Mutations in PIK3CA are infrequent in neuroblastoma

BACKGROUND: Neuroblastoma is a frequently lethal pediatric cancer in which MYCN genomic amplification is highly correlated with aggressive disease. Deregulated MYC genes require co-operative lesions to foster tumourigenesis and both direct and indirect evidence support activated Ras signaling for this purpose in many cancers. Yet Ras genes and Braf, while often activated in cancer cells, are infrequent targets for activation in neuroblastoma. Recently, the Ras effector PIK3CA was shown to be activated in diverse human cancers. We therefore assessed PIK3CA for mutation in human neuroblastomas, as well as in neuroblastomas arising in transgenic mice with MYCN overexpressed in neural-crest tissues. In this murine model we additionally surveyed for Ras family and Braf mutations as these have not been previously reported. METHODS: Sixty-nine human neuroblastomas (42 primary tumors and 27 cell lines) were sequenced for PIK3CA activating mutations within the C2, helical and kinase domain "hot spots" where 80% of mutations cluster. Constitutional DNA was sequenced in cases with confirmed alterations to assess for germline or somatic acquisition. Additionally, Ras family members (Hras1, Kras2 and Nras) and the downstream effectors Pik3ca and Braf, were sequenced from twenty-five neuroblastomas arising in neuroblastoma-prone transgenic mice. RESULTS: We identified mutations in the PIK3CA gene in 2 of 69 human neuroblastomas (2.9%). Neither mutation (R524M and E982D) has been studied to date for effects on lipid kinase activity. Though both occurred in tumors with MYCN amplification the overall rate of PIK3CA mutations in MYCN amplified and single-copy tumors did not differ appreciably (2 of 31 versus 0 of 38, respectively). Further, no activating mutations were identified in a survey of Ras signal transduction genes (including Hras1, Kras2, Nras, Pik3ca, or Braf genes) in twenty-five neuroblastic tumors arising in the MYCN-initiated transgenic mouse model. CONCLUSION: These data suggest that activating mutations in the Ras/Raf-MAPK/PI3K signaling cascades occur infrequently in neuroblastoma. Further, despite compelling evidence for MYC and RAS cooperation in vitro and in vivo to promote tumourigenesis, activation of RAS signal transduction does not constitute a preferred secondary pathway in neuroblastomas with MYCN deregulation in either human tumors or murine models

A modern network approach to revisiting the positive and negative affective schedule (PANAS) construct validity

Introduction: The factor structure of the Positive and Negative Affective Schedule (PANAS) is still a topic of debate. There are several reasons why using Exploratory Graph Analysis (EGA) for scale validation is advantageous and can help understand and resolve conflicting results in the factor analytic literature. Objective: The main objective of the present study was to advance the knowledge regarding the factor structure underlying the PANAS scores by utilizing the different functionalities of the EGA method. EGA was used to (1) estimate the dimensionality of the PANAS scores, (2) establish the stability of the dimensionality estimate and of the item assignments into the dimensions, and (3) assess the impact of potential redundancies across item pairs on the dimensionality and structure of the PANAS scores. Method: This assessment was carried out across two studies that included two large samples of participants. Results and Conclusion: In sum, the results are consistent with a two-factor oblique structure.Fil: Flores Kanter, Pablo Ezequiel. Universidad Empresarial Siglo XXI; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Garrido, Luis Eduardo. Pontificia Universidad Católica Madre y Maestra; República DominicanaFil: Moretti, Luciana Sofía. Universidad Empresarial Siglo XXI; Argentina. Pontificia Universidad Católica Madre y Maestra; República Dominicana. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Medrano, Leonardo. Universidad Empresarial Siglo XXI; Argentina. Pontificia Universidad Católica Madre y Maestra; República Dominicana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Suicide risk in schizophrenia: learning from the past to change the future

Suicide is a major cause of death among patients with schizophrenia. Research indicates that at least 5–13% of schizophrenic patients die by suicide, and it is likely that the higher end of range is the most accurate estimate. There is almost total agreement that the schizophrenic patient who is more likely to commit suicide is young, male, white and never married, with good premorbid function, post-psychotic depression and a history of substance abuse and suicide attempts. Hopelessness, social isolation, hospitalization, deteriorating health after a high level of premorbid functioning, recent loss or rejection, limited external support, and family stress or instability are risk factors for suicide in patients with schizophrenia. Suicidal schizophrenics usually fear further mental deterioration, and they experience either excessive treatment dependence or loss of faith in treatment. Awareness of illness has been reported as a major issue among suicidal schizophrenic patients, yet some researchers argue that insight into the illness does not increase suicide risk. Protective factors play also an important role in assessing suicide risk and should also be carefully evaluated. The neurobiological perspective offers a new approach for understanding self-destructive behavior among patients with schizophrenia and may improve the accuracy of screening schizophrenics for suicide. Although, there is general consensus on the risk factors, accurate knowledge as well as early recognition of patients at risk is still lacking in everyday clinical practice. Better knowledge may help clinicians and caretakers to implement preventive measures. This review paper is the results of a joint effort between researchers in the field of suicide in schizophrenia. Each expert provided a brief essay on one specific aspect of the problem. This is the first attempt to present a consensus report as well as the development of a set of guidelines for reducing suicide risk among schizophenia patients