RESUMO
The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.
Assuntos
Carcinoma Neuroendócrino/genética , Genoma Humano/genética , Genômica , Neoplasias Pancreáticas/genética , Sequência de Bases , Proteínas de Ligação a Calmodulina/genética , Montagem e Desmontagem da Cromatina/genética , Aberrações Cromossômicas , Variações do Número de Cópias de DNA/genética , DNA Glicosilases/genética , Análise Mutacional de DNA , Reparo do DNA/genética , Feminino , Mutação em Linhagem Germinativa/genética , Humanos , Masculino , Proteína EWS de Ligação a RNA , Proteínas de Ligação a RNA/genética , Serina-Treonina Quinases TOR/metabolismo , Telômero/genética , Telômero/metabolismoRESUMO
This corrects the article DOI: 10.1038/nature21063.
RESUMO
BACKGROUND: Despite multiple reminders, education sessions, and multidisciplinary team involvement, adherence to an evidence-based mechanical ventilation weaning protocol had been less than 1% in a general systems intensive care unit since implementation. OBJECTIVE: To assess the effectiveness of using an implementation program, the Model for Accelerating Improvement, to improve adherence and clinical outcomes after restarting a mechanical ventilation weaning protocol in an adult general systems intensive care unit. METHODS: A prospective comparative design, before and after implementation of the Model for Accelerating Improvement, was used with a consecutive sample of 129 patients and 112 multidisciplinary team members. Clinical outcomes were rate of unsuccessful extubations, rate of ventilator-associated pneumonia, and duration of mechanical ventilation; practice outcomes were staff's understanding of the mechanical ventilation weaning protocol, perceptions of the practice safety climate, and adherence to the weaning protocol. RESULTS: After the intervention, the rate of unsuccessful extubations decreased, and staff's understanding of and adherence to the weaning protocol increased significantly. The rate of ventilator-associated pneumonia, duration of mechanical ventilation, and staff's perceptions of the practice safety climate did not change significantly. CONCLUSION: Implementing the Model for Accelerating Improvement improved understanding of and adherence to protocol-directed weaning and reduced the rate of unsuccessful extubations.