bluuebunny/crossref_metadata_2025 huggingface dataset:
A NEW FEASIBLE NATURAL LANGUAGE DATABASE QUERY METHOD
Authors: BOONJING VEERA , HSU CHENG
Published: March 2006

A metadata search approach is proposed to provide practical solutions to the natural language database query problem; where the metadata grow in largely linear manner and the search is linguistics-free. A new class of reference dictionary integrates four types of enterprise metadata: enterprise information models, database values, user-words, and query cases. The layered and scalable information models allow user-words to stay in original forms as users articulated them, as opposed to relying on permutations of individual words contained in the original query. A graphical representation method turns the dictionary into searchable graphs representing all possible interpretations of the input. A branch-and-bound algorithm then identifies optimal interpretations, which lead to SQL implementation of the original queries. Query cases enhance both the metadata and the search of metadata, as well as providing case-based reasoning to directly answer the queries. This design assures feasible solutions at the termination of the search, even when the search is incomplete (i.e., the results contain the correct answer to the original query). The necessary condition is that the text input contains at least one entry in the reference dictionary. The sufficient condition is that the text input contains a set of entries corresponding to a complete, correct single SQL query. Laboratory testing shows that the system obtained accurate results for most cases that satisfied only the necessary condition.
NATURAL KILLER CELL DEVELOPMENTAL PATHWAYS: A Question of Balance
Authors: Di Santo James P.
Published: March 2006

NK cells sit at the crossroads of innate and adaptive immunity and help coordinate tumor immunosurveillance and the immune response against pathogens. Balancing signals to NK cell precursors is crucial for their early development, when transcription factors compete to specify the different lymphocyte subsets. Despite an elaborate schema for NK cell development and differentiation, several major issues remain to be addressed, such as identifying the sites for NK cell maturation and defining the peripheral NK cell niche.
Vestibulo-Ocular Reflex to Transient Surge Translation: Complex Geometric Response Ablated by Normal Aging
Authors: Tian Jun-ru , Mokuno Eriko , Demer Joseph L.
Published: March 2006

The linear vestibulo-ocular reflex (LVOR) to surge (fore-aft) translation has complex kinematics varying with target eccentricity and distance. To determine normal responses and aging changes, 9 younger [age, 28 ± 2 (SE) yr] and 11 older subjects (age, 69 ± 2 yr) underwent 0.5 g whole body surge transients while wearing binocular scleral search coils. Linear chair position and head acceleration were measured with a potentiometer and accelerometer. Subjects viewed centered and 10° horizontally and vertically eccentric targets 50, 25, or 15 cm distant before unpredictable onset of randomly directed surge in darkness (LVOR) and light (V-LVOR). Response directions were kinematically appropriate to eccentricity in all subjects, but there were significantly more measurable LVOR and V-LVOR responses (63–79%) in younger than older subjects (38–44%, P < 0.01). Minimal LVOR latency averaged 48 ± 4 ms for younger and significantly longer at 70 ± 6 ms for older subjects. In the interval 200–300 ms after surge onset, horizontal LVOR gain (relative to ideal velocity) of younger subjects averaged over all target distances was 0.55 ± 0.04 and was significantly reduced in older subjects to 0.33 ± 0.04. Horizontal V-LVOR gain was 0.58 ± 0.04 in younger and significantly lower at 0.35 ± 0.06 in older subjects. Vertical gains did not differ significantly between groups. Target visibility had no effect in either group during the initial 200 ms. The LVOR and V-LVOR were augmented by saccades in younger more than older subjects. Aging thus decreases LVOR velocity gain, response rate, and saccade augmentation, but prolongs latency.
Modeling Lung Cancer Risk in Case-Control Studies Using a New Dose Metric of Smoking
Authors: Thurston Sally W. , Liu Geoffrey , Miller David P. , Christiani David C.
Published: March 2006

Many approaches have been taken to adjust for smoking in modeling cancer risk. In case-control studies, these metrics are often used arbitrarily rather than being based on the properties of the metric in the context of the study. Depending on the underlying study design, hypotheses, and base population, different metrics may be deemed most appropriate. We present our approach to evaluating different smoking metrics. We examine the properties of a new metric, “logcig-years”, that we initially derived from using a biological model of DNA adduct formation. We compare this metric to three other smoking metrics, namely pack-years, square-root pack-years, and a model in which smoking duration and intensity are separate variables. Our comparisons use generalized additive models and logistic regression to examine the relationship between the logit probability of cancer and each of the metrics, adjusting for other covariates. All models were fit using data from a lung cancer study of 1,275 cases and 1,269 controls that has focused on gene-smoking relationships. There was a very significant, linear relationship between logcig-years and the logit probability of lung cancer in this sample, without any need to adjust for smoking status. These properties together were not shared by the other metrics. In this sample, logcig-years captured more information about smoking that is important in lung cancer risk than the other metrics. In conclusion, we provide a general framework for evaluating different smoking metrics in studies where smoking is a critical variable.
Genetic Variation in the Growth Hormone Synthesis Pathway in Relation to Circulating Insulin-Like Growth Factor-I, Insulin-Like Growth Factor Binding Protein-3, and Breast Cancer Risk: Results from the European Prospective Investigation into Cancer and Nutrition Study
Authors: Canzian Federico , McKay James D. , Cleveland Rebecca J. , Dossus Laure , Biessy Carine , Boillot Catherine , Rinaldi Sabina , Llewellyn Midge , Chajès Véronique , Clavel-Chapelon Françoise , Téhard Bertrand , Chang-Claude Jenny , Linseisen Jakob , Lahmann Petra H. , Pischon Tobias , Trichopoulos Dimitrios , Trichopoulou Antonia , Zilis Dimosthenes , Palli Domenico , Tumino Rosario , Vineis Paolo , Berrino Franco , Bueno-de-Mesquita H. Bas , van Gils Carla H. , Peeters Petra H.M. , Pera Guillem , Barricarte Aurelio , Chirlaque María-Dolores , Quirós J. Ramon , Larrañaga Nerea , Martínez-García Carmen , Allen Naomi E. , Key Timothy J. , Bingham Sheila A. , Khaw Kay-Tee , Slimani Nadia , Norat Teresa , Riboli Elio , Kaaks Rudolf
Published: March 2006

Insulin-like growth factor-I (IGF-I) stimulates cell proliferation and can enhance the development of tumors in different organs. Epidemiologic studies have shown that an elevated level of circulating IGF-I is associated to increased risk of breast cancer as well as other cancers. Genetic variants affecting the release or biological action of growth hormone (GH), the main stimulator of IGF-I production, may predict circulating levels of IGF-I and have an effect on cancer risk. We tested this hypothesis with a large case-control study of 807 breast cancer patients and 1,588 matched control subjects nested within the European Prospective Investigation into Cancer and Nutrition. We genotyped 22 common single nucleotide polymorphisms in 10 genes involved in GH production and action (GHRH, GHRHR, SST, SSTR1-SSTR5, POU1F1, and GH1), and in parallel, we measured serum levels of IGF-I and IGFBP-3, its major binding protein, in samples of cases and controls. SST and SSTR2 polymorphisms showed weak but statistically significant associations with breast cancer risk. SSTR5 polymorphisms were associated with IGF-I levels, whereas one polymorphism in GHRHR and one in POU1F1 were associated with IGFBP-3 levels. Our conclusion is that common genetic variation in the GH synthesis pathway, as measured by single nucleotide polymorphisms selected in the present study, is not a major determinant of IGF-I and IGFBP-3 circulating levels, and it does not play a major role in altering breast cancer risk.
Role of Lipid Peroxidation in the Epidemiology and Prevention of Breast Cancer
Authors: Gago-Dominguez Manuela , Castelao J. Esteban , Pike Malcolm C. , Sevanian Alex , Haile Robert W.
Published: March 2006

We have recently proposed a common mechanistic pathway by which obesity and hypertension lead to increased renal cell cancer risk. Our hypothesis posits lipid peroxidation, which is a principal mechanism in rodent renal carcinogenesis, as an intermediate step that leads to a final common pathway shared by numerous observed risks (including obesity, hypertension, smoking, oophorectomy/hysterectomy, parity, preeclampsia, diabetes, and analgesics) or protective factors (including oral contraceptive use and alcohol) for renal cell cancer [Cancer Causes Control 2002;13:287–93]. During this exercise, we have noticed how certain risk factors for renal cell carcinoma are protective for breast cancer and how certain protective factors for renal cell carcinoma increase risk for breast cancer. Parity and oophorectomy, for example, are positively associated with renal cell carcinoma but are negatively associated with breast cancer. Similarly, obesity and hypertension are positively associated with renal cell carcinoma, but obesity is negatively associated with breast cancer in premenopausal women and hypertension during pregnancy is negatively associated with breast cancer. Furthermore, alcohol intake, negatively associated with renal cell carcinoma, is also positively associated with breast cancer. We propose here the possibility that lipid peroxidation may represent a protective mechanism in breast cancer. Although this runs counter to the conventional view that lipid peroxidation is a process that is harmful and carcinogenic, we present here the chemical and biological rationale, based on epidemiologic and biochemical data, which may deserve further consideration and investigation. (Cancer Epidemiol Biomarkers Prev 2005;14(12):2829–39)
Prostate Cancer Screening Behavior in Men from Seven Ethnic Groups: the Fear Factor
Authors: Consedine Nathan S. , Morgenstern Amy H. , Kudadjie-Gyamfi Elizabeth , Magai Carol , Neugut Alfred I.
Published: March 2006

Rates of prostate cancer screening are known to vary among the major ethnic groups. However, likely variations in screening behavior among ethnic subpopulations and the likely role of psychological characteristics remain understudied. We examined differences in prostate cancer screening among samples of 44 men from each of seven ethnic groups (N = 308; U.S.-born European Americans, U.S.-born African Americans, men from the English-speaking Caribbean, Haitians, Dominicans, Puerto Ricans, and Eastern Europeans) and the associations among trait fear, emotion regulatory characteristics, and screening. As expected, there were differences in the frequency of both digital rectal exam (DRE) and prostate-specific antigen (PSA) tests among the groups, even when demographic factors and access were controlled. Haitian men reported fewer DRE and PSA tests than either U.S.-born European American or Dominican men, and immigrant Eastern European men reported fewer tests than U.S.-born European Americans; consistent with prior research, U.S.-born African Americans differed from U.S.-born European Americans for DRE but not PSA frequency. Second, the addition of trait fear significantly improved model fit, as did the inclusion of a quadratic, inverted U, trait fear term, even where demographics, access, and ethnicity were controlled. Trait fear did not interact with ethnicity, suggesting its effect may operate equally across groups, and adding patterns of information processing and emotion regulation to the model did not improve model fit. Overall, our data suggest that fear is among the key psychological determinants of male screening behavior and would be usefully considered in models designed to increase male screening frequency. (Cancer Epidemiol Biomarkers Prev 2006;15(2):228–37)
Dietary Patterns and Risk of Prostate Cancer in U.S. Men
Authors: Wu Kana , Hu Frank B. , Willett Walter C. , Giovannucci Edward
Published: March 2006

We prospectively investigated the associations between dietary patterns and risk of prostate cancer in the Health Professionals Follow-up Study. Between 1986 and 2000, 3,002 incident prostate cancer cases were identified in our cohort. Using factor analysis, two major dietary patterns were identified, a prudent and a western dietary pattern. Dietary patterns were not appreciably associated with risk of total prostate cancer. For the highest versus the lowest quintiles, the multivariable relative risk (RR) for the prudent pattern was 0.94 [95% confidence interval (CI), 0.83-1.06], and for the western pattern, the multivariable RR was 1.03 (95% CI, 0.92-1.17). Neither were these associated with risk of advanced prostate cancer [highest versus lowest quintile, prudent pattern (RR, 1.01; 95% CI, 0.68-1.49); western pattern (RR, 1.13; 95% CI, 0.77-1.67)]. Higher western pattern scores were suggestively associated with a greater risk of advanced prostate cancer among older men [highest versus lowest quintile (RR, 1.35; 95% CI, 0.97-1.90)], but not after adding processed meat to the model [highest versus lowest quintile (RR, 1.11; 95% CI, 0.75-1.65)]. We did not find any evidence for a protective association between prudent pattern and risk of prostate cancer. The lack of association between a western dietary pattern as identified by factor analysis in our cohort and prostate cancer risk suggests that dietary risk factors for prostate cancer are likely to differ from those for other conditions, such as cardiovascular disease and type 2 diabetes, that have been associated with a western dietary pattern in this cohort. (Cancer Epidemiol Biomarkers Prev 2006;15(1):167–71)
Associations of Mammographic Density with Dietary Factors in Japanese Women
Authors: Nagata Chisato , Matsubara Tomoko , Fujita Hiroshi , Nagao Yasuko , Shibuya Chiken , Kashiki Yoshitomo , Shimizu Hiroyuki
Published: March 2006

Background: A high percentage of mammographic dense area has been strongly associated with a risk of beast cancer. The present cross-sectional study evaluated the relations of percent density with dietary factors, such as fats, protein, dietary fiber, and soy isoflavones.

Methods: Study subjects were 601 (348 premenopausal and 253 postmenopausal) Japanese women who were recruited from a mammographic screening center. The size of the total breast area and the dense area were measured quantitatively using an automated mammographic mass detection method. Intakes of nutrients were estimated with a validated semiquantitative food-frequency questionnaire.

Results: The crude means of the percent density were 39.2% and 18.9% in premenopausal and postmenopausal women, respectively. There were no significant associations of any dietary factors with the percent density in premenopausal women. In postmenopausal women, percent density was significantly positively associated with intakes of protein, total fat, and saturated fat after controlling for covariates; the increase in the means of percent density were 7.2%, 5.6%, and 9.2% in the highest versus lowest quartile of intakes for protein, total fat, and saturated fat, respectively (P for linear trend were 0.006, 0.04, and 0.01, respectively). Carbohydrate intake was inversely associated with percent density; the mean of percent density was 6.0% lower in the highest versus the lowest quartile of intake (Ptrend = 0.03). The associations of dietary factors with dense area were very similar to those with percent density.

Conclusion: These dietary factors may have implications for the risk of breast cancer in postmenopausal women. (Cancer Epidemiol Biomarkers Prev 2005;14(12):2877–80)
Body Mass Index and Serum 1,1,1-Trichloro-2,2-Bis(p-Chlorophenyl)Ethane in Nulliparous Chinese Women
Authors: Perry Melissa J. , Ouyang Fengxiu , Korrick Susan , Venners Scott A. , Altshul Larisa , Xu Xiping , Wang Xiaobin
Published: March 2006

Background: Basic health indicators, such as body mass index (BMI), have been associated with serum 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane/1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDT/DDE) levels; however, both positive and inverse associations of BMI with serum DDT/DDE have been reported. Given the association of BMI with a number of outcomes, it may confound studies of DDT/DDE-associated health effects. We investigated the relationship of BMI with serum DDT/DDE accounting for other determinants of exposure among women with relatively recent environmental exposures to DDT.

Methods: Serum DDT/DDE was analyzed in 466 nonsmoking, nulliparous women recruited from Anhui province in China between 1996 and 1998 as part of a reproductive health study of textile workers. The women in the sample were born between 1963 and 1977, 8 to 21 years before China's 1984 DDT ban. We used multivariate linear regression to investigate associations of BMI, age, and birth year with serum DDT/DDE.

Results: Mean (SD) serum total DDT concentration was 32 ng/g (17.8 ng/g). Birth year showed an inverse relationship with serum DDT independent of age. Despite limited variability in BMI, there was a consistent inverse relationship between BMI and serum DDT. Specifically, each kg/m2 increase in BMI was associated with a −1.34 ng/g (95% confidence interval, −2.12 to −0.56 ng/g) decrease in serum total DDT.

Conclusions: There were high total DDT levels in this sample of nulliparous Chinese women relative to Western populations, birth year was more strongly associated with serum DDT than age, and BMI was inversely related to serum DDT in this study.
A Randomized Trial of an Intervention to Increase Fruit and Vegetable Intake in Curatively Treated Patients with Early-Stage Head and Neck Cancer
Authors: Cartmel Brenda , Bowen Deborah , Ross Douglas , Johnson Elizabeth , Mayne Susan T.
Published: March 2006

The leading cause of death in patients who have had curatively treated early-stage head and neck cancer is a second primary cancer of the upper aerodigestive tract (lung, esophagus, larynx, pharynx, and oral cavity cancers). Low fruit and vegetable intake has been associated with increased risk of primary head and neck cancer and the available data suggest that increasing intake following diagnosis may reduce the risk of a second primary cancer. The goal of this study was to develop and test an easily administered intervention to increase fruit and vegetable intake in these patients following diagnosis and treatment. The 6-month intervention was based on the Stage of Change model. Seventy-five early-stage head and neck cancer patients were randomized to either the intervention group or to the “blinded” control group, with diet change data available on 65 patients. Fruit and vegetable intake, assessed using a food frequency questionnaire, and plasma carotenoid concentrations were measured at baseline and at the end of the study period. The change in self-reported intake of fruit and vegetables (servings per day) over the study period was significantly greater (P = 0.009) in the intervention group (n = 35; +2.1) compared with the control group (n = 30; +0.5). Total plasma carotenoids, a biomarker of fruit and vegetable intake, increased by 70 nmol/L in the intervention group as compared with a reduction of 42 nmol/L in the control group, a relative difference of 12% (nonsignificant). An intervention that can be delivered in a physician's office resulted in a significant increase in intake of fruit and vegetables in early-stage head and neck cancer patients. (Cancer Epidemiol Biomarkers Prev 2005;14(12):2848-54)
Cutting Cost and Increasing Access to Colorectal Cancer Screening: Another Approach to Following the Guidelines
Authors: Fisher Judith A. , Fikry Christopher , Troxel Andrea B.
Published: March 2006

Context: Through medical decision making, physicians in the U.S. influence the spending of >$1.3 trillion or 15% of the gross domestic product. U.S. physicians are challenged to identify areas of clinical practice to improve while cutting cost and increasing access. Primary screening for colorectal cancer is a good example to illustrate this point.

Objective: To apply a population-based method of medical decision making in the area of primary screening for colorectal cancer in order to illustrate a reduction in health care costs while increasing access and maintaining quality of care.

Design: We used a combination of (a) census population data, (b) National Cancer Institute Survey data on screening rates, and (c) charge data to estimate the current costs of colorectal cancer screening. We also estimated cost and capacity increases that would occur under various other screening scenarios. These included all currently screened subjects receiving annual fecal occult blood testing (FOBT), all currently unscreened individuals undergoing either colonoscopy every decade or annual FOBT, and all eligible subjects undergoing annual FOBT.

Main outcome measures: Cost and access differences between current screening activity and other potential scenarios compliant with guidelines.

Results: Screening for colorectal cancer with yearly, six-window, rehydrated FOBT for all normal-risk individuals over the age of 50 has the potential to screen 3,813,095 more Americans for colon cancer yearly than are currently being screened, while costing $8.7 billion less per decade than what is currently being spent on screening a fraction of the population. Looking into the future, it is possible to increase screening rates from 50% to 100%, while saving almost $10 billion per decade by using FOBT for all eligible Americans. In practice, some proportion of these benefits would be realized as the calculations assume a 100% patient compliance rate.

Conclusions: Considering a population-based approach and the balance among quality, accessibility, and cost parameters, we recommend primary screening for colorectal cancer to be based on yearly six-window, rehydrated FOBT. Colonoscopy due to cost and access issues should be relegated to secondary screening and case finding. (Cancer Epidemiol Biomarkers Prev 2006;15(1):108–13)
Factorial Validity and Invariance of a Survey Measuring Psychosocial Correlates of Colorectal Cancer Screening among African Americans and Caucasians
Authors: Tiro Jasmin A. , Vernon Sally W. , Hyslop Terry , Myers Ronald E.
Published: March 2006

Background: Psychosocial constructs are widely used to predict colorectal cancer screening and are targeted as intermediate outcomes in behavioral intervention studies. Reliable and valid instruments for measuring general colorectal cancer screening psychosocial constructs are needed; yet, few studies have conducted psychometric analyses. This study replicated a five-factor structure for 16 theory-based, general colorectal cancer screening items measuring salience and coherence, cancer worries, perceived susceptibility, response efficacy, and social influence. In addition, we examined factorial invariance across race and sex.

Methods: African American and Caucasian patients (n = 1,413) attending an urban, primary care clinic were included in this study. These individuals completed a baseline survey as part of a colorectal cancer screening intervention trial. Single and multigroup confirmatory factor analyses using maximum-likelihood estimation were done.

Results: The five-factor general colorectal cancer screening model provided excellent fit and was invariant across race-sex subgroups.

Conclusions: The findings of invariance across sex and race subgroups support the use of these scales to measure group differences. (Cancer Epidemiol Biomarkers Prev 2005;14(12):2855-61)
Smoking, The Missing Drug Interaction in Clinical Trials: Ignoring the Obvious
Authors: Gritz Ellen R. , Dresler Carolyn , Sarna Linda
Published: March 2006

Tobacco use is universally recognized as the foremost preventable cause of cancer in the United States and globally and is responsible for 30% of all cancer-related deaths in the United States. Tobacco use, including exposure to secondhand smoke has been implicated as a causal or contributory agent in an ever-expanding list of cancers, including lung, oral cavity and pharynx, pancreas, liver, kidney, ureter, urinary bladder, uterine cervix, and myeloid leukemia. In addition to and independent of the etiologic effects of tobacco carcinogens in numerous cancers, there is a growing literature on the direct and indirect effects of smoking on treatment efficacy (short-term and long-term outcomes), toxicity and morbidity, quality of life (QOL), recurrence, second primary tumors (SPT), and survival time as summarized below. Oncology health professionals have called for increased advocacy for tobacco control. Despite the critical relevance of smoking to cancer outcomes, most oncology clinical trials do not collect data on smoking history and status unless the malignancy is widely acknowledged as smoking related (e.g., lung or head and neck cancer). Usually, these data are collected only at trial registration. Changes in smoking status during treatment or follow-up are monitored in very few trials and are infrequently reported in sample descriptions or included in analysis plans as a potential moderator of outcomes. Based on mounting evidence that tobacco use affects cancer treatment outcomes and survival, we recommend that smoking history and status be systematically collected as core data in all oncology clinical trials: at diagnosis, at trial registration, and throughout treatment and follow-up to long-term survival or death. We feel that the inclusion and analysis of such data in clinical trials will add important information to the interpretation of outcomes and the development of scientific knowledge in this area. Smoking status has been called another “vital sign” because of its relevance to a patient's immediate medical condition. We explain the critical value of knowing the smoking status of every patient with cancer at every visit by providing a brief overview of the following research findings: (a) the effects of tobacco use on cancer treatment and outcome; (b) recent findings on the role of nicotine in malignant processes; (c) some unexpected results concerning tobacco status, treatment, and disease outcome; and (d) identifying key questions that remain to be addressed. We provide a suggested set of items for inclusion in clinical trial data sets that also are useful in clinical practice.
Association of Polymorphisms in ERCC2 Gene with Non-Familial Thyroid Cancer Risk
Authors: Silva Susana N. , Gil Octávia Monteiro , Oliveira Vanessa C. , Cabral Marisa N. , Azevedo Ana Paula , Faber Ana , Manita Isabel , Ferreira Teresa Cruz , Limbert Edward , Pina Julieta Esperança , Rueff José , Gaspar Jorge
Published: March 2006

The ERCC2 protein is an evolutionary conserved ATP-dependent helicase that is associated with a TFIIH transcription factor complex and plays an important role in nucleotide excision repair. Mutations in this gene are responsible for xeroderma pigmentosum and also for Cocayne syndrome and trichothiodystrophy. Several single nucleotide polymorphisms have been identified in the ERCC2 locus. Among them, a G23591A polymorphism in the codon 312 results in an Asp → Asn substitution in a conserved region and a A35931C polymorphism in the codon 751 results in a Lys → Gln substitution. Because these polymorphisms have been associated with an increased risk for several types of cancers, we carried out an hospital based case-control study in a Caucasian Portuguese population to evaluate the potential role of these polymorphisms on the individual susceptibility to thyroid cancer. The results obtained did not reveal a significant association between each individual polymorphism studied (G23591A and A35931C) and an increased thyroid cancer risk, but individuals homozygous for non-wild-type variants are overrepresented in patients group. The evaluation of the different haplotypes generated by these polymorphisms showed that individuals simultaneously homozygous for rare variants of both polymorphisms have an increased risk for thyroid cancer [adjusted odds ratio (OR) 3.084; 95% confidence interval (95% CI), 1.347-7.061; P = 0.008] and for papillary thyroid–type tumors (adjusted OR, 2.997; 95% CI, 1.235-7.272; P = 0.015) but not for follicular thyroid–type tumors. These results suggest that genetic polymorphisms in this gene might be associated with individual susceptibility towards thyroid cancer, mainly papillary-type tumors, but larger studies are required to confirm these results.
Association between Quantitative High-Risk Human Papillomavirus DNA Load and Cervical Intraepithelial Neoplasm Risk
Authors: Tsai Hsiu-Ting , Wu Ching-Hu , Lai Hsiao-Ling , Li Ruei-Nian , Tung Yi-Ching , Chuang Hung-Yi , Wu Trong-Neng , Lin Li-Jen , Ho Chi-Kung , Liu Hon-Wein , Wu Ming-Tsang
Published: March 2006

Human papillomavirus (HPV) infection is a high-risk factor for cervical intraepithelial neoplasm (CIN) but the association between the quantitative HPV DNA load and the severity of CIN remains controversial. We conducted a community study to investigate the correlation between the two. Potential study subjects were selected through Pap smear screening in Kaohsiung County, Taiwan. Ninety-one subjects with either their first case of inflammation or ≥CIN1 by biopsy confirmation were assigned to a case group; 175 normal subjects with negative findings by Pap smears or biopsies were assigned to a control group. Cervical HPV load was detected with Hybrid Capture II assay for high-risk HPV infection, with nested PCR for high- and low-risk HPV infection, and with type-specific PCR for HPV type 16 (HPV-16). Individuals with positive high-risk HPV infection had an increased risk of developing CIN. Compared with HPV-negative subjects, the odds ratios were 32.2 [95% confidence interval (95% CI), 10.4-99.5] for subjects with CIN1, 37.2 (95% CI, 7.4-187.6) for subjects with CIN2, and 68.3 (95% CI, 14.1-328.5) for subjects with ≥CIN3 after adjusting for other confounding factors. The similar trend was also found among the HPV-16–negative individuals. In addition, high-risk HPV DNA load levels were highly correlated with the different grades of CINs in the overall population (Spearman's correlation coefficient r = 0.67, P < 0.0001, n = 266) and the HPV-16–negative population (Spearman's correlation coefficient r = 0.58, P < 0.0001, n = 234). We concluded that high-risk HPV infection, irrespective of HPV-16 infection, was highly and positively associated with the development of CIN.
Genetic Mechanisms of TP53 Loss of Heterozygosity in Barrett's Esophagus: Implications for Biomarker Validation
Authors: Wongsurawat V. Jon , Finley Jennifer C. , Galipeau Patricia C. , Sanchez Carissa A. , Maley Carlo C. , Li Xiaohong , Blount Patricia L. , Odze Robert D. , Rabinovitch Peter S. , Reid Brian J.
Published: March 2006

Background and Aims: 17p (TP53) loss of heterozygosity (LOH) has been reported to be predictive of progression from Barrett's esophagus to esophageal adenocarcinoma, but the mechanism by which TP53 LOH develops is unknown. It could be (a) DNA deletion, (b) LOH without copy number change, or (c) tetraploidy followed by genetic loss. If an alternative biomarker assay, such as fluorescence in situ hybridization (FISH), provided equivalent results, then translation to the clinic might be accelerated, because LOH genotyping is presently limited to research centers.

Methods: We evaluated mechanisms of TP53 LOH to determine if FISH and TP53 LOH provided equivalent results on the same flow-sorted samples (n = 43) representing established stages of clonal progression (diploid, diploid with TP53 LOH, aneuploid) in 19 esophagectomy specimens.

Results: LOH developed by all three mechanisms: 32% had DNA deletions, 32% had no copy number change, and 37% had FISH patterns consistent with a tetraploid intermediate followed by genetic loss. Thus, FISH and LOH are not equivalent (P < 0.000001).

Conclusions: LOH develops by multiple chromosome mechanisms in Barrett's esophagus, all of which can be detected by genotyping. FISH cannot detect LOH without copy number change, and dual-probe FISH is required to detect the complex genetic changes associated with a tetraploid intermediate. Alternative biomarker assay development should be guided by appreciation and evaluation of the biological mechanisms generating the biomarker abnormality to detect potential sources of discordance. FISH will require validation in adequately powered longitudinal studies before implementation as a clinical diagnostic for esophageal adenocarcinoma risk prediction. (Cancer Epidemiol Biomarkers Prev 2006;15(3):509–16)
Preventive Health Behaviors and Familial Breast Cancer
Authors: Madlensky Lisa , Vierkant Robert A. , Vachon Celine M. , Pankratz V. Shane , Cerhan James R. , Vadaparampil Susan Thomas , Sellers Thomas A.
Published: March 2006

Aim: To examine medical and lifestyle preventive behaviors among women with varying levels of familial breast cancer risk.

Methods: Using cross-sectional data from the Minnesota Breast Cancer Family Study, a historical cohort of 426 families, we compared medical (mammography adherence, antiestrogen use, and prophylactic surgery) and lifestyle (physical activity, smoking, alcohol, and diet) behaviors across three groups of cancer-free women ages 18 to 95 defined by their family history of breast cancer. Family history was classified as high-risk, moderate-risk, or average to low-risk depending on the number and degree of relationship of family members with breast cancer.

Results: After adjusting for age and education, high-risk women were twice as likely to have ever used an antiestrogenic agent (9.0% versus 4.6% among moderate-risk and 4.1% among average to low-risk; P = 0.002). Among women ages <40, the high-risk group were more likely to have ever had a mammogram (82% versus 47% among moderate-risk and 35% among average to low-risk; P < 0.001). Average to low-risk women were the least likely to be current smokers and high-risk women may consume slightly fewer fruits and vegetables compared with the other groups, but there were no other differences in lifestyle behaviors, including physical activity and alcohol use.

Conclusions: Women with strong family histories of breast cancer are more likely to undertake medical but not lifestyle preventive behaviors.
Polymorphisms in the Reduced Folate Carrier, Thymidylate Synthase, or Methionine Synthase and Risk of Colon Cancer
Authors: Ulrich Cornelia M. , Curtin Karen , Potter John D. , Bigler Jeannette , Caan Bette , Slattery Martha L.
Published: March 2006

Folate metabolism supports the synthesis of nucleotides as well as the transfer of methyl groups. Polymorphisms in folate-metabolizing enzymes have been shown to affect risk of colorectal neoplasia and other malignancies. Using data from a population-based incident case-control study (1,600 cases and 1,962 controls), we investigated associations between genetic variants in the reduced folate carrier (RFC), thymidylate synthase (TS), methionine synthase (MTR), and 5,10-methylenetetrahydrofolate reductase (MTHFR) and colon cancer risk. The TS enhancer region (TSER) variant was associated with a reduced risk among men [2rpt/2rpt versus 3rpt/3rpt wild-type; odds ratio (OR), 0.7; 95% confidence interval, 0.6-0.98] but not women. When combined genotypes for both TS polymorphisms (TSER and 3′-untranslated region 1494delTTAAAG) were evaluated, ORs for variant genotypes were generally below 1.0, with statistically significantly reduced risks among women. Neither MTR D919G nor RFC 80G>A polymorphisms were associated with altered colon cancer risk. Because folate metabolism is characterized by interrelated reactions, we evaluated gene-gene interactions. Genotypes resulting in reduced MTHFR activity in conjunction with low TS expression were associated with a reduced risk of colon cancer. When dietary intakes were taken into account, individuals with at least one variant TSER allele (3rpt/2rpt or 2rpt/2rpt) were at reduced risk in the presence of a low folate intake. This study supports findings from adenoma studies indicating that purine synthesis may be a relevant biological mechanism linking folate metabolism to colon cancer risk. A pathway-based approach to data analysis is needed to help discern the independent and combined effects of dietary intakes and genetic variability in folate metabolism.
DNA Repair Polymorphisms and Risk of Colorectal Adenomatous or Hyperplastic Polyps
Authors: Bigler Jeannette , Ulrich Cornelia M. , Kawashima Toana , Whitton John , Potter John D.
Published: March 2006

Genetic variability in DNA repair genes may contribute to differences in DNA repair capacity and susceptibility to cancer, especially in the presence of exposures such as smoking. In a Minnesota-based case-control study of cases with only adenomatous polyps (n = 384), only hyperplastic polyps (n = 191), or both types of polyps (n = 119) versus polyp-free controls (n = 601), we investigated the role of polymorphisms in the DNA repair genes O6-methylguanine methyltransferase (MGMT; p.L84F and p.I143V), XPD (p.D312N and p.K751Q), and XPG (p.D1104H). MGMT polymorphisms were not associated with polyp risk. Overall, a homozygous variant XPD–combined genotype was associated with an increased risk of adenomatous polyps [odds ratio (OR), 1.57; 95% confidence interval (95% CI), 1.04-2.38] and an XPGHH1104 genotype with a decreased risk of hyperplastic polyps (OR, 0.36; 95% CI, 0.13-0.98). However, age stratification showed that the XPD association was present only in subjects ≥60 years old (OR, 3.77; 95% CI, 1.94-7.35), whereas the XPG association was observed largely in subjects <60 years old (OR, 0.20; 95% CI, 0.05-0.91). Smokers did not have a significantly increased risk of adenomatous polyps in the absence of synchronous hyperplastic polyps, except for subjects with a homozygous variant XPD genotype or a homozygous wild-type XPG genotype (OR, 3.93; 95% CI, 1.68-9.21 and OR, 1.59; 95% CI, 1.01-2.50, respectively). Smoking was associated with a statistically significant 2.5- to 6-fold increased risk of hyperplastic polyps for individuals with most of the DNA repair genotypes. However, no substantial increase was observed among individuals who were homozygous variant for XPG (1104HH; OR, 1.38; 95% CI, 0.25-7.65). Our data suggest that polymorphisms in DNA repair genes may be risk factors for colorectal neoplasia and that they may exacerbate the effects of exposures to carcinogens.
Associations Between Polymorphisms in the Vitamin D Receptor and Breast Cancer Risk
Authors: Chen Wendy Y. , Bertone-Johnson Elizabeth R. , Hunter David J. , Willett Walter C. , Hankinson Susan E.
Published: March 2006

Biological and epidemiologic data suggest that vitamin D levels may influence breast cancer development. The vitamin D receptor (VDR) is a crucial mediator for the cellular effects of vitamin D and additionally interacts with other cell-signaling pathways that influence cancer development. Because functional data exist on FOK1 and previous studies have suggested a relation between BSM1 and breast cancer risk, we evaluated the associations of the FOK1 and BSM1 VDR polymorphisms and breast cancer risk. In a case-control study nested within the Nurses' Health Study, we genotyped 1,234 incident cases (diagnosed between return of a blood sample in 1989-1990 and June 1, 2000) and 1,676 controls for FOK1, and 1,180 cases and 1,547 controls for BSM1. We observed a significantly increased risk of breast cancer among carriers of the ff genotype of FOK1 (multivariate odds ratio, 1.34; 95% confidence intervals, 1.06-1.69) compared with those with FF. We did not observe an association between polymorphisms in BSM1 and breast cancer risk (multivariate odds ratio, 0.93; 95% confidence intervals, 0.72-1.20) for BB versus bb). The FOK1 association did not vary significantly by menopausal status, estrogen, and progesterone receptor status of the tumors, or plasma levels of 25 hydroxyvitamin D or 1,25 dihydroxyvitamin D. Our results suggest that the VDR may be a mediator of breast cancer risk and could represent a target for cancer prevention efforts.
Genetic Polymorphisms of Flavin Monooxygenase 3 in Sulindac-Induced Regression of Colorectal Adenomas in Familial Adenomatous Polyposis
Authors: Hisamuddin Irfan M. , Wehbi Mohammad A. , Schmotzer Brian , Easley Kirk A. , Hylind Linda M. , Giardiello Francis M. , Yang Vincent W.
Published: March 2006

Sulindac is a nonsteroidal antiinflammatory drug with a chemopreventive effect in patients with familial adenomatous polyposis (FAP). In vivo, the active form of sulindac is sulindac sulfide, which is inactivated by the hepatic microsomal enzyme, flavin monooxygenase 3 (FMO3). In humans, numerous polymorphisms exist in FMO3, which alter enzymatic activity and subsequent substrate metabolism. We recently showed that certain polymorphic forms of FMO3 with reduced activity were associated with a more favorable response to sulindac in preventing the formation of adenomas in patients with FAP without polyps at baseline. Here, we determined whether these FMO3 polymorphisms correlated with the ability of sulindac to regress polyposis in patients with FAP who had polyps prior to treatment. Nineteen patients were treated with 150 mg sulindac twice a day for 6 months. The size and number of polyps in each patient was assessed at baseline (prior to the administration of sulindac), and at 3 and 6 months. Genotyping was done on seven established FMO3 polymorphisms with functional significance—M66I, E158K, P153L, V257M, E305X, E308G, and R492W. Statistical analyses were done with Wilcoxon rank sum test. Of the loci examined, only E158K and E308G showed polymorphic changes. Six patients exhibited polymorphisms in both E158K and E308G loci and were designated as genotype combination 1. The remaining patients were designated as genotype combination 2. Over the course of treatment, patients with genotype combination 1 had a greater reduction in both the size and number of polyps than those with genotype combination 2. These results suggest that combined polymorphic changes in the E158K and E308G alleles may protect against polyposis in patients with FAP treated with sulindac.
Circulating Levels of Inflammatory Markers and Cancer Risk in the Health Aging and Body Composition Cohort
Authors: Il'yasova Dora , Colbert Lisa H. , Harris Tamara B. , Newman Anne B. , Bauer Douglas C. , Satterfield Suzanne , Kritchevsky Stephen B.
Published: March 2006

Background: Chronic inflammation is associated with processes that contribute to the onset or progression of cancer. This study examined the relationships between circulating levels of the inflammatory markers interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-α (TNF-α) and total as well as site-specific cancer incidence.

Methods: Study subjects (n = 2,438) were older adults (ages 70-79 years) participating in the Health Aging and Body Composition study, who did not report a previous cancer diagnosis (except for nonmelanoma skin cancer) at baseline. Incident cancer events (n = 296) were ascertained during an average follow-up of 5.5 years. Inflammatory markers were measured in stored baseline fasting blood samples.

Results: The adjusted hazard ratios (95% confidence intervals) for incident cancer associated with a 1-unit increase on the natural log-scale were 1.13 (0.94-1.37), 1.25 (1.09-1.43), and 1.28 (0.96-1.70) for IL-6, CRP, and TNF-α, respectively. Markers were more strongly associated with cancer death: hazard ratios were 1.63 (1.19-2.23) for IL-6, 1.64 (1.20-2.24) for CRP, and 1.82 (1.14-2.92) for TNF-α. Although precision was low for site-specific analyses, our results suggest that all three markers were associated with lung cancer, that IL-6 and CRP were associated with colorectal cancer, and that CRP was associated with breast cancer. Prostate cancer was not associated with any of these markers.

Conclusions: These findings suggest that (a) the associations between IL-6, CRP, and TNF-α and the risk of cancer may be site specific and (b) increased levels of inflammatory markers are more strongly associated with the risk of cancer death than cancer incidence.
Molecular Profiling of Computed Tomography Screen-Detected Lung Nodules Shows Multiple Malignant Features
Authors: Pajares María J. , Zudaire Isabel , Lozano María D. , Agorreta Jackeline , Bastarrika Gorka , Torre Wenceslao , Remírez Ana , Pio Ruben , Zulueta Javier J. , Montuenga Luis M.
Published: March 2006

Rationale and Purpose: Low-dose spiral computerized axial tomography (spiral CT) is effective for the detection of small early lung cancers. Although published data seem promising, there has been a significant degree of discussion concerning the potential of overdiagnosis in the context of spiral CT–based screening. The objective of the current study was to analyze the phenotypic and genetic alterations in the small pulmonary malignancies resected after detection in the University of Navarra/International Early Lung Cancer Action Project spiral CT screening trial and to determine whether their malignant molecular features are similar to those of resected lung tumors diagnosed conventionally.

Experimental Design: We analyzed 17 biomarkers of lung epithelial malignancy in a series of 11 tumors resected at our institution during the last 4 years (1,004 high-risk individuals screened), using immunohistochemistry and fluorescence in situ hybridization (FISH). A parallel series of 11 gender-, stage-, and histology-matched lung cancers diagnosed by other means except screening was used as control.

Results: The molecular alterations and the frequency of phenotypic or genetic aberrations were very similar when screen-detected and nonscreen-detected lung cancers were compared. Furthermore, most of the alterations found in the screen-detected cancers from this study were concordant with what has been described previously for stage I-II lung cancer.

Conclusions: Small early-stage lung cancers resected after detection in a spiral CT-based screening trial reveal malignant molecular features similar to those found in conventionally diagnosed lung cancers, suggesting that the screen-detected cancers are not overdiagnosed. (Cancer Epidemiol Biomarkers Prev 2006;15(2):373–80)
Discovery of Novel Methylation Biomarkers in Cervical Carcinoma by Global Demethylation and Microarray Analysis
Authors: Sova Pavel , Feng Qinghua , Geiss Gary , Wood Troy , Strauss Robert , Rudolf Vania , Lieber Andre , Kiviat Nancy
Published: March 2006

A genome-wide screening study for identification of hypermethylated genes in invasive cervical cancer (ICC) was carried out to augment our previously discovered panel of three genes found to be useful for detection of ICC and its precursor neoplasia. Putatively hypermethylated and silenced genes were reactivated in four ICC cell lines by treatment with 5-aza-2′-deoxycytidine and trichostatin A and identified on expression microarrays. Thirty-nine of the 235 genes up-regulated in multiple ICC cell lines were further examined to determine the methylation status of associated CpG islands. The diagnostic use of 23 genes that were aberrantly methylated in multiple ICC cell lines were then analyzed in DNA from exfoliated cells obtained from patients with or without ICC. We show, for the first time, that aberrant methylation of six genes (SPARC, TFPI2, RRAD, SFRP1, MT1G, and NMES1) is present in a high proportion of ICC clinical samples but not in normal samples. Of these genes, SPARC and TFPI2 showed the highest frequency of aberrant methylation in ICC specimens (86.4% for either) and together were hypermethylated in all but one ICC cases examined. We conclude that expression profiling of epigenetically reactivated genes followed by methylation analysis in clinical samples is a powerful tool for comprehensive identification of methylation markers. Several novel genes identified in our study may be clinically useful for detection or stratification of ICC and/or of its precursor lesions and provide a basis for better understanding of mechanisms involved in development of ICC. (Cancer Epidemiol Biomarkers Prev 2006;(15)1:114–23)