Association of SULT1A1 phenotype and genotype with prostate cancer risk in African-Americans and Caucasians.

Exposure to heterocyclic amines may increase prostate cancer risk. Human sulfotransferase 1A1 (SULT1A1) is involved in the bioactivation of some dietary procarcinogens, including the N-hydroxy metabolite of the food-borne heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo(4,5-b) pyridine. This study compares a polymorphism in the SULT1A1 gene, SULT1A1 enzyme activity, meat consumption, and the risk of prostate cancer in a population based case-control study. Prostate cancer patients (n = 464) and control individuals (n = 459), frequency matched on age and ethnicity, provided informed consent, answered a survey, and provided a blood sample. Platelets were isolated for phenotype analysis, and DNA was isolated from lymphocytes for genotype determination. Meat consumption was assessed using a dietary questionnaire. Caucasians homozygous for the SULT1A1*1 high activity allele were at increased risk for prostate cancer [odds ratio (OR), 1.68; 95% confidence interval (CI), 1.05-2.68] compared with individuals homozygous for the low-activity allele. The association between SULT1A1 genotype and prostate cancer risk in African-Americans did not reach significance (OR, 1.60; 95% CI, 0.46-5.62). When SULT1A1 activity was considered, there was a strong association between increased SULT1A1 activity and prostate cancer risk in Caucasians (OR, 3.04; 95% CI, 1.8-5.1 and OR, 4.96; 95% CI, 3.0-8.3, for the second and third tertiles of SULT1A1 activity, respectively) compared with individuals in the low enzyme activity tertile. A similar association was also found in African-American patients, with ORs of 6.7 and 9.6 for the second and third tertiles of SULT1A1 activity (95% CI, 2.1-21.3 and 2.9-31.3, respectively). When consumption of well-done meat was considered, there was increased risk of prostate cancer (OR, 1.42; 95% CI, 1.01-1.99 and OR, 1.68; 95% CI, 1.20-2.36 for the second and third tertiles, respectively). When SULT1A1 activity was stratified by tertiles of meat consumption, there was greater risk of prostate cancer in the highest tertile of meat consumption. These results indicate that variations in SULT1A1 activity contributes to prostate cancer risk and the magnitude of the association may differ by ethnicity and be modified by meat consumption.     

Correlation of serum hormone concentrations in maternal and umbilical cord samples.

Evidence suggests that adult cancer risk of hormonally related tumors may be influenced by the in utero environment, and most speculation on the biological mechanism has focused on the hormonal component. Epidemiological studies investigating the biological nature of pregnancy and maternal factors associated with offspring's cancer risk have relied on maternal hormone measurements. The degree to which maternal hormone levels represent the fetal environment, however, is not widely known. Pregnancy estrogen, androstenedione, testosterone, dehydroepiandrosterone (DHEA), and DHEA-sulfate concentrations were measured in maternal and mixed umbilical cord sera from 86 singleton pregnancies. Spearman correlations between maternal and cord hormone levels generally ranged between 0.2 and 0.3. The correlation was 0.26 for estriol, the estrogen of highest concentration in pregnancy, and 0.27 for estradiol, the most biologically active estrogen. The correlations between mother and offspring for the estrogens and DHEA appeared similar for males and females, whereas there was a suggestion that the maternal-umbilical cord correlations for other androgens varied in magnitude by fetal sex, and all correlations appeared higher in pregnancies lasting <38 weeks compared with longer gestational lengths, although these stratified findings may have been attributable to chance. These data show a moderate degree of correlation in hormone concentrations between the maternal and fetal circulation. Studies using maternal hormone concentrations as a proxy for the fetal environment should consider the misclassification resulting with the use of this marker.     

MATERNAL ANEMIA AND POSTPARTUM WEIGHT CHANGE ASSOCIATED WITH DECREASED MATERNAL-INFANT INTERACTION IN A RURAL KENYAN POPULATION

Associations between maternal nutritional factors including energy intake, body mass index, postpartum weight change, and anemia status and maternal-infant interactions were examined in 124 mother-infant pairs from a marginally malnourished, rural Kenyan population. Anemic mothers spent less time holding and caring for their infants than nonanemic mothers. Mothers who retained their pregnancy weight gain or were able to gain weight postpartum spent more time looking at their infants than mothers who lost weight postpartum. Maternal food intake per se was not associated with patterns of infant interaction. Lower birth weight infants were held more, cared for more, and looked at face-to-face more by their mothers. Older sisters tended to be more involved in infant interactions with higher birth weight infants.     

Temozolomide pharmacodynamics in patients with metastatic melanoma: dna damage and activity of repair enzymes O6-alkylguanine alkyltransferase and poly(ADP-ribose) polymerase-1.

PURPOSE: Temozolomide, a DNA methylating agent used to treat melanoma, induces DNA damage, which is repaired by O6-alkylguanine alkyltransferase (ATase) and poly(ADP-ribose) polymerase-1 (PARP-1)-dependent base excision repair. The current study was done to define the effect of temozolomide on DNA integrity and relevant repair enzymes as a prelude to a phase I trial of the combination of temozolomide with a PARP inhibitor. EXPERIMENTAL DESIGN: Temozolomide (200 mg/m2 oral administration) was given to 12 patients with metastatic malignant melanoma. Peripheral blood lymphocytes (PBL) were analyzed for PARP activity, DNA single-strand breakage, ATase levels, and DNA methylation. PARP activity was also measured in tumor biopsies from 9 of 12 patients and in PBLs from healthy volunteers. RESULTS: Temozolomide pharmacokinetics were consistent with previous reports. Temozolomide therapy caused a substantial and sustained elevation of N7-methylguanine levels, a modest and sustained reduction in ATase activity, and a modest and transient increase in DNA strand breaks and PARP activity in PBLs. PARP-1 activity in tumor homogenates was variable (828 +/- 599 pmol PAR monomer/mg protein) and was not consistently affected by temozolomide treatment. CONCLUSIONS: The effect of temozolomide reported here are consistent with those documented in previous studies with temozolomide and similar drug, dacarbazine, demonstrating that a representative patient population was investigated. Furthermore, PARP activity was not inhibited by temozolomide treatment and this newly validated pharmacodynamic assay is therefore suitable for use in a proof-of-principle phase I trial a PARP-1 inhibitor in combination with temozolomide.     

Phase II study of low-dose decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylate.

PURPOSE: To determine the activity of decitabine, a DNA methylation inhibitor, in imatinib-refractory or intolerant chronic myelogenous leukemia. MATERIALS AND METHODS: Thirty-five patients were enrolled in this phase II study (12 in chronic phase, 17 in accelerated phase, and six in blastic phase). Decitabine was administered at 15 mg/m2 intravenously over 1 hour daily, 5 days a week for 2 weeks. DNA methylation was measured using a LINE1 bisulfite/pyrosequencing assay. RESULTS: Complete hematologic responses were seen in 12 patients (34%) and partial hematologic responses in seven patients (20%), for an overall hematologic response rate of 54% (83% in chronic phase, 41% in accelerated phase, and 34% in blastic phase). Major cytogenetic responses were observed in six patients (17%), and minor cytogenetic responses were seen in 10 patients (29%) for an overall cytogenetic response rate of 46%. Median response duration was 3.5 months (range, 2 to 13+ months). Myelosuppression was the major adverse effect, with neutropenic fever in 28 (23%) of 124 courses of therapy. LINE1 methylation decreased from 71.3% +/- 1.4% (mean +/- standard error of the mean) to 60.7% +/- 1.4% after 1 week, 50.9% +/- 2.4% after 2 weeks, and returned to 66.5% +/- 2.7% at recovery of counts (median, 46 days). LINE1 methylation at the end of week 1 did not correlate with subsequent responses. However, at day 12, the absolute decrease in methylation was 14.5% +/- 3.0% versus 26.8% +/- 2.7% in responders versus nonresponders (P = .007). CONCLUSION: Decitabine induces hypomethylation and has clinical activity in imatinib refractory chronic myelogenous leukemia. We hypothesize that the inverse correlation between hypomethylation 2 weeks after therapy and response is due to a cell death mechanism of response, whereby resistant cells can withstand more hypomethylation.     

Crack and cocaine use among female prostitutes in Glasgow: Risky business

The experience of cocaine and 'crack' use among participants involved in (n = 19) or exiting (n = 10) prostitution in Glasgow, Scotland, is described. In-depth semi-structured qualitative interviews enquired about their use and experience of using cocaine and their perception of its effect on working practice. Twenty-three of 29 participants had used cocaine and 15 out of 29 had used crack cocaine. In reality, freebase not 'crack' was being self-manufactured from cocaine powder. Participants considered that cocaine use in the city was not restricted to prostitution but was reflected throughout the drug scene generally. One possible reason suggested for this was a perceived reduction in heroin availability at a time when cocaine was increasingly readily available. There was no evidence from participants to suggest that they were first introduced to cocaine through prostitution. Most participants believed that using cocaine did not affect how they worked, however they perceived that other prostitutes were prepared to take more risks to support their cocaine use and had to work longer hours to finance a cocaine habit compared to financing a heroin habit. Only participants recruited from the east end of the city spoke about their desperation for money and the sexual risks that they were prepared to take to buy cocaine. Harm-reduction messages should address the sexual and personal risks that some female prostitutes may be taking to support their cocaine use. Treatment and support services in the city, traditionally established to work with problematic heroin users, need to adapt to the changing drug trends among female drug users, including those involved in prostitution, and offer appropriate treatment options and harm-reduction advice to cocaine users.