Dynamic telomerase gene suppression via network effects of GSK3 inhibition

<b>Background</b>: Telomerase controls telomere homeostasis and cell immortality and is a promising anti-cancer target, but few small molecule telomerase inhibitors have been developed. Reactivated transcription of the catalytic subunit hTERT in cancer cells controls telomerase expression. Better understanding of upstream pathways is critical for effective anti-telomerase therapeutics and may reveal new targets to inhibit hTERT expression. <b>Methodology/Principal Findings</b>: In a focused promoter screen, several GSK3 inhibitors suppressed hTERT reporter activity. GSK3 inhibition using 6-bromoindirubin-3′-oxime suppressed hTERT expression, telomerase activity and telomere length in several cancer cell lines and growth and hTERT expression in ovarian cancer xenografts. Microarray analysis, network modelling and oligonucleotide binding assays suggested that multiple transcription factors were affected. Extensive remodelling involving Sp1, STAT3, c-Myc, NFκB, and p53 occurred at the endogenous hTERT promoter. RNAi screening of the hTERT promoter revealed multiple kinase genes which affect the hTERT promoter, potentially acting through these factors. Prolonged inhibitor treatments caused dynamic expression both of hTERT and of c-Jun, p53, STAT3, AR and c-Myc. <b>Conclusions/Significance</b>: Our results indicate that GSK3 activates hTERT expression in cancer cells and contributes to telomere length homeostasis. GSK3 inhibition is a clinical strategy for several chronic diseases. These results imply that it may also be useful in cancer therapy. However, the complex network effects we show here have implications for either setting

Dioxin Exposure and Age of Pubertal Onset Among Russian Boys

Background: Animal data demonstrate associations of dioxin, furan, and PCB exposures with altered male gonadal maturation. It is unclear whether these associations apply to human populations. Objectives: We investigated the association of dioxins, furans, PCBs and corresponding toxic equivalent (TEQ) concentrations with pubertal onset among boys in a dioxin-contaminated region. Methods: Between 2003-2005, 489 boys were enrolled at ages 8-9 years in a longitudinal study in Chapaevsk, Russia. Pubertal onset - stages 2 or higher for genitalia (G2+) or testicular volume (TV) \u3e 3 ml - was assessed annually between ages 8-12 years. Serum levels at enrollment were analyzed by the Centers for Disease Control and Prevention, Atlanta, GA. Cox proportional hazards models were used to assess age at pubertal onset as a function of exposure adjusted for potential confounders. Sensitivity analyses were conducted excluding boys with pubertal onset at enrollment. Results: The median (range) total serum TEQ concentration was 21 (4-175) pg/g lipid, approximately three times higher than values in European children. At enrollment, boys were generally healthy and normal weight (mean BMI 15.9 kg/m2), with 30% having entered puberty by G2+ and 14% by TV criteria. Higher dioxin TEQs were associated with later pubertal onset by TV, hazard ratio = 0.68, 95% CI: 0.49-0.95 for the highest compared with the lowest quartile. Similar associations were observed for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and dioxin concentrations for TV but not G2+. Results were robust to sensitivity analyses. Conclusions: Findings support an association of higher peri-pubertal serum dioxin TEQs and concentrations with later male pubertal onset reflected in delayed testicular maturation

Global Adoption of Genetically Modified (GM) Crops: Challenges for the Public Sector

Advances in biotechnology continue to drive the development of a wide range of insect-protected, herbicide-tolerant, stress-tolerant, and nutritionally enhanced genetically modified (GM) crops, yet societal and public policy considerations may slow their commercialization. Such restrictions may disproportionately affect developing countries, as well as smaller entrepreneurial and public sector initiatives. The 2014 IUPAC International Congress of Pesticide Chemistry (San Francisco, CA, USA; August 2014) included a symposium on “Challenges Associated with Global Adoption of Agricultural Biotechnology” to review current obstacles in promoting GM crops. Challenges identified by symposium presenters included (i) poor public understanding of GM technology and the need for enhanced communication strategies, (ii) nonharmonized and prescriptive regulatory requirements, and (iii) limited experience with regulations and product development within some public sector programs. The need for holistic resistance management programs to enable the most effective use of insect-protected crops was also a point of emphasis. This paper provides details on the symposium discussion and provides background information that can be used in support of further adoption of beneficial GM crops. Overall, it emphasizes that global adoption of modern agricultural biotechnology has not only provided benefits to growers and consumers but has great potential to provide solutions to an increasing global population and diminishing agricultural land. This potential will be realized by continued scientific innovation, harmonized regulatory systems, and broader communication of the benefits of the high-yielding, disease-resistant, and nutritionally enhanced crops attainable through modern biotechnology

ARE EXPOSURE PREDICTIONS, USED FOR THE PRIORITISATION OF PHARMACEUTICALS IN THE ENVIRONMENT, FIT FOR PURPOSE?

Prioritisation methodologies are often used for identifying those pharmaceuticals that pose the greatest risk to the natural environment and to focus laboratory testing or environmental monitoring towards pharmaceuticals of greatest concern. Risk-based prioritisation approaches, employing models to derive exposure concentrations, are commonly used but the reliability of these models is unclear. The present study evaluated the accuracy of exposure models commonly used for pharmaceutical prioritisation. Targeted monitoring was conducted for 95 pharmaceuticals in the Rivers Foss and Ouse in the City of York, UK. Predicted environmental concentration (PEC) ranges were estimated based on localised prescription, hydrological data, reported metabolism and wastewater treatment plant (WwTP) removal rates, and were compared to measured environmental concentrations (MECs). For the River Foss, PECs, obtained using highest metabolism and lowest WwTP removal, were similar to MECs. In contrast, this trend was not observed for the River Ouse, possibly due to pharmaceutical inputs beyond our modelling. Pharmaceuticals were ranked by risk based on either MECs or PECs. With two exceptions (dextromethorphan and diphenhydramine), risk ranking based on both MECs and PECs produced similar results in the River Foss. Overall, these findings indicate that PECs may well be appropriate for prioritisation of pharmaceuticals in the environment when robust and local data on the system of interest are available and reflective of most source inputs to the system. This article is protected by copyright. All rights reserved