[Objective] To explore the relationship between neutrophil activation under cardiopulmonary bypass (CPB) and the incidence of cardiac surgery-associated acute kidney injury (CS-AKI). [Methods] This prospective cohort study enrolled adult patients who scheduled for cardiac surgery under CPB at West China Hospital between May 1, 2022 and March 31, 2023. The primary outcome was acute kidney injury (AKI). Blood samples (5 mL) were obtained from the central vein before surgery, at rewarming, at the end of CPB, and 24 hours after surgery. Neutrophils were labeled with CD11b, CD54 and other markers. To assess the effect of neutrophils activation on AKI, propensity score matching (PSM) was employed to equilibrate covariates between the groups. [Results] A total of 120 patients included into the study, and 17 (14.2%) developed AKI. Both CD11b⁺ and CD54⁺ neutrophils significantly increased during the rewarming phase and the increases were kept until 24 hours after surgery. During rewarming, the numbers of CD11b⁺ neutrophils were significantly higher in AKI compared to non-AKI (4.71×10⁹/L vs 3.31×10⁹/L, Z=-2.14, P<0.05). Similarly, the CD54⁺ neutrophils counts were also significantly higher in AKI than in non-AKI before surgery (2.75×10⁹/L vs 1.79×10⁹/L, Z=-2.99, P<0.05), during rewarming (3.12×10⁹/L vs 1.62×10⁹/L, Z=-4.34, P<0.05), and at the end of CPB (4.28×10⁹/L vs 2.14×10⁹/L, Z=-3.91, P<0.05). An analysis of 32 matched patients (16 in each group) revealed that CD11b⁺ and CD54⁺ neutrophil levels of AKI were 1.74 folds (4.83×10⁹/L vs 2.77×10⁹/L, Z=-2.72, P<0.05) and 2.34 folds (3.32×10⁹/L vs 1.42×10⁹/L, Z=-4.12, P<0.05), respectively, of non-AKI at rewarming phase. [Conclusion] Neutrophils are activated during CPB, and they can be identified by CD11b/CD54 markers. The activated neutrophils of AKI patients are approximately 2 folds of non-AKI during the rewarming phase, with disparity reached peak between groups during rewarming. These findings suggest the removal of 50% of activated neutrophils during the rewarming phase may be effective to reduce the risk of AKI.

Antibody-drug conjugate (ADC), a novel class of antineoplastic agents, combines tumor-specific targeting with potent cytotoxic activity. In recent years, ADC has achieved notable advances in the treatment of non-small cell lung cancer (NSCLC), particularly within therapeutic sequencing after failure of first-line therapy or the emergence of resistance. This paper will systematically review the efficacy and safety evidence of representative ADC in NSCLC, and further to discuss progress and challenges in ADC structural optimization, toxicity management, biomarker identification, and combination strategies, aiming to provide a comprehensive theoretical foundation and practical reference for clinical practice and future research.
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Humans ; Carcinoma, Non-Small-Cell Lung/drug therapy* ; Immunoconjugates/chemistry* ; Lung Neoplasms/drug therapy* ; Drug Resistance, Neoplasm/drug effects* ; Antineoplastic Agents/chemistry*

Ischemic stroke (IS) is a globally life-threatening disease. Presently, few therapeutic medicines are available for treating IS, and rt-PA is the only drug approved by the US Food and Drug Administration (FDA) in the US. In fact, many agents showing excellent neuroprotection but no blood flow-improving activity in animals have not achieved ideal clinical efficacy, while thrombolytic drugs only improving blood flow without neuroprotection have limited their wider application. To address these challenges and meet the huge unmet clinical need, we have designed and identified a novel compound AAPB with dual effects of neuroprotection and cerebral blood flow improvement. AAPB significantly reduced cerebral infarction and neural function deficit in tMCAO rats, pMCAO rats, and IS rhesus monkeys, as well as displayed exceptional safety profiles and excellent pharmacokinetic properties in rats and dogs. AAPB has now entered phase I of clinical trials fighting IS in China.

Cuproptosis, a recently identified form of regulated cell death triggered by excess intracellular copper, has emerged as a promising cytotoxic strategy for cancer therapy. However, the therapeutic efficacy of copper ionophores such as elesclomol (ES) is often hindered by cellular copper homeostasis mechanisms that limit copper influx and cuproptosis induction. To address this challenge, we developed a nanoagent utilizing outer membrane vesicle (OMV) derived from Akkermansia muciniphila (Akk) for co-delivery of antioxidant 1 copper chaperone (Atox1)-targeting siRNA and ES (siAtox1/ES@OMV) to tumors. In vitro, we demonstrated that Atox1 knockdown via siRNA significantly disrupted copper export mechanisms, resulting in elevated intracellular copper levels. Simultaneously, ES facilitated efficient copper influx and mitochondrial transport, leading to Fe-S cluster depletion, increased proteotoxic stress, and robust cuproptosis. In vivo, siAtox1/ES@OMV achieved targeted tumor delivery and induced pronounced cuproptosis. Furthermore, leveraging the immunomodulatory properties of OMVs, siAtox1/ES@OMV promoted T-cell infiltration and the activation of tumor-reactive cytotoxic T cells, enhancing tumor immune responses. The combination of siAtox1/ES-induced cuproptosis and immunogenic cell death synergistically suppressed tumor growth in both subcutaneous breast cancer and orthotopic rectal cancer mouse models. This study highlights the potential of integrating copper homeostasis disruption with a copper ionophore using an immunomodulatory OMV-based vector, offering a promising combinatorial strategy for cancer therapy.

Interferon regulatory factor 4 (IRF4) is a critical transcription factor that governs the differentiation of cluster of differentiation 4⁺ (CD4⁺) T cells. The pathogenesis and progression of psoriasis are primarily attributed to an immune imbalance stemming from the overproduction of interleukin-17A (IL-17A) by T lymphocytes. However, the role of IRF4 in psoriasis remains unexplored. In this study, we found that IRF4 activity is increased in the cutaneous lesions of patients with psoriasis in response to stimulation by IL-23A and IL-1β. This IRF4 elevation heightens its binding to the E1A binding protein p300 (EP300) promoter, triggering the transcription of downstream retinoic acid receptor-related orphan receptor-γt (RORγt) and increasing the secretion of IL-17A, thereby establishing the IL-1β/IL-23A-IRF4-EP300-RORC-IL-17A inflammatory cascade in psoriasis. The alleviation of imiquimod (IMQ)-induced psoriatic-like symptoms was achieved through the creation of a Irf4 ^-/- gene deletion mouse model and pharmacological inhibition using antisense oligonucleotides targeted for Irf4. This amelioration was accompanied by a decreased number of IL-17A-producing CD4⁺ T cells in the skin. The findings of this study suggest that IRF4 plays a crucial role in the promotion of inflammation and exacerbation of IMQ-induced psoriasiform dermatitis. Consequently, IRF4 targeting could be a promising therapeutic strategy.

Objective: To establish a risk assessment system for infectious disease prevention and control in schools in Shangcheng District, Hangzhou and determine risk levels for each school, and propose corresponding risk management measures, so as to provide a scientific reference for infectious disease prevention and control in primary and secondary schools. Methods: Based on the Failure Mode and Effects Analysis (FMEA) method, potential failure analysis and current situation investigation of infectious disease prevention and control risks were conducted in 110 primary and secondary schools from 2022 to 2024 in Shangcheng District, Hangzhou. Risk levels were classified using K-Means cluster analysis. Results: Through expert panel discussions using FMEA, 6 first level indicators and 28 second level indicators were identified. The top three risk priority numbers were implementation of required prevention and control measures for clustered infectious disease outbreaks in schools in the past three years ( 189.00 ), student morning/afternoon health checks (168.00), and reporting status of clustered infectious disease outbreaks in schools in the past three years (144.00). The comprehensive prevention scores of schools ranged from 61.00 to 98.00 (mean: 87.40 ). There were no statistically significant differences in the average scores(primary school: 88.17±7.39, nine year consistent education: 86.26±7.68, junior high school: 85.55±8.20, and high school: 88.72±4.91) and risk level distribution of schools with different educational stages( F/H=0.95,1.47, P >0.05).K-Means cluster analysis divided the schools into 5 risk levels with cluster centers at 93.25, 85.78, 79.69, 70.29, 61.00 ( F=309.21, P <0.05), with 80% of schools classified as low risk or below. Conclusion The infectious disease prevention and control risk assessment system for primary and secondary schools can be established, and hierarchical management can be conducted according to school risk levels, thereby improving the efficiency and effectiveness of school infectious disease prevention and control, and enhancing the precision and sustainability of prevention efforts.

Objective:To explore the distribution of allergen-specific IgE (sIgE) for children with atopic dermatitis in Tianjin City and provide the evidences of clinical diagnosis and treatment.Methods:A retrospective cross-sectional study was conducted to analyze the children who were suspected of atopic dermatitis and tested for serum sIgE in the Tianjin Children′s Hospital from March 2021 to February 2023. Using first detection results only, a total of 1 841 serum samples were tested for twenty common allergens. The method was the enzyme-linked immune capture assay. The allergen epidemiological characteristics were statistically analyzed by Chi square test based on the children′s characteristics and factors such as different sexes, ages and seasons by the mass data.Results:Among the 1 841 cases, the results showed that 1 247 (67.73%) were sensitized to at least 1 allergen-sIgE, comprising to 49.86% (918/1 841) to food allergen-sIgE and 47.96% (883/1 841) to aeroallergen-sIgE. The top three food allergens-sIgE were egg 32.10% (591/1 841), milk 25.91% (477/1 841) and wheat flour 14.61% (269/1 841); the top three positive rates of aeroallergens-sIgE were house dust 24.33% (448/1 841), alternaria 20.59% (379/1 841) and dermatophagoides farinae 14.83% (273/1 841). The positive rates of food allergens-sIgE were the highest in the 1-3 years old group (64.11%, 434/677) ( χ2=122.854, P<0.001), while the positive rates of aeroallergens-sIgE were higher in the 11-14 years old group (71.26%, 62/87) ( χ2=134.968, P<0.001). No seasonal difference was revealed in the overall positive rate of food allergen-sIgE and aeroallergen-sIgE ( χ2=4.047, P=0.256; χ2=7.549, P=0.056). The positive rates of soybean-sIgE and milk-sIgE were the highest in summer ( χ2=11.329, P=0.010; χ2=28.720 , P<0.001), whereas alternaria-sIgE and mugwort-sIgE were the highest in summer and autumn, respectively ( χ2=8.462, P=0.037; χ2=10.641 , P=0.014). Among the 1 841 cases, 32.21% were sensitized to three or more allergens-sIgE. The sIgE concentration levels of egg, milk and house dust were mainly level 1 to 2, and the proportions of level 3 and above were all under 15%; although the positive rates of crab, shrimp, and peanut were low, the proportions of grade 3 and above were all beyond 30%. Children sensitized to alternaria, dermatophagoides farinae, mugwort, and cat dander had higher sIgE concentration levels, which were 68.07%, 49.45%, 56.57% and 47.83% respectively. Conclusions:This study can reflect the epidemic characteristics of allergen-sIgE in children with atopic dermatitis in Tianjin region to a certain extent. Allergen-sIgE positivity in patients differed by age, and there were seasonal differences and grade distribution differences in the positive rates of some allergens-sIgE. It is necessary to reasonably avoid the high-risk allergens according to the epidemiological characteristics and clinical symptoms, which provide valuable information for the prevention, diagnosis and treatment of atopic dermatitis.

Objective:To study the distribution characteristics of natural killer(NK)cells and their subsets in normal peripheral blood in China,and to explore their normal value and significance.Methods:In this study,peripheral blood was collected from 200 healthy adults.Their age range was 18-87 years.All the subjects were divided into 6 age groups:18-30,31-40,41-50,51-60,61-70,and 71-87 years.With CD16,CD56,CD4,CD19,as surface markers,fluid cytology detection tech-niques were used to detect NK cells and the relative and absolute counts.SPSS 27.0 was used for system-atic analysis of the data,and the measurement data were expressed as mean±standard deviations.A t test,variance analysis or rank sum test were performed to compare the differences between the age groups and the sex groups.The significance level was set at α=0.05,and P＜0.05 was considered statistically significant.Results:The range of NK B cells in the 200 healthy adult subjects was(0.46±0.24)× 106/L,that of CD3-CD56+NK cells was(13.14±7.56)× 106/L,that of CD56dimCD16+NK cells was(5.23±3.12)×106/L,that of CD56bright NK cells was(85.61±7.40)× 106/L,and that of NK T cells was(4.16±3.34)×106/L.There were no statistically significant differences in CD3-CD56+NK cells and NK T cells with respect to age(P=0.417,P=0.217).However,there was a decreasing trend in the number of NK B cells and CD56dimCD16+NK cells with increasing age(r=0.234,P＜0.001;r=0.099,P＜0.001),particularly after the age of 50.Conversely,CD56bright NK cells showed an increasing trend with age(r=0.143,P＜0.001).Conclusion:The detection of NK cells and their subsets has significant reference value for the diagnosis,treatment,and prognosis of autoimmune diseases,infectious diseases,and tumors.This study provides a preliminary reference range for clinical detection of NK cell subsets,but further research with a larger sample size and multi-center trials are needed to confirm these findings.

Objective To analyze the safety and efficacy of neuroendoscopic minimally invasive surgery and traditional extraventricular drainage in the treatment of severe hypertensive intraventricular hemorrhage.Methods The clinical data of 50 cases with neuroendoscopic ventricular hematoma evacuation(endoscopy group)and 44 cases with traditional ventricles external puncture drainage(drainage group)from July 2020 to July 2023 were retrospectively analyzed,and the hematoma clearance rates,classification of activities of daily living(ADL)scale,incidence of hydrocephalus,secondary bleeding,intracranial infection,and pulmonary infection were observed between the two groups of patients.Results After surgery,the proportion of patients with hematoma clearance rate>60％and ADL grades Ⅰ,Ⅱ,and Ⅲ in the endoscopy group were significantly higher than those in the drainage group[the proportion of patients with hematoma clearance rate>60％:88.0％(44/50)vs.47.7％(21/44),χ2=17.794,P<0.001;the proportion of individuals with ADL grades Ⅰ,Ⅱ,and Ⅲ:94.0％(47/50)vs.77.3％(33/44),respectively,χ2=5.459,P=0.019],the incidence of complications in endoscopy group was significantly lower in the drainage group[8.0％(4/50)vs.34.1％(15/44),χ2=9.879,P=0.002].Conclusion Compared with traditional ventricular puncture drainage surgery,neuroendoscopic minimally invasive surgery for the treatment of severe hypertensive intracerebral hemorrhage with ventricular casting can achieve better treatment outcomes,a higher hematoma clearance rate,and fewer postoperative complications.

Renal fibrosis, especially tubulointerstitial fibrosis, is the most common pathway of all chronic kidney diseases progressing to end-stage renal diseases. Several adaptive reactions occur in renal tubular epithelial cells after chronic injury, such as changes in glycolipid metabolism, unfolded protein response, autophagy and senescence, epithelial-to-mesenchymal transition and G2/M cell cycle arrest. Maladaptive repair mechanisms can induce tubulointerstitial fibrosis. This article will discuss the molecular mechanism of these adaptive responses of renal tubular epithelial cells driving renal tubulointerstitial fibrosis, and provide a basis for exploring new drug targets for renal tubulointerstitial fibrosis.