Identification of Novel Protein Biomarkers of Preterm Birth in Human Cervical−Vaginal Fluid

Introduction: To date, there are limited data on the potential role of proteomic biomarkers to predict future cardiovascular (CV) events among patients with type 2 diabetes mellitus (DM). Hypothesis: Specific protein biomarkers will be predictive of major adverse CV events (MACE) and incident heart failure hospitalization (HFH) among patients with DM. Methods: Using the Olink aptamer-based platform, we performed proteomic profiling (>700 proteins) on 440 paired cases and matched controls from placebo-assigned participants in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). Cases were defined as having met the primary composite outcome of MACE or incident HFH and matched to controls on baseline prevalent heart failure, coronary artery disease, BMI, hemoglobin A1C, creatinine, low-density lipoprotein cholesterol, fasting status and ejection fraction. Conditional logistic regression was used to determine the association between log-transformed relative protein expression and incident MACE or HFH. False-discovery-rate (FDR) was used to adjust for multiple comparisons. Results: We identified three specific proteins that were significantly associated with prevalent MACE or HFH: METRNL, Notch 3, and ROR1 (OR 2.1, 1.6, 1.7 and q-value 0.01, 0.02, and 0.05 respectively) (Figure 1). METRNL, in particular, performed similarly to the established biomarker NT-proBNP (Figure 1). When MACE and HFH were analyzed separately, METRNL, in particular, remained strongly associated with both outcomes (OR 2.0, p<0.001 and OR 2.7, p=0.05). Conclusions: Three novel protein biomarkers, in particular METRNL (a circulating adipokine that regulates insulin-sensitivity), may identify diabetic patients at high risk for subsequent HF and MACE. Additional studies are needed to replicate these findings and uncover the biologic mechanism linking adipokine signaling and heart failure.

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Vaginal Microbiota, Genital Inflammation and Extracellular Matrix Remodelling Collagenase: MMP-9 in Pregnant Women With HIV, a Potential Preterm Birth Mechanism Warranting Further Exploration

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.750103 ◽

2021 ◽

Vol 11 ◽

Author(s):

Charlotte-Eve S. Short ◽

Rachael A. Quinlan ◽

Xuan Wang ◽

Veronica Georgiana Preda ◽

Ann Smith ◽

...

Keyword(s):

Preterm Birth ◽

Pregnant Women ◽

Genital Tract ◽

Amplicon Sequencing ◽

Vaginal Microbiota ◽

Vaginal Fluid ◽

Polymorphonuclear Leucocytes ◽

Genital Tract Infection ◽

Maternal Characteristics ◽

Tnf Α

BackgroundPregnant women living with HIV infection (PWLWH) have elevated rates of preterm birth (PTB) in which HIV and cART are implicated. PWLWH also have a high prevalence of adverse vaginal microbiota, which associate with genital tract inflammation. The mechanism underlying PTB in PWLWH is unknown. We present the first data in PWLWH on genital-tract matrix-metalloproteinase-9(MMP-9), an important collagenase implicated in labour onset, and tissue inhibitor of metalloproteinases-1(TIMP-1) and explore correlations with local inflammation and vaginal bacteria.Material and MethodsCervical vaginal fluid (CVF) collected by a soft cup and high vaginal swabs (HVS) were obtained from PWLWH and HIV uninfected pregnant women (HUPW) at three antenatal time points. Maternal characteristics, combination antiretroviral therapy (cART) exposure, and pregnancy outcome were recorded. Concentrations of MMP-9, TIMP-1 and ten cytokines were measured by immunoassays. Vaginal microbiota composition was determined through 16S rRNA amplicon sequencing. MMP-9, TIMP-1 and cytokine concentrations were compared by HIV status, cART, and prematurity and in PWLWH correlations with polymorphonuclear leucocytes, cytokines and bacterial genera were explored.ResultsCVF was available for 50 PWLWH (108 samples) and 12 HUPW (20 samples) between gestation weeks 14-38. Thirty-six PWLWH conceived on cART and 14 initiated post-conception. There were five and one PTB outcomes in PWLWH and HUPW respectively. PWLWH had higher mean CVF concentrations of MMP-9 (p<0.001) and TIMP-1 (p=0.035) in the second trimester compared with HUPW with a similar trend in the third trimester. PWLWH also had higher CVF values of cytokines: IL-1β, IL-8, IL-12 and TNF-α in both trimesters compared to HUPW (p ≤ 0.003). In PWLWH, MMP-9 positively correlated with TIMP-1 (r=0.31, p=0.002) and CVF polymorphonuclear leucocytes (r=0.57, p=0.02). Correlations were observed between MMP-9 and three cytokines: IL-1β (r=0.61), IL-8 (r=0.57) and TNF-α (r=0.64), p<0.001, similarly for TIMP-1. Abundance of anaerobic pathobionts correlated with MMP-9: Gardnerella (r=0.44, p<0.001), Atopobium (r=0.33, p=0.005), and Prevotella genera (r=0.39, p<0.001). Conversely proportion of Lactobacillus genera negatively correlated with MMP-9 (rho=-0.46, p<0.001). MMP-9/TIMP-1 ratio increased with gestational age at sampling in PWLWH, but this was no longer significant after adjusting for confounders and no difference by prematurity was observed in this sub-study.ConclusionsHere we show strong correlations of MMP-9 to genital tract inflammation and sub-optimal bacterial genera in PWLWH indicating the ascending genital tract infection pathway may be a contributory mechanism to the high risk of PTB.

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Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau

Neuropsychopharmacology ◽

10.1038/s41386-020-00840-3 ◽

2020 ◽

Vol 46 (1) ◽

pp. 98-115 ◽

Cited By ~ 2

Author(s):

Sruti Rayaprolu ◽

Lenora Higginbotham ◽

Pritha Bagchi ◽

Caroline M. Watson ◽

Tian Zhang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Brain Network ◽

Protein Biomarkers ◽

Cellular Processes ◽

Complex Protein ◽

Underlying Mechanisms ◽

Novel Protein

AbstractThe repeated failures of amyloid-targeting therapies have challenged our narrow understanding of Alzheimer’s disease (AD) pathogenesis and inspired wide-ranging investigations into the underlying mechanisms of disease. Increasing evidence indicates that AD develops from an intricate web of biochemical and cellular processes that extend far beyond amyloid and tau accumulation. This growing recognition surrounding the diversity of AD pathophysiology underscores the need for holistic systems-based approaches to explore AD pathogenesis. Here we describe how network-based proteomics has emerged as a powerful tool and how its application to the AD brain has provided an informative framework for the complex protein pathophysiology underlying the disease. Furthermore, we outline how the AD brain network proteome can be leveraged to advance additional scientific and translational efforts, including the discovery of novel protein biomarkers of disease.

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Identification of four novel serum protein biomarkers in sepsis patients encoded by target genes of sepsis-related miRNAs

Clinical Science ◽

10.1042/cs20130301 ◽

2014 ◽

Vol 126 (12) ◽

pp. 857-867 ◽

Cited By ~ 16

Author(s):

Hui-juan Wang ◽

Bao-zeng Wang ◽

Peng-jun Zhang ◽

Jie Deng ◽

Zhi-rui Zhao ◽

...

Keyword(s):

Serum Protein ◽

Sofa Score ◽

Predictive Value ◽

Mirna Target ◽

Target Genes ◽

Apache Ii Score ◽

Protein Biomarkers ◽

Combined Analysis ◽

Better Than ◽

Novel Protein

Four novel protein biomarkers encoded by the miRNA target genes were identified for patients with sepsis. The combined analysis of the four proteins indicated that their predictive value for sepsis prognosis was better than the values for the SOFA score and APACHE II score.

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Research Profile: The cervical–vaginal fluid proteome and possible biomarkers of preterm birth

Journal of Proteome Research ◽

10.1021/pr070737o ◽

2007 ◽

Vol 6 (4) ◽

pp. 1241-1242 ◽

Cited By ~ 2

Author(s):

Katie Cottingham

Keyword(s):

Preterm Birth ◽

Vaginal Fluid ◽

Research Profile

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Bacterial Vaginosis, Vaginal Fluid Neutrophil Defensins, and Preterm Birth

Obstetrics and Gynecology ◽

10.1097/00006250-200305000-00007 ◽

2003 ◽

Vol 101 (5, Part 1) ◽

pp. 862-868

Author(s):

Rukmini B. Balu ◽

David A. Savitz ◽

Cande V. Ananth ◽

Katherine E. Hartmann ◽

William C. Miller ◽

...

Keyword(s):

Preterm Birth ◽

Bacterial Vaginosis ◽

Vaginal Fluid

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Determination of pH as a method of prevention of preterm birth of infectious genesis in women with a history of miscarrage

Journal of obstetrics and women s diseases ◽

10.17816/jowd64129-33 ◽

2015 ◽

Vol 64 (1) ◽

pp. 29-33

Author(s):

Tamara Aleksandrovna Pluzhnikova

Keyword(s):

Preterm Birth ◽

Ph Control ◽

Control Group ◽

Vaginal Fluid ◽

Urogenital Infection ◽

Vaginal Ph ◽

Fold Reduction ◽

History Of ◽

Group 2

There is substantial evidence that urogenital infection is one of the major causes of preterm birth, with bacterial vaginosis being one of these infections. Timely diagnosis and treatment of this condition significantly reduce the rate of preterm birth. The aim of this study was to evaluate the method of pH determination of vaginal fluid in women at a risk of preterm birth. A total of 66 women were included in the study. The women were divided into two groups. Group 1 consisted of 30 women, who measured vaginal pH from week 12 and 36 of gestation twice a week using the test рН-Balance (PremiumDiagnostics, Germany). Group 2 comprised 36 women, who did not measure vaginal pH (control group). Abnormal рН (>4,4) were observed in 9 women (30.0 %). Of them, in 8 women a urogenital infection was observed. All patients received etiotropic treatment. pH measuring in women with a history of miscarriage resulted in 4.5-fold reduction of preterm birth (from 30.0 to 6.7 %). In the control group the was no significant reduction in the rate of preterm birth (from 22.2 to 19.4 %).

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