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摘要： BackgroundFumarate is a small molecule metabolite accumulating in fumarate hydratase-deficient renal cell carcinoma (FH-RCC) cells and plays a key role in the malignant transformation. However, the underlying mechanism remains to be *** comprehensive transcriptomic profiling of FH-knockdown cells was meticulously examined through RNA-sequencing. Differentially expressed genes were validated using qPCR, WB, and IHC. ChIP-qPCR experiments were conducted to evaluate the histones involved in the process. In vivo and in vitro studies revealed fumarate exerts an inhibitory effect on KDM4C activity. Cell proliferation and invasion assays were utilized to assess the roles of FH and KDM4C in FH-RCC *** discovered that accumulated fumarate in FH-knockdown ACHN and HK-2 cells competitively binds to alpha-ketoglutaric acid (alpha-KG), effectively inhibiting the activity of the histone demethylase KDM4C and significantly increasing the level of histone 3 lysine 36 trimethylation (H3K36me3). The upregulation of H3K36me3 expression triggered the activation of the IL-6/JAK/STAT3 oncogenic signaling pathway and increased the expression of the chemokine CXCL10. Phosphorylated STAT3 (p-STAT3) further enhanced programmed cell death ligand 1 (PD-L1) ***, these findings suggest that combining immune checkpoint blockade (ICB) with a STAT3 inhibitor may hold promise for patients with fumarate hydratase-deficient renal cell carcinoma.

关键词： Genetics   Immunology   Data encryption  

摘要：

关键词： 雾化乙酰半胱氨酸   老年   糖尿病   重症肺炎   治疗效果  

摘要： 对雾化乙酰半胱氨酸治疗老年糖尿病合并重症肺炎后细胞因子、呼吸力学改善情况进行探析。方法 以随机数字表法将2024年3月至2025年3月收治的56例糖尿病合并重症肺炎患者进行分组(对照组、观察组),对照组获得26例患者行常规对症治疗与护理。观察组获得患者26例在此基础上联用雾化乙酰半胱氨酸治疗,比较两组血糖指标的变化、重症肺炎病情(临床症状、细胞因子水平、呼吸力学)、预后改善程度。结果 观察组的治疗方案在降低空腹血糖、缓解临床症状上的效果更为显著(P<0.05);两组细胞因子水平与呼吸力学指标到正向改善且呈现出观察组优于对照组的结果(P<0.05);观察组呼吸机时间短于对照组,差异显著(P<0.05)。结论 在老年糖尿病合并重症肺炎中,雾化乙酰半胱氨酸在临床中应用具有促进痰液排出的作用,可进一步解除炎症加重风险,与常规治疗联用,可使得患者在降低空腹血糖、细胞因子与呼吸力学指标改善上受益,利于患者获得更为理想的预后。

关键词： 糖尿病足病   感染   白细胞介素-6   细胞因子   小截肢  

摘要： 目的 探讨糖尿病足溃疡(DFU)患者血清细胞因子水平与感染严重程度及预后的关系。方法 选取2021年7月—2023年12月,在解放军总医院第九医学中心内分泌科住院的104例DFU患者,根据国际糖尿病足病工作组(IWGDF/IDSA)分级标准,按感染程度分为轻度组(IWGDF/IDSA 2级,24例)和中重度组(IWGDF/IDSA3～4级,80例)。根据是否接受小截肢手术分为小截肢组(20例)和非小截肢组(84例)。比较各组患者的基线资料及白细胞介素(IL)-6等细胞因子的水平,采用logistic回归分析IL-6、超敏C-反应蛋白(hs-CRP)、白细胞水平与感染严重程度及小截肢的关系。结果 中重度感染组血清IL-6升高的患者占76.3%(61例),高于轻度组的54.2%(13例),差异具有统计学意义(P<0.05),而其他细胞因子的水平差异无统计学意义。中重度感染组患者的hs-CRP、白细胞水平均高于轻度感染组(均P<0.05)。logistic回归分析在校正多种混杂因素后,IL-6仍是中重度感染的影响因素,IL-6每增加1个单位,中重度感染的风险增加1.066倍(95%CI:1.005～1.130,P=0.032)。hs-CRP、白细胞水平在小截肢组与非小截肢组之间差异具有统计学意义(均P<0.05)。logistic回归分析显示hs-CRP、白细胞水平及IL-6均不是小截肢的影响因素。结论 IL-6水平与DFU患者感染严重程度密切相关,是中重度感染的独立影响因素。临床上积极检测DFU患者IL-6水平有助于为患者提供及时规范的抗菌治疗。

关键词： Cytokines   Cytokine therapy   Vitamin D   Serum proteins   Multiple sclerosis   Antiviral therapy   Chemokines   Interferons  

摘要： Introduction Dysfunctional regulatory T cells and subnormal responses to interferon-beta disrupt the immune system in multiple sclerosis. We probed dysregulated type I IFN pathways in vitro and in vivo IFN-beta to induce transcription factors, cytokines, and neurotrophic *** 36 MS-relevant serum proteins curated to be relevant to MS were detected with multiplex and IFN activity assays plus western blots of mononuclear cells from 15 partial responders (PR) to IFN-beta therapy with exacerbations over five years of treatment, and 12 clinical responders (CR) without exacerbations. Response was measured 0, 4, and 24 hours after injection of 16 million units (MU) of IFN-beta (double-dose) and 8 MU (standard dose), in clinically stable PR and CR, and 16 MU IFN-beta in paired PR during exacerbations, an IFN-resistant state. IFN-beta effects after therapy washout were compared to 15 therapy-na & iuml;ve stable and 13 active RRMS and 18 healthy controls (HC).Results IFN-beta injection corrected subnormal levels of p-S-STAT1 transcription factor and induced antiviral MxA and type I IFNs. IFN-beta induced anti-inflammatory IL-4, IL-10, IL-12p40, and TNFRII more strongly in stable PR than CR. Th2 cytokines correlated with serum vitamin D levels in CR. During exacerbations, IFN-beta injections induced Th1, Th2, and neurotropic proteins. After therapy washout, serum IFN-alpha/beta and pro-inflammatory IL-12p70 levels were lower in stable CR than in PR. In therapy-na & iuml;ve MS, Th1, Th2, and neurotrophic protein levels were surprisingly subnormal and poorly intercorrelated. Long-term IFN-beta therapy elevated serum proteins and brought them to a balanced positively-correlated state, echoing *** IFN-beta corrects low serum type I IFN levels, enhances responses to subsequent IFN exposure, induces immunoregulatory and neuroprotective proteins, and balances dysregulated and subnormal serum cytokine levels. Low serum IFN and IFN-beta-induced proteins link to be

关键词： HAV   hepatitis A   NK cells   T cells   interferons   mouse models  

摘要： A limited number of studies on human subjects with type-A hepatitis have found a positive correlation between activated natural killer (NK) cell frequencies in blood and the severity of liver injury. However, without knowledge of differences in viral burdens, it remains unclear whether NK cells are elevated due to hepatitis A virus (HAV) replication and ongoing associated injury, or if NK cell responses directly cause pathogenesis. To gain insight into how NK cells respond during the early stages of hepatitis A virus infection, we generated mice that are permissive for HAV infection in the liver but are otherwise immunocompetent. HAV readily infected the liver of these hepatocyte-specific type-I interferon receptor knockout mice (Ifnar1 Delta Hep), resulting in fecal virus shedding, elevated serum alanine aminotransferase levels, and immune cell infiltrates in the liver. Single-cell RNA sequencing analyses of liver leukocytes from infected Ifnar1 Delta Hep mice revealed a rapid accumulation of activated NK cells in the liver within 2 days. HAV infection and liver inflammation were brief and substantially reduced in magnitude in these mice compared to global Ifnar1-/- knockout mice that failed to induce substantial antiviral NK cell responses. NK cells were the principal source of interferon (IFN)-gamma in Ifnar1 Delta Hep mice. Ifnar1 Delta Hep mice that were experimentally depleted of NK cells or IFN-gamma showed greatly increased viral replication and liver damage. Moreover, IFN-gamma alone was sufficient to suppress HAV replication in primary mouse hepatocytes. Collectively, these findings establish a critical role for type-I IFN induction of NK cells, their expression of IFN-gamma, and protection against hepatitis *** A virus remains a leading cause of foodborne illness among unvaccinated individuals. Infection can result in severe liver injury that can progress to fatal fulminant viral hepatitis. Despite its clinical significance, the molecula

关键词： 局部晚期直肠癌   壁外血管侵犯   高分辨率磁共振成像   CALLY指数   C反应蛋白   淋巴细胞   白蛋白   新辅助放化疗  

摘要： 目的 探讨新辅助放化疗（NCRT）前高分辨率磁共振成像（HR-MRI）联合CALLY指数对局部晚期直肠癌（LARC）患者壁外血管侵犯（EMVI）的预测价值。方法 回顾性选取129例LARC患者作为研究对象,收集其NCRT前HR-MRI影像学特征及相关血清学指标,计算CALLY指数[由C反应蛋白（CRP）、淋巴细胞（LYM）计数、白蛋白（ALB）构成的复合指数]。根据术后病理结果,将患者分为EMVI阳性组（48例）和EMVI阴性组（81例）。采用Logistic回归分析筛选EMVI发生的影响因素;绘制受试者工作特征（ROC）曲线,分析CALLY指数和HR-MRI评估结果对EMVI的预测效能。结果EMVI阳性组T分期为T3～4期者占比、HR-MRI评估EMVI阳性者占比均高于EMVI阴性组,CRP、中性粒细胞（NEU）、癌胚抗原（CEA）、红细胞分布宽度（RDW）水平高于EMVI阴性组,LYM、ALB、CALLY指数水平低于EMVI阴性组,差异有统计学意义（P<0.05）。多因素Logistic回归分析显示,年龄、T分期、HR-MRI评估EMVI结果、CEA、CALLY指数均为LARC患者EMVI阳性的独立影响因素（P<0.05）。ROC曲线分析显示,NCRT前CALLY指数预测EMVI的曲线下面积（AUC）为0.757（95%CI:0.674～0.828）,HR-MRI评估结果的AUC为0.779（95%CI:0.697～0.847）,两者联合预测的AUC为0.870（95%CI:0.799～0.923）。结论 NCRT前HR-MRI联合CALLY指数对LARC患者EMVI具有较高的预测价值,可为个体化治疗提供重要参考。

关键词： Interleukin-8   Magnetic nanoparticles   Carbon dots   Ratio-fluorescent assay  

摘要： Ratio-based fluorescence assays can reduce environmental interference, allowing for the identification of biomarkers with higher specificity. However, the complicated preparation procedures involved in developing multi-fluorescent emission probes and the challenges associated with isolating and enriching specific biomarkers from complex samples present formidable obstacles. Magnetic nanoparticles enable the quick separation and enrichment of biomarkers, hence, the present study developed a ratio-fluorescence assay for the detection of interleukin-8 (IL-8) using carbon dots (CDs) with both magnetic and fluorescent properties. In this approach, magnetic and fluorescent Fe3O4-CDs-1 (FCs) hybrid nanoparticles were initially synthesized, followed by the growth of SiO2 nanorods on their surface. FCs@SiO2-Ab1 was then prepared by immobilizing capture IL-8 antibody (Ab1) through amino modification onto FCs@SiO2 to selectively capture and enrich target IL-8 from samples. Subsequently, CDs-2 modified with detection IL-8 antibody (Ab2) served as IL-8 detection probe, which formed sandwich structure with FCs@SiO2-Ab1 in the presence of IL-8. As the concentration of IL-8 increased, the fluorescence intensity of CDs-2 enhanced accordingly while the fluorescence intensity of FCs remained relatively unchanged. This ratio-fluorescence sensing platform exhibits a wide linear range (20-1000 pgmL-1) and an impressive low detection limit (6.9 pgmL-1). Furthermore, this method enables the reliable detection of IL-8 in human serum, thereby offering promising prospects for the development of enrichment and detection systems for other biomarkers.

关键词： Inflammation   Arthritis, Psoriatic   Fibroblasts  

摘要： Objectives Psoriatic arthritis (PsA) is an IL-23/IL-17/TNF-driven inflammatory arthritis, commonly accompanied by vitamin D deficiency. Here, we investigate the interaction between PsA synovial fibroblasts (SFs) and human memory CCR6+Th17 (hmemCCR6+Th17) cells and evaluate the therapeutic effects of TNF alpha and/or IL-17A inhibitors, and the adjunctive therapy potential of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3).Methods SF derived from PsA biopsies were co-cultured with hmemCCR6+Th17 cells to construct a PsA SF activation model. SF phenotypes were analysed by flow cytometry. Treatments included adalimumab (anti-TNF alpha), secukinumab (anti-IL-17A), and/or 1,25(OH)2D3, applied alone or in combination. A transwell system was used to assess treatment effects on SF and hmemCCR6+Th17 cells. Cytokines and matrix metalloproteinases (MMPs) were quantified by *** PsA SF were composed of heterogeneous subpopulations and constructed a pro-inflammatory feedback loop with hmemCCR6+Th17 cells. Anti-TNF alpha and/or anti-IL-17A significantly suppressed proinflammatory cytokines and tissue-destructive mediators in the PsA SF activation model, but showed limited effect on IL-22 and IFN gamma. Adding 1,25(OH)2D3 to anti-TNF alpha treatment effectively overcame the limitations of single anti-TNF alpha in suppressing Th17 cytokines, while significantly enhancing the inhibition of IL-6, IL-8 and MMPs. In addition, 1,25(OH)2D3 promoted the production of *** TNF alpha or IL-17A inhibition alone does not completely inhibit the proinflammatory loop between hmemCCR6+Th17 cells and PsA SF, although the combination shows additive effect on suppressing proinflammatory and tissue-destructive mediators. Importantly, 1,25(OH)2D3 plays a complementary role in the treatment of this proinflammatory loop alongside anti-TNF alpha therapy and significantly induces IL-10. Clinical PsA studies are needed to explore the additional therapeutic potential of this combination.