A major concern for cardiac arrest (CA) survivors is the manifestation of long-term cognitive impairments. Physical exercise (PE) is a well-established approach to improve cognitive functions under ...certain pathological conditions. We previously showed that PE post-CA mitigates cognitive deficits, but the underlying mechanisms remain unknown. To define neuroprotective mechanisms, we analyzed whether PE post-CA protects neurons involved in memory. We first performed a contextual fear conditioning (CFC) test to confirm that PE post-CA preserves memory in rats. We then conducted a cell-count analysis and determined the number of live cells in the hippocampus, and septal and thalamic nuclei, all areas involved in cognitive functions. Lastly, we performed RNA-seq to determine PE post-CA effect on gene expression. Following CA, exercised rats had preserved CFC memory than sham PE animals. Despite this outcome, PE post-CA did not protect hippocampal cells from dying. However, PE ameliorated cell death in septal and thalamic nuclei compared to sham PE animals, suggesting that these nuclei are crucial in mitigating cognitive decline post-CA. Interestingly, PE affected regulation of genes related to neuroinflammation, plasticity, and cell death. These findings reveal potential mechanisms whereby PE post-CA preserves cognitive functions by protecting septal and thalamic cells via gene regulation.
Growing evidence has demonstrated that DNA methylation (DNAm) plays an important role in Alzheimer's disease (AD) and that DNAm differences can be detected in the blood of AD subjects. Most studies ...have correlated blood DNAm with the clinical diagnosis of AD in living individuals. However, as the pathophysiological process of AD can begin many years before the onset of clinical symptoms, there is often disagreement between neuropathology in the brain and clinical phenotypes. Therefore, blood DNAm associated with AD neuropathology, rather than with clinical data, would provide more relevant information on AD pathogenesis.
We performed a comprehensive analysis to identify blood DNAm associated with cerebrospinal fluid (CSF) pathological biomarkers for AD. Our study included matched samples of whole blood DNA methylation, CSF Aβ
, phosphorylated tau
(pTau
), and total tau (tTau) biomarkers data, measured on the same subjects and at the same clinical visits from a total of 202 subjects (123 CN or cognitively normal, 79 AD) in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. To validate our findings, we also examined the association between premortem blood DNAm and postmortem brain neuropathology measured on a group of 69 subjects in the London dataset.
We identified a number of novel associations between blood DNAm and CSF biomarkers, demonstrating that changes in pathological processes in the CSF are reflected in the blood epigenome. Overall, the CSF biomarker-associated DNAm is relatively distinct in CN and AD subjects, highlighting the importance of analyzing omics data measured on cognitively normal subjects (which includes preclinical AD subjects) to identify diagnostic biomarkers, and considering disease stages in the development and testing of AD treatment strategies. Moreover, our analysis revealed biological processes associated with early brain impairment relevant to AD are marked by DNAm in the blood, and blood DNAm at several CpGs in the DMR on HOXA5 gene are associated with pTau
in the CSF, as well as tau-pathology and DNAm in the brain, nominating DNAm at this locus as a promising candidate AD biomarker.
Our study provides a valuable resource for future mechanistic and biomarker studies of DNAm in AD.
GATAD2B (GATA zinc finger domain containing 2B) variants are associated with the neurodevelopmental syndrome GAND, characterized by intellectual disability (ID), infantile hypotonia, apraxia of ...speech, epilepsy, macrocephaly and distinct facial features. GATAD2B encodes for a subunit of the Nucleosome Remodeling and Histone Deacetylase (NuRD) complex. NuRD controls transcriptional programs critical for proper neurodevelopment by coupling histone deacetylase with ATP-dependent chromatin remodeling activity. To study mechanisms of pathogenesis for GAND, we characterized a mouse model harboring an inactivating mutation in Gatad2b. Homozygous Gatad2b mutants die perinatally, while haploinsufficient Gatad2b mice exhibit behavioral abnormalities resembling the clinical features of GAND patients. We also observed abnormal cortical patterning, and cellular proportions and cell-specific alterations in the developmental transcriptome in these mice. scRNAseq of embryonic cortex indicated misexpression of genes key for corticogenesis and associated with neurodevelopmental syndromes such as Bcl11b, Nfia and H3f3b and Sox5. These data suggest a crucial role for Gatad2b in brain development.
In line with the World Health Organizations' health definition, patient-reported outcome (PRO) measures frequently cover aspects of social health. Our study aimed to evaluate the role functioning ...(RF) and social functioning (SF) contents assessed by PRO measures commonly used in cancer patients.
We analysed the item content of the SF and RF domains of the EORTC CAT Core, the EORTC QLQ-C30, the SF-36, and the FACT-G as well as the PROMIS item bank covering the Ability to Participate in Social Roles and Activities. Following an established methodology we linked item content to the International Classification of Functioning, Disability and Health (ICF) framework.
The content of 85 items was assigned to three ICF components ('Activities and Participation', 'Body Functions', and 'Environmental Factors'). The EORTC CAT Core RF items were mostly related to the first-level ICF categories 'Domestic life' and 'Community, social and civic life', while its SF item bank focused on 'Interpersonal interactions and relationships'. These three categories were also covered by the PROMIS social participation item bank. The FACT-G Social/Family scale focused on environmental factors ('Support and Relationships' and 'Attitudes') while the SF-36 Role-physical/emotional scales had a stronger focus on 'General tasks and demands' and 'Major life areas'.
Our results highlight conceptual overlap and differences among PRO measures for the assessment of social health in cancer. This information may help to select the most appropriate measure for a specific setting or study purpose and to better understand the possibilities of linking scores across different PRO measures.
Neuroprotective agents administered post-cerebral ischemia have failed so far in the clinic to promote significant recovery. Thus, numerous efforts were redirected toward prophylactic approaches such ...as preconditioning as an alternative therapeutic strategy. Our laboratory has revealed a novel long-term window of cerebral ischemic tolerance mediated by resveratrol preconditioning (RPC) that lasts for 2 weeks in mice. To identify its mediators, we conducted an RNA-seq experiment on the cortex of mice 2 weeks post-RPC, which revealed 136 differentially expressed genes. The majority of genes (116/136) were downregulated upon RPC and clustered into biological processes involved in transcription, synaptic signaling, and neurotransmission. The downregulation in these processes was reminiscent of metabolic depression, an adaptation used by hibernating animals to survive severe ischemic states by downregulating energy-consuming pathways. Thus, to assess metabolism, we used a neuronal-astrocytic co-culture model and measured the cellular respiration rate at the long-term window post-RPC. Remarkably, we observed an increase in glycolysis and mitochondrial respiration efficiency upon RPC. We also observed an increase in the expression of genes involved in pyruvate uptake, TCA cycle, and oxidative phosphorylation, all of which indicated an increased reliance on energy-producing pathways. We then revealed that these nuclear and mitochondrial adaptations, which reduce the reliance on energy-consuming pathways and increase the reliance on energy-producing pathways, are epigenetically coupled through acetyl-CoA metabolism and ultimately increase baseline ATP levels. This increase in ATP would then allow the brain, a highly metabolic organ, to endure prolonged durations of energy deprivation encountered during cerebral ischemia.
Both sleep deprivation and hypoxia have been shown to impair executive function. Conversely, moderate intensity exercise is known to improve executive function. In a multi-experiment study, we tested ...the hypotheses that moderate intensity exercise would ameliorate any decline in executive function after i) three consecutive nights of partial sleep deprivation (PSD) (Experiment 1) and ii) the isolated and combined effects of a single night of total sleep deprivation (TSD) and acute hypoxia (Experiment 2).
Using a rigorous randomised controlled crossover design, 12 healthy participants volunteered in each experiment (24 total, 5 females). In both experiments seven executive function tasks (2-choice reaction time, logical relations, manikin, mathematical processing, 1-back, 2-back, 3-back) were completed at rest and during 20 min semi-recumbent, moderate intensity cycling. Tasks were completed in the following conditions: before and after three consecutive nights of PSD and habitual sleep (Experiment 1) and in normoxia and acute hypoxia (F
O
= 0.12) following one night of habitual sleep and one night of TSD (Experiment 2).
Although the effects of three nights of PSD on executive functions were inconsistent, one night of TSD (regardless of hypoxic status) reduced executive functions. Significantly, regardless of sleep or hypoxic status, executive functions are improved during an acute bout of moderate intensity exercise.
These novel data indicate that moderate intensity exercise improves executive function performance after both PSD and TSD, regardless of hypoxic status. The key determinants and/or mechanism(s) responsible for this improvement still need to be elucidated. Future work should seek to identify these mechanisms and translate these significant findings into occupational and skilled performance settings.
Ischemic preconditioning is an innate neuroprotective mechanism in which a sub-injurious ischemic exposure increases the brain’s ability to withstand a subsequent, normally injurious ischemic insult. ...Part of ischemic preconditioning neuroprotection stems from an epigenetic reprogramming of the brain to a phenotype of ischemic tolerance, which results in a gene expression profile different from that observed in the non-injured and ischemia-injured brains. Such neuroprotective reprograming, activated by ischemic preconditioning, requires specific changes in DNA accessibility coordinated with activation of transcriptional activator and repressor proteins, which allows for expression of specific neuroprotective proteins despite a general repression of gene expression. In this review we examine the effects of injurious ischemia and ischemic preconditioning on the regulation of DNA methylation, histone post-translational modifications, and non-coding RNA expression. There is increasing interest in the role of epigenetics in disease pathobiology, and whether and how pharmacological manipulation of epigenetic processes may allow for ischemic neuroprotection. Therefore, a better understanding of the epigenomic determinants underlying the modulation of gene expression that lead to ischemic tolerance or cell death offers the promise of novel neuroprotective therapies that target global reprograming of genomic activity versus individual cellular signaling pathways.
The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Lung Cancer 13 (QLQ-LC13) assesses quality of life (QOL) in patients with lung cancer and was the ...first EORTC module developed for use in international clinical trials. Since its publication in 1994, major treatment advances with possible effects on QOL have occurred. These changes called for an update of the module and its international psychometric validation. We aimed to investigate the scale structure and psychometric properties of the updated lung cancer module, QLQ-LC29, in patients with lung cancer.
This international, observational field study was done in 19 hospitals across 12 countries. Patients aged older than 18 years with a confirmed diagnosis of lung cancer and no other previous primary tumour, and who were mentally fit with sufficient language skills to understand and complete the questionnaire were included. Patients were asked during a hospital visit to fill in the paper versions of the core questionnaire EORTC QLQ-C30 plus QLQ-LC29, and investigators selected half of these patients to complete the questionnaire again 2–4 weeks later. Our primary aim was to assess the scale structure and psychometric properties of EORTC QLQ-LC29. We analysed scale structure using confirmatory factor analysis; reliability using Cronbach's α value (internal consistency) and intra-class coefficient (test–retest reliability); sensitivity using independent t tests stratified by Karnofsky performance status; and responsiveness to change over time by ANOVA. This study is registered with ClinicalTrials.gov, NCT02745691.
Between April 12, 2016, and Sept 26, 2018, 523 patients with a confirmed diagnosis of either non-small-cell lung cancer (n=442) or small-cell lung cancer (n=81) were recruited. Confirmatory factor analysis provided a solution composed of five multi-item scales (coughing, shortness of breath, fear of progression, hair problems, and surgery-related symptoms) plus 15 single symptom or side-effect items: χ2=370·233, root mean square error of approximation=0·075, and comparative-fit index=0·901. Cronbach's α for internal consistencies of all multi-item scales were above the threshold of 0·70. Intra-class coefficients for test–retest reliabilities ranged between 0·82 and 0·97. Three (shortness of breath, fear of progression, and hair problems) of the five multi-item scales showed responsiveness to change over time (p values <0·05), as did nine of 15 single symptom items. Four (coughing, shortness of breath, fear of progression, and surgery-related symptoms) of the five multi-item scales and ten of the 15 single symptom items were sensitive to known group differences (ie, lower vs higher Karnofsky performance status).
Results determined the psychometric properties of the updated lung cancer module, which is ready for use in international clinical studies.
EORTC Quality of Life Group.
Abstract
Background
Neurofibromatosis type 2 (NF2) is a genetic tumor-predisposition disorder caused by NF2/merlin tumor suppressor gene inactivation. The hallmark of NF2 is formation of bilateral ...vestibular schwannomas (VS). Because merlin modulates activity of the Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway, we investigated repurposing drugs targeting MEK1 and/or MEK2 as a treatment for NF2-associated schwannomas.
Methods
Mouse and human merlin-deficient Schwann cell lines (MD-MSC/HSC) were screened against 6 MEK1/2 inhibitors. Efficacious drugs were tested in orthotopic allograft and NF2 transgenic mouse models. Pathway and proteome analyses were conducted. Drug efficacy was examined in primary human VS cells with NF2 mutations and correlated with DNA methylation patterns.
Results
Trametinib, PD0325901, and cobimetinib were most effective in reducing MD-MSC/HSC viability. Each decreased phosphorylated pERK1/2 and cyclin D1, increased p27, and induced caspase-3 cleavage in MD-MSCs. Proteomic analysis confirmed cell cycle arrest and activation of pro-apoptotic pathways in trametinib-treated MD-MSCs. The 3 inhibitors slowed allograft growth; however, decreased pERK1/2, cyclin D1, and Ki-67 levels were observed only in PD0325901 and cobimetinib-treated grafts. Tumor burden and average tumor size were reduced in trametinib-treated NF2 transgenic mice; however, tumors did not exhibit reduced pERK1/2 levels. Trametinib and PD0325901 modestly reduced viability of several primary human VS cell cultures with NF2 mutations. DNA methylation analysis of PD0325901-resistant versus -susceptible VS identified genes that could contribute to drug resistance.
Conclusion
MEK inhibitors exhibited differences in antitumor efficacy resistance in schwannoma models with possible emergence of trametinib resistance. The results support further investigation of MEK inhibitors in combination with other targeted drugs for NF2 schwannomas.
Non-syndromic cleft lip with or without cleft palate (NSCLP) is the most common craniofacial birth defect. The etiology of NSCLP is complex with multiple genes and environmental factors playing ...causal roles. Although studies have identified numerous genetic markers associated with NSCLP, the role of epigenetic variation remains relatively unexplored. Because of their identical DNA sequences, monozygotic (MZ) twins discordant for NSCLP are an ideal model for examining the potential contribution of DNA methylation to non-syndromic orofacial clefting. In this study, we compared the patterns of whole genome DNA methylation in six MZ twin pairs discordant for NSCLP. Differentially methylated positions (DMPs) and regions (DMRs) were identified in NSCLP candidate genes, including differential methylation in
and
in two independent MZ twin pairs. In addition to DNA methylation differences in NSCLP candidate genes, we found common differential methylation in genes belonging to the Hippo signaling pathway, implicating this mechanosensory pathway in the etiology of NSCLP. The results of this novel approach using MZ twins discordant for NSCLP suggests that differential methylation is one mechanism contributing to NSCLP, meriting future studies on the role of DNA methylation in familial and sporadic NSCLP.
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