Previously, we reported NELL-1 as a novel molecule overexpressed during premature cranial suture closure in patients with craniosynostosis (CS), one of the most common congenital craniofacial deformities. Here we describe the creation and analysis of transgenic mice overexpressing Nell-1. Nell-1 transgenic animals exhibited CS-like phenotypes that ranged from simple to compound synostoses. Histologically, the osteogenic fronts of abnormally closing/closed sutures in these animals revealed calvarial overgrowth and overlap along with increased osteoblast differentiation and reduced cell proliferation. Furthermore, anomalies were restricted to calvarial bone, despite generalized, non-tissue-specific overexpression of Nell-1. In vitro, Nell-1 overexpression accelerated calvarial osteoblast differentiation and mineralization under normal culture conditions. Moreover, Nell-1 overexpression in osteoblasts was sufficient to promote alkaline phosphatase expression and micronodule formation. Conversely, downregulation of Nell-1 inhibited osteoblast differentiation in vitro. In summary, Nell-1 overexpression induced calvarial overgrowth resulting in premature suture closure in a rodent model. Nell-1, therefore, has a novel role in CS development, perhaps as part of a complex chain of events resulting in premature suture closure. On a cellular level, Nell-1 expression may modulate and be both sufficient and required for osteoblast differentiation

Introduction Craniosynostosis (CS), the premature closure of cranial sutures, affects 1 in 3,000 infants and therefore is one of the most common human congenital craniofacial deformities (1). Premature suture closure, which results in cranial dysmorphism, can be either familial or sporadic in origin (1). Neither gender nor ethnicity can be used to predict which infants will be affected. Although genetic linkage analyses of CS-related syndromes have provided a wealth of new information about the molecular control of suture formation, the biology of local suture closure, especially in nonsyndromic, nonfamilial CS, is still largely unknown. Presently, more than 85 human mutations, which produce various familial CS syndromes, have been localized to the FGF receptor genes FGFR1, FGFR2, and FGFR3. All are "gain-of-function" mutations that result in increased receptor activity (1). No human CS syndromes have been linked to the FGF ligands; however, several animal models of CS have been associated with FGF overexpression (2, 3). The only described MSX2 mutation associated with CS (4) also results in increased MSX2 activity (5-7). While these candidate genes are known to play important roles in osteoblast proliferation and differentiation, they also have more generalized roles during embryogenesis. Thus, it is not surprising that transgenic mouse models with mutations in these genes often manifest extracranial abnormalities not observed in the majority of patients with CS (1, 2, 8).

Purpose. Primary brainstem lymphoma (PBSL) is rare and malignant. Understanding of this disease is lacking. We aimed to characterize clinical features, estimate survival and explore survival-related factors of PBSL.Methods. Patients with a histological diagnosis of primary lymphoma in the brainstem (C71.7) from 1975 to 2016 were retrieved from Surveillance, Epidemiology, and End Results (SEER) program. Log-rank tests, univariate and multivariate Cox proportional hazard analyses were used to identify survival-related factors. Results. PBSL constituted 2.7% of brainstem malignancies. The median age of the PBSL patients were 59.5 years. Diffuse large B cell lymphoma (n = 49, 84.5%) was the most prevalent histology among the 58 cases with reported specific lymphoma subtype. The majority of PBSLs were localized (n = 46, 52.3%), at low Ann Arbor Stage (I/II, n = 63, 70.5%), and presented as a single primary (n = 71, 80.7%). Chemotherapy was applied in 50 (56.8%) cases. Three-year overall survival (OS) and disease-specific survival (DSS) rates were 42.7% and 53.5%, respectively. Multivariate analyses showed that independent predictive/prognostic factors for OS were age (P = 0.004), tumor number (P = 0.029), and chemotherapy (P = 0.001); DSS-related factors only included age (P = 0.014) and chemotherapy (P = 0.008). Conclusions. We estimated survival rates for PBSL patients. Factors associated with OS and DSS were also identified. Our findings addressed the importance of chemotherapy in treating PBSL patients.