bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biomarkers of Exposure, Effect, and Susceptibility in Workers Exposed to Nitrotoluenes
Authors: Sabbioni Gabriele , Jones Christopher R. , Sepai Ovnair , Hirvonen Ari , Norppa Hannu , Järventaus Hilkka , Glatt Hansruedi , Pomplun Doreen , Yan Huifang , Brooks Lance R. , Warren Sarah H. , DeMarini David M. , Liu Yu-Ying 
Published: March 2006

AbstractNitrotoluenes, such as 2-nitrotoluene, 2,4-dinitrotoluene (24DNT), and 26DNT, are carcinogenic in animal experiments. Humans are exposed to such chemicals in the workplace and in the environment. It is therefore important to develop methods to biomonitor people exposed to nitrotoluenes to prevent the potential harmful effects. For the present study, workers exposed to high levels of these chemicals were investigated. The external dose (air levels), the internal dose (urine metabolites), the biologically effective dose [hemoglobin (Hb) adducts and urine mutagenicity], and biological effects (chromosomal aberrations and health effects) were determined. Individual susceptibility was assessed by determining genetic polymorphisms of enzymes assumed to function in nitrotoluene metabolism, namely glutathione S-transferases (GSTM1, GSTT1, GSTP1), N-acetyltransferases (NAT1, NAT2), and sulfotransferases (SULT1A1, SULT1A2). The levels of urinary metabolites did not correlate with the air levels. The urinary mutagenicity levels determined in a subset of workers correlated with the levels of a benzylalcohol metabolite of DNT. The Hb-adducts correlated with the urine metabolites but not with the air levels. The frequency of chromosomal aberrations (gaps included) was increased (P &lt; 0.05) in the exposed workers in comparison with a group of factory controls and correlated with the level of 24DNT Hb-adducts in young subjects (&lt;31 years). The GSTM1-null genotype was significantly more prevalent in the controls than in the exposed group, which probably reflected an elevated susceptibility of the GSTM1-null genotype to adverse health effects of DNT exposure, such as nausea (odds ratio, 8.8; 95% confidence interval, 2.4-32.2). A statistically significant effect was seen for SULT1A2 genotype on a 24DNT Hb-adduct; GSTP1 genotype on a 2,4,6-trinitrotoluene Hb-adduct; and SULT1A1, SULT1A2, NAT1, GSTT1, and GSTP1 genotypes on chromosomal aberrations in the exposed workers. (Cancer Epidemiol Biomarkers Prev 2006;15(3):559–66)
Fruit and Vegetable Consumption in Relation to Pancreatic Cancer Risk: A Prospective Study
Authors: Larsson Susanna C. , Håkansson Niclas , Näslund Ingmar , Bergkvist Leif , Wolk Alicja 
Published: March 2006

Abstract
High consumption of fruits and vegetables has been associated with a lower risk of pancreatic cancer in many case-control studies. However, cohort studies on this relationship are limited and do not support an association. We examined the associations of overall consumption of fruits and vegetables and consumption of certain subgroups of fruits and vegetables with the incidence of pancreatic cancer among 81,922 women and men in the Swedish Mammography Cohort and the Cohort of Swedish Men. Hazard ratios (HR) with 95% confidence intervals (95% CI) were estimated using Cox proportional hazards models. During an average follow-up of 6.8 years (1998-2004), 135 incident pancreatic cancer cases were diagnosed. After adjustment for age and other risk factors for pancreatic cancer, the HRs for the highest compared with the lowest category of intake were 1.13 (95% CI, 0.66-1.94) for total fruits and vegetables, 1.10 (95% CI, 0.64-1.88) for total fruits, and 1.08 (95% CI, 0.63-1.85) for total vegetables. Among specific subgroups of fruits and vegetables, a nonsignificant inverse association was observed with cruciferous vegetable consumption (≥3 servings/wk versus &lt;1 serving/wk: HR, 0.70; 95% CI, 0.43-1.13). Cabbage consumption was associated with a statistically significant lower risk of pancreatic cancer (≥1 serving/wk versus never consumption: HR, 0.62; 95% CI, 0.39-0.99). Findings from this prospective study do not support a relationship of overall fruit and vegetable consumption with pancreatic cancer risk. The association between consumption of cruciferous vegetables and pancreatic cancer risk warrants further investigation. (Cancer Epidemiol Biomarkers Prev 2006;15(2):301–5)
Modeling Exposures for DNA Methylation Profiles
Authors: Siegmund Kimberly D. , Levine A. Joan , Chang Jing , Laird Peter W. 
Published: March 2006

Abstract
We extend the finite mixture model to estimate the association between exposure and latent disease subtype measured by DNA methylation profiles. Estimates from this model are compared with those obtained from the simpler two-phase approach of first clustering the DNA methylation data followed by associating exposure with disease subtype using logistic regression. The two models are fit to data from a study of colorectal adenomas and are compared in a simulation study. Depending on the analytic approach, we obtain different estimates of the odds ratio (OR) and its 95% confidence interval (95% CI) for the association of RBC folate and DNA methylation subtype in colorectal adenomas (OR, 0.31; 95% CI, 0.08-1.26 from the extended finite mixture model; OR, 0.44; 95% CI, 0.15-1.28 from the two-phase approach; n = 58 case subjects). Although our results could be a chance occurrence due to fluctuations from small sample size, we did a simulation study using larger samples and found that differences between the two approaches emerge when there is noise in the cluster analysis. In the naive two-phase approach, the estimate of the OR is biased towards the null, and its SE is underestimated when there is error in the cluster assignment. Estimates from the extended mixture model are unbiased and have the correct SE estimate but may require larger sample sizes for convergence. Thus, when the clusters are not identified with certainty, the extended mixture model is preferred for valid estimation of the OR and CI. (Cancer Epidemiol Biomarkers Prev 2006;15(3):567–72)
Genetic Variation in the Nucleotide Excision Repair Pathway and Bladder Cancer Risk
Authors: García-Closas Montserrat , Malats Núria , Real Francisco X. , Welch Robert , Kogevinas Manolis , Chatterjee Nilanjan , Pfeiffer Ruth , Silverman Debra , Dosemeci Mustafa , Tardón Adonina , Serra Consol , Carrato Alfredo , García-Closas Reina , Castaño-Vinyals Gemma , Chanock Stephen , Yeager Meredith , Rothman Nathaniel 
Published: March 2006

Abstract
Nucleotide excision repair (NER) is critical for protecting against damage from carcinogens in tobacco smoke. We evaluated the influence of common genetic variation in the NER pathway on bladder cancer risk by analyzing 22 single nucleotide polymorphisms (SNP) in seven NER genes (XPC, RAD23B, ERCC1, ERCC2, ERCC4, ERCC5, and ERCC6). Our study population included 1,150 patients with transitional cell carcinoma of the urinary bladder and 1,149 control subjects from Spain. Odds ratios (OR) and 95% confidence intervals (95% CI) were adjusted for age, gender, region, and smoking status. Subjects with the variant genotypes for SNPs in four of the seven genes evaluated had small increases in bladder cancer risk compared to subjects with the homozygous wild-type genotypes: RAD23B IVS5-15A&gt;G (OR, 1.3; 95% CI, 1.1-1.5; P = 0.01), ERCC2 R156R (OR, 1.3; 95% CI, 1.1-1.6; P = 0.006), ERCC1 IVS5+33A&gt;C (OR, 1.2; 95% CI, 1.0-1.5; P = 0.06; Ptrend = 0.04), and ERCC5 M254V (OR, 1.4; 95% CI, 1.0-2.0; P = 0.04). A global test for pathway effects indicated that genetic variation in NER characterized by the 22 SNPs analyzed in this study significantly predicts bladder cancer risk (P = 0.04). Pairwise comparisons suggested that carrying variants in two genes could result in substantial increases in risk. Classification tree analyses suggested the presence of subgroups of individuals defined by smoking and NER genotypes that could have substantial increases in risk. In conclusion, these findings provide support for the influence of genetic variation in NER on bladder cancer risk. A detailed characterization of genetic variation in key NER genes is warranted and might ultimately help identify multiple susceptibility variants that could be responsible for substantial joint increases in risk. (Cancer Epidemiol Biomarkers Prev 2006;15(3):536–42)
Selenium, Apoptosis, and Colorectal Adenomas
Authors: Connelly-Frost Alexandra , Poole Charles , Satia Jessie A. , Kupper Lawrence L. , Millikan Robert C. , Sandler Robert S. 
Published: March 2006

Abstract
Background: Selenium is an essential trace element found in cereals, wheat, dairy products, meat, and fish. This micronutrient may prevent carcinogenesis through several biochemical pathways; one suggested pathway is enhanced apoptosis.
Objectives: The relation between selenium and colorectal adenomas was evaluated because the colorectal adenoma is the established precursor lesion of most colorectal cancers. Apoptosis was a pathway of interest because decreased apoptosis has been associated with an increased prevalence of adenomas. Our objectives were as follows: to investigate the association between (a) selenium and colorectal adenomas and (b) selenium and apoptosis.
Methods: The study population was assembled for the Diet and Health Study III (n = 803), a cross-sectional study conducted at the University of North Carolina Hospital (Chapel Hill, NC). There were 451 participants in the analysis of selenium and adenoma prevalence and 351 participants in the analysis of selenium and apoptosis. Selenium was measured from serum collected at the time of colonoscopy. Apoptosis was measured in biopsies from normal rectal epithelium obtained during the colonoscopy procedure.
Results: Participants in the highest fifth of serum selenium were less likely to have adenomas in comparison with those in the lowest fifth (prevalence ratio, 0.6; 95% confidence interval, 0.4-1.1). Selenium and apoptosis (&gt;2.76 cells per crypt) were not strongly related, but results collectively suggested a roughly inverse association.
Conclusions: High selenium was associated with a reduced prevalence of colorectal adenomas. Apoptosis, however, did not seem to be the mechanism by which selenium was related to adenoma prevalence in our data. (Cancer Epidemiol Biomarkers Prev 2006;15(3):486–93)
Role of Polymorphic Human Cytochrome P450 Enzymes in Estrone Oxidation
Authors: Cribb Alastair E. , Knight M. Joy , Dryer Dagny , Guernsey Judy , Hender Kimberly , Tesch Marvin , Saleh Tarek M. 
Published: March 2006

AbstractEstrogen and its metabolites are believed to play important roles in breast cancer. The influence of genetic polymorphisms in the enzymes responsible for formation and disposition of estrogen on breast cancer risk may shed light on the importance of estrogen metabolites in this disease. However, for such studies to be valid, it is important to correctly identify the enzymes involved in estrogen bioactivation. Therefore, we assessed the human cytochrome P450–dependent oxidation of estrone using substrate concentrations that more closely approximate the maximum expected concentrations in breast tissue. The in vitro metabolism of estrone by recombinant human cytochrome P450 enzymes and human liver microsomes was studied. The formation of estrone metabolites (2-hydroxyestrone, 4-hydroxyestrone, and 16α-hydroxyestrone) was monitored by high-performance liquid chromatography. 2-Hydroxyestrone formation was catalyzed predominantly by CYP1A2, CYP1A1, and CYP1B1 enzymes; 4-hydroxyestrone formation was catalyzed predominantly by CYP1B1, CYP1A2, and CYP1A1 enzymes; and 16α-hydroxyestrone formation was catalyzed predominantly by CYP2C19, CYP1A1, and CYP3A5. This study confirms the important role of members of the CYP1 family in the 2-hydroxylation and 4-hydroxylation of estrone, but the enzymes identified as responsible for the 16α-hydroxylation of estrone are different from those previously identified. The relative importance of these enzymes in vivo would depend on the specific tissue expression of the enzymes. These enzymes are all known to be genetically variant in the human population, and additional studies to assess the role CYP1A2, CYP2C19, and CYP3A5 in breast cancer risk are indicated. (Cancer Epidemiol Biomarkers Prev 2006;15(3):551–8)
Prostacyclin Synthase and Arachidonate 5-Lipoxygenase Polymorphisms and Risk of Colorectal Polyps
Authors: Poole Elizabeth M. , Bigler Jeannette , Whitton John , Sibert Justin G. , Potter John D. , Ulrich Cornelia M. 
Published: March 2006

Abstract
Prostacyclin synthase (PGIS) and arachidonate 5-lipoxygenase (ALOX5) are enzymes relevant to prostaglandin and leukotriene synthesis, both important pathways for colon cancer risk. We hypothesized that genetic variation altering the function of these enzymes would modify risk of colorectal polyps. In a Minnesota-based case-control study of adenomatous (n = 517) or hyperplastic (n = 192) polyps versus polyp-free controls (n = 618), we investigated the role of promoter repeat polymorphisms in PGIS and ALOX5 as well as ALOX5 −1700 G&gt;A. Having fewer than six repeats on both PGIS alleles (&lt;6R/&lt;6R) was associated with an increased risk of adenomas compared with the 6R/6R (wild-type) genotype (OR, 1.90; 95% CI, 1.09-3.30). Having more repeats (&gt;6R/≥6R) reduced risk (OR, 0.73; 95% CI, 0.40-1.35; Ptrend = 0.03). In allele-based analyses, fewer repeats were associated with a modestly increased risk of adenomas and perhaps hyperplastic polyps. There were no risk differences for either the ALOX5 VNTR or −1700 G&gt;A polymorphisms. Associations with regular use of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) differed by PGIS genotype. Among individuals with at least one wild-type allele, NSAID use was associated with a decreased risk; however, those with fewer PGIS repeats (&lt;6R/&lt;6R) did not benefit (Pinteraction = 0.06). There was also evidence of an interaction between the COX-2 −765 G&gt;C and ALOX5 −1700 G&gt;A genotypes (Pinteraction = 0.07). The PGIS promoter polymorphism may affect risk of colorectal polyps and modify the effects of NSAID use on polyp risk. A more comprehensive investigation of genetic variability in prostaglandin synthesis in relation to risk of colorectal neoplasia and NSAID pharmacogenetics is warranted. (Cancer Epidemiol Biomarkers Prev 2006;15(3):502–8)
Measurements of Breast Density: No Ratio for a Ratio
Authors: Haars Gerco , van Noord Paulus A.H. , van Gils Carla H. , Grobbee Diederick E. , Peeters Petra H.M. 
Published: March 2006

AbstractBreast density, as visible on mammograms, is generally assessed as the occupied percentage of the breast and is a risk factor for breast cancer. Various studies have looked into the causation and alteration of relative density but the relation of a determinant with a relative measure does not allow a direct etiologic interpretation. It was our goal to compare the effects of known determinants on relative density and the absolute amounts of dense and nondense tissues. We measured the absolute and relative densities in a population of 418 postmenopausal women participating in a breast cancer screening program. The occupied surface area was calculated after manually tracing the contours of the tissues on digitized mammograms. Information on determinants was available through physical examination and questionnaires. Data were analyzed by multivariate linear regression. Age and parity were found to decrease the amount of dense tissue and the ages at menarche and menopause were found to increase it (R2 = 13%). The amount of nondense tissue was increased by higher body mass index (BMI), age, and parity (R2 = 43%). Relative density was affected by a combination of these factors (R2 = 29%) with directionalities of effects that are comparable to those of dense tissue. However, the magnitudes of these effects were the resultant of the effects on dense and nondense tissues. The influence of BMI on relative density was completely due to an effect on nondense tissue. Although relative density is a relevant prognostic factor, inferences about the etiology of breast density should be made on the basis of absolute measures.
Activation of Stat3 in Primary Tumors from High-Risk Breast Cancer Patients Is Associated with Elevated Levels of Activated Src and Survivin Expression
Authors: Diaz Nills , Minton Susan , Cox Charles , Bowman Tammy , Gritsko Tanya , Garcia Roy , Eweis Ibrahim , Wloch Marek , Livingston Sandy , Seijo Ed , Cantor Alan , Lee Ji-Hyun , Beam Craig A. , Sullivan Daniel , Jove Richard , Muro-Cacho Carlos A. 
Published: March 2006

Abstract
Purpose: Constitutive activation of signal transducer and activator of transcription 3 (Stat3) protein has been observed in a wide variety of tumors, including breast cancer, and contributes to oncogenesis at least in part by prevention of apoptosis. In a study of 45 patients with high-risk breast cancer enrolled in a phase II neoadjuvant chemotherapy trial with docetaxel and doxorubicin, we evaluated the levels of Stat3 activation and potentially associated molecular biomarkers in invasive breast carcinoma compared with matched nonneoplastic tissues.
Experimental Design: Using immunohistochemistry and image analysis, we quantified the levels of phospho-Stat3 (pY-Stat3), phospho-Src (pY-Src), epidermal growth factor receptor, HER2/neu, Ki-67, estrogen receptor, Bcl-2, Bcl-xL, Survivin, and apoptosis in formalin-fixed, paraffin-embedded sections from invasive carcinomas and their paired nonneoplastic parenchyma. The levels of molecular biomarkers in nonneoplastic and tumor tissues were analyzed as continuous variables for statistically significant correlations.
Results: Levels of activated pY-Stat3 and pY-Src measured by immunohistochemistry were significantly higher in invasive carcinoma than in nonneoplastic tissue (P &lt; 0.001). In tumors, elevated levels of pY-Stat3 correlated with those of pY-Src and Survivin. Levels of pY-Stat3 were higher in partial pathologic responders than in complete pathologic responders. In partial pathologic responders, pY-Stat3 levels correlated with Survivin expression.
Conclusions: Our findings suggest important roles for elevated activities of Stat3 and Src, as well as Survivin expression, in malignant progression of breast cancer. Furthermore, elevated Stat3 activity correlates inversely with complete pathologic response. These findings suggest that specific Stat3 or Src inhibitors could offer clinical benefits to patients with breast cancer.
Persistent Activation of Stat3 Signaling Induces Survivin Gene Expression and Confers Resistance to Apoptosis in Human Breast Cancer Cells
Authors: Gritsko Tanya , Williams Ann , Turkson James , Kaneko Satoshi , Bowman Tammy , Huang Mei , Nam Sangkil , Eweis Ibrahim , Diaz Nils , Sullivan Daniel , Yoder Sean , Enkemann Steve , Eschrich Steven , Lee Ji-Hyun , Beam Craig A. , Cheng Jin , Minton Susan , Muro-Cacho Carlos A. , Jove Richard 
Published: March 2006

Abstract
Purpose: Signal transducer and activator of transcription 3 (Stat3) protein is persistently activated in breast cancer and promotes tumor cell survival. To gain a better understanding of the role of constitutive Stat3 signaling in breast cancer progression, we evaluated the expression profile of potential Stat3-regulated genes that may confer resistance to apoptosis.
Experimental Design: Stat3 signaling was blocked with antisense oligonucleotides in human MDA-MB-435s breast cancer cells and Affymetrix GeneChip microarray analysis was done. The candidate Stat3 target gene Survivin was further evaluated in molecular assays using cultured breast cancer cells and immunohistochemistry of breast tumor specimens.
Results: Survivin, a member of the inhibitor of apoptosis protein family, was identified as a potential Stat3-regulated gene by microarray analysis. This was confirmed in Survivin gene promoter studies and chromatin immunoprecipitation assays showing that Stat3 directly binds to and regulates the Survivin promoter. Furthermore, direct inhibition of Stat3 signaling blocked the expression of Survivin protein and induced apoptosis in breast cancer cells. Direct inhibition of Survivin expression also induced apoptosis. Increased Survivin protein expression correlates significantly (P = 0.001) with elevated Stat3 activity in primary breast tumor specimens from high-risk patients who were resistant to chemotherapy treatment.
Conclusions: We identify Survivin as a direct downstream target gene of Stat3 in human breast cancer cells that is critical for their survival in culture. Our findings suggest that activated Stat3 signaling contributes to breast cancer progression and resistance to chemotherapy by, at least in part, inducing expression of the antiapoptotic protein, Survivin.
Gene Expression Profiles of B-lineage Adult Acute Lymphocytic Leukemia Reveal Genetic Patterns that Identify Lineage Derivation and Distinct Mechanisms of Transformation
Authors: Chiaretti Sabina , Li Xiaochun , Gentleman Robert , Vitale Antonella , Wang Kathy S. , Mandelli Franco , Foà Robin , Ritz Jerome 
Published: March 2006

Abstract
Purpose: To characterize gene expression signatures in acute lymphocytic leukemia (ALL) cells associated with known genotypic abnormalities in adult patients.
Experimental Design: Gene expression profiles from 128 adult patients with newly diagnosed ALL were characterized using high-density oligonucleotide microarrays. All patients were enrolled in the Italian GIMEMA multicenter clinical trial 0496 and samples had &gt;90% leukemic cells. Uniform phenotypic, cytogenetic, and molecular data were also available for all cases.
Results: T-lineage ALL was characterized by a homogeneous gene expression pattern, whereas several subgroups of B-lineage ALL were evident. Within B-lineage ALL, distinct signatures were associated with ALL1/AF4 and E2A/PBX1 gene rearrangements. Expression profiles associated with ALL1/AF4 and E2A/PBX1 are similar in adults and children. BCR/ABL+ gene expression pattern was more heterogeneous and was most similar to ALL without known molecular rearrangements. We also identified a set of 83 genes that were highly expressed in leukemia blasts from patients without known molecular abnormalities who subsequently relapsed following therapy. Supervised analysis of kinase genes revealed a high-level FLT3 expression in a subset of cases without molecular rearrangements. Two other kinases (PRKCB1 and DDR1) were highly expressed in cases without molecular rearrangements, as well as in BCR/ABL-positive ALL.
Conclusions: Genomic signatures are associated with phenotypically and molecularly well defined subgroups of adult ALL. Genomic profiling also identifies genes associated with poor outcome in cases without molecular aberrations and specific genes that may be new therapeutic targets in adult ALL.