W. Distler

The expansion of the neocortex during mammalian brain evolution results primarily from an increase in neural progenitor cell divisions in its two principal germinal zones during development, the ventricular zone (VZ) and the subventricular zone (SVZ). Using mRNA sequencing, we analyzed the transcriptomes of fetal human and embryonic mouse VZ, SVZ, and cortical plate. In mouse, the transcriptome of the SVZ was more similar to that of the cortical plate than that of the VZ, whereas in human the opposite was the case, with the inner and outer SVZ being highly related to each other despite their cytoarchitectonic differences. We describe sets of genes that are up- or down-regulated in each germinal zone. These data suggest that cell adhesion and cell-extracellular matrix interactions promote the proliferation and self-renewal of neural progenitors in the developing human neocortex. Notably, relevant extracellular matrix-associated genes include distinct sets of collagens, laminins, proteoglycans, and integrins, along with specific sets of growth factors and morphogens. Our data establish a basis for identifying novel cell-type markers and open up avenues to unravel the molecular basis of neocortex expansion during evolution.

PURPOSE: Third-generation aromatase inhibitors have been widely used in postmenopausal women for the adjuvant treatment of hormone receptor-positive breast cancer. As aromatase inhibitors work by inhibiting the conversion of androgens to estrogens in adipose tissue, we hypothesized that anastrozole may be more effective in women with a high body mass index (BMI). PATIENTS AND METHODS: The Arimidex, Tamoxifen Alone or in Combination (ATAC) study was a double-blind randomized clinical trial in which postmenopausal women with early-stage breast cancer were randomly assigned to receive oral daily anastrozole (1 mg) alone, tamoxifen (20 mg) alone, or the combination in a double-blind fashion. Analyses were based on the 100-month median follow-up for women with hormone receptor-positive breast cancers (estrogen [ER] and/or progesterone [PgR] positive). Here, we investigate the impact of BMI on recurrence and the relative benefit of anastrozole versus tamoxifen according to baseline BMI. Results Overall, women with a high BMI (BMI > 35 kg/m(2)) at baseline had more recurrences than those women with a low BMI (BMI < 23 kg/m(2); adjusted hazard ratio [HR], 1.39; 95% CI, 1.06 to 1.82; P(heterogeneity) = .03) and significantly more distant recurrences (adjusted HR, 1.46; 95% CI, 1.07 to 1.61; P(heterogeneity) = .01). Overall, the relative benefit of anastrozole versus tamoxifen was nonsignificantly better in thin women compared to overweight women. CONCLUSION: These results confirm the poorer prognosis of obese women with early-stage breast cancer. Recurrence rates were lower for anastrozole than tamoxifen for all BMI quintiles. Our results suggest that the relative efficacy of anastrozole compared to tamoxifen is greater in thin postmenopausal women and higher doses or more complete inhibitors might be more effective in overweight women, but this requires independent confirmation.

CONTEXT: Antenatal glucocorticoid (GC) exposure has been discussed as a potent programming factor of hypothalamus-pituitary-adrenal (HPA) axis activity, producing sustained alterations in cortisol secretion throughout life. So far, the assessment of HPA-axis activity in offspring of mothers treated with synthetic GC has been limited to a time period shortly after birth, with prematurity being an important confound in most prior studies. OBJECTIVE: The present study aimed to investigate HPA-axis reactivity of term-born children with antenatal GC exposure in a larger sample, allowing us to further address sex- and drug-specific effects. DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional study comprised of 209 term-born children between 6 and 11 yr of age. Cortisol secretion patterns in response to a standardized laboratory stressor (Trier Social Stress Test for Children) were assessed in children with antenatal GC exposure (a single course of either dexamethasone or betamethasone) and compared to different control groups. RESULTS: We observed significantly increased cortisol reactivity to acute psychosocial stress in 6- to 11-yr-old, term-born children exposed to antenatal synthetic GC treatment compared to controls (F(3.4,345.9)=5.8; P<0.001). This finding appeared to be independent of the specific synthetic GC used and was found to be more pronounced in females. CONCLUSIONS: The present study provides the first evidence for long-lasting effects of antenatal synthetic GC exposure on HPA-axis reactivity in term-born children. These findings may bear important implications regarding the vulnerability for stress-related physical and psychiatric disorders, for which dysregulation of the HPA-axis has been discussed as a potential causal factor.