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Background Seronegative joint diseases are characterized by a lack of well-defined biomarkers since autoantibodies are not elevated. Calprotectin (S100A8/A9) is a damage-associated molecular pattern (DAMP) which is released by activated phagocytes, and high levels are found in seronegative arthritides. In this study, we investigated the biomarker potential of systemic and local levels of these S100 proteins to assess joint inflammation and joint destruction in an experimental model for seronegative arthritis. Methods Serum levels of S100A8/A9 and various cytokines were monitored during disease development in interleukin-1 receptor antagonist (IL-1Ra) –/– mice using ELISA and multiplex bead-based immunoassay, and were correlated to macroscopic and microscopic parameters for joint inflammation, bone erosion, and cartilage damage. Local expression of S100A8 and S100A9 and matrix metalloproteinase (MMP)-mediated cartilage damage in the ankle joints were investigated by immunohistochemistry. In addition, local S100A8 and activated MMPs were monitored in vivo by optical imaging using anti-S100A8-Cy7 and AF489-Cy5.5, a specific tracer for activated MMPs. Results Serum levels of S100A8/A9 were significantly increased in IL-1Ra –/– mice and correlated with macroscopic joint swelling and histological inflammation, while serum levels of pro-inflammatory cytokines did not correlate with joint swelling. In addition, early serum S100A8/A9 levels were prognostic for disease outcome at a later stage. The increased serum S100A8/A9 levels were reflected by an increased expression of S100A8 and S100A9 within the ankle joint, as visualized by molecular imaging. Next to inflammatory processes, serum S100A8/A9 also correlated with histological parameters for bone erosion and cartilage damage. In addition, arthritic IL-1Ra –/– mice with increased synovial S100A8 and S100A9 expression showed increased cartilage damage that coincided with MMP-mediated neoepitope expression and in vivo imaging of activated MMPs. Conclusions Expression of S100A8 and S100A9 in IL-1Ra –/– mice strongly correlates with synovial inflammation, bone erosion, and cartilage damage, underlining the potential of S100A8/A9 as a systemic and local biomarker in seronegative arthritis not only for assessing inflammation but also for assessing severity of inflammatory joint destruction.

Background Infections and inflammation in the prostate play a critical role in carcinogenesis, and S100A8 and S100A9 are key mediators in acute and chronic inflammation. Therefore, we investigated the differences of S100A8/A9 expression between prostate cancer (CaP) and benign prostatic hyperplasia (BPH) tissues, and we evaluated the possibilities of urinary nucleic acids of S100A8/A9 as diagnostic and prognostic markers. Methods Tissues from 132 CaP patients who underwent prostatectomy or transurethral resection and 90 BPH patients who underwent transurethral prostatectomy were assessed.sd In addition, S100A8 and S100A9 nucleic acid levels were measured in the urine of 283 CaP patients and 363 BPH controls. Results S100A8 and S100A9 mRNA levels were lower in CaP than BPH tissues ( P  < 0.001). S100A8 and S100A9 expression was increased in cancer tissues with poorer prognosis. In 69 specimens from prostatectomy patients, S100A8/A9 were the independent predictor of biochemical recurrence (hazard ratio 5.22, 95 % confidence interval 1.800–15.155, P  = 0.002). Immunohistochemical staining revealed that BPH tissues stained more strongly for both S100A8 and S100A9 than CaP tissues ( P  < 0.001). S100A8 and S100A9 urinary nucleic acid levels were lower in CaP than in BPH ( P  = 0.001 and <0.001, respectively). Conclusions S100A8/A9 levels are lower in CaP than in BPH. Both were more highly expressed in patients with aggressive disease and shorter biochemical recurrence-free time. S100A8/A9 urinary cell-free nucleic acid levels correlated positively with expression levels obtained from tissue staining. Therefore, S100A8/A9 measurement in tissues and urine may have diagnostic and prognostic value in CaP.

In order to investigate the two members of the EF-hand Ca2+ binding protein S100 family, S100A8 and S100A9, in renal cell carcinoma (RCC), serum samples were collected from patients with RCC, transitional cell carcinoma in the kidney, benign renal masses and normal controls. The samples were analyzed by isobaric tags for relative and absolute quantification technology to identify the differential expression of S100A8 and S100A9 in the respective groups. Hierarchical clustering analysis was then conducted for the samples and the relevant selected gene. The cross-platform analysis for the external validation was performed by means of The Cancer Genome Atlas database, containing the gene/microRNA expression pattern and clinical information of patients with RCC. Immunohistochemical staining was used to verify the expression of S100A8 and S100A9 in the four groups. As a result, serum and mRNA expression levels of S100A8 and S100A9 were found to be upregulated in patients with RCC compared with the other three groups, which was consistent with the result of the upregulated expression of mRNA levels in RCC tissue. The overexpression of S100A8 and S100A9 in cancer cells was also confirmed by immunohistochemistry. In addition, bioinformatics revealed that let-7, a microRNA formerly identified as an inhibiting factor of RCC was downregulated in RCC, which contrasted with S100A8. It was also complementary to the sequence at the 3′ untranslated region terminal of S100A8. Therefore, indicating that S100A8 and S100A9 may serve as biomarkers for the detection of RCC.

The development of a rapid and affordable assay to screen participants for Q12 additional testing could streamline TB screening in resource-limited settings and for community-wide health screens. Sputum remains the primary testing sample, making it potentially ideal for a screening testing. Neutrophils are highly expanded in sputum from individuals with pulmonary TB with high specificity and have potential as a biomarker for TB. Three neutrophil associated proteins, neutrophil gelatinase associated-lipocalin (NGAL), the protein heterodimer S100A8/A9 and the protein death ligand-1 (PDL-1), were measured in presumptive TB cases from participants attending a primary healthcare clinic in Durban, South Africa, using commercially available ELISAs on a total of 79 participants from a 109-participant cohort. Participants with microbiologically confirmed TB were sampled after 1 month of treatment. Proteins were also measured in tongue swab samples in participants from this cohort at baseline. Baseline results were confirmed in a second TB cohort which recruited a total of 51 participants with presumptive TB from the Western Cape. Finally, we investigate sputum neutrophil protein levels in individuals with community diagnosed asymptomatic TB. Significant increases in all proteins were detectable in sputum from clinic-diagnosed TB participants relative to symptomatic controls. Performance approached the WHO target product profile for a TB triage test, with ROC AUCs reaching 0.866 (with a 95% confidence interval of 0.7683 - 0.9633) in the case of S100A8/A9. Sputum protein levels did not correlate with bacterial burden and did not consistently decrease following one month of drug therapy. Only PDL-1 was detectable in mouth swab samples. Sputum neutrophil proteins tended to be elevated in participants with asymptomatic community diagnosed TB, as compared to asymptomatic community controls within the Vukuzazi cohort using a sample size of 42 participants, although this was not significant. This study provides a proof of principle that neutrophil proteins can be easily measured in standard sputum samples and have potential as a screening test for TB. However, more work is needed to explore whether this approach, using these three neutrophil proteins, can meet the WHO target product profile for a triage test worth developing further.

S100A8 and S100A9 are calcium-binding proteins expressed in myeloid cells and are markers of numerous inflammatory diseases in humans. S100A9 has been associated with dystrophic calcification in human atherosclerosis. Here we demonstrate S100A8 and S100A9 expression in murine and human bone and cartilage cells. Only S100A8 was seen in preosteogenic cells whereas osteoblasts had variable, but generally weak expression of both proteins. In keeping with their reported high-mRNA expression, S100A8 and S100A9 were prominent in osteoclasts. S100A8 was expressed in alkaline phosphatase-positive hypertrophic chondrocytes, but not in proliferating chondrocytes within the growth plate where the cartilaginous matrix was calcifying. S100A9 was only evident in the invading vascular osteogenic tissue penetrating the degenerating chondrocytic zone adjacent to the primary spongiosa, where S100A8 was also expressed. Whilst, S100A8 has been shown to be associated with osteoblast differentiation, both S100A8 and S100A9 may contribute to calcification of the cartilage matrix and its replacement with trabecular bone, and to regulation of redox in bone resorption.

Background and Objectives: S100A8 regulates inflammatory responses and immune cell activation and is overexpressed in several solid tumors. However, its clinicopathological significance in endometrial carcinoma (EC) remains unclear. This study aimed to evaluate the expression patterns of S100A8 in both tumor and immune cells of EC and examine its association with clinicopathological features. Materials and Methods: Fifty-two formalin-fixed, paraffin-embedded EC specimens were analyzed using tissue microarray-based immunohistochemistry. S100A8 expression was assessed in tumor and immune cells. The tumor proportion score (TPS), tumor staining intensity (TI), and immune proportion score (IPS) were dichotomized into low and high categories (TPS/IPS: ≤30% vs. ≥31%; TI: 0–1+ vs. 2–3+). Correlations with clinicopathological parameters were examined using the chi-square and Fisher’s exact tests. Results: A low TPS, high TI, and high IPS were observed in 51.9%, 63.5%, and 57.7% of patients, respectively. TPS and TI showed no significant correlation with clinicopathological variables, including age, tumor size, invasion depth, histologic grade, T stage, and N stage (all p > 0.05). By contrast, IPS was significantly associated with patients’ age (p = 0.044) and histologic grade (p = 0.012), with older patients and those with higher-grade tumors demonstrating a higher IPS. A positive correlation was observed between TPS and IPS (p = 0.044), whereas TI did not correlate with IPS (p = 0.253). Conclusions: S100A8 expression in immune cells, but not in tumor cells, is associated with age and tumor grade in EC. Therefore, immune-related S100A8 expression may serve as a biomarker of the tumor immune microenvironment, warranting further investigation into its prognostic and therapeutic implications.

MRP8/14, a calcium-binding protein of the S100 family, is predominantly expressed in myeloid cells and exhibits proinflammatory and prothrombotic properties. Platelet-neutrophil interactions can trigger MRP8/14 release, but their role in atherosclerosis (AS) remains unclear. To investigate the effect of MRP8/14 on AS progression and the underlying mechanisms involved, focusing on neutrophil activation and the toll-like receptor 4 (TLR4)-ERK1/2-p90RSK and NRF2-ARE pathways. Ex vivo and animal study. Neutrophils isolated from mouse bone marrow were stimulated with P-selectin to induce MRP8/14 release, which was subsequently quantified using ELISA. Neutrophil extracellular traps (NET) formation was induced by phobolol 12-myristate 13-acetate, and Mrp8/14 expression was examined via fluorescence labeling. Cytokine release and CD11b expression were assessed using flow cytometry. An AS mouse model was established by administering a high-fat diet. Atherosclerotic plaque size was analyzed using Oil Red O staining. Proteins from the TLR4-ERK1/2-p90RSK and NRF2-ARE pathways were analyzed by Western blotting. P-selectin induced MRP8/14 release, which was inhibited by P-selectin antagonists. NET formation also contributed to MRP8/14 secretion. hMRP8/14 treatment enhanced CD11b expression, neutrophil adhesion, and proinflammatory cytokine secretion. In AS mice, MRP8/14 secretion was linked to TLR4 upregulation, ERK1/2-p90RSK signaling activation, and NRF2-ARE pathway inhibition. Paquinimod, an MRP8/14 antagonist, mitigated neutrophil activation, inflammation, and arterial plaque formation. MRP8/14 secreted from neutrophils activates the ERK1/2-p90RSK pathway via TLR4 and suppresses the NRF2-ARE pathway, driving inflammation and promoting AS progression.

Key Points An unmet clinical need exists for accurate, noninvasive assays, which enable the accurate diagnosis of bladder cancer and monitoring of patients for recurrence Urine is the most appropriate bodily fluid for biomarker research owing to its noninvasive and easy collection, stability of samples and proximity to bladder tumours Proteomics platforms have the advantages of providing large datasets with numerous putative biomarker candidates at high resolution; these technologies might also potentially enable validation of biomarker candidates Multiple biomarker panels are likely to be more effective than single biomarkers, owing to the high level of disease heterogeneity observed among patients with bladder cancer Multiple proteomic biomarkers for bladder cancer have already been discovered; however, a lack of validation in the appropriate patient populations and in specific contexts of use precludes clinical implementation Current methods for the diagnosis and monitoring of bladder cancer are invasive, and might lack the sensitivity required for detection of all types of bladder cancer. Here, authors describe the proteomic identification of biomarkers of urinary bladder cancer, findings of studies investigating individual biomarker proteins and/or panels and the clinical potential of proteomic biomarkers for the diagnosis and management of patients with bladder cancer. Clinical use of proteomic biomarkers has the potential to substantially improve the outcomes of patients with bladder cancer. An unmet clinical need evidently exists for noninvasive biomarkers, which might enable improvements in both the diagnosis and prognosis of patients with bladder cancer, as well as improved monitoring of patients for the presence of recurrence. Urine is considered the optimal noninvasive source of proteomic biomarkers in patients with bladder cancer. Currently, a number of single-protein biomarkers have been detected in urine and tissue using a variety of proteomic techniques, each having specific conceptual considerations and technical implications. Promising preclinical data are available for several of these proteins; however, the combination of single urinary proteins into multimarker panels might better encompass the molecular heterogeneity of bladder cancer within this patient population, and prove more effective in clinical use.

Background Elucidation of the biochemical pathways involved in activation of preterm and term human labour would facilitate the development of effective management and inform judgements regarding the necessity for preterm tocolysis and post-term induction. Prostaglandins act at all stages of human reproduction, and are potentially activators of labour. Methods Expression of 15 genes involved in prostaglandin synthesis, transport and degradation was measured by qPCR using tissue samples from human placenta, amnion and choriodecidua at preterm and full-term vaginal and caesarean delivery. Cellular localisation of eight prostaglandin pathway proteins was determined by immunohistochemistry. Results Expression of prostaglandin pathway genes was differentially affected by factors including gestational age at delivery, and the incidence and duration of labour. Chorioamnionitis/deciduitis was associated with upregulation of PTGS2 (prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase)), along with the inflammatory genes IL8 (interleukin 8), S100A8 (S100 calcium binding protein A8) and TLR2 (toll-like receptor 2), in amnion and choriodecidua, and with downregulation of CBR1 (carbonyl reductase 1) and HPGD (hydroxyprostaglandin dehydrogenase 15-(NAD)) in choriodecidua. Protein localisation differed greatly between the various maternal and fetal cell types. Conclusions Preterm and term labour are associated with distinct prostaglandin pathway expression profiles; inflammation provokes specific changes, unrelated to the presence of labour; spontaneous and induced term labour are indistinguishable.

Candida auris is an emerging fungal species, and several reports have recently identified C. auris in patients with vulvovaginal candidiasis (VVC), although few studies have investigated the relationship between C. auris and VVC or the associated host factors. Our study, using the VVC mouse model, confirmed persistent vaginal colonization by C. auris , especially clades I, III, and IV, along with reduced neutrophil infiltration and lower S100A8 secretion under interleukin-17A-deficient conditions. In addition, in vitro assays demonstrated enhanced C. auris adhesion to vaginal epithelial cells, especially microaerobic conditions imitating human vaginal microenvironments. Our findings suggest that C. auris exhibits strong vaginal tropism, and IL-17A plays a critical role in controlling C. auris -associated VVC.