Radiation Type- and Dose-Specific Transcriptional Responses across Healthy and Diseased Mammalian Tissues
Abstract
:1. Introduction
2. Materials and Methods
2.1. Data Hybrid Collection and Transcriptomic Analyses
2.2. Functional Enrichment Analysis
2.3. Database Construction
2.4. Machine Learning Approach
2.5. Functional Network
3. Results and Discussion
3.1. Development of RadBioBase
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- Differential expression of genes: The expression status of the corresponding genes (i.e., up or downregulated in irradiated compared to non-irradiated tissue/cell control groups). In this version of the database, the canonical, full-length transcripts for each gene were used.
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- Biological characteristics: Cell type (cancer or normal), organism and tissue/cell line.
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- Type of irradiation: X-rays, γ-rays, protons, carbon ions or α-particles.
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- Post-irradiation time when provided in the original study.
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- Physical characteristics: LET (keV/μm), beam energy (MeV or kV for X-rays), dose (Gy) and average dose rate (Gy/min or Gy/h). In the cases where the LET of particles was not included in the original paper, it was calculated with the Stopping and Range of Ions in Matter (SRIM/TRIM) software, using as entrance parameters the type of ion, the target density and the energy of the irradiation beam when provided. For tissue targets not included in the compound dictionary of SRIM, the elemental compositions and mass densities were obtained from the bibliography [66,67,68]. Notably, the SRIM-calculated LET values were calculated only when provided in the relative studies, for the entrance point (highest energy values) of the beam instead of the Bragg peak, and thus were much smaller than the expected LET values for the Bragg peak region. According to the different energies in the various studies, LET values for protons were calculated as such: energies 100 MeV----> 0.76 keV/μm, 250 MeV----> 0.34 keV/μm, 190.6 MeV----> 0.5 keV/μm, 230 MeV----> 0.38 keV/μm, 4.5 MeV----> 9.54 keV/μm (Table S1). Moreover, those α-particle energies not provided in the original paper were calculated empirically with the help of LET-energy curves [69].
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- Comparison with low-LET irradiation: X-rays, γ-rays or electrons, depending on the information given in the original paper.
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- DNA damage (in clusters per Gy per Gbp): DSBs and total clusters of DNA damage were calculated using the Monte Carlo Damage Simulation (MCDS) software [70,71] for each radiation type (Table S1). For each MCDS input file, the parameters were set as CELL: DNA = 1 ndia = 5 cdia = 10, SIMCON: nocs = 10,000 seed = 987,654,321, and the oxygen concentration was set to 20%, while X-ray and γ-ray radiation was simulated by a 10 keV electron beam. The inclusion of the “complex damages” is based on the well-documented importance of clustered DNA damages in defying biological responses and can provide the first hints for possible connections of the quality and quantity of DNA damage with specific gene expression [72]. PubMed ID of the corresponding article.
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- Type of validation: depending on the method used in the original studies for data validation, we defined values as (a) microarrays, (b) RNA-Seq, (c) qPCR, (d) microarrays and qPCR, and (e) RNA-Seq and qPCR.
3.2. Commonalities among Radiation Types across a Number of Mammalian Tissues
3.3. Radiation Type-Specific Disease Pathways Inferred from Transcriptomes of Irradiated Cells
3.4. Machine Learning-Generated Gene Signatures of Cell Sensitivity to High- Versus Low-LET Radiation Types
3.5. Low-Dose Irradiation Is Associated with Cytokine Cascades, While High with ROS Metabolism
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Sagkrioti, E.; Biz, G.M.; Takan, I.; Asfa, S.; Nikitaki, Z.; Zanni, V.; Kars, R.H.; Hellweg, C.E.; Azzam, E.I.; Logotheti, S.; et al. Radiation Type- and Dose-Specific Transcriptional Responses across Healthy and Diseased Mammalian Tissues. Antioxidants 2022, 11, 2286. https://doi.org/10.3390/antiox11112286
Sagkrioti E, Biz GM, Takan I, Asfa S, Nikitaki Z, Zanni V, Kars RH, Hellweg CE, Azzam EI, Logotheti S, et al. Radiation Type- and Dose-Specific Transcriptional Responses across Healthy and Diseased Mammalian Tissues. Antioxidants. 2022; 11(11):2286. https://doi.org/10.3390/antiox11112286
Chicago/Turabian StyleSagkrioti, Eftychia, Gökay Mehmet Biz, Işıl Takan, Seyedehsadaf Asfa, Zacharenia Nikitaki, Vassiliki Zanni, Rumeysa Hanife Kars, Christine E. Hellweg, Edouard I. Azzam, Stella Logotheti, and et al. 2022. "Radiation Type- and Dose-Specific Transcriptional Responses across Healthy and Diseased Mammalian Tissues" Antioxidants 11, no. 11: 2286. https://doi.org/10.3390/antiox11112286