It is very limited that the benefit of perioperative chemotherapy in early non-small cell lung cancer (NSCLC), and the 5-year survival rate is only 5% higher than surgery. Antibodies that block programmed cell death protein 1/programmed death-ligand 1 significantly improve the survival of advanced NSCLC. The value of immunotherapy in early NSCLC is also being explored. This paper firstly summarized and analyzed the progress of immunotherapy in the perioperative period of NSCLC. Secondly, the safety and feasibility of surgical resection after neoadjuvant immunotherapy were discussed. Finally, the clinical value of different therapeutic efficacy prediction indicators was summarized, in order to clarify the current status of immunotherapy in the perioperative period, so as to improve the clinical benefits of early NSCLC patients.

OBJECTIVE To investigate the ameliorative effects of Imperatae Rhizoma （RI） extract against doxorubicin （DOX）-induced myocardial injury and its potential molecular mechanisms. METHODS Network pharmacology was employed to screen for target overlap between the predicted core targets of RI’s active components and targets associated with myocardial injury， followed by gene ontology （GO） and Kyoto Encyclopedia of Genes and Genomes （KEGG） enrichment analyses. Based on the network pharmacology results， a DOX-induced myocardial injury mouse model was established using male C57BL/6J mice to observe the effects of RI extract [1 g/（kg·d）] on the survival rate， body weight， and cardiac damage. A DOX-injured HL-1 cardiomyocyte model was established to assess the effects of different mass concentrations of RI extract （50， 100， 200 μg/mL） on mitochondrial membrane potential， adenosine triphosphate （ATP） production， reactive oxygen species （ROS） generation， apoptosis， and expression of the relevant target proteins. The mechanism was validated by transfecting with small interfering RNA of estrogen receptor 1 （ESR1）. RESULTS A total of 58 overlapping targets were screened， which were enriched in biological processes such as hormone response and hypoxia response， as well as pathways including apoptosis， tricarboxylic acid cycle， and pyruvate metabolism. Key target proteins， such as ESR1， were also identified. Animal experiments confirmed that the survival rate of mice in the DOX+RI group was obviously higher than that in the DOX group， with a slower rate of weight loss and improved pathological changes， such as cardiac atrophy and inflammatory cell infiltration， compared to the DOX group. Cell experiments showed that， compared with the DOX group， the DOX+RI groups exhibited significantly increased or upregulated mitochondrial membrane potential， relative ATP levels， and mRNA expressions of isocitrate dehydrogenase 3A （IDH3A）， succinate dehydrogenase A （SDHA） and peroxisome proliferators-activated receptor γ coactivator-1α （PGC-1α）， as well as mRNA and protein expressions of ESR1； conversely， relative ROS levels and apoptosis rates were significantly reduced （ P ＜0.05）. Following ESR1 knockdown， the anti-apoptotic effect of the RI extract on cardiomyocytes was significantly attenuated （ P ＜0.05）. CONCLUSIONS The RI extract may alleviate DOX-induced myocardial injury by activating the ESR1 signaling pathway， improving mitochondrial function， and inhibiting excessive ROS production and cardiomyocyte apoptosis.

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.

Computational approaches, encompassing both physics-based and machine learning (ML) methodologies, have gained substantial traction in drug repurposing efforts targeting specific therapeutic entities. The human dopamine (DA) transporter (hDAT) is the primary therapeutic target of numerous psychiatric medications. However, traditional hDAT-targeting drugs, which interact with the primary binding site, encounter significant limitations, including addictive potential and stimulant effects. In this study, we propose an integrated workflow combining virtual screening based on weighted holistic atom localization and entity shape (WHALES) descriptors with in vitro experimental validation to repurpose novel hDAT-targeting drugs. Initially, WHALES descriptors facilitated a similarity search, employing four benztropine-like atypical inhibitors known to bind hDAT's allosteric site as templates. Consequently, from a compound library of 4,921 marketed and clinically tested drugs, we identified 27 candidate atypical inhibitors. Subsequently, ADMETlab was employed to predict the pharmacokinetic and toxicological properties of these candidates, while induced-fit docking (IFD) was performed to estimate their binding affinities. Six compounds were selected for in vitro assessments of neurotransmitter reuptake inhibitory activities. Among these, three exhibited significant inhibitory potency, with half maximal inhibitory concentration (IC₅₀) values of 0.753 μM, 0.542 μM, and 1.210 μM, respectively. Finally, molecular dynamics (MD) simulations and end-point binding free energy analyses were conducted to elucidate and confirm the inhibitory mechanisms of the repurposed drugs against hDAT in its inward-open conformation. In conclusion, our study not only identifies promising active compounds as potential atypical inhibitors for novel therapeutic drug development targeting hDAT but also validates the effectiveness of our integrated computational and experimental workflow for drug repurposing.

OBJECTIVE: Angiogenesis is a critical target for hepatocellular carcinoma (HCC) treatment. The previous studies indicated that Jiedu Fang (JDF) could inhibit hypoxia-induced angiogenesis through interleukin-8 (IL-8). Therefore, the present study further explores the mechanisms behind JDF's inhibition of HCC angiogenesis. METHODS: Angiogenesis was assessed with the capillary-like tube formation assay in vitro and the matrigel plug angiogenesis assay in vivo. A liver cancer-related gene set and genes associated with angiogenesis and the hypoxic microenvironment were analyzed using a bioinformatics platform. Real-time reverse transcription-polymerase chain reaction and Western blotting assays were used to assess the targeted mRNA and protein levels, respectively. The Transwell assay was used to assess the migration and invasion potential of EA.hy 926 cells. The orthotopic tumor xenograft model was established, and immunohistochemistry and immunofluorescence assays were used to detect cluster of differentiation 31 and angiopoietin 2 expression, while an enzyme-linked immunosorbent assay was used to detect vascular endothelial growth factor and IL-8 protein levels. RESULTS: In vitro and in vivo assays showed that IL-8 promoted angiogenesis, and JDF could antagonize this effect. Bioinformatics analysis indicated that aurora kinase A (Aurora A) was an important candidate, which can promote IL-8 expression through activation of signal transducer and activator of transcription 3 (STAT3). The overexpression of Aurora A increased IL-8 secretion and promoted HCC migration, invasion, and angiogenesis, which was partly inhibited by JDF. Such effects were validated by in vivo assays. Further validation using the STAT3 inhibitor S3I-201 demonstrated that STAT3 was regulated by Aurora A. CONCLUSION JDF exhibits efficacy in reducing hypoxia-induced angiogenesis in HCC through a mechanism involving the Aurora A/STAT3/IL-8 signaling pathway. Therefore, JDF holds promise as a potential therapeutic approach for targeting HCC angiogenesis. Please cite this article as: Zhong MF, Luo YJ, Guo YY, Xiang S, Lin WF. Jiedu Fang inhibits hypoxia-induced angiogenesis in hepatocellular carcinoma by targeting Aurora A/STAT3/IL-8 signaling pathway. J Integr Med. 2025; 23(6):683-693.
Carcinoma, Hepatocellular/blood supply* ; Humans ; STAT3 Transcription Factor/metabolism* ; Interleukin-8/metabolism* ; Liver Neoplasms/blood supply* ; Aurora Kinase A/metabolism* ; Neovascularization, Pathologic/drug therapy* ; Animals ; Signal Transduction/drug effects* ; Mice ; Drugs, Chinese Herbal/therapeutic use* ; Cell Line, Tumor ; Mice, Inbred BALB C ; Mice, Nude ; Angiogenesis

Objective : To evaluate the coverage and spatial clustering of 13-valent pneumococcal conjugate vaccine(PCV13) among the 2017—2023 birth cohorts in Anhui Province. Methods : Obtained vaccination data of PCV13 for children born in 2017—2023 from the Anhui Immunization Information Management System.We estimated coverage levels and described characteristics of coverage.The spatial autocorrelation analysis of coverage was conducted. Results : Cumulative coverage,cumulative primary immunization coverage and cumulative full-series coverage of PCV13 were 17.19%,12.12% and 9.09% among the 2017—2023 birth cohort in Anhui Province.The coverage of PCV13 increased from 1.14% in the 2017 birth cohort to 41.59% in the 2022 birth cohort.The first dose of PCV13 at ages under 3,3—6,7—11,12—23 and not less than 24 months were 45.35%,29.84%,5.52%,10.75% and 8.53%,respectively.There were significant differences in the ages of the first dose between children of different years of born and kinds of PCV13(P<0.001).Significant differences were also observed in the cumulative coverage,cumulative primary immunization coverage,cumulative full-series coverage of PCV13 and ages of the first dose among children from various residence regions(P<0.001).From 2018 to 2023 birth cohort,the coverage of PCV13 in Anhui Province showed obvious positive spatial autocorrelation.Local spatial autocorrelation analysis showed that the "high-high" agglomeration areas were concentrated in the central area of Anhui. Conclusion The coverage of PCV13 was low in Anhui Province with significant regional differences.

Objective:To analyze the epidemiological characteristics of mumps in China under the immunization strategies of different doses of mumps-containing vaccines(MuCV) by analyzing the national mumps surveillance data from 2020 to 2023.Methods:Based on the national mumps surveillance data from 2020 to 2023, a comparative analysis was conducted on the mumps incidence and the distribution characteristics of mumps cases in time, region and population in the three different periods of 2004-2007 (without MuCV implementation), 2008-2019 (one-dose MuCV implementation) and 2020-2023 (two-dose MuCV implementation) in China.Results:From 2020 to 2023, the annual incidence rate of mumps was 6.48-9.20/100 000, and the annual number of reported cases was 91 303-129 120 cases. After the implementation of the 2-dose MuCV immunization strategy, the epidemiological characteristics of mumps in China have changed to some extent. Compared with the period of 2004-2007 and 2008-2019, the traditional seasonal epidemic pattern of mumps disappeared from 2020 to 2023, with no obvious epidemic peak throughout the year. There was no significant regional difference in the incidence of mumps. Children and adolescents under 15 years of age were the main population of mumps (accounting for 85.46%), of which children aged 5-9 years accounted for 45.07%. Compared with the period of 2004-2007 and 2008-2019, the proportion of mumps cases in the 0-4 years old group showed an increasing trend, the proportion of mumps cases in the 10-14 years old group showed a decreasing trend, and the proportion of adult cases over 40 years old also increased from 2020 to 2023. The age group with the highest incidence of mumps was found to have shifted from 7 years old to 4 years old.Conclusions:The 2-dose MuCV immunization strategy has effectively reduced the incidence of mumps in China. It is necessary to strengthen the surveillance of mumps in kindergartens and primary school children.

Objective To investigate the prognostic value of perfusion MRI in elderly patients with posterior circulation cerebral ischemia after interventional therapy.Methods A prospective study was conducted on 200 patients with posterior circulation cerebral ischemia who received interven-tional therapy in our hospital from June 2021 to March 2024.According to the prognosis,they were divided into a good prognosis group(142 patients)and a poor prognosis group(58 patients).The detection rate of abnormal sequences and related parameters were compared between the two groups.ROC curve analysis was adopted to evaluate the diagnostic efficiency of cerebral blood vo-lume(CBV),time to peak(TTP),mean transmit time(MTT)and cerebral blood flow(CBF)alone and combined together.Results The poor prognosis group had significantly higher abnor-mal detection rates than the good prognosis group(all P＜0.05).Obvious differences were observed between the two groups in terms of lesion location,stenosis rate,and CBF values in bilateral occipital lobes and cerebelli(all P＜0.01).The good prognosis group exhibited higher CBV and CBF values and lower TTP and MTT values than the poor prognosis group(P＜0.01).The above four values combined together showed better diagnostic efficiency than any single va-lues and obtained biggest AUC value,and the cut-off value of CBV,TTP,MTT,and CBF was 751.23 ml,21.03 s,590.55 s,and 257.88 ml/(100 g·min),respectively.Conclusion The com-bined diagnosis of perfusion MRI indicators can significantly improve the prognostic efficiency after interventional therapy in elderly patients with posterior circulation cerebral ischemia.

Objective:To observe the tumor control and the degree of radiation-induced lung injury (RILI) between FLASH irradiation and conventional dose rate (CONV) irradiation, and compare the changes in plasma proteomic profiles of mice following whole-lung FLASH and CONV irradiation using proteomics method.Methods:A mouse model with metastatic lung cancer was established. After whole-lung irradiation, changes in normal lung capacity were monitored using CT scans. Then, a RILI model was constructed to examine pathological alterations in lung tissues following whole-lung CONV and FLASH irradiation. Plasma samples were collected from mice receiving whole-lung CONV irradiation ( n = 5) and whole-lung FLASH irradiation ( n = 5), followed by comparison with samples from the control group of healthy mice (also referred to as the healthy control group). These plasma samples were analyzed using isobaric tags for relative and absolute quantification (iTRAQ)-based proteomics, followed by the screening and identification of differentially expressed proteins using high-throughput bioinformatics. Moreover, protein-protein interaction (PPI) network analysis was conducted to identify hub genes using the STRING database and Cytoscape software. Results:Whole-lung FLASH and CONV irradiation produced consistent tumor control, with the former significantly reducing RILI compared to the latter. A total of 609 proteins were identified through proteomic analysis. Among them, 89 differentially expressed proteins were detected in the whole-lung FLASH group. Gene Ontology (GO) enrichment analysis indicated that up-regulated genes were primarily associated with stress and inflammatory responses, whereas down-regulated genes were related to ATP metabolism and angiogenesis regulation. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that up-regulated genes were predominantly enriched in unfolded protein response pathways, while down-regulated genes were mainly involved in metabolic pathways and oxidative phosphorylation. Integrated PPI analysis and subsequent validation via reverse transcription-polymerase chain reaction (RT-PCR) revealed four key genes.Conclusions:Compared to the whole-lung CONV irradiation, whole-lung FLASH irradiation reduces the RILI of normal lung tissues while maintaining equivalent tumor control in metastatic lung cancer. Proteomic analysis of differentially expressed proteins in plasma after whole-lung FLASH and CONV irradiation provides valuable insights into the molecular mechanisms underlying the FLASH effect.

Objective:To conduct a comparative analysis of the oxygen depletion and oxygen effect of FLASH irradiation and conventional irradiation by direct measurement of oxygen content.Methods:The oxygen content in different tissues and organs of mice was measured using a phosphorescent probe. A subcutaneous xenograft tumor model in mice was established, to receive electron-beam irradiation at different doses and dose rates. The oxygen depletion of tumor and normal tissue was analyzed, and tumor control was evaluated. The oxygen depletion of conventional irradiation and FLASH irradiation was further analyzed using an in vitro model. The survival fraction (SF) of normal cells after conventional irradiation and FLASH irradiation was calculated using colony formation assay under different partial pressures of oxygen, and the data were fitted to the oxygen enhancement ratio (OER) curve. Results:The mean oxygen content of subcutaneous xenograft tumor in mice was 1.28%, suggesting hypoxia. The mean oxygen content of normal tissue ranged from 3.51% to 6.53%, suggesting physioxia. In animal experiments, oxygen depletion was not observed during conventional irradiation. High-dose-rate (20 Gy/s) and ultra-high-dose-rate (FLASH, 40 Gy/s) irradiation produced oxygen depletion. During FLASH irradiation, with the increase of oxygen content, the oxygen depletion was 0.1-0.2 mm Hg/Gy for tumor tissue and 0.19-0.21 mm Hg/Gy for skin tissue, which tended to stabilize. FLASH irradiation maintained equivalent tumor control compared to conventional irradiation. The tumoricidal effect was significantly enhanced with the increase of oxygen content in the tissue ( t=3.46, P<0.01). In in vitro experiments, the mean oxygen depletion rate was about 0.16 mm Hg/Gy for conventional irradiation and 0.16-0.18 mm Hg/Gy for FLASH irradiation, which did not change significantly with the increase of oxygen content. FLASH irradiation was associated with an oxygen effect. When the partial pressure of oxygen decreased from physioxia to hypoxia, the OER value significantly reduced. Conclusions:Normal tissues and organs are in physioxia, which exhibits a lower oxygen content than that in the air. FLASH irradiation can consume a proportion of oxygen, producing an oxygen effect. When oxygen content decreases, the oxygen depletion rate slows down after FLASH irradiation.