The αPD-L1 antibody-based immune checkpoint blockade therapy is still limited by the poor clinical response rate as it is mainly utilized to block surface PD-L1 on tumor cells while ignoring abundant PD-L1 exosomes secreted in the environment, causing tumor immune evasion. Here, we proposed an exosome biogenesis inhibition strategy to suppress tumor exosomes secretion from the source, reducing the inhibitory effect on T cells and enhancing chemo-immunotherapy efficacy. We developed sulfafurazole homodimers (SAS) with disulfide linkages, effectively releasing the drug in response to glutathione (GSH) and inhibiting 4T1 tumor-derived exosomes secretion. Subsequently, gemcitabine (Gem) was encapsulated to induce immunogenic cell death (ICD). Consequently, Gem@SAS inhibited the secretion of tumor exosomes by more than 70%, increased proliferation and granzyme B secretion ability of T cells by more than 2 times, and showed superior efficacy in breast cancer treatment as well as lung metastasis of breast cancer.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a severe dose-limiting adverse event of chemotherapy. Presently, the mechanism underlying the induction of CIPN remains unclear, and no effective treatment is available. In this study, through metabolomics analyses, we found that nab-paclitaxel therapy markedly increased serum serotonin [5-hydroxtryptamine (5-HT)] levels in both cancer patients and mice compared to the respective controls. Furthermore, nab-paclitaxel-treated enterochromaffin (EC) cells showed increased 5-HT synthesis, and serotonin-treated Schwann cells showed damage, as indicated by the activation of CREB3L3/MMP3/FAS signaling. Venlafaxine, an inhibitor of serotonin and norepinephrine reuptake, was found to protect against nerve injury by suppressing the activation of CREB3L3/MMP3/FAS signaling in Schwann cells. Remarkably, venlafaxine was found to significantly alleviate nab-paclitaxel-induced CIPN in patients without affecting the clinical efficacy of chemotherapy. In summary, our study reveals that EC cell-derived 5-HT plays a critical role in nab-paclitaxel-related neurotoxic lesions, and venlafaxine co-administration represents a novel approach to treating chronic cumulative neurotoxicity commonly reported in nab-paclitaxel-based chemotherapy.
Paclitaxel/toxicity* ; Animals ; Albumins/adverse effects* ; Serotonin/metabolism* ; Mice ; Humans ; Male ; Female ; Venlafaxine Hydrochloride/therapeutic use* ; Neurotoxicity Syndromes/metabolism* ; Middle Aged ; Schwann Cells/metabolism* ; Peripheral Nervous System Diseases/drug therapy* ; Antineoplastic Agents

Objective:To analyze the characteristics of CD4 + T cell subsets and cytokines in patients with mixed connective tissue disease (MCTD) and the correlation of MCTD disease activity, laboratory data, and clinical symptoms with cytokines. Methods:A total of 48 MCTD patients (including 24 newly diagnosed patients and 24 treated patients) were enrolled from the Department of Rheumatology and Immunology, the Second Hospital of Shanxi Medical University from 2018 to 2021. Meanwhile, 49 healthy subjects who underwent physical examination were recruited (healthy control group). The absolute counts of CD4 + T cell subsets in peripheral blood samples were analyzed by flow cytometry. The levels of serum cytokines were detected by flow bead array. Analysis of variance and Mann-Whitney U test were used to compare the differences between groups. Pearson or Spearman correlation analysis was used for correlation analysis. Logistic regression analysis was used to analyze related factors. The receiver operating characteristic curve was used to detect the best cut-off value and effectiveness. Results:The absolute counts of Th1 ( P<0.01), Th2 ( P<0.01) and Treg cells ( P<0.01) in the newly diagnosed MCTD patients and the treated MCTD patients were lower than those in the healthy subjects. The levels of cytokines (IL-2, IL-4, IL-6, IL-10, IL-17, IFN-γ, and TNF-α) in the two MCTD groups were higher than those in the healthy control group ( P<0.01). Further analysis revealed that the cardiac enzymes in MCTD patients included creatine kinase, creatine kinase-MB, aspartate aminotransferase, α-hydroxybutyrate dehydrogenase, and lactate dehydrogenase were positively correlated with cytokines ( P<0.05). In addition, it was found that IL-2 was positively correlated with erythrocyte sedimentation rate ( r=0.477, P<0.001), but it was negatively correlated with complement C3 ( r=-0.546, P=0.002) and complement C4 ( r=-0.422, P=0.02). IL-10 was correlated with the myositis symptoms in MCTD patients and the area under the receiver operator characteristic curve was 0.745 (95% CI: 0.576-0.915, P<0.05). Conclusions:This study provides insights into the unique immunological characteristics of CD4 + T lymphocyte subsets and cytokines in patients with MCTD, and also reveals a close correlation between cytokines and cardiac enzymes in MCTD patients. IL-2 has been shown to be associated with disease activity in MCTD patients. The level of IL-10 may be related to the occurrence of myositis symptoms in MCTD.

Objective:To investigate the feasibility and safety of intracardiac echocardiography(ICE)combined with total three-dimensional(T3D)technique in zero-fluoroscopy individualized transseptal puncture.Methods:A total of 112 patients with atrial fibrillation who underwent radiofrequency ablation in Yongchuan Hospital Affiliated to Chongqing Medical University from April 2021 to March 2024 were enrolled,and according to the method for transseptal puncture,they were randomly divided into ICE+T3D group with 56 patients and ICE group with 56 patients.The two groups were analyzed in terms of baseline data,time to atrial reconstruc-tion,time to coronary sinus electrode placement,frequency of ICE probe adjustment during transseptal puncture,duration of transsep-tal puncture,pretreatment time before ablation,incidence rate of complications,and the duration and dosage of X-ray exposure.Results:There were no significant differences in baseline data between the two groups.Compared with the ICE group,the ICE+T3D group had a significantly lower frequency of ICE probe adjustment during transseptal puncture(1.70±0.63 vs.5.34±1.71,P<0.001)and the duration of transseptal puncture(3.66±1.09 min vs.4.90±1.92 min,P<0.001).Compared with the ICE group,the ICE+T3D group had significantly longer time to atrial reconstruction(22.44±3.13 min vs.12.34±2.12 min,P<0.001)and pretreatment time be-fore ablation(49.41±3.52 min vs.37.65±4.04 min,P<0.001).In the ICE+T3D group,43(76.8%)patients achieved zero radiation during pretreatment before ablation,and 13 patients received X-ray due to the difficulty in catheter placement;compared with the ICE group,the ICE+T3D group had a significantly shorter duration of X-ray exposure(1.68±0.72 min vs.3.14±1.95 min,P=0.010)and a significantly lower dosage of X-ray exposure(6.28±2.78 mGy vs.23.85±21.32 mGy,P=0.004).During the stage of transseptal punc-ture,all patients in the ICE+T3D group achieved zero radiation,while 45 patients(80.4%)in the ICE patients received X-ray.In terms of complications,there were no life-threatening complications such as cardiac tamponade,perforation of the aorta by mistake,and embolization in either group,while there was one case(1.8%)of vascular complications in each group.Conclusions:ICE combined with T3D after integration and improvement is a safe and reliable procedure for zero-fluoroscopy individualized transseptal puncture.

Objective To systematically integrate the best evidence on pulmonary rehabilitation nursing for patients with tracheostomy after stroke(TAS),so as to provide evidence-based basis for clinical practice.Methods Following evidence-based medicine principles,we conducted a systematic search of literatures related to pulmonary rehabilitation nursing for patients with TAS in databases including UpToDate,BMJ Best Practice,PubMed,China National Knowledge Infrastructure(CNKI),Wanfang Database,VIP Database,and China Biology Medicine(CBM).Literature types included guidelines,expert consensus,systematic reviews,meta-analyses,evidence summaries,and original studies,with the search period spanning from the inception of the database to Jan.2025.Two researchers independently assessed the quality of the included literatures using standardized tools such as Appraisal of Guidelines for Research and Evaluation-Ⅱ and Joanna Briggs Institute tools,followed by grading and synthesizing evidences meeting the criteria.Results A total of 20 articles were included,including 6 guidelines,5 expert consensuses,4 meta-analyses,3 clinical decision-making papers,1 systematic review,and 1 randomized controlled trial.A total of 32 recommendations were formed,covering 6 dimensions:airway management(8 items),comprehensive pulmonary rehabilitation training(8 items),basic treatment(5 items),safety management(4 items),extubation nursing(3 items)and prevention of complications during the peri-extubation period(4 items).The evidence grades ranged from grade A(strong recommendation)to grade B(recommendation).Conclusion This study systematically synthesizes core elements of pulmonary rehabilitation nursing for patients with TAS through evidence-based methodology.The established multidimensional evidence framework provides scientific guidance for improving respiratory function,reducing complications,and optimizing extubation decisions.Clinicians are advised to adapt these recommendations to local contexts for practical implementation.

Objective The combined entropy weight technique for order preference by similarity to an ideal solution(TOPSIS)and rank sum ratio(RSR)methods were utilized to rate the protective performance of ice hockey helmets,and the effectiveness and influencing factors of the rating system,as well as the relationship between protective performance and purchase price were explored.Methods The linear acceleration data during impact drops of twenty-four ice hockey helmets were collected using a uniaxial accelerometer in a collision test machine after low and ambient temperature treatments.The protective performance of ice hockey helmets was rated using the STAR model combined with the entropy weight TOPSIS and RSR methods.One-way ANOVA or the Kruskal-Wallis H test was employed to assess the differences in protective performance among helmets across different grade groups.The correlation between different indicators was analyzed by Pearson's correlation coefficient.Results The comprehensive protective performance ratings of the CCM TACKS 310,IBX,BAUD,and WARRIORS COVERT RS PRO helmets were classified as poor,whereas the BAUER REAKT 150,HYPERLITE,and REAKT 200 helmets were rated as excellent.The remaining helmets were rated as moderate.There was a moderate to high positive correlation between the ambient temperature STAR(A)and Rowson's STAR values,the comprehensive Ti and low temperature Ti,the comprehensive T,and ambient temperature Ti(P＜0.05).The comprehensive Ti satisfied the homogeneity of variance(P＞0.05)and exhibited significant differences among groups(P＜0.05).Significant differences were found in the low temperature indicators among different groups(P＜0.05),and their weight coefficients ranked among the top three.The ambient temperature indicators were not affected by the protective performance grade(P＞0.05).A weak positive correlation existed between the comprehensive Ti and purchase price(P＜0.05).Conclusions According to the energy absorption test protocol,the combined entropy weight TOPSIS and RSR methods can efficiently rate the comprehensive protective performance of ice hockey helmets.The effectiveness of using low temperature indicators for the comprehensive evaluation and rating of ice hockey helmet protective performance is superior to that of ambient temperature indicators and purchase price.Consumers are advised not to use price as a criterion for evaluating the comprehensive protective performance of ice hockey helmets.

Objective The combined entropy weight technique for order preference by similarity to an ideal solution(TOPSIS)and rank sum ratio(RSR)methods were utilized to rate the protective performance of ice hockey helmets,and the effectiveness and influencing factors of the rating system,as well as the relationship between protective performance and purchase price were explored.Methods The linear acceleration data during impact drops of twenty-four ice hockey helmets were collected using a uniaxial accelerometer in a collision test machine after low and ambient temperature treatments.The protective performance of ice hockey helmets was rated using the STAR model combined with the entropy weight TOPSIS and RSR methods.One-way ANOVA or the Kruskal-Wallis H test was employed to assess the differences in protective performance among helmets across different grade groups.The correlation between different indicators was analyzed by Pearson's correlation coefficient.Results The comprehensive protective performance ratings of the CCM TACKS 310,IBX,BAUD,and WARRIORS COVERT RS PRO helmets were classified as poor,whereas the BAUER REAKT 150,HYPERLITE,and REAKT 200 helmets were rated as excellent.The remaining helmets were rated as moderate.There was a moderate to high positive correlation between the ambient temperature STAR(A)and Rowson's STAR values,the comprehensive Ti and low temperature Ti,the comprehensive T,and ambient temperature Ti(P＜0.05).The comprehensive Ti satisfied the homogeneity of variance(P＞0.05)and exhibited significant differences among groups(P＜0.05).Significant differences were found in the low temperature indicators among different groups(P＜0.05),and their weight coefficients ranked among the top three.The ambient temperature indicators were not affected by the protective performance grade(P＞0.05).A weak positive correlation existed between the comprehensive Ti and purchase price(P＜0.05).Conclusions According to the energy absorption test protocol,the combined entropy weight TOPSIS and RSR methods can efficiently rate the comprehensive protective performance of ice hockey helmets.The effectiveness of using low temperature indicators for the comprehensive evaluation and rating of ice hockey helmet protective performance is superior to that of ambient temperature indicators and purchase price.Consumers are advised not to use price as a criterion for evaluating the comprehensive protective performance of ice hockey helmets.

Objective:To analyze the characteristics of CD4 + T cell subsets and cytokines in patients with mixed connective tissue disease (MCTD) and the correlation of MCTD disease activity, laboratory data, and clinical symptoms with cytokines. Methods:A total of 48 MCTD patients (including 24 newly diagnosed patients and 24 treated patients) were enrolled from the Department of Rheumatology and Immunology, the Second Hospital of Shanxi Medical University from 2018 to 2021. Meanwhile, 49 healthy subjects who underwent physical examination were recruited (healthy control group). The absolute counts of CD4 + T cell subsets in peripheral blood samples were analyzed by flow cytometry. The levels of serum cytokines were detected by flow bead array. Analysis of variance and Mann-Whitney U test were used to compare the differences between groups. Pearson or Spearman correlation analysis was used for correlation analysis. Logistic regression analysis was used to analyze related factors. The receiver operating characteristic curve was used to detect the best cut-off value and effectiveness. Results:The absolute counts of Th1 ( P<0.01), Th2 ( P<0.01) and Treg cells ( P<0.01) in the newly diagnosed MCTD patients and the treated MCTD patients were lower than those in the healthy subjects. The levels of cytokines (IL-2, IL-4, IL-6, IL-10, IL-17, IFN-γ, and TNF-α) in the two MCTD groups were higher than those in the healthy control group ( P<0.01). Further analysis revealed that the cardiac enzymes in MCTD patients included creatine kinase, creatine kinase-MB, aspartate aminotransferase, α-hydroxybutyrate dehydrogenase, and lactate dehydrogenase were positively correlated with cytokines ( P<0.05). In addition, it was found that IL-2 was positively correlated with erythrocyte sedimentation rate ( r=0.477, P<0.001), but it was negatively correlated with complement C3 ( r=-0.546, P=0.002) and complement C4 ( r=-0.422, P=0.02). IL-10 was correlated with the myositis symptoms in MCTD patients and the area under the receiver operator characteristic curve was 0.745 (95% CI: 0.576-0.915, P<0.05). Conclusions:This study provides insights into the unique immunological characteristics of CD4 + T lymphocyte subsets and cytokines in patients with MCTD, and also reveals a close correlation between cytokines and cardiac enzymes in MCTD patients. IL-2 has been shown to be associated with disease activity in MCTD patients. The level of IL-10 may be related to the occurrence of myositis symptoms in MCTD.

Systemic lupus erythematosus (SLE) shows a significant gender difference. In addition to X chromosome inactivation (XCI) abnormalities, which may lead to the gender difference in SLE, studies have found that estrogen plays a key role in regulating Th17/Treg immune balance in SLE. Estrogen indirectly affects the quantity and function of Th17 and Treg cells by acting on B cells. In this process, the mutual influence and the interaction between B and T cells promote the development of SLE. Recent studies have reported gender differences in intestinal microbiota, which may lead to sex-dependent genetic susceptibility and epigenetic changes in autoimmune diseases represented by SLE. The interaction between estrogen and intestinal microbiota in SLE affects the immune balance of Th17/Treg cells. This paper mainly reviews the way estrogen works, and the mechanisms by which estrogen regulates Th17/Treg immune balance and the interaction between B and T cells in SLE, hoping to provide new targets for new therapeutic strategies such as selective estrogen receptor modulators.

Cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) pathway, as an important part of the innate immune system, is the main pathway for cytoplasmic DNA recognition and cGAS can be triggered by a variety of cytoplasmic dsDNA. This pathway has become an important bridge connecting autoimmunity, aseptic inflammatory response and cell aging. In recent years, cGAS-STING pathway has attracted increasing attention in autoimmune diseases. In rheumatoid arthritis (RA), neutrophil extracellular traps (NETs) induce typeⅠ interferon response and accelerate the production of anti-citrullinated peptide antibody (ACPA) through the cGAS-STING pathway. In addition, the cGAS-STING pathway also participates in synovitis, bone destruction and RA progression by promoting the proliferation and activation of fibroblast-like synovitis cells and the polarization of M1 macrophages. Inhibition of the cGAS-STING pathway or its downstream signaling pathway can reduce synovial inflammation in RA, suggesting that cGAS-STING pathway may be a potential therapeutic target for RA.