RESUMO
BACKGROUND: Acute Kawasaki disease (KD) induces central nervous system inflammation and excessive irritability. Long-term impacts on children's neurodevelopment have only been studied marginally. This pilot study aimed to describe the neuropsychological profile of primary school-aged children with a history of KD and to explore the impacts of KD on electroencephalography (EEG) markers associated with attention and brain maturation. METHODS: Fifteen children (8.8 ± 2.5 years) were recruited 4.9 ± 2.7 years after KD onset. Intellectual abilities, long-term memory, and auditory sustained attention were evaluated. Parents completed standardized questionnaires assessing (1) executive functioning; (2) internalizing and externalizing difficulties; (3) attention deficit hyperactivity disorder symptoms; and (4) autism spectrum disorder symptoms. Theta/beta ratio (TBR) and alpha peak (AP) were extracted from resting-state EEG and compared with 32 controls (8.9 ± 2.1 years). The alpha band was analyzed using a feature reduction algorithm to detect potential groupings. RESULTS: Performances showed preserved intellectual abilities and memory. Sustained attention performance was within the lower range for 4/14 participants (29%), with considerable parental reports of inattention (43%), working memory difficulties (50%), and hyperactivity-impulsivity (36%). No alterations in the TBR were found but the KD group presented a significantly lower AP amplitude ratio. A clear separation of KD cohort into two clusters showed that acute irritability is associated with a weaker AP. CONCLUSIONS: Despite overall preserved cognitive functions, there is a possible association between KD and attention deficit concerns. This first EEG-based study indicates alpha peak abnormality after KD, predominantly in children with acute irritability. Longitudinal studies are warranted to better characterize patients' neurodevelopmental trajectory.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Transtorno do Espectro Autista , Síndrome de Linfonodos Mucocutâneos , Criança , Humanos , Projetos Piloto , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/psicologia , Síndrome de Linfonodos Mucocutâneos/complicações , Síndrome de Linfonodos Mucocutâneos/diagnóstico , Eletroencefalografia , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/etiologia , Transtorno do Deficit de Atenção com Hiperatividade/psicologiaRESUMO
Children with neurofibromatosis type 1 (NF1) are at increased risk of developing cognitive problems, including attention deficits and learning difficulties. Alterations in brain response to repetition and change have been evidenced in other genetic conditions associated with cognitive dysfunctions. Whether the integrity of these fundamental neural responses is compromised in school-aged children with NF1 is still unknown. In this study, we examined the repetition suppression (RS) and change detection responses in children with NF1 (n = 36) and neurotypical controls (n = 41) aged from 4 to 13 years old, using a simple sequence of vowels. We performed time-frequency analyses to compare spectral power and phase synchronization between groups, in the theta, alpha and beta frequency bands. Correlational analyses were performed between the neural responses and the level of intellectual functioning, as well as with behavioral symptoms of comorbid neurodevelopmental disorders measured through parental questionnaires. Children with NF1 showed preserved RS, but increased spectral power in the change detection response. Correlational analyses performed with measures of change detection revealed a negative association between the alpha-band spectral power and symptoms of inattention and hyperactivity. These findings suggest atypical neural response to change in children with NF1. Further studies should be conducted to clarify the interaction with comorbid neurodevelopmental disorders and the possible role of altered inhibitory mechanisms in this enhanced neural response.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Neurofibromatose 1 , Humanos , Criança , Pré-Escolar , Adolescente , Neurofibromatose 1/complicações , Encéfalo , Cognição , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Neurofibromatosis type 1 (NF1) is a genetic disorder often associated with cognitive dysfunctions, including a high occurrence of deficits in visuoperceptual skills. The neural underpinnings of these visuoperceptual deficits are not fully understood. We used steady-state visual evoked potentials (SSVEPs) to investigate possible alterations in the synchronization of neural activity in the occipital cortex of children with NF1. METHODS: SSVEPs were measured using electroencephalography and compared between children with NF1 (n = 28) and neurotypical controls (n = 28) aged between 4 and 13 years old. SSVEPs were recorded during visual stimulation with coloured icons flickering at three different frequencies (6 Hz, 10 Hz, and 15 Hz) and analyzed in terms of signal-to-noise ratios. A mixed design ANCOVA was performed to compare SSVEP responses between groups at the three stimulation frequencies. Pearson's correlations with levels of intellectual functioning as well as with symptoms of ADHD, ASD and emotional/behavioral problems were performed. The impact of psychostimulant medication on the SSVEP responses was analyzed in a subset of the NF1 group (n = 8) with paired t-tests. RESULTS: We observed reduced signal-to-noise ratios of the SSVEP responses in children with NF1. The SSVEP responses were negatively correlated with symptoms of inattention and with symptoms of emotional/behavioral problems in the NF1 group. The SSVEP response generated by the lowest stimulation frequency (i.e., 6 Hz) was rescued with the intake of psychostimulant medication. CONCLUSIONS: Impaired processing of rhythmic visual stimulation was evidenced in children with NF1 through measures of SSVEP responses. Those responses seem to be more reduced in children with NF1 who exhibit more symptoms of inattention and emotional/behavioral problems in their daily life. SSVEPs are potentially sensitive electrophysiological markers that could be included in future studies investigating the impact of medication on brain activity and cognitive functioning in children with NF1.
Assuntos
Potenciais Evocados Visuais , Neurofibromatose 1 , Adolescente , Escala de Avaliação Comportamental , Criança , Pré-Escolar , Eletroencefalografia , Humanos , Neurofibromatose 1/complicações , Estimulação LuminosaRESUMO
Lung adenocarcinoma (LUAD) is the most common type of lung cancer and a leading cause of cancer-related deaths worldwide. Despite important recent advances, the prognosis for LUAD patients is still unfavourable, with a 5 year-survival rate close to 15%. Improving the characterization of lung tumors is important to develop alternative options for the diagnosis and the treatment of this disease. Zinc-finger protein 768 (ZNF768) is a transcription factor that was recently shown to promote proliferation and repress senescence downstream of growth factor signaling. Although ZNF768 protein levels were found to be elevated in LUAD compared to normal lung tissue, it is currently unknown whether ZNF768 expression associates with clinicopathological features in LUAD. Here, using tissue microarrays of clinical LUAD surgical specimens collected from 364 patients, we observed that high levels of ZNF768 is a common characteristic of LUAD. We show that ZNF768 protein levels correlate with high proliferative features in LUAD, including the mitotic score and Ki-67 expression. Supporting a role for ZNF768 in promoting proliferation, we report that ZNF768 depletion severely impairs proliferation in several lung cancer cell lines in vitro. A marked decrease in the expression of key proliferative genes was observed in cancer cell lines depleted from ZNF768. Altogether, our findings support a role for ZNF768 in promoting proliferation of LUAD.
RESUMO
We recently identified Zinc-finger protein 768 (ZNF768) as a novel transcription factor controlling cell fate decision downstream of Rat sarcoma virus (RAS). We showed that ZNF768 depletion impairs cell cycle progression and triggers cellular senescence, while its overexpression allows cells to bypass oncogene-induced senescence. Elevated ZNF768 levels is common in tumors, suggesting that ZNF768 may help to escape cellular senescence, sustain proliferation and promote malignant transformation. Here, we discuss these recent findings and highlight key questions emerging from our work.
RESUMO
RAS proteins are GTPases that lie upstream of a signaling network impacting cell fate determination. How cells integrate RAS activity to balance proliferation and cellular senescence is still incompletely characterized. Here, we identify ZNF768 as a phosphoprotein destabilized upon RAS activation. We report that ZNF768 depletion impairs proliferation and induces senescence by modulating the expression of key cell cycle effectors and established p53 targets. ZNF768 levels decrease in response to replicative-, stress- and oncogene-induced senescence. Interestingly, ZNF768 overexpression contributes to bypass RAS-induced senescence by repressing the p53 pathway. Furthermore, we show that ZNF768 interacts with and represses p53 phosphorylation and activity. Cancer genomics and immunohistochemical analyses reveal that ZNF768 is often amplified and/or overexpressed in tumors, suggesting that cells could use ZNF768 to bypass senescence, sustain proliferation and promote malignant transformation. Thus, we identify ZNF768 as a protein linking oncogenic signaling to the control of cell fate decision and proliferation.
Assuntos
Senescência Celular/genética , Genes ras/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Carcinogênese , Ciclo Celular , Diferenciação Celular , Proliferação de Células , Transformação Celular Neoplásica , Replicação do DNA , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Genômica , Células HeLa , Humanos , Oncogenes , Fenótipo , Fosfoproteínas , Fosforilação , Repressão Psicológica , Transdução de Sinais , Proteínas ras/genéticaRESUMO
We engineered a machine learning approach, MSHub, to enable auto-deconvolution of gas chromatography-mass spectrometry (GC-MS) data. We then designed workflows to enable the community to store, process, share, annotate, compare and perform molecular networking of GC-MS data within the Global Natural Product Social (GNPS) Molecular Networking analysis platform. MSHub/GNPS performs auto-deconvolution of compound fragmentation patterns via unsupervised non-negative matrix factorization and quantifies the reproducibility of fragmentation patterns across samples.