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.

Objective: To investigate the role mechanism of doublecortin(DCX) in glioma and screen DCX overexpression-related differentially expressed genes, so as to provide new targets for glioma targeted therapy. Methods: Using rat glioma C6 cells as the target cells, LV-DCX-EGFP, LV-Cas9-Puro, and LV-Ctrl-EGFP lentiviruses were constructed. DCX overexpressing and control C6 cell lines were established through Cas9 dual-vector system transfection and screening. Transcriptome sequencing was used to obtain the differentially expressed gene profiles. iDEP and DESeq2 were applied to screen differentially expressed genes with the threshold of |Log_2FC|>2 and P0.7, indicating good diagnostic value. RT-qPCR validation showed that the mRNA expression levels of some upregulated genes(POU2F3, LPAR6, SREBF1) significantly increased ( P < 0. 001) , while the mRNA expression levels of some downregulated genes (UBB , ACTB , UBE2I) also significantly increased (P < 0. 001) , which might be relat⁃ed to transcriptional and post⁃transcriptional regulation. Conclusion Differentially expressed genes and their regu⁃latory networks related to DCX overexpression in glioma are successfully screened , providing a theoretical basis for revealing the role mechanism of DCX in glioma development and laying a foundation for the development of potential therapeutic strategies.

Objective To compare the clinical effect of Multiloc nailing and Philos locking plate for treating proximal humerus fracture.Methods A retrospective analysis of 34 surgery treated proximal humeral fractures patients in Department of Orthopedics,Beijing Haidian Hospital and Department of Orthopedics,Beijing Chaoyang Hospital,Capital Medical University from January 2015 to June 2016,in which 3 cases of high-energy injury and multiple fractures andonecase of humerus head replacement and onecase of non-surgical treatment were excluded.Finally,29 patients were included and clinical followed up to 12 months after surgery.The 29 paients were divided into the locking plate group (n =13) and intramedullary nail group (n =16),The operative time,volume of intraoperative blood loss,preoperative to postoperative 24 patients were compared between the locking plate group and intramedullary nail group underwent open reduction and internal fixation with philos locking plate hemoglobin changes,24 h postoperative visual analogue scale and 3,6,12 months postoperative Constant-Murley shoulder function score.SPSS13.0 statistical software was used to analyze the data.Measurement data were expressed as ((x) ± s).Comparison of groups used independent samples t test,repeated measurement data used repeated measures analysis of variance.Results The age of the locking plate group was (65.7 ± 9.3) years,and the age of the intramedullary nailing group was (65.6 ± 11.1) years.In the locking plate group,the operation time was (150 ± 17) minutes,the intraoperative blood volume was (300 ± 53) ml,the change of blood pigment between before surgery to 24 hours after surgery was (26 ± 8) mg/L,and the vision algetic standard of 24 hours after surgery was (3.4 ± 0.8) scores.In intramedullary nailing group,the operation time was (119 ± 13) minutes,the intraoperative blood volume was (130 ± 25) ml,and the change of blood pigment between before surgery to 24 hours after surgery was (11 ± 5) g/L,the vision algetic standard of 24 hours after surgery was (2.3 ± 0.5) scores.No serious postoperative complications occurred in either group,including infection,internal fixationfailure,and humeral head necrosis.In locking plate group,for the Constant-Murley shoulder joint function score,3 months after surgery was (76.0 ± 11.6) scores,6 months was (78.0 ± 13.4) scores,12 months was (88.0 ± 12.1) score.In intramedullary nailing group 3 months was (85.0 ± 9.7) scores,6 months was (87.0 ± 8.9) scores,12 months was (89.0 ± 10.3) scores.There were no statistical difference between the two groups at incidence of serious complications after surgery,postoperative 12 months Constant-Murley shoulder joint function score.Muhiloc intramedullary nailing group was better than Philos locking plate group in the operation time,the intraoperative blood volume,etc.Conclusion Multiloc intramedullary nail is an effective method for treating proximal humerus fracture,and it has the advantages of less surgical injury and early postoperativesatisfactory than the locking plate.