bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predicting and preventing postconcussive problems in paediatrics (5P) study: protocol for a prospective multicentre clinical prediction rule derivation study in children with concussion
Authors: Zemek Roger , Osmond Martin H , Barrowman Nick 
Published: August 2013

IntroductionPersistent postconcussive symptoms (PCSs) is the persistence of somatic, cognitive, physical, psychological and/or behavioural changes lasting more than 1 month following concussion. Persistent concussion impacts the quality of life through impaired cognition, memory and attention affecting school performance, mood and social engagement. No large epidemiological studies have determined the true prevalence of persistent concussion symptoms. Validated, easy-to-use prognosticators do not exist for clinicians to identify children at highest risk. The goal of Predicting and Preventing Postconcussive Problems in Pediatrics study is to derive a clinical prediction rule for the development of persistent postconcussion symptoms in children and adolescents presenting to emergency department following acute head injury.Methods and analysisThis study is a prospective, multicentre cohort study across nine academic Canadian paediatric emergency departments. We will recruit the largest prospective epidemiological cohort of children with concussion. Eligible children will be followed using Post-Concussion Symptom Inventory, a validated tool in children as young as 5 years. Patients will follow-up at 1, 2, 4, 8 and 12 weeks postinjury. The main outcome will be the presence/absence of PCSs defined as three or more persistent concussion symptoms 1 month following the injury. 1792 patients provide adequate power to derive a clinical decision rule using multivariate analyses to find predictor variables sensitive for detecting cases of persistent postconcussion symptoms.Ethics and disseminationResults of this large prospective study will enable clinicians to identify children at highest risk, optimise treatment and provide families with realistic and appropriate anticipatory guidance. Ethics has been obtained through the Children's Hospital of Eastern Ontario Research Ethics Board. Results will be disseminated at international conferences and in four manuscripts to peer-reviewed journals.Trial registrationThis study is registered at Clinicaltrials.gov through the US National Institute of Health/National Library of Medicine (NCT01873287;http://clinicaltrials.gov/ct2/show/NCT01873287).
Urinary excretion of porphyrins, porphobilinogen and δ-aminolaevulinic acid following an attack of acute intermittent porphyria
Authors: Marsden Joanne T , Rees David C 
Published: August 2013

Background and objectivesThe porphyrias are a group of rare, mainly inherited, diseases caused by a deficiency of one of the enzymes of the haem biosynthesis pathway. The biochemical hallmark of an acute attack is an increase in urine porphobilinogen (PBG), together with an increase in urinary excretion of δ-aminolaevulinic acid (ALA) and total urine porphyrins (TUP). In patients with acute intermittent porphyria (AIP) the concentrations of the porphyrin precursors are thought to remain elevated for many years following an acute attack, although this has not been well documented.MethodsWe measured urine ALA, PBG and TUP excretion in 20 patients with AIP following an attack of acute porphyria over a time period of 3 months to 23 years after their last documented acute attack.ResultsWe showed that urinary concentrations of all metabolites remain elevated for many years. The urinary half life of TUP was 5.3 years, ALA 7.7 years and PBG 10.6 years. Even after 20 years, PBG concentrations remained elevated above the normal range.ConclusionsOur study highlights the difficulties of using urinary analysis for diagnosing recurrent attacks, and also raises important questions about the pathophysiology of the condition.
Chromosome 17 polysomy: correlation with histological parameters andHER2NEUgene amplification
Authors: Orsaria Maria , Khelifa Sihem , Buza Natalia , Kamath Anitha , Hui Pei 
Published: August 2013

AimsHER2NEUgene amplification is present in the majority of invasive breast carcinomas that have HER2 protein overexpression. A subset of breast cancers harbour an increased chromosome 17 (CEP17) copy number (polysomy 17). We investigated the clinicopathologic significance of polysomy 17 in correlation with various histological parameters andHER2NEUgene amplification.MethodsWe collected the surgical specimens of 266 consecutive cases of primary invasive breast carcinomas.HER2NEUgene status and CEP17 copy numbers were assessed by fluorescent in situ hybridisation (FISH). Chromosome 17 polysomy was determined by the presence of ≥3 average CEP17 signals per nucleus.Results63 tumours (23.7%) harboured polysomy 17. Carcinomas with polysomy 17 were associated with adverse histological indicators including high histological grade, high nuclear grade, poor Nottingham Prognostic Index, advanced local tumour extent and progesterone receptor negativity. Polysomy 17 was common toHER2NEUamplified and unamplified tumours, and more frequently observed inHER2NEUunamplified (71.4%) cases.ConclusionsIn the absence of the gene amplification, HER2 protein overexpression may be explained by other mechanisms including polysomy 17.
Provenance models: the role of sandstone mineral–chemical stratigraphy
Authors: Hurst Andrew , Morton Andrew 
Published: August 2013

Abstract
Three distinct analytical approaches are embraced in mineral–chemical stratigraphy: mineralogy, whole-rock geochemistry and single-grain geochemical analysis. Mineralogical studies identify and quantify the clastic components of sandstone, even though any clast category may be geochemically diverse. Whole-rock geochemical studies (sometimes referred to as chemostratigraphy), by contrast, quantify the abundance of major and trace elements in sandstone, but provide no information on the distribution and location of the elements in minerals. These approaches are linked by single-grain geochemical analysis, which enables further characterization and subdivision of individual mineralogical components, and identifies sites where specific major and trace elements reside.
In this paper, we consider the relationships between minerals, mineral chemistry and whole-rock composition, before exploring the value of mineral–chemical stratigraphy for lithostratigraphic correlation and evaluation of sediment provenance, using published examples from the North Sea region, where the great majority of such studies have been undertaken. We conclude by discussing the important role that alluvial basins play in controlling mineral–chemical signatures.
SOX10 Ablation Arrests Cell Cycle, Induces Senescence, and Suppresses Melanomagenesis
Authors: Cronin Julia C. , Watkins-Chow Dawn E. , Incao Art , Hasskamp Joanne H. , Schönewolf Nicola , Aoude Lauren G. , Hayward Nicholas K. , Bastian Boris C. , Dummer Reinhard , Loftus Stacie K. , Pavan William J. 
Published: August 2013

Abstract
The transcription factor SOX10 is essential for survival and proper differentiation of neural crest cell lineages, where it plays an important role in the generation and maintenance of melanocytes. SOX10 is also highly expressed in melanoma tumors, but a role in disease progression has not been established. Here, we report that melanoma tumor cell lines require wild-type SOX10 expression for proliferation and SOX10 haploinsufficiency reduces melanoma initiation in the metabotropic glutamate receptor 1 (Grm1Tg) transgenic mouse model. Stable SOX10 knockdown in human melanoma cells arrested cell growth, altered cellular morphology, and induced senescence. Melanoma cells with stable loss of SOX10 were arrested in the G1 phase of the cell cycle, with reduced expression of the melanocyte determining factor microphthalmia-associated transcription factor, elevated expression of p21WAF1 and p27KIP2, hypophosphorylated RB, and reduced levels of its binding partner E2F1. As cell-cycle dysregulation is a core event in neoplastic transformation, the role for SOX10 in maintaining cell-cycle control in melanocytes suggests a rational new direction for targeted treatment or prevention of melanoma. Cancer Res; 73(18); 5709–18. ©2013 AACR.
ERG Is a Critical Regulator of Wnt/LEF1 Signaling in Prostate Cancer
Authors: Wu Longtao , Zhao Jonathan C. , Kim Jung , Jin Hong-Jian , Wang Cun-Yu , Yu Jindan 
Published: August 2013

Abstract
Chromosomal translocations juxtaposing the androgen-responsive TMPRSS2 promoter with the ETS-family transcription factor ERG result in aberrant ERG upregulation in approximately 50% of prostate cancers. Studies to date have shown important roles of ERG in inducing oncogenic properties of prostate cancer. Its molecular mechanisms of action, however, are yet to be fully understood. Here, we report that ERG activates Wnt/LEF1 signaling cascade through multiple mechanisms. ERG bound to the promoters of various Wnt genes to directly increase ligand expression. Consequently, ERG overexpression increased active β-catenin level in the cells and enhanced TCF/LEF1 luciferase reporter activity, which could be partially blocked by WNT-3A inhibitor IWP-2. Most importantly, our data defined LEF1 as a direct target of ERG and that LEF1 inhibition fully abolished ERG-induced Wnt signaling and target gene expression. Furthermore, functional assays showed that Wnt/LEF1 activation phenocopied that of ERG in inducing cell growth, epithelial-to-mesenchymal transition, and cell invasion, whereas blockade of Wnt signaling attenuated these effects. Concordantly, LEF1 expression is significantly upregulated in ERG-high human prostate cancers. Overall, this study provides an important mechanism of activation of Wnt signaling in prostate cancer and nominates LEF1 as a critical mediator of ERG-induced tumorigenesis. Wnt/LEF1 pathway might provide novel targets for therapeutic management of patients with fusion-positive prostate cancer. Cancer Res; 73(19); 6068–79. ©2013 AACR.
Abstract 40: Arsenic exposure in pregnancy increases the risk of adverse birth outcomes of newborns in Taiwan.
Authors: Chou W.C. , Chuang C.Y. , Huang P.C. , Wang C.J. , Chen H.Y. , Chuang Y.D. , Wang S.L. 
Published: August 2013

Abstract
Background: Previous studies have reported that arsenic (As) exposure in pregnancy induces DNA damage and increased risk of fetal health and development. However, the associations between As-induced DNA damage and adverse birth outcomes in newborns have yet to be established. We aimed to elucidate the association between As exposure and DNA damages in pregnant women, and link it to the increased risks of adverse birth outcomes in newborn.
Methods: A birth cohort study of 309 mother-newborn pairs was recruited during 2001-2002. We collected maternal urine samples in the third trimester of pregnancy for measurements of metabolites of inorganic arsenic (iAs) using high-performance liquid chromatography/ inductively coupled plasma mass spectrometry, and DNA damage biomarkers by liquid chromatography tenden mass spectrometer. Information of birth weight, birth length, head circumference, chest girth and Apgar score of newborns were collected to assess newborn health.
Results: We found a significant correlation between maternal As exposure and increased levels of 8-OHdG (β=0.39, p&lt;0.001) and N7-MeG (β=0.26, p&lt;0.001) in pregnant women. The significant increased risk of low Apgar score at 1st min (&lt;7) in newborns were associated with increased levels of urinary iAs (OR: 1.03, 95% confidence interval (CI): 1.01-1.06) and N7-MeG (OR: 1.24, 95% CI: 1.10-1.25).
Conclusions: These findings suggest that maternal As exposure may contribute to the formation of DNA damages and affect fetal and infant health. DNA methylation altered by arsenic exposure was hypothesized and tested.
Citation Format: W.C. Chou, C.Y. Chuang, P.C. Huang, C.J. Wang, H.Y. Chen, Y.D. Chuang, S.L. Wang. Arsenic exposure in pregnancy increases the risk of adverse birth outcomes of newborns in Taiwan. [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 40.
Abstract 51: Prospective study of LINE-1 hypomethylation in peripheral leukocyte DNA and colorectal cancer risk.
Authors: Huang Wen-Yi , Su L. Joseph , Berndt Sonja I. , Moore Lee E. , Katki Hormuzd A. , Yegnasubramanian Srinivasan , Purdue Mark P. 
Published: August 2013

Abstract
Background: The family of long interspersed nuclear elements (LINE-1) retrotransposons is reportedly hypomethylated in many cancers and reflects global methylation status in the genome. Global hypomethylation in peripheral blood leukocyte DNA has been increasingly studied and associated with increased risk of cancer, including colorectal cancer and adenoma in cross-sectional studies.
Methods: To minimize disease- and/or treatment-related effects, we studied LINE-1 methylation levels in prospectively collected blood specimens from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial in relation to subsequent colorectal cancer risk. In a nested study of 398 cases and 519 controls who were cancer-free at blood collection, the extent of LINE-1 hypomethylation was measured by using the McrBC methylation specific restriction enzyme to cut methylated but not unmethylated DNA, followed by real-time PCR of the undigested/unmethylated LINE1 promoter sequences. We estimated the association between colorectal cancer risk and LINE-1 methylation categories by computing odds ratios (ORs) and 95% confidence intervals (CIs) through multivariable logistic regression modeling.
Results: Overall, we observed no clear association between colorectal cancer and LINE-1 methylation categories (lowest tertile vs. highest: OR=1.06, 95% CI=0.74-1.52; P trend=0.72). However, we observed a nearly significant trend of decreasing LINE-1 methylation (hypomethylation) associated with increasing colorectal cancer risk, after excluding cases diagnosed within 1 year (lowest tertile vs. highest: OR=1.40, 95% CI=0.87-2.27; P trend=0.14) and 5 years (OR=2.65, 95% CI=0.96-7.36; P trend=0.07) following the blood collection. We noted no significant risk modification by folate intake or other suspected risk factors of colorectal cancer, such as smoking, obesity, and aspirin/ ibuprofen use in analyses including all subjects or excluding cases diagnosed within 5 years following blood collection (P interaction ranged between = 0.12 to 0.98).
Conclusion: Findings from this prospective investigation offer further support for a potential dose-dependent relationship between LINE-1 hypomethylation in leukocyte DNA and subsequent colorectal cancer risk.
Citation Format: Wen-Yi Huang, L. Joseph Su, Sonja I. Berndt, Lee E. Moore, Hormuzd A. Katki, Srinivasan Yegnasubramanian, Mark P. Purdue. Prospective study of LINE-1 hypomethylation in peripheral leukocyte DNA and colorectal cancer 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 51.
Abstract 62: A genome-wide association study identifies two new susceptibility loci for lung adenocarcinoma in the Japanese population.
Authors: Shiraishi Kouya , Kunitoh Hideo , Daigo Yataro , Takahashi Atsushi , Goto Koichi , Sakamoto Hiromi , Ohnami Sumiko , Shimada Yoko , Ashikawa Kyota , Saito Akira , Watanabe Shun-ichi , Tsuta Koji , Kamatani Naoyuki , Yoshida Teruhiko , Nakamura Yusuke , Yokota Jun , Kubo Michiaki , Kohno Takashi 
Published: August 2013

Abstract
Adenocarcinoma is the most common type, comprising ˜40% of all lung cancer cases, and its incidence is increasing both in Asian and Western countries. The development of lung adenocarcinoma is more weakly associated with smoking than other histological types of lung cancer, such as squamous and small cell carcinomas, indicating that the mechanisms of carcinogenesis differ among these types. A better understanding of the genetic factors underlying lung adenocarcinoma development is strongly needed to elucidate the disease etiology and to identify high-risk individuals for targeted screening and/or prevention. To identify genetic factors that influence the risk of lung adenocarcinoma, we conducted a genome-wide association study and two validation studies in the Japanese population that consisted of a total of 6,029 lung adenocarcinoma cases and 13,535 controls (Shiraishi et al, Nat Genet, 2012).
Associations of two previously reported loci, 5p15.33 (rs2853677 in TERT; PCombined = 2.8x10-40, odds ratio (OR) = 1.41) and 3q28 (rs10937405 in TP63; PCombined = 6.9x10-17, OR = 1.25) (Landi et al, AJHG, 2009; Miki et al, Nat Genet, 2010), were validated. In addition, we identified two new susceptibility loci, 17q24.3 (rs7216064 in BPTF; PCombined = 7.4x10-11, OR = 1.20) and 6p21.3 (rs3817963 in BTNL2; PCombined = 2.7x10-10, OR = 1.18). BPTF encodes a chromatin remodeling factor that regulates transcription via specific recognition of methylated histone proteins. BPTF mRNA levels in noncancerous lung tissues were different depending on the genotype of the rs7216064 SNP (P = 0.02), implying a low expression from the risk allele. The BTNL2 gene encodes a T cell co-stimulatory molecule, and associations between BTNL2 SNPs and risk have been reported in several immune-related diseases. These data provide further evidence supporting genetic susceptibility to the development of lung adenocarcinoma.
Citation Format: Kouya Shiraishi, Hideo Kunitoh, Yataro Daigo, Atsushi Takahashi, Koichi Goto, Hiromi Sakamoto, Sumiko Ohnami, Yoko Shimada, Kyota Ashikawa, Akira Saito, Shunichi Watanabe, Koji Tsuta, Naoyuki Kamatani, Teruhiko Yoshida, Yusuke Nakamura, Jun Yokota, Michiaki Kubo, Takashi Kohno. A genome-wide association study identifies two new susceptibility loci for lung adenocarcinoma in the Japanese population. [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 62.
Abstract IA05: Integrative approaches for understanding the functional relevance of cancer susceptibility loci.
Authors: Fridley Brooke L. 
Published: August 2013

Abstract
Genome-wide association studies (GWAS) have identified hundreds of single nucleotide polymorphisms (SNPs) that confer susceptibility to a variety of cancers. However, as with the vast majority of common genetic variants, the functional rationale underlying cancer risk is largely unknown. In addition, other variants, which failed to reach genome-wide significance, remain undiscovered. Understanding the functional rationale underlying the cancer susceptibility loci is complex, requiring an integrated approach that combines epidemiology, biostatistics, next generation genomics, and cell biology. In this presentation, I will discuss a variety of integrative statistical and bioinformatics approaches being applied to determine the functional relevance of confirmed loci and approaches to discover additional risk loci.
Citation Format: Brooke L. Fridley. Integrative approaches for understanding the functional relevance of cancer susceptibility loci. [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 IA05.
Abstract IA11: Extracting predictive networks from high-dimensional data.
Authors: Quackenbush John 
Published: August 2013

Abstract
Two trends are driving innovation and discovery in biological sciences: technologies that allow holistic surveys of genes, proteins, and metabolites and the growing realization that analysis and interpretation of the resulting requires an understanding of the complex phenotypic and environmental data regarding the samples from which they were derived. The growing body of biological and biomedical information in the public domain provides outstanding opportunities for leveraging what we already “know” in a systematic way to understand the problems we are studying. Here, I will provide an overview of some of the methods we are using to investigate the complexities of human cancers and to explore how we can use biological data to uncover the cellular networks and pathways that underlie human disease, building predictive models of those networks that may help to direct therapies.
Citation Format: John Quackenbush. Extracting predictive networks from high-dimensional data. [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 IA11.
Abstract IA21: Using mouse models to identify breast cancer metastasis susceptibility genes.
Authors: Hunter Kent W. 
Published: August 2013

Abstract
Approximately 200,000 women are diagnosed with breast cancer and about 40,000 patients will succumb to this disease per year. The vast majority of these deaths are due to metastatic disease, rather than the primary tumor, so better understanding of the terminal stages of breast cancer is of great importance for the design of improved clinical interventions. Mouse genetic studies from our laboratory previously demonstrated that like susceptibility to the development of breast cancer, a significant inherited component exists for disseminated disease. However, despite the tremendous success of GWAS in identifying inherited variants associated with cancer etiology, significantly less success has been achieved in identifying SNPs associated with disease prognosis. This may be due in part to the complexity of the metastatic process, which involves genetic, epigenetic as well as stochastic somatic events. The ability to directly detect inherited metastasis susceptibility loci in human populations may be further complicated by clinical interventions, including surgical resection, radiation and/or adjuvant therapy which may alter or interrupt the natural progression of the disease in patient cohorts, reducing the power of detection. Therefore to complement human studies of inherited susceptibility to progression, our laboratory has employed a dominant metastatic genetically engineered mouse model and a quantitative trait analysis strategy to identify genes associated with disseminated disease. The results of these studies will be presented in this presentation.
Citation Format: Kent W. Hunter. Using mouse models to identify breast cancer metastasis susceptibility genes. [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 IA21.