HMGB‐1, TLR4, IL‐1R1, TNF‐α, and IL‐1β: novel epilepsy markers?

Aim: The purpose of this study was to compare HMGB‐1, TLR4, IL‐1β, IL‐1R1, and TNF‐α levels in patients with mild and severe epilepsy with those in a healthy control group. Methods: Children aged 4–17 years, diagnosed with epilepsy for at least three years and with no progressive neurological disease, metabolic disease or infection, were selected for the study. The severe epilepsy group consisted of 28 children with at least one episode a week despite receiving three or more antiepileptic drugs. The mild epilepsy group consisted of 29 children with no seizures in the previous year, receiving only one antiepileptic drug, while 27 healthy children were selected as the control group. HMGB‐1, TLR4, IL‐1R1, TNF‐α and IL‐1β levels were investigated in these three groups. The MRI findings and clinical characteristics of the patients in the epilepsy group were also compared with these markers. Results: HMGB‐1, TLR4, TNF‐α, and IL‐1β levels in the severe epilepsy group were higher than in the control group and the mild epilepsy group (p<0.05), and were higher in the mild epilepsy group than in the control group (p<0.05). IL‐1R1 was also higher in the severe epilepsy group than in the control group (p<0.05). Conclusion: In this first report to identity a possible correlation between HMGB‐1, TLR4, IL‐1β, IL‐1R1, and TNF‐α levels and severity of epilepsy, our data demonstrates that the serum level of these cytokines is higher in cases of drug‐refractory epilepsy.     

冠状病毒复制分子生物学与防控措施研发进展

目的以新冠肺炎致病菌2019-nCoV,中东呼吸综合征相关冠状病毒MERS-CoV和严重急性呼吸综合征相关冠状病毒SARS-CoV为代表的冠状病毒成为最近重大公共卫生关注焦点。研发更好的防控措施需要更好地认识冠状病毒,尤其是其基因组和复制分子生物学。方法文献综述和基因组序列分析。结果全球14673篇相关文章,美国NCBI有40个冠状病毒全基因组序列,GEO(Gene expression omnibus)有33个冠状病毒相关转录组数据。结论冠状病毒基因组具有独特的性质,复制特点,不少病毒蛋白具有多功能,包括与宿主相互作用,影响宿主蛋白质翻译后修饰如泛素化和去泛素化,调控宿主免疫病理。这些为疫苗、诊断和药物等新防控措施研发提供了基础。     

Relationship between MLH1, PMS2, MSH2 and MSH6 gene-specific alterations and tumor mutational burden in 1057 microsatellite instability-high solid tumors

Microsatellite instability-high (MSI-H) and tumor mutational burden (TMB) are predictive biomarkers for immune-checkpoint inhibitors (ICIs). Still, the relationship between the underlying cause(s) of MSI and TMB in tumors remains poorly defined. We investigated associations of TMB to mismatch repair (MMR) protein expression patterns by immunohistochemistry (IHC) and MMR mutations in a diverse sample of tumors. Hypothesized differences were identified by the protein/gene affected/mutated and the tumor histology/primary site. Overall, 1057 MSI-H tumors were identified from the 32 932 tested. MSI was examined by NGS using 7000+ target microsatellite loci. TMB was calculated using only nonsynonymous missense mutations sequenced with a 592-gene panel; a subset of MSI-H tumors also had MMR IHC performed. Analyses examined TMB by MMR protein heterodimer impacted (loss of MLH1/PMS2 vs. MSH2/MSH6 expression) and gene-specific mutations. The sample was 54.6% female; mean age was 63.5 years. Among IHC tested tumors, loss of co-expression of MLH1/PMS2 was more common (n = 544/705, 77.2%) than loss of MSH2/MSH6 (n = 81/705, 11.5%; P < .0001), and was associated with lower mean TMB (MLH1/PMS2: 25.03 mut/Mb vs MSH2/MSH6 46.83 mut/Mb; P < .0001). TMB also varied by tumor histology: colorectal cancers demonstrating MLH1/PMS2 loss had higher TMBs (33.14 mut/Mb) than endometrial cancers (20.60 mut/Mb) and other tumors (25.59 mut/Mb; P < .0001). MMR gene mutations were detected in 42.0% of tumors; among these, MSH6 mutations were most common (25.7%). MSH6 mutation patterns showed variability by tumor histology and TMB. TMB varies by underlying cause(s) of MSI and tumor histology; this heterogeneity may contribute to differences in response to ICI.     

B7-H4及Fas、FasL与宫颈癌免疫逃逸机制的关系

目的:检测免疫共刺激分子B7-H4及Fas、FasL在不同宫颈组织中的表达，研究三者的异常表达与宫颈癌免疫逃逸机制的关系。方法:选择陕西省肿瘤医院病理科2014-2018年的石蜡包埋标本162例，采用免疫组织化学方法检测20例正常宫颈、30例宫颈上皮内瘤变(CIN)和112例I期-IV期宫颈癌组织中B7-H4及Fas、FasL的表达水平。结果:B7-H4在正常宫颈组、CIN组、宫颈癌组的阳性表达率分别为0、20.0%、47.32%，两两相比，具有显著性差异（P<0.05）。在112例宫颈癌病例中FIGO临床分期I期至IV期各期别宫颈癌组织B7-H4的阳表达率分别为16.67%、43.18%、70.83%、85.71%，各组间相比差异具有统计学意义。正常对照组Fas的阳性表达率是85.00％，CIN组43.33％，宫颈癌组41.96％，正常组与CIN、正常组与宫颈癌组相比差异均具有统计学意义（P<0.05），CIN组与宫颈癌组相比，无明显差异（P>0.05）。FasL的阳性表达率在正常组为20.00%，CIN组为50.00%，宫颈癌组为56.25%，正常组与CIN、宫颈癌组比较，差异具有统计学意义(P<0.05)，CIN组与宫颈癌组比较无显著差异;B7-H4阳性宫颈癌组Fas阳性表达率28.30%明显较B7-H4阴性宫颈癌组Fas阳性表达率54.24%低，差异具有统计学意义（P<0.05）；而B7-H4阳性宫颈癌组FasL阳性表达率79.25%明显高于B7-H4阴性宫颈癌组FasL阳性表达率35.59%，差异具有统计学意义（P<0.05）。结论:负性免疫共刺激分子B7-H4和Fas、FasL凋亡蛋白在宫颈癌的发生、进展中起到了重要作用，其协同作用可能为宫颈癌细胞逃逸机体免疫的机制之一。     

The role of immunosuppressive agents in the management of severe and refractory immune‐related adverse events

The advent of immune checkpoint inhibitors has improved survival in some types of cancer and brought promising prospects to cancer immunotherapy. Despite their clinical benefits, significant off‐target toxicities resulting from the immune system activation have been observed, namely immune‐related adverse events (irAEs), which pose to clinicians a new challenge of optimal management. With steroids being the mainstay of current management of irAEs, immunosuppressive agents are especially indicated for severe or steroid‐refractory cases, based on current immunopathophysiological knowledge and on extrapolations of treatment options for primary autoimmune disorders. This review focuses on the status and recent clinical progress of immunosuppressive agents in the management of severe and steroid‐refractory irAEs.     

近30年中国文献报道恶性淋巴瘤合并自身免疫性血细胞减少症的系统性分析

本文通过收集1989年1月至2019年12月国内学者发表在国内外期刊上的文献及参考文献,共纳入符合标准的140例恶性淋巴瘤(malignant lymphoma,ML)合并自身免疫性血细胞减少(autoimmune cytopenia,AIC)病例,包括溶血性贫血(autoimmune hemolytic anemia,AIHA)、免疫性血小板减少症(immune thrombocytopenia,ITP)、纯红细胞再生障碍性贫血(pure red cell aplasia,PRCA)及Evans综合征等。虽然各亚型淋巴瘤病例数均较少(n=1~28),但通过系统性分析仍得到部分有意义的发现。除免疫性中性粒细胞减少(autoimmune neutropenia,AIN)外,各类AIC均有报道,发生率依次为AIHA>ITP>冷凝集素综合征(cold agglutinin syndrome,CAS)>PRCA>Evans综合征。AIC见于各亚型淋巴瘤,但各类AIC在不同亚型发生率存在差异。CAS仅见于淋巴瘤B细胞非霍奇金淋巴瘤(B cell nonHodgkin′slymphoma,B-NHL)、AIHA、ITP,Evans综合征多见于B-NHL,PRCA则多见于T细胞非霍奇金淋巴瘤(T cell non Hodgkin′s lymphoma,T-NHL)。相较于糖皮质激素等常规治疗,合并ML的AIC抗肿瘤治疗对有效率更高。恶性淋巴瘤合并AIC临床情况复杂,需引起临床关注。