摘要
背景与目的:
先天性发育缺陷是指人类出生时表现的所有类型的发育异常,包括结构畸形、功能缺陷、代谢异常、遗传及行为等各方面所有的异常。流行病学、遗传学、分子生物学等研究提示,导致出生缺陷发生的原因,约有20%-25%主要由遗传因素所致,10%由环境因素(包括物理、生物、化学及营养因素等)引起,65-70%可能是环境与遗传因素相互作用的结果。据各有关资料统计,先天发育缺陷出生人数占总出生人数的2%-7%,神经管畸形及染色体异常是先天性发育缺陷中最为常见的疾病之一。降低出生人口的缺陷、提高出生人口素质是人类共同关注的问题。鉴于我国人口基数大、出生人口多,出生缺陷是影响我国人口素质的重要因素,已成为影响我国国民经济发展和人们正常生活的社会问题,提高出生人口素质,是提高中华民族人口素质的前提和基础,是促进我国经济繁荣和社会健康发展的有利保障。
产前诊断(prenatal diagnosis)又称宫内诊断(intrauterine diagnosis)或出生前诊断(antenatal diagnosis),是在胎儿出生前,应用各种检测方法对某些先天性、遗传性疾病作出诊断,进行选择性流产或宫内治疗,从而降低先天性缺陷儿的出生率,达到优生目的。它需要影像学、产科、细胞遗传学、生物化学以及分子生物学等技术相互协作共同完成,是跨专业、跨学科的一门学科,是对近代诊断学的重大进展,已成为临床产科学的重要组成部分。
然而,目前产前诊断工作主要局限于对胎儿异常的发现和干预,而对胎儿异常的发病因素、发病机制及预防的研究鲜见报道,因此选择适当的检查方法研究胎儿先天性发育缺陷的各种生物学变化、发病机制、疾病的相关标记分子、药物靶点、筛选高敏感性和特异性的胎儿异常标志物等势在必行,蛋白质组学的出现为我们攻克这一难题带来了希望和曙光。
蛋白质组学是以蛋白质为研究对象,其指的是一个细胞、组织或体液中所表达的全部蛋白质。蛋白质组学研究基因组在不同时间和空间编码的全部蛋白质的组成及作用规律,动态描述基因调节,对蛋白质进行定量的测定,研究疾病、药物对生命过程的影响,以及解释基因表达调控的机制。
蛋白质组学的研究核心是通过对常见病理个体蛋白质组的测试分析,搜索出与疾病相关的有共性的特异性蛋白质分子,为探讨发病机制,设计新药物,为疾病的早期诊断和对预后的预测提供分子水平的实验与理论依据。作为基因组学研究的拓展,蛋白质组学研究成为世界生命科学领域的一个极其活跃的部分,是功能基因组时代或“后基因组时代”的核心部分,成为生物医学领域探索性研究的强有力工具。
蛋白质组技术是最近才开始用于生殖医学的研究,虽然在生殖医学领域尚未广泛应用,但它的出现为生殖医学研究提供了新技术,增加了新的研究方向。应用这些方法有助于全面理解产前诊断相关疾病的病理生理变化,成功确定相应的蛋白质生物标志物有可能改变产前诊断相关疾病的早期诊断和治疗。
目前蛋白质组学研究多采用传统的蛋白组学技术,例如双向电泳、质谱等,但这些技术受到技术条件要求高、步骤繁琐、耗时冗长等因素的限制,使差异蛋白质组学研究大规模地迅速开展受到限制。表面增强激光解吸电离飞行时间质谱(Surface-enhanced laser desorption ionization time of flight massstectrometry,SELDI-TOF-MS)是近几年发展起来的一种新的蛋白质组学研究方法,融合了质谱和芯片两大技术的优点,具有高通量、高灵敏度等特点,能对样品中蛋白质进行全景式分析,进而同时发现多个特异性标志物,为肿瘤早期诊断、疗效监测等提供了崭新的技术平台。
羊水,是指怀孕时子宫羊膜腔内的液体,是维持胎儿生命所不可缺少的重要成分,并是诊断胎儿疾病生物标志物的潜在、丰富的来源。本研究在当前正在开展的孕母血清筛查、超声筛查,超声引导下羊膜腔穿刺,羊水细胞培养及染色体核型分析的工作基础上,利用SELDI-TOF-MS蛋白质芯片飞行质谱技术研究正常胎儿与染色体异常胎儿、正常胎儿与神经系统异常胎儿的羊水蛋白质组学,建立正常胎儿羊水蛋白质组指纹图谱,利用蛋白质组学技术结合基因组学方法和生物信息学,研究比较正常胎儿与异常胎儿羊水在正常生理或病理状态下所表达的蛋白质的差异,寻找异常胎儿的特异性蛋白质分子,为探索胎儿染色体异常、胎儿神经系统畸形的病因学、发病机制、病理生理学变化提供蛋白质水平的研究依据,为异常胎儿的早期诊断提供分子标志,为染色体异常胎儿、神经系统畸形胎儿的预防、治疗、新药设计提供新的分子靶点。
第一部分应用SELDI-TOF-MS筛选染色体异常胎儿羊水中特异性蛋白质的研究
目的:分析染色体异常胎儿羊水和染色体正常胎儿羊水的蛋白质表达差异。方法:运用SELDI-TOF-MS技术检测染色体异常胎儿羊水和染色体正常胎儿羊水蛋白质表达图谱。胎儿羊水采用WCX2(弱阳离子交换芯片)捕获蛋白、PBSⅡC型蛋白质芯片阅读仪读取数据、Protein-Chip software 3.2软件采集数据、Biomarker wizard软件分析2组之间差异蛋白。结果:发现染色体异常胎儿羊水和染色体正常胎儿羊水的蛋白质表达图谱存在5个差异蛋白,其中4967.526Da、5258.056 Da、6868.197 Da3个蛋白及4134.51 Da 5423.397 Da2个蛋白在染色体异常组表达分别下调或上调。结论:SELDI-TOF-MS技术发现的表达于染色体正常胎儿和染色体异常胎儿羊水中的5个差异蛋白,为胎儿染色体异常的病因、发病机制、病理生理学变化提供了蛋白质水平的研究依据,可能成为预防、治疗、新药设计的新的分子靶点和早期诊断染色体异常胎儿的重要标志物。
第二部分应用SELDI-TOF-MS筛选神经系统畸形胎儿羊水特异性蛋白质的研究
目的:分析神经系统畸形胎儿羊水和神经系统正常胎儿羊水的蛋白质表达差异。方法:运用SELDI-TOF-MS技术检测神经系统先天畸形胎儿羊水和神经系统正常胎儿羊水蛋白质表达图谱。胎儿羊水采用WCX2(弱阳离子交换芯片)捕获蛋白、PBSⅡC型蛋白质芯片阅读仪读取数据、Protein-Chip software 3.2软件采集数据、Biomarker wizard软件分析2组之间差异蛋白。结果:发现神经系统先天畸形胎儿羊水和神经系统正常胎儿羊水的蛋白质表达图谱存在9个差异蛋白,其中4967.5Da、5258.0 Da、11717.0 Da3个蛋白及2540.4 Da、3107.1 Da、3396.8 Da、4590.965 Da、5589.2 Da、6429.4 Da6个蛋白在神经系统异常组表达分别下调或上调。结论:SELDI-TOF-MS技术发现的表达于神经系统先天畸形及神经系统正常的胎儿羊水之间的9个差异蛋白,为神经系统畸形胎儿的病因、发病机制、病理生理学变化提供了蛋白质水平的研究依据,可能成为预防、治疗、新药设计的新的分子靶点和早期诊断神经系统先天畸形胎儿的重要标志物。
总结
1.本研究是由影像、超声介入、遗传、基础、产科各学科相互协调配合共同完成,是一项跨专业、跨学科的综合性研究,产前筛查、诊断胎儿先天性发育缺陷的工作流程为利用SELDI-TOF-MS技术研究胎儿羊水蛋白质组学打下坚实的研究基础。
2.应用SELDI-TOF-MS技术获得胎儿羊水蛋白质表达图谱的实验方法稳定可靠,具有良好的重复性,是研究胎儿羊水蛋白质组学的有效方法。
3.应用SELDI-TOF-MS技术初步建立了正常胎儿、染色体异常胎儿、神经系统畸形胎儿羊水蛋白质组指纹图谱。
4.m/z 4134.51 Da、4967.526Da、5258.056 Da、6868.197 Da、5423.397 Da的5个差异蛋白质可能是染色体异常胎儿羊水潜在的特异性生物标志物。
5.m/z 2540.4 Da、3107.1 Da、3396.8 Da、4590.965 Da、4967.5 Da、5258.0 Da、5589.2 Da、6429.4 Da、11717.0 Da的9个差异蛋白质可能是胎儿神经系统畸形羊水潜在的特异性生物标志物。
6.SELDI-TOF-MS技术在分子水平对开展胎儿先天性发育缺陷的研究工作具有广阔的应用前景。
创新点
1.首次在中期妊娠产前筛查、诊断胎儿先天性发育缺陷的工作流程基础上利用SELDI-TOF-MS先进技术体系对胎儿羊水进行蛋白质组学研究。
2.首次应用SELDI-TOF-MS技术初步建立了正常胎儿、染色体异常胎儿、神经系统畸形胎儿羊水蛋白质组指纹图谱。
3.首次在染色体异常胎儿的羊水中检测出5个差异蛋白质,它们可能是染色体异常胎儿潜在的羊水特异性生物标志物。
4.首次在神经系统畸形胎儿的羊水中筛选出9个差异蛋白质,它们可能是胎儿神经系统畸形潜在的羊水特异性生物标志物。
Background and Purpose:
Congenital defect is a widely-used term for a congenital malformation, including structural abnormalities,functional defects,metabolic disorders,genetic abnormalities and behavioral aspects of all the anomalies.In a variety of human congenital defects,their etiology and pathogenesis have not yet completely clear, but the epidemiology,genetics,molecular biology studies suggest the direct cause was genetic factors,environmental factors or the interaction of genetic factors and environmental factors.For 65-70%of anomalies there seems to be a "multi factorial" cause,meaning a complex interaction of genetic factors and environmental factors. For 20%-25%of anomalies have a purely genetic cause,only 10%of anomalies have a purely environmental cause(including physical factors,biological factors, chemical factors and nutritional factors and else).According to statistics,the incidence of congenital developmental defects of the total number of births was 2% -7%,nervous system malformations and chromosome abnormalities were the two most common defects.Reduce congenital defects,improve the quality of newborn babies are human mutual concern.Due to our country large population base and large birth population,congenital defects have become an important affecting factor to our national economic development and people normal life.Improve the quality of newborn babies is the prerequisite and foundation of improve the quality of the Chinese population,and promote China's economic prosperity and social stability development.
Prenatal diagnosis,also known as intrauterine diagnosis or antenatal diagnosis,is employs a variety of techniques to determine the health and condition of an unborn fetus,determining the diagnosis of certain congenital,hereditary diseases,planning for selective abortion,or intrauterine treatment,reducing the birth rate of birth defects children and achieve the purpose of eugenics.Prenatal diagnosis is a major step forward in modem medical science and an important part of clinical obstetrics.In recent years,with the rapid progress of medical imaging,cell genetics, biochemistry and molecular biology,prenatal diagnosis has constantly enhanced.
However,the current diagnostic methods are mainly limit to the discovery of fetal anomalies and reduce these the incidence of birth defects,rather than study a variety of abnormal fetal biological changes,pathogenesis,disease-related molecular markers,drug targets and else,it is imperative to select an appropriate method to inspect a variety of fetal abnormalities biological changes,pathogenesis, disease-related molecular markers,drug targets,screening of high sensitivity and specificity of fetal abnormalities markers.The emergence of proteomics has brought hope and the dawn for us to overcome this problem.
Proteomics is the large-scale study of proteins,including all expressed proteins of cell,tissue or body fluids.Proteomics research the composition and the law of all protein encoded by genome in different time and space,the dynamic description of gene regulation,the quantitative study of proteins,the disease and drug impact to life processes,as well as the interpretation of gene expression and regulation mechanism.
The cores of proteomics research is compare the common pathology individuals and search the specific disease-related protein molecules,in order to explore the pathogenesis,design new drugs for the disease,and provide the molecular level experimental and theoretical basis for early diagnosis and prognosis prediction.As genomics research development,proteomics research has become an extremely active part of the world's life sciences,the core of the functional genomics era or "post-genome era",and a powerful tool of the biomedical field.
Proteomic technology is only recently beginning to be employed in pregnancy research.Although proteomics study is not widely used in reproductive medicine, but the emergence of proteomics research added a new research technology and a new research dimension to the field of reproductive medicine.Application of these high throughput methodologies in pregnancy-related pathology has contributed to the comprehension of the underlying pathophysiologies and the successful identification of relevant protein biomarkers that can potentially change early diagnosis and treatments of several medical conditions related to human pregnancy and significantly improve maternal health.
Currently,proteomics research is mainly using the traditional proteomics techniques such as two-dimensional gel electrophoresis,mass spectrometry,but these technologies are not suitable for a large scale difference proteome study because of their high request,complicated procedure,time consuming,et al. Surface-enhanced laser desorption ionization time of flight mass spectrometry (SELDI-TOF-MS) which convergence the two major advantages of mass spectrometry and chip technology is a new proteomics research methods in recent years,which has numerour advantages,such as high-throughput,high sensitivity and eles.It has the ability of identification of potential biomarkers for a variety of diseases through overall view analysis in samples and provided a brand-new technology platform for early diagnosis and treatment efficacy monitoring tool of diseases.
Amniotic fluid is the nourishing and protecting liquid contained by the amnion of a pregnant woman and an important and indispensable element for maintenance fetal life.The magic water can be the potential and rich biomarkers source of maternal and fetal disease.Based on the current traditional maternal serum prenatal screening,ultrasound screening for fetal malformation,ultrasound-guided puncture the amniotic cavity,amniotic cell culture,chromosome karyotype analysis,this study has been used SELDI-TOF-MS to study amniotic fluid proteomics of normal fetuses and chromosome abnormalities fetuses,normal fetuses and nervous system malformations fetuses,to establish a normal fetal amniotic fluid proteomic fingerprint / database,to study the amniotic fluid protein expressed difference between physiological and pathological state of fetuses by using proteomics, genomics and bioinformatics technologies,to search specific protein molecules for abnormal fetuses,to explore etiology,pathogenesis,pathophysiological changes in protein levels of chromosome abnormalities fetuses and nervous system malformations fetuses,to provide molecular biomarker for early diagnosis of abnormal fetuses,to avoid a heavy burden to families and society by timely prenatal diagnosis of chromosome abnormalities fetuses and nervous system malformations fetuses prevention,to provide new molecular targets for designed new prevention and treatment drugs.
PartⅠDetection of Distinct Protein in Amniotic Fluid of Chromosome Abnormalities fetuses by SELDI-TOF-MS Technology
Objective To detect the distinct protein in amniotic fluid between chromosome abnormalities fetuses and chromosome normal fetuses.Methods Surface-enhanced laser desorption-ionization/time-of-flight mass spectrometry was used to characterize amniotic fluid peptides in amniotic fluid between chromosome abnormalities fetuses and normal fetuses.WCX2 protein chips were used to characterize amniotic fluid peptides in amniotic fluid.Protein chips were examined in PBSⅡC protein reader,the protein profiling was collected by proteinchip software 3.1 and analyzed by Biomarker Wizard software.Results 5 distinct proteins were identified in amniotic fluid between chromosome abnormalities fetuses and normal fetuses.Compared with control group,three proteins with m/z 4967.526Da,5258.056 Da,6868.197 Da were down-regulated,and two proteins with m/z 4134.51 Da,5423.397 Da up-regulated in chromosome abnormalities fetuses.Conclusion Proteomic analysis was able to detect distinct proteins in protein profiling of amniotic fluid between chromosome abnormalities fetuses and normal fetuses.
Objective To detect the distinct protein in amniotic fluid between nervous system malformations fetuses and normal fetuses.Methods Surface-enhanced laser desorption-ionization/time-of-flight mass spectrometry was used to characterize amniotic fluid peptides in amniotic fluid between nervous system malformations fetuses and normal fetuses.WCX2 protein chips were used to characterize amniotic fluid peptides in amniotic fluid.Protein chips were examined in PBSⅡC protein reader,the protein profiling was collected by proteinchip software 3.1 and analyzed by Biomarker Wizard software.Results 9 distinct proteins were identified in amniotic fluid between nervous system malformations fetuses and normal fetuses.Compared with control group,three proteins with m/z 4967.5Da,5258.0 Da,11717.0 Da were down-regulated,and six proteins with m/z 2540.4 Da,3107.1 Da,3396.8 Da,4590.965 Da,5589.2 Da,6429.4 Da up-regulated in nervous system malformations fetuses.Conclusion:Proteomic analysis was able to detect distinct proteins in protein profiling of amniotic fluid between nervous system malformations fetuses and normal fetuses.
Conclusion
1.This study is a multidisciplinary,interdisciplinary and comprehensive research coordinate with medical imaging,ultrasound intervention,genetic,basic medicine, obstetrics.The work flow of prenatal screening,prenatal diagnosis of fetal abnormality in the second trimesters had laid a solid foundation for the preliminary application of SELDI-TOF-MS in prenatal diagnosis.
2.SELDI-TOF-MS was a stable and reliable technology for fetal amniotic fluid protein expression with good repeatability and can be an effective method for the fetal amniotic fluid proteomics.
3.This study preliminarily established the amniotic fluid proteomic fingerprint / database of normal fetuses,chromosome abnormalities fetuses,nervous system malformations fetuses with the application of SELDI-TOF-MS SELDI technology.
4.Five proteins peaks M / z 4134.51 Da,4967.526Da,5258.056 Da,5423.397 Da, 6868.197 Da could be specific biomarkers for chromosome abnormalities fetuses.
5.Nine proteins peaks M / z 2540.4 Da,3107.1 Da,3396.8 Da,4590.965 Da, 4967.5 Da,5258.0 Da,5589.2 Da,6429.4 Da,11717.0 Da could be specific biomarkers for nervous system malformations fetuses.
6.SELDI-TOF-MS technique has a broad application prospects in prenatal diagnosis.
Main Innovative Points
1.Based on a complete,scientific,effective work flow for congenital defect in the second trimesters,this study first used SELDI-TOF-MS to study amniotic fluid proteomics of fetuses for prenatal diagnosis.
2.SELDI-TOF-MS technology application preliminarily established amniotic fluid proteomic fingerprint / database of normal fetuses,chromosome abnormalities fetuses and nervous system malformations fetuses.
3.This study was the first to investigate the value of proteomic in the diagnosis of fetal chromosomal abnormalities,and five proteins could be specific biomarkers for chromosome abnormalities fetuses.
4.This study was the first to investigate the value of proteomic in the diagnosis fetal nervous system malformations,and nine proteins could be specific biomarkers for nervous system malformations fetuses.
引文
1.李正,王慧贞,吉士俊.先天畸形学.北京:人民卫生出版社,2000.
2.胡桂英自然流产.见:乐杰主编.妇产科学.第6版.北京:人民卫生出版社.2004.89.
3.Hsu L YF.Prenatal diagnosis of chromosomal abnormalities through amniocentesis.In:Milunsky A ed.Genetic Disorders and the Fetus:diagnosis,prevention,and treatment.4th ed.Baltimore:Johns Hopkins University Press.1998:179
4.张军,王树玉,产前诊断技术及进展.北京医学.2003;25(5)343-345.
5.Mai A.Hulten,seema Dhanjal,Barbara Peal.Rapid and simple prenatal diagnosis of commom chromosome disorders:advantages and disadvantages of the molecular methods FISH and QF-PCR.Reproduction.2003;126,279-297
6.Cederh01m M,Axelsson O。A prospective coIIlparative study on transabdominal chorionic villus sampling and amniocentesis performedatlO-23 weeks' gestatiom Prenat Diagn.1997;4:311-317
7.Nikkila A,Valentin L,Thel in A,et al Early amniocentesis and congenital foot defomities Fetal Diagn Ther.2002;17:129-132.
8.Greenough A,Naik S,Yuksel B,et al.First2trimester invasive procedures and congenital abnormalities.Acta Paediatr.1997;86:1220-1223.
9.Tharapel SA,Dev VG,Shulman L P,et al.Prenatal karyotyping using fetal blood obtained by cordocentesis:rapid and accurate results within 24 hours.Ann Genet.1998;41:69-72.
10.Arduini D,Rizzo G,Capponi A,et al.Fetal pH value determined by cordocentesis:an independent predictor of the development of anteparturn fetal heart rate decelerations in growth retarded fetuses with absent end2diastolic velocity in umbilical artery.J Perinat Med.1996;24:601-607.
11.Berry SM,Leonardi MR,Wolfe HM,et al.Maternal thrombocy topenia.Predicting neonatal thrombocytopenia with cordocentesis.J Reprod Med.1997;42:276-280.
12.Ostlund E,Bang P,Hagenas L,et al.Insulin21ike growth factor Ⅰ in fetal serum obtained by cordocentesis is correlated with intrauterine growth retardation.Hum Reprod.1997;12:840-844.
13.廖灿,潘敏,李东至,等.B超引导下的脐静脉穿刺术在产前诊断应用中的安全性研究[J].中华妇产科杂志,2004,39(12):813-815
14.Kanavakis E,Traeger-Synodinos J.Preimplantation genetic diagnosis in clinical practice.J Med Genet.2002;39:6-11.
15.Verlinsky Y,Handyside A,Grifo J,et al.Preimplantation diagnosis of genetic and chromosomal disorders.J Assist Reprod Geent.1994;11:236-243.
16.Van den Veyver IB,Chong SS,Cota J,et al.Single2cell analysis of the RhD blood type for use in preimplantation diagnosis in the prevention of severe hemolytic disease of the newborn.AmJ Obstet Gynecol.1995;172(2 Pt 1):533-540.
17.李胜利.胎儿畸形产前超声诊断学[M].北京:人民军医出版社.2004:560-564
18.严英榴,杨秀雄,沈理.产前超声诊断学[M].北京:人民卫生出版社,20Q5:440-468
19.李玮璟.胎儿染色体异常血清学及超声形态学产前筛查的临床意义.实用妇产科杂志.2006;22(3):134-136.
20.徐伯成,宋伊丽,正常胎儿颈项皮肤厚度的超声检测.中华超声影像学杂志.2003;12(4):233-235.
21.Ginsberg N,Cadkin A,Pergament E,Verlinsky Y.Ultrasonographic detection of the second-trimester fetus with trisomy 18 and trisomy 21.Am J Obstet Gynecol.1990 Oct;163(4 Pt 1):1186-90.
22.Gray DL,Crane JP.Optimal nuchal skin-fold thresholds based on gestational age for prenatal detection of Down syndrome.Am J Obstet Gynecol.1994 Nov;171(5):1282-6.
23.Suchet IB.Ultrasonography of the fetal neck in the first and second trimesters.Part 2.Anomalies of the posterior nuchal region.Can Assoc Radiol J.1995 Oct;46(5):344-52.
24.Brumfield CG,Wenstrom KD,Owen J,Davis RO.Ultrasound findings and multiple marker screening in trisomy 18.Obstet Gynecol.2000 Jan;95(1):51-4.
25.Nyberg DA,Kramer D,Resta RG,Kapur R,Mahony BS,Luthy DA,Hickok D.Prenatal sonographic findings of trisomy 18:review of 47 cases.J Ultrasound Med.1993Feb;12(2):103-13.
26.Bianchi DW,Zickwolf GK,Weil GJ,et al.Male fetal progenitor cells persist in maternal blood for as long as 27 years postpartum.Proc Natl Acad Sci USA.1996;93:705-708.
27.马旭,王毅,王琳,等.经母血采集胎儿细胞进行产前诊断的最佳时间探讨.中华妇产科杂志.1997;32:293-295.
28.Cheung MC,Goldberg JD,Kan YW.Prenatal diagnosis of sickle cell anaemia and thalassaemia by analysis of fetal cells in maternal blood.Nat Genet.1996;14:264-268.
29.Maggi F,Berdusco F,Liuti R,et al.First2trimester chromosome diagnosis by lavage of the uterine cavity.Prenat Diagn.1996;16:823-827.
30.Ishai D,Amiel A,Diukman R,et al.Uterine cavity lavage:adding FISH to conventional cytogenetics for embryonic sexing and diagnosing common chromosomal aberrations.Prenat Diagn.1995;15:961-965.
31.赵林淑,胡静,黄冰玉,等.应用宫腔冲洗滋养细胞行产前诊断.中华妇产科杂志.1997;32:55-56.
32.赵林淑,宋杰,张爱臣,等.经子宫颈冲洗宫腔收集滋养细胞进行产前性别诊断初步研究.中华医学遗传学杂志.1998;15:187-188.
33.O samu Sa皿ura,SatoshiSohda,KirbyL,etal Diagnosis of teisomy 21 in fetal nucleated erythrocytes from maternal blood by use of short tandem repeated sequences[J].Clin Chem.2001;46:1622-1626.
34.Van den Veyver IB,Chong SS,Cota J,et al.Single2cell analysis of the RhD blood type for use in preimplantation diagnosis in the prevention of severe hemolytic disease of the newborn.AmJ Obstet Gynecol.1995;172(2 Pt 1):533-540.
35.Sermon K,Lissens W,Messiaen L,et al.Preimplantation genetic diagnosis of Marfan syndrome with the use of fluorescent polymerase chain reaction and the Automated Laser Fluorescence DNA Sequencer.Fertil Steril.1999;71:163-166.
36.Sermon K,Seneca S,Vanderfaeillie A,et al.Preimplantation diagnosis for fragile X syndrome based on the detection of the non-expanded atemal and maternal CGG.Prenat Diagn.1999;19:1223-1230.
37.De Vos A,Van Steirteghem A.Aspects of biopsy procedures prior to preimplantation genetic diagnosis.Prenat Diagn.2001;21:767-780.
38.Nath J,Johnson KL.Fluorescence in situ hybridization(FISH):DNA probe production and hybridization criteria.Biotech Histochem.1998;73:6-22.
39.Ishai D,Amiel A,Diukman R,et al.Uterine cavity lavage:adding FISH to conventional cytogenetics for embryonic sexing and diagnosing common chromosomal aberrations.Prenat Diagn.1995;15:961-965.
40.Blackstock W,Mann M.Aboundless future for proteomics[J].Trends Biotechnol.2001;19(suppl):s1-s2.
41.Patel PS,Telang SD,Rawal RM,et al.A review of proteomics in cancer research.Asian Pac J Cancer Pre.2.005;6(2):113-I17.
42.Chiehester C,Nikitin F,Ravarini JC,et al.Consistency checks for characterizing protein forms.Comput Biol Chem,2003;27(1):29-35.
43.Chevalier F。Martin O。Rofidal V.et al.Barteau S,SommererN,Rossignol M.Protecmic investigation of natural variation between Arabidopsis ecotypes.Proteomics,2004;4(5):1372-1381.
44.何大澄,肖雪媛.SELDI蛋白质芯片技术在蛋白质组学中的应用[J].现代仪器.2002;38(1):1-4.
45.Merchant M,Weinberger SR.Recent advancements in surface-enhanced laser desorption-ionizafion-time of flight-mass spectrometry.Electrophoresis.2000;21(6):1164-1177
46.Issaq HJ,Conrads TP,Prieto DA,et al.SELDI-TOF-MS for diagnostic proteomics.Anal Chem.2003;75(7):148-155A
47.Buhimschi IA,Christner R,Buhimschi CS,et al.Proteomic biomarker analysis of amniotic fluid for identification of intra-amniotic inflammation.BJOG.2005;112(2):173-181
48.Buhimschi IA,Buhimschi CS,Weiner CP,et al.Proteomic but not enzyme-linked immunosorbent assay technology detects amniotic fluid monomeric calgranulins from their complexed calprotectin form.Clin Diagn Lab Immunol.2005;2(7):837-844
49.Klein LL,Freitag BC,Gibbs RS,et al.Detection of intra-amniotie infection in a rabbit model by proteomics-based amniotic fluid analysis.AmJ Obstet Gynecol.2005;193(4):1302-1306
50.Park JS,Oh KJ,Norwitz ER,et al.Identification of proteomic biomarkers of preeclampsia in amniotie fluid using SELDI-TOF mass spectrometry.Reprod Sci.2008 May;15(5):457-68.
51.陶国伟;刘韶平;杨瑞芳;王明毅;展新风;程琳;234例羊膜腔穿刺诊断胎儿染色体异常的研究,现代妇产科进展.2006:15(8):611-613.
52.陶国伟;刘韶平;傅庆诏;展新凤;介入超声技术在产前诊断胎儿染色体异常中的应用研究[J].中华超声影像学杂志.2005;14(8):591-593.
53.杨瑞芳;王明毅;丁凤华;张丽华;吕怡静;10484例孕中期唐氏综合征筛查结果分析,中国优生与遗传杂志.2008:16(6):46-48.
54.杨瑞芳:王明毅;丁凤华;张丽华;吕怡静;孕中期产前筛查435例高风险孕妇妊娠的结局.现代妇产科进展.2006:15(10):776-777.
55.吕怡静;王明毅;杨瑞芳;丁凤华;张丽华;Turner综合征的临床与实验检查研究,中国优生与遗传杂志.2005:13(7),55-56.
56.杨瑞芳,王明毅,丁凤华,刘韶平.2000例孕中期唐氏综合征的筛查分析[J].现代妇产科进展.2003;(05).
1.贾士美,房兴仁.浅谈出生缺陷和出生缺陷干预工程.中国农村卫生事业管理.2002;22(5):52.
2.郑晓瑛.给你一个更完美的孩子-谈出生缺陷干预工程.科学中国人.2001:10:36-38.
3.Pinar H.Postmortem findings in term neonates.Semin Neonatol.2004;9(4):289302.
4.曲梅,李竹.神经管畸形相关基因研究进展.遗传.2002;24(6):695-698.
5.Ismayilova,Samaya,Mammadova,Madina.Air pollution and birth defect in Sumgayit.Epidemiology.2004;15(4):pp s50-s51.
6.全国妇幼卫生监测年会会议资料.全国妇幼卫生监测办公室.成都:华西医科大学.2000;11
7.Speer MC,Nye J,McLone D,et al.Possible interaction of genotypes at cystathionine beta synthase and methylene tetrahydrofolate reductase(MTHFR)in neural tube defects.Clin Genet.1999;56(2) 142-144,
8.Richter B,Stegmann K,Roper B,Boddeker I,Ngo ET,Koch MC.Interaction of folate and homocysteine pathway genotypes evaluated in susceptibility to neural tube defects(NTD)in a German population.J Hum Genet.2001;46(3):105-9.
9.Nicolaides DH,Gabba SG,Campbell S.et al.Ultrasound screening for spina bifida cranial and cerebellar signs[J].Lancet.1986;1:72-74.
10.Goldstein RB.Podrasky AIE.Filly RA.et al.Effacement of the fetal cisterna magna in association with myelomeningocele[J].Radiology.1989;172:409-413.
11.Platt LD,Ca rlson DE,Medearis AL.et al.Fatal choroids ptexus cysts in the second trimester of pregnancy:a cause for concern[J].Am J Obstet Gynecol.1991;164:1652-1656.
12.Achiron R,BarkaiG.katznelsonMB-M,et al.Fetal lateral ventricle choroid plexus cysts:the dilemma of amniocentesis[J].Obstet Gynecol.1991;78:815-818.
13.Platt LD,Carlson DE,Medearis AL.et al.Fatal choroids ptexus cysts in the second trimester of pregnancy: a cause for concern[J]. Am J Obstet Gynecol. 1991;164: 1652—1656.
14. SandrasegaranK, Lall CG, Aisen AA.Fetal magnetic resonancei maging.Curr Opin Obstet Gynecol. 2006; 18(6):605-612.
15. LevineD .Obstetric MRI.J Magn Reson Imaging. 2006; 24(1):1-15.
16. Wang GB,Shan RQ,Ma YX,et al.Fetal central nervous system anomalies:comparison of magnetic resonance imaging and ultrasonography for diagnosis.Chin Med J (Engl). 2006; 119(15): 1272-1277.
17. Glenn OA.Fetal central nervous system MR imaging.Neuroimaging Clin N Am.2006; 16(1):1-17.
18. de Certaines JD, Cathelineau G. Safety aspects and quality assessment in MRI and MRS: a challenge for health care systems in Europe[J]. J Magn Reson Imaging.2001;13(4): 632-638
19. GAREL C. New advances in fetal MR neuroimaging[J]. Pediatr Radiol. 2006 Jul;36(7):621-625. Epub 2006 May 3.
20. GRESSENS P, LUTON D. Fetal MRI: obstetrical and neurological perspectives[J]Pediatr Radiol.2004;34(9): 682—684
21. FULFORD J, VADEYAR S H, DODAMPAHALA S H, et al. Fetal brain actvity in response to a visual stimulus[J]. Hum Brain Mapp, 2003, 20(4): 239. 245.
22. KOKRD, VAN DEN BERG P P, VAN DEN BERGH A J, et al. Maturation ofthe human fetal brain as observed by H MR spectroscopy[J]. Magn Reson Med.2002;48(4): 611-616.
23. Brown PO, Botstein D.Exploring the new world of the genome with DNA microarrays.Nat Genet. 1999 Jan; 21(1 Suppl):33-7.
24. Sato N, Sugimura Y, Hayashi Y, Murase T, Kanou Y, Kikkawa F, Murata Y.Identification of genes differentially expressed in mouse fetuses from streptozotocin-induced diabetic pregnancy by cDNA subtraction. Endocr J.2008 May; 55(2):317-23. Epub 2008 Mar 7.
25. Nagy GR, Gyorffy B, Galamb O, Molnar B, Nagy B, Papp Z.Use of routinely collected amniotic fluid for whole-genome expression analysis of polygenic disorders.Clin Chem. 2006 Nov; 52(11):2013-20. Epub 2006 Sep 28.
26. Da Lee R, Rhee GS, An SM, Kim SS, Kwack SJ, Seok JH, Chae SY, Park CH, Yoon HJ,Cho DH,Kim HS,Park KL.Differential gene profiles in developing embryo and fetus after in utero exposure to ethanol.J Toxicol Environ Health A.2004 Dec;67(23-24):2073-84.
27.Anderson N L,Anderson N G.Proteome and prteomics:new technologies,new concepts,and new words.Electrophoresis.1998;19:1853-1861
28.Gygi SP,Rochon Y,Franza BR,Aebersold R.Correlation between protein and mRNA abundance in yeast[J].Mol Cell Biol.1999 Mar;19(3):1720-30.
29.Jensen PK,Pasa-Tolic L,Peden KK,Martinovic S,Lipton MS,Anderson GA,Tolic N,Wong KK,Smith RD.Mass spectrometric detection for capillary isoelectric focusing separations of complex protein mixtures.[J].Electrophoresis.2000;21(7):1 372-1 380.
30.何大澄,肖雪媛.SELDI蛋白质芯片技术在蛋白质组学中的应用.[J].现代仪器.2002;38(1):1-4.
31.Kolialexi A,Mavrou A,Spyrou G,et al.Mass spectrometry-based proteomics in reproductive medicine.Mass Spectrom Rev.2008 Nov-Dec;27(6):624-34.
32.Merchant M,Weinberger SR.Recent advancements in surface-enhanced laser desorption-ionizafion-time of flight-mass spectrometry.Electrophoresis.2000;21(6):1164-1177
33.Issaq HJ,Conrads TP,Prieto DA,et al.SELDI-TOF-MS for diagnostic proteomics.Anal Chem.2003;75(7):148-155A
34.Buhimschi IA,Christner R,Buhimschi CS,et al.Proteomic biomarker analysis of amniotic fluid for identification of intra-amniotic inflammation.BJOG.2005;112(2):173-181
35.Buhimschi IA,Buhimschi CS,Weiner CP,et al.Proteomic but not enzyme-linked immunosorbent assay technology detects amniotic fluid monomeric calgranulins from their complexed calprotectin form.Clin Diagn Lab Immunol.2005;2(7):837-844
36.Klein LL,Freitag BC,Gibbs RS,et al.Detection of intra-amniotic infection in a rabbit model by proteomics-based amniotic fluid analysis.AmJ Obstet Gynecol.2005;193(4):1302-1306
37.Park JS,Oh KJ,Norwitz ER,et al.Identification of proteomic biomarkers of preeclampsia in amniotic fluid using SELDI-TOF mass spectrometry.Reprod Sci.2008 May;15(5):457-68.
1. Blackstock W, Mann M. Aboundless future for proteomics[J]. Trends Biotechnol.2001; 19(suppl): s1—s2.
2. Patel PS, Telang SD, Rawal RM, et al.A review of proteomics in cancer research. Asian PacJ Cancer Pre.2005;6(2): 113-117.
3. Chiehester C, Nikitin F, Ravarini JC, et al. Consistency checks for characterizing protein forms. Comput Biol Chem.2003;27(1): 29—35.
4. Chevalier F。 Martin Oo Rofidal V. et al. Barteau S, Sommerer N, Rossignol M . Protecmic investigation of natural variation between Arabidopsis ecotypes. Proteomics.2004;4(5): 1372-1381.
5. Wulfkuhle JD, Paweletz CP, Steeg PS, et al. Proteomic approaches to the diagnosis, treatment, and monitoring of cancer. Adv Exp Med Biol.2003; 532:59-68.
6. Lilley KS. Friedman DB. AII about DIGE: quantification technology for differential-display 2D—gel proteomics. Expert Rev Proteomics.2004;1 (4):401-409.
7. Zhou G, Li H. Decamp D, et al. 2D differential in gel electrophoresis for the identification of esophageal scans cell cancer specific protein markers. Mol Cell Proteomics.2002;l(2): 117—127.
8. 甄朱.蛋白质组学进展.生物工程学报.2001;17(5): 491-493.
9. Goodchild A. Raftery M, Saunders NF, et al. Cold adaptation of the Antarctic arehaeon , Methanoceccoides burtonii assessed by protemics using ICAT. Proteome Res.2005;4(2): 473-480.
10. Moore LE, Pfeiffer R, Warner M, et al. Identification of biomarkers of arsenic exposure and metabolism in urine using SELDI technology. Biochern Mol Toxlcol.2005;19(3): 176.
11. Kiga C, Nakagawa T, Koizumi K, et al. Expression patterns of plasma proteins in spontaneously diabetic rats after oral administration of a Kampo medicine. Hachimi-jio-gan, using SELDI ProteinChip platform. Biol Pharm Bull.2005;28(6):1031-1037。
12.赵从建,宇峰,丁勤学,等.神经蛋白质组分析中双向电泳技术的建立.生物化学与生物物理进展.2000;27:645-651.
13.陈主初.肿瘤蛋白质组学的研究进展.癌症.2004;23:113-117.
14.Shankar R,Cullinane F,Brennecke SP,Moses EK.Applications of proteomic methodologies to human pregnancy research:A growing gestation approaching delivery? Proteomics.2004;4:1909-1917.
15.Pellicer A,Albert C,Mercader A,Bonilla-Musoles F,Remohi J,Simo'n C.The pathogenesis of ovarian hyperstimulation syndrome:In vivo studies investigating the role of interleukin-1beta,interleukin-6,and vascular endothelial growth factor.Fertil Steril.1999;71:482-489.
16.Wunder DM,Kretschmer R,Bersinger NA.Concentrations of leptin and C-reactive protein in serum and follicular fluid during assisted reproductive cycles.Hum Reprod.2005;20:1266-1271.
17.WHO.The hypertensive disorders of pregnancy.In:World Health Organization Technical Report Series,1987.758.Geneva:World Health Organization.
18.Kolialexi A,Mavrou A,Spyrou G,Tsangaris GT.Mass spectrometry-based proteomics in reproductive medicine.Mass Spectrom Rev.2008 Nov-Dec;27(6):624-34.
19.Hu S,Loo JA,Wong DT.Human body fluid proteome analysis.Proteomics.2006Dec;6(23):6326-53.
20.Riding GA,Hill JR,Jones A,Holland MK,Josh PF,Lehnert SA.Differential proteomic analysis of bovine conceptus fluid proteins in pregnancies generated by assisted reproductive technologies.Proteomics.2008 Jul;8(14):2967-82.
21.Dasari S,Pereira L,Reddy AP,Michaels JE,Lu X,Jacob T,Thomas A,Rodland M,Roberts CT Jr,Gravett MG,Nagalla SR.Comprehensive proteomic analysis of human cervical-vaginal fluid.J Proteome Res.2007 Apr;6(4):1258-68.Epub 2007 Mar 21.Comment in:J Proteome Res.2007 Apr;6(4):1241-2.
22.Joo WA,Lee DY,Kim CW.Development of an effective sample preparation method for the proteome analysis of body fluids using 2-D gel electrophoresis.Biosci Biotechnol Biochem.2003 Jul;67(7):1574-7.
23.Nilsson S,Ramstr(o|¨)m M,Palmblad M,Axelsson O,Bergquist J.Explorative study of the protein composition of amniotic fluid by liquid chromatography electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry. J Proteome Res. 2004 Jul-Aug; 3(4):884-9.
24. Michaels JE, Dasari S, Pereira L, Reddy AP, Lapidus JA, Lu X, Jacob T, Thomas A, Rodland M, Roberts CT Jr, Gravett MG, Nagalla SR.Comprehensive proteomic analysis of the human amniotic fluid proteome:gestational age-dependent changes. J Proteome Res. 2007 Apr; 6(4): 1277-85. Epub 2007 Mar 21.
25. Cho CK, Shan SJ, Winsor EJ, Diamandis EP. Proteomics analysis of human amniotic fluid.Mol Cell Proteomics. 2007 Aug; 6(8):1406-15. Epub 2007 May 10.
26. Roubelakis MG, Pappa KI, Bitsika V, Zagoura D, Vlahou A, Papadaki HA,Antsaklis A, Anagnou NP.Molecular and proteomic characterization of human mesenchymal stem cells derived from amniotic fluid: comparison to bone marrow mesenchymal stem cells.Stem Cells Dev. 2007 Dec;16(6):931-52.
27. Jungblut PR, Zimny Amdt U, Zeindl Eberhart E, el al. Protecmic in human diseases: cancer,heart and infectious diseases. Electrophoresis, 1999. 20(10):2100-2110.
28. Buhimschi CS, Bhandari V, Hamar BD, Bahtiyar MO, Zhao G, Sfakianaki AK,Pettker CM, Magloire L, Funai E, Norwitz ER, Paidas M, Copel JA, Weiner CP,Lockwood CJ, Buhimschi IA.Proteomic profiling of the amniotic fluid to detect inflammation, infection, and neonatal sepsis.PLoS Med. 2007 Jan;4(1):e18.
29. Buhimschi IA, Buhimschi CS, Weiner CP, Kimura T, Hamar BD, Sfakianaki AK,Norwitz ER, Funai EF, Ratner E. Proteomic but not enzyme-linked immunosorbent assay technology detects amniotic fluid monomeric calgranulins from their complexed calprotectin form.Clin Diagn Lab Immunol. 2005 Jul;12(7):837-44.
30. Buhimschi IA, Buhimschi CS, Christner R, Weiner CP.Proteomics technology for the accurate diagnosis of inflammation in twin pregnancies.BJOG 2005 Feb;112(2):250-5.
31. Buhimschi IA, Christner R, Buhimschi CS. Proteomic biomarker analysis of amniotic fluid for identification of intra-amniotic inflammation.BJOG 2005 Feb;112(2): 173-81.Comment in: BJOG 2006 Apr; 113(4):2 p preceding 369.
32. Buhimschi IA, Buhimschi CS, Christner R, Norwitz E, Weiner CP.Proteomic Profiling and Intra-amniotic Infection.JAMA. 2004 Nov 17; 292(19):2338; author reply 2338-9.Comment on: JAMA. 2004 Jul 28; 292(4):462-9.
33. Buhimschi CS, Buhimschi IA, Abdel-Razeq S, Rosenberg VA, Thung SF, Zhao G,Wang E, Bhandari V. Proteomic biomarkers of intra-amniotic inflammation:relationship with funisitis and early-onset sepsis in the premature neonate.Pediatr Res. 2007 Mar;61(3):318-24.
34. Buhimschi IA, Zambrano E, Pettker CM, Bahtiyar MO, Paidas M, Rosenberg VA,Thung S, Salafia CM, Buhimschi CS.Using proteomic analysis of the human amniotic fluid to identify histologic chorioamnionitis. Obstet Gynecol. 2008 Feb;111(2 Pt 1):403-12.
35. Pettker CM, Buhimschi IA, Magloire LK, Sfakianaki AK, Hamar BD, Buhimschi CS.Value of placental microbial evaluation in diagnosing intra-amniotic infection.Obstet Gynecol. 2007 Mar;109(3):739-49.
36. Buhimschi CS, Abdel-Razeq S, Cackovic M, Pettker CM, Dulay AT, Bahtiyar MO,Zambrano E, Martin R, Norwitz ER, Bhandari V, Buhimschi IA.Fetal heart rate monitoring patterns in women with amniotic fluid proteomic profiles indicative of inflammation.Am J Perinatal. 2008 Jun; 25(6):359-72. Epub 2008 May 29.
37. Klein LL, Freitag BC, Gibbs RS, Reddy AP, Nagalla SR, Gravett MGDetection of intra-amniotic infection in a rabbit model by proteomics-based amniotic fluid analysis.Am J Obstet Gynecol. 2005 Oct;193(4): 1302-6.
38. Park SJ, Yoon WG, Song JS, Jung HS, Kim CJ, Oh SY, Yoon BH, Jung G, Kim HJ, Nirasawa T.Proteome analysis of human amnion and amniotic fluid by two-dimensional electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.Proteomics. 2006 Jan; 6(1):349-63.
39. Gravett MG, Novy MJ, Rosenfeld RG, Reddy AP, Jacob T, Turner M,McCormack A,Lapidus JA, Hitti J, Eschenbach DA, Roberts CT Jr, Nagalla SR.Diagnosis of intra-amniotic infection by proteomic profiling and identification of novel biomarkers.JAMA. 2004 Jul 28; 292(4):462-9.Erratum in: JAMA. 2004 Nov; 292(19):2340.Comment in: JAMA. 2004 Nov 17; 292(19):2338; author reply 2338-9.
40. Gravett MG, Thomas A, Schneider KA, Reddy AP, Dasari S, Jacob T, Lu X,Rodland M,Pereira L, Sadowsky DW, Roberts CT Jr, Novy MJ, Nagalla SR.Proteomic analysis of cervical-vaginal fluid: identification of novel biomarkers for detection of intra-amniotic infection.J Proteome Res. 2007 Jan;6(1):89-96.
41. Crawford JT, Pereira L, Buckmaster J, Gravett MG, Tolosa JE.Amniocentesis results and novel proteomic analysis in a case of occult candidal chorioamnionitis.J Matem Fetal Neonatal Med. 2006 Oct;19(10):667-70.
42. Klein LL, Jonscher KR, Heerwagen MJ, Gibbs RS, McManaman JL.Shotgun proteomic analysis of vaginal fluid from women in late pregnancy.Reprod Sci.2008 Apr,15(3):263-73.
43. Vuadens F, Benay C, Crettaz D, Gallot D, Sapin V, Schneider P, Bienvenut WV,Lemery D, Quadroni M, Dastugue B, Tissot JD.Identification of biologic markers of the premature rupture of fetal membranes: proteomic approach. Proteomics.2003 Aug;3(8):1521-5.
44. Michel PE, Crettaz D, Morier P, Heller M, Gallot D, Tissot JD, Reymond F,Rossier JS.Proteome analysis of human plasma and amniotic fluid by Off-Gel isoelectric focusing followed by nano-LC-MS/MS.Electrophoresis. 2006 Mar;27(5-6):1169-81.
45. Thadikkaran L, Crettaz D, Siegenthaler MA, Gallot D, Sapin V, Iozzo RV, Queloz PA, Schneider P, Tissot JD.The role of proteomics in the assessment of premature rupture of fetal membranes.Clin Chim Acta. 2005 Oct; 360(1-2):27-36.
46. Tinnakorn C. A proteomic approach for the identif ication of biological markers of preeclampsia [J]. Am J Obstet and Gynecol. 2003; 11 (1):S95.
47. Mert OB, Ray BS, J oshua A, et al. Serum proteomics distinguish preeclamptic women from normal women [J] .Obstet & Gynecol. 2003; 4:S82.
48. Watanabe H,HamadaH, Yamada N,el al. Proteomeanalysis reveals elevated serum levels of clustein in patients with preeclampsia. Proteomics. 2004;4(2):537-543.
49. Koy C, Heitner JC, Woisch R, el al. Cryodelector mass spectrometry profiling of plasma samples for HELLP diagnosis: all exploratory study. Proteomics. 2005;5(12): 3079—3087
50. Norwitz ER Tsen LC, Park JS, el al. Discriminatory proteomic biomarker analysis identifies free hemoglobin in the cerebrospinal fluid of women with severe preeclampsia. Am J Obstet Gynecol.2005;193 (3): 957-964
51. Park JS, Oh KJ, Norwitz ER, Han JS, Choi HJ, Seong HS, Kang YD, Park CW, Kim BJ, Jun JK, Syn HC.Identification of proteomic biomarkers of preeclampsia in amniotic fluid using SELDI-TOF mass spectrometry.Reprod Sci. 2008 May;15(5):457-68.
52. Vascotto C, Salzano AM, D'Ambrosio C, Fruscalzo A, Marchesoni D, di Loreto C,Scaloni A, Tell G, Quadrifoglio F.Oxidized transthyretin in amniotic fluid as an early marker of preeclampsia. J Proteome Res. 2007 Jan;6(1):160-70.
53. Genbacev O, Miller R K. Post-implantation differentiation and proliferation of cytotrophoblast cells: in vit ro models a review [J]. Placenta. 2000; 3 (21 A):S45 -S49.
54. Gratton RJ, Gandley RE, Genbacev O, el al. Conditioned medium from hypoxic cytotrophoblasts alters arterial function. Am J Obstet Gynecol.2001;184 (5):984-990
55. Hoang VM, Foulk R, Clauser K, et al. Functional proteomics: examining the effects of hypoxia on the cytotrophoblast protein repertoi re [J]. Endocrinology.2003; 144(4):1147-1154.
56. Than NG, Pick E, Bellyei S, et al. Functional analyses of placental protein 13/galectin-13. Eur J Biochem.2004;271(6): 1065-1078
57. Sawicki G,Dakour J,Morrish DW. Functional proteomics of neurokinin B in the placenta indicates a novel role in regulating cytotrophoblast antioxidant defences. Proteomics.2003; 3(10): 2044—2051
58. Batorfi J, Ye B, Mok SC, elal. Protein profiling of complete mole and normal placenta using ProteinChip analysis on laser capture microdissected cells.Gyneeol Oncol.2003;88(3): 424-428
59. Vorum H . Ostergaard M , Hensechke P,et al . Proteomic analysis of hyperoxia-induced responses jn the human choriocarcinoma cell line JEG-3. Proteomics.2004;4(3): 861-867
60. Bahtiyar MO, Copel JA, Mahoney MJ, Buhimschi IA, Buhimschi CS.Proteomics:a novel methodology to complement prenatal diagnosis of chromosomal abnormalities and inherited human diseases. Am J Perinatol. 2007 Mar; 24(3):167-81.Epub 2007 Mar 19.
61. Tsangaris GT, Kolialexi A, Karamessinis PM, Anagnostopoulos AK, Antsaklis A,Fountoulakis M, Mavrou A.The normal human amniotic fluid supernatant proteome.In Vivo. 2006 Jul-Aug; 20(4):479-90.
62. Tsangaris GT, Karamessinis P, Kolialexi A, Garbis SD, Antsaklis A, Mavrou A,Fountoulakis M.Proteomic analysis of amniotic fluid in pregnancies with Down syndrome. Proteomics. 2006 Aug; 6(15):4410-9.
63. Wang TH, Chang YL, Peng HH, Wang ST, Lu HW, Teng SH, Chang SD, Wang HS.Rapid detection of fetal aneuploidy using proteomics approaches on amniotic fluid supernatant. Prenat Diagn. 2005 Jul; 25(7):559-66.
64. Datta S, Turner D, Singh R, Ruest LB, Pierce WM Jr, Knudsen TB.Fetal alcohol syndrome (FAS) in C57BL/6 mice detected through proteomics screening of the amniotic fluid.Birth Defects Res A Clin Mol Teratol. 2008 Apr; 82(4):177-86.
65. Hassan MI, Kumar V, Singh TP, Yadav S. Proteomic analysis of human amniotic fluid from Rh(-) pregnancy.Prenat Diagn. 2008 Feb; 28(2): 102-8.
66. Chevalier RL.Biomarkers of congenital obstructive nephropathy: past, present and future.J Urol. 2004 Sep; 172(3):852-7.Comment in: J Urol. 2005 Jun;173(6):2207; author reply 2207-8.
1. Kolialexi A, Mavrou A, Spyrou G, Tsangaris GT. Mass spectrometry-based proteomics in reproductive medicine.Mass Spectrom Rev. 2008 Nov-Dec;27(6):624-34.
2. Shiwa M, Nishimura Y, Wakatabe R, et al. Rapid discovery and identification of a tissue-specific tumor biomarker from 39 human cancer cell lines using the SELDI ProteinChip platform. Biochem Biophys Res Commun. 2003;309:18-25.
3. Paweletz CP, Trock B, Pennanen M, Tsangaris T, Magnant C, Liotta LA, et al.Proteomic patterns of nipple aspirate fluids obtained by SELDI-TOF: potential for new biomarkers to aid in the diagnosis of breast cancer. Dis Markers. 2001;17:301-7.
4. Miguet L, Bogumil R, Decloquement P, Herbrecht R, Potier N, Mauvieux L,et al.Discovery and identification of potential biomarkers in a prospective study of chronic lymphoid malignancies using SELDI-TOF-MS. J Proteome Res. 2006;5:2258-69.
5. Lin Z, Jenson SD, Lim MS, Elenitoba-Johnson KS. Application of SELDI-TOF mass spectrometry for the identification of differentially expressed proteins in transformed follicular lymphoma. Mod Pathol. 2004; 17:670-8.
6. Tsangaris GT, Kolialexi A, Karamessinis PM, Anagnostopoulos AK, Antsaklis A,Fountoulakis M, Mavrou A. The normal human amniotic fluid supernatant proteome. In Vivo. 2006;20:479-490.
7. Boeckmann, B., Bairoch, A., Apweiler, R., et al. The Swiss-Prot protein knowledgebase and its supplement TrEMBL in 2003. Nucleic Acids Res. 2003;31,354-370.
8. Gasteiger, E., Gattiker, A., Hoogland, C., Ivanyi, I., Appel, R. D. and Bairoch, A.ExPASy—the proteomics server for in-depth protein knowledge and analysis.Nucleic Acids Res. 2003; 31, 3784-3788.
9. Wang TH, Chang YL, Peng HH, Wang ST, Lu HW, Teng SH, Chang SD, Wang HS. Rapid detection of fetal aneuploidy using proteomics approaches on amniotic fluid supernatant. Prenat Diagn. 2005; 25:559- 566.
10. Oh JE, Fountoulakis M, Juranville JF, Rosner M, Hengstschlager M, Lubec G.Proteomic determination of metabolic enzymes of the amnion cell: Basis for a possible diagnostic tool? Proteomics. 2004; 4:1145-1158.
11. Tsangaris GT, Karamessinis P, Kolialexi A, Garbis SD, Antsaklis A, Mavrou A,Foun-toulakis M. Proteomic analysis of amniotic fluid in pregnancies with Down syndrome. Proteomics. 2006;6:4410-4419.
12. Mavrou A, Anagnostopoulos AK, Kolialexi A, Vougas K, Papantoniou N,Antsaklis A, Fountoulakis M, Tsangaris GT. Proteomic analysis of amniotic fluid in pregnancies with turner syndrome fetuses. J Proteome Res. 2008; 7:1862-1866.
13. Nagalla SR, Canick JA, Jacob T, Schneider KA, Reddy AP, Thomas A, Dasari S,Lu X, Lapidus JA, Lambert-Messerlian GM, Gravett MG, Roberts CT Jr, Luthy D, Malone FD, D'Alton ME. Proteomic analysis of maternal serum in Down syndrome: Identification of novel protein biomarkers. J Proteome Res. 2007;6:1245-1257.
14. Li J, Zhang Z, Rosenzweig J, Wang YY, Chan DW. L Proteomics and bioinformatics approaches for identification of serum biomarkers to detect breast cancer. Clin Chem. 2002; 48:1296-304.
15. Buhimschi IA, Christner R, Buhimschi CS. Proteomic biomarker analysis of amniotic fluid for identification of intra-amniotic inflammation. Br J Obstet Gynaecol. 2005; 112:173-181.
16. Gravett MG, Novy MJ, Rosenfeld RG, Reddy AP, Jacob T, Turner M,McCor-mack A, Lapidus JA, Hitti J, Eschenbach DA, Roberts CT Jr, Nagalla SR.Diagnosis of intra-amniotic infection by proteomic profiling and identification of novel bio-markers. J Am Med Assoc, 2004;28:462-469
17. Buhimschi IA, Buhimschi CS, Christner R, Weiner CP. Proteomics technology for the accurate diagnosis of inflammation in twin pregnancies. Br J Obstet Gynaecol, 2005; 112:250-255.
18. Buhimschi CS, Weiner CP, Buhimschi IA. Proteomics. Part II. The emerging role of proteomics over genomics in spontaneous preterm labor/birth. Obstet Gynecol Survey, 2006; 61:543-553.
19. Park JS, Oh KJ, Norwitz ER, et al.Identification of proteomic biomarkers of preeclampsia in amniotic fluid using SELDI-TOF mass spectrometry.Reprod Sci.2008 May;15(5):457-68.
20. Tolson J, Bogumil R, Brunst E, Beck H, Eisner R, Humeny A, et al. Serum protein profiling by SELDI mass spectrometry: detection of multiple variants of serum amyloid alpha in renal cancer patients. Lab Invest. 2004; 84:845-56.
1. Barkovich AJ. Brain development: normal and abnormal. In: Atlas S, editor. Magnetic Resonance Imaging of the brain and spine. New York: Raven. 1991;129-75.
2. Barkovich AJ. Magnetic resonance imaging: role in the understanding of cerebral malformations. Brain Develop. 2002;24:2-12.
3. Izabela Herman-Sucharska, Monika Bekiesinska-Figatowska, Andrzej Urbanik,Fetal central nervous system malformations on MR images Brain & Development.2009;31:185-199.
4. Christianson A. et al. March of Dimes Global Report of Birth Defects: The Hidden Toll of Dying and Disabled Children. (2006) (accessed August 28, 2008).
5. Coakley F, Glenn OA, Qayyum A, Barkovich AJ, Goldstein R, Filly RA. Fetal MRI: a developing technique for the developing patient. AJR. 2004; 182: 243-252.
6. Tannus JF, Dagoglu G, Oto A.Magnetic resonance imaging of maternal diseases of the abdomen and pelvis in the pregnant patient. Am J Perinatal. 2008 Nov;25(10):605-10. Epub 2008 Oct 7.
7. Wright C, Sibley C, Baker P.The role of Fetal Magnetic Resonance Imaging.Arch Dis Child Fetal Neonatal Ed. 2009 Feb 10. Epub ahead of print
8. Kolialexi A, Mavrou A, Spyrou G, Tsangaris GT. Mass spectrometry-based proteomics in reproductive medicine.Mass Spectrom Rev. 2008 Nov-Dec; 27(6):624-34.
9. Shiwa M, Nishimura Y, Wakatabe R, et al. Rapid discovery and identification of a tissue-specific tumor biomarker from 39 human cancer cell lines using the SELDI ProteinChip platform. Biochem Biophys Res Commun. 2003;309:18-25.
10. Paweletz CP, Trock B, Pennanen M, Tsangaris T, Magnant C, Liotta LA, et al.Proteomic patterns of nipple aspirate fluids obtained by SELDI-TOF: potential for new biomarkers to aid in the diagnosis of breast cancer. Dis Markers. 2001;17:301-7.
11. Miguet L, Bogumil R, Decloquement P, Herbrecht R, Potier N, Mauvieux L,et al.Discovery and identification of potential biomarkers in a prospective study of chronic lymphoid malignancies using SELDI-TOF-MS. J Proteome Res. 2006; 5:2258-69.
12. Lin Z, Jenson SD, Lim MS, Elenitoba-Johnson KS. Application of SELDI-TOF mass spectrometry for the identification of differentially expressed proteins in transformed follicular lymphoma. Mod Pathol 2004; 17:670-8.
13. Tsangaris GT, Kolialexi A, Karamessinis PM, Anagnostopoulos AK, Antsaklis A,Fountoulakis M, Mavrou A. The normal human amniotic fluid supernatant proteome. In Vivo. 2006; 20:479-490.
14. Anderson NL, Anderson NG.Proteome and proteomics: new technologies, new concepts, and new words. Electrophoresis. 1998 Aug; 19(11):1853-61.
15. Blackstock WP, Weir MP.Proteomics: quantitative and physical mapping of cellular proteins. Trends Biotechnol. 1999 Mar; 17(3):121-7.
16. James P.Protein identification in the post-genome era: the rapid rise of proteomics. Q Rev Biophys. 1997 Nov; 30(4):279-331.
17. Wilkins MR, Pasquali C, Appel RD, Ou K, Golaz O, Sanchez JC, Yan JXGooley AA, Hughes G, Humphery-Smith I, Williams KL, Hochstrasser DF.From proteins to proteomes: large scale protein identification by two-dimensional electrophoresis and amino acid analysis. Biotechnology (N Y). 1996 Jan; 14(1):61-5.
18. Brewis IA. Proteomics in reproductive research: The potential importance of proteomics to research in reproduction. Hum Reprod.1999; 14:2927-2929.
19. Page NM, Kemp CF, Butlin DJ, Lowry PJ. Placental peptides as markers of gestational disease. Reproduction. 2002; 123:487-494.
20. Jauniaux E, Greenwold N, Hempstock J, Burton GJ. Comparison of ultrasonographic and Doppler mapping of the intervillous circulation in normal and abnormal early pregnancies. Fertil Steril.2003; 79:100-106.
21. Li J, Zhang Z, Rosenzweig J, Wang YY, Chan DW. L Proteomics and bioinformatics approaches for identification of serum biomarkers to detect breast cancer. Clin Chem. 2002; 48:1296-304.
22. Buhimschi IA, Christner R, Buhimschi CS. Proteomic biomarker analysis of amniotic fluid for identification of intra-amniotic inflammation. Br J Obstet Gynaecol.2005; 112:173-181.
23. Gravett MG, Novy MJ, Rosenfeld RG, Reddy AP, Jacob T, Turner M,McCor-mack A, Lapidus JA, Hitti J, Eschenbach DA, Roberts CT Jr, Nagalla SR.Diagnosis of intra-amniotic infection by proteomic profiling and identification of novel bio-markers. J Am Med Assoc. 2004; 28:462-469
24. Buhimschi IA, Buhimschi CS, Christner R, Weiner CP. Proteomics technology for the accurate diagnosis of inflammation in twin pregnancies. Br J Obstet Gynaecol 2005; 112:250-255.
25. Buhimschi CS, Weiner CP, Buhimschi IA. Proteomics. Part II. The emerging role of proteomics over genomics in spontaneous preterm labor/birth. Obstet Gynecol Survey 2006; 61:543-553.
26. Park JS, Oh KJ, Norwitz ER, et al. Identification of proteomic biomarkers of preeclampsia in amniotic fluid using SELDI-TOF mass spectrometry. Reprod Sci.2008; May; 15(5): 457-68.
27. Tolson J, Bogumil R, Brunst E, Beck H, Eisner R, Humeny A, et al. Serum protein profiling by SELDI mass spectrometry: detection of multiple variants of serum amyloid alpha in renal cancer patients. Lab Invest 2004; 84:845-56.