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关键词： Elastomers  

摘要： Immunotherapies are a powerful strategy to treat cancer by modulating the immune system to raise an anti-tumor immune response. A prime example of immunotherapies are cytokines - small immunomodulatory molecules that are widely used to stimulate immune cells. Undirected administration of cytokines, however, can cause severe side effects, preventing the use of potent cytokines, such as Interleukin (IL)-12, which induces IFNγ responses by cytotoxic effector lymphocytes, including NK cells. Biomaterials, like nanoparticles, can encapsulate IL-12 and accumulate at the tumor site to alleviate side effects. Yet, the released IL-12 might not be directly targeted to extracellular IL-12 receptors on the specific effector cells, thereby potentially compromising the cytokine's therapeutic efficacy. Here, we develop a polymer-based platform to target NK cells, which we call immunofilaments. Immunofilaments are nanosized linear polymers that present an anti-CD16 antibody and IL-12 effectively to NK cells and lead to synergistic NK cell activation as highlighted by an increase in TNFα and IFNγ production and upregulation of multiple activation markers, including CD25, CD69, and degranulation marker CD107a. NK cell proliferation is enhanced in the presence of both anti-CD16 antibody and IL-12 compared to giving IL-12 separately. Finally, we demonstrate that the IF platform is suitable for in vivo applications, as immunofilaments readily activate human NK cells upon administration to mice. Statement of Significance: IL-12 is a potent cytokine that stimulates IFNγ responses in NK cells, which supports an anti-tumor immune response. Due to its high potency, the delivery of IL-12 needs to be highly controlled to prevent severe adverse side effects, which can be achieved by using biomaterials. This study shows that nanosized polymers termed Immunofilaments can be used to immobilize IL-12 and effectively target and activate NK cells by co-conjugation of anti-CD16 antibodies. This work i

关键词： Squamous cell carcinoma   Radiotherapy   Immunotherapy   TGF-(3   PD-L1   MHC class I   T cell  

摘要： Radiation therapy (RT), a mainstay treatment for head and neck squamous cell carcinoma (HNSCC), kills cancer cells and modulates the tumor immune microenvironment. We sought to assess the effect of RT in combination with PD-L1/TGF-(3 dual blockade in squamous cell carcinomas (SCC) and analyze the underlying mechanisms. We transplanted mouse SCC cells derived from keratin-15 (K15) stem cells harboring KrasG12D/Smad4- /- mutations into syngeneic recipients and irradiated tumors followed by PD-L1/TGF-(3 dual blockade. We identified a responder line and a non-responder line to this combination therapy. Responder hosts eradicated SCCs by the combined therapy and rejected re-transplanted SCC cells 6 months post tumor eradication, which correlated with clonotype expansions of splenic CD8 T cells and effector memory gene expression identified by single cell sequencing of TCR and transcriptomes, respectively. Mechanistically, RT upregulated MHC-I (major histocompatibility complex I) and its transcriptional regulators including NLRC5, in SCCs of the responders but not nonresponders. These data are consistent with the TCGA HNSCC database in which NLRC5 correlated to MHC-I genes and CD8 T cell gene expression. Functional contribution of MHC-I to PD-L1/TGF-(3 blockade response was confirmed by knocking out beta-2-microglobulin in responder cells that attenuated the response to the same therapy. Thus, the therapeutic effectiveness appeared to largely depend on cancer-cell MHC-I expression, triggering CD8 T cell effector memory-driven responses against tumor cell antigens. Identifying the differential RT response to MHC-I induction may serve as a predictive marker for stratifying patients that are most likely to benefit from this combination therapy.

关键词： cancer‐associated fibroblast   interferon‐licenced fibroblast   non‐small cell lung cancer   secretome   tumour microenvironment  

摘要： Cancer-associated fibroblasts (CAFs) are the dominant nonmalignant component of the tumour microenvironment (TME). CAFs demonstrate a high level of inter- and intra-tumour heterogeneity in solid tumours, though the drivers of CAF subpopulations are not fully understood. Here, we demonstrate that non-small cell lung cancer (NSCLC) patient-derived CAFs upregulate the secretion of inflammatory cytokines (IL6, LIF, IL33, GM-CSF, IL1ra) and chemokines (CCL2, CCL3, CCL4, CCL20, CXCL8, CXCL9, CXCL10, CXCL11) in response to in vitro co-culture with anti-CD3/anti-CD28-stimulated peripheral blood mononuclear cells (PBMCs) via IFNγ and TNFα. Furthermore, T-cell-derived IFNγ inhibits CXCL12 secretion by CAFs in vitro. Our results highlight the ability of T-cell effector cytokines to modulate the CAF secretome in NSCLC.

关键词： 凡纳滨对虾   肌质钙结合蛋白   稳定性   抗原表位  

摘要： 以凡纳滨对虾(Penaeus vannamei)为原料,分离纯化和鉴定过敏原肌质钙结合蛋白(sarcoplasmiccalcium-binding protein,SCP),对其理化性质(免疫活性、热稳定性、pH值稳定性及消化稳定性)、二级结构和抗原表位进行研究。结果表明:采用蛋白粗提、硫酸铵分级沉淀、阴离子交换层析等步骤纯化得到的蛋白分子质量为21.6 kDa,经鉴定,该蛋白为凡纳滨对虾SCP,肽段覆盖率达93.26%。凡纳滨对虾SCP具有较强的免疫活性,在热处理温度≥65℃和强酸强碱条件下免疫活性减弱;SCP对肠液消化具有较强的稳定性,而对胃液消化稳定性较差。凡纳滨对虾SCP的二级结构中α-螺旋、β-折叠、β-转角和无规卷曲的相对含量分别为26%、16.9%、17.5%、39.6%。利用生物信息学工具结合免疫学技术最终预测识别出8条凡纳滨对虾SCP抗原表位。

关键词： 慢性阻塞性肺疾病急性加重期   肺栓塞   老年   中性粒细胞与淋巴细胞比值   红细胞分布宽度  

摘要： 目的 观察老年慢性阻塞性肺疾病急性加重期(AECOPD)合并肺栓塞(PE)患者中性粒细胞与淋巴细胞比值(NLR)、红细胞分布宽度(RDW)水平,为临床提供参考。方法 回顾性分析2021年12月至2023年12月民乐县人民医院收治的120例老年AECOPD患者的临床资料,根据CT肺动脉造影及下肢静脉彩色超声检查结果的不同分为PE组(35例)和非PE组(85例),根据早期死亡风险的不同将PE组患者分为高危组(6例)、中危组(18例)和低危组(11例)。比较PE组和非PE组患者临床资料,分析影响老年AECOPD合并PE的独立危险因素;比较PE组不同早期死亡风险患者的NLR、RDW水平,分析NLR、RDW水平与PE病情严重程度的相关性。结果 PE组患者NLR、RDW水平均高于非PE组(均P<0.05)。多因素Logistic回归分析结果显示,NLR、RDW水平升高均是影响老年AECOPD合并PE的独立危险因素(均P<0.05)。高危组、中危组患者的NLR、RDW水平均高于低危组,高危组均高于中危组(均P<0.05)。Spearman相关性分析结果显示,NLR、RDW水平与PE病情严重程度均呈正相关(均P<0.05)。结论 NLR、RDW水平升高均是老年AECOPD合并PE的独立危险因素,且NLR、RDW水平与老年AECOPD合并PE患者病情呈正相关,临床应予以监测。

关键词： 白细胞介素-17C   细胞因子   自身免疫性皮肤病   银屑病   特应性皮炎  

摘要： 白细胞介素17家族(interleukin-17s,IL-17s)具有促炎效应,参与各种自身免疫性疾病的发生发展。IL-17C是IL-17细胞因子家族中的重要成员之一,不同于广泛来源于各种免疫细胞的IL-17A,IL-17C主要由上皮细胞分泌并通过IL-17RE/A受体复合物发挥作用,在银屑病、特应性皮炎等自身免疫性皮肤病中均存在表达异常。本文综述了IL-17C与自身免疫性皮肤病之间关系的研究进展。

关键词： 间质性肺疾病   涎液化糖链抗原-6   C-反应蛋白/白蛋白比值   改良临床-影像-病理诊断评分   严重程度   预后  

摘要： 目的:探讨涎液化糖链抗原-6(KL-6)、C-反应蛋白/白蛋白比值(CAR)联合改良临床-影像-病理诊断(CRP)评分在间质性肺疾病(ILD)严重程度和预后评估中的应用。方法:选取间质性肺疾病患者167例,根据病情严重程度分为轻度组(n=106)和重度组(n=61),根据预后情况分为预后良好组(n=122)和预后不良组(n=45),另选103例同期健康体检者为对照组。比较不同病情严重程度患者血清KL-6水平、CAR以及改良CRP评分,多因素Logistic分析ILD患者预后不良的危险因素,分析KL-6、CAR联合改良CRP评分在间质性肺疾病严重程度和预后评估中的应用价值。结果:与对照组比较,轻度组和重度组患者血清KL-6水平、CAR、改良CRP评分均显著升高(均P<0.05),与轻度组比较,重度组患者血清KL-6水平、CAR、改良CRP评分均显著升高(均P<0.05)。两组年龄、性别、病程、吸烟史、饮酒史、高血压史、慢性阻塞性肺疾病(COPD)合并情况无统计学差异(均P>0.05),预后不良组患者肺功能异常患者占比、血清KL-6水平、CAR、改良CRP评分明显高于预后良好组(均P<0.05)。肺功能异常、高血清KL-6水平、高CAR、高改良CRP评分是间质性肺疾病患者预后不良的危险因素(均P<0.05)。血清KL-6、CAR联合改良CRP评分诊断重度间质性肺疾病的灵敏度、特异度明显高于三者独立检查(均P<0.05)。血清KL-6、CAR联合改良CRP评分预测间质性肺疾病患者预后不良的灵敏度、特异度明显高于三者独立检查(均P<0.05)。结论:KL-6、CAR联合改良CRP评分在重度ILD患者的严重程度诊断中具有较高准确度,且对ILD患者的预后也具有较高的预测价值。

关键词： cancer   immune checkpoint   immunoregulation   immunotherapy   TNF alpha-TNFR2  

摘要： Despite the tremendous advances that have been made in biomedical research, cancer remains one of the leading causes of death worldwide. Several therapeutic approaches have been suggested and applied to treat cancer with impressive results. Immunotherapy based on targeting immune checkpoint signaling pathways proved to be one of the most efficient. In this review article, we will focus on the recently discovered TNF alpha-TNFR2 signaling pathway, which controls the immunological and pro-angiogenic properties of many immunoregulatory and pro-angiogenic cells such as endothelial progenitor cells (EPCs), mesenchymal stem cells (MSCs), and regulatory T cells (Tregs). Due to their biological properties, these cells can play a major role in cancer progression and metastasis. Therefore, we will discuss the advantages and disadvantages of an anti-TNFR2 treatment that could carry two faces under one hood. It interrupts the immunosuppressive and pro-angiogenic behaviors of the above-mentioned cells and interferes with tumor growth and survival.

关键词： Lung cancer  

摘要： Breast cancer (BC) is the most common malignancy in women and the leading cause of cancer death. Microplastics (MPs) are plastic fragments with a diameter of less than 5 mm, easily ingested by organisms. Although MPs have been reported to enter the human body through diet, surgery, etc., whether MPs accumulate in BC and their effects have been largely unknown. Our study revealed a significant accumulation of MPs in BC patient samples. MPs pull-down experiments and mass spectrometry (MS) studies showed that MPs bound to annexin A2 (ANXA2) and were endocytosed into cells. This process resulted in mitochondrial damage and subsequent induction of mitophagy. Furthermore, after binding to ANXA2, MPs regulated mitophagy by inhibiting IL-17 exocytosis. These findings revealed the mechanism of toxic effects of MPs in patients with BC, clarified the molecular mechanism of ANXA2-IL-17 signaling pathway causing mitochondrial damage by MPs, and suggested the potential toxic effects and toxicological mechanisms of MPs. © 2024 Elsevier Ltd

关键词： Group 3 innate lymphoid cells (ILC3s)   Inflammatory bowel disease (IBD)   Mucosal Immunity   NRP1  

摘要： Group 3 innate lymphoid cells (ILC3s) control tissue homeostasis and orchestrate mucosal inflammation; however, the precise mechanisms governing ILC3 activity are fully understood. Here, we identified the transmembrane protein neuropilin-1 (NRP1) as a positive regulator of interleukin (IL)-17-producing ILC3s in the intestine. NRP1 was markedly upregulated in intestinal mucosal biopsies from patients with inflammatory bowel disease (IBD) compared with healthy controls. Genetic deficiency of NRP1 reduces the frequency of ILC3s in the gut and impairs their production of IL-17A in an NF-κB signaling-dependent and cell-intrinsic manner. The diminished IL-17A production in ILC3s altered the composition of the microbiota and improved the outcome of dextran sodium sulfate (DSS)-induced colitis. Furthermore, pharmacological inhibition of NRP1 with EG00229 alleviated the severity of colitis. These observations demonstrated the critical role of NRP1 in the control of intestinal ILC3s, suggesting that NRP1 is a potential therapeutic target for IBD.