Loss of tumor suppressive microRNA-31 enhances TRADD/NF-κB signaling in glioblastoma

Glioblastomas (GBMs) are deadly tumors of the central nervous system. Most GBM exhibit homozygous deletions of the CDKN2A and CDKN2B tumor suppressors at 9p21.3, although loss of CDKN2A/B alone is insufficient to drive gliomagenesis. MIR31HG, which encodes microRNA-31 (miR-31), is a novel non-coding tumor suppressor positioned adjacent to CDKN2A/B at 9p21.3. We have determined that miR-31 expression is compromised in >72% of all GBM, and for patients, this predicts significantly shortened survival times independent of CDKN2A/B status. We show that miR-31 inhibits NF-κB signaling by targeting TRADD, its upstream activator. Moreover, upon reintroduction, miR-31 significantly reduces tumor burden and lengthens survival times in animal models. As such, our work identifies loss of miR-31 as a novel non-coding tumor-driving event in GBM.     

MicroRNA‐31 is required for astrocyte specification

Previously, we determined microRNA‐31 (miR‐31) is a noncoding tumor suppressive gene frequently deleted in glioblastoma (GBM); miR‐31 suppresses tumor growth, in part, by limiting the activity of NF‐κB. Herein, we expand our previous studies by characterizing the role of miR‐31 during neural precursor cell (NPC) to astrocyte differentiation. We demonstrate that miR‐31 expression and activity is suppressed in NPCs by stem cell factors such as Lin28, c‐Myc, SOX2 and Oct4. However, during astrocytogenesis, miR‐31 is induced by STAT3 and SMAD1/5/8, which mediate astrocyte differentiation. We determined miR‐31 is required for terminal astrocyte differentiation, and that the loss of miR‐31 impairs this process and/or prevents astrocyte maturation. We demonstrate that miR‐31 promotes astrocyte development, in part, by reducing the levels of Lin28, a stem cell factor implicated in NPC renewal. These data suggest that miR‐31 deletions may disrupt astrocyte development and/or homeostasis.     

Variability of the analysis of the tear meniscus height by optical coherence tomography.

PURPOSE: Tear meniscus height (TMH) is an established parameter indicative of tear film volume and has recently been determined using an optical coherence tomographer (OCT). The purpose of this study was to evaluate the inter and intra observer variability in TMH assessment using OCT. METHODS: Ten subjects (6 M, 4 F; aged 32.5 +/- 6.4 years) had 10 consecutive scans taken of their inferior central tear meniscus (5 scans originating at 90 degrees and 5 origination at 270 degrees) using the OCT2 (Humphrey-Zeiss). Images were analyzed by two observers using custom software on three separate occasions. Following a training session among observers, the images were reevaluated to assess differences in variability. Data were analyzed for differences within and across examiners, for the effect of examiner training and between scan directions. RESULTS: The mean TMH and tear volume collapsed across subjects were between 0.24 and 0.25 mm and 25 to 27 nL/mm, respectively. No difference was noted within observers. An interobserver mean volume difference (p = 0.044) was present but was eliminated post training (p = 0.167). Variability was less with scans originating at 90 degrees. CONCLUSIONS: The values of the TMH and tear volume are similar to those reported in the literature. Due to the interobserver differences observed, a training session between examiners may prove to be valuable, especially in a large or multicenter study.     

Bis-anthracycline antibiotics inhibit human immunodeficiency virus type 1 transcription

The increasing numbers of human immunodeficiency virus type 1 (HIV-1) strains that exhibit resistance to antiretroviral agents used at present require the development of new effective antiretroviral compounds. Tat transactivation was recognized early on as an attractive target for drug interference. To screen for and analyze the effects of compounds that interfere with Tat transactivation, we developed several cell-based reporter systems in which enhanced green fluorescence protein is a direct and quantitative marker of HIV-1 expression or Tat-dependent long terminal repeat activity. Using these reporter cell lines, we found that the bis-anthracycline WP631, a recently developed DNA intercalator, efficiently inhibits HIV-1 expression at subcytotoxic concentrations. WP631 also abrogated acute HIV-1 replication in peripheral blood mononuclear cells infected with various primary virus isolates. We demonstrate that WP631-mediated HIV-1 inhibition is caused by the inhibition of Tat transactivation. The data presented suggest that WP631 could serve as a lead compound for a new type of HIV-1 inhibitor.     

Early-Onset Parkinsonism Is a Manifestation of the PPP2R5D p.E200K Mutation

PPP2R5D-related neurodevelopmental disorder is characterized by a range of neurodevelopmental and behavioral manifestations. We report the association of early-onset parkinsonism with the PPP2R5D p.E200K mutation. Clinical characterization and exome sequencing were performed on three patients, with postmortem neuropathologic examination for one patient. All patients had mild developmental delay and developed levodopa-responsive parkinsonism between the ages of 25 and 40 years. The PPP2R5D c.598G>A (p.E200K) mutation was identified in all patients. Neuropathologic examination demonstrated uneven, focally severe neuronal loss and gliosis in the substantia nigra pars compacta, without Lewy bodies. Our findings suggest the PPP2R5D p.E200K mutation to be a possible new cause of early-onset parkinsonism. ANN NEUROL 2020;88:1028–1033