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Medulloblastoma (MB) is an aggressive brain tumor that predominantly affects children. Recent high-throughput sequencing studies suggest that the noncoding RNA genome, in particular long noncoding RNAs (lncRNAs), contributes to MB subgrouping. Here we report the identification of a novel lncRNA, lnc-HLX-2-7, as a potential molecular marker and therapeutic target in Group 3 MBs.
Publicly available RNA sequencing (RNA-seq) data from 175 MB patients were interrogated to identify lncRNAs that differentiate between MB subgroups. After characterizing a subset of differentially expressed lncRNAs in vitro and in vivo, lnc-HLX-2-7 was deleted by CRISPR/Cas9 in the MB cell line. check details Intracranial injected tumors were further characterized by bulk and single-cell RNA-seq.
Lnc-HLX-2-7 is highly upregulated in Group 3 MB cell lines, patient-derived xenografts, and primary MBs compared with other MB subgroups as assessed by quantitative real-time, RNA-seq, and RNA fluorescence in situ hybridization. Depletion of lnc-HLX-2-7 significantly reduced cell proliferation and 3D colony formation and induced apoptosis. Lnc-HLX-2-7-deleted cells injected into mouse cerebellums produced smaller tumors than those derived from parental cells. Pathway analysis revealed that lnc-HLX-2-7 modulated oxidative phosphorylation, mitochondrial dysfunction, and sirtuin signaling pathways. The MYC oncogene regulated lnc-HLX-2-7, and the small-molecule bromodomain and extraterminal domain family‒bromodomain 4 inhibitor Jun Qi 1 (JQ1) reduced lnc-HLX-2-7 expression.
Lnc-HLX-2-7 is oncogenic in MB and represents a promising novel molecular marker and a potential therapeutic target in Group 3 MBs.
Lnc-HLX-2-7 is oncogenic in MB and represents a promising novel molecular marker and a potential therapeutic target in Group 3 MBs.The clinical effectiveness of any disease-modifying treatment for prion disease, as for other neurodegenerative disorders, will depend on early treatment before damage to neural tissue is irrevocable. Thus, there is a need to identify markers that predict disease onset in healthy at-risk individuals. Whilst imaging and neurophysiological biomarkers have shown limited use in this regard, we recently reported progressive neurophysiological changes in individuals with the inherited prion disease mutation P102L. We have also previously demonstrated a signature pattern of fronto-parietal dysfunction in mild prion disease. Here we address whether these cognitive features anticipate the onset of symptoms in a unique sample of patients with inherited prion disease. In the cross-sectional analysis, we analysed the performance of patients at three time points in the course of disease onset prior to symptoms (n = 27), onset of subjective symptoms without positive clinical findings (n = 8) and symptomatic with positive catients and converters before the onset of clinical symptoms [area under the curve = 0.83 (95% confidence interval, 0.62-1.00), P = 0.009]. Thus, we report here, for the first time, neuropsychological abnormalities in healthy patients prior to either symptom onset or clinical diagnosis of inherited prion disease. This constitutes an important component of an evolving profile of clinical and biomarker abnormalities in this crucial group for preventive medicine.
The purpose of this study was to determine if the rate of change in the depth of the surface of the lamina cribrosa due to glaucomatous remodeling differs between glaucoma patients of African descent (AD) and European descent (ED).
There were 1122 images taken longitudinally over an average of 3 years (range = 0.9-4.1 years) from 122 patients with glaucoma followed in the African Descent and Glaucoma Evaluation Study (ADAGES) and Diagnostic Intervention and Glaucoma Study (DIGS) were automatically segmented to compute anterior lamina cribrosa surface depth (ALCSD). The rate of ALCSD change was compared across racial groups after adjusting for baseline characteristics known to be associated with ALCSD or disease progression (visual field, ALCSD, corneal thickness, optic disk size, and age).
After adjusting for all other covariates, the ED group had significantly greater ALCSD posterior migration (deepening) than the AD group (difference = 2.57 µm/year, P = 0.035). There was a wider range of ALCSD change in the ED compared with the AD group, and more individuals had greater magnitude of both deepening and shallowing. No other covariates measured at baseline had independent effects on the longitudinal changes in ALCSD (baseline visual field severity, baseline ALCSD, corneal thickness, Bruch's membrane opening [BMO] area, or age).
Glaucomatous remodeling of the lamina cribrosa differs between AD and ED patients with glaucoma. Unlike the cross-sectional associations seen with aging, in which a deeper ALCSD was seen with age in the ED group, glaucomatous remodeling in this longitudinal study resulted in more posterior migration of ALCSD in ED compared to AD patients.
Glaucomatous remodeling of the lamina cribrosa differs between AD and ED patients with glaucoma. Unlike the cross-sectional associations seen with aging, in which a deeper ALCSD was seen with age in the ED group, glaucomatous remodeling in this longitudinal study resulted in more posterior migration of ALCSD in ED compared to AD patients.
Comparison of the parasympathetic and sympathetic neurons, including the dopaminergic neural system, in dry eye (DE)-induced pathophysiology has not been elucidated well. This study investigated the presence of dopamine receptors (DRs) and their functional roles in the lacrimal glands (LGs) of DE-induced mice.
After DE was induced in B6 mice for 2 weeks, the expression of tyrosine hydroxylase (TH), dopamine, and DRs (DR1, DR2, etc.) in the LGs and corneas were measured by quantitative RT-PCR, immunoblot, and ELISA. Using flow cytometry and ELISA, immune cell infiltration and inflammatory cytokine expression were determined in DE-induced LGs with or without DR blockers, SCH-23390 (DR1i), or melperone (DR2i). Corneal erosion scores were also investigated.
The mRNA and protein levels of TH significantly increased in DE-induced LGs. The dopamine concentration of LGs was 9.51 pmol in DE (versus naive 1.39 pmol; P < 0.001). Both DR1 and DR2 mRNA expression were significantly enhanced in desiccating stress compared with those in naive (3.
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