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Supplemental Excel File 5 - Enrichment analysis of 153 Down-regulated Antihormone-resistance Genes.

Supplemental Excel File 6 - Consensus ERalpha Inversely-related Genes

Table showing Pyrosequencing Assay Interrogation Positions

Supplemental Excel File 4 - Enrichment analysis of 324 Up-regulated Antihormone-resistance Genes

Supplemental Excel File 2 - Up-regulated Genes Associated with Antihormone resistance.

Supplemental Excel File 7 - Consensus ERalpha Directly-related Genes

Supplemental Excel File 10 - Enrichment Analysis of 39 candidate ERalpha methylation targets

Resistance to hormonal therapies is a major clinical problem in the treatment of estrogen receptor α–positive (ERα+) breast cancers. Epigenetic marks, namely DNA methylation of cytosine at specific CpG sites (5mCpG), are frequently associated with ERα+ status in human breast cancers. Therefore, ERα may regulate gene expression in part via DNA methylation. This hypothesis was evaluated using a panel of breast cancer cell line models of antiestrogen resistance. Microarray gene expression profiling was used to identify genes normally silenced in ERα+ cells but derepressed upon exposure to the demethylating agent decitabine, derepressed upon long-term loss of ERα expression, and resuppressed by gain of ERα activity/expression. ERα-dependent DNA methylation targets (n = 39) were enriched for ERα-binding sites, basal-up/luminal-down markers, cancer stem cell, epithelial–mesenchymal transition, and inflammatory and tumor suppressor genes. Kaplan–Meier survival curve and Cox proportional hazards regression analyses indicated that these targets predicted poor distant metastasis–free survival among a large cohort of breast cancer patients. The basal breast cancer subtype markers LCN2 and IFI27 showed the greatest inverse relationship with ERα expression/activity and contain ERα-binding sites. Thus, genes that are methylated in an ERα-dependent manner may serve as predictive biomarkers in breast cancer.Implications: ERα directs DNA methylation–mediated silencing of specific genes that have biomarker potential in breast cancer subtypes. Mol Cancer Res; 15(2); 152–64. ©2016 AACR.

Supplemental Material and Methods

Supplemental Excel File 3 - Down-regulated Genes Associated with Antihormone resistance

Supplemental Excel File 9 - Candidate ERalpha DNA methylation targets

This file contains Supplemental Figures S1 to S6 with corresponding legends. It also contains Supplementary Tables 1-6.

Supplementary Tables 1-5, Supplementary Figure 1 from Melanocytic Nevi, Nevus Genes, and Melanoma Risk in a Large Case-Control Study in the United Kingdom

Background: Increased number of melanocytic nevi is a potent melanoma risk factor. We have carried out a large population-based case-control study to explore the environmental and genetic determinants of nevi and the relationship with melanoma risk.Methods: We report nevus phenotype in relation to differing patterns of sun exposure, inherited variation at loci shown in recent genome-wide association studies to be nevus genes, and risk.Results: Increased numbers of nevi were associated with holiday sun exposure, particularly on intermittently sun-exposed body sites (test for Ptrend < 0.0001). Large nevi were also associated with holiday sun exposure (P = 0.002). Single nucleotide polymorphisms (SNP) on chromosomes 9 and 22 were associated with increased numbers of nevi (P = 0.04 and P = 0.002 respectively) and larger nevi (P = 0.03 and P = 0.002), whereas that on chromosome 6 was associated only with large nevi (P = 0.01). Melanoma risk was associated with increased nevus count, large nevi, and atypical nevi for tumors in all body sites (including rare sites) irrespective of age. The risk persisted when adjusted for inheritance of nevus SNPs.Conclusions: The at-risk nevus phenotype is associated with behaviors known to increase melanoma risk (holiday sun exposure). Although SNPs on chromosomes 6, 9, and 22 were shown to be nevus genes, they explained only a small proportion of melanoma risk and nevus phenotype; therefore, several nevus genes likely remain to be identified.Impact: This article confirms the importance of nevi in melanoma pathogenesis and increases understanding of their genetic determinants. Cancer Epidemiol Biomarkers Prev; 19(8); 2043–54. ©2010 AACR.

Background Patients with colonic cancer who require emergency colonic cancer surgery often experience poorer outcomes compared with their elective counterparts. In this setting, several treatments approaches are available. In 2009, Danish guidelines recommended treatment with stent for obstruction in left-sided tumours as a bridge to surgery, if expertise is accessible. The aim of this study was to compare the use of elective and emergency resections for colonic cancer and postoperative mortality in two similar demographic populations. Methods All patients who underwent a major resection for colonic cancer, between 2005 and 2016 in Denmark and Yorkshire (UK) were identified. The proportion undergoing emergency surgery, the proportion receiving a stent procedure before their resection, and 30-day postoperative mortality were compared between the populations. Logistic regression was used to determine changes in the proportion of those undergoing emergency surgery and 30-day postoperative mortality. Results Out of 45 397 patients treated during the study interval, 41 880 were selected. Emergency surgery decreased in Denmark from 16.6 per cent in 2005–07 to 12.9 per cent in 2014–16, but increased in Yorkshire (13.5 per cent to 16.8 per cent). Danish patients with left-sided tumours were less likely to undergo emergency surgery (risk ratio 0.90, 95 per cent c.i. 0.82 to 0.99) and an increase in stent use coincided with a statistically significant decrease in emergency surgery in these patients. Thirty-day postoperative mortality in all resections (elective and emergency) decreased in both populations, but a larger decrease was observed in Denmark (7.7 per cent to 3.0 per cent in Denmark and 7.1 per cent to 3.3 per cent in Yorkshire). Conclusion Patients in Denmark experienced a reduction in the use of emergency resection and increase in stenting procedures, following the policy implemented in some departments of converting potential emergency resections into elective resections.

Pathogenic germline variants in the protection of telomeres 1 gene (

Pathogenic germline variants in the protection of telomeres 1 gene (POT1) have been associated with predisposition to a range of tumor types, including melanoma, glioma, leukemia and cardioangiosarcoma. We sequenced all coding exons of the POT1 gene in 2,929 European-descent melanoma cases and 3,298 controls, identifying 43 protein-changing genetic variants. We performed POT1-telomere binding assays for all missense and stop gained variants, finding nine variants that impair or disrupt protein-telomere complex formation, and we further define the role of variants in the regulation of telomere length and complex formation through molecular dynamics simulations. We determine that POT1 variants are a minor contributor to melanoma burden in the general population, with only about 0.5% of melanoma cases carrying germline pathogenic variants in this gene, but should be screened in individuals with a strong family history of melanoma and/or multiple malignancies.

Background/Aims Rituximab is widely used to treat rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) but clinical response varies. Efficacy is determined by the efficiency of depletion, which may depend on a variety of Fc gamma receptor (FcγR)-dependent mechanisms. Previous research was limited by complexity of the FCGR locus, not integrating copy number variation with functional SNP, and small sample size. Here, we aimed to assess the effect of the full range of FcγRs variants on depletion, clinical response and functional effect on NK-cell-mediated killing in two rheumatic diseases with a view to personalised B-cell depleting therapies. Methods A prospective longitudinal study was conducted in 873 patients (RA = 611; SLE=262) from four cohorts (BSRBR-RA, BILAG-BR, Leeds RA and Leeds SLE Biologics). For RA, the outcome measures were 3C-DAS28CRP and 2C-DAS28CRP at 6 (+/-3) months post-rituximab (adjusted for baseline DAS28). For SLE, major clinical response (MCR) was defined as improvement of active BILAG-2004 domains to grade C/better at 6 months. B-cell depletion was evaluated by highly-sensitive flow cytometry. Qualitative and quantitative polymorphisms for five major FcγRs were measured using a commercial multiplex ligation-dependent probe amplification. Median NK cell FcγRIIIa expression (CD3-CD56+CD16+) and NK-cell degranulation (CD107a) in the presence of rituximab-coated Daudi/Raji B-cell lines were assessed using flow cytometry. Results In RA, for FCGR3A, carriage of V allele (coefficient -0.25 [SE 0.11]; p = 0.02) and increased copies of V allele (-0.20 [0.09]; p = 0.02) were associated with better 2C-DAS28 response. Irrespective of FCGR3A genotype, increased gene copies were associated with a better response. In SLE, 177/262 (67.6%) achieved BILAG response (MCR=34.4%; Partial=33.2%). MCR was associated with increased copies of FCGR3A-158V allele, OR 1.64 (95% CI 1.12-2.41) and FCGR2C-ORF allele 1.93 (1.09-3.40). Of patients with B-cells data in the combined cohort, 236/413 (57%) achieved complete depletion post-rituximab. Only homozygosity for V allele and higher copies of FCGR3A V allele were associated with increased odds of depletion. Patients with complete depletion had higher NK cell FcγRIIIa expression at rituximab initiation than those with incomplete depletion (p = 0.04) and this higher expression was associated with improved EULAR response in RA. Moreover, for FCGR3A, degranulation activity was increased in V allele carriers vs FF genotype in the combined cohort; p = 0.02. Conclusion FcγRIIIa is the major low affinity FcγR and increased copies of the FCGR3A-158V allele, encoding the allotype with a higher affinity for IgG1, was associated with clinical and biological responses to rituximab in two autoimmune diseases. This was supported by functional data on NK cell-mediated cytotoxicity. In SLE, increased copies of the FCGR2C-ORF allele was also associated with improved response. Our findings indicate that enhancing FcγR-effector functions could improve the next generation of CD20-depleting therapies and genotyping could stratify patients for optimal treatment protocols. Disclosure M. Md Yusof: None. J. Robinson: None. V. Davies: None. D. Wild: None. M. Morgan: None. J. Taylor: None. Y. El-Sherbiny: None. D. Morris: None. L. Liu: None. A. Rawstron: None. M. Buch: None. D. Plant: None. H. Cordell: None. J. Isaacs: None. I. Bruce: None. P. Emery: Grants/research support; PE has received consultancy fees and funding for research from Roche within the last 3 years. A. Barton: None. T. Vyse: None. J. Barrett: None. E. Vital: Grants/research support; EMV has received consultancy fees and funding for research from Roche within the last 3 years. A. Morgan: None.

AIM: Denmark and Yorkshire are demographically similar and both have undergone changes in their management of colorectal cancer to improve outcomes. The differential provision of surgical treatment, especially in the older age groups, may contribute to the magnitude of improved survival rates. This study aimed to identify differences in the management of colorectal cancer surgery and postoperative outcomes according to patient age between Denmark and Yorkshire.METHOD: This was a retrospective population-based study of colorectal cancer patients diagnosed in Denmark and Yorkshire between 2005-2016. Proportions of patients undergoing major surgical resection, postoperative mortality and relative survival were compared between Denmark and Yorkshire across several age groups (18-59, 60-69, 70-79 and ≥80 years) and over time.RESULTS: The use of major surgical resection was higher in Denmark than Yorkshire, especially for patients aged ≥80 years (70.5% versus 50.5% for colon cancer, 49.3% versus 38.1% for rectal cancer ). Thirty-day postoperative mortality for Danish patients aged ≥80 was significantly higher than that for Yorkshire patients with colonic cancer: OR (95% CI) = 1.22 (1.07, 1.38) but not for rectal cancer or for 1-year postoperative mortality. Relative survival significantly increased in all patients aged ≥80 years except for Yorkshire patients with colonic cancer.CONCLUSION: This study suggests there are major differences between the management of elderly patients with colorectal cancer between the two populations. Improved selection for surgery and better peri- and post-operative care in these patients appears to improve long-term outcomes, but may come at the cost of a higher 30-day mortality.

B cell depletion using rituximab is widely used to treat autoimmune diseases, but patient response varies. The efficacy of rituximab is limited by the efficiency of depletion. Strategies to improve response include altering rituximab dosing, switching anti-CD20-mAb, alternative B cell targets, or non-B cell targeted therapies. Implementing an appropriate strategy requires understanding of the mechanism(s) of resistance to depletion and, if this varies between individuals, a means to test for it. Rituximab kills B cells via a variety of Fcγ receptor (FcγR)-dependent mechanisms, including antibody-dependent cellular cytotoxicity (ADCC), as well as non-FcγR mechanisms. We conducted a longitudinal cohort study in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) using two national registries. Qualitative and quantitative FCGR functional variants were measured using multiplexed ligation-dependent probe amplification, supplemented by novel FCGR2C assays.We provide consistent evidence that FCGR3A, specifically increased number of copies of the FCGR3A-158V allele, was the major FcγR gene associated with rituximab response, including clinical response in RA and SLE and depth of B cell depletion in the combined cohort. In SLE, we provide preliminary data suggesting increased FCGR2C ORF copies were also associated with improved clinical response. Furthermore, we demonstrated the impact of disease status and concomitant therapies on both natural killer cell FcγRIIIa expression and rituximab-induced ADCC; demonstrating increased FcγRIIIa expression and FCGR3A genotype were independently associated with clinical response and B cell depletion. Our findings highlight the importance of enhancing FcγR-effector functions, may help stratify patients, and support ongoing development of next-generation CD20 depleting therapeutics.One Sentence SummaryThe high affinity FcγRIIIa allotype on NK cells explains depth of B cell depletion and clinical response in rituximab therapy for autoimmune disease

Aim Evidence on patterns of use of pulmonary metastasectomy in colorectal cancer patients is limited. This population‐based study aims to investigate the use of pulmonary metastasectomy in the colorectal cancer population across the English National Health Service (NHS) and quantify the extent of any variations in practice and outcome. Methods All adults who underwent a major resection for colorectal cancer in an NHS hospital between 2005 and 2013 were identified in the COloRECTal cancer data Repository (CORECT‐R). All inpatient episodes corresponding to pulmonary metastasectomy, occurring within 3 years of the initial colorectal resection, were identified. Multi‐level logistic regression was used to determine patient and organizational factors associated with the use of pulmonary metastasectomy for colorectal cancer, and Kaplan–Meier and Cox models were used to assess survival following pulmonary metastasectomy. Results In all, 173 354 individuals had a major colorectal resection over the study period, with 3434 (2.0%) undergoing pulmonary resection within 3 years. The frequency of pulmonary metastasectomy increased from 1.2% of patients undergoing major colorectal resection in 2005 to 2.3% in 2013. Significant variation was observed across hospital providers in the risk‐adjusted rates of pulmonary metastasectomy (0.0%–6.8% of patients). Overall 5‐year survival following pulmonary resection was 50.8%, with 30‐day and 90‐day mortality of 0.6% and 1.2% respectively. Conclusions This study shows significant variation in the rates of pulmonary metastasectomy for colorectal cancer across the English NHS.

Analysis of routine population-based data has previously shown that patterns of surgical treatment for colorectal cancer can vary widely but there is limited evidence available to determine if such variation is also seen in the use of chemotherapy. This study quantified variation in adjuvant chemotherapy across both England using cancer registry data, and in more detail across the representative Yorkshire and Humber region. Individuals with stage II and III colorectal cancer who underwent major resection from 2014-2015 were identified. Rates of chemotherapy were calculated from the Systemic Anti-Cancer Treatment database using multilevel logistic regression. Additionally, questionnaires addressing different clinical scenarios were sent to regional oncologists to investigate the treatment preferences of clinicians. The national adjusted chemotherapy treatment rate ranged from 2-46% (stage II cancers), 19%-81% (stage III cancers), 24%-75% (patients aged

Genome-wide association studies (GWAS) have identified ~20 melanoma susceptibility loci, most of which are not functionally characterized. Here we report an approach integrating massively-parallel reporter assays (MPRA) with cell-type-specific epigenome and expression quantitative trait loci (eQTL) to identify susceptibility genes/variants from multiple GWAS loci. From 832 high-LD variants, we identify 39 candidate functional variants from 14 loci displaying allelic transcriptional activity, a subset of which corroborates four colocalizing melanocyte cis-eQTL genes. Among these, we further characterize the locus encompassing the HIV-1 restriction gene, MX2 (Chr21q22.3), and validate a functional intronic variant, rs398206. rs398206 mediates the binding of the transcription factor, YY1, to increase MX2 levels, consistent with the cis-eQTL of MX2 in primary human melanocytes. Melanocyte-specific expression of human MX2 in a zebrafish model demonstrates accelerated melanoma formation in a BRAFV600E background. Our integrative approach streamlines GWAS follow-up studies and highlights a pleiotropic function of MX2 in melanoma susceptibility., There are more than 20 known melanoma susceptibility genes. Here, using a massively parallel reporter assay, the authors identify risk-associated variants that alter gene transcription, and demonstrate that expression of one such gene, MX2, leads to the promotion of melanoma in a zebrafish model.

Methotrexate (MTX) monotherapy is a common first treatment for rheumatoid arthritis (RA), but many patients do not respond adequately. In order to identify genetic predictors of response, we have combined data from two consortia to carry out a genome-wide study of response to MTX in 1424 early RA patients of European ancestry. Clinical endpoints were change from baseline to 6 months after starting treatment in swollen 28-joint count, tender 28-joint count, C-reactive protein and the overall 3-component disease activity score (DAS28). No single nucleotide polymorphism (SNP) reached genome-wide statistical significance for any outcome measure. The strongest evidence for association was with rs168201 in NRG3 (p = 10−7 for change in DAS28). Some support was also seen for association with ZMIZ1, previously highlighted in a study of response to MTX in juvenile idiopathic arthritis. Follow-up in two smaller cohorts of 429 and 177 RA patients did not support these findings, although these cohorts were more heterogeneous.

Containerization has had an outsized impact on the growth of global trade over the past 60 years. The Great Lakes-St. Lawrence Seaway is an important bi-national waterway. Since the advent of containerization in the 1950’s there has been much excitement about the prospects of scheduled container shipping in the Great Lakes. There is a perception that direct container service will add value to the economy of the Great Lakes- St. Lawrence Basin (GLSLB). However, due to unique shipping constraints in the Great Lakes-St. Lawrence Seaway, significant container service has not materialized. This research seeks to explain the current state of container shipping in the Great Lakes, as well as provide an analysis of the feasibility of future container shipping in the Great Lakes. It is very important for policymakers to understand both the opportunities for container shipping, and the barriers and issues with such services. A lack of understanding of these points can lead to missed opportunities and/or the potential for significant expenditures of time and money on unrealistic projects.

The aim of this study was to investigate variation in the frequency of resections for colorectal cancer liver metastases across the English NHS.Previous research has shown significant variation in access to liver resection surgery across the English NHS. This study uses more recent data to identify whether inequalities in access to liver resection still persist.All adults who underwent a major resection for colorectal cancer in an NHS hospital between 2005 and 2012 were identified in the COloRECTal cancer data Repository (CORECT-R). All episodes of care, occurring within 3 years of the initial bowel operation, corresponding to liver resection were identified.During the study period 157,383 patients were identified as undergoing major resection for a colorectal tumor, of whom 7423 (4.7%) underwent ≥1 liver resections. The resection rate increased from 4.1% in 2005, reaching a plateau around 5% by 2012. There was significant variation in the rate of liver resection across hospitals (2.1%-12.2%). Patients with synchronous metastases who have their primary colorectal resection in a hospital with an onsite specialist hepatobiliary team were more likely to receive a liver resection (odds ratio 1.22; 95% confidence interval, 1.10-1.35) than those treated in one without. This effect was absent in resection for metachronous metastases.This study presents the largest reported population-based analysis of liver resection rates in colorectal cancer patients. Significant variation has been observed in patient and hospital characteristics and the likelihood of patients receiving a liver resection, with the data showing that proximity to a liver resection service is as important a factor as deprivation.

Genome-wide association studies (GWAS) have identified ∼20 melanoma susceptibility loci. To identify susceptibility genes and variants simultaneously from multiple GWAS loci, we integrated massively-parallel reporter assays (MPRA) with cell type-specific epigenomic data as well as melanocyte-specific expression quantitative trait loci (eQTL) profiling. Starting from 16 melanoma loci, we selected 832 variants overlapping active regions of chromatin in cells of melanocytic lineage and identified 39 candidate functional variants displaying allelic transcriptional activity by MPRA. For four of these loci, we further identified four colocalizing melanocytecis-eQTL genes (CTSS,CASP8,MX2, andMAFF) matching the allelic activity of MPRA functional variants. Among these, we further characterized the locus encompassing the HIV-1 restriction gene,MX2, on chromosome band Chr21q22.3 and validated a functional variant, rs398206, among multiple high LD variants. rs398206 mediates allelic transcriptional activity via binding of the transcription factor, YY1. This allelic transcriptional regulation is consistent with a significantcis-eQTL ofMX2in primary human melanocytes, where the melanoma risk-associated A allele of rs398206 is correlated with higherMX2levels. Melanocyte-specific transgenic expression of humanMX2in a zebrafish model demonstrated accelerated melanoma formation in aBRAFV600Ebackground. Thus, using an efficient scalable approach to streamline GWAS follow-up functional studies, we identified multiple candidate melanoma susceptibility genes and variants, and uncovered a pleiotropic function ofMX2in melanoma susceptibility.

The importance of business schools collaborating with industry, and especially local companies, is selfevident. One way that the Global Supply Chain Management Program in the Mike Ilitch School of Business at Wayne State University has collaborated with General Motors and several major suppliers, and potential employers of students, is through an automotive industry supply chain management (SCM) case competition. In 2016, the Global Supply Chain Management Program, along with General Motors, will host the 6th annual General Motors/Wayne State University Supply Chain Case Competition. Supply Chain Management students from universities around the world travel to Detroit, MI to participate in the competition and learn about the global automotive industry. In addition to the competition, students tour an automotive assembly plant and network with industry executives and young managers. General Motors and other sponsoring companies utilize the competition to recruit top talent for entry level supply chain management positions, and to help with the education of students. Wayne State and its students benefit from increased exposure to companies with benefits relating to research, faculty recruiting, placement of students, and general development of the Wayne State SCM brand name. This article discusses the nature of the competition and the competitors, issues involved in producing such an event, the costs, and other benefits and challenges related to hosting such a competition.

Although a number of treatments are available for rheumatoid arthritis (RA), each of them shows a significant nonresponse rate in patients. Therefore, predicting a priori the likelihood of treatment response would be of great patient benefit. Here, we conducted a comparison of a variety of statistical methods for predicting three measures of treatment response, between baseline and 3 or 6 months, using genome‐wide SNP data from RA patients available from the MAximising Therapeutic Utility in Rheumatoid Arthritis (MATURA) consortium. Two different treatments and 11 different statistical methods were evaluated. We used 10‐fold cross validation to assess predictive performance, with nested 10‐fold cross validation used to tune the model hyperparameters when required. Overall, we found that SNPs added very little prediction information to that obtained using clinical characteristics only, such as baseline trait value. This observation can be explained by the lack of strong genetic effects and the relatively small sample sizes available; in analysis of simulated and real data, with larger effects and/or larger sample sizes, prediction performance was much improved. Overall, methods that were consistent with the genetic architecture of the trait were able to achieve better predictive ability than methods that were not. For treatment response in RA, methods that assumed a complex underlying genetic architecture achieved slightly better prediction performance than methods that assumed a simplified genetic architecture.

An understanding of the determinants of holdings of financial assets is of crucial importance for a number of macroeconomic issues. The growth of non-bank financial intermediaries, the substitutability between money and other assets, the determination of interest rates and so on are all related to the pattern of financial asset holdings. The most popular approach to modelling holdings of financial assets is the multivariate stock adjustment model due to Brainard and Tobin (1968). This has the distinct advantage over single equation approaches that the balance sheet constraints are built in, so that the asset demands sum to total wealth. The Brainard-Tobin model does, however, suffer from the problem that there is a large number of unconstrained parameters to be estimated, with the result that many applications are characterized by statistical imprecision of a substantial proportion of the estimates. 1 The source of the problem is that interest rates are highly collinear, so that the data cannot determine such a large number of free parameters.

It is unclear to what degree genomic and traditional (phenotypic and environmental) risk factors overlap in their prediction of melanoma risk. We evaluated the incremental contribution of common genomic variants (in pigmentation, nevus, and other pathways) and their overlap with traditional risk factors, using data from two population-based case-control studies from Australia (n = 1,035) and the United Kingdom (n = 1,460) that used the same questionnaires. Polygenic risk scores were derived from 21 gene regions associated with melanoma and odds ratios from published meta-analyses. Logistic regression models were adjusted for age, sex, center, and ancestry. Adding the polygenic risk score to a model with traditional risk factors increased the area under the receiver operating characteristic curve (AUC) by 2.3% (P = 0.003) for Australia and by 2.8% (P = 0.002) for Leeds. Gene variants in the pigmentation pathway, particularly MC1R, were responsible for most of the incremental improvement. In a cross-tabulation of polygenic by traditional tertile risk scores, 59% (Australia) and 49% (Leeds) of participants were categorized in the same (concordant) tertile. Of participants with low traditional risk, 9% (Australia) and 21% (Leeds) had high polygenic risk. Testing of genomic variants can identify people who are susceptible to melanoma despite not having a traditional phenotypic risk profile.

This chapter examines how college union professionals can keep up with changes in technology and address student expectations regarding information technology.

BACKGROUND: The NLRP3-inflammasome, implicated in the pathogenesis of several inflammatory disorders, has been analysed in rheumatoid arthritis (RA). METHODS: Relative gene expression of NLRP3-inflammasome components was characterised in PBMCs of 29 patients receiving infliximab. A total of 1278 Caucasian patients with RA from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS) cohort receiving tumour necrosis factor (TNF) antagonists (infliximab, adalimumab and etanercept) were genotyped for 34 single nucleotide polymorphisms (SNPs), spanning the genes NLRP3, MEFV and CARD8. Regression analyses were performed to test for association between genotype and susceptibility and treatment response (disease activity score across 28 joints (DAS28) and EULAR improvement criteria) at 6 months, with secondary expression quantitative trait loci (eQTL) analyses. RESULTS: At baseline, gene expression of ASC, MEFV, NLRP3-FL, NLRP3-SL and CASP1 were significantly higher compared with controls whereas CARD8 was lower in the patients. Caspase-1 and interleukin-18 levels were significantly raised in patients with RA. SNPs in NLRP3 showed association with RA susceptibility and EULAR response to anti-TNF in the BRAGGSS cohort, and in monocytes but not B cells, in eQTL analysis of 283 healthy controls. CARD8 SNPs were associated with RA susceptibility and DAS28 improvement in response to anti-TNF and eQTL effects in monocytes and B cells. CONCLUSIONS: This study found evidence of modulation of the NLRP3-inflammasome in patients with RA prior to receiving infliximab and some evidence of association for SNPs at NLRP3 and CARD8 loci with RA susceptibility and response to anti-TNF. The SNPs associated with susceptibility/response are not the main eQTL variants for either locus, and the associations with treatment response require replication in an independent cohort.

Genome-wide association studies (GWASs) have mainly focused on top significant single nucleotide polymorphisms (SNPs), most of which did not have clear biological functions but were just surrogates for unknown causal variants. Studying SNPs with modest association and putative functions in biologically plausible pathways has become one complementary approach to GWASs. To unravel the key roles of mitogen-activated protein kinase (MAPK) pathways in cutaneous melanoma (CM) risk, we re-evaluated the associations between 47 818 SNPs in 280 MAPK genes and CM risk using our published GWAS dataset with 1804 CM cases and 1026 controls. We initially found 105 SNPs with P ≤ 0.001, more than expected by chance, 26 of which were predicted to be putatively functional SNPs. The risk associations with 16 SNPs around DUSP14 (rs1051849) and a previous reported melanoma locus MAFF/PLA2G6 (proxy SNP rs4608623) were replicated in the GenoMEL dataset (P < 0.01) but failed in the Australian dataset. Meta-analysis showed that rs1051849 in the 3ʹ untranslated regions of DUSP14 was associated with a reduced risk of melanoma (odds ratio = 0.89, 95% confidence interval: 0.82–0.96, P = 0.003, false discovery rate = 0.056). Further genotype–phenotype correlation analysis using the 90 HapMap lymphoblastoid cell lines from Caucasians showed significant correlations between two SNPs (rs1051849 and rs4608623) and messenger RNA expression levels of DUSP14 and MAFF (P = 0.025 and P = 0.010, respectively). Gene-based tests also revealed significant SNPs were over-represented in MAFF, PLA2G6, DUSP14 and other 16 genes. Our results suggest that functional SNPs in MAPK pathways may contribute to CM risk. Further studies are warranted to validate our findings.

Amtrak operates three trains on routes in Michigan: the Wolverine, the Blue Water, and the Pere Marquette. Using the methodology established in the 2009 Michigan Passenger Rail Station Community Benefits Study, this study considered the economic impacts of Michigan Amtrak service in the 22 communities served by these routes. Results from the 2009 study were updated to reflect current ridership and ticket revenue data, as well as findings from passenger surveys conducted in spring 2011. Considering individual traveler savings, passenger spending at local businesses, and Amtrak-related expenditures, Amtrak service generated an estimated economic impact to the state of Michigan in excess of $45.8 million in 2011. The average economic impact (excluding Amtrak expenditures) was $37.87 per passenger. Every $1.00 invested by the state of Michigan for operations of the Blue Water and Pere Marquette routes returned $1.84 in economic impact to local communities and travelers along these routes. The findings of this analysis contribute to a small but growing body of literature that quantifies the economic impacts of existing Amtrak passenger rail service and have several applications for passenger rail planning, policy development, and outreach activities.

Resistance to hormonal therapies is a major clinical problem in the treatment of estrogen receptor α–positive (ERα+) breast cancers. Epigenetic marks, namely DNA methylation of cytosine at specific CpG sites (5mCpG), are frequently associated with ERα+ status in human breast cancers. Therefore, ERα may regulate gene expression in part via DNA methylation. This hypothesis was evaluated using a panel of breast cancer cell line models of antiestrogen resistance. Microarray gene expression profiling was used to identify genes normally silenced in ERα+ cells but derepressed upon exposure to the demethylating agent decitabine, derepressed upon long-term loss of ERα expression, and resuppressed by gain of ERα activity/expression. ERα-dependent DNA methylation targets (n = 39) were enriched for ERα-binding sites, basal-up/luminal-down markers, cancer stem cell, epithelial–mesenchymal transition, and inflammatory and tumor suppressor genes. Kaplan–Meier survival curve and Cox proportional hazards regression analyses indicated that these targets predicted poor distant metastasis–free survival among a large cohort of breast cancer patients. The basal breast cancer subtype markers LCN2 and IFI27 showed the greatest inverse relationship with ERα expression/activity and contain ERα-binding sites. Thus, genes that are methylated in an ERα-dependent manner may serve as predictive biomarkers in breast cancer. Implications: ERα directs DNA methylation–mediated silencing of specific genes that have biomarker potential in breast cancer subtypes. Mol Cancer Res; 15(2); 152–64. ©2016 AACR.

Operating as the center of student life, college unions have a central role to teach citizenship, social responsibility, and leadership. The perspective of stewardship is adopted in this chapter to advance a discussion about college unions as a model for campus sustainability.

Aim The aim of this study was to assess whether acute symptomatic epileptic seizures associated with central nervous system infections (ASinf) have a different ictal and postictal course to seizures of other aetiologies. Method A case note analysis of 81 children (47 males; 34 females; age range 1mo–15y 6mo; median age 12mo) with central nervous system infections was undertaken. Seizure type, duration, aetiology, and timing were recorded. Recovery time to full consciousness in those not intubated was determined. Intubation rates and recovery times were compared with those from previous studies. Results Of the 81 children, 40 (49.4%) had one or more ASinf. The different aetiologies were bacterial meningitis, aseptic meningitis, abscess/empyema, encephalitis, and postoperative infection. Twenty-two had status epilepticus. The intubation rate in children with ASinf was higher than that in children with seizures of other aetiologies (21/40 [52.5%] vs 4/124 [3.23%]; p < 0.0001). Median postictal recovery time was 4.33 hours (0–207h). Children with ASinf took 4.3 (p

Passenger rail service is perceived to provide important benefits to Michigan communities. However, the extent of these benefits has never been quantified in a systematic way. The study reported on here involved the performance of a broad based assessment of the community level benefits of passenger rail serv ice. The main objective of the research project was to estimate the full range of these benefits at the community level, as opposed to at the state level. Benefits were estimated for individual travelers, Amtrak expenditures, and local businesses. This research indicates local communities currently realize $62.0 million annually in benefits. Additional benefits accrue to the region, state, and nation in the form of congestion relief, air quality improvement, energy conservation, and safety.

Delayed diagnosis of ventriculo-peritoneal (VP) shunt malfunction results in avoidable morbidity and mortality. One reason is that most of the signs of shunt malfunction have low specificity. The objective of this study was to evaluate the presence of bradycardia as a sign of VP shunt malfunction in children with treated hydrocephalus. Children presenting with clinical features suggestive of possible VP shunt malfunction were retrospectively identified. Children with confirmed shunt malfunction formed the study group. Those who did not have shunt malfunction formed the control group, and the symptoms and signs were compared between the two groups. In particular, the presence of bradycardia (a heart rate less than the second centile of age-related norms) was sought. The positive predictive value (PPV) of bradycardia was compared with other common features of shunt malfunction. Data were obtained for 52 patients: 34 in the study group (data from 40 admissions) and 18 controls. Bradycardia was present in 18 of 40 (45%) of the study group and 2 of 18(11%) controls (p = 0.011). Only two of the patients with bradycardia had associated hypertension. The PPV for bradycardia was 90% compared with 92% for reduced conscious level and 65% for both headache and vomiting (the four commonest presenting features). Bradycardia without hypertension is common in children with VP shunt malfunction. The significance of bradycardia is often not recognised; the value of this sign should be emphasised.