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关键词： Cancer   Neoplasm   Malignancy   Tumor necrosis factor alpha inhibitors   Inflammation   Immunosuppression   Adalimumab   Infliximab   Etanercept  

摘要： BackgroundTumor necrosis factor-alpha (TNF) is an inflammatory cytokine implicated in the development of many chronic inflammatory diseases and TNF-alpha inhibitors (TNF-I) are frequently prescribed as treatment. Their malignancy risk is debated, with pro-oncogenic effects of decreased immune surveillance and anti-oncogenic effects of decreasing chronic inflammation. As such, the literature is inconclusive in the malignancy risk of these medications. Here we investigate the malignancy risk in patients with chronic TNF-I *** is a single health system, retrospective non-matched cohort study of patients with chronic inflammatory conditions between 1996 and 2023. Patients exposed to TNF-I were identified using the generic medication names and the chronic inflammatory disease indication. The unmatched control cohort consisted of patients with the same chronic inflammatory conditions but without TNF-I exposure. Malignancies in this population were identified using ICD-9 and ICD-10 codes. TNF-I exposure was analyzed as a time-varying covariate prior to model fitting. Hazard ratios (HR) for TNF-I exposure on overall and individual cancer risk were estimated using two-sided Cox proportional hazards *** were 12,941 patients exposed to TNF-I and 37,402 patients unexposed to TNF-I. TNF-I exposure was not associated with overall cancer risk (HR 1.05, 95% CI 0.92-1.19). TNF-I exposure was positively associated with melanoma (HR 1.45, 95% CI 1.01-2.08), basal cell carcinoma (BCC) (HR 1.6, 95% CI 1.18-2.15) and squamous cell carcinoma (SCC) (HR 1.8, 95% CI 1.15-2.83), and negatively associated with prostate cancer (PCa) (HR = 0.51, 95% CI 0.29-0.91), leukemia (HR 0.12, 95% CI 0.02-0.83), and non-Hodgkin lymphoma (NHL) (HR 0.36, 95% CI 0.13-0.98). There was an increased risk of overall malignancy in TNF-I exposed patients with Psoriasis (HR 1.53, 95% CI 1.15-2.03, p = 0.003) but not in other inflammatory *** with TNF-I

关键词： Rheumatic diseases   TNF inhibitors   drug response prediction   cell-based assays   biomarkers   peripheral blood mononuclear cells   immune responses  

摘要： IntroductionTumor necrosis factor inhibitors (TNFi) have revolutionized rheumatic and inflammatory diseases therapy. Despite their efficacy, at least 30% of patients do not respond to TNFi therapy. There are five FDA-approved TNFis and several TNFi biosimilars, which are equivalent to their reference drugs. Although all TNFi drugs neutralize the TNF cytokine, they differ in many structural and pharmacokinetic properties. These differences may lead to varying patient responses, making one TNFi, but not another, effective for a given patient. An accurate prediction of a priori responsiveness to therapy, rather than trial and error, would therefore be of great value. Biomarkers that may guide the optimal TNFi choice are an unmet *** coveredThe authors discuss the diagnostic and predictive utilities of Cell-Based Assays (CBAs) for individualized TNFi therapy. Selection of TNFi can be based upon a given patient's immune cell response to the various TNFi drugs to predict their clinical outcomes to those *** opinionCBAs allow to assess the response of multiple TNFi drugs simultaneously by measuring biomarkers that could distinguish between TNFi responders and non-responders, effectively prioritizing the TNFi of choice. This literature search focuses on biomarkers and techniques that could be used as predictive CBAs for clinical response to TNFi.

关键词： Aurora kinase   alisertib   doxorubicin   fibrosis   hepatotoxicity  

摘要： Doxorubicin (DOXO) is effective against various types of cancer; however, it is associated with hepatotoxicity that may eventually lead to liver fibrosis, limiting its clinical use. Aurora kinase A (AURKA) has emerged as a crucial regulator of essential cellular processes and a promising target to overcome tumors resistant to some anticancer drugs, including DOXO. However, the potential beneficial effect of targeting AURKA on DOXO-induced toxicities has not been explored yet. Therefore, the current study aimed to explore the potential protective effect of the AURKA-selective inhibitor alisertib on DOXO-induced hepatotoxicity in mice and address the possible underlying mechanism. Mice were treated with alisertib (10 and 20 mg/kg) daily for five consecutive days and challenged with DOXO (20 mg/kg, i.p.) once on day two. Our findings revealed that alisertib significantly reduced biomarkers of liver dysfunction and oxidative stress elevated by the DOXO challenge. Interestingly, alisertib suppressed DOXO-induced IL-17A upsurge along with NF-κB and STAT3 activation. Alisertib also suppressed the upregulated expression of HIF-1α and VEGF-A as well as PERK activation associated with the DOXO challenge. Moreover, alisertib counteracted DOXO-induced TGF-β1 and α-SMA overexpression in the liver. These beneficial effects of alisertib were further reflected in the histopathological findings, which indicated the ability of alisertib to ameliorate DOXO-induced hepatic necroinflammation and fibrosis. Alisertib mitigates DOXO-induced hepatotoxicity in mice via targeting the IL-17A/NF-κB and IL-17A/STAT3/HIF-1α/VEGF-A signaling pathways, attenuating oxidative stress, inflammation, ER stress, and fibrosis.

关键词： breast   cytokines   gene expression   inflammation   neoplasm  

摘要： Chronic inflammation is associated with several neoplasms. Many studies tried to evaluate the correlation between cytokines and the pathogenesis of various cancer types and , , , and are often target of these analyses. The aim of the present study was to analyze cytokines mRNA expression in breast cancer samples to better understand pathogenesis and clinical aspects. Patients were selected from the oncology service of Centro Universitário FMABC; tumor RNA was obtained from formalin-fixed paraffin-embedded biopsies of breast cancer tissue. Gene expression was assessed by qPCR. Samples from 95 patients were obtained, presenting tumor stages varying from 0 to IIIB, with most of them in stage IIIA (33.68%). and expression presented a significant correlation with tumor stage. There was no correlation of cytokines expression with Ki-67 and prognostic factors. The study illustrated the pleiotropic role of , with no expression in early stages of cancer, varying according to "stage worsening". Regarding progesterone receptor (PR), correlation with and can reinforce the role of PR as an indicator of positive prognosis. The findings of this investigation suggest and could be evaluated in a larger study to better understanding pathogenesis and prognosis for this patient profile.

关键词： 猪流行性腹泻病毒   仔猪   免疫器官   病理损伤   免疫相关因子   病毒分布  

摘要： 为探究猪流行性腹泻病毒（porcine epidemic diarrhea virus，PEDV）感染对仔猪免疫器官的影响，选取8头5日龄健康仔猪作为研究对象，随机分为对照组（n=4）和PEDV感染组（n=4）。PEDV感染仔猪后观察并记录临床症状，在病毒感染2 d后实施安乐死并采集胸腺、脾、肠系膜淋巴结、髂下淋巴结、腹股沟淋巴结、肩前淋巴结、下颌淋巴结和肺门淋巴结。利用HE染色观察各免疫器官的病理学变化，通过IHC、Western blot和RT-qPCR分别检测病毒在免疫器官的分布、表达量以及肿瘤坏死因子-α（tumor necrosis factor α，TNF-α）、干扰素-β（interferon β，IFN-β）、白细胞介素-1（interleukin 1，IL-1）与白细胞介素-6（interleukin 6，IL-6）表达量的变化。结果显示：仔猪感染PEDV 1 d后发生水样腹泻。第二天剖检观察到各淋巴结有不同程度的肿大。HE染色发现PEDV主要引起脾脏红髓部分增多，脾索和脾窦界限模糊，脾窦中可见大量的细胞破裂；肠系膜淋巴结中小梁增生变厚，淋巴小结结构模糊不清，数量减少。IHC和RT-qPCR结果显示，PEDV在脾脏、肠系膜淋巴结等免疫器官均有分布，其中肠系膜淋巴结内病毒载量最高；而Western blot未能在以上组织中检测到该病毒。RT-qPCR检测脾脏和肠系膜淋巴结结果表明TNF-α、IFN-β和IL-1均有不同程度的升高，IL-6未发生明显变化。上述结果说明PEDV感染仔猪后部分免疫器官结构受到破坏，且影响了脾脏和肠系膜淋巴结中免疫相关因子TNF-α、IFN-β和IL-1的转录水平，这也为深入研究PEDV的致病机制提供了坚实的基础。

关键词： 慢性阻塞性肺疾病   IL-17A   MMP12   肺气肿   细胞凋亡  

摘要： 探讨补肺汤对慢性阻塞性肺疾病（chronic obstructive pulmonary disease， COPD）肺气肿小鼠Th17细胞免疫反应及细胞凋亡的影响。将C57BL/6小鼠50只随机分为空白组、模型组、补肺汤组、白细胞介素-17A（interleukin-17A， IL-17A）组、甲泼尼龙组。采用烟熏联合腹腔注射弹性蛋白酶方法构建COPD肺气肿小鼠模型，补肺汤及IL-17A单克隆抗体进行干预。小动物肺功能仪检测小鼠肺功能，苏木精-伊红（hematoxylin-eosin，HE）染色观察病理改变，蛋白免疫印迹法检测肺组织B细胞淋巴瘤/白血病-2蛋白（B-cell lymphoma/leukemia-2 protein，Bcl-2）、Bcl-2相关X蛋白（Bcl-2-associated X protein，Bax）、半胱氨酸天冬氨酸蛋白酶-3（cysteine aspartic acid protease-3， caspase-3）、剪切型半胱氨酸天冬氨酸蛋白酶-3（cleaved cysteine aspartic acid protease-3， cleaved caspase-3）表达，酶联免疫吸附测定法（enzyme-linked immunosorbent assay， ELISA）测定肺泡灌洗液基质金属蛋白酶-12（matrix metalloproteinase-12， MMP12）、IL-17A含量及炎症因子白细胞介素-6（interleukin-6， IL-6）、白细胞介素-8（interleukin-8， IL-8）表达，流式细胞术检测细胞凋亡率、CD4+和CD8+T淋巴细胞。结果显示，与空白组比较，模型组小鼠肺组织HE染色符合COPD病理改变，肺功能检测最大呼气后0.2 s的容积与用力呼气容积的比值（FEV0.2/FVC）、呼气量占肺活量25%～75%的平均流速（MMEF）、呼气峰流量（PEF）显著降低，肺泡灌洗液中MMP12、IL-17A、IL-6、IL-8及CD8+T淋巴细胞比例显著升高，肺组织细胞凋亡率、促凋亡蛋白Bax、cleaved caspase-3显著增加，抗凋亡蛋白Bcl-2表达显著减少。与模型组比较，补肺汤组MMP12、IL-17A、Bax、cleaved caspase-3表达显著减少，CD8+T淋巴细胞比例和细胞凋亡率显著降低，抗凋亡蛋白Bcl-2表达显著升高。研究结果揭示补肺汤可能通过调控MMP12及IL-17A介导的免疫炎症反应，减少肺组织细胞凋亡，从而改善COPD肺气肿。

关键词： HLA-C*07:01:130   HLA-genotyping   Illumina   next generation sequencing   novel allele  

摘要： The HLA-C*07:01:130 allele differs from the HLA-C*07:01:01:01 allele by a single nucleotide substitution in exon 3.

摘要： Ankylosing spondylitis (AS) is a chronic and progressive inflammatory arthritis involving disorders of both the immune and skeletal systems. Multiple osteochondromas (MO) is a rare skeletal disorder with a variety of clinical manifestations characterized by multiple benign exostoses. Here, we investigate a Chinese family with HLA-B27-negative AS complicated with MO. Whole-exome sequencing (WES) and Sanger sequencing were used to screen and identify the pathogenic gene. In vitro functional analysis was performed, and a pathogenesis-associated interleukin (IL)-17 receptor C (IL17RC) mutation was analyzed to investigate its effect on phenotypes. WES was used to identify a known missense mutation, NM_000127.3:c.1019 G > A(***340His), in the pathogenic gene EXT1 that is causal for MO. Moreover, a missense mutation, NM_153461.3:c.1067 C > T(***356Met), in the IL17RC gene was identified as potentially responsible for AS or spondyloarthritis symptoms in this family. In vitro over-expression of mutant IL17RC decreased its expression and increased the expression of IL17RA, consistent with the expression of these two genes in patients. Mechanistically, mutant IL17RC enhanced the activation of the NF-κB pathway. This study increases our understanding of the pathogenesis and progression of these diseases. Our findings broaden the risk factors in non-HLA-B genes associated with the NF-κB pathway in AS.

关键词： Interferon-beta   Nitrogen-containing bisphosphonates   Alendronate   cGAS   LPS receptor  

摘要： BackgroundAlendronate (ALN), a nitrogen-containing bisphosphonate (NBP), augments proinflammatory cytokine production by mouse macrophage-like cells incubated with ligands of Toll-like receptor (TLR) 2 and TLR4. The present study investigated whether ALN augments the production of interferon (IFN)-beta, which has anti-viral *** macrophage-like J774.1 cells were pretreated with or without ALN and then incubated with or without lipid A, a TLR4 ligand. Levels of secreted mouse IFN-beta were measured by enzyme-linked immunosorbent assay (ELISA). Expression of interferon regulatory factor (IRF)-5, cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), retinoic acid-inducible gene-I (RIG-I), downstream of kinase (DOK) 3, caspase-11, Nur77, laminB1, and beta-actin was analyzed by Western blot analysis. Cell viability was evaluated by measuring the reduction of 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) to formazan by living *** with ALN significantly augmented lipid A-induced IFN-beta production and nuclear IRF-5 expression in J774.1 cells. In addition, treatment with ALN upregulated the expression of cGAS, RIG-I, and DOK3. Pretreatment of J774.1 cells with RU.521, a cGAS inhibitor, inhibited ALN-augmented IFN-beta production, IRF-5 activation, and caspase-11 expression. Similar results were shown in the pretreatment of cells with another inhibitor, G140. RIG012, a RIG-I antagonist, also suppressed ALN-augmented lipid A-induced IFN-beta production. Furthermore, pretreatment with ALN significantly upregulated lipid A-induced Nur77 expression, which was also inhibited by *** results suggest that pretreatment with ALN augments lipid A-induced IFN-beta production by J774.1 cells via the upregulation of cGAS expression.

关键词： CSBF   SUSD2   ACT1   Keratinocytes   Psoriasis  

摘要： Overactivation of inflammatory signaling in keratinocytes is critical for psoriatic skin inflammation, but its regulatory mechanisms remain incompletely understood. Here, we demonstrate that the cytokine CSBF inhibits both individual and synergistic proinflammatory signaling induced by IL-17A and TNF-alpha (IL-17A/TNF-alpha) in keratinocytes, playing a protective role in psoriatic inflammation. The expression of CSBF was increased in the skin lesions and serum of psoriatic patients, and IL-17A/TNF-alpha enhanced its production. Csbf deletion exacerbated IMQ-induced psoriasis-like skin inflammation and led to hyperactivation of IL-17A/TNF-alpha signaling in keratinocytes. The CSBF protein significantly ameliorated psoriatic manifestations and suppressed IL-17A/TNF-alpha signaling through the receptor SUSD2. Mechanistically, CSBF-SUSD2 competed with TRAF6 and TNFR1 for interaction with ACT1, inhibiting the IL-17A/TNF-alpha signaling pathway. Overall, the anti-inflammatory cytokine CSBF has the potential to be a therapeutic option for psoriasis by targeting keratinocytes.