卵巢癌脂质组学诊断标志物的筛选及其效果研究

目的 卵巢癌是女性生殖器官常见的恶性肿瘤之一,90％的卵巢癌患者诊断时已进展到晚期(Ⅲ/Ⅳ期).尽管治疗方式的不断改进,但晚期卵巢癌患者5年总生存率为20％,而早期卵巢癌患者5年总生存率＞90％.本研究旨在识别卵巢癌脂质组学诊断生物标志物,提高卵巢癌早期诊断的准确性.方法 采用稀疏组lasso变量筛选方法和单因素分析相结合的方法,对2011-03-01-2013-07-31哈尔滨医科大学附属肿瘤医院的139例卵巢癌患者和76例对照患者的血浆脂质组学数据进行分析,筛选可用于诊断卵巢癌脂质组学的生物标志物,在差异代谢物中选择与CA125相关性小的物质作为最终诊断标志物,通过七折交叉验证方法来评价其预测效果及与CA125联合的诊断准确性.进一步采用cytoscape软件研究差异脂质物质间的相互作用.通过Wilcoxon秩和检验方法筛选出能够区分早晚期卵巢癌的生物标志物.结果 共筛选出20种可用于区分卵巢癌和对照的差异脂质生物标志物,其中Stearamide、Stearic acid、Arachidic acid和PI(42∶9)与CA125不相关(P＜0.05),这4个脂质与CA125联合AUC值为0.94,大于CA125单独的诊断性能.另外,其中8个差异脂质在早期与晚期上皮性卵巢癌患者中有差异,分别为PC(35∶4)、PC(38∶6)、PC(46∶4)、PC(P-35∶2)、PE(P-36∶6)、PG(34∶2)、Cer(d18∶1/16∶0)和3-Deoxyvitamin D3,均P值＜0.05.结论 卵巢癌血浆脂质组学筛选出的物质提高了CA125单独诊断的准确性,其中8个差异物质可以作为卵巢癌早期诊断潜在的生物标志物.     

Systemic effects of ionizing radiation at the proteome and metabolome levels in the blood of cancer patients treated with radiotherapy: the influence of inflammation and radiation toxicity

Purpose: Blood is the most common replacement tissue used to study systemic responses of organisms to different types of pathological conditions and environmental insults. Local irradiation during cancer radiotherapy induces whole body responses that can be observed at the blood proteome and metabolome levels. Hence, comparative blood proteomics and metabolomics are emerging approaches used in the discovery of radiation biomarkers. These techniques enable the simultaneous measurement of hundreds of molecules and the identification of sets of components that can discriminate different physiological states of the human body. Radiation-induced changes are affected by the dose and volume of irradiated tissues; hence, the molecular composition of blood is a hypothetical source of biomarkers for dose assessment and the prediction and monitoring of systemic responses to radiation. This review aims to provide a comprehensive overview on the available evidence regarding molecular responses to ionizing radiation detected at the level of the human blood proteome and metabolome. It focuses on patients exposed to radiation during cancer radiotherapy and emphasizes effects related to radiation-induced toxicity and inflammation.

Conclusions: Systemic responses to radiation detected at the blood proteome and metabolome levels are primarily related to the intensity of radiation-induced toxicity, including inflammatory responses. Thus, several inflammation-associated molecules can be used to monitor or even predict radiation-induced toxicity. However, these abundant molecular features have a rather limited applicability as universal biomarkers for dose assessment, reflecting the individual predisposition of the immune system and tissue-specific mechanisms involved in radiation-induced damage.     

Omega-3 polyunsaturated fatty acids: photoprotective macronutrients

Ultraviolet radiation (UVR) in sunlight has deleterious effects on skin, while behavioural changes have resulted in people gaining more sun exposure. The clinical impact includes a year-on-year increase in skin cancer incidence, and topical sunscreens alone provide an inadequate measure to combat overexposure to UVR. Novel methods of photoprotection are being targeted as additional measures, with growing interest in the potential for systemic photoprotection through naturally sourced nutrients. Omega-3 polyunsaturated fatty acids (n-3 PUFA) are promising candidates, showing potential to protect the skin from UVR injury through a range of mechanisms. In this review, we discuss the biological actions of n-3 PUFA in the context of skin protection from acute and chronic UVR overexposure and describe how emerging new technologies such as nutrigenomics and lipidomics assist our understanding of the contribution of such nutrients to skin health.     

非律平和制霉菌素对人羊膜上皮细胞鞘脂类代谢的影响

目的研究脂类干扰剂非律平和制霉菌素对人羊膜上皮细胞鞘脂类代谢的影响是否相同。方法应用基质辅助激光解吸附飞行时间质谱分析方法分析不同剂量非律平和制霉菌素对人FL细胞株鞘脂类代谢的影响。结果非律平和制霉菌素均可影响FL细胞鞘脂类代谢,但是非律平(0.2和10μmol.L-1)诱导了多种新的神经酰胺类分子的合成,推测主要影响神经酰胺类分子的代谢。而制霉菌素(0.054和0.108μmol.L-1)在诱导了新的神经酰胺分子合成的同时,还导致鞘磷脂含量的增高,0.108μmo.lL-1可诱导更多神经酰胺分子的合成,推测制霉菌素可能对鞘磷脂类分子和神经酰胺类分子的代谢都有影响。结论非律平和制霉菌素均干扰鞘脂类代谢,但二者的靶点可能不同。     

Translocation and effects of gold nanoparticles after inhalation exposure in rats

This study was carried out to test the hypothesis that nanogold particles can accumulate in the olfactory bulb, and translocate from the lung to other organs after inhalation exposure. Gold nanoparticles were aerosolized and introduced through an exposure chamber. The number concentration of airborne nano-sized particles was 2×10⁶ #NSPs/cm³ with >75% of particulates between 30 and 110 nm. Exposure for 5 days resulted in significant increase of Au in the lung and olfactory bulb as detected by ICP-MS, but after 15 days, significant accumulation of gold was detected in the lung, esophagus, tongue, kidney, aorta, spleen, septum, heart and blood. Microarray analysis showed downregulation of many genes related to muscle in the nanogold-exposed lung. Lipidomic analysis of the lung showed a specific decrease in phosphatidylserine 36:1 species. We conclude that nanogold is able to translocate from the lung to other organs with time, and causes significant effects in exposed tissues.     

Changes in lipidomic profile by anti-retroviral treatment regimen: An ACTG 5257 ancillary study

High cardiovascular disease risk in people living with HIV is partly attributed to antiretroviral therapy (ART). Lipid response to ART has been extensively studied, yet, little is known how small molecule lipids respond to Integrase inhibitor-based (INSTI-based) compared to Protease inhibitor-based (PI-based) ART regimens.Ancillary study to a phase 3, randomized, open-label trial [AIDS Clinical Trial Group A5257 Study] in treatment-naive HIV-infected patients randomized in a 1:1:1 ratio to receive ritonavir-boosted atazanavir (ATV/r), ritonavir-boosted darunavir (DRV/r) (both PI-based), or raltegravir with Tenofovir Disoproxil Fumarate-TDF plus emtricitabine (RAL, INSTI-based).We examined small molecule lipid response in a subcohort of 75 participants. Lipidomic assays of plasma samples collected pre- and post-ART treatment (48 weeks) were conducted using ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry. The effect of ART regimens was regressed on lipid species response adjusting for the baseline covariates (lipids, age, sex, race, CD4 level, BMI, and smoking). Results were validated in the Centers for AIDS Research Network of Integrated Clinical Systems study (N = 16).Out of 417 annotated lipids, glycerophospholipids (P = .007) and sphingolipids (P = .028) had a higher response to ATV/r and DRV/r compared to RAL. The lysophosphatidylcholine (LPCs(16:1),(17:1),(20:3)) and phosphophatidylcholine species (PCs(40:7),(38:4)) had an opposite response to RAL versus ATV/r in the discovery and validation cohort. The INSTI-based regimen had an opposite response of ceramide species ((d38:1), (d42:2)), PCs((35:2), (38:4)), phosphatidylethanolamines (PEs(38:4), (38:6)), and sphingomyelin(SMd38:1) species compared with the PI-based regimens. There were no differences observed between 2 PI-based regimens.We observed differences in response of small molecule lipid species by ART regimens in treatment-naive people living with HIV.     

孕晚期大鼠暴露于七氟醚对其子代神经发育潜在毒性的脂质组学和转录组学研究

 目的 基于脂质组学和转录组学,探讨孕晚期大鼠七氟醚暴露对子代神经发育的潜在毒性作用。方法 将28只孕18天大鼠随机均分为七氟醚组（S组）和对照组（C组）,S组给予2%七氟醚和98%氧气6 h,C组给予100%氧气6 h。采用偏最小二乘判别分析（partial least squares discriminant analysis,PLS-DA）、超高效液相色谱（UPLC/TOF-MS）及代谢组学数据的统计、功能和综合分析（MetaboAnalyst）方法分析两组新生大鼠血清中脂质组学变化;采用转录组学分析两组新生大鼠皮层组织RNA-seq变化;采用免疫组化分析两组新生大鼠海马和皮层组织中神经细胞凋亡变化。结果 在S组中,潜在内源性代谢产物甘油磷脂和鞘磷脂的差异有统计学意义,且甘油磷脂代谢是6种代谢途径中最重要的。qRT-PCR结果显示,与C组相比,S组Vcan基因与神经元发育、功能和修复相关的mRNAs表达显著增加（P<0.05）。HE和TUNEL染色显示S组神经细胞凋亡数目增加,但与C组相比差异无统计学意义。结论 甘油磷脂和鞘脂代谢紊乱可能与孕晚期大鼠七氟醚暴露导致的子代神经发育潜在毒性机制有关,七氟醚诱导子代RNA-seq的变化,因此保持甘油磷脂和鞘脂代谢动态平衡,维持Vcan基因正常水平,可能是预防吸入麻醉药诱导的神经潜在毒性的相关治疗方法。     

Integrated eicosanoid lipidomics and gene expression reveal decreased prostaglandin catabolism and increased 5-lipoxygenase expression in aggressive subtypes of endometrial cancer

Eicosanoids comprise a diverse group of bioactive lipids which orchestrate inflammation, immunity, and tissue homeostasis, and whose dysregulation has been implicated in carcinogenesis. Among the various eicosanoid metabolic pathways, studies of their role in endometrial cancer (EC) have very much been confined to the COX-2 pathway. This study aimed to determine changes in epithelial eicosanoid metabolic gene expression in endometrial carcinogenesis; to integrate these with eicosanoid profiles in matched clinical specimens; and, finally, to investigate the prognostic value of candidate eicosanoid metabolic enzymes. Eicosanoids and related mediators were profiled using liquid chromatography–tandem mass spectrometry in fresh frozen normal, hyperplastic, and cancerous (types I and II) endometrial specimens (n = 192). Sample-matched epithelia were isolated by laser capture microdissection and whole genome expression analysis was performed using microarrays. Integration of eicosanoid and gene expression data showed that the accepted paradigm of increased COX-2-mediated prostaglandin production does not apply in EC carcinogenesis. Instead, there was evidence for decreased PGE₂/PGF_2α inactivation via 15-hydroxyprostaglandin dehydrogenase (HPGD) in type II ECs. Increased expression of 5-lipoxygenase (ALOX5) mRNA was also identified in type II ECs, together with proportional increases in its product, 5-hydroxyeicosatetraenoic acid (5-HETE). Decreased HPGD and elevated ALOX5 mRNA expression were associated with adverse outcome, which was confirmed by immunohistochemical tissue microarray analysis of an independent series of EC specimens (n = 419). While neither COX-1 nor COX-2 protein expression had prognostic value, low HPGD combined with high ALOX5 expression was associated with the worst overall and progression-free survival. These findings highlight HPGD and ALOX5 as potential therapeutic targets in aggressive EC subtypes. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

脂质组学在疾病生物标记物研究应用现状

脂质组学通过研究脂质的结构和功能及其在体内的代谢变化,明确其对疾病诊断和治疗的作用,以期提高疾病风险预测的能力。常用脂质组学分析方法包括直接质谱注入法（鸟枪法）、色谱质谱联用法和核磁共振法等。脂质组学在疾病早期诊断、生物标志物的发现、新药研发以及系统研究方面都发挥了很大作用。本文旨在介绍脂质组学在疾病生物标志物发现中的应用及其研究方法。