Caution! Overestimation of treatment effects of corticosteroid therapy for community-acquired pneumonia in a meta-analysis of randomized controlled trials

It is well known that a meta-analysis of randomized controlled trials aims to increase the power and precision of the estimated intervention effects. However, when a meta-analysis includes a limited number of patients and a small number of events, overestimation of intervention effect estimates may occur and could cause spurious results. Although many biases can cause the overestimation, random error may be the most common cause. Trial sequential analysis (TSA) can explore the independent effect of random error on intervention effect estimates in meta-analyses and protect meta-analyses against overestimation due to random error.     

血清LSA测定在恶性肿瘤临床诊断中的初步应用

本文根据Svennerholm和蒋谷人等的方法略加改良,测定了蚌埠地区113例正常人,71例恶性肿瘤患者和82例非肿瘤疾病患者血清脂质结合唾液酸(LSA)的含量。正常值为12.4mg/dl(SD=±3.6mg/dl),71例不同肿瘤患者的平均值为28.2mg/dl(SD=±9.7mg/dl),阳性率为88.7％,82例非肿瘤疾病患者的平均值为16.82mg/dl(SD=±5.4mg/dl),假阳性率为17％。方法的灵敏度,重复性(平均CV=3.6％)和回收率(平均回收率=101.4％)测定结果是满意的。本研究的初步结果表明,血清LSA测定对肺癌、白血病、胃癌和食管癌具有一定的临床诊断价值。     

胸腹水中唾液酸含量在鉴别良恶性疾病上的价值

本文测定恶性、炎性和肝硬化3组胸腹水中的总唾液酸(TotalSialic Acid TSA)和脂质结合唾液酸(Lipid-bound Sialic Acid LSA)含量,结果表明恶性组和炎性组的 TSA 和 LSA 明显高于肝硬化组,但恶性组和炎性组的 TSA 和 LSA 则无明显差异。恶性、炎性和肝硬化组的 TSA 值分别为499.52±183.98mg/L、508.68±208.79mg/L 和117.71±70.46mg/L;LSA则分别为146.28±103.62mg/L、115.26±72.13mg/L 和58.90±35.46mg/L。以肝硬化组的 TSA+2SD 作为恶性组和肝硬化组的鉴别值,其敏感性为88%,特异性为90.47%,有效性为89.13%。LSA 则无鉴别价值。     

唾液酸作为肺癌标志物的ROC分析

用受试者试验特征性曲线（ROC）建立了血清TSA与LSA对肺癌与非癌患者的最佳诊断分界值（Cut－off），TSA为76mg／dl，LSA为23mg／dl，肺癌组TSA与LSA的含量均明显高林非癌组，同时比较了TSA与LSA的诊断灵敏度，特异性，符合率，ROCAUC和信息量。血清唾液酸作为肺癌标志物时，TSA与LSA的ROCAUC无显著性差异（P＞O．05），二者间信息量的u值为0．91，P＞0．05。提示只要选一个最佳cut－off值，单测血清TSA就有可能达到筛选肺癌的目的。     

Histone deacetylase inhibitors inhibit cervical cancer growth through Parkin acetylation-mediated mitophagy

Parkin, an E3 ubiquitin ligase, plays a role in maintaining mitochondrial homeostasis through targeting damaged mitochondria for mitophagy. Accumulating evidence suggests that the acetylation modification of the key mitophagy machinery influences mitophagy level, but the underlying mechanism is poorly understood. Here, our study demonstrated that inhibition of histone deacetylase (HDAC) by treatment of HDACis activates mitophagy through mediating Parkin acetylation, leading to inhibition of cervical cancer cell proliferation. Bioinformatics analysis shows that Parkin expression is inversely correlated with HDAC2 expression in human cervical cancer, indicating the low acetylation level of Parkin. Using mass spectrometry, Parkin is identified to interact with two upstream molecules, acetylase acetyl-CoA acetyltransferase 1 (ACAT1) and deacetylase HDAC2. Under treatment of suberoylanilide hydroxamic acid (SAHA), Parkin is acetylated at lysine residues 129, 220 and 349, located in different domains of Parkin protein. In in vitro experiments, combined mutation of Parkin largely attenuate the interaction of Parkin with PTEN induced putative kinase 1 (PINK1) and the function of Parkin in mitophagy induction and tumor suppression. In tumor xenografts, the expression of mutant Parkin impairs the tumor suppressive effect of Parkin and decreases the anticancer activity of SAHA. Our results reveal an acetylation-dependent regulatory mechanism governing Parkin in mitophagy and cervical carcinogenesis, which offers a new mitophagy modulation strategy for cancer therapy.     

组蛋白修饰变化参与曲古抑菌素A缓解的烟草烟雾暴露所致小鼠子宫损伤过程

目的研究组蛋白修饰变化在曲古抑菌素A(trichostatin A,TSA)缓解烟草烟雾(cigarette smoke,CS)暴露所致的雌性小鼠子宫损伤过程中的作用。方法通过CS暴露30 d方法制备CS暴露小鼠子宫损伤模型,CS暴露的同时给予TSA进行治疗;HE染色观察各组小鼠子宫组织形态学变化;Western blot技术检测各组小鼠子宫组织H3K4me1、H3K4me2、H3K4me3、H3K9me1、H3K9me2、H3K9me3和H3K27me3总的修饰水平变化以及GLP(euchromatic histone lysine methyltransferase 1,H3K9甲基转移酶),G9ɑ(euchromatic histone lysine methyltransferase 2,H3K9甲基转移酶),EZH2(enhancer of zeste homolog 2,H3K27me3甲基转移酶)的表达水平。结果TSA缓解CS暴露所致的雌性小鼠子宫间质细胞和腺体数量减少等结构改变。TSA有效抑制了CS暴露激活的小鼠子宫组织H3K9me1的表达,但却进一步激活CS暴露诱导的总H3K27me3修饰水平。TSA可以抑制CS暴露激活的小鼠子宫组织GLP和G9ɑ的表达,进一步激活CS暴露诱导的EZH2表达水平。结论组蛋白修饰变化参与CS暴露所致的小鼠子宫损伤以及TSA的缓解损伤过程。     

5-氮脱氧胞苷及曲古抑菌素A影响供核细胞H19基因表达的时间依赖性及浓度依赖性

目的:探讨甲基转移酶抑制剂——5-氮脱氧胞苷(5-aza-2′-deoxycytidine,5-aza-dC)和组蛋白去乙酰基酶抑制剂——曲古抑菌素A(trichostatin A,TSA)影响供核细胞H19基因表达的时间依赖性和浓度依赖性。方法:用不同浓度5-aza-dC及TSA按不同作用时间处理供核细胞(鼠尾尖成纤维样细胞),利用实时定量PCR法检测处理后H19基因的表达。结果:不同浓度的5-aza-dC处理组之间H19的表达无明显差异,但延长作用时间可使H19表达增强;TSA使H19的表达下降,但无时间依赖性。结论:长时间低浓度的5-aza-dC能增强供核细胞中H19基因的表达,而TSA则使H19的表达减弱,为体细胞克隆中表观遗传修饰抑制剂的选择及后续基因印迹研究提供了依据。     

Natural indoles,indole-3-carbinol and 3,3′-diindolymethane,inhibit T cell activation by staphylococcal enterotoxin B through epigenetic regulation involving HDAC expression

Staphylococcal enterotoxin B (SEB) is a potent exotoxin produced by the Staphylococcus aureus. This toxin is classified as a superantigen because of its ability to directly bind with MHC-II class molecules followed by activation of a large proportion of T cells bearing specific Vβ-T cell receptors. Commonly associated with classic food poisoning, SEB has also been shown to induce toxic shock syndrome, and is also considered to be a potential biological warfare agent because it is easily aerosolized. In the present study, we assessed the ability of indole-3-carbinol (I3C) and one of its byproducts, 3,3′-diindolylmethane (DIM), found in cruciferous vegetables, to counteract the effects of SEB-induced activation of T cells in mice. Both I3C and DIM were found to decrease the activation, proliferation, and cytokine production by SEB-activated Vβ8 ⁺ T cells in vitro and in vivo. Interestingly, inhibitors of histone deacetylase class I (HDAC-I), but not class II (HDAC-II), showed significant decrease in SEB-induced T cell activation and cytokine production, thereby suggesting that epigenetic modulation plays a critical role in the regulation of SEB-induced inflammation. In addition, I3C and DIM caused a decrease in HDAC-I but not HDAC-II in SEB-activated T cells, thereby suggesting that I3C and DIM may inhibit SEB-mediated T cell activation by acting as HDAC-I inhibitors. These studies not only suggest for the first time that plant-derived indoles are potent suppressors of SEB-induced T cell activation and cytokine storm but also that they may mediate these effects by acting as HDAC inhibitors.     

Molecular Epidemiology and Genetic Diversity of Orientia tsutsugamushi from Patients with Scrub Typhus in 3 Regions of India

Scrub typhus, an acute febrile illness that is widespread in the Asia-Pacific region, is caused by the bacterium Orientia tsutsugamushi, which displays high levels of antigenic variation. We conducted an investigation to identify the circulating genotypes of O. tsutsugamushi in 3 scrub typhus–endemic geographic regions of India: South India, Northern India, and Northeast India. Eschar samples collected during September 2010–August 2012 from patients with scrub typhus were subjected to 56-kDa type-specific PCR and sequencing to identify their genotypes. Kato-like strains predominated (61.5%), especially in the South and Northeast, followed by Karp-like strains (27.7%) and Gilliam and Ikeda strains (2.3% each). Neimeng-65 genotype strains were also observed in the Northeast. Clarifying the genotypic diversity of O. tsutsugamushi in India enhances knowledge of the regional diversity among circulating strains and provides potential resources for future region-specific diagnostic studies and vaccine development.