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摘要： Therapies for acute myeloid leukemia (AML) face formidable challenges due to relapse, often driven by leukemia stem cells (LSCs). Strategies targeting LSCs hold promise for enhancing outcomes, yet paired comparisons of functionally defined LSCs at diagnosis and relapse remain underexplored. We present transcriptome analyses of functionally defined LSC populations at diagnosis and relapse, revealing significant alterations in IL-1 signaling. Interleukin-1 receptor type I (IL1R1) and interleukin-1 receptor accessory protein (IL1RAP) were notably upregulated in leukemia stem and progenitor cells at both diagnosis and relapse. Knockdown of and reduced the clonogenicity and/or engraftment of primary human AML cells. In leukemic MLL-AF9 mice, knockout reduced LSC frequency and extended survival. To target IL-1 signaling at both diagnosis and relapse, we developed UR241-2, a novel interleukin-1 receptor-associated kinase 1 and 4 (IRAK1/4) inhibitor. UR241-2 robustly suppressed IL-1/IRAK1/4 signaling, including NF-κB activation and phosphorylation of p65 and p38, following IL-1 stimulation. UR241-2 selectively inhibited LSC clonogenicity in primary human AML cells at both diagnosis and relapse, while sparing normal hematopoietic stem and progenitor cells. It also reduced AML engraftment in leukemic mice. Our findings highlight the therapeutic potential of UR241-2 in targeting IL-1/IRAK1/4 signaling to eradicate LSCs and improve AML outcomes.

关键词： Olaparib   Radiosensitization   Antimetastatic   IL-17A   Oral squamous cell carcinoma  

摘要： PurposeWe tested whether the PARP inhibitor, Olaparib, can effectively enhance radiosensitivity while inhibiting OSCC growth and metastasis in vitro and in vivo. Patient samples were used for survival *** present study investigated the effect of Olaparib and ionizing radiation (IR) on clonogenic, migratory, and invasive ability in human IR-sensitive (OML1) and IR-resistant (OML1-R) OSCC cell lines. We next explored the underlying mechanism with ELISA and a Western blotting assay. Two in vivo mouse models were established to investigate the efficacy of Olaparib combined with radiotherapy (RT) on local tumor growth and lung metastasis. IL-17 A expression was confirmed in tissue specimens of OSCC patients by *** found that Olaparib, in combination with IR, substantially inhibited cell growth, migration, and invasion in vitro. Mechanistically, the Olaparib treatment significantly reduced the secretion of IL-17 A in irradiated OSCC cells by attenuating NF-kappa B and p38 activity. Consistently, Olaparib enhanced the radiosensitivity and, with RT, synergistically reduced both tumor growth and lung metastasis in mice. In addition, OSCC patients with high IL-17 A expression were substantially associated with an increased risk of lymph node involvement and worse *** study has highlighted that Olaparib displays radiosensitizing and antimetastatic effects by inhibiting the IL-17 A-dependent signal. Remarkably, Olaparib could provide a remarkable anticancer efficacy to improve treatment response in OSCC patients with recurrent/metastatic disease after RT.

关键词： COVID-19   SARS-CoV-2   Biochemistry   Haematology   Cytokines   Immunological signature  

摘要： BackgroundAlterations in haematological, biochemical parameters and cytokine levels, were reported in patients with COVID-19, however, there is an underrepresentation of the African population, which could provide evidence for understanding SARS-CoV-2 pathogenesis and useful tools for clinical management of cases. In this study, we aimed to determine the haematological, biochemical and cytokine profile in Mozambican individuals with SARS-CoV-2. MethodsA cohort of 85 Mozambican individuals with RT-PCR SARS-CoV-2 results, was stratified into negative, asymptomatic, mild, moderate, and severe categories. Haematological, biochemical and cytokines measurement were performed on samples from the study participants. Principal component analysis (PCA) was performed to identify similar patterns among the study cases. Comparisons between groups were performed using the Kruskal-Wallis test. Receiver operating characteristic (ROC) and area under the curve (AUC) analysis were conducted to evaluate the ability of these parameters to distinguish severe from non-severe cases of SARS-CoV-2 infection. ResultsSARS-CoV-2 infection was associated with a significant (p < 0.05) decrease in peripheral blood absolute counts of total lymphocytes and eosinophils, below the reference values along with no abnormal change (p > 0.05) in red blood cell count, haemoglobin, platelets and other red series parameters. At the serum level, SARS-CoV-2 infection was associated with an increase in serum levels of C-reactive protein (C-RP) and glucose above the reference values and to a significant reduction a significant (p < 0.05) reduction in levels of interferon-gamma (INF-gamma), Tumour Necrosis Factor alfa (TNF-alpha) and the interleukin 1 beta (IL-1 beta) and IL-6 in severe cases, when compared to negative cases. Haematological, biochemical and cytokine profiles segregate severe from non-severe cases of COVID-19 with an excellent performance of C-RP (AUC = 0.95;p < 0.001) and good performance of lymph

关键词： Hepatocellular carcinoma   Sorafenib   Macrophage extracellular traps   ARHGDIG   IL4   PADI4   Ferroptosis  

摘要： BackgroundHepatocellular carcinoma (HCC) is one of the most common as well as leading causes of mortality worldwide, and sorafenib is the first-line treatment in HCC patients. Unfortunately, drug resistance to sorafenib often develops. However, the underlying mechanism remains unclear. Here, we reveal the important role of macrophage extracellular traps (METs)-mediated crosstalk between macrophages and tumor cells in sorafenib *** in HCC tumor tissues were detected using immunofluorescence. The concentrations of MPO-DNA, elastase and cytokines were measured using ELISA. The mRNA expression levels of genes were confirmed by qRT-PCR. The siRNAs were conducted to knock ARHGDIG in Hepa1-6 and Hep3B cells. Western Blot assay was performed to determine protein expression of Rho GDP dissociation inhibitor gamma (ARHGDIG, or RHOGDI-3), PADI2, and PADI4. Cell viability and migration were evaluated by CCK-8 assay and transwell assay, respectively. Cell ferroptosis was assessed by measurement of Fe2+ concentration, flow cytometry assay of lipid ROS, and western blot assay of GPX4. The functions of sorafenib, DNase I, IL4 neutralization antibody and GPX4 in tumor growth were explored through in vivo *** induced MET formation in M2 macrophages rather than M1 macrophages derived from both human and mice. In Hepa1-6 HCC mice, METs clearance by DNase I improved response to sorafenib therapy, detected by tumor weight, tumor growth curve, tumor volume, and survival. By screening candidate cytokines that affect macrophage function, we found that sorafenib-promoting IL4 secretion by HCC cells plays a crucial role in sorafenib-induced MET formation. Understanding the critical role of IL4 in sorafenib-induced MET formation led us to find that IL4 neutralization significantly improved the efficiency of sorafenib in HCC models. Mechanistically, we discovered that sorafenib increased the expression of ARHGDIG in HCC cells, which led to the release

关键词： 大肠杆菌   高致病性毒力岛   耶尔森杆菌素   进化分析   TNF/NF-κB信号通路  

摘要： 为研究猪源大肠杆菌（Escherichia coli，E. coli）高致病性毒力岛（high pathogenicity island，HPI）结构基因的进化趋势及其对TNF/NF-κB通路的影响。本研究运用MEGA等软件分析HPI结构基因的遗传进化，使用R语言功能包挖掘***感染细胞的基因表达综合数据库（gene expression omnibus，GEO），并进行差异基因富集分析；使用分子对接预测HPI-Ybt与TNF/NF-κB通路相关蛋白的结合；将E. coli及前期构建的HPI缺陷株***ΔHPI感染IPEC-J2细胞，运用qPCR、ELISA和Western blot对TNF/NF-κB通路中的关键调控点进行检测。系统进化树分析显示，分离株YUNAN001的intb基因与AF2156.1.亲缘关系最近，而与CQ903045.1亲缘关系较远。KEGG富集发现TNF和NF-κB通路均参与了E. coli感染，且共同基因有10个；火山图及热图富集显示，E. coli感染显著促进了TNF/NF-κB通路中PTGS2、NF-κB、TRAF6等的表达（P<0.05）；分子对接显示，HPI-Ybt能与同属于TNF/NF-κB通路的10个蛋白相结合，其中与MAP3K14、TNFAIP3的结合最强；感染E. coli组的NF-κB、PTGS2、TNF-α、TRAF6、TRIF、ATF4、cxcl2和IL-6 mRNA水平显著高于E. coliΔHPI组（P<0.01），且相对于E. coliΔHPI组，E. coli组显著激活了TNF/NF-κB通路蛋白的表达；此外，与E. coliΔHPI组相比，E. coli感染显著升高了NF-κB和IL-6的水平（P<0.01）。结果提示，E. coli-HPI通过合成Ybt结合TNF/NF-κB通路中的关键蛋白，进而激活TNF/NF-κB通路。

关键词： 多重耐药肺炎克雷伯菌   铜绿假单胞菌   拮抗作用   绿脓素   细胞膜  

摘要： 目的 探究铜绿假单胞菌拮抗多重耐药肺炎克雷伯菌的作用及其机制，以期为临床治疗多重耐药肺炎克雷伯菌感染提供实验依据。方法 收集本院临床分离的4株铜绿假单胞菌(PA)和1株多重耐药肺炎克雷伯菌(MDR-KP8)，建立两种菌共培养模型和平板互作模型，观察两者间的互作关系；收集菌株上清液，盐酸-氯仿、硫酸-蒽酮法对绿脓素和鼠李糖脂进行初步提取和定量，探究PA与MDR-KP8共培养的变化；硅胶吸附法和高效液相色谱法对绿脓素进行纯化和定量，肉汤稀释法测定绿脓素对MDR-KP8的最小抑菌浓度(MIC)和最小杀菌浓度(MBC)，评价绿脓素的抗菌活性；碱性磷酸酶试剂盒、傅里叶红外光谱(FTIR)法探究绿脓素对MDR-KP8作用机理。结果 共培养4 d,4株PA菌落数均多于MDR-KP8菌落数；平板互作实验显示随着4株PA与MDR-KP8距离的增加，MDR-KP8菌落面积也在增加，而PA菌落面积未发生明显变化；定量结果显示4株PA共培养分泌的绿脓素和鼠李糖脂含量均多于单独培养时的含量。绿脓素对MDR-KP8最小抑菌浓度为128μg/mL；经绿脓素处理后，上清液中碱性磷酸酶、核酸、蛋白质等物质含量增加，蛋白质的二级结构发生变化。结论 PA与MDR-KP8间存在拮抗关系，PA分泌的绿脓素通过破坏细菌细胞壁，破坏蛋白质的二级结构，从而抑制MDR-KP8的生长繁殖。

关键词： clonality-restricted immunological profile   heparin-induced thrombocytopenia   HLA   PF4-derived peptides   vaccine-induced immune thrombotic thrombocytopenia  

摘要： Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare prothrombotic disorder with a unique clonality-restricted immunological profile. The study by Petito and Bury et al. provides insight into the role of HLA polymorphisms and an inherent predisposition to VITT. Commentary on: Petito et al. Association of human leucocyte antigen loci with vaccine-induced immune thrombotic thrombocytopenia: Potential role of the interaction between platelet factor 4-derived peptides and MHC-II. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19838.

关键词： Glycosylation   leishmania tarentolae   Interferon-beta  

摘要： The production of therapeutic glycoproteins is primarily expensive due to the necessity of culturing mammalian cells. These systems often require complex and costly culture media and typically yield low amounts of protein. Leishmania tarentolae, , a non-pathogenic protozoan to mammals, has emerged as a cost-effective alternative system for heterologous glycoprotein expression due to its suitability for large-scale production using low-cost culture media, and its ability to perform mammalian-like post-translational modifications, including glycosylation. Nevertheless, differences in the carbohydrate residues at the end of N-glycan chains are observed in Leishmania compared to mammalian cells due to the absence of biosynthetic enzymes in Leishmania that are required for the incorporation of terminal sialic acid. In this study, a genetically optimized L. tarentolae cell line was engineered for the production of recombinant interferon-beta (IFN-beta) featuring a complete mammalian Nglycosylation profile. Genomic and metabolomic analyses revealed that heterologous expression of the sialyltransferase enzyme and cultivation in a medium containing sialic acid were sufficient to generate mammalian- like protein N-glycosylation. N-glycan mass spectrometry analysis demonstrated a glycosylation pattern compatible with the incorporation of sialic acid into the glycan structure. In vitro IFN-beta activity indicated that the expressed protein exhibited reduced inflammatory effects compared to IFN-beta produced by other platforms, such as bacteria, non-optimized L. tarentolae, , and mammalian cells.

关键词： anti-TNF   HLADQA1*05   immunogenicity  

摘要： In a retrospective study of inflammatory bowel disease patients, the risk of the HLADQA1*05 genotype and association with anti-TNF treatment loss of response was evaluated. Findings show an association with increased need for dose escalation but not increased incidence of treatment cessation.

摘要： Malignant glioma is a highly fatal central nervous system malignancy with high recurrence rates. Oncolytic viruses offer potential treatment but need improvement in efficacy and safety. Here we describe a phase I, dose-escalating, single arm trial (ChiCTR2000032402) to study the safety of Ad-TD-nsIL12, an oncolytic adenovirus expressing non-secreting interleukin-12, in patients with recurrent high-grade glioma that connects with the ventricular system. Eight patients received intratumoral treatment via stereotaxis or an Ommaya reservoir, with doses ranging from 5 x 109 to 5 x 1010vp. The primary end point was to determine the maximal tolerated dose. Secondary endpoints included toxicity and anti-tumour ability. Minimal adverse events were observed at doses of 5 x 109 and 1 x 1010vp. Grade 3 seizure was observed in two patients from Cohort 3 (5 x 1010vp). Therefore, the maximum tolerated dose was determined to be 1 x 1010vp. Four patients developed hydrocephalus during follow-up. Among them, symptoms in two patients were relieved after placement of a ventriculo-peritoneal shunt, and the other two only showed ventriculomegaly on MRI scan without neurological deterioration. Complete response (according to Response Assessment in Neuro-Oncology Criteria) in one patient, a partial response in one patient and post-treatment infiltrations of CD4+ and CD8 + T cells into the tumour were documented during this trial. In conclusion, Ad-TD-nsIL12 has demonstrated safety and preliminary efficacy in patients with recurrent high-grade glioma. Oncolytic viruses have been tested in patients with malignant glioma, however clinical efficacy remains limited. Here the authors report the results of a phase I trial of Ad-TD-nsIL12, an oncolytic adenovirus expressing a mutant (non-secreting) form of IL12, in patients with high-grade glioma.