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P2X receptors are cation channels that sense extracellular ATP. Many therapeutic candidates targeting P2X receptors have begun clinical trials or acquired approval for the treatment of refractory chronic cough (RCC) and other disorders. However, the present negative allosteric modulation of P2X receptors is primarily limited to the central pocket or the site below the left flipper domain. Here, we uncover a mechanism of allosteric regulation of P2X3 in the inner pocket of the head domain (IP-HD), and show that the antitussive effects of quercetin and PSFL2915 (our nM-affinity P2X3 inhibitor optimized based on quercetin) on male mice and guinea pigs were achieved by preventing allosteric changes of IP-HD in P2X3. While being therapeutically comparable to the newly licensed P2X3 RCC drug gefapixant, quercetin and PSFL2915 do not have an adverse effect on taste as gefapixant does. Thus, allosteric modulation of P2X3 via IP-HD may be a druggable strategy to alleviate RCC. P2X3 activation requires tightening the inner pocket of the head domain (IP-HD) following ATP binding. Here the authors demonstrate that targeting the IP-HD with allosteric small molecules presents a potential strategy for the development of therapeutics for refractory chronic cough without taste abnormalities.

Human genetic and pharmacological studies have demonstrated that voltage-gated sodium channels (VGSCs) are promising therapeutic targets for the treatment of pain. Spider venom contains many toxins that modulate the activity of VGSCs. To date, only 0.01% of such spider toxins has been explored, and thus there is a great potential for discovery of novel VGSC modulators as useful pharmacological tools or potential therapeutics. In the current study, we identified a novel peptide, µ-TRTX-Ca1a (Ca1a), in the venom of the tarantula Cyriopagopus albostriatus . This peptide consisted of 38 residues, including 6 cysteines, i.e. IFECSISCEIEKEGNGKKCKPKKCKGGWKCKFNICVKV. In HEK293T or ND7/23 cells expressing mammalian VGSCs, this peptide exhibited the strongest inhibitory activity on Na v 1.7 (IC 50 378 nM), followed by Na v 1.6 (IC 50 547 nM), Na v 1.2 (IC 50 728 nM), Na v 1.3 (IC 50 2.2 µM) and Na v 1.4 (IC 50 3.2 µM), and produced negligible inhibitory effect on Na v 1.5, Na v 1.8, and Na v 1.9, even at high concentrations of up to 10 µM. Furthermore, this peptide did not significantly affect the activation and inactivation of Na v 1.7. Using site-directed mutagenesis of Na v 1.7 and Na v 1.4, we revealed that its binding site was localized to the DIIS3-S4 linker region involving the D816 and E818 residues. In three different mouse models of pain, pretreatment with Cala (100, 200, 500 µg/kg) dose-dependently suppressed the nociceptive responses induced by formalin, acetic acid or heat. These results suggest that Ca1a is a novel neurotoxin against VGSCs and has a potential to be developed as a novel analgesic.

Several species of the genus Veratrum that produce steroid alkaloids are commonly used to treat pain and hypertension in China and Europe. However, Veratrum alkaloids (VAs) induce serious cardiovascular toxicity. In China, Veratrum treatment often leads to many side effects and even causes the death of patients, but the pathophysiological mechanisms under these adverse effects are not clear. Here, two solanidine-type VAs (isorubijervine and rubijervine) isolated from Veratrum taliense exhibited strong cardiovascular toxicity. A pathophysiological study indicated that these VAs blocked sodium channels NaV1.3–1.5 and exhibited the strongest ability to inhibit NaV1.5, which is specifically expressed in cardiac tissue and plays an essential role in cardiac physiological function. This result reveals that VAs exert their cardiovascular toxicity via the NaV1.5 channel. The effects of VAs on NaV1.3 and NaV1.4 may be related to their analgesic effect and skeletal muscle toxicity, respectively.

Various peptide toxins in animal venom inhibit voltage-gated sodium ion channel Nav1.7, including Nav-targeting spider toxin (NaSpTx) Family I. Toxins in NaSpTx Family I share a similar structure, i.e., Nterminal, loops 1-4, and C-terminal. Here, we used Mu-theraphotoxin-Ca2a (Ca2a), a peptide isolated from Cyriopagopus albostriatus, as a template to investigate the general properties of toxins in NaSpTx Family I. The toxins interacted with the cell membrane prior to binding to Nav1.7 via similar hydrophobic residues. Residues in loop 1, loop 4, and the C-terminal primarily interacted with the S3-S4 linker of domain II, especially basic amino acids binding to E818. We also identified the critical role of loop 2 in Ca2a regarding its affinity to Nav1.7. Our results provide further evidence that NaSpTx Family I toxins share similar structures and mechanisms of binding to Nav1.7.

Various kinds of biologically active peptides have previously been isolated from the skin secretions of Amolops loloensis frog, such as antimicrobial peptides, bradykinin-like peptides and algesic peptides. A novel insulinotropic peptide named amolopin was identified in A. loloensis frog’s skin secretion. Its primary structure sequence was determined by Edman degradation as: FLPIVGKSLSGLSGKL-NH2. BLAST search indicates that the amino acid sequence of amolopin is quite different from other known insulin secretagogues, including mastoparan, exendins and α-latrotoxin, nor does it like incretins (e.g. glucagons like peptide-1 and glucose-dependent insulinotropic ploypeptide) either. However, amolopin shows certain structural similarity with amphibian antimicrobial temporins and vespid chemotactic peptides isolated from Vespa magnific a. Amolopin can stimulate insulin release in INS-1 cells in a dose-dependent manner. Primary investigation on its action mechanisms reveals that amolopin does not increase the influx of Ca 2+ . In conclusion, a novel 16-amino acid peptide with insulin-releasing activity is initially discovered from the skin secretion of A. loloensis frog. Further work is necessary to evaluate its potential as novel anti-diabetic candidate.

The need for adjuvant therapy (AT) following neoadjuvant chemoimmunotherapy (nICT) and surgery in esophageal squamous cell cancer (ESCC) remains uncertain. This study aims to investigate whether AT offers additional benefits in terms of recurrence-free survival (RFS) for ESCC patients after nICT and surgery. Retrospective analysis was conducted between January 2019 and December 2022 from three centers. Eligible patients were divided into two groups: the AT group and the non-AT group. Survival analyses comparing different modalities of AT (including adjuvant chemotherapy and adjuvant chemoimmunotherapy) with non-AT were performed. The primary endpoint was RFS. Propensity score matching(PSM) was used to mitigate inter-group patient heterogeneity. Kaplan-Meier survival curves and Cox regression analysis were employed for recurrence-free survival analysis. A total of 155 nICT patients were included, with 26 patients experiencing recurrence. According to Cox analysis, receipt of adjuvant therapy emerged as an independent risk factor(HR:2.621, 95%CI:[1.089,6.310], P=0.032), and there was statistically significant difference in the Kaplan-Meier survival curves between non-AT and receipt of AT in matched pairs (p=0.026). Stratified analysis revealed AT bring no survival benefit to patients with pathological complete response(p= 0.149) and residual tumor cell(p=0.062). Subgroup analysis showed no significant difference in recurrence-free survival between non-AT and adjuvant chemoimmunotherapy patients(P=0.108). However, patients receiving adjuvant chemotherapy exhibited poorer recurrence survival compared to non-AT patients (p= 0.016). In terms of recurrence-free survival for ESCC patients after nICT and surgery, the necessity of adjuvant therapy especially the adjuvant chemotherapy, can be mitigated.

Background In recent years, evidence has suggested that subanesthetic doses of esketamine may have beneficial effects on perioperative anxiety and depression. Concurrently, various factors contribute to a high incidence of perioperative depression and anxiety in the breast cancer patient population. This study aimed to explore the impact of preoperative induction and intraoperative maintenance of subanesthetic doses of esketamine on postoperative anxiety and depressive symptoms in patients undergoing breast cancer surgery. Methods A total of 120 patients with pathologically confirmed malignant breast cancer who were hospitalized and scheduled for elective surgery were randomly divided into an experimental group (ES group) or a control group (P group), with 60 patients in each group. The ES group received esketamine at a dose of 0.2 mg/kg at anesthesia induction, which was maintained with an infusion of 0.1 mg/kg/h until the end of surgery. The P group received an equivalent volume of 0.9% sodium chloride solution during the corresponding periods. The primary outcome was the Patient Health Questionnaire-9 (PHQ-9) scores at postoperative day 30 (POD30), analyzed using analysis of covariance (ANCOVA) with adjustment for baseline scores. Additionally, Anxiety Self-Rating Scale (SAS) scores were recorded at preoperative day 1 (baseline), postoperative day 7 (POD7), and POD30; postoperative adverse reactions within the first 24 h were documented; and pain was assessed using the Numerical Rating Scale (NRS) scores at rest at baseline and on POD1. Results The primary endpoint analysis revealed that at POD30, the ES group achieved a significantly greater reduction in PHQ-9 scores compared to the P group, with an adjusted mean difference of 0.96 points (95% CI 0.42–1.51, P  < 0.01). Mixed-effects modeling demonstrated significant group-by-time interactions for both SAS and PHQ-9 scores, indicating superior symptom improvement in the ES group at all postoperative timepoints (SAS: POD7 β = 5.83, 95% CI 4.13–7.53; POD30 β = 7.15, 95% CI 5.45–8.85; PHQ-9: POD7 β = 1.25, 95% CI 0.45–2.05; POD30 β = 1.05, 95% CI 0.25–1.85; all P  < 0.01). The ES group also exhibited significantly lower NRS pain scores at rest on postoperative day 1 ( P  < 0.05). Importantly, the incidence of postoperative adverse reactions within the first 24 h, including nausea, vomiting, drowsiness, and psychiatric symptoms, did not differ significantly between groups (all P  > 0.05). Subgroup analyses showed consistent treatment effects across age, surgery type, comorbidity, and surgical history strata, with no significant interactive effects detected ( P  > 0.05 for all interactions). Conclusion Preoperative induction and intraoperative administration of a subanesthetic dose of esketamine reduced PHQ-9 and SAS scores at postoperative day 7 and postoperative day 30, decreased postoperative pain scores, and did not increase the incidence of postoperative adverse reactions. Trial registration Registration number: Chinese Clinical Trial Registry ChiCTR2400087464. Date of registration: 29/07/2024.

Current medical examinations and biomarkers struggle to assess the efficacy of chemoimmunotherapy (nICT) for locally advanced esophageal squamous cell carcinoma (ESCC). This study aimed to develop a machine learning model integrating habitat imaging and deep learning (DL) to predict the treatment response of ESCC patients to nICT. The study retrospectively collected 309 ESCC patients from 6 medical centers, divided into training and external validation cohorts. For habitat imaging analysis, intratumoral subregions were clustered using the K-means clustering method. DL features from intratumoral and peritumoral subregions were extracted by Vision Transformer (ViT) respectively and then subjected to feature selection. Subsequently, 11 machine learning models were constructed for predictive model. The model's performance was evaluated using the area under the curve (AUC), decision curve analysis (DCA), calibration curve, and accuracy. A total of 18 DL features were selected. The model of ExtraTrees, which was optimal, demonstrated superior performance with AUCs of 0.917 in training cohort and 0.831 in external validation cohort. Similarly, ExtraTrees showed good predictive capabilities in patients undergoing 2 cycles of nICT with AUC of 0.862 in validation cohort. This model also showed good calibration for prediction probability and satisfied clinical value on DCAs. Finally, the SHapley Additive exPlanations method elucidated the model's precise predictions. The ExtraTrees model leveraging habitat imaging and ViT offered a non-invasive and accurate method to predict pathological response to nICT, guiding personalized treatment strategies, and decreasing the risk of immune-related adverse effects.

This Escherichia coli-produced bivalent HPV 16 and 18 vaccine was well tolerated and effective against HPV 16 and 18 associated high-grade genital lesions and persistent infection in interim analysis of this phase 3 trial. We now report data on long-term efficacy and safety after 66 months of follow-up. This phase 3, double-blind, randomised, controlled trial was done in five study sites in China. Eligible participants were women aged 18–45 years, with intact cervix and 1–4 lifetime sexual partners. Women who were pregnant or breastfeeding, had chronic disease or immunodeficiency, or had HPV vaccination history were excluded. Women were stratified by age (18–26 and 27–45 years) and randomly (1:1) allocated by software (block randomisation with 12 codes to a block) to receive three doses of the E coli-produced HPV 16 and 18 vaccine or hepatitis E vaccine (control) and followed-up for 66 months. The primary outcomes were high-grade genital lesions and persistent infection (longer than 6 months) associated with HPV 16 or 18 in the per-protocol susceptible population. This trial was registered with ClinicalTrials.gov, NCT01735006. Between Nov 22, 2012, and April 1, 2013, 8827 women were assessed for eligibility. 1455 women were excluded, and 7372 women were enrolled and randomly assigned to receive the HPV vaccine (n=3689) or control (n=3683). Vaccine efficacy was 100·0% (95% CI 67·2–100·0) against high-grade genital lesions (0 [0%] of 3310 participants in the vaccine group and 13 [0·4%] of 3302 participants in the control group) and 97·3% (89·9–99·7) against persistent infection (2 [0·1%] of 3262 participants in the vaccine group and 73 [2·2%] of 3271 participants in the control group) in the per-protocol population. Serious adverse events occurred at a similar rate between vaccine (267 [7·2%] of 3691 participants) and control groups (290 [7·9%] of 3681); none were considered related to vaccination. The E coli-produced HPV 16 and 18 vaccine was well tolerated and highly efficacious against HPV 16 and 18 associated high-grade genital lesions and persistent infection and would supplement the global HPV vaccine availability and accessibility for cervical cancer prevention. National Natural Science Foundation of China, National Key R&D Program of China, Fujian Provincial Project, Fundamental Funds for the Central Universities, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, and Xiamen Innovax.

Copper nanoclusters represent a promising yet underdeveloped frontier in materials science. Here, we propose a general and efficient strategy for enhancing photothermal conversion efficiency through the incorporation of rotor-stator ligand architectures onto copper nanocluster surfaces. As a representative example, we design carboxylate ligands functionalized with adamantane groups to stabilize a [Cu 36 (4-F-PhS) 24 (AdmCOO) 6 (PPh 3 ) 4 H 8 ] 2- nanocluster. In this architecture, the adamantane unit functions as a molecular rotor, while the carboxylate group serves as a molecular stator. The engineered nanocluster achieves a photothermal conversion efficiency of 75%. The adamantane rotors exhibit a lowered rotational energy barrier within the cluster framework, enabling stable and rapid molecular rotation that effectively promotes non-radiative transitions. This mechanism optimizes the conversion of light into thermal energy, enabling the nanocluster to rapidly heat up to 200 °C under 445 nm laser irradiation at a power density of 1.0 W cm -2 . The proposed strategy could be applicable to other rotor types, yielding a broad family of copper nanoclusters with enhanced photothermal conversion capabilities and multifunctional potential. Copper nanoclusters are promising photothermal heaters, but their conversion efficiency is limited efficiency. Here, the authors present a rotor-stator ligand architecture that enables enhanced photothermal conversion efficiency of copper nanoclusters.