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摘要： Purpose: IL1 pathway upregulation is implicated in pancreatic ductal adenocarcinoma (PDAC) progression, therapy resistance, and survival. Nadunolimab is an IL1 receptor accessory protein (IL1RAP)-targeting antibody with enhanced antibody-dependent cellular cytotoxicity that blocks IL1 alpha/IL1 beta signaling. We investigated efficacy and safety of nadunolimab in PDAC, in combination with gemcitabine/nab-paclitaxel (GN).Patients and Methods: Patients with previously untreated locally advanced/metastatic PDAC received nadunolimab (1.0-7.5 mg/kg) every 2 weeks with standard GN. The primary objective was safety;secondary objectives were antitumor response, progression-free survival, and overall survival (OS). Correlations between serum and tumor biomarkers and clinical response were ***: Seventy-six patients were enrolled;the median age was 63 years (range, 43-89), 42% were female, 97% had metastatic disease, and 9% had received adjuvant chemotherapy. The most frequent grade >= 3 adverse event was neutropenia (66%), typically during cycle 1. Infusion-related reactions occurred in 29% (grade 3, 3%). Only 1 of the 76 patients had grade 3 or above peripheral neuropathy. No marked dose-dependent differences in safety or efficacy were observed among the four dose groups. The median OS was 13.2 months (95% confidence interval, 11.0-15.6), and the 1-year survival rate was 58%. The median immune PFS (immune Response Evaluation Criteria in Solid Tumours) was 7.1 months (95% confidence interval, 5.2-7.4). Treatment efficacy was higher in patients with high versus low tumor baseline IL1RAP expression (OS 14.2 vs. 10.6 months;P = 0.012). A reduction in serum IL8 on treatment correlated with prolonged ***: Nadunolimab combined with GN shows promising efficacy and manageable safety in locally advanced/metastatic PDAC. Higher tumor baseline IL1RAP expression correlated with better outcome.

关键词： Hydrogen bonds  

摘要： Understanding how membrane composition influences the dynamics and function of transmembrane proteins is crucial for the comprehensive elucidation of cellular signaling mechanisms and the development of targeted therapeutics. In this study, we employed all-atom molecular dynamics simulations to investigate the impact of different membrane compositions on the conformational dynamics of the NKG2A/CD94/HLA-E immune receptor complex, a key negative regulator of natural killer cell cytotoxic activity. Our results reveal significant variations in the behavior of the immune complex structure across five different membrane compositions, which include POPC, POPA, DPPC, and DLPC phospholipids, and a mixed POPC/cholesterol system. These variations are particularly evident in the intracellular domain of NKG2A, manifested as changes in mobility, tyrosine exposure, and interdomain communication. Additionally, we found that a large concentration of negative charge at the surface of the POPA-based membrane greatly increased the number of contacts with lipid molecules and significantly decreased the exposure of intracellular NKG2A ITIM regions to water molecules, thus likely halting the signal transduction process. Furthermore, the DPPC model with a membrane possessing a high transition temperature in a gel-like state became curved, affecting the exposure of one ITIM region. The decreased membrane thickness in the DPLC model caused a significant transmembrane domain tilt, altering the linker protrusion angle and potentially disrupting the hydrogen bonding network in the extracellular domain. Overall, our findings highlight the importance of considering membrane composition in the analysis of transmembrane protein dynamics and in the exploration of novel strategies for the external modulation of their signaling pathways.

关键词： 白细胞介素-34   脂质运载蛋白2   成纤维细胞生长因子23   2型糖尿病   骨质疏松  

摘要： 目的探讨血清白细胞介素-34(IL-34)、脂质运载蛋白2(LCN2)、成纤维细胞生长因子23(FGF23)在2型糖尿病合并骨质疏松患者中的水平及意义。方法选取2020年6月至2022年7月该院收治的82例老年2型糖尿病合并骨质疏松患者为观察组,另选择同期82例老年2型糖尿病合并骨量减少患者为骨量减少组,82例在该院体检的健康者为对照组。根据骨质疏松严重程度将观察组患者分为轻度骨质疏松组和严重骨质疏松组。检测所有研究对象血清IL-34、LCN2、FGF23水平。采用受试者工作特征(ROC)曲线分析血清IL-34、LCN2、FGF23对2型糖尿病合并骨质疏松的诊断价值。结果与对照组比较,观察组和骨量减少组血清IL-34、FGF23水平均升高,且观察组高于骨量减少组,差异均有统计学意义(P<0.05)。与对照组比较,观察组和骨量减少组LCN2水平均降低,且观察组低于骨量减少组,差异均有统计学意义(P<0.05)。轻度骨质疏松组有48例患者,严重骨质疏松组有34例患者。严重骨质疏松组血清IL-34、FGF23水平均高于轻度骨质疏松组,严重骨质疏松组LCN2水平低于轻度骨质疏松组,差异均有统计学意义(P<0.05)。ROC曲线分析结果显示,IL-34、LCN2、FGF23单项及3项指标联合检测诊断2型糖尿病合并骨质疏松的曲线下面积(AUC)分别为0.867、0.796、0.717、0.949。结论血清IL-34、LCN2及FGF23联合检测对2型糖尿病合并骨质疏松具有较高的诊断价值,可为临床制订科学治疗方案提供参考依据。

关键词： 结直肠癌   复发   巨噬细胞炎性蛋白-3α   白细胞介素-37   CC类趋化因子配体5  

摘要： 目的探究结直肠癌患者血清巨噬细胞炎性蛋白-3α(MIP-3α)、白细胞介素-37(IL-37)、CC类趋化因子配体5(CCL5)水平并分析其临床意义。方法前瞻性选择辽宁省肿瘤医院2018年1月至2020年12月收治的结直肠癌患者158例作为癌症组,并根据随访情况分为多发组(41例)和无复发组(117例)。另选择同时期在辽宁省肿瘤医院健康查体的健康志愿者158例作为对照组;利用酶联免疫吸附试验(ELISA)检测血清MIP-3α、IL-37、CCL5水平;采用Pearson相关分析癌症组血清中MIP-3α、IL-37、CCL5水平的相关性;采用多因素Logistic回归分析影响结直肠癌患者术后复发的因素;采用受试者工作特征(ROC)曲线分析血清MIP-3α、IL-37、CCL5联合对结直肠癌患者术后复发的预测价值。结果癌症组血清MIP-3α、CCL5水平明显高于对照组,IL-37水平明显低于对照组(P<0.05);与无复发组相比,复发组TNM分期为Ⅲ期的患者比例较高(P<0.05),且复发组血清MIP-3α、CCL5水平明显升高,IL-37水平明显降低(P<0.05);癌症组血清MIP-3α与IL-37水平呈负相关(r=-0.540,P<0.05),与CCL5水平呈正相关(r=0.623,P<0.05),IL-37与CCL5水平呈负相关(r=-0.551,P<0.05);TNM分期为Ⅲ期、MIP-3α水平升高、CCL5水平升高是影响结直肠癌患者术后复发的危险因素(P<0.05),IL-37水平升高是影响结直肠癌患者术后复发的保护因素(P<0.05);血清MIP-3α、IL-37、CCL5联合预测结直肠癌患者术后复发的曲线下面积(AUC)为0.889(95%CI:0.830~0.948),MIP-3α、IL-37、CCL5单独预测结直肠癌患者术后复发的AUC分别为0.780(95%CI:0.692~0.868)、0.755(95%CI:0.673~0.838)、0.803(95%CI:0.730~0.876),三者联合预测的AUC较MIP-3α(Z=2.015,P=0.022),IL-37(Z=2.596,P=0.005),CCL5(Z=1.805,P=0.036)单独预测的AUC更大。MIP-3α高表达患者无复发生存率(55/86,63.95%)低于MIP-3α低表达患者(62/72,86.11%;Log-Rankχ^(2)=11.709,P<0.05);IL-37高表达无复发生存率(86.62%,77/89)高于IL-37低表达患者(57.97%,40/69;Log-Rankχ^(2)=19.917,P<0.05);CCL5高表达患者无复发生存率(51/84,60.71%)低于CCL5低表达患者(66/74,89.19%;Log-Rankχ^(2)=19.366,P<0.05)。结论结直肠癌术后复发患者血清MIP-3α、CCL5呈高表达,IL-37呈低表达,三者均与患者术后无复发生存率有关,且三者联合可用于结直肠癌患者术后复发的预测,临床应用价值较高。

关键词： 稀有血型抗原   冰冻保存   抗原强度  

摘要： 目的为保存含有稀有血型抗原的红细胞,建立冰冻保存红细胞方法,验证冰冻及复融对红细胞抗原性的影响。方法选择含有不同稀有血型抗原的新鲜红细胞,按照标准方法进行红细胞冻存及复融,比较红细胞冻存前后抗原强度变化,并研究红细胞冰冻保存条件及保存时限。结果冰冻保存2年,红细胞抗原强度无显著性差异。结论本研究冻存的红细胞适用于不规则抗体筛选及鉴定。

关键词： Biochemical simulations   Free energy   Drug screening   Hydrogen bonding   Drug interactions   Molecular dynamics   Toxicity   Rheumatoid arthritis  

摘要： Rheumatoid arthritis (RA) affects an estimated 0.1% to 2.0% of the world’s population, leading to a substantial impact on global health. The adverse effects and toxicity associated with conventional RA treatment pathways underscore the critical need to seek potential new therapeutic candidates, particularly those of natural sources that can treat the condition with minimal side effects. To address this challenge, this study employed a deep-learning (DL) based approach to conduct a virtual assessment of natural compounds against the Tumor Necrosis Factor-alpha (TNF-α) protein. TNF-α stands out as the primary pro-inflammatory cytokine, crucial in the development of RA. Our predictive model demonstrated appreciable performance, achieving MSE of 0.6, MAPE of 10%, and MAE of 0.5. The model was then deployed to screen a comprehensive set of 2563 natural compounds obtained from the Selleckchem database. Utilizing their predicted bioactivity (pIC₅₀), the top 128 compounds were identified. Among them, 68 compounds were taken for further analysis based on drug-likeness analysis. Subsequently, selected compounds underwent additional evaluation using molecular docking (< − 8.7 kcal/mol) and ADMET resulting in four compounds posing nominal toxicity, which were finally subjected to MD simulation for 200 ns. Later on, the stability of complexes was assessed via analysis encompassing RMSD, RMSF, Rg, H-Bonds, SASA, and Essential Dynamics. Ultimately, based on the total binding free energy estimated using the MM/GBSA method, Imperialine, Veratramine, and Gelsemine are proven to be potential natural inhibitors of TNF-α. © 2024 Nabi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

关键词： 年龄相关性黄斑变性   补体系统   细胞实验   动物模型   治疗  

摘要： 年龄相关性黄斑变性(age-related macular degeneration,AMD)是发生在视网膜黄斑区的一种退行性疾病,发病人群主要为中老年人,常导致患者失去中心视野和视力,严重妨碍患者的日常生活[1-2]。依据玻璃膜疣大小及有无视网膜色素上皮(retinal pigment epithelium,RPE)异常,AMD可分为早、中和晚期,晚期AMD包括以脉络膜新生血管为特征的湿性AMD和以地图样萎缩为特征的干性AMD[3]。

关键词： neutrophils   granuloma   respiratory  

摘要： Mutations in CYBB,encoding gp91^(phox)subunit of NADPH oxidase in phagocytes,impair the respiratory burst of neutrophils and result in X-linked chronic granulomatous disease(CGD).While inflammatory response and NETosis are important modalities employed by neutrophils for pathogen clearance,variants in these cell functions in CGD neutrophils(CGD-PMN)could possibly explain the insufficient defense and accumulation of phagocytes in the sites of infection.

关键词： IL-9   Th9   Tc9   CAR-T   Immunotherapy  

摘要： IL-9-producing T cells (T9) regulate immunological responses that affect various cellular biological processes, though their precise function remains fully understood. Previous studies have linked T9 cells to conditions such as allergic disorders, parasitic infection clearance, and various types of cancers. While the functional heterogeneity of IL-9 and T9 cells in cancer development has been documented, these cells present promising therapeutic opportunities for treating solid tumors. This review highlights the roles of IL-9 and T9 cells in cancer progression and treatment responses, focusing on potential discrepancies in IL-9/IL-9R signaling between murine tumors and cancer patients. Additionally, we discuss the regulation of tumor-specific Th9/Tc9 cell differentiation, the therapeutic potential of these cells, and current strategies to enhance their anti-tumor activities.

关键词： Exosomes   Immunomodulation   Inflammatory regulation   Mesenchymal stem cells   Retinitis pigmentosa  

摘要： Background: Retinitis pigmentosa is a neurodegenerative disease with major pathologies of photoreceptor apoptosis and immune imbalance. Mesenchymal stem cells (MSCs) have been approved for clinical application for treating various immune-related or neurodegenerative diseases. The objective of this research was to investigate the mechanisms underlying the safeguarding effects of MSC-derived exosomes in a retinal degenerative disease model. Methods: Interferon gamma-stimulated exosomes (IFNγ-Exos) secreted from MSCs were isolated, purified, and injected into the vitreous body of RCS rats on postnatal day (P) 21. Morphological and functional changes in the retina were examined at P28, P35, P42, and P49 in Royal College of Surgeons (RCS) rats. The mechanism was explored using high-throughput sequencing technology and confirmed in vitro. Results: Treatment with IFNγ-Exo produced better protective effects on photoreceptors and improved visual function in RCS rats. IFNγ-Exo significantly suppressed the activated microglia and inhibited the inflammatory responses in the retina of RCS rats, which was also confirmed in the lipopolysaccharide-activated microglia cell line BV2. Furthermore, through tRNA-derived small RNA (tsRNA) sequencing, we found that IFNγ-Exos from MSCs contained higher levels of Other-1_17-tRNA-Phe-GAA-1-M3, Other-6_23-tRNA-Lys-TTT-3, and TRF-57:75-GLN-CGG-2-m2 than native exosomes, which mainly regulated inflammatory and immune-related pathways, including the mTOR signaling pathway and EGFR tyrosine kinase inhibitor resistance. Conclusions: IFNγ stimulation enhanced the neuroprotective effects of MSC-derived exosomes on photoreceptors of the degenerative retina, which may be mediated by immune regulatory tsRNAs acting on microglia. In conclusion, IFNγ-Exo is a promising nanotherapeutic agent for the treatment of retinitis pigmentosa. Graphical Abstract: (Figure presented.) © The Author(s) 2024.