Alpha-Particle Exposure Induces Mainly Unstable Complex Chromosome Aberrations which do not Contribute to Radiation-Associated Cytogenetic Risk

2021 ◽  
Author(s):  
C. Hartel ◽  
E. Nasonova ◽  
S. Ritter ◽  
T. Friedrich
Keyword(s):  
Ex Vivo ◽  
Human Peripheral Blood ◽  
Mitotic Cell ◽  
Peripheral Blood Lymphocytes ◽  
Small Scale ◽  
X Rays ◽  
Carcinogenic Effect ◽  
High Let Radiation ◽  
High Let ◽  
Α Particles

The mechanism underlying the carcinogenic potential of α radiation is not fully understood, considering that cell inactivation (e.g., mitotic cell death) as a main consequence of exposure efficiently counteracts the spreading of heritable DNA damage. The aim of this study is to improve our understanding of the effectiveness of α particles in inducing different types of chromosomal aberrations, to determine the respective values of the relative biological effectiveness (RBE) and to interpret the results with respect to exposure risk. Human peripheral blood lymphocytes (PBLs) from a single donor were exposed ex vivo to doses of 0–6 Gy X rays or 0–2 Gy α particles. Cells were harvested at two different times after irradiation to account for the mitotic delay of heavily damaged cells, which is known to occur after exposure to high-LET radiation (including α particles). Analysis of the kinetics of cells reaching first or second (and higher) mitosis after irradiation and aberration data obtained by the multiplex fluorescence in situ hybridization (mFISH) technique are used to determine of the cytogenetic risk, i.e., the probability for transmissible aberrations in surviving lymphocytes. The analysis shows that the cytogenetic risk after α exposure is lower than after X rays. This indicates that the actually observed higher carcinogenic effect of α radiation is likely to stem from small scale mutations that are induced effectively by high-LET radiation but cannot be resolved by mFISH analysis.

scholarly journals Strong Shift to ATR-Dependent Regulation of the G2-Checkpoint after Exposure to High-LET Radiation

Life ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 560
Author(s):  
Veronika Mladenova ◽  
Emil Mladenov ◽  
Michael Scholz ◽  
Martin Stuschke ◽  
George Iliakis
Keyword(s):  
Chromosomal Abnormalities ◽  
Biological Effects ◽  
Cell Killing ◽  
Space Environment ◽  
Low Doses ◽  
X Rays ◽  
G2 Checkpoint ◽  
High Let Radiation ◽  
High Let ◽  
Α Particles

The utilization of high linear-energy-transfer (LET) ionizing radiation (IR) modalities is rapidly growing worldwide, causing excitement but also raising concerns, because our understanding of their biological effects is incomplete. Charged particles such as protons and heavy ions have increasing potential in cancer therapy, due to their advantageous physical properties over X-rays (photons), but are also present in the space environment, adding to the health risks of space missions. Therapy improvements and the protection of humans during space travel will benefit from a better understanding of the mechanisms underpinning the biological effects of high-LET IR. There is evidence that high-LET IR induces DNA double-strand breaks (DSBs) of increasing complexity, causing enhanced cell killing, owing, at least partly, to the frequent engagement of a low-fidelity DSB-repair pathway: alternative end-joining (alt-EJ), which is known to frequently induce severe structural chromosomal abnormalities (SCAs). Here, we evaluate the radiosensitivity of A549 lung adenocarcinoma cells to X-rays, α-particles and 56Fe ions, as well as of HCT116 colorectal cancer cells to X-rays and α-particles. We observe the expected increase in cell killing following high-LET irradiation that correlates with the increased formation of SCAs as detected by mFISH. Furthermore, we report that cells exposed to low doses of α-particles and 56Fe ions show an enhanced G2-checkpoint response which is mainly regulated by ATR, rather than the coordinated ATM/ATR-dependent regulation observed after exposure to low doses of X-rays. These observations advance our understanding of the mechanisms underpinning high-LET IR effects, and suggest the potential utility for ATR inhibitors in high-LET radiation therapy.

scholarly journals Immunomodulatory Effects of Radiotherapy

2020 ◽  
Vol 21 (21) ◽  
pp. 8151
Author(s):  
Sharda Kumari ◽  
Shibani Mukherjee ◽  
Debapriya Sinha ◽  
Salim Abdisalaam ◽  
Sunil Krishnan ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Carbon Particle ◽  
Dna Lesions ◽  
X Rays ◽  
Adaptive Immune ◽  
High Let Radiation ◽  
Different Types ◽  
High Let ◽  
Radiation Induced ◽  
Tumor Death

Radiation therapy (RT), an integral component of curative treatment for many malignancies, can be administered via an increasing array of techniques. In this review, we summarize the properties and application of different types of RT, specifically, conventional therapy with x-rays, stereotactic body RT, and proton and carbon particle therapies. We highlight how low-linear energy transfer (LET) radiation induces simple DNA lesions that are efficiently repaired by cells, whereas high-LET radiation causes complex DNA lesions that are difficult to repair and that ultimately enhance cancer cell killing. Additionally, we discuss the immunogenicity of radiation-induced tumor death, elucidate the molecular mechanisms by which radiation mounts innate and adaptive immune responses and explore strategies by which we can increase the efficacy of these mechanisms. Understanding the mechanisms by which RT modulates immune signaling and the key players involved in modulating the RT-mediated immune response will help to improve therapeutic efficacy and to identify novel immunomodulatory drugs that will benefit cancer patients undergoing targeted RT.

Mutagenic adaptive response to high-LET radiation in human lymphoblastoid cells exposed to X-rays

2011 ◽  
Vol 706 (1-2) ◽  
pp. 46-52 ◽  
Author(s):  
Guillaume Varès ◽  
Bing Wang ◽  
Kaoru Tanaka ◽  
Ayana Kakimoto ◽  
Kyomi Eguchi-Kasai ◽  
...  
Keyword(s):  
Adaptive Response ◽  
X Rays ◽  
Lymphoblastoid Cells ◽  
High Let Radiation ◽  
High Let

Potential for Therapeutic Gain - 29 MeV Neutrons versus 6 MeV Neutrons

2015 ◽  
Vol 1084 ◽  
pp. 559-566
Author(s):  
Jacobus Slabbert ◽  
Anne Vral
Keyword(s):  
Radiation Therapy ◽  
Tumor Cell ◽  
Cell Types ◽  
Cancer Type ◽  
X Rays ◽  
High Let Radiation ◽  
Therapeutic Gain ◽  
High Let

When a cancer type proves to be radioresistant to treatment with X-rays, the use of neutrons may constitute therapeutic gain provided the cells are relatively sensitive to high-LET radiation. In this work studies with different tumor cell types are reported following exposure to either photons or different neutron energies used in clinical radiation therapy. Potential for therapeutic gain is clearly noted for neutrons with a mean energy of 6 MeV whilst that for 29 MeV neutrons is dependent on the cell types used in the study.

scholarly journals A Biomarker Panel of Radiation-Upregulated miRNA as Signature for Ionizing Radiation Exposure

Life ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 361
Author(s):  
Man Song ◽  
Dafei Xie ◽  
Shanshan Gao ◽  
Chen-Jun Bai ◽  
Mao-Xiang Zhu ◽  
...  
Keyword(s):  
Ionizing Radiation ◽  
Target Gene ◽  
Ex Vivo ◽  
Human Peripheral Blood ◽  
Mirna Gene ◽  
Peripheral Blood Lymphocytes ◽  
Pathway Network ◽  
Network Analyses ◽  
Serious Injury ◽  
New Biomarkers

Ionizing radiation causes serious injury to the human body and has long-time impacts on health. It is important to find optimal biomarkers for the early quick screening of exposed individuals. A series of miRNAs signatures have been developed as the new biomarkers for diagnosis, survival, and prognostic prediction of cancers. Here, we have identified the ionizing radiation-inducible miRNAs profile through microarray analysis. The biological functions were predicted for the top six upregulated miRNAs by 4 Gy γ-rays: miR-1246, miR-1307-3p, miR-3197, miR-4267, miR-5096 and miR-7641. The miRNA-gene network and target gene-pathway network analyses revealed that DNAH3 is the target gene associated with all the six miRNAs. GOLGB1 is related to 4 miRNAs and other 26 genes targeted by 3 miRNAs. The upregulation of fifteen miRNAs were further verified at 4 h and 24 h after 0 to 10 Gy irradiation in the human lymphoblastoid AHH-1 cells, and some demonstrated a dose-dependent increased. Six miRNAs, including miR-145, miR-663, miR-1273g-3p, miR-6090, miR-6727-5p and miR-7641, were validated to be dose-dependently upregulated at 4 h or 24 h post-irradiation in both AHH-1 and human peripheral blood lymphocytes irradiated ex vivo. This six-miRNA signature displays the superiority as a radiation biomarker for the translational application of screening and assessment of radiation exposed individuals.

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