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See detailDistinct gene-set burden patterns underlie common generalized and focal epilepsies
Koko, Mahmoud; Krause, Roland UL; Sander, Thomas et al

in EBioMedicine (2021), 72

Background Analyses of few gene-sets in epilepsy showed a potential to unravel key disease associations. We set out to investigate the burden of ultra-rare variants (URVs) in a comprehensive range of ... [more ▼]

Background Analyses of few gene-sets in epilepsy showed a potential to unravel key disease associations. We set out to investigate the burden of ultra-rare variants (URVs) in a comprehensive range of biologically informed gene-sets presumed to be implicated in epileptogenesis. Methods The burden of 12 URV types in 92 gene-sets was compared between cases and controls using whole exome sequencing data from individuals of European descent with developmental and epileptic encephalopathies (DEE, n = 1,003), genetic generalized epilepsy (GGE, n = 3,064), or non-acquired focal epilepsy (NAFE, n = 3,522), collected by the Epi25 Collaborative, compared to 3,962 ancestry-matched controls. Findings Missense URVs in highly constrained regions were enriched in neuron-specific and developmental genes, whereas genes not expressed in brain were not affected. GGE featured a higher burden in gene-sets derived from inhibitory vs. excitatory neurons or associated receptors, whereas the opposite was found for NAFE, and DEE featured a burden in both. Top-ranked susceptibility genes from recent genome-wide association studies (GWAS) and gene-sets derived from generalized vs. focal epilepsies revealed specific enrichment patterns of URVs in GGE vs. NAFE. Interpretation Missense URVs affecting highly constrained sites differentially impact genes expressed in inhibitory vs. excitatory pathways in generalized vs. focal epilepsies. The excess of URVs in top-ranked GWAS risk-genes suggests a convergence of rare deleterious and common risk-variants in the pathogenesis of generalized and focal epilepsies. [less ▲]

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See detailBurden of rare variants in synaptic genes in patients with severe tinnitus: An exome based extreme phenotype study
Amanat, Sana; Gallego-Martinez, Alvaro; Sollini, Joseph et al

in EBioMedicine (2021), 66(103309),

Background: tinnitus is a heterogeneous condition associated with audio logical and/or mental disorders. Chronic, severe tinnitus is reported in 1% of the population and it shows a relevant heritability ... [more ▼]

Background: tinnitus is a heterogeneous condition associated with audio logical and/or mental disorders. Chronic, severe tinnitus is reported in 1% of the population and it shows a relevant heritability, according to twins, adoptees and familial aggregation studies. The genetic contribution to severe tinnitus is unknown since large genomic studies include individuals with self-reported tinnitus and large heterogeneity in the phenotype. The aim of this study was to identify genes for severe tinnitus in patients with extreme phenotype. Methods: for this extreme phenotype study, we used three different cohorts with European ancestry (Spanish with Meniere disease (MD), Swedish tinnitus and European generalized epilepsy). In addition, four independent control datasets were also used for comparisons. Whole-exome sequencing was performed for the MD and epilepsy cohorts and whole-genome sequencing was carried out in Swedish with tinnitus. Findings: we found an enrichment of rare missense variants in 24 synaptic genes in a Spanish cohort, the most significant being PRUNE2, AKAP9, SORBS1, ITGAX, ANK2, KIF20B and TSC2 (p < 2E−04), when they were compared with reference datasets. This burden was replicated for ANK2 gene in a Swedish cohort with 97 tinnitus individuals, and in a subset of 34 Swedish patients with severe tinnitus for ANK2, AKAP9 and TSC2 genes (p < 2E−02). However, these associations were not significant in a third cohort of 701 generalized epilepsy individuals without tinnitus. Gene ontology (GO) and gene-set enrichment analyses revealed several pathways and biological processes involved in severe tinnitus, including membrane trafficking and cytoskeletal protein binding in neurons. Interpretation: a burden of rare variants in ANK2, AKAP9 and TSC2 is associated with severe tinnitus. ANK2, encodes a cytoskeleton scaffolding protein that coordinates the assembly of several proteins, drives axonal branching and influences connectivity in neurons. [less ▲]

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See detailSevere metabolic alterations in liver cancer lead to ERK pathway activation and drug resistance
Nwosu, Zeribe Chike; Piorońska, Weronika; Battello, Nadia UL et al

in EBioMedicine (2020)

Background: The extracellular signal-regulated kinase (ERK) pathway regulates cell growth, and is hyper-activated and associated with drug resistance in hepatocellular carcinoma (HCC). Metabolic pathways ... [more ▼]

Background: The extracellular signal-regulated kinase (ERK) pathway regulates cell growth, and is hyper-activated and associated with drug resistance in hepatocellular carcinoma (HCC). Metabolic pathways are profoundly dysregulated in HCC. Whether an altered metabolic state is linked to activated ERK pathway and drug response in HCC is unaddressed. Methods: We deprived HCC cells of glutamine to induce metabolic alterations and performed various assays, including metabolomics (with 13C-glucose isotope tracing), microarray analysis, and cell proliferation assays. Glutamine-deprived cells were also treated with kinase inhibitors (e.g. Sorafenib, Erlotinib, U0126 amongst other MEK inhibitors). We performed bioinformatics analysis and stratification of HCC tumour microarrays to determine upregulated ERK gene signatures in patients. Findings: In a subset of HCC cells, the withdrawal of glutamine triggers a severe metabolic alteration and ERK phosphorylation (pERK). This is accompanied by resistance to the anti-proliferative effect of kinase inhibitors, despite pERK inhibition. High intracellular serine is a consistent feature of an altered metabolic state and contributes to pERK induction and the kinase inhibitor resistance. Blocking the ERK pathway facilitates cell proliferation by reprogramming metabolism, notably enhancing aerobic glycolysis. We have identified 24 highly expressed ERK gene signatures that their combined expression strongly indicates a dysregulated metabolic gene network in human HCC tissues. Interpretation: A severely compromised metabolism lead to ERK pathway induction, and primes some HCC cells to pro-survival phenotypes upon ERK pathway blockade. Our findings offer novel insights for understanding, predicting and overcoming drug resistance in liver cancer patients. [less ▲]

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See detailIdentifying and targeting cancer-specific metabolism with network-based drug target prediction
Pacheco, Maria UL; Bintener, Tamara Jean Rita UL; Ternes, Dominik UL et al

in EBioMedicine (2019), 43(May 2019), 98-106

Background Metabolic rewiring allows cancer cells to sustain high proliferation rates. Thus, targeting only the cancer-specific cellular metabolism will safeguard healthy tissues. Methods We developed the ... [more ▼]

Background Metabolic rewiring allows cancer cells to sustain high proliferation rates. Thus, targeting only the cancer-specific cellular metabolism will safeguard healthy tissues. Methods We developed the very efficient FASTCORMICS RNA-seq workflow (rFASTCORMICS) to build 10,005 high-resolution metabolic models from the TCGA dataset to capture metabolic rewiring strategies in cancer cells. Colorectal cancer (CRC) was used as a test case for a repurposing workflow based on rFASTCORMICS. Findings Alternative pathways that are not required for proliferation or survival tend to be shut down and, therefore, tumours display cancer-specific essential genes that are significantly enriched for known drug targets. We identified naftifine, ketoconazole, and mimosine as new potential CRC drugs, which were experimentally validated. Interpretation The here presented rFASTCORMICS workflow successfully reconstructs a metabolic model based on RNA-seq data and successfully predicted drug targets and drugs not yet indicted for colorectal cancer. [less ▲]

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See detailGut microbiota in Parkinson's disease: Temporal stability and relations to disease progression
Aho, Velma UL; Pereira, P. A. B.; Voutilainen, S. et al

in EBioMedicine (2019), 44

Background: Several publications have described differences in cross-sectional comparisons of gut microbiota between patients with Parkinson's disease and control subjects, with considerable variability ... [more ▼]

Background: Several publications have described differences in cross-sectional comparisons of gut microbiota between patients with Parkinson's disease and control subjects, with considerable variability of the reported dif- ferentially abundant taxa. The temporal stability of such microbiota alterations and their relationship to disease progression have not been previously studied with a high-throughput sequencing based approach. Methods: We collected clinical data and stool samples from 64 Parkinson's patients and 64 control subjects twice, on average 2·25 years apart. Disease progression was evaluated based on changes in Unified Parkinson's Disease Rating Scale and Levodopa Equivalent Dose, and microbiota were characterized with 16S rRNA gene amplicon sequencing. Findings: We compared patients to controls, and patients with stable disease to those with faster progression. There were significant differences between microbial communities of patients and controls when corrected for confounders, but not between timepoints. Specific bacterial taxa that differed between patients and controls at both timepoints included several previously reported ones, such as Roseburia, Prevotella and Bifidobacterium. In progression comparisons, differentially abundant taxa were inconsistent across methods and timepoints, but there was some support for a different distribution of enterotypes and a decreased abundance of Prevotella in faster-progressing patients. Interpretation: The previously detected gut microbiota differences between Parkinson's patients and controls persisted after 2 years. While we found some evidence for a connection between microbiota and disease progres- sion, a longer follow-up period is required to confirm these findings. [less ▲]

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