, St. Joseph, MI), Metaboanalyst, and in house software MetaboLyzer 53 as previously described 52 .…”

Section: Methodsmentioning

confidence: 99%

Alterations in Cell Motility, Proliferation, and Metabolism in Novel Models of Acquired Temozolomide Resistant Glioblastoma

Tiek

Rone

Graham

et al. 2018

Sci Rep

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Glioblastoma (GBM) is an aggressive and incurable tumor of the brain with limited treatment options. Current first-line standard of care is the DNA alkylating agent temozolomide (TMZ), but this treatment strategy adds only ~4 months to median survival due to the rapid development of resistance. While some mechanisms of TMZ resistance have been identified, they are not fully understood. There are few effective strategies to manage therapy resistant GBM, and we lack diverse preclinical models of acquired TMZ resistance in which to test therapeutic strategies on TMZ resistant GBM. In this study, we create and characterize two new GBM cell lines resistant to TMZ in vitro, based on the 8MGBA and 42MGBA cell lines. Analysis of the TMZ resistant (TMZres) variants in conjunction with their parental, sensitive cell lines shows that acquisition of TMZ resistance is accompanied by broad phenotypic changes, including increased proliferation, migration, chromosomal aberrations, and secretion of cytosolic lipids. Importantly, each TMZ resistant model captures a different facet of the “go” (8MGBA-TMZres) or “grow” (42MGBA-TMZres) hypothesis of GBM behavior. These in vitro model systems will be important additions to the available tools for investigators seeking to define molecular mechanisms of acquired TMZ resistance.

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“…The temperature of the inlet, transfer line, and ion source was set to 150, 270, and 230 °C, respectively. The GC temperature programming was set to 0.2 min of isothermal heating at 70 °C, followed by 10 °C/min ramp to 270 °C, a 4.0 min isothermal heating of 270 °C, 20 °C/min ramp to 320 °C, and a 2.0 min isothermal heating of 320 °C as previously described 38 . Electron impact ionization (70 eV) at full scan mode (m/z 40-600) was used, with an acquisition rate of 30 spectra/sec.…”

Section: Gas Chromatography Time-of-flight Mass Spectrometry (Gc-tof-ms)mentioning

confidence: 99%

“…Fatty acid methyl esters (C 4 -C 24 FAMEs; Sigma-Aldrich), alkanes (alkane standard mix [C 10 -C 40 ]; Sigma-Aldrich), and quality control standards (oxalic acid, malonic acid, malic acid, citric acid, methionine, and 2-butenedioic acid) were run to ensure reproducibility of retention indices and derivatization. Data was processed, aligned, and analyzed using ChromaTOF v. 4.51.6.0 with the statistical compare function (Leco, St. Joseph, MI) and in house software MetaboLyzer 39 as previously described 38 .…”

Section: Gas Chromatography Time-of-flight Mass Spectrometry (Gc-tof-ms)mentioning

confidence: 99%

Alterations in Cell Motility, Proliferation, and Metabolism in Novel Models of Acquired Temozolomide Resistant Glioblastoma

Tiek

Rone

Graham

et al. 2017

Preprint

Self Cite

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Glioblastoma (GBM) is an aggressive and incurable tumor of the brain with limited treatment options. Current first-line standard of care is the DNA alkylating agent temozolomide (TMZ), but this treatment strategy adds only ~4 months to median survival due to the rapid development of resistance. While some mechanisms of TMZ resistance have been identified, they are not fully understood. There are few effective strategies to manage therapy resistant GBM, and we lack diverse preclinical models of acquired TMZ resistance in which to test therapeutic strategies on TMZ resistant GBM. In this study, we create and characterize two new GBM cell lines resistant to TMZ, based on the 8MGBA and 42MGBA cell lines. Analysis of the TMZ resistant (TMZres) variants in conjunction with their parental, sensitive cell lines shows that acquisition of TMZ resistance is accompanied by broad phenotypic changes, including increased proliferation, migration, chromosomal aberrations and secretion of cytosolic lipids. Importantly, each TMZ resistant model captures a different facet of the "go" (8MGBA-TMZres) or "grow" (42MGBA-TMZres) hypothesis of GBM behavior. These model systems will be important additions to the available tools for investigators seeking to define molecular mechanisms of acquired TMZ resistance.. CC-BY 4.0 International license peer-reviewed) is the author/funder. It is made available under a

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Gas Chromatography/Mass Spectrometry Metabolomics of Urine and Serum from Nonhuman Primates Exposed to Ionizing Radiation: Impacts on the Tricarboxylic Acid Cycle and Protein Metabolism

Cited by 36 publications

References 48 publications

Nonhuman primates as models for the discovery and development of radiation countermeasures

Nonhuman primates as models for the discovery and development of radiation countermeasures

Alterations in Cell Motility, Proliferation, and Metabolism in Novel Models of Acquired Temozolomide Resistant Glioblastoma

Alterations in Cell Motility, Proliferation, and Metabolism in Novel Models of Acquired Temozolomide Resistant Glioblastoma

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