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Abstract Otopetrin 1 (OTOP1) is a proton-activated channel crucial for animals’ perception of sour taste. Despite its significance, the gating mechanism of OTOP1 remains poorly understood. Here, we demonstrate that carvacrol activates the mouse OTOP1 (mOTOP1) channel under neutral and acidic conditions. Functional analysis showed that carvacrol enhances pH fluorescence signals in OTOP1-expressing cells, with reduced efficacy at lower pH levels. Carvacrol selectively activates mOTOP1, while mOTOP2, mOTOP3, and Chelonia mydas OTOP1 (CmOTOP1) are insensitive to carvacrol activation under neutral pH. Through chimera and point mutation experiments, swapping S134 in transmembrane segment 3 (TM3) and T247 in the TM5-6 linker abolished carvacrol activation of mOTOP1 and conferred activation on CmOTOP1, suggesting these two residues are critical for carvacrol sensitivity. These findings highlight TM3 and TM5-6 linker as pivotal gating apparatus of OTOP1 channels and potential docking sites for drug design.

The prognosis of patients with locally advanced rectal cancer (LARC) has improved with the adoption of a multidisciplinary treatment approach combining neoadjuvant chemoradiotherapy (nCRT) and total mesorectal excision (TME). Developing real-time, sensitive biomarkers to monitor systemic changes during nCRT is of paramount importance. Although the association between albumin-derived neutrophil-to-lymphocyte ratio (Alb-dNLR) and prognosis in various cancers is established, its prognostic value in LARC patients undergoing nCRT is not well-studied. This study enrolled a cohort of 618 LARC patients, stratifying them into two groups according to their change in Alb-dNLR (∆Alb-dNLR) values, using an optimal cut-off point: a low ∆Alb-dNLR group (≤ 0.90) and a high ∆Alb-dNLR group (> 0.90). The prognostic significance of ∆Alb-dNLR was evaluated using a Cox proportional hazards model. The 5-year overall survival (OS) rates were 75.2% in the low ∆Alb-dNLR group (≤ 0.90) and 85.9% in the high ∆Alb-dNLR group (>0.90) (P < 0.001). The 5-year disease-free survival (DFS) rates were 71.2% and 80.6%, respectively (P = 0.016). Multivariate analyses demonstrated that both ∆Alb-dNLR and pre-Alb-dNLR were independent prognostic factors for OS (P ≤ 0.001), while ∆Alb-dNLR was demonstrated as an independent prognostic factor for DFS (P = 0.016). A predictive nomogram, incorporating the ∆Alb-dNLR subgroup, demonstrated enhanced performance (concordance index [C-index] of 0.720 for OS and 0.690 for DFS) compared to the pre-treatment Alb-dNLR subgroup (C-index of 0.700 for OS and of 0.680 for DFS). Therefore, ∆Alb-dNLR shows significant potential as a usable and prognostic biomarker for predicting OS and DFS in LARC patients undergoing nCRT.

While the prognosis of patients with partial SRCC (PSRCC) has been rarely reported, colorectal signet-ring cell carcinoma (SRCC) has been associated with poor prognosis. The aim of this study was to analyze the prognosis of patients with different SRCC composition and establish a prediction model. A total of 91 patients with SRC component were included in the study. These patients were divided into two groups: SRCC group (SRC composition > 50%; n=41) and partial SRCC (PSRCC) group (SRC composition ≤ 50%; n=50). COX regression model was used to identify independent prognostic factors for overall survival (OS). A predictive nomogram was established and compared with the 7th AJCC staging system. After a median follow-up of 16 months, no significant difference in OS was observed in either group. Preoperative carcinoembryonic antigen (CEA) level, pN stage, M stage, preoperative ileus, and adjuvant chemotherapy were independent prognostic risk factors for OS (p