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Objective: To evaluate the occurrence of genotoxic and cytotoxic effects in oral epithelium after exposure of patients to cone beam computed tomography (CBCT)., Methods: A systematic review (SR) was conducted following the PECO (Population, Exposure, Comparison, Outcome) criteria. The study was registered in the International Prospective Register of Systematic Reviews (PROSPERO). A search was performed on the PubMed, Scopus, ScienceDirect, and Google Scholar databases. Effect size and heterogeneity of data were evaluated statistically. The Joanna Briggs Institute questionnaire for observational studies was utilized to assess the risk of bias. The GRADE tool was applied for the assessment of the quality of evidence. Begg's funnel plot was used to evaluate publication bias., Results: In total, 10 full-text articles were included in the SR, with 6 of them in the meta-analysis. The SR showed a significant increase in micronuclei after exposure, with a large effect size of 1.03. For genotoxicity, the tau 2 for heterogeneity was 0.96, the chi-squared test for heterogeneity P < .00001, the I 2 statistics for random effects was 91%, and the overall effect for Z value was 2.46 (P = .01). The risk of bias was low, the quality of evidence was strong, and publication bias was absent., Conclusion: CBCT can cause genotoxicity in the oral epithelium with a large effect size. The measure of cytotoxicity after CBCT exposure was not possible due to the lack of homogeneity of the included articles., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The prevalence of Light-emitting diodes (LEDs) has exposed us to an excessive amount of blue light (BL) which causes various ophthalmic diseases. Previous studies have shown that conjunctiva is vulnerable to BL. In this study, we aimed to investigate the underlying mechanism of BL-induced injury in conjunctiva. We placed C57BL/6 mice and human conjunctival epithelial cell lines (HCECs) under BL (440 nm ± 15 nm, 0.2 mW/cm 2 ) to establish a BL injury model in vivo and in vitro. Immunohistochemistry and MDA assay were used to identify lipid peroxidation (LPO) in vivo. HE staining was applied to detect morphological damage of conjunctival epithelium. DCFH-DA, C11-BODIPY 581/591, Calcein-AM, and FeRhoNox™-1 probes were performed to identify ferroptosis levels in vitro. Real-time qPCR and Western blotting techniques were employed to uncover signaling pathways of blue light-induced ferroptosis. Our findings demonstrated that BL affected tear film instability and induced conjunctival epithelium injury in vivo. Ferrostatin-1 significantly alleviated blue light-induced ferroptosis in vivo and in vitro. BL downregulates the levels of solute carrier family 7 member 11 (SLC7A11), Ferritin heavy chain (FTH1), and glutathione peroxidase (GPX4) by inhibiting the activation and translocation of the Signal transducer and activator of transcription 3 (STAT3) from inducing Fe 2+ burst, ROS and LPO accumulation, ultimately resulting in ferroptosis. This study will offer new insight into BL-induced conjunctival injury and LED-induced dry eye., Competing Interests: Declaration of competing interest There are no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Objectives: The aim of this study was to assess the MUC1 expression in the oral epithelium of normal, oral epithelial dysplasia (OED), oral squamous cell carcinoma (OSCC), and irradiated oral epithelium (IROE) and its association with smoking habits in non-smokers and smokers., Design: Oral mucosal biopsies from controls, OED, OSCC, and IROE groups were obtained and categorized based on the smoking history as non-smokers, smoker I (25 pack-years), and smoker II (>25 pack-years). Immunohistochemical staining of MUC1 using human milk fat globule 1 (HMFG 1) antibody was performed, and the MUC1 score was calculated. The relation between MUC1 expression and clinicopathological findings was examined., Results: MUC1 staining of superficial oral epithelial cells with mild MUC1 score was detected in all control samples. The MUC1 staining extended from superficial to basal cell layer of oral epithelium with the increase in MUC1 score from moderate to strong in OED, OSCC, and IROE, and the difference was significant (p < 0.004, p < 0.002 and p < 0.004, respectively) compared to controls. A positive association between smoking and MUC1 score was observed within groups (p < 0.05)., Conclusion: The depolarization of MUC1 protein expression is associated with smoking habits in OED and OSCC. In the IROE, the radiation causes subcellular and molecular changes, observed as altered MUC1 expression and accelerated by smoking, furthermore, complicating the oral mucosal adaptation and progress to radiation-induced lesions as a delayed effect., Competing Interests: Conflict of Interest None declared., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Skin wounds represent a burden in healthcare. Our aim was to investigate for the first time the effects of defocused high-power diode laser (DHPL) on skin healing in an animal experimental model and compare it with gold standard low-level laser therapy. Male Wistar rats were divided into 5 groups: Negative control; Sham; 0.1 W laser (L0.1 W); DHPL Dual 1 W (DHPLD1 W); and DHPL Dual 2 W (DHPLD2 W). Rats were euthanized on days 3, 5, 10, 14 and 21. Clinical, morphological, PicroSirus, oxidative stress (MDA, SOD and GSH) and cytokines (IL-1β, IL-10 and TNF-α) analyses were performed. A faster clinical repair was observed in all laser groups at D10 and D14. DHPLD1 W exhibited lower inflammation and better reepithelization compared to other groups at D10. DHPL protocols modulated oxidative stress by decreasing MDA and increasing SOD and GSH. Collagen maturation was triggered by all protocols tested and L0.1 W modulated cytokines release (IL-1β and TNF-α) at D3. In conclusion, DHPL, especially DHPL1 W protocol, accelerated skin healing by triggering reepithelization and collagen maturation and modulating inflammation and oxidative stress., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Endometrial regeneration is a dynamic process that is not well understood. The destruction of the endometrium with the formation of intrauterine adhesions is known as Asherman's syndrome. The lesions range from minor to severe adhesions and their impact on pregnancy is well documented. Operative hysteroscopy is the mainstay of diagnosis and treatment of intrauterine adhesions. Nevertheless, the recurrence rates remain high. It was recorded that low-level laser therapy in low doses has a stimulatory effect on different tissues while the high dose produces a suppressive effect. Organoid is a three-dimensional assembly that displays architectures and functionalities similar to in vivo organs that are being developed from human or animal stem cells or organ-specific progenitors through a self-organization process. Our prospective was to study the effect of Low-Level Laser Therapy (LLLT) on mouse epithelial endometrial organoids regarding cell proliferation and endometrial regeneration as a new modality of treatment. An in vitro clinical trial to generate mouse epithelial organoid model and testing LLLT using He:Ne 632.8 nm device on organoids proliferation, function, and their response to ovarian hormones was performed. Trying endometrial regeneration by culturing organoids with decellularized uterine matrix (DUM) and studying the LLLT effect on the regeneration process. LLLT produced a proliferative effect on the epithelial mouse organoids confirmed by Ki67 and PCNA IHC. The organoids could regenerate the epithelial layer of the endometrium in vitro on DUM and LLLT could help in this process. In conclusion, organoids whether control or bio-stimulated proved a new modality to regenerate the endometrium., Competing Interests: Declaration of Competing Interest The authors declare that they do not have any conflict of interest., (Copyright © 2021 Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish Academy of Sciences in Olsztyn. Published by Elsevier B.V. All rights reserved.)

In studies of electron and proton radiotherapy, ultrahigh dose rates of FLASH radiotherapy appear to produce fewer toxicities than standard dose rates while maintaining local tumor control. FLASH-proton radiotherapy (F-PRT) brings the spatial advantages of PRT to FLASH dose rates (>40 Gy/second), making it important to understand if and how F-PRT spares normal tissues while providing antitumor efficacy that is equivalent to standard-proton radiotherapy (S-PRT). Here we studied PRT damage to skin and mesenchymal tissues of muscle and bone and found that F-PRT of the C57BL/6 murine hind leg produced fewer severe toxicities leading to death or requiring euthanasia than S-PRT of the same dose. RNA-seq analyses of murine skin and bone revealed pathways upregulated by S-PRT yet unaltered by F-PRT, such as apoptosis signaling and keratinocyte differentiation in skin, as well as osteoclast differentiation and chondrocyte development in bone. Corroborating these findings, F-PRT reduced skin injury, stem cell depletion, and inflammation, mitigated late effects including lymphedema, and decreased histopathologically detected myofiber atrophy, bone resorption, hair follicle atrophy, and epidermal hyperplasia. F-PRT was equipotent to S-PRT in control of two murine sarcoma models, including at an orthotopic intramuscular site, thereby establishing its relevance to mesenchymal cancers. Finally, S-PRT produced greater increases in TGFβ1 in murine skin and the skin of canines enrolled in a phase I study of F-PRT versus S-PRT. Collectively, these data provide novel insights into F-PRT-mediated tissue sparing and support its ongoing investigation in applications that would benefit from this sparing of skin and mesenchymal tissues. SIGNIFICANCE: These findings will spur investigation of FLASH radiotherapy in sarcoma and additional cancers where mesenchymal tissues are at risk, including head and neck cancer, breast cancer, and pelvic malignancies., (©2021 The Authors; Published by the American Association for Cancer Research.)

Ultraviolet radiation (UVR) is the major etiologic agent of cutaneous photoaging, and different strategies are used to prevent and treat this condition. The polysaccharide fraction (LBPF) isolated from Lycium Barbarum fruits (goji berry) contains several active ingredients with antioxidant, immune system modulation, and antitumor effects. In addition, the photobiomodulation (PBM) is widely applied in photoaging treatment. This study investigated the effects of LBPF and PBM against the UVR-induced photodamage in the skin of hairless mice. The mice were photoaged for 6 weeks in a chronic and cumulative exposure regimen using a 300-W incandescent lamp that simulates the UVR effects. From the third to the sixth week of photoaging induction, the animals received topical applications of LBPF and PBM, singly or combined, in different orders (first LBPF and then PBM and inversely), three times per week after each session of photoaging. After completion of experiments, the dorsal region skin was collected for the analysis of thickness, collagen content, and metalloproteinases (MMP) levels. A photoprotective potential against the increase of the epithelium thickness and the fragmentation of the collagen fibers was achieved in the skin of mice treated with LBPF or PBM singly, as well as their combination. All treatments maintained the skin collagen composition, except when PBM was applied after the LBPF. However, no treatment protected against the UVR-induced MMP increase. Taken together, we have shown that the LBPF and PBM promote a photoprotective effect in hairless mice skin against epidermal thickening and low collagen density. Both strategies, singly and combined, can be used to reduce the UVR-induced cutaneous photoaging.

Radon is a leading cause of lung cancer in indoor public and mining workers. Inhaled radon progeny releases alpha particles, which can damage cells in the airway epithelium. The extent and complexity of cellular damage vary depending on the alpha particle's kinetic energy and cell characteristics. We developed a framework to quantitate the cellular damage on the nanometer and micrometer scales at different intensities of exposure to radon progenies Po-218 and Po-214. Energy depositions along the tracks of alpha particles that were slowing down were simulated on a nanometer scale using the Monte Carlo code Geant4-DNA. The nano-scaled track histories in a 5 μm radius and 1 μm-thick cylindrical volume were integrated into the tracking scheme of alpha trajectories in a micron-scale bronchial epithelium segment in the user-written SNU-CDS program. Damage distribution in cellular DNA was estimated for six cell types in the epithelium. Deep-sited cell nuclei in the epithelium would have less chance of being hit, but DNA damage from a single hit would be more serious, because low-energy alpha particles of high LET would hit the nuclei. The greater damage in deep-sited nuclei was due to the 7.69 MeV alpha particles emitted from Po-214. From daily work under 1 WL of radon concentration, basal cells would respond with the highest portion of complex DSBs among the suspected progenitor cells in the most exposed regions of the lung epithelium.

Tritium has been receiving worldwide attention, particularly because of its production and use in existing fission reactors and future nuclear fusion technologies, leading to an increased risk of release in the environment. Linking human health effects to low-dose tritium exposures presents a challenge for many reasons. Among these: biological effects strongly depend on the speciation of tritiated products and exposure pathway; large dosimetric uncertainties may exist; measurements using in vitro cell cultures generally lack a description of effects at the tissue level, while large-scale animal studies might be ethically questionable and too highly demanding in terms of resources. In this context, three-dimensional models of the human airway epithelium are a powerful tool to investigate potential toxicity induced upon inhalation of radioactive products in controlled physiological conditions. In this study we exposed such a model to tritiated water (HTO) for 24 h, with a range of activity levels (up to ∼33 kBq µl-1 cm-2). After the exposures, we measured cell viability, integrity of epithelial layer and pro-inflammatory response at different post-exposure time-points. We also quantified tritium absorption and performed dosimetric estimates considering HTO passage through the epithelial layer, leading to reconstructed upper limits for the dose to the tissue of less than 50 cGy cumulative dose for the highest activity. Upon exposure to the highest activity, cell viability was not decreased; however, we observed a small effect on epithelial integrity and an inflammatory response persisting after seven days. These results represent a reference condition and will guide future experiments using human airway epithelium to investigate the effects of other peculiar tritiated products., (©2021 by Radiation Research Society. All rights of reproduction in any form reserved.)

WLEDs have lately been the preferred lighting device based on properties such as energy saving, high efficiency, longevity, and environmental protection. However, studies on the safety of white light-emitting diode (WLED) are limited. In our previous study, we found that WLED light (4000 K ± 500 K color temperature, 250 lx, and 20 min exposure) is photocytotoxic to three mammalian cell lines by causing cell lipid peroxidation. To further investigate the potential photocytotoxicity of WLEDs on the human body, we used two human eye cell lines SRA01/04 and D407 as target cells for evaluating its potential phototoxicity on the human eye in the present study based on cell viability, apoptosis, and intracellular oxidative stress assays, as well as the activation levels of reactive oxygen species (ROS)-related apoptosis pathways, including extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK) and p38 kinase (p38), using mitogen-activated protein kinase (MAPK) signaling pathway assays. The results showed that WLED light has photocytotoxicities on SRA01/04 and D407 cells, which were both in a time-, irradiance-, and color temperature-dependent manner and strongest at the conditions of 2 h irradiation time, 60 W/m 2 irradiance, and 4000 K color temperature. Moreover, the photocytotoxicity of red light-emitting diode (LED) light was the strongest in the three tested monochromatic light compositions of WLED. Mechanism studies show that the potential phototoxicity of WLED on human lens epithelium and retinal pigment epithelium may be caused by its induced oxidative stress damage via the JNK and p38 MAPKs pathways., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Radiotherapy is one of the principal approaches employed in the treatment of pelvic cancers. Nevertheless, testicular dysfunction and infertility are among the most common adverse effects in young adult cancer survivors. Clinically, alpha-lipoic acid (LA) has been applied to improve the quality of sperm with a satisfactory effect. Therefore, the present study investigated the underlying mechanisms of the radioprotective effects of LA against testicular damage. Male Sprague-Dawley rats were exposed to 10 Gy of whole-body ϒ-radiation and LA (50 mg/kg, P.O.) was administered one week before and three days post-irradiation. LA showed remarkable capacity in preserving testicular tissue against radiation damage by improving histological and ultrastructural changes of disorganized seminiferous tubules, besides enhancing its diameter, germinal epithelial thickness, and Johnsen's score. Radiation instigated a significant decrease in sperm quality and quantity associated with depletion of serum testosterone levels, while the LA administration maintained spermatogenesis. Strikingly, LA exhibited antioxidant properties by restoring reduced glutathione levels and antioxidant enzyme activities such as catalase and glutathione-s-transferase, besides diminishing malondialdehyde levels in the testis of irradiated group. Furthermore, LA alleviated testicular inflammation through downregulation of nuclear factor-ĸB (NF-ĸB) expression with a subsequent reduction in interleukin (IL)-6 and cyclooxygenase-2 expression, accompanied by the augmented expression of the anti-inflammatory cytokine IL-10. Additionally, testicular fibrosis markers including Masson's trichrome and transforming growth factor (TGF)-β expression were noticeably declined in LA-treated irradiated rats, together with the upregulation of peroxisome proliferator-activated receptor-ϒ expression. Collectively, LA ameliorates radiation-mediated spermatogenesis-defects and testicular-damage via suppression of oxidative stress/NF-ĸB/TGF-β signaling., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Increasing evidence suggests that interference with growth factor receptor tyrosine kinase (RTK) signaling can affect DNA damage response (DDR) networks, with a consequent impact on cellular responses to DNA-damaging agents widely used in cancer treatment. In that respect, the MET RTK is deregulated in abundance and/or activity in a variety of human tumors. Using two proteomic techniques, we explored how disrupting MET signaling modulates global cellular phosphorylation response to ionizing radiation (IR). Following an immunoaffinity-based phosphoproteomic discovery survey, we selected candidate phosphorylation sites for extensive characterization by targeted proteomics focusing on phosphorylation sites in both signaling networks. Several substrates of the DDR were confirmed to be modulated by sequential MET inhibition and IR, or MET inhibition alone. Upon combined treatment, for two substrates, NUMA1 S395 and CHEK1 S345, the gain and loss of phosphorylation, respectively, were recapitulated using invivo tumor models by immunohistochemistry, with possible utility in future translational research. Overall, we have corroborated phosphorylation sites at the intersection between MET and the DDR signaling networks, and suggest that these represent a class of proteins at the interface between oncogene-driven proliferation and genomic stability., (© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Present study highlighted the ultramicroscopic (SEM) alterations of the skin, eye, barbel, and fins of spawn of an air-breathing teleost (Clarias batrachus, Linn. 1758) induced by UV-B radiation (280-320 nm) at a dose (@4.07 × 10 -20 J/photon/m 2 ) under the time-frame of 5, 10 and 15 min/d in the laboratory condition for the periods of 5 and 10 days. Limnological parameters revealed no significant changes throughout the period of experimentation which were measured by PCS Testr 35 Multi-Parameter. Morphometric analysis revealed that during the extended exposure period of 10 days the spawn size and weight were reduced as analysed through Specific Growth Rate (SGR). SGR values in terms of weight for 5 and 10 days under 3 time-frames were 17.12%, 12.52%, 11.46% and 9.09%, 6.43%, 6.09% respectively, which revealed a declined trend along with the exposure days. In the skin of C. batrachus, the compact regular orientation of the stratified epithelial cells and mucous cells became distorted and the microridges and double-ridged structures showed destruction and fragmentations. The body striations and microfolds became shrinked and swollen and finally degenerated to form a mass. The distribution of mucous cells throughout the epidermis was disorganised and releasing secretory contents on the surface through small pores. Appearance of huge quantity of biogenic semi-hexagonal plate like crystals (guanine platelets) on the skin surface of the body was the most significant observations during UV-B radiation. In the developmental phases the eyeball showed shrinkage loosing normal regular concave structure and to become a dome-shaped one. The supportive connective infoldings became loosened. The choroid coat displayed deformities and the iris deformed the pupil. The fibroblast on the epithelium and melanocytes depicted dispersed arrangement. The pairs of ventral barbels near the mouth depicted the presence of taste buds that became severely damaged exposing the sensory as well as neuroepithelial cells. Compact regular arrangement of the SECs was completely destroyed leaving long and deep channels inbetween them; the disintegrated concentric MRs also showed a mass., Competing Interests: Declaration of competing interest The authors whose names are listed there have no conflict of interest in the subject matter or materials discussed in this manuscript., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: The purposes of this split-mouth pilot study were to investigate the efficacy of the Er:YAG laser use for the de-epithelialization of the palatal graft in the treatment of the multiple gingival recessions using the bilaminar procedure and also to evaluate the patient-reported esthetic outcomes after 6 months. Materials and methods: Five systemically healthy participants with total 28 bilateral-multiple adjacent maxillary Miller I recessions were included. The treatment was performed with the bilaminar technique [coronally advanced flap (CAF)+de-epithelialized free gingival graft]. De-epithelialization procedure was done with scalpel (control site) or Er:YAG laser (Versawave, Hoya ConBio, San Francisco, CA; 40 hz, 50 mJ/pulse), under water irrigation, noncontact mode (∼1 mm away from the target tissue) in sweeping motion with chisel-type laser (test site). Root coverage and patient-reported outcomes were evaluated at 6 months after the operations. Results: Clinical outcomes of the both treatment sites did not show any statistically significant differences except for the gingival thickness parameter. However, patient-reported outcomes regarding the esthetic appearance of the gingiva was detected in favor of the Er:YAG laser applied sites. Conclusions: Within the limits of the study, it can be concluded that both de-epithelialization techniques were highly effective at 6 months. However, Er:YAG laser-applied grafted sites revealed more uniform and esthetic gingival appearance compared with scalpel-used grafted sites.

Functional and esthetic recovery of the patient after tooth extraction is a concern in the nowadays-dental medicine. Immediate implant placement in fresh sockets in posterior sides of the jaws is difficult because of the high amount of bone loss and the disparity between the diameter of the alveolus and the implant. The objective is to evaluate the effect of laser biomodulation alveolar socket healing process of healthy patients. A number of 36 molars have been extracted due to advanced caries lesions from the same dental arch but on opposite sites. Laser irradiation was performed on one side after extraction; the other side was used as control. An Epic-X laser diode (Biolase) Indium-Gallium-Arsenide-Phosphorus (In-Ga-As-P) 940 nm was used in a continuous mode, 0.9 W, 36 J for 80 seconds, daily exposure, in the first seven days after extraction. Specimens of soft and hard tissue were surgically incised and removed by a 4.4 mm diameter trepan from the extraction sites, eight weeks after the surgical procedure. The specimens were prepared by use of two staining procedures: Hematoxylin-Eosin (HE) and Mallory's trichrome. The prepared slides were examined under Leica DM750 optical microscope, 5× and 10× magnification. Laser biomodulation therapy accelerates bone formation by increasing osteoblastic activity. The histological study demonstrates early new bone formation, the regeneration effects in fresh intact bony alveolus compared with the soft and bone regeneration level of non-treated fresh alveolus. Laser biomodulation therapy accelerates soft tissue regeneration and bone formation.

Objectives: The aim of the study was to investigate the possible effects of radiofrequency radiation (RFR) at different frequencies for different exposure durations on caspase-dependent apoptosis pathways in human colon adenocarcinoma (HT-29)., Methods: HT-29 cells were exposed to 1800 MHz; 2100 MHz and 2600 MHz RFR for 3 h cont., 6 h int. and 6 h cont.. Cell viability measurements were performed by Trypan Blue exclusion assay and the gene expressions of CASP8, CASP9, CASP3 and CASP12 were analyzed using qRT-PCR., Results: Exposure to 2100 MHz RFR for all 3 durations of exposures was more effective for the ratio of the number of viable HT-29 cells w.r.t 1800 MHz RFR and 2600 MHz RFR exposures. After 2100 MHz RFR exposure, caspase activation increased significantly (for 3h cont. and 6 h int. exposures CASP8 and CASP9 levels; for 6 h cont. exposure CASP3 levels) (p 0.05)., Conclusion: Decreases in the cell viability of HT-29 cells for certain frequencies and also durations are consistent with significant increases in caspase activations. The results of caspase activation after 1800 MHz or 2600 MHz RFR exposures can be interpreted as the activation of different types of cell death pathway by caspase signaling cascades (Fig. 15, Ref. 56).

Purpose: Epidemiological evidence regarding the radiosensitivity of the lens of the eye and radiation cataract development has led to changes in the EU Basic Safety Standards for protection of the lens against ionizing radiation. However, mechanistic details of lens radiation response pathways and their significance for cataractogenesis remain unclear. Radiation-induced DNA damage and the potential impairment of repair pathways within the lens epithelium, a cell monolayer that covers the anterior hemisphere of the lens, are likely to be involved., Materials and Methods: In this work, the lens epithelium has been analyzed for its DNA double-strand break (DSB) repair response to ionizing radiation. The responses of epithelial cells located at the anterior pole (central region) have been compared to at the very periphery of the monolayer (germinative and transitional zones). Described here are the different responses in the two regions and across four strains (C57BL/6, 129S2, BALB/c and CBA/Ca) over a low dose (0-25 mGy) in-vivo whole body X-irradiation range up to 24 hours post exposure., Results: DNA damage and repair as visualized through 53BP1 staining was present across the lens epithelium, although repair kinetics appeared non-uniform. Epithelial cells in the central region have significantly more 53BP1 foci. The sensitivities of different mouse strains have also been compared., Conclusions: 129S2 and BALB/c showed higher levels of DNA damage, with BALB/c showing significantly less inter-individual variability and appearing to be a more robust model for future DNA damage and repair studies. As a result of this study, BALB/c was identified as a suitable radiosensitive lens strain to detect and quantify early low dose ionizing radiation DNA damage effects in the mouse eye lens specifically, as an indicator of cataract formation.

Purpose: The most exposed tissue upon radon exposure is the bronchial epithelium where goblet cells serve as responsive and adaptable front-line defenders. They can rapidly produce a vast amount of mucus, and can change in number, in response to airway insults. The objective of the present study is to quantify the effects of mucus discharge and goblet cell hyperplasia on the microscopic dose consequences of macroscopic radon exposures., Methods: For this purpose, computational models of the bronchial epithelium and alpha-particle transport have been prepared and applied to quantify the hits received and doses absorbed by cell nuclei in case of different mucus thicknesses and goblet cell number., Results and Conclusions: Both mucus discharge and induction of goblet cell hyperplasia reduce radiation burden at the cellular level, and as such they both can be considered as radioadaptive responses to radon exposure. As compared to basal cell hyperplasia, goblet cell hyperplasia is more effective in reducing the microscopic dose consequences of a given macroscopic exposure. Such changes in exposure geometry highlight the need for improvements in the application of biokinetic and dosimetry models for incorporated radionuclides as well as the dose and dose rate effectiveness factor.

Objectives: Wound healing of the oral mucosal epithelium through the application of far infrared radiation emitted by isotropic high-density carbon was investigated in order to clarify the preventive and therapeutic effects of isotropic high-density carbon on oral mucosal injury., Materials and Methods: A carbon massager with an isotropic high-density carbon tip was used. Far infrared radiation was applied to the human buccal mucosal squamous cell carcinoma cell line, HO-1-N-1 using a carbon massager, and cell growth factors and heat shock protein levels were measured using real-time RT-PCR and ELISA. Far infrared radiation was applied to oral mucosal injury in SD rats over time using the carbon massager, and its effects were examined by HE staining and immunostaining. The immunostaining positive rate was measured and analyzed using image analysis software., Results: Far infrared radiation induced stronger mRNA expression and higher HSP27 and HSP70 protein levels on real-time RT-PCR and ELISA than in the control group. The far infrared radiation of oral mucosal injury in rats induced strong positive reactions, and positive rates for Ki67, HSP27, and HSP70 were higher than those in the control group., Conclusions: The treatment of oral mucosal injury with far infrared radiation emitted by isotropic high-density carbon appears to have promoted heat shock protein production and induced regenerative reactions more strongly than in the control group., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Adequate and rapid mucosal regeneration is one of the most important factors in the healing process of nasal mucosa after surgery or trauma. In particular, delayed mucosal regeneration after surgery is an important cause of surgical failure. However, no effective treatment is available yet. Non-thermal plasma (NTP) has several medical effects, but the existing probe type is limited to local direct treatment. Therefore, we investigated the various effects using liquid type plasma to overcome this limitation. In addition, the therapeutic effects of non-thermal plasma treated solution (NTS) on nasal mucosa have yet to be determined. Experiments were carried out using BEAS-2B, a human bronchial epithelial cell line similar to nasal mucosa epithelium. NTS had no cytotoxicity to the BEAS-2B cells and enhanced cell proliferation. NTS also promoted migration of BEAS-2B cells. NTS increased cell proliferation and migration via epidermal growth factor receptor (EGFR) activities and epithelial-to-mesenchymal transition (EMT) signaling. Furthermore, NTS enhanced wound healing of nasal mucosa in an animal model. Accordingly, NTS promotes nasal mucosa wound healing by increasing cell proliferation and migration. These findings suggest the therapeutic potential of NTS in nasal mucosa wound healing.

In this work, we develop multicellular models of healthy and cancerous human soft tissues, which are used to investigate energy deposition in subcellular targets, quantify the microdosimetric spread in a population of cells, and determine how these results depend on model details. Monte Carlo (MC) tissue models combining varying levels of detail on different length scales are developed: microscopically-detailed regions of interest (>1500 explicitly-modelled cells) are embedded in bulk tissue phantoms irradiated by photons (20 keV-1.25 MeV). Specific energy (z; energy imparted per unit mass) is scored in nuclei and cytoplasm compartments using the EGSnrc user-code egs&#95;chamber; specific energy mean, [Formula: see text], standard deviation, [Formula: see text], and distribution, [Formula: see text], are calculated for a variety of macroscopic doses, D. MC-calculated [Formula: see text] are compared with normal distributions having the same mean and standard deviation. For  ∼mGy doses, there is considerable variation in energy deposition (microdosimetric spread) throughout a cell population: e.g. for 30 keV photons irradiating melanoma with 7.5 μm cell radius and 3 μm nuclear radius, [Formula: see text] for nuclear targets is [Formula: see text], and the fraction of nuclei receiving no energy deposition, f z=0 , is 0.31 for a dose of 10 mGy. If cobalt-60 photons are considered instead, then [Formula: see text] decreases to [Formula: see text], and f z=0 decreases to 0.036. These results correspond to randomly arranged cells with cell/nucleus sizes randomly sampled from a normal distribution with a standard deviation of 1 μm. If cells are arranged in a hexagonal lattice and cell/nucleus sizes are uniform throughout the population, then [Formula: see text] decreases to [Formula: see text] and [Formula: see text] for 30 keV and cobalt-60, respectively; f z=0 decreases to 0.25 and 0.000 94 for 30 keV and cobalt-60, respectively. Thus, specific energy distributions are sensitive to cell/nucleus sizes and their distributions: variations in specific energy deposited over a cell population are underestimated if targets are assumed to be uniform in size compared with more realistic variation in target size. Bulk tissue dose differs from [Formula: see text] for nuclei (cytoplasms) by up to [Formula: see text] ([Formula: see text]) across all cell/nucleus sizes, bulk tissues, and incident photon energies, considering a 50 mGy dose level. Overall, results demonstrate the importance of microdosimetric considerations at low doses, and indicate the sensitivity of energy deposition within subcellular targets to incident photon energy, dose level, elemental compositions, and microscopic tissue model.

Background: There is no study of whether the dysplastic changes in the ovarian surface epithelium of X-ray-exposed rats during hysterosalpingography (HSG) decrease or not with the use of Lipiodol and melatonin given both intraperitoneally (i.p.) and into the suspensorium ovarii., Objectives: We investigated the restorative effects of melatonin and Lipiodol administration during the HSG procedure on the dysplastic changes in the ovarian surface epithelium of X-ray-exposed rats., Material and Methods: A total of 50 Wistar rats with regular estrous cycles were randomly divided into 5 groups. Group 1 was the control group. In other groups, X-ray was applied (group 2), 0.1 mL Lipiodol was applied to each uterine horn (group 3), 20 mg/kg intraperitoneal melatonin application was followed by 0.1 mL Lipiodol administration to each uterine horn after 15 min (group 4), and 20 mg/kg melatonin was administered to the ligamentum suspensorium ovarii, followed by 0.1 mL Lipiodol application to each uterine horn after 15 min (group 5). The rats in groups 2-5 were exposed to whole body radiation 3 times. After 3 h, the abdomens of all rats were reopened and left oophorectomy was performed., Results: The presence of nucleoli and mitosis values were found similar among the groups. All other parameters were significantly higher in group 2 compared to other groups, except for the presence of nucleoli and mitosis values (p < 0.05). The presence of hyperchromasia and the total score were found to be the highest in group 2, followed by group 3, when compared to other groups (p < 0.05). It was detected that the detrimental effects of X-ray exposure diminished with Lipiodol use, and were further reduced by the use of melatonin in combination., Conclusions: We suggest that the use of melatonin and Lipiodol during HSG may prevent the carcinogenic changes exerted by radiation on the ovarian surface epithelium.

Background: Women who have been treated for cervical cancer have persistent changes in their sexual function, which result in considerable distress. The aim of this study was to investigate the morphology of the vaginal epithelium in cervical cancer survivors treated with radiotherapy and its correlation to serum levels of sex steroid hormones and sexual function., Material and Methods: We included 34 patients treated for cervical cancer with radiotherapy and 37 healthy age-matched control women scheduled for benign gynecological surgery. After inspection and grading of vaginal atrophy, vaginal biopsies were taken. Epithelial structures were analyzed by measuring epithelial thickness as well as the number, height and width of the dermal papillae and the dermal papillae distance. Sex steroid hormone levels were analyzed and a questionnaire designed to assess sexual function was filled out., Results: In the cervical cancer survivors treated with radiotherapy, the vaginal epithelium volume was reduced compared to control women. Longer distance between the dermal papillae (p < .001) and a shorter distance from basal layer to epithelial surface (p < .05) were measured. Mucosal atrophy was observed in 91% of the survivors. There was no difference in serum estradiol between cancer survivors and control women, implying that the cancer survivors were sufficiently substituted. The epithelial thickness correlated to serum levels of estradiol. The cervical cancer survivors reported more physical sexual symptoms. The highest relative risk (RR) was found for insufficient vaginal lubrication (RR 12.6), vaginal inelasticity (RR 6.5), reduced genital swelling when sexually aroused (RR 5.9), and for reduction of vaginal length during intercourse (RR 3.9)., Conclusion: We found that cervical cancer treatment including radiotherapy is associated with vaginal epithelial atrophy and sexual dysfunction. To hamper the atrophic process affecting the sexual function, an early start of local estrogen after therapy might be of importance.

The chemokine C-X-C motif chemokine 12 (CXCL12) greatly impacts various biological processes in mammals, including cell survival, growth and migration. Mesenchymal stem cells (MSCs) are promising tools for carrying foreign genes to treat radiation-induced injuries in the intestinal epithelium. In this study, human adipose-derived MSCs were constructed to over-express the mouse cxcl12 gene to treat such injuries. In vitro, because of the high levels of mouse CXCL12 in conditioned medium produced by mouse cxcl12 gene-modified cells, phosphorylation of Akt at Ser473 and Erk1/2 at Thr202/Thr204 was increased within crypt cells of irradiated organoids compared with unmodified controls. Moreover, intracellular stabilization of β-catenin was achieved after treatment of mouse cxcl12 gene-modified cells with conditioned medium. As a result, survival of crypt cells was maintained and their proliferation was promoted. When delivering mouse cxcl12 gene-modified cells into irradiated BALB/c nude mice, mice were rescued despite the clearance of cells from the host within 1 week. Irradiated mice that received mouse cxcl12 gene-modified MSCs exhibited reduced serum levels of interleukin-1α (IL-1α) and IL-6 as well as elevated levels of CXCL12. Additionally, epithelial recovery from radiation stress was accelerated compared with the irradiated-alone controls. Moreover, mouse cxcl12 gene-modified MSCs were superior to unmodified cells at strengthening host repair responses to radiation stress as well as presenting increased serum CXCL12 levels and decreased serum IL-1α levels. Furthermore, the number of crypt cells that were positive for phosphorylated Akt at Ser473 and phosphorylated Erk1/2 at Thr202/Thr204 increased following treatment with mouse cxcl12 gene-modified MSCs. Thus, cxcl12 gene-modified MSCs confer radioresistance to the intestinal epithelium.

Exposure to a small number of high-energy heavy charged particles (HZE ions), as found in the deep space environment, could significantly affect astronaut health following prolonged periods of space travel if these ions induce mutations and related cancers. In this study, we used an in vivo mutagenesis assay to define the mutagenic effects of accelerated 56Fe ions (1 GeV/amu, 151 keV/μm) in the mouse kidney epithelium exposed to doses ranging from 0.25 to 2.0 Gy. These doses represent fluences ranging from 1 to 8 particle traversals per cell nucleus. The Aprt locus, located on chromosome 8, was used to select induced and spontaneous mutants. To fully define the mutagenic effects, we used multiple endpoints including mutant frequencies, mutation spectrum for chromosome 8, translocations involving chromosome 8, and mutations affecting non-selected chromosomes. The results demonstrate mutagenic effects that often affect multiple chromosomes for all Fe ion doses tested. For comparison with the most abundant sparsely ionizing particle found in space, we also examined the mutagenic effects of high-energy protons (1 GeV, 0.24 keV/μm) at 0.5 and 1.0 Gy. Similar doses of protons were not as mutagenic as Fe ions for many assays, though genomic effects were detected in Aprt mutants at these doses. Considered as a whole, the data demonstrate that Fe ions are highly mutagenic at the low doses and fluences of relevance to human spaceflight, and that cells with considerable genomic mutations are readily induced by these exposures and persist in the kidney epithelium. The level of genomic change produced by low fluence exposure to heavy ions is reminiscent of the extensive rearrangements seen in tumor genomes suggesting a potential initiation step in radiation carcinogenesis.

The expression of Ki-67 proliferation marker was studied in vaginal biopsy specimens from women with stress urinary incontinence treated using a Fotona nonablative erbium laser. Cells expressing Ki-67 were located in all cases in the parabasal and basal levels of stratified squamous epithelium, the index of labeled nuclei before Er:YAG laser exposure was 19.05±2.86%. After 1-2 months of laser therapy, the index of labeled nuclei in the epithelium increased significantly and reached 31.79±2.25%. These changes were interpreted as a result of epithelial-stromal interactions. Presumably, the increase in proliferative activity of the vaginal epithelium after exposure to Er:YAG laser was due to the presence of an appreciable level of synthetically active fibroblasts in the subepithelial stroma.

Radiation treatment of head and neck cancer frequently causes severe collateral damage to normal tissues including mouth mucosa, salivary glands and skin. This toxicity limits the radiation dose that can be delivered and affects the patient's quality of life. Previous studies in mice and nonhuman primates showed that entolimod, a toll-like receptor 5 (TLR5) agonist derived from bacterial flagellin, effectively reduced radiation damage to hematopoietic and gastrointestinal tissues in both total-body and local irradiation scenarios, with no protection of tumors. Here, using a mouse model, we analyzed the efficacy of entolimod administered before or after irradiation in reducing damage to normal tissues. Animals received local fractionated radiation to the head and neck area, thus modeling radiotherapy of head and neck cancer. Tissue damage was evaluated through histomorphological examination of samples collected at different time points up to four weeks, mice were exposed locally to five daily fractions of 5, 6 or 7 Gy. A semiquantitative scoring system was used to assess the severity of observed pathomorphological changes. In this model, radiation damage was most severe in the lips, tongue and skin, moderate in the upper esophagus and minor in salivary glands. The kinetics of injury appearance and recovery of normal morphology varied among tissues, with maximal damage to the tongue, esophagus and salivary glands developing at earlier times (days 8-11 postirradiation) relative to that of lip and skin mucosa (days 11-15 postirradiation). While both tested regimens of entolimod significantly reduced the extent of radiation damage and accelerated restoration of normal structure in all tissues analyzed, administration of entolimod 1 h after each irradiation was more effective than treatment 30 min before irradiation. These results support the potential clinical use of entolimod as an adjuvant for improving the therapeutic index of head and neck cancer radiotherapy by reducing the radiation toxicity in normal tissues.

In cancer, vulnerable breast epithelium malignance tendency correlates with number and activation of ErbB receptor tyrosine kinases. In the presented work, we observe ErbB receptors activated by irradiation-induced DNA injury or neuregulin- 1 β application, or alternatively, attenuated by a therapeutic antibody using high resolution fluorescence localization microscopy. The gap junction turnover coinciding with ErbB receptor activation and co-transport is simultaneously recorded. DNA injury caused by 4 Gray of 6 MeV photon γ -irradiation or alternatively neuregulin- 1 β application mobilized ErbB receptors in a nucleograde fashion-a process attenuated by trastuzumab antibody application. This was accompanied by increased receptor density, indicating packing into transport units. Factors mobilizing ErbB receptors also mobilized plasma membrane resident gap junction channels. The time course of ErbB receptor activation and gap junction mobilization recapitulates the time course of non-homologous end-joining DNA repair. We explain our findings under terms of DNA injury-induced membrane receptor tyrosine kinase activation and retrograde trafficking. In addition, we interpret the phenomenon of retrograde co-trafficking of gap junction connexons stimulated by ErbB receptor activation.

Regeneration of the intestinal epithelium is driven by multiple intestinal stem cell (ISC) types, including an active, radiosensitive Wnt high ISC that fuels turnover during homeostasis and a reserve, radioresistant Wnt low/off ISC capable of generating active Wnt high ISCs. We examined the role of the Msi family of oncoproteins in the ISC compartment. We demonstrated that Msi proteins are dispensable for normal homeostasis and self-renewal of the active ISC, despite their being highly expressed in these cells. In contrast, Msi proteins are required specifically for activation of reserve ISCs, where Msi activity is both necessary and sufficient to drive exit from quiescence and entry into the cell cycle. Ablation of Msi activity in reserve ISCs rendered the epithelium unable to regenerate in response to injury that ablates the active stem cell compartment. These findings delineate a molecular mechanism governing reserve ISC quiescence and demonstrate a necessity for the activity of this rare stem cell population in intestinal regeneration., (© 2016 Yousefi et al.)

There is experimental and histological evidence that chronic irritation and cell death may cause hyperplasia in the exposed tissue. As the heterogeneous deposition of inhaled radon progeny results in high local doses at the peak of the bronchial bifurcations, it was proposed earlier that hyperplasia occurs in these deposition hot spots upon chronic radon exposure. The objective of the present study is to quantify how the induction of basal cell hyperplasia modulates the microdosimetric consequences of a given radon exposure. For this purpose, computational epithelium models were constructed with spherical cell nuclei of six different cell types based on histological data. Basal cell hyperplasia was modelled by epithelium models with additional basal cells and increased epithelium thickness. Microdosimetry for alpha-particles was performed by an own-developed Monte-Carlo code. Results show that the average tissue dose, and the average hit number and dose of basal cells decrease by the increase of the measure of hyperplasia. Hit and dose distribution reveal that the induction of hyperplasia may result in a basal cell pool which is shielded from alpha-radiation. It highlights that the exposure history affects the microdosimetric consequences of a present exposure, while the biological and health effects may also depend on previous exposures. The induction of hyperplasia can be considered as a radioadaptive response at the tissue level. Such an adaptation of the tissue challenges the validity of the application of the dose and dose rate effectiveness factor from a mechanistic point of view. As the location of radiosensitive target cells may change due to previous exposures, dosimetry models considering the tissue geometry characteristic of normal conditions may be inappropriate for dose estimation in case of protracted exposures. As internal exposures are frequently chronic, such changes in tissue geometry may be highly relevant for other incorporated radionuclides.

The eIF4F complex regulated by a various group of eIF4E-binding proteins (4E-BPs) can initial the protein synthesis. Small molecule compound 4EGI-1, an inhibitor of the cap-dependent translation initiation through disturbing the interaction between eIF4E and eIF4G which are main elements of the eIF4E complex, has been reported to suppress cell proliferation by inducing apoptosis in many types of cancer. And death receptor 5 (DR5) is a major component in the extrinsic apoptotic pathway. However, the correlation among 4EGI-1, DR5 and 4E-BPs have not been discovered in NPC now. Therefore, we intend to find out the effect of 4EGI-1 on the apoptosis process of NPC and the relationship among 4EGI-1, DR5 and 4E-BPs. Our results revealed a significant down regulation of DR5 expression in NPC tissues, which inversely correlated with lymph node metastasis status and clinical stages. Depressed DR5 expression was an independent biomarker for poor prognosis in NPC, and elevated DR5 expression showed longer overall survival time in 174 NPC patients. Besides, 4EGI-1 induced apoptosis in NPC cells through the DR5-caspase-8 axis on 4E-BP1 and eIF4E dephosphorylation exerting positive influence on their anti-tumor activities. The induction of DR5 also sensitized NPC cells to radiotherapy, and the SER was 1.195. These results establish the death receptor pathway as a novel anticancer mechanism of eIF4E/eIF4G interaction inhibitor in NPC., Competing Interests: The authors declare they have no conflicts of interest.

Gingival augmentation techniques proposed in the international literature do not exclude a surgical component, which determines consequent post-surgical discomfort and results are not always predictable. In recent years, the introduction of laser biostimulation has led to a less invasive approach, particularly in the treatment of periodontally compromised patients, limiting the surgical phase to seriously compromised cases, with regeneration techniques for the restoration of a correct periodontal tissue anatomy. The aim of this in vitro study is to establish the validity of laser biostimulation in order to develop the epithelial keratinized layer of the tissue by stimulating fibroblasts-keratinocytes organotypic cultures and fibroblasts and keratinocytes mono-cultures. We created two groups (test and control), each one composed of 3 fibroblast cultures, 3 keratinocyte cultures and 3 organotypic cultures. We performed laser irradiation of test group with Wiser Doctor Smile Lambda, Flat Top Handpiece, at 50 J/cm2 of fluency with one application every 40 h for a total of 5 applications. Forty-eight h after the last laser application, we investigated the presence and amount of keratins 5 and 8 with citofluorymetric and western blotting analyses. Analyses showed an increase in keratin synthesis in test group cultures, showing a remarkable increase in production of keratin 8 in co-cultures test. Laser biostimulation can considerably enhance keratin synthesis when applied with high energy doses and repeated applications to keratinocytes-fibroblasts co-cultures.

Aim: The authors assessed the influence of preoperative radiotherapy on autophagy process using a quantitative assessment of LC3 expression on both normal and tumoral colorectal tissues., Materials and Methods: Normal and malignant tissue samples were taken from 50 patients that underwent surgery for colorectal adenocarcinoma of which 11 received preoperative radiotherapy. Tissue samples were included in paraffin and sections were immunomarked for LC3 expression. LC3 percentage was assessed with dedicated software on 10 randomly selected fields with 40× objective from both normal and malignant tissue samples of each patient. The resulting data were assessed and compared with a statistical apparatus., Results: LC3 was overexpressed in tumoral tissue as compared with normal one. The LC3 percentage is different from person to person and the higher it is in normal epithelium, the higher will be in tumoral epithelium of the same person, regardless the irradiation. The LC3 expression levels are decreasing from tumoral non-irradiated epithelia to normal irradiated epithelia. LC3 expression in tumoral cells is granular, with particular perinuclear disposal and often "annular" pattern., Conclusions: The autophagy process has a basal level in the normal tissue, with interindividual variability. The autophagy process proved to be upregulated in the tumoral cells, with a particular morphological expression, namely the presence of cytoplasmic coarse granules disposed in an "annular" pattern. Preoperative radiotherapy is downregulating the autophagy process both in normal and tumoral tissue but to a lesser extent in the latter.

Introduction: Epithelitis is a frequent side effect in radiotherapy treatments (RT)., Objective: To evaluate the effectiveness of Rosehip Oil (ARM, Repavar®) in the prevention of epithelitis in patients with head and neck cancer (HNC) treated with intensity modulated radiotherapy (IMRT)., Material and Methods: An interventionist, prospective, exploratory, controlled and open clinical study. Between May and October 2013, 28 patients were included in the study. After signing the informed consent form, the patients were provided with ARM to apply this twice daily from the beginning of the treatment. All of them had a prescribed dose of IMRT ≥ 60 Gy. They were evaluated weekly by nurses on the ward. A photographic monitoring of the skin with a registered grade of epithelitis and with signs of pain or other was carried out. The control group was formed of 34 consecutive patients with HNC treated with IMRT months prior to the study, whose skin treatment had been different products., Results: Both groups were comparable (age, sex, region and RT dose). In the study group (ARM), the number of treatments per patient (p = 0.3) and the natural days for treatment per patient (p = 0.38) were less; also, the number of patients who required treatments and who suffered from radiodermitis of III-IV grade, were less. It is probable that the limited specimen size may have influenced in the statistics., Conclusions: The effectiveness of ARM in the prevention of severe epithelitis in patients with HNC treated with RT is, at least, as effective (or more effective) as other and more common skin treatments. A randomized study would be required to confirm these findinas.

Low-level laser therapy (LLLT) has been extensively employed to improve epithelial wound healing, though the exact response of epithelium maturation and stratification after LLLT is unknown. Thus, this study aimed to assess the in vitro growth and differentiation of keratinocytes (KCs) and in vivo wound healing response when treated with LLLT. Human KCs (HaCaT cells) showed an enhanced proliferation with all the employed laser energy densities (3, 6 and 12 J/cm(2) , 660 nm, 100 mW), together with an increased expression of Cyclin D1. Moreover, the immunoexpression of proteins related to epithelial proliferation and maturation (p63, CK10, CK14) all indicated a faster maturation of the migrating KCs in the LLLT-treated wounds. In that way, an improved epithelial healing was promoted by LLLT with the employed parameters; this improvement was confirmed by changes in the expression of several proteins related to epithelial proliferation and maturation. Immunofluorescent expression of cytokeratin 10 (red) and Cyclin D1 (green) in (A) Control keratinocytes and (B) Low-level laser irradiated cells. Blue color illustrates the nuclei of the cells (DAPI staining)., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Exposure to high-energy charged particles (HZE ions) at low fluence could significantly affect astronaut health after prolonged missions in deep space by inducing mutations and related cancers. We tested the hypothesis that the mutagenic effects of HZE ions could be detected at low fluence in a mouse model that detects autosomal mutations in vivo. Aprt heterozygous mice were exposed to 0.2, 0.4 and 1.4 Gy of densely ionizing (48)Ti ions (1 GeV/amu, LET = 107 keV/μm). We observed a dose-dependent increase in the Aprt mutant fraction in kidney epithelium at the two lowest doses (an average of 1 or 2 particles/cell nucleus) that plateaued at the highest dose (7 particles/cell nucleus). Mutant cells were expanded to determine mutation spectra and translocations affecting chromosome 8, which encodes Aprt. A PCR-based analysis for loss of heterozygosity (LOH) events on chromosome 8 demonstrated a significant shift in the mutational spectrum from Ti ion exposure, even at low fluence, by revealing "radiation signature" mutations in mutant cells from exposed mice. Likewise, a cytogenetic assay for nonreciprocal chromosome 8 translocations showed an effect of exposure. A genome-wide LOH assay for events affecting nonselected chromosomes also showed an effect of exposure even for the lowest dose tested. Considered in their entirety, these results show that accelerated (48)Ti ions induce large mutations affecting one or more chromosomes at low dose and fluence.

The effect of mobile phone radiation on human reproduction system is still a matter of debate. In this study, 18 male rabbits were randomly divided into two experimental groups and one control group. Experimental groups received simulated microwaves with the frequency of 950 MHz and the output power of 3 and 6 watts for 2 weeks, 2 h a day. After a week of rest, the microscopic slides from the quada of the excised epididymis were prepared. Then, the diameter of epididymis, the height of epithelium and the number of apoptotic cells in epithelium in study groups were determined. The data were compared using spss software and one-way anova test. The epithelial height and diameter of the epididymis in 3 watt and 6 watt groups had a significant decrease compared to the control group (P < 0.001), while the testosterone level only in 6 watt group was significantly decreased compared to control group. The rate of apoptosis in the epithelial cells of the epididymis had a significant increase only in 6 watt group compared to the control group (P < 0.001). This study showed that the microwaves with the frequency of 950 MHz can have negative impacts on morphometric and apoptotic changes of rabbit epididymis., (© 2014 Blackwell Verlag GmbH.)

Strategies for attenuating decline in balance function with increasing age are predominantly focused on physical therapies including balance tasks and exercise. However, these approaches do not address the underlying causes of balance decline. Using mice, the impact of near infrared light (NIr) on the metabolism of cells in the vestibular sensory epithelium was assessed. Data collected shows that this simple and safe intervention may protect these vulnerable cells from the deleterious effects of natural aging. mRNA was extracted from the isolated peripheral vestibular sensory epithelium (crista ampullaris and utricular macula) and subsequently transcribed into a cDNA library. This library was then probed for the expression of ubiquitous antioxidant (SOD-1). Antioxidant gene expression was then used to quantify cellular metabolism. Using transcranial delivery of NIr in young (4 weeks) and older (8-9 months) mice, and a brief treatment regime (90 sec/day for 5 days), this work suggests NIr alone may be sufficient to improve mitochondrial function in the vestibular sensory epithelium. Since there are currently no available, affordable, non-invasive methods of therapy to improve vestibular hair cell function, the application of external NIr radiation provides a potential strategy to counteract the impact of aging on cellular metabolism inthe vestibular sensory epithelium.

Vaginal atrophy occurring during menopause is closely related to the dramatic decrease in ovarian estrogens due to the loss of follicular activity. Particularly, significant changes occur in the structure of the vaginal mucosa, with consequent impairment of many physiological functions. In this study, carried out on bioptic vaginal mucosa samples from postmenopausal, nonestrogenized women, we present microscopic and ultrastructural modifications of vaginal mucosa following fractional carbon dioxide (CO2) laser treatment. We observed the restoration of the vaginal thick squamous stratified epithelium with a significant storage of glycogen in the epithelial cells and a high degree of glycogen-rich shedding cells at the epithelial surface. Moreover, in the connective tissue constituting the lamina propria, active fibroblasts synthesized new components of the extracellular matrix including collagen and ground substance (extrafibrillar matrix) molecules. Differently from atrophic mucosa, newly-formed papillae of connective tissue indented in the epithelium and typical blood capillaries penetrating inside the papillae, were also observed. Our morphological findings support the effectiveness of fractional CO2 laser application for the restoration of vaginal mucosa structure and related physiological trophism. These findings clearly coupled with striking clinical relief from symptoms suffered by the patients before treatment.

Objective: The purpose of this in vivo study was to examine morphologic alterations in the periodontal pocket epithelium with presence or absence of clinical inflammation following the use of the Neodymium: Yttrium-Aluminum-Garnet (Nd:YAG) laser irradiation., Background Data: Subgingival Nd:YAG laser irradiation has been proposed as an alternative technique for treatment of chronic periodontitis. Several published studies have reported the clinical outcomes of such treatment., Methods: Twenty patients, diagnosed with moderate chronic periodontitis, were selected for the study. A total of 32 sites was identified and divided into a control (n=18) and laser-treated test groups (n=14). Probing depth (PD) and bleeding on probing (BOP) were recorded for all sites. Test sites were irradiated with an Nd:YAG laser using parameters of 2 W, 200 mJ pulse energy, and 10 pps delivered through a 320 μm diameter tip. Total laser treatment time ranged from 1 to 2 min. Following treatment, all specimens were harvested via biopsy and processed for scanning electron microscopy (SEM) and histologic examination., Results: Control group specimens, depending upon initial PD, exhibited either a relatively smooth and intact epithelium with little desquamation (PD≤3 mm), or increasing degrees of epithelial desquamation and leukocytic infiltration at a PD of ≥4 mm. In the laser-treated test group, the specimens with PD≤3 mm that were BOP negative (-) exhibited a thin layer of epithelium that was disrupted. In the specimens with initial PD of ≥4 mm, complete removal of the epithelium whose extent and degree were increasing, was observed in the inflamed portion, while epithelium remained in the uninflamed portion., Conclusions: The SEM and histologic findings demonstrated the feasibility of ablating pocket epithelium with an Nd:YAG laser irradiation using parameters of 2 W of power (200 mJ, 10 pps). Furthermore, the presence or absence of clinical inflammation appeared to have an impact on the degree of laser-mediated epithelial ablation.

The aim of this study was to evaluate effects of intermediate frequency magnetic fields (IFMF) generated by a wireless power transmission (WPT) based on magnetic resonance from the perspective of cellular genotoxicity on cultured human lens epithelial cells (HLECs). We evaluated the effects of exposure to 90 kHz magnetic fields at 93.36 µT on cellular genotoxicity in vitro for 2 and 4 h. The magnetic flux density is approximately 3.5 times higher than the reference level recommended by the International Commission on Non-Ionizing Radiation Protection (ICNIRP) guidelines. For assessment of genotoxicity, we studied cellular proliferation, apoptosis and DNA damage by Cell Counting Kit-8 (CCK-8) assay, flow cytometry analysis, alkaline comet assay and phosphorylated histone H2AX (γH2AX) foci formation test. We did not detect any effect of a 90 kHz IFMF generated by WPT based on magnetic resonance on cell proliferation, apoptosis, comet assay, and γH2AX foci formation test. Our results indicated that exposure to 90 kHz IFMF generated by WPT based on magnetic resonance at 93.36 µT for 2 and 4 h does not cause detectable cellular genotoxicity., (© 2014 Wiley Periodicals, Inc.)

Oral mucositis (ulcer) is a serious and painful side effect for patients with head and neck cancer following radiation therapy. However, current clinical strategies cannot efficiently prevent the occurrence of oral mucositis. In this study, we investigated whether bone marrow-derived cells (BMDCs) prevented the occurrence and/or decreased the severity of radiation-induced oral mucositis. Fresh concentrated BMDCs from male C3H mice were transplanted intravenously into female mice after tongue irradiation. For 14 days postirradiation, the changes of body weight and the time courses of ulceration were observed. Until the ulcer reached maximum size (7 days postirradiation), macroscopic and histologic analyses of harvested tongues were performed to detect the behavior of donor BMDCs. Between 2 and 5 days postirradiation, BMDCs-transplanted mice showed more expression of stem cell markers (c-Kit, Sca-1) and EGFR and fewer apoptotic cells when compared with nontransplanted control mice (irradiation group). On day 7, there were fewer and smaller ulcers observed in the BMDCs-transplanted group. Tongues of these mice had preserved their epithelial thickness, and regenerative activities (blood vessels formation, cell proliferation) were higher than they were in the irradiation group. Fluorescently labeled BMDCs were not detected in tongue epithelium but rather in connective tissue (dermis) just below the basal cell layer. These findings suggest that exogenous BMDCs behave to reduce radiogenic oral mucositis in a paracrine manner., (© International & American Associations for Dental Research.)

A mathematical model, which describes the dynamics of acutely irradiated skin epidermal epithelium in swine, is developed. This model embodies the key mechanisms of regulation of skin epidermal epithelium and the principal stages of development of its cells (basal, prickle, and corneal). The model is implemented as a system of nonlinear ordinary differential equations, whose variables and parameters have clear biological meaning. The modeling results for the dose- and time-dependent changes in basal and prickle cell populations are in a good agreement with relevant experimental data. The correlation between the experimental data on the dynamics of moist reaction in acutely irradiated swine skin epidermal epithelium and the corresponding modeling results on the dynamics of corneal cells is revealed. Proceeding from this, the threshold level of corneal cells, which indicates the appearance of the moist reaction, is found. All this bears witness to the validity of employment of the developed model, after appropriate identification, in the investigation and prediction of radiation effects on skin epidermal epithelium in humans.

There is a considerable debate between research groups applying the two-stage clonal expansion model for lung cancer risk estimation, whether radon exposure affects initiation and transformation or promotion. The aim of the present study is to quantify the effects of radon progeny on these stages with biophysical models. For this purpose, numerical models of mutation induction and clonal growth were applied in order to estimate how initiation, transformation and promotion rates depend on tissue dose rate. It was found that rates of initiation and transformation increase monotonically with dose rate, whereas effective promotion rate decreases with time but increases sublinearly with dose rate. Despite the uncertainty of results due to the lack of experimental data, present study suggests that effects of radon exposure on both mutational events and clonal growth are significant and should be considered in mechanistic models of carcinogenesis applied for analysing epidemiological data., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: The biostimulation effects of low-level laser therapy (LLLT) have been demonstrated recently. This study investigated the effects of LLLT on palatal mucoperiosteal wound healing and oxidative stress status in rats., Material and Method: Forty-two male Wistar rats weighing 250-300 g were used in this study. A standardized full-thickness wound was created in the mucoperiosteum of the hard palates of the rats using a 3-mm-diameter biopsy punch. Treatment using a GaAlAs laser at a wavelength of 940 nm and a dose of 10 J/cm(2) was initiated after surgery and repeated on the 2nd, 4th, and 6th days post-surgery. Seven animals from each group were sacrificed on the 7th, 14th, and 21st days after surgery. Total antioxidant status and total oxidative status were measured in serum., Results: The histopathological findings revealed reduced numbers of inflammatory cells on the 7th day, increased mitotic activity of fibroblasts on the 14th and 21st day, and the same degree of collagen synthesis and vascularization on the days 7, 14, and 21 in the LLLT group compared with the control group. No significant differences in total oxidative status and total antioxidant status were observed between the groups., Conclusion: LLLT using a GaAlAs laser at a wavelength of 940 nm and a dose of 10 J/cm(2) elicited a positive healing effect on palatal mucoperiosteal wounds likely via the induction of fibroblasts. The oxidative stress status was not affected by LLLT., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Fractionation can improve photodynamic therapy (PDT) efficacy for potentially malignant oral lesion treatment. The aim of this study was to demonstrate the apoptosis/proliferation index of oral keratinocytes after two sessions of topical 5-ALA-mediated PDT in 4-Nitroquinoline-1-oxide-induced potentially malignant oral lesion, and to suggest the ideal interval between PDT sessions. Immuno-histochemical tests for proliferating cell nuclear antigen and caspase-3, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay were performed at 6h, 24h, 48h, and 72h time intervals after PDT. The number of positive cells showing caspase-3 expression was significantly higher, mainly at 6h after PDT. In the first cycle of PDT, the highest frequency of positive cells for TUNEL was found at 24h. At 72h after PDT, proliferating cell nuclear antigen positive cells increased significantly, indicating that there was an epithelial response in direction towards DNA repair and cell proliferation at this time. Because cell proliferation increases and cell death index decreases at 72h after PDT, it is recommended that the interval between the PDT sessions must not be longer than 2days up to total lesion remission., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The aim of this study was to evaluate the suitability of tissue-engineered mucosa (TEM) as a model for studying the acute effects of ionizing radiation (IR) on the oral mucosa. TEM and native non-keratinizing oral mucosa (NNOM) were exposed to a single dose of 16.5Gy and harvested at 1, 6, 24, 48, and 72h post-irradiation. DNA damage induced by IR was determined using p53 binding protein 1 (53BP1), and DNA repair was determined using Rad51. Various components of the epithelial layer, basement membrane, and underlying connective tissue were analyzed using immunohistochemistry. The expression of cytokines interleukin-1β (IL-1β) and transforming growth factor beta 1 (TGF-β1) was analyzed using an enzyme-linked immunosorbent assay. The expression of DNA damage protein 53BP1 and repair protein Rad51 were increased post-irradiation. The expression of keratin 19, vimentin, collage type IV, desmoglein 3, and integrins α6 and β4 was altered post-irradiation. Proliferation significantly decreased at 24, 48, and 72h post-irradiation in both NNOM and TEM. IR increased the secretion of IL-1β, whereas TGF-β1 secretion was not altered. All observed IR-induced alterations in TEM were also observed in NNOM. Based on the similar response of TEM and NNOM to IR we consider our TEM construct a suitable model to quantify the acute biological effects of IR., (Copyright © 2013 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Good vision requires a healthy cornea, and a healthy cornea needs healthy stem cells. Limbal epithelial stem cells (LESCs) are a traditional source of corneal epithelial cells and are recruited for the continuous production of epithelium without seizing throughout an animal's life, which maintains corneal transparency. Like the maintenance of other adult somatic stem cells, the maintenance of LESCs depends on the specific microenvironmental niche in which they reside. The purpose of this study was to determine the microenvironmental damage associated with LESCs fate due to ultraviolet (UV)-B exposure in a mouse model. Structural alteration and deregulation of the stem cell and its neighboring niche components were observed by using clinical, morphological, explant culture study, and flowcytometric analysis, which demonstrated that the limbal microenvironment plays an important role in cornea-related disease development. In UV-exposed mice, overexpression of vascular endothelial growth factor receptor 2 indicated neovascularization, decreased CD38 expression signified the alteration of limbal epithelial superficial cells, and the loss of limbal stem cell marker p63 indicated limbal stem cell deficiency in the limbal vicinity. We concluded that LESC deficiency diseases (LESCDDs) are associated with pathophysiological changes in the LESC niche, with some inhibitory interception such as UV-B irradiation, which results in corneal defects.

Lingual keratinized epithelial cells, which constitute the filiform papillae of the tongue, have one of the most rapid tissue turnover rates in the mammalian body and are thought to be the source of squamous cell carcinoma of the tongue. However, the mechanism of tissue maintenance and regeneration is largely unknown for these cells. Here, we show that stem cells positive for Bmi1, keratin 14 and keratin 5 are present in the base but not at the very bottom of the interpapillary pit (observed most frequently in the second or third layer (position +2 or +3) from the basal cells). Using a multicolour lineage tracing method, we demonstrated that one stem cell per interpapillary pit survives long-term. The cells were shown to be unipotent stem cells for keratinized epithelial cells but not for taste bud cells, and were found to usually be in a slow-growing or resting state; however, on irradiation-induced injury, the cells rapidly entered the cell cycle and regenerated tongue epithelium. The elimination of Bmi1-positive stem cells significantly suppressed the regeneration. Taken together, these results suggest that the stem cells identified in this study are important for tissue maintenance and regeneration of the lingual epithelium.

After injection of green fluorescent protein-positive (GFP(+)) bone marrow (BM) cells into lethally irradiated wild-type mice, the organs of the recipient mice [BM transplantation (BMT) mice] were regenerated; however, irradiation of the cecum or spleen (only) blocked their regeneration with loss of injected BM cells. These results suggest that the donor cells first enter the BM and then migrate to the peripheral organs. The maintenance of epithelial structure and function is controlled by interactions between stromal cells and the epithelia; the organ is stable only if the stroma is functioning normally. In BMT mice, intestinal GFP(+) stromal cells were regenerated fairly rapidly although GFP(+) cells were observed only rarely in the intestinal epithelium even if it passes several weeks or months post BMT, indicating that BM-derived stromal cells play a pivotal role in epithelial renewal and are crucial for maintaining organ structure and function. BM-derived cells in the periphery possess a special key to return to the BM and then to migrate to various organs to become resident cells., (Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)