Genetic polymorphisms in PTPN22, PADI-4, and CTLA-4 and risk for rheumatoid arthritis in two longitudinal cohort studies: evidence of gene-environment interactions with heavy cigarette smoking

Introduction: PTPN22, PADI-4, and CTLA-4 have been associated with risk for rheumatoid arthritis (RA). We investigated whether polymorphisms in these genes were associated with RA in Caucasian women included in two large prospective cohorts, adjusting for confounding factors and testing for interactions with smoking. Methods: We studied RA risk associated with PTPN22 (rs2476601), PADI-4 (rs2240340), and CTLA-4 (rs3087243) in the Nurses' Health Study (NHS) and NHSII. Participants in NHS were aged 30 to 55 years at entry in 1976; those in NHSII were aged 25 to 42 years at entry in 1989. We confirmed incident RA cases through to 2002 in NHS and to 2003 in NHSII by questionnaire and medical record review. We excluded reports not confirmed as RA. In a nested case-control design involving participants for whom there were samples for genetic analyses (45% of NHS and 25% of NHSII), each incident RA case was matched to a participant without RA by year of birth, menopausal status, and postmenopausal hormone use. Genotyping was performed using Taqman single nucleotide polymorphism allelic discrimination on the ABI 7900 HT (Applied Biosystems, 850 Lincoln Centre Drive, Foster City, CA 94404 USA) with published primers. Human leukocyte antigen shared epitope (HLA-SE) genotyping was performed at high resolution. We employed conditional logistic regression analyses, adjusting for smoking and reproductive factors. We tested for additive and multiplicative interactions between each genotype and smoking. Results: A total of 437 incident RA cases were matched to healthy female control individuals. Mean (± standard deviation) age at RA diagnosis was 55 (± 10), 57% of RA cases were rheumatoid factor (RF) positive, and 31% had radiographic erosions at diagnosis. PTPN22 was associated with increased RA risk (pooled odds ratio in multivariable dominant model = 1.46, 95% confidence interval [CI] = 1.02 to 2.08). The risk was stronger for RF-positive than for RF-negative RA. A significant multiplicative interaction between PTPN22 and smoking for more than 10 pack-years was observed (P = 0.04). CTLA-4 and PADI-4 genotypes were not associated with RA risk in the pooled results (pooled odds ratios in multivariable dominant models: 1.27 [95% CI = 0.88 to 1.84] for CTLA-4 and 1.04 [95% CI = 0.77 to 1.40] for PADI-4). No gene-gene interaction was observed between PTPN22 and HLA-SE. Conclusion: After adjusting for smoking and reproductive factors, PTPN22 was associated with RA risk among Caucasian women in these cohorts. We found both additive and multiplicative interactions between PTPN22 and heavy cigarette smoking

Bulk rock composition and geochemistry of olivine-hosted melt inclusions in the Grey Porri Tuff and selected lavas of the Monte dei Porri volcano, Salina, Aeolian Islands, southern Italy.

The Aeolian Islands are an arcuate chain of submarine seamounts and volcanic islands, lying just north of Sicily in southern Italy. The second largest of the islands, Salina, exhibits a wide range of compositional variation in its erupted products, from basaltic lavas to rhyolitic pumice. The Monte dei Porri eruptions occurred between 60 ka and 30 ka, following a period of approximately 60,000 years of repose. The bulk rock composition of the Monte dei Porri products range from basaltic-andesite scoria to andesitic pumice in the Grey Porri Tuff (GPT), with the Monte dei Porri lavas having basaltic-andesite compositions. The typical mineral assemblage of the GPT is calcic plagioclase, clinopyroxene (augite), olivine (Fo72−84) and orthopyroxene (enstatite) ± amphibole and Ti-Fe oxides. The lava units show a similar mineral assemblage, but contain lower Fo olivines (Fo57−78). The lava units also contain numerous glomerocrysts, including an unusual variety that contains quartz, K-feldspar and mica. Melt inclusions (MI) are ubiquitous in all mineral phases from all units of the Monte dei Porri eruptions; however, only data from olivine-hosted MI in the GPT are reported here. Compositions of MI in the GPT are typically basaltic (average SiO2 of 49.8 wt %) in the pumices and basaltic-andesite (average SiO2 of 55.6 wt %) in the scoriae and show a bimodal distribution in most compositional discrimination plots. The compositions of most of the MI in the scoriae overlap with bulk rock compositions of the lavas. Petrological and geochemical evidence suggest that mixing of one or more magmas and/or crustal assimilation played a role in the evolution of the Monte dei Porri magmatic system, especially the GPT. Analyses of the more evolved mineral phases are required to better constrain the evolution of the magma

A SLAM-based augmented reality app for the assessment of spatial short-term memory using visual and auditory stimuli

A SLAM-based Augmented Reality (AR) app has been designed, developed, and validated to assess spatial short-term memory. Our app can be used with visual and auditory stimuli and can run on mobile devices. It can be used in any indoor environment. The anchors and data of the app are persistently stored in the cloud. As an authoring tool, the type of stimulus, its number, and specific positions in the real environment can be customized for each session. A study involving 48 participants was carried out to analyze the performance outcomes comparing the location and remembering of stimuli in a real environment using visual versus auditory stimuli. The number of objects placed correctly was similar for the two different stimuli used. However, the group that used the auditory stimulus spent significantly more time completing the task and required significantly more attempts. The performance outcomes were independent of age and gender. For the auditory stimuli, correlations among all of the variables of the AR app and the variables of two other tasks (object-recall and map-pointing) were found. We also found that the greater the number of correctly placed auditory stimuli, the greater the perceived competence and the less mental effort required. The greater the number of errors, the less the perceived competence. Finally, the auditory stimuli are valid stimuli that may benefit the assessment of the memorization of spatial-auditory associations, but the memorization of spatial-visual associations is dominant, as our results suggest

Investigating the Structure and Meaning of Public Service Motivation across Populations: Developing an International Instrument and Addressing Issues of Measurement Invariance

The growth in international research on public service motivation (PSM) raises a number of important questions about the degree to which the theory and research developed in one country can contribute to our understanding of PSM in other counties. To help address this issue, this study revisits the conceptual and operational definitions of PSM to address weaknesses previously noted in the literature. Although some important steps have been taken to both improve and internationalize the PSM scale, this work has been done incrementally. In contrast, this study takes a more systematic and comprehensive approach by combining the efforts of international PSM scholars to develop and then test a revised measurement instrument for PSM in 12 countries. Although the resulting four dimensional 16-item measure of PSM reported here provides a better theoretical and empirical foundation for the measurement of PSM, our results suggest that the exact meaning and scaling of PSM dimensions are likely to differ across cultures and languages. These results raise serious concerns regarding the ability to develop a single universal scale of PSM, or making direct comparisons of PSM across countrie

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

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

Sigma-2 receptor ligands potentiate conventional chemotherapies and improve survival in models of pancreatic adenocarcinoma

<p>Abstract</p> <p>Background</p> <p>We have previously reported that the sigma-2 receptor is highly expressed in pancreas cancer. Furthermore, we have demonstrated that sigma-2 receptor specific ligands induce apoptosis in a dose-dependent fashion. Here, we examined whether sigma-2 receptor ligands potentiate conventional chemotherapies such as gemcitabine and paclitaxel.</p> <p>Methods</p> <p>Mouse (Panc-02) and human (CFPAC-1, Panc-1, AsPC-1) pancreas cancer cell lines were used in this study. Apoptosis was determined by FACS or immunohistochemical analysis after TUNEL and Caspase-3 staining. Combination therapy with the sigma-2 ligand SV119 and the conventional chemotherapies gemcitabine and paclitaxel was evaluated in an allogenic animal model of pancreas cancer.</p> <p>Results</p> <p>SV119, gemcitabine, and paclitaxel induced apoptosis in a dose-dependent fashion in all pancreas cancer cell lines tested. Combinations demonstrated increases in apoptosis. Mice were treated with SV119 (1 mg/day) which was administered in combination with paclitaxel (300 μg/day) over 7 days to mice with established tumors. A survival benefit was observed with combination therapy (p = 0.0002). Every other day treatment of SV119 (1 mg/day) in combination with weekly treatment of gemcitabine (1.5 mg/week) for 2 weeks also showed a survival benefit (p = 0.046). Animals tolerated the combination therapy and no gross toxicity was noted in serum biochemistry data or on necropsy.</p> <p>Conclusion</p> <p>SV119 augments tumoricidal activity of paclitaxel and gemcitabine without major side effects. These results highlight the potential utility of the sigma-2 ligand as an adjuvant treatment in pancreas cancer.</p

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

2-Year Change in Revised Hammersmith Scale Scores in a Large Cohort of Untreated Paediatric Type 2 and 3 SMA Participants

The Revised Hammersmith Scale (RHS) is a 36-item ordinal scale developed using clinical expertise and sound psychometrics to investigate motor function in participants with Spinal Muscular Atrophy (SMA). In this study, we investigate median change in the RHS score up to two years in paediatric SMA 2 and 3 participants and contextualise it to the Hammersmith Functional Motor Scale-Expanded (HFMSE). These change scores were considered by SMA type, motor function, and baseline RHS score. We consider a new transitional group, spanning crawlers, standers, and walkers-with-assistance, and analyse that alongside non-sitters, sitters, and walkers. The transitional group exhibit the most definitive change score trend, with an average 1-year decline of 3 points. In the weakest patients, we are most able to detect positive change in the RHS in the under-5 age group, whereas in the stronger patients, we are most able to detect decline in the RHS in the 8-13 age group. The RHS has a reduced floor effect compared to the HFMSE, although we show that the RHS should be used in conjunction with the RULM for participants scoring less than 20 points on the RHS. The timed items in the RHS have high between-participant variability, so participants with the same RHS total can be differentiated by their timed test items