Author: Claire Hornung

Evaluation of Biomarkers in PJI After Hip and Knee Arthroplasty

Posted on by Claire Hornung

Evaluation of biomarkers in patients with potential periprosthetic joint infections after hip and knee arthroplasty

Introduction

The number of total joint replacements performed each year to treat pain related to end stage knee osteoarthritis (OA) has steadily increased in the last decade. Despite overall efficacy in the majority of patients, a subset of about 20% experience prosthetic complications in the short or in the long run, most often due to aseptic failure or prosthetic joint infection. Accurate diagnosis is therefore crucial. Biomarkers of tissue remodeling are promising diagnostic tools to characterize joint pathological mechanisms, provide a better understanding of how prosthetic complications affect the tissue remodeling to improve diagnosis and intervention

Poster

OARSI2024_Biomarkers in PJI_Nordic BioscienceDownload

Conclusion

This study aimed to investigate the relationship between joint tissue remodeling and inflammation biomarkers with diagnosis in patients with hip or knee prosthetic joint complications, as well as to assess the effect of joint corrective surgery on acute and long-term biomarker levels.

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    COMP-M: A Potential Serological Biomarker of Osteoarthritis

    Posted on by Claire Hornung

    Introduction

    Cartilage oligomeric matrix protein (COMP) is an extracellular matrix (ECM) glycoprotein, consisting of five identical chains. It plays a crucial role in maintaining ECM integrity, facilitating collagen fibrils formation, and regulating cell phenotypes and functions. It is primarily found in human skeleton system, also present in adipose tissue, heart etc. Osteoarthritis (OA) involves increased activity of matrix-degrading enzymes, leading to the fragmentation of ECM.

    In this study, we developed a high-sensitive chemiluminescence immunoassay for quantifying a neoepitope of COMP (DACGMQQS77↓) and explored its application as a biomarker of OA.

    Poster

    OARSI 2024_COMP-M_Nordic BioscienceDownload

    Conclusion

    The data generated interest in the use of COMP-M as a tissue degradation biomarker of osteoarthritis.

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      BigH3 Is a Promising Biomarker in NSLC Patients

      Posted on by Claire Hornung

      Proteolytic degradation of BigH3 can be quantified non-invasively in serum with biomarker potential for patients with non-small cell lung cancer

      Introduction

      Transforming growth factor beta induced protein ig-h3 (BigH3/TGFBI) is widely expressed and is participating in various biological processes including adhesion, migration, and angiogenesis. BigH3 is known to bind multiple collagens and are often embedded in the matrix where it seems
      to function as a linker between ECM and cell surfaces. In non-small cell lung cancer (NSCLC), the increased proteolytic activity found may degrade BigH3, disrupting its ECM interactions and generating peptide fragments that could potentially serve as novel non-invasive biomarkers if released into circulation.

      Our aim is to develop a tool to quantify degraded BigH3 non-invasively and explore its potential as a biomarker in NSCLC.

      Poster

      AACR2024_BigH3_Nordic BioscienceDownload

      Conclusion

      Degradation of BIGH3 can be reflected by non-invasive quantification of the cleaved fragment of BigH3,
      BigH3M-N, in serum. This suggests BigH3M-N as a promising biomarker in NSCLC with potential for discriminating between subtypes. However, as BigH3M-N is connected to fibroblast matrix biology, the optimal use for this biomarker might be in combination with other ECM biomarkers.

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        Tissue-Derived Peripheral Biomarkers (C4G, VICM, Cpa9-HNE) in Patients with Solid Tumors

        Posted on by Claire Hornung

        Tissue-derived peripheral biomarkers that reflect activity of T-cells, macrophages, and neutrophils in patients with solid tumors

        Introduction

        By identifying and quantifying specific extracellular protein fragments with neo-epitopes that are generated by proteolytic cleavage and post-translational modifications specific for T-cells, neutrophils and macrophages, respectively, it is possible to develop peripheral biomarkers that reflect the activity of these immune cells.

        Poster

        AACR2024 Tissue-derived biomarkers_Nordic BioscienceDownload

        Conclusion

        Tissue-derived peripheral biomarkers that reflect the activity of T-cells (C4G), macrophages (VICM) and neutrophils (nordicCPa9-HNE™) has biomarker potential in solid tumors and may serve as prognostic, predictive and pharmacodynamic biomarkers in clinical trials investigating cancer immunotherapy.

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          myCAF Activity Can Be Assessed by Specific Collagen Pro-Peptide Biomarkers

          Posted on by Claire Hornung

          Serological assessment of cancer associated myo-fibroblast (myCAF) activity by collagen pro-peptide biomarkers provides high prognostic power

          Introduction

          Myofibroblast Cancer Associated Fibroblasts (myCAFs) are the main tumor fibrosis drivers and hence different from inflammatory CAFs (iCAFs). CAFs produce type III, V, VI and XI collagen that are the essential components of tumor fibrosis. Pro-peptides of these collagens can be quantified both in serum with the nordicPRO-C3™, PRO-C5, nordicPRO-C6™ and PRO-C11 biomarkers where they are prognostic for poor overall survival in patients with various solid tumor types and may be applied in vitro.

          In this study we investigated the association and difference between myCAFs and iCAFs and their collagen expression profile and related that to data available data on serological assessments of nordicPRO-C3™, PRO-C5, nordicPRO-C6™ and PRO-C11, and cultured CAFs.

          Poster

          AACR2024 myCAF pro-peptides_Nordic BioscienceDownload

          Conclusion

          Profiling collagen expression in fibroblast from PDAC and NSCLC reveals that type V collagen and type XI collagen are found in myCAF. Biomarkers of these collagens can be measured in serum from cancer patients and are prognostic for poor overall survival. Thus, these data suggest that cancer associated myo-fibroblast (myCAF) activity can be assessed non-invasively by specific collagen pro-peptide biomarkers.

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            IL1RAP Blockade Mediates Anti-Fibrotic Effects in Pancreatic Cancer-Associated Fibroblasts

            Posted on by Claire Hornung

            Introduction

            Pancreatic ductal adenocarcinoma (PDAC) patients have poor prognosis partly due to excessive activity of cancer-associated fibroblasts (CAFs). CAFs drive the fibrosis that causes excessive type III collagen and extracellular matrix deposition that in turn reduces drug response resulting in poor survival. High levels of the type III collagen serum biomarker nordicPRO-C3™ correlates with poor survival in PDAC. While TGF-β is thought to be one of the main drivers of nordicPRO-C3™ and tumor fibrosis, cytokines such as Interleukin 1 (IL-1) play a key role in the pancreatic tumor microenvironment and may play a significant role in also tumor fibrosis.
            In this study, we first investigated the potential of IL-1 in activating fibroblasts to drive fibrosis and produce nordicPRO-C3™. Subsequently, we established a co-culture of pancreatic cancer cells and pancreatic CAFs to investigate the anti-fibrotic properties of nadunolimab, a fully humanized ADCC-enhanced monoclonal IgG1 antibody that targets IL1RAP and disrupts both IL-1α and IL-1β signaling.

            Poster

            AACR2024 IL1RAP_Nordic BioscienceDownload

            Conclusion

            Co-cultures of pancreatic tumor cells and CAFs induced formation, including collagen type III formation, and nadunolimab inhibited the collagen type III formation, suggesting anti-fibrotic properties. Activated fibroblasts had induced type III collagen formation (nordicPRO-C3™) suggesting that IL-1 is a driver of tumor fibrosis in PDAC. Nadunolimab, which is currently in clinical development for treatment of pancreatic cancer, has the potential to counteract the detrimental, fibrotic progression in tumors by targeting IL1RAP and blocking both IL-1α and IL-1β signaling. These findings suggest that nordicPRO-C3™ could potentially be used for prognostic/predictive enrichment and as a pharmacodynamic marker in future studies evaluating anti-IL-1 modalities in PDAC.

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                ECM Turnover Biomarkers as Prognostic Tools in Immunotherapy for Solid Tumors

                Posted on by Claire Hornung

                Non-invasive biomarkers of ECM turnover are prognostic for combinations of checkpoint inhibition immunotherapy in solid tumors

                Introduction

                Immune checkpoint inhibitors (ICIs) are being investigated in many different combinations (Table 1) but only a fraction of patients respond. This highlights the need for prognostic biomarkers that can help identify patients most likely to respond. Tumor fibrosis and the high collagen/ECM turnover in the tumor microenvironment – processes are closely related to response to ICIs and survival outcomes.

                In this study we investigated the clinical utility of non-invasive biomarkers of collagen-1 (reC1M), collagen-III (nordicPRO-C3™), collagen-4 (C4M), collagen-19 (PRO-C19), collagen-20 (PRO-C20) and TGF-β activity in metastatic cancer patients treated with ICIs.

                Poster

                AACR2024 ECM turnover_Nordic BioscienceDownload

                Conclusion

                Across a diverse cohort of patients with metastatic cancer treated with different checkpoint inhibition regimens, non-invasive biomarkers associated with tumor fibrosis and collagen/ECM turnover (nordicPRO-C3™, PRO-C19, PRO-C20, TGF-β, reC1M and C4M) could identify cancer patients with poor prognosis.

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                  Unraveling Collagen Signatures in Cancer-Associated Fibroblasts

                  Posted on by Claire Hornung

                  Unraveling collagen signatures in cancer-associated fibroblasts: A biomarker-driven approach

                  Introduction

                  The tumor microenvironment (TME) plays a crucial role in driving tumor development. Among the constituents of the tumor stroma, cancer-associated fibroblasts (CAFs) are a pivotal component.
                  CAFs are actively involved in tumor progression by modulating the architecture of the TME through increased deposition of various collagens resulting in tumor fibrosis. Several studies have shown that CAFs have heterogeneity within, and between, individual tissues. TGF-β is thought to be the main driver of tumor fibrosis, however, the field lacks a characterization of the specific collagen deposition of CAFs from different tissues.

                  In this study, we investigated the fibrotic activity of CAFs from various tissues by measuring the production of three specific collagen peptides in vitro by use of non-invasive clinically validated biomarkers.

                  Poster

                  AACR2024 CAFs_Collagen Signatures_Nordic BioscienceDownload

                  Conclusion

                  These findings underscore the heterogeneity in collagen production among CAFs from different indications, providing valuable insights into the ECM dynamics within distinct TMEs. Collagen-based non-invasive biomarkers further demonstrate the capability to differentiate between the fibrotic activity of CAFs isolated from different tissues. These insights support the utility of this model as a useful tool for anti-fibrotic drug screening.

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                    Novel ECM Biomarkers Are Associated with Prolonged QTc and PAH in Patients with SSc

                    Posted on by Claire Hornung

                    Novel tissue turnover biomarkers are associated with prolonged QTc and pulmonary arterial hypertension in patients with systemic sclerosis

                    Introduction

                    Systemic sclerosis (SSc) is characterized by vasculopathy and fibrosis of the skin and internal organs. Cardiovascular involvement is a frequent and significant contributor to morbidity and mortality in SSc. They can develop clinically silent and be difficult to detect. Novel tissue turnover biomarkers hold the potential to detect the manifestations before clinical overt disease, identify risk patients and monitor the disease course as well as improve our understanding of the pathophysiology in SSc.

                    The objective of this study is to measure a panel of collagen biomarkers in SSc and explore associations to cardiac involvement detected by ECG and to PAH.

                    Poster

                    SSWC2024 QTc and PAH in SSc_Nordic BioscienceDownload

                    Conclusion

                    Patients with SSc and prolonged ECG presented an altered tissue turnover, by an increased level of nordicPRO-C3™ and nordicPRO-C6™. In addition, SSc patients with presence of PAH had increased levels of nordicPRO-C3™ and nordicPRO-C6™ as well. presented an altered tissue turnover in presence of PAH, and with a QTc>450 ms. Our study indicates that they could serve as biomarkers of these manifestations and warrant further studies in cardiac disease in SSc.

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                      TNF-α and TGF-β Synergistically Promote Fibrogenesis

                      Posted on by Claire Hornung

                      TNF-α and TGF-β Synergistically Promote Fibrogenesis in a In Vitro Model of Fibro-inflammation

                      Introduction

                      Systemic sclerosis (SSc) is a skin disease characterized by chronic inflammation leading to
                      fibrosis, a process called fibro-inflammation. TNF-α is an inflammatory cytokine driving chronic inflammation in SSc, while TGF-β activation is a hallmark of fibrotic pathology. Fibrogenesis (wound healing) is characterized by granulation tissue formation consisting of mainly type III collagen.

                      The aim of this study was to investigate if primary human dermal fibroblasts treated with TNF-α
                      and TGF-β1 had increased fibrogenesis compared to fibroblasts treated only with TGF-β1.

                      Poster

                      AAD2024_Fibro-inflammation_Nordic BioscienceDownload

                      Conclusion

                      Inflammatory TNF-α stimulation increases TGF-β driven fibrogenesis in dermal fibroblasts, by promoting their formation of type III collagen and fibronectin. Consequently, biomarkers of type III collagen formation and fibronectin formation may be markers of early fibrosis in fibro-inflammatory skin disease.

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