bluuebunny/crossref_metadata_2025 huggingface dataset:
A COMPUTATIONAL STUDY ON CIRCUIT SIZE VERSUS CIRCUIT DEPTH
Authors: LAPPAS G. , FRANK R. J. , ALBRECHT A. A.
Published: March 2006

We investigate the circuit complexity of classification problems in a machine learning setting, i.e. we attempt to find some rule that allows us to calculate a priori the number of threshold gates that is sufficient to achieve a small error rate after training a circuit on sample data [Formula: see text]. The particular threshold gates are computed by a combination of the classical perceptron algorithm with a specific type of stochastic local search. The circuit complexity is analysed for depth-two and depth-four threshold circuits, where we introduce a novel approach to compute depth-four circuits. For the problems from the UCI Machine Learning Repository we selected and investigated, we obtain approximately the same size of depth-two and depth-four circuits for the best classification rates on test samples, where the rates differ only marginally for the two types of circuits. Based on classical results from threshold circuit theory and our experimental observations on problems that are not linearly separable, we suggest an upper bound of [Formula: see text] threshold gates as sufficient for a small error rate, where [Formula: see text].
MUTUAL INFORMATION CLUSTERING FOR EFFICIENT MINING OF FUZZY ASSOCIATION RULES WITH APPLICATION TO GENE EXPRESSION DATA ANALYSIS
Authors: PAPADIMITRIOU STERGIOS , MAVROUDI SEFERINA , LIKOTHANASSIS SPIRIDON D.
Published: March 2006

Fuzzy association rules can reveal useful dependencies and interactions hidden in large gene expression data sets. However their derivation perplexes very difficult combinatorial problems that depend heavily on the size of these sets. The paper follows a divide and conquer approach to the problem that obtains computationally manageable solutions. Initially we cluster genes that more probably are associated. Thereafter, the fuzzy association rule extraction algorithms confront many but significantly reduced computationally problems that usually can be processed very fast.

The clustering phase is accomplished by means of an approach based on mutual information (MI). This approach uses the mutual information as a similarity measure. However, the numerical evaluation of the MI is subtle. We experiment with the main methods and we compare between them. As the device that implements the mutual information clustering we use a SOM (Self-Organized Map) based approach that is capable of effectively incorporating supervised bias.

After the mutual information clustering phase the fuzzy association rules are extracted locally on a per cluster basis. The paper presents an application of the techniques for mining the gene expression data. However, the presented techniques can easily be adapted and can be fruitful for intelligent exploration of any other similar data set as well.
ADE — AN ARCHITECTURE DEVELOPMENT ENVIRONMENT FOR VIRTUAL AND ROBOTIC AGENTS
Authors: ANDRONACHE VIRGIL , SCHEUTZ MATTHIAS
Published: March 2006

In this paper we present the agent architecture development environment ADE, intended for the design, implementation, and testing of distributed agent architectures. After a short review of architecture development tools, we discuss ADE's unique features that place it in the intersection of multi-agent systems and development kits for single agent architectures. A detailed discussion of the general properties of ADE, its implementation philosophy, and its user interface is followed by examples from virtual and robotic domains that illustrate how ADE can be used for designing, implementing, testing, and running agent architectures.
EVOLUTIONARY NEURAL LOGIC NETWORKS IN SPLICE-JUNCTION GENE SEQUENCES CLASSIFICATION
Authors: TSAKONAS ATHANASIOS , TSILIGIANNI THEODORA , DOUNIAS GEORGIOS
Published: March 2006

The paper demonstrates the efficient use of hybrid intelligent systems for solving the classification problem of splice-junction gene sequences. The aim of the study is to obtain classification schemes able to recognize, given a sequence of DNA, the boundaries between exons and introns. Previous attempts to form efficient classifiers for the same problem using intelligent or standard statistical techniques are discussed throughout the paper. The authors propose the use of evolutionary neural logic networks, an advantageous approach for their ability to interpret their structure into expert rules, a desirable feature for field experts. Evolutionary neural logic networks in fact consist an innovative hybrid intelligent methodology, by which evolutionary programming techniques are used for obtaining the best possible topology of a neural logic network. The genetic programming process is guided using a context-free grammar and indirect encoding of the neural logic networks into the genetic programming individuals. Indicative classification results are presented and discussed in detail in terms of both, classification accuracy and solution interpretability.
GENETIC ANALYSIS OF HOST RESISTANCE: Toll-Like Receptor Signaling and Immunity at Large
Authors: Beutler Bruce , Jiang Zhengfan , Georgel Philippe , Crozat Karine , Croker Ben , Rutschmann Sophie , Du Xin , Hoebe Kasper
Published: March 2006

Classical genetic methods, driven by phenotype rather than hypotheses, generally permit the identification of all proteins that serve nonredundant functions in a defined biological process. Long before this goal is achieved, and sometimes at the very outset, genetics may cut to the heart of a biological puzzle. So it was in the field of mammalian innate immunity. The positional cloning of a spontaneous mutation that caused lipopolysaccharide resistance and susceptibility to Gram-negative infection led directly to the understanding that Toll-like receptors (TLRs) are essential sensors of microbial infection. Other mutations, induced by the random germ line mutagen ENU (N-ethyl-N-nitrosourea), have disclosed key molecules in the TLR signaling pathways and helped us to construct a reasonably sophisticated portrait of the afferent innate immune response. A still broader genetic screen—one that detects all mutations that compromise survival during infection—is permitting fresh insight into the number and types of proteins that mammals use to defend themselves against microbes.
Breast Cancer Risk Reduction Options: Awareness, Discussion, and Use among Women from Four Ethnic Groups
Authors: Kaplan Celia Patricia , Haas Jennifer S. , Pérez-Stable Eliseo J. , Gregorich Steven E. , Somkin Carol , Des Jarlais Genevieve , Kerlikowske Karla
Published: March 2006

Background: With recent advances in breast cancer risk reduction practices, it is increasingly important to assess both the breadth of and disparities in use across different racial/ethnic groups.

Methods: We conducted telephone interviews with 1,700 women ages 40 to 74, from four racial/ethnic groups, without prior history of breast cancer, who received mammograms at one of five mammography facilities in San Francisco. Main outcomes measured included recognition of tamoxifen, raloxifene, genetic testing, and prophylactic surgery. Global indicators (recognition of any therapy, discussion of breast cancer risk) were developed from original outcome measures and analyzed using logistic regression.

Results: Multivariate analyses indicate that race/ethnicity and interview language affected recognition of therapies and discussion of risk. White women were more likely than all other women to recognize any therapy and more likely than Asian-Americans to discuss risk. Women at high risk, who had a prior abnormal mammogram, who perceived themselves to be at high risk, or who were exposed to breast health information were more likely to discuss risk.

Conclusions: Women are aware of preventive therapies, although discussion and use is limited. Interventions to increase use of therapies should focus on those at high risk. (Cancer Epidemiol Biomarkers Prev 2006;15(1):162–6)
Melanocortin-1 Receptor (MC1R) Gene Variants and Dysplastic Nevi Modify Penetrance ofCDKN2AMutations in French Melanoma-Prone Pedigrees
Authors: Chaudru Valérie , Laud Karine , Avril Marie-Françoise , Minière Annie , Chompret Agnès , Bressac-de Paillerets Brigitte , Demenais Florence ,   The French Familial Melanoma Study Group
Published: March 2006

Germline mutations in CDKN2A gene predispose to melanoma with high but incomplete penetrance. Penetrance of CDKN2A gene was found to be significantly influenced by host factors (nevus phenotypes and sunburn) on one hand and by variants of MC1R gene (RHC variants consistently associated with red hair and fair skin) on the other hand. Our goal was to examine the joint effects of MC1R variants and other potential risk factors [total nevi, dysplastic nevi, pigmentary traits (skin, hair and eye color), skin reactions to sunlight, and degree of sun exposure] on CDKN2A penetrance. Clinical, genetic, and covariate data were recorded in 20 French melanoma-prone families with cosegregating CDKN2A mutations. Analysis of the cotransmission of melanoma and CDKN2A mutations was conducted by likelihood-based methods using the regressive logistic models, which can account for a variation of disease risk with age and can include the aforementioned risk factors as covariates. RHC variants, considered either alone or in the presence of pigmentation and nevus phenotypes, were found to increase significantly CDKN2A penetrance. Multivariate analysis, using a stepwise selection procedure, showed significant effects of two factors on melanoma risk in CDKN2A mutations carriers: RHC variants [odds ratio of hazard function (OR), 2.21; P = 0.03] and dysplastic nevi (OR, 2.93; P < 0.01). Such results may have important consequences to improve the prediction of melanoma risk in families.
Tartrate-Resistant Acid Phosphatase 5b Activity Is a Useful Bone Marker for Monitoring Bone Metastases in Breast Cancer Patients after Treatment
Authors: Chung Yoke-Chun , Ku Chih-Hung , Chao Tsu-Yi , Yu Jyh-Cherng , Chen Mary M. , Lee Su-Huei
Published: March 2006

Metabolic markers of bone metabolism may be useful for the diagnosis and monitoring of bone metastasis in breast cancer patients. Serum tartrate-resistant acid phosphatase 5b (TRACP5b) activity is a novel bone resorption marker. The treatment response of serum TRACP5b activity, bone alkaline phosphatase (BAP) activity, and concentrations of NH2-terminal telopeptide of type 1 collagen (NTX) in 68 breast cancer patients with bone metastasis were determined. These patients were treated and followed up as clinically indicated. Fifty-four healthy women were recruited as control. Serum TRACP5b activity, BAP activity, and NTX level of breast cancer patients with bone metastasis were significantly higher than those of normal controls. In normal subjects, serum TRACP5b activity and NTX level are significantly correlated (P < 0.0001). Neither was correlated with BAP activity. In breast cancer patients with bone metastasis, all marker pairs correlated to each other significantly (P < 0.0001). Biomarkers were examined repeatedly in 38 patients who were evaluable for treatment response. Based on clinical criteria, 20 patients were responders and 18 were nonresponders. In the 20 responders, serum TRACP5b activity and NTX level decreased significantly (P < 0.0001 and 0.0107, respectively) after treatment. In the 18 nonresponders, only NTX level showed significant increase (P = 0.0342) after treatment; TRACP5b and BAP were unchanged. By means of multiple logistic regression with stepwise selection, we determined that TRACP5b activity has a higher probability than NTX level to indicate treatment response as a function of percent change after treatment (18 times versus 12 times). Our data support the use of either TRACP5b activity or NTX level to follow up breast cancer patients with bone metastasis after treatment instead of the prevailing BAP activity. (Cancer Epidemiol Biomarkers Prev 2006;15(3):424–8)
Active and Passive Smoking and Lifestyle Determinants of 8-Oxo-7,8-Dihydro-2′-Deoxyguanosine Levels in Human Leukocyte DNA
Authors: Lodovici Maura , Caldini Silvia , Luceri Cristina , Bambi Franco , Boddi Vieri , Dolara Piero
Published: March 2006

We investigated the effects of smoking and exposure to environmental tobacco smoke (ETS) on oxidative DNA damage by measuring 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodGuo) levels in DNA of leukocytes of healthy donors (30 smokers, 29 nonsmokers, and 28 ETS-exposed subjects). Nonsmokers had lower 8-oxodGuo levels compared with smokers (5.94 ± 0.87 × 10−6 and 19.85 ± 4.75 × 10−6 2-deoxyguanosine, respectively, means ± SE, P = 0.00007). Subjects exposed to ETS had higher mean value of 8-oxodGuo compared with nonsmokers (9.18 ± 1.53 × 10−6 2-deoxyguanosine, mean ± SE), nonsignificant by univariate analysis (P = 0.074). Multiregression analysis indicated that the increase of 8-oxodGuo levels induced by ETS was significant (P = 0.045) and that coffee and tea consumption reduced DNA oxidation (P = 0.0053). Oxidative leukocyte DNA damage was positively correlated with plasma cotinine levels in ETS-exposed subjects (r = 0.47, P < 0.01, n = 28) and was increased by age in nonsmokers and ETS-exposed subjects (P = 0.049). The results seem to confirm that ETS exposure is capable of inducing some oxidative DNA damage in circulating leukocytes and that coffee and tea consumption might partially protect against smoking-induced oxidation damage. (Cancer Epidemiol Biomarkers Prev 2005;14(12):2975–7)
Serum YKL-40, A New Prognostic Biomarker in Cancer Patients?
Authors: Johansen Julia S. , Jensen Benny Vittrup , Roslind Anne , Nielsen Dorte , Price Paul A.
Published: March 2006

YKL-40, a member of the “mammalian chitinase–like proteins,” is expressed and secreted by several types of solid tumors. The exact function of YKL-40 in cancer diseases is unknown and is an important objective of future studies. YKL-40 exhibits growth factor activity for cells involved in tissue remodeling processes. YKL-40 may have a role in cancer cell proliferation, survival, and invasiveness, in the inflammatory process around the tumor, angiogenesis, and remodeling of the extracellular matrix. YKL-40 is neither organ- nor tumor-specific. However, the present retrospective clinical studies of patients with eight different types of primary or advanced solid tumors suggest that serum concentration of YKL-40 may be a new biomarker in cancer patients used as a “prognosticator.” Elevated serum YKL-40 is found in a subgroup of patients with different types of solid tumors, including several types of adenocarcinomas, small cell lung carcinoma, glioblastoma, and melanoma. The highest serum YKL-40 is detected in patients with advanced cancer and with the poorest prognosis. In many cases, serum YKL-40 provides independent information of survival. Serum YKL-40 cannot be used as a single screening test for cancer. The use of serum YKL-40 has not received Food and Drug Administration approval for use as a biomarker for cancer or any other disease. Large multicenter retrospective and prospective studies of patients with different types of cancer are required to determine: (a) if serum YKL-40 is a useful prognostic cancer biomarker, (b) if serum YKL-40 can be of value in monitoring patients with cancer in order to provide information about metastases before these are detected by routine methods, and (c) if serum YKL-40 can be useful for screening of cancer together with a panel of other cancer biomarkers and imaging techniques. (Cancer Epidemiol Biomarkers Prev 2006;15(2):194–202)
Genetic Polymorphisms in XRCC1, APE1, ADPRT, XRCC2, and XRCC3 and Risk of Chronic Benzene Poisoning in a Chinese Occupational Population
Authors: Zhang Zhongbin , Wan Junxiang , Jin Xipeng , Jin Taiyi , Shen Hongbing , Lu Daru , Xia Zhaolin
Published: March 2006

DNA damage induced by benzene is an important mechanism of its genotoxicity that leads to chronic benzene poisoning (CBP). Therefore, genetic variation in DNA repair genes may contribute to susceptibility to CBP in the exposed population. Because benzene-induced DNA damage includes single- and double-strand breaks, we hypothesized that single-nucleotide polymorphisms in X-ray repair cross-complementing group 1 (XRCC1), apurinic/apyrimidinic endonuclease (APE1), ADP ribosyltransferase (ADPRT), X-ray repair cross-complementing group 2 (XRCC2), and X-ray repair cross-complementing group 3 (XRCC3) are associated with risk of CBP. We genotyped single-nucleotide polymorphisms at codons 194, 280, and 399 of XRCC1, codon 148 of APE1, codon 762 of ADPRT, codon 188 of XRCC2, and codon 241 of XRCC3 in 152 CBP patients and 152 healthy workers frequency matched on age and sex among those who were occupationally exposed to benzene. The genotypes were determined by PCR-RFLP technique with genomic DNA. We found that no individuals had the XRCC2 codon 188 variant alleles or Met/Met genotype of XRCC3 codon 241 in this study population. However, individuals carrying the XRCC1 194Trp allele (i.e., Arg/Trp+Trp/Trp genotypes) had a decreased risk of CBP [adjusted odds ratio (ORadj), 0.60; 95% confidence interval (95% CI), 0.37-0.98; P = 0.041] compared with subjects with the Arg/Arg genotype whereas individuals carrying the XRCC1 280His allele (i.e., Arg/His+His/His genotypes) had an increased risk of CBP compared with those with the Arg/Arg genotype (ORadj, 1.91; 95% CI, 1.17-3.10; P = 0.009). The analysis of haplotypes of polymorphisms in XRCC1 showed that there was a 2.96-fold (OR, 2.96; 95% CI, 1.60-5.49; χ2 = 12.39, P = 0.001) increased risk of CBP for subjects with alleles of XRCC1 194Arg, XRCC1 280His, and XRCC1 399Arg compared with those carrying alleles of XRCC1 194Arg, XRCC1 280Arg, and XRCC1 399Arg. Therefore, our results suggest that polymorphisms at codons 194 and 280 of XRCC1 may contribute to CBP in a Chinese occupational population.
Evaluating the Risk of Cervical Precancer with a Combination of Cytologic, Virologic, and Visual Methods
Authors: Wang Sophia S. , Walker Joan L. , Schiffman Mark , Solomon Diane ,   for the Atypical Squamous Cell of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study Group
Published: March 2006

Several test modalities (cytologic, molecular, and visual) may be used for cervical cancer screening, triage, and follow-up. Although no currently available single test for cervical neoplasia can detect disease with both high sensitivity and specificity, combinations of available tests allow for improved risk prediction. We therefore evaluated the combination of liquid-based cytology (LBC), human papillomavirus (HPV) DNA testing, and visual inspection (cervicography), taken at a single point in time, to predict risk of subsequent cervical intraepithelial neoplasia 3 (CIN3) or cancer developing within 2 years in a triage population of 5,060 women referred for equivocal or mildly abnormal cytology. The concurrent administration of all three test modalities showed that combinations of these test modalities permitted clear and distinct risk stratification. Among HPV-positive women with high-grade LBC and high-grade cervicography results, 79.1 % [95% confidence interval (95% CI), 64.0- 90.0] were diagnosed with histologic CIN3 or cancer within 2 years, supporting a “see-and-treat” clinical application. Conversely, only 1.4% (95% CI, 0.7-2.5) of women with a negative HPV, normal cervigram, and second normal cytology result developed CIN3 or cancer. Because this low absolute risk was largely attributable to the negative HPV test, our results suggest a lack of benefit for a secondary or tertiary test result given an HPV-negative test result. Within HPV-positive women, however, we observed a steadily increasing absolute risk for cervical precancer/cancer with increasing numbers and severity of abnormal test results. We conclude that the clear discrimination of cervical cancer risk provided by multiple test modalities is consistent with our understanding of cervical etiology related to HPV natural history.
Low-Fat, High Fruit and Vegetable Diets and Weight Loss Do Not Affect Biomarkers of Cellular Proliferation in Barrett Esophagus
Authors: Kristal Alan R. , Blount Patricia L. , Schenk Jeannette M. , Sanchez Carissa A. , Rabinovitch Peter S. , Odze Robert D. , Standley Judi , Vaughan Thomas L. , Reid Brian J.
Published: March 2006

Risk factors for esophageal adenocarcinoma include obesity, high fat intake, and low consumption of fruits and vegetables. This trial tested whether an intervention to reduce these risk factors in patients with Barrett esophagus, a preneoplastic condition for esophageal adenocarcinoma, could reduce biomarkers of cellular proliferation and, by inference, the risk of neoplastic progression. Eighty-seven men and women with Barrett esophagus were randomized to an intensive dietary intervention or control group. At baseline, 18 and 36 months after intervention, biopsies were obtained at 2-cm intervals throughout the length of the Barrett segment. Ki67/DNA content flow cytometry was used to assess (a) % Ki67-positive proliferating diploid G1 cells, (b) % total Ki67-positive proliferating cells, (c) presence of aneuploidy, and (d) presence of >6% of cells in the 4N (G2/tetraploid) fraction of the cell cycle. We also assessed re-epithelialization and length of the Barrett segment, reflux symptoms, and medication use. The intervention effects for energy, fat, fruits and vegetables, and weight were, respectively, −314 kcal, −12.2% energy, 1.8 servings/d, and −4.0 kg at 18 months (all P < 0.005) and were smaller but remained significant at 36 months. There were no significant effects of the intervention on any biomarker of cellular proliferation. The intervention effects ± SE for mean %G1 Ki67+ cells were 0.98 ± 1.58 at 18 months and 1.79 ± 1.31 at 36 months; the relative risks (95% confidence interval) for developing >6% of cells in 4N were 0.5 (0.1-2.6) at 18 months and 0.75 (0.2-3.1) at 36 months. A single control participant developed aneuploidy. There were no significant effects on re-epithelialization, segment length, or reflux medication use. We conclude that substantial dietary change has no short-term effects on biomarkers of cellular proliferation in Barrett esophagus or on clinical observations of the Barrrett segment.
Relationship of Obesity and Physical Activity with C-Peptide, Leptin, and Insulin-Like Growth Factors in Breast Cancer Survivors
Authors: Irwin Melinda L. , McTiernan Anne , Bernstein Leslie , Gilliland Frank D. , Baumgartner Richard , Baumgartner Kathy , Ballard-Barbash Rachel
Published: March 2006

Introduction: Obese and physically inactive breast cancer patients may have poorer survival compared with lighter weight and more active women. Several obesity-related and physical activity–related hormones and peptides may explain this association, including insulin, leptin, insulin-like growth factor-I (IGF-I), and IGF-binding protein-3. Few studies have examined the associations between obesity, physical activity, and these hormones/peptides among breast cancer survivors.

Purpose: To determine whether obesity and physical activity are associated with insulin, IGFs, and leptin levels in a population-based sample of 710 women diagnosed with in situ to stage IIIA breast cancer and enrolled in the Health, Eating, Activity, and Lifestyle Study.

Methods: We collected a blood sample and information on physical activity among women diagnosed 2 to 3 years earlier using an interview-administered questionnaire. Trained staff measured weight. C-peptide, leptin, and IGFs were assayed by RIA. Mean hormone levels within body mass index and physical activity categories were adjusted for confounders using analysis of covariance methods.

Results: We observed higher C-peptide (P for trend = 0.0001) and leptin (P for trend = 0.0001) levels and lower IGF-I levels (P for trend = 0.0001) with higher levels of body mass index. We observed lower C-peptide (P for trend = 0.001) and leptin (P for trend = 0.001) levels and higher IGF-I (P for trend = 0.0037) and IGF-binding protein-3 (P for trend = 0.055) levels with higher levels of physical activity.

Conclusions: Increasing physical activity and decreasing body fat may be a reasonable intervention approach toward changing insulin and leptin, thereby potentially influencing breast cancer prognosis. (Cancer Epidemiol Biomarkers Prev 2005;14(12):2881–8)
Polymorphisms/Haplotypes in DNA Repair Genes and Smoking: A Bladder Cancer Case-Control Study
Authors: Matullo Giuseppe , Guarrera Simonetta , Sacerdote Carlotta , Polidoro Silvia , Davico Laura , Gamberini Sara , Karagas Margaret , Casetta Giovanni , Rolle Luigi , Piazza Alberto , Vineis Paolo
Published: March 2006

Bladder cancer is associated with tobacco smoking and occupational exposure. The repair of DNA damage has a key role in protecting the genome from the insults of cancer-causing agents. We analyzed 13 polymorphisms in seven DNA repair genes belonging to different repair pathways [X-ray repair cross-complementing group 1 (XRCC1): 26304C>T, 26651A>G, 28152A>G; xeroderma pigmentosum-D (XPD): 23591A>G, 35931A>C; excision repair complementing defective in Chinese hamster, group 1 (ERCC1): 19007C>T; XRCC3: 4541T>C, 17893A>G, 18067C>T; proliferating cell nuclear antigen (PCNA): 6084G>C; ERCC4: 30028C>T, 30147A>G; and XRCC2-31479A>G] in 317 incident bladder cancer patients and 317 controls. After adjustment for age and smoking, the PCNA-6084C variant was significantly associated with an increased risk of bladder cancer [CC + CG versus GG, odds ratio (OR), 1.61; 95% confidence interval (95% CI), 1.00-2.61], as well as the XRCC1-26651G variant (GG+AG versus AA: OR, 1.73; 95% CI, 1.17-2.56). After stratifying by smoking habits, an elevated risk for carriers of the XRCC3-18067T allele was detected both in current (TT versus CC: OR, 2.65; 95% CI, 1.21-5.80; CT versus CC: OR, 1.96; 95% CI, 1.09-3.52) and never smokers (TT versus CC: OR, 4.34; 95% CI, 1.14-16.46; CT versus CC: OR, 2.02; 95% CI, 0.72-5.66), whereas an opposite and slightly weaker effect was associated to the XRCC3-17893G allele in current smokers (GG versus AA: OR, 0.30; 95%CI, 0.11-0.82; AG versus AA: OR, 0.73; 95% CI, 0.42-1.27). XRCC3,XRCC1, ERCC4, and XPD-ERCC1 haplotype frequencies were estimated by the maximum likelihood method. The XRCC3-TAT haplotype was associated with an enhanced risk in the current smokers group (OR, 1.62; 95% CI, 1.15-2.29), whereas a reduction of the risk in the overall sample was observed in the presence of the XRCC3-TAC (OR, 0.69; 95% CI, 0.50-0.97). A significant protective effect of the XPD-ERCC1-ACC haplotype was observed among never smokers (OR, 0.16; 95% CI, 0.03-0.81). Our results suggest that polymorphisms and/or haplotypes in XRCC3, XRCC1, and PCNA genes and spanning XPD-ERCC1 region may modulate bladder cancer risk and that some of these effects may preferentially affect current smokers.
Mitochondrial DNA Content Increase in Response to Cigarette Smoking
Authors: Masayesva Brett G. , Mambo Elizabeth , Taylor Rodney J. , Goloubeva Olga G. , Zhou Shaoyu , Cohen Yoram , Minhas Khalid , Koch Wayne , Sciubba James , Alberg Anthony J. , Sidransky David , Califano Joseph
Published: March 2006

An increase in mitochondrial DNA (mtDNA) content and decline in mitochondrial function occurs with aging and in response to DNA-damaging agents, including tobacco smoke. We did a cross-sectional study and quantified changes in mtDNA content in a population of individuals with varied smoking and alcohol exposure. Age, smoking history, ethanol intake, and other demographic data were characterized for 604 individuals participating in a screening study for smoking-related upper aerodigestive malignancy. Total DNA was extracted from exfoliated cells in saliva. DNA from a nuclear gene, β-actin, and two mitochondrial genes, cytochrome c oxidase I and II (Cox I and Cox II), were quantified by real-time PCR. mtDNA content was correlated with age, exposure history, and other variables using multivariate regression analyses. A significant increase (P < 0.001) in mtDNA content was noted in smokers (31% and 29% increase for Cox I and Cox II, respectively) and former smokers (31% and 34%) when compared with never smokers. This association persisted after adjustment for other significant factors including age, alcohol drinking, and income (P < 0.001). Increased mtDNA content was positively associated with pack-years of smoking (P = 0.02). Despite an average smoking cessation interval of 21 years in former smokers, tobacco cessation interval was not statistically significantly associated with mtDNA content. Smoking is associated with increased mtDNA content in a dose-dependent fashion. Mitochondrial DNA alterations in response to smoking persist for several decades after smoking cessation, consistent with long-term, smoking-related damage. (Cancer Epidemiol Biomarkers Prev 2006;15(1):19–24)
Breast Cancer Screening, Outside the Population-Screening Program, of Women from Breast Cancer Families without Proven BRCA1/BRCA2 Mutations: a Simulation Study
Authors: Jacobi Catharina E. , Nagelkerke Nico J.D. , van Houwelingen J. (Hans) C. , de Bock Geertruida H.
Published: March 2006

Purpose: We assessed the cost-effectiveness of mammography screening for women under the age of 50, from breast cancer families without proven BRCA1/BRCA2 mutations, because current criteria for screening healthy women from breast cancer families are not evidence-based.

Methods: We did simulation studies with mathematical models on the cost-effectiveness of mammography screening of women under the age of 50 with breast cancer family histories. Breast cancer screening was simulated with varying screening intervals (6, 12, 18, and 24 months) and screening cohorts (starting at ages 30, 35, 40, and 45, and continuing to age 50). Incremental costs of screening were compared with those of women ages 50 to 52 years, the youngest age group currently routinely screened in the nationwide screening program of the Netherlands, to determine cost-effectiveness. Sensitivity analyses were done to explore the effects of model assumptions. The cost-effectiveness of breast cancer screening for women over the age of 50 was not debated.

Results: The most effective screening interval was found to be 12 months, which, however, seems only to be cost-effective in a small group of women under the age of 50 with at least two affected relatives, including at least one affected in the first degree diagnosed under the age of 50. Significantly, early breast cancer screening never seemed to be cost-effective in women with only one affected first-degree or second-degree relative.

Conclusion: Annual breast cancer screening with mammography for women under the age of 50 seems to be cost-effective in women with strong family histories of breast cancer, even when no BRCA1/BRCA2 mutation was found in affected family members. (Cancer Epidemiol Biomarkers Prev 2006;15(3):429–36)
Eliminating Carcinogenic Acetaldehyde By Cysteine From Saliva During Smoking
Authors: Salaspuro Ville J. , Hietala Jaana M. , Marvola Martti L. , Salaspuro Mikko P.
Published: March 2006

Tobacco smoking is one of the strongest risk factors not only for lung cancer but also for cancers of the upper gastrointestinal tract. Acetaldehyde has been shown to dissolve into the saliva during smoking and to be a local carcinogen in the human upper digestive tract. Cysteine can bind to acetaldehyde and eliminate its toxicity. We developed a tablet that releases cysteine into the oral cavity during smoking and could therefore be a potential chemopreventive agent against toxicity of tobacco smoke. In this study, the efficacy of l-cysteine–containing tablets to reduce the carcinogenic acetaldehyde in the saliva during tobacco smoking was examined. Seven volunteers smoked five cigarettes. During every smoking period, each volunteer sucked a blinded tablet containing 0, 1.25, 2.5, 5, or 10 mg of l-cysteine. Acetaldehyde was analyzed from salivary samples gas chromatographically at 0, 5, and 10 minutes from the beginning of the smoking. All tablets containing l-cysteine reduced highly significantly the salivary acetaldehyde; 5 mg of l-cysteine was the minimum concentration to totally eliminate the acetaldehyde from saliva. The mean salivary acetaldehyde concentrations in samples collected immediately after smoking with 0, 1.25, 2.5, 5, or 10 mg of l-cysteine were 228 ± 115 μmol/L, 85 ± 42 μmol/L (P = 0.007), 9 ± 7 μmol/L, 0.09 ± 0.2 μmol/L, 0 ± 0 μmol/L (P < 0.001), respectively. In conclusion, carcinogenic acetaldehyde could be totally inactivated in the saliva during smoking by sucking tablet containing 5 mg of l-cysteine. Even a small reduction of the carcinogenicity of cigarette smoke could gain benefit at the population level. Hence, this finding warrants for further clinical trials for l-cysteine tablet in the prevention of upper digestive tract cancers in smokers. (Cancer Epidemiol Biomarkers Prev 2006;15(1):146–9)
Endocrine Biomarkers in Ductal Lavage Samples from Women at High Risk for Breast Cancer
Authors: Bhandare Deepa , Nayar Ritu , Bryk Michele , Hou Nanjiang , Cohn Rachel , Golewale Nazar , Parker Noah P. , Chatterton Robert T. , Rademaker Alfred , Khan Seema A.
Published: March 2006

Background: Ductal lavage is a method of minimal epithelial sampling of the breast, with potential utility for repeat sampling and biomarker analysis in chemoprevention studies. We report here the baseline findings from a study designed to assess the utility of ductal lavage in this setting.

Methods: Tamoxifen-eligible, high-risk women underwent ductal lavage; epithelial cell number (ECN) and morphology were assessed on Papanicolaou-stained slides. Additional slides were immunostained for estrogen receptor (ER) α, Ki-67, and cyclooxygenase-2, and the labeling index (LI) was established by counting negative and positive cells. The ductal lavage supernatant (DLS) was assayed for estradiol, several of its precursors, progesterone, cathepsin D, interleukin-6, and epidermal growth factor (EGF).

Results: One hundred sixty-eight women have entered the study (mean age, 51 years; mean 5-year Gail score, 2.8). Ductal lavage was accomplished in 145 (86.3%) women. Data were analyzed by duct and by woman (averaging data across all ducts). Mild atypia was seen in 43 of 145 (29.6%), whereas severe atypia was seen in 2 (1.4%) of women. We observed significant positive correlations between ECN and cytologic atypia, ER LI, cyclooxygenase-2 LI, and Ki-67 LI. EGF levels in supernatant were significantly associated with estrogenic precursors, ER LI and ECN. A factor representing the DLS hormone and protein variables explained 36% of the variance; total ECN was highest when factor score and ER LI were high and was lowest when both were low (P for interaction = 0.001).

Conclusions: Biomarker analyses in epithelial cells and DLS are feasible. The significant associations of EGF with other markers suggest a possible role in increasing epithelial cell mass.
Toenail Arsenic Concentrations, GSTT1 Gene Polymorphisms, and Arsenic Exposure from Drinking Water
Authors: Kile Molly L. , Houseman E. Andres , Rodrigues Ema , Smith Thomas J. , Quamruzzaman Quazi , Rahman Mahmuder , Mahiuddin Golam , Su Li , Christiani David C.
Published: March 2006

Toenail arsenic (As) concentrations were evaluated as a biomarker of inorganic As (Asin) exposure in a population residing in an As-endemic region of Bangladesh. Drinking water and toenail samples were collected from 48 families (n = 223) every 3 months for 2 years and analyzed for As using inductively coupled plasma-mass spectrometry. Drinking water collected 3, 6, and 9 months before each toenail sample collection was combined into a weighted lagged exposure variable. The contribution of each water sample to the measured toenail As concentration was estimated using maximum likelihood that accounted for fluctuations in drinking water exposure and toenail growth. The best model attributed 69%, 14%, and 17% of the toenail As content to drinking water exposures that occurred 3, 6, and 9 months before toenail collection [95% confidence intervals (95% CI), 0.46-0.97, 0.00-0.31, and 0.03-0.35, respectively]. Generalized additive mixed models using penalized regression splines were employed to model the data. Below a drinking water concentration of 2 μg As/L, no relationship between drinking water As and toenail As concentrations was observed. Above this concentration, toenail As content increased in a dose-dependent fashion as drinking water As increased. Age was a significant effect modifier of drinking water As exposure on toenail As (β = 0.01; 95% CI, 0.002-0.02). Individuals possessing GSTT1-null genotypes had significantly more As in their toenails in contrast to GSTT1 wild-type individuals (β = 0.11; 95% CI, 0.06-0.2). Therefore, it seems that GSTT1 modifies the relationship between Asin exposure and toenail Asin content.
Regional Differences in Breast Cancer Survival Despite Common Guidelines
Authors: Eaker Sonja , Dickman Paul W. , Hellström Vivan , Zack Matthew M. , Ahlgren Johan , Holmberg Lars ,   the Uppsala/Örebro Breast Cancer Group
Published: March 2006

Purpose: Despite a uniform regional breast cancer care program, breast cancer survival differs within regions. We therefore examined breast cancer survival in relation to differences in diagnostic activity, tumor characteristics, and treatment in seven Swedish counties within a single health care region.

Methods: We conducted a population-based observational study using a clinical breast cancer register in one Swedish health care region. Eligible women (n = 7,656) ages 40 to 69 years diagnosed with primary breast cancer between 1992 and 2002 were followed up until 2003. The 7-year relative survival ratio was used to estimate breast cancer survival. Excess mortality was modeled using Poisson regression to study differences in survival between counties.

Results: The 7-year relative survival for breast cancer patients was significantly lower (up to 7% in absolute risk difference) in one county (county A) compared with the others. This difference existed only among women diagnosed before 1998, ages 50 to 59 years, and was strongest among stage II breast cancer patients. Adjustment for amount of diagnostic activity eliminated the survival differences among the counties. The amount of diagnostic activity was also lower in county A during the same time period. After county A, during 1997-1998, began to adhere strictly to the regional breast cancer care program, neither any survival differences nor diagnostic activity differences were observed.

Interpretations: Markers of diagnostic activity explained survival differences within our region, and the underlying mechanisms may be several. Low diagnostic activity may entail later diagnosis or inadequate characterization of the tumor and thereby missed treatment opportunities. Strengthening of multidisciplinary management of breast cancer can improve survival. (Cancer Epidemiol Biomarkers Prev 2005;14(12):2914–8)
Interleukin-8Promoter Polymorphism Increases the Risk of Atrophic Gastritis and Gastric Cancer in Japan
Authors: Taguchi Ayumu , Ohmiya Naoki , Shirai Kennosuke , Mabuchi Nobuyuki , Itoh Akihiro , Hirooka Yoshiki , Niwa Yasumasa , Goto Hidemi
Published: March 2006

Host genetic susceptibility may influence gastric carcinogenesis caused by Helicobacter pylori infection. We aimed to clarify the relationship of interleukin (IL)-8 polymorphism with the risk of atrophic gastritis and gastric cancer. We examined IL-8 −251 T > A, IL-1B −511 C > T, and IL-1RN intron 2 polymorphisms in 252 healthy controls, 215 individuals with atrophic gastritis, and 396 patients with gastric cancer. We also investigated the effect of the IL-8 polymorphism on IL-8 production and histologic degree of gastritis in noncancerous gastric mucosa. Although no correlation was found in the analysis of the IL-1B and IL-1RN polymorphisms, IL-8 −251 A/A genotype held a higher risk of atrophic gastritis [odds ratio (OR), 2.35; 95% confidence interval (CI), 1.12-4.94] and gastric cancer (OR, 2.22; 95% CI, 1.08-4.56) compared with the T/T genotype. We also found that the A/A genotype increased the risk of upper-third location (OR, 3.66; 95% CI, 1.46-9.17), diffuse (OR, 2.79; 95% CI, 1.21-6.39), poorly differentiated (OR, 2.70; 95% CI, 1.14-6.38), lymph node (OR, 2.50; 95% CI, 1.01-6.20), and liver metastasis (OR, 5.63; 95% CI, 1.06-30.04), and p53-mutated (OR, 1.91; 95% CI, 1.13-3.26) subtypes of gastric cancer. The A/A and A/T genotypes were significantly associated with higher levels of IL-8 protein compared with the T/T genotype. Neutrophil infiltration score was significantly higher in the A/A genotype than in the T/T genotype. In conclusion, we showed that the IL-8 −251 T > A polymorphism is associated with higher expression of IL-8 protein, more severe neutrophil infiltration, and increased risk of atrophic gastritis and gastric cancer.
Polymorphisms and Haplotypes in the Cytochrome P450 17A1, Prolactin, and Catechol-O-Methyltransferase Genes and Non-Hodgkin Lymphoma Risk
Authors: Skibola Christine F. , Bracci Paige M. , Paynter Randi A. , Forrest Matthew S. , Agana Luz , Woodage Trevor , Guegler Karl , Smith Martyn T. , Holly Elizabeth A.
Published: March 2006

Expression of prolactin and of prolactin and estrogen receptors in lymphocytes, bone marrow, and lymphoma cell lines suggests that hormonal modulation may influence lymphoma risk. Prolactin and estrogen promote the proliferation and survival of B cells, factors that may increase non-Hodgkin lymphoma risk, and effects of estrogen may be modified by catechol-O-methyltransferase (COMT), an enzyme that alters estrogenic activity. Cytochrome P450 17A1 (CYP17A1), a key enzyme in estrogen biosynthesis, has been associated with increased cancer risk and may affect lymphoma susceptibility. We studied the polymorphisms prolactin (PRL) −1149G>T, CYP17A1 −34T>C, and COMT 108/158Val>Met, and predicted haplotypes among a subset of participants (n = 308 cases, n = 684 controls) in a San Francisco Bay Area population-based non-Hodgkin lymphoma study (n = 1,593 cases, n = 2,515 controls) conducted from 1988 to 1995. Oral contraceptive and other hormone use also was analyzed. Odds ratios (OR) for non-Hodgkin lymphoma and follicular lymphoma were reduced for carriers of the PRL −1149TT genotype [OR, 0.64; 95% confidence interval (95% CI), 0.41-1.0; OR, 0.53; 95% CI, 0.26-1.0, respectively]. Diffuse large-cell lymphoma risk was increased for those with CYP17A1 polymorphisms including CYP17A1 −34CC (OR, 2.0; 95% CI, 1.1-3.5). ORs for all non-Hodgkin lymphoma and follicular lymphoma among women were decreased for COMT IVS1 701A>G [rs737865; variant allele: OR, 0.53; 95% CI, 0.34-0.82; OR, 0.42; 95% CI, 0.23-0.78, respectively]. Compared with never users of oral contraceptives, a 35% reduced risk was observed among oral contraceptive users in the total population. Reduced ORs for all non-Hodgkin lymphoma were observed with use of exogenous estrogens among genotyped women although 95% CIs included unity. These results suggest that PRL, CYP17A1, and COMT may be relevant genetic loci for non-Hodgkin lymphoma and indicate a possible role for prolactin and estrogen in lymphoma pathogenesis.
Effects of Glucosinolate-Rich Broccoli Sprouts on Urinary Levels of Aflatoxin-DNA Adducts and Phenanthrene Tetraols in a Randomized Clinical Trial in He Zuo Township, Qidong, People's Republic of China
Authors: Kensler Thomas W. , Chen Jian-Guo , Egner Patricia A. , Fahey Jed W. , Jacobson Lisa P. , Stephenson Katherine K. , Ye Lingxiang , Coady Jamie L. , Wang Jin-Bing , Wu Yan , Sun Yan , Zhang Qi-Nan , Zhang Bao-Chu , Zhu Yuan-Rong , Qian Geng-Sun , Carmella Stephen G. , Hecht Stephen S. , Benning Lorie , Gange Stephen J. , Groopman John D. , Talalay Paul
Published: March 2006

Residents of Qidong, People's Republic of China, are at high risk for development of hepatocellular carcinoma, in part due to consumption of aflatoxin-contaminated foods, and are exposed to high levels of phenanthrene, a sentinel of hydrocarbon air toxics. Cruciferous vegetables, such as broccoli, contain anticarcinogens. Glucoraphanin, the principal glucosinolate in broccoli sprouts, can be hydrolyzed by gut microflora to sulforaphane, a potent inducer of carcinogen detoxication enzymes. In a randomized, placebo-controlled chemoprevention trial, we tested whether drinking hot water infusions of 3-day-old broccoli sprouts, containing defined concentrations of glucosinolates, could alter the disposition of aflatoxin and phenanthrene. Two hundred healthy adults drank infusions containing either 400 or <3 μmol glucoraphanin nightly for 2 weeks. Adherence to the study protocol was outstanding; no problems with safety or tolerance were noted. Urinary levels of aflatoxin-N7-guanine were not different between the two intervention arms (P = 0.68). However, measurement of urinary levels of dithiocarbamates (sulforaphane metabolites) indicated striking interindividual differences in bioavailability. An inverse association was observed for excretion of dithiocarbamates and aflatoxin-DNA adducts (P = 0.002; R = 0.31) in individuals receiving broccoli sprout glucosinolates. Moreover, trans, anti-phenanthrene tetraol, a metabolite of the combustion product phenanthrene, was detected in urine of all participants and showed a robust inverse association with dithiocarbamate levels (P = 0.0001; R = 0.39), although again no overall difference between intervention arms was observed (P = 0.29). Understanding factors influencing glucosinolate hydrolysis and bioavailability will be required for optimal use of broccoli sprouts in human interventions.
Interactions among Smoking, Obesity, and Symptoms of Acid Reflux in Barrett's Esophagus
Authors: Smith Kylie J. , O'Brien Suzanne M. , Smithers B. Mark , Gotley David C. , Webb Penelope M. , Green Adèle C. , Whiteman David C. ,   for the Study of Digestive Health
Published: March 2006

Background: Barrett's esophagus, a metaplastic precursor to esophageal adenocarcinoma, is becoming increasingly prevalent in many populations. Clinical studies suggest acid reflux causes Barrett's esophagus; however, no population-based estimates of risk have been reported, and the role of other health factors in modifying risk is unclear.

Methods: We conducted a population-based case-control study in Brisbane, Australia. Cases were 167 patients with histologically confirmed Barrett's esophagus diagnosed between February and December 2003. Age-matched and sex-matched controls (n = 261) were randomly selected from a population register. Data on exposure to self-reported symptoms of acid reflux, smoking, obesity, and other factors were collected through self-completed questionnaires followed by telephone interview. Risks of Barrett's esophagus and Barrett's esophagus with dysplasia associated with these exposures were estimated by the odds ratio (OR) and 95% confidence interval (95% CI), both crude and adjusted for other factors.

Results: Self-reported weekly episodes of acid reflux were associated with greatly increased risks of Barrett's esophagus (adjusted OR, 29.7; 95% CI, 12.2-72.6) and Barrett's esophagus with dysplasia (OR, 59.7; 95% CI, 18.5-193). Smoking was also associated with risk of Barrett's esophagus. We found evidence of interactions between symptoms of acid reflux and smoking and obesity. Obese people with self-reported symptoms of acid reflux had markedly higher risks of Barrett's esophagus (OR, 34.4; 95% CI, 6.3-188) than people with reflux alone (OR, 9.3; 95% CI, 1.4-62.2) or obesity alone (OR, 0.7; 95% CI, 0.2-2.4). Similarly, those reporting both acid reflux symptoms and smoking were at substantially higher risks of Barrett's esophagus (OR, 51.4; 95% CI, 14.1-188) than those reporting acid reflux or smoking alone.

Conclusions: Although history of symptoms of acid reflux is the principle factor associated with Barrett's esophagus, risks are substantially increased by obesity and smoking.