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关键词： inflammation-related colorectal cancer   polydopamine nanoparticles   Paeonol   interleukin-6/signal transducer and activator of transcription 3 pathway   Bcl-2  

摘要： Background Polydopamine (PDA) shows promising potential in disease diagnosis and targeted drug *** This study aimed to investigate the role of Paeonol (PAE)-modified PDA nanoparticles (NPs) in the treatment of colitis-associated cancer (CAC).Methods First, PAE-modified PDA NPs were prepared, and then the mouse model of the CAC model was set up. The mice were divided into a blank control group, a CAC model group, a PAE group, and PAE + nano group (n = 10). After treatment, cell apoptosis was detected by flow cytometry, and staining was conducted to observe tissues. Additionally, to explore the interaction between signal transducer and activator of transcription 3 (STAT-3) and the effect of PAE-modified PDA NPs, the WP1066 (STAT-3 inhibitor) group and PAE + nano + WP1066 group were *** PAE alleviated the pathological injury of colonic tissue in CAC mice and promoted the apoptosis of CAC cells, and a PDA NPs carrying PAE exhibited a greater curative effect when dramatically decreasing IL-6 and STAT-3 expression. The presence of STAT-3 inhibitors decreased the CAC cell proliferation and induced apoptosis. A combination of PAE + nano and WP1066 resulted in the most significant *** PAE-modified PDA NPs can attenuate injuries of the colon tissue in CAC mice and promote the apoptosis of CAC cells by inhibiting the IL-6/STAT-3 pathway and increasing the expression level of Bcl-2, thereby improving the condition of CAC.

关键词： CIPN   DRG   tumor necrosis factor alpha   neurite regeneration   DNA damage   mitochondrial damage   TNFR2   nerve growth factor  

摘要： Nerve injury caused by chemotherapy drugs is a common side effect. How to reduce this kind of nerve injury and promote neuron recovery is of great significance. In this study, we found that tumor necrosis factor-alpha (TNF-alpha) promoted the recovery of dorsal root ganglion (DRG) neuron from cisplatin-induced injury. On DRG neurons cultured in vitro, we found that TNF-alpha promoted neurite regeneration after cisplatin injury. In addition, TNF-alpha accelerated the removal of DNA damage and promoted the regeneration of mitochondria on DRG neurons. Study of the mechanism showed that this effect of TNF-alpha was independent from the NGF signaling pathway and occurred mostly through the activation of TNFR2 receptors, together with nucleus translocation of p65 and upregulation of NF-kappa B expression. This study provides a new theoretical basis and therapeutic strategy for the treatment of nerve injury caused by chemotherapy drugs.

关键词： 结节病，肺   中性粒细胞   淋巴细胞   单核细胞   C反应蛋白   降钙素原   体层摄影术，X线计算机  

摘要： 目的：分析血清炎症指标联合胸部CT对良恶性肺结节的鉴别诊断价值。方法：收取2022年8月至2024年8月在昆明市第三人民医院就诊的253例肺结节患者作为研究对象，所有研究对象均在入院后通过CT引导下经皮肺穿刺技术诊断，有明确的病理检查结果。127例肺癌患者作为恶性肺结节组，126例良性肺结节患者作为良性肺结节组。收集患者的病史资料、影像学资料、血清炎症标志物等数据，探讨细胞计数相关指标、细胞因子、急性期反应蛋白多项指标在两组之间的差异，进而以这些具有统计学意义的指标为自变量，利用二元logistic回归分析筛选出肺癌的独立危险因素，最后应用受试者工作特征曲线（receiver operating characteristic curve，ROC）评价其在良恶性肺结节鉴别中的诊断价值。结果：结节数量、结节直径、分叶征、毛刺征、血管束集征、CT值、中性粒细胞-淋巴细胞比值（NLR）、淋巴细胞-单核细胞比值（LMR）、系统性免疫-炎症指数（SII）、白细胞介素-5（IL-5）、白细胞介素-2（IL-2）、白细胞介素-6（IL-6）、白细胞介素-1β（IL-1β）、白细胞介素-10（IL-10）、γ-干扰素（IFN-γ）、白细胞介素-8（IL-8）、白细胞介素-17（IL-17）、肿瘤坏死因子-α（TNF-α）、C反应蛋白（CRP）、降钙素原（PCT）、血清淀粉样蛋白A（SAA）在良恶性肺结节中差异均有统计学意义（P值均<0.05）。二元logistic回归分析结果显示结节直径在8～15mm(OR=10.268， 95%CI: 1.719～61.321)、结节直径在15～30mm（OR=59.194， 95%CI: 11.155～314.124）、毛刺征为阳性（OR=27.373， 95%CI: 3.901～192.055）、LMR（OR=0.469， 95%CI: 0.282～0.779）、IL-5（OR=1.557， 95%CI: 1.145～2.118）、IL-2（OR=0.831， 95%CI: 0.748～0.924）、SAA（OR=2.625， 95%CI: 1.407～4.897）、PCT（OR=1.763， 95%CI: 1.240～2.507）是鉴别良性和恶性结节的相关因素。经ROC曲线分析，结节直径、毛刺征、LMR、IL-5、IL-2、SAA、PCT区分良恶性结节的AUC(95% CI)分别为0.732（0.669～0.795）、0.649（0.581～0.717）、0.398（0.532～0.672）、0.516（0.445～0.588）、0.380（0.311～0.450）、0.773（0.715～0.830）、0.821（0.767～0.874）。联合检测指标区分良恶性肺结节的AUC（95% CI）达到0.983（0.971～0.995）。结论：血清炎症指标联合胸部CT检查对区分良恶性肺结节有着较好的鉴别诊断价值。

关键词： In vivo expansion of endogenous CD8+T-cells   Tumor antigen-specific CD8+T-cells   Valency of p-MHC   Artificial antigen-presenting cells   Antitumor therapeuticefficacy  

摘要： Expanding tumor antigen-specific T-cells in vivo remains a major challenge in developing effective cancer immunotherapeutics. Artificial antigen-presenting cells (aAPCs) have the potential to overcome this challenge, but formulating aAPCs without correlating the in vivo dynamics of T-cell expansion often leads to suboptimal T-cell responses. Here, we have defined the critical effect of the peptide-major histocompatibility complex (p-MHC) valency displayed along with co-stimulatory molecules on iron-oxide nanoparticle-based aAPCs in vivo and demonstrated that the functionality of these aAPCs is governed by the p-MHC valency. Nanoscale aAPCs engage cognate CD8+ T-cells directly to induce the formation of T-cell receptor (TCR) microclusters, leading to nuclear translocation of nuclear factor of activated T-cells (NFAT) in a p-MHC valency-dependent manner. Nanoscale aAPCs, presenting p-MHCs above the threshold valencies, promoted the expansion and tumor infiltration of adoptively transferred and endogenous tumor-specific CD8+ T-cells in tumor situations. The treatment effectively inhibited tumor growth, highlighting the importance of defining the threshold valency of p-MHC in developing aAPCs for effective immunotherapies.

关键词： endometriosis   estrogen receptor   EZH2   inflammation   TNF alpha  

摘要： Endometriosis is a chronic inflammatory gynecological condition marked by the presence of tissue similar to the endometrium grows outside the uterus, often leading pelvic pain and infertility. This study explores how enhancer of zeste homolog 2 (EZH2) influences endometriosis, particularly through its interaction with estrogen receptors (ERs). We found that EZH2 reduces ER alpha expression, allowing ER beta to bind to the tumor necrosis factor alpha (TNF alpha) promoter and increase TNF alpha levels, fueling inflammation. In mice, the EZH2 inhibitor GSK343 reduced TNF alpha levels and endometriosis progression, similar to gene knockdown of ER beta or EZH2. In human samples, endometriotic tissue showed higher levels of EZH2 and ER beta and lower levels of ER alpha than in controls. Thus, EZH2 promotes TNF alpha-driven inflammation, contributing to endometriosis. Targeting EZH2, as with GSK343, could be a promising therapeutic strategy for endometriosis treatment.

关键词： Circinate balanitis   HLA B27   reactive arthritis  

摘要： Circinate balanitis is a characteristic mucocutaneous lesion commonly associated with reactive arthritis (ReA), previously described as Reiter's disease. It typically presents alongside other ReA symptoms, including urethritis, conjunctivitis, and arthritis, but can occasionally occur as an isolated finding. We report two cases of circinate balanitis occurring in patients with HLA B27-positive spondyloarthritis, without the classical triad of reactive arthritis. A 32-year-old male presented with recurrent erosions on the glans penis for 2 years, with a history of HLA B27-positive spondyloarthritis. He was on treatment with tofacitinib, deflazacort, and sulfasalazine. A skin biopsy from the scrotum confirmed the diagnosis of psoriasis. MRI spine and sacrum showed anterior syndesmophyte formation and right-sided sacroillitis. The final diagnosis was circinate balanitis in association with HLA B27-positive psoriatic spondyloarthritis. A 41-year-old male presented with recurrent erosions on the glans penis for 4 years with history of HLA B27 positivity, and ankylosing spondyloarthritis. The biopsy from the glans penis showed squamous hyperplasia. MRI spine and pelvis was suggestive of inflammatory spondyloarthropathy of the cervical, dorsal and lumbar spine with bilateral sacroilitis. The final diagnosis was circinate balanitis with primary ankylosing spondylitis. Both cases highlight the diagnostic challenge of distinguishing between different forms of spondyloarthritis in the presence of circinate balanitis.

关键词： interleukin-12   hematopoeisis   innate and adaptive immunity   toxicity   infection  

摘要： Interleukin-12 (IL-12) stimulates natural killer (NK) and T cell production of interferon gamma (IFN-gamma), but adverse events from NK cell activation have limited its clinical use. This study shows the impact of halflife-extended, full (IL-12Fc) and partial (IL-12 3x AlaFc) IL-12 agonists on the immune system. In naive mice, serial treatment with IL-12Fc induces systemic IFN-gamma, multi-organ pathology, and alterations in myelopoiesis. IL-12 Fc stimulates NK cell production of IFN-gamma but also activates CD4 +, CD8 + T, and NKT cells. IL-12 Fc's ability to enhance the production of IFN-gamma facilitates myelopoiesis, but IFN-gamma is not required for the development of systemic toxicity. In contrast, IL-12 3x Ala Fc avoids overt disease, activates CD4+ and CD8+ T cells, and induces myelopoiesis. These differential activities were harnessed to enhance resistance to infection, indicating that a threshold of IL-12 signaling is tolerated under steady-state conditions and that fine-tuning IL-12 agonism can bolster resistance without triggering pathology.

关键词： macrophages   neutrophils   lung   acute   ventilator   ARDS  

摘要： Although mechanical ventilation is a critical intervention for acute respiratory distress syndrome (ARDS), it can trigger an IL-1 beta-associated complication known as ventilator-induced lung injury. In mice, we found that lipopolysaccharide (LPS) and high-volume ventilation, LPS-HVV, lead to hypoxemia with neutrophil extracellular traps (NETs) formation in the alveoli. Furthermore, Il1r1(-/-) LPS-HVV mice did not develop hypoxemia and had reduced NETs, indicating that IL-1R1 signaling is important for NETs formation and hypoxemia. Therapeutic hypothermia (TH) is known to reduce the release of inflammatory mediators. In LPS-HVV mice, TH (32 degrees C body temperature) prevented hypoxemia development, reducing albumin leakage, IL-1 beta, gasdermin D (GSDMD), and NETs formation. We also observed that LPS-primed macrophages, when stimulated at 32 degrees C with ATP or nigericin, release less IL-1 beta associated with reduced GSDMD cleavage. Thus, hypothermia is an important modulating factor in the NLRP3 inflammasome activation, IL-1 beta release, and NETs formation, preventing LPS-HVV-induced acute respiratory failure.

关键词： Adaptive immunity   Cell biology   Immunology   Lung cancer   Oncology   T cells  

摘要： Since the lung is a mucosal barrier organ with a unique immunologic environment, mechanisms of immunoregulation in lung cancer may differ from those of other malignancies. Consistent with this notion, we found that CD8+ T cells play a paradoxical role in facilitating, rather than ameliorating, the growth of multiple lung adenocarcinoma models. These include spontaneous, carcinogen-induced, and transplantable tumor cell line models. Specifically, we found that CD8+ T cells promote homing of CD4+Foxp3+ T regulatory cells to the tumor bed by increasing levels of CCR5 chemokines in the tumor microenvironment in an IFN-γ and TNF-α dependent manner. Contrary to their canonical role, these Th1 cytokines contributed to accelerated growth of murine lung adenocarcinomas while suppressing the growth of other malignancies. Surprisingly, lung cancer cells themselves can serve as a dominant source of IFN-γ, and deletion of this cytokine from cancer cells using CRISPR/Cas-9 decreases tumor growth. Importantly for translational applications, a high level of IFN-γ was also found in human lung cancer patients at both the mRNA and protein level. Our data outlines what we deem a novel and previously undefined lung cancer specific immunoregulatory pathway that may be harnessed to tailor immune based therapy specifically for this malignancy.

关键词： single-cell   multi-omics   CITE-seq   rheumatoid arthritis   dendritic cells   TNF-alpha   TNFR1   TNFR2   inflammation   immune regulation  

摘要： Dendritic cells (DCs) play a central role in the immunopathogenesis of rheumatoid arthritis (RA), yet their regulation by tumor necrosis factor alpha (TNF) and associated receptors remains poorly characterized. We applied a single-cell multi-omics approach (CITE-seq) to profile peripheral blood mononuclear cells (PBMCs) from RA patients and healthy donors, before and after in vitro TNF stimulation. Using integrated analysis of surface protein expression and transcriptomic data, we focused on phenotypic and transcriptional changes in dendritic cell populations. DCs from RA patients exhibited elevated surface expression of CD14 and CD16, indicative of an inflammatory phenotype, and showed marked responsiveness to TNF. Upon stimulation, RA-derived DCs upregulated genes involved in antigen presentation (CD83, LAMP3), lymph node migration (CCR7, ADAM19), and inflammation (TRAF1, IL24) whereas such activation was absent in healthy controls. Our data reveal a TNF-responsive, pro-inflammatory transcriptional program in dendritic cells from RA patients and underscore the relevance of the TNF receptor profile in shaping DC function. These findings provide new insights into the immunobiology of RA and identify dendritic cells as potential targets for personalized immunomodulatory therapy.