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GSX2 is a homeobox transcription factor (TF) controlling the specification of the ventral lateral ganglionic eminence and its major derivative, the corpus striatum. Medium spiny neurons (MSNs) represent the largest cell component of the striatum and they are primarily affected in Huntington disease (HD). Here, we used CRISPR technology to generate a pluripotent GSX2-reporter human embryonic stem cell (hESC) line that can be leveraged to monitor striatal differentiation in real-time and to enrich for MSN-committed progenitors. [ABSTRACT FROM AUTHOR]

Introduction: Antineoplastic drugs may induce several side effects, including chemotherapy-induced nausea and vomiting (CINV). Two neurotransmitters play a central role in mediating the emetic response: serotonin acting on the 5HT3 receptor and the substance P targeting the NK1 receptor. Indeed, a combination of a 5HT3 receptor antagonist (5HT3-RA) and a NK1 receptor antagonist (NK1-RA) together with dexamethasone has been shown to be very effective. In fact, this combination is actually widely used and recommended for CINV prophylaxis for highly emetogenic cisplatin-based adriamycin/cyclophosphamide (AC) and carboplatin-based regimens. NEPA (netupitant/palonosetron) is the only fixed combination antiemetic available and it is composed by the long-lasting second-generation 5HT3-RA palonosetron and the highly selective NK1-RA netupitant., Aim: The aims of this short review were to analyze the role of NEPA in CINV prophylaxis and management taking in account the risk factors related to the patient and to the antineoplastic treatment., Evidence Review: CINV development is not only correlated to the emetogenic potential of the antineoplastic drugs but is also very influenced by the patient characteristics and history, such as gender, age, alcohol intake, nausea during pregnancy and motion sickness. In pivotal and post-registration studies, NEPA has demonstrated to be effective and safe in both highly and moderately emetogenic chemotherapy., Conclusion: A proper assessment of both chemotherapy- and patient-related risk factors is paramount to properly evaluate an appropriate prophylaxis of CINV and NEPA by simplifying the therapy, guarantees fully adherence to antiemetic guidelines, and consequently improves the control of CINV, especially in high risk patients., Competing Interests: PC is an employee of Italfarmaco SpA. The other authors report no possible conflicts of interest for this work., (© 2020 Lorusso et al.)

Inhibitors of mutant isocitrate dehydrogenase (mIDH) 1 and 2 cancer-associated enzymes prevent the accumulation of the oncometabolite d-2-hydroxyglutarate (2-HG) and are under clinical investigation for the treatment of several cancers harboring an IDH mutation. Herein, we describe the discovery of vorasidenib (AG-881), a potent, oral, brain-penetrant dual inhibitor of both mIDH1 and mIDH2. X-ray cocrystal structures allowed us to characterize the compound binding site, leading to an understanding of the dual mutant inhibition. Furthermore, vorasidenib penetrates the brain of several preclinical species and inhibits 2-HG production in glioma tissue by >97% in an orthotopic glioma mouse model. Vorasidenib represents a novel dual mIDH1/2 inhibitor and is currently in clinical development for the treatment of low-grade mIDH glioma., Competing Interests: The authors declare the following competing financial interest(s): All Agios authors were employees and stockholders at the time of the study., (Copyright © 2020 American Chemical Society.)

Transport of macromolecules through the nuclear pore by importins and exportins plays a critical role in the spatial regulation of protein activity. How cancer cells co-opt this process to promote tumorigenesis remains unclear. The epidermal growth factor receptor (EGFR) plays a critical role in normal development and in human cancer. Here we describe a mechanism of EGFR regulation through the importin β family member RAN-binding protein 6 (RanBP6), a protein of hitherto unknown functions. We show that RanBP6 silencing impairs nuclear translocation of signal transducer and activator of transcription 3 (STAT3), reduces STAT3 binding to the EGFR promoter, results in transcriptional derepression of EGFR, and increased EGFR pathway output. Focal deletions of the RanBP6 locus on chromosome 9p were found in a subset of glioblastoma (GBM) and silencing of RanBP6 promoted glioma growth in vivo. Our results provide an example of EGFR deregulation in cancer through silencing of components of the nuclear import pathway.

Adult neurogenic niches harbor quiescent neural stem cells; however, their in vivo identity has been elusive. Here, we prospectively isolate GFAP(+)CD133(+) (quiescent neural stem cells [qNSCs]) and GFAP(+)CD133(+)EGFR(+) (activated neural stem cells [aNSCs]) from the adult ventricular-subventricular zone. aNSCs are rapidly cycling, highly neurogenic in vivo, and enriched in colony-forming cells in vitro. In contrast, qNSCs are largely dormant in vivo, generate olfactory bulb interneurons with slower kinetics, and only rarely form colonies in vitro. Moreover, qNSCs are Nestin negative, a marker widely used for neural stem cells. Upon activation, qNSCs upregulate Nestin and EGFR and become highly proliferative. Notably, qNSCs and aNSCs can interconvert in vitro. Transcriptome analysis reveals that qNSCs share features with quiescent stem cells from other organs. Finally, small-molecule screening identified the GPCR ligands, S1P and PGD2, as factors that actively maintain the quiescent state of qNSCs., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Light adaptation in vertebrate photoreceptors is mediated by multiple mechanisms, one of which could involve nuclear feedback and changes in gene expression. Therefore, we have investigated light adaptation-associated changes in gene expression using microarrays and real-time PCR in isolated photoreceptors, in cultured isolated retinas and in acutely isolated retinas. In all three preparations after 2 h of an exposure to a bright light, we observed an up-regulation of almost 100% of three genes, Sag, Guca1a and Guca1b, coding for proteins known to play a major role in phototransduction: arrestin, GCAP1 and GCAP2. No detectable up-regulation occurred for light exposures of less than 1 h. Functional in vivo electroretinographic tests show that a partial recovery of the dark current occurred 1-2 h after prolonged illumination with a steady light that initially caused a substantial suppression of the photoresponse. These observations demonstrate that prolonged illumination results in the up-regulation of genes coding for proteins involved in the phototransduction signalling cascade, possibly underlying a novel component of light adaptation occurring 1-2 h after the onset of a steady bright light.

Cyclic nucleotide-gated (CNG) ion channels, underlying sensory transduction in vertebrate photoreceptors and olfactory sensory neurons, require cyclic nucleotides to open. Here, we present structural models of the tetrameric CNG channel pore from bovine rod in both open and closed states, as obtained by combining homology modeling-based techniques, experimentally derived spatial constraints and structural patterns present in the PDB database. Gating is initiated by an anticlockwise rotation of the N-terminal region of the C-linker, which is then, transmitted through the S6 transmembrane helices to the P-helix, and in turn from this to the pore lumen, which opens up from 2 to 5A thus allowing for ion permeation. The approach, here presented, is expected to provide a general methodology for model ion channels and their gating when structural templates are available and an extensive electrophysiological analysis has been performed.