Radiation research最新文献

Variable relative biological effectiveness (RBE) of carbon radiotherapy may be calculated using several models, including the microdosimetric kinetic model (MKM), stochastic MKM (SMKM), repair-misrepair-fixation (RMF) model, and local effect model I (LEM), which have not been thoroughly compared. In this work, we compared how these four models handle carbon beam fragmentation, providing insight into where model differences arise. Monoenergetic and spread-out Bragg peak carbon beams incident on a water phantom were simulated using Monte Carlo. Using these beams, input parameters for each model (microdosimetric spectra, DNA double-strand break yield, kinetic energy spectra, physical dose fragment contributions) were calculated for each contributing carbon beam fragment (hydrogen, helium, lithium, beryllium, boron, secondary carbon, primary carbon, electrons, and "other"). Scored input parameters for each fragment were used to calculate linear (α) and quadratic (β) parameters according to each model, which were combined with reference α and β values and absorbed physical dose to calculate RBE. Contributions from secondary fragments were found to exceed 30% of the total physical dose. Using identical beam parameters, the four models produced not only different RBE values but also different RBE trends. In all models, RBE was highest for secondary carbon ions. Beyond secondary carbons, the RBE magnitude typically increased with the atomic number of the fragment, but RBE trends differed dramatically by model and beamline region (entrance, spread-out Bragg peak, and tail). Variations in fragment RBE were large enough to be apparent in biological dose predictions. This study demonstrated that fragmentation is a nonnegligible consideration in carbon radiotherapy. Our findings identified differences in RBE among specific fragments and the four models, contributing to variability in the total biological dose across models. Because these findings emphasize differences in how various models handle carbon beam fragments, greater care should be taken in characterization of secondary fragments in particle therapy.

Ionizing radiation exposure during perinatal development can produce various biological effects on the developing offspring. These effects are dependent on a number of factors, including total dose, dose rate and the developmental processes occurring at the time of irradiation. The present study conducted an analysis of historical radiobiological archived data involving 60Co-gamma irradiation of beagle dogs at specific periods of prenatal or postnatal development. The original studies were performed at two sites where animals were exposed to a single, acute dose of 0.2 or 1.0 Gy at six different stages of perinatal development or with protracted exposures ranging from 0.004 to 0.35 Gy per day, over multiple days of gestation. A number of outcomes were investigated after perinatal irradiation including changes in sex ratio, survival probability, disease incidence and growth of animals, based on collected size and weight measurements of animals and different tissues. Protracted irradiations with doses up to 0.35 Gy per day did not significantly affect survival in animals when irradiated prenatally, although significant increases in the incidence of neoplasms and diseases related to the cardiovascular and urogenital system were observed at the time of death. Dogs irradiated at a dose rate of 0.10 Gy per day, with the irradiations continuing after birth and resulting in the accumulation of large total doses, were observed to have chronic radiation syndrome symptoms based on pathologies related to the hematopoietic system. Acute irradiation with 0.2 and 1.0 Gy resulted in changes of different body or tissue sizes measured in animals terminally, with changes detected after irradiation at all tested prenatal and postnatal time points, with the exception of irradiation at 365 days after birth. The present analysis provides new information regarding the biological effects of ionizing radiation during perinatal development in offspring in the unique mammalian study model of the beagle dog.

Data from animal experiments show that the radiation-related risk of cancer decreases if the dose rate is reduced, even though the cumulative dose is unchanged (i.e., a dose-rate effect); however, the underlying mechanism is not well understood. To explore factors underlying the dose-rate effect observed in experimental rat mammary carcinogenesis, we developed a mathematical model that accounts for cellular dynamics during carcinogenesis, and then examined whether the model predicts cancer incidence. A mathematical model of multistage carcinogenesis involving radiation-induced cell death and mutagenesis was constructed using differential equations. The mutation rate was changed depending on the dose rate. The model also considered competition among cells with various mutation levels. The main parameters of the model were determined using previous experimental data. The parameters of the model were consistent with experimental observations. A dose-rate effect on carcinogenesis became apparent when the relationship between dose rate and mutation rate was linear quadratic or quadratic. The dose-rate effect became prominent when cells with more mutations preferentially compensated for the radiation-induced death of cells with fewer mutations. The phenomenon by which mutated cells gain a competitive advantage over normal cells is known as super-competition. Here, we identified super-competition as a novel mechanism underlying the dose-rate effects on carcinogenesis. The data also confirmed the relevance of the shape of the relationship between dose rate and the mutation rate. Thus, this study provides new evidence for the mechanism underlying the dose-rate effect, which is important for predicting the cancer-related risks of low-dose-rate irradiation.

The role of genetics in susceptibility to radiotherapy-induced toxicities is unclear. A strong impact of genetics should cause correlated toxicities in patients with metachronous double radiotherapy. We ascertained information about demographics, lifestyle, radiotherapy and early toxicities in irradiated tissues for a retrospective cohort of 98 patients from 2 hospitals who underwent two metachronous radiotherapeutic treatments (2007-2022) of different anatomical regions. European Organisation for Research and Treatment of Cancer/Radiation Therapy Oncology Group (EORTC/RTOG) toxicity scores per organ system were combined to a single mean score. We considered as genetic component the variation of toxicity not explained by radiation dose to the tumor, age at radiotherapy, sex, smoking status, and surgery. Variance components of toxicity were evaluated by ordinal logistic regression with random intercept. Common site combinations were breast/contralateral breast (N = 16), breast/endometrium (N = 6), and cervix/breast (N = 5). Mean toxicity over exposed tissues was 0.70 (range, 0-3). Prescribed radiation dose was significantly associated with mean toxicity, with a 5% (95% CI 3-8) increase of the odds for a higher toxicity level per Gy. Sex, surgery, age and smoking were not. There was no genetic contribution to risk of toxicities after adjustment. Toxicity levels were not more similar within patients than between patients, suggesting a negligible impact of genotype on radiotherapy-related toxicities.

It is thought that cells surviving ionizing radiation exposure repair DNA double-strand breaks (DSBs) and restore their genomes. However, the recent biochemical and genetic characterization of DSB repair pathways reveals that only homologous recombination (HR) can function in an error-free manner and that the non-homologous end joining (NHEJ) pathways canonical NHEJ (c-NHEJ), alternative end joining (alt-EJ), and single-strand annealing (SSA) are error-prone, and potentially leave behind genomic scars and altered genomes. The strong cell cycle restriction of HR to S/G2 phases and the unparalleled efficiency of c-NHEJ throughout the cell cycle, raise the intriguing question as to how far a surviving cell "reaches" after repairing the genome back to its pre-irradiation state. Indeed, there is evidence that the genomes of cells surviving radiation treatment harbor extensive genomic alterations. To directly investigate this possibility, we adopted next-generation sequencing (NGS) technologies and tested a normal human fibroblast cell line, 82-6 hTert, after exposure up to 6 Gy. Cells were irradiated and surviving colonies expanded and the cells frozen. Sequencing analysis using the Illumina sequencing platform and comparison with the unirradiated genome detected frequent genomic alterations in the six investigated radiation survivor clones, including translocations and large deletions. Translocations detected by this analysis and predicted to generate visible cytogenetic alterations were frequently (three out of five) confirmed using mFISH cytogenetic analysis. PCR analysis of selected deletions also confirmed seven of the ten examined. We conclude that cells surviving radiation exposure tolerate and pass to their progeny a wide spectrum of genomic alterations. This recognition needs to be integrated into the interpretation of biological results at all endpoints, as well as in the formulation of mathematical models of radiation action. NGS analysis of irradiated genomes promises to enhance molecular cytogenetics by increasing the spectrum of detectable genomic alterations and advance our understanding of key molecular radiobiological effects and the logic underpinning DSB repair. However, further developments in the technology will be required to harness its full potential.

Biodosimetry is a key diagnostic tool for radiation exposure, risk assessment and treatment planning of acute radiation sickness. To effectively respond to a large-scale radiological incident, there is a need for the development of biodosimetric methods with fast, portable, and convenient operating advantages. We employed the recombinase polymerase amplification specific high-sensitivity enzymatic reporter unlocking (RPA-SHERLOCK) technology to establish a method for fast radiation dose assessment by measuring the expression level of radiation-inducible genes. Moreover, we proposed for the first time the principle of quantitative detection of curve slopes based on this method. Using this new method, changes in mRNA expression were confirmed in a number of radiation-sensitive genes (XPC, CDKN1A, and ATM) in human lymphocytes after irradiation. The standard curve of the dose-effect relationship was established, which can be used to quickly determine the exposed dose of the irradiated samples. Compared with traditional detection methods such as RT-qPCR, this method was found to be more convenient, fast and easy to operate. With the same amount of template input as RT-qPCR, the detection time of this method can be shortened to less than 20 min. The detection instrument required by this method is also more portable than a qPCR system.

Estimation of absorbed organ doses used in computed tomography (CT) using time-intensive Monte Carlo simulations with virtual patient anatomic models is not widely reported in the literature. Using the library of computational phantoms developed by the University of Florida and the National Cancer Institute, we performed Monte Carlo simulations to calculate organ dose values for 9 CT categories representing the most common body regions and indications for imaging (reflecting low, routine, and high radiation dose examinations), stratified by patient age (in children) and effective diameter (in adults, using "diameter" as a measure of patient size). Our sample of 559,202 adult and 103,423 pediatric CT examinations was prospectively assembled between 2015-2020 from 156 imaging facilities from 27 healthcare organizations in 20 U.S. states and 7 countries in the University of California San Francisco International CT Dose Registry. Organ doses varied by body region and exam type. For example, the mean brain dose associated with head CT was 20 mGy [standard deviation (SD) 14] for head low dose, 46 mGy (SD 21) for head routine dose, and 64 mGy (SD 31) for head high dose scan protocols. The mean colon doses associated with abdomen and pelvis CT were 19 mGy (SD 12), 32 mGy (SD 28), and 69 mGy (SD 42) for low, routine, and high dose examinations, respectively. Organ doses in general varied modestly by patient diameter, and for many categories the organ doses among the largest quartile of patients were no more than 10% higher than doses in the smallest quartile. For example, for abdomen and pelvis high dose, the colon dose increased from 67 to 74 mGy from the smallest to the largest patients (10% increase). With few exceptions, pediatric organ doses also varied relatively little by patient age, except for the youngest children who, on average, had higher organ doses. Thyroid dose, however, tended to increase with age in neck or cervical spine and chest CT. Overall, the highest organ doses were to the skin, thyroid, brain, and eye lens. Mean organ doses differ substantially by site. The organ dose values included in this report are derived from empirical clinical exams and offer useful, representative values. Large inter-site variations demonstrate areas for radiation dose reduction.

Diffuse intrinsic pontine gliomas (DIPG) are highly aggressive and treatment-resistant childhood primary brainstem tumors with a median survival of less than one year after diagnosis. The prevailing standard of care for DIPG, radiation therapy, does not prevent fatal disease progression, with most patients succumbing to this disease 3-8 months after completion of radiation therapy. This underscores the urgent need for novel combined-modality approaches for enhancing therapy responses. This study demonstrates that the cellular redox modulating drug, copper (II)-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) dose-dependently (1-3 μM) decreased clonogenic cell survival in SU-DIPG50 and SU-DIPG36 cell lines during 6 h of exposure but had no significant effect on survival in normal human astrocytes (NHA). Additional significant (>90%) decreases in DIPG clonogenic survival were observed at 24 h of Cu-ATSM exposure. However, NHAs also began to show dose-dependent 10-70% survival decreases at this point. Notably, 3 μM Cu-ATSM for 6 h resulted in additive clonogenic cell killing of DIPG lines when combined with radiation, which was not seen in NHAs and was partially inhibited by the copper chelator, bathocuproinedisulfonic acid. Cu-ATSM toxicity in DIPG cells was also inhibited by overexpression of mitochondrial-targeted catalase. These results support the hypothesis that Cu-ATSM is selectively cytotoxic to DIPGs by a mechanism involving H2O2 generation and copper and being additively cytotoxic with ionizing radiation.

Although multiple studies suggest that ionizing radiation can induce bystander effects (radiation-induced bystander effect, RIBE) in cultured cell lines, it is still unclear whether RIBE is evolutionarily conserved in invertebrates. In this study, we investigated the frequency of cell death of unirradiated starfish (Patiria pectinifera) oocytes co-cultured with oocytes irradiated with X rays (0, 2 and 4 Gy). We observed increased frequencies of cell death determined by morphological abnormality and TUNEL-positive cells in unirradiated oocytes co-cultured with oocytes irradiated with 2 Gy or 4 Gy oocytes. In addition, the seawater cultured with 4 Gy irradiated oocytes induced cell death in unirradiated oocytes, and TUNEL-positive cells were observed. Our results suggest that RIBE is evolutionarily conserved in starfish.