bluuebunny/crossref_metadata_2025 huggingface dataset:
1H NMR Based Targeted Metabolite Profiling for Understanding the Complex Relationship Connecting Oxidative Stress with Endometriosis
Authors: Jana Saikat K. , Dutta Mainak , Joshi Mamata , Srivastava Sudha , Chakravarty Baidyanath , Chaudhury Koel
Published: August 2013

Accumulating evidence indicates the active role of oxidative stress in the development of endometriosis; however, the mechanism of reactive oxygen species generation is poorly understood. Metabonomics/metabolomics is a scientific discipline that can be used to study changes in metabolite ensembles associated with disease pathophysiology. The present study focuses on the use of proton nuclear magnetic resonance spectroscopy based targeted metabolite profiling approach to explore dysregulation in metabolites expression in women with endometriosis. Further, association of oxidative stress with the metabolite ensembles, if any, is investigated. Using multivariate statistics, partial least square discriminant analysis model was generated which could classify endometriosis patients with sensitivity and specificity of 92.83% and 100%, respectively, and with a classification rate of 96.4%. In conjunction with increased glucose metabolism, citrate and succinate were found to be elevated in endometriosis patients. Higher levels of reactive oxygen species, lipid peroxidation, and advanced oxidation protein products and lower levels of total antioxidant capacity, superoxide dismutase, catalase, and glutathione were also observed. Increased glucose metabolism and defects in the mitochondrial respiratory system are suggested to be the possible sources of excessive reactive oxygen species generation in endometriosis.
Attitude Determination with Magnetometers and Accelerometers to Use in Satellite Simulator
Authors: Kuga Helio Koiti , Carrara Valdemir
Published: August 2013

Attitude control of artificial satellites is dependent on information provided by its attitude determination process. This paper presents the implementation and tests of a fully self-contained algorithm for the attitude determination using magnetometers and accelerometers, for application on a satellite simulator based on frictionless air bearing tables. However, it is known that magnetometers and accelerometers need to be calibrated so as to allow that measurements are used to their ultimate accuracy. A calibration method is implemented which proves to be essential for improving attitude determination accuracy. For the stepwise real-time attitude determination, it was used the well-known QUEST algorithm which yields quick response with reduced computer resources. The algorithms are tested and qualified with actual data collected on the streets under controlled situations. For such street runaways, the experiment employs a solid-state magnetoresistive magnetometer and an IMU navigation block consisting of triads of accelerometers and gyros, with MEMS technology. A GPS receiver is used to record positional information. The collected measurements are processed through the developed algorithms, and comparisons are made for attitude determination using calibrated and noncalibrated data. The results show that the attitude accuracy reaches the requirements for real-time operation for satellite simulator platforms.
Comparison of Optical versus Ultrasonic Biometry in Keratoconic Eyes
Authors: Çınar Yasin , Cingü Abdullah Kürşat , Şahin Muhammed , Şahin Alparslan , Yüksel Harun , Türkcü Fatih Mehmet , Çınar Tuba , Çaça İhsan
Published: August 2013

Purpose. To compare the measurements of optical versus ultrasonic biometry devices in keratoconic eyes.Materials and Methods. Forty-two eyes of 42 keratoconus (KC) patients enrolled in the study were examined. Clinical and demographic characteristics of the patients were noted, and detailed ophthalmological examination was performed. Following Pentacam measurements, central corneal thickness (CCT), anterior chamber depth (ACD), lens thickness (LT), and axial length (AL) were obtained using the Lenstar and US biometer to determine the reproducibility of the measurements between the two devices in keratoconic eyes. The Bland-Altman method was used to describe the agreement between the two devices.Results. The Lenstar could not measure at least one of the biometric properties in one eye and did not automatically give the corrected ACD in 2/3 of our study population. The Lenstar measured CCT (average difference 5.4 ± 19.6 µm; ICC = 0.90; ), LT (average difference 0.13 ± 0.17 mm; ICC = 0.67; ), and AL (average difference 0.10 ± 0.76 mm; ICC = 0.75; ) thinner than US biometer, whereas it measured ACD (average difference 0.18 ± 0.17 mm; ICC = 0.85; ) deeper than US biometer in keratoconic eyes.Conclusion. Although the difference between the measurements obtained using the two devices might be clinically acceptable, US biometry and Lenstar should not be used interchangeably for biometric measurements in KC patients.
Two Cases of Accidental Injection of Epinephrine into a Digit Treated with Subcutaneous Phentolamine Injections
Authors: Bodkin Ryan P. , Acquisto Nicole M. , Gunyan Holly , Wiegand Timothy J.
Published: August 2013

Accidental injection into the digit from an epinephrine autoinjection device can cause discoloration, pain, and paresthesias. Although loss of digit is rare, treatment in the emergency department is commonly aimed at vasodilation of the affected tissue. We report two cases of accidental injection of epinephrine into the digits that were successfully treated with subcutaneous phentolamine injection with no adverse events.
Isolated Jejunal Perforation Following Bicycle Handlebar Injury in Adults: A Case Report
Authors: Neofytou Kyriakos , Michailidou Maria , Petrou Athanasios , Loizou Sakis , Andreou Charalampos , Pedonomou Marios
Published: August 2013

The small intestine is the third in frequency intraperitoneal organ which is injured after blunt trauma of the abdomen. In most of the cases, this type of injuries is accompanied by other injuries, which make it more difficult to diagnose. Failure of diagnosis and delay in treating these injuries significantly increase the morbidity and mortality of these patients. Abdominal visceral injuries after flipping the handlebar of the bike are common in children. Such injuries can cause injury to both solid and hollow abdominal viscera. Unlike children, adults’ abdominal visceral injuries after flipping the bike’s handlebar are extremely rare. A 25-year-old man was admitted to our department due to progressively abdominal pain after an accident with the handlebar of his bike. The subsequent CT scan after per os administration of contrast medium revealed the presence of free intraperitoneal contrast. It is a rare case of jejunal perforation after flipping the handlebar of the bicycle which was treated by partial removal of the injured part of jejunum and end-to-end anastomosis. To the best of our knowledge this is the first time we describe such an injury with this mechanism to an adult.
Preoperative Localization and Surgical Margins in Conservative Breast Surgery
Authors: Corsi F. , Sorrentino L. , Bossi D. , Sartani A. , Foschi D.
Published: August 2013

Breast-conserving surgery (BCS) is the treatment of choice for early breast cancer. The adequacy of surgical margins (SM) is a crucial issue for adjusting the volume of excision and for avoiding local recurrences, although the precise definition of an adequate margins width remains controversial. Moreover, other factors such as the biological behaviour of the tumor and subsequent proper systemic therapies may influence the local recurrence rate (LRR). However, a successful BCS requires preoperative localization techniques or margin assessment techniques. Carbon marking, wire-guided, biopsy clips, radio-guided, ultrasound-guided, frozen section analysis, imprint cytology, and cavity shave margins are commonly used, but from the literature review, no single technique proved to be better among the various ones. Thus, an association of two or more methods could result in a decrease in rates of involved margins. Each institute should adopt its most congenial techniques, based on the senologic equipe experience, skills, and technologies.
Estimating the Optimal Control of Zoonotic Visceral Leishmaniasis by the Use of a Mathematical Model
Authors: Ribas Laila Massad , Zaher Vera Lucia , Shimozako Helio Junji , Massad Eduardo
Published: August 2013

We argue that the strategy of culling infected dogs is not the most efficient way to control zoonotic visceral leishmaniasis (ZVL) and that, in the presence of alternative control strategies with better potential results, official programs of compulsory culling adopted by some countries are inefficient and unethical. We base our arguments on a mathematical model for the study of control strategies against ZVL, which allows the comparison of the efficacies of 5, alternative strategies. We demonstrate that the culling program, previously questioned on both theoretical and practical grounds is the less effective control strategy. In addition, we show that vector control and the use of insecticide‐impregnated dog collars are, by far, more efficient at reducing the prevalence of ZVL in humans.
Analytic Solutions for Heat Conduction in Functionally Graded Circular Hollow Cylinders with Time-Dependent Boundary Conditions
Authors: Lee Sen-Yung , Huang Chih-Cheng
Published: August 2013

An analytic solution method, without integral transformation, is developed to find the exact solutions for transient heat conduction in functionally graded (FG) circular hollow cylinders with time-dependent boundary conditions. By introducing suitable shifting functions, the governing second-order regular singular differential equation with variable coefficients and time-dependent boundary conditions is transformed into a differential equation with homogenous boundary conditions. The exact solution of the system with thermal conductivity and specific heat in power functions with different orders is developed. Finally, limiting studies and numerical analyses are given to illustrate the efficiency and the accuracy of the analysis.
In Vivo Evaluation of the Skin Tensile Strength by the Suction Method: Pilot Study Coping with Hysteresis and Creep Extension
Authors: Piérard Gérald E. , Piérard Sébastien , Delvenne Philippe , Piérard-Franchimont Claudine
Published: August 2013

From an engineering standpoint, both the skin and subcutaneous tissue act as interconnected load-transmitting structures. They are subject to a variety of intrinsic and environmental influences. Changes in the cutaneous viscoelasticity represent an important aspect in a series of skin conditions. The aim of this work was to explore the methodology of biomechanical measurements in order to better appreciate the evolution and severity of some connective tissue diseases. The Cutometer MPA 580 (C+K electronic) was used in the steep and progressive suction procedures. Adapting measurement modalities was explored in order to mitigate any variability in data collection. The repeat steep suction procedure conveniently reveals the creep phenomenon. By contrast, the progressive suction procedure highlights the hysteresis phenomenon. These viscoelastic characteristics are presently described using the 2 and 4 mm probes on normal skin and in scleroderma, acromegaly, corticosteroid-induced dermatoporosis, and Ehlers-Danlos syndrome. The apposition of an additional outer contention on the skin altered differently the manifestations of the creep extension and hysteresis among the tested skin conditions. Any change in the mechanical test procedure affects the data. In clinical and experimental settings, it is mandatory to adhere to a strict and controlled protocol.
Using Social Network Analysis to Identify Key Child Care Center Staff for Obesity Prevention Interventions: A Pilot Study
Authors: Marks Jennifer , Barnett Lisa M. , Foulkes Chad , Hawe Penelope , Allender Steven
Published: August 2013

Introduction. Interest has grown in how systems thinking could be used in obesity prevention. Relationships between key actors, represented by social networks, are an important focus for considering intervention in systems.Method. Two long day care centers were selected in which previous obesity prevention programs had been implemented. Measures showed ways in which physical activity and dietary policy are conversations and actions transacted through social networks (interrelationships) within centers, via an eight item closed-ended social network questionnaire. Questionnaire data were collected from (17/20; response rate 85%) long day care center staff. Social network density and centrality statistics were calculated, using UCINET social network software, to examine the role of networks in obesity prevention.Results. “Degree” (influence) and “betweeness” (gatekeeper) centrality measures of staff inter-relationships about physical activity, dietary, and policy information identified key players in each center. Network density was similar and high on some relationship networks in both centers but markedly different in others, suggesting that the network tool identified unique center social dynamics. These differences could potentially be the focus of future team capacity building.Conclusion. Social network analysis is a feasible and useful method to identify existing obesity prevention networks and key personnel in long day care centers.
A UWB Band-Pass Antenna with Triple-Notched Band Using Common Direction Rectangular Complementary Split-Ring Resonators
Authors: Yan Bo , Jiang Di , Xu Ruimin , Xu Yuehang
Published: August 2013

A novel ultrawideband (UWB) antenna which has a triple-band notch function is presented. The proposed antenna can block interfering signals from C-band satellite communication systems, IEEE802.11a, and HIPERLAN/2 WLAN systems for example. The antenna is excited by using novel common direction rectangular complementary split-ring resonators (CSRR) fabricated on radiating patch of the dielectric substrate with coplanar waveguide (CPW) feed strip line. The voltage standing wave ratio (VSWR) of the proposed antenna is less than 2.0 in the frequency band from 2.8 to 12 GHz, while showing a very sharp band-rejection performance at 3.9 GHz, 5.2 GHz, and 5.9 GHz. The measurement results show that the proposed antenna provides good omnidirectional field pattern over its whole frequency band excluding the rejected band, which is suitable for UWB applications.
Exceptional Values of Meromorphic Function on Annulus
Authors: Xu Hong-Yan
Published: August 2013

The main purpose of this paper is to study the exceptional values of meromorphic function and its derivative on annulus. We also give some theorems and corollaries about exceptional values of meromorphic function on the annulus, which are the improvement of the previous results given by Chen and Wu.
Sonication-Based Improvement of the Physicochemical Properties of Guar Gum as a Potential Substrate for Modified Drug Delivery Systems
Authors: Ansari Siddique Akber , Matricardi Pietro , Cencetti Claudia , Di Meo Chiara , Carafa Maria , Mazzuca Claudia , Palleschi Antonio , Capitani Donatella , Alhaique Franco , Coviello Tommasina
Published: August 2013

Guar Gum is a natural polysaccharide that, due to its physicochemical properties, is extensively investigated for biomedical applications as a matrix for modified drug delivery, but it is also used in the food industry as well as in cosmetics. A commercial sample of Guar Gum was sonicated for different periods of time, and the reduction in the average molecular weight was monitored by means of viscometric measurements. At the same time, the rheological behaviour was also followed, in terms of viscoelasticity range, flow curves, and mechanical spectra. Sonicated samples were used for the preparation of gels in the presence of borate ions. The effect of borax on the new samples was investigated by recording mechanical spectra, flow curves, and visible absorption spectra of complexes with Congo Red. The anisotropic elongation, observed in previous studies with tablets of Guar Gum and borax, was remarkably reduced when the sonicated samples were used for the preparation of the gels.
Abstract 13: Telomere length and pancreatic cancer in the alpha-tocopherol beta-carotene cancer prevention (ATBC) study.
Authors: Lynch Shannon M. , Major Jacqueline M. , Cawthon Richard , Weinstein Stephanie J. , Virtamo Jarmo , Lan Qing , Rothman Nathaniel , Albanes Demetrius , Stolzenberg-Solomon Rachael Z.
Published: August 2013

Genome-wide association studies have found an association between pancreatic cancer and the TERT or telomerase gene. Smoking and diabetes, consistent risk factors for pancreatic cancer, are also factors that influence telomere length maintenance. To test whether blood leukocyte telomere length is associated with pancreatic cancer risk, we conducted a nested case-control study in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort of male smokers, aged 50-69 years at baseline. Between 1992 and 2004, 193 incident cases of pancreatic adenocarcinoma occurred (mean follow-up from blood draw: 6.3 years) among participants with whole blood samples available for telomere length assays. For these cases and 660 controls, we calculated odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, adjusting for age, number of years smoked regularly, and history of diabetes mellitus. Telomere length was categorized into quartiles (shortest to longest) and analyzed as both a categorical and a continuous normal variable (reported per 0.2 unit increase in telomere length). All statistical tests were two-sided. Longer telomere length was significantly associated with increased pancreatic cancer risk (continuous OR=1.26 95% CI=1.09-1.46; highest quartile compared to lowest, OR=1.57, 95% CI=1.01-2.43, p-trend=0.007). This effect remained for subjects diagnosed within the first five years of blood draw (continuous OR=1.46, 95% CI=1.19-1.79 highest quartile OR=2.92, 95%CI=1.47-5.77, p-trend=0.002), but not subjects diagnosed greater than five years from blood draw (continuous OR=1.03, 95%CI=0.85-1.22; highest quartile OR=1.04, 95%CI=0.60-1.79). This is the first study to suggest an association between longer blood leukocyte telomere length and increased pancreatic cancer risk.

Citation Format: Shannon M. Lynch, Jacqueline M. Major, Richard Cawthon, Stephanie J. Weinstein, Jarmo Virtamo, Qing Lan, Nathaniel Rothman, Demetrius Albanes, Rachael Z. Stolzenberg-Solomon. Telomere length and pancreatic cancer in the alpha-tocopherol beta-carotene cancer prevention (ATBC) study. [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 13.
Abstract 17: Innate Immunity Pathways and Breast Cancer Risk in African American and European American Women in the Women's Circle of Health Study (WCHS).
Authors: Gong Zhihong , Quan Lei , Yao Song , Zirpoli Gary , Bandera Elisa , Hwang Helena , Roberts Michelle , Sucheston Lara , Ciupak Gregory , Davis Warren , Ambrosone Christine , Hong Chi-Chen
Published: August 2013

Although the incidence of breast cancer is highest in American women of European ancestry (EA), women of African ancestry (AA) are more likely to have early, aggressive breast cancer, characterized by negative estrogen receptor (ER) status. There are few explanations for these differences between ancestral groups. We hypothesized that differential distribution of genetic variants in innate immunity pathways could be related to these breast cancer disparities, and evaluated variant-breast cancer associations in a case-control study, the Women's Circle of Health Study (WCHS). In the first stage, 44 SNPs were genotyped among 1010 AA and 757 EA women who participated in the WCHS. For 38 of the 44 SNPs, genotype frequencies differed significantly between AA and EA women, and differential risk relationships were observed between groups for some SNPs. For example, in premenopausal women, CXCL5 (rs425535) was significantly associated with breast cancer risk for only AA women (P=0.008) and for EAs, associations were observed for CRP (rs1205) and TNFA (rs1799724) (P≤0.01). In post-menopausal women, two SNPs in IL1B (rs1143627, rs16944) and one SNP in NOD2 (rs2066842) were associated with risk in EAs (all P=0.01) but not AA women. The association was limited to ER positive cancers for TNFA-rs1799724 and to ER negative cancers for NOD2-rs2066842. In the second stage, with additional accruals in WCHS, we extended analysis for four SNPs with suggested associations from the first stage in a larger dataset of 1602 AA and 1542 EA women, which yielded similar results. Associations for CRP-rs1205 and CXCL5-rs425535 with breast cancer risk were strengthened in premenopausal women and were statistically different between AA and EA women (P for interaction=0.0009 and 0.002, respectively) in this larger dataset. In summary, AA and EA populations exhibited differential association patterns of these genetic variants with breast cancer risk. Our findings suggest that innate immune pathways may be differentially associated with breast cancer by ancestry, and that relationships vary according to menopausal and ER status.

Citation Format: Zhihong Gong, Lei Quan, Song Yao, Gary Zirpoli, Elisa Bandera, Helena Hwang, Michelle Roberts, Lara Sucheston, Gregory Ciupak, Warren Davis, Christine Ambrosone, Chi-Chen Hong. Innate Immunity Pathways and Breast Cancer Risk in African American and European American Women in the Women's Circle of Health Study (WCHS). [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 17.
Abstract 18: Association of polymorphisms in MCP-1 and CCR2 genes with the risk of cancer: A meta-analysis.
Authors: Kim Jeongseon , Cho Young Ae
Published: August 2013

Background: Chemokines and their receptors are known to play an important role in tumor progression, particularly as key mediators of tumor-stroma interactions. Studies have investigated the impact of monocyte chemotactic protein-1 (MCP-1) and CC chemokine receptor 2 (CCR2) polymorphisms on the susceptibility of cancer, but the results remain inconclusive.

Methods: We performed a meta-analysis using 20 eligible studies to summarize the data on the association between MCP-1 A2518G and CCR2 V64I polymorphisms and cancer risk. Q-statistics and I2 statistics were calculated to examine heterogeneity, and summary odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using a random effects model. Potential sources of heterogeneity were sought out via stratification and sensitivity analyses, and publication biases were estimated.

Results: In overall, MCP-1 and CCR2 polymorphisms showed no significant association with cancer risk (MCP-1 A2518G, GG + GA versus AA: OR = 0.94, 95% CI=0.76, 1.17; CCR2 V64I, AA + AG versus GG: OR= 1.30, 95% CI = 0.86, 1.95). The effect of these polymorphisms was further evaluated in stratification analyses. It was demonstrated that the increased risk of cancer was observed among Asian populations carrying at least one A allele of CCR2 V64I than those with GG homozygotes (AA + AG versus GG: OR=1.80; 95% CI=1.40, 2.33).

Conclusions: This meta-analysis demonstrates that gene polymorphism of CCR2 V64I may influence the susceptibility of cancer in Asian populations. Further well-designed studies with large sample size should be conducted.

Citation Format: Jeongseon Kim, Young Ae Cho. Association of polymorphisms in MCP-1 and CCR2 genes with the risk of cancer: A meta-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 18.
Abstract 19: Soluble RAGE modestly inversely associated with liver cancer risk in male Finnish smokers.
Authors: Moy Kristin A. , Jiao Li , Freedman Neal D. , Weinstein Stephanie J. , Sinha Rashmi , Virtamo Jarmo , Albanes Demetrius , Stolzenberg-Solomon Rachael
Published: August 2013

Laboratory experiments suggest that activation of receptor for advanced glycation end products (RAGE) contributes to liver injury and blockade of RAGE with soluble RAGE (sRAGE) may mitigate the effects of RAGE activation. Epidemiologic studies examining sRAGE and advanced glycation end products (AGEs) in relation to liver cancer are sparse. Within a cohort of 29,133 Finnish male smokers who completed questionnaires and donated blood samples between 1985-1988, we conducted a case-cohort study examining the associations between serum concentrations of sRAGE or Nϵ-(carboxymethyl)-lysine (CML)-AGE, the most abundant AGE in humans, in association with liver cancer. During follow-up that began 5 years after enrollment through April 2006, 145 liver cancer cases occurred. Serum levels of sRAGE, CML-AGE, glucose and insulin were measured in cases and 485 randomly sampled cohort participants. Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) were also measured. Weighted Cox proportional hazards regression was used to calculate relative risks (RR) and 95% confidence intervals (CI). Multivariate models were adjusted for age, years of smoking, and body mass index. Among subcohort participants, carbohydrate and sucrose intake increased across increasing tertiles of serum sRAGE (P-values ≤0.01). After adjusting for age, BMI and years of smoking, serum sRAGE concentration was inversely associated with liver cancer risk [continuous RR (95% CI): 0.86 (0.75-0.99), P-value=0.04]. Unexpectedly, serum CML concentration was also inversely associated with liver cancer risk [continuous RR (95% CI): 0.74(0.65-0.84), P-value <0.0001]. Further adjustment for serum glucose and insulin did not change the associations. The prevalence of hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (anti-HBc) titers measured on 135 cases were 0.75% and 13%, respectively and 3% for hepatitis C exposure (anti-HCV). Exclusion of cases with chronic HBV or HCV did not change our results. Our results support the hypothesis that sRAGE is inversely associated with liver cancer. The findings need confirmation, particularly in populations that include women and non-smokers.

Citation Format: Kristin A. Moy, Li Jiao, Neal D. Freedman, Stephanie J. Weinstein, Rashmi Sinha, Jarmo Virtamo, Demetrius Albanes, Rachael Stolzenberg-Solomon. Soluble RAGE modestly inversely associated with liver cancer risk in male Finnish smokers. [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 19.
Abstract 20: Whole exome sequencing of aristolochic acid induced upper urothelial carcinomas.
Authors: Rosenquist Thomas A. , Hoang Margaret , Moriya Maasaki , Sidorenko Victoriya S. , Dickman Kathleen , Chen Chung-Hsin , Wu Lin , Papadopoulos Nickolas , Pu Yeong-Shiau , Kinzler Kenneth W. , Vogelstein Bert , Grollman Arthur P.
Published: August 2013

Aristolochic acid (AA), a human carcinogen and nephrotoxin, produced by Aristolochia plants and used extensively in traditional herbal medicines, was shown to be responsible for the clinical syndromes known as Chinese herb nephropathy and endemic (Balkan) nephropathy (EN), and to contribute to the high rate of upper urinary tract carcinoma (UUC) observed in certain Asian countries such as Taiwan. After bio-activation, AA gives rise to long-lived, pro-mutagenic aristolactam-DNA (AL-DNA) adducts that serve as specific biomarkers of exposure. Our studies of the TP53 gene in AA-induced UUC tumors detected a mutation spectrum that was dominated by A>T transversions located almost exclusively on the non-transcribed DNA strand, reflecting a failure to excise AL-DNA adducts by global genomic nucleotide excision repair. In the present study we undertook the whole exome sequencing of a set of AAN/UUC tumors from Taiwanese patients, and matching normal DNAs, to establish the genome wide consequence of AA-exposure. To establish that AA was critical in tumor formation we selected patients who had: 1) detectable AL-DNA adducts in kidney cortex DNA, and 2) the TP53 gene in tumor DNA contained an A>T mutation on the non-transcribed strand. The results indicate that these tumors indeed harbor a very high number of single base substitutions (SBS) in their coding exons (median of 545 SBS per tumor). Of these, 70% were A>T mutations with the majority of the mutated adenines on the non-transcribed strand. We are currently completing whole exome sequencing of an additional set of AA-induced UUC tumors, and ten smoking-induced UUC tumors for comparison. We will present an analysis of the driver mutations found in these tumors and the pathways harboring oncogenic mutations. Our goal is to define a panel of AA-specific mutations useful for developing biomarker screens for early detection of UUC in at risk populations.

Citation Format: Thomas A. Rosenquist, Margaret Hoang, Maasaki Moriya, Victoriya S. Sidorenko, Kathleen Dickman, Chung-Hsin Chen, Lin Wu, Nickolas Papadopoulos, Yeong-Shiau Pu, Kenneth W. Kinzler, Bert Vogelstein, Arthur P. Grollman. Whole exome sequencing of aristolochic acid induced upper urothelial carcinomas. [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 20.
Abstract 21: Variations in DNA repair gene expression and breast cancer risk in the New York site of the Breast Cancer Family Registry.
Authors: Kappil Maya , Terry Mary Beth , Liao Yuyan , Santella Regina
Published: August 2013

Reduced DNA repair capacity contributes to genomic instability, a hallmark of carcinogenesis. The link between DNA repair capacity and cancer is especially relevant in breast cancer, where women with suboptimal repair capacity have been reported to have up to a five-fold increase in breast cancer risk compared to women with greater repair capacity. We investigated the expression level of several DNA repair-related genes and their association with breast cancer risk among participants of the New York site of the Breast Cancer Family Registry. We examined RNA from viable mononuclear cells in 213 sisters (N=511 women). A total of five genes, ATM, BRCA1, MSH2, MUTYH and XPC, were selected and assayed using Taqman gene expression kits from Applied Biosystems. With the exception of BRCA1, expression of these genes was lower, but not statistically significant, among sisters with breast cancer compared with their unaffected sisters. Using generalized estimating equations (GEE), we found that individuals in the lowest quartile of expression for MSH2, a gene involved in DNA mismatch repair, had significantly higher odds of breast cancer compared to individuals in the highest quartile of expression, adjusting for age at blood draw (OR=1.82, 95% CI=1.11, 2.99). These findings suggest that a reduction in MSH2 expression compromises mismatch repair capacity and, thereby, increases breast cancer susceptibility.

Citation Format: Maya Kappil, Mary Beth Terry, Yuyan Liao, Regina Santella. Variations in DNA repair gene expression and breast cancer risk in the New York site of the Breast Cancer Family Registry. [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 21.
Abstract 27: Telomere length in relation to the risk of Barrett's esophagus and esophageal adenocarcinoma.
Authors: Persson E. Christina , Liao Linda M. , Risques Rosana , Prunkard Donna , Giffen Carol , Chow Wong-Ho , Vaughan Thomas L. ,   on behalf of the Barrett's Esophagus, Adenocarcinoma Consortium (BEACON) Investigators
Published: August 2013

Background: Repeated injury of the esophagus by chronic gastroesophageal reflux (GER) is associated with the development of Barrett's esophagus (BE), a condition in which the squamous epithelium is replaced by a metaplastic columnar epithelium. A proportion of individuals diagnosed with BE progress to esophageal adenocarcinoma (EAC), which has considerably increased in incidence in many Western countries over the past four decades. Major risk factors associated with BE and EAC, such as obesity, smoking and gastroesophageal reflux (GER), are all contributors to the presence of chronic inflammation and oxidative damage. Unlike other areas of the chromosome that have effective repair systems to deal with oxidative damage, telomeres are not as well maintained and telomere length may reflect the impact of chronic inflammation. We investigated whether leukocyte telomere length was associated with BE or EAC risk compared to population-based controls in a pooled analysis of seven studies from the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON).

Methods: Telomere length was measured by quantitative-PCR using leukocyte DNA samples. Participants included 1,198 cases (395 with EAC, 403 with BE, 400 with GER) and 749 population-based controls. The association of telomere length (in tertiles) along the continuum of disease progression from GER to BE to EAC was calculated using study-specific odds ratios (OR) and 95% confidence intervals (CI) from logistic regression models, adjusted for age, sex, smoking status, alcohol consumption, BMI and education. Summary risk estimates were obtained using a random effects meta-analysis models.

Results: Shorter telomeres were associated with decreased risks of EAC (OR 0.84; 95% CI 0.47-1.48) and BE (OR 0.68; 95% CI 0.46-1.01), when compared to population-based controls, though not statistically significant. In addition, subjects with shorter telomeres were associated with a decreased risk of GER (OR 0.43; 95% CI 0.18-1.01), compared to population-based controls.

Conclusion: Telomere length may play a role in the progression from chronic reflux to BE and EAC.

Citation Format: E. Christina Persson, Linda M. Liao, Rosana Risques, Donna Prunkard, Carol Giffen, Wong-Ho Chow, Thomas L. Vaughan, on behalf of the Barrett's Esophagus, Adenocarcinoma Consortium (BEACON) Investigators. Telomere length in relation to the risk of Barrett's esophagus and esophageal adenocarcinoma. [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 27.
Abstract 28: Characterization of SNPs associated with prostate cancer in men of Ashkenazic descent from the set of GWAS identified SNPs: Impact of cancer family history.
Authors: Agalliu Ilir , Wang Zhaoming , Dunn Anne , Parikh Hemang , Myers Timothy , Burk Robert , Amundadottir Laufey
Published: August 2013

Background: Genome-wide association studies (GWAS) have identified several SNPs that are independently associated with prostate cancer (PrCa) in Caucasian men. Population isolates with unique allele frequencies are likely to have different sets of risk alleles for PrCa constituting personalized population risk stratification in addition to individual risk profiles.

Methods: To test this hypothesis, we examined associations between 31 GWAS SNPs and PrCa among 979 cases and 1,251 controls of Ashkenazic descent. Odds ratios (OR) and 95% confidence intervals (CIs) were estimated for each SNP using logistic regression models adjusted for age. We also investigated risk in strata by age at diagnosis, pathological features of PrCa, as well as family history of PrCa and other cancers.

Results: Of 31 SNPs, 19 (62%) were associated with PrCa at p<0.05 in one or more genetic risk models. The strongest associations with PrCa were for rs6983267 at 8q24 (OR=1.78, p=5.7 x 10−7;comparison of GG vs. TT genotype), and rs1465618 at 2p21 (OR=2.19; p=0.003; AA vs. AG/GG). Six SNPs were associated with aggressive PrCa, while six others with less aggressive cancer. Four SNPs showed statistically significant interactions between PrCa and family history of PrCa (rs8102476 at 19q13), lung cancer (rs17021918 at 4q22), colorectal cancer (rs6983267 at 8q24), and breast cancer (rs10896449 at 11q13).

Conclusion: These data define a specific set of risk alleles associated with PrCa in Ashkenazic men. Results demonstrate differences between men of European and Ashkenazic ancestry in relation to genetic susceptibility of PrCa. Interactions of genetic variants with family history of specific cancers indicate a complex network of inherited cancer risk syndromes still to be defined. Use of genetic markers to identify men at higher risk of PrCa will provide an opportunity for personalized care of PrCa prevention through screening of high-risk individuals, independent of family history information.

Citation Format: Ilir Agalliu, Zhaoming Wang, Anne Dunn, Hemang Parikh, Timothy Myers, Robert Burk, Laufey Amundadottir. Characterization of SNPs associated with prostate cancer in men of Ashkenazic descent from the set of GWAS identified SNPs: Impact of cancer family history. [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 28.
Abstract 30: The epidemiology of triple-negative breast cancer: A review.
Authors: McCullough Lauren E. , Family Leila , O'Brien Katie M. , Razzaghi Hilda , Backes Danielle M. , Mordukhovich Irina , Reiter Paul L. , Olshan Andrew F.
Published: August 2013

Background: Molecular profiling of breast tumors has enhanced our knowledge of the heterogeneity of breast cancer, including the identification of subtypes associated with differences in prognosis. However, the etiology of these intrinsic subtypes remains unknown. The triple-negative subtype accounts for 10-25% of breast tumors and is most common among African-American and premenopausal women. The purpose of this review was to summarize the existing literature on the risk factors for triple-negative disease.

Methods: Epidemiologic studies published between January 2000 and December 2011 that reported subtype-specific effect measure estimates for hormonal and other breast cancer risk factors in case-only or case-control analyses were included. A total of 20 studies from 17 populations met our pre-specified inclusion criteria.

Results: Compared to luminal A, triple-negative cases were more likely to have younger age at menarche, higher parity, shorter duration of breastfeeding, and increased premenopausal body mass. Case-control data suggest that there may be positive associations between parity, premenopausal body mass and risk of triple-negative disease, while inverse associations were observed for age at first term full-term pregnancy.

Conclusions: Our review confirms that risk factor profiles may vary by subtype; although we were unable to draw definitive conclusions regarding all hormonal risk factors and risk of triple-negative disease.

Impact: Because this subtype represents a small proportion of tumors, collaborative efforts should be undertaken to precisely evaluate potential associations. In addition, future investigations should focus on enrolling a greater number of African-American participants, as this population is underrepresented in the majority of current studies.

Citation Format: Lauren E. McCullough, Leila Family, Katie M. O'Brien, Hilda Razzaghi, Danielle M. Backes, Irina Mordukhovich, Paul L. Reiter, Andrew F. Olshan. The epidemiology of triple-negative breast cancer: A review. [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 30.
Abstract 39: Exposure to heavy metals and polycyclic aromatic hydrocarbons and DNA damage in Taiwanese traffic conductors.
Authors: Huang Han-Bin , Chen Guan-Wen , Wang Chien-Jen , Lin Yong-Yang , Liou Saou-Hsing , Lai Ching-Huang , Wang Shu-Li
Published: August 2013

Introduction: Exposure to traffic-related air pollutants, including polycyclic aromatic hydrocarbons (PAHs) and heavy metals, has been associated with the etiology and prognosis of many illnesses. However, the specific causal agents and underlying mechanisms for different health outcomes remain unclear. The aims of this study were to assess the relations between urinary biomarkers of exposure to PAHs (1-hydroxypyrene-glucuronide, 1-OHPG) and heavy metals (cadmium, Cd; nickel, Ni; arsenic, As; lead, Pb; copper, Cu) and their interaction effect on DNA damage (8-oxo-7,8-dihydro-guanine, 8-oxodG).

Methods: We recruited 91 traffic conductors and 53 indoor office workers between May 2009 and June 2011 in Taipei, Taiwan. Post-shift urine samples from 2 consecutive days were analyzed for 1-OHPG, Cd, Ni, As, Pb, Cu and 8-oxodG. To estimate the effects from PAHs and metals on DNA damage, we constructed a linear mixed model adjusted for confounding variables.

Results: We found that urinary 1-OHPG and Cd levels were independent predictors of urinary 8-oxodG levels (β=0.112, p=0.015 for 1-OHPG; β=0.138, p=0.031 for urinary Cd). The joint effect of urinary 1-OHPG and Cd levels was associated with urinary 8-oxodG levels (p=0.001).

Conclusions: Co-exposure to environmental PAHs and Cd could cause oxidative DNA damage. These findings suggest that the additive interaction between exposure to environmental PAHs and Cd could enhance the burden of oxidative stress.

Citation Format: Han-Bin Huang, Guan-Wen Chen, Chien-Jen Wang, Yong-Yang Lin, Saou-Hsing Liou, Ching-Huang Lai, Shu-Li Wang. Exposure to heavy metals and polycyclic aromatic hydrocarbons and DNA damage in Taiwanese traffic conductors. [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 39.
Abstract 69: Blood leukocyte DNA methylation and colorectal cancer among male smokers in Finland.
Authors: Gao Ying , Paul Meltzer , Caporaso Neil
Published: August 2013

Aim: To explore the association between methylation in leukocyte DNA and colorectal cancer (CRC) risk in male smokers using the α-tocopherol, β-carotene cancer prevention study.

Methods: About 221 incident CRC cases, and 219 controls, frequency-matched on age and smoking intensity were included. DNA methylation of 1505 CpG sites selected from 807 genes were evaluated using Illumina GoldenGate Methylation Cancer Panel I in pre-diagnostic blood leukocytes of study subjects. Tertiles of methylation level classified according to the distribution in controls for each CpG site were used to analyze the association between methylation level and CRC risk with logistic regression. The time between blood draw to cancer diagnosis (classifying cases according to latency) was incorporated in further analyses using proportional odds regression.

Results: We found that methylation changes of 31 CpG sites were associated with CRC risk at P < 0.01 level. Though none of these 31 sites remained statistically significant after Bonferroni correction, the most statistically significant CpG site associated with CRC risk achieved a P value of 1.0 × 10(-4). The CpG site is located in DSP gene, and the risk estimate was 1.52 (95% CI: 0.91-2.53) and 2.62 (95% CI: 1.65-4.17) for the second and third tertile comparing with the lowest tertile respectively. Taking the latency information into account strengthened some associations, suggesting that the methylation levels of corresponding sites might change over time with tumor progression.

Conclusion: The results suggest that the methylation level of some genes were associated with cancer susceptibility and some were related to tumor development over time. Further studies are warranted to confirm and refine our results.

Citation Format: Ying Gao, Paul Meltzer, Neil Caporaso. Blood leukocyte DNA methylation and colorectal cancer among male smokers in Finland. [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 69.
Abstract 73: Evaluation of bead-based assays of inflammation markers for epidemiologic studies.
Authors: Poole Elizabeth M. , Townsend Mary K. , Eliassen A Heather , Neville-Golden Janine , Tworoger Shelley S.
Published: August 2013

Given finite sample availability in epidemiologic studies, minimizing assay volumes is an important consideration in studies of biomarker-disease relationships. Consequently, there is great interest in multiplex assays that use less volume than standard assays and provide data on multiple markers in one assay. This is particularly true for markers of inflammation, a key factor in cancer and other age-related diseases. Therefore, we conducted pilot studies of three bead-based, multiplex, inflammatory marker panels at three laboratories. The first pilot evaluated assay reproducibility by calculating the coefficient of variation (CV) using 12 blinded replicate samples, and the second evaluated the role of delayed processing using samples from 12 participants who had one-third of their sample processed immediately after blood draw, and one-third each processed 24 and 48 hours later. Minimum criteria for an analyte to pass the pilots were: (1) >50% of samples had levels above the limit of detection (LOD), (2) a CV ≤20%, and (3) an intraclass correlation across processing times >0.80. For Panel 1, 200uL of plasma was used to assess 10 biomarkers in 2007. For Panel 2, 50uL of plasma was used to assess 17 markers in 2011. For Panel 3, 250uL of plasma was used to assess 12 markers in 2012. More than half of the biomarkers in two of the panels (1 and 3) had >50% of samples with levels less than the LOD; in Panel 2 29% of biomarkers had >50% of samples below the LOD. Of the biomarkers with more than half the samples above the LOD, all had CVs <20%. Overall, 3 (30%) of markers passed the LOD and CV criteria in Panel 1, 12 (71%) passed in Panel 2, and 4 (33%) passed in Panel 3. Among these, none of the markers in Panels 1 and 3 and 7 markers in Panel 2 were stable with delayed processing, resulting in an overall pass rate of 0% in Panels 1 and 3 and 41% in Panel 2. Further, for Panel 2, we observed that the correlation between the multiplex and the standard ELISA for IL-6 was only 0.25. Our results suggest that assessing inflammatory markers on bead-based multiplex platforms may not be appropriate for epidemiologic studies, possibly reflecting poor assay optimization for specific biomarkers and thus lowered overall assay sensitivity and specificity.

Citation Format: Elizabeth M. Poole, Mary K. Townsend, A Heather Eliassen, Janine Neville-Golden, Shelley S. Tworoger. Evaluation of bead-based assays of inflammation markers for epidemiologic 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 73.