Humans have systematic sex differences in brain-related behavior, cognition, and pattern of mental illness risk. Many of these differences emerge during adolescence, a developmental period of intense neurostructural and endocrine change. Here, by creating "movies" of sexually dimorphic brain development using longitudinal in vivo structural neuroimaging, we show regionally specific sex differences in development of the cerebral cortex during adolescence. Within cortical subsystems known to underpin domains of cognitive behavioral sex difference, structural change is faster in the sex that tends to perform less well within the domain in question. By stratifying participants through molecular analysis of the androgen receptor gene, we show that possession of an allele conferring more efficient functioning of this sex steroid receptor is associated with "masculinization" of adolescent cortical maturation. Our findings extend models first established in rodents, and suggest that in humans too, sex and sex steroids shape brain development in a spatiotemporally specific manner, within neural systems known to underpin sexually dimorphic behaviors.

BackgroundGlioblastomas are the most common primary brain tumour in adults. While the prognosis for patients is poor, gene expression profiling has detected signatures that can sub-classify GBMs relative to histopathology and clinical variables. One category of GBM defined by a gene expression signature is termed ProNeural (PN), and has substantially longer patient survival relative to other gene expression-based subtypes of GBMs. Age of onset is a major predictor of the length of patient survival where younger patients survive longer than older patients. The reason for this survival advantage has not been clear.MethodsWe collected 267 GBM CEL files and normalized them relative to other microarrays of the same Affymetrix platform. 377 probesets on U133A and U133 Plus 2.0 arrays were used in a gene voting strategy with 177 probesets of matching genes on older U95Av2 arrays. Kaplan-Meier curves and Cox proportional hazard analyses were applied in distinguishing survival differences between expression subtypes and age.ResultsThis meta-analysis of published data in addition to new data confirms the existence of four distinct GBM expression-signatures. Further, patients with PN subtype GBMs had longer survival, as expected. However, the age of the patient at diagnosis is not predictive of survival time when controlled for the PN subtype.ConclusionThe survival benefit of younger age is nullified when patients are stratified by gene expression group. Thus, the main cause of the age effect in GBMs is the more frequent occurrence of PN GBMs in younger patients relative to older patients.

a-Fetoprotein (AFP) is a self protein expressed by fetal liver at high levels, but is transcriptionally repressed at birth. AFP is up-regulated in hepatocellular carcinomas, and patients with active disease could have plasma levels as high as1mg/mL.We previously identified four immunodominant HLA-A*0201-restricted peptides [hAFP [137][138][139][140][141][142][143][144][145] (PLFQVPEPV), hAFP [158][159][160][161][162][163][164][165][166] (FMNKFIYEI), hAFP [325][326][327][328][329][330][331][332][333][334] (GLSPNLNRFL), and hAFP 542-550 (GVALQTMKQ)] derived from human AFP that could stimulate specific T cell responses in healthy donor peripheral blood lymphocytes in vitro. We conducted a phase I/II clinical trial in which HLA-A*0201patients with AFP-positive hepatocellular carcinoma were immunized with three biweekly intradermal vaccinations of the four AFP peptides pulsed onto autologous dendritic cells (DC). DCs were prepared from adherent peripheral blood mononuclear cells cultured with granulocyte-macrophage colony-stimulating factor and interleukin-4 for 7 days. Sixteen subjects were enrolled and 10 were treated. Peripheral blood lymphocytes were isolated from these patients before, during, and afterAFP peptide/DC immunization and were tested ex vivo with MHC tetramer and IFNg ELISPOTanalysis. Six of 10 subjects expanded statistically significant levels of AFP-specificTcells postvaccine to at least one peptide by MHC tetramer. Also, 6 of10 subjects increased IFNg producing AFP-specificTcell responses to at least one of the peptides postvaccination, by ELISPOT. We conclude that the humanTcell repertoire is capable of responding to the AFP self antigen after the administration of AFP peptidepulsed DC even in an environment of high circulating levels of this oncofetal antigen.We originally reported that the self antigen a-fetoprotein (AFP) could be recognized by both murine and human T cells and serve as a tumor rejection antigen in a murine tumor model (1, 2). AFP is produced by 50% to 80% of hepatocellular carcinomas (HCC), and its measurement in serum has played an important role in diagnosis and monitoring responses to treatment for the last several decades (3). AFP is expressed by the fetal liver with serum levels of 1 mg/mL, but is transcriptionally repressed shortly after birth (4 -6). Our ability to generate potent AFP-specific T cell immunity to murine AFP in mice and to human AFP in in vitro human T cell cultures clearly indicates that, despite being exposed to high plasma levels of this protein during embryonic development, some AFP-specific T cells are not deleted during ontogeny.Using a combination of strategies (HLA-A*0201/K b transgenic mice, human T cell cultures, and mass spectrometric analysis), we identified four immunodominant AFP-derived peptides that are naturally processed and presented in the context of HLA-A*0201 (1, 7 -9). At least three of these peptides could be isolated from the surface of an HLA-A*0201/AFP-positive human HCC cell line, HepG2. These peptides can stimulate T ...

SUMMARY Defects in brain development are believed to contribute towards on-set of neuropsychiatric disorders but identifying specific underlying mechanisms has proven difficult. Here, we took a multi-faceted approach to investigate why 15q11.2 copy number variants are prominent risk factors for schizophrenia and autism. First, we show that human iPSC-derived neural progenitors carrying 15q11.2 microdeletion exhibit deficits in adherens junctions and apical polarity. This results from haploinsufficiency of CYFIP1, a gene within 15q11.2 that encodes a subunit of the WAVE complex, which regulates cytoskeletal dynamics. In developing mouse cortex, deficiency in CYFIP1 and WAVE signaling similarly affects radial glial cells, leading to their ectopic localization outside of the ventricular zone. Finally, targeted human genetic association analyses revealed an epistatic interaction between CYFIP1 and WAVE signalling mediator ACTR2 and risk for schizophrenia. Our findings provide insight into how CYFIP1 regulates neural stem cell function and may contribute to the susceptibility of neuropsychiatric disorders.

Activating epidermal growth factor receptor (EGFR) mutations are common in many cancers including glioblastoma. However, clinical responses to EGFR inhibitors are infrequent and short-lived. We show that the Src family kinases (SFK) Fyn and Src are effectors of oncogenic EGFR signaling, enhancing invasion and tumor cell survival in vivo. Expression of a constitutively active EGFR mutant, EGFRvIII, resulted in activating phosphorylation and physical association with Src and Fyn, promoting tumor growth and motility. Gene silencing of Fyn and Src limited EGFR-and EGFRvIIIdependent tumor cell motility. The SFK inhibitor dasatinib inhibited invasion, promoted tumor regression, and induced apoptosis in vivo, significantly prolonging survival of an orthotopic glioblastoma model expressing endogenous EGFRvIII. Dasatinib enhanced the efficacy of an anti-EGFR monoclonal antibody (mAb 806) in vivo, further limiting tumor growth and extending survival. Examination of a large cohort of clinical samples showed frequent coactivation of EGFR and SFKs in glioblastoma patients. These results establish a mechanism linking EGFR signaling with Fyn and Src activation to promote tumor progression and invasion in vivo and provide rationale for combined anti-EGFR and anti-SFK targeted therapies. [Cancer Res 2009;69(17):6889-98]