Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

Is the music industry stuck between rock and a hard place? The role of the Internet and three possible scenarios

The Internet through the world-wide-web has well and truly opened ‘Pandora's Box’ as far as the record industry is concerned, and there is no going back. The extensive use of illegal file-sharing and illegal downloads of music tracks (totally for free) threatens the very survival of the record industry as we know it. Furthermore this behaviour threatens the very livelihoods of the employees, artists, and bands who work within the record industry. This paper reviews the current situation and then offers three possible scenarios for the future of the record industry (The Good, The Bad, and The Ugly). Firstly, The Good, where the record industry survives; secondly, The Bad where the record industry dies a slow death; and finally The Ugly, where the record industry dies very quickly. The consideration of several key factors involved will help the industry to focus on maintaining The Good

Intra-functional conflict: an investigation of antecedent factors in marketing functions

Purpose - The objective of this paper is to contribute empirical evaluation of the factors, behaviours; and processes that lead to intra-functional conflict, and in so doing to contribute to theory building on these issues, which have important contemporary relevance for theorists and practitioners. Design/methodology/approach - A survey of 1,000 firms was conducted to elucidate the associations between both functional and dysfunctional intra-functional conflict and a number of intra- and extra-organisational variables. Findings - Evidence was found indicating that participative decision making (positively), heterogeneity and centrality of marketing (both negatively) are linked to functional intra-departmental conflict, while leadership quality of senior staff, team spirit and risk-taking proclivity are positively associated with functional intradepartmental conflict and negatively with dysfunctional intra-departmental conflict. No support was found for the claims that departmentalisation and Organisation size were associated with either form of conflict. Research limitations/implications - The study supplies an empirical contribution through conceptualising, and subsequently empirically verifying, a model of the antecedents of intra-functional conflict. Empirical contributions stem from findings that, while some parallels exist between the antecedents of intra-functional and inter-functional conflict, differences are evident, and in some cases even orthogonal. This study further reinforces suggestions that marketers have over-emphasised the negative dimensions of conflict and have overlooked the positive (that is, the functional) aspects of conflict. Practical implications - The findings of the study also have numerous implications for practitioners. At a strategic level, the study suggests that executives should acknowledge in their change processes that decisions at an organisational level could have a profound effect on both the functional and dysfunctional conflict in their organisation. Further, given the significant effect of inter-group dynamics, managers of functions may find it beneficial to manipulate a range of intra-functional variables to enhance functional conflict. Originality/value - The value of the current study centres on the conceptual and empirical contributions regarding the drivers of intra-functional conflict

Estimating consumer satisfaction: OLS versus ordered probability models

This paper reviews the use of logit and probit models in marketing and focuses on demonstrating the use of ordered probability models. This type of model is appropriate for many applications in marketing and business where the dependent variable of interest is ordinal (e.g., likert scales). A comparison between the properties of the ordinary least squares (OLS) model and ordered logit and probit models is made using consumer satisfaction data on automobiles. This comparison between the two models shows that the use of OLS for ordered categorical data gives misleading results and produces biased estimates, leading to inaccurate hypothesis testing. The paper concludes that ordered probability models, such as the ones illustrated, should be employed in marketing and business research where the dependent variable is ordinal

BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers

Background: The K3326X variant in BRCA2 (BRCA2∗c.9976A>T p.Lys3326∗rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormonerelated cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76637 cancer case patients and 83796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9×10-6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8×10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4×10-5 and ORw = 1.50, 95% CI = 1.28 t