Peptide-drug conjugates (PDCs) have emerged as a promising modality in precision oncology, enabling targeted delivery of cytotoxic payloads while minimizing off-target toxicity. The integration of covalent warheads, such as those based on sulfur(VI) fluoride exchange (SuFEx) chemistry, enhances drug-target residence time and tumor accumulation. However, existing screening methods for covalent peptide (CP) libraries require post-translational warhead conjugation, limiting throughput. Here, we present an integrated mRNA display platform that incorporates covalent warheads during ribosomal synthesis, enabling efficient screening of ultra-diverse covalent macrocyclic peptide libraries (>10¹³ variants). This approach, using site-specific incorporation of N-chloroacetyl-d-phenylalanine and fluorosulfate-l-tyrosine, accelerated the discovery of irreversibly binding (K _i = 3.58 μmol/L) Nectin-4-targeting peptide CP-N1-N₃ via proximity-triggered SuFEx. The peptide was further conjugated to cytotoxic payloads, yielding the covalent PDC CP-N1-MMAE with potent cytotoxicity (IC₅₀ ≈ 43 nmol/L) against MDA-MB-468 cells. This platform establishes a new paradigm for precision covalent drug discovery.

BACKGROUND: To date, results on relationship between CYP3A4 gene polymorphism were limited and inconclusive, and no study focused on the influence of CYP3A4 gene-obesity interaction on breast cancer risk, especially in Chinese women. The purpose of this study was to evaluate the impact of four single nucleotide polymorphisms (SNPs) of CYP3A4 gene, the SNP-SNP and gene-environment interactions on the susceptibility to breast cancer in Chinese women. METHODS: Logistic regression was used to explore the relationship between four SNPs of CYP3A4 gene and the risk of breast cancer. Generalized multifactor dimensionality reduction (GMDR) was used to screen the best SNP-SNP and gene-abdominal obesity interaction combinations among four SNPs and abdominal obesity. Haplotype examination among 4 SNPs was conducted using the SHEsis web-based platform. RESULTS: Logistic regression analysis showed that carriers of rs2242480- T allele have significantly higher breast cancer risk, than those with rs2242480- CC genotype, adjusted OR (95%CI) was 1.68 (1.23-2.16) and 2.03 (1.53-2.58) for participants with CT genotype and TT genotype under additive model. We did not find any notable interactions between the four SNPs within the CYP3A4 gene. GMDR model found a significant association in a two-locus model involving rs2242480 and obesity, with a p-value of 0.018. Stratified analysis found that breast cancer risk was the highest in obese participants with rs2242480- CT or TT genotype, compared to those non-obese participants with rs2242480- CC genotype, OR (95%CI) was 3.02 (1.83-4.25). We found that all haplotype combinations were not correlated with breast cancer risk. CONCLUSIONS We found that the T allele of rs2242480 within the CYP3A4 gene and interaction between rs2242480 and obesity were associated with an increased risk of breast cancer. However, the results of this study were only applicable to the Han ethnic group and cannot be generalized to other ethnic groups in China, and more SNPs of CYP3A4 gene should been enrolled in the analysis in the future, to verify the results obtained in this study.
Adult ; Aged ; Female ; Humans ; Middle Aged ; Breast Neoplasms/etiology* ; China/epidemiology* ; Cytochrome P-450 CYP3A/metabolism* ; Gene-Environment Interaction ; Genetic Predisposition to Disease ; Haplotypes ; Obesity/epidemiology* ; Polymorphism, Single Nucleotide ; Risk Factors ; East Asian People

Objective To design an enhanced postoperative recovery checklist for the patients who had surgery for laryngeal cancer,hence to instruct the patient with a standard procedure in rehabilitation.Methods A total of 72 patients who had surgery for laryngeal cancer in our department from April 2020 and April 2021 were enrolled as study subjects for a controlled study before and after surgery of different patients.A total of 37 patients who had surgery between April and September 2020 were assigned in the control group,while another 37 patients who had the surgery between October 2020 and April 2021 were assigned in the trial group.Patients in the control group were managed with a routine enhanced perioperative recovery plan,and those in the trial group were managed with the checklist,which was drafted by modification and improvement of the routine enhanced perioperative recovery plan through literature reviews and expert consultations.The two groups were compared in terms of the standardised rate of enhanced recovery compliance,medical staff satisfaction,average hospital-stay and patient satisfaction.Results The trial group showed significant improvement in comparison with the control group in terms of the standardised rate of enhanced recovery compliance(93.28%versus 84.08%),score of satisfaction level[(95.57±2.25)versus(92.60±2.49)],score of doctor satisfaction[(35.75±0.89)versus(32.88±1.50)],and the score of nurse satisfaction[(35.45±1.10)versus(33.00±1.30)](all P<0.05).The average hospital-stay in the trial group was significantly shorter than that in the control group[(9.89±3.32)days versus(12.60±4.33)days](P<0.05).Conclusion The designed checklist can improve the standardised rate of enhanced recovery compliance,the satisfaction of both medical staff and patients and facilitate the recovery of patient.

Article 1220 of the Civil Code of the People's Republic of China is specifically formulated for medical in-stitutions and medical personnel to rescue patients with life-threatening conditions,aiming to adjust the contradic-tion between the right of emergency rescue in medical institutions and the right of informed consent of patients.In view of the lack of relevant laws and regulations,poor organizational structure and loopholes in the system,medical institutions may have certain risks when implementing emergency treatment.After sorting out and examining the rele-vant provisions of the current law on emergency treatment in medical institutions,it is found that it is necessary to optimize the relevant legal provisions and judicial interpretations,establish and improve the case evaluation system with ethics committee as the core,improve the medical assistance fund and insurance system,and avoid the dilem-ma of"feeling and reason"for medical personnel.

Article 1220 of the Civil Code of the People's Republic of China is specifically formulated for medical in-stitutions and medical personnel to rescue patients with life-threatening conditions,aiming to adjust the contradic-tion between the right of emergency rescue in medical institutions and the right of informed consent of patients.In view of the lack of relevant laws and regulations,poor organizational structure and loopholes in the system,medical institutions may have certain risks when implementing emergency treatment.After sorting out and examining the rele-vant provisions of the current law on emergency treatment in medical institutions,it is found that it is necessary to optimize the relevant legal provisions and judicial interpretations,establish and improve the case evaluation system with ethics committee as the core,improve the medical assistance fund and insurance system,and avoid the dilem-ma of"feeling and reason"for medical personnel.

Article 1220 of the Civil Code of the People's Republic of China is specifically formulated for medical in-stitutions and medical personnel to rescue patients with life-threatening conditions,aiming to adjust the contradic-tion between the right of emergency rescue in medical institutions and the right of informed consent of patients.In view of the lack of relevant laws and regulations,poor organizational structure and loopholes in the system,medical institutions may have certain risks when implementing emergency treatment.After sorting out and examining the rele-vant provisions of the current law on emergency treatment in medical institutions,it is found that it is necessary to optimize the relevant legal provisions and judicial interpretations,establish and improve the case evaluation system with ethics committee as the core,improve the medical assistance fund and insurance system,and avoid the dilem-ma of"feeling and reason"for medical personnel.

Article 1220 of the Civil Code of the People's Republic of China is specifically formulated for medical in-stitutions and medical personnel to rescue patients with life-threatening conditions,aiming to adjust the contradic-tion between the right of emergency rescue in medical institutions and the right of informed consent of patients.In view of the lack of relevant laws and regulations,poor organizational structure and loopholes in the system,medical institutions may have certain risks when implementing emergency treatment.After sorting out and examining the rele-vant provisions of the current law on emergency treatment in medical institutions,it is found that it is necessary to optimize the relevant legal provisions and judicial interpretations,establish and improve the case evaluation system with ethics committee as the core,improve the medical assistance fund and insurance system,and avoid the dilem-ma of"feeling and reason"for medical personnel.

Article 1220 of the Civil Code of the People's Republic of China is specifically formulated for medical in-stitutions and medical personnel to rescue patients with life-threatening conditions,aiming to adjust the contradic-tion between the right of emergency rescue in medical institutions and the right of informed consent of patients.In view of the lack of relevant laws and regulations,poor organizational structure and loopholes in the system,medical institutions may have certain risks when implementing emergency treatment.After sorting out and examining the rele-vant provisions of the current law on emergency treatment in medical institutions,it is found that it is necessary to optimize the relevant legal provisions and judicial interpretations,establish and improve the case evaluation system with ethics committee as the core,improve the medical assistance fund and insurance system,and avoid the dilem-ma of"feeling and reason"for medical personnel.

Article 1220 of the Civil Code of the People's Republic of China is specifically formulated for medical in-stitutions and medical personnel to rescue patients with life-threatening conditions,aiming to adjust the contradic-tion between the right of emergency rescue in medical institutions and the right of informed consent of patients.In view of the lack of relevant laws and regulations,poor organizational structure and loopholes in the system,medical institutions may have certain risks when implementing emergency treatment.After sorting out and examining the rele-vant provisions of the current law on emergency treatment in medical institutions,it is found that it is necessary to optimize the relevant legal provisions and judicial interpretations,establish and improve the case evaluation system with ethics committee as the core,improve the medical assistance fund and insurance system,and avoid the dilem-ma of"feeling and reason"for medical personnel.

Article 1220 of the Civil Code of the People's Republic of China is specifically formulated for medical in-stitutions and medical personnel to rescue patients with life-threatening conditions,aiming to adjust the contradic-tion between the right of emergency rescue in medical institutions and the right of informed consent of patients.In view of the lack of relevant laws and regulations,poor organizational structure and loopholes in the system,medical institutions may have certain risks when implementing emergency treatment.After sorting out and examining the rele-vant provisions of the current law on emergency treatment in medical institutions,it is found that it is necessary to optimize the relevant legal provisions and judicial interpretations,establish and improve the case evaluation system with ethics committee as the core,improve the medical assistance fund and insurance system,and avoid the dilem-ma of"feeling and reason"for medical personnel.