LC3 Accelerated Brain-Lung Axis Abscopal Effects after Fractionated Whole-Brain Radiation by Promoting Motoneurons to Secrete Periostin.

The effect of autophagy on the radiation-induced bystander effect (RIBE) in vivo is unclear. Here, the whole brains of microtubule-associated protein 1A/1B-light chain 3 (LC3) and C57BL/6 (B6) mice were irradiated once (10 Gy)(IR1), given 3 fractions in three weeks (IR3), or 6 fractions in six weeks (IR6). The median survival of LC3 mice was 56.5 days, and that of B6 mice was 65 days after IR6. LC3 mice showed more congestion and fibrosis in the lung after the IR3 and IR6 irradiation protocols than B6 mice. Quantitative proteomics of serum samples and lung RNA sequencing of the LC3 group showed that the common most clustered pathway of the IR3 group was the elastic fiber formation pathway, which contained Periostin (POSTN). POSTN in the motoneurons increased with increasing number of radiation fractions in LC3 mice. A 1 µg/g POSTN neutralizing antibody reduced the lung fibrosis of LC3 mice exposed to IR3 by one-third, and significantly prolonged the survival time of LC3 mice exposed to IR6. LDN-214117 and LRRK2-in-1 were the best two of sixteen transforming growth factor-beta1 (TGF-ß) receptor and autophagy mediators to decrease Postn mRNA. These data led us to conclude that LC3 accelerated motoneuron secretion of POSTN and aggravated the RIBE in the lung after brain irradiation.

Exosome-coated polydatin nanoparticles in the treatment of radiation-induced intestinal damage.

This study aimed to develop an exosome-coated polydatin (PD) nanoparticles (exo-PD) for improving the water solubility and bioavailability of polydatin and explore its salutary effects on intestinal radiation injury. Exosomes (exo) were extracted from the medium of human amniotic fluid stem cells (hAFSc). Mice were divided into control group, irradiation (IR) group, irradiation+PD (IR+PD) group, irradiation+exo (IR+exo) group and irradiation+exo-PD (IR+exo-PD) group. The results of characterization of protein markers, particle size, morphology and cellular uptake ability confirmed that exosomes were effectively isolated using ultracentrifugation. Compared with the IR group, exo-PD improved cell viability, prolonged survival of mice, improved leukocyte count and reduced diarrhea rate. Histological results showed that the exo-PD group had significant improvements in small intestinal villus length and crypt number and less crypt cell damage. exo-PD could reduce IL-1α and IL-6 levels, reduced γ-H2AX expression, increased mitochondrial membrane potential, enhanced oxidative phosphorylation, and delayed cellular senescence. exo-PD could alleviate intestinal injury by improving mitochondrial function through PI3K-AKT pathway. The exo-PD was able to reduce radiation damage to intestinal cells and could be a potential candidate for salvage of intestinal radiation damage.

Radiation Protection of Polydatin Against Radon Exposure Injury of Epithelial Cells and Mice.

Radon exposure is significantly associated with lung cancer. Radon concentration is currently reduced mainly by physical methods, but there is a lack of protective drugs or biochemical reagents for radon damage. This study aimed to explore the protective effect of polydatin (PD) on the radon-exposed injury. The results showed that PD can significantly reduce ROS level, raise SOD activity, weaken the migration ability, increase E-cad, and decrease mesenchymal cell surface markers (FN1, Vimentin, N-cad, α-SMA, and Snail) in radon-exposed epithelial cells. In vivo, PD increased the mice weight, promoted SOD activity, and decreased MDA content, the number of bullae, pulmonary septum thickness, lung collagenous fibers, and mesenchymal cell surface markers. Furthermore, PD inhibited p-PI3K, p-AKT, and p-mTOR expression. Compared with directly adding PD on radon-exposed cells, adding PD before and after radon exposure could more obviously improve the adhesion of radon-exposed cells, significantly alleviate the migration ability, and more significantly reduce mesenchyme markers and p-AKT and p-mTOR. These results indicate that PD can reduce oxidative stress, weaken epithelial-mesenchymal transition (EMT) and lung fibrosis in radon-exposed cells/mice, and have good radiation protection against radon injury. The mechanism is related to the inhibition of the PI3K/AKT/mTOR pathway.

Identification and validation of diagnostic signature genes in non-obstructive azoospermia by machine learning.

Non-obstructive azoospermia (NOA) is a common cause of male infertility, and no specific diagnostic indicators exist. In this study, we used human testis datasets GSE45885, GSE45887, and GSE108886 from GEO database as training datasets, and screened 6 signature genes (all lowly expressed in the NOA group) using Boruta algorithm and Lasso regression: C12orf54, TSSK6, OR2H1, FER1L5, C9orf153, XKR3. The diagnostic efficacy of the above genes was examined by constructing models with LightGBM algorithm: the AUC (Area Under Curve) of both ROC and Precision-Recall curves for internal validation was 1.0 (p < 0.05). For the external validation dataset GSE145467 (human testis), the AUC of its ROC curve was 0.9 and that of its Precision-Recall curve was 0.833 (p < 0.05). Next, we confirmed the cellular localization of the above genes using human testis single-cell RNA sequencing dataset GSE149512, which were all located in spermatid. Besides, the downstream regulatory mechanisms of the above genes in spermatid were inferred by GSEA algorithm: C12orf54 may be involved in the repression of E2F-related and MYC-related pathways, TSSK6 and C9orf153 may be involved in the repression of MYC-related pathways, while FER1L5 may be involved in the repression of spermatogenesis pathway. Finally, we constructed a NOA model in mice using X-ray irradiation, and quantitative Real-time PCR results showed that C12orf54, TSSK6, OR2H1, FER1L5, and C9orf153 were all lowly expressed in NOA group. In summary, we have identified novel signature genes of NOA using machine learning methods and complete experimental validation, which will be helpful for its early diagnosis.

Novel treatment and insight for irradiation-induced injuries: Dibucaine ameliorates irradiation-induced testicular injury by inhibiting fatty acid oxidation in primary Leydig cells.

BACKGROUND: Male infertility is a worldwide problem but few treatments, especially irradiation-induced testicular injury. The aim of this research was to investigate novel drugs for the treatment of irradiation-induced testicular injury. METHODS: We administered dibucaine (0.8 mg/kg) intraperitoneally to male mice (6 mice per group) after five consecutive daily 0.5 Gy whole-body irradiation, and evaluated its ameliorating efficacy by testicular HE staining and morphological measurements. Drug affinity responsive target stability assay (Darts) were used to find target protein and pathway; mouse primary Leydig cells were isolated and to explore the mechanism (Flow cytometry, Western blot, and Seahorse palmitate oxidative stress assays); finally rescue experiments were completed by combining dibucaine with fatty acid oxidative pathway inhibitors and activators. RESULTS: The testicular HE staining and morphological measurements in dibucaine treatment group was significantly better than that in irradiation group (P < 0.05); sperm motility and mRNA levels of spermatogenic cell markers were also higher than those in the latter (P < 0.05). Darts and Western blot results showed that dibucaine targets CPT1A and downregulate fatty acid oxidation. Flow cytometry, Western blot, and Palmitate oxidative stress assays of primary Leydig cells demonstrated that dibucaine inhibits fatty acid oxidation in Leydig cells. Dibucaine combined with etomoxir/baicalin confirmed that its inhibition of fatty acid oxidation was beneficial in ameliorating irradiation-induced testicular injury. CONCLUSIONS: In conclusion, our data suggest that dibucaine ameliorates irradiation-induced testicular injury in mice by inhibiting fatty acid oxidation in Leydig cells. This will provide novel ideas for the treatment of irradiation-induced testicular injury.

Improving effects of telmisartan on spermatogenic disorder induced by fractionated low-dose irradiation in mice.

BACKGROUND: Male infertility is a hot problem worldwide, but there are few treatments, especially male infertility caused by irradiation is difficult to treat. The aim of this study was to investigate and evaluate novel drugs for the treatment of male infertility caused by irradiation. METHODS: we randomly divided 18 male BALB/c mice into 3 groups: control, irradiated, and telmisartan. Both irradiated and telmisartan group completed whole-body 0.5 Gy five times irradiation, and the telmisartan group received intraperitoneal injection of telmisartan (1.2 mg/kg) daily on the next day after irradiation, and all groups were sampled on day 25 after irradiation. RESULTS: Sperm motility results show that total sperm motility of irradiated group was significantly lower compared with control group, and testicular HE results showed that testis in irradiated group were severely damaged. Compared with irradiated group, the total sperm motility, sperm concentration, testicular index, Johnsen score, and the seminiferous tubule layer numbers were higher in telmisartan group (P < 0.05). The immunohistochemical staining showed γ-H2AX expression is higher in telmisartan group compared with irradiated group. And the relative mRNA expression of PLZF, GFRA1, STRA8, DMRT1, SPO11, SYCP2, OVOL2, CCNA1, TJP3, RUNX2, TXNDC2 TNP1, and PRM3 in telmisartan group was all significantly higher than irradiated group (P < 0.05). CONCLUSION: In conclusion, in vivo experiments confirmed that telmisartan ameliorated the spermatogenic disorder in mice caused by fractionated low-dose irradiation via promoting spermatogenesis.

[Differential expressions of seminal plasma piRNAs in men and its significance].

OBJECTIVE: To study the differential expressions of piRNAs in the seminal plasma of men and the role of piRNAs in spermatogenesis. METHODS: We sequenced the seminal plasma samples collected from 187 male infertility patients and 58 normal healthy men, obtained differentially expressed piRNAs, and detected the relative expressions of piRNAs in different types of sperm by RT-qPCR to explore their significance in the diagnosis of male infertility. Using histopathology, RNA-protein pull-down and Western blot, we investigated the action mechanism of piRNAs in spermatogenesis in the mouse model. RESULTS: RT-qPCR of the seminal plasma samples revealed a high expression of hsa_piR_000478 in teratozoospermia and ROC curve analysis showed an auxiliary significance of hsa_piR_000478 in the diagnosis of the disease (AUC = 0.7549). Transfection of hsa_piR_000478 and its homologous sequence piR_mmu_54800729 into the seminiferous tubules of the mouse model significantly decreased sperm motility, increased the percentage of morphologically abnormal sperm and destroyed the testicular structure. Molecular biological experiments exhibited a close correlation between piRNAs and the energy metabolism-related pathway, which elevated the level of cell glycolysis and interfered with normal spermatogenesis. CONCLUSION: hsa_piR_000478 has an auxiliary significance in the diagnosis of male infertility, and piRNAs may interfere with spermatogenesis by affecting the glycolysis-related pathway in the spermatogenic microenvironment of the testis.

Protective Effects of Polydatin on Reproductive Injury Induced by Ionizing Radiation.

The reproductive system is vulnerable to ionizing radiation, which is a hot research topic at present. We tested the effect of polydatin on spermatocytes(GC-1 cells) after X-ray irradiation. The reproductive damage model of C.elegans was established by 60Coγ-ray, and the protective effect of polydatin on reproductive damage caused by ionizing radiation was evaluated. We quantified the ROS levels of GC-1 cells and C.elegans after irradiation with polydatin and evaluated the anti-apoptosis effect of polydatin at proper concentration. Differential genes of C.elegans reproductive damage were screened out from transcriptome sequencing results and comparable GEO datasets. It was proved that 100µM polydatin significantly reduced the apoptosis of GC-1 cells induced by 2 Gy X-ray. In addition, the longevity, reproductive capacity, germ cell apoptosis and spawning and hatching capacity of polydatin were tested. The results showed that 100 µM polydatin content significantly increased the influence of 50 Gy 60Coγ-ray on reproductive capacity of C.elegans. Quantitative analysis of mRNA and protein levels of apoptosis-related genes and reproductive-related genes by qRT-PCR and Western blotcon firmed that polydatin with appropriate dosage had good protective effects on reproductive damage caused by radiation, which laid a foundation for the application research of polydatin in radiation protection.

Proteomic and miRNA profiling of radon-induced skin damage in mice: FASN regulated by miRNAs.

Radon is a naturally occurring radioactive gas and considered as a serious carcinogen to humans. Continuous radioactive decay of this gas emits high-energy alpha particles. Long-term radon exposure induces oxidative stress and inflammatory response, which results in chronic lung diseases. However, biological effects after radon exposure in other organs have been rarely reported. As the outermost organ of the human body, the skin suffers from environmental damage to agents such as air pollution. Epidemiological studies indicated that areas with high level of radon had a high incidence of skin cancer. However, whether radon exposure induces skin damage has not been reported yet. In this study, we established a radon-exposed mouse model and found that radon exposure affected the structure of skin tissues, which was manifested by inflammatory cell infiltration and skin atrophy. Using proteomic approach, we found 45 preferentially expressed proteins in 60 Working Level Months (WLM) group and 314 preferentially expressed proteins in 120 WLM group from radon-exposed skin tissues. Through microRNA (miRNA) sequencing profiling analysis, 57 dysregulated miRNAs were screened between the control and radon-treated mouse skin. By integrating the dysregulated proteins and miRNAs, radon-induced fatty acid synthase (FASN) was investigated in greater detail. Results showed that FASN was regulated by miR-206-3p and miR-378a-3p and involved in the pathogenesis of radon-induced skin damage. Overexpression of FASN inhibited the proliferation, and induced in WS1 cells. Our present findings illustrate the molecular change during radon-induced skin damage and the potential role of FASN during this process.

Analysis of circRNA-miRNA-mRNA Regulatory Network in Peripheral Blood of Radiation Workers.

The health of radiation workers has always been our focus. Epidemiological investigation shows that long-term exposure to low-dose ionizing radiation can affect human health, especially cancer and cardiovascular disease, and there are many studies on it. However, up to now, there have been few reports on the research of blood and biological samples from radiation workers. In this study, radiation workers and healthy control groups were strictly screened, and the transcriptome of mRNA and circRNA was sequenced by extracting their peripheral venous blood. At the same time, appropriate data sets were selected in the GEO database for bioinformatics analysis, and circRNA-miRNA-mRNA network was constructed. We identified 9 different circular ribonucleic acids, 3 tiny ribonucleic acids, and 2 central genes (NOD 2 and IRF 7). These differentially expressed genes and non-coding RNA are closely related to ionizing radiation damage, and play an important role as biological markers. In conclusion, this study may provide new insights into the role of the circRNA-miRNA-mRNA regulatory network in the health of radiation workers, and provides a new strategy for the future study of radiation biology.

Puerarin Reduces Radiation-Induced Vascular Endothelial Cell Damage Via miR-34a/Placental Growth Factor.

The aim is to explore the protective effects of Puerarin on radiation-induced vascular endothelial cell damage and its underlying mechanism. The apoptosis and DNA damage of Human umbilical vascular endothelial cells (HUVECs) exposed to radiation alone or in combination with glucose in the exposed group were significantly elevated (P < .05) compared with those in the control group. The Puerarin-treated HUVECs showed significant reduction in the radiation-induced apoptosis and DNA damage (P < .05). Furthermore, X-ray irradiation significantly increased the expression of miR-34a, which was reversed by pre-treatment with Puerarin. Placental Growth Factor (PLGF) was a target gene of miR-34a. The expression of PLGF in the peripheral blood of patients receiving radiotherapy significantly increased with an increase in the cumulative dose of radiation (P < .05), after which it began to decrease at the fourth week (P < .05) and then remained at a low level until the end of radiotherapy. Puerarin exerts a radioprotective effect by decreasing DNA damage and apoptosis through miR-34a-targeted PLGF.

Integrative effects based on behavior, physiology and gene expression of tritiated water on zebrafish.

Tritium is a water-soluble hydrogen isotope that releases beta rays during decay. In nature, tritium primarily exists as tritiated water (HTO), and its main source is nuclear power/processing plants. In recent decades, with the development of nuclear power industry, it is necessary to evaluate the impact of tritium on organisms. In this study, fertilized zebrafish embryos are treated with different HTO concentrations (3.7 × 103 Bq/ml, 3.7 × 104 Bq/ml, 3.7 × 105 Bq/ml). After treatment with HTO, the zebrafish embryos developed without evident morphological changes. Nevertheless, the heart rate increased and locomotor activity decreased significantly. In addition, RNA-sequencing shows that HTO can affect gene expressions. The differentially expressed genes are enriched through many physiological processes and intracellular signaling pathways, including cardiac, cardiovascular, and nervous system development and the metabolism of xenobiotics by cytochrome P450. Moreover, the concentrations of thyroid hormones in the zebrafish decrease and the expression of thyroid hormone-related genes is disordered after HTO treatment. Our results suggest that exposure to HTO may affect the physiology and behaviors of zebrafish through physiological processes and intracellular signaling pathways and provide a theoretical basis for ecological risk assessment of tritium.

Monte Carlo determination of dose coefficients at different developmental stages of zebrafish (Danio rerio) in experimental condition.

The release of liquid effluent of nuclear power into aquatic system increases with the rapid development of nuclear facilities in coastal and inland regions. Aquatic model animals are very important for the study of the radiation hazards to non-human biota in water environment and its extrapolation of dose-effect relationship to human models. However, the study of the radiation dose rate calculation model of the aquatic animal zebrafish is still on the homogeneous isotropic model used for the protection of the environment. A series of zebrafish models (including adults, larvae and embryos, named zebrafish-family: ZF-family) with multiple internal organs are established in this study to investigate the mechanism of radiation damage effect in order to protect non-human species. The internal and external dose coefficients (DCs) of the whole body, heart and gonads of zebrafishes are calculated in water environment with the combination of the real experimental culture condition, using Monte Carlo application package GATE (Geant4 Application for Emission Tomography) and eight nuclides, i.e., 3H, 14C, 90Sr, 60Co, 110mAg, 134Cs, 137Cs, 131I, which are commonly found in the liquid effluent of nuclear power plants, as the source items, The results show that the level of nuclide γ energy determines the external DCs (DCext), and 90Sr plays the most important role in internal DCs (DCint). The comparison between the external DCs of the heart and gonad and that of the whole body shows that DCs (DCext) of heart and gonad for females are 80% and 43% lower than that of whole body, respectively, while for males, the DCs (DCext) of heart is 44% lower than that of the whole body, and DCs (DCext) of gonad is slightly higher than that of the whole body for most nuclides (up to 25%).The dose of internal radiation makes greater contribution than that of external radiation to pure beta emitter (3H, 14C, 90Sr). This internal DCs of ZF-family model with complex internal structure turns out to demonstrate more sensitive DCs change trend and higher calculation values compared with the internal DCs of the simple ellipsoid model. In this model, the photon emitter with strong penetrating power has higher internal DCs, while the low-energy pure beta nuclide does not alter much. In conclusion, it is vital to carry out refined systematic modeling for model organisms, and the determination of DCs of model organs can promote the evaluation of the radiation effects on non-human species.

Development and Characterization of a Novel Hydrogel for the Decontaminating of Radionuclide-Contaminated Skin Wounds.

Designing skin decontaminating materials with outstanding therapeutic effects, adhesiveness, and suitable mechanical property has great practical significance in radionuclide-contaminated skin wound healing. Here, a physically crosslinked hydrogel is constructed via hydrogen bonding of poly acrylamide, sodium alginate (SA), and the complexing agent diethylene triamine pentaacetic acid (DTPA). The physical and chemical properties of the poly(AAm-SA-DTPA) hydrogel (PASD) are detected according to established methods. The decontaminating property and skin wound healing of the PASD are investigated to confirm multi-functions of wound dressing. The physical and chemical properties results show that the synthesis of the PASD hydrogel is effective and that DTPA is present in the hydrogel. The hydrogel also shows great mechanical and swelling properties. In vitro tests find that PASD shows significant scavenging abilities for strontium and cerium. In vivo experiments show that the PASD hydrogel can remove radioactive strontium from the skin wounds of mice, and can effectively prevent the absorption of radioactive strontium through the skin wound. Furthermore, the PASD hydrogel can effectively promote the formation of granulation tissue in a radioactive contaminated wound. Taken together, the PASD hydrogels, which has good mechanical properties and radionuclides decontamination, is expected to be used as a dressing for radionuclide-contaminated skin wound healing.

Repeated radon exposure induced lung injury and epithelial-mesenchymal transition through the PI3K/AKT/mTOR pathway in human bronchial epithelial cells and mice.

Radon exposure is the most frequent cause of lung cancer in non-smokers. The high linear energy transfer alpha-particles from radon decay cause the accumulation of multiple genetic changes and lead to cancer development. Epithelial-mesenchymal transition (EMT) plays an important role in oncogenesis. However, the mechanisms underlying chronic radon exposure-induced EMT attributed to carcinogenesis are not understood. This study aimed to explore the EMT and potential molecular mechanisms induced by repeated radon exposure. The EMT model of 16HBE and BEAS-2B cells was established with radon exposure (20000 Bq/m3, 20 min each time every 3 days). We found repeated radon exposure facilitated epithelial cell migration, proliferation, reduced cell adhesion and ability to undergo EMT through a decrease in epithelial markers and an increase in mesenchymal markers. Radon regulated the expression of matrix metalloproteinase 2 (MMP2) and tissue inhibitors of metalloproteinase 2 (TIMP2) to disrupt the balance of MMP2/TIMP2. In vivo, BALB/c mice were exposed to 105 Bq/m3 radon gas for cumulative doses of 60 and 120 Working Level Months (WLM). Radon inhalation caused lung damage and fibrosis in mice, which was aggravated with the increase of exposure dose. EMT-like transformation also occurred in lung tissues of radon-exposure mice. Moreover, radon radiation increased p-PI3K, p-AKT and p-mTOR in cells and mice. Radon reduced the GSK-3ß level and elevated the active ß-catenin in 16HBE cells. The m-TOR and AKT inhibitors attenuated radon exposure-induced EMT by regulation related biomarkers. These data demonstrated that radon exposure induced EMT through the PI3K/AKT/mTOR pathway in epithelial cells and lung tissue.

Tritiated Water Induces Toxicity in Human Umbilical Vein Vascular Endothelial Cells via IL8.

We aimed to determine the toxic effects of tritiated water (HTO) on 12 generations (T1-T12) of human umbilical vein vascular endothelial cells (HUVECs) and elucidate the underlying mechanisms. We evaluated cellular senescence, interleukin (IL) 8 concentrations, and angiogenesis using ß-galactosidase staining, enzyme-linked immunosorbent assay, and in vitro assays, respectively. The adhesion properties of contaminated cells and differentially expressed genes were assessed using the xCELLigence RTCA SP system and gene chip analysis, respectively. We found that long-term exposure to low levels of HTO can reduce the adhesion of HUVECs to the cellular matrix as well as their angiogenic capacity, while increasing their permeability, senescence, and adhesion to monocytes. Interleukin 8 activated the p38 and Epidermal Growth Factor Receptor (EGFR) pathways in HTO-treated cells and hence was identified as a key candidate of biomarker. The present study clarified the toxicity of HTO in vascular endothelial cells and identified IL8 as a novel protective target with important theoretical and practical values.

Ionizing radiation induces epithelial-mesenchymal transition in human bronchial epithelial cells.

OBJECTIVE: The present study aimed to analyze the mechanism by which long-term occupational exposure of workers to low-dose ionizing irradiation induces epithelial-mesenchymal transition (EMT) of the human bronchial epithelial cells using transcriptome profiling. METHODS: RNA-seq transcriptomics was used to determine gene expression in blood samples from radiation-exposed workers followed by bioinformatics analysis. Normal bronchial epithelial cells (16HBE) were irradiated for different durations and subjected to immunofluorescence, Western blotting, scratch healing, and adhesion assays to detect the progression of EMT and its underlying molecular mechanisms. RESULTS: Transcriptomics revealed that exposure to ionizing radiation led to changes in the expression of genes related to EMT, immune response, and migration. At increased cumulative doses, ionizing radiation-induced significant EMT, as evidenced by a gradual decrease in the expression of E-cadherin, increased vimentin, elevated migration ability, and decreased adhesion capability of 16HBE cells. The expression of fibronectin 1 (FN1) showed a gradual increase with the progression of EMT, and may be involved in EMT. CONCLUSION: Ionizing radiation induces EMT. FN1 may be involved in the progression of EMT and could serve as a potential biomarker for this process.

LKB1 inactivation leads to centromere defects and genome instability via p53-dependent upregulation of survivin.

Inactivating mutations in the liver kinase B1 (LKB1) tumor suppressor gene underlie Peutz-Jeghers syndrome (PJS) and occur frequently in various human cancers. We previously showed that LKB1 regulates centrosome duplication via PLK1. Here, we report that LKB1 further helps to maintain genomic stability through negative regulation of survivin, a member of the chromosomal passenger complex (CPC) that mediates CPC targeting to the centromere. We found that loss of LKB1 led to accumulation of misaligned and lagging chromosomes at metaphase and anaphase and increased the appearance of multi- and micro-nucleated cells. Ectopic LKB1 expression reduced these features and improved mitotic fidelity in LKB1-deficient cells. Through pharmacological and genetic manipulations, we showed that LKB1-mediated repression of survivin is independent of AMPK, but requires p53. Consistent with the key influence of LKB1 on survivin expression, immunohistochemical analysis indicated that survivin is highly expressed in intestinal polyps from a PJS patient. Lastly, we reaffirm a potential therapeutic avenue to treat LKB1-mutated tumors by demonstrating the increased sensitivity to survivin inhibitors of LKB1-deficient cells.

Repression of PCGF1 Decreases the Proliferation of Glioblastoma Cells in Association with Inactivation of c-Myc Signaling Pathway.

PURPOSE: Glioblastoma (GBM) is the most common primary brain tumor with a poor therapeutic outcome. Polycomb group factor 1 (PCGF1), a member of the PcG (Polycomb group) family, is highly expressed in the developing nervous system of mice. However, the function and the mechanism of PCGF1 in GBM proliferation still remain unclear. METHODS: Knockdown of PCGF1 was performed in U87 GBM cell by shRNA strategy via lentivirus vector. MTT assay, colony formation assays, and flow cytometry were used to measure the properties of cell proliferation and cell cycle distribution, respectively. GeneChip analysis was performed to identify the downstream effector molecules. Rescue assay was constructed to verify the screening results. RESULTS: We first found that knockdown of PCGF1 led to the inhibition of U87 cells proliferation and decreased colony formation ability. The data from GeneChip expression profiling and Ingenuity Pathway Analysis (IPA) indicated that many of the altered gene cells are associated with the cell proliferation control pathways. We have further confirmed the suppression of AKT/GSK3ß/c-Myc/cyclinD1 expressions by Western blotting analysis. The over-expression of c-Myc could partly restore the attenuated proliferation ability caused by knockdown of PCGF1. CONCLUSION: All the above evidences suggested that PCGF1 might be closely associated with tumorigenesis and progression of glioblastoma (GBM), in which process the oncoprotein c-Myc may participate. PCGF1 could thus be a potential therapeutic target for the treatment of glioblastoma (GBM).

Monitoring of Tritium Internal Exposure Doses of Heavy-Water Reactor Workers in Third Qinshan Nuclear Power Plant.

To analyze the tritium internal exposure dose of workers in the Third Qinshan Nuclear Power Plant over the past 15 years. Urine samples provided by workers are tested directly to analyze the tritium concentrations and estimate internal exposure dose. Since 2004, an average of approximately 1600 workers have been monitored annually, with an average annual monitoring frequency of approximately 11 000. Since 2004, the average annual collective dose of tritium internal exposure was 149.62 person·mSv, accounting for 19.07% of the total annual collective dose. A total of 18 workers' annual individual internal tritium radiation doses exceeded 2 mSv, of which 5 workers' internal tritium radiation doses in a single intake exceeded 2 mSv. The occupational population with the largest total internal tritium radiation doses consists of maintenance personnel, fuel operators, and radiation protection personnel, whose collective doses of internal exposure account for 75.51% of the total collective doses within the plant. Over 15 years of operation, the internal tritium radiation doses of workers in the Third Qinshan Nuclear Power Plant have been strictly controlled within the national regulatory limit and power plant management target, ensuring the health and safety of the workers.