Mammographic density in relation to daidzein-metabolizing phenotypes in overweight, postmenopausal women.

Circulating hormones are associated with mammographic density, an intermediate marker of breast cancer risk. Differences in circulating hormones, including estrone and testosterone, have been observed in premenopausal women based on their capacity to metabolize daidzein, an isoflavone found predominantly in soybeans. Equol and O-desmethylangolensin (O-DMA) are products of intestinal bacterial metabolism of daidzein. There is interindividual variability in the capacity to produce daidzein metabolites; individuals can be equol producers or non-producers and O-DMA producers or non-producers. We tested the hypothesis that daidzein-metabolizing phenotypes are associated with mammographic density. Participants were recruited from among 92 sedentary, postmenopausal women, ages 50 to 75 years, who participated in a 1-year physical activity intervention. Pre-intervention mammographic density was determined using a computer-assisted, gray-scale thresholding technique. Fifty-five of these women consumed supplemental soy protein (>10 mg daidzein/d) for 3 days and collected a first-void urine sample on the fourth day to determine daidzein-metabolizing phenotypes. Equol and O-DMA concentrations were measured using gas chromatography-mass spectrometry. Associations between daidzein-metabolizing phenotypes and percent mammographic density were adjusted for age, maximum adult weight, gravidity, family history of breast cancer, and serum follicle-stimulating hormone and free testosterone concentrations. Mammographic density was 39% lower in equol producers compared with non-producers (P = 0.04). O-DMA producers had mammographic density 69% greater than non-producers (P = 0.05). These results suggest that particular intestinal bacterial profiles are associated with postmenopausal mammographic density, and these associations are not entirely explained by differences in reproductive or anthropometric characteristics or circulating hormones.     

Flavonoids and breast cancer risk in Italy.

Few epidemiologic studies have investigated the potential relation between flavonoids and breast cancer risk. We have applied recently published data on the composition of foods and beverages in terms of six principal classes of flavonoids (i.e., flavanones, flavan-3-ols, flavonols, flavones, anthocyanidines, and isoflavones) on dietary information collected in a large-case control study of breast cancer conducted in Italy between 1991 and 1994. The study included 2,569 women with incident, histologically confirmed breast cancer, and 2,588 hospital controls. Odds ratios (OR) and 95% confidence intervals were estimated by multiple logistic regression models. After allowance for major confounding factors and energy intake, a reduced risk of breast cancer was found for increasing intake of flavones (OR, 0.81, for the highest versus the lowest quintile; P-trend, 0.02), and flavonols (OR, 0.80; P-trend, 0.06). No significant association was found for other flavonoids, including flavanones (OR, 0.95), flavan-3-ols (OR, 0.86), anthocyanidins (OR, 1.09), as well as for isoflavones (OR, 1.05). The findings of this large study of an inverse association between flavones and breast cancer risk confirm the results of a Greek study.     

High stem cell frequency in acute myeloid leukemia at diagnosis predicts high minimal residual disease and poor survival.

PURPOSE: In CD34-positive acute myeloid leukemia (AML), the leukemia-initiating event originates from the CD34(+)CD38(-) stem cell compartment. Survival of these cells after chemotherapy may lead to minimal residual disease (MRD) and subsequently to relapse. Therefore, the prognostic impact of stem cell frequency in CD34-positive AML was investigated. EXPERIMENTAL DESIGN: First, the leukemogenic potential of unpurified CD34(+)CD38(-) cells, present among other cells, was investigated in vivo using nonobese diabetic/severe combined immunodeficient mice transplantation experiments. Second, we analyzed whether the CD34(+)CD38(-) compartment at diagnosis correlates with MRD frequency after chemotherapy and clinical outcome in 92 AML patients. RESULTS: In vivo data showed that engraftment of AML blasts in nonobese diabetic/severe combined immunodeficient mice directly correlated with stem cell frequency of the graft. In patients, a high percentage of CD34(+)CD38(-) stem cells at diagnosis significantly correlated with a high MRD frequency, especially after the third course of chemotherapy. Also, it directly correlated with poor survival. In contrast, total CD34(+) percentage showed no such correlations. CONCLUSIONS: Both in vivo data, as well as the correlation studies, show that AML stem cell frequency at diagnosis offers a new prognostic factor. From our data, it is tempting to hypothesize that a large CD34(+)CD38(-) population at diagnosis reflects a higher percentage of chemotherapy-resistant cells that will lead to the outgrowth of MRD, thereby affecting clinical outcome. Ultimately, future therapies should be directed toward malignant stem cells.     

Quantitative methylation-specific polymerase chain reaction gene patterns in urine sediment distinguish prostate cancer patients from control subjects.

PURPOSE: Aberrant promoter hypermethylation of several known or putative tumor suppressor genes occurs frequently during the pathogenesis of prostate cancers and is a promising marker for cancer detection. We sought to develop a test for prostate cancer based on a quantitative methylation-specific polymerase chain reaction (QMSP) of multiple genes in urine sediment DNA. PATIENTS AND METHODS: We tested urine sediment DNA for aberrant methylation of nine gene promoters (p16INK4a, p14(ARF), MGMT, GSTP1, RARbeta2, CDH1 [E-cadherin], TIMP3, Rassf1A, and APC) from 52 patients with prostate cancer and 21 matched primary tumors by quantitative fluorogenic real-time polymerase chain reaction. We also analyzed urine sediments from 91 age-matched individuals without any history of genitourinary malignancy as controls. RESULTS: Promoter hypermethylation of at least one of the genes studied was detected in urine samples from all 52 prostate cancer patients. Urine samples from the 91 controls without evidence of genitourinary cancer revealed no methylation of the p16, ARF, MGMT, and GSTP1 gene promoters, whereas methylation of RARbeta2, TIMP3, CDH1, Rassf1A, and APC was detected at low levels. CONCLUSION: Overall, methylation found in urine samples matched the methylation status in the primary tumor. A combination of only four genes (p16, ARF, MGMT, and GSTP1) would theoretically allow us to detect 87% of prostate cancers with 100% specificity. Our data support further development of the noninvasive QMSP assay in urine DNA for early detection and surveillance of prostate cancer.     

Delivery and stability of LHRH and Nafarelin in human skin: the effect of constant/pulsed iontophoresis.

Poor absorption and stability of peptides are the major obstacles concerning the development of therapeutically relevant iontophoretic devices for the transdermal delivery of peptides. The present study examined the impact of constant and pulsed (direct/alternating) current profiles on the transport and stability of two decapeptides LHRH and Nafarelin. The stability of these peptides was studied in a physiological buffer solution, with electrical current, and when the peptide solution was exposed to the stratum corneum or to the epidermal/dermal side of human skin. Pulsed direct current profile was shown to be the most efficient in transporting both LHRH and Nafarelin across the human epidermis. Furthermore, the percentage of intact LHRH in the receiver phase was slightly higher when a pulsed current profile was used. Both the peptides were stable in a physiological buffer and under the influence of current, but LHRH was degraded especially in contact with the dermal side of the skin. Altogether five hydrolytic degradation products of LHRH were observed, and they were identified by LC-ESI/MS and LC-ESI/MS/MS. No degradation products of Nafarelin were observed. It is concluded that the pulsed direct current profile may provide at least a partial solution for the transdermal delivery of peptides in terms of improved transport efficacy and peptide stability.