Dataset Information

Measuring Dynamic Changes in the Labile Iron Pool in Vivo with a Reactivity-Based Probe for Positron Emission Tomography.

ABSTRACT: Redox cycling of iron powers various enzyme functions crucial for life, making the study of iron acquisition, storage, and disposition in the whole organism a worthy topic of inquiry. However, despite its important role in biology and disease, imaging iron in animals with oxidation-state specificity remains an outstanding problem in biology and medicine. Here we report a first-generation reactivity-based probe of labile ferrous iron suitable for positron emission tomography studies in live animals. The responses of this reagent to systemic changes in labile iron disposition were revealed using iron supplementation and sequestration treatments in mice, while the potential of this approach for in vivo imaging of cancer was demonstrated using genetically and pathologically diverse mouse models, including spontaneous tumors arising in a genetically engineered model of prostate cancer driven by loss of PTEN.

SUBMITTER: Muir RK

PROVIDER: S-EPMC6487455 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Measuring Dynamic Changes in the Labile Iron Pool in Vivo with a Reactivity-Based Probe for Positron Emission Tomography.

Muir Ryan K RK Zhao Ning N Wei Junnian J Wang Yung-Hua YH Moroz Anna A Huang Yangjie Y Chen Ying-Chu YC Sriram Renuka R Kurhanewicz John J Ruggero Davide D Renslo Adam R AR Evans Michael J MJ

ACS central science 20190403 4

Redox cycling of iron powers various enzyme functions crucial for life, making the study of iron acquisition, storage, and disposition in the whole organism a worthy topic of inquiry. However, despite its important role in biology and disease, imaging iron in animals with oxidation-state specificity remains an outstanding problem in biology and medicine. Here we report a first-generation reactivity-based probe of labile ferrous iron suitable for positron emission tomography studies in live anima ...[more]

PMID: 31041393

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Project description:Fluorine-18-fluoro-2-deoxy-D-glucose (FDG) is widely used as positron-emission-tomography (PET) radiotracer for the detection and staging of human cancer. Tumor uptake of FDG varies substantially between different cancer types and between patients with the same tumor type. The molecular basis for this heterogeneity is unknown. Using cancer cell lines and primary human tumors of distinct histologic origins, we here show that increased FDG uptake is universally associated with coordinate upregulation of genes within the glycolysis, pentose-phosphate, and other related metabolic pathways. In primary human breast cancers, this FDG signature shows significant overlap with established breast cancer signatures for the “basal-like” disease subtype and “poor prognosis”. FDG high breast cancer showed significantly more gene copy number alterations genome wide than FDG low cancers. About 50 % of primary breast cancers with high FDG uptake and FDG gene expression signature show DNA copy gain encompassing the c-myc gene locus and express gene sets regulated by the transcription factor MYC. Our data shows that FDG-PET marks a distinct subset of “basal-like” human breast cancer which is characterized by MYC and prognostically unfavorable gene expression signatures, suggesting that FDG-PET imaging may be useful to risk-stratify patients with locally advanced breast cancer. Our general strategy to identify molecular determinants of FDG-retention through a genome-wide approach consisted of FDG uptake measurements in cancer cell lines and primary human tumors, the selection of samples with particularly high versus low FDG-retention, and subsequent pathway-based analysis of RNA expression data collected from these samples. Cell line RNA was extracted from a 10 cm plate seeded simultaneously and at the same density as the wells for FDG-uptake assays. For primary human tumor samples, RNA was extracted from macrodissected frozen tumor tissue. All cell line RNA samples and the astrocytoma RNA aliquots were hybridized to Affymetrix U133 Plus 2.0 arrays. All primary breast cancer RNA samples were hybridized to Affymetrix U133A arrays.

Project description:ImportanceThe recent proliferation of phosphorylated tau (p-tau) biomarkers has raised questions about their preferential association with the hallmark pathologies of Alzheimer disease (AD): amyloid-β plaques and tau neurofibrillary tangles.ObjectiveTo determine whether cerebrospinal fluid (CSF) and plasma p-tau biomarkers preferentially reflect cerebral β-amyloidosis or neurofibrillary tangle aggregation measured with positron emission tomography (PET).Design, setting, and participantsThis was a cross-sectional study of 2 observational cohorts: the Translational Biomarkers in Aging and Dementia (TRIAD) study, with data collected between October 2017 and August 2021, and the Alzheimer's Disease Neuroimaging Initiative (ADNI), with data collected between September 2015 and November 2019. TRIAD was a single-center study, and ADNI was a multicenter study. Two independent subsamples were derived from TRIAD. The first TRIAD subsample comprised individuals assessed with CSF p-tau (p-tau181, p-tau217, p-tau231, p-tau235), [18F]AZD4694 amyloid PET, and [18F]MK6240 tau PET. The second TRIAD subsample included individuals assessed with plasma p-tau (p-tau181, p-tau217, p-tau231), [18F]AZD4694 amyloid PET, and [18F]MK6240 tau PET. An independent cohort from ADNI comprised individuals assessed with CSF p-tau181, [18F]florbetapir PET, and [18F]flortaucipir PET. Participants were included based on the availability of p-tau and PET biomarker assessments collected within 9 months of each other. Exclusion criteria were a history of head trauma or magnetic resonance imaging/PET safety contraindications. No participants who met eligibility criteria were excluded.ExposuresAmyloid PET, tau PET, and CSF and plasma assessments of p-tau measured with single molecule array (Simoa) assay or enzyme-linked immunosorbent assay.Main outcomes and measuresAssociations between p-tau biomarkers with amyloid PET and tau PET.ResultsA total of 609 participants (mean [SD] age, 66.9 [13.6] years; 347 female [57%]; 262 male [43%]) were included in the study. For all 4 phosphorylation sites assessed in CSF, p-tau was significantly more closely associated with amyloid-PET values than tau-PET values (p-tau181 difference, 13%; 95% CI, 3%-22%; P = .006; p-tau217 difference, 11%; 95% CI, 3%-20%; P = .003; p-tau231 difference, 15%; 95% CI, 5%-22%; P < .001; p-tau235 difference, 9%; 95% CI, 1%-19%; P = .02) . These results were replicated with plasma p-tau181 (difference, 11%; 95% CI, 1%-22%; P = .02), p-tau217 (difference, 9%; 95% CI, 1%-19%; P = .02), p-tau231 (difference, 13%; 95% CI, 3%-24%; P = .009), and CSF p-tau181 (difference, 9%; 95% CI, 1%-21%; P = .02) in independent cohorts.Conclusions and relevanceResults of this cross-sectional study of 2 observational cohorts suggest that the p-tau abnormality as an early event in AD pathogenesis was associated with amyloid-β accumulation and highlights the need for careful interpretation of p-tau biomarkers in the context of the amyloid/tau/neurodegeneration, or A/T/(N), framework.

Dataset Information

Measuring Dynamic Changes in the Labile Iron Pool in Vivo with a Reactivity-Based Probe for Positron Emission Tomography.

Publications

Measuring Dynamic Changes in the Labile Iron Pool in Vivo with a Reactivity-Based Probe for Positron Emission Tomography.

Similar Datasets

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