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Background: To clearly reveal the correlations between tumor characteristics, age at diagnosis, and epidermal growth factor receptor (EGFR) mutation rates in patients with pulmonary ground-glass opacities (GGOs)., Methods: We retrospectively reviewed 1473 patients with GGOs between January 2015 and May 2020 from two cancer centers. The tumor characteristics and EGFR mutation rates were compared between different age groups. Multivariate logistic regression was fitted to analyze the relationship between age, tumor characteristics, and EGFR mutation rates., Results: The older patients had more large tumors, mixed GGOs with a consolidation-to-tumor ratio (CTR) of >0.5, and invasive adenocarcinoma (IAC) and pathologic stage IA2-IB. Overall, the rate of EGFR mutations in GGOs was 57.3% and the main subtypes were L858R and 19del mutations. The distribution of EGFR subtypes varied in different age and GGO diameter groups. Age (p = 0.036), GGO types (p = 0.005), tumor diameter (p = 0.039), and pathological types (p < 0.001) were significant predictors for EGFR mutation status. Importantly, significant differences in EGFR mutation rates between age groups were mainly observed in the GGO ≤2 cm diameter (p < 0.001), pure GGOs (p = 0.001), and IAC (p = 0.039) cohorts. Overall, those diagnosed at >50 years of age had a 47.0% increased likelihood of harboring EGFR mutations. Compared with the older group, the increased chance of harboring EGFR mutations for patients with larger tumors, mixed GGOs, and IAC was greater in the younger group., Conclusions: The EGFR mutation rates were varied among different tumor characteristics and age at diagnosis. These findings provide new insights into the treatment of GGOs., Competing Interests: Discloure: Wen-Fang Tang, Zhen-Bin Qiu, Xiang-Peng Chu, Yu-Mei Zeng, Yi-Bin Hu, Xuan Tang, Ye-Feng Yu, Wen-Hao Li, Wen-Zhao Zhong, Wei-Zhao Huang, and Yi Liang have declared no conflicts of interest that may be relevant to the contents of this study., (© 2024. The Author(s).)

Strokes are the second-leading cause of death worldwide, and the cellular and molecular mechanisms underlying stroke-induced brain damage are still uncertain. The present therapy for acute ischemic stroke is limited to thrombolysis with the recombinant tissue plasminogen activator (rtPA). However, rtPA has a narrow therapeutic timeframe of 3-4.5 h, and only approximately 5% of stroke patients can benefit from rtPA treatment. Neuroprotective agents, such as N-methyl-D-aspartate receptor antagonists, have shown great promise in preclinical studies. However, due to a limited therapeutic time window and/or intolerable side effects, they have failed in clinical trials. Extending the time window and reducing side effects for neuroprotective drugs against strokes are critical for effective therapy for stroke patients. A recent study published in Proceedings of the National Academy of Sciences by Irène R. Chassagnon et al. (2017) indicates that Hi1a, a disulfide-rich spider venom peptide, is a highly neuroprotective agent in both in vitro and in vivo studies against experimental stroke. Hi1a reveals neuroprotection through inhibition of acid-sensing ion channel 1a. Thus, Hi1a might be a promising neuroprotective agent to protect the brain from ischemic injury in humans.

Acidosis that occurs under pathological conditions not only affects intracellular signaling molecules, but also directly activates a unique family of ligand-gated ion channels: acid-sensing ion channels (ASICs). ASICs are widely expressed throughout the central and peripheral nervous systems and play roles in pain sensation, learning and memory, and fear conditioning. Overactivation of ASICs contributes to neurodegenerative diseases such as ischemic brain/spinal cord injury, multiple sclerosis, Parkinson's disease, and Huntington's disease. Thus, targeting ASICs might be a potential therapeutic strategy for these conditions. This mini-review focuses on the electrophysiology and pharmacology of ASICs and roles of ASICs in neuronal toxicity.

Acidosis is a common feature of brain in acute neurological injury, particularly in ischemia where low pH has been assumed to play an important role in the pathological process. However, the cellular and molecular mechanisms underlying acidosis-induced injury remain unclear. Recent studies have demonstrated that activation of Ca(2+)-permeable acid-sensing ion channels (ASIC1a) is largely responsible for acidosis-mediated, glutamate receptor-independent, neuronal injury. In cultured mouse cortical neurons, lowering extracellular pH to the level commonly seen in ischemic brain activates amiloride-sensitive ASIC currents. In the majority of these neurons, ASICs are permeable to Ca(2+), and an activation of these channels induces increases in the concentration of intracellular Ca(2+) ([Ca(2+)](i)). Activation of ASICs with resultant [Ca(2+)](i) loading induces time-dependent neuronal injury occurring in the presence of the blockers for voltage-gated Ca(2+) channels and the glutamate receptors. This acid-induced injury is, however, inhibited by the blockers of ASICs, and by reducing [Ca(2+)](o). In focal ischemia, intracerebroventricular administration of ASIC1a blockers, or knockout of the ASIC1a gene protects brain from injury and does so more potently than glutamate antagonism. Furthermore, pharmacological blockade of ASICs has up to a 5 h therapeutic time window, far beyond that of glutamate antagonists. Thus, targeting the Ca(2+)-permeable acid-sensing ion channels may prove to be a novel neuroprotective strategy for stroke patients.