Disparate results between proliferation rates of surgically excised prostate tumors and an in vitro bioassay using sera from a positive randomized controlled trial.

In vitro bioassay has been used extensively to test the effects of culturing cancer cells in sera from humans participating in dietary interventions, i.e, studies of modified intake of nutrients for the purpose of reducing cancer risk or progression. It has been hypothesized that cell proliferation rates determined by the in vitro bioassay indicate whether modification of dietary intake could decrease cancer cell growth in vivo. It has been suggested, however, that the in vitro bioassay may not correlate with tumor cell proliferation rates in prostate cancer. We investigated the concordance of cell proliferation rates from surgically excised prostate tumor tissue with the in vitro bioassay using sera from matched patients. We used samples from an earlier randomized clinical trial that showed that supplementation with flaxseed significantly inhibited prostate cancer cell proliferation rates in vivo as indicated by Ki67 staining in tumor specimens. Proliferation rates of LNCaP, DU145 and PC3 cell lines cultured in 10% human sera from participants in the flaxseed trial were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Spearman's Rho correlation coefficients (ρ) indicated no association between Ki67 staining in prostate tumors and the in vitro bioassay for the three cell lines. These disparate findings suggest that the in vitro bioassay may not provide an accurate assessment of the environment in vivo.

Repurposing the open access malaria box to discover potent inhibitors of Toxoplasma gondii and Entamoeba histolytica.

Toxoplasmosis and amebiasis are important public health concerns worldwide. The drugs currently available to control these diseases have proven limitations. Therefore, innovative approaches should be adopted to identify and develop new leads from novel scaffolds exhibiting novel modes of action. In this paper, we describe results from the screening of compounds in the Medicines for Malaria Venture (MMV) open access Malaria Box in a search for new anti-Toxoplasma and anti-Entamoeba agents. Standard in vitro phenotypic screening procedures were adopted to assess their biological activities. Seven anti-Toxoplasma compounds with a 50% inhibitory concentration (IC50) of <5 µM and selectivity indexes (SI) of >6 were identified. The most interesting compound was MMV007791, a piperazine acetamide, which has an IC50 of 0.19 µM and a selectivity index of >157. Also, we identified two compounds, MMV666600 and MMV006861, with modest activities against Entamoeba histolytica, with IC50s of 10.66 µM and 15.58 µM, respectively. The anti-Toxoplasma compounds identified in this study belong to scaffold types different from those of currently used drugs, underscoring their novelty and potential as starting points for the development of new antitoxoplasmosis drugs with novel modes of action.

Development of exchange lists for Mediterranean and Healthy Eating diets: implementation in an intervention trial.

BACKGROUND: There has been little research published on the adaptation of diabetic exchange list diet approaches for the design of intervention diets in health research despite their clinical utility. The exchange list approach can provide clear and precise guidance on multiple dietary changes simultaneously. The present study aimed to develop exchange list diets for Mediterranean and Healthy Eating, and to evaluate adherence, dietary intakes and markers of health risks with each counselling approach in 120 subjects at increased risk for developing colon cancer. METHODS: A randomised clinical trial was implemented in the USA involving telephone counselling. The Mediterranean diet had 10 dietary goals targeting increases in mono-unsaturated fats, n-3 fats, whole grains and the amount and variety of fruits and vegetables. The Healthy Eating diet had five dietary goals that were based on the US Healthy People 2010 recommendations. RESULTS: Dietary compliance was similar in both diet arms, with 82-88% of goals being met at 6 months, although subjects took more time to achieve the Mediterranean goals than the Healthy Eating goals. The relatively modest fruit and vegetable goals in the Healthy Eating arm were exceeded, resulting in fruit and vegetable intakes of approximately eight servings per day in each arm after 6 months. A significant (P < 0.05) weight loss and a decrease in serum C-reactive protein concentrations were observed in the overweight/obese subgroup of subjects in the Mediterranean arm in the absence of weight loss goals. CONCLUSIONS: Counselling for the Mediterranean diet may be useful for both improving diet quality and for achieving a modest weight loss in overweight or obese individuals.

High vegetable and fruit diet intervention in premenopausal women with cervical intraepithelial neoplasia.

OBJECTIVE: To examine whether diet intervention can promote increased vegetable and fruit intake, as reflected in increased plasma carotenoid and decreased plasma total homocysteine concentrations, in premenopausal women with cervical intraepithelial neoplasia, a precancerous condition. DESIGN: Randomized controlled diet intervention study. SUBJECTS: Fifty-three free-living premenopausal women who had been diagnosed with cervical intraepithelial neoplasia, were randomly assigned to an intervention (n = 27) or a control (n = 26) group. INTERVENTION: Individualized dietary counseling to increase vegetable and fruit intake. MAIN OUTCOME MEASURES: Diet was assessed by food frequency questionnaire. Plasma carotenoids and total homocysteine were measured at enrollment and at 6 months follow up. ANALYSIS: Associations between baseline plasma concentrations of carotenoids and homocysteine and influencing factors were examined with multiple regression analysis. Repeated measures analysis of variance was used to test for group by time effects in these plasma concentrations. Plasma carotenoids at baseline and 6 months in the study groups, and differences in homocysteine concentrations from baseline to 6 months, were compared with independent sample t tests. RESULTS: Repeated measures analysis of variance showed significant group by time effects (P<.01) in plasma carotenoid and homocysteine concentrations. In the intervention group, total plasma carotenoids increased by an average of 91%, from 2.04+/-0.13 (mean+/-standard error of the mean) to 3.90+/-0.56 micromol/L and plasma total homocysteine was reduced by 11%, from 9.01+/-0.40 to 8.10+/-0.44 micromol/L (P<.003). Neither changed significantly in the control group. APPLICATIONS: Individualized dietary counseling can effectively promote increased vegetable and fruit intake in premenopausal women. This dietary pattern may reduce risk for cancer and other chronic diseases and also promote an improvement in folate status.

Do antioxidants still have a role in the prevention of human cancer?

Antioxidants are components of diet that are involved in DNA and cell maintenance and repair. Dietary antioxidants include carotenoids, vitamin C, vitamin E, and selenium. Across a variety of cancers, the observational studies have inconsistent results with respect to the relationship shown of specific dietary intake or serum levels of antioxidants and risk of certain cancers. The results of the micronutrient supplement trials clearly do not support a reductionist approach to promoting regression of precancerous lesions or prevention of new cancer, except in a few cancers and specific populations. The ability of the antioxidant micronutrients to influence the risk for tissue injury and for cancer, mediated by their antioxidant activities, remains hypothetical.

Colonic mucosal prostaglandin E2 and cyclooxygenase expression before and after low aspirin doses in subjects at high risk or at normal risk for colorectal cancer.

UNLABELLED: Development of potential cancer chemopreventive drugs involves the systematic evaluation of these drugs in preliminary Phase I and II studies in human beings to identify the optimal drug dose, drug toxicity, and surrogate end point biomarker modulation. OBJECTIVES: We tested the hypothesis that aspirin, at a single, once-daily 81-mg dose, will reduce colonic mucosal concentration of prostaglandin estradiol (E2) in individuals at high risk for colorectal cancer development similar to our prior observations in a young normal-risk population. METHODS: Aspirin was administered at a dose of 81 mg once daily for 28 days in a cohort of 92 matched high-risk and normal-risk colorectal cancer subjects. Prostaglandin E2 and cyclooxygenase expression were assayed from distal sigmoid biopsies from all of the subjects before and after treatment. RESULTS: The mean prostaglandin E2 for normal-risk subjects before aspirin treatment was 11.3 +/- 1.7 pg/microg (mean +/- SE) tissue protein and after aspirin treatment was 4.9 +/- 0.91 pg/microg tissue protein (P < 0.0001). In high-risk subjects, mean pretreatment prostaglandin E2 was 14.4 +/- 1.7 pg/microg tissue protein and after aspirin treatment was 4.7 +/- 0.70 pg/microg tissue protein (P < 0.0001). Aspirin treatment did not alter cyclooxygenase-1 protein expression. CONCLUSIONS: Aspirin treatment at a dose of 81 mg reduces colorectal mucosal prostaglandin E2 concentration after 28 daily doses. Risk for colorectal carcinoma did not modify colorectal mucosal baseline or post-aspirin prostaglandin E2, or cyclooxygenase expression. Colorectal mucosal prostaglandin concentration may be used as a "drug-effect surrogate biomarker," that is, a surrogate to assess sufficient delivery and tissue effect of a chemopreventive agent.

Prevention of cervix cancer.

Cervix carcinoma is an important health problem world-wide, being the second most common cancer among women, ranking first in many developing countries. A number of important epidemiological risk factors have been identified as contributing to the development of CIN and invasive cervix carcinoma. Of key importance is infection with human papillomavirus (HPV), which is the primary risk factor. There are evolving primary and secondary preventive strategies that could further reduce the burden from cervical carcinoma. The possible primary preventive strategies include risk reduction, diet or dietary supplements, HPV vaccines, and other chemopreventive agents. The possible advances in secondary preventive strategies include new technologies for Pap smears, HPV typing triage, and other adjuvant screening procedures. The impact of these strategies will depend upon evidence to support their use along with the characteristics of the population and environment in which they are used.

Recruiting subjects in cancer prevention and control studies.

Recruitment of subjects is a critical aspect of prevention trials that is often overlooked by investigators. As a consequence, accrual time is often extended, workloads may become heavy, and resource utilization is increased in an effort to complete projects. Recruitment of healthy subjects in cancer prevention and control studies presents unique issues that need to be considered. The barriers to recruitment include participant issues, physician variables, features of the study design, and characteristics of the health care system in the United States. The authors provide their experience in overcoming these difficulties.

Predictors of screening for breast, cervical, colorectal, and prostatic cancer among community-based primary care practices.

BACKGROUND: As we enter the year 2000, it is worth looking at whether primary care practices are reaching the goals established in Healthy People 2000 for breast, cervical, colorectal, and prostatic cancer screening. The objectives of this study were (1) to determine the current rates of cancer screening; and (2) to determine which factors predict completion of a single screening test, of all tests for each cancer, and of all procedures for age and sex. METHODS: Medical records of 200 eligible patients (100 men and 100 women) from each of 24 community-based primary care practices were abstracted for cancer-screening events. RESULTS: We audited 5125 charts. A Papanicolaou smear was documented for 63.8% of women with an intact cervix within 3 years of the audit.. We found that 46.8% of women had documentation of ever having a discussion of breast self-examination. For breast cancer screening, 41.8% of the women had a clinical breast examination within 1 year, 48.2% aged 40 to 49 years had a mammogram within 2 years, and 38.5% aged 50 years and older had a mammogram within 1 year. Only 29% of women aged 40 to 49 years and 17% of women 50 years and older were current for all breast cancer-screening tests. Among patients 50 years and older, 33% of men and 38% of women had a digital rectal examination within 1 year, 26% of men and 28% of women had a fecal occult blood test within 1 year, and 22% of men and 16.8% of women had a flexible sigmoidoscopy within 5 years. Of all men 28.7% had a prostate-specific antigen test within 1 year. Completion of all tests relevant for age and sex were documented for 8.6% of women aged 40 to 49 years, 3% of women 50 years and older, and 5% of men 50 years and older. The single most significant predictor of documented cancer screening was a health maintenance visit. CONCLUSIONS: This sample of primary care clinicians has not reached the goals set in Healthy People 2000 for cancer screening. Interventions aimed at increasing the percentage of patients who schedule a health maintenance visit could serve to increase cancer screening and help us reach goals set for the year 2010.

Genetic taste markers and preferences for vegetables and fruit of female breast care patients.

OBJECTIVE: To explore links between genetic responsiveness to the bitter taste of 6-n-propylthiouracil (PROP) and self-reported preferences for vegetables and fruit of female breast care patients. METHODS: PROP tasting was defined by detection thresholds and by perceived bitterness and hedonic ratings for PROP solutions. Nontasters, medium tasters, and supertasters were identified by their PROP thresholds and by the ratio of perceived bitterness of PROP to the perceived saltiness of sodium chloride solutions. Subjects rated preferences for vegetables and fruit using 9-point category scales. SUBJECTS/SETTING: A clinical sample of 170 patients with newly diagnosed breast cancer and 156 cancer-free control subjects were recruited from the University of Michigan Breast Care Center. STATISTICAL ANALYSES: Principal components factor analysis, one-way analyses of variance, and Pearson correlations and chi 2 tests were used to analyze taste and food preference data. RESULTS: Genetic responsiveness to PROP was associated with lower acceptance of cruciferous and selected green and raw vegetables (P < .05). Women who reported disliking such foods were medium tasters or supertasters of PROP. Preference ratings for fruit were unrelated to PROP taster status. APPLICATIONS/CONCLUSIONS: Women who are PROP tasters may be less likely to comply with dietary strategies for cancer prevention that emphasize consumption of cruciferous vegetables and bitter salad greens. Alternatively, PROP-sensitive women may seek to reduce bitter taste by adding fat, sugar, or salt.

The psychosexual impact of human papillomavirus cervical infections.

BACKGROUND: Occult human papillomavirus (HPV) infection, present in approximately 20% of women in the United States, is usually sexually transmitted, associated with substantial health risks, and unpredictable in its resolution. The potential for adverse psychosexual alterations due to HPV infection in women considered at low risk for bacterial sexually transmitted diseases is substantial, but data is lacking. METHODS: This cross-sectional study was conducted with sexually active women aged 18 to 60 years who had been enrolled at community-based offices in the University of Michigan Vaginitis Study. Women found to have occult HPV infection of the cervix were notified, received physician consultation, and were encouraged to have colposcopy performed to assess lesion status. Responses to a follow-up written questionnaire for differences in psychosexual functioning and attitudes following diagnosis were compared among these women and those without HPV infection. RESULTS: The women enrolled were primarily white and had a current sexual partner at the time of enrollment. They had few sexually transmitted infections and few risk factors, yet 20% had unsuspected HPV infection. Psychosexual characteristics at baseline and at follow-up, as well as perceived changes in these characteristics by the women, did not differ between women with HPV infection and those without. Stratification by potential confounders, including the presence of a vaginal infection at the time of study enrollment, household income level, ethnic background, age, marital status, and sexual history, did not alter these results. CONCLUSIONS: Women at low risk for sexually transmitted diseases, but who had a cervical HPV infection, were similar to those not infected in reported psychosexual characteristics and functioning. Adverse changes in these characteristics between the time of the diagnosis and subsequent follow-up were no more likely in those with the diagnosis than in those without.

Cancer chemoprevention. A new way to treat cancer before it happens.

Cancer chemoprevention uses noncytotoxic drugs or nutrients to prevent, retard, or delay carcinogenesis. The future of cancer chemoprevention depends on understanding key cellular growth and proliferation-controlling events, developing markers of molecular carcinogenesis, surrogate endpoint biomarkers, and targeted chemopreventive approaches.

Bioavailability of beta-carotene is lower in raw than in processed carrots and spinach in women.

Populations at risk of vitamin A deficiency usually rely on dietary provitamin A carotenoids to meet vitamin A needs, yet bioavailability of these compounds is influenced by several factors as follows: location in the plant source, the presence of other influencing dietary components, and type and extent of processing. The purpose of this study was to examine the plasma beta-carotene response to raw vs. processed carrots and spinach. Subjects were eight healthy females aged 23-36 y who consumed approximately 9.3 mg beta-carotene daily from either raw or thermally processed and pureed vegetables in two 4-wk treatment periods in a crossover study. Plasma concentrations of total, all-trans-, and cis-beta-carotene and alpha-carotene were measured at base line and the end of each treatment period by using HPLC assays. Total and all-trans (but not cis) plasma beta-carotene concentrations were significantly greater than base-line concentrations in the processed feeding period (P < 0. 04) and tended to be greater in the raw feeding period (P = 0.08). Daily consumption of processed carrots and spinach over a 4-wk period produced an increase in plasma beta-carotene concentration that averaged three times that associated with consumption of the same amount of beta-carotene from these vegetables in the raw form (P = 0.09). Increased cis isomers provided in the processed vegetables did not result in significantly greater plasma cis-beta-carotene isomer concentrations. These results suggest that isomerization of beta-carotene by heat treatment does not negate the enhanced beta-carotene uptake associated with consuming commercially processed vegetables compared with raw vegetables.

Clinical models of chemoprevention for colon cancer.

Colon cancer is a common malignancy in the westernized world and is incurable in its advanced stages. This article summarizes the currently available information on colorectal cancer chemoprevention. A brief outline of the incidence and etiologic factors is followed by a discussion of the evidence on which chemopreventive strategies for colon cancer are modeled. This includes a description of the development of surrogate endpoint biomarkers and experimental models to study colorectal cancer chemopreventives, a review of the promising colorectal cancer chemopreventives, and a discussion of the issues to be addressed in the design of future chemoprevention trials. The article concludes with an emphasis on the development and validation of biomarkers and selection of high-risk cohorts using genetic and epidemiologic tools as the main goals of future colon cancer chemoprevention trials before large-scale, risk-reduction trials are conducted.

Clinical models of chemoprevention for cervical cancer.

Cervical carcinoma creates a worldwide, significant population burden that potentially could be reduced by new preventive strategies for cervical cancer such as chemoprevention. Given the vast array of clinical and molecular information available relating to cervical cancer and the precursor lesions along with a growing number of new molecular techniques, a model is needed to guide further investigation. Such a model would facilitate research design, guide hypothesis development and testing, and focus the use of molecular data collection and analysis. This article reviews the clinical and molecular data of cervical cancer and the precursor lesions in order to develop a model for chemoprevention research in cervical cancer.