The unanswered question

Soitinnus: trumpetti, orkesteri.

The Roots of Neurofibromas in Neurofibromatosis 1 — A Question of Multipotency, Differentiation and Hiding

Neurofibromatosis type 1 (NF1) is an autosomal dominant cancer predisposition syndrome that affects about 1 in 3500 individuals worldwide. NF1 is caused by mutations in the NF1 gene that encodes the tumor suppressor protein neurofibromin, an inactivator of the Ras oncogene. The hallmarks of NF1 include pigmentary lesions of the skin, Lisch nodules of the iris and cutaneous neurofibromas. Cutaneous neurofibromas are benign tumors composed of all the cell types of normal peripheral nerve. The traditional view of neurofibroma development has been that cutaneous neurofibromas arise from the disruption of the small nerve tributaries of the skin and subsequent proliferation of the resident cells. The second hit mutation in the NF1 gene has been considered as a prerequisite for neurofibroma development. The second hit is detectable in a subpopulation of primary Schwann cells cultured from neurofibromas. This thesis challenges the traditional concept of neurofibroma development. The results show that cutaneous neurofibromas are intimately associated with hair follicular structures and contain multipotent precursor cells (NFPs), suggesting that neurofibromas may arise from the multipotent cells which reside in hair follicles. Furthermore, this study presents that neurofibroma-derived Schwann cells that harbor bi-allelic inactivation in the NF1 gene express HLA class II genes and may act as nonprofessional antigen presenting cells. The CD4- and FoxP3-positive cells detected in cutaneous neurofibromas suggest that these cells may represent regulatory T cells (Tregs) which interact with HLA II –positive cells and aid the tumor cells in hiding from the immune system and are thus mediators of immune tolerance. This thesis also investigated neurofibroma development in the oral cavity and the use of different biomarkers to characterize cellular differentiation in neurofibromas. The results revealed that oral neurofibromas are not rare, but they usually appear as solitary lesions contrary to multiple cutaneous neurofibromas and present high heterogeneity within and between tumors. The use of class III beta-tubulin as a marker for neuronal differentiation led to an unexpected finding showing that multiple cell types express class III beta-tubulin during mitosis. The increased understanding of the multipotency of tumor cells, cellular differentiation and ability to hide from immune system will aid in the development of future treatments. Specifically, targeting Tregs in NF1 patients could provide a novel therapeutic approach to interfere with the development of neurofibromas.

School Bullies’ Quest for Power: Implications for Group Dynamics and Intervention

Bullying is characterized by an inequality of power between perpetrator and target. Findings that bullies can be highly popular have helped redefine the old conception of the maladjusted school bully into a powerful individual exerting influence on his peers from the top of the peer status hierarchy. Study I is a conceptual paper that explores the conditions under which a skillful, socially powerful bully can use the peer group as a means of aggression and suggests that low cohesion and low quality of friendships make groups easier to manipulate. School bullies’ high popularity should be a major obstacle for antibullying efforts, as bullies are unlikely to cease negative actions that are rewarding, and their powerful position could discourage bystanders from interfering. Using data from the Finnish program KiVa, Study II supported the hypothesis that antibullying interventions are less effective with popular bullies in comparison to their unpopular counterparts. In order to design interventions that can address the positive link between popularity and aggression, it is necessary to determine in which contexts bullies achieve higher status. Using an American sample, Study III examined the effects of five classroom features on the social status that peers accord to aggressive children, including classroom status hierarchy, academic level and grade level, controlling for classroom mean levels of aggression and ethnic distribution. Aggressive children were more popular and better liked in fifth grade relative to fourth grade and in classrooms of higher status hierarchy. Surprisingly, the natural emergence of status hierarchies in children’s peer groups has long been assumed to minimize aggression. Whether status hierarchies hinder or promote bullying is a controversial question in the peer relations’ literature. Study IV aimed at clarifying this debate by testing the effects of the degree of classroom status hierarchy on bullying. Higher hierarchy was concrrently associated with bullying and predictive of higher bullying six months later. As bullies’ quest for power is increasingly acknowledged, some researchers suggest teaching bullies to attain the elevated status they yearn for through prosocial acts. Study V cautions against such solutions by reviewing evidence that prosocial behaviors enacted with the intention of controlling others can be as harmful as aggression.