bluuebunny/crossref_metadata_2025 huggingface dataset:
Human lung density is not altered following normoxic and hypoxic moderate-intensity exercise: implications for transient edema
Authors: Hodges Alastair N. H. , Sheel A. William , Mayo John R. , McKenzie Donald C.
Published: April 2007

The purpose of this study was to examine the effects of exercise on extravascular lung water as it may relate to pulmonary gas exchange. Ten male humans underwent measures of maximal oxygen uptake (V̇o2 max) in two conditions: normoxia (N) and normobaric hypoxia of 15% O2 (H). Lung density was measured by quantified MRI before and 48.0 ± 7.4 and 100.7 ± 15.1 min following 60 min of cycling exercise in N (intensity = 61.6 ± 9.5% V̇o2 max) and 55.5 ± 9.8 and 104.3 ± 9.1 min following 60 min cycling exercise in H (intensity = 65.4 ± 7.1% hypoxic V̇o2 max), where V̇o2 max = 65.0 ± 7.5 ml·kg−1·min−1 (N) and 54.1 ± 7.0 ml·kg−1·min−1 (H). Two subjects demonstrated mild exercise-induced arterial hypoxemia (EIAH) [minimum arterial oxygen saturation (SaO2 min) = 94.5% and 93.8%], and seven subjects demonstrated moderate EIAH (SaO2 min = 91.4 ± 1.1%) as measured noninvasively during the V̇o2 max test in N. Mean lung densities, measured once preexercise and twice postexercise, were 0.177 ± 0.019, 0.181 ± 0.019, and 0.173 ± 0.019 g/ml (N) and 0.178 ± 0.021, 0.174 ± 0.022, and 0.176 ± 0.019 g/ml (H), respectively. No significant differences ( P > 0.05) were found in lung density following exercise in either condition or between conditions. Transient interstitial pulmonary edema did not occur following sustained steady-state cycling exercise in N or H, indicating that transient edema does not result from pulmonary capillary leakage during sustained submaximal exercise.
Decreased left ventricular function, myocarditis, and coronary arteriolar medial thickening following monocrotaline administration in adult rats
Authors: Akhavein F. , St.-Michel E. Jean , Seifert E. , Rohlicek C. V.
Published: April 2007

Decreased right as well as left ventricular function can be associated with pulmonary hypertension (PH). Numerous investigations have examined cardiac function following induction of pulmonary hypertension with monocrotaline (MCT) assuming that MCT has no direct cardiac effect. We tested this assumption by examining left ventricular function and histology of isolated and perfused hearts from MCT-treated rats. Experiments were performed on 50 male Sprague-Dawley rats [348 ± 6 g (SD)]. Thirty-seven rats received MCT (50 mg/kg sc; MCT group) while the remainder did not (Control group). Three weeks later, pulmonary artery pressure was assessed echocardiographically in 20 MCT and 8 Control rats. The hearts were then excised and perfused in the constant pressure Langendorff mode to determine peak left ventricular pressure (LVP), the peak instantaneous rate of pressure increase (+dP/d tmax) and decrease (−dP/d tmax), as well as the rate pressure product (RPP). Histological sections were subsequently examined. Pulmonary artery pressure was higher in the MCT-treated group compared with the Control group [12.9 ± 6 vs. 51 ± 35.3 mmHg ( P < 0.01)]. Left ventricular systolic function and diastolic relaxation were decreased in the MCT group compared with the Control group (+dP/d tmax4,178 ± 388 vs. 2,801 ± 503 mmHg/s, LVP 115 ± 11 vs. 83 ± 14 mmHg, RPP 33,688 ± 1,910 vs. 23,541 ± 3,858 beats·min−1·mmHg−1, −dP/d tmax−3,036 ± 247 vs. −2,091 ± 389 mmHg/s; P < 0.0001). The impairment of cardiac function was associated with myocarditis and coronary arteriolar medial thickening. Similarly depressed ventricular function and inflammatory infiltration was seen in 12 rats 7 days after MCT administration. Our findings appear unrelated to the degree of PH and indicate a direct cardiotoxic effect of MCT.
Medulloblastomas Derived from Cxcr6 Mutant Mice Respond to Treatment with a Smoothened Inhibitor
Authors: Sasai Ken , Romer Justyna T. , Kimura Hiromichi , Eberhart Derek E. , Rice Dennis S. , Curran Tom
Published: April 2007

The sonic hedgehog (Shh) pathway is activated in ∼30% of human medulloblastoma resulting in increased expression of downstream target genes. In about half of these cases, this has been shown to be a consequence of mutations in regulatory genes within the pathway, including Ptc1, Smo, and Sufu. However, for some tumors, no mutations have been detected in known pathway genes. This suggests that either mutations in other genes promote tumorigenesis or that epigenetic alterations increase pathway activity in these tumors. Here, we report that 3% to 4% of mice lacking either one or both functional copies of Cxcr6 develop medulloblastoma. Although CXCR6 is not known to be involved in Shh signaling, tumors derived from Cxcr6 mutant mice expressed Shh pathway target genes including Gli1, Gli2, Ptc2, and Sfrp1, indicating elevated pathway activity. Interestingly, the level of Ptc1 expression was decreased in tumor cells although two normal copies of Ptc1 were retained. This implies that reduced CXCR6 function leads to suppression of Ptc1 thereby increasing Smoothened function and promoting tumorigenesis. We used a direct transplant model to test the sensitivity of medulloblastoma arising in Cxcr6 mutant mice to a small-molecule inhibitor of Smoothened (HhAntag). We found that transplanted tumors were dramatically inhibited in mice treated for only 4 days with HhAntag. These findings suggest that HhAntag may be effective against tumors lacking mutations in known Shh pathway genes. [Cancer Res 2007;67(8):3871–7]
Perceived Risk of Colorectal Cancer: Sources of Risk Judgments
Authors: Robb Kathryn A. , Miles Anne , Wardle Jane
Published: April 2007

Perceived risk of disease plays a key role in health behaviors, making it an important issue for cancer-preventive behavior research. This study describes studies using complimentary methodologies to investigate the determinants of perceived risk of developing colorectal cancer. In study 1, questionnaires were mailed to a community sample of 1,056 adults ages 45 to 65 years. They assessed risk factors for colorectal cancer and perceived risk of colorectal cancer and asked respondents to explain why they had rated their risk as they had. Consistent with previous studies, risk factors for colorectal cancer were significantly correlated with perceived risk, although associations were relatively weak. The most frequently cited reasons for risk judgments were diet, family history, and symptoms/general health. Not surprisingly, correlations between each risk factor and perceived risk were stronger among participants who had attributed their risk to that factor. Study 2 used semi-structured interviews to explore individuals' explanations for their perceived risk of colorectal cancer. Adults (n = 18) ages 60 to 63 years volunteered a variety of explanations, but their experiences of cancer seemed to be most salient to their risk estimates. These studies suggest that attributions people make for their risk judgments are important in understanding how they conceptualize risk, but appreciation of experiential and affective influences may be useful in fully understanding perceptions of risk. (Cancer Epidemiol Biomarkers Prev 2007;16(4):694–702)
The Epidemiology of Arm and Hand Swelling in Premenopausal Breast Cancer Survivors
Authors: Paskett Electra D. , Naughton Michelle J. , McCoy Thomas P. , Case L. Douglas , Abbott Jill M.
Published: April 2007

Background: Breast cancer survivors suffer from lymphedema of the arm and/or hand. Accurate estimates of the incidence and prevalence of lymphedema are lacking, as are the effects of this condition on overall quality of life.

Methods: Six hundred twenty-two breast cancer survivors (age, ≤45 years at diagnosis) were followed with semiannual questionnaires for 36 months after surgery to determine the incidence of lymphedema, prevalence of persistent swelling, factors associated with each, and quality of life.

Results: Of those contacted and eligible for the study, 93% agreed to participate. Fifty-four percent reported arm or hand swelling by 36 months after surgery, with 32% reporting persistent swelling. Swelling was reported to occur in the upper arm (43%), the hand only (34%), and both arm and hand (22%). Factors associated with an increased risk of developing swelling included having a greater number of lymph nodes removed [hazards ratio (HR), 1.02; P < 0.01], receiving chemotherapy (HR, 1.76; P = 0.02), being obese (HR, 1.51 versus normal weight; P = 0.01), and being married (HR, 1.36; P = 0.05). Factors associated with persistent swelling were having more lymph nodes removed (odds ratio, 1.03; P = 0.01) and being obese (odds ratio, 2.24 versus normal weight; P < 0.01). Women reporting swelling had significantly lower quality of life as measured by the functional assessment of cancer therapy-breast total score and the SF-12 physical and mental health subscales (P < 0.01 for each).

Conclusions: Lymphedema occurs among a substantial proportion of young breast cancer survivors. Weight management may be a potential intervention for those at greatest risk of lymphedema to maintain optimal health-related quality of life among survivors. (Cancer Epidemiol Biomarkers Prev 2007;16(4):775–82)
Detecting an Association between Socioeconomic Status and Late Stage Breast Cancer Using Spatial Analysis and Area-Based Measures
Authors: MacKinnon Jill Amlong , Duncan Robert C. , Huang Youjie , Lee David J. , Fleming Lora E. , Voti Lydia , Rudolph Mark , Wilkinson James D.
Published: April 2007

Objectives: To assess the relationship between socioeconomic status (SES) and late stage breast cancer using the cluster detection software SaTScan and U.S. census–derived area-based socioeconomic measures.

Materials and Methods: Florida's 18,683 women diagnosed with late stage breast cancer (regional or distant stage) between 1998 and 2002 as identified by Florida's population–based, statewide, incidence registry were analyzed by SaTScan to identify areas of higher-than-expected incidence. The relationship between SES and late stage breast cancer was assessed at the neighborhood (block group) level by combining the SaTScan results with area-based SES data.

Results: SaTScan identified 767 of Florida's 9,112 block groups that had higher-than-expected incidence of late stage breast cancer. After controlling for patient level insurance status, county level mammography prevalence, and urban/rural residence in the logistic regression model, women living in neighborhoods of severe and near poverty were respectively 3.0 and 1.6 times more likely to live in areas of higher-than-expected incidence of late stage breast cancer when compared with women living in nonpoverty. Additionally, areas in the lowest quartile of mammography usage were almost seven times more likely to have higher-than-expected incidence than areas in the higher quartiles.

Conclusions: In addition to confirming the importance of mammography, results from the present study suggest that “where” you live plays an important role in defining the risk of presenting with late stage breast cancer. Additional research is urgently needed to understand this risk and to leverage the strengths and resources present in all communities to lower the late stage breast cancer burden. (Cancer Epidemiol Biomarkers Prev 2007;16(4):756–62)
Gastric Cancer is Related to Early Helicobacter pylori Infection in a High-Prevalence Country
Authors: Ferreccio Catterina , Rollán Antonio , Harris Paul R. , Serrano Carolina , Gederlini Alessandra , Margozzini Paula , Gonzalez Claudia , Aguilera Ximena , Venegas Alejandro , Jara Alejandro
Published: April 2007

Background and Aims: Chile ranks fifth in the world among countries with the highest incidence of gastric cancer. The aim was to quantify the association between Helicobacter pylori infection and gastric cancer mortality at the county of residence.

Methods: A cross-sectional household survey, a probability sample of the Chilean adult population, provided 2,615 participants in whom serum H. pylori IgG antibodies were measured (ELISA). The spatial pattern of 48,367 deaths due to gastric cancer which occurred from 1985 to 2002 was analyzed using a hierarchical Poisson regression model; 333 counties were categorized as low, medium, and high gastric cancer mortality with median gastric cancer death rates of 11.4, 19.1, and 26.0 per 100,000 inhabitants, respectively. The association between H. pylori positivity and gastric cancer mortality in the county of residence was assessed by multivariate Poisson regression for complex samples.

Results: H. pylori prevalence was 73.0% [95% confidence intervals (CI), 70.0-76.0], higher in men [prevalence rate ratio (PRR), 1.1 (95% CI, 1.01-1.20)], peaked at ages 45 to 64, and dropped after age 65. It was higher among residents in counties with high gastric cancer mortality (79.7%; 95% CI, 76.4-82.6) compared to counties with low gastric cancer mortality (62.3%; 95% CI, 53.8-70.2; corresponding PRR, 1.3; 95% CI, 1.1-1.5); under age 24, H. pylori infection was 79.7% (95% CI, 72.2-85.6) versus 39.8% (95% CI, 19.6-64.2) among residents in counties with high and low gastric cancer mortalities, respectively (PRR, 2.0; 95% CI, 1.1-3.7).

Conclusions: The high prevalence of H. pylori at younger ages was associated with high gastric cancer mortality in the base population. (Cancer Epidemiol Biomarkers Prev 2007;16(4):662–7)
IL6, Aspirin, Nonsteroidal Anti-inflammatory Drugs, and Breast Cancer Risk in Women Living in the Southwestern United States
Authors: Slattery Martha L. , Curtin Karen , Baumgartner Richard , Sweeney Carol , Byers Tim , Giuliano Anna R. , Baumgartner Kathy B. , Wolff Roger R.
Published: April 2007

Interleukin-6 is a cytokine thought to be involved in inflammation, insulin, and estrogen-related pathways. We evaluate genetic variation in the IL6 gene with risk of breast cancer. We also evaluate breast cancer associations with aspirin and nonsteroidal anti-inflammatory drugs. A breast cancer case-control study (n = 1,527 non-Hispanic white cases, 1,601 non-Hispanic white controls, 798 Hispanic/Native American cases, and 924 Hispanic/Native American controls) was conducted among women living in the southwestern United States (4-Corner's Breast Cancer Study). Five IL6 single nucleotide polymorphisms (SNP) and IL6 haplotypes based on these SNPs were evaluated. Allele frequencies were significantly different between non-Hispanic white and Hispanic/Native American women. Among postmenopausal women not recently exposed to hormones, the AG/GG genotypes of rs1800797 (−596A>G) and the GC/CC genotypes of rs1800795 (−174G>C) significantly reduced risk of breast cancer among non-Hispanic white women [odds ratio (OR), 0.69; 95% confidence interval (95% CI), 0.48-1.00 and OR, 0.68; 95% CI, 0.47-0.99, respectively] and Hispanic/Native American women (OR, 0.48; 95% CI, 0.28-0.83 and OR, 0.44; 95% CI, 0.26-0.99, respectively). Haplotypes of the five IL6 SNPs further defined these associations. Recent aspirin use significantly decreased risk of breast cancer among postmenopausal Hispanic/Native American women not recently exposed to hormones (OR, 0.56; 95% CI, 0.33-0.96). Among non-Hispanic white, the inverse association with aspirin was not statistically significant. IL6 genotype and haplotype significantly modified the association between aspirin and breast cancer, with the greatest effect modification being among women not recently exposed to hormones [P interaction = 0.06 (for non-Hispanic white) and 0.04 (for Hispanic/Native American) and SNP rs1800796 or −572G>C]. These data suggest that IL6 is associated with breast cancer risk and modifies the association between estrogen and aspirin and breast cancer risk. (Cancer Epidemiol Biomarkers Prev 2007;16(4):747–55)
Can We Trust National Smoking Prevalence Figures? Discrepancies Between Biochemically Assessed and Self-Reported Smoking Rates in Three Countries
Authors: West Robert , Zatonski Witold , Przewozniak Krzysztof , Jarvis Martin J.
Published: April 2007

Background: National smoking prevalence estimates are the primary basis for assessing progress in tobacco control across the world. They are based on surveys of self-reported cigarette smoking. It has been assumed that this is sufficiently accurate for policy purposes, but this assumption has not been adequately tested.

Methods: We report data from the 2003 Health Survey for England, the U.S. National Health and Nutrition Examination Survey for 2001-2002, and the 2004 national smoking behaviors survey in Poland as examples of countries at different stages in the “tobacco epidemic.” Self-reported cigarette and total tobacco smoking prevalence were assessed by means of the standard questions used in each country. In subsamples, specimens were collected for analysis of cotinine (saliva, N = 1,613 in England; serum, N = 4,687 in the United States; and saliva, N = 388 in Poland) providing an objective means of determining active smoking. A cut point of 15 ng/mL was used to discriminate active smoking from passive smoke exposure.

Results: Self-reported cigarette smoking prevalence using the standard methods underestimated true tobacco smoking prevalence by an estimated 2.8% in England, 0.6% in the United States, and 4.4% in Poland. Cotinine concentrations in those misclassified as nonsmokers were indicative of high levels of smoke intake.

Interpretation: Underestimation of smoking prevalence was minimal in the United States but significant in England and Poland. A review of methodologies for assessing tobacco smoking prevalence worldwide is urgently needed. (Cancer Epidemiol Biomarkers Prev 2007;16(4):820–2)
Physical Activity and Endometrial Cancer Risk, a Systematic Review of Current Evidence
Authors: Voskuil Dorien W. , Monninkhof Evelyn M. , Elias Sjoerd G. , Vlems Femke A. , van Leeuwen Flora E. ,   Task Force Physical Activity and Cancer
Published: April 2007

Objective: To assess the epidemiologic evidence for the association between physical activity and endometrial cancer risk, taking into account the methodologic quality of each study.

Design: Systematic review, best evidence synthesis.

Data Sources: Studies were identified through a systematic review of literature available on PubMed through December 2006.

Review Methods: We included cohort and case-control studies that assessed total and/or leisure time and/or occupational activities in relation to the incidence of endometrial cancer. The methodologic quality of the studies was assessed with a comprehensive scoring system.

Results: The included cohort (n = 7) and case-control (n = 13) studies consistently show that physical activity is associated with a decreased risk of endometrial cancer. The best evidence synthesis showed that the majority (80%) of 10 high-quality studies found risk reductions of >20%. Pooling of seven high-quality cohort studies that measured total, leisure time, or occupational activity showed a significantly decreased risk of endometrial cancer (summary estimate: OR, 0.77; 95% CI, 0.70-0.85) for the most active women. Case control studies with relatively unfavorable quality scores reported divergent risk estimates, between 2-fold decreased and 2-fold increased risk. Effect modification by body mass index or menopausal status was not consistently observed. Evidence for an effect of physical activity during childhood or adolescence was limited.

Conclusions: Physical activity seems to be associated with a reduction in the risk of endometrial cancer, which is independent of body weight. Further studies, preferably prospective cohort studies, are needed to determine the magnitude of the risk reduction and to assess which aspects of physical activity contribute most strongly to the reduced risk and in which period of life physical activity is most effective. (Cancer Epidemiol Biomarkers Prev 2007;16(4):639–48)
A Systematic Approach to Analysing Gene-Gene Interactions: Polymorphisms at the Microsomal Epoxide Hydrolase EPHX and Glutathione S-transferase GSTM1, GSTT1, and GSTP1 Loci and Breast Cancer Risk
Authors: Spurdle Amanda B. , Chang Jiun-Horng , Byrnes Graham B. , Chen Xiaoqing , Dite Gillian S. , McCredie Margaret R.E. , Giles Graham G. , Southey Melissa C. , Chenevix-Trench Georgia , Hopper John L.
Published: April 2007

Objective: We undertook a case-control study in an Australian Caucasian population-based sample of 1,246 cases and 664 controls to assess the roles of detoxification gene polymorphisms EPHX T>C Tyr113His, GSTT1 deletion, GSTM1 deletion, and GSTP1 A>G Ile105Val on risk of breast cancer.

Methods: We systematically addressed the main effects and possible gene-gene interactions using unconditional logistic regression to estimate odds ratios (OR) adjusted for potential confounders and using standard model building approaches based on likelihood theory.

Results: There was a decreased risk associated with the EPHX CC genotype [OR, 0.60; 95% confidence interval (95% CI), 0.43-0.84; P = 0.003], marginally significant evidence of increased risk with GSTM1 null genotype (OR, 1.21; 95% CI, 1.00-1.47; P = 0.05), but no association with GSTT1 null genotype (OR, 1.12; 95% CI, 0.86-1.45; P = 0.4) or GSTP1 (OR, 0.95; 95% CI, 0.82-1.10; P = 0.5) genotype. The full model with all interactions gave a significantly better fit than a main-effects-only model (P < 0.001), providing evidence for gene-gene interactions. The most parsimonious model included main effects for EPHX, GSTT1, and GSTM1; a two-way interaction between EPHX and GSTM1; and a three-way interaction between EPHX, GSTM1, and GSTT1. Predicted risks were greatest for women carrying deletions of both GSTT1 and GSTM1, with either the EPHX TC genotype (OR, 2.02; 95% CI, 1.19-3.45; P = 0.009) or EPHX CC genotype (OR, 3.54; 95% CI, 1.29-9.72; P = 0.14).

Conclusion: Detoxification gene polymorphisms may interact with each other to result in small groups of individuals at modestly increased risk. We caution against overinterpretation and suggest that pooling of similarly large studies is needed to clarify the possible role of such complex gene-gene interactions on breast cancer risk. (Cancer Epidemiol Biomarkers Prev 2007;16(4):769–74)
Effects of Aerobic Exercise Training on Estrogen Metabolism in Premenopausal Women: A Randomized Controlled Trial
Authors: Campbell Kristin L. , Westerlind Kim C. , Harber Vicki J. , Bell Gordon J. , Mackey John R. , Courneya Kerry S.
Published: April 2007

Background: Regular physical activity may alter estrogen metabolism, a proposed biomarker of breast cancer risk, by shifting metabolism to favor production of 2-hydroxyestrone (2-OHE1). Few studies, however, have examined this question using a randomized controlled trial.

Purpose: To examine the effects of 12 weeks of aerobic exercise training on 2-OHE1 and 16α-hydroxyestrone (16α-OHE1) in premenopausal women.

Methods: Participants were healthy, regularly menstruating, Caucasian women, 20 to 35 years, body mass index of 18 to 29.9, not using pharmacologic contraceptives, with average or below average fitness [maximal oxygen consumption (VO2max), <40 mL/kg/min]. Following a baseline menstrual cycle, participants (N = 32) were randomly assigned to a 12-week aerobic exercise training intervention (n = 17) or usual lifestyle (n = 15). Height, body mass, body composition by dual-energy X-ray absorptiometry, and VO2max were measured at baseline and following the intervention. Urine samples were collected in the luteal phase of four consecutive menstrual cycles.

Results: The exercise group increased VO2max by 14% and had significant, although modest, improvements in fat and lean body mass. No significant between-group differences were observed, however, for the changes in 2-OHE1 (P = 0.944), 16α-OHE1 (P = 0.411), or the ratio of 2-OHE1 to 16α-OHE1 (P = 0.317). At baseline, there was an inverse association between body fat and 2-OHE1 to 16α-OHE1 ratio (r = −0.40; P = 0.044); however, it was the change in lean body mass over the intervention that was positively associated with a change in 2-OHE1 to 16α-OHE1 ratio (r = 0.43; P = 0.015).

Conclusions: A 12-week aerobic exercise training intervention significantly improved aerobic fitness and body composition but did not alter estrogen metabolism in premenopausal women. Interestingly, an increase in lean body mass was associated with a favorable change in 2-OHE1 to 16α-OHE1 ratio. (Cancer Epidemiol Biomarkers Prev 2007;16(4):731–9)
Incidence and Duration of Cervical Human Papillomavirus 6, 11, 16, and 18 Infections in Young Women: An Evaluation from Multiple Analytic Perspectives
Authors: Insinga Ralph P. , Dasbach Erik J. , Elbasha Elamin H. , Liaw Kai-Li , Barr Eliav
Published: April 2007

Objective: To estimate the incidence and duration of cervical human papillomavirus (HPV)-6, HPV-11, HPV-16, and HPV-18 infections in a population of young American women.

Methods: The study population consisted of U.S. women who at baseline were 16 to 23 years of age, reported zero to five lifetime sexual partners, never having been pregnant, and never having had a prior abnormal Papanicolaou test and were enrolled in the placebo arm of a randomized multicenter clinical trial of a HPV-16 L1 virus-like particle vaccine. Women underwent type-specific endocervical/ectocervical swab HPV DNA testing at ∼6-month intervals for up to 48 months of follow-up. To contribute person-time in the analyses of type-specific HPV incidence, a woman must have had at least three satisfactory swab specimens available and been negative for the relevant HPV type (HPV-6, HPV-11, HPV-16, or HPV-18) on her first two trial swabs. The duration of incident HPV infections was estimated using Kaplan-Meier survival analysis methods.

Results: Person-years of exposure ranged by type-specific analysis from 2,645 to 3,188, with an incidence rate per 100 person-years of 3.6 for HPV-6, 0.4 for HPV-11, 5.4 for HPV-16, and 2.1 for HPV-18. With censoring at the time of treatment for cervical intraepithelial neoplasia, where done, the mean duration of incident infections was 9.3, 8.4, 18.2, and 16.4 months, respectively, for HPV-6 (n = 103), HPV-11 (n = 13), HPV-16 (n = 142), and HPV-18 (n = 62). When the duration of HPV infections was truncated at the time of cervical intraepithelial neoplasia detection (any grade), where applicable, mean duration figures were 8.4, 8.1, 14.0, and 15.1 months for HPV-6, HPV-11, HPV-16, and HPV-18 infections, respectively.

Conclusions: Previous studies of the mean duration of cervical HPV infection have been based on prevalent infections and/or featured relatively short duration of follow-up. This study tested women for HPV infection over a period of up to 48 months and observed a mean duration of incident HPV-16/HPV-18 infections approximately twice that of HPV-6/HPV-11. (Cancer Epidemiol Biomarkers Prev 2007;16(4):709–15)
Do Factors Related to Endogenous and Exogenous Estrogens Modify the Relationship between Obesity and Risk of Colorectal Adenomas in Women?
Authors: Wolf Lesley A. , Terry Paul D. , Potter John D. , Bostick Roberd M.
Published: April 2007

Obesity has consistently been associated with increased colorectal cancer risk in men, but not in women. In the absence of postmenopausal hormone use (PMH), adipose-derived estrogen is the primary determinant of circulating estrogen levels in postmenopausal women, perhaps ameliorating the mitogenic effects of obesity in this group. Using data from a case-control study in the United States, we examined associations among obesity, potential modifying effects of factors related to endogenous and exogenous estrogen levels, and risk of colorectal adenoma. Cases (n = 219) were women of ages 30 to 74 years with colonoscopy proven, incident, sporadic, pathology-confirmed, adenomatous polyps of the colon and rectum. Two control groups were recruited: colonoscopy-confirmed polyp-free women (n = 438) and age- and zip code frequency–matched women randomly selected from the community (n = 247). Multivariate odds ratios and 95% confidence intervals (95% CI) for obese [body mass index (BMI) ≥30.0; compared with nonobese, BMI <25.0] premenopausal women were 2.09 (95% CI, 0.81-5.41) versus colonoscopy controls, and 5.18 (95% CI, 1.40-19.32) versus population controls. For PMH users, the corresponding odds ratios were 0.29 (95% CI, 0.12-0.70) versus colonoscopy controls and 0.64 (95% CI, 0.23-1.83) versus population controls. There was no significant association of BMI with adenoma risk for PMH nonusers. Findings for waist-to-hip ratio were similar to those for BMI. These data support the hypothesis that risk for colorectal adenoma may be increased with obesity among premenopausal women but decreased among postmenopausal women, especially if they also take PMH. (Cancer Epidemiol Biomarkers Prev 2007;16(4):676–83)
Exposure to Ethylene Oxide in Hospitals: Biological Monitoring and Influence of Glutathione S-Transferase and Epoxide Hydrolase Polymorphisms
Authors: Haufroid Vincent , Merz Brigitte , Hofmann Annette , Tschopp Alois , Lison Dominique , Hotz Philippe
Published: April 2007

Ethylene oxide is considered as a human carcinogen. A biomarker of exposure would be a useful instrument to assess the risk in occupationally exposed workers. This cross-sectional study aimed at examining (a) whether the urinary excretion of a metabolite of ethylene oxide, 2-hydroxyethyl mercapturic acid (HEMA), could be used for monitoring occupational exposure and (b) whether glutathione S-transferase (GST) and epoxide hydrolase genotypes influenced biological monitoring. Exposure to ethylene oxide was measured by personal sampling in 80 hospital workers (95% of those eligible). HEMA concentrations were determined in three urine samples (baseline, end of shift, and next morning) by liquid chromatography with tandem mass spectrometry. GSTs (GSTT1, GSTM1, and GSTP1) and epoxide hydrolase (EPHX1) were also genotyped. The influence of exposure, genotypes, and several other factors was examined in multiple regression analyses. Exposure was always <1 parts per million. On a group basis, exposure and a non-null GSTT1 genotype increased the HEMA concentrations in the urine sample collected at the end of the shift and these factors remained statistically significant after considering possible confounding or modifying factors. (Cancer Epidemiol Biomarkers Prev 2007;16(4):796–802)
Insulin-like Growth Factor-I and Risk of High-Grade Cervical Intraepithelial Neoplasia
Authors: Schaffer Andrea , Koushik Anita , Trottier Helen , Duarte-Franco Eliane , Mansour Nabil , Arseneau Jocelyne , Provencher Diane , Gilbert Lucy , Gotlieb Walter , Ferenczy Alex , Coutlée François , Pollak Michael N. , Franco Eduardo L. ,   The Biomarkers of Cervical Cancer Risk Study Team
Published: April 2007

Insulin-like growth factors (IGF) and their binding proteins (IGFBP) have been implicated in the risk of several epithelial or glandular tumors, including prostate cancer, breast cancer, and colon cancer. Cervical cancer, which is also of epithelial origin, has been shown to overexpress receptors for IGF-I, and plasma levels of IGF-I have been positively associated with cervical cancer precursors in one epidemiologic study. In this case-control study, we investigated plasma levels of IGF-I and IGFBP-3 in relation to the risk of histologically confirmed high-grade cervical intraepithelial neoplasia (HGCIN) and the risk of human papillomavirus (HPV) infection. Included in this analysis were 329 cases and 621 controls recruited from clinics affiliated with two Montréal-area hospital centers. We observed a reduced risk of HGCIN for increasing levels of IGF-I, with an adjusted odds ratio (OR) of 0.40 (95% confidence interval, 0.19-0.87) for the highest quartile relative to the lowest quartile of IGF-I. No association was observed between IGFBP-3 levels and HGCIN. Among controls, IGF-I was associated with a decreased risk of being positive for HPV-16 or HPV-18, with an adjusted odds ratio of 0.20 (95% confidence interval, 0.05-0.87) for the highest quartile relative to the lowest quartile of IGF-I. There was no association observed between IGFBP-3 levels and HPV infection status. IGF-I–mediated effects seemed to predominate among women <30 years of age. In contrast to the previously reported study, our results suggest that levels of IGF-I in young women may be inversely associated with HGCIN, a precursor to cervical cancer. (Cancer Epidemiol Biomarkers Prev 2007;16(4):716–22)
Induction of the Phase 2 Response in Mouse and Human Skin by Sulforaphane-containing Broccoli Sprout Extracts
Authors: Dinkova-Kostova Albena T. , Fahey Jed W. , Wade Kristina L. , Jenkins Stephanie N. , Shapiro Theresa A. , Fuchs Edward J. , Kerns Michelle L. , Talalay Paul
Published: April 2007

The isothiocyanate sulforaphane was isolated from broccoli extracts in a bioactivity-guided fractionation as the principal and very potent inducer of cytoprotective phase 2 enzymes and subsequently shown to inhibit tumor development in animal models that involve various carcinogens and target organs. Because broccoli and broccoli sprouts are widely consumed, extracts obtained from them are viewed as convenient vehicles for sulforaphane delivery to humans. In relation to our current interest in devising strategies for protection against UV light–induced skin cancer, it was necessary to examine the safety and efficacy of topical application of sulforaphane-containing broccoli sprout extracts as single and multiple doses in both mice and humans. Topical application of an extract delivering 100 nmol sulforaphane/cm2 increased the protein levels of NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione S-transferase A1, and heme oxygenase 1, three representative phase 2 enzymes, in mouse skin epidermis. Quantitative assessment of the activity of NQO1 24 h after dosing showed increases of 1.5- and 2.7-fold after application of single and multiple (thrice, every 24 h) doses, respectively. A dose-escalation safety study in healthy human subjects revealed no adverse reactions when doses as high as 340 nmol of sulforaphane in the form of broccoli sprout extracts were applied topically to the center of a 1-cm-diameter circle drawn on the volar forearm. A subsequent efficacy study showed that despite the interindividual differences in basal levels, the enzyme activity of NQO1 in homogenates of 3-mm full thickness skin punch biopsies increased in a dose-dependent manner, with maximum increases of 1.5- and 4.5-fold after application of 150 nmol doses, once or three times (at 24 h-intervals), respectively, thus providing direct evidence for induction of the phase 2 response in humans. (Cancer Epidemiol Biomarkers Prev 2007;16(4):847–51)
Circulating Insulin-Like Growth Factor-I and Binding Protein-3 and the Risk of Breast Cancer
Authors: Baglietto Laura , English Dallas R. , Hopper John L. , Morris Howard A. , Tilley Wayne D. , Giles Graham G.
Published: April 2007

Four meta-analyses and literature reviews have concluded that a positive association exists between circulating levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) and breast cancer risk for premenopausal but not postmenopausal women. Recently, a large prospective study reported an association with IGF-I and IGFBP-3 concentration for breast cancer diagnosed after, but not before, the age of 50 years; and in a large cohort of primarily premenopausal women, IGF-I and IGFBP-3 were not associated with breast cancer risk. We did a case-cohort study within the Melbourne Collaborative Cohort Study, which included a random sample of 1,901 women (subcohort) and 423 breast cancer cases diagnosed during a mean of 9.1 years of follow-up. IGF-I and IGFBP-3 concentrations were measured in plasma collected at baseline. The association between quartiles of IGF concentration and breast cancer risk was tested using a Cox model adjusted for known and potential confounders. The hazard ratio (HR) for breast cancer comparing the fourth with the first quartiles was 1.20 [95% confidence interval (95% CI), 0.87-1.65] for IGF-I and 1.09 (95% CI, 0.78-1.53) for IGFBP-3. Both associations varied with age: for IGF-I, the HRs for breast cancer comparing the fourth with the first quartiles were 0.60 (95% CI, 0.25-1.45) before age 50 and 1.61 (95% CI, 1.04-2.51) after age 60 (test for the log-linear trend of HR according to age, P = 0.05); for IGFBP-3, the HRs were 0.79 (95% CI, 0.34-1.83) before age 50 and 1.62 (95% CI, 1.03-2.55) after age 60 (test for log-linear trend, P = 0.08). IGF-I and IGFBP-3 were positively associated with breast cancer risk in older women but not in younger women. More prospective studies are needed to clarify the age dependence of the association between IGF-I and IGFBP-3 and breast cancer. (Cancer Epidemiol Biomarkers Prev 2007;16(4):763–8)
Dietary Mutagen Exposure and Risk of Pancreatic Cancer
Authors: Li Donghui , Day Rena Sue , Bondy Melissa L. , Sinha Rashmi , Nguyen Nga T. , Evans Douglas B. , Abbruzzese James L. , Hassan Manal M.
Published: April 2007

To investigate the association between dietary exposure to food mutagens and risk of pancreatic cancer, we conducted a hospital-based case-control study at the University of Texas M. D. Anderson Cancer Center during June 2002 to May 2006. A total of 626 cases and 530 noncancer controls were frequency matched for race, sex and age (±5 years). Dietary exposure information was collected via personal interview using a meat preparation questionnaire. A significantly greater portion of the cases than controls showed a preference to well-done pork, bacon, grilled chicken, and pan-fried chicken, but not to hamburger and steak. Cases had a higher daily intake of food mutagens and mutagenicity activity (revertants per gram of daily meat intake) than controls did. The daily intakes of 2-amino-3,4,8-trimethylimidazo[4,5−f]quinoxaline (DiMeIQx) and benzo(a)pyrene (BaP), as well as the mutagenic activity, were significant predictors for pancreatic cancer (P = 0.008, 0.031, and 0.029, respectively) with adjustment of other confounders. A significant trend of elevated cancer risk with increasing DiMeIQx intake was observed in quintile analysis (Ptrend = 0.024). A higher intake of dietary mutagens (those in the two top quintiles) was associated with a 2-fold increased risk of pancreatic cancer among those without a family history of cancer but not among those with a family history of cancer. A possible synergistic effect of dietary mutagen exposure and smoking was observed among individuals with the highest level of exposure (top 10%) to PhIP and BaP, Pinteraction = 0.09 and 0.099, respectively. These data support the hypothesis that dietary mutagen exposure alone and in interaction with other factors contribute to the development of pancreatic cancer. (Cancer Epidemiol Biomarkers Prev 2007;16(4):655–61)
Glioma Risk in Relation to Serum Levels of Insulin-Like Growth Factors
Authors: Lönn Stefan , Inskip Peter D. , Pollak Michael N. , Weinstein Stephanie J. , Virtamo Jarmo , Albanes Demetrius
Published: April 2007

Several studies have suggested that insulin-like growth factors (IGF) are related to cancer risk. We investigated the associations between serum levels of IGF-I and IGF-binding protein-3 and glioma risk. A nested case-control study was conducted within a cancer prevention study, including 29,133 men (ages 50-69 years). In total, 22 glioma cases and 400 randomly selected controls were included. Serum samples were collected a minimum of 5 years before cancer diagnosis. Serum concentrations were measured using ELISA and divided into tertiles based on measurements among controls. Odds ratios and 95% confidence intervals were calculated using the lowest tertile as the reference category. No statistical association was detected between glioma and IGF-binding protein-3. IGF-I was inversely associated with glioma when comparing the lowest tertile with the other tertiles combined (odds ratio, 0.3; 95% confidence interval, 0.1-0.7). The results encourage future research on IGFs in relation to brain tumors in larger studies. (Cancer Epidemiol Biomarkers Prev 2007;16(4):844–6)
β-Catenin Downregulation Is Required for Adaptive Cardiac Remodeling
Authors: Baurand Anthony , Zelarayan Laura , Betney Russell , Gehrke Christina , Dunger Sandra , Noack Claudia , Busjahn Andreas , Huelsken Joerg , Taketo Makoto Mark , Birchmeier Walter , Dietz Rainer , Bergmann Martin W.
Published: April 2007

The armadillo-related protein β-catenin has multiple functions in cardiac tissue homeostasis: stabilization of β-catenin has been implicated in adult cardiac hypertrophy, and downregulation initiates heart formation in embryogenesis. The protein is also part of the cadherin/catenin complex at the cell membrane, where depletion might result in disturbed cell–cell interaction similar to N-cadherin knockout models. Here, we analyzed the in vivo role of β-catenin in adult cardiac hypertrophy initiated by angiotensin II (Ang II). The cardiac-specific mifepristone-inducible αMHC-CrePR1 transgene was used to induce β-catenin depletion (loxP-flanked exons 3 to 6, β-cat
Δex3–6
mice) or stabilization (loxP-flanked exon 3, β-cat
Δex3
mice). Levels of β-catenin were altered both in membrane and nuclear extracts. Analysis of the β-catenin target genes Axin2 and Tcf-4 confirmed increased β-catenin–dependent transcription in β-catenin stabilized mice. In both models, transgenic mice were viable and healthy at age 6 months. β-Catenin appeared dispensable for cell membrane function. Ang II infusion induced cardiac hypertrophy both in wild-type mice and in mice with β-catenin depletion. In contrast, mice with stabilized β-catenin had decreased cross-sectional area at baseline and an abrogated hypertrophic response to Ang II infusion. Stabilizing β-catenin led to impaired fractional shortening compared with control littermates after Ang II stimulation. This functional deterioration was associated with altered expression of the T-box proteins Tbx5 and Tbx20 at baseline and after Ang II stimulation. In addition, atrophy-related protein IGFBP5 was upregulated in β-catenin–stabilized mice. These data suggest that β-catenin downregulation is required for adaptive cardiac hypertrophy.
TNF-α Contributes to Endothelial Dysfunction by Upregulating Arginase in Ischemia/Reperfusion Injury
Authors: Gao Xue , Xu Xiangbin , Belmadani Souad , Park Yoonjung , Tang Zhonghua , Feldman Arthur M. , Chilian William M. , Zhang Cuihua
Published: April 2007

Background—

We tested whether tumor necrosis factor (TNF)-α increases arginase expression in endothelial cells as one of the primary mechanisms by which this inflammatory cytokine compromises endothelial function during ischemia-reperfusion (I/R) injury.

Methods and Results—

Mouse hearts were subjected to 30 minutes of global ischemia followed by 90 minutes of reperfusion and their vasoactivity before and after I/R was examined in wild-type (WT), tumor necrosis factor knockout (TNF
−/−
), and TNF 1.6 (TNF
++/++
) mice. In WT mice, dilation to the endothelium-dependent vasodilator ACh was blunted in I/R compared with sham control. L-arginine or arginase inhibitor NOHA restored NO-mediated coronary arteriolar dilation in WT I/R mice. O
2
−
production was reduced by eNOS inhibitor, L-NAME, or NOHA in WT I/R mice. In TNF
−/−
mice, I/R did not alter Ach-induced vasodilation and O
2
−
production compared with sham mice. The increase in arginase expression that occurs during I/R in WT mice was absent in TNF
−/−
mice. Arginase expression was confined largely to the endothelium and independent of inflammatory cell invasion. Arginase activity was markedly lower in TNF
−/−
, but higher in WT I/R than that in WT sham mice.

Conclusions—

Our data demonstrate TNF-α upregulates expression of arginase in endothelial cells, which leads to O
2
−
production then induces endothelial dysfunction in I/R injury.
Expression of Heme Oxygenase-1 in Human Vascular Cells Is Regulated by Peroxisome Proliferator-Activated Receptors
Authors: Krönke Gerhard , Kadl Alexandra , Ikonomu Elena , Blüml Stefan , Fürnkranz Alexander , Sarembock Ian J. , Bochkov Valery N. , Exner Markus , Binder Bernd R. , Leitinger Norbert
Published: April 2007

Objective—

Activation of peroxisome proliferator-activated receptors (PPARs) by lipid-lowering fibrates and insulin-sensitizing thiazolidinediones inhibits vascular inflammation, atherosclerosis, and restenosis. Here we investigate if the vasculoprotective and anti-inflammatory enzyme heme oxygenase-1 (HO-1) is regulated by PPAR ligands in vascular cells.

Methods and Results—

We show that treatment of human vascular endothelial and smooth muscle cells with PPAR ligands leads to expression of HO-1. Analysis of the human HO-1 promoter in transient transfection experiments together with mutational analysis and gel shift assays revealed a direct transcriptional regulation of HO-1 by PPARα and PPARγ via 2 PPAR responsive elements. We demonstrate that a clinically relevant polymorphism within the HO-1 promoter critically influences its transcriptional activation by both PPAR isoforms. Moreover, inhibition of HO-1 enzymatic activity reversed PPAR ligand-mediated inhibition of cell proliferation and expression of cyclooxygenase-2 in vascular smooth muscle cells.

Conclusion—

We demonstrate that HO-1 expression is transcriptionally regulated by PPARα and PPARγ, indicating a mechanism of anti-inflammatory and antiproliferative action of PPAR ligands via upregulation of HO-1. Identification of HO-1 as a target gene for PPARs provides new strategies for therapy of cardiovascular diseases and a rationale for the use of PPAR ligands in the treatment of other chronic inflammatory diseases.
Plasmin Triggers Cytokine Induction in Human Monocyte-Derived Macrophages
Authors: Li Qun , Laumonnier Yves , Syrovets Tatiana , Simmet Thomas
Published: April 2007

Objective—

Fibrinolytic activity is upregulated in atherosclerotic lesions, yet little is known about the role of plasmin in macrophage function. We postulated a direct effect of plasmin on human monocyte-derived macrophages.

Methods and Results—

Plasmin activates macrophages via the annexin A2 heterotetramer composed of annexin A2 and S100A10 with subsequent stimulation of Janus kinase JAK1/TYK2 signaling. JAK1/TYK2 leads to STAT3 activation, Akt-dependent NF-κB activation, and phosphorylation of extracellular signal-regulated kinase 1/2 and mitogen-activated kinase p38. These signaling pathways trigger nuclear translocation of STAT3 and p65 transcription factors and the induction of the proinflammatory cytokines tumor necrosis factor-α and IL-6. Inhibitors of JAK, p38, and NF-κB revealed that these signaling pathways are indispensable for the plasmin-mediated tumor necrosis factor-α and IL-6 induction. By contrast, the extracellular signal-regulated kinase 1/2 activation is essential only for the IL-6 expression. The activation clearly depends on the proteolytic activity of plasmin, which cleaves the A2 subunit of the annexin A2 heterotetramer. Downregulation of each of the receptor subunits by antisense oligodeoxynucleotides abolished the plasmin-induced expression of proinflammatory cytokines stressing the crucial role the annexin A2 heterotetramer.

Conclusions—

Plasmin generated at sites of inflammation such as atherosclerotic lesions will trigger cytokine expression in human macrophages.