High USP6NL levels in breast cancer sustain chronic AKT phosphorylation and GLUT1 stability fueling aerobic glycolysis

USP6NL, also named RN-tre, is a GTPase activating protein (GAP) involved in control of endocytosis and signal transduction. Here we report that USP6NL is overexpressed in breast cancer (BC), mainly of the basal-like/integrative cluster 10 subtype. Increased USP6NL levels were accompanied by gene amplification and were associated with worse prognosis in the METABRIC dataset, retaining prognostic value in multivariable analysis. High levels of USP6NL in BC cells delayed endocytosis and degradation of the epidermal growth factor receptor (EGFR), causing chronic AKT activation. In turn, AKT stabilized the glucose transporter GLUT1 at the plasma membrane, increasing aerobic glycolysis. In agreement, elevated USP6NL sensitized BC cells to glucose deprivation, indicating that their glycolytic capacity relies on this protein. Depletion of USP6NL accelerated EGFR/AKT downregulation and GLUT1 degradation, impairing cell proliferation exclusively in BC cells that harbored increased levels of USP6NL. Overall, these findings argue that USP6NL overexpression generates a metabolic rewiring that is essential to foster the glycolytic demand of BC cells and promote their proliferation

Epidemiology of neurocysticercosis in Brazil Epidemiologia da neurocisticercose no Brasil

A revision of literature was done with the objective of tracing an epidemiologic profile of neurocysticercosis (NCC) in Brazil. The prevalence was 0.12-9% in autopsies. The frequency was 0.03-7.5% in clinical series and 0.68-5.2% in seroepidemiological studies. The disease corresponds to 0.08-2.5% of admissions to general hospitals. Patient origin was rural in 30-63% of cases. The most involved age range (64-100%) was 11 to 60 years, with a predominance (22-67%) between 21 and 40 years. The male sex was the most affected (51-80%). In the severe forms there was a predominance of urban origin (53-62%) and of the female sex (53-75%). The period of hospitalization ranges from 1 to 254 days and 33 to 50% of patients suffer 1.7 &plusmn; 1.4 admissions. The clinical picture was variable, with a predominance of epileptic syndrome (22-92%) and intracranial hypertension (19-89%). Psychiatric manifestations were associated in 9-23% of patients. Lethality was 0.29% in terms of all diseases in general and 4.8-25.9% in terms of neurologic diseases. The asymptomatic form was detected in 6% of patients in clinical serie and in 48.5% of case from autopsies. The racemose form and ventricular localization also was observed as asymptomatic form. Among the patients with cutaneous cysticercosis 65% of them showed neurologic manifestations.<br>Realizou-se revisão da literatura com o objetivo de tentar delinear um perfil epidemiológico da neurocisticercose no Brasil. A prevalência em necrópsias variou de 0,12-9%. A freqüência, nas casuísticas clínicas foi de 0,03-7,5% e, nos estudos soroepidemiológicos, de 0,68-5,2%. Compreendeu 0,08-2,5% das internações em hospitais gerais. A procedência foi rural em 30-63% dos doentes. Comprometeu mais (64-100%) na faixa etária dos 11 aos 60 anos, predominantemente (22-67%) entre 21 e 40 anos. O sexo masculino foi mais atingido (51-80%). Nas formas graves, houve predomínio da origem urbana (53-62%) e do sexo feminino (53-75%). O período de internação variou de 1 -254 dias, com 33 a 50% dos doentes necessitando 1.7 &plusmn; 1,4 admissões. Houve variabilidade no quadro clínico, predominando síndrome epiléptica (22-92%) e hipertensão intracraniana (19-89%). A presença de manifestações psiquiátricas foi observada em 9-23% dos doentes. A letalidade, frente as doenças em geral, foi de 0,29% e, entre as doenças neurológicas, de 4,8-25,9%. A forma assintomática foi detectada em 6% dos doentes de casuística clínica e em 48,5% dos casos de necrópsia. A forma racemosa e a localização ventricular também se apresentaram de maneira assintomática. Entre os doentes com cisticercose cutânea, 65% apresentavam manifestações neurológicas

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation; analyses timings and patterns of tumour evolution; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity; and evaluates a range of more-specialized features of cancer genomes