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Objectives: Epidermal growth factor receptor (EGFR) mutations (EGFRm) are common oncogene drivers in non-small cell lung cancer (NSCLC). This real-world study explored treatment patterns and time to receive EGFRm test results in patients with advanced EGFRm NSCLC., Methods: A cross-sectional medical chart review was completed May-August 2020 in Australia, Canada, Germany, Italy, South Korea, Taiwan, UK, and USA. Eligible patients had advanced NSCLC and a positive EGFRm test result January-December 2017. Data were abstracted from NSCLC diagnosis to end of follow-up (31 March 2020) or patient's death whichever occurred earlier. The index date was the date of EGFRm confirmation., Results: 223 physicians provided data for 1,793 patients. Patients' mean age was 64.7 years, 54 % were male, 30.7 % had no history of smoking. Overall, 78 % of EGFRm test results were received ≤ 2 weeks after request (range of median 7-14 days across countries). Median time from advanced NSCLC diagnosis to EGFRm test result was 18 days (median range 10-22 days across countries). Over a third (37 %) of patients received a systemic treatment prior to EGFRm result; chemotherapy (25 %) and EGFR-TKI (15 %) were most commonly prescribed; post-EGFR test-result was EGFR-TKI (68 %); 80 % of patients initiated EGFR-TKI at any time point post-NSCLC diagnosis. Of those receiving a first-line EGFR-TKI post-EGFRm testing, 84 % received a TKI alone, 12 % in combination with chemotherapy, and 3 % with other treatments. Median time from first-line EGFR-TKI initiation post-EGFRm testing to first subsequent treatment was 19.8 months., Conclusion: Over one-fifth of patients wait >14 days for their EGFRm test results, affecting their likelihood of receiving first-line EGFR-TKI with 20 % of patients never receiving EGFR TKI treatment. There was significant inter-country variability in the proportion of patients receiving EGFR TKIs. Our study highlights the need to improve EGFRm testing turnaround times and treatment initiation across countries., Competing Interests: Declaration of Competing Interest Janakiraman Subramanian: Advisory board member for AstraZeneca, Boehringer Ingelheim, Daichi-Sankyo, Eli Lilly, G1 therapeutics, Jazz Pharma, Janssen, Novartis, Pfizer; Takeda; Speaker honorarium from AstraZeneca, G1 therapeutics, Janssen, Jazz Pharma & Boehringer Ingelheim. Natasha Leighl: Honoraria received for CME lectures from Amgen, BMS, GlaxoSmithKline, MSD, Novartis, Puma Biotechnology, Sanofi Genzyme and Takeda; Institutional research funding received from Amgen, Array, AstraZeneca, Bayer, BMS, Eli Lilly, EMD Serono, Guardant Health, Inivata, MSD, Novartis, Pfizer, Roche and Takeda. Yoon-La Choi: No disclosures or potential conflicts of interest. Teh-Ying Chou: No disclosures or potential conflicts of interest. Jeffrey Gregg is an employee of Harbinger Oncology, Cambridge, MA, USA. Rina Hui: Advisory board member for AstraZeneca, BMS, Eisai, Eli Lilly, Merck, MSD, Novartis, OncoSec, Pfizer, Roche, Seagen; Speaker honorarium from AstraZeneca, Eli Lilly, MSD, Novartis. Antonio Marchetti: No disclosures or potential conflicts of interest. Neal Navani is supported by an MRC Clinical Academic Research Partnership (MR/T02481X/1), and has received honoraria or non-financial support for advisory boards or speaker bureau from Amgen, AstraZeneca, Bristol-Meyers Squibb, Guardant, Janssen, Lilly & Co, Merck Sharp and Dohme, Olympus, Oncimmune, OncLive, PeerVoice, Pfizer and Takeda, outside of the submitted work. Maiyan Chau and Aliki Taylor are employees of AstraZeneca, Cambridge, UK; Maiyan Chau owns stock and stock options in AstraZeneca. Doreen A Kahangire is a Consultant of AZ Cambridge, UK and does not own or hold stock options. Tom Bailey, Mark Silvey, Rebecca Makin, and Liane Gillespie‑Akar are employees of Adelphi Real World, Bollington, Cheshire, UK., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The retinal pigment epithelium (RPE) is critical to the survival of the overlying photoreceptors. Subject to light exposure and active metabolism, the RPE and photoreceptors are particularly susceptible to oxidative damage that plays an important part in age-related macular degeneration (AMD). Recent meta-analyses identified TMEM97 as a new putative AMD risk locus, though it is yet to be functionally verified. The role of TMEM97 in the retina and RPE is not known. Here we investigated TMEM97 function using the sodium iodate model of oxidant-induced retinal degeneration in TMEM97 knockout (KO) mice. We found markedly increased reactive oxygen species (ROS) and loss of photoreceptos in TMEM97 KO mouse retinas relative to wild type (WT) controls. In vitro, sodium iodate treatment of CRISPR-mediated TMEM97 KO RPE cells resulted in diminished abundance of the master antioxidant transcription factor NRF2 and its target gene product SOD2, the mitochondrial superoxide dismutase, as well as elevated ROS and apoptosis markers. Moreover, TMEM97 KO affected proteins key to mitochondrial and lysosomal stability and impeded autophagy flux. These findings suggest that the absence of TMEM97 in RPE cells disturbs redox-balancing systems, thereby heightening oxidative stress. As TMEM97 is a druggable target, this study may inspire interest in basic and translational research in the context of retinal degeneration., (Copyright © 2021. Published by Elsevier Inc.)

Neural activity is tightly coupled to energy consumption, particularly sugars such as glucose. However, we find that, unlike mature neurons and astrocytes, neural stem/progenitor cells (NSPCs) do not require glucose to sustain aerobic respiration. NSPCs within the adult subventricular zone (SVZ) express enzymes required for fatty acid oxidation and show sustained increases in oxygen consumption upon treatment with a polyunsaturated fatty acid. NSPCs also demonstrate sustained decreases in oxygen consumption upon treatment with etomoxir, an inhibitor of fatty acid oxidation. In addition, etomoxir decreases the proliferation of SVZ NSPCs without affecting cellular survival. Finally, higher levels of neurogenesis can be achieved in aged mice by ectopically expressing proliferator-activated receptor gamma coactivator 1 alpha (PGC1α), a factor that increases cellular aerobic capacity by promoting mitochondrial biogenesis and metabolic gene transcription. Regulation of metabolic fuel availability could prove a powerful tool in promoting or limiting cellular proliferation in the central nervous system. Stem Cells 2015;33:2306-2319., (© 2015 AlphaMed Press.)