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Air operating atomic force microscopy has been used to study human B lymphoblastoid (Raji) cells exposed to a 50 Hz 2 mT sinusoidal magnetic field (MF), up to 64 h. A statistical analysis performed on mean height and membrane roughness of the cells showed a loss of microvilli and several modifications of the overall shape and membrane surface at

The EBV genome in latently infected lymphoid cells offers an opportunity to follow effects on the transcriptional and translational product clearly distinguishable from those of the host cell genome. Exposure of Akata cells, a human lymphoid cell line latently infected by the EBV genome, to a 50 Hz EMF resulted in an increased number of cells expressing the virus early antigens. This finding provides additional evidence that DNA can be modulated by a magnetic field.

Bellocco, R Pasquali, E Rota, M Bagnardi, V Tramacere, I Scotti, L Pelucchi, C Boffetta, P Corrao, G La Vecchia, C eng Meta-Analysis England 2012/03/09 06:00 Ann Oncol. 2012 Sep;23(9):2235-44. doi: 10.1093/annonc/mds022. Epub 2012 Mar 7.; International audience; BACKGROUND: The role of alcohol consumption in relation with renal cell carcinoma is still unclear; a few studies have reported a beneficial effect of moderate levels of alcohol consumption, whereas it remains still under debate whether there is a dose-response association. MATERIALS AND METHODS: Twenty observational studies (4 cohort, 1 pooled and 15 case-control) reporting results on at least three levels of alcohol consumption were selected through a combined search with PubMed and EMBASE of articles published before November 2010. Overall relative risks (RRs) and 95% confidence intervals (CIs) were estimated using random-effects models, and both second-order fractional polynomials and random effect meta-regression models were implemented for the study of dose-risk relation. RESULTS: The estimated RRs were 0.85 (95% CI: 0.80-0.92) for any alcohol drinking, 0.90 (95% CI: 0.83-0.97) for light drinking (0.01-12.49 g/day), 0.79 (95% CI: 0.71-0.88) for moderate drinking (12.5-49.9 g/day) and 0.89 (95% CI: 0.58-1.39) for heavy drinking (>/=50 g/day), respectively. CONCLUSION: Our meta-analysis supports the hypothesis of a negative effect of moderate alcohol consumption on the risk of renal cell cancer.

DSBs are harmful lesions produced through endogenous metabolism or by exogenous agents such as ionizing radiation, that can trigger genomic rearrangements. We have recently shown that exposure to 2 Gy of X-rays has opposite effects on the induction of Shh-dependent MB in NHEJ- and HR-deficient Ptch1+/− mice. In the current study we provide a comprehensive link on the role of HR/NHEJ at low doses (0.042 and 0.25 Gy) from the early molecular changes through DNA damage processing, up to the late consequences of their inactivation on tumorigenesis. Our data indicate a prominent role for HR in genome stability, by preventing spontaneous and radiation-induced oncogenic damage in neural precursors of the cerebellum, the cell of origin of MB. Instead, loss of DNA-PKcs function increased DSBs and apoptosis in neural precursors of the developing cerebellum, leading to killing of tumor initiating cells, and suppression of MB tumorigenesis in DNA-PKcs-/-/Ptch1+/− mice. Pathway analysis demonstrates that DNA-PKcs genetic inactivation confers a remarkable radiation hypersensitivity, as even extremely low radiation doses may deregulate many DDR genes, also triggering p53 pathway activation and cell cycle arrest. Finally, by showing that DNA-PKcs inhibition by NU7441 radiosensitizes human MB cells, our in vitro findings suggest the inclusion of MB in the list of tumors beneficiating from the combination of radiotherapy and DNA-PKcs targeting, holding promise for clinical translation.

The advent of new 'omics' techniques determined a massive boost in the measurement of the whole spectra of molecules within cells, favoring promising new radiobiological studies at low doses. The main aim of this work was to assess the radiation-induced perturbations of miRNA profiles and their temporal dynamics. Human Umbilical Vein Endothelial Cells were irradiated with low doses of γ-rays. At different time points post-irradiation, cells were harvested and miRNAs isolated. A full mapping of the miRNA sequences via Next-Generation-Sequencing analysis was performed followed by bioinformatic analyses. Pathway enrichment analyses on the differentially expressed miRNAs focused both on the averaged effects of different doses over the 24-h experiment and on the altered temporal dynamics of the miRNA profiles. These complementary analyses provided a picture of the dose- and time-dependent miRNAs responses, allowing to better explore the candidate biomarkers linked to radiation exposures and their corresponding pathways and functions.

High-dose ionizing radiation is known to induce adverse effects such as inflammation and fibrosis in the heart. Transcriptional regulators PPARα and TGFβ are known to be involved in this radiation response. PPARα, an anti-inflammatory transcription factor controlling cardiac energy metabolism, is inactivated by irradiation. The pro-inflammatory and pro-fibrotic TGFβ is activated by irradiation via SMAD-dependent and SMAD-independent pathways. The goal of this study was to investigate how altering the level of PPARα influences the radiation response of these signaling pathways. For this purpose, we used genetically modified C57Bl/6 mice with wild type (+/+), heterozygous (+/-) or homozygous (-/-) PPARα genotype. Mice were locally irradiated to the heart using doses of 8 or 16 Gy; the controls were sham-irradiated. The heart tissue was investigated using label-free proteomics 20 weeks after the irradiation and the predicted pathways were validated using immunoblotting, ELISA, and immunohistochemistry. The heterozygous PPARα mice showed most radiation-induced changes in the cardiac proteome, whereas the homozygous PPARα mice showed the least changes. Irradiation induced SMAD-dependent TGFβ signaling independently of the PPARα status, but the presence of PPARα was necessary for the activation of the SMAD-independent pathway. These data indicate a central role of PPARα in cardiac response to ionizing radiation.

Medulloblastoma (MB) is the most common pediatric brain tumor, comprising four distinct molecular variants, one of which characterized by activation of the Sonic Hedgehog (SHH) pathway, driving 25–30% of sporadic MB. SHH-dependent MBs arise from granule cell precursors (GCPs), are fatal in 40–70% of cases and radioresistance strongly contributes to poor prognosis and tumor recurrence. Patched1 heterozygous (Ptch1+/−) mice, carrying a germ-line heterozygous inactivating mutation in the Ptch1 gene, the Shh receptor and negative regulator of the pathway, are uniquely susceptible to MB development after radiation damage in neonatal cerebellum. Here, we irradiated ex-vivo GCPs isolated from cerebella of neonatal WT and Ptch1+/− mice. Our results highlight a less differentiated status of Ptch1-mutated cells after irradiation, influencing DNA damage response. Increased expression levels of pluripotency genes Nanog, Oct4 and Sal4, together with greater clonogenic potential, clearly suggest that radiation induces expansion of the stem-like cell compartment through cell-reprogramming and self-renewal maintenance, and that this mechanism is strongly dependent on Nanog. These results contribute to clarify the molecular mechanisms that control radiation-induced Shh-mediated tumorigenesis and may suggest Nanog as a potential target to inhibit for adjuvant radiotherapy in treatment of SHH-dependent MB.

Objectives This study compared the MR measurement of minimum uninvolved cervical stroma and maximum stromal invasion, and the detection of positive lymph nodes with the pathological results. In addition, tumour type and grade were correlated with nodal status and apparent diffusion coefficient (ADC) values. Methods Patients who underwent surgery and MR at our centre for early stage cervical cancer (FIGO IA1-IIB) were included. Data recorded included: age, date of MR, clinical FIGO (International Federation of Gynacology and Obstetrics) stage, histological type and grade, adjuvant therapy, pre-surgical conisation. MR evaluation included: measurement of the minimum uninvolved stroma, maximum thickness of stromal involvement, presence and site of positive pelvic lymph nodes, calculation of ADC values. Statistical analysis was performed to compare MR and pathological results. The agreement between MR and pathology in measuring depth of stromal invasion was analysed by Bland-Altman plot, calculating the limits of agreement (LoA). Results 113/217 patients underwent adjuvant therapies. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy of MR in evaluation of minimum thickness of uninvolved cervical stroma were 88%, 75%, 70%, 90% and 80%; the same values in evaluation of pelvic positive lymph nodes were 64%, 85%, 65%, 84% and 78%. The mean difference between MR and pathological results in measuring maximum depth of stromal invasion was -0.65 mm (95% LoA: -9.37 mm; 8.07 mm). Depth of stromal invasion was strongly related to positive nodal status (p < 0.001). ADC values (available in 51/217 patients) were not associated with the features assessed. Conclusions Pre-surgical MR is accurate (80%) in evaluating the minimum thickness of uninvolved cervical stroma; MR measurements of maximum depth of stromal invasion differed ±9 mm from the pathological results in 95% of cases. Furthermore, a strong association was found between the depth of stromal invasion and the presence of positive lymph nodes, suggesting that inclusion of these measurements in the MR report might guide the choice of the best treatment option for early cervical cancer patients. © 2014 Elsevier Ireland Ltd.

While most of the evidence for radiation-induced late health effects relates to cancer, there has been increasing interest recently in the development of non-cancer diseases, including lens opacity, observed in populations exposed to low-dose radiation. In a recent study, we reported that mice heterozygous for the Patched1 (Ptch1) gene represented a novel and powerful animal model for this disorder, and a useful tool for investigating the mechanisms of radiogenic cataract development. Given the ongoing and considerable uncertainty in allowable lens dose levels and the existence of a threshold for the development of cataracts, we tested the effects of a decreasing range of radiation doses (2 Gy, 1 Gy and 0.5 Gy X rays) by irradiating groups of Ptch1+/- mice at 2 days of age. Our findings showed that at this dose range, acute exposure of this highly susceptible mouse model did not induce macroscopically detectable cataracts, and only the 2 Gy irradiated mice showed microscopic alterations of the lens. Molecular analyses performed to evaluate the induction of epithelial-mesenchymal transition (EMT) and subsequent fibrotic alterations in mouse lens cells also indicated the existence of a dose threshold for such effects in the mouse model used. The mechanisms of cataractogenesis remain unclear, and further experimental studies are essential to elucidate those mechanisms specific for cataract initiation and development after irradiation, as well as the underlying genetic factors controlling cataract susceptibility. © 2016 by Radiation Research Society.

A long-held dogma in radiation biology has been that the biological effects of exposure to ionizing radiation occur as a result of damage in directly irradiated cells and that no effect would occur in neighboring unirradiated cells. This paradigm has been frequently challenged by reports of radiation effects in unirradiated or 'bystander' cells receiving signals from directly irradiated cells, an issue that may have substantial impact on radiation risk assessment and development of radiation-based therapies. Radiation-induced bystander effects have been shown in single-cell systems in vitro for an array of cancer relevant endpoints, and may trigger damage in more complex 3-D tissue systems. They may be mediated by soluble factors released by irradiated cells into the extracellular environment and/or by the passage of mediator molecules through gap-junction intercellular communication. To date, evidence that radiation-associated bystander or abscopal responses are effectual in vivo has been limited, but new data suggest that they may significantly affect tumor development in susceptible mouse models. Further understanding of how the signal/s is transmitted to unirradiated cells and tissues and how it provokes long-range and significant responses is crucial. By summarizing the existing evidence of radiation induced bystander-like effects in various systems with emphasis on in vivo findings, we will discuss the potential mechanisms involved in these observations and how effects in bystander cells contribute to uncertainties in assessing cancer risks associated with radiation exposure.

Aberrant activation of the Hedgehog (Hh) signaling pathway is implicated in the pathogenesis of many cancers, including medulloblastoma and basal cell carcinoma (BCC). In this study, using neonatally irradiated Ptch1+/− mice as a model of Hh-dependent tumors, we investigated the in vivo effects of MK-4101, a novel SMO antagonist, for the treatment of medulloblastoma and BCC. Results clearly demonstrated a robust antitumor activity of MK-4101, achieved through the inhibition of proliferation and induction of extensive apoptosis in tumor cells. Of note, beside antitumor activity on transplanted tumors, MK-4101 was highly efficacious against primary medulloblastoma and BCC developing in the cerebellum and skin of Ptch1+/− mice. By identifying the changes induced by MK-4101 in gene expression profiles in tumors, we also elucidated the mechanism of action of this novel, orally administrable compound. MK-4101 targets the Hh pathway in tumor cells, showing the maximum inhibitory effect on Gli1. MK-4101 also induced deregulation of cell cycle and block of DNA replication in tumors. Members of the IGF and Wnt signaling pathways were among the most highly deregulated genes by MK-4101, suggesting that the interplay among Hh, IGF, and Wnt is crucial in Hh-dependent tumorigenesis. Altogether, the results of this preclinical study support a therapeutic opportunity for MK-4101 in the treatment of Hh-driven cancers, also providing useful information for combination therapy with drugs targeting pathways cooperating with Hh oncogenic activity. Mol Cancer Ther; 15(6); 1177–89. ©2016 AACR.

BackgroundLifestyle-related health problems are an important health concern in the transport service industry. Web- and telephone-based interventions could be suitable for this target group requiring tailored approaches. ObjectiveTo evaluate the effect of tailored Web-based health feedback and optional telephone coaching to improve lifestyle factors (body mass index—BMI, dietary intake, physical activity, stress, sleep, tobacco and alcohol consumption, disease history, self-perceived health, and motivation to change health habits), in comparison to no health feedback or telephone coaching. MethodsOverall, 3,876 employees in the Swedish transport services were emailed a Web-based questionnaire. They were randomized into: control group (group A, 498 of 1238 answered, 40.23%), or intervention Web (group B, 482 of 1305 answered, 36.93%), or intervention Web + telephone (group C, 493 of 1333 answered, 36.98%). All groups received an identical questionnaire, only the interventions differed. Group B received tailored Web-based health feedback, and group C received tailored Web-based health feedback + optional telephone coaching if the participants’ reported health habits did not meet the national guidelines, or if they expressed motivation to change health habits. The Web-based feedback was fully automated. Telephone coaching was performed by trained health counselors. Nine months later, all participants received a follow-up questionnaire and intervention Web + telephone. Descriptive statistics, the chi-square test, analysis of variance, and generalized estimating equation (GEE) models were used. ResultsOverall, 981 of 1473 (66.60%) employees participated at baseline (men: 66.7%, mean age: 44 years, mean BMI: 26.4 kg/m2) and follow-up. No significant differences were found in reported health habits between the 3 groups over time. However, significant changes were found in motivation to change. The intervention groups reported higher motivation to improve dietary habits (144 of 301 participants, 47.8%, and 165 of 324 participants, 50.9%, for groups B and C, respectively) and physical activity habits (181 of 301 participants, 60.1%, and 207 of 324 participants, 63.9%, for B and C, respectively) compared with the control group A (122 of 356 participants, 34.3%, for diet and 177 of 356 participants, 49.7%, for physical activity). At follow-up, the intervention groups had significantly decreased motivation (group B: P

Ionizing radiation is a genotoxic agent and human carcinogen. Recent work has questioned long-held dogmas by showing that cancer-associated genetic alterations occur in cells and tissues not directly exposed to radiation, questioning the robustness of the current system of radiation risk assessment. In vitro, diverse mechanisms involving secreted soluble factors, gap junction intercellular communication (GJIC) and oxidative metabolism are proposed to mediate these indirect effects. In vivo, the mechanisms behind long-range 'bystander' responses remain largely unknown. Here, we investigate the role of GJIC in propagating radiation stress signals in vivo, and in mediating radiation-associated bystander tumorigenesis in mouse central nervous system using a mouse model in which intercellular communication is downregulated by targeted deletion of the connexin43 (Cx43) gene. We show that GJIC is critical for transmission of oncogenic radiation damage to the non-targeted cerebellum, and that a mechanism involving adenosine triphosphate release and upregulation of Cx43, the major GJIC constituent, regulates transduction of oncogenic damage to unirradiated tissues in vivo. Our data provide a novel hypothesis for transduction of distant bystander effects and suggest that the highly branched nervous system, similar to the vascular network, has an important role.

Background To know how moderate-to-vigorous physical activity (MVPA) and sedentary time change across lifespan periods is needed for designing successful lifestyle interventions. We aimed to study changes in objectively measured (accelerometry) MVPA and sedentary time from childhood to adolescence and from adolescence to young adulthood. Methods Estonian and Swedish participants from the European Youth Heart Study aged 9 and 15 years at baseline (N = 2312) were asked to participate in a second examination 6 (Sweden) to 9/10 (Estonia) years later. 1800 participants with valid accelerometer data were analyzed. Results MVPA decreased from childhood to adolescence (−1 to −2.5 min/d per year of follow-up, P = 0.01 and, his study was also supported by grants from the Estonian Ministry of Education and Science (No 0180027 and 0942706) and the Estonian Science Foundation (No 6932 and 6788). The study was supported by grants from the Stockholm County Council. This study is also being supported by grants from Spanish Ministry of Economy and Competitiveness (RYC-2010-05957; RYC-2011-09011).