Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually. To identify genetic factors that modify disease risk, we conducted a genome-wide association study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 x 10(-10)). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 x 10(-20) overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to N'-nitrosonornicotine and potential lung carcinogens. A non-synonymous variant of CHRNA5 that induces an amino acid substitution (D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets.

/pdf/a-susceptibility-locus-for-lung-cancer-maps-to-nicotinic-586jes8ljw.pdf

A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25

The International Agency for Research on Cancer (IARC) was established in 1965 by the World Health Assembly, as an independently funded organisation within the framework of the World Health Organization. The headquarters of the Agency are in Lyon, France. The Agency conducts a programme of research concentrating particularly on the epidemiology of cancer and the study of potential carcinogens in the human environment. Its field studies are supplemented by biological and chemical research carried out in the Agency's laboratories in Lyon and, through collaborative research agreements, in national research institutions in many countries. The Agency also conducts a programme for the education and training of personnel for cancer research. The publications of the Agency contribute to the dissemination of authoritative information on different aspects of cancer research. Information about IARC publications, and how to order them, is available via the Internet at: http:// The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of any country, territory, city, or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. The mention of specific companies or of certain manufacturers' products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. The authors alone are responsible for the views expressed in this publication.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/cncr.11334

IARC Handbooks of Cancer Prevention

Aims To re-examine various aspects of the benzodiazepines (BZDs), widely prescribed for 50 years, mainly to treat anxiety and insomnia. It is a descriptive review based on the Okey Lecture delivered at the Institute of Psychiatry, King's College London, in November 2010.

Methods  A search of the literature was carried out in the Medline, Embase and Cochrane Collaboration databases, using the codeword ‘benzodiazepine(s)’, alone and in conjunction with various terms such as ‘dependence’, ‘abuse’, etc. Further hand-searches were made based on the reference lists of key papers. As 60 000 references were found, this review is not exhaustive. It concentrates on the adverse effects, dependence and abuse.

Results  Almost from their introduction the BZDs have been controversial, with polarized opinions, advocates pointing out their efficacy, tolerability and patient acceptability, opponents deprecating their adverse effects, dependence and abuse liability. More recently, the advent of alternative and usually safer medications has opened up the debate. The review noted a series of adverse effects that continued to cause concern, such as cognitive and psychomotor impairment. In addition, dependence and abuse remain as serious problems. Despite warnings and guidelines, usage of these drugs remains at a high level. The limitations in their use both as choice of therapy and with respect to conservative dosage and duration of use are highlighted. The distinction between low-dose ‘iatrogenic’ dependence and high-dose abuse/misuse is emphasized.

Conclusions  The practical problems with the benzodiazepines have persisted for 50 years, but have been ignored by many practitioners and almost all official bodies. The risk–benefit ratio of the benzodiazepines remains positive in most patients in the short term (2–4 weeks) but is unestablished beyond that time, due mainly to the difficulty in preventing short-term use from extending indefinitely with the risk of dependence. Other research issues include the possibility of long-term brain changes and evaluating the role of the benzodiazepine antagonist, flumazenil, in aiding withdrawal.

Benzodiazepines revisited—will we ever learn?

http://nascholingnoord.nl/presentaties/2013-02-07_Saksvik_2010_Individual_differences_in_tolerance_to_shift_work.pdf

Individual differences in tolerance to shift work – A systematic review

Circadian rhythms are near 24-h patterns of physiology and behaviour that are present independent of external cues including hormones, body temperature, mood, and sleep propensity. The term ‘ circadian misalignment ’ describes a variety of circumstances, such as inappropriately timed sleep and wake, misalignment of sleep/wake with feeding rhythms, or misaligned central and peripheral rhythms. The predominance of early research focused on misalignment of sleep to the biological night. However, discovery of clock genes and the presence of peripheral circadian oscillators have expanded the defi nitions of misalignment. Experimental studies conducted in animal models and humans have provided evidence of potential mechanisms that link misalignment to negative outcomes. These include dysregulation of feeding behaviours, changes in appetite stimulating hormones, glucose metabolism and mood. This review has two foci: (1) to describe how circadian misalignment has been defi ned and evaluated in laboratory and fi eld experiments, and (2) to describe evidence linking different types of circadian misalignment to increased risk for physical (cardiovascular disease, diabetes, obesity, cancer) and psychiatric (depression, bipolar, schizophrenia, attention defi cit) disorders. This review will describe the role of circadian misalignment as a risk factor for disease in the general population and in clinical populations, including circadian rhythm sleep disorders and psychiatric disorders.

Circadian misalignment and health

Shift work and cardiovascular risk factors: new knowledge from the past decade.

Comparison of the Heavy Smoking Index and of the Fagerstrom Test for Nicotine Dependence in a sample of 749 cigarette smokers.

NicotineDependence(FTND)wasadministeredtoasampleof749adultsmokers.TheHeavySmoking Index (HSI) which combines two items of the FTND (the number of cigarettes per day and the time of the first cigarette of the day) was compared to the FTND. A cut-off score equal or greater than 4 on the HSI detected a similar rate of nicotine dependence as a cut-off score equal or greater than 6 on the FTND. HSI had good sensitivity (79.5%) and specificity (96.5%). The concordance between the two instruments was high (Cohen’s kappa=0.74). The HSI performed as well on men as on women. The HSI provides a good measure of high nicotine dependence, particularly appropriate for epidemiological surveys. D 2005 Elsevier Ltd. All rights reserved.

M. Niezborala

Papers

Shift work and cardiovascular risk factors: new knowledge from the past decade.

Comparison of the Heavy Smoking Index and of the Fagerstrom Test for Nicotine Dependence in a sample of 749 cigarette smokers.

Short communication Comparison of the Heavy Smoking Index and of the Fagerstrom Test for Nicotine Dependence in a sample of 749 cigarette smokers

Effects of working conditions and sleep of the previous day on cognitive performance.

A study of the psychometric properties of the Fagestrom Test for Nicotine Dependence.