bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting Angiogenesis for Mammary Cancer Prevention: Factors to Consider in Experimental Design and Analysis
Authors: Thompson Henry J. , McGinley John N. , Wolfe Pamela , Spoelstra Nicole S. , Knott Katrina K.
Published: June 2022

An experimental model developed to investigate premalignant stages of breast cancer was used to establish a rationale for designing experiments that target angiogenesis for cancer prevention. Blood vessels were identified via CD31 immunostaining, and all vessels that occurred in a 50 μm wide region circumscribing each pathology were counted using a digital imaging technique. The blood vessel density associated with terminal end buds was unaffected by carcinogen treatment, whereas vessel density was higher in intraductal proliferations and ductal carcinoma in situ than in terminal end buds (P < 0.001) and total vascularity increased with morphologic progression. In comparison with intraductal proliferation or ductal carcinoma in situ, mammary carcinomas had higher vascular density in the tissue surrounding the cancer with a marked increase in the number of blood vessels <25 μm2. These data suggest that antiangiogenic chemopreventive agents would inhibit cancer occurrence if initiated at any premalignant stage of the carcinogenic process. Because increased vascular density observed during premalignancy could be explained by the size expansion of the lesion and its encroachment on a preexisting blood supply, by pathology-associated vessel expansion, and/or by angiogenesis, it remains to be determined if antiangiogenic agents will reduce the prevalence of premalignant lesions or cause their accumulation by blocking conversion to carcinomas. Failure to recognize the patterns of vascularization that accompany morphologic progression could limit the success of efforts to target angiogenesis for cancer prevention and lead to misinformation about how agents that affect blood vessel formation or growth inhibit the carcinogenic process.
Consumption of the Putative Chemopreventive Agent Curcumin by Cancer Patients: Assessment of Curcumin Levels in the Colorectum and their Pharmacodynamic Consequences
Authors: Garcea Giuseppe , Berry David P. , Jones Donald J.L. , Singh Raj , Dennison Ashley R. , Farmer Peter B. , Sharma Ricky A. , Steward William P. , Gescher Andreas J.
Published: June 2022

Curcumin, a constituent of the spice turmeric, has been shown to reduce the adenoma burden in rodent models of colorectal cancer accompanied by a reduction of levels of the oxidative DNA adduct 3-(2-deoxy-β-di-erythro-pentafuranosyl)-pyr[1,2-α]-purin-10(3H)one (M1G) and of expression of the enzyme cyclooxygenase-2 (COX-2). We tested the hypothesis that pharmacologically active levels of curcumin can be achieved in the colorectum of humans as measured by effects on levels of M1G and COX-2 protein. Patients with colorectal cancer ingested curcumin capsules (3,600, 1,800, or 450 mg daily) for 7 days. Biopsy samples of normal and malignant colorectal tissue, respectively, were obtained at diagnosis and at 6 to 7 hours after the last dose of curcumin. Blood was taken 1 hour after the last dose of curcumin. Curcumin and its metabolites were detected and quantitated by high-performance liquid chromatography with detection by UV spectrophotometry or mass spectrometry. M1G levels and COX-2 protein expression were measured by immunoslot blot and Western blotting, respectively. The concentrations of curcumin in normal and malignant colorectal tissue of patients receiving 3,600 mg of curcumin were 12.7 ± 5.7 and 7.7 ± 1.8 nmol/g, respectively. Curcumin sulfate and curcumin glucuronide were identified in the tissue of these patients. Trace levels of curcumin were found in the peripheral circulation. M1G levels were 2.5-fold higher in malignant tissue as compared with normal tissue (P < 0.05 by ANOVA). Administration of curcumin (3,600 mg) decreased M1G levels from 4.8 ± 2.9 adducts per 107 nucleotides in malignant colorectal tissue to 2.0 ± 1.8 adducts per 107 nucleotides (P < 0.05 by ANOVA). COX-2 protein levels in malignant colorectal tissue were not affected by curcumin. The results suggest that a daily dose of 3.6 g curcumin achieves pharmacologically efficacious levels in the colorectum with negligible distribution of curcumin outside the gut.
Effect of Folic Acid Supplementation on the Folate Status of Buccal Mucosa and Lymphocytes
Authors: Basten Graham P. , Hill Marilyn H. , Duthie Susan J. , Powers Hilary J.
Published: June 2022

Folate deficiency may be associated with an increased risk of cancer at certain sites. There is a need to measure folate status and putative biomarkers of cancer risk in the same target tissue, or in surrogate tissues. A study was carried out to develop a method for the rapid measurement of folate in human buccal mucosa and lymphocytes and to evaluate the responsiveness of this measurement in both tissues to folic acid supplementation in healthy subjects, relative to conventional markers of folate status. Three hundred and twenty-three adults, ages between 20 and 60 years, were screened for RBC folate concentrations. Sixty-five subjects with red cell folate between 200 and 650 nmol/L participated in a randomized, double blind, placebo-controlled, folic acid (1.2 mg) intervention trial, lasting 12 weeks. As anticipated, a significant baseline correlation (r = 0.36, P < 0.01) was observed between red cell folate and plasma 5-methyltetrahydrofolate (5-MeTHF). Lymphocyte total folate was significantly associated with plasma 5-MeTHF (r = 0.28, P < 0.05) and plasma total homocysteine concentration (r = −0.34, P < 0.05). Buccal mucosa total folate showed no correlation with either red cell folate or 5-MeTHF, but was significantly associated with lymphocyte total folate (r = 0.35, P < 0.01). Supplementation elicited a significant increase in lymphocyte total folate (P < 0.01), and this was strongly associated with the increase in RBC total folate (P < 0.01) and plasma 5-MeTHF (P < 0.01). Buccal mucosa total folate was not influenced by folate supplementation. Methods have been developed for the rapid measurement of lymphocyte and buccal mucosal total folate. Lymphocyte folate is sensitive to folate intake and is reflected by plasma 5-MeTHF.
Specimen Allocation in Longitudinal Biomarker Studies: Controlling Subject-Specific Effects by Design
Authors: Tworoger Shelley S. , Yasui Yutaka , Chang Lilly , Stanczyk Frank Z. , McTiernan Anne
Published: June 2022

It is important to understand specimen allocation factors that may impact the validity and reliability of results in longitudinal studies examining within-person changes in biomarker levels. Using data from a randomized clinical trial of an exercise intervention in 136 postmenopausal women, we determined the effect of assaying the baseline and follow-up samples of some subjects in different batches on the intervention effect estimates for serum concentrations of estrone, estradiol, testosterone, androstenedione, and dehydroepiandrosterone. Twenty-five subjects had their baseline and 3-month follow-up samples and 50 subjects had their baseline and 12-month samples assayed in different batches; all other subjects had their baseline, 3-month, and 12-month samples assayed in the same batch. Subjects with split samples were reassayed with all samples in the same batch. We compared the estimated regression coefficient for the intervention effect using the split sample data with one estimated excluding the split sample data and one estimated replacing the split sample data with the reassayed data. The median percentage difference in the intervention effect estimate was 59.6% between using versus excluding the split sample data and 74.6% between using the split sample versus using the reassayed data. In general, the coefficients from the model including the split sample data were closer to zero and statistically less significant than those from the models excluding the split sample data or using the reassayed data. These results suggest that bias can be artificially introduced into intervention effect estimates of longitudinal studies if samples from a subject are not assayed in the same batch.
Improved Method for Determination of 1-Hydroxypyrene in Human Urine
Authors: Carmella Steven G. , Le Ky-Anh , Hecht Stephen S.
Published: June 2022

We have developed an improved method for the analysis of human urine for 1-hydroxypyrene (1-HOP), an accepted biomarker of polycyclic aromatic hydrocarbon uptake. This method takes advantage of commercially available 96-well format devices, which expedite sample preparation before quantitation by HPLC with fluorescence detection. In addition to improved speed of analysis, which is critical for the application of this assay in molecular epidemiology studies, the method described here uses an internal standard, 1-hydroxybenz[a]anthracene, improved sample preparation methods, and optimized HPLC and fluorescence detection conditions. The resulting method for analysis of 1-HOP is sensitive (detection limit, 0.05 pmol/mL urine), accurate (as determined by known addition of 1-HOP to urine), and precise [relative SD (RSD), 4.13%]. A longitudinal study of 1-HOP levels in the urine of 10 nonsmokers showed considerable day-to-day (mean RSD, 55.1 %) and week-to-week (mean RSD, 38.2 %) intra-individual variation, indicating the necessity for multiple sampling in studies concerned with relatively small differences in polycyclic aromatic hydrocarbon exposure.
Carbohydrates and the Risk of Breast Cancer among Mexican Women
Authors: Romieu Isabelle , Lazcano-Ponce Eduardo , Sanchez-Zamorano Luisa Maria , Willett Walter , Hernandez-Avila Mauricio
Published: June 2022

Objective: High carbohydrate intake has been hypothesized to be a risk factor for breast cancer, possibly mediated by elevated levels of free insulin, estrogens, and insulin-like growth factor-1. Therefore, we conducted a population-based case-control study among a Mexican population characterized by relatively low fat and high carbohydrate intakes. Methods: Women ages 20 to 75 years, identified through six hospitals in Mexico City (n = 475), were interviewed to obtain data relating to diet (using a food frequency questionnaire) and breast cancer risk factors. Controls (n = 1,391) were selected from the Mexico City population using a national sampling frame. Results: Carbohydrate intake was positively associated with breast cancer risk. Compared with women in the lowest quartile of total carbohydrate intake, the relative risk of breast cancer for women in the highest quartile was 2.22 [95% confidence interval (95% CI) 1.63-3.04], adjusting for total energy and potential confounding variables (P for trend < 0.0001). This association was present in premenopausal and postmenopausal women (for highest versus lowest quartile, odds ratio 2.31, 95% CI 1.36-3.91 in premenopausal women and odds ratio 2.22, 95% CI 1.49-3.30 in postmenopausal women). Among carbohydrate components, the strongest associations were observed for sucrose and fructose. No association was observed with total fat intake. Discussion: In this population, a high percentage of calories from carbohydrate, but not from fat, was associated with increased breast cancer risk. This relation deserves to be investigated further, particularly in populations highly susceptible to insulin resistance.
Relationship between Methylenetetrahydrofolate Reductase C677T and A1298C Genotypes and Haplotypes and Prostate Cancer Risk and Aggressiveness
Authors: Cicek Mine S. , Nock Nora L. , Li Li , Conti David V. , Casey Graham , Witte John S.
Published: June 2022

Previous reports indicate that polymorphisms in the MTHFR gene play a role in cancer development, but their potential impact on prostate cancer has not been well studied. Here, we evaluate the association between two MTHFR polymorphisms, C677T and A1298C, and prostate cancer risk and aggressiveness in a moderately large family-based case-control study (439 cases and 479 sibling controls). Among all study subjects, we observed no association between the C677T variant and prostate cancer but a slight positive association between the A1298C variant and risk of this disease [odds ratio (OR) 1.41, 95% confidence interval (CI) 0.96-2.06; P = 0.08]. When stratifying the study population by disease aggressiveness at diagnosis, the C677T variant was positively associated with risk among men with less advanced disease (OR 1.86, 95% CI 1.00-3.46; P = 0.05). In contrast, when looking at men with more advanced disease, the C677T variant was inversely associated with risk (OR 0.51, 95% CI 0.32-0.82; P = 0.01), whereas the A1298C variant was positively associated with risk (OR 1.79, 95% CI 1.06-3.02; P = 0.03). Furthermore, the 677T-1298A haplotype was positively associated with prostate cancer among men with less advanced disease (OR 1.84, 95% CI 1.07-3.16; P = 0.03) and inversely associated with risk of more advanced disease (OR 0.47, 95% CI 0.29-0.76; P = 0.002). Our findings suggest that 677T and 1298A, or another variant on their haplotype, may be associated with a reduced risk of progression to more advanced prostate cancer.
Validation of p16INK4a as a Marker of Oncogenic Human Papillomavirus Infection in Cervical Biopsies from a Population-Based Cohort in Costa Rica
Authors: Wang Sophia S. , Trunk Marcus , Schiffman Mark , Herrero Rolando , Sherman Mark E. , Burk Robert D. , Hildesheim Allan , Bratti M. Concepcion , Wright Tom , Rodriguez Ana Cecilia , Chen Sabrina , Reichert Anja , von Knebel Doeberitz Christina , Ridder Ruediger , von Knebel Doeberitz Magnus
Published: June 2022

Due to the high prevalence of cancer-associated types of human papillomavirus (HPV) and the poorly reproducible histologic classification of low-grade lesions, identifying infected women at highest risk for cancer prior to neoplastic progression remains a challenge. We therefore explored the utility of p16INK4a immunostaining as a potential diagnostic and prognostic biomarker for cervical neoplasia using paraffin-embedded tissue blocks (punch biopsies and loop electrosurgical excision procedures) obtained from women referred to colposcopy during the enrollment phase of the Guanacaste Project (1993 to 1994). All blocks from 292 women selected by HPV status (HPV negative, nononcogenic HPV positive, or oncogenic HPV positive) and representing the diagnostic spectrum of the population [normal to precancer: cervical intraepithelial neoplasia (CIN) 3] were immunostained for p16INK4a using the p16INK4a research kit based on the monoclonal antibody clone E6H4 (MTM Laboratories, Heidelberg, Germany). For CIN3, the sensitivity of diffuse p16INK4a immunostaining was 100% and the specificity was 95%. For CIN2, the sensitivity and specificity for diffuse staining were 81.1% and 95.4%, respectively. Generalized to the 10,000-woman cohort, this translated to positive predictive value and negative predictive value of 13.9% and 100% for CIN3, respectively, and 20.4% and 99.7% for CIN2 or CIN3, respectively. Of women with an initial diagnosis of less than CIN2 for whom follow-up data for up to 5 to 7 years were available, 44% with diffuse staining developed persistent infection (CIN2 or CIN3). Whereas our data support the diagnostic potential for p16INK4a, further prospective studies with detailed follow-up determining the prognostic capacity of this marker are needed.
Dietary Glycemic Load, Carbohydrate, Sugar, and Colorectal Cancer Risk in Men and Women
Authors: Michaud Dominique S. , Fuchs Charles S. , Liu Simin , Willett Walter C. , Colditz Graham A. , Giovannucci Edward
Published: June 2022

Hyperinsulinemia may explain excess colorectal cancer among individuals who are overweight or inactive. Recent studies have observed elevated colorectal cancer risk among individuals with elevated insulin levels 2 hours after oral glucose challenge or with elevated plasma C-peptide levels. The effect of consuming a high glycemic diet on colorectal risk, however, remains uncertain. Two prospective cohort studies, the Nurses' Health Study and the Health Professionals Follow-up Study, contributed up to 20 years of follow-up. After exclusions, 1,809 incident colorectal cancers were available for analyses. Dietary glycemic load (GL) was calculated as a function of glycemic index (postprandial blood glucose response as compared with a reference food), carbohydrate content, and frequency of intake of individual foods reported on food frequency questionnaires. Multivariable Cox proportional hazards models were used to adjust for potential confounders. Intakes of dietary carbohydrate, GL, overall glycemic index, sucrose, and fructose were not associated with colorectal cancer risk in women. A small increase in risk was observed in men with high dietary GL (multivariate relative risk, 1.32; 95% confidence interval, 0.98-1.79; highest versus lowest quintile), sucrose or fructose (multivariate relative risk, 1.37; 95% confidence interval, 1.05-1.78; highest versus lowest quintile of fructose, P = 0.008). Associations were slightly stronger among men with elevated body mass index (≥25 kg/m2). Results among women were similar after stratifying by body mass index or physical activity. High intakes of GL, fructose, and sucrose were related to an elevated colorectal cancer risk among men. For women, however, these factors did not seem to increase the risk of colorectal cancer.
Risk of Non-Hodgkin's Lymphoma and Family History of Lymphatic, Hematologic, and Other Cancers
Authors: Chatterjee Nilanjan , Hartge Patricia , Cerhan James R. , Cozen Wendy , Davis Scott , Ishibe Naoko , Colt Joanne , Goldin Lynn , Severson Richard K.
Published: June 2022

Background: An elevated risk of developing non-Hodgkin's lymphoma (NHL) has been associated with a family history of NHL and several other malignancies, but the magnitude of risks and mechanisms are uncertain. Methods: We used self-reported family history data from a recent multicenter U.S.-based case-control studies of NHL to evaluate familial aggregation of NHL with various hematolymphoproliferative and other cancers. Estimates of familial aggregation were obtained as hazard ratios (HR) that compare incidence of different cancers in first-degree relatives of NHL cases with that in the first-degree relatives of NHL controls. Limitations of the study included low participation rates (76% for cases and 52% for controls) and potential differential accuracy of recall. Results: Risk of NHL was elevated in relatives of NHL cases [HR, 2.9; 95% confidence interval (95% CI), 0.95–8.53]; the aggregation seems to be stronger for siblings (HR, 7.6; 95% CI, 0.98–58.8) and for male relatives (HR, 6.2; 95% CI, 0.77–50.0). Risk of Hodgkin's lymphoma seems to be also elevated among relatives of early-onset (<50 years) NHL cases (HR, 3.2; 95% CI, 0.88–11.6). Evaluation of family history of other cancers provided modest evidence for an increased risk of melanoma of the skin (HR, 2.9; 95% CI, 1.08–7.75), pancreatic cancer (HR, 2.1; 95% CI, 0.96–4.43), stomach cancer (HR, 1.8; 95% CI, 0.91–3.63), and prostate cancer (HR, 1.3; 95% CI, 0.87–1.99). Conclusions: These results are consistent with previous findings of familial aggregation of NHL, Hodgkin's lymphoma, and a few other cancers. The pattern of male-specific and sibling-specific familial aggregation of NHL we observed, if confirmed, may shed new light on the possible mechanisms that underlie familial aggregation of the disease.
Dietary Intake of Conjugated Linoleic Acids and Risk of Premenopausal and Postmenopausal Breast Cancer, Western New York Exposures and Breast Cancer Study (WEB Study)
Authors: McCann Susan E. , Ip Clement , Ip Margot M. , McGuire Michelle K. , Muti Paola , Edge Stephen B. , Trevisan Maurizio , Freudenheim Jo L.
Published: June 2022

Specific fatty acids may have differential effects on breast cancer etiology. Animal studies have suggested that conjugated linoleic acids (CLA), a group of fatty acids found predominantly in dairy products and the meat of ruminants, have potent anticarcinogenic properties. We examined breast cancer risk and dietary CLA intake among 1,122 women with primary, incident, histologically confirmed breast cancer and 2,036 controls frequency matched to cases by age, race, and county of residence. Diet was assessed with a self-administered 104-item food frequency questionnaire and other relevant data were collected by detailed in-person interviews. We examined risk with intake of total CLAs and the 9c,11t-18:2 isomer of CLA (9,11 CLA). Odds ratios and 95% confidence intervals were estimated by unconditional logistic regression, adjusting for age, the residual of fat adjusted for energy, and other breast cancer risk factors. No association was observed between intakes of total CLA or 9,11 CLA and overall risk of premenopausal or postmenopausal breast cancer. We observed little association between CLA intakes and risk of estrogen receptor (ER)–negative or ER-positive tumors, although, compared with premenopausal women in the lowest quartile of 9,11 CLA intake, those in the highest quartile had a marginally significant reduction in risk of having an ER-negative tumor (odds ratio, 0.40; 95% confidence interval, 0.16–1.01). Our findings suggest that, although CLA intake was not related to overall breast cancer risk, there may be associations with tumor biology at least among premenopausal women.
Overexpression of m-Calpain in Human Colorectal Adenocarcinomas
Authors: Lakshmikuttyamma Ashakumary , Selvakumar Ponniah , Kanthan Rani , Kanthan Selliah Chandra , Sharma Rajendra K.
Published: June 2022

Background: Calpains represent a well-conserved family of Ca2+-dependent proteolytic enzymes. Recently, the importance of calpain in the metastatic process has received great attention. To investigate whether m-calpain contributes to the pathogenesis of colorectal cancer, we investigated the expression of m-calpain and its inhibitors, calpastatin and high-molecular-weight calmodulin-binding protein (HMWCaMBP), in human colorectal surgical specimens. Methods: Fifty cases of colon carcinoma were evaluated for this study. Of 50 cases evaluated, we presented in this report six cases for m-calpain, calpastatin and HMWCaMBP protein expression by Western blot analyses was done in both normal and invasive tumor components of human samples. In addition, immunohistochemistry analysis was also carried out in all patients. Results: The activity and protein expression of m-calpain was significantly higher in colorectal adenocarcinoma than in normal colonic mucosa. This finding was corroborated by immunohistochemical studies that showed strong cytoplasmic staining in the colon tumors with m-calpain antibody. The decreased expression of these calpain inhibitors (calpastatin and HMWCaMBP) paralleled increased activity and expression of calpain in colorectal adenocarcinoma and the well-documented involvement of this Ca2+-dependent protease in colon tumor. Conclusion: Increased activity and moderate staining of m-calpain in polyps show the usage of this enzyme as a marker for the early detection of colorectal adenocarcinoma using immunologic approaches. These findings represent the first description of calpain overexpression in colorectal cancer. This has implications with regard to the design of chemotherapeutic drugs as well as in monitoring colorectal cancer in early stages of the metastatic process.
Ursodiol Use Is Possibly Associated with Lower Incidence of Hepatocellular Carcinoma in Hepatitis C Virus–Associated Liver Cirrhosis
Authors: Tarao Kazuo , Fujiyama Shigetoshi , Ohkawa Shinichi , Miyakawa Kaoru , Tamai Setsuo , Hirokawa Satoru , Masaki Takahiro , Tanaka Katsuaki
Published: June 2022

In a previous study of patients with hepatitis C virus (HCV)–associated liver cirrhosis (HCV-LC), we showed that increased liver inflammation, as assessed by higher serum alanine aminotransferase (ALT), was associated with increased risk for the development of hepatocellular carcinoma (HCC). This suggested that suppression of inflammation might inhibit HCC development in HCV-LC. Several agents have been suggested to possess chemopreventive potential against the development of HCC in chronic HCV-associated liver disease, including herbal medicines, such as Stronger-Neo-Minophagen C (glycyrrhizin) and Sho-saiko-to (TJ-9). Ursodiol [ursodeoxycholic acid (UDCA)], a bile acid widely used to treat cholestatic liver diseases, also possesses anti-inflammatory properties in liver disease. We hypothesized that suppression of liver inflammation, as assessed by decreases in serum ALT, might inhibit HCC occurrence in patients with HCV-LC. In this study, the preventive effect of UDCA on HCC was examined in patients with early-stage HCV-LC. One hundred two patients with HCV-LC (Child stage A) were treated with anti-inflammatory drugs, Stronger-Neo-Minophagen C,Sho-saiko-to, or UDCA, with the goal of lowering the average serum ALT level to <80 IU. Iftheaverage ALT level did not remain <80 IU after treatment with one agent, multiagent therapy was initiated. The patients were followed up for >5 years and were retrospectively subdivided into two groups: 56 UDCA users (group A) and 46 UDCA nonusers (group B). The mean ± SD dosage of UDCA administered in group A was 473.7 ± 183.0 mg/d. The average duration of UDCA administration in group A was 37.3 ± 15.9 months over the 5-year study period. The cumulative incidence of HCC was recorded. The 5-year incidence of HCC in group A was 17.9% (10 of 56) and was significantly lower than that in group B (39.1%, 18 of 46; P = 0.025). The risk for HCC incidence, calculated by a logistic regression model, showed that the administration of UDCA significantly decreased hepatocarcinogenesis (P = 0.036). The herbal medicines used were comparable in dosage and treatment duration in the UDCA and non-UDCA groups. In conclusion, UDCA might prevent HCC development in HCV-LC. Interestingly, because the serum ALT trends over time were nearly the same in both groups, the chemopreventive effectiveness of UDCA was not accompanied by greater reductions in ALT compared with the UDCA nonusers.
Temporal Variation and Identification of Factors Associated with Endogenous Retinoic Acid Isomers in Serum from Brazilian Women
Authors: Siegel Erin M. , Craft Neal E. , Roe Denise J. , Duarte-Franco Eliane , Villa Luisa L. , Franco Eduardo L. , Giuliano Anna R.
Published: June 2022

Objective: Retinoids (natural and synthetic derivatives of vitamin A) have cancer chemotherapeutic and chemopreventive activities. Retinoic acid (RA) treatment has been associated with significant regression of preneoplastic lesions. However, serious toxicity associated with some therapies has made long-term chemoprevention in healthy populations unfeasible. Recently, serum RA has been shown to increase in response to oral retinol (vitamin A) supplementation. Here, we assess the variability of circulating RA levels and the lifestyle, demographic, and nutritional factors that explain such variability.

Method: Total RA concentration and the concentrations of RA isomers (all-trans-RA, 13-cis-RA, and 9-cis-RA) were measured by high-pressure liquid chromatography in serum samples obtained 4 months apart from 502 women participating in the Ludwig-McGill Cohort (São Paulo, Brazil).

Results: The relative abundance of the three RA isomers was similar for each visit (baseline and month 4), with 13-cis-RA having the highest concentrations followed by 9-cis-RA and all-trans-RA. The within-person variability of total RA and individual isomers was low. Using multivariate logistic regression models (upper tertile versus low/middle tertile of serum RA), we found that age, race, oral contraceptive use, total number of pregnancies, and season of initial blood draw were significantly associated with at least one endogenous RA isomer level. All endogenous RA isomers were positively associated with serum retinol, β-carotene, and β-cryptoxanthin levels.

Conclusion: These results have implications for the design of future epidemiologic studies focused on assessing RA-disease association and intervention studies aimed at modulating RA levels.
p53 Codon 72 Polymorphic Variants, Loss of Allele-Specific Transcription, and Human Papilloma Virus 16 and/or 18 E6 Messenger RNA Expression in Squamous Cell Carcinomas of the Head and Neck
Authors: Scheckenbach Kathrin , Lieven Oliver , Götte Karl , Bockmühl Ulrike , Zotz Rainer , Bier Henning , Balz Vera
Published: June 2022

A polymorphism at codon 72 of the human tumor suppressor p53 determines translation into either arginine or proline. Yet, the impact of this amino acid variability on the risk to develop malignant tumors, particularly carcinomas associated with human papilloma virus (HPV) infections, remains unresolved because of contradictory results. To address a potential correlation between the different genotypes and the manifestation of squamous cell carcinomas of the head and neck (SCCHN), we determined the p53 codon 72 in 193 healthy subjects and 122 unselected SCCHN with known HPV status. Furthermore, loss of allele-specific transcription was analyzed in p53 codon 72 heterozygous (Arg/Pro) SCCHN and correlated with HPV 16 and/or 18 E6 transcript expression. We found a moderately increased risk (odds ratio, 1.86; 95% confidence interval, 1.0-3.3) for individuals with germ line heterozygosity to develop SCC of the pharynx. On the other hand, p53 codon 72 polymorphic variants, most notably the Arg/Arg genotype, showed no association with the presence of HPV 16 and/or 18 E6 transcript. Moreover, there was no evidence for HPV-driven selection in SCCHN with allele-specific loss of transcription. Our data suggest that the p53 codon 72 polymorphism has a minor impact on the development of SCCHN.
Nuclear Morphometry and Molecular Biomarkers of Actinic Keratosis, Sun-Damaged, and Nonexposed Skin
Authors: Carpenter Philip M. , Linden Kenneth G. , McLaren Christine E. , Li Kuo-Tung , Arain Shehla , Barr Ronald J. , Hite Pamela , Sun Joannie D. , Meyskens Frank L.
Published: June 2022

Computer-assisted image analysis is useful for quantifying the histologic and molecular changes of sun-induced squamous cell carcinoma progression. We used the CAS 200 image analysis system to measure nuclear morphometric parameters, p53 expression, and proliferation markers in actinic keratosis (AK), sun-exposed, and normal skin in 51 patients. Nuclear morphometry revealed significant increases in nuclear absorbance, irregularity of nuclear shape, and nuclear size in AK compared with normal and sun-damaged skin. These parameters showed significantly greater variability in AK nuclei. Argyrophyllic nucleolar organizer area and number were also significantly greater in AK compared with sun-damaged skin and normal skin. Ki67 and p53 expressions were both increased in sun-damaged skin relative to normal and greater still in AK. These data are evidence that sun damage induces proliferation and p53 abnormalities before the appearance of nuclear abnormalities and their associated DNA instability. Following these changes during a skin cancer chemopreventative trial can then help assess the efficacy of the agent and help determine where in the progression of neoplastic changes it exerts its biological effects.
Sex Differences in Numbers of Nevi on Body Sites of Young European Children: Implications for the Etiology of Cutaneous Melanoma
Authors: Autier Philippe , Boniol Mathieu , Severi Gianluca , Pedeux Remy , Grivegnée André-Robert , Doré Jean-François ,   European Organisation for Research and Treatment of Cancer Melanoma Group
Published: June 2022

Background: Since 1950, the greatest increase in cutaneous melanoma incidence in fair-skinned males took place on the trunk and on the head and neck, whereas in females, it took place on the limbs, mainly on the lower limbs. We examined the influence of sex on numbers and size of nevi on different body sites in white European schoolchildren.

Methods: Information about each holiday period since birth to interview was recorded from parents of six hundred twenty-eight 6- to 7-year-old children in four European cities (Brussels (Belgium), Bochum (Germany), Lyons (France), and Rome (Italy)). Number and anatomic location of small (2-4.9 mm) and large (≥5 mm) nevi and individual susceptibility to sunlight were independently assessed.

Results: After adjustment for host characteristics, sun exposure, and sun protection habits, males had 7% [95% confidence interval (95% CI), −7 to 19] more small nevi than females. However, compared to females, numbers of small nevi were increased by 17% (95% CI, 1-31) on the head and neck and by 16% (95% CI, 2-27) on the trunk and shoulders. In contrast, in males, the number of small nevi on upper limbs was decreased by −5% (95% CI, −26 to 13), and on lower limbs by −8% (95% CI, −34 to 13). The number of large nevi was 6% higher in males than in females (95% CI, −26 to 30).

Conclusions: The sex differences in small nevus distribution in schoolchildren reflect the sex differences in the anatomic distribution of melanoma in adults. Sex differences in sun exposure behaviors, dressing, and clothing would just add their effects to the sex-dependent inherited propensity to develop nevi on a given body site. These results reinforce the hypothesis by which childhood would be a decisive period for the occurrence of sun-induced biological events implicated in the genesis of cutaneous melanoma.
Plasma Enterolactone and Breast Cancer Incidence by Estrogen Receptor Status
Authors: Olsen Anja , Knudsen Knud Erik Bach , Thomsen Birthe L. , Loft Steffen , Stripp Connie , Overvad Kim , Møller Susanne , Tjønneland Anne
Published: June 2022

The phytoestrogen enterolactone has been hypothesized to prevent breast cancer. Because one of the biological effects of enterolactone is probably estrogenic, it is possible that the preventive effect on breast cancer differs with the estrogen receptor (ER) α status of the tumor. The objective of this study was to investigate whether high plasma levels of enterolactone are associated with breast cancer risk and whether the ERα status of the tumor influences this relation. The cohort study Diet, Cancer and Health included 29,785 women, ages 50 to 64 years, between 1993 and 1997. Information about diet and life-style factors was obtained by questionnaire, and blood was drawn from each participant. We matched 381 postmenopausal breast cancer cases to 381 controls and analyzed the concentration of enterolactone in plasma with a time-resolved fluoroimmunoassay. Associations between plasma concentrations of enterolactone and breast cancer were analyzed by logistic regression. The incidence rate ratio (IRR) for all breast cancer was 0.93 [95% confidence interval (CI), 0.86-1.01] per 20 nmol/L higher plasma concentration of enterolactone. For ERα-positive cancers (n=273) only a weak association was seen (IRR, 0.97; 95% CI, 0.88-1.06), whereas for ERα-negative cancers (n = 80; IRR, 0.71; 95% CI, 0.53-0.94) a protective effect was seen per 20 nmol/L higher plasma enterolactone. In accordance with earlier research, we found a tendency toward a lower risk for breast cancer with higher concentrations of enterolactone, which was restricted almost entirely to ERα-negative breast cancer.
Association of Genetic Variants in the Calcium-Sensing Receptor with Risk of Colorectal Adenoma
Authors: Peters Ulrike , Chatterjee Nilanjan , Yeager Meredith , Chanock Stephen J. , Schoen Robert E. , McGlynn Katherine A. , Church Timothy R. , Weissfeld Joel L. , Schatzkin Arthur , Hayes Richard B.
Published: June 2022

Objective: Evidence suggests that calcium prevents colorectal cancer, possibly mediated through the calcium-sensing receptor (CASR). We assessed the associations between CASR gene variants and risk for colorectal adenoma, a cancer precursor. We further investigated gene-diet interactions between the CASR variants and calcium intake on adenoma risk.

Methods: Individuals with advanced distal adenomas (n = 716) and controls with a negative sigmoidoscopy exam (n = 729) were randomly selected from participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Three nonsynonymous variants in the intracellular signaling region of CASR (A986S, R990G, Q1011E) were analyzed by Taqman.

Results: Compared with the most common diplotype (haplotype pair), the odds ratios for advanced adenoma were 0.80 [95% confidence interval (CI), 0.60-1.06], 0.79 (95% CI, 0.55-1.13), and 0.56 (95% CI, 0.36-0.88) for the other three common diplotypes (>5% frequency). Although calcium intake was inversely associated with adenoma risk, CASR diplotypes did not modify this association. However, the power to investigate interactions was limited.

Conclusion: Variants in the CASR intracellular signaling region were significantly associated with the risk of advanced adenoma.
Urinary Estrogen Metabolites and Their Ratio among Asian American Women
Authors: Falk Roni T. , Fears Thomas R. , Xu Xia , Hoover Robert N. , Pike Malcolm C. , Wu Anna H. , Nomura Abraham M.Y. , Kolonel Laurence N. , West Dee W. , Sepkovic Daniel W. , Bradlow H. Leon , Ziegler Regina G.
Published: June 2022

Controversy persists regarding the role of a low ratio of 2-hydroxyestone (2-OHE1)/16α-hydroxyestrone (16α-OHE1) as a potential estrogen metabolism marker of increased risk for breast cancer. Most of the evidence has been provided by case-control studies, where tumor effects on hormone metabolism are not known. Studies in populations at various risk of breast cancer are not consistent, with some suggesting that levels of the ratio may be altered by changes in diet and exercise. We studied Asian American women participating as controls in a case-control study of breast cancer in which migration history—a composite of the subject's place of birth, type of residence in Asia (urban or rural), length of time living in the West, and grandparents' place of birth—was associated with a 6-fold risk gradient that paralleled the historical differences in incidence rates between the United States and Asian countries. This population offered the possibility to address whether the ratio of 2-OHE1:16α-OHE1 differs according to recognized breast cancer risk factors, including migration history. Overnight 12-hour urines were obtained from 368 premenopausal and 143 naturally postmenopausal women of Chinese, Japanese, or Filipino descent who donated urines between 1985 and 1988. The estrogen metabolites 2-OHE1 and 16α-OHE1 were measured with an ELISA kit and adjusted for creatinine levels. In each ethnic group, the ratio of 2-OHE1:16α-OHE1 was consistently lower in women born in the West than in those who had migrated from Asia. For premenopausal women, the ratio declined 20% due to lower levels of 2-OHE1. Among postmenopausal women, the ratio was 23% lower in those born in the West, but no consistent patterns based on place of birth were observed for either 2-OHE1 or 16α-OHE1. The ratio did not vary with most recognized breast cancer risk factors, except for lower metabolite ratios in women with a younger age at first birth and more children, which runs contrary to the hypothesis, because both characteristics reduce breast cancer risk. Our study suggests that the ratio of 2-OHE1:16α-OHE1 may be a marker for lifestyle influences on estrogen metabolism associated with westernization.
Randomized Study of High-Dose Pulse Calcitriol or Placebo prior to Radical Prostatectomy
Authors: Beer Tomasz M. , Myrthue Anne , Garzotto Mark , O'Hara Michael F. , Chin Raymond , Lowe Bruce A. , Montalto Michelle A. , Corless Christopher L. , Henner W. David
Published: June 2022

Background: Cancer chemoprevention trials require enormous resources due to the large numbers of patients and the years of follow-up needed to achieve sufficient statistical power. Examination of candidate prevention agents using biomarkers as surrogate end points has been proposed as a method to rapidly identify promising agents for prevention trials. Treatment of patients with candidate agents prior to scheduled biopsy or surgical resection of malignancy allows for direct examination of the treatment effects on tumor tissue. In this study, we selected this approach to test several hypotheses about the effect of calcitriol (1,25-dihydroxycholecalciferol), the active form of vitamin D, on early-stage human prostate cancer.

Methods: After selection of surgical treatment for histologically confirmed adenocarcinoma of the prostate, patients were randomized to either calcitriol 0.5 μg/kg or placebo weekly for 4 weeks. The expression levels of the vitamin D receptor (VDR), proliferating cell nuclear antigen, PTEN (MMAC1/TEP1), c-Myc, transforming growth factor (TGF) β receptor type II (TGFβ RII), and Bcl-2 were quantified using immunohistochemistry in the patients' prostate specimens post surgery.

Results: Thirty-seven of 39 prostate tumors were evaluable for molecular end points. VDR expression was reduced in patients treated with calcitriol (mean, 75.3% of cells) compared with those that received placebo (mean, 98.6%; P = 0.005). Calcitriol treatment did not result in a statistically significant change in the fraction of cells expressing TGFβ RII, PTEN, or proliferating cell nuclear antigen. Bcl-2 and c-Myc expression was at the lower limits of detection in both the calcitriol group and the placebo group; therefore, we were unable to determine whether drug treatment induced a significant change in these biomarkers.

Conclusions: High-dose calcitriol down-regulates VDR expression in human prostate cancer. Further study is needed to determine the biological consequences of VDR down-regulation in prostate cancer. This study shows that the use of the preprostatectomy model is feasible and can be used to test the effect of candidate chemopreventive agents on prostate cancer.
Comparison of Archival Plasma and Formalin-Fixed Paraffin-Embedded Tissue for Genotyping in Hepatocellular Carcinoma
Authors: Sjöholm Malin I.L. , Hoffmann Gunilla , Lindgren Stefan , Dillner Joakim , Carlson Joyce
Published: June 2022

Biobanks containing formalin-fixed paraffin-embedded tissue, as well as frozen serum or plasma, are important resources for molecular epidemiologic studies. However, few studies have compared the reliability of formalin-fixed tissue samples and archival plasma samples for genotyping. We determined the genotype of four proposed genetic risk factors for hepatocellular carcinoma [hereditary hemochromatosis (HFE 63 and 282), α1-antitrypsin deficiency (AAT 342) and cystic fibrosis (CFTR 508)] on formalin-fixed tissue samples, stored for up to 25 years, from 318 patients diagnosed with hepatocellular carcinoma and on plasma or serum samples from 31 of these patients. The genotypes were analyzed by RFLP or allele-specific amplification as well as by TaqMan assays. In addition, genotyping was attempted after whole genome amplification by multiple displacement amplification (MDA). Genotyping was successful in 94% of the tissue samples and successful and identical to the tissue samples from the same subjects in 98% of the plasma/serum samples. DNA from plasma samples could be amplified >5,000-fold by MDA and genotyping after MDA gave identical results to the genotyping of the same subjects before whole genome amplification. MDA amplification of the tissue samples was not successful. In summary, archival plasma was found to be an adequate source of efficiently amplifiable DNA. MDA on plasma samples allows analysis of multiple genotypes in epidemiologic studies.
Vitamin E Supplements and Risk of Prostate Cancer in U.S. Men
Authors: Rodriguez Carmen , Jacobs Eric J. , Mondul Alison M. , Calle Eugenia E. , McCullough Marjorie L. , Thun Michael J.
Published: June 2022

Supplementation with α-tocopherol (a form of vitamin E) was associated with decreased risk of prostate cancer in a randomized trial among Finnish smokers. We examined the association between vitamin E supplement use and prostate cancer incidence in the Cancer Prevention Study II Nutrition Cohort. Participants in the study completed a detailed questionnaire at enrollment in 1992–1993. Historical information was also available from a questionnaire completed in 1982 at enrollment in a previous cohort. Through August 31, 1999, we documented 4,281 cases of incident prostate cancer among 72,704 men. Multivariate-adjusted rate ratios (RRs) were calculated using Cox Proportional Hazards models. Regular vitamin E supplement use (≥4 times per week) was not associated with overall risk of prostate cancer or with risk of advanced prostate cancer at diagnosis. No trend was seen with increasing dose of vitamin E. Men who reported regular vitamin E use in both 1982 and in 1992–1993 were not at lower risk of prostate cancer. Among current smokers, there was a suggestion of slightly reduced risk with regular vitamin E supplement use [RR = 0.87, 95% confidence interval (CI) = 0.67–1.11]. Our results do not support an important role for vitamin E supplements in prostate cancer prevention.
Distribution of Persistent, Lipid-Soluble Chemicals in Breast and Abdominal Adipose Tissues: Lessons Learned from a Breast Cancer Study
Authors: Petreas Myrto , Smith Daniel , Hurley Susan , Jeffrey Stefanie S. , Gilliss Debra , Reynolds Peggy
Published: June 2022

Objective: We sought to determine differences between concentrations of persistent, lipid-soluble chemical contaminants in breast and abdominal adipose tissues and to explore whether concentrations measured in one tissue could predict concentrations in the other tissue. Methods: We analyzed surgical specimens and measured concentrations of prevalent dioxins, furans, polychlorinated biphenyls, organochlorine pesticides, and brominated diphenyl ethers to determine their partitioning between breast and abdominal adipose tissues of 21 women. The women constituted a subgroup, undergoing mastectomies with simultaneous breast reconstruction, of a case-control study evaluating links between breast cancer and body burdens of organohalogen contaminants. Results: For every contaminant, differences between concentrations in breast and abdominal adipose tissues did not exceed the analytical error. Results indicated that, with some notable exceptions, measurements in breast and abdominal adipose tissues were correlated and that concentrations of target chemicals in one tissue could be derived from measurements in the other tissue. Conclusions: This information will allow comparison of results from body burden studies that used different tissues. It may also facilitate future breast cancer studies by allowing selection of controls among patients undergoing surgical procedures other than breast surgery, minimizing concerns about overmatching. We also observed large differences in the lipid content of surgical specimens. These differences underscore the need for lipid adjustment of concentrations to avoid misclassification.