Radiosensitive Tissues Research Articles

M6A-modified circCREBBP enhances radiosensitivity of esophageal squamous cell carcinoma by reducing the stability of MYC through interaction with IGF2BP3.

Substantial evidence has showed a close relationship between circRNAs and m6A modification in tumorigenesis and development. However, limited research has explored the regulatory role and underlying mechanism of m6A-modified circRNAs in regulating the radiosensitivity of esophageal squamous cell carcinoma (ESCC). The aim of this study was to clarify the molecular pathway by which m6A-modified circCREBBP enhances the radiosensitivity of ESCC. Differentially expressed circRNAs were identified from radiosensitive and radioresistant ESCC tissues and cells, followed by methylated RNA immunoprecipitation analysis. The effects of these circRNAs on radiosensitivity were subsequently assessed. We identified that CircCREBBP is closely associated with m6A and radiosensitivity in ESCC. CircCREBBP expression was significantly reduced in ESCC patients resistant to concurrent radiochemotherapy. In vitro and in vivo experiments demonstrated that circCREBBP knockdown enhanced the ESCC radioresistance. Mechanistic investigations revealed that circCREBBP, modified by m6A, interacted with IGF2BP3 and competitively bound to it, thereby reducing MYC mRNA stability. This study identified circCREBBP as a new m6A-modified circRNA and confirmed the METTL3/IGF2BP3/circCREBBP/MYC axis as a potential therapeutic target in enhancing radiosensitivity in ESCC.

Estimation and analysis of S values for 131I using paediatric mesh type reference computational phantoms

This study examines the effect of paediatric mesh-type reference computational phantoms on organSvalues resulting from radioiodine (131I) intake. Using Geant4, we estimated131ISvalues for 30 radiosensitive target tissues due to emission from the thyroid (Target ← Thyroid) in these phantoms. Our results show thatSvalues differ between male and female phantoms of the same age andSvalues also decrease as phantom age increases. The male-to-femaleSvalue ratio typically varies within 10%, with larger differences observed for the esophagus, extra-thoracic regions, muscles, bladder, and sex organs. On average,Svalues for mesh phantoms are approximately 17% higher than those for voxel phantoms, with larger discrepancies for organs remodelled separately in mesh phantoms. The study provides organSvalues for the paediatric population due to131I exposure from the thyroid, based on the reference mesh-type computational phantoms, enhancing organ dose estimation in emergency situations and during radioiodine treatment.

The impact of Radioresistant-Related Telomere Genes in the prognosis and immune infiltration in lung adenocarcinoma

IntroductionLung adenocarcinoma (LUAD), a common subtype of NSCLC, has a high mortality rate. Telomere genes are influenced by radiation therapy, affecting treatment response. Additionally, immune cell presence in the tumor microenvironment plays a crucial role in cancer prognosis. However, the role of Radioresistant-Related Telomere Genes (RRTGs) in LUAD prognosis and immune infiltration remains unclear.MethodsIn this research, we utilized diverse bioinformatics techniques to examine our personally tested information along with publicly accessible datasets. We conducted a comprehensive study on the genetic and transcriptional differences, predictive significance, and expression profiles of RRTGs. Afterwards, a RRTGs score was developed to forecast the overall survival (OS) and ascertain its reliable predictive capacity for patients with LUAD. Following this, dependable nomograms were developed to enhance the practicality of RRTGs scoring in a clinical setting. Furthermore, the investigation delved into the associations among RRTGs, infiltration of immune cells, prognosis, and clinical treatments of patients. Gene Set Enrichment Analysis (GSEA) was conducted to explore the potential mechanisms by which RRTGs influence the regulation of LUAD. Then, Western blot, qRT-PCR and Immunohistochemistry were used to detect the expression levels of RRTGs in cell lines and LUAD tumor tissues.ResultsOur research indicates that certain genes related to telomeres have a notable correlation with the prognosis of patients diagnosed with LUAD. The RRTGs score, which includes three key genes (ARRB1, PLK1, and DSG2), was developed to forecast the OS and its dependable predictive capability for individuals diagnosed with LUAD was ascertained. Afterwards, extremely reliable nomograms were developed to improve the practicality of the RRTGs score. Moreover, as illustrated, genetic characteristics can be utilized to assess the infiltration of immune cells in tumors, as well as clinical attributes and prognosis. RRTGs score characterizes tumor mutational burden, immune activity, and notable survival probabilities in addition. Furthermore, GSEA results revealed that RRTGs may influence LUAD by modulating immune-related pathways in high-risk groups and regulating cell cycle and DNA repair processes in low-risk groups. The RRTGs (ARRB1 and PLK1) were upregulated in A549 cells and radiosensitive NSCLC tissues compared to radioresistant A549 cells and NSCLC tissues.ConclusionIn conclusion, this research emphasizes the significance of RRTGs in the outlook of LUAD. The findings contributed to a better understanding of the link between radiotherapy, telomere-related genes, and prognosis in LUAD, and identified potential therapeutic targets for patients with LUAD.

Rectal Epithelial Stem Cell Kinetics in Acute Radiation Proctitis

The intestinal tract is a typical radiosensitive tissue, and radiation rectal injury is a severe side effect that limits the prescribed dose in radiotherapy of the abdominal and pelvic region. Understanding the post-irradiation kinetics of Lgr5-positive stem cells is crucial in comprehending this adverse process. In this study, we utilized Lgr5-EGFP knock-in mice expressing EGFP and LGR5 antibody fluorescence staining of wild-type mice. At the state of radiation injury, the qPCR analysis showed a significant decrease in the expression level of Lgr5 in the rectal epithelial tissue. The dose-response relationship analysis showed that at low to moderate doses up to 10 gray (Gy), Lgr5-clustered populations were observed at the base of the crypt, whereas at sublethal doses (20 Gy and 29 Gy), the cells exhibited a dot-like scatter pattern, termed Lgr5-dotted populations. During recovery, 30 days post-irradiation, Lgr5-clustered populations gradually re-emerged while Lgr5-dotted populations declined, implying that some of the Lgr5-dotted stem cell populations re-clustered, aiding regenerations. Based on statistical analysis of the dose-response relationship using wild-type mice, the threshold dose for destroying these stem cell structures is 18 Gy. These findings may help set doses in mouse abdominal irradiation experiments for radiation intestinal injury and for understanding the histological process of injury development.

Breast Cancer Adjuvant Radiotherapy and Chemotherapy Sequencing: Sequential, Concomitant, or What Else? A Comprehensive Review of the Adjuvant Combinations Journey.

Background: To date, in breast cancer (BC) treatment, adjuvant chemotherapy (A-CT) has preceded adjuvant radiotherapy (A-RT). In the last twenty years, the adjuvant treatment of BC has quickly evolved due to better knowledge of its molecular biology, genetic profile, and α/β ratio of 3/4 Gy for tumor and normal tissue radiosensitivity. Thus, new schedules with hypofractionated radiotherapy have been tested, and a third generation of A-CT has been introduced, raising the question of whether it is time to rethink the sequencing between these two approaches. Methods: In the last 20 years, many attempts have been made worldwide to optimize the best sequencing strategy between these two approaches in terms of sequential CT-RT and RT-CT and concomitant and sandwich modalities using drugs and schedules. This paper presents a comprehensive review of the state of the art, analyzing all the available studies to assess the sequencing between A-CT and A-RT with different generations of chemotherapy schedules. Results: More than 8000 patients from 30 studies treated with adjuvant chemotherapy and whole breast radiotherapy who were enrolled in randomized, retrospective, and prospective studies were analyzed. Sequential, concomitant, and sandwich modalities of chemotherapy with conventional or hypofractionated RT schedules from the most important studies were included. The most used sequence was adjuvant chemotherapy followed by conventional or hypofractionated radiotherapy. In the concomitant approach, i.v. CMF has been the most important adopted schedule, while the concomitant use of anthracyclines and taxanes with conventional or hypofractionated radiotherapy has been found to be more toxic. One study analyzed the benefit in terms of reducing adjuvant treatment time with upfront hypofractionated radiotherapy and third-generation chemotherapy. Conclusions: At present, the best sequencing strategy has not yet been defined. This comprehensive review is a journey among the most important randomized, retrospective, and prospective studies that highlights the past, current, and novel time sequencing proposals between A-CT and A-RT to assess the state of the art and provide useful information for future adjuvant approaches in breast cancer treatment.

N-formylmethionine-leucyl-phenylalanine protects against irradiation-induced damage to hematopoiesis and intestines

BackgroundIonizing radiation (IR), including radiotherapy, can exert lasting harm on living organisms. While liposaccharide (LPS) offers resistance to radiation damage, it also induces toxic responses. Thankfully, an LPS analogue called N-formylmethionine-leucyl-phenylalanine (fMLP) holds the potential to mitigate this toxicity, offering hope for radiation protection.MethodsSurvival of C57BL/6 mice exposed to IR after administration with fMLP/LPS/WR-2721 or saline was recorded. Cell viability and apoptosis assay of bone marrow (BMC), spleen and small intestinal epithelial (HIECs) cells were tested by Cell Counting Kit-8 (CCK-8) and flow cytometry assay. Tissue damage was evaluated by Hematoxilin and Eosin (H&E), Ki-67, and TUNEL staining. RNA sequencing was performed to reveal potential mechanisms of fMLP-mediated radiation protection. Flow cytometry and western blot were performed to verify the radiation protection mechanism of fMLP on the cell cycle.ResultsThe survival rates of C57BL/6 mice exposed to ionizing radiation after administering fMLP increased. fMLP demonstrated low toxicity in vitro and in vivo, maintaining cell viability and mitigating radiation-induced apoptosis. Moreover, it protected against tissue damage in the hematopoietic and intestinal system. RNA sequencing shed light on fMLP’s potential mechanism, suggesting its role in modulating innate immunity and cell cycling. This was evidenced by its ability to reverse radiation-induced G2/M phase arrests in HIECs.ConclusionfMLP serves as a promising radioprotective agent, preserving cells and radiosensitive tissues from IR. Through its influence on the cell cycle, particularly reversing radiation-induced arrest in G2/M phases, fMLP offers protection against IR’s detrimental effects.

242. BRD4 INHIBITION ENHANCES THE RADIOSENSITIVITY OF ESOPHAGEAL SQUAMOUS CELL CARCINOMA THROUGH REGULATING ATF3-MEDIATED SERINE AND NUCLEOTIDE SYNTHESIS

Abstract Background Radioresistance is a major culprit for radiotherapy failure in esophageal squamous cell carcinoma (ESCC). This study aimed to investigate the underlying mechanism of Brd4 in radiosensitivity of ESCC. Methods Brd2/3/4 proteins were assessed in radiosensitive and radioresistant ESCC tissues using IHC. A serial of functional experiments was performed to verify the significance of Brd4 in ESCC. RNA-seq and bioinformatics analyses were used to determine the potential downstream targets. The dual-luciferase reporter and ChIP assay were further examined the underlying regulatory mechanism among targets. Besides, we further verified the importance of ATF3-mediated serine and nucleotide metabolism in radiated ESCC cells. Results Brd4 is highly expressed in radio-resistant ESCC tissue. Knockdown of Brd4 led to increased DNA damage and cell apoptosis in irradiated ESCC cells. RNA-seq analyses exhibited that ATF3 was a potential downstream target of Brd4. The dual-luciferase reporter and ChIP assay demonstrated that Brd4 upregulated ATF3 expression via activation its promoter region. Besides, we found that ATF3 could facilitate the enzyme activities involved in serine and nucleotide biosynthesis pathway to promote radiation-induced DNA damage repair. Conclusion Brd4 facilitates ATF3 expression via binding to and activating ATF3 promoter region. Enhanced ATF3 further increases crucial enzymes activity in serine and nucleotide biosynthesis pathway to promote radiation-induced DNA damage repair. Targeting Brd4 is a promising treatment strategy to improve radiosensitivity in ESCC.

Overexpression of ESYT3 improves radioimmune responses through activating cGAS-STING pathway in lung adenocarcinoma

BackgroundRadiotherapy can modulate systemic antitumor immunity, while immune status in the tumor microenvironment also influences the efficacy of radiotherapy, but relevant molecular mechanisms are poorly understood in lung adenocarcinoma (LUAD).MethodsIn this study, we innovatively proposed a radiotherapy response classification for LUAD, and discovered ESYT3 served as a tumor suppressor and radioimmune response sensitizer. ESYT3 expression was measured both in radioresistant and radiosensitive LUAD tissues and cells. The influence of ESYT3 on radiotherapy sensitivity and resistance was then investigated. Interaction between ESYT3 and STING was evaluated through multiple immunofluorescent staining and coimmunoprecipitation, and downstream molecules were further analyzed. In vivo models were constructed to assess the combination treatment efficacy of ESYT3 overexpression with radiotherapy.ResultsWe found that radioresistant subtype presented immunosuppressive state and activation of DNA damage repair pathways than radiosensitive subtype. ESYT3 expression was remarkably attenuated both in radioresistant LUAD tissues and cells. Clinically, low ESYT3 expression was linked with radioresistance. Overexpression of ESYT3 enabled to alleviate radioresistance, and sensitize LUAD cells to DNA damage induced by irradiation. Mechanically, ESYT3 directly interacted with STING, and activated cGAS-STING signaling, subsequently increasing the generation of type I IFNs as well as downstream chemokines CCL5 and CXCL10, thus improving radioimmune responses. The combination treatment of ESYT3 overexpression with radiotherapy had a synergistic anticancer effect in vitro and in vivo.ConclusionsIn summary, low ESYT3 expression confers resistance to radiotherapy in LUAD, and its overexpression can improve radioimmune responses through activating cGAS-STING-dependent pathway, thus providing an alternative combination therapeutic strategy for LUAD patients.

Prostate radiotherapy may cause fertility issues: a retrospective analysis of testicular dose following modern radiotherapy techniques

BackgroundProstate cancer in younger men is rare but not exceptional. Radiotherapy is a cornerstone of prostate cancer treatment and yet, its impact on fertility is scarcely reported in literature. Given the radiosensitivity of testicular tissue, this study aimed to determine the testicular dose using modern radiotherapy techniques for definitive prostate irradiation.MethodsOne hundred radiotherapy plans were reviewed. Testicles were contoured retrospectively without dosimetric optimization on testicles.ResultsThe median testicular dose was 0.58 Gy: 0.18 Gy in stereotactic plans, 0.62 Gy in Volumetric Modulated Arc Therapy plans and 1.50 Gy in Tomotherapy plans (p < 0.001). Pelvic nodal irradiation increased the median testicular dose to 1.18 Gy versus 0.26 Gy without nodal irradiation (p < 0.001). Weight and BMI were inversely associated with testicular dose (p < 0.005). 65% of patients reached the theoretical dose threshold for transient azoospermia, and 10% received more than 2 Gy, likely causing definitive azoospermia.ConclusionDespite being probably lower than doses from older techniques, the testicular dose delivered with modern prostate radiotherapy is not negligible and is often underestimated because the contribution of daily repositioning imaging is not taken into account and most Treatment Planning Systems underestimate the out of field dose. Radiation oncologists should consider the impact on fertility and gonadal endocrine function, counseling men on sperm preservation if they wish to maintain fertility.Trial registration: retrospectively registered.

Two-dimensional oxygen-diffusion modelling for FLASH proton therapy with pencil beam scanning—Impact of diffusive tissue properties, dose, dose rate and scan patterns

Objective. Oxygen depletion is generally believed to play an important role in the FLASH effect—a differential reduction of the radiosensitivity of healthy tissues, relative to that of the tumour under ultra-high dose-rate (UHDR) irradiation conditions. In proton therapy (PT) with pencil-beam scanning (PBS), the deposition of dose, and, hence, the degree of (radiolytic) oxygen depletion varies both spatially and temporally. Therefore, the resulting oxygen concentration and the healthy-tissue sparing effect through radiation-induced hypoxia varies both spatially and temporally as well. Approach. We propose and numerically solve a physical oxygen diffusion model to study these effects and their dependence on tissue parameters and the scan pattern in pencil-beam delivery. Since current clinical FLASH PT (FLASH-PT) is based on 250 MeV shoot-through (transmission) beams, for which dose and dose rate (DR) hardly vary with depth compared to the variation transverse to the beam axis, we focus on the two-dimensional case. We numerically integrate the model to obtain the oxygen concentration in each voxel as a function of time and extract voxel-based and spatially and temporarily integrated metrics for oxygen (FLASH) enhanced dose. Furthermore, we evaluate the impact on oxygen enhancement of standard pencil-beam delivery patterns and patterns that were optimised on dose-rate. Our model can contribute to the identification of tissue properties and pencil-beam delivery parameters that are critical for FLASH-PT and it may be used for the optimisation of FLASH-PT treatment plans and their delivery. Main results. (i) the diffusive properties of oxygen are critical for the steady state concentration and therefore the FLASH effect, even more so in two dimensions when compared to one dimension. (ii) The FLASH effect through oxygen depletion depends primarily on dose and less on other parameters. (iii) At a fixed fraction dose there is a slight dependence on DR. (iv) Scan patterns optimised on DR slightly increase the oxygen induced FLASH effect. Significance. To our best knowledge, this is the first study assessing the impact of scan-pattern optimization (SPO) in FLASH-PT with PBS on a biological FLASH model. While the observed impact of SPO is relatively small, a larger effect is expected for larger target volumes. A better understanding of the FLASH effect and the role of oxygen (depletion) therein is essential for the further development of FLASH-PT with PBS, and SPO.

Radiation-induced eye impairments

The problem of the impact of ionizing radiation on eye structures is one of the most important and topical in radiobiology. Knowledge of tissue radiosensitivity and induced tissue changes in the eye is essential for understanding the nature of radiation damage and the behavior of medical professionals. In this publication, the early and late determined radiation-induced impairments of the eye are presented as a result of radiotherapy or radiation incidents. The risk factors determining post-irradiation eye reactions, pathophysiological mechanisms, clinical picture, diagnosis, prevention, and new approaches in therapy are presented. We found that the typically found radiation-induced eye impairments are those of the eyelids – dermatosis and madarosis, conjunctiva – acute conjunctivitis, varied damage to the lacrimal apparatus, cornea – edema and ulceration, iris – rarely inflammation or neovascularization, sclera – rarely atrophy or necrosis, eye lens – cataract, retina – characteristic retinopathy, and optical nerve – rarely neuropathy. We provide the current consensus on prevention and treatment protocols in radiation-induced eye impairments, though most suggested treatment so far should qualify as experimental.

DNA Repair Genetics and the Risk of Radiation Pneumonitis in Patients With Lung Cancer: A Systematic Review and Meta-analysis

AimsERCC1 rs11615 and ERCC2 rs238406 single nuclear polymorphism (SNPs) are known for their association with treatment outcome, likely related to radiosensitivity of both tumor and normal tissue in patients with non-small-cell lung cancer. This study aimed to review the effect of 1) these ERCC1/2 SNPs and 2) other SNPs of DNA repair genes on radiation pneumonitis (RP) in patients with lung cancer. Materials and methodsSNPs of our interest included ERCC1 rs11615 and ERCC2 rs238406 and other genes of DNA repair pathways that are functional and biologically active. DNA repair SNPs reported by at least two independent studies were pooled for meta-analysis. The study endpoint was radiation pneumonitis (RP) after radiotherapy. Recessive, dominant, homozygous, heterozygous, and allelic genotype models were used where appropriate. ResultsA total of 16 studies (3080 patients) were identified from the systematic review and 12 studies (2090 patients) on 11 SNPs were included in the meta-analysis. The SNPs were ATM rs189037, ATM rs373759, NEIL1 rs4462560, NEIL1 rs7402844, APE1 rs1130409, XRCC3 rs861539, ERCC1 rs11615, ERCC1 rs3212986, ERCC2 rs238406, ERCC2 rs13181, and XRCC1 rs25487. ERCC1 rs11615 (236 patients) and ERCC2 rs238406 (254 patients) were not significantly associated with RP. Using the allelic model, the G allele for NEIL1 gene was significantly associated with a reduced odds of developing symptomatic (grade ≥2) RP compared to the C allele for rs7402844 (OR 0.70, 95% CI: 0.49, 0.99, P = 0.04). Similarly, the T allele for APE1 gene was significantly associated with a reduced odds of developing symptomatic (grade ≥2) RP compared to the G allele for rs1130409 (OR 0.59, 95% CI: 0.43, 0.81, P = 0.001). ConclusionGenetic variation in the DNA repair pathway genes may play a significant role in the risk of developing radiation pneumonitis in patients with lung cancer. Further studies are needed on genotypic features of DNA repair pathway genes and their association with treatment sensitivity, as such knowledge may guide personalized radiation dose prescription.

A novel approach of using Maca root as a radioprotector in a rat testicular damage model focusing on GRP78/CHOP/Caspase-3 pathway

PurposeDespite the effectiveness of ionizing radiation in treating cancer, it can damage healthy tissues in the vicinity. Due to the high radio-sensitivity of testicular tissues, radiation therapy may affect spermatogenesis, which may result in infertility. Hence, in this study testicular damage model is constructed to investigate the mitigation effect of Maca root powder and its potential radioprotective activity through both oxidative and endoplasmic reticulum (ER) stresses, besides the apoptotic pathway. MethodsMale albino rats were exposed to 6Gy of whole-body gamma radiation single dose. Maca root powder (1 g/kg b.wt./day, by oral gavage) was administered for a week before irradiation, then d-galactose (300 mg/kg, by oral gavage) and Maca daily for another week. ResultsGamma radiation and d-galactose revealed a significant decrease in serum testosterone, sperm count, and motility and higher percentage of the sperm head abnormality, while Maca root treatment maintained all sperm morphology parameters. Maca root treatment demonstrated a notable defense against radiation-induced oxidative stress and ameliorated malonaldehyde (MDA), reactive oxygen species (ROS), nitric oxide (NO), glutathione-S-transferase (GST) levels, reduced glutathione (GSH), oxidized glutathione (GSSG) and the ratio of GSH/GSSG in testis tissues. Exposure to gamma rays and d-galactose displayed a significant elevation in GRP78, CHOP, total caspase-3 as well as active (cleaved) caspase-3 levels, whereas treatment with Maca significantly reduced the ER and apoptotic markers levels. Also, Maca improved the histological changes of the disorganized seminiferous tubules induced by irradiation. ConclusionOur findings show for the first time that Maca has a protective effect on male reproductive damage induced by radiotherapy. Maca root reveals anti-apoptotic effect and protection against testicular damage via GRP78/CHOP/caspase-3 pathway.

Ocular radiation exposure is negligible in normal volume endourological practice.

The annual dose limit for radiation exposure to the eye has been reduced recently; the eye is widely recognised as one of the most radiosensitive tissues in the body. There is minimal good quality research as to the radiation dose that the eye receives during endourological surgery and this study aimed to address this. A prospective study was performed over an 8-month period at a single large teaching hospital in the UK. Three index procedures were included: ureteric stent insertion, ureteroscopy (URS) and percutaneous nephrolithotomy (PCNL). Surgeons wore a dosimeter on the glabella with fluoroscopy time (FT) and dose area product (DAP) recorded for each case. A total of 404 procedures were included (247 URSs, 150 ureteric stent insertions and 7 PCNLs). Dosimeters were worn by ten surgeons. Mean FTs (URS 20.56s; ureteric stent 18.96s; PCNL 360.67s) and mean DAP (URS 100.82cGy/m2, ureteric stent 119.82cGy/m2 and PCNL 1121.62cGy/m2) were identified with significant intersurgeon variability. No surgeon had a total dosimeter dose >0.00mSv. The International Commission on Radiological Protection recently reduced the yearly eye dose limit from 150 to 20mSv. Cataractogenesis is no longer considered a typical deterministic effect, with a threshold level below which no effect occurs. Even in higher volume centres, these annual limits are unlikely to be reached. Lead glasses may be considered for surgeons and radiologists with the highest exposure but, for the majority, ocular radiation exposure is negligible.

Hypoxia-informed RBE-weighted beam orientation optimization for intensity modulated proton therapy.

Variable relative biological effectiveness (RBE) models in treatment planning have been proposed to optimize the therapeutic ratio of proton therapy. It has been reported that proton RBE decreases with increasing tumor oxygen level, offering an opportunity to address hypoxia-related radioresistance with RBE-weighted optimization. Here, we obtain a voxel-level estimation of partial oxygen pressure to weigh RBE values in a single biologically informed beam orientation optimization (BOO) algorithm. Three glioblastoma patients with [18 F]-fluoromisonidazole (FMISO)-PET/CT images were selected from the institutional database. Oxygen values were derived from tracer uptake using a nonlinear least squares curve fitting. McNamara RBE, calculated from proton dose, was then weighed using oxygen enhancement ratios (OER) for each voxel and incorporated into the dose fidelity term of the BOO algorithm. The nonlinear optimization problem was solved using a split-Bregman approach, with FISTA as the solver. The proposed hypoxia informed RBE-weighted method (HypRBE) was compared to dose fidelity terms using the constant RBE of 1.1 (cRBE) and the normoxic McNamara RBE model (RegRBE). Tumor homogeneity index (HI), maximum biological dose (Dmax), and D95%, as well as OAR therapeutic index (TI=gEUDCTV /gEUDOAR ) were evaluated along with worst-case statistics after normalization to normal tissue isotoxicity. Compared to [cRBE, RegRBE], HypRBE increased tumor HI, Dmax, and D95% across all plans by on average [31.3%, 31.8%], [48.6%, 27.1%], and [50.4%, 23.8%], respectively. In the worst-case scenario, the parameters increase on average by [12.5%, 14.7%], [7.3%,-8.9%], and [22.3%, 2.1%]. Despite increased OAR Dmean and Dmax by [8.0%, 3.0%] and [13.1%, -0.1%], HypRBE increased average TI by [22.0%, 21.1%]. Worst-case OAR Dmean, Dmax, and TI worsened by [17.9%, 4.3%], [24.5%, -1.2%], and [9.6%, 10.5%], but in the best cases, HypRBE escalates tumor coverage significantly without compromising OAR dose, increasing the therapeutic ratio. We have developed an optimization algorithm whose dose fidelity term accounts for hypoxia-informed RBE values. We have shown that HypRBE selects bE:\Alok\aaeams better suited to deliver high physical dose to low RBE, hypoxic tumor regions while sparing the radiosensitive normal tissue.

Targeting Ferroptosis as a New Approach for Radiation Protection and Mitigation

Abstract: Radiation-induced normal cell toxicity (RINCT) is a major factor to consider while treating any ailment with radiotherapy. Clinical irradiation of tumors necessitates an understanding of the potential efficacy of radiation protective agents in reducing radiation damage to healthy tissues and their effects on tumor tissue radiosensitivity. Ferroptosis is a relatively new form of iron-dependent cell death that has been linked to a variety of disease pathologies. The key mediators of ferroptosis have been identified as lipid peroxidation and iron metabolism. Lipid peroxidation is the result of a reaction between reactive oxygen (ROS) and reactive nitrogen species (RNS) with phosphatidylethanolamine-containing polyunsaturated fatty acids (PUFAs). Ferroptosis inhibitors have been demonstrated to have anti-inflammatory effects in animal models of disease. It was recently shown that ionizing radiation (IR) generates severe ferroptosis, a critical component of RT-mediated normal cell toxicity. These findings support the use of ferroptosis inhibitor treatments for the treatment of radiation normal cell toxicity. Targeting lipid metabolic substrates and controlling ferroptosis by radiation could reduce toxicity and improve clinical outcomes. In this study, we address the relationships between radiotherapy and various types of radiation-induced cell death, and we discuss the interactions between ferroptosis and other kinds of controlled cell death generated by radiotherapy, and we investigate combination treatment options targeting ferroptosis in radiotherapy. This review will be a foundation for future research on ferroptosis in radiotherapy. Additionally, the relevant patents on ferroptosis inhibitors with various therapeutic potentials have been discussed.

LGR5+ Intestinal Stem Cells Display Sex-Dependent Radiosensitivity.

Tissue radiosensitivity plays a critical role in the overall outcome of radiation therapy. Identifying characteristics that predict how a patient may respond to radiotherapy enables clinicians to maximize the therapeutic window. Limited clinical data have suggested a difference in male and female radiotherapy outcomes. Radiotherapy for gastrointestinal malignancy is still a challenge due to intestinal sensitivity to radiation toxicity. In this manuscript, we demonstrated sex-specific differences in intestinal epithelial radiosensitivity. In a mouse model of abdominal irradiation, we observed a significant increase in oxidative stress and injury in males compared to females. Lgr5+ve intestinal stem cells from male mice showed higher sensitivity to radiation-induced toxicity. However, sex-specific differences in intestinal radiosensitivity were not dependent on sex hormones, as we demonstrated similar sex-specific radiosensitivity differences in pre-pubescent mice. In an ex vivo study, we found that patient-derived intestinal organoid (PID) from males showed higher sensitivity to radiation compared to females as evident from loss of budding crypts, organoid size, and membrane integrity. Transcriptomic analysis of human Lgr5+ intestinal stem cells suggested radiation-induced upregulation of mitochondrial oxidative metabolism in males compared to females, a possible mechanism for radiosensitivity differences.

Evaluation of Optical and Radiation Protection Parameters of High Refractive Index Polymers

The optical properties of the prescription and non-prescription (plano) samples of the MR-8 high index lens were examined by UV/VIS spectrometry. The results showed that the light transmittance of the two MR-8 lens samples examined was over 90%, and the transmittance at the wavelength (~550nm) to which the human eye is most sensitive was 83.437% and 84.602% for the prescription and non-prescription samples, respectively. In terms of quality of vision, it is expected that the visible light transmittance will be high and the ultraviolet light transmittance will be minimal. It is very important that both the prescription and non-prescription organic MR-8 lenses tested have no transmittance below approximately 398nm. This means that this lens material protects against UVA and UVB rays, even though it is uncoated. It is also important to reduce the dose to the lens, which is a radiosensitive tissue. In the study, the mass absorption coefficients of MR-8 and Ormix lens materials in the 0.15-2.00 MeV energy range were calculated using the web-based XCOM programme. LAC, HVL, TVL, MFP, RPE and TF values were calculated from the MAC values obtained. At energies below 0.05 MeV, the maximum MAC value was 0.974 and 4.416 for the MR-8 and Ormix lenses, respectively. The RPE and TF values were 0.807-16.235%, 0.996-0.992% for the MR-8 lens and 0.862-55.233%, 0.448-0.991% for the Ormix lens. The results showed that the photon absorption ability of the Ormix lens is relatively better in the region where the photoelectric interaction is dominant. This research is also important in terms of determining the optical and nuclear radiation parameters of the material used in the manufacture of high index lenses and investigating its effectiveness in reducing the dose to the eyepiece.

Feasibility study for the evaluation of doses received by organs during medical exposure for pediatric patient undergoing CT scan and estimation of the potential risk of radiation-induced cancers

Computed Tomography (CT) continues to contribute a significant portion of the total collective dose delivered to the public from medical procedures involving ionizing radiation. Children are considered to be at higher risk of developing radiation induced cancer due to the young age of exposure and increased tissue radio sensitivity. Organ dose estimation is essential for pediatric patient cancer risk assessment. The aim of this study was to evaluate the excess risk of radiation induced cancer following exposure to low-dose ionizing radiation from pediatric CT scans.We collected information from Radiation Dose Structured Report (RDSR) in 2 radiology department for 3 protocols and three (3) different age group in pediatric CT scan.We estimated the excess of cancer risk by using the Radiation Risk Assessment Tool RadRAT). For that, we calculate first the organ doses with National Cancer Institute for CT (NCICT). Effective dose and Size Specific Dose Estimate were also estimated, CTDI and DLP recorded from the RDSR were compared by the ones given by the software. The doses received by 30 organs including both inside and outside the scanning range were calculated and compared for the different age groups and protocols.The excess risk observed here range between 0.6 and 10.1‰ for respectively the thorax and Abdomen protocol in boy's cohort. This can be due to the significant dose variability observed among radiological protocols defined for the same CT scan and patient of the same age. For a head examination, a ratio of 2–4, depending on the age of the child, is estimated between the maximum and minimum doses delivered to the brain. For the other types of examination, this ratio is even greater: around 9 for chest examinations, 16 for abdominopelvic explorations.Careful justification of pediatric CT scans and dose optimization should be available in hospitals to minimize risks.

Eye radiation dose from breast cancer screening using full field digital mammography and digital breast tomosynthesis: A phantom study

IntroductionThe eye lens is recently classified as one of the most radiosensitive tissues by the International Commission on Radiological Protection (ICRP), and it has been suggested that the eye lens receives radiation dose during mammography due to scatter radiation. The aim of this study was to investigate the radiation dose received by the lens of the clients’ eye from Full Field Digital Mammography (FFDM) and Digital Breast Tomosynthesis (DBT) screening. MethodsThe eye radiation dose received by ATOM dosimetry phantom was estimated with thermo-luminescent dosemeters (TLDs). One TLD was utilised for each eye. A breast phantom was exposed for four-view screening mammography using 16 FFDM machines and one DBT machine. The breast phantom was exposed three times for each mammographic position and an average TLD dose reading was considered to minimise random error. ResultsFor four-view FFDM screening, the phantom eye radiation dose ranges from 0.013 mGy to 0.029 mGy with a mean±sd of 0.019 ± 0.005 mGy. A higher eye radiation dose of 0.041 mGy was recorded from four-view DBT screening. The statistical analysis demonstrated that the eye lens radiation dose is strongly and significantly correlated to breast organ dose and X-ray tube voltage. ConclusionThe phantom eye lens was exposed to scatter radiation from FFDM and DBT screening. The measured dose via the four-view DBT screening was higher than the four-view FFDM screening, but sits below the internationally acceptable ranges. If the findings of our paper hold true in practice, then the risk to the lens of the eyes for women attending breast screening is acceptable. Implications for practiceThe new lens radiation dose levels recommended by the ICRP necessitate the reevaluation of eye radiation dose from different radiographic examinations, especially those used for screening purpose where healthy individuals involved.