bluuebunny/crossref_metadata_2025 huggingface dataset:
Biochemical Alterations from Normal Mucosa to Gastric Cancer by Ex vivo Magnetic Resonance Spectroscopy
Authors: Calabrese Carlo , Pisi Annamaria , Di Febo Giulio , Liguori Giuseppina , Filippini Gianfranco , Cervellera Maurizio , Righi Valeria , Lucchi Patrizia , Mucci Adele , Schenetti Luisa , Tonini Valeria , Tosi Maria Raffaella , Tugnoli Vitaliano
Published: June 2008

Background and Aims: The metabolic profile and morphologic aspects of normal and pathologic human gastric mucosa were studied. The aim of the present research was the application of ex vivo high-resolution magic angle spinning magnetic resonance spectroscopy (HR-MAS MRS) to the human gastric tissue to get information on the molecular steps involved in gastric carcinogenesis and the identification of biochemical markers useful for the development of in vivo MRS methodologies to diagnose gastric pathologies in clinical situations.

Methods: Twelve normal subjects, five with autoimmune atrophic gastritis, five with Helicobacter pylori infection, and five with adenocarcinoma were examined. Ten biopsies were taken during endoscopy from each patient. Specimens from carcinoma were also obtained during gastrectomy. Of the 10 biopsies, 4 were used for histologic evaluation, 4 were fixed in glutaraldehyde and processed for transmission and scanning electron microscopy, and 2 were immersed in liquid nitrogen and stored at −85°C for monodimensional and bidimensional ex vivo HR-MAS MRS analysis.

Results: Ex vivo HR-MAS MRS identified glycine, alanine, free choline, and triglycerides as possible molecular markers related to the human gastric mucosa differentiation toward preneoplastic and neoplastic conditions. Ultrastructural studies of autoimmune atrophic gastritis and gastric adenocarcinoma revealed lipid accumulations intracellularly and extracellularly associated with a severe prenecrotic hypoxia and mitochondria degeneration.

Conclusions: This is the first report of synergic applications of ex vivo HR-MAS MRS and electron microscopy in studying the human gastric mucosa differentiation. This research provides useful information about some molecular steps involved in gastric carcinogenesis. The biochemical data obtained on gastric pathologic tissue could represent the basis for clinical applications of in vivo MRS. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1386–95)
Correlates and Determinants of Nuclear Epidermal Growth Factor Receptor Content in an Oropharyngeal Cancer Tissue Microarray
Authors: Psyrri Amanda , Egleston Brian , Pectasides Eirini , Weinberger Paul , Yu Ziwei , Kowalski Diane , Sasaki Clarence , Haffty Bruce , Rimm David , Burtness Barbara
Published: June 2008

Background: We have previously reported nuclear localization of epidermal growth factor receptor (EGFR) protein in oropharyngeal cancer tissue. Nuclear EGFR levels were inversely correlated with survival and response to radiotherapy. Here, we sought to identify the determinants and correlates of nuclear EGFR content.

Methods: We analyzed an oropharyngeal cancer tissue microarray for the expression of the key molecules of the EGFR signaling cascade using an automated image analysis technique (AQUA) scored on a scale of 0 to 255, which permits protein quantitation and subcellular localization. Patients with oropharyngeal squamous cell cancer treated with radiotherapy or surgery and radiotherapy were eligible. Data were analyzed using Spearman correlations and multiple linear regression with robust SEs.

Results: Of the 95 tumors included in this study, 72 (75%) had sufficient tissue for analysis of nuclear EGFR. Nuclear EGFR levels were associated with membranous/cytoplasmic EGFR levels (ρ = 0.82, P < 0.001), nuclear extracellular signal-regulated kinase-2 (ρ = 0.30, P = 0.01), and nuclear proliferating cell nuclear antigen (PCNA; ρ = 0.36, P = 0.003). Nuclear phosphorylated-Akt, cyclin D1, phosphatase and tensin homolog (mutated in multiple cancers 1) (PTEN), p53, and proliferation marker Ki-67 levels did not correlate with nuclear EGFR level. In multivariable analysis, only PCNA retained its significant association (P = 0.01).

Conclusions: These results are consistent with preclinical data showing that EGFR may function as a tyrosine kinase in the nucleus, phosphorylating and stabilizing PCNA. The nuclear activity of EGFR may constitute a novel therapeutic target. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1486–92)
Reproducibility of Proteomic Profiles Over 3 Years in Postmenopausal Women Not Taking Postmenopausal Hormones
Authors: Tworoger Shelley S. , Spentzos Dimitrios , Grall Franck T. , Liebermann Towia A. , Hankinson Susan E.
Published: June 2008

Most proteomics studies examine one blood specimen per participant; however, it is unknown how well measures at one time point reflect an individual's long-term proteome pattern. Therefore, we examined the stability of the proteome over 3 years in postmenopausal women not taking hormones for at least 3 months using surface-enhanced laser desorption and ionization time-of-flight mass spectrometry. Using the Nurses' Health Study blood cohort, we randomly selected 60 women from a subset providing 2 to 3 blood samples over 3 years. Four different protein chip surfaces/plasma fractions were examined: unfractionated plasma on a CM10 and H50 chip, pH ≥ 9, plasma fraction on a CM10 chip, and the organic fraction on the H50 chip, all with a low- and high-energy transfer protocol. Participant and quality control samples were aligned to a reference sample and then peak intensity was assessed for all peaks identified in the reference sample. The average coefficient of variation (CV) of the peak intensity within conditions ranged from 16% (H50, organic, low protocol) to 63% (CM10, pH ≥ 9, high protocol). Generally, the CV and mean peak intensity of the quality control samples were inversely correlated (median −0.48). The mean intraclass correlation (ICC) within conditions ranged from 0.37 (H50, unfractionated, low protocol) to 0.68 (CM10, unfractionated, high protocol). For a signal-to-noise cutoff of 2.0, we observed 334 peaks, of which 241 (72%) had an ICC of ≥0.40. Although we observed a large range of CVs and ICCs, sufficient numbers of peaks had reasonable ICCs to suggest that protein peak reproducibility over 3 years was reasonable among postmenopausal women not taking hormones. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1480–5)
Gains and Amplifications of c-myc, EGFR, and 20.q13 Loci in the No Dysplasia–Dysplasia–Adenocarcinoma Sequence of Barrett's Esophagus
Authors: Rygiel Agnieszka M. , Milano Francesca , ten Kate Fibo J. , Schaap Annet , Wang Kenneth K. , Peppelenbosch Mackel P. , Bergman Jacques J.G.H.M. , Krishnadath Kausillia K.
Published: June 2008

The progression of Barrett's esophagus to esophageal adenocarcinoma is often characterized by the accumulation of genetic abnormalities. The goal was to evaluate the copy number alterations of several oncogene loci, including 7p12 [epidermal growth factor receptor (EGFR)], 8q24 (c-myc), and 20q13 in the sequence of no dysplasia–dysplasia–adenocarcinoma of Barrett's esophagus. Fluorescence in situ hybridization with DNA probes for the centromeric region of chromosome 7 and the locus-specific regions of 7p12 (EGFR), 8q24 (c-myc), and 20q13 was applied on 99 brush cytology specimens of patients with Barrett's esophagus with different stages of dysplasia or esophageal adenocarcinoma. Gains (3-4 copies) of chromosome 17, 8q24 (c-myc), and 20q.13 loci were found in the low frequencies in nondysplastic Barrett's esophagus. Their frequencies increased with the stage of dysplasia and reached a high incidence in esophageal adenocarcinoma. Amplification (>4 copies) of at least 1 of the loci was observed in 14% of high-grade dysplasia and increased to 50% in esophageal adenocarcinoma (P = 0.015). The most frequently amplified locus was c-myc (18%), followed by 20q13 (13%) and EGFR (11%) in the high-grade dysplasia/esophageal adenocarcinoma cases. High amplification levels (>10 copies) of the loci were more frequent in esophageal adenocarcinoma (72%) compared with high-grade dysplasia (20%; P = 0.049). Amplifications of the c-myc, EGFR, and 20q12 loci may serve as diagnostic markers to identify patients with Barrett's esophagus with high-grade dysplasia or esophageal adenocarcinoma. Gains of the loci might be of value as prognostic markers because they are already present in nondysplasia cases and may precede the later event of the amplification as observed in high-grade dysplasia and esophageal adenocarcinoma. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1380–5)
Polycyclic Aromatic Hydrocarbon Exposure, Urinary Mutagenicity, and DNA Adducts in Rubber Manufacturing Workers
Authors: Peters Susan , Talaska Glenn , Jönsson Bo A.G. , Kromhout Hans , Vermeulen Roel
Published: June 2008

Objectives: Several studies have suggested that genotoxic risks might still be present in the contemporary rubber manufacturing industry. Previously, we observed elevated levels of urinary mutagenicity and bladder DNA adducts in rubber workers. Presently, we investigated whether DNA adducts in peripheral blood mononuclear cells (PBMC) and/or urothelial cells may be caused by polycyclic aromatic hydrocarbons or other genotoxic compounds.

Methods: Spot urine samples from 116 rubber manufacturing workers were collected on Sunday and during the workweek (post-shift) to determine 1-hydroxypyrene and mutagenicity levels. For 52 nonsmokers, urothelial cell DNA adducts and PBMC DNA adducts were measured additionally.

Results: Urinary 1-hydroxypyrene levels were significantly higher in workweek samples compared with Sunday (P = 0.0001). This increase was not uniform across tasks and only reached statistical significance for the curing department (+99%; P = 0.003). Weekday urinary mutagenicity was significantly increased for mixing (+56%) and curing (+21%) workers when compared with that for Sunday. Total urothelial cell DNA adducts were related to urinary 1-hydroxypyrene (P = 0.021) and mutagenicity (P = 0.027). No significant relationship was found between the adduct levels in PBMC and urothelial cells or between the former and urinary 1-hydroxypyrene or mutagenicity.

Conclusions: Workers in the compounding, mixing, and curing departments were at highest genotoxic risk among rubber manufacturing workers. Increased levels of urinary 1-hydroxypyrene, mutagenicity, and urothelial cell DNA adducts were found in these workers. Urothelial cell and PBMC DNA adducts were not related, hinting possibly to the presence of specific bladder carcinogens in the rubber manufacturing industry. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1452–9)
Differential Expression of Genes Related to Androgen and Estrogen Metabolism in Hereditary versus Sporadic Prostate Cancer
Authors: Fromont Gaelle , Yacoub Mokrane , Valeri Antoine , Mangin Philippe , Vallancien Guy , Cancel-Tassin Geraldine , Cussenot Olivier
Published: June 2008

The hereditary predisposition to prostate cancer is rare and accounts for <5% of cases. Except for younger age at diagnosis, no phenotypic features have been clearly associated with hereditary prostate cancer. The aim of the study was to analyze the expression of genes related to androgen and estrogen metabolism in both hereditary and sporadic prostate cancers in patients matched for clinicopathologic features. Tissues were obtained from patients included in a national familial prostate cancer registry. From the 120 cases of hereditary forms suggesting autosomal dominant Mendelian inheritance, 21 patients were treated by radical prostatectomy for whom formalin-fixed tissue was available. Twenty-one sporadic cases were then matched according to age, Gleason score, and pathologic stage. Immunohistochemistry was done on tissue microarray using antibodies directed against androgen receptor (AR), estrogen receptor α (ERA), estrogen receptor β, 5α-reductase I and II, aromatase, and the proliferation marker Ki67. The percentage of AR-positive cancer cells was higher in hereditary cancer compared with sporadic cases (P < 0.004). In contrast, the mean number of ERA-positive stromal cells was lower in hereditary versus sporadic cancer (P < 0.03). This differential expression of AR and ERA suggests that a specific pattern of hormone receptors is associated with hereditary predisposition to prostate cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1505–9)
Antibiotic Use and the Risk of Lung Cancer
Authors: Zhang Hui , García Rodríguez Luis A. , Hernández-Díaz Sonia
Published: June 2008

Antibiotic use has been associated with an increased risk of cancer in epidemiologic studies. We evaluated the association between antibiotic use and the risk of primary lung cancer by conducting a prospective case-control study nested in a cohort of subjects who were 40 to 84 years old in 1995 to 2004, with at least 2 years of enrollment in The Health Improvement Network. There were 4,336 cases of primary lung cancer. A random sample of 10,000 controls was frequency matched to the cases for age, sex, and calendar year of diagnosis. Antibiotic exposure was measured by the total number of antibiotic prescriptions and the cumulative number of days on antibiotics since enrollment. We discounted exposure 1 year before the date of cancer diagnosis. Relative risks (RR) and 95% confidence intervals (95% CI) were estimated using conditional logistic regression. Variables such as smoking, chronic obstructive pulmonary disease, respiratory infections, body mass index, and health care utilization were introduced in the model. Compared with subjects with no prescription of antibiotics before the index date, the crude RR of lung cancer was 2.52 (95% CI, 2.25-2.83) among those who received 10 or more prescriptions. The corresponding RR was 1.31 (95% CI, 1.10-1.57) upon adjustment for confounders. We used directed acyclic graphs to illustrate that the observed higher risk of lung cancer among antibiotic users may be due to the increased frequency of infections in patients with subclinical cancer and to shared causes between cancer and infections. Current evidence is insufficient to support or refute a carcinogenic effect of antibiotics. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1308–15)
Pathway Analysis of Single-Nucleotide Polymorphisms Potentially Associated with Glioblastoma Multiforme Susceptibility Using Random Forests
Authors: Chang Jeffrey S. , Yeh Ru-Fang , Wiencke John K. , Wiemels Joseph L. , Smirnov Ivan , Pico Alexander R. , Tihan Tarik , Patoka Joe , Miike Rei , Sison Jennette D. , Rice Terri , Wrensch Margaret R.
Published: June 2008

Glioma is a complex disease that is unlikely to result from the effect of a single gene. Genetic analysis at the pathway level involving multiple genes may be more likely to capture gene-disease associations than analyzing genes one at a time. The current pilot study included 112 Caucasians with glioblastoma multiforme and 112 Caucasian healthy controls frequency matched to cases by age and gender. Subjects were genotyped using a commercially available (ParAllele/Affymetrix) assay panel of 10,177 nonsynonymous coding single-nucleotide polymorphisms (SNP) spanning the genome known at the time the panel was constructed. For this analysis, we selected 10 pathways potentially involved in gliomagenesis that had SNPs represented on the panel. We performed random forests (RF) analyses of SNPs within each pathway group and logistic regression to assess interaction among genes in the one pathway for which the RF prediction error was better than chance and the permutation P < 0.10. Only the DNA repair pathway had a better than chance classification of case-control status with a prediction error of 45.5% and P = 0.09. Three SNPs (rs1047840 of EXO1, rs12450550 of EME1, and rs799917 of BRCA1) of the DNA repair pathway were identified as promising candidates for further replication. In addition, statistically significant interactions (P < 0.05) between rs1047840 of EXO1 and rs799917 or rs1799966 of BRCA1 were observed. Despite less than complete inclusion of genes and SNPs relevant to glioma and a small sample size, RF analysis identified one important biological pathway and several SNPs potentially associated with the development of glioblastoma. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1368–73)
Urinary Total Isothiocyanates and Colorectal Cancer: A Prospective Study of Men in Shanghai, China
Authors: Moy Kristin A. , Yuan Jian-Min , Chung Fung-Lung , Van Den Berg David , Wang Renwei , Gao Yu-Tang , Yu Mimi C.
Published: June 2008

Laboratory and epidemiologic evidence suggests that dietary isothiocyanates (ITCs) may have a chemopreventive effect on cancer. Humans are exposed to ITCs primarily through ingestion of cruciferous vegetables that contain glucosinolates, the precursors to ITCs. The association between urinary total ITC level and colorectal cancer risk was examined in a cohort of 18,244 men in Shanghai, China, with 16 years of follow-up. Urinary total ITCs were quantified on 225 incident cases of colorectal cancer and 1,119 matched controls. Odds ratios (ORs) and their 95% confidence intervals (95% CIs) were calculated using logistic regression models. High levels of urinary total ITCs were associated with a reduced risk of colorectal cancer 5 years after baseline measurements of ITCs, whereas a statistically nonsignificant increase in the risk of colorectal cancer was observed for cases within 5 years of post-enrollment (OR, 1.93; 95% CI, 0.85-4.39 for the upper three quartiles of urinary ITCs versus the lowest quartile). The inverse ITC-colorectal cancer association became stronger with a longer duration of follow-up. Compared with the first quartile, ORs (95% CIs) for the second, third, and fourth quartiles of total ITCs in urine collected 10 or more years before cancer diagnosis were 0.61 (0.35-1.05), 0.51 (0.29-0.92), and 0.46 (0.25-0.83), respectively, for risk of colorectal cancer (P for trend = 0.006). The present study suggests that dietary ITCs may exert tumor inhibitory effects, especially during earlier stages of the multistage process of carcinogenesis. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1354–9)
Risk of Second Primary Cancer among Esophageal Cancer Patients: a Pooled Analysis of 13 Cancer Registries
Authors: Chuang Shu-Chun , Hashibe Mia , Scelo Ghislaine , Brewster David H. , Pukkala Eero , Friis Soren , Tracey Elizabeth , Weiderpass Elisabete , Hemminki Kari , Tamaro Sharon , Chia Kee-Seng , Pompe-Kirn Vera , Kliewer Erich V. , Tonita Jon M. , Martos Carmen , Jonasson Jon G. , Dresler Carolyn M. , Boffetta Paolo , Brennan Paul
Published: June 2008

Background: The objective of this study is to assess the risk of second primary cancers following a first primary esophageal cancer as well as the risk of esophageal cancer as a second primary, following first primary cancers of other sites.

Methods: The present investigation is a multicenter study of 13 population-based cancer registries in Europe, Australia, Canada, and Singapore. To assess excess occurrence of second cancers after esophageal cancers, we calculated standardized incidence ratios (SIR) by dividing the observed numbers of second cancers by the expected number of cancers calculated from the accumulated person-years and the age-, sex-, calendar period-, and registry-specific first primary cancer incidence rates.

Results: During the study period, 959 cases of second primary cancers occurred after an initial esophageal cancer, resulting in a SIR of 1.15 (95% confidence interval, 1.08-1.22). Second primary stomach cancers were associated with first primary esophageal adenocarcinomas (SIR, 2.13; 95% confidence interval, 1.26-3.37) and second primary cancers of the oral cavity and pharynx (6.68; 5.33-8.26), stomach (1.53; 1.14-2.01), larynx (3.24; 1.88-5.18), lung (1.55; 1.28-1.87), kidney (1.88; 1.18-2.85), and thyroid (2.92; 1.18-6.02) were associated with first primary squamous cell carcinomas of the esophagus. An excess of esophageal cancer as a second primary were observed following first primary cancers of the aerodigestive tract, female breast, cervix, testis, bladder, Hodgkin's lymphoma, and non–Hodgkin lymphoma.

Conclusion: We observed associations of esophageal cancer with second primary head and neck cancers and lung cancer regardless of years of follow-up, which may suggest that common risk factors play a role in multiple tumor development. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1543–9)
Does Folic Acid Supplementation Prevent or Promote Colorectal Cancer? Results from Model-Based Predictions
Authors: Luebeck E. Georg , Moolgavkar Suresh H. , Liu Amy Y. , Boynton Alanna , Ulrich Cornelia M.
Published: June 2008

Folate is essential for nucleotide synthesis, DNA replication, and methyl group supply. Low-folate status has been associated with increased risks of several cancer types, suggesting a chemopreventive role of folate. However, recent findings on giving folic acid to patients with a history of colorectal polyps raise concerns about the efficacy and safety of folate supplementation and the long-term health effects of folate fortification. Results suggest that undetected precursor lesions may progress under folic acid supplementation, consistent with the role of folate role in nucleotide synthesis and cell proliferation. To better understand the possible trade-offs between the protective effects due to decreased mutation rates and possibly concomitant detrimental effects due to increased cell proliferation of folic acid, we used a biologically based mathematical model of colorectal carcinogenesis. We predict changes in cancer risk based on timing of treatment start and the potential effect of folic acid on cell proliferation and mutation rates. Changes in colorectal cancer risk in response to folic acid supplementation are likely a complex function of treatment start, duration, and effect on cell proliferation and mutations rates. Predicted colorectal cancer incidence rates under supplementation are mostly higher than rates without folic acid supplementation unless supplementation is initiated early in life (before age 20 years). To the extent to which this model predicts reality, it indicates that the effect on cancer risk when starting folic acid supplementation late in life is small, yet mostly detrimental. Experimental studies are needed to provide direct evidence for this dual role of folate in colorectal cancer and to validate and improve the model predictions. (Cancer Epidemiol Biomarkers Prev 2008;17(6):OF1360–8)
Long-term Stability of Human Aflatoxin B1 Albumin Adducts Assessed by Isotope Dilution Mass Spectrometry and High-Performance Liquid Chromatography–Fluorescence
Authors: Scholl Peter F. , Groopman John D.
Published: June 2008

The measurement of the aflatoxin B1-lysine serum albumin adduct in human blood samples is the most facile biomarker for the assessment of chronic exposure to aflatoxin B1. Many technologies have been developed for the measurement of this protein adduct including immunoassays, high-performance liquid chromatography (HPLC) with fluorescence detection, and a newly developed isotope-dilution mass spectrometry method. Irrespective of the technology used to determine this adduct level, an important question remains about the long-term stability of this damage product in stored samples. To address this issue, 19 human serum samples that had been previously analyzed for the aflatoxin B1-lysine adduct by high-performance liquid chromatography–fluorescence in 1989 were re-analyzed by isotope dilution mass spectrometry after storage at −80°C. The adduct concentrations measured by these two techniques were identical within 4% over the range 5 to 100 pg of aflatoxin B1-lysine/mg albumin. In addition, the specific chemical structure of the aflatoxin B1-lysine adduct in human samples was confirmed for the first time by collision-induced dissociation full scan mass spectrometry analysis of the protonated adduct molecular ion. These results illustrate that the aflatoxin B1-lysine serum albumin adduct can be stable in human serum stored at −80°C since 1989, and this provides confidence for the measurement of this biomarker in repository samples from epidemiologic investigations. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1436–9)
CDKN2A/p16 Genetic Test Reporting Improves Early Detection Intentions and Practices in High-Risk Melanoma Families
Authors: Aspinwall Lisa G. , Leaf Samantha L. , Dola Erin R. , Kohlmann Wendy , Leachman Sancy A.
Published: June 2008

Genetic testing for melanoma has yet to enter routine clinical use because of the scarcity of available data on the effect of test reporting. A prospective study of 59 members of Utah CDKN2A/p16 mutation–positive pedigrees was conducted to establish the effect of CDKN2A/p16 genetic test reporting on melanoma early detection intentions and behaviors (total body skin examination and skin self-examination) in a high-risk population. Behavioral assessments were made at baseline, immediately after CDKN2A/p16 test reporting and counseling, and at 1-month follow-up (42 participants). Baseline screening practices were poor relative to current recommendations, especially among participants without a personal history of melanoma. Changes from baseline practice were evaluated in three groups of participants (CDKN2A/p16+ with history of melanoma, CDKN2A/p16+ without melanoma history, and CDKN2A/p16−). Across multiple measures, test reporting caused CDKN2A/p16 mutation carriers without a melanoma history to improve to the level of adherence reported by participants with a melanoma history, without decreasing compliance of the CDKN2A/p16− group. Compared with baseline, CDKN2A/p16+ participants without a melanoma history reported greater intention to obtain total body skin examinations (P < 0.0001), increased intentions and adherence to skin self-examination recommendations (P < 0.01 and P < 0.001, respectively), and increased number of body sites examined at 1 month (P < 0.002); further, 55% reported adopting a new screening behavior at follow-up. Test reporting also improved skin self-examination adherence among CDKN2A/p16− participants (P < 0.03). The finding that CDKN2A/p16 test reporting enhances compliance with early detection measures among CDKN2A/p16+ participants without diminishing the compliance of CDKN2A/p16− participants suggests a favorable risk-benefit ratio for melanoma genetic testing in high-risk patients. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1510–9)
Familial and Perceived Risk of Breast Cancer in Relation to Use of Complementary Medicine
Authors: Myers Cynthia D. , Jacobsen Paul B. , Huang Yifan , Frost Marlene H. , Patten Christi A. , Cerhan James R. , Sellers Thomas A.
Published: June 2008

Aim: To examine the use of complementary and alternative medicine (CAM) by women with varying levels of familial and perceived risk of breast cancer with the goal of preventing breast cancer.

Methods: Cross-sectional data on CAM use were collected on 2,198 women (mean age, 63 years) personally unaffected by breast cancer in the Minnesota Breast Cancer Family Study. CAM use was compared across women at high, moderate, or average risk based on family history, as well as across categories of perceived risk of breast cancer. CAM use was also examined in relation to screening and general health behaviors, worry about breast cancer, and optimism.

Results: Half (49.5%) of the women reported using at least one CAM modality with the intent of preventing breast cancer. Univariate analyses indicated that greater overall CAM use was related to greater perceived risk (P = 0.018), more general health behaviors (P < 0.0001), more breast cancer screening behaviors (P = 0.0002), greater optimism (P = 0.0002), and higher educational attainment (P < 0.0001). Multivariate analysis revealed that general health behaviors (P < 0.0001), education (P = 0.0027), and optimism (P = 0.037) were significant predictors of CAM use when in the same model with perceived risk and breast cancer screening behaviors.

Conclusions: Many women use CAM with the goal of preventing breast cancer. General health-promoting behaviors, education, and optimism predict CAM use. Evidence-based guidance is needed for the public and health care providers on the potential and limitations of specific CAM approaches to affect cancer risk. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1527–34)
Anti-Mesothelin Antibodies and Circulating Mesothelin Relate to the Clinical State in Ovarian Cancer Patients
Authors: Hellstrom Ingegerd , Friedman Eitan , Verch Thorsten , Yang Yi , Korach Jacob , Jaffar Jade , Swisher Elizabeth , Zhang Boxin , Ben-Baruch Gilad , Tan Marcus C.B. , Goedegebuure Peter , Hellstrom Karl Erik
Published: June 2008

Most human ovarian carcinomas express mesothelin, which is shed as a diagnostically useful biomarker. We applied an ELISA to measure antibodies to native mesothelin in serum from a series of patients with divergent clinical outcomes. The level of anti-mesothelin antibodies determined as OD450 nm and referred to as absorption units (AU) for 1:20 diluted serum was higher in patients who remained disease-free after therapy [no evidence of disease (NED); n = 14] than in patients whose disease recurred [clinical evidence of disease (CED); n = 21; P < 0.01]. Applying AU ≥ 0.5 at a serum dilution of 1:20 as cutoff, 10 of 14 (71%) ovarian carcinoma patients with NED and 9 of 21 (43%) patients with CED had antibodies to mesothelin compared with 6 of 23 (26%) healthy women (P < 0.008) and 5 of 24 (21%) women with other benign gynecologic diseases (P < 0.003), whereas 7 of 9 (78%) of women with pelvic inflammatory disease were positive. Three of the 14 (21%) NED patients had circulating mesothelin detected as an AU ≥ 0.2 at a serum dilution of 1:40 (P < 0.005) compared with 15 of 21 (71%) CED patients, and 9 of 14 (64%) NED patients (P < 0.0002) were positive for antibodies and negative for antigen compared with 1 of 21 (5%) CED patients. Although our data indicate that an antibody response to mesothelin is an important correlate of ovarian carcinoma, prospective studies are needed to show whether the measurement of such antibodies (alone or together with antigen) aids the diagnosis and monitoring of patients. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1520–6)
Serum Concentrations of Insulin-Like Growth Factor and Insulin-Like Growth Factor Binding Protein 3 and Recurrent Colorectal Adenomas
Authors: Flood Andrew , Mai Volker , Pfeiffer Ruth , Kahle Lisa , Rosen Clifford J. , Lanza Elaine , Schatzkin Arthur
Published: June 2008

Insulin-like growth factor I (IGF-I) and its primary binding protein, IGFBP-3, have been associated with colorectal cancer incidence in prior epidemiologic studies. High concentrations of IGF-I generally result in increasing risk and high concentrations of IGFBP-3 in decreasing risk. Only one prior study of IGF-I and IGFBP-3 and adenoma recurrence has been reported. We assayed fasting serum from 375 subjects with and 375 subjects without a recurrent adenoma during the course of the Polyp Prevention Trial to determine baseline concentrations of IGF-I and IGFBP-3. To estimate relative risk of adenoma recurrence over the course of 4 years of follow-up for each of these serum measures, we calculated odds ratios (OR) and 95% confidence intervals (CI) using multivariable logistic regression models adjusting for age, gender, body mass index, intervention group, aspirin, smoking, ethnicity, and education. For both IGF-I and IGFBP-3, we found trends indicating decreased risk for subjects in the high compared with the low quartile (for IGF-I: OR, 0.65; 95% CI 0.41-1.01; for IGFBP-3: OR, 0.66; 95% CI, 0.42-1.05). The associations were even greater for advanced adenomas (for IGF-I: OR, 0.51; 95% CI, 0.21-1.29; for IGFBP-3: OR, 0.32; 95% CI, 0.13-0.82). These results showed an unexpected null association, or even the suggestion of a reduction in risk for recurrent adenoma, with not just high IGFBP-3 concentration but also with high levels of IGF-I. Why IGF-I would decrease risk of recurrent adenoma (as distinct from incident adenoma or colorectal cancer) is not clear. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1493–8)
Informed Consent for Biorepositories: Assessing Prospective Participants' Understanding and Opinions
Authors: Beskow Laura M. , Dean Elizabeth
Published: June 2008

Purpose: Obtaining informed consent for the collection, storage, and future research use of biospecimens is challenging, as potentially complex and controversial information must be communicated clearly. We gathered input on a consent template developed for the Duke Biorepository from individuals representative of those who might one day consider contributing specimens.

Methods: Forty subjects were recruited from the Durham, NC area and screened to achieve diversity by race/ethnicity, education, age, and sex. Cognitive interviews assessed participants' (a) understanding of information in the template, and (b) opinions about that information. Participants also completed a survey assessing trust in medical researchers.

Results: Interviewees seemed to understand the template. Although responses were diverse, majority views emerged: more than half were comfortable with indefinite biospecimen storage, periodic contact to update information and to inform participants of additional research opportunities, the prospect that commercial products could be developed, and the fact that profits would not be shared. More than half were willing to provide medical record access, although this was a primary concern for others. More than two thirds were comfortable with not receiving individual research results as a matter of routine, but many thought they should be informed of findings with serious health implications. Lack of trust in researchers was associated with declining certain consent options.

Conclusions: Protecting and promoting trust in research is essential to fostering widespread participation in biorepositories. Biorepositories should also devise ways to communicate clearly about the research being conducted and what is being learned.(Cancer Epidemiol Biomarkers Prev 2008;17(6)1440:–51)
Infant Feeding and the Incidence of Endometrial Cancer
Authors: Xue Fei , Hilakivi-Clarke Leena A. , Maxwell G. Larry , Hankinson Susan E. , Michels Karin B.
Published: June 2008

Biological mechanisms could support both an inverse and a direct association between exposure to breast milk in infancy and the risk of cancer. Having been breast-fed has been investigated in relation to the risk of breast and other cancer sites, and conflicting results have been reported. The association between infant feeding and the risk of endometrial cancer has not been explored. From 1976 to 2004, we followed 74,757 cancer-free participants in the Nurses' Health Study who had not undergone hysterectomy. Information on infant feeding was self-reported by study participants. A total of 708 incident cases of endometrial cancer were diagnosed during follow-up. After adjusting for age, family history of endometrial cancer, birth weight, premature birth, and birth order, the incidence of endometrial cancer was not associated with ever having been breast-fed (hazards ratio, 0.94; 95% confidence interval, 0.79-1.11) or duration of having been breast-fed [hazards ratio (95% confidence interval): 1.11 (0.80-1.54), 0.84 (0.62-1.13), 1.02 (0.79-1.31), respectively, for ≤3, 4-8, and ≥9 months of having been breastfed; P for trend = 0.88]. There was no significant effect modification by menopausal status, anthropometric factors (somatotype at age 5 or 10 years, body mass index at age 18 years, or current body mass index), or by other early-life exposures (birth weight, premature birth or exposure to parental smoking in childhood). Additional adjustment for adulthood risk factors of endometrial cancer did not materially change the results. Having been breast-fed was not associated with the incidence of endometrial cancer in this cohort, but statistical power for analyses restricted to premenopausal women was limited. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1316–21)
Association betweenGSTGenetic Polymorphism and Dose-Related Production of Urinary Benzene Metabolite Markers,trans, trans-Muconic Acid andS-Phenylmercapturic Acid
Authors: Lin Lung-Cheng , Chen Wan-Jou , Chiung Yin-Mei , Shih Tung-Sheng , Liao Pao-Chi
Published: June 2008

The urinary benzene metabolites, trans, trans-muconic acid (ttMA) and S-phenylmercapturic acid (SPMA), are widely used as benzene exposure biomarkers. The influence of the glutathione S-transferase (GST) genetic polymorphism on the excretion levels of urinary ttMA and/or SPMA has been investigated. The association between dose-related production of urinary benzene metabolites and benzene exposure level was also reported. However, the association between the dose-related productions of urinary benzene metabolites and GST genetic polymorphism was not described in the literature. The purpose of this study was to investigate the association between the GST genetic polymorphism and dose-related production of the two widely used biomarkers, urinary ttMA and SPMA. Seventy male workers in a chemical factory were measured for their benzene exposure levels and provided blood and urine specimens at the end of work-shift. The atmospheric benzene exposure levels of these workers were determined by passive samplers with gas chromatograph mass spectrometer. The urinary ttMA and SPMA levels were quantitated by an online dual-loop cleanup device with an electrospray ionization tandem mass spectrometer. The analyses of GST genotypes, including M1, T1, and P1, were done using PCR. Mean (± SD) of benzene exposure levels in participants was 7.2 ± 15 ppm. The ttMA and SPMA levels in the high benzene exposure group (≧1 ppm) were higher than those in the low benzene exposure group (<1 ppm; P < 0.001). Among the GST genotypes investigated in this study, the results showed that only the GSTT1 genotype was related to the level and dose-related production of SPMA. Using SPMA for evaluating benzene exposure, the results suggest that the GSTT1 genetic polymorphism, especially in a comparison study between two populations with different GSTT1 genotype frequencies, should be considered. Additionally, the biological exposure index value of SPMA should be set based on the levels of subjects with GSTT1-deficient genotypes for protection of all subjects.(Cancer Epidemiol Biomarkers Prev 2008;17(6):1460–9)
TheGc2Allele of the Vitamin D Binding Protein Is Associated with a Decreased Postmenopausal Breast Cancer Risk, Independent of the Vitamin D Status
Authors: Abbas Sascha , Linseisen Jakob , Slanger Tracy , Kropp Silke , Mutschelknauss Elke Jonny , Flesch-Janys Dieter , Chang-Claude Jenny
Published: June 2008

Vitamin D pathway gene polymorphisms may influence breast cancer risk by altering potential anticarcinogenic effects of vitamin D. The association between polymorphisms in the vitamin D binding protein (Gc) and postmenopausal breast cancer risk, with additional focus on the influence of serum 25-hydroxyvitamin D [25(OH)D], the biomarker for vitamin D status in humans, has not been examined thus far. We assessed the combined effects of two known functional polymorphisms in the Gc gene (rs4588 and rs7041), composing the phenotypic alleles Gc1s, Gc1f (combined: Gc1), and Gc2, on postmenopausal breast cancer risk and potential effect modification by 25(OH)D status in a population-based case-control study including 1,402 cases and 2,608 matched controls. Odds ratios (OR) for breast cancer risk adjusted for potential confounders were calculated for Gc genotypes. ANOVA was used to compare geometric means of serum 25(OH)D across Gc genotypes. Serum 25(OH)D concentrations in the control group significantly differed by Gc genotype, being lowest in Gc2 allele carriers. The geometric means of 25(OH)D were 53.0, 47.8, and 40.4 nmol/L for Gc1-1, Gc2-1, and Gc2-2 genotypes, respectively (Ptrend < 0.0001). Gc2-2 genotype was associated with a significantly decreased risk of postmenopausal breast cancer with an odds ratio (95% confidence interval) of 0.72 (0.54-0.96), compared with homozygote Gc1s allele carriers. No interaction between 25(OH)D status and Gc genotype was observed, nor did the association change considerably after adjustment for 25(OH)D status. Our results provide evidence for a serum 25(OH)D-independent effect of Gc2 allele carrier status in postmenopausal breast cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1339–43)
Stability of the Nicotine Metabolite Ratio inad Libitumand Reducing Smokers
Authors: Mooney Marc E. , Li Zhong-ze , Murphy Sharon E. , Pentel Paul R. , Le Chap , Hatsukami Dorothy K.
Published: June 2008

Background: The ratio of two nicotine metabolites, cotinine and trans-3′-hydroxycotinine (3-HC), has been validated as a method of phenotyping the activity of the liver enzyme cytochrome P450 (CYP) 2A6 and, thus, the rate of nicotine metabolism. Our objective was to evaluate the correlates and stability of the 3-HC to cotinine ratio in ad libitum and reducing smokers, using nicotine replacement therapy (NRT), over a period of months.

Methods: Smokers (n = 123, 94% Caucasian) participated in a smoking reduction study, where one-third of the sample smoked ad libitum for 8 weeks (Waitlist phase), before joining the rest of the participants for 12 weeks of cigarette reduction (Reduction phase) using NRT. Urinary nicotine, cotinine, and 3-HC were measured at each visit.

Results: The baseline 3-HC to cotinine ratio was significantly but weakly correlated with cigarettes per day (r = 0.19), BMI (r = −0.27), and waking at night to smoke (r = 0.23). As assessed by repeated measure ANOVA, the 3-HC to cotinine ratio was stable in the Waitlist phase [coefficient of variation for 3 to 4 measurements, 38% (range, 5-110%)], whereas minor variation was noted in the Reduction phase [coefficient of variation for 3-5 measurements, 35% (range, 10-107%)].

Conclusions: In nonreducing ad libitum smokers, the 3-HC to cotinine ratio was generally stable, whereas during smoking reduction using NRT, some small variation was detected. Although the current findings are suggestive of the stability of the 3-HC to cotinine ratio in a predominantly Caucasian sample smoking freely or reducing smoking with NRT, additional research is needed in more diverse populations. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1396–400)
Down-Regulation of Hedgehog-Interacting Protein through Genetic and Epigenetic Alterations in Human Hepatocellular Carcinoma
Authors: Tada Motohisa , Kanai Fumihiko , Tanaka Yasuo , Tateishi Keisuke , Ohta Miki , Asaoka Yoshinari , Seto Motoko , Muroyama Ryosuke , Fukai Kenichi , Imazeki Fumio , Kawabe Takao , Yokosuka Osamu , Omata Masao
Published: June 2008

Purpose: Hedgehog (Hh) signaling is activated in several cancers. However, the mechanisms of Hh signaling activation in hepatocellular carcinoma (HCC) have not been fully elucidated. We analyzed the involvement of Hh-interacting protein (HHIP) gene, a negative regulator of Hh signaling, in HCC.

Experimental Design: Glioma-associated oncogene homologue (Gli) reporter assay, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay, and quantitative real-time reverse transcription–PCR for the target genes of the Hh signals were performed in HHIP stably expressing hepatoma cells. Quantitative real-time PCR for HHIP was performed in hepatoma cells and 36 HCC tissues. The methylation status of hepatoma cells and HCC tissues was also analyzed by sodium bisulfite sequencing, demethylation assay, and quantitative real-time methylation-specific PCR. Loss of heterozygosity (LOH) analysis was also performed in HCC tissues.

Results: HHIP overexpression induced significant reductions of Gli reporter activity, cell viability, and transcription of the target genes of the Hh signals. HHIP was hypermethylated and transcriptionally down-regulated in a subset of hepatoma cells. Treatment with a demethylating agent led to the HHIP DNA demethylation and restoration of HHIP transcription. HHIP transcription was also down-regulated in the majority of HCC tissues, and more than half of HCC tissues exhibited HHIP hypermethylation. The HHIP transcription level in HHIP-methylated HCC tissues was significantly lower than in HHIP-unmethylated HCC tissues. More than 30% of HCC tissues showed LOH at the HHIP locus.

Conclusions: The down-regulation of HHIP transcription is due to DNA hypermethylation and/or LOH, and Hh signal activation through the inactivation of HHIP may be implicated in the pathogenesis of human HCC.
Increase in Brain Tumor Permeability in Glioma-Bearing Rats with Nitric Oxide Donors
Authors: Yin Dali , Wang Xiao , Konda Bindu M. , Ong John M. , Hu Jinwei , Sacapano Manuel R. , Ko MinHee K. , Espinoza Andres J. , Irvin Dwain K. , Shu Yan , Black Keith L.
Published: June 2008

Purpose: The blood-brain tumor barrier (BTB) significantly limits the delivery of chemotherapeutics to brain tumors. Nitric oxide (NO) is involved in the regulation of cerebral vascular permeability. We investigated the effects of NO donors, l-arginine and hydroxyurea, on BTB permeability in 9L gliosarcoma-bearing Fischer rats.

Experimental Design: The rats implanted with 9L gliosarcoma were dosed orally with hydroxyurea and l-arginine. BTB permeability, defined by the unidirectional transport constant, Ki, for [14C]sucrose was measured. The expression of neural and endothelial NO synthase (NOS) in tumors and normal brain tissue was examined. Further, the levels of NO, l-citrulline, and cGMP in the tumor and normal brain tissue were measured.

Results: Oral administration of l-arginine or hydroxyurea significantly increased BTB permeability when compared with the nontreated control. The selective effects were abolished by iberiotoxin, an antagonist of calcium-dependent potassium (KCa) channel that is a cGMP pathway effector. The expression of endothelial NOS, but not neural NOS, was higher in tumor vessels than in those of normal brain. Moreover, the levels of NO, l-citrulline, a byproduct of NO formation from l-arginine, and cGMP were enhanced in the tumor tissue by oral administration of l-arginine and/or hydroxyurea.

Conclusions: Oral administration of l-arginine or hydroxyurea selectively increased tumor permeability, which is likely mediated by alteration in cGMP levels. The findings suggest that use of oral NO donors may be a strategy to enhance the delivery of chemotherapeutics to malignant brain tumors.
Affibody Molecules for In vivo Characterization of HER2-Positive Tumors by Near-Infrared Imaging
Authors: Lee Sang Bong , Hassan Moinuddin , Fisher Robert , Chertov Oleg , Chernomordik Victor , Kramer-Marek Gabriela , Gandjbakhche Amir , Capala Jacek
Published: June 2008

Purpose: HER2 overexpression has been associated with a poor prognosis and resistance to therapy in breast cancer patients. We are developing molecular probes for in vivo quantitative imaging of HER2 receptors using near-infrared (NIR) optical imaging. The goal is to provide probes that will minimally interfere with the studied system, that is, whose binding does not interfere with the binding of the therapeutic agents and whose effect on the target cells is minimal.

Experimental Design: We used three different types of HER2-specific Affibody molecules [monomer ZHER2:342, dimer (ZHER2:477)2, and albumin-binding domain-fused-(ZHER2:342)2] as targeting agents and labeled them with Alexa Fluor dyes. Trastuzumab was also conjugated, using commercially available kits, as a standard control. The resulting conjugates were characterized in vitro by toxicity assays, Biacore affinity measurements, flow cytometry, and confocal microscopy. Semiquantitative in vivo NIR optical imaging studies were carried out using mice with s.c. xenografts of HER2-positive tumors.

Results: The HER2-specific Affibody molecules were not toxic to HER2-overexpressing cells and their binding to HER2 did interfere with neither binding nor effectives of trastuzumab. The binding affinities and specificities of the Affibody-Alexa Fluor fluorescent conjugates to HER2 were unchanged or minimally affected by the modifications. Pharmacokinetics and biodistribution studies showed the albumin-binding domain-fused-(ZHER2:342)2-Alexa Fluor 750 conjugate to be an optimal probe for optical imaging of HER2 in vivo.

Conclusion: Our results suggest that Affibody-Alexa Fluor conjugates may be used as a specific NIR probe for the noninvasive semiquantitative imaging of HER2 expression in vivo.