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The complexity of preterm birth (PTB), both spontaneous and medically indicated, and its various etiologies and associated risk factors pose a significant challenge for developing tools to accurately predict risk. This review focuses on the discovery of proteomics signatures that might be useful for predicting spontaneous PTB or preeclampsia, which often results in PTB. We describe methods for proteomics analyses, proteomics biomarker candidates that have so far been identified, obstacles for discovering biomarkers that are sufficiently accurate for clinical use, and the derivation of composite signatures including clinical parameters to increase predictive power., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Although most causes of death and morbidity in premature infants are related to immune maladaptation, the premature immune system remains poorly understood. We provide a comprehensive single-cell depiction of the neonatal immune system at birth across the spectrum of viable gestational age (GA), ranging from 25 weeks to term. A mass cytometry immunoassay interrogated all major immune cell subsets, including signaling activity and responsiveness to stimulation. An elastic net model described the relationship between GA and immunome (R=0.85, p=8.75e-14), and unsupervised clustering highlighted previously unrecognized GA-dependent immune dynamics, including decreasing basal MAP-kinase/NFκB signaling in antigen presenting cells; increasing responsiveness of cytotoxic lymphocytes to interferon-α; and decreasing frequency of regulatory and invariant T cells, including NKT-like cells and CD8 + CD161 + T cells. Knowledge gained from the analysis of the neonatal immune landscape across GA provides a mechanistic framework to understand the unique susceptibility of preterm infants to both hyper-inflammatory diseases and infections., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Peterson, Hedou, Ganio, Stelzer, Feyaerts, Harbert, Adusumelli, Ando, Tsai, Tsai, Han, Ringle, Houghteling, Reiss, Lewis, Winn, Angst, Aghaeepour, Stevenson and Gaudilliere.)

Motivation: High-parameter single-cell technologies can reveal novel cell populations of interest, but studying or validating these populations using lower-parameter methods remains challenging., Results: Here, we present GateFinder, an algorithm that enriches high-dimensional cell types with simple, stepwise polygon gates requiring only two markers at a time. A series of case studies of complex cell types illustrates how simplified enrichment strategies can enable more efficient assays, reveal novel biomarkers and clarify underlying biology., Availability and Implementation: The GateFinder algorithm is implemented as a free and open-source package for BioConductor: https://nalab.stanford.edu/gatefinder., Supplementary Information: Supplementary data are available at Bioinformatics online.

Unlabelled: The objectives of this study were to test the feasibility of measuring inflammatory and nociceptive biochemical mediators at the surgical site and to evaluate the relationship between wound and serum levels as well as determine any associations between mediator release, pain, and analgesic consumption after cesarean delivery. Twenty healthy women undergoing elective cesarean delivery with spinal anesthesia were enrolled. Wound exudate and serum mediators, pain scores, and analgesic consumption were measured at 1, 6, 24, and 48 hours after cesarean. In wound exudate, 19 of 20 mediators were reliably detected including interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, tumor necrosis factor-alpha, interferon-gamma, granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), monocyte chemoattractant protein 1 (MCP-1) and macrophage inflammatory protein 1 (MIP-1beta), nerve growth factor (NGF), prostaglandin E2 (PG-E2), and substance P. Wound PG-E2 and various cytokines peaked early, whereas NGF showed a more delayed release. There were no correlations between the concentration versus time profile of wound and serum cytokines. Analgesic consumption during the first 24 hours after surgery was negatively correlated with IL-1beta, IL-6, and G-CSF in the wound exudate. This study demonstrates the feasibility of collecting and measuring nociceptive and inflammatory mediators in surgical wounds at specific time points. The lack of significant correlations between wound and serum levels emphasizes the importance of determining site-specific release if localized pathologies are to be studied., Perspective: This study demonstrates the feasibility of measuring real-time nociceptive and inflammatory mediators in surgical wounds. Our findings confirm the lack of correlation between wound and serum levels of many pro-inflammatory and anti-inflammatory cytokines and nerve growth factor.

Estimating the time of delivery is of high clinical importance because pre- and postterm deviations are associated with complications for the mother and her offspring. However, current estimations are inaccurate. As pregnancy progresses toward labor, major transitions occur in fetomaternal immune, metabolic, and endocrine systems that culminate in birth. The comprehensive characterization of maternal biology that precedes labor is key to understanding these physiological transitions and identifying predictive biomarkers of delivery. Here, a longitudinal study was conducted in 63 women who went into labor spontaneously. More than 7000 plasma analytes and peripheral immune cell responses were analyzed using untargeted mass spectrometry, aptamer-based proteomic technology, and single-cell mass cytometry in serial blood samples collected during the last 100 days of pregnancy. The high-dimensional dataset was integrated into a multiomic model that predicted the time to spontaneous labor [R = 0.85, 95% confidence interval (CI) [0.79 to 0.89], P = 1.2 × 10-40, N = 53, training set; R = 0.81, 95% CI [0.61 to 0.91], P = 3.9 × 10-7, N = 10, independent test set]. Coordinated alterations in maternal metabolome, proteome, and immunome marked a molecular shift from pregnancy maintenance to prelabor biology 2 to 4 weeks before delivery. A surge in steroid hormone metabolites and interleukin-1 receptor type 4 that preceded labor coincided with a switch from immune activation to regulation of inflammatory responses. Our study lays the groundwork for developing blood-based methods for predicting the day of labor, anchored in mechanisms shared in preterm and term pregnancies.

Abstract: Objectives: We previously described a panel of four cytokines biomarkers in knee synovial fluid for acute knee pain associated with meniscal pathology. The cytokine biomarkers included interferon gamma (IFN-γ), interleukin 6 (IL-6), monocyte chemotactic protein 1 (MCP-1), and macrophage inflammatory protein-1 beta (MIP-1β). Validation studies using other immunologic techniques confirmed the presence of IL-6, MCP-1 and MIP-1β, but not IFN-γ. Therefore we sought the identity of the IFN-γ signal in synovial fluid. Methods: Knee synovial fluid was collected from patients with an acute, painful meniscal injury, as well as asymptomatic volunteers. A combination of high-pressure chromatography, mass spectrometry and immunological techniques were used to enrich and identify the protein components representing the IFN-γ signal. Results: A protein complex of fibronectin and the aggrecan G3 domain was identified in the synovial fluid of patients with a meniscal tear and pain that was absent in asymptomatic controls. This protein complex correlated to the IFN-γ signal. A novel enzyme-linked immunosorbent assay (ELISA) was developed to specifically identify the complex in synovial fluid. Conclusions: We have identified a protein complex of fibronectin and aggrecan G3 domain that is a candidate biomarker for pain associated with meniscal injury. [Copyright &y& Elsevier]

Abstract: Background context: The pathophysiology underlying degenerative disc disease and its implication in painful syndromes remain unclear. However, spine magnetic resonance imaging (MRI) can demonstrate changes in disc water content and the annulus; provocative discography purportedly identifies degenerate discs causing serious low back pain; and biochemical assays have identified local inflammatory markers. No study to date has correlated pain on disc injection during discography evaluation with relevant MRI findings and biochemical markers. Purpose: The purpose of this study was to correlate concordant pain on during discography to biochemical markers obtained by disc lavage and MRI findings. Study design: This is a Phase 1 Diagnostic Test Assessment Cohort Study (Sackett and Haynes). Patient sample: The patient sample included 21 symptomatic patients with suspected discogenic pain and three Phase 1 control subjects. Outcome measures: The outcome measures included discography pain scores, MRI degenerative grades, and immunoreactivity to various inflammatory cytokine concentrations present in disc lavage samples. Methods: Twenty-one symptomatic patients with lumbar degenerative disc disease and three control subjects underwent discography, MRI, and biochemical analysis of disc lavage fluid. Lumbar MRI was scored for Pfirrmann grading of the lumbar discs, and annular disruption was identified by nuclear disc lavage. Disc lavage samples were analyzed for biochemical markers by high-sensitivity immunoassay. Results: Eighty-three discs from 24 patients were studied: 67 discs from 21 patients with axial back pain (suspected discogenic pain group) and 16 discs from 3 scoliosis patients without back pain (Phase 1 control subjects). Among the biochemical markers surveyed, interferon gamma (IFN-γ) immunoreactivity was most consistently identified in patients with axial back pain. Discs with annular disruption and concordant pain reproduction at a visual analog scale of 7 to 10/10 had greater IFN-γ immunoreactivity than those without this finding (p=.003); however, at least some IFN-γ immunoreactivity was found in all but one disc in the symptomatic group. Conclusions: Among the potential inflammatory markers tested in this Phase 1 study, IFN-γ immunoreactivity was most commonly elevated in discogram “positive” discs but absent in asymptomatic controls. However, this marker was also frequently elevated in degenerative but “negative” discography discs. From these findings, Phase 2 and Phase 3 validity studies are reasonable to pursue. Phase 4 utility studies may be performed concurrently to assess this method''s predictive value in outcome studies. [Copyright &y& Elsevier]

The article presents a study on epidural inflammatory cytokines in steroid injection for patients with lumbar nerve root irritation. Lavage samples had measured immunoreactivity of cytokines and compares it with therapeutic injection. Results showed that the most consistent cytokine is interferon gamma (IFNγ) which is considered a part of biochemical cascade that increases the pain in sciatica. Its immunoreactivity can act as a biomarker to predict reaction to steroid therapy.