Associations between e-cigarette access and smoking and drinking behaviours in teenagers

Background: Public health concerns regarding e-cigarettes and debate on appropriate regulatory responses are focusing on the need to prevent child access to these devices. However, little is currently known about the characteristics of those young people that are accessing e-cigarettes. Methods: Using a cross-sectional survey of 14-17 year old school students in North West England (n = 16,193) we examined associations between e-cigarette access and demographics, conventional smoking behaviours, alcohol consumption, and methods of accessing cigarettes and alcohol. Access to e-cigarettes was identified through a question asking students if they had ever tried or purchased e-cigarettes. Results: One in five participants reported having accessed e-cigarettes (19.2%). Prevalence was highest among\ud smokers (rising to 75.8% in those smoking >5 per day), although 15.8% of teenagers that had accessed e-cigarettes had never smoked conventional cigarettes (v.13.6% being ex-smokers). E-cigarette access was independently associated with male gender, having parents/guardians that smoke and students’ alcohol use. Compared with non-drinkers, teenagers that drank alcohol at least weekly and binge drank were more likely to have accessed e-cigarettes (adjusted odds ratio [AOR] 1.89, P < 0.001), with this association particularly strong among never-smokers (AOR 4.59, P < 0.001). Among drinkers, e-cigarette access was related to: drinking to get drunk, alcohol-related violence, consumption of spirits; self-purchase of alcohol from shops or supermarkets; and accessing alcohol by recruiting adult proxy purchasers outside shops. Conclusions: There is an urgent need for controls on the promotion and sale of e-cigarettes to children. Findings suggest that e-cigarettes are being accessed by teenagers more for experimentation than smoking cessation. Those most likely to access e-cigarettes may already be familiar with illicit methods of accessing age-restricted substances

Breast cancer and childhood anthropometry: emerging hypotheses?

In this issue of Breast Cancer Research, Baer and colleagues report a strong protective effect of childhood and adolescent body fatness on premenopausal breast cancer risk based on a large prospective study. Methodological issues are discussed, as are tentative biological interpretations regarding the findings

Variational Methods for Biomolecular Modeling

Structure, function and dynamics of many biomolecular systems can be characterized by the energetic variational principle and the corresponding systems of partial differential equations (PDEs). This principle allows us to focus on the identification of essential energetic components, the optimal parametrization of energies, and the efficient computational implementation of energy variation or minimization. Given the fact that complex biomolecular systems are structurally non-uniform and their interactions occur through contact interfaces, their free energies are associated with various interfaces as well, such as solute-solvent interface, molecular binding interface, lipid domain interface, and membrane surfaces. This fact motivates the inclusion of interface geometry, particular its curvatures, to the parametrization of free energies. Applications of such interface geometry based energetic variational principles are illustrated through three concrete topics: the multiscale modeling of biomolecular electrostatics and solvation that includes the curvature energy of the molecular surface, the formation of microdomains on lipid membrane due to the geometric and molecular mechanics at the lipid interface, and the mean curvature driven protein localization on membrane surfaces. By further implicitly representing the interface using a phase field function over the entire domain, one can simulate the dynamics of the interface and the corresponding energy variation by evolving the phase field function, achieving significant reduction of the number of degrees of freedom and computational complexity. Strategies for improving the efficiency of computational implementations and for extending applications to coarse-graining or multiscale molecular simulations are outlined.Comment: 36 page

Accuracy and cost-effectiveness of dynamic contrast-enhanced CT in the characterisation of solitary pulmonary nodules — the SPUtNIk study

$\textbf{Introduction:}$ Solitary pulmonary nodules (SPNs) are common on CT. The most cost-effective investigation algorithm is still to be determined. Dynamic contrastenhanced CT (DCE-CT) is an established diagnostic test not widely available in the UK currently. $\textbf{Methods and analysis:}$ The SPUtNIk study will assess the diagnostic accuracy, clinical utility and cost-effectiveness of DCE-CT, alongside the current CT and 18-flurodeoxyglucose-positron emission tomography) ($^{18}$FDG-PET)-CT nodule characterisation strategies in the National Health Service (NHS). Image acquisition and data analysis for $^{18}$FDG-PET-CT and DCE-CT will follow a standardised protocol with central review of 10% to ensure quality assurance. Decision analytic modelling will assess the likely costs and health outcomes resulting from incorporation of DCE-CT into management strategies for patients with SPNs. $\textbf{Ethics and dissemination:}$ Approval has been granted by the South West Research Ethics Committee. Ethics reference number 12/SW/0206. The results of the trial will be presented at national and international meetings and published in an Health Technology Assessment (HTA) Monograph and in peer-reviewed journals.The trial is funded by the National Institute for Health Research HTA Programme (grant no: 09/22/117) and is being run by Southampton Clinical Trials Unit, directed by Professor Gareth Griffiths and part funded by Cancer Research UK. NRQ and RCR are part funded by the Cambridge Biomedical Research Centre and the Cancer Research Network: Eastern

TbPIF5 Is a Trypanosoma brucei Mitochondrial DNA Helicase Involved in Processing of Minicircle Okazaki Fragments

Trypanosoma brucei's mitochondrial genome, kinetoplast DNA (kDNA), is a giant network of catenated DNA rings. The network consists of a few thousand 1 kb minicircles and several dozen 23 kb maxicircles. Here we report that TbPIF5, one of T. brucei's six mitochondrial proteins related to Saccharomyces cerevisiae mitochondrial DNA helicase ScPIF1, is involved in minicircle lagging strand synthesis. Like its yeast homolog, TbPIF5 is a 5′ to 3′ DNA helicase. Together with other enzymes thought to be involved in Okazaki fragment processing, TbPIF5 localizes in vivo to the antipodal sites flanking the kDNA. Minicircles in wild type cells replicate unidirectionally as theta-structures and are unusual in that Okazaki fragments are not joined until after the progeny minicircles have segregated. We now report that overexpression of TbPIF5 causes premature removal of RNA primers and joining of Okazaki fragments on theta structures. Further elongation of the lagging strand is blocked, but the leading strand is completed and the minicircle progeny, one with a truncated H strand (ranging from 0.1 to 1 kb), are segregated. The minicircles with a truncated H strand electrophorese on an agarose gel as a smear. This replication defect is associated with kinetoplast shrinkage and eventual slowing of cell growth. We propose that TbPIF5 unwinds RNA primers after lagging strand synthesis, thus facilitating processing of Okazaki fragments

Microstructural control and optimization of Haynes 282 manufactured through laser powder bed fusion

The microstructure and properties of alloy Haynes 282 produced through laser powder bed fusion were investigated as a function of the post-deposition heat-treatment. Scanning electron microscopy and X-ray diffraction were utilized to characterize the microstructure, whilst electro-thermal mechanical testing was used to evaluate the tensile and creep properties at 900 °C. In the as-deposited state, the initial microstructure consisted of the γ and γʹ phases along with M6C and M23C6 carbides. These carbides were observed to govern the recrystallization behaviour of the material and resulted in a minimum recrystallization temperature of 1240 °C. Following post-deposition heat-treatments, the microstructures consisted of a monomodal distribution of γʹ with M6C and M23C6 carbides along the grain boundaries. Tertiary γʹ particles were found to form in the vicinity of carbides in samples that employed a γʹ super-solvus step prior to ageing at 788 °C. The tensile properties were found to be similar in all heat-treated states, consistent with the minimal differences observed in the microstructures. In contrast, significant differences in the creep behaviour of the alloy were observed following the different heat-treatments, although no correlation with the microstructures was observed

Targeting cholesterol-rich microdomains to circumvent tamoxifen-resistant breast cancer

Adjuvant treatment with tamoxifen substantially improves survival of women with estrogen-receptor positive (ER+) tumors. Tamoxifen resistance (TAMR) limits clinical benefit. RRR alpha tocopherol ether-linked acetic acid analogue (alpha-TEA) is a small bioactive lipid with potent anticancer activity. We evaluated the ability of alpha-TEA in the presence of tamoxifen to circumvent TAMR in human breast cancer cell lines. Methods: Two genotypically matched sets of TAM-sensitive (TAMS) and TAM-resistant (TAMR) human breast cancer cell lines were assessed for signal-transduction events with Western blotting, apoptosis induction with Annexin V-FITC/PI assays, and characterization of cholesterol-rich microdomains with fluorescence staining. Critical involvement of selected mediators was determined by using RNA interference and chemical inhibitors. Results: Growth-factor receptors (total and phosphorylated forms of HER-1 and HER-2), their downstream prosurvival mediators pAkt, pmTOR, and pERK1/2, phosphorylated form of estrogen receptor-alpha (pER-alpha at Ser-167 and Ser-118, and cholesterol-rich lipid microdomains were highly amplified in TAMR cell lines and enhanced by treatment with TAM. alpha-TEA disrupted cholesterol-rich microdomains, acted cooperatively with TAM to reduce prosurvival mediators, and induced DR5-mediated mitochondria-dependent apoptosis via an endoplasmic reticulum stress-triggered pro-death pJNK/CHOP/DR5 amplification loop. Furthermore, methyl-beta-cyclodextrin (M beta CD), a chemical disruptor of cholesterol rich microdomains, acted cooperatively with TAM to reduce prosurvival mediators and to induce apoptosis. Conclusions: Data for the first time document that targeting cholesterol-rich lipid microdomains is a potential strategy to circumvent TAMR, and the combination of alpha-TEA + TAM can circumvent TAMR by suppression of prosurvival signaling via disruption of cholesterol-rich lipid microdomains and activation of apoptotic pathways via induction of endoplasmic reticulum stress.Clayton Foundation for ResearchCenter for Molecular and Cellular Toxicology at the University of TexasNIEHS/NIH T32 ES07247Nutritional Science

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis

Control of Ca2+ Influx and Calmodulin Activation by SK-Channels in Dendritic Spines

© 2016 Griffith et al. The key trigger for Hebbian synaptic plasticity is influx of Ca2+ into postsynaptic dendritic spines. The magnitude of [Ca2+] increase caused by NMDA-receptor (NMDAR) and voltage-gated Ca2+ -channel (VGCC) activation is thought to determine both the amplitude and direction of synaptic plasticity by differential activation of Ca2+ -sensitive enzymes such as calmodulin. Ca2+ influx is negatively regulated by Ca2+ -activated K+ channels (SK-channels) which are in turn inhibited by neuromodulators such as acetylcholine. However, the precise mechanisms by which SK-channels control the induction of synaptic plasticity remain unclear. Using a 3-dimensional model of Ca2+ and calmodulin dynamics within an idealised, but biophysically-plausible, dendritic spine, we show that SK-channels regulate calmodulin activation specifically during neuron-firing patterns associated with induction of spike timing-dependent plasticity. SK-channel activation and the subsequent reduction in Ca2+ influx through NMDARs and L-type VGCCs results in an order of magnitude decrease in calmodulin (CaM) activation, providing a mechanism for the effective gating of synaptic plasticity induction. This provides a common mechanism for the regulation of synaptic plasticity by neuromodulators