Adiposity and sex hormones in girls.

Greater body fatness during childhood is associated with reduced risk of premenopausal breast cancer, but few studies have addressed the relation of adiposity with sex hormones in girls. We prospectively examined associations between adiposity and circulating levels of sex hormones and sex hormone-binding globulin (SHBG) among 286 girls in the Dietary Intervention Study in Children. Participants were 8 to 10 years old at baseline and were followed for an average of 7 years. Anthropometric measurements were taken at baseline and at subsequent annual visits, and blood samples were collected every 2 years. Concentrations of dehydroepiandrosterone sulfate (DHEAS) during follow-up were higher among girls with greater body mass index (BMI) at baseline. The mean for the lowest BMI quartile was 63.0 microg/dL compared with 78.8 microg/dL for the highest quartile, and each kg/m(2) increment in baseline BMI was associated with a 4.3% increase (95% confidence interval, 1.6-7.0%) in DHEAS levels during follow-up (P(trend) = 0.002). Concentrations of SHBG during follow-up were lower among girls with greater BMI at baseline. The mean for the lowest BMI quartile was 94.8 nmol compared with 57.5 nmol for the highest quartile, and each kg/m(2) increment in baseline BMI was associated with an 8.8% decrease (95% confidence interval, 7.0-10.6%) in SHBG levels during follow-up (P(trend) < 0.0001). Estrogen and progesterone concentrations were similar across BMI quartiles. These findings suggest that adiposity may alter DHEAS and SHBG levels in girls. Whether and how these differences affect breast development and carcinogenesis requires further research.     

An anti-CD44 antibody does not enhance engraftment of DLA-identical marrow after low-dose total body irradiation

920 cGy total body irradiation (TBI) is adequate for consistently successful engraftment of marrow from dog leukocyte antigen (DLA)-identical littermates; however, the dose is inadequate to ensure a marrow graft from DLA-nonidentical unrelated donors. Such mismatched grafts are successful only after 1800 cGy, given in three fractions. While anti-T-cell reagents enhance engraftment of DLA-identical littermate marrow after 920 cGy, they fail to be effective in the DLA-nonidentical setting. However, a monoclonal antibody (mAb) to CD44, S5, was found to be very effective in enhancing engraftment of DLA-nonidentical marrow. The current study asked whether mAb S5 was also effective in the setting of DLA-identical littermate transplants. To this purpose, the TBI dose was lowered to 450 cGy, a dose after which 70% of such grafts failed. Four dogs were treated with antibody S5, 0.2 mg/kg on days −7 though −2 (per previously published protocol), given 450 cGy TBI followed by marrow grafts from their DLA-identical littermates. All four dogs rejected their grafts; two of these died from marrow aplasia, and two survived with endogenous marrow recovery. This result was not statistically significantly different from that in 17, historical (n = 5) and concurrent (n = 12), control dogs where 11 of 17 animals rejected. Even if ten experimental animals were transplanted and all six remaining dogs engrafted, the results still would not have been significantly different from control. This result is in contrast to the successful engraftment promoted by pretreatment with antibody S5 of DLA-nonidentical unrelated dogs, consistent with the notion that different host cells are involved in graft rejection in the two disparate histocompatibility settings.     

Frequent loss of heterozygosity targeting the inactive X chromosome in melanoma.

After previous preliminary observations of paradoxical deletion events affecting the inactive X chromosome in melanoma, we have surveyed the X chromosome for deletions using 23 polymorphic microsatellite markers in 28 informative (female XX) metastatic melanomas. Ten tumors (36%) showed at least one loss of heterozygosity (LOH) event, and in two cases an entire chromosome showed LOH at all informative loci. Four distinct X chromosome smallest regions of overlap can be resolved. An 18.6-Mb region on the p arm involving 9 of 28 (32%) samples lies between the markers DXS1061 and DXS1068. An equally frequently deleted smallest region of overlap straddled the centromere, bounded by DX1204 on the p arm and DXS983 14.6 Mb away in Xq11-12. One tumor potentially defines this region more tightly to a 10.6-Mb smallest region of overlap bounded by DXS1190 and DXS981 that contains the androgen receptor (AR) gene. A 6.2-Mb deleted region can be defined between the markers DXS8051 and DXS9902 in 8 of 28 (28%) tumors. An additional, less frequently deleted region of 25.7 Mb was found on distal Xq between the markers DXS1212 and DXS1193 in 5 of 28 (18%) tumors. X inactivation analysis of five tumors with LOH, using the AR exon 1 CAG repeat, showed that in each case, the inactive, hypermethylated allele was the one deleted. Analysis of copy number in this region by quantitative PCR showed restoration to disomy and, in one case, trisomy at AR.