The MRN complex is transcriptionally regulated by MYCN during neural cell proliferation to control replication stress

The MRE11/RAD50/NBS1 (MRN) complex is a major sensor of DNA double strand breaks, whose role in controlling faithful DNA replication and preventing replication stress is also emerging. Inactivation of the MRN complex invariably leads to developmental and/or degenerative neuronal defects, the pathogenesis of which still remains poorly understood. In particular, NBS1 gene mutations are associated with microcephaly and strongly impaired cerebellar development, both in humans and in the mouse model. These phenotypes strikingly overlap those induced by inactivation of MYCN, an essential promoter of the expansion of neuronal stem and progenitor cells, suggesting that MYCN and the MRN complex might be connected on a unique pathway essential for the safe expansion of neuronal cells. Here, we show that MYCN transcriptionally controls the expression of each component of the MRN complex. By genetic and pharmacological inhibition of the MRN complex in a MYCN overexpression model and in the more physiological context of the Hedgehog-dependent expansion of primary cerebellar granule progenitor cells, we also show that the MRN complex is required for MYCN-dependent proliferation. Indeed, its inhibition resulted in DNA damage, activation of a DNA damage response, and cell death in a MYCN- and replication-dependent manner. Our data indicate the MRN complex is essential to restrain MYCN-induced replication stress during neural cell proliferation and support the hypothesis that replication-born DNA damage is responsible for the neuronal defects associated with MRN dysfunctions.Cell Death and Differentiation advance online publication, 12 June 2015; doi:10.1038/cdd.2015.81

Alteration of gene expression profiles during mycoplasma-induced malignant cell transformation

BACKGROUND: Mycoplasmas are the smallest microorganisms capable of self-replication. Our previous studies show that some mycoplasmas are able to induce malignant transformation of host mammalian cells. This malignant transformation is a multistage process with the early infection, reversible and irreversible stages, and similar to human tumor development in nature. The purpose of this study is to explore mechanisms for this malignant transformation. METHODS: To better understand mechanisms for this unique process, we examined gene expression profiles of C3H cells at different stages of the mycoplasma-induced transformation using cDNA microarray technology. A total of 1185 genes involved in oncogenesis, apoptosis, cell growth, cell-cycle regulation, DNA repair, etc. were examined. Differences in the expression of these genes were compared and analyzed using the computer software AtlasImage. RESULTS: Among 1185 genes screened, 135 had aberrant expression at the early infection stage, 252 at the reversible stage and 184 at the irreversible stage. At the early infection stage, genes with increased expression (92 genes) were twice more than those with decreased expression (42 genes). The global gene expression at the reversible stage appeared to be more volatile than that at any other stages but still resembled the profile at the early infection stage. The expression profile at the irreversible stage shows a unique pattern of a wide range of expression levels and an increased number of expressing genes, especially the cancer-related genes. Oncogenes and tumor suppressors are a group of molecules that showed significant changes in expression during the transformation. The majority of these changes occurred in the reversible and irreversible stages. A prolonged infection by mycoplasmas lead to the expression of more cancer related genes at the irreversible stage. CONCLUSION: The results indicate that the expression profiles correspond with the phenotypic features of the cells in the mycoplasma induced transformation process. The early mycoplasma infection stage shares a common phenomenon with many other acute infections, genes with increased expression significantly outnumbering those with decreased expression. The reversible stage is a transition stage between benignancy and malignancy at the molecular level. Aberrant expression of oncogenes and tumor repressors plays a key role in mycoplasma-induced malignant transformation

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

Sexual uses of alcohol and drugs and the associated health risks: A cross sectional study of young people in nine European cities

<p>Abstract</p> <p>Background</p> <p>Young people in European countries are experiencing high levels of alcohol and drug use and escalating levels of sexually transmitted infections. Individually these represent major public health priorities. Understanding of the association between sex and substance use, and specifically the strategic roles for which young people utilise substances to facilitate sexual activity, remains limited.</p> <p>Methods</p> <p>Respondent driven sampling methodology was used in nine European cities to survey 1,341 16–35 year olds representing youth and younger adults who routinely engage in nightlife. Participants self-completed questionnaires, designed to gather demographic, social, and behavioural data on historic and current substance use and sexual behaviour.</p> <p>Results</p> <p>Respondents reported strategic use of specific substances for different sexual purposes. Substances differed significantly in the purposes for which each was deployed (e.g. 28.6% of alcohol users use it to facilitate sexual encounters; 26.2% of cocaine users use it to prolong sex) with user demographics also relating to levels of sexual use (e.g. higher levels of: ecstasy use by males to prolong sex; cocaine use by single individuals to enhance sensation and arousal). Associations between substance use and sex started at a young age, with alcohol, cannabis, cocaine or ecstasy use before age 16 all being associated with having had sex before the age of 16 (odds ratios, 3.47, 4.19, 5.73, 9.35 respectively). However, sexes differed and substance use under 16 years was associated with a proportionately greater increase in early sex amongst girls. Respondents' current drug use was associated with having multiple sexual partners. Thus, for instance, regular cocaine users (c.f. never users) were over five times more likely to have had five or more sexual partners in the last 12 months or have paid for sex.</p> <p>Conclusion</p> <p>An epidemic of recreational drug use and binge drinking exposes millions of young Europeans to routine consumption of substances which alter their sexual decisions and increase their chances of unsafe and regretted sex. For many, substance use has become an integral part of their strategic approach to sex, locking them into continued use. Tackling substances with both physiological and psychological links to sex requires approaching substance use and sexual behaviour in the same way that individuals experience them; as part of the same social process.</p

Psychological and behavioural factors associated with sexual risk behaviour among Slovak students

Background: Knowledge about the prevalence of sexual risk behaviour (SRB) in adolescence is needed to prevent unwanted health consequences. Studies on SRB among adolescents in Central Europe are rare and mostly rely on a single indicator for SRB. This study aims to assess the association of behavioural and psychological factors with three types of SRB in adolescents in Central Europe. Methods: We obtained data on behavioural factors (having been drunk during previous month, smoking during previous week, early sexual initiation), psychological factors (self-esteem, wellbeing, extroversion, neuroticism, religiousness), and SRB (intercourse under risky conditions, multiple sexual partners, and inconsistent condom use) in 832 Slovak university students (response 94.3%). Results: Among those with sexual experience (62%), inconsistent condom use was the most prevalent risk behaviour (81% in females, 72% in males). With the exception of having been drunk in males, no factor was associated with inconsistent condom use. Regarding the other types of SRB, early sexual initiation was most strongly associated. In addition, other, mostly behavioural, factors were associated, in particular having been drunk. Conclusion: Results suggest that behavioural factors are more closely related to SRB than psychological factors. Associations differ by type of SRB and gender but offer few clues to target risk groups for inconsistent condom use. Results show a high need for health-promotion programmes in early adolescence that target SRB in conjunction with other health risk behaviours such as alcohol abuse

Alcohol use and extramarital sex among men in Cameroon

<p>Abstract</p> <p>Background</p> <p>The spread of HIV in sub-Saharan Africa is believed to be driven by unsafe sex, and identification of modifiable risk factors of the latter is needed for comprehensive HIV prevention programming in the region. Some previous studies suggest an association between alcohol abuse and unsafe sexual behaviour, such as multiple concurrent sexual partnerships and inconsistent condom use in sex with non-spousal non-cohabiting partners. However, most of these studies were conducted in developed countries and the few studies in Africa were conducted among well-defined social groups such as men attending beer halls or sexually transmitted infection clinics. We therefore examined the association between alcohol and extramarital sex (a sign of multiple concurrent sexual partnerships) among men in a population-based survey in Cameroon; a low-income country in sub-Saharan Africa with a high rate of alcohol abuse and a generalised HIV epidemic.</p> <p>Methods</p> <p>We analyzed data from 2678 formally married or cohabiting men aged 15 to 59 years, who participated in the 2004 Cameroon Demographic and Health Survey, using a multivariate regression model.</p> <p>Results</p> <p>A quarter of the men (25.8%) declared having taken alcohol before their last sexual intercourse and 21% indicated that the last sex was with a woman other than their wife or cohabiting partner. After controlling for possible confounding by other socio-demographic characteristics, alcohol use was significantly associated with having extramarital sex: adjusted odds ratio (OR) 1.70, 95% confidence intervals (CI) 1.40 to 2.05. Older age (30–44 years: OR 3.06, 95%CI 2.16–4.27 and 45–59 years: OR 4.10, 95%CI 2.16–4.27), higher education (OR 1.25, 95%CI 1.10–1.45), and wealth (OR 1.71, 95%CI 1.50–1.98) were also significantly associated with higher odds of having extramarital sex. The men were more likely to have used a condom in their last sex if it was extramarital (OR 10.50, 95%CI 8.10–13.66). Older age at first sex (16–19 years: OR 0.81, 95%CI 0.72–0.90 and > 19 years: OR 0.74, 95% CI 0.65–0.87) and being the head of a household (OR 0.17, 95%CI 0.14–0.22) significantly decreased the odds of having sex outside of marriage. Religion and place of residence (whether urban or rural) were not significantly associated with extramarital sex.</p> <p>Conclusion</p> <p>Alcohol use is associated with having multiple concurrent non-spousal sexual partnerships among married men in Cameroon. We cannot infer a causal relationship between alcohol abuse and unsafe sex from this cross-sectional study, as both alcohol use and unsafe sexual behaviour may have a common set of causal personal and social factors. However, given the consistency with results of studies in other settings and the biologic plausibility of the link between alcohol intake and unsafe sex, our findings underscore the need for integrating alcohol abuse and HIV prevention efforts in Cameroon and other African countries with similar social profiles.</p

The glutathione redox system is essential to prevent ferroptosis caused by impaired lipid metabolism in clear cell renal cell carcinoma

The publisher's final edited version of this article is available at Oncogene. 2018 Oct;37(40):5435-5450. doi: 10.1038/s41388-018-0315-z. Epub 2018 Jun 5. Non-commercial use onlyThis study was funded by Cancer Research UK, the German Research Foundation (FOR2314) and the German Cancer Aid (111917)

Myc Prevents Apoptosis and Enhances Endoreduplication Induced by Paclitaxel

BACKGROUND: The role of the MYC oncogene in the apoptotic pathways is not fully understood. MYC has been reported to protect cells from apoptosis activation but also to sensitize cells to apoptotic stimuli. We have previously demonstrated that the down-regulation of Myc protein activates apoptosis in melanoma cells and increases the susceptibility of cells to various antitumoral treatments. Beyond the well-known role in the G1-->S transition, MYC is also involved in the G2-M cell cycle phases regulation. METHODOLOGY/PRINCIPAL FINDINGS: In this study we have investigated how MYC could influence cell survival signalling during G2 and M phases. We used the microtubules damaging agent paclitaxel (PTX), to arrest the cells in the M phase, in a p53 mutated melanoma cell line with modulated Myc level and activity. An overexpression of Myc protein is able to increase endoreduplication favoring the survival of cells exposed to antimitotic poisoning. The PTX-induced endoreduplication is associated in Myc overexpressing cells with a reduced expression of MAD2, essential component of the molecular core of the spindle assembly checkpoint (SAC), indicating an impairment of this checkpoint. In addition, for the first time we have localized Myc protein at the spindle poles (centrosomes) during pro-metaphase in different cell lines. CONCLUSIONS: The presence of Myc at the poles during the prometaphase could be necessary for the Myc-mediated attenuation of the SAC and the subsequent induction of endoreduplication. In addition, our data strongly suggest that the use of taxane in antitumor therapeutic strategies should be rationally based on the molecular profile of the individual tumor by specifically analyzing Myc expression levels