Increased Radiation Resistance Research Articles

The effect of particles size of Gd2O3 on the radiation protection mechanisms of ZnO

There are two mechanisms established for increasing the radiation resistance of optical properties of micron-sized zinc oxide (mZnO) powder modified by gadolinium oxide (nGd2O3) nanoparticles by means of relaxation of the primary radiation defects (electrons and holes): — in atoms of rare-earth element gadolinium; — on Gd2O3 nanoparticles. During modification with gadolinium oxide micron-sized particles, only one (first) mechanism for radiation resistance increasing is enabled. These results are obtained by recording diffuse reflectance spectra in high vacuum in the range of 0.2–2.5 μm under radiation exposure by accelerated electrons (in situ). The established mechanisms for increasing radiation resistance refer not only to the types of powders under the study, but also to other types of oxide semiconductor powders and rare-earth elements. These mechanisms can also be extended to the photo résistance of oxide powders modified by nanoparticles and solid solutions based on them.

Complex dislocation loop networks as natural extensions of the sink efficiency of saturated grain boundaries in irradiated metals.

The development of radiation-tolerant structural materials is an essential element for the success of advanced nuclear energy concepts. A proven strategy to increase radiation resistance is to create microstructures with a high density of internal defect sinks, such as grain boundaries (GBs). However, as GBs absorb defects, they undergo internal transformations that limit their ability to capture defects indefinitely. Here, we show that, as the sink efficiency of GBs becomes exhausted with increasing irradiation dose, networks of irradiation loops form in the vicinity of saturated or near-saturated GB, maintaining and even increasing their capacity to continue absorbing defects. The formation of these networks fundamentally changes the driving force for defect absorption at GB, from "chemical" to "elastic." Using thermally-activated dislocation dynamics simulations, we show that these networks are consistent with experimental measurements of defect densities near GB. Our results point to these networks as a natural continuation of the GB once they exhaust their internal defect absorption capacity.

Th2 Cells Are Associated with Tumor Recurrence Following Radiation.

The curative treatment of multiple solid tumors, including head and neck squamous cell carcinoma (HNSCC), utilizes radiation. The outcomes for HPV/p16-negative HNSCC are significantly worse than HPV/p16-positive tumors, with increased radiation resistance leading to worse locoregional recurrence (LRR) and ultimately death. This study analyzed the relationship between immune function and outcomes following radiation in HPV/p16-negative tumors to identify mechanisms of radiation resistance and prognostic immune biomarkers. A discovery cohort of 94 patients with HNSCC treated uniformly with surgery and adjuvant radiation and a validation cohort of 97 similarly treated patients were utilized. Tumor immune infiltrates were derived from RNAseq gene expression. The immune cell types significantly associated with outcomes in the discovery cohort were examined in the independent validation cohort. A positive association between high Th2 infiltration and LRR was identified in the discovery cohort and validated in the validation cohort. Tumor mutations in CREBBP/EP300 and CASP8 were significantly associated with Th2 infiltration. A pathway analysis of genes correlated with Th2 cells revealed the potential repression of the antitumor immune response and the activation of BRCA1-associated DNA damage repair in multiple cohorts. The Th2 infiltrates were enriched in the HPV/p16-negative HNSCC tumors and associated with LRR and mutations in CASP8, CREBBP/EP300, and pathways previously shown to impact the response to radiation.

Germline specific genes increase DNA double-strand break repair and radioresistance in lung adenocarcinoma cells

In principle, germline cells possess the capability to transmit a nearly unaltered set of genetic material to infinite future generations, whereas somatic cells are limited by strict growth constraints necessary to assure an organism’s physical structure and eventual mortality. As the potential to replicate indefinitely is a key feature of cancer, we hypothesized that the activation of a “germline program” in somatic cells can contribute to oncogenesis. Our group recently described over one thousand germline specific genes that can be ectopically expressed in cancer, yet how germline specific processes contribute to the malignant properties of cancer is poorly understood. We here show that the expression of germ cell/cancer (GC) genes correlates with malignancy in lung adenocarcinoma (LUAD). We found that LUAD cells expressing more GC genes can repair DNA double strand breaks more rapidly, show higher rates of proliferation and are more resistant to ionizing radiation, compared to LUAD cells that express fewer GC genes. In particular, we identified the HORMA domain protein regulator TRIP13 to be predominantly responsible for this malignant phenotype, and that TRIP13 inhibition or expression levels affect the response to ionizing radiation and subsequent DNA repair. Our results demonstrate that GC genes are viable targets in oncology, as they induce increased radiation resistance and increased propagation in cancer cells. Because their expression is normally restricted to germline cells, we anticipate that GC gene directed therapeutic options will effectively target cancer, with limited side effects besides (temporary) infertility.

The effect of secondary phases on microstructure and irradiation damage in an as-built additively manufactured 316 L stainless steel with a hafnium compositional gradient

Additive manufacturing (AM) or rapid prototyping has become a crucial tool for reducing both cost and time while increasing efficiency in qualifying structural materials for reactor use. In this study, directed energy deposition (DED) was used to develop an as-built 316 L stainless steel sample with three regions of increasing Hf-dopant to study the effects of Hf on the irradiation response of the material. Morphological and microstructural changes were analyzed before and after 2 MeV proton irradiation at 360 °C to a damage of 2.5 dpa at ∼ 10 µm below the surface. The addition of Hf effectively suppressed radiation-induced damage (dislocation loops, radiation-induced segregation) due to enhanced point defect recombination. The radiation damage seen in the as-built sample was further compared to a thermo-mechanically treated counterpart of the same fabrication and irradiation parameters which was found to behave superiorly. The increased radiation resistance of this material may be attributed to the as-built microstructure, which includes undissolved Hf particles, delta ferrite grains and cellular sub-grain boundaries that can hinder defect motion.

Neuromedin U contributes to radiation resistance in colorectal cancer via YAP/TAZ signaling activation.

Resistance to radiation therapy remains a treatment obstacle for patients with high‑risk colorectal cancer. Neuromedin U (NMU) has been identified as a potential predictor of the response to radiation therapy by RNA sequencing analysis of colorectal cancer tissues obtained from patients. However, the role of NMU in colorectal cancer remains unknown. In order to investigate role of NMU in colorectal cancer, NMU expression was regulated using small interfering RNA or an NMU‑expression pCMV3 vector, and cell counting, wound‑healing and clonogenic assays were subsequently performed. NMU knockdown decreased colorectal cancer cell proliferation and migration, and sensitized the cells to radiation. Conversely, NMU overexpression increased radiation resistance, proliferation and migration of colorectal cancer cells. Furthermore, by western blotting and nuclear fractionation experiments, NMU knockdown inhibited the nuclear translocation of yes‑associated protein (YAP) and transcriptional co‑activator with PDZ‑binding motif (TAZ), resulting from the phosphorylation of these proteins. By contrast, the nuclear translocation of YAP and TAZ was increased following NMU overexpression in colorectal cancer cells. Recombinant NMU regulated YAP and TAZ activity, and the expression of the YAP and TAZ transcriptional target genes AXL, connective tissue growth factor and cysteine‑rich angiogenic inducer 61 in an NMU receptor 1 activity‑dependent manner. These results suggested that NMU may contribute to the acquisition of radioresistance in colorectal cancer by enhancing the Hippo signaling pathway via YAP and TAZ activation.

Long noncoding RNA BBOX1-AS1 increased radiotherapy sensitivity in colorectal cancer by stabilizing and activating PFK1

PurposeOur study explored the effect of long noncoding RNA BBOX1-AS1 on colorectal cancer (CRC) radiosensitivity in vivo and in vitro. MethodsDifferentially expressed lncRNAs in CRC were screened using a bioinformatics database and an online prediction website. The expression of BBOX1-AS1 in tissue samples was analyzed via real-time quantitative PCR (RT-qPCR). Subcellular localization of BBOX1-AS1 in CRC cells was analyzed using fluorescence in situ hybridization (FISH). The correlation between BBOX1-AS1 and PFK1 expression levels in CRC tissues was analyzed via Pearson's correlation coefficient. The effect of BBOX1-AS1 on PFK1 stability was investigated using RNA and protein stability testing. RNA Binding Protein Immunoprecipitation (RIP) and RNA pull-down assays were used to confirm the binding of BBOX1-AS1 to PFK1. ResultsBBOX1-AS1 was highly expressed in CRC and associated with poor prognosis. Similarly, it was highly expressed in CRC tissues and CRC cell lines. In addition, BBOX1-AS1 promoted the proliferation, invasion, migration, and glycolysis of CRC cells and inhibited apoptosis. RIP and RNA pull-down experiments confirmed that BBOX1-AS1 bound to PFK1. RNA stability and protein stability experiments showed that BBOX1-AS1 affected the stability of PFK1 mRNA and protein. Furthermore, we confirmed that BBOX1-AS1 increased radiation resistance through the regulation of PFK1 expression. ConclusionsBBOX1-AS1 promoted the proliferation, invasion, migration, and glycolysis of CRC cells through stabilization of the expression of PFK1. BBOX1-AS1 also inhibited CRC cell apoptosis and increased radiotherapy resistance in CRC cells.

Investigating ionizing radiation-induced changes in breast cancer cells using stimulated Raman scattering microscopy.

Altered lipid metabolism of cancer cells has been implicated in increased radiation resistance. A better understanding of this phenomenon may lead to improved radiation treatment planning. Stimulated Raman scattering (SRS) microscopy enables label-free and quantitative imaging of cellular lipids but has never been applied in this domain. We sought to investigate the radiobiological response in human breast cancer MCF7 cells using SRS microscopy, focusing on how radiation affects lipid droplet (LD) distribution and cellular morphology. MCF7 breast cancer cells were exposed to either 0 or 30Gy (X-ray) ionizing radiation and imaged using a spectrally focused SRS microscope every 24hrs over a 72-hr time period. Images were analyzed to quantify changes in LD area per cell, lipid and protein content per cell, and cellular morphology. Cell viability and confluency were measured using a live cell imaging system while radiation-induced lipid peroxidation was assessed using BODIPY C11 staining and flow cytometry. The LD area per cell and total lipid and protein intensities per cell were found to increase significantly for irradiated cells compared to control cells from 48 to 72hrs post irradiation. Increased cell size, vacuole formation, and multinucleation were observed as well. No significant cell death was observed due to irradiation, but lipid peroxidation was found to be greater in the irradiated cells than control cells at 72hrs. This pilot study demonstrates the potential of SRS imaging for investigating ionizing radiation-induced changes in cancer cells without the use of fluorescent labels.

ERCC1 Overexpression Increases Radioresistance in Colorectal Cancer Cells.

Simple SummaryThe 20–30% of locally advanced rectal cancer patients undergoing preoperative concurrent chemoradiotherapy had no expected efficacy, and ERCC1 overexpression was found in these tumor tissue patients. In the interest of confirming and adding details to our understanding of that correlation, The Tet-on gene expression system was used to examine ERCC1 functionality and stability. Our data from regulatable HCT116-Tet-on and COLO205-Tet-on cell lines verified the increased radioresistance in colorectal cancer cells that are associated with ERCC1 overexpression, and they confirmed a high correlation between ERCC1 levels and radiotherapeutic efficiency. Furthermore, overexpression of ERCC1 also increases cell migration under radiation exposure. Additional data from ERCC1 expression regulation in vivo confirmed that the overexpression of increased cancer radiation resistance suggests that ERCC1 expression plays a key role.Preoperative concurrent chemoradiotherapy (CCRT) is a standard treatment for locally advanced rectal cancer patients, but 20–30% do not benefit from the desired therapeutic effects. Previous reports indicate that high levels of ERCC1 reduce the effectiveness of cisplatin-based CCRT; however, it remains unclear as to whether ERCC1 overexpression increases radiation resistance. To clarify the correlation between ERCC1 levels and radiation (RT) resistance, we established two cell lines (HCT116-Tet-on and COLO205-Tet-on), induced them to overexpress ERCC1, detected cell survival following exposure to radiation, established HCT116-Tet-on and COLO205-Tet-on heterotopic cancer animal models, and detected tumor volume following exposure to radiation. We found that ERCC1 overexpression increased radiation resistance. After regulating ERCC1 levels and radiation exposure to verify the correlation, we noted that increased radiation resistance was dependent on ERCC1 upregulation in both cell lines. For further verification, we exposed HCT116-Tet-on and COLO205-Tet-on heterotopic cancer animal models to radiation and observed that ERCC1 overexpression increased colorectal cancer tumor radioresistance in both. Combined, our results suggest that ERCC1 overexpression may serve as a suitable CCRT prognostic marker for colorectal cancer patients.

Targeting AKT-Dependent Regulation of Antioxidant Defense Sensitizes AKT-E17K Expressing Cancer Cells to Ionizing Radiation.

Aberrant activation of the phosphatidyl-inositol-3-kinase/protein kinase B (AKT) pathway has clinical relevance to radiation resistance, but the underlying mechanisms are incompletely understood. Protection against reactive oxygen species (ROS) plays an emerging role in the regulation of cell survival upon irradiation. AKT-dependent signaling participates in the regulation of cellular antioxidant defense. Here, we were interested to explore a yet unknown role of aberrant activation of AKT in regulating antioxidant defense in response to IR and associated radiation resistance.We combined genetic and pharmacologic approaches to study how aberrant activation of AKT impacts cell metabolism, antioxidant defense, and radiosensitivity. Therefore, we used TRAMPC1 (TrC1) prostate cancer cells overexpressing the clinically relevant AKT-variant AKT-E17K with increased AKT activity or wildtype AKT (AKT-WT) and analyzed the consequences of direct AKT inhibition (MK2206) and inhibition of AKT-dependent metabolic enzymes on the levels of cellular ROS, antioxidant capacity, metabolic state, short-term and long-term survival without and with irradiation.TrC1 cells expressing the clinically relevant AKT1-E17K variant were characterized by improved antioxidant defense compared to TrC1 AKT-WT cells and this was associated with increased radiation resistance. The underlying mechanisms involved AKT-dependent direct and indirect regulation of cellular levels of reduced glutathione (GSH). Pharmacologic inhibition of specific AKT-dependent metabolic enzymes supporting defense against oxidative stress, e.g., inhibition of glutathione synthase and glutathione reductase, improved eradication of clonogenic tumor cells, particularly of TrC1 cells overexpressing AKT-E17K.We conclude that improved capacity of TrC1 AKT-E17K cells to balance antioxidant defense with provision of energy and other metabolites upon irradiation compared to TrC1 AKT-WT cells contributes to their increased radiation resistance. Our findings on the importance of glutathione de novo synthesis and glutathione regeneration for radiation resistance of TrC1 AKT-E17K cells offer novel perspectives for improving radiosensitivity in cancer cells with aberrant AKT activity by combining IR with inhibitors targeting AKT-dependent regulation of GSH provision.

KLK5 is associated with the radioresistance, aggression, and progression of cervical cancer

ObjectiveThe role of kallikrein-related peptidase 5 (KLK5) has been studied in several diseases, including skin and ovarian cancers. However, its role in cervical cancer remains unclear, particularly in regulating the radiation resistance and growth of cervical cancer cells. Radiation resistance of cervical cancer is associated with local recurrence, distant metastasis, and reduced survival. MethodsWe first analyzed radiotherapy-naive samples and relevant clinical data from patients with cervical cancer who received radiotherapy without surgery or other antitumor treatment from 2014 to 2016. Subsequently, biopsied tissues, in vitro cells, and transplanted tumors in nude mice were investigated. ResultsGene sequencing and clinical data analysis showed that KLK5 overexpression was associated with a poor prognosis post-radiotherapy. In in vitro cell and tumor transplantation experiments, KLK5 overexpression significantly increased radiation resistance. However, downregulating KLK5 expression increased radiosensitivity. ConclusionOur results confirm that KLK5 is vital to the radioresistance of cervical cancer, and provide a new target and marker for the treatment of radioresistance in cervical cancer.

Полупроводниковые технологии для реализации радиационно-стойких СБИС

High values of photocurrents associated with instantaneous radiation can cause a transient voltage drop on the power buses, and some circuits are sensitive to currents generated in the element. This can lead to malfunctions ranging from temporary loss of functioning to data loss by memory and even to final damage to the product. The library elements are accessed at several levels of radiation, as for the design of elements, options for special simulation modeling and methods for creating topology. The article discusses the technologies of radiation-resistant ICS, their effectiveness on silicon-on-insulator structures, compared with a similar scheme on bulk silicon with the same design standards. Radiation-resistant semiconductor specialized devices with increased radiation resistance are also considered. Special attention is paid to the technology of implementation of radiation-resistant semiconductor storage devices. In relation to radiation-resistant logic devices, two directions are considered: the use of specialized logic circuits and user-programmable gate arrays.

Study of the Application Efficiency of Irradiation with Heavy Ions to Increase the Helium Swelling Resistance of BeO Ceramics

This paper considers the possibilities of increasing radiation resistance to helium swelling of beryllium oxide ceramics due to preliminary irradiation with heavy ions. Interest in this topic is due to the possibility of using these ceramics as materials for inert matrices of nuclear fuel and structural materials reflectors of high-temperature reactors. The samples studied were irradiated in two stages, namely irradiation with heavy Ar8+, Kr15+, and Xe22+ ions with a fluence of 1012 ion/cm2 and subsequent irradiation with He2+ ions with a fluence of 5x1017 ion/cm2. The main parameters used to compare and determine radiation modification efficiency were the crystal-structure swelling degree, a decrease in the hardness, and wear resistance of ceramics after irradiation with He2+ ions. During the studies carried out, it was found that preliminary irradiation with heavy Ar8+, Kr15+, and Xe22+ ions leads to a significant increase in radiation swelling resistance, as well as to an increase in crack resistance and wear resistance.

Photodarkening mechanisms of Pr3+ singly doped and Pr3+/Ce3+ co‐doped silicate glasses and fibers

AbstractIn this work, we revealed the possible mechanisms of the photodarkening in Pr3+ ions singly doped and Pr3+/Ce3+ co‐doped silicate glasses and fibers induced by X‐ray and 488‐nm laser radiations and studied the role of Ce3+ in increasing radiation resistance in Pr3+‐doped silicate glasses and fibers. The absorption, emission, electron paramagnetic resonance (EPR), radiation induced attenuation spectra, and X‐ray photoelectron spectroscopy (XPS) of Pr3+ singly doped and Pr3+/Ce3+ co‐doped silicate glasses before and after X‐ray radiation were measured and analyzed. The fluorescence intensity and photoinduced attenuation of Pr3+ singly doped and Pr3+/Ce3+ co‐doped silicate fibers at visible wavelengths pumped by 488‐nm laser were measured and analyzed. The influence of Ce3+ ions co‐doping on the spectroscopic properties of Pr3+ ions as well as the radiation‐induced defects in silicate glasses was studied. Results demonstrate that both X‐ray and 488‐nm laser radiations will induce photodamage in Pr3+ ions‐doped silicate glasses and fibers. Co‐doping Ce3+ (by up to 1 mol%) is efficient to suppress the darkening induced by both X‐ray and 488‐nm laser radiations without influence on the luminescence behavior of Pr3+ ions in silicate glasses and fibers. Our studies demonstrate the promising potential of Pr3+/Ce3+ co‐doped silicate glasses for visible lasing applications.

CBIO-24. NF2 LOSS-OF-FUNCTION COOPERATES WITH HYPOXIA TO DRIVE RADIATION RESISTANCE IN GRADE 2 MENINGIOMAS

Abstract World health organization grade 2 meningiomas (G2M) are associated with an aggressive natural history characterized by frequent recurrence, resistance to radiation therapy (RT), and poor survival. We and others have shown that intratumoral necrosis is an independent predictor of disease progression in G2Ms treated with RT, suggesting that necrosis is a histopathological biomarker of radiation resistance. However, the mechanisms of radiation resistance in G2M remain unclear and treatment of radioresistant G2M is challenging. We performed genetic sequencing and histopathological analysis of 121 G2Ms and found that NF2 mutations are associated with intratumoral necrosis. To further investigate the relationship between NF2 loss-of-function, necrosis, and radiation resistance, we developed an in vitro model system using the IOMM-Lee meningioma cell line. In clonogenic survival assays, we found that NF2 knockdown under normoxia had little to no effect on radiation resistance compared to control. However, in the setting of hypoxia, NF2 knockdown significantly increased radiation resistance by maintaining cellular proliferation without impacting cell death. To understand the molecular basis of NF2 loss-of-function on radiation resistance, we performed bulk RNA sequencing of cells in our in vitro hypoxia/RT model and 10 patient G2Ms (5 necrotic and 5 non-necrotic tumors). GO and KEGG pathway analysis of the in vitro dataset revealed that NF2 deficiency triggers upregulation of pathways involved in DNA damage repair and cellular proliferation. Integration of differentially expressed genes between the in vitro NF2 loss-of-function model and necrotic patient tumors identified shared upregulation of S100A4, which promotes cell cycle progression, and downregulation of WNK2, a cell proliferation inhibitor. Together, these results suggest NF2 loss-of-function in the setting of hypoxia confers radiation resistance through a transcriptional program that promotes proliferation and DNA repair.

Tensoelectrical Properties of Electron-Irradiated N-Si Single Crystals

Tensoresistance at uniaxial pressure for electron-irradiated n-Si single crystals at room temperature has been studied. Silicon single crystals for research were doped with phosphorus, concentration Nd=2.2·1016 cm-3, and irradiated by the electron flows of 5·1016 el./cm2, 1·1017 el./cm2 and 2·1017 el./cm2 with the energy of 12 MeV. Measurements of tensoresistance and Hall constant were performed for the uniaxially deformed n-Si single crystals along the crystallographic directions [100] and [111]. Mechanisms of tensoresistance for the investigated n-Si single crystals were established based on the measurements of the tenso-Hall effect and infrared Fourier spectroscopy. It is shown that the tensoresistance of such single crystals is determined only by changes in the electron mobility under the deformation. In this case, the electron concentration will not change under the action of uniaxial pressure, because the deep levels of radiation defects belonging to the VOi VOiP complexes will be completely ionized. Ionization of the deep level of EV+0.35 eV, which belongs to the defect of CiOi, under the deformation will not be manifested and will not be affect on the tensoresistance of n-Si. It is established that the anisotropy of electron scattering on the created radiation defects, which occurs at the uniaxial pressure along the crystallographic direction [100], is the cause of different values of the magnitude of tensoresistance of n‑Si single crystals, irradiated by different electron flows. For the case of tensoresistance of the uniaxially deformed n-Si single crystals along the crystallographic direction [111], the dependence of its magnitude on the electron irradiation flow is associated with changes in the screening radius due to an increase in the effective electron mass. For the first time obtained at room temperature the increase of the magnitude of tensoresistance for the n-Si single crystals due to their irradiation by the electron flows of Ω ≥1·1017 el./cm2 can be used in designing high uniaxial pressure sensors based on such n-Si single crystals with the higher value of tensosensitivity coefficient regarding available analogues. Such sensors will have increased radiation resistance and a wide scope of operation.

Optimal frequency for magnetic resonant wireless power transfer in conducting medium

In this article, we investigated the efficiency of a magnetic resonant wireless power transfer (MR-WPT) in conducting medium and found out an optimal frequency for designing the system. In conducting environment, the eddy current loss is generated by the high-frequency alternating currents in the coils. It is manifested by increased radiation resistance of resonator coil leads to decrease the quality factor (Q-factor), which reduces the wireless power transfer (WPT) efficiency in conducting medium. The Q-factor of the resonator coil strongly depending on the conductivity, frequency, and thickness of conducting block. Two MR-WPT systems operating at 10.0 MHz and 20.0 MHz are implemented to study the effect of conducting medium on efficiency. The achieved results indicated that the 20.0 MHz system has higher efficiency at a conductivity smaller than 6.0 S/m. However, at the larger conductivity, the 10.0 MHz system is more efficient. The results provide a method to determine the optimal frequency of a WPT system operating in the conducting medium with various conductivities and thickness blocks. This method can be used to design MR-WPT systems in numerous situations, such as autonomous underwater vehicles and medical implants.

Unraveling the Big Sleep: Molecular Aspects of Stem Cell Dormancy and Hibernation.

Tissue-resident stem cells may enter a dormant state, also known as quiescence, which allows them to withstand metabolic stress and unfavorable conditions. Similarly, hibernating mammals can also enter a state of dormancy used to evade hostile circumstances, such as food shortage and low ambient temperatures. In hibernation, the dormant state of the individual and its cells is commonly known as torpor, and is characterized by metabolic suppression in individual cells. Given that both conditions represent cell survival strategies, we here compare the molecular aspects of cellular quiescence, particularly of well-studied hematopoietic stem cells, and torpor at the cellular level. Critical processes of dormancy are reviewed, including the suppression of the cell cycle, changes in metabolic characteristics, and cellular mechanisms of dealing with damage. Key factors shared by hematopoietic stem cell quiescence and torpor include a reversible activation of factors inhibiting the cell cycle, a shift in metabolism from glucose to fatty acid oxidation, downregulation of mitochondrial activity, key changes in hypoxia-inducible factor one alpha (HIF-1α), mTOR, reversible protein phosphorylation and autophagy, and increased radiation resistance. This similarity is remarkable in view of the difference in cell populations, as stem cell quiescence regards proliferating cells, while torpor mainly involves terminally differentiated cells. A future perspective is provided how to advance our understanding of the crucial pathways that allow stem cells and hibernating animals to engage in their ‘great slumbers.’

Abstract 2426: SERPINB3 promotes radiation resistance in cervical cancer by inhibiting lysosome-mediated cell death

Abstract The purpose of this study was to determine if squamous cell carcinoma antigen (SCCA), also known as SERPINB3, protects cervical cancer cells from ionizing radiation (IR)-induced death, and to determine the mechanism(s) of IR-induced cell death with or without SERPINB3. Cervical cancer remains a leading cause of cancer death in women worldwide despite advances in screening, vaccination and treatment. Recurrence after definitive chemoradiation occurs in up to 30-50% of patients with locally advanced disease. We and others have demonstrated that elevated serum SCCA portends poor prognosis in cervical cancer. In addition, CRISPR-Cas9-mediated knock out of SERPINB3 significantly sensitizes cervical tumor cells to IR in vitro. We hypothesize that SERPINB3 promotes radioresistance by protecting cells against lysosome damage and lysosomal mediated necrosis. Two cervical cancer cell lines with high SERPINB3 expression were edited using CRISPR-Cas9 technology at the SERPINB3 locus resulting in knock out (KO). B3-KO cells were significantly more radiation sensitive compared to control cells at all doses and time points evaluated. Cell death morphology in the B3-KO cells was necrotic, with large cytoplasmic single membraned vesicles, many of which were ruptured, consistent with that seen in lysosome-mediated necrosis. Live-cell time-lapse imaging showed loss of lysosome integrity in the hours leading up to cell death (propidium iodide nuclear staining). Western blot analysis showed low levels of caspase-3 and caspase-7 cleavage only at high doses and late time points after IR, with no evidence of phospho-MLKL or phospo-RIPK3 (markers of necroptosis), or gasdermin-D cleavage (marker of pyroptosis). Necrostatin, ferrostatin, liproxstatin and YVAD-Cho had little to no effect on cell death following IR, while pan-caspase inhibitors decreased IR-induced cell death in both control and B3-KO cells, and E64D decreased IR-induced cell death in B3-KO cells to a greater degree than control cells. Additionally, cervical tumor cell lines that had no detectable expression of SERPINB3 were engineered to expressed high levels of SERPINB3 (B3-wt) or SERPINB3 containing the P14 mutation A351R (B3-P14m), which lacks protease inhibitory function. B3-wt expressing cells displayed increased radiation resistance in clonogenic survival assays and mouse tumor models. Growth rate and radiation response of B3-p14m expressing tumors was similar to vector control. These data suggest that SERPINB3 is an important mediator of radiation response in cervical cancer and protects cells by inhibiting cysteine protease-dependent cell death, likely via lysosome-mediated necrosis. These findings support SERPINB3 as a potential target for novel radiosensitizing therapies. Citation Format: Songyan Wang, Clifford Luke, Victoria Shi, Perry Grigsby, Gary Silverman, Stephanie Markovina. SERPINB3 promotes radiation resistance in cervical cancer by inhibiting lysosome-mediated cell death [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2426.

Influence of ion doping temperature on the distribution of dopant

In this paper, we analyze the redistribution of dopant and radiation defects during ion doping of materials at various values of temperature. We obtain that increasing of temperature of ion doping leads to increasing radiation resistance of the considered materials. At the same time depth of p–n-junctions, manufactured in the framework of the technological process, increases in this situation. We also introduce an analytical approach for the prognosis of mass and heat transfer, while taking into account the nonlinearity of these processes and at the same time the simultaneous changing of their parameters in space and time.