Citations

ObjectiveTo identify new genetic associations with juvenile and adult dermatomyositis (DM).MethodsWe performed a genome‐wide association study (GWAS) of adult and juvenile DM patients of European ancestry (n = 1,178) and controls (n = 4,724). To assess genetic overlap with other autoimmune disorders, we examined whether 141 single‐nucleotide polymorphisms (SNPs) outside the major histocompatibility complex (MHC) locus, and previously associated with autoimmune diseases, predispose to DM.ResultsCompared to controls, patients with DM had a strong signal in the MHC region consisting of GWAS‐level significance (P < 5 × 10–8) at 80 genotyped SNPs. An analysis of 141 non‐MHC SNPs previously associated with autoimmune diseases showed that 3 SNPs linked with 3 genes were associated with DM, with a false discovery rate (FDR) of <0.05. These genes were phospholipase C–like 1 (PLCL1; rs6738825, FDR = 0.00089), B lymphoid tyrosine kinase (BLK; rs2736340, FDR = 0.0031), and chemokine (C‐C motif) ligand 21 (CCL21; rs951005, FDR = 0.0076). None of these genes was previously reported to be associated with DM.ConclusionOur findings confirm the MHC as the major genetic region associated with DM and indicate that DM shares non‐MHC genetic features with other autoimmune diseases, suggesting the presence of additional novel risk loci. This first identification of autoimmune disease genetic predispositions shared with DM may lead to enhanced understanding of pathogenesis and novel diagnostic and therapeutic approaches.

ABSTRACTBackgroundPrescription drug abuse has prompted considerable concern. We evaluated a retrospective drug utilization review program to reduce controlled substance use among individuals with high‐risk utilization.MethodsWe analyzed pharmacy claims from a large pharmaceutical benefits manager. For each eligible member, we calculated a controlled substance score based on the number and type of claims, prescribers and pharmacies, and utilization patterns over three months. Two state health plans sent controlled substance letters to prescribers of members meeting or exceeding a plan‐ and pre‐specified controlled substance score. Two different state health plans did not send such letters. We used a difference‐in‐difference design and generalized estimating equations to quantify the impact of the program on the mean difference in reduction of the controlled substance score over six months.ResultsEligible members in the intervention and comparison states had similar baseline mean controlled substance scores (19.0 vs. 18.6, p = 0.36). Adjusting for individuals' age, sex and pharmacy risk group score, reductions in the mean controlled substance score were greater in the intervention than comparison cohort (5.67 vs. 4.31, p = 0.01), corresponding with a 34.0% reduction in the intervention cohort compared to a 25.5% reduction in the comparison cohort. Changes were driven primarily by reductions in the number of controlled substance claims filled (30.5% vs. 23.1%, p = 0.01), as well as by a non‐statistically significant trend towards reductions in the number of prescribers and pharmacies used (26.9% vs. 20.1%, p = 0.07).ConclusionsRetrospective drug utilization review programs may reduce controlled substance scores and claims among individuals with patterns suggesting high‐risk utilization. Copyright © 2013 John Wiley & Sons, Ltd.

Depletion of interstitial cells of Cajal (ICC) networks is known to occur in several gastrointestinal motility disorders. Although confocal microscopy can effectively image and visualize the spatial distribution of ICC networks, current descriptors of ICC depletion are limited to cell numbers and volume computations. Spatial changes in ICC network structural properties have not been quantified. Given that ICC generate electrical signals, the organization of a network may also affect physiology. In this study, six numerical metrics were formulated to automatically determine complex ICC network structural properties from confocal images: density , thickness , hole size , contact ratio , connectivity and anisotropy . These metrics were validated and applied in proof-of-concept studies to quantitatively determine jejunal ICC network changes in mouse models with decreased ( 5-HT 2 B receptor knockout (KO)) and normal ( Ano1 KO) ICC numbers, and during post-natal network maturation. Results revealed a novel remodelling phenomenon occurring during ICC depletion, namely a spatial rearrangement of ICC and the preferential longitudinal alignment. In the post-natal networks, an apparent pruning of the ICC network was demonstrated. The metrics developed here enabled the first detailed quantitative analyses of structural changes that may occur in ICC networks during depletion and development.

Genetic College Many genomic elements in humans are associated with behavior, including educational attainment. In a genome-wide association study including more than 100,000 samples, Rietveld et al. (p. 1467 , published online 30 May; see the Perspective by Flint and Munafò ) looked for genes related to educational attainment in Caucasians. Small genetic effects at three loci appeared to impact educational attainment.

ABSTRACT We are developing oncolytic vesicular stomatitis viruses (VSVs) for systemic treatment of multiple myeloma, an incurable malignancy of antibody-secreting plasma cells that are specifically localized in the bone marrow. One of the presumed advantages for using VSV as an oncolytic virus is that human infections are rare and preexisting anti-VSV immunity is typically lacking in cancer patients, which is very important for clinical success. However, our studies show that nonimmune human and mouse serum can neutralize clinical-grade VSV, reducing the titer by up to 4 log units in 60 min. In addition, we show that neutralizing anti-VSV antibodies negate the antitumor efficacy of VSV, a concern for repeat VSV administration. We have investigated the potential use of covalent modification of VSV with polyethylene glycol (PEG) or a function-spacer-lipid (FSL)–PEG construct to inhibit serum neutralization and to limit hepatosplenic sequestration of systemically delivered VSV. We report that in mice passively immunized with neutralizing anti-VSV antibodies, PEGylation of VSV improved the persistence of VSV in the blood circulation, maintaining a more than 1-log-unit increase in VSV genome copies for up to 1 h compared to the genome copy numbers for the non-PEGylated virus, which was mostly cleared within 10 min after intravenous injection. We are currently investigating if this increase in PEGylated VSV circulating half-life can translate to increased virus delivery and better efficacy in mouse models of multiple myeloma.

ABSTRACT Vesicular stomatitis virus (VSV) is potent and a highly promising agent for the treatment of cancer. However, translation of VSV oncolytic virotherapy into the clinic is being hindered by its inherent neurotoxicity. It has been demonstrated that selected picornaviral internal ribosome entry site (IRES) elements possess restricted activity in neuronal tissues. We therefore sought to determine whether the picornavirus IRES could be engineered into VSV to attenuate its neuropathogenicity. We have used IRES elements from human rhinovirus type 2 (HRV2) and foot-and-mouth disease virus (FMDV) to control the translation of the matrix gene (M), which plays a major role in VSV virulence. In vitro studies revealed slowed growth kinetics of IRES-controlled VSVs in most of the cell lines tested. However, in vivo studies explicitly demonstrated that IRES elements of HRV2 and FMDV severely attenuated the neurovirulence of VSV without perturbing its oncolytic potency.

Abstract Phospholipase C epsilon (PLCε or PLC∈ 1) is a phosphoinositide-specific enzyme phospholipase C that converts phosphatidylinositol 4,5-biphosphate to two intracellular second messengers, diacylglycerol and inositol 1,4,5-trisphosphate, which regulate protein kinase C activity and calcium mobilization, respectively. These responses are involved in the regulation of cell growth, differentiation and oncogenesis. However, the involvement of PLCε in human carcinogenesis, particularly in esophageal cancer, was not been recognized until a susceptible SNP (rs2274223: A5780G:His1927Arg) was recently identified in a large genome-wide association study (GWAS). This SNP, located within exon 26 and C2 domain of the PLCε gene at chromosome 10q23, leads to a nonsynonymous alteration from CAC (A allele, encoding histidine) to CGC (G allele, encoding arginine), which was associated with an increased risk of both squamous cell carcinoma and esophagus-cardia gastric adenocarcinoma. In the current report, we demonstrate that the presence of the G allele (AG or GG) at this locus leads to increased PLCε mRNA and protein expression in human esophageal cancer tissues and in human esophageal cancer cell lines. The present of G allele also leads o a higher enzyme activity in esophageal cancer cells in vitro. Quantitative analysis of the C2 domain sequences revealed that A:G allelic imbalance is strongly associated with esophageal malignancy. Moreover, the analysis of 10,614 non-cancer subjects from high- and low-risk areas of China demonstrated that the presence of the G allele is strongly associated with moderate to severe esophagitis in the subjects from the high-risk areas of China: 77% of the severe esophagitis individuals in high-risk areas had AG/GG genotypes vs. only 37% of these subjects in low-risk areas (OR 6.03 with 95% CI 1.59-22.9 vs. OR 0.74 with 95% CI 0.33-1.64; p=0.008). These data suggest that the interaction of potential environmental factors with PLCε, particularly in individuals with AG or GG allele, not only exists in high-risk areas for esophageal cancer development in China, but also correlates with the severity of esophagitis. In conclusion, PLCε is likely to play a pivotal role in esophageal carcinogenesis: the presence of the 5780G allele may not only predict a high risk of future esophageal cancer development, but may also participate in esophageal cancer growth and progression by upregulating levels of PLCε mRNA, protein, and enzyme activity, ultimately leading to augmentation of the inflammatory process in esophageal epithelium. Thus, the 5780G allele in PLCε may constitute a promising biomarker for esophageal squamous carcinoma risk stratification, early detection, and progression prediction. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4704. doi:10.1158/1538-7445.AM2011-4704