title: Evolutionarily conserved serum microRNAs predict radiation-induced fatality in nonhuman primates.
abstract: Effective planning for the medical response to a radiological or nuclear accident is complex. Because of limited resources for medical countermeasures, the key would be to accurately triage and identify victims most likely to benefit from treatment. We used a mouse model system to provide evidence that serum microRNAs (miRNAs) may effectively predict the impact of radiation on the long-term viability of animals. We had previously used nonhuman primates (NHPs) to demonstrate that this concept is conserved and serum miRNA signatures have the potential to serve as prediction biomarkers for radiation-induced fatality in a human population. We identified a signature of seven miRNAs that are altered by irradiation in both mice and NHPs. Genomic analysis of these conserved miRNAs revealed that there is a combination of seven transcription factors that are predicted to regulate these miRNAs in human, mice, and NHPs. Moreover, a combination of three miRNAs (miR-133b, miR-215, and miR-375) can identify, with nearly complete accuracy, NHPs exposed to radiation versus unexposed NHPs. Consistent with historical data, female macaques appeared to be more sensitive to radiation, but the difference was not significant. Sex-based stratification allowed us to identify an interaction between gender and miR-16-2 expression, which affected the outcome of radiation exposure. Moreover, we developed a classifier based on two miRNAs (miR-30a and miR-126) that can reproducibly predict radiation-induced mortality. Together, we have obtained a five-miRNA composite signature that can identify irradiated macaques and predict their probability of survival.
authors.affiliation: Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz 91-738, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Fendler
authors.affiliation: Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz 91-738, Poland.
authors.forename: Beata
authors.initials: B
authors.lastname: Malachowska
authors.affiliation: Department of Radiation Oncology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Khyati
authors.identifier: 0000-0002-4113-6284
authors.initials: K
authors.lastname: Meghani
authors.affiliation: Medical Gynecologic Oncology Program, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Panagiotis A
authors.initials: PA
authors.lastname: Konstantinopoulos
authors.affiliation: Department of Radiation Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY 10461, USA. dipanjan_chowdhury@dfci.harvard.edu vijay.singh@usuhs.edu cguha@montefiore.org.|Department of Pathology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY 10461, USA.
authors.forename: Chandan
authors.identifier: 0000-0002-1906-2186
authors.initials: C
authors.lastname: Guha
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA. dipanjan_chowdhury@dfci.harvard.edu vijay.singh@usuhs.edu cguha@montefiore.org.|Armed Forces Radiobiology Research Institute, Bethesda, MD 20814, USA.
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Singh
authors.affiliation: Department of Radiation Oncology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA 02215, USA. dipanjan_chowdhury@dfci.harvard.edu vijay.singh@usuhs.edu cguha@montefiore.org.
authors.forename: Dipanjan
authors.identifier: 0000-0001-5645-3752
authors.initials: D
authors.lastname: Chowdhury
mesh_terms: D000818:Animals; D017124:Conserved Sequence; D019143:Evolution, Molecular; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008253:Macaca mulatta; D008297:Male; D035683:MicroRNAs / Q000097:blood* / Q000235:genetics*; D011832:Radiation Injuries / Q000097:blood* / Q000235:genetics*; D015203:Reproducibility of Results; D012727:Sex Characteristics; D016019:Survival Analysis
chemical_list: D035683:MicroRNAs