Genome-wide association study identifies a new melanoma susceptibility locus at 1q21.3

We performed a genome-wide association study of melanoma in a discovery cohort of 2,168 Australian individuals with melanoma and 4,387 control individuals. In this discovery phase, we confirm several previously characterized melanoma-associated loci at MC1R, ASIP and MTAP-CDKN2A. We selected variants at nine loci for replication in three independent case-control studies (Europe: 2,804 subjects with melanoma, 7,618 control subjects; United States 1: 1,804 subjects with melanoma, 1,026 control subjects; United States 2: 585 subjects with melanoma, 6,500 control subjects). The combined meta-analysis of all case-control studies identified a new susceptibility locus at 1q21.3 (rs7412746, P = 9.0 × 10(-11), OR in combined replication cohorts of 0.89 (95% CI 0.85-0.95)). We also show evidence suggesting that melanoma associates with 1q42.12 (rs3219090, P = 9.3 × 10(-8)). The associated variants at the 1q21.3 locus span a region with ten genes, and plausible candidate genes for melanoma susceptibility include ARNT and SETDB1. Variants at the 1q21.3 locus do not seem to be associated with human pigmentation or measures of nevus density.     

The forecasting attributes of trend- and difference-stationary representations for macroeconomic time series

We analyse the forecasting attributes of trenc and diffence-stationary representations of the U.S. macroeconomic time series sudied by Nelson and Plosser (1982). Predictive densities based on models estimated for these series (which terminate in 1970) are compared with subsequent realizations compiled by Schotman and van Dijk (1991) which terminate in (1988). Predictive densities obtained using the, extended series are also derived to assess the impact of the subsequent realization on long-range forecasts. Of particular interest are comparisons of the average intervals of predictive densities corresponding to the competing specifications In general, we find that coverage intervals based on diference-stationary specifications are far wider than those based or. trend-stationary specifications for the real series, and slightly wider for the nominal series. This additional width is often a virtue in forecasting nuninal series over the 1971-1988 period, as the inflation experienced durnig this time was unprecedented in the 1900s. However, the evolution of the real series has been relatively stable in the 1900s, hence the uncertainty associated with difference-stationary specifications generally seems excessive for these data.     

Common sequence variants on 20q11.22 confer melanoma susceptibility

We conducted a genome-wide association pooling study for cutaneous melanoma and performed validation in samples totaling 2,019 cases and 2,105 controls. Using pooling, we identified a new melanoma risk locus on chromosome 20 (rs910873 and rs1885120), with replication in two further samples (combined P < 1 x 10(-15)). The per allele odds ratio was 1.75 (1.53, 2.01), with evidence for stronger association in early-onset cases.     

Cognitive change and the APOE epsilon 4 allele

There is a marked variation in whether people retain sufficient cognitive function to maintain their quality of life and independence in old age, even among those without dementia, so it would be valuable to identify the determinants of normal age-related cognitive change. We have retested non-demented 80-year-olds who were participants in the Scottish Mental Survey of 1932, and find that the variation in their non-pathological cognitive change from age 11 to 80 is related to their apolipoprotein E (APOE) genotype. This effect of the APOE epsilon 4 allele on normal cognitive ageing may be mediated by a mechanism that is at least partly independent of its predisposing effect towards Alzheimer's disease.     

Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci

We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10??). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.     

β-phenylethyl isothiocyanate-mediated apoptosis in hepatoma HepG2 cells

-Phenylethyl isothiocyanate (PEITC) is a promising chemoprotective compound that is routinely consumed in the diet as its glucosinolate precursor. Previous studies have shown that PEITC can inhibit phase I enzymes and induce phase II detoxification enzymes along with apoptosis in vitro. The detailed mechanisms involved in the apoptotic cascade, however, have not been elucidated. In the present study, we demonstrate that PEITC can induce apoptosis in hepatoma HepG2 cells in a concentration- and time-dependant manner as determined by TUNEL positive and SubG1 population analysis. Caspase-3-like activity and poly(ADP-ribosyl)polymerase cleavage increased during treatment with 20 µM PEITC; high concentrations, however, induced necrosis. Pre-treatment with Z-VAD-FMK and the caspase-3-specific inhibitor Ac-DEVD-CHO prevented PEITC-induced apoptosis, as determined by caspase-3-like activity and DNA fragmentation. Additional investigations also showed that at concentrations of 5-C10 µM PEITC, DNA synthesis was inhibited and G2/M phase cell cycle arrest occurred, correlating with an alteration in cyclin B1 and p34^cdc2 protein levels. Furthermore, we also demonstrate a concentration- and time-dependant burst of superoxide (O₂^-) in PEITC-treated cells. However, pre- and co-treatment with the free radical scavengers Trolox, ascorbate, mannitol, uric acid and the superoxide mimetic manganese (III) tetrakis (N-methyl-2-pyridyl) porphyrin failed to prevent PEITC-mediated apoptosis. Taken together, these results suggest that PEITC potently induces apoptosis and cell cycle arrest in HepG2 cells and that the generation of reactive oxygen species appears to be a secondary effect.Received 23 December 2002; accepted 22 April 2003     

Empirical Bayesian Density Forecasting in Iowa and Shrinkage for the Monte Carlo Era

The track record of a 20‐year history of density forecasts of state tax revenue in Iowa is studied, and potential improvements sought through a search for better‐performing ‘priors’ similar to that conducted three decades ago for point forecasts by Doan, Litterman and Sims (Econometric Reviews, 1984). Comparisons of the point and density forecasts produced under the flat prior are made to those produced by the traditional (mixed estimation) ‘Bayesian VAR’ methods of Doan, Litterman and Sims, as well as to fully Bayesian ‘Minnesota Prior’ forecasts. The actual record and, to a somewhat lesser extent, the record of the alternative procedures studied in pseudo‐real‐time forecasting experiments, share a characteristic: subsequently realized revenues are in the lower tails of the predicted distributions ‘too often’. An alternative empirically based prior is found by working directly on the probability distribution for the vector autoregression parameters—the goal being to discover a better‐performing entropically tilted prior that minimizes out‐of‐sample mean squared error subject to a Kullback–Leibler divergence constraint that the new prior not differ ‘too much’ from the original. We also study the closely related topic of robust prediction appropriate for situations of ambiguity. Robust ‘priors’ are competitive in out‐of‐sample forecasting; despite the freedom afforded the entropically tilted prior, it does not perform better than the simple alternatives. Copyright © 2014 John Wiley & Sons, Ltd.     

BVAR as a category management tool: An illustration and comparison with alternative techniques

Category management—a relatively new function in marketing—involves large-scale, real-time forecasting of multiple data series in complex environments. In this paper, we illustrate how Bayesian Vector Auto regression (BVAR) fulfils the category manager's decision-support requirements by providing accurate forecasts of a category's state variables (prices, volumes and advertising levels), incorporating management interventions (merchandising events such as end-aisle displays), and revealing competitive dynamics through impulse response analyses. Using 124 weeks of point-of-sale scanner data comprising 31 variables for four brands, we compare the out-of-sample forecasts from BVAR to forecasts from exponential smoothing, univariate and multivariate Box-Jenkins transfer function analyses, and multivariate ARMA models. Theil U's indicate that BVAR forecasts are superior to those from alternate approaches. In large-scale forecasting applications, BVAR's ease of identification and parsimonious use of degrees of freedom are particularly valuable.     

Lactacystin-induced apoptosis of cultured mouse cortical neurons is associated with accumulation of PTEN in the detergent-resistant membrane fraction

The tumor suppressor function of PTEN is attributed to its phospholipid phosphatase activity that dephosphorylates the plasma membrane phosphatidylinositol-(3,4,5)-triphosphate [PtdIns(3,4,5)P₃]. Implicit in this notion is that PTEN needs to be targeted to the plasma membrane to dephosphorylate PtdIns(3,4,5)P₃. However, the recruitment of PTEN to the plasma membrane is not fully understood. Here, we demonstrate PTEN accumulation in the detergent-insoluble fraction of neuronal cells in response to treatment by the proteasome inhibitor lactacystin. First, lactacystin induces apoptosis and the activation of caspase-3 in cultured cortical neurons. Second, PTEN undergoes proteolysis to form a truncated 50-kDa form that lacks parts of its C-terminal tail. Third, the truncated PTEN is stably associated with the detergent-insoluble fraction in which the plasma membrane marker protein flotillin-1 resides. Taken together, our results suggest that truncation and accumulation of PTEN to the detergent-insoluble membrane fraction are two events associated with the apoptotic signals of the proteasome inhibitor in cortical neurons.Received 24 March 2004; received after revision 26 May 2004; accepted 5 June 2004