-
Advances in Radiation Oncology Jul 2024For lung stereotactic body radiation therapy, 4-dimensional computed tomography is often used to delineate target volumes, whereas organs at risk (OARs) are typically...
PURPOSE
For lung stereotactic body radiation therapy, 4-dimensional computed tomography is often used to delineate target volumes, whereas organs at risk (OARs) are typically outlined on either average intensity projection (AIP) or midventilation (MidV = 30% phase) images. AIP has been widely adopted as it represents a true average, but image blurring often precludes accurate contouring of critical structures such as central airways. Here, we compare AIP versus MidV planning for centrally located tumors via respiratory motion-inclusive (RMI) plans to better evaluate dose delivered throughout the breathing cycle.
METHODS AND MATERIALS
Independently contoured and optimized AIP and MidV plans were created for 16 treatments and rigidly copied to each of the 10 breathing phase-specific computed tomography image sets. Resulting dose distributions were deformably registered back to the MidV image set (used as reference because of clearer depiction of anatomy compared with motion-blurred AIP) and averaged to create RMI plans. Doses to central OARs were compared between plans.
RESULTS
Mean absolute dose differences were low for all comparisons (range, 0.01-2.87 Gy); however, individual plans exhibited differences >20 Gy. Dose differences >5 Gy were observed most often for plan comparisons involving AIP-based plans (MidV vs AIP 23, AIP RMI vs AIP 12, MidV RMI vs AIP RMI 7, and MidV RMI vs MidV 8 times). Inclusion of respiratory motion reduced large dose differences. Standard OAR thresholds were exceeded up to 5 times for each plan comparison scenario and always involved proximal bronchial tree D4 cc tolerance dose. AIP-based contours were larger by, on average, 3% to 15%.
CONCLUSIONS
Large dose differences were observed when plans with AIP-based contours were compared with MidV-based contours, indicating that observed dose differences were likely due to contoured volume differences rather than the effect of motion. Because of blurring with AIP images, MidV RMI-based planning may offer a more accurate method to determine dose to critical OARs in the presence of respiratory motion.
PubMed: 38948918
DOI: 10.1016/j.adro.2024.101525 -
Journal of Cancer 2024Current radiotherapy regimens for glioblastoma (GBM) have limited efficacy and fails to eradicate tumors. Regenerative medicine brings hope for repairing damaged...
Current radiotherapy regimens for glioblastoma (GBM) have limited efficacy and fails to eradicate tumors. Regenerative medicine brings hope for repairing damaged tissue, opening opportunities for elevating the maximum acceptable radiation dose. In this study, we explored the effect of ultra-high dose fractionated radiation on tumor responses and brain injury in immunocompetent mice which can better mimic the tumor-host interactions observed in patients. We also evaluated the role of the hypoxia-inducible factor-1 alpha under radiation as potential target for combating radiation-induced brain injury. : Naïve and Hif-1α heterozygous mice received a fractionated daily dose of 20 Gy for three or five consecutive days. Magnetic resonance imaging (MRI) and histology were performed to assess brain injury post-radiation. The 2×10 human GBM1 luciferase-expressing cells were transplanted with tolerance induction protocol. Fractionated radiotherapy was performed during the exponential phase of tumor growth. Bioluminescence imaging, MRI, and immunohistochemistry staining were performed to evaluate tumor growth dynamics and radiotherapy responses. Additionally, animal lifespan was recorded. : Fractionated radiation of 5×20 Gy induced severe brain damage, starting 3 weeks after radiation. All animals from this group died within 12 weeks. In contrast, later onset and less severe brain injury were observed starting 12 weeks after radiation of 3×20 Gy. It resulted in complete GBM eradication and survival of all treated animals. Furthermore, Hif-1α mice exhibited more severe vascular damage after fractionated radiation of 3×20 Gy. : Ultra-high dose fractionated 3×20 Gy radiation has the potential to fully eradicate GBM cells at the cost of only mild brain injury. The Hif-1α gene is a promising target for ameliorating vascular impairment post-radiation, encouraging the implementation of neurorestorative strategies.
PubMed: 38947383
DOI: 10.7150/jca.95148 -
Science Bulletin May 2024During the past 3000 years, cattle on the Qinghai-Xizang Plateau have developed adaptive phenotypes under the selective pressure of hypoxia, ultraviolet (UV) radiation,...
During the past 3000 years, cattle on the Qinghai-Xizang Plateau have developed adaptive phenotypes under the selective pressure of hypoxia, ultraviolet (UV) radiation, and extreme cold. The genetic mechanism underlying this rapid adaptation is not yet well understood. Here, we present whole-genome resequencing data for 258 cattle from 32 cattle breeds/populations, including 89 Tibetan cattle representing eight populations distributed at altitudes ranging from 3400 m to 4300 m. Our genomic analysis revealed that Tibetan cattle exhibited a continuous phylogeographic cline from the East Asian taurine to the South Asian indicine ancestries. We found that recently selected genes in Tibetan cattle were related to body size (HMGA2 and NCAPG) and energy expenditure (DUOXA2). We identified signals of sympatric introgression from yak into Tibetan cattle at different altitudes, covering 0.64%-3.26% of their genomes, which included introgressed genes responsible for hypoxia response (EGLN1), cold adaptation (LRP11), DNA damage repair (LATS1), and UV radiation resistance (GNPAT). We observed that introgressed yak alleles were associated with noncoding variants, including those in present EGLN1. In Tibetan cattle, three yak introgressed SNPs in the EGLN1 promoter region reduced the expression of EGLN1, suggesting that these genomic variants enhance hypoxia tolerance. Taken together, our results indicated complex adaptation processes in Tibetan cattle, where recently selected genes and introgressed yak alleles jointly facilitated rapid adaptation to high-altitude environments.
PubMed: 38945748
DOI: 10.1016/j.scib.2024.05.030 -
Cureus May 2024Primary central nervous system (CNS) lymphoma is a rare and aggressive form of extranodal non-Hodgkin's lymphoma, limited to the brain, eyes, spinal cord, or...
Primary central nervous system (CNS) lymphoma is a rare and aggressive form of extranodal non-Hodgkin's lymphoma, limited to the brain, eyes, spinal cord, or leptomeninges without systemic involvement. This group of malignant tumors is characterized by a particular diagnostic, therapeutic, and evolutionary profile compared to other types of non-Hodgkin's lymphomas. We report a case of a young patient treated in our university hospital center for primary cerebral lymphoma who benefited from primary chemotherapy and then consolidation radiotherapy with good disease control and good tolerance.
PubMed: 38939239
DOI: 10.7759/cureus.61219 -
Vaccines Jun 2024Therapeutic modified mRNAs are being developed for a broad range of human diseases. However, the impact of potential miscoding of modified mRNAs on self-tolerance...
Therapeutic modified mRNAs are being developed for a broad range of human diseases. However, the impact of potential miscoding of modified mRNAs on self-tolerance remains unknown. Additionally, more studies are needed to explore the effects of nucleoside alkylation on translation. While all six tested modifications are tolerated as substrates by T7 RNA polymerase and inhibited mRNA immunogenicity, the translation efficiency varied significantly depending on the type of modification. In contrast to methylation, ethylation at the N1 position of pseudouridine (Ψ) hindered translation, suggesting that the C5-C1' glycosidic bond alone is not a critical element for high translation. Inhibition of mRNA translation was also observed with 5-methoxyuridine modification. However, this inhibition was partially alleviated through the optimization of mRNA coding sequences. BALB/c mice immunized with syngeneic ψ-modified mRNA encoding for Wilms' tumor antigen-1 (WT1) developed a low but significant level of anti-WT1 IgG antibodies compared to those immunized with either unmodified or N1-methyl ψ-modified mRNA. Overall, the data indicate that adding a simple ethyl group (-CHCH) at the N1 position of ψ has a major negative effect on translation despite its reduced immunogenicity. Additionally, mRNA containing Ψ may alter translation fidelity at certain codons, which could lead to a breakdown of immune tolerance to self-antigens. This concern should be taken into account during gene replacement therapies, although it could benefit mRNA-based vaccines by generating a diverse repertoire of antigens.
PubMed: 38932353
DOI: 10.3390/vaccines12060624 -
International Journal of Molecular... Jun 2024Application of laser-generated electron beams in radiotherapy is a recent development. Accordingly, mechanisms of biological response to radiation damage need to be...
Application of laser-generated electron beams in radiotherapy is a recent development. Accordingly, mechanisms of biological response to radiation damage need to be investigated. In this study, telomere length (TL) as endpoint of genetic damage was analyzed in human blood cells (leukocytes) and K562 leukemic cells irradiated with laser-generated ultrashort electron beam. Metaphases and interphases were analyzed in quantitative fluorescence in situ hybridization (Q-FISH) to assess TL. TLs were shortened compared to non-irradiated controls in both settings (metaphase and interphase) after irradiation with 0.5, 1.5, and 3.0 Gy in blood leukocytes. Radiation also caused a significant TL shortening detectable in the interphase of K562 cells. Overall, a negative correlation between TL and radiation doses was observed in normal and leukemic cells in a dose-dependent manner. K562 cells were more sensitive than normal blood cells to increasing doses of ultrashort electron beam radiation. As telomere shortening leads to genome instability and cell death, the results obtained confirm the suitability of this biomarker for assessing genotoxic effects of accelerated electrons for their further use in radiation therapy. Observed differences in TL shortening between normal and K562 cells provide an opportunity for further development of optimal radiation parameters to reduce side effects in normal cells during radiotherapy.
Topics: Humans; K562 Cells; Leukocytes; Electrons; Telomere; Leukemia; Telomere Homeostasis; In Situ Hybridization, Fluorescence; Telomere Shortening; DNA Damage; Dose-Response Relationship, Radiation
PubMed: 38928414
DOI: 10.3390/ijms25126709 -
Radiation Oncology (London, England) Jun 2024At present, it has been found that many patients have acquired resistance to radiotherapy, which greatly reduces the effect of radiotherapy and further affects the...
BACKGROUND
At present, it has been found that many patients have acquired resistance to radiotherapy, which greatly reduces the effect of radiotherapy and further affects the prognosis. CircRNAs is involved in the regulation of radiosensitivity of many kinds of tumor cells. Therefore, the main purpose of this study is to explore the regulatory effect of CircRNA_101491 on radiosensitivity of ESCC and its related mechanism.
METHODS
We established ESCC radiation-resistant cell line (KYSE150R cell) by gradient dose method, and tested the difference of KYSE150 between KYSE150R cell and parent cell in vitro. Then, after knocking down the expression of CircRNA_101491, a series of in vitro experiments were conducted to verify the effects of CircRNA_101491 on the phenotype and radiosensitivity of KYSE150R cells, and further analyzed the related regulatory mechanism. In addition, we also used the model of transplanted tumor in nude mice to investigate the effect of CircRNA_101491 on the radiosensitivity of ESCC in vivo.
RESULTS
According to a series of in vitro experiments, we confirmed that KYSE150R cells lost the epithelial phenotype and obtained interstitial cell-like phenotype, and found that CircRNA_101491 was highly expressed in KYSE150R cells. In addition, we found that knocking down the expression of CircRNA_101491 will lift the inhibition of miR-125a-5p, and then reverse the process of EMT, accelerate the process of apoptosis, thus play a role in radiosensitization. The in vivo experiment of transplanted tumor in nude mice also showed that knocking down the expression of CircRNA_101491 could enhance the radiosensitivity of ESCC.
CONCLUSION
In conclusion, we confirmed that interfering with the expression of CircRNA_101491 can relieve the inhibition of miR-125a-5p, thus reverse the process of interstitial phenotype, accelerate the process of apoptosis, and enhance the radiosensitivity of ESCC.
Topics: MicroRNAs; Radiation Tolerance; Animals; RNA, Circular; Humans; Mice; Esophageal Neoplasms; Mice, Nude; Esophageal Squamous Cell Carcinoma; Apoptosis; Cell Proliferation; Gene Expression Regulation, Neoplastic; Mice, Inbred BALB C; Cell Line, Tumor; Xenograft Model Antitumor Assays; Tumor Cells, Cultured
PubMed: 38926729
DOI: 10.1186/s13014-024-02478-7 -
Scientific Reports Jun 2024Ultra-high dose rate (UHDR) irradiation has been shown to have a sparing effect on healthy tissue, an effect known as 'FLASH'. This effect has been studied across...
Ultra-high dose rate (UHDR) irradiation has been shown to have a sparing effect on healthy tissue, an effect known as 'FLASH'. This effect has been studied across several radiation modalities, including photons, protons and clinical energy electrons, however, very little data is available for the effect of FLASH with Very High Energy Electrons (VHEE). pBR322 plasmid DNA was used as a biological model to measure DNA damage in response to Very High Energy Electron (VHEE) irradiation at conventional (0.08 Gy/s), intermediate (96 Gy/s) and ultra-high dose rates (UHDR, (2 × 10 Gy/s) at the CERN Linear Electron Accelerator (CLEAR) user facility. UHDRs were used to determine if the biological FLASH effect could be measured in the plasmid model, within a hydroxyl scavenging environment. Two different concentrations of the hydroxyl radical scavenger Tris were used in the plasmid environment to alter the proportions of indirect damage, and to replicate a cellular scavenging capacity. Indirect damage refers to the interaction of ionising radiation with molecules and species to generate reactive species which can then attack DNA. UHDR irradiated plasmid was shown to have significantly reduced amounts of damage in comparison to conventionally irradiated, where single strand breaks (SSBs) was used as the biological endpoint. This was the case for both hydroxyl scavenging capacities. A reduced electron energy within the VHEE range was also determined to increase the DNA damage to pBR322 plasmid. Results indicate that the pBR322 plasmid model can be successfully used to explore and test the effect of UHDR regimes on DNA damage. This is the first study to report FLASH sparing with VHEE, with induced damage to pBR322 plasmid DNA as the biological endpoint. UHDR irradiated plasmid had reduced amounts of DNA single-strand breaks (SSBs) in comparison with conventional dose rates. The magnitude of the FLASH sparing was a 27% reduction in SSB frequency in a 10 mM Tris environment and a 16% reduction in a 100 mM Tris environment.
Topics: Plasmids; DNA Damage; Electrons; Dose-Response Relationship, Radiation; Humans; Particle Accelerators; DNA Breaks, Single-Stranded
PubMed: 38926450
DOI: 10.1038/s41598-024-65055-8 -
Anticancer Research Jul 2024Pre-clinical studies have shown that irradiation with electrons at an ultra-high dose-rate (FLASH) spares normal tissue while maintaining tumor control. However, most in...
BACKGROUND/AIM
Pre-clinical studies have shown that irradiation with electrons at an ultra-high dose-rate (FLASH) spares normal tissue while maintaining tumor control. However, most in vitro experiments with protons have been conducted using a non-clinical irradiation system in normoxia alone. This study evaluated the biological response of non-tumor and tumor cells at different oxygen concentrations irradiated with ultra-high dose-rate protons using a clinical system and compared it with the conventional dose rate (CONV).
MATERIALS AND METHODS
Non-tumor cells (V79) and tumor cells (U-251 and A549) were irradiated with 230 MeV protons at a dose rate of >50 Gy/s or 0.1 Gy/s under normoxic or hypoxic (<2%) conditions. The surviving fraction was analyzed using a clonogenic cell survival assay.
RESULTS
No significant difference in the survival of non-tumor or tumor cells irradiated with FLASH was observed under normoxia or hypoxia compared to the CONV.
CONCLUSION
Proton irradiation at a dose rate above 40 Gy/s, the FLASH dose rate, did not induce a sparing effect on either non-tumor or tumor cells under the conditions examined. Further studies are required on the influence of various factors on cell survival after FLASH irradiation.
Topics: Humans; Cell Survival; Protons; Proton Therapy; Dose-Response Relationship, Radiation; Cell Hypoxia; Animals; Cell Line, Tumor; Cricetulus; A549 Cells; Oxygen
PubMed: 38925851
DOI: 10.21873/anticanres.17109 -
Anticancer Research Jul 2024The aim of this study was to develop an enhanced intestinal toxicity assay with three outputs assessing proliferation, villi morphology and DNA damage after irradiation.
BACKGROUND/AIM
The aim of this study was to develop an enhanced intestinal toxicity assay with three outputs assessing proliferation, villi morphology and DNA damage after irradiation.
MATERIALS AND METHODS
Whole 5 cm jejunal lengths were collected from mice following total body x-ray irradiation (0-15 Gy) at 0-84 h. Tissues were wrapped into swirls for cryopreservation and immunohistochemically stained for EdU, CD31, and γH2AX. A semi-automated image analysis was developed for the proliferation, villi morphology, and DNA damage models.
RESULTS
Proliferation assessed via EdU staining varied with cycles of damage repair, hyperproliferation, and homeostasis after radiation, with the time to onset of each cycle variable based on radiation dose. An analysis model evaluating the amount of proliferation per unit length of jejunum analyzed was developed, with a dose-response curve identified at 48 h post treatment. The villi length model measured the length of intact and healthy CD31-stained capillary beds between the crypts and villi tips at 3.5 days post treatment within a 0-10 Gy dose range. The DNA damage model evaluated the intensity of γH2AX staining within cellular nuclei, with a useful dose-response identified at 1 h post-radiation treatment.
CONCLUSION
This assay demonstrates flexibility for assessing radiation-induced damage, with analysis of proliferation, villi length, or direct DNA damage achievable at defined time points and within useful radiation dose curves. The software-assisted image analysis allows for rapid, comprehensive, and objective data generation with an assay turnover time of days instead of weeks on samples that are representative of most of the treated jejunum.
Topics: Animals; Mice; Cell Proliferation; DNA Damage; Jejunum; Radiation Tolerance; Intestinal Mucosa; Intestines; Whole-Body Irradiation; Dose-Response Relationship, Radiation; Histones; Male; Mice, Inbred C57BL
PubMed: 38925821
DOI: 10.21873/anticanres.17091