Identification and Quantification of Preterm Birth Biomarkers in Human Cervicovaginal Fluid by Liquid Chromatography/Tandem Mass Spectrometry

Shah, Sameena; Yu, Kenneth H.; Sangar, Vineet; Parry, Samuel; Blair, Ian A.

doi:10.1021/pr8010342

Cited by 62 publications

(75 citation statements)

References 57 publications

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“…There have been a limited number of proteomic studies endeavouring to discover differentially expressed proteins in the CVF in association with preterm birth (Pereira et al 2007, Shah et al 2009). As we continue to elucidate the role of these biochemical markers in preterm birth, there is yet to be developed a predictive test superior to the current 'gold standards' of fFN and the IGFBP1.…”

Section: Discussionmentioning

confidence: 99%

Prediction of spontaneous preterm labour in at-risk pregnant women

Liong¹,

Quinzio²,

Fleming³

et al. 2013

Reproduction

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The ability to recognise women who are at-risk of preterm labour (PTL) is often difficult. Over 50% of women who are identified with factors associated with an increased risk of preterm birth will ultimately deliver at term. The cervicovaginal fluid (CVF) comprises a range of proteins secreted by gestational tissues, making it an ideal candidate for the screening of differentially expressed proteins associated with PTL. CVF samples were collected from at-risk asymptomatic women. Two-dimensional gel electrophoresis techniques were used to examine the CVF proteome of women who spontaneously delivered preterm 11-22 days later compared with gestation-matched women who delivered at term. Five candidate biomarkers were selected for further validation in a larger independent cohort of asymptomatic women. Thioredoxin (TXN) and interleukin 1 receptor antagonist (IL1RN) concentrations in the CVF were found to be significantly reduced up to 90 days prior to spontaneous PTL compared with women who subsequently delivered at term. TXN was able to predict spontaneous PTL within 28 days after sampling with a high positive predictive value (PPV) and negative predictive value (NPV) of 75.0% and 96.4% respectively. IL1RN also showed comparable PPV and NPV of 72.7% and 95.7% respectively. The discovery of these differentially expressed proteins may assist in the development of a new predictive bedside test in identifying asymptomatic women who have an increased risk of spontaneous PTL.

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Section: Discussionmentioning

confidence: 99%

Prediction of spontaneous preterm labour in at-risk pregnant women

Liong¹,

Quinzio²,

Fleming³

et al. 2013

Reproduction

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“…This may explain why statistical significance was not observed in the validation cohort. FABP5 has been identified in the CVF by at least eight other groups but the existence of different isoforms could not be described using the technologies employed (Venkataraman et al 2005, Shaw et al 2007, Tang et al 2007, Klein et al 2008, Shah et al 2009, Zegels et al 2009). The significance of the different isoforms therefore remains unclear.…”

Section: Discussionmentioning

confidence: 99%

“…The CVF proteome has been comprehensively characterised in pregnant and non-pregnant women , Di Quinzio et al 2007, Shaw et al 2007, Tang et al 2007, Klein et al 2008, Shah et al 2009, Zegels et al 2009, Heng et al 2010a. Using two-dimensional PAGE (2D-PAGE) proteomic analysis of human CVF, we have demonstrated temporal protein changes in association with impending spontaneous term labour (Di Quinzio et al 2008, Heng et al 2010a.…”

Section: Introductionmentioning

confidence: 99%

Proteomic analysis of human cervicovaginal fluid collected before preterm premature rupture of the fetal membranes

et al. 2013

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A significant obstetric complication facing contemporary materno-fetal medicine is preterm premature rupture of the fetal membranes (preterm PROM), which occurs in 30% of all preterm births. The objective of this study was to identify differentially expressed proteins in the cervicovaginal fluid of asymptomatic women before the clinical manifestation of preterm PROM. The preterm PROM group comprised of women with samples collected 6-23 days before PROM, who subsequently delivered preterm (nZ5). Women who spontaneously delivered at term served as gestation-matched controls (nZ10). Two-dimensional difference in-gel electrophoresis was used to distinguish differential expression between the pooled groups and fold changes were subsequently confirmed by two-dimensional PAGE of individual samples. Spots of interest were identified by mass spectrometry. Proteins that were significantly reduced with impending preterm PROM included the following: thioredoxin (2.7-fold), interleukin 1 receptor antagonist (1.7-fold), fatty acid-binding protein 5 (2.1-fold), cystatin A (dimer; 1.9-fold), monocyte/neutrophil elastase inhibitor (1.6-fold), squamous cell carcinoma antigen-1 (2.1-fold) and g-glutamyl cyclotransferase (3.0-fold). By contrast, annexin A3 (3.7-fold) and vitamin D binding protein (3.9-fold) were significantly increased with impending preterm PROM. Western blot analysis was also performed on an independent cohort of preterm PROM and control samples to validate these candidate biomarkers. These proteins have known biological functions in oxidative balance, anti-inflammatory activity, metabolism or protease inhibition that may facilitate membrane rupture.

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“…Quantitative selected reaction monitoring (SRM) assays (13,14) were introduced as a means to supplement antibody-based ELISAs that are widely used in clinical practice. Quantification and verification of biomarkers by SRM assays is an emerging field of proteomics (15)(16)(17).…”

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confidence: 99%

Verification of Male Infertility Biomarkers in Seminal Plasma by Multiplex Selected Reaction Monitoring Assay

Drabovich

Jarvi

Diamandis

2011

Molecular & Cellular Proteomics

101

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Seminal plasma is a promising biological fluid to use for noninvasive clinical diagnostics of male reproductive system disorders. To verify a list of prospective male infertility biomarkers, we developed a multiplex selected reaction monitoring assay and measured the relative abundance of 31 proteins in 30 seminal plasma samples from normal, nonobstructive azoospermia and post-vasectomy individuals. Median levels of some proteins were decreased by more than 100-fold in nonobstructive azoospermia or post-vasectomy samples, in comparison with normal samples. To follow up the most promising candidates and measure their concentrations in seminal plasma, heavy isotope-labeled internal standards were synthesized and used to reanalyze 20 proteins in the same set of samples. Concentrations of candidate proteins in normal seminal plasma were found in the range 0.1-1000 g/ml but were significantly decreased in nonobstructive azoospermia and post-vasectomy. These data allowed us to select, for the first time, biomarkers to discriminate between normal, nonobstructive azoospermia, and post-vasectomy (simulated obstructive azoospermia) seminal plasma samples. Some testis-specific proteins (LDHC, TEX101, and SPAG11B) performed with absolute or nearly absolute specificities and sensitivities. Cell-specific classification of protein expression indicated that Sertoli or germ cell dysfunction, but not Leydig cell dysfunction, was observed in nonobstructive azoospermia seminal plasma. The proposed panel of biomarkers, pending further validation, could lead to a clinical assay that can eliminate the need for testicular biopsy to diagnose the category of male infertility, thus providing significant benefits to patients as well as decreased costs associated with the differential diagnosis of azoospermia. Molecular & Cellular Proteomics 10: 10.1074/mcp.M110.004127, 1-13, 2011.Human infertility affects ϳ15% of couples, with the male contributing to the infertility in 50% of all cases (1, 2). One of the most severe forms of male infertility is azoospermia, which is characterized by an absence of sperm in the semen (3). Azoospermia is diagnosed in 20% of subfertile men and has two forms: obstructive azoospermia (OA) 1 and nonobstructive azoospermia (NOA). OA is caused by a physical obstruction in the male reproductive tract. The biological outcome of OA is thus identical to that of vasectomy, which is a surgical severance of the vas deferens. NOA is a more complicated infertility syndrome with the azoospermia being secondary to a failure to produce sperm; NOA may be further subclassified as maturation arrest, Sertoli cell-only syndrome, and hypospermatogenesis (4).For most men with azoospermia, testicular biopsy is the only currently used method to definitively distinguish between OA and NOA (5, 6). Thus, there is an urgent need for an alternative noninvasive approach with better diagnostic potential. The differential diagnosis of normal, NOA, and OA (or post-vasectomy (PV)) men is required for the following reasons: (i) in infertile pati...

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Identification and Quantification of Preterm Birth Biomarkers in Human Cervicovaginal Fluid by Liquid Chromatography/Tandem Mass Spectrometry

Cited by 62 publications

References 57 publications

Prediction of spontaneous preterm labour in at-risk pregnant women

Prediction of spontaneous preterm labour in at-risk pregnant women

Proteomic analysis of human cervicovaginal fluid collected before preterm premature rupture of the fetal membranes

Verification of Male Infertility Biomarkers in Seminal Plasma by Multiplex Selected Reaction Monitoring Assay

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