Intraocular tumour necrosis factor ligand related molecule 1 A links disease progression of proliferative diabetic retinopathy after primary vitrectomy

Tumour necrosis factor ligand related molecule 1 A (TL1A), a member of tumour necrosis factor superfamily, has been identified as a crucial regulator for vascular homeostasis and inflammation. However, the function of TL1A in diabetic retinopathy (DR) is largely unknown. This study aims to examine levels of TL1A in serum and intraocular fluid in patients with proliferative diabetic retinopathy (PDR), and to explore the correlation of intraocular TL1A with the prognosis of PDR progression after primary vitrectomy. Seventy-five patients (75 eyes) with PDR who underwent pars plana vitrectomy (PPV) and 19 patients (19 eyes) who received vitrectomy for idiopathic macular holes (IMH) as non-diabetic control group were enrolled in this prospective study. Serum, aqueous and vitreous fluid samples were collected during cataract and PPV surgery. Protein expressions of TL1A as well as other angiogenic and inflammatory cytokines in serum and intraocular fluid were measured. Correlations of intraocular TL1A concentrations with inflammatory cytokines were analyzed. We found both aqueous and vitreous TL1A levels were significantly higher in the PDR group than in control group (P_aqueous = 0.026; P_vitreous <0.001). Angiogenic and inflammatory cytokines such as VEGF, IL-6, IL-8, MCP-1, MIP-1α, and MIP-1β were significantly higher in intraocular fluid in PDR group than in controls, which MCP-1 and MIP-1α showed positive correlation with intraocular TL1A levels. There is no significant difference in the levels of serum TL1A as well as other inflammatory cytokines between PDR patients and controls. Intraocular levels of TL1A were significantly lower in PDR progression group than in the stable group (P_aqueous <0.001; P_vitreous <0.001). Multivariate logistic regression analyses revealed that lower levels of intraocular TL1A was an important risk factor for predicting PDR progression after primary PPV (OR_aqueous = 0.717, P_aqueous = 0.001; OR_vitreous = 0.684; P_vitreous = 0.002). In conclusion, TL1A and multiple inflammatory cytokines were highly enriched in the intraocular fluid of PDR patients compared with the controls. Lower levels of intraocular TL1A were associated with development of PDR complications after primary PPV and might be used as prognostic factor in predicting the vitrectomy outcome in PDR patients.     

系统性肥大细胞增生症致继发性骨髓纤维化PET/CT显像一例

笔者报道了一例系统性肥大细胞增生症伴继发性骨髓纤维化的18F-FDG PET/CT显像病例。从临床症状、实验室检查、影像学检查以及骨髓穿刺等结果综合分析了该病的特点。并通过文献复习加深了对骨髓纤维化及肥大细胞增生症的认识。继发性骨髓纤维化的病因多种多样,肥大细胞增生症就是其病因之一。肥大细胞增生症是一种以肥大细胞多组织器官异常增生为特征的血液系统疾病,肥大细胞分泌的组胺会导致骨质密度弥漫性增高,肝脾淋巴结肿大一方面是因为肥大细胞的浸润,另一方面则是因为髓外造血所致。另外,此类患者出现的诸多临床症状也与肥大细胞分泌的化学介质密切相关。     

不同类型CT和MR血管成像诊断颅内动脉瘤准确率的Meta分析

目的 分析评价不同类型CT血管成像（CTA）和MR血管成像（MRA）诊断颅内动脉瘤（IAN）的准确率。 方法 检索PubMed、EMbase、Cochralle图书馆和中国知网、中国生物医学文献数据库、维普网、万方数据库,收集2018年1月以前有关不同类型CTA和MRA诊断IAN的中、英文文献,按照诊断性研究的纳入标准筛选文献,并依据诊断准确性试验质量评价工具2标准进行质量评价。采用Stata 12.0及Meta-Disc 1.4软件对纳入的文献进行Meta分析,分别比较CTA、MRA及亚组之间的合并灵敏度（SEN_合并）、合并特异度（SPE_合并）、诊断比值比（DOR）、合并阳性似然比（PLR_合并）、合并阴性似然比（NLR_合并）、验前概率和验后概率等性能指标,绘制森林图和综合受试者工作特征（SROC）曲线并计算曲线下面积（AUC）。采用Stata 12.0统计分析软件绘制Deek's漏斗图评估纳入文献的发表偏倚。通过Q检验和I2进行异质性分析。 结果 检索获得1754篇文献,最终纳入38篇临床诊断研究,包括5212例患者。Meta分析结果显示:①CTA诊断IAN的SEN_合并、SPE_合并、DOR、PLR_合并、NLR_合并、AUC、验前概率和验后概率分别为0.947（95%CI:0.926,0.963）、0.916（95%CI:0.864,0.949）、195.328（95%CI:97.367,391.847）、11.218（95%CI:6.861,18.341）、0.057（95%CI:0.040,0.082）、0.98（95%CI:0.96,0.99）、20%和74%;②MRA诊断IAN的SEN_合并、SPE_合并、DOR、PLR_合并、NLR_合并、AUC、验前概率和验后概率分别为0.935（95%CI:0.899,0.958）、0.956（95%CI:0.917,0.977）、311.421（95%CI:126.935,764.038）、21.285（95%CI:11.114,40.766）、0.068（95%CI:0.044,0.107）、0.98（95%CI:0.97,0.99）、20%和84%;③亚组分析结果显示:不同类型的CTA和MRA诊断IAN之间AUC的差异均无统计学意义。 结论 不同类型CTA与MRA均可以诊断IAN,诊断准确性均较高且基本一致,CTA和MRA均可作为诊断IAN的首选检查手段。     

MRI-based treatment planning for brain stereotactic radiosurgery: Dosimetric validation of a learning-based pseudo-CT generation method

Magnetic resonance imaging (MRI)-only radiotherapy treatment planning is attractive since MRI provides superior soft tissue contrast without ionizing radiation compared with computed tomography (CT). However, it requires the generation of pseudo CT from MRI images for patient setup and dose calculation. Our machine-learning-based method to generate pseudo CT images has been shown to provide pseudo CT images with excellent image quality, while its dose calculation accuracy remains an open question. In this study, we aim to investigate the accuracy of dose calculation in brain frameless stereotactic radiosurgery (SRS) using pseudo CT images which are generated from MRI images using the machine learning-based method developed by our group. We retrospectively investigated a total of 19 treatment plans from 14 patients, each of whom has CT simulation and MRI images acquired during pretreatment. The dose distributions of the same treatment plans were calculated on original CT simulation images as ground truth, as well as on pseudo CT images generated from MRI images. Clinically-relevant DVH metrics and gamma analysis were extracted from both ground truth and pseudo CT results for comparison and evaluation. The side-by-side comparisons on image quality and dose distributions demonstrated very good agreement of image contrast and calculated dose between pseudo CT and original CT. The average differences in Dose-volume histogram (DVH) metrics for Planning target volume (PTVs) were less than 0.6%, and no differences in those for organs at risk at a significance level of 0.05. The average pass rate of gamma analysis was 99%. These quantitative results strongly indicate that the pseudo CT images created from MRI images using our proposed machine learning method are accurate enough to replace current CT simulation images for dose calculation in brain SRS treatment. This study also demonstrates the great potential for MRI to completely replace CT scans in the process of simulation and treatment planning.     

过表达脑源性神经营养因子的神经干细胞移植对受照海马内神经营养因子的影响

目的 探讨过表达脑源性神经营养因子（BDNF）的神经干细胞（NSCs）移植入放射性脑损伤大鼠模型后,对海马内神经营养因子水平及小胶质细胞活化的影响。方法 从胎鼠脑中分离海马神经干细胞并进行培养。选用绿色荧光蛋白（GFP）-慢病毒、GFP-BDNF-慢病毒感染神经干细胞。将SD大鼠按随机数表法分为4组：健康对照组、单纯照射组（R组）、照射后GFP修饰的神经干细胞移植组（R+NSCs组）、照射后GFP-BDNF修饰的神经干细胞移植组（R+BDNF-NSCs组）。全脑单次20 Gy照射后1个月将神经干细胞移植入大鼠双侧海马内。移植后2和8周检测海马组织中BDNF、胶质源性神经营养因子（GDNF）、神经生长因子（NGF）的表达情况;免疫荧光染色观察小胶质细胞活化情况。结果 移植后2和8周时,与R组相比,R+BDNF-NSCs组海马组织中BDNF、NGF蛋白表达均水平明显增高（P<0.05）;移植后8周R+NSCs组和R+BDNF-NSCs组活化的小胶质细胞与R组相比并未显著减少（P>0.05）。结论 过表达BDNF的神经干细胞移植后促进BDNF、NGF的产生,增加了辐射暴露后的海马内神经营养因子水平。     

miR-124靶向STAT3改善脑恶性胶质瘤细胞辐射敏感性

目的 研究miR-124在放射敏感及耐受的脑恶性胶质瘤细胞LN229和LN229R中的表达以及miR-124对细胞放射敏感性的影响,并深入探讨miR-124调控LN229R细胞放射敏感性的作用机制。方法 将miR-124模拟物（miR-124）及阴性对照（miR-NC）,STAT3过表达质粒（STAT3）及pcDNA3.1质粒（pcDNA）单独或共转染到放射抵抗的胶质瘤细胞LN229R中。qRT-PCR检测LN229和LN229R细胞中miR-124的表达;克隆形成实验分析不同放射剂量下LN229R细胞的生存率以及敏感性相关参数值;流式细胞术分析LN229R细胞的凋亡情况;生物信息学预测miR-124和STAT3的靶向关系,并利用双荧光素酶报告分析加以验证;Western blot分析STAT3的蛋白表达水平。结果 与LN229组（1.02±0.09）相比,miR-124在LN229R细胞中的表达水平（0.32±0.03）显著降低,差异有统计学意义（t=12.780,P<0.05）;与miR-NC组（0.95±0.06）相比,转染miR-124模拟物可促进LN229R细胞中miR-124的表达（4.02±0.39）（t=13.476,P<0.05）;8 Gy照射条件下,miR-124过表达组癌细胞的生存率（0.003±0.000 4）显著低于miR-NC组（0.033±0.005 0）（t=5.655,P<0.05）,细胞凋亡率（22.34±2.42）%显著高于miR-NC组（4.69±0.51）%（t=12.361,P<0.05）;STAT3是miR-124的靶基因;外源回补STAT3可逆转miR-124对LN229R细胞生存的抑制作用。结论 miR-124通过靶向STAT3改善LN229R细胞的放射敏感性。     

匹伐他汀钙有关物质的合成

目的：为控制匹伐他汀钙的质量,合成原药中3种有关物质。方法：以（8）为原料经不对称羟醛缩合、反立体选择性还原得到了有关物质（3）和有关物质（4）。匹伐他汀钙经DDQ氧化得到了有关物质（7）。结果与结论：合成了匹伐他汀钙原药中3种有关物质,并经1H-NMR和MS等确证结构,纯度经HPLC 检测均在96%以上,可以作为匹伐他汀钙原药质量控制的对照品。     

Synthesis,molecular docking and biological evaluation of 1‐phenylsulphonyl‐2‐(1‐methylindol‐3‐yl)‐benzimidazole derivatives as novel potential tubulin assembling inhibitors

A series of new 1‐phenylsulphonyl‐2‐(1‐methylindol‐3‐yl)‐benzimidazole derivatives were designed, synthesized and evaluated as potential inhibitors of tubulin polymerization and anthropic cancer cell lines. Among them, compound 33 displayed the most potent tubulin polymerization inhibitory activity in vitro (IC₅₀ = 1.41 μM) and strong antiproliferative activities against A549, Hela, HepG2 and MCF‐7 cell lines in vitro with GI₅₀ value of 1.6, 2.7, 2.9 and 4.3 μM, respectively, comparable with the positive control colchicine (GI₅₀ value of 4.1, 7.2, 9.5 and 14.5 μM, respectively) and CA‐4 (GI₅₀ value of 2.2, 4.3, 6.4 and 11.4 μM, respectively). Simultaneously, we evaluated that compound 33 could effectively induce apoptosis of A549 associated with G2/M phase cell cycle arrest. Immunofluorescence microscopy also clearly indicated compound 33 a potent antimicrotubule agent. Docking simulation showed that compound 33 could bind tightly with the colchicine‐binding site and act as a tubulin inhibitor. Three‐dimensional‐QSAR model was also built to provide more pharmacophore understanding that could be used to design new agents with more potent tubulin assembling inhibitory activity in the future.     

北京市2019年腹泻病例中札如病毒基因特征分析

目的 了解北京市肠道门诊散发腹泻病例中札如病毒的基因型别及特征。方法 收集2019年北京市肠道门诊散发腹泻病例的粪便样本,应用实时荧光RT-PCR对样本进行札如病毒核酸检测,对阳性样本应用不同种RT-PCR方法进行札如病毒衣壳蛋白VP1区和聚合酶RdRp区部分基因片段扩增,对扩增阳性产物进行测序,应用BioEdit 7.0.9.0软件对序列进行比对,应用Mega 6.06软件构建进化树进行分析。结果 札如病毒总检出率为2.89%（44/1 522）,<5岁病例的检出率为3.34%（18/539）,≥5岁病例的检出率为2.64%（26/983）。衣壳蛋白VP1区基因测序成功23株,包括8个基因型（GⅠ.2型6株、GⅠ.1型和GⅡ.3型各5株,GⅠ.3型和GⅡ.5型各2株,GⅠ.5型、GⅡ.1型和GⅣ.1型各1株）;≥5岁病例占16株,GⅠ.2型构成比最高（37.50%,6/16）,<5岁病例占7株,GⅠ.1型和GⅡ.3型构成比最高（均为42.86%,3/7）;每个基因型内部相似性为95.5%~100.0%,与不同年份、不同国家的人源或污水源的51株参考株相似性为92.2%~100.0%。聚合酶RdRp区测序成功25株8个基因型（9株GⅡ.P3型,4株GⅠ.P3型,GⅠ.P1型、GⅠ.P2型和GⅡ.P1型各为3株,GⅠ.P5型、GⅡ.P5型和GⅣ.P1型各为1株）;≥5岁病例占15株,GⅡ.P3型构成比最高（40.00%,6/15）,<5岁病例占10株,GⅠ.P1型、GⅡ.P1型和GⅡ.P3型构成比最高（均为30.00%,3/10）;每个基因型内部相似性为94.0%~100.0%,与不同年份、不同国家的人源或污水源的39株参考株相似性为90.2%~99.1%。结论 札如病毒是北京市散发腹泻病例的病原之一,主要基因组为GⅠ和GⅡ,基因型多样且分散;≥5岁和<5岁人群腹泻病例主要基因型不同。