bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 77: Analgesic use in relation to sex hormone and prolactin concentrations in premenopausal women.
Authors: Bauer Scott R. , Fortner Renee T. , Gates Margaret A. , Eliassen Heather , Hankinson Susan E. , Tworoger Shelley S.
Published: August 2013

The use of common analgesics, such as aspirin, non-aspirin NSAIDs and acetaminophen, may be associated with the risk of several hormone-related cancers, possibly via effects on sex hormone and prolactin concentrations. Therefore, we assessed the cross-sectional relationship between analgesic (aspirin, non-aspirin NSAIDS, and acetaminophen) use and sex hormone and prolactin concentrations among 2,034 premenopausal women, 32 to 54 years old, from the Nurses' Health Study II. Approximately 84% of women provided timed luteal and follicular blood samples; the remainder provided a single untimed sample. After adjustment for age, BMI, parity, and other potential confounders, acetaminophen use was inversely associated with prolactin levels (ptrend= 0.04). Compared to non-users, prolactin concentrations were 11.8% lower among women who reported using acetaminophen at least 2 times per week (p<0.01). Similarly, acetaminophen was inversely associated with free testosterone, when comparing use at least 2 times per week to non-users (7.1% lower, p = 0.04; ptrend= 0.04). Use of non-aspirin NSAIDs was positively associated with follicular free estradiol, with 13.5% higher levels in women who reported use 4 or more days per week as compared to non-users (p = 0.04; ptrend= 0.11); results for free follicular estradiol were similar (13.2% higher, p = 0.06; ptrend= 0.11) though not statistically significant. There were no clear associations observed between analgesic use and luteal estradiol, estrone, estrone sulfate, DHEA, DHEAS, androstenedione, and estrogen/androgen ratios. After adjustment for multiple comparisons, none of the associations were statistically significant. In conclusion, our study provides modest evidence for an association of acetaminophen use with prolactin and free testosterone concentrations in premenopausal women, and the suggestion of an association between non-aspirin NSAIDs and follicular free estradiol among those with frequent use.

Citation Format: Scott R. Bauer, Renee T. Fortner, Margaret A. Gates, Heather Eliassen, Susan E. Hankinson, Shelley S. Tworoger. Analgesic use in relation to sex hormone and prolactin concentrations in premenopausal women. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 77.
Abstract IA01: New assays, old specimens: Multiplexing for plasma and urine.
Authors: Sluss Patrick M.
Published: August 2013

A key concept in medical science is that by comparing DNA, RNA, or proteins from healthy and diseased individuals, insight can be gained into the etiology of disease leading to better diagnostics and therapeutics. In this context, biorepositories have long played a key role by allowing the accumulation of biological fluids and tissues from large numbers of individuals for longitudinal or cross-sectional comparisons. Approaches to understanding human disease are based on the central dogma that information flow in living systems is from DNA to RNA to protein. At all levels, aberrations could indicate either the presence of disease or suggest underlying mechanisms of disease. However, historically DNA and RNA have been more useful for identifying risk of disease than the presence of disease, except in surgical specimens. Proteins in biological fluids [blood, urine, aspirates, etc.] have played a more prominent role in diagnostics. Indeed given that proteins are in essence the effectors of gene expression a long held goal has been to associate specific proteins in peripheral circulation that indicate the presence of disease, e.g. biomarkers of disease, especially early disease before the appearance of symptoms or other clinical indicators.

This presentation will focus on issues associated with the use of biorepository fluids in this context. Three issues are fundamental: 1) specimen volume is limited and precious, 2) specimen processing requirements are not known a'priori, and 3) analytical targets are often not precisely defined. Limited specimen volume is an inherent problem because each blood draw represents a discrete end point. Unlike nucleic acids, proteins are subject to numerous post-translational biological modifications and to extensive, often rapid, degradation post specimen collection. These issues drive method development and validation, ultimately determining the amount and quality of data that can be obtained from biorepository specimens. Protein analytical methods will be reviewed from this perspective with emphasis on recent developments in multi-analyte systems and newer, highly sensitive methods.

Citation Format: Patrick M. Sluss. New assays, old specimens: Multiplexing for plasma and urine. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr IA01.
Abstract IA02: New specimens: Buccal cells, nasal swabs, fecal samples.
Authors: Cox David
Published: August 2013

Buccal swabs have been used for decades as an economical method to obtain biomaterials suitable for genomic DNA extraction for use in forensics and molecular epidemiology studies. Using buccal swabs, as opposed to methods such as saliva collection or rinsing with mouthwash, was considered sub-optimal as they contained large quantities of microbial DNA. As there is roughly an order of magnitude more non-human than human cells in our bodies, a large proportion of non-human DNA in many biospecimens is to be expected. While some bacteria are pathological, many carry out important functions or protect the body. The complex interactions between environmental factors, the human microbiome, and the human host can provide important clues with respect to various diseases and response to treatment. Advances in technology with respect to DNA sequencing allow for not only highly accurate determination of specific strains of bacteria but also the detection of very low proportions of those strains in biological samples. Similarly, advanced techniques such as mass spectroscopy provide information as to how changes in the microbiome and/or the host influence overall metabolism. These techniques have opened the door for a new wave of interest in the microbiome and its influence on metabolism and human health.

Citation Format: David Cox. New specimens: Buccal cells, nasal swabs, fecal samples. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr IA02.
Abstract IA04: Searching for GxE interactions in genome-wide association studies.
Authors: Conti David V.
Published: August 2013

Although both genetic and environmental factors play important roles in the etiology of many complex human traits, scans for gene(G)-environment(E) interaction have been mostly neglected in current GWAS. This is mainly due to the substantial lack of power for interaction tests coupled with the massive number of interactions available for testing. The conventional statistical approach for interactions, the case-control analysis, suffers from low power. The alternative case-only analysis can be more powerful but slight violations in the underlying assumption of independence can greatly bias the results. In this talk, I discuss several recently proposed alternatives ranging from two-step analyses to Bayesian approaches. Each approach attempts to leverage various aspects of the data, from ascertainment, to marginal test, to estimates of G-E association in the controls. For example, in the two-step approach proposed by Murcray et al. (2009), a preliminary screening step tests the association of G with E in the combined sample of cases and controls, thus capturing any G-E association that may be present in the study sample by leveraging the oversampling of cases from the population. This step is followed by a conventional case-control analysis. Overall, there is a substantial increase in power compared to a genome-wide scan of interactions due to the drastic reduction in the number of tests evaluated. In contrast, several Bayesian approaches (Mukherjee and Chatterjee, 2008; Li and Conti 2009) attempt to obtain an estimate of interaction that is a combined estimate between the case-only and case-control estimates. While originally conceived as an approach for a single GxE interaction test, I will discuss recent extensions leveraging the fact that most SNPs in a GWAS are not associated with either the outcome nor the environmental factor. For these and several other approaches, I will discuss the underlying assumptions and the sensitivity of the performance of each to G-E association in the population, population prevalence, and the assumed causal model.

Citation Format: David V. Conti. Searching for GxE interactions in genome-wide association studies. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr IA04.
Abstract IA06: Identification of tumor-associated cassette exons in human cancer through exon-array and RNA-Seq data analysis.
Authors: Valletti Alessio , Palumbo Orazio , D'Antonio Mattia , Castrignano' Tiziana , Gigante Margherita , Carella Massimo , Picardi Ernesto , Maria D'Erchia Anna , Elena Ranieri , Pesole Graziano
Published: August 2013

Many evidences report that alternative splicing, the mechanism producing mRNAs and proteins with different structures and functions from the same gene, is altered in cancer cells. Thus, the identification and characterization of cancer-specific splice variants may give large impulse to the discovery of novel diagnostic and prognostic tumor biomarkers, as well as of new targets for more selective and effective therapies.

We developed novel and effective computational tools for performing a genome-wide analysis of the alternative splicing pattern of human genes using both exon array and RNA-Seq data. Notably, we sought to identify “cassette exon” generated by exon skipping differentially expressed in the tumor and normal conditions.

To this aim we analyzed data obtained by exon array hybridization from clear cell renal carcinoma (ccRC) and colorectal cancer (CRC) samples as well as from the corresponding normal controls. Furthermore, high-throughput transcriptome sequencing from CRC and control samples were also analyzed. By using our computational strategy we identified several cassette exons differentially expressed in the tumoral and normal conditions.

In order to test the effectiveness of our computational strategy, we experimentally verified the occurrence of tumor- and normal-specific cassette exons by RT-qPCR assay. Remarkably, we were able to confirm “in vivo” the differential expression of these predicted cassette exons in patients affected by CRC and ccRC.

This study presents a novel computational methodology for the identification of tumor-associated transcript variants to be used as cancer molecular biomarkers, provides its experimental validation, and reports specific candidate biomarkers for CRC and ccRC.

Citation Format: Alessio Valletti, Orazio Palumbo, Mattia D'Antonio, Tiziana Castrignano, Margherita Gigante, Massimo Carella, Ernesto Picardi, Anna Maria D'Erchia, Elena Ranieri, Graziano Pesole. Identification of tumor-associated cassette exons in human cancer through exon-array and RNA-Seq data analysis. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr IA06.
Abstract IA10: Deciphering the signals from the GWAS hits: From function to epidemiology and back again.
Authors: Gayther Simon A.
Published: August 2013

Genome wide association studies (GWAS) have identified hundreds of single nucleotide polymorphisms (SNPs) that confer susceptibility to a multitude of complex, multifactorial disease traits including cardiovascular disease, diabetes, and several cancers. For the vast majority of identified common genetic variants, the functional rationale underlying disease is largely unknown. The functional effects of common risk associated SNPs are likely to be subtle given that they confer smaller risks (ORs <1.2). More than 90% of confirmed common risk-SNPs lie in non-coding DNA, often several kilobases from the nearest gene suggesting a critical role for non-coding DNA in the functional influence of these SNPs. A significant focus of functional follow-up studies at common susceptibility loci has therefore been to understand the interplay between non-coding DNA elements such as regulators and enhancers, non-coding RNA species such as micro- and long non-coding RNAs, and risk associated germline variants.

GWAS studies have also highlighted regions of the genome that contain plausible cancer susceptibility genes that may be specific to disease etiology (e.g. the FGFR gene in breast cancer), and other genes that may play more general role in cancer (e.g. the TERT gene, multi-cancer risk locus). The current presentation will focus on ovarian cancer. The Ovarian Cancer Association Consortium (OCAC) has identified 11 confirmed susceptibility loci, and suggest multiple candidate genes that have either previously been implicated in ovarian cancer development, or function in pathways such as double strand DNA break and nucleotide excision repair, which suggests they may play a significant role in ovarian cancer risk and/or clinical outcome. Data presented will describe approaches to understanding the functional role of both susceptibility SNPs and candidate genes in the underlying cellular etiology of different subtypes of ovarian cancer, and provide evidence suggesting a role of candidate genes in disease initiation and treatment response. Overall, these studies highlight the challenges we face in the developing field of functional-epidemiology, in particular in understanding common low-penetrance susceptibility loci. However, the emerging data also provide support for the role of GWAS in unearthing critical, previously unknown mechanisms that underlie cancer biology, suggesting these studies may have a substantial clinical impact in the future.

Citation Format: Simon A. Gayther. Deciphering the signals from the GWAS hits: From function to epidemiology and back again. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr IA10.
Abstract IA13: Chemicals in the environment: BPA and other worries.
Authors: Prins Gail S.
Published: August 2013

While early-life estrogens are thought to play a physiological role in normal prostate gland development and function, inappropriate estrogenic exposures either in timing, dose or type can reprogram the gland and increase susceptibility to abnormal growth with aging including carcinogenesis. Our research using a rat model indicates that estrogen imprinting of the prostate is mediated through structural reorganization of the gland early in life as well as epigenomic reprogramming that together permits life-long memory of the inappropriate developmental exposures. While high-dose estrogen exposures during a critical developmental window (as a model for pharmacologic agents such as DES) lead directly to prostate neoplasia that can progress to carcinoma with aging, early-life exposure to low-dose estradiol or the endocrtine disruptor bisphenol A (BPA) over a range of doses (0.1 to 5,000 ug BPA/kg BW) increases susceptibility of the adult prostate to carcinogenesis driven by elevated estradiol, as occurs in aging males. Data presented will provide a conceptual frame-work for understanding how early life estrogen-exposures via epigenetic reprogramming interact with later-life events through the disruption of pre-set gene expression programs for multiple genes. To assess whether the human prostate may be similarly reprogrammed during early life by hormones and EDCs, we have developed in vitro and in vivo models using normal human prostate stem/progenitor cells. Cultured prostaspheres composed of prostate stem and early-stage progenitor cells express robust levels of ERα, ERβ and GPR30 and exhibit a proliferative response with increased stem cell side populations to low-dose estradiol and BPA. Although AR negative, prostasphere cells express RARs, RXRs and aryl hydrocarbon receptor. While low-dose retinoic acid stimulated prostasphere cell differentiation, arsenic and dioxin perturbed their growth. Together these findings indicate that early stage progenitor and stem cells in the human prostate may be direct targets of EDCs and suggest that humans may be susceptible to prostate disease in a manner similar to the rodent models.

Citation Format: Gail S. Prins. Chemicals in the environment: BPA and other worries. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr IA13.
Abstract IA16: Susceptibility to neoplasia following HPV infection.
Authors: Schiffman Mark
Published: August 2013

Cervical cancer is caused by persistent infection with one of approximately a dozen carcinogenic human papillomavirus (HPV) infections. HPV16 is the most carcinogenic HPV type, causing one half of cases worldwide.

Cervical cancer arises via three well-defined steps: acute HPV infection; viral persistence linked to development of a high-grade intraepithelial lesion, and invasion. Infections peak in late adolescence and early adulthood, high-grade lesions grow superficially in the years following infection, and invasion of high-grade lesions typically takes decades to occur.

Host susceptibility given exposure to HPV is best considered by stage of the carcinogenic process. Infection is nearly ubiquitous among sexually active women, who appear (at our present state of knowledge) to be universally susceptible if previously unexposed. Common exposure leads to at least partial type-specific immunity as women age. Virtually all infections “clear” within 1-2 years and failure to clear, i.e., persistence, is highly associated with development of a high-grade lesion. Susceptibility to viral persistence is poorly understood, but is apparently the major determinant of carcinogenic risk from infection. If undiagnosed and untreated, high-grade lesions invade in a substantial minority of cases and we have determined no definitively established determinants of susceptibility to invasion.

Accordingly, this talk will focus on what is known about risk factors for HPV persistence/high-grade lesions given HPV infection. The risk factors can be divided conceptually into three groups: 1) viral factors, 2) host behavioral factors, and 3) intrinsic host factors.

Definite viral factors include HPV genetic factors (type and variant lineage) and HPV epigenetic factors (viral methylation). Established host behavioral factors include smoking, long-term oral contraceptive use, and multiparity; the associations are firm but mechanisms are not known. The few known intrinsic host factors include immune status (e.g., HIV immunosuppression), possibly specific HLA associations, and possibly some common genetic variants and methylation patterns. The leading candidates will be mentioned.

Understanding of the viral-host interaction has led to promising biomarkers used to distinguish between acute HPV infection and high-grade lesions, most notably p16 staining, a marker of disruption of the Rb pathway.

Citation Format: Mark Schiffman. Susceptibility to neoplasia following HPV infection. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr IA16.
Abstract IA18: Large-scale familial whole genome sequencing to evaluate genetic risk.
Authors: Vockley Joseph , Iyer Ramaswamy , Huddleston Kathi , Niederhuber John
Published: August 2013

Whole genome sequencing (WGS) technology and analysis is quickly approaching the stage of development where it can become a medically recognized procedure for prognostics as well as diagnostics. Critical to the development of medical-grade whole genome sequencing is the ability to recognize and minimize technological and biological variation in WGS data. The Inova Translational Medicine Institute (ITMI) has completed a study that generated 1500 whole genome sequences in 15 months and recently launched a study that will generate 20,000 WGS over the next two years. The 1500 sequenced genomes were from individuals from 53 countries, representing four major ancestral groups and many minor sub-groups. ITMI used these data to generate a database of ancestral-specific variants. This database can be used to identify single nucleotide variants in patients with a specific ancestral background as ancestral-specific sequences instead of mutations. This ancestral information was applied to the 487 cancer genes identified in the Wellcome Trust Sanger Institute's Cancer Gene Census, in an attempt to identify germline mutations in these genes, in our cohort of 1500 participants. The result of this analysis identifies the incidence and type of germline mutations in various ethnic groups. The ethical question that remains is what to do with incidental finding of this type as medical whole genome sequencing becomes a common tool in the practice of medicine.

Citation Format: Joseph Vockley, Ramaswamy Iyer, Kathi Huddleston, John Niederhuber. Large-scale familial whole genome sequencing to evaluate genetic risk. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr IA18.
Abstract IA19: The GAME-ON (Genetic Associations and Mechanisms in Oncology) Consortium: Assessing the functional relevance of genetic variation.
Authors: Monteiro Alvaro N.A.
Published: August 2013

Recently, significant advances in genetics, in particular in genome-wide association studies (GWAS), have uncovered a large number of chromosomal loci associated with cancer risk. Despite these advances the determination of the molecular mechanism behind the detected associations has proven to be a significant challenge. The design of most GWAS genotyping chips take advantage of well characterized tagging single nucleotide polymorphisms (SNPs). These “tags” represent specific proxy markers for a series of other SNPs in high linkage disequilibrium with the tagging SNP in a defined chromosomal region. While the use of tagging SNPs result in reproducible and robust signals during genotyping and minimize the number of SNPs to be tested, the expectation is that they may not necessarily constitute the causal SNP, the nucleotide change that result in a relevant biological activity responsible for cancer predisposition.

Identification of predisposition loci in prostate, ovary, and breast have been accelerated by the COGS (Collaborative Oncologic Gene-Environment Study) project which typed 200,000 SNPs and genotyped an unprecedented number of cancer cases and controls (˜200,000). The GAME-ON (Genetic Associations and Mechanisms in Oncology) consortium has poured over GWAS data for prostate, ovary, breast, lung, and colorectal cancers to develop systematic procedures to dissect functional contribution of SNPs and their target genes. Here I describe our experience in conducting functional analyses for these loci, focusing on ovarian cancer susceptibility loci.

The overall approach can be loosely divided in three stages: in the first we use the most significant SNP found in GWAS analyses or meta-analyses as a starting point to interrogate other candidate functional SNPs in the region. The second stage explores potential target genes in the region. Finally, we focus on tying the candidate functional SNP to the candidate target gene. This final stage may also focus on, depending on the availability of in vivo models, attempts to uncover direct evidence for the participation of the SNP/target gene pairs in the mechanism of oncogenesis. Although in some cases the analytic approaches and tools might be specific to the cancer in question, we feel that the main framework can be utilized for different cancers. Most importantly, perhaps, are the lessons learned during this process as well as identifying the limitations and challenges that lay ahead.

Citation Format: Alvaro N.A. Monteiro. The GAME-ON (Genetic Associations and Mechanisms in Oncology) Consortium: Assessing the functional relevance of genetic variation. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr IA19.
Abstract IA20: The NCI Cohort Consortium: Increasing power, enhancing collaborations, advancing science.
Authors: Winn Deborah M.
Published: August 2013

The Cohort Consortium is an extramural-intramural partnership formed by the National Cancer Institute (NCI) to foster communication among investigators leading cohort studies of cancer; promote collaborative research projects for topics not easily addressed in a single study; and identify common challenges in cohort research and search for solutions. The Cohort Consortium includes investigators responsible for more than 40 high-quality cancer epidemiology cohorts involving more than 4 million people. The cohorts are international in scope and cover large, rich, and diverse populations. Extensive risk factor data are available on each cohort, and biospecimens, including germline DNA collected at baseline, are available on more than 2 million individuals. Investigators team up to use common protocols and methods, and to conduct coordinated parallel and pooled analyses. Some recent accomplishments include publications of genome-wide association studies of pancreatic cancer and on the effect of high body mass index on mortality after eliminating the influence of tobacco smoking and co-morbidities. The Consortium provides a forum to discuss scientific questions in cancer research that cohort studies can help address such as how metabolomics can best be examined in human population studies and how cohort studies can better address the role of physical and chemical agents on cancer risk. It also can focus attention on new methodologies such as the use of social media and new ways of interacting with cohort study participants that could enhance data collection, data quality, and study participant retention and engagement.

Citation Format: Deborah M. Winn. The NCI Cohort Consortium: Increasing power, enhancing collaborations, advancing science. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr IA20.
Abstract IA22: From the genome to the metabolome: The promises and limits of metabolomics.
Authors: Daniel Hannelore
Published: August 2013

Metabolomics is the youngest of the profiling techniques employed in the life sciences. It assesses alterations in the pool of metabolites in a biological sample by using nuclear magnetic resonance (NMR) or mass spectrometry techniques (MS) coupled to liquid or gas chromatography. Metabolite profiling is mainly employed to identify exposure markers or disease related biomarkers. The latter currently dominates by profiling of plasma and/or urine samples in large cohort studies associated with disease endpoints. It may also include genotyping with the goal to link changes in the metabolome to single nucleotide polymorphisms or changes in gene/protein expression. By examples from research on type 2 diabetes and partly on cancers a critical assessment of identified “biomarkers” in terms of specificity and sensitivity will be presented. Intrinsic to most cohort studies is that only a few samples (usually collected after overnight fasting) are available for analysis. This neglects the dynamics of changes in the metabolome as a continuum of adaptations to environmental cues. Challenge experiments may allow a more comprehensive metabolic phenotyping of healthy and diseased humans. Moreover, metabolomics needs to move from the descriptive level that just measures concentrations of selected metabolites to new avenues that cover metabolites in entire pathways and by carrying out flux analysis for being explanatory.

Citation Format: Hannelore Daniel. From the genome to the metabolome: The promises and limits of metabolomics. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr IA22.
Abstract IA23: Using metabolomics in epidemiologic studies: An example for pancreatic cancer.
Authors: Wolpin Brian Matthew
Published: August 2013

Pancreatic cancer is the fourth-leading cause of cancer-related death in the United States. Among individuals who develop pancreatic adenocarcinoma, only 5% will survive 5 years after diagnosis and most patients live for <12 months. Novel strategies for prevention and risk stratification are greatly needed.

Glucose intolerance has emerged as an important predisposing factor for pancreatic adenocarcinoma. Prospective studies have demonstrated an increased risk of pancreatic cancer with increasing body-mass index, a determinant of peripheral insulin resistance and a central risk factor for type II diabetes. Although controversy remains regarding causation versus consequence, diabetes has been associated with pancreatic cancer risk and fasting serum glucose and post-load plasma glucose have been linked with the subsequent risk of pancreatic cancer. Furthermore, studies have linked levels of circulating hormones to pancreatic cancer risk, including insulin, C-peptide and adiponectin. Studies are needed to better understand mechanisms underlying the higher risk of pancreatic cancer among individuals with impaired glucose processing

Metabolism denotes the conversion of food products into energy and the building blocks for cellular functioning. The high-throughput identification and quantification of small molecule metabolites produced by metabolism, including lipids, fatty acids, sugars, nucleotides, and amino acids, has been termed metabolomics. Metabolomics is increasingly being used to evaluate alterations in metabolism and their relationship to human disease. In epidemiologic studies, this technology has particular potential to advance our understanding of disease, as participants have provided information on a variety of exposures and diseases in addition to biologic samples.

Given the strong link between glucose intolerance and pancreatic cancer risk, we pursued a rigorous pilot program of a liquid chromatography/mass spectrometry (LC-MS) metabolomics platform for application to prospectively collected, archived plasma specimens in a nested case-control study of pancreatic adenocarcinoma. This pilot program highlighted important issues relevant to data analysis, including accounting for sample preservative type, sample processing delays, and fasting times. Furthermore, it helped define reproducibility of metabolites using actual archived participant samples. The application of metabolomics to large epidemiologic studies holds promise for defining new biomarkers of disease, including for pancreatic adenocarcinoma.

Citation Format: Brian Matthew Wolpin. Using metabolomics in epidemiologic studies: An example for pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr IA23.
Abstract PR1: LINE-1 %5-methyl cytosine levels in prediagnostic leukocyte DNA and future bladder cancer risk among PLCO and ATBC cohort subjects.
Authors: Andreotti Gabriella , Karami Sara , Pfeiffer Ruth , Hurwitz Lauren , Liao Linda , Weinstein Stephanie , Albanes Demetrius , Virtamo Jarmo , Silverman Debra , Rothman Nathaniel , Moore Lee
Published: August 2013

Background: Low global methylation levels measured in post-diagnostic case compared to healthy control blood DNA have been associated with elevated bladder cancer risk.

Objective: To examine this association using blood DNA collected prior to bladder cancer diagnosis.

Methods: Cases (n=437) and controls (N=847) were selected from the Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial (PLCO). A replication case-control study was conducted among males from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) cohort (391 cases/778 controls). LINE-1 percent 5-methyl-cytosine (LINE-1 %5-MeC) levels were quantified using bisulfite treated blood DNA and pyrosequencing. Cancer risk was assessed in deciles (D1-D10: 10-100%) and quartiles (Q1-Q4:25-100%) of methylation levels based on controls. Logistic regression was used to evaluate individual and pooled study data.

Findings: In PLCO, significantly lower bladder cancer risk was associated with the lowest LINE-1 %5-MeC decile (D1) compared to D2-D10 subjects adjusted for sex and pack-years of smoking (OR=0.35; 95% CI: 0.18-0.68, p=0.002). Findings were corroborated in the ATBC study, (D1 vs. D2-D10: OR=0.31;95% CI:0.17-0.57, p<0.001) adjusting for pack-years of smoking and intervention assignment. When male data were pooled, a similar association was observed comparing D1 to D2-D10 subjects (OR=0.35;95% CI:0.21-0.57, p<0.001) and by quartiles (OR Q1=0.53;95% CI:0.41-0.70, p<0.001). Smoking status did not modify the associations.

Interpretation: Findings observed in two independent studies using pre-diagnostically collected bladder cancer case/control subject DNA support that higher methylation levels may reflect higher bladder cancer risk prior to diagnosis. Associations using pre-diagnostically collected blood DNA were opposite to those from previous case-control studies using post-diagnostic DNA, suggesting changes in methylation levels associated with the carcinogenic process. Additional prospective studies evaluating LINE1 and gene-specific CpG methylation levels are needed to replicate and extend these findings.

This proffered talk is also presented as Poster 11.

Citation Format: Gabriella Andreotti, Sara Karami, Ruth Pfeiffer, Lauren Hurwitz, Linda Liao, Stephanie Weinstein, Demetrius Albanes, Jarmo Virtamo, Debra Silverman, Nathaniel Rothman, Lee Moore. LINE-1 %5-methyl cytosine levels in prediagnostic leukocyte DNA and future bladder cancer risk among PLCO and ATBC cohort subjects. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr PR1.
Abstract PR2: Pathway-based gene-environment interactions in ovarian cancer.
Authors: Braem Marieke GM , Charlotte Onland-Moret N. , H. Moore Jason , HM Peeters Petra
Published: August 2013

Genome-wide association studies (GWAS) have identified 19 loci associated with the risk of ovarian cancer. In this post-GWAS era interest shifts towards elucidating the interplay of these susceptibility loci and known risk factors for ovarian cancer, i.e. reproductive and hormonal factors, height and smoking.

In this study, we investigate gene-environment interactions between the GWAS loci and single nucleotide polymorphisms (SNPs) in the accompanying genetic pathways and risk factors for ovarian cancer. Currently, a golden standard for the analysis of gene-environment interactions is lacking. Therefore, we use a multifaceted analytical approach by using a series of machine learning methods, including regression analysis, multifactor dimensionality reduction (MDR), entropy-based interaction networks, computational evolution systems and learning classifier systems.

A case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) is being conducted including 590 ovarian cancer cases and 1190 healthy controls. In addition to all known GWAS hits for ovarian cancer, genetic pathways were selected in which the genes of these GWAS hits are potentially involved. A total of 754 SNPs are investigated. The environmental factors of interest are parity, miscarriages, breastfeeding, oral contraceptive (OC) use, age at menarche, age at menopause, height and smoking.

Preliminary results from regression analyses show statistically significant interactions between SNPs identified through GWAS and smoking (in interaction with rs12379687, p=0.0435), height (in interaction with rs2072590, p=0.01563) and OC use (in interaction with rs10098821, p=0.03621). These interactions were confirmed by multifactor dimensionality reduction, based on 10-fold cross-validation and 1000-fold permutation testing. Subsequent analyses are still ongoing and will be presented at the conference. Moreover, the analyses will be supplemented by an additional 289 cases and 578 controls from the Nijmegen Polygene and the Nijmegen Biomedical Study.

The results of this study will provide important insight into the etiology of ovarian cancer and reveal better understanding of the complexity of this disease.

This proffered talk is also presented as Poster 41.

Citation Format: Marieke GM Braem, N. Charlotte Onland-Moret, Jason H. Moore, Petra HM Peeters. Pathway-based gene-environment interactions in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr PR2.
The Invisible Arm of Immunity in Common Cancer Chemoprevention Agents
Authors: Marzbani Edmond , Inatsuka Carol , Lu Hailing , Disis Mary L.
Published: August 2013

Immunoprevention refers to a strategy of preventing pathogen-associated and spontaneous cancers through the use of vaccines, antibodies, and immune modulators. Immune modulators function by enhancing the endogenous ability of the immune system to monitor for malignancy, so-called “immunosurveillance.” There is growing evidence that many of the most promising cancer chemoprevention agents including aspirin, COX-2 inhibitors, aromatase inhibitors, and bisphosphonates mediate their effects, in part, by enhancing immunosurveillance and reversing the immune evasive mechanisms that premalignant lesions use. In the following review, we introduce critical components of the human immune surveillance system—dendritic cells, T cells, and immune suppressive cells—and discuss the emerging data suggesting that common chemoprevention agents may modulate the function of these immunologic cells. Cancer Prev Res; 6(8); 764–73. ©2013 AACR.
Bacterial Intracellular Sulfur Globules: Structure and Function
Authors: Maki James S.
Published: August 2013

Bacteria that oxidize reduced sulfur compounds like H2S often transiently store sulfur in protein membrane-bounded intracellular sulfur globules; intracellular in this case meaning found inside the cell wall. The cultured bacteria that form these globules are primarily phylogenetically classified in the Proteobacteria and are chemotrophic or photoautotrophic. The current model organism is the purple sulfur bacterium Allochromatium vinosum. Research on this bacterium has provided the groundwork for understanding the protein membranes and the sulfur contents of globules. In addition, it has demonstrated the importance of different genes (e.g. sulfur oxidizing, sox) in their formation and in the final oxidation of sulfur in the globules to sulfate (e.g. dissimilatory sulfite reductase, dsr). Pursuing the characteristics of other intracellular sulfur globule-forming bacteria through genomics, transcriptomics and proteomics will eventually lead to a complete picture of their formation and breakdown. There will be commonality to some of the genetic, physiological and morphological characteristics involved in intracellular sulfur globules of different bacteria, but there will likely be some surprises as well.
The African-American Labor Supply after Reconstruction: Added Worker Effects in Urban Families
Authors: Murray John E. , Troesken Werner
Published: August 2013

Econometric analysis of a hitherto unused 1896 survey of African-American families in American cities, mostly located in the South, reveals the classic added worker effect: Longer intervals of husbands' unemployment—not counting work missed on account of illness—led to a greater share of wives taking paid employment outside the home. The analysis also shows that household structure and composition, as well as the health of husbands, influenced the decision of wives to enter the labor force. The data and analysis provide some of first econometric evidence about the labor-force decisions of urban-dwelling blacks in late nineteenth-century America.
Faces of Opposition: Juvenile Resistance, High Treason, and the People's Court in Nazi Germany
Authors: Geerling Wayne , Magee Gary B. , Brooks Robert
Published: August 2013

Analysis of the sixty-nine juveniles tried for high treason before the People's Court in Nazi Germany between 1933 and 1945, based on the available court records, finds that juvenile resistance in Nazi Germany possessed a distinct form and character; it was a phenomenon rather than an exceptional act. Juvenile resisters charged with high treason were typically working-class males of German ethnicity, motivated primarily by left-wing and religious beliefs, acting in small groups free of significant adult supervision and direction. Examination of the verdicts and sentencing of these juvenile resisters sheds light on how the Nazi justice system reacted to such serious internal resistance from its young.
Stages of Processing in Associative Recognition: Evidence from Behavior, EEG, and Classification
Authors: Borst Jelmer P. , Schneider Darryl W. , Walsh Matthew M. , Anderson John R.
Published: August 2013

In this study, we investigated the stages of information processing in associative recognition. We recorded EEG data while participants performed an associative recognition task that involved manipulations of word length, associative fan, and probe type, which were hypothesized to affect the perceptual encoding, retrieval, and decision stages of the recognition task, respectively. Analyses of the behavioral and EEG data, supplemented with classification of the EEG data using machine-learning techniques, provided evidence that generally supported the sequence of stages assumed by a computational model developed in the Adaptive Control of Thought-Rational cognitive architecture. However, the results suggested a more complex relationship between memory retrieval and decision-making than assumed by the model. Implications of the results for modeling associative recognition are discussed. The study illustrates how a classifier approach, in combination with focused manipulations, can be used to investigate the timing of processing stages.
The lichen genera Aspiciliopsis, and Placopsis (Trapeliales: Trapeliaceae: Ascomycota) in New Zealand
Authors: GALLOWAY DAVID J.
Published: August 2013

Aspiciliopsis macrophthalma and 38 species of Placopsis are recognized in the New Zealand mycobiota. Placopsis campbelliana, and P. erosa are newly described. A key to species is given, together with details of synonymy and typification, descriptions of all taxa, their chemistry, distribution, ecology and biogeographical affinities. Lichenicolous fungi parasitising species of Placopsis are recorded. The importance of Placopsis as a fast-growing and active nitrogen-fixer in natural ecosystems is noted as well as the role of certain species in processes of soil consolidation and natural environmental repair processes. The utility of some species for lichenometric studies in recently deglaciated environments of the Southern Hemisphere is also noted.
Description of two new species of the genus Tmesiphodimerus gen. n. (Coleoptera: Staphylinidae: Pselaphinae) from South Asia
Authors: YIN ZI-WEI , COULON GEORGES , LI LI-ZHEN
Published: August 2013

Tmesiphodimerus Coulon and Yin, new genus (Pselaphitae: Tmesiphorini) is proposed for T. sinensis Yin and Coulon, new species from Hainan, South China (type species), and T. malaysianus Coulon and Yin, new species from Perak, West Malaysia. The new taxa are described, with their major diagnostic features illustrated. The taxonomic placement of Tmesiphodimerus is discussed.
A new species of the sponge-associated pontoniine shrimp genus Nippontonia Bruce & Bauer, 1997 (Decapoda, Caridea, Palaemonidae) from Sabah, Malaysia
Authors: FRANSEN CHARLES H.J.M.
Published: August 2013

A sponge-associated species of the genus Nippontonia new to science is described from Semporna, Sabah, Malaysia. The only other species in the genus is also known to be a sponge-dweller. The new species can be distinguished from its congener by a suite of characters mainly of the anterior appendages.
New species and records of Anacroneuria (Plecoptera: Perlidae) from Rio de Janeiro State, Brazil
Authors: BALDIN CAROLINA , BISPO PITÁGORAS DA CONCEIÇÃO , NOVAES MARCOS CARNEIRO
Published: August 2013

Six species of Anacroneuria are recorded from Parque Nacional do Itatiaia and Bacia do Rio Macaé, Rio de Janeiro State, Brazil including the description of a new species, A. itatiaiensis. Anacroneuria debilis (Pictet) is redescribed from newly collected specimens. Comments on other Anacroneuria species from Rio de Janeiro State, Brazil are also presented.