The TP53 gene (encoding the p53 tumor suppressor) is rarely mutated, although frequently inactivated, in medulloblastoma and ependymoma. Recent work in mouse models showed that the loss of p53 accelerated the development of medulloblastoma. The mechanism underlying p53 inactivation in human brain tumors is not completely understood. We show that ubiquitination factor E4B (UBE4B), an E3 and E4 ubiquitin ligase, physically interacts with p53 and Hdm2 (also known as Mdm2 in mice). UBE4B promotes p53 polyubiquitination and degradation and inhibits p53-dependent transactivation and apoptosis. Notably, silencing UBE4B expression impairs xenotransplanted tumor growth in a p53-dependent manner and overexpression of UBE4B correlates with decreased expression of p53 in these tumors. We also show that UBE4B overexpression is often associated with amplification of its gene in human brain tumors. Our data indicate that amplification and overexpression of UBE4B represent previously undescribed molecular mechanisms of inactivation of p53 in brain tumors.

Background:Published literature documents the substantial burden of hereditary angioedema (HAE) with C1 inhibitor deficiency on the quality of life and work productivity of patients. However, despite advances in the field and the availability of guidelines to advise health care providers (HCP) on the diagnosis and management of HAE, there are still many challenges to overcome. For example, delayed diagnosis and misdiagnosis are common, and treatment practices vary worldwide.Objective:An international expert panel was convened to consider opportunities for improvements that would benefit patients with HAE.Methods:Based on professional and personal experiences, the experts developed schematics to describe the journey of patients through the following stages: (1) onset of symptoms and initial evaluation; (2) referral/diagnosis; and (3) management of HAE. More importantly, the panel identified key areas in which it was possible to optimize the support provided to patients and HCPs along this journey.Results:Overall, this approach highlighted the need for wider dissemination of algorithms and scientific data to more effectively educate HCPs from multiple disciplines and the need for more research to inform appropriate treatment decisions. Furthermore, HAE awareness campaigns, accurate online information, and referral to patient advocacy groups were all considered helpful approaches to support patients.Conclusion:More detailed and widespread information on the diagnosis and management of HAE is needed and may lead to advancements in care throughout the journey of the patient with HAE.

RESUMOA anafilaxia apresenta uma incidência crescente, particularmente em idade pediátrica. Constituindo uma emergência médica, o sucesso terapêutico depende de uma intervenção precoce e adequada. A adrenalina por via intramuscular constitui o fármaco de eleição para o seu tratamento, devendo a dose ser ajustada ao peso e à idade. Resolvida a reação aguda, o doente deve ser mantido sob vigilância médica por um período de 6 a 24 horas, pelo risco de ocorrência de reações bifásicas. Deverá ser considerada a prescrição de um dispositivo de autoadministração de adrenalina em todos os doentes com diagnóstico ou suspeita de anafilaxia; adicionalmente estes doentes têm indicação formal para estudo em consulta de imunoalergologia, de modo a permitir uma adequada intervenção diagnóstica e terapêutica que reduzirá o risco futuro. Todos os episódios de anafilaxia devem ser registados no Catálogo Português de Alergias e outras Reações Adversas (CPARA), constituindo este um instrumento fundamental de partilha de informação clínica dentro do Sistema de Saúde. Este manuscrito pretende divulgar as orientações para o diagnóstico e tratamento da anafilaxia, tornando a sua abordagem clínica mais eficiente e consertada a nível nacional, e promover a adesão ao Catálogo Português de Alergias e outras Reações Adversas como um instrumento essencial de registo e partilha de informação dos episódios de anafilaxia ocorridos em Portugal. Palavras-chave: Anafilaxia; Epinefrina; Portugal; Sistema de Registos. ABSTRACTAnaphylaxis has a growing incidence, especially in children. It represents a medical emergency and its successful therapy depends on early and proper intervention. Intramuscular epinephrine, with dose adjustment according to weight and age, is the drug of choice for anaphylaxis treatment. After resolution of the acute reaction, the patient should be kept under clinical surveillance for 6 to 24 hours, due to possible biphasic reactions. Prescription of an epinephrine auto-injectable device should be considered in all patients with diagnosed or suspected anaphylaxis; additionally these patients should always be referred to an Immunoallergy consultation, to perform adequate investigation and management in order to reduce future risk. All anaphylaxis episodes must be recorded in The Portuguese Catalogue of Allergies and other Adverse Reactions (Catálogo Português de Alergias e outras Reações Adversas, CPARA), which represents a fundamental tool to share clinical information within the Health System. The present manuscript intends to disclose the most recent Portuguese guidelines for the diagnosis and treatment of anaphylaxis, making its clinical approach more effective and homogeneous, and to promote the use of The Portuguese Catalogue of Allergies and other Adverse Reactions as an essential tool to register and share information on anaphylaxis in Portugal. Keywords: Anaphylaxis; Epinephrine; Portugal; Registries. INTRODUÇÃOA anafilaxia é uma reação sistémica de gravidade variável, habitualmente com início rápido, potencialmente fat...