课程文献中心 更多>>

关键词： 4-1BBL   AAV vector   cytotoxic CD8 T cells   gene therapy   glioblastoma   IL-12   immunotherapy  

摘要：

关键词： span id="cetext0002">AMLMRDMFCalloHCT  

关键词： poly(CL-co-TOSUO)   curcumin   IL-6   foam macrophages   biocompatibility  

摘要： Atherosclerotic plaque instability, driven by macrophage-derived foam cells and exacerbated by interleukin-6 (IL-6), necessitates localized anti-inflammatory strategies. To address this, we developed curcumin-loaded poly(epsilon-caprolactone-co-4-ethylenediol ketal-epsilon-caprolactone) (PCT) membranes via electrospinning, characterizing their sustained drug release, biodegradability, and morphology through SEM. Comprehensive in vitro assessments included endothelial/macrophage viability assays, hemolysis testing, foam cell modeling using Ox-LDL (80 mu g/mL for 48 h, optimized for IL-6 upregulation), and inflammatory cytokine quantification (IL-6/TNF-alpha/IFN-gamma) via RT-qPCR. Subcutaneous implantation in rats enabled histological evaluation via HE staining and IL-6 immunohistochemistry. Our results demonstrated that curcumin-PCT membranes exhibited sustained drug release and biodegradability while maintaining exceptional hemocompatibility and endothelial safety. The membrane extracts significantly inhibited macrophage activity and downregulated pro-inflammatory cytokines, with IL-6 suppression being the most pronounced. In vivo analyses corroborated these findings, showing reduced leukocyte infiltration and attenuated IL-6 expression compared to poly(epsilon-caprolactone) controls. Collectively, this study establishes curcumin-loaded PCT as a biocompatible platform with targeted efficacy against macrophage-driven vascular inflammation.

关键词： gastrointestinal tumors   the IFN-gamma/STAT1 pathway   immunity   inflammation   tumor cell proliferation and metastasis   tumor cell death   precisely targeted therapy  

摘要： Gastrointestinal malignant tumors exhibit a high incidence and mortality rate among all malignancies worldwide, making them a significant concern within the field of oncology. Targeted therapy for gastrointestinal tumors has become a hot topic in recent years, and its specific mechanism remains to be further elucidated. Secreted factors, including cytokines, chemokines, and growth factors, as components of the tumor microenvironment, play a crucial role in the progression of gastrointestinal tumors. Interferon-gamma (IFN-gamma) can activate these factors through JAK1/2 and STAT1 signaling (the IFN-gamma/STAT1 pathway). This pathway is considered "a double-edged sword" and maintains a dual role in promoting or inhibiting tumor progression by activating different downstream factors. In this review, we summarize the functions, mechanisms, and key factors of the IFN-gamma/STAT1 pathway that promote or inhibit gastrointestinal tumor progression and discuss therapeutic prospects for targets of the pathway.

关键词： Lipid Nanoparticles   Lung-Targeted   IL-12 mRNA   Docetaxel Prodrug  

摘要： Despite the remarkable success of mRNA vaccines, extrahepatic tissue-specific delivery of therapeutic mRNAs remains challenging. Here, we report a lung-tropic lipid nanoparticles (LNPs) platform that is rationally engineered for simultaneously co-delivering interleukin-12 (IL-12) mRNA and docetaxel prodrug to address the lung metastatic issue. By optimizing a panel of synthetic cationic lipids, we identified N112 as the optimal cationic lipid, with N112-DOTAP LNP formulation demonstrating moderately enhanced transfection efficiency in lung tissue compared to the benchmark MC3-DOTAP LNP. Moreover, N112-DOTAP LNP has a uniform particle size and high encapsulation efficiency for both therapeutic payloads. In a B16F10 lung metastasis model, the combination therapy demonstrated superior antitumor efficacy, reducing tumor nodules compared to the saline treatment, while maintaining the safety profile with no significant body weight loss or organ toxicity. This study provides a robust therapeutic strategy for mRNA-based combination cancer therapy.

关键词： Inhibitors   7-azaindole-3-acrylamide   Inflammasome   IL-1 beta   Inflammatory bowel disease  

摘要： Currently, a significant proportion of patients with inflammatory bowel disease (IBD) fail to respond to conventional drug therapies such as immunosuppressants and biologic agents. IL-1 signaling blockade is a promising therapeutic strategy for these unresponsive IBD patients. In this study, we identified a novel anti-NLRP3/ IL-1 beta inhibitor, the 7-azaindole analogue Y19, which exhibits an IC50 value of 1.26 mu M. Mechanistic investigations revealed that it suppresses NLRP3 inflammasome assembly and activation by disrupting critical protein-protein interactions, including NEK7-NLRP3, NLRP3-NLRP3, NLRP3-ASC, and ASC-ASC. Additionally, it also inhibits the AIM2 and NLRC4 inflammasome pathways. In a murine model of colitis, Y19, as a pan-inflammasome inhibitor, demonstrates anti-inflammatory efficacy comparable to that of tofacitinib, a Janus kinase inhibitor commonly prescribed for IBD patients refractory to conventional therapies. This finding highlights the potential of inflammasomes/ IL-1 beta inhibitors as a promising strategy for the treatment of IBD.

关键词： KIR   anti-EGFR   cetuximab   metastatic colorectal cancer   natural killer cells   HLA ligands  

摘要： Colorectal cancer (CRC) remains a major cause of cancer-related mortality. Cetuximab improves survival by combining EGFR inhibition with immune activation. This study evaluated the influence of killer cell immunoglobulin-like receptor (KIR)-mediated immune responses on cetuximab efficacy in 124 metastatic CRC patients: 55 with wild-type (WT) KRAS and 69 with KRAS mutations. Peripheral blood was genotyped for 19 KIR genes and relevant HLA alleles, focusing on key KIR-HLA interactions (2DL1-C2, 3DL1-Bw4, 3DS1-Bw4). KRAS-WT patients showed better outcomes, receiving more treatment cycles (median: 17 vs. 4) and showing slower disease progression (60% vs. 92.8% at 12 months). WT patients had higher frequencies of inhibitory KIRs and the Bw4 allele, with KIR3DS1-Bw4 heterozygosity linked to longer survival (p = 0.013). In KRAS-mutant patients, heterozygous KIR genotypes (AB) and mixed A/B semi-haplotypes were associated with improved survival (p = 0.002). Multivariate analysis confirmed KIR3DS1-Bw4 as a favorable factor in WT patients and AB genotypes as beneficial in KRAS-mutants. In conclusion, KIR-HLA interactions significantly impact cetuximab efficacy in metastatic CRC, with distinct immunogenetic profiles in WT and KRAS-mutant patients. These results highlight the potential of KIR-HLA profiling to guide personalized treatment strategies.

关键词： 肺腺癌胸腔积液   体液细胞形态学检查   联合检测   胸腔积液癌胚抗原   血清癌胚抗原  

摘要： 探讨体液细胞形态学检查联合癌胚抗原对老年肺腺癌相关胸腔积液的诊断价值。方法 收集2023年月6月至2024年10月老年患者标本,分为肺腺癌胸腔积液组143例和良性胸腔积液组150例,分别进行体液细胞形态学检查、胸腔积液CEA及血清CEA测定,计算胸腔积液/血清CEA比值,分析定量指标最适诊断临界值,并对诊断效能进行评价。结果 肺腺癌胸腔积液组中,体液细胞形态学检查、胸腔积液CEA、血清CEA及胸腔积液/血清CEA比值检测水平及阳性率均高于良性胸腔积液组(P<0.01),最适诊断值分别为5.4μg/L、5.88μg/L、2.41时;敏感度和特异度分别为88.11%、88%;72.03%、68%及86.01%、86%。联合检测中,四项指标并联检测敏感度(97.2%)高于任一单项指标检测(P<0.01)。四项指标串联检测特异度(97.33%)均高于任一单项指标检测(P<0.01)。结论 体液细胞形态学检查联合胸腔积液CEA、血清CEA以及二者比值,并联检测可提高敏感度,串联检测可提升特异度,在辅助诊断肺腺癌相关胸腔积液中具备良好的诊断价值和临床适用性。

摘要： Allogeneic hematopoietic cell transplantation (alloHCT) from 8/10 HLA-matched unrelated donor is performed in a minority of patients. There is little data on its outcomes and consequently, guidelines on optimal transplantation procedures are lacking. The Transplant complications working party of the EBMT performed a registry study comparing approaches to graft-versus-host disease (GVHD) prophylaxis in recipients of alloHCT from 8/10 HLA-mismatched unrelated donors (8/10 MMUD). The analysis included 450 adult patients with hematological malignancies receiving a first alloHCT between 2015 and 2021, GVHD prophylaxis strategies included ATG in 318 and PTCy in 132 patients. AlloHCT from 8/10 MMUD resulted in 21.1% non-relapse mortality, 28.5% cumulative incidence of relapse, 55.7% overall survival (OS), 50.4% progression-free-survival and 39.8% GVHD-relapse-free survival (GRFS). PTCy decreased the risk of grade II-IV (HR 0.63, 95%CI 0.40-0.99) and III-IV acute GVHD (HR 0.31, 95%CI 0.13-0.74), improved OS (HR 0.63, 95%CI 0.41-0.95) and GRFS (HR 0.65, 95%CI 0.47-0.91). No other differences between the groups were documented. Transplantation from female donors to male recipients increased the incidence of extensive chronic GVHD (HR 2.39, 95%CI 1.10-5.19) and decreased PFS (HR 1.49, 95%CI 1.01-2.20). AlloHCT from 8/10 HLA-matched unrelated donor is feasible and the use of PTCy in GVHD prophylaxis improves outcomes.