Subject(s)
Multiple Sclerosis, Relapsing-Remitting , Multiple Sclerosis , Neutropenia , Humans , Multiple Sclerosis/drug therapy , Antibodies, Monoclonal, Humanized/adverse effects , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Neutropenia/chemically induced , Neutropenia/diagnosis , Immunologic Factors/adverse effectsABSTRACT
Non-coding RNA from pericentromeric satellite repeats are involved in stress-dependent splicing processes, maintenance of heterochromatin, and are required to protect genome stability. Here we show that the long non-coding satellite III RNA (SatIII) generates resistance against the topoisomerase IIa (TOP2A) inhibitor etoposide in lung cancer. Because heat shock conditions (HS) protect cells against the toxicity of etoposide, and SatIII is significantly induced under HS, we hypothesized that the protective effect could be traced back to SatIII. Using genome methylation profiles of patient-derived xenograft mouse models we show that the epigenetic modification of the SatIII DNA locus and the resulting SatIII expression predict chemotherapy resistance. In response to stress, SatIII recruits TOP2A to nuclear stress bodies, which protects TOP2A from a complex formation with etoposide and results in decreased DNA damage after treatment. We show that BRD4 inhibitors reduce the expression of SatIII, restoring etoposide sensitivity.
Subject(s)
Drug Resistance, Neoplasm/genetics , Etoposide/therapeutic use , RNA, Long Noncoding/physiology , Animals , Antineoplastic Agents/pharmacology , Cell Cycle Proteins/antagonists & inhibitors , Centromere/genetics , Centromere/metabolism , DNA Methylation/physiology , DNA Topoisomerases, Type II/drug effects , DNA Topoisomerases, Type II/genetics , DNA Topoisomerases, Type II/metabolism , Drug Resistance, Neoplasm/drug effects , Gene Expression Regulation, Neoplastic/drug effects , HEK293 Cells , HeLa Cells , Humans , Male , Mice, Inbred NOD , Mice, SCID , Poly-ADP-Ribose Binding Proteins/drug effects , Poly-ADP-Ribose Binding Proteins/genetics , Poly-ADP-Ribose Binding Proteins/metabolism , RNA, Long Noncoding/genetics , Transcription Factors/antagonists & inhibitors , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Background and Purpose: Dysphagia is a common and severe symptom of acute stroke. Although intracerebral hemorrhages (ICHs) account for 10% to 15% of all strokes, the occurrence of dysphagia in this subtype of stroke has not been widely investigated. The aim of this study was to evaluate the overall frequency and associated lesion locations and clinical predictors of dysphagia in patients with acute ICH. Methods: Our analysis included 132 patients with acute ICH. Clinical swallowing assessment was performed within 48 hours after admission. All patients underwent computed tomography imaging. Voxel-based lesion-symptom mapping was performed to determine lesion sites associated with dysphagia. Results: Eighty-four patients (63.6%) were classified as dysphagic. Higher scores on the National Institutes of Health Stroke Scale, larger ICH volumes, and higher degree of disability were associated with dysphagia. Voxels showing a statistically significant association with dysphagia were mainly located in the right insular cortex, the right central operculum, as well as the basal ganglia, corona radiata, and the left thalamus and left internal capsule. In contrast to lobar regions, in subcortical deep brain areas also small lesion volumes (<10 mL) were associated with a substantial risk of dysphagia. Intraventricular ICH extension and midline shift as imaging findings indicating a space-occupying effect were not associated with dysphagia in multivariate analysis. Conclusions: Dysphagia is a frequent symptom in acute ICH. Distinct cortical and subcortical lesion sites are related to swallowing dysfunction and predictive for the development of dysphagia. Therefore, patients with ICH should be carefully evaluated for dysphagia independently from lesion size, in particular if deep brain regions are affected.
