Protein expression and cellular localization in two prognostic subgroups of diffuse large B-cell lymphoma: higher expression of ZAP70 and PKC-beta II in the non-germinal center group and poor survival in patients deficient in nuclear PTEN.

Patients diagnosed with diffuse large B-cell lymphoma (DLBCL) show varying responses to conventional therapy, and this might be contributed to the differentiation stage of the tumor B-cells. The aim of the current study was to evaluate a panel of kinases (ZAP70, PKC-beta I and II and phosphorylated PKB/Akt) and phosphatases (PTEN, SHP1 and SHP2) known to be frequently deregulated in lymphoid malignancies. De novo DLBCL cases were divided into two subgroups, the germinal center (GC) group (14/28) and the non-germinal center (non-GC) or activated B-cell (ABC) group (14/28). ZAP70 and PKC-beta II were expressed in a significantly higher percentage of tumor cells in the clinically more aggressive non-GC group compared with the prognostically favourable GC group. Also, the subcellular localization of PKC-beta I and II differed in DLBCL cells, with the PKC-beta I isoform being expressed in both the cytoplasm and nucleus, while PKC-beta II was found exclusively in the cytoplasm. Loss of nuclear PTEN correlated with poor survival in cases from both subgroups. In addition, five cell lines of DLBCL origin were analyzed for protein expression and for mRNA levels of PTEN and SHP1. For the first time, we show that ZAP70 is expressed in a higher percentage of tumor cells in the aggressive non-GC subgroup of DLBCL and that PKC-beta I and II are differently distributed in the two prognostic subgroups of de novo DLBCL.

Prenatal androgens and gender-typed behavior: a study of girls with mild and severe forms of congenital adrenal hyperplasia.

Gender-typed behaviors and interests were investigated in 26 girls, aged 2-10 years, affected with congenital adrenal hyperplasia (CAH) and in 26 unaffected girls matched for age. Girls with CAH were more interested in masculine toys and less interested in feminine toys and were more likely to report having male playmates and to wish for masculine careers. Parents of girls with CAH rated their daughters' behaviors as more boylike than did parents of unaffected girls. A relation was found between disease severity and behavior indicating that more severely affected CAH girls were more interested in masculine toys and careers. No parental influence could be demonstrated on play behavior, nor did the comparison of parents' ratings of wished for behavior versus perceived behavior in their daughters indicate an effect of parental expectations. The results are interpreted as supporting a biological contribution to differences in play behavior between girls with and without CAH.

Sex-typed toy play behavior correlates with the degree of prenatal androgen exposure assessed by CYP21 genotype in girls with congenital adrenal hyperplasia.

Previous studies have shown that girls with congenital adrenal hyperplasia (CAH), a syndrome resulting in overproduction of adrenal androgens from early fetal life, are behaviorally masculinized. We studied play with toys in a structured play situation and correlated the results with disease severity, assessed by CYP21 genotyping, and age at diagnosis. Girls with CAH played more with masculine toys than controls when playing alone. In addition, we could demonstrate a dose-response relationship between disease severity (i.e. degree of fetal androgen exposure) and degree of masculinization of behavior. The presence of a parent did not influence the CAH girls to play in a more masculine fashion. Four CAH girls with late diagnosis are also described. Three of the four girls played exclusively with one of the masculine toys, a constructional toy. Our results support the view that prenatal androgen exposure has a direct organizational effect on the human brain to determine certain aspects of sex-typed behavior.