Advances in the Study of Antitumour Immunotherapy for Newcastle Disease Virus

This article reviews the preclinical research, clinical application and development of Newcastle disease virus (NDV) in the field of cancer therapy. Based on the distinctive antitumour properties of NDV and its positive interaction with the patient''s immune system, this biologic could be considered a major breakthrough in cancer treatment. On one hand, NDV infection creates an inflammatory environment in the tumour microenvironment, which can directly activate NK cells, monocytes, macrophages and dendritic cells and promote the recruitment of immune cells. On the other hand, NDV can induce the upregulation of immune checkpoint molecules, which may break immune tolerance and immune checkpoint blockade resistance. In fact, clinical data have shown that NDV combined with immune checkpoint blockade can effectively enhance the antitumour response, leading to the regression of local tumours and distant tumours when injected, and this effect is further enhanced by targeted manipulation and modification of the NDV genome. At present, recombinant NDV and recombinant NDV combined with immune checkpoint blockers have entered different stages of clinical trials. Based on these studies, further research on NDV is warranted.     

Regulation of Toll-like receptor-mediated inflammatory response by microRNA-152-3p-mediated demethylation of MyD88 in systemic lupus erythematosus

Objective

microRNAs (miRNAs) play critical roles in embryogenesis, cell differentiation and the pathogenesis of several human diseases, including systemic lupus erythematosus (SLE). Toll-like receptors (TLRs) are also known to exert crucial functions in the immune response activation occurring in the pathogenesis of autoimmune diseases like SLE. Herein, the current study aimed to explore the potential role of miR-152-3p in TLR-mediated inflammatory response in SLE.

Methods

We determined the miR-152-3p expression profiles in CD4⁺ T cells and peripheral blood mononuclear cells (PBMCs) harvested from patients with SLE and healthy controls, and analyzed the correlation between miR-152-3p expression and clinicopathological parameters. CD70 and CD40L expression patterns in CD4⁺ T cells were assessed by RT-qPCR and flow cytometry. ChIP was adopted to determine the enrichment of DNA methyltransferase 1 (DNMT1) in the promoter region of myeloid differentiation factor 88 (MyD88).

Results

The obtained findings revealed that miR-152-3p was highly-expressed in CD4⁺ T cells and PBMCs of patients with SLE, and this high expression was associated with facial erythema, joint pain, double-stranded DNA, and IgG antibody. DNMT1 could be enriched in the MyD88 promoter, and miR-152-3p inhibited the methylation of MyD88 by targeting DNMT1. We also found that silencing miR-152-3p inhibited MyD88 expression not only to repress the autoreactivity of CD4⁺ T cells and but also to restrain their cellular inflammation, which were also validated in vivo.

Conclusion

Our study suggests that miR-152-3p promotes TLR-mediated inflammatory response in CD4⁺ T cells by regulating the DNMT1/MyD88 signaling pathway, which highlights novel anti-inflammatory target for SLE treatment.

     

Identification of key genes and pathways in scleral extracellular matrix remodeling in glaucoma: Potential therapeutic agents discovered using bioinformatics analysis

Background: Glaucoma is a leading cause of irreversible blindness. Remodeling of the scleral extracellular matrix (ECM) plays an important role in the development of glaucoma. The aim of this study was to identify the key genes and pathways for the ECM remodeling of sclera in glaucoma by bioinformatics analysis and to explore potential therapeutic agents for glaucoma management.Methods: Genes associated with glaucoma, sclera and ECM remodeling were detected using the text mining tool pubmed2ensembl, and assigned Gene Ontology (GO) biological process terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways using the GeneCodis program. A protein-protein interaction (PPI) network was constructed by STRING and visualized in Cytoscape, module analysis was performed using the Molecular Complex Detection (MCODE) plugin, and GO and KEGG analyses of the gene modules were performed using the Database of Annotation, Visualization and Integrated Discovery (DAVID) platform. The genes that clustered in the significant module were selected as core genes, and functions and pathways of the core genes were visualized using ClueGO and CluePedia. Lastly, the drug-gene interaction database was used to explore drug-gene interactions of the core genes to find drug candidates for glaucoma.Results: We identified 125 genes common to “Glaucoma”, “Sclera”, and “ECM remodeling” by text mining. Gene functional enrichment analysis yielded 30 enriched GO terms and 20 associated KEGG pathways. A PPI network that included 60 nodes with 249 edges was constructed, and three gene modules were obtained using the MCODE. We selected 13 genes that clustered in module 1 as core candidate genes that were associated mainly with ECM degradation and cell proliferation and division. The HIF-1 signaling pathway, FOXO signaling pathway, PI3K-Akt signaling pathway and TGFB signaling pathway were found to be enriched. We found that 11 of the 13 selected genes could be targeted by 26 existing drugs.Conclusions: The results showed that VEGFA, TGFB1, TGFB2, TGFB3, IGF2, IGF1, EGF, FN1, KNG1, TIMP1, SERPINE1, THBS1, and VWF were potential key genes involved to scleral ECM remodeling. Furthermore, 26 drugs were identified as potential therapeutic agents for glaucoma treatment and management.     

3D打印个体化人工椎体在胸腰椎肿瘤整块切除后脊柱稳定性重建中的应用

目的探索3D打印个体化人工椎体在胸腰椎肿瘤整块切除后脊柱稳定性重建中的临床疗效。方法回顾性分析华中科技大学同济医学院附属同济医院2015年7月至2020年6月收治的接受一期后路全脊椎整块切除术的胸腰椎肿瘤患者28例,分为2组,每组14例。其中3D组使用3D打印个体化人工椎体重建,常规组使用钛笼重建。对比两组的住院时间、手术时间、术中出血量,记录术前、术后7 d及末次随访时视觉模拟评分(VAS),Frankel分级情况,测量节段高度及角度,评估临床疗效。结果两组患者住院时间、手术时间、术中出血量和VAS评分比较,差异无统计学意义。共8例患者Frankel评分获得一个等级的改善(28.6%)。3D组椎间高度丢失(1.9±2.2)mm,内植物沉降2例,沉降率14.3%;常规组椎间高度丢失(6.6±5.5)mm,内植物沉降8例,沉降率57.1%;两组比较差异有统计学意义(<0.05)。在节段角度丢失方面组间差异无统计学意义(=0.571)。3D组所有患者内固定良好,常规组1例患者发生断棒情况。结论 3D打印人工椎体可以更好地维持节段高度,降低椎间隙塌陷和内固定失败的风险。     

SPOP negatively regulates Toll-like receptor-induced inflammation by disrupting MyD88 self-association

Toll-like receptor (TLR) signaling pathways need to be tightly controlled to avoid excessive inflammation and unwanted damage to the host. Myeloid differentiation primary response gene 88 (MyD88) is a critical adaptor of TLR signaling. Here, we identified the speckle-type POZ protein (SPOP) as a MyD88-associated protein. SPOP was recruited to MyD88 following TLR4 activation. TLR4 activation also caused the translocation of SPOP from the nucleus to the cytoplasm. SPOP depletion promoted the aggregation of MyD88 and recruitment of the downstream signaling kinases IRAK4, IRAK1 and IRAK2. Consistently, overexpression of SPOP inhibited the TLR4-mediated activation of NF-κB and production of inflammatory cytokines, whereas SPOP depletion had the opposite effects. Furthermore, knockdown of SPOP increased MyD88 aggregation and inflammatory cytokine production upon TLR2, TLR7 and TLR9 activation. Our findings reveal a mechanism by which MyD88 is regulated and highlight a role for SPOP in limiting inflammatory responses.     

Future Interventional Radiologists and Where to Find Them–Insights from Five UK Interventional Radiology Symposia for Junior Doctors and Medical Students

CardioVascular and Interventional Radiology - The interventional radiology (IR) trainee recruitment in the UK is lagging behind the pace of service expansion and is potentially hindered by...     

颅内生殖细胞瘤适形调强放射治疗及剂量学研究

目的应用半野和适形调强全脑全脊髓放射治疗技术治疗颅内生殖细胞瘤,评价其疗效及毒性反应。方法 12例颅内生殖细胞瘤患者,其中男性10例,女性2例;年龄15～28岁,中位年龄21岁。给予CT模拟定位,采用半野和适形调强放射治疗技术治疗,全脑全脊髓的放射治疗剂量为25.2 Gy（14次）,肿瘤病灶的放射治疗总剂量为45 Gy（25次）,每天每次1.8 Gy,5次/周,治疗后及随后每3个月评价1次疗效,随访时间为1～60个月,中位随访时间36个月。结果放射治疗结束后评价,完全缓解11例,部分缓解1例,近期临床受益率为100%。除1例失访外,其余11例均生存。放射治疗剂量学研究：经适形调强优化后的技术剂量分布优于常规定位技术,定位时间明显缩短[（8.83±1.55）s vs（40.8±2.4）s]。结论半野技术结合适形调强放射治疗技术治疗颅内生殖细胞瘤,优化了放射治疗剂量学,操作方便,疗效好,并发症少。     

Magnetic core–shell Fe3O4@Cu2O and Fe3O4@Cu2O–Cu materials as catalysts for aerobic oxidation of benzylic alcohols assisted by TEMPO and N-methylimidazole

In this work, core–shell Fe₃O₄@Cu₂O and Fe₃O₄@Cu₂O–Cu nanomaterials for aerobic oxidation of benzylic alcohols are reported with 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) and N-methylimidazole (NMI) as the co-catalysts. To anchor Cu₂O nanoparticles around the magnetic particles under solvothermal conditions, the magnetic material Fe₃O₄ was modified by grafting a layer of l-lysine (l-Lys) to introduce –NH₂ groups at the surface of the magnetic particles. With amine groups as the anchor, Cu(NO₃)₂ was used to co-precipitate the desired Cu₂O by using ethylene glycol as the reducing agent. Prolonging the reaction time would lead to over-reduced forms of the magnetic materials in the presence of copper, Fe₃O₄@Cu₂O–Cu. The nanomaterials and its precursors were fully characterized by a variety of spectroscopic techniques. In combination with both TEMPO and NMI, these materials showed excellent catalytic activities in aerobic oxidation of benzylic alcohols under ambient conditions. For most of the benzylic alcohols, the conversion into aldehydes was nearly quantitative with aldehydes as the sole product. The materials were recyclable and robust. Up to 7 repeat runs, its activity dropped less than 10%. The over-reduced materials, Fe₃O₄@Cu₂O–Cu, exhibited slightly better performance in durability. The magnetic properties allowed easy separation after reaction by simply applying an external magnet.

Robust core–shell magnetic materials catalyse quantitatively the aerobic oxidation of a wide range of benzylic alcohols into corresponding aldehydes at room temperature showing excellent tolerance towards the substituents on the phenyl ring.