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Dinh, Tru-Khang T.

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Dinh

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Tru-Khang T.

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Dinh, Tru-Khang T.
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    Circulating miR-29a and miR-150 correlate with delivered dose during thoracic radiation therapy for non-small cell lung cancer
    (BioMed Central, 2016) Dinh, Tru-Khang T.; Fendler, Wojciech; Chałubińska-Fendler, Justyna; Acharya, Sanket S.; O’Leary, Colin; Deraska, Peter V.; D’Andrea, Alan D.; Chowdhury, Dipanjan; Kozono, David
    Background: Risk of normal tissue toxicity limits the amount of thoracic radiation therapy (RT) that can be routinely prescribed to treat non-small cell lung cancer (NSCLC). An early biomarker of response to thoracic RT may provide a way to predict eventual toxicities—such as radiation pneumonitis—during treatment, thereby enabling dose adjustment before the symptomatic onset of late effects. MicroRNAs (miRNAs) were studied as potential serological biomarkers for thoracic RT. As a first step, we sought to identify miRNAs that correlate with delivered dose and standard dosimetric factors. Methods: We performed miRNA profiling of plasma samples obtained from five patients with Stage IIIA NSCLC at five dose-points each during radical thoracic RT. Candidate miRNAs were then assessed in samples from a separate cohort of 21 NSCLC patients receiving radical thoracic RT. To identify a cellular source of circulating miRNAs, we quantified in vitro miRNA expression intracellularly and within secreted exosomes in five NSCLC and stromal cell lines. Results: miRNA profiling of the discovery cohort identified ten circulating miRNAs that correlated with delivered RT dose as well as other dosimetric parameters such as lung V20. In the validation cohort, miR-29a-3p and miR-150-5p were reproducibly shown to decrease with increasing radiation dose. Expression of miR-29a-3p and miR-150-5p in secreted exosomes decreased with radiation. This was concomitant with an increase in intracellular levels, suggesting that exosomal export of these miRNAs may be downregulated in both NSCLC and stromal cells in response to radiation. Conclusions: miR-29a-3p and miR-150-5p were identified as circulating biomarkers that correlated with delivered RT dose. miR-150 has been reported to decrease in the circulation of mammals exposed to radiation while miR-29a has been associated with fibrosis in the human heart, lungs, and kidneys. One may therefore hypothesize that outlier levels of circulating miR-29a-3p and miR-150-5p may eventually help predict unexpected responses to radiation therapy, such as toxicity. Electronic supplementary material The online version of this article (doi:10.1186/s13014-016-0636-4) contains supplementary material, which is available to authorized users.
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    Circulating Micro-RNAs as Biomarkers for Thoracic Radiation Therapy in Lung Cancer
    (2016-05-17) Dinh, Tru-Khang T.
    Risk of normal tissues toxicity limits the amount of thoracic radiation therapy that can be routinely prescribed for the treatment of non-small cell lung cancer (NSCLC). An early biomarker of response to thoracic radiation may provide a way to predict eventual toxicities during the multi-week treatment regimen. This enables dose adjustment before the symptomatic onset of late effects, such as radiation pneumonitis and esophagitis. Micro-RNAs (miRNAs) are small, non-coding RNAs that regulate gene expression by decreasing the translation of messenger RNAs. miRNAs constitute a major fraction of small RNAs reproducibly found in circulation, in part due to their protective encapsulation within exosomes. They are therefore attractive candidates as serological biomarkers. In this study, we performed miRNA profiling of the blood of 5 NSCLC patients at 5 dose-points during thoracic RT and found 10 miRNAs that correlated well with total radiation dose as well as other common dosimetric parameters. We then assessed these 10 miRNAs in samples from a separate cohort of 21 NSCLC patients receiving RT and identified miR-29a-3p and miR-150-5p as potential, reproducible biomarkers that decreased in circulation with increasing radiation dose. We also conducted in-vitro experiments to measure the expression levels of these miRNAs intracellularly and within exosomes in three NSCLC cell lines and two lung bronchoepithelial and fibroblast lines. The exosomal expression of miR-29a-3p and miR-150-5p decreased with radiation. However, this was concomitant with an increase in intracellular levels, suggesting that exosomal export of these miRNAs may be downregulated in NSCLC and stromal cells as a response to radiation. One may therefore hypothesize that outlier trends in levels of circulating miR-29a-3p and miR-150-5p may predict unexpected responses to radiation therapy, such as toxicity.