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 impact of Pseudomonas aeruginosa(PA)infection on the function of pulmonary vascular endothelial cells,and explore the mechanism of this bacterium in exacerbating lung inflammation in mice.Methods Two hours after human lung microvascular endothelial cell(HULEC-5a)were infected with the PA strain PAO1,the mRNA levels of autophagy-related gene 5(ATG5),6-phosphofruc-to-2-kinase/fructose-2,6-bisphosphatase 3(PFKFB3),and calcium adhesion protein 5(CDH5)were deter-mined by reverse transcription real-time fluorescent quantitative PCR(RT-qPCR).The protein levels of ATG5,PFKFB3,and vascular endothelial calcium adhesion protein(VE-cadherin)were detected by immunofluores-cence.After the expression of ATG5 and PFKFB3 was respectively knocked down by small interfering RNA(siRNA),RT-qPCR was employed to measure the mRNA levels of ATG5,PFKFB3,and CDH5,and immunofluorescence to detect the protein levels of PFKFB3 and VE-cadherin.In addition,the lactate assay kit was used to determine the level of lactate in the cells.After mice were infected with PAO1,lung inflammation was assessed through his-topathological section staining.Confocal microscopy was employed to capture and analyze fluorescence-labeled PFKFB3 and VE-cadherin in endothelial cells.Results Compared with the control group,the HULEC-5a cells infected with PAO1 showed up-regulated mRNA and protein levels of PFKFB3(all P<0.05),down-regulated mRNA level of CDH5(P =0.023),disrupted continuity and down-regulated protein level of VE-cadherin(P<0.001),and elevated lactate level(P =0.017).Compared with PAO1-infected HULEC-5a cells,knocking down PFKFB3 led to the up-regulated mRNA level of CDH5(P =0.043),lowered lactate level(P =0.047),and restored continuity of VE-cadherin;knocking down ATG5 led to up-regulated mRNA and protein levels of PFKFB3(P =0.013 and P =0.003),elevated lactate level(P =0.015),and down-regulated mRNA level of CDH5(P =0.020)and protein level of VE-cadherin(P =0.001).The HE staining results showed obvious red blood cell leakage,inflammatory cell infiltration,alveolar septal widening,and partial detachment of vascu-lar endothelial cells in the alveoli of PA-infected mice.Immunofluorescence staining showed up-regulated expres-sion of PFKFB3 and decreased fluorescence signal of VE-cadherin in endothelial cells of infected mice compared with normal mice.Conclusion PA may regulate the PFKFB3 pathway via AGT5 to disrupt the function of pulmo-nary vascular endothelial cells,thereby exacerbating the inflammation in the lungs of mice.

Objective·To develope an auditory brainstem implant(ABI)vocoder based on cochlear implant(CI)vocoder characteristics and ABI electrode array topology,and to verify its reliability.Methods·An"n-of-m"coding strategy CI/ABI vocoder was constructed based on MATLAB.Within each frame,only the envelopes of the n channels with the highest energy were selected.The interaction coefficient(IC)(range:1?3),channel numbers(range:5?22),and electrode array topology(CI/ABI)were adjustable parameters,allowing for the synthesis of simulated speech.Psychoacoustic evaluation was employed,recruiting normal hearing subjects to perform closed-set simulated phoneme perception.The phoneme recognition accuracy(20 vowel questions/condition,11 consonant questions/condition)was compared with the corresponding conditions of CI and ABI from reference literature to determine the IC value of the vocoder and verify its reliability.Results·The vocoder successfully synthesized all test stimuli.In the closed-set CI-simulated speech recognition,the simulated vowel and consonant recognition accuracy for IC2 and IC3 conditions showed no significant difference compared to the accuracy reported in the CI reference literature(P＞0.05).The difference in vowel and consonant accuracy between IC2 and the literature was smaller than that between IC3 and the literature(vowel|d|=1.6%vs.20%,consonant|d|=8.4%vs.9.9%),thus determining the optimal interaction coefficient of this model as 2.Subsequently,when modifying the electrode array topology to ABI,it was found that the simulated phoneme recognition accuracy for a 16-channel ABI was significantly lower than that for the 16-channel CI group,consistent with the reported literature.The simulated vowel and consonant accuracy within the 5?8 channel range for ABI showed no significant difference(P＞0.05),also aligning with the trend reported in the literature.Conclusion·A CI/ABI vocoder based on"n-of-m"coding strategy is established and the optimal IC is determined.The established ABI encoder has been evaluated for high reliability through psychoacoustic experiments.It provides suitable technical means for validating ABI-specific coding strategies.

Background: Recent studies have reported that costoclavicular blocks (CCBs) can consistently block almost all branches of the brachial plexus while sparing the phrenic nerve and provide effective analgesia after shoulder surgery. We aimed to compare the efficacy of the CCB with that of the interscalene block (ISB) as the sole blocking technique for shoulder surgery. Methods: A total of 212 patients undergoing elective arthroscopic shoulder surgery were randomized to receive an ISB or CCB based on a non-inferiority design. All patients received titration sedation with propofol under monitored anesthesia during surgery. The primary outcomes were the proportion of patients with complete motor blockade of the suprascapular nerve (SSN) and incidence of hemidiaphragmatic paralysis (HDP). The secondary outcomes included block-related variables, complications, and postoperative pain scores. Results: The proportion of patients with complete motor blockade of the SSN at 20 min between the CCB and ISB groups (53% vs. 66%) exceeded the predefined non-inferiority margin of −5%, but was comparable at 30 min (87% vs. 91%). The CCB resulted in a significantly lower incidence of HDP (7.55% vs. 92.45%), Horner’s syndrome (0% vs. 18.87%), and dyspnea (0% vs. 10.38%) than the ISB. None of the patients experienced failed blocks or required conversion to general anesthesia. Pain scores were comparable between the groups. Conclusions Ultrasound-guided CCBs may be comparable to ISBs, with fewer unfavorable complications in patients with impaired lung function undergoing arthroscopic shoulder surgery.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an idiopathic chronic, progressive interstitial lung disease with a diagnosed median survival of 3-5 years. IPF is associated with an increased risk of lung cancer. Therefore, exploring the shared pathogenic genes and molecular pathways between IPF and lung adenocarcinoma (LUAD) holds significant importance for the development of novel therapeutic approaches and personalized precision treatment strategies for IPF combined with lung cancer. METHODS: Bioinformatics analysis was conducted using publicly available gene expression datasets of IPF and LUAD from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis was employed to identify common genes involved in the progression of both diseases, followed by functional enrichment analysis. Subsequently, additional datasets were used to pinpoint the core shared genes between the two diseases. The relationship between core shared genes and prognosis, as well as their expression patterns, clinical relevance, genetic characteristics, and immune-related functions in LUAD, were analyzed using The Cancer Genome Atlas (TCGA) database and single-cell RNA sequencing datasets. Finally, potential therapeutic drugs related to the identified genes were screened through drug databases. RESULTS: A total of 529 shared genes between IPF and LUAD were identified. Among them, SULF1 emerged as a core shared gene associated with poor prognosis. It exhibited significantly elevated expression levels in LUAD tissues, concomitant with high mutation rates, genomic heterogeneity, and an immunosuppressive microenvironment. Subsequent single-cell RNA-seq analysis revealed that the high expression of SULF1 primarily originated from tumor-associated fibroblasts. This study further demonstrated an association between SULF1 expression and tumor drug sensitivity, and it identified potential small-molecule drugs targeting SULF1 highly expressed fibroblasts. CONCLUSIONS This study identified a set of shared molecular pathways and core genes between IPF and LUAD. Notably, SULF1 may serve as a potential immune-related biomarker and therapeutic target for both diseases.
Humans ; Lung Neoplasms/genetics* ; Adenocarcinoma of Lung/genetics* ; Idiopathic Pulmonary Fibrosis/genetics* ; Adenocarcinoma ; Cancer-Associated Fibroblasts ; Prognosis ; Tumor Microenvironment ; Sulfotransferases

ObjectiveTo explore the imbalance of paravertebral muscle group for patients with unilateral lumbar disc herniation. MethodsFrom January, 2022 to January, 2023, 30 patients with unilateral lumbar disc herniation (observation group) and 30 healthy people matching in general data (control group) were measured the tension and stiffness of multifidus and erector spinae with MyotonPRO, while the observation group was assessed with Visual Analogue Scale (VAS) for pain and Japanese Orthopaedic Association (JOA) score, and the time of disease was also recorded. ResultsThe mean of bilateral tension and hardness of multifidus and erector spinae was more in the observation group than in the control group (|t| > 5.407, P < 0.001), and the tension and hardness of multifidus and erector spinae of the affected side were more than those of the unaffected side in the observation group (|t| > 11.219, P < 0.001). The tension and hardness of multifidus and erector spinae of the affected side were positively correlated with VAS score (r > 0.942, P < 0.001), and negatively correlated with JOA score (|r| > 0.886, P < 0.001). ConclusionThe tension and hardness of multifidus and erector spinae of the affected side increase after unilateral lumbar disc herniation, resulting in asymmetry.

ObjectiveTo evaluate the inter-rater and test-retest reliability of echo intensity of ultrasound image for quality of quadriceps femoris in patients with knee osteoarthritis (KOA). MethodsFrom March to December, 2021, 33 patients with unilateral KOA in Guangdong Provincial Second Hospital of Traditional Chinese Medicine were included. Ultrasound was used to observe the cross sections of rectus femoris (RF), vastus medialis (VM) and vastus lateralis (VL), and the images were saved. Two independent raters analyzed the average gray value of the picture with the Image J. One of the raters repeated the measurement. The intra-class correlation coefficient (ICC), standard error of measurement (SEM), minimum detectable change (MDC) and coefficient of variation (CV) were calculated and the Bland-Altman charts were drawn. ResultsThe gray value was higher in the RF, VM and VL in the affected side than in the healthy side (t > 2.262, P < 0.05). The inter-rater reliability was excellent, with ICC 0.982 to 0.995, SEM 1.60 to 3.82, CV 1.49% to 5.90%, and MDC value 4.43 to 10.59. The test-retest reliability of the rater was excellent, with ICC 0.969 to 0.990, SEM 2.37 to 5.41, CV 2.22% to 4.84%, and MDC value 6.57 to 15.00. Bland-Altman charts analysis showed that the consistency was good. ConclusionThe quadriceps femoris muscle quality is different between the affected and the healthy sides in patients with unilateral KOA. It is reliable to evaluate muscle echo intensity by Image J.

ObjectiveTo test the inter-tester reliability and test-retest reliability of MyotonPRO for evaluating neck and shoulder muscle performance parameters in patients with unilateral chronic neck pain, observe the difference of muscle performance between the healthy and affected sides of patients with chronic neck pain, and analyze the factors that cause the imbalance of muscle performance in patients with chronic neck pain. MethodsFrom January to June, 2023, 32 patients with unilateral chronic neck pain in Guangdong Second Traditional Chinese Medicine Hospital were selected. Two testers used the same MyotonPRO equipment to measure the muscle tone, muscle hardness and muscle elasticity on both sides of the sternocleidomastoid muscle and the upper trapezius muscle in the relaxed position. Tester 1 repeated the measurement after an interval of 30 minutes, and Tester 2 was measured within the time interval between the two measurements of Tester 1. The intraclass correlation coefficient (ICC), standard error of mean (SEM) and minimum detectable change (MDC) were calculated simultaneously. The measurement results were plotted into Bland-Altman diagram and systematic bias analysis was performed. The difference in muscle characteristics between the affected side and the healthy side was compared. At the same time, the Visual Analogue Scale (VAS) score and body mass index (BMI) of the subjects were collected for correlation analysis. ResultsExcept the sternocleidomastoid muscle elasticity of the affected side (ICC = 0.697), the inter-tester reliability of all other parameters was high to very high (ICC = 0.719 to 0.952, SEM = 0.04 to 6.53, MDC = 0.12 to 18.11). The test-retest reliability of all parameters was high (ICC = 0.883 to 0.981, SEM = 0.03 to 5.72, MDC = 0.09 to 15.84). Bland-Altman plot analysis showed that the scatter distribution was consistent. The muscle tone, muscle hardness and muscle elasticity of sternocleidomastoid muscle and upper trapezius muscle were higher on the affected side than on the healthy side (t > 2.846, P < 0.05). The asymmetry index of tension, hardness and elasticity of upper trapezius muscle and sternocleidomastoid muscle was significantly positively correlated with VAS score and BMI (r > 0.385, P < 0.05). ConclusionMyotonPRO has good inter-tester reliability and retest reliability in evaluating the muscle performance of both sides of patients with chronic neck pain. The muscle tone, muscle hardness and muscle elasticity of sternocleidomastoid muscle and upper trapezius muscle on the affected side were higher than on the healthy side, and the difference of muscle performance was positively correlated with pain and BMI.

Objective:To analyze the clinical effect of extracorporeal membrane oxygenation (ECMO) in the treatment of burn patients with acute respiratory distress syndrome (ARDS).Methods:The retrospective observational study and the systematic review were applied. From March 2014 to July 2020, five burn patients with ARDS received ECMO treatment in the First Affiliated Hospital of Army Medical University (the Third Military Medical University). All the five patients were male, aged from 40 to 62 years. The average total burn surface area was 58.8% total body surface area (TBSA) and four cases had severe inhalation injury. Patient's ECMO starting time, duration and mode, and whether successfully weaned or the cause of death, and others. were recorded. Furthermore, the changes of oxygenation and infection before, during, and after utilizing ECMO were analyzed. PubMed and Web of Science from the establishment of each database to August 2021 were searched using "Extracorporeal Membrane Oxygenation", "ECMO", "burn", "inhalation" as the search terms and "Title/Abstract" as the field to retrieve the clinical articles that meet the selection criteria . Basic information were extracted from the articles, including sample size, gender, age, total burn area, inhalation injury, the indication of ECMO, the start and lasting time of ECMO, ECMO mode, rate of successful weaning, complications of ECMO, mortality, the combined application of continuous renal replacement therapy (CRRT). Results:Five patients started venovenous ECMO on an average of 10.2 days after injury and lasted an average of 180.4 hours. Three out of 5 patients were weaned successfully with one patient survived. Four patients died of multiple organ dysfunction syndrome (MODS) and septic shock. Compared with those before ECMO treatment, the arterial oxygen partial pressure (PaO 2) and oxygen saturation in arterial blood (SaO 2) of three successfully weaned patients obviously increased during and after ECMO treatment. The fraction of inspired oxygen (FiO 2) decreased below 50% and PaO 2/FiO 2 ratio increased above 200 mmHg (1 mmHg=0.133 kPa) during and after ECMO. Furthermore, lactic acid and respiratory rate decreased, basically. Compared with those before ECMO, PaO 2 and SaO 2 in the other two patients during ECMO, who failed to be weaned, continuously decreased while lactic acid increased. Before and during ECMO, the PaO 2/FiO 2 ratios of unsuccessfullg weaned cases were less than 200 mmHg, and partial pressure of carbon dioxide in arterial blood (PaCO 2) were more than 40 mmHg. Compared with those before ECMO, there were no significant changes in body temperature during and after ECMO, which were less than 38 ℃. Compared with those before ECMO, the leucocyte number (the index without this in unsuccessfully weaned cases was omitted, the same as below) in four patients showed a significant decrease during ECMO, but rose after removal of ECMO. The proportion of neutrophils in three patients were slightly higher during ECMO than before ECMO, and did not change significantly after removal of ECMO. Compared with those before ECMO, platelet counts in three patients were significantly reduced during ECMO, and all five patients during ECMO were below normal levels. Compared with those before ECMO, the procalcitonin levels in four deaths were significantly increased during ECMO. Catheter culture of microorganism was performed in three successfully weaned patients, all of which were negative. A total of 13 literature were included, ranging from 1990 to 2019. The sample size in 6 studies was less than 10, and the sample size in 4 studies was between 10 and 20, and only 2 literatures had a sample size larger than 50. ECMO was applied in 295 burn patients with overall mortality of 48.8% (144/295), including 157 adults and 138 children. The most common indication of ECMO was severe ARDS. Among 157 adult burn patients (95 males and 65 females), 36 cases had inhalation injury. The average burn area was 27%-37%TBSA in 5 reported studies and was more than 50%TBSA in 2 reported studies. The most common mode was venovenous ECMO. ECMO treatment began 26.5 hours to 7.4 days after injury and lasted from 90 hours to 18 days, and the rate of successful weaning ranged from 50% to 100%. The most common complications were bleeding and infection. The mortality was 52.9% (83/157). MODS and sepsis were the leading causes of death. Among 138 pediatric burn patients (77 boys and 61 girls), 29 patients had inhalation injury. The average burn area was 17%-50.2%TBSA in 3 studies. ECMO treatment lasted from 165.2 hours to 324.4 hours. Bleeding was the most common complication. The mortality was 44.2% (61/138). Conclusions:ECMO is an effective strategy for the salvage treatment of burns complicated with ARDS. Furthermore, the prevention and treatment of bleeding, infection and organ dysfunction should be emphasized during the use of ECMO. More importantly, evidence-based guidelines for burns are urgently needed to further improve the clinical effect of ECMO.

Amino Acid Substitution ; Antineoplastic Agents/pharmacology* ; Cell Line, Tumor ; Drug Resistance, Neoplasm/genetics* ; Gastrointestinal Neoplasms/pathology* ; Humans ; MAP Kinase Signaling System/genetics* ; Mutation, Missense ; Receptor, ErbB-3/metabolism* ; Receptor, Fibroblast Growth Factor, Type 1/metabolism*