International Journal of Molecular Sciences

Editorial

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3 pages, 176 KiB

Open AccessEditorial

Radiation Damage in Biomolecules and Cells

by Mario P. Carante and Francesca Ballarini

Int. J. Mol. Sci. 2020, 21(21), 8188; https://doi.org/10.3390/ijms21218188 - 1 Nov 2020

Cited by 4 | Viewed by 1927

Abstract

Ionizing radiation is widely used in medicine, both as a diagnostic tool and as a therapeutic agent [...] Full article

(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells)

Research

Jump to: Editorial, Review

19 pages, 1855 KiB

Open AccessArticle

Molecular Investigation on a Triple Negative Breast Cancer Xenograft Model Exposed to Proton Beams

by Francesco P. Cammarata, Giusi I. Forte, Giuseppe Broggi, Valentina Bravatà, Luigi Minafra, Pietro Pisciotta, Marco Calvaruso, Roberta Tringali, Barbara Tomasello, Filippo Torrisi, Giada Petringa, Giuseppe A. P. Cirrone, Giacomo Cuttone, Rosaria Acquaviva, Rosario Caltabiano and Giorgio Russo

Int. J. Mol. Sci. 2020, 21(17), 6337; https://doi.org/10.3390/ijms21176337 - 1 Sep 2020

Cited by 28 | Viewed by 4313

Abstract

Specific breast cancer (BC) subtypes are associated with bad prognoses due to the absence of successful treatment plans. The triple-negative breast cancer (TNBC) subtype, with estrogen (ER), progesterone (PR) and human epidermal growth factor-2 (HER2) negative receptor status, is a clinical challenge for [...] Read more.

Specific breast cancer (BC) subtypes are associated with bad prognoses due to the absence of successful treatment plans. The triple-negative breast cancer (TNBC) subtype, with estrogen (ER), progesterone (PR) and human epidermal growth factor-2 (HER2) negative receptor status, is a clinical challenge for oncologists, because of its aggressiveness and the absence of effective therapies. In addition, proton therapy (PT) represents an effective treatment against both inaccessible area located or conventional radiotherapy (RT)-resistant cancers, becoming a promising therapeutic choice for TNBC. Our study aimed to analyze the in vivo molecular response to PT and its efficacy in a MDA-MB-231 TNBC xenograft model. TNBC xenograft models were irradiated with 2, 6 and 9 Gy of PT. Gene expression profile (GEP) analyses and immunohistochemical assay (IHC) were performed to highlight specific pathways and key molecules involved in cell response to the radiation. GEP analysis revealed in depth the molecular response to PT, showing a considerable immune response, cell cycle and stem cell process regulation. Only the dose of 9 Gy shifted the balance toward pro-death signaling as a dose escalation which can be easily performed using proton beams, which permit targeting tumors while avoiding damage to the surrounding healthy tissue. Full article

(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells)

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25 pages, 5952 KiB

Open AccessArticle

Genome-Wide DNA Alterations in X-Irradiated Human Gingiva Fibroblasts

by Neetika Nath, Lisa Hagenau, Stefan Weiss, Ana Tzvetkova, Lars R. Jensen, Lars Kaderali, Matthias Port, Harry Scherthan and Andreas W. Kuss

Int. J. Mol. Sci. 2020, 21(16), 5778; https://doi.org/10.3390/ijms21165778 - 12 Aug 2020

Cited by 2 | Viewed by 2994

Abstract

While ionizing radiation (IR) is a powerful tool in medical diagnostics, nuclear medicine, and radiology, it also is a serious threat to the integrity of genetic material. Mutagenic effects of IR to the human genome have long been the subject of research, yet [...] Read more.

While ionizing radiation (IR) is a powerful tool in medical diagnostics, nuclear medicine, and radiology, it also is a serious threat to the integrity of genetic material. Mutagenic effects of IR to the human genome have long been the subject of research, yet still comparatively little is known about the genome-wide effects of IR exposure on the DNA-sequence level. In this study, we employed high throughput sequencing technologies to investigate IR-induced DNA alterations in human gingiva fibroblasts (HGF) that were acutely exposed to 0.5, 2, and 10 Gy of 240 kV X-radiation followed by repair times of 16 h or 7 days before whole-genome sequencing (WGS). Our analysis of the obtained WGS datasets revealed patterns of IR-induced variant (SNV and InDel) accumulation across the genome, within chromosomes as well as around the borders of topologically associating domains (TADs). Chromosome 19 consistently accumulated the highest SNVs and InDels events. Translocations showed variable patterns but with recurrent chromosomes of origin (e.g., Chr7 and Chr16). IR-induced InDels showed a relative increase in number relative to SNVs and a characteristic signature with respect to the frequency of triplet deletions in areas without repetitive or microhomology features. Overall experimental conditions and datasets the majority of SNVs per genome had no or little predicted functional impact with a maximum of 62, showing damaging potential. A dose-dependent effect of IR was surprisingly not apparent. We also observed a significant reduction in transition/transversion (Ti/Tv) ratios for IR-dependent SNVs, which could point to a contribution of the mismatch repair (MMR) system that strongly favors the repair of transitions over transversions, to the IR-induced DNA-damage response in human cells. Taken together, our results show the presence of distinguishable characteristic patterns of IR-induced DNA-alterations on a genome-wide level and implicate DNA-repair mechanisms in the formation of these signatures. Full article

(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells)

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15 pages, 2345 KiB

Open AccessArticle

In Vitro Comparison of Passive and Active Clinical Proton Beams

by Anna Michaelidesová, Jana Vachelová, Jana Klementová, Tomáš Urban, Kateřina Pachnerová Brabcová, Stanislav Kaczor, Martin Falk, Iva Falková, Daniel Depeš, Vladimír Vondráček and Marie Davídková

Int. J. Mol. Sci. 2020, 21(16), 5650; https://doi.org/10.3390/ijms21165650 - 6 Aug 2020

Cited by 8 | Viewed by 2736

Abstract

Nowadays, the irradiation methodology in proton therapy is switching from the use of passively scattered beams to active pencil beams due to the possibility of more conformal dose distributions. The dose rates of active pencil beams are much higher than those of passive [...] Read more.

Nowadays, the irradiation methodology in proton therapy is switching from the use of passively scattered beams to active pencil beams due to the possibility of more conformal dose distributions. The dose rates of active pencil beams are much higher than those of passive beams. The purpose of this study was to investigate whether there is any difference in the biological effectiveness of these passive and active irradiation modes. The beam qualities of double scattering and pencil beam scanning were measured dosimetrically and simulated using the Monte Carlo code. Using the medulloblastoma cell line DAOY, we performed an in vitro comparison of the two modes in two positions along the dose–deposition curve plateau and inside the Bragg peak. We followed the clonogenic cell survival, apoptosis, micronuclei, and γH2AX assays as biological endpoints. The Monte Carlo simulations did not reveal any difference between the beam qualities of the two modes. Furthermore, we did not observe any statistically significant difference between the two modes in the in vitro comparison of any of the examined biological endpoints. Our results do not show any biologically relevant differences related to the different dose rates of passive and active proton beams. Full article

(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells)

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18 pages, 2293 KiB

Open AccessArticle

Different Mechanisms Underlie the Metabolic Response of GBM Stem-Like Cells to Ionizing Radiation: Biological and MRS Studies on Effects of Photons and Carbon Ions

by Alessandra Palma, Sveva Grande, Lucia Ricci-Vitiani, Anna Maria Luciani, Mariachiara Buccarelli, Mauro Biffoni, Valentina Dini, Giuseppe A. P. Cirrone, Mario Ciocca, Laura Guidoni, Roberto Pallini, Vincenza Viti and Antonella Rosi

Int. J. Mol. Sci. 2020, 21(14), 5167; https://doi.org/10.3390/ijms21145167 - 21 Jul 2020

Cited by 10 | Viewed by 3271

Abstract

Glioblastoma multiforme (GBM) is a malignant primary brain tumor with very poor prognosis, high recurrence rate, and failure of chemo-radiotherapy, mainly due to a small fraction of cells with stem-like properties (GSCs). To study the mechanisms of GSCs resistance to radiation, two GSC [...] Read more.

Glioblastoma multiforme (GBM) is a malignant primary brain tumor with very poor prognosis, high recurrence rate, and failure of chemo-radiotherapy, mainly due to a small fraction of cells with stem-like properties (GSCs). To study the mechanisms of GSCs resistance to radiation, two GSC lines, named line #1 and line #83, with different metabolic patterns and clinical outcome, were irradiated with photon beams and carbon ions and assessed by ¹H Magnetic Resonance Spectroscopy (MRS). Both irradiation modalities induced early cytotoxic effects in line #1 with small effects on cell cycle, whereas a proliferative G2/M cytostatic block was observed in line #83. MR spectroscopy signals from mobile lipids (ML) increased in spectra of line #1 after photon and C-ion irradiation with effects on lipid unsaturation level, whereas no effects were detected in line #83 spectra. Gamma-Aminobutyric Acid (GABA), glutamic acid (glu) and Phosphocreatine (pCr) signals showed a significant variation only for line #1 after carbon ion irradiation. Glucose (glc) level and lactate (Lac) extrusion behaved differently in the two lines. Our findings suggest that the differences in irradiation response of GSCs #1 and #83 lines are likely attributable to their different metabolic fingerprint rather than to the different radiation types. Full article

(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells)

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11 pages, 1023 KiB

Open AccessArticle

In Vivo Validation of the BIANCA Biophysical Model: Benchmarking against Rat Spinal Cord RBE Data

by Mario P. Carante, Giulia Aricò, Alfredo Ferrari, Christian P. Karger, Wioletta Kozlowska, Andrea Mairani, Paola Sala and Francesca Ballarini

Int. J. Mol. Sci. 2020, 21(11), 3973; https://doi.org/10.3390/ijms21113973 - 1 Jun 2020

Cited by 17 | Viewed by 2928

Abstract

(1) Background: Cancer ion therapy is constantly growing thanks to its increased precision and, for heavy ions, its increased biological effectiveness (RBE) with respect to conventional photon therapy. The complex dependence of RBE on many factors demands biophysical modeling. Up to now, only [...] Read more.

(1) Background: Cancer ion therapy is constantly growing thanks to its increased precision and, for heavy ions, its increased biological effectiveness (RBE) with respect to conventional photon therapy. The complex dependence of RBE on many factors demands biophysical modeling. Up to now, only the Local Effect Model (LEM), the Microdosimetric Kinetic Model (MKM), and the “mixed-beam” model are used in clinics. (2) Methods: In this work, the BIANCA biophysical model, after extensive benchmarking in vitro, was applied to develop a database predicting cell survival for different ions, energies, and doses. Following interface with the FLUKA Monte Carlo transport code, for the first time, BIANCA was benchmarked against in vivo data obtained by C-ion or proton irradiation of the rat spinal cord. The latter is a well-established model for CNS (central nervous system) late effects, which, in turn, are the main dose-limiting factors for head-and-neck tumors. Furthermore, these data have been considered to validate the LEM version applied in clinics. (3) Results: Although further benchmarking is desirable, the agreement between simulations and data suggests that BIANCA can predict RBE for C-ion or proton treatment of head-and-neck tumors. In particular, the agreement with proton data may be relevant if the current assumption of a constant proton RBE of 1.1 is revised. (4) Conclusions: This work provides the basis for future benchmarking against patient data, as well as the development of other databases for specific tumor types and/or normal tissues. Full article

(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells)

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16 pages, 5932 KiB

Open AccessArticle

SRC Tyrosine Kinase Inhibitor and X-rays Combined Effect on Glioblastoma Cell Lines

by Filippo Torrisi, Luigi Minafra, Francesco P. Cammarata, Gaetano Savoca, Marco Calvaruso, Nunzio Vicario, Laura Maccari, Elodie A. Pérès, Hayriye Özçelik, Myriam Bernaudin, Lorenzo Botta, Giorgio Russo, Rosalba Parenti and Samuel Valable

Int. J. Mol. Sci. 2020, 21(11), 3917; https://doi.org/10.3390/ijms21113917 - 30 May 2020

Cited by 22 | Viewed by 2863

Abstract

Glioblastoma (GBM) is one of the most lethal types of tumor due to its high recurrence level in spite of aggressive treatment regimens involving surgery, radiotherapy and chemotherapy. Hypoxia is a feature of GBM, involved in radioresistance, and is known to be at [...] Read more.

Glioblastoma (GBM) is one of the most lethal types of tumor due to its high recurrence level in spite of aggressive treatment regimens involving surgery, radiotherapy and chemotherapy. Hypoxia is a feature of GBM, involved in radioresistance, and is known to be at the origin of treatment failure. The aim of this work was to assess the therapeutic potential of a new targeted c-SRC inhibitor molecule, named Si306, in combination with X-rays on the human glioblastoma cell lines, comparing normoxia and hypoxia conditions. For this purpose, the dose modifying factor and oxygen enhancement ratio were calculated to evaluate the Si306 radiosensitizing effect. DNA damage and the repair capability were also studied from the kinetic of γ-H2AX immunodetection. Furthermore, motility processes being supposed to be triggered by hypoxia and irradiation, the role of c-SRC inhibition was also analyzed to evaluate the migration blockage by wound healing assay. Our results showed that inhibition of the c-SRC protein enhances the radiotherapy efficacy both in normoxic and hypoxic conditions. These data open new opportunities for GBM treatment combining radiotherapy with molecularly targeted drugs to overcome radioresistance. Full article

(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells)

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10 pages, 1618 KiB

Open AccessArticle

Modeling Direct and Indirect Action on Cell Survival After Photon Irradiation under Normoxia and Hypoxia

by Hans Liew, Stewart Mein, Jürgen Debus, Ivana Dokic and Andrea Mairani

Int. J. Mol. Sci. 2020, 21(10), 3471; https://doi.org/10.3390/ijms21103471 - 14 May 2020

Cited by 12 | Viewed by 2533

Abstract

The demand for personalized medicine in radiotherapy has been met by a surge of mechanistic models offering predictions of the biological effect of ionizing radiation under consideration of a growing number of parameters. We present an extension of our existing model of cell [...] Read more.

The demand for personalized medicine in radiotherapy has been met by a surge of mechanistic models offering predictions of the biological effect of ionizing radiation under consideration of a growing number of parameters. We present an extension of our existing model of cell survival after photon irradiation to explicitly differentiate between the damage inflicted by the direct and indirect (radicals-mediated) action of ionizing radiation. Within our approach, we assume that the oxygenation status affects the indirect action. The effect of different concentrations of dimethyl sulfoxide (DMSO), an effective radical scavenger, has been simulated at different dose levels in normoxic and hypoxic conditions for various cell lines. Our model is found to accurately predict experimental data available in literature, validating the assumptions made in our approach. The presented extension adds further flexibility to our model and could act as basis for further developments of our model. Full article

(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells)

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15 pages, 2579 KiB

Open AccessArticle

Checkpoint Kinase 1 (CHK1) Inhibition Enhances the Sensitivity of Triple-Negative Breast Cancer Cells to Proton Irradiation via Rad51 Downregulation

by Changhoon Choi, Won Kyung Cho, Sohee Park, Sung-Won Shin, Won Park, Haeyoung Kim and Doo Ho Choi

Int. J. Mol. Sci. 2020, 21(8), 2691; https://doi.org/10.3390/ijms21082691 - 13 Apr 2020

Cited by 25 | Viewed by 4100

Abstract

Due to a superior dose conformity to the target, proton beam therapy (PBT) continues to rise in popularity. Recently, considerable efforts have been directed toward discovering treatment options for use in combination with PBT. This study aimed to investigate the targeting of checkpoint [...] Read more.

Due to a superior dose conformity to the target, proton beam therapy (PBT) continues to rise in popularity. Recently, considerable efforts have been directed toward discovering treatment options for use in combination with PBT. This study aimed to investigate the targeting of checkpoint kinase 1 (CHK1), a critical player regulating the G2/M checkpoint, as a promising strategy to potentiate PBT in human triple-negative breast cancer (TNBC) cells. Protons induced cell-cycle arrest at the G2/M checkpoint more readily in response to increased CHK1 activation than X-rays. A clonogenic survival assay revealed that CHK1 inhibition using PF-477736 or small interfering RNA (siRNA) enhanced the sensitivity toward protons to a greater extent than toward X-rays. Western blotting demonstrated that PF-477736 treatment in the background of proton irradiation increased the pro-apoptotic signaling, which was further supported by flow cytometry using annexin V. Immunofluorescence revealed that proton-induced DNA double-strand breaks (DSBs) were further enhanced by PF-477736, which was linked to the downregulation of Rad51, essential for the homologous recombination repair of DSBs. Direct inactivation of Rad51 resulted in enhanced proton sensitization. Collectively, these data suggest that targeting CHK1 may be a promising approach for improving PBT efficacy in the treatment of TNBC. Full article

(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells)

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17 pages, 2024 KiB

Open AccessArticle

Effects of High-Dose Ionizing Radiation in Human Gene Expression: A Meta-Analysis

by Dimitrios S. Kanakoglou, Theodora-Dafni Michalettou, Christina Vasileiou, Evangelos Gioukakis, Dorothea Maneta, Konstantinos V. Kyriakidis, Alexandros G. Georgakilas and Ioannis Michalopoulos

Int. J. Mol. Sci. 2020, 21(6), 1938; https://doi.org/10.3390/ijms21061938 - 12 Mar 2020

Cited by 10 | Viewed by 6076

Abstract

The use of high-dose Ionizing Radiation (IR) is currently one of the most common modalities in treatment of many types of cancer. The objective of this work was to investigate the effects of high-dose ionizing radiation on healthy human tissue, utilizing quantitative analysis [...] Read more.

The use of high-dose Ionizing Radiation (IR) is currently one of the most common modalities in treatment of many types of cancer. The objective of this work was to investigate the effects of high-dose ionizing radiation on healthy human tissue, utilizing quantitative analysis of gene expression. To this end, publicly available transcriptomics datasets from human samples irradiated with a high dose of radiation and non-irradiated (control) ones were selected, and gene expression was determined using RNA-Seq data analysis. Raw data from these studies were subjected to quality control and trimming. Mapping of RNA-Seq reads was performed by the partial selective alignment method, and differential gene expression analysis was conducted. Subsequently, a meta-analysis was performed to select differentially expressed genes across datasets. Based on the differentially expressed genes discovered by meta-analysis, we constructed a protein-to-protein interaction network, and we identified biological pathways and processes related to high-dose IR effects. Our findings suggest that cell cycle arrest is activated, supported by our top down-regulated genes associated with cell cycle activation. DNA repair genes are down-regulated in their majority. However, several genes implicated in the nucleotide excision repair pathway are upregulated. Nevertheless, apoptotic mechanisms seem to be activated probably due to severe high-dose-induced complex DNA damage. The significant upregulation of CDKN1A, as a downstream gene of TP53, further validates programmed cell death. Finally, down-regulation of TIMELESS, signifies a correlation between IR response and circadian rhythm. Nonetheless, high-dose IR exposure effects regarding normal tissue (radiation toxicity) and its possible long-term outcomes should be studied to a greater extend. Full article

(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells)

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18 pages, 2919 KiB

Open AccessArticle

Correlative Light and Electron Microscopy (CLEM) Analysis of Nuclear Reorganization Induced by Clustered DNA Damage Upon Charged Particle Irradiation

by Susanne Tonnemacher, Mikhail Eltsov and Burkhard Jakob

Int. J. Mol. Sci. 2020, 21(6), 1911; https://doi.org/10.3390/ijms21061911 - 11 Mar 2020

Cited by 10 | Viewed by 4777

Abstract

Chromatin architecture plays major roles in gene regulation as well as in the repair of DNA damaged by endogenous or exogenous factors, such as after radiation. Opening up the chromatin might provide the necessary accessibility for the recruitment and binding of repair factors, [...] Read more.

Chromatin architecture plays major roles in gene regulation as well as in the repair of DNA damaged by endogenous or exogenous factors, such as after radiation. Opening up the chromatin might provide the necessary accessibility for the recruitment and binding of repair factors, thus facilitating timely and correct repair. The observed formation of ionizing radiation-induced foci (IRIF) of factors, such as 53BP1, upon induction of DNA double-strand breaks have been recently linked to local chromatin decompaction. Using correlative light and electron microscopy (CLEM) in combination with DNA-specific contrasting for transmission electron microscopy or tomography, we are able to show that at the ultrastructural level, these DNA damage domains reveal a chromatin compaction and organization not distinguishable from regular euchromatin upon irradiation with carbon or iron ions. Low Density Areas (LDAs) at sites of particle-induced DNA damage, as observed after unspecific uranyl acetate (UA)-staining, are thus unlikely to represent pure chromatin decompaction. RNA-specific terbium-citrate (Tb) staining suggests rather a reduced RNA density contributing to the LDA phenotype. Our observations are discussed in the view of liquid-like phase separation as one of the mechanisms of regulating DNA repair. Full article

(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells)

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21 pages, 3960 KiB

Open AccessArticle

Valine Radiolysis by H⁺, He⁺, N⁺, and S¹⁵⁺ MeV Ions

by Cíntia A. P. da Costa, Gabriel S. Vignoli Muniz, Philippe Boduch, Hermann Rothard and Enio F. da Silveira

Int. J. Mol. Sci. 2020, 21(5), 1893; https://doi.org/10.3390/ijms21051893 - 10 Mar 2020

Cited by 13 | Viewed by 3200

Abstract

Radiolysis of biomolecules by fast ions has interest in medical applications and astrobiology. The radiolysis of solid D-valine (0.2–2 μm thick) was performed at room temperature by 1.5 MeV H⁺, He⁺, N⁺, and 230 MeV S¹⁵⁺ [...] Read more.

Radiolysis of biomolecules by fast ions has interest in medical applications and astrobiology. The radiolysis of solid D-valine (0.2–2 μm thick) was performed at room temperature by 1.5 MeV H⁺, He⁺, N⁺, and 230 MeV S¹⁵⁺ ion beams. The samples were prepared by spraying/dropping valine-water-ethanol solution on ZnSe substrate. Radiolysis was monitored by infrared spectroscopy (FTIR) through the evolution of the intensity of the valine infrared 2900, 1329, 1271, 948, and 716 cm⁻¹ bands as a function of projectile fluence. At the end of sample irradiation, residues (tholins) presenting a brownish color are observed. The dependence of the apparent (sputtering + radiolysis) destruction cross section, σ_d, on the beam stopping power in valine is found to follow the power law σ_d = aS_eⁿ, with n close to 1. Thus, σ_d is approximately proportional to the absorbed dose. Destruction rates due to the main galactic cosmic ray species are calculated, yielding a million year half-life for solid valine in space. Data obtained in this work aim a better understanding on the radioresistance of complex organic molecules and formation of radioproducts. Full article

(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells)

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13 pages, 1531 KiB

Open AccessArticle

A Simplified Cluster Analysis of Electron Track Structure for Estimating Complex DNA Damage Yields

by Yusuke Matsuya, Toshiaki Nakano, Takeshi Kai, Naoya Shikazono, Ken Akamatsu, Yuji Yoshii and Tatsuhiko Sato

Int. J. Mol. Sci. 2020, 21(5), 1701; https://doi.org/10.3390/ijms21051701 - 2 Mar 2020

Cited by 19 | Viewed by 3575

Abstract

Complex DNA damage, defined as at least two vicinal lesions within 10–20 base pairs (bp), induced after exposure to ionizing radiation, is recognized as fatal damage to human tissue. Due to the difficulty of directly measuring the aggregation of DNA damage at the [...] Read more.

Complex DNA damage, defined as at least two vicinal lesions within 10–20 base pairs (bp), induced after exposure to ionizing radiation, is recognized as fatal damage to human tissue. Due to the difficulty of directly measuring the aggregation of DNA damage at the nano-meter scale, many cluster analyses of inelastic interactions based on Monte Carlo simulation for radiation track structure in liquid water have been conducted to evaluate DNA damage. Meanwhile, the experimental technique to detect complex DNA damage has evolved in recent decades, so both approaches with simulation and experiment get used for investigating complex DNA damage. During this study, we propose a simplified cluster analysis of ionization and electronic excitation events within 10 bp based on track structure for estimating complex DNA damage yields for electron and X-ray irradiations. We then compare the computational results with the experimental complex DNA damage coupled with base damage (BD) measured by enzymatic cleavage and atomic force microscopy (AFM). The computational results agree well with experimental fractions of complex damage yields, i.e., single and double strand breaks (SSBs, DSBs) and complex BD, when the yield ratio of BD/SSB is assumed to be 1.3. Considering the comparison of complex DSB yields, i.e., DSB + BD and DSB + 2BD, between simulation and experimental data, we find that the aggregation degree of the events along electron tracks reflects the complexity of induced DNA damage, showing 43.5% of DSB induced after 70 kVp X-ray irradiation can be classified as a complex form coupled with BD. The present simulation enables us to quantify the type of complex damage which cannot be measured through in vitro experiments and helps us to interpret the experimental detection efficiency for complex BD measured by AFM. This simple model for estimating complex DNA damage yields contributes to the precise understanding of the DNA damage complexity induced after X-ray and electron irradiations. Full article

(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells)

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18 pages, 9069 KiB

Open AccessArticle

Impact of Target Oxygenation on the Chemical Track Evolution of Ion and Electron Radiation

by Daria Boscolo, Michael Krämer, Martina C. Fuss, Marco Durante and Emanuele Scifoni

Int. J. Mol. Sci. 2020, 21(2), 424; https://doi.org/10.3390/ijms21020424 - 9 Jan 2020

Cited by 46 | Viewed by 4863

Abstract

The radiosensitivity of biological systems is strongly affected by the system oxygenation. On the nanoscopic scale and molecular level, this effect is considered to be strongly related to the indirect damage of radiation. Even though particle track radiolysis has been the object of [...] Read more.

The radiosensitivity of biological systems is strongly affected by the system oxygenation. On the nanoscopic scale and molecular level, this effect is considered to be strongly related to the indirect damage of radiation. Even though particle track radiolysis has been the object of several studies, still little is known about the nanoscopic impact of target oxygenation on the radical yields. Here we present an extension of the chemical module of the Monte Carlo particle track structure code TRAX, taking into account the presence of dissolved molecular oxygen in the target material. The impact of the target oxygenation level on the chemical track evolution and the yields of all the relevant chemical species are studied in water under different irradiation conditions: different linear energy transfer (LET) values, different oxygenation levels, and different particle types. Especially for low LET radiation, a large production of two highly toxic species (

{HO}_{2}^{•}

and

O_{2}^{• -}

), which is not produced in anoxic conditions, is predicted and quantified in oxygenated solutions. The remarkable correlation between the

{HO}_{2}^{•}

and

O_{2}^{• -}

production yield and the oxygen enhancement ratio observed in biological systems suggests a direct or indirect involvement of

{HO}_{2}^{•}

and

O_{2}^{• -}

in the oxygen sensitization effect. The results are in agreement with available experimental data and previous computational approaches. An analysis of the oxygen depletion rate in different radiation conditions is also reported. The radiosensitivity of biological systems is strongly affected by the system oxygenation. On the nanoscopic scale and molecular level, this effect is considered to be strongly related to the indirect damage of radiation. Even though particle track radiolysis has been the object of several studies, still little is known about the nanoscopic impact of target oxygenation on the radical yields. Here we present an extension of the chemical module of the Monte Carlo particle track structure code TRAX, taking into account the presence of dissolved molecular oxygen in the target material. The impact of the target oxygenation level on the chemical track evolution and the yields of all the relevant chemical species are studied in water under different irradiation conditions: different linear energy transfer (LET) values, different oxygenation levels, and different particle types. Especially for low LET radiation, a large production of two highly toxic species (

{HO}_{2}^{•}

and

O_{2}^{• -}

), which is not produced in anoxic conditions, is predicted and quantified in oxygenated solutions. The remarkable correlation between the

{HO}_{2}^{•}

and

O_{2}^{• -}

production yield and the oxygen enhancement ratio observed in biological systems suggests a direct or indirect involvement of

{HO}_{2}^{•}

and

O_{2}^{• -}

in the oxygen sensitization effect. The results are in agreement with available experimental data and previous computational approaches. An analysis of the oxygen depletion rate in different radiation conditions is also reported. Full article

(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells)

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19 pages, 2438 KiB

Open AccessArticle

Assessment of Radio-Induced Damage in Endothelial Cells Irradiated with 40 kVp, 220 kVp, and 4 MV X-rays by Means of Micro and Nanodosimetric Calculations

by Nicolas Tang, Marta Bueno, Sylvain Meylan, Yann Perrot, Hoang N. Tran, Amélie Freneau, Morgane Dos Santos, Aurélie Vaurijoux, Gaëtan Gruel, Mario A. Bernal, Marie-Claude Bordage, Dimitris Emfietzoglou, Ziad Francis, Susanna Guatelli, Vladimir Ivanchenko, Mathieu Karamitros, Ioanna Kyriakou, Wook-Geun Shin, Sébastien Incerti and Carmen Villagrasa

Int. J. Mol. Sci. 2019, 20(24), 6204; https://doi.org/10.3390/ijms20246204 - 9 Dec 2019

Cited by 26 | Viewed by 3762

Abstract

The objective of this work was to study the differences in terms of early biological effects that might exist between different X-rays energies by using a mechanistic approach. To this end, radiobiological experiments exposing cell monolayers to three X-ray energies were performed in [...] Read more.

The objective of this work was to study the differences in terms of early biological effects that might exist between different X-rays energies by using a mechanistic approach. To this end, radiobiological experiments exposing cell monolayers to three X-ray energies were performed in order to assess the yields of early DNA damage, in particular of double-strand breaks (DSBs). The simulation of these irradiations was set in order to understand the differences in the obtained experimental results. Hence, simulated results in terms of microdosimetric spectra and early DSB induction were analyzed and compared to the experimental data. Human umbilical vein endothelial cells (HUVECs) were irradiated with 40, 220 kVp, and 4 MV X-rays. The Geant4 Monte Carlo simulation toolkit and its extension Geant4-DNA were used for the simulations. Microdosimetric calculations aiming to determine possible differences in the variability of the energy absorbed by the irradiated cell population for those photon spectra were performed on 10,000 endothelial cell nuclei representing a cell monolayer. Nanodosimetric simulations were also carried out using a computation chain that allowed the simulation of physical, physico-chemical, and chemical stages on a single realistic endothelial cell nucleus model including both heterochromatin and euchromatin. DNA damage was scored in terms of yields of prompt DSBs per Gray (Gy) and per giga (10⁹) base pair (Gbp) and DSB complexity was derived in order to be compared to experimental data expressed as numbers of histone variant H2AX (γ-H2AX) foci per cell. The calculated microdosimetric spread in the irradiated cell population was similar when comparing between 40 and 220 kVp X-rays and higher when comparing with 4 MV X-rays. Simulated yields of induced DSB/Gy/Gbp were found to be equivalent to those for 40 and 220 kVp but larger than those for 4 MV, resulting in a relative biological effectiveness (RBE) of 1.3. Additionally, DSB complexity was similar between the considered photon spectra. Simulated results were in good agreement with experimental data obtained by IRSN (Institut de radioprotection et de sûreté nucléaire) radiobiologists. Despite differences in photon energy, few differences were observed when comparing between 40 and 220 kVp X-rays in microdosimetric and nanodosimetric calculations. Nevertheless, variations were observed when comparing between 40/220 kVp and 4 MV X-rays. Thanks to the simulation results, these variations were able to be explained by the differences in the production of secondary electrons with energies below 10 keV. Full article

(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells)

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11 pages, 851 KiB

Open AccessArticle

Modeling the Effect of Hypoxia and DNA Repair Inhibition on Cell Survival after Photon Irradiation

by Hans Liew, Carmen Klein, Frank T. Zenke, Amir Abdollahi, Jürgen Debus, Ivana Dokic and Andrea Mairani

Int. J. Mol. Sci. 2019, 20(23), 6054; https://doi.org/10.3390/ijms20236054 - 30 Nov 2019

Cited by 13 | Viewed by 3961

Abstract

Mechanistic approaches to modeling the effects of ionizing radiation on cells are on the rise, promising a better understanding of predictions and higher flexibility concerning conditions to be accounted for. In this work we modified and extended a previously published mechanistic model of [...] Read more.

Mechanistic approaches to modeling the effects of ionizing radiation on cells are on the rise, promising a better understanding of predictions and higher flexibility concerning conditions to be accounted for. In this work we modified and extended a previously published mechanistic model of cell survival after photon irradiation under hypoxia to account for radiosensitization caused by deficiency or inhibition of DNA damage repair enzymes. The model is shown to be capable of describing the survival data of cells with DNA damage repair deficiency, both under norm- and hypoxia. We find that our parameterization of radiosensitization is invariant under change of oxygen status, indicating that the relevant parameters for both mechanisms can be obtained independently and introduced freely to the model to predict their combined effect. Full article

(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells)

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13 pages, 22761 KiB

Open AccessArticle

Radiation-Stimulated Translocation of CD166 and CRYAB to the Endothelial Surface Provides Potential Vascular Targets on Irradiated Brain Arteriovenous Malformations

by Lucinda S. McRobb, Matthew J. McKay, Andrew J. Gauden, Vivienne S. Lee, Sinduja Subramanian, Santhosh George Thomas, Markus K. H. Wiedmann, Vaughan Moutrie, Michael Grace, Zhenjun Zhao, Mark P. Molloy and Marcus A. Stoodley

Int. J. Mol. Sci. 2019, 20(23), 5830; https://doi.org/10.3390/ijms20235830 - 20 Nov 2019

Cited by 9 | Viewed by 3584

Abstract

Vascular targeting with pro-thrombotic antibody-conjugates is a promising biological treatment for brain arteriovenous malformations (bAVMs). However, targeted drug delivery relies on the identification of unique or overexpressed markers on the surface of a target cell. In the absence of inherent biological markers, stereotactic [...] Read more.

Vascular targeting with pro-thrombotic antibody-conjugates is a promising biological treatment for brain arteriovenous malformations (bAVMs). However, targeted drug delivery relies on the identification of unique or overexpressed markers on the surface of a target cell. In the absence of inherent biological markers, stereotactic radiosurgery may be used to prime induction of site-specific and targetable molecular changes on the endothelial surface. To investigate lumen-accessible, endothelial targets induced by radiation, we combined Gamma knife surgery in an AVM animal model with in vivo biotin-labeling and comparative proteomics. Two proteins, αB-crystallin (CRYAB)—a small heat shock protein that normally acts as an intracellular chaperone to misfolded proteins—and activated leukocyte cell adhesion molecule CD166, were further validated for endothelial surface expression after irradiation. Immunostaining of endothelial cells in vitro and rat AVM tissue ex vivo confirmed de novo induction of CRYAB following irradiation (20 Gy). Western analysis demonstrated that CRYAB accumulated intracellularly as a 20 kDa monomer, but, at the cell surface, a novel 65 kDa protein was observed, suggesting radiation stimulates translocation of an atypical CRYAB isoform. In contrast, CD166 had relatively high expression in non-irradiated cells, localized predominantly to the lateral surfaces. Radiation increased CD166 surface exposure by inducing translocation from intercellular junctions to the apical surface without significantly altering total protein levels. These findings reinforce the dynamic molecular changes induced by radiation exposure, particularly at the cell surface, and support further investigation of radiation as a priming mechanism and these molecules as putative targets for focused drug delivery in irradiated tissue. Full article

(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells)

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18 pages, 1308 KiB

Open AccessArticle

Proton Therapy and Src Family Kinase Inhibitor Combined Treatments on U87 Human Glioblastoma Multiforme Cell Line

by Francesco P Cammarata, Filippo Torrisi, Giusi I Forte, Luigi Minafra, Valentina Bravatà, Pietro Pisciotta, Gaetano Savoca, Marco Calvaruso, Giada Petringa, Giuseppe A. P. Cirrone, Anna L Fallacara, Laura Maccari, Maurizio Botta, Silvia Schenone, Rosalba Parenti, Giacomo Cuttone and Giorgio Russo

Int. J. Mol. Sci. 2019, 20(19), 4745; https://doi.org/10.3390/ijms20194745 - 24 Sep 2019

Cited by 31 | Viewed by 3859

Abstract

Glioblastoma Multiforme (GBM) is the most common of malignant gliomas in adults with an exiguous life expectancy. Standard treatments are not curative and the resistance to both chemotherapy and conventional radiotherapy (RT) plans is the main cause of GBM care failures. Proton therapy [...] Read more.

Glioblastoma Multiforme (GBM) is the most common of malignant gliomas in adults with an exiguous life expectancy. Standard treatments are not curative and the resistance to both chemotherapy and conventional radiotherapy (RT) plans is the main cause of GBM care failures. Proton therapy (PT) shows a ballistic precision and a higher dose conformity than conventional RT. In this study we investigated the radiosensitive effects of a new targeted compound, SRC inhibitor, named Si306, in combination with PT on the U87 glioblastoma cell line. Clonogenic survival assay, dose modifying factor calculation and linear-quadratic model were performed to evaluate radiosensitizing effects mediated by combination of the Si306 with PT. Gene expression profiling by microarray was also conducted after PT treatments alone or combined, to identify gene signatures as biomarkers of response to treatments. Our results indicate that the Si306 compound exhibits a radiosensitizing action on the U87 cells causing a synergic cytotoxic effect with PT. In addition, microarray data confirm the SRC role as the main Si306 target and highlights new genes modulated by the combined action of Si306 and PT. We suggest, the Si306 as a new candidate to treat GBM in combination with PT, overcoming resistance to conventional treatments. Full article

(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells)

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Review

Jump to: Editorial, Research

14 pages, 379 KiB

Open AccessReview

FLASH Radiotherapy: Current Knowledge and Future Insights Using Proton-Beam Therapy

by Jonathan R. Hughes and Jason L. Parsons

Int. J. Mol. Sci. 2020, 21(18), 6492; https://doi.org/10.3390/ijms21186492 - 5 Sep 2020

Cited by 166 | Viewed by 18412

Abstract

FLASH radiotherapy is the delivery of ultra-high dose rate radiation several orders of magnitude higher than what is currently used in conventional clinical radiotherapy, and has the potential to revolutionize the future of cancer treatment. FLASH radiotherapy induces a phenomenon known as the [...] Read more.

FLASH radiotherapy is the delivery of ultra-high dose rate radiation several orders of magnitude higher than what is currently used in conventional clinical radiotherapy, and has the potential to revolutionize the future of cancer treatment. FLASH radiotherapy induces a phenomenon known as the FLASH effect, whereby the ultra-high dose rate radiation reduces the normal tissue toxicities commonly associated with conventional radiotherapy, while still maintaining local tumor control. The underlying mechanism(s) responsible for the FLASH effect are yet to be fully elucidated, but a prominent role for oxygen tension and reactive oxygen species production is the most current valid hypothesis. The FLASH effect has been confirmed in many studies in recent years, both in vitro and in vivo, with even the first patient with T-cell cutaneous lymphoma being treated using FLASH radiotherapy. However, most of the studies into FLASH radiotherapy have used electron beams that have low tissue penetration, which presents a limitation for translation into clinical practice. A promising alternate FLASH delivery method is via proton beam therapy, as the dose can be deposited deeper within the tissue. However, studies into FLASH protons are currently sparse. This review will summarize FLASH radiotherapy research conducted to date and the current theories explaining the FLASH effect, with an emphasis on the future potential for FLASH proton beam therapy. Full article

(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells)

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11 pages, 487 KiB

Open AccessReview

The Effect of Low Temperatures on Environmental Radiation Damage in Living Systems: Does Hypothermia Show Promise for Space Travel?

by Hisanori Fukunaga

Int. J. Mol. Sci. 2020, 21(17), 6349; https://doi.org/10.3390/ijms21176349 - 1 Sep 2020

Cited by 8 | Viewed by 4942

Abstract

Low-temperature treatments (i.e., hypothermia) may be one way of regulating environmental radiation damage in living systems. With this in mind, hibernation under hypothermic conditions has been proposed as a useful approach for long-term human space flight. However, the underlying mechanisms of hypothermia-induced radioresistance [...] Read more.

Low-temperature treatments (i.e., hypothermia) may be one way of regulating environmental radiation damage in living systems. With this in mind, hibernation under hypothermic conditions has been proposed as a useful approach for long-term human space flight. However, the underlying mechanisms of hypothermia-induced radioresistance are as yet undetermined, and the conventional risk assessment of radiation exposure during hibernation remains insufficient for estimating the effects of chronic exposure to galactic cosmic rays (GCRs). To promote scientific discussions on the application of hibernation in space travel, this literature review provides an overview of the progress to date in the interdisciplinary research field of radiation biology and hypothermia and addresses possible issues related to hypothermic treatments as countermeasures against GCRs. At present, there are concerns about the potential effects of chronic radiation exposure on neurological disorders, carcinogenesis, ischemia heat failures, and infertility in astronauts; these require further study. These concerns may be resolved by comparing and integrating data gleaned from experimental and epidemiological studies. Full article

(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells)

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34 pages, 1834 KiB

Open AccessReview

Ionizing Radiation-Induced Epigenetic Modifications and Their Relevance to Radiation Protection

by Mauro Belli and Maria Antonella Tabocchini

Int. J. Mol. Sci. 2020, 21(17), 5993; https://doi.org/10.3390/ijms21175993 - 20 Aug 2020

Cited by 66 | Viewed by 10958

Abstract

The present system of radiation protection assumes that exposure at low doses and/or low dose-rates leads to health risks linearly related to the dose. They are evaluated by a combination of epidemiological data and radiobiological models. The latter imply that radiation induces deleterious [...] Read more.

The present system of radiation protection assumes that exposure at low doses and/or low dose-rates leads to health risks linearly related to the dose. They are evaluated by a combination of epidemiological data and radiobiological models. The latter imply that radiation induces deleterious effects via genetic mutation caused by DNA damage with a linear dose-dependence. This picture is challenged by the observation of radiation-induced epigenetic effects (changes in gene expression without altering the DNA sequence) and of non-linear responses, such as non-targeted and adaptive responses, that in turn can be controlled by gene expression networks. Here, we review important aspects of the biological response to ionizing radiation in which epigenetic mechanisms are, or could be, involved, focusing on the possible implications to the low dose issue in radiation protection. We examine in particular radiation-induced cancer, non-cancer diseases and transgenerational (hereditary) effects. We conclude that more realistic models of radiation-induced cancer should include epigenetic contribution, particularly in the initiation and progression phases, while the impact on hereditary risk evaluation is expected to be low. Epigenetic effects are also relevant in the dispute about possible “beneficial” effects at low dose and/or low dose-rate exposures, including those given by the natural background radiation. Full article

(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells)

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22 pages, 1509 KiB

Open AccessReview

Ionizing Radiation as a Source of Oxidative Stress—The Protective Role of Melatonin and Vitamin D

by Jarosław Nuszkiewicz, Alina Woźniak and Karolina Szewczyk-Golec

Int. J. Mol. Sci. 2020, 21(16), 5804; https://doi.org/10.3390/ijms21165804 - 13 Aug 2020

Cited by 76 | Viewed by 8334

Abstract

Ionizing radiation (IR) has found widespread application in modern medicine, including medical imaging and radiotherapy. As a result, both patients and healthcare professionals are exposed to various IR doses. To minimize the negative side effects of radiation associated with oxidative imbalance, antioxidant therapy [...] Read more.

Ionizing radiation (IR) has found widespread application in modern medicine, including medical imaging and radiotherapy. As a result, both patients and healthcare professionals are exposed to various IR doses. To minimize the negative side effects of radiation associated with oxidative imbalance, antioxidant therapy has been considered. In this review, studies on the effects of melatonin and vitamin D on radiation-induced oxidative stress are discussed. According to the research data, both substances meet the conditions for use as agents that protect humans against IR-induced tissue damage. Numerous studies have confirmed that melatonin, a hydro- and lipophilic hormone with strong antioxidant properties, can potentially be used as a radioprotectant in humans. Less is known about the radioprotective effects of vitamin D, but the results to date have been promising. Deficiencies in melatonin and vitamin D are common in modern societies and may contribute to the severity of adverse side effects of medical IR exposure. Hence, supporting supplementation with both substances seems to be of first importance. Interestingly, both melatonin and vitamin D have been found to selectively radiosensitise cancer cells, which makes them promising adjuvants in radiotherapy. More research is needed in this area, especially in humans. Full article

(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells)

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Graphical abstract

12 pages, 289 KiB

Open AccessReview

Stage-Specific Effects of Ionizing Radiation during Early Development

by Yasuko Honjo and Tatsuo Ichinohe

Int. J. Mol. Sci. 2020, 21(11), 3975; https://doi.org/10.3390/ijms21113975 - 1 Jun 2020

Cited by 12 | Viewed by 3966

Abstract

Early embryonic cells are sensitive to genotoxic stressors such as ionizing radiation. However, sensitivity to these stressors varies depending on the embryonic stage. Recently, the sensitivity and response to ionizing radiation were found to differ during the preimplantation period. The cellular and molecular [...] Read more.

Early embryonic cells are sensitive to genotoxic stressors such as ionizing radiation. However, sensitivity to these stressors varies depending on the embryonic stage. Recently, the sensitivity and response to ionizing radiation were found to differ during the preimplantation period. The cellular and molecular mechanisms underlying the change during this period are beginning to be elucidated. In this review, we focus on the changes in radio-sensitivity and responses to ionizing radiation during the early developmental stages of the preimplantation (before gastrulation) period in mammals, Xenopus, and fish. Furthermore, we discuss the underlying cellular and molecular mechanisms and the similarities and differences between species. Full article

(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells)

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