Mechanisms Of Radiation Resistance Research Articles

Food Polyphenols in Radiation-Related Diseases: The Roles and Possible Mechanisms.

As science and technology continue to evolve, the potential harm of radiation to the human body cannot be overlooked. Radiation has the capacity to inflict cellular and body-wide damage. Polyphenols are a group of naturally occurring compounds that are found in an array of plant foods. Scientific studies have demonstrated that these compounds possess noteworthy anti-radiation efficacy. Furthermore, they have been observed to be less toxic at higher doses. In the present review, we discussed the mechanisms of ionizing radiation damage and the progress in the research on the radiation resistance mechanism of polyphenol compounds, to provide guidance for the prevention and treatment of radiation related diseases. Food polyphenols can reduce the oxidative damage caused by ionizing radiation, clear free radicals, reduce DNA damage, regulate NF-KB, MAPK, JAK/STAT, Wnt and other signaling pathways, improve immune function, and have significant protective effects on radiation-induced inflammation, fibrosis, cancer and other aspects. In addition, it also has significant dual effects on radiation sensitization and radiation protection. Food polyphenols come from a wide range of sources, are abundant in daily food, and have no toxic side effects, demonstrating that food polyphenols have great advantages in preventing and treating radiation-related diseases.

Synonymous rpsH variants: the common denominator in Escherichia coli adapting to ionizing radiation.

Ionizing radiation (IR) in high doses is generally lethal to most organisms. Investigating mechanisms of radiation resistance is crucial for gaining insights into the underlying cellular responses and understanding the damaging effects of IR. In this study, we conducted a comprehensive analysis of sequencing data from an evolutionary experiment aimed at understanding the genetic adaptations to ionizing radiation in Escherichia coli. By including previously neglected synonymous mutations, we identified the rpsH c.294T > G variant, which emerged in all 17 examined isolates across four subpopulations. The identified variant is a synonymous mutation affecting the 30S ribosomal protein S8, and consistently exhibited high detection and low allele frequencies in all subpopulations. This variant, along with two additional rpsH variants, potentially influences translational control of the ribosomal spc operon. The early emergence and stability of these variants suggest their role in adapting to environmental stress, possibly contributing to radiation resistance. Our findings shed light on the dynamics of ribosomal variants during the evolutionary process and their potential role in stress adaptation, providing valuable implications for understanding clinical radiation sensitivity and improving radiotherapy.

Genomic Functional Analysis of Novel Radiation-Resistant Species of Knollia sp. nov. S7-12T from the North Slope of Mount Everest.

Radiation protection is an important field of study, as it relates to human health and environmental safety. Radiation-resistance mechanisms in extremophiles are a research hotspot, as this knowledge has great application value in bioremediation and development of anti-radiation drugs. Mount Everest, an extreme environment of high radiation exposure, harbors many bacterial strains resistant to radiation. However, owing to the difficulties in studying them because of the extreme terrain, many remain unexplored. In this study, a novel species (herein, S7-12T) was isolated from the moraine of Mount Everest, and its morphology and functional and genomic characteristics were analyzed. The strain S7-12T is white in color, smooth and rounded, non-spore-forming, and non-motile and can survive at a UV intensity of 1000 J/m2, showing that it is twice as resistant to radiation as Deinococcus radiodurans. Radiation-resistance genes, including IbpA and those from the rec and CspA gene families, were identified. The polyphasic taxonomic approach revealed that the strain S7-12T (=KCTC 59114T =GDMCC 1.3458T) is a new species of the genus Knoellia and is thus proposed to be named glaciei. The in-depth study of the genome of strain S7-12T will enable us to gain further insights into its potential use in radiation resistance. Understanding how microorganisms resist radiation damage could reveal potential biomarkers and therapeutic targets, leading to the discovery of potent anti-radiation compounds, thereby improving human resistance to the threat of radiation.

Insights into the radiation and oxidative stress mechanisms in genus Deinococcus

Deinococcus species, noted for their exceptional resistance to DNA-damaging environmental stresses, have piqued scientists' interest for decades. This study dives into the complex mechanisms underpinning radiation resistance in the Deinococcus genus. We have examined the genomes of 82 Deinococcus species and classified radiation-resistance proteins manually into five unique curated categories: DNA repair, oxidative stress defense, Ddr and Ppr proteins, regulatory proteins, and miscellaneous resistance components. This classification reveals important information about the various molecular mechanisms used by these extremophiles which have been less explored so far. We also investigated the presence or lack of these proteins in the context of phylogenetic relationships, core, and pan-genomes, which offered light on the evolutionary dynamics of radiation resistance. This comprehensive study provides a deeper understanding of the genetic underpinnings of radiation resistance in the Deinococcus genus, with potential implications for understanding similar mechanisms in other organisms using an interactomics approach. Finally, this study reveals the complexities of radiation resistance mechanisms, providing a comprehensive understanding of the genetic components that allow Deinococcus species to flourish under harsh environments. The findings add to our understanding of the larger spectrum of stress adaption techniques in bacteria and may have applications in sectors ranging from biotechnology to environmental research.

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.

Molecular dynamics simulations of interaction of cascade damage with self-interstitial atom-loaded grain boundaries in tungsten

In this study, we conducted systematic molecular dynamics simulations to investigate the radiation resistance of grain boundaries (GBs) in tungsten with/without self-interstitial atoms (SIAs) loaded on them. The simulation results show that the presence of SIAs can extend the width of the Σ3<110>{112} twin GB compared to the SIA-free GB. When cascade damage occurs near Σ3, the presence of SIAs at Σ3 enhances radiation resistance. Specifically, it inhibits producing residual defects, particularly vacancies and prevents their aggregating into clusters. The radiation-resistant performance is most excellent when the SIA concentration at Σ3 is approximately 5 %. The influence of temperature and primary knock-on atom energy on radiation damage is also discussed. However, SIA-loaded high angle GBs and low angle GBs do not significantly enhance their radiation-resistant performance compared to their SIA-free counterparts. This study provides valuable insights into the radiation damage behaviors near GBs and contributes to understanding their radiation-resistant mechanisms.

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.

RBIO-09. HMGB2 INHIBITION RADIO-SENSITIZES GLIOBLASTOMA CELLS INDEPENDENTLY OF THEIR TP53-MUTATION STATUS

Abstract Alterations in TP53 are major drivers of radiation resistance in gliomas. High Mobility Group Box 2 (HMGB2) has been implicated in resistance to temozolomide through p53-phosphorylation during DNA double-strand break repair and in silico analysis suggests its involvement in the p53-p21-RB signaling pathway. Nevertheless, the role of HMGB2 in radiation response has not been fully explored in gliomas. While HMGB2 is virtually not expressed in the normal adult brain, increasing expression with histopathological glioma grade correlates with poor patient survival. We confirmed increased HMGB2 expression in grade 3 compared to grade 2 gliomas using ClariomD and observed spatial heterogeneous HMGB2 expression in glioblastomas (GBMs) in histopathology-targeted supervised proteomic analysis employing liquid chromatography tandem mass spectroscopy (LC-MS-MS). Here, we aimed to study HMGB2 effects in cell proliferation and response to radiation in a set of molecularly distinct genetically engineered GBM cell lines (IDHwt). Using an established U87 GBM cell line and isogenic primary GBM cell lines GBM3359 TP53wt and CRISPR/Cas9-engineered mutant TP53 (R248W) generated in our laboratory, we successfully produced clones with either HMGB2 shRNA knockdown (KD – over 70% reduction) or HMGB2 lentiviral-mediated overexpression (OE – 3-76x higher expression). HMGB2-KD reduced cell proliferation (10% in U87; 20-25% in isogenic GBM3359 cell lines) and colony formation (more than 50% reduction), which was further rescued with HMGB2 OE in all cell lines. Half maximal inhibitory concentration (IC50) for radiation was determined by methylene blue cell proliferation and clonogenic assays, which showed that HMGB2-KD decreased the IC50 while rescued HMGB2 OE increased RT resistance of all clones. Taken together, our data suggest that HMGB2 inhibition may improve radiation response independently of TP53 status in gliomas. Further mechanistic studies to elucidate the relationship between HMGB2 and TP53 are underway to unfold the contribution of heightened HMGB2 expression to radiation resistance mechanisms in gliomas.

New Insights into Radio-Resistance Mechanism Revealed by (Phospho)Proteome Analysis of Deinococcus Radiodurans after Heavy Ion Irradiation.

Deinococcus radiodurans (D. radiodurans) can tolerate various extreme environments including radiation. Protein phosphorylation plays an important role in radiation resistance mechanisms; however, there is currently a lack of systematic research on this topic in D. radiodurans. Based on label-free (phospho)proteomics, we explored the dynamic changes of D. radiodurans under various doses of heavy ion irradiation and at different time points. In total, 2359 proteins and 1110 high-confidence phosphosites were identified, of which 66% and 23% showed significant changes, respectively, with the majority being upregulated. The upregulated proteins at different states (different doses or time points) were distinct, indicating that the radio-resistance mechanism is dose- and stage-dependent. The protein phosphorylation level has a much higher upregulation than protein abundance, suggesting phosphorylation is more sensitive to irradiation. There were four distinct dynamic changing patterns of phosphorylation, most of which were inconsistent with protein levels. Further analysis revealed that pathways related to RNA metabolism and antioxidation were activated after irradiation, indicating their importance in radiation response. We also screened some key hub phosphoproteins and radiation-responsive kinases for further study. Overall, this study provides a landscape of the radiation-induced dynamic change of protein expression and phosphorylation, which provides a basis for subsequent functional and applied studies.

High-dose radiation-resistant lung cancer cells stored many functional lipid drops through JAK2/p-STAT3/FASN pathway.

The understanding of radiation resistance is still unclear. This study aims to explore the new mechanism of radiation resistance in lung cancer from the perspective of lipid metabolism. Oil red O was used to detect the amount of lipid droplets in high-dose radiation-resistant lung cancer cells (HDRR-LCCs) and the primary lung cancer cells. Western blot analysis was used to determine the protein expression levels of key molecules related to de novo fatty acid synthesis and fatty acid transport. Orlistat was used to inhibit the de novo fatty acid synthesis. The prediction of the transcriptional regulators of fatty acid synthetase (FASN) was analyzed by bioinformatics. AZD-1480 was used to inhibit the JAK2/STAT3 pathway to observe its effects on FASN and intracellular lipid droplets. The regulation of the transcription factor p-STAT3 on the FASN gene was verified by Chip-qPCR. Finally, we used the public data of lung cancer patients to analyze the correlation between FASN and LPL gene expression with the prognosis. There were more lipid drops in the HDRR-LCCs than in the primary lung cancer cells. HDRR-LCCs preferred de novo synthesis of fatty acids, and high expression of LPL homodimers indicated a high intake of extracellular fatty acids. The expression of FASN was increased in HDRR-LCCs compared with the primary lung cancer cells in a radiation-dose-dependent way, while LPL homodimers did not show such a trend. The lipid droplets, cell proliferation, and radiation resistance were decreased in HDRR-LCCs after orlistat treatment. Lipid droplets were significantly reduced, and the protein expression of FASN also decreased when using AZD-1480 to inhibit the JAK2/STAT3 pathway. The Chip-qPCR showed that p-STAT3 was the upstream regulator which binds to the promoter region of FASN. Survival analysis showed that high expression of the FASN gene was associated with a poor prognosis in lung cancer patients who received radiotherapy. Our studies discovered that lipids deposited in HDRR-LCCs were due to endogenous de novo fatty acids synthesis and exogenous lipids uptake. JAK2/p-TAT3/FASN could be used as promising targets for radiotherapy sensitization. Our study provided a new theoretical basis for studying the mechanism of radiation resistance in lung cancer.

Primary radiation damage in tungsten-based high-entropy alloy: Interatomic potential and collision cascade simulations

Tungsten (W)-based high-entropy alloys (HEAs) have shown promising properties as nuclear fusion materials. Characterizing the primary damage is a critical step in describing and revealing the irradiation-induced damage and radiation resistance mechanism. However, there are a limited number of studies on collision cascades and primary radiation damage in W-based HEAs, owing to the large amount of calculations involved and a lack of appropriate interatomic interaction potentials. In this work, we developed a semi-empirical interatomic potential for W–Ta–Cr–V. By using the developed potential, molecular dynamics simulations of collision cascades in W-based HEAs were performed to assess the primary damage due to irradiation. Based on experimental samples, we reported defect production in W38Ta36Cr15V11 and compared it to pure W for primary knock-on atom with energies ranging from 1 keV to 100 keV. Our findings showed that the number of FPs at the thermal spike and the number of surviving FPs at the end of the cascade in W38Ta36Cr15V11 are more than those in pure W, mainly due to the lower threshold displacement energy, melting temperature, and formation energy of point defects. Collision cascades in the W38Ta36Cr15V11 are less likely to result in the formation of dislocation loops compared to pure W. After collision cascade, in W38Ta36Cr15V11, the concentrations of Cr and V atoms in defects is significantly higher than their corresponding concentrations in the system, showing an aggregation tendency. The current collision cascade results provide insights into the primary damage of W-based HEA system under irradiation and should provide reliable guidance for describing the primary damage source terms needed in the kinetic models used to simulate radiation-induced microstructural evolution.

Physicochemical properties and cytocompatibility of radiation-resistant and anti-washout calcium phosphate cement by introducing artemisia sphaerocephala krasch gum

The anti-washout ability of calcium phosphate cement (CPC) determines the effectiveness of CPC in clinical application. The γ-ray irradiation method often used in the sterilization process of CPC products is easy to degrade some commonly polymer anti-washout agent, which greatly reduces its anti-washout performance. Artemisia sphaerocephala Krasch gum (ASKG) has the potential of radiation resistance and anti-washout, but no one has considered its performance as anti-washout agent of CPC and mechanism of radiation resistance and anti-washout so far. In this study, we report the effect of γ-ray on ASKG and the effectiveness of ASKG for enhancing of radiation resistance and anti-washout ability of CPC, the physical, chemical properties and in vitro cell behaviors of ASKG-CPCs were also investigated. The results showed that addition of ASKG before and after irradiation could significantly enhanced the anti-washout performance of CPC, which is differ from conventional anti-washout agents. Meanwhile, ASKG-CPCs had an excellent injectable property and biocompatibility, and low content of irradiated ASKG could promote bone differentiation well. We anticipate that the radiation-resistant and anti-washout ASKG-CPCs have potential application prospect in orthopaedic surgery.

The effect of grain boundary on irradiation resistance of CoCrCuFeNi high entropy alloy

Defect traps have been well known to influence the irradiation resistance of traditional structural materials, but to what extent is not fully clear for high entropy alloys. Herein, the effect of grain boundary on irradiation resistance of CoCrCuFeNi is investigated through defects capture, strength variation, and void annihilation via molecular dynamics simulations and compared to that of pure Ni, taking ∑5(210) as a representative grain boundary. The grain boundaries in both CoCrCuFeNi and Ni are effective in capturing point defects. The number of captured defects is related to the distance between primary knock-on atoms and grain boundary. The change in tensile stress of CoCrCuFeNi after irradiation is smaller than that of Ni. The grain boundary of CoCrCuFeNi can annihilate voids at room temperature. However, that of Ni is hindered in the migration process and cannot annihilate voids completely. Our results provide atomistic insights into the mechanism of radiation resistance via grain boundaries as recombination centers.

Characterization of radiation-resistance mechanism in Spirosoma montaniterrae DY10T in terms of transcriptional regulatory system

To respond to the external environmental changes for survival, bacteria regulates expression of a number of genes including transcription factors (TFs). To characterize complex biological phenomena, a biological system-level approach is necessary. Here we utilized six computational biology methods to infer regulatory network and to characterize underlying biologically mechanisms relevant to radiation-resistance. In particular, we inferred gene regulatory network (GRN) and operons of radiation-resistance bacterium Spirosoma montaniterrae DY10^T and identified the major regulators for radiation-resistance. Our results showed that DNA repair and reactive oxygen species (ROS) scavenging mechanisms are key processes and Crp/Fnr family transcriptional regulator works as a master regulatory TF in early response to radiation.

Atomistic simulations of enhanced irradiation resistance and defect properties in body-centered cubic W-V-Cr and W-Ta-V alloys

Compared to face-centered cubic (fcc) high-entropy alloys (HEAs), body-centered cubic (bcc) medium/high-entropy alloys (M/HEAs) generally possess larger lattice distortion and exhibit distinct defect properties. In this work, molecular dynamics (MD) simulations of collision cascades and molecular statics (MS) calculations of defect properties were performed to investigate the irradiation resistance mechanism revealed from the point defect behaviors in W-V-Cr and W-Ta-V alloys. Low vacancy formation and migration energies with large energy spreads suggest the higher vacancy concentration and fast diffusions near the thermal spike. Slow self-interstitial atom (SIA) diffusions and fast vacancy diffusions lead to the closer mobilities of vacancies and SIAs, which significantly promotes the encountering probability and enhances the defect recombination in the cooling process of the thermal spike. Furthermore, formation and binding energies of W- and Ta-containing dumbbells are significantly larger than that of V- and Cr-related dumbbells, leading to higher occurrence probabilities and surviving fractions of V and Cr SIAs. Weak binding abilities of V and Cr SIAs can effectively suppress the clustering behaviors and make the surviving SIA clusters smaller. Our findings suggest that the irradiation resistance mechanisms in bcc M/HEAs are different from that in fcc M/HEAs, providing a deeper understanding of the radiation resistance mechanism in bcc M/HEAs with large lattice distortion.

Nanocrystalline-to-amorphous Transformation of Silicon Carbide Induced by Atomic Displacement Events

In nanocrystalline silicon carbide (NC-SiC), nanocrystalline-to-amorphous (NC-A) transformation can be induced due to atomic displacement events. To evaluate the detailed mechanisms of radiation resistance to amorphization and understand the role of grain boundaries (GBs), it is significantly critical to determine the amorphized dose of NC-SiC by inducing atomic displacements and obtain the information of defect behaviors in the NC-A transformation by using molecular dynamics methods. The results of this study revealed that full amorphization of NC-SiC was achieved by randomly displace (1) a Si atom or (2) a Si/C atom at the same dose of displacement per atom (dpa). The migration of carbon interstitial is the driving force in the amorphization process of NC-SiC according to the low migration energy of carbon in 3C-SiC. Moreover, defect clusters subsequently form and merge into the amorphous domains at the GBs, which will reveal the microscopic mechanism of the irradiation-induced NC-SiC amorphization.

Radiation-induced precipitates in ferritic-martensitic steels and their radiation resistance effects

Designing high-performance radiation-tolerant materials and understanding the atomistic mechanism of radiation resistance are important topics in nuclear energy structural materials research. In this study, we investigated the atomistic mechanism of the formation of rod-like precipitates in helium-irradiated ferritic-martensitic steels (F-M steels) by positron annihilation spectroscopy (PAS) and transmission electron microscopy with energy dispersive X-ray spectroscopy (TEM/EDX). The results indicated that vacancies tended to accumulate near dislocation lines to form complexes in the reduced activation ferritic-martensitic (RAFM) steel. Moreover, Fe and Cr atoms diffused toward these complexes and eventually depleted therein, which was not conducive to the formation of rod-like precipitates. Conversely, impurity atoms such as C atoms were found to segregate near dislocations in the Y-bearing oxide dispersion strengthened (Y-ODS) steel. When Fe and Cr diffused toward dislocations, they exchanged positions with C atoms until Fe and Cr exceeded their saturation solubilities and precipitated on the glide plane. We also analyzed the distribution of vacancy defects and bubbles/voids in the four irradiated materials and discussed the radiation resistance mechanism of the precipitates. The results of this study are significant in demonstrating a microscopic mechanism of radiation-induced precipitates to swelling resistance in materials. The raw/processed data required to reproduce these findings cannot be shared online at this time due to technical limitations, but they are available upon contacting the corresponding author. Materials exposed to extreme environments have received great attention recently in the context of advanced energy systems, defense, and aerospace technologies. Specifically, radiation-damage-tolerant materials are in great demand for the safe operation and advancement of nuclear energy and accelerator systems. Designing high-performance radiation-tolerant materials and understanding the atomistic mechanism of radiation resistance are important materials science topics. In this study, we reported the contribution of a microscopic mechanism of radiation-induced precipitates to swelling resistance in helium-irradiated ferritic-martensitic (F-M) steels/alloys. Significant findings included the formation of large areas of rod-like precipitates, which exhibited swelling resistance effects in steels subjected to helium irradiation and a possible microscopic mechanism for their formation. • Dense rod-like precipitates were observed in samples irradiated with high-dose helium ions. • The Cr and C contents were important factors affecting the formation of rod-like precipitates. • We clarified the atomistic mechanism of the formation of rod-like precipitates in the steels. • High-density rod-like precipitates as "radiation-damage antibodies" reduced void swelling.

Heat treatment to regulate bismuth valence toward enhanced radiation resistance in barium gallo‐germanate glass

AbstractDue to the excellent infrared transparency, low phonon energy, and high rare‐earth solubility, germanate laser glass has attracted much attention in mid‐infrared fiber lasers for potential coherent laser radar systems, optical detection, remote sensing, and laser surgery. However, radiation‐induce darkening often occurs in fiber lasers that operate in radiation environment. Here, we report a useful strategy to improve the radiation resistance by adding multivalence Bi ions and discuss its radiation resistance mechanism. In order to study the effect of valence states on the radiation resistance of barium gallo‐germanate glass, we adjust the valence states of Bi ions by heat treatment, the potential mechanism of which is discussed in detail based on the absorption, photoluminescence (PL), and Raman spectra. The absorption, electron paramagnetic resonance, and photoluminescence spectra have proved the interconversion of Bi ions between low and high valence, which inhibits the formation of Ge‐related electron center (GEC) and non‐bridging oxygen hole center defects in the irradiation process. In addition, the Bi3+ content increased by heat treatment is beneficial to serve as electron‐trapping centers in γ‐ray irradiation, thus further reducing the formation of GEC. This study provides a simple method to achieve Bi valence regulation, so as to improve the radiation resistance.

Association of Tumor Microbiome and Hypoxia Expression Signatures in Different Anatomic Subsites of Head and Neck Cancer

<h3>Purpose/Objective(s)</h3> Tumor response to radiation is dependent on the presence of oxygen with hypoxic tumors requiring a two to three-fold higher dose of radiation to achieve clinical equipoise. Head and neck squamous cell cancers (HNSCC) are the most hypoxic among various cancers, as observed in the The Cancer Genome Atlas (TCGA) dataset of 10,700 samples. Potentially related to this, tumor microenvironment (TME) in specific subsites has more anaerobes compared to the normal oral mucosa. The purpose of our study was to analyze the relationship between tumor subsite, hypoxia, and the local tumor microbiome in HNSCC using data from TCGA. <h3>Materials/Methods</h3> Tumor RNAseq samples from TCGA were processed through the exoTIC (exogenous sequencing in tumors and immune cells) pipeline to identify and count exogenous sequences, filter contaminants, and normalize expression values. The software ‘tmesig' was used to calculate gene expression signatures of the TME, including the Buffa hypoxia (BH) score, a validated gene signature that uses 52 hypoxia-regulated genes. Microbe relative abundances were modeled as the response variable with primary tumor location and a high vs low tertile BH score as predictor variables using a gamma-distributed generalized linear regression via the "stats'' package in R. Adjusted p-value of <0.05 was considered significant. <h3>Results</h3> A total of 357 patients were included [Oral cavity (OC) = 226, Oropharynx (OPx) = 53 and Larynx/Hypopharynx (LHPx) = 78] out of which HPV was present in 12.8%, 71.7% and 10.3% patients respectively in OC, OPx and LHPx tumors. The mean (SD) BH scores were 2.38 (18.17), -3.38 (20.45) and -4.97 (16.74) in OC, OPx and LHPx tumors, respectively, with higher values indicating greater hypoxia. The hypoxia signature was significantly higher for OC tumors compared to OPx (p= 0.044) and LHPx (p = 0.002), but was not statistically different between OPx and LHPx tumors (p= 0.625). Patients with upper tertile of BH scores had 395 microbes significantly enriched in tumors vs 307 microbes in patients with lower tertile of BH. The hypoxia expression signature was significantly associated with 413, 206 and 130 microbes in the OC, OPx and LHPx, respectively. Different strains of microbes were significantly associated with hypoxia depending on the tumor location, specifically, <i>Pseudomonas sp</i> in OC, <i>Actinomyces sp</i> and <i>Sulfurimonas sp</i> in OPx, and <i>Filifactor sp</i> in LHPx. In OPx cancer, there were no microbes significantly associated with hypoxia conditional in the presence of HPV. <h3>Conclusion</h3> Oral cavity tumors were associated with the greatest degree of hypoxia among HNSCC subsites, suggesting a potential mechanism for radiation resistance. In this study, we were able to identify an association between specific anaerobic microbes and relative hypoxia in different tumor subsites. Further investigation is required to determine if this is a causal relationship and whether modification of the microbiome in the TME can lead to reduced hypoxia and improved radiosensitivity and outcomes.

Genomic Insights into the Radiation-Resistant Capability of Sphingomonas qomolangmaensis S5-59T and Sphingomonas glaciei S8-45T, Two Novel Bacteria from the North Slope of Mount Everest.

Mount Everest provides natural advantages to finding radiation-resistant extremophiles that are functionally mechanistic and possess commercial significance. (1) Background: Two bacterial strains, designated S5-59T and S8-45T, were isolated from moraine samples collected from the north slope of Mount Everest at altitudes of 5700m and 5100m above sea level. (2) Methods: The present study investigated the polyphasic features and genomic characteristics of S5-59T and S8-45T. (3) Results: The major fatty acids and the predominant respiratory menaquinone of S5-59T and S8-45T were summed as feature 3 (comprising C16:1 ω6c and/or C16:1 ω7c) and ubiquinone-10 (Q-10). Phylogenetic analyses based on 16S rRNA sequences and average nucleotide identity values among these two strains and their reference type strains were below the species demarcation thresholds of 98.65% and 95%. Strains S5-59T and S8-45T harbored great radiation resistance. The genomic analyses showed that DNA damage repair genes, such as mutL, mutS, radA, radC, recF, recN, etc., were present in the S5-59T and S8-45T strains. Additionally, strain S5-59T possessed more genes related to DNA protection proteins. The pan-genome analysis and horizontal gene transfers revealed that strains of Sphingomonas had a consistently homologous genetic evolutionary radiation resistance. Moreover, enzymatic antioxidative proteins also served critical roles in converting ROS into harmless molecules that resulted in resistance to radiation. Further, pigments and carotenoids such as zeaxanthin and alkylresorcinols of the non-enzymatic antioxidative system were also predicted to protect them from radiation. (4) Conclusions: Type strains S5-59T (=JCM 35564T =GDMCC 1.3193T) and S8-45T (=JCM 34749T =GDMCC 1.2715T) represent two novel species of the genus Sphingomonas with the proposed name Sphingomonas qomolangmaensis sp. nov. and Sphingomonas glaciei sp. nov. The type strains, S5-59T and S8-45T, were assessed in a deeply genomic study of their radiation-resistant mechanisms and this thus resulted in a further understanding of their greater potential application for the development of anti-radiation protective drugs.