Homo- or heterodimeric compounds that affect dimeric protein function through interaction between monomeric moieties and protein subunits can serve as valuable sources of potent and selective drug candidates. Here, we screened an in-house dimeric natural product collection, and panepocyclinol A (PecA) emerged as a selective and potent STAT3 inhibitor with profound anti-tumor efficacy. Through cross-linking C712/C718 residues in separate STAT3 monomers with two distinct Michael receptors, PecA inhibits STAT3 DNA binding affinity and transcription activity. Molecular dynamics simulation reveals the key conformation changes of STAT3 dimers upon the di-covalent binding with PecA that abolishes its DNA interactions. Furthermore, PecA exhibits high efficacy against anaplastic large T cell lymphoma in vitro and in vivo, especially those with constitutively activated STAT3 or STAT3^Y640F. In summary, our study describes a distinct and effective di-covalent modification for the dimeric compound PecA to disrupt STAT3 function.

Benzylisoquinoline alkaloids (BIAs) are a structurally diverse group of plant metabolites renowned for their pharmacological properties. However, sustainable sources for these compounds remain limited. Consequently, researchers are focusing on elucidating BIA biosynthetic pathways and genes to explore alternative sources using synthetic biology approaches. CYP80B, a family of cytochrome P450 (CYP450) enzymes, plays a crucial role in BIA biosynthesis. Previously reported CYP80Bs are known to catalyze the 3'-hydroxylation of (S)-N-methylcoclaurine, with the N-methyl group essential for catalytic activity. In this study, we successfully cloned a full-length CYP80B gene (StCYP80B) from Stephania tetrandra (S. tetrandra) and identified its function using a yeast heterologous expression system. Both in vivo yeast feeding and in vitro enzyme analysis demonstrated that StCYP80B could catalyze N-methylcoclaurine and coclaurine into their respective 3'-hydroxylated products. Notably, StCYP80B exhibited an expanded substrate selectivity compared to previously reported wild-type CYP80Bs, as it did not require an N-methyl group for hydroxylase activity. Furthermore, StCYP80B displayed a clear preference for the (S)-configuration. Co-expression of StCYP80B with the CYP450 reductases (CPRs, StCPR1, and StCPR2), also cloned from S. tetrandra, significantly enhanced the catalytic activity towards (S)-coclaurine. Site-directed mutagenesis of StCYP80B revealed that the residue H205 is crucial for coclaurine catalysis. Additionally, StCYP80B exhibited tissue-specific expression in plants. This study provides new genetic resources for the biosynthesis of BIAs and further elucidates their synthetic pathway in natural plant systems.
Cytochrome P-450 Enzyme System/chemistry* ; Benzylisoquinolines/chemistry* ; Hydroxylation ; Plant Proteins/chemistry* ; Alkaloids/metabolism* ; Stephania tetrandra/genetics*

Objective To assess the clinical value of a novel surgical technique—Tubeless subxiphoid uniportal video-assisted thoracoscopic surgery with percutaneous suspension technique via balance-shaped sternal elevation device in the resection of anterior mediastinal masses. Methods Patients who underwent tubeless subxiphoid uniportal video-assisted thoracoscopic surgery via balance-shaped sternal elevation device in anterior mediastinal masses process at the Department of Thoracic Surgery, West China Hospital, Sichuan University from March to April 2025 were included, and their clinical data were analyzed. Results A total of 4 patients were included, with 2 males and 2 females, aged 58-75 years. The diameter of the tumor was 2.5-3.0 cm. The operation time was 60.0-150.0 min, intraoperative blood loss was 5-10 mL, pain score on the 3rd day after surgery was 0 points, and postoperative hospital stay was 2-3 days. All patients achieved complete resection of the masses and thymus without perioperative complications. Conclusion The tubeless subxiphoid uniportal video-assisted thoracoscopic surgery with percutaneous suspension technique via balance-shaped sternal elevation device technique optimizes surgical visualization and instrument maneuverability while avoiding complications related to conventional anesthesia and tubing, thereby markedly enhancing the minimally invasive profile of anterior mediastinal masses resections. In addition to maintaining procedural safety, this approach effectively reduces postoperative pain and accelerates patient recovery, highlighting its potential for widespread clinical adoption.

Objective:To investigate the prognostic value of myocardial flow reserve (MFR) measured by SPECT myocardial blood flow (MBF) quantitative technique in patients with intermediate stenoses of coronary arteries.Methods:From September 2019 to May 2021, patients with intermediate stenoses (50% to 80%) identified by invasive coronary angiography in Fuwai Hospital, Chinese Academy of Medical Sciences, Fuwai Center China Cardiovascular Hospital, and TEDA International Cardiovascular Hospital were prospectively included. All patients underwent a one-day rest/stress SPECT myocardial perfusion imaging (MPI) and SPECT MBF quantification. The radioactivity distribution of each segment of the MPI bullseye polar maps were obtained according to the standard 5-point method to obtain the summed stress score (SSS) and the summed difference score (SDS) to determine the existence of abnormality. ROC curve analysis was used to obtain the optimal prognostic cut-off value for MFR. The primary endpoint was defined as cardiovascular endpoint events. Survival and prognostic analyses were conducted by Kaplan-Meier method and Cox proportional hazard models. The difference of AUCs was analyzed by Delong test.Results:A total of 314 patients (194 males, 120 females; age (59.4±8.6) years) were enrolled. Over a median follow-up duration of 754 (range: 628-914) d, 54 patients had endpoint events. ROC curve showed that the prediction ability of MFR was significantly better than that of conventional MPI (AUCs: 0.713 and 0.512; z=3.76, P<0.001). The optimal prognostic cut-off value for MFR to predict endpoint events in patients with intermediate stenoses was 2.04. Cox multivariate analysis showed that MFR (hazard ratio ( HR)=0.434, 95% CI: 0.282-0.669, P<0.001) was an independent predictor of endpoint events in patients with intermediate stenoses. Kaplan-Meier survival analysis showed that the prevalence of endpoint events in patients with MFR≤2.04 was significantly higher than that in patients with MFR>2.04 (25.4%(43/169) vs 7.6%(11/145); χ2=21.27, P<0.001). Conclusion:The MFR measured by SPECT MBF quantitative technique has an independent predictive value for cardiovascular endpoint events in patients with intermediate stenoses.

Objective:To assess the clinical application of bedside X-ray photography assistor (Patent No. 202 023 219 898.1) in neonatal bedside photography.Methods:From April 2021 to February 2022, a total of 180 pediatric patients were selected who underwent bedside chest X-ray photography in neonatal intensive care unit (NICU) of Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology. These patients were divided into contrpol group, consisting of 48 males and 42 females aged at (3.3 ± 2.0) d (0-10 d), and experimental group, including 50 males and 40 females aged (3.1±2.2) d (0-12 d). For chest photography, routine workflow was followed in the control group while in experimental group bedside photography protection and body position fixing device was used. The examination time, reshoot rate and image quality were compared between the two groups.Results:The diagnostic physician score and patient comfort score in the experimental group were higher than those in the control group, with statistically significant differences ( t = 3.98, 3.82, P < 0.001). The success rate in the experimental group was higher than that in the control group, with statistically significant difference ( χ2= 7.84, P < 0.05). The average time of examination in the experimental group was not significantly different from in the control group ( P>0.05 ). Conclusions:The application of bedside X-ray photography assistor in neonatal bedside photography can significantly improve the success rate and image quality and reduce the radiation dose to pediatric patients without significantly increased examination time, which is worthy of clinical application and promotion.

Anaplastic lymphoma kinase (ALK) is the most common fusion gene involved in non-small cell lung cancer (NSCLC), and remarkable response has been achieved with the use of ALK tyrosine kinase inhibitors (ALK-TKIs). However, the clinical efficacy is highly variable. Pre-existing intratumoral heterogeneity (ITH) has been proven to contribute to the poor treatment response and the resistance to targeted therapies. In this work, we investigated whether the variant allele frequencies (VAFs) of ALK fusions can help assess ITH and predict targeted therapy efficacy. Through the application of next-generation sequencing (NGS), 7.2% (326/4548) of patients were detected to be ALK positive. On the basis of the adjusted VAF (adjVAF, VAF normalization for tumor purity) of four different threshold values (adjVAF < 50%, 40%, 30%, or 20%), the association of ALK subclonality with crizotinib efficacy was assessed. Nonetheless, no statistical association was observed between median progression-free survival (PFS) and ALK subclonality assessed by adjVAF, and a poor correlation of adjVAF with PFS was found among the 85 patients who received first-line crizotinib. Results suggest that the ALK VAF determined by hybrid capture-based NGS is probably unreliable for ITH assessment and targeted therapy efficacy prediction in NSCLC.
Humans ; Carcinoma, Non-Small-Cell Lung/pathology* ; Anaplastic Lymphoma Kinase/therapeutic use* ; Crizotinib/therapeutic use* ; Lung Neoplasms/pathology* ; Protein Kinase Inhibitors/pharmacology* ; Gene Frequency

COVID-19 is caused by coronavirus SARS-CoV-2. Current systemic vaccines generally provide limited protection against viral replication and shedding within the airway. Recombinant VSV (rVSV) is an effective vector which inducing potent and comprehensive immunities. Currently, there are two clinical trials investigating COVID-19 vaccines based on VSV vectors. These vaccines were developed with spike protein of WA1 which administrated intramuscularly. Although intranasal route is ideal for activating mucosal immunity with VSV vector, safety is of concern. Thus, a highly attenuated rVSV with three amino acids mutations in matrix protein (VSV_MT) was developed to construct safe mucosal vaccines against multiple SARS-CoV-2 variants of concern. It demonstrated that spike protein mutant lacking 21 amino acids in its cytoplasmic domain could rescue rVSV efficiently. VSV_MT indicated improved safeness compared with wild-type VSV as the vector encoding SARS-CoV-2 spike protein. With a single-dosed intranasal inoculation of rVSV_ΔGMT-S_Δ21, potent SARS-CoV-2 specific neutralization antibodies could be stimulated in animals, particularly in term of mucosal and cellular immunity. Strikingly, the chimeric VSV encoding S_Δ21 of Delta-variant can induce more potent immune responses compared with those encoding S_Δ21 of Omicron- or WA1-strain. VSV_MT is a promising platform to develop a mucosal vaccine for countering COVID-19.

Objective:To analyze the epidemiological characteristics of reinfection of 2019-nCoV and influencing factors, and provide evidence for effective prevention and control of COVID-19 epidemic.Methods:The incidence data of COVID-19 in Ningbo from January 1, 2020 to November 30, 2022 were collected from the infectious disease surveillance system of Chinese information system for disease control and prevention. The incidence of reinfection of 2019-nCoV was investigated by using questionnaire. logistic regression analysis was used to analyze the influences of gender, age, time interval from the first infection, history of underlying disease, 2019-nCoV vaccination dose and disease severity on the reinfection.Results:A total of 897 previous 2019-nCoV infection cases were investigated, of which 115 experienced the reinfection of 2019-nCoV, the reinfection rate was 12.82%. The interval between the two infections M( Q1, Q3) was 1 052 (504, 1 056) days. Univariate analysis showed that age, 2019-nCoV vaccination dose, history of underlying disease, type of 2019-nCoV variant causing the first infection, time interval from the first infection and severity of the first infection were associated with the reinfection rate (all P<0.05). Multivariate logistic regression analysis showed that the risk for reinfection in age group 30- years was higher than that in age group ≥60 years ( OR=2.10, 95% CI: 1.11-3.97). No reinfection occurred in those with time interval from the first infection of <6 months, and the risk for reinfection was higher in those with the time interval of ≥12 months than in those with the time interval of 6- months ( OR=6.68, 95% CI: 3.46-12.90). The risk for reinfection was higher in the common or mild cases than in the asymptomatic cases ( OR=2.64, 95% CI: 1.18-5.88; OR=2.79, 95% CI: 1.27-6.11). Conclusion:The time interval from the first infection was an important influencing factor for the reinfection of 2019-nCoV, and the probability of the reinfection within 6 months was low.

Blast injury of the chest injury is the most common wound in modern war trauma and terrorist attacks, and is also the most fatal type of whole body explosion injury. Most patients with severe blast injury of the chest die in the early stage before hospitalization or during transportation, so first aid is critically important. At present, there exist widespread problems such as non-standard treatment and large difference in curative effect, while there lacks clinical treatment standards for blast injury of the chest. According to the principles of scientificity, practicality and advancement, the Trauma Society of Chinese Medical Association has formulated the guidance of classification, pre-hospital first aid, in-hospital treatment and major injury management strategies for blast injury of the chest, aiming to provide reference for clinical diagnosis and treatment.

Objective:To explore the value of monoenergetic imaging on dual-layer spectral detector CT combined with individual injection protocol of contrast medium in brain CT angiography (CTA).Methods:Seventy-six patients who underwent brain CTA on the Philips IQon dual-layer spectral detector CT and individual injection protocol of contrast medium in Union Hospital of Tongji Medical College, Huazhong University of Science and Technology from August to November 2020 were retrospectively analyzed. Objective and subjective evaluation of image quality was performed in conventional energetic images (conventional group) which derived from 120 kVp hybrid iterative reconstruction algorithm and 50 keV virtual monoenergetic images (test group) which derived from spectral reconstruction algorithm. The objective evaluation content included CT values, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of internal carotid artery and middle cerebral artery, CT values and standard deviation (SD) of brain parenchyma. The subjective evaluation was completed by two senior radiologists according to the 5-point scale, and the inter-agreement between two radiologists was evaluated by Kappa test. Paired t test or Wilcoxon rank test was used for analysis between two groups. Results:The SNR and CNR of both internal carotid artery and middle cerebral artery, as well as CT values of internal carotid artery, middle cerebral artery and brain parenchyma, were significantly higher in test group than that in conventional group (all P<0.001). The subjective scores of two radiologists for test group were both 5 (5, 5) points, and the subjective scores for conventional group were both 4 (4, 4) points. The subjective scores of the radiologists were in good agreement, and the Kappa values were 0.74 and 0.84 respectively. The subjective scores of test group were significantly higher than that of conventional group ( Z=-11.15, P<0.001). Conclusion:Monoenergetic imaging on dual-layer spectral detector CT combined with individual injection protocol of contrast medium can improve SNR, CNR and the image quality of brain CTA.