Unraveling mechanisms underlying epileptogenesis after brain injury is an unmet medical challenge. Although histopathological studies have revealed that reactive astrogliosis and tissue acidosis are prominent features in epileptogenic foci, their roles in epileptogenesis remain unclear. Here, we explored whether astrocytic acid-sensing ion channel-1a (ASIC1a) contributes to the development of chronic epilepsy. High levels of ASIC1a were measured in reactive astrocytes in the hippocampi of patients with temporal lobe epilepsy (TLE) and epileptic mice. Extracellular acidosis caused a significant Ca2+ influx in cultured astrocytes, and this influx was sensitive to inhibition by the ASIC1a-specific blocker psalmotoxin 1 (PcTX1). In addition, recombinant adeno-associated virus (rAAV) vectors carrying a GFAP promoter in conjunction with ASIC1a shRNA or cDNA were generated to suppress or restore, respectively, ASIC1a expression in astrocytes. Injection of rAAV-ASIC1a-shRNA into the dentate gyrus of the wide type TLE mouse model resulted in the inhibition of astrocytic ASIC1a expression and a reduction in spontaneous seizures. By contrast, rAAV-ASIC1a-cDNA restored astrocytic ASIC1a expression in an ASIC1a knock-out TLE mouse model and increased the frequency of spontaneous seizures. Taken together, our results reveal that astrocytic ASIC1a may be an attractive new target for the treatment of epilepsy.

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Purpose: This study aimed to assess the antitumor activity and safety of neoadjuvant chemotherapy combined with PD-1 inhibitor camrelizumab in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Patients and Methods: In this single-center, single-arm, phase 2 trial, patients with resectable stage III–IVB HNSCC received chemotherapy [albumin-bound paclitaxel 260 mg/m2 (or docetaxel 75 mg/m2) plus cisplatin 75 mg/m2] and camrelizumab 200 mg on day 1 of each 21-day cycle for three cycles, followed by surgery, and adjuvant radiotherapy. Co-primary end points were pathological complete response (pCR) rate and safety. Results: Thirty patients were enrolled and completed the neoadjuvant therapy, with an objective response rate (ORR) of 96.7% (29/30). Twenty-seven patients underwent surgery without delay, with an R0 resection rate of 92.6% (25/27). The clinical to pathological downstaging rate was 100% (27/27). The pCR rate was 37.0% [95% confidence interval (CI), 19.4%–57.6%], and the major pathological response (MPR) rate was 74.1% (95% CI, 53.7%–88.9%). The median follow-up duration was 16.1 months (range, 8.3–28.5), and the disease-free survival rate at 12 months was 95.8% (95% CI, 73.9%–99.4%). Grade 3 neoadjuvant therapy–related adverse events included rash (1; 3.3%), pruritis (1; 3.3%), and thrombocytopenia (1; 3.3%), and no grade 4 or 5 treatment-related events occurred. The most common surgical complication was delayed wound healing (5; 18.5%). Conclusions: Neoadjuvant chemotherapy plus camrelizumab for locally advanced HNSCC showed high ORR, pCR, and MPR rates, with an acceptable safety profile. These data support further evaluation of neoadjuvant chemoimmunotherapy for the treatment of locally advanced HNSCC.