Cellular death, aging, and tissue damage trigger inflammation that leads to enzymatic and non-enzymatic lipid peroxidation of polyunsaturated fatty acids present on cellular membranes and lipoproteins. This results in the generation of highly reactive degradation products, such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), that covalently modify free amino groups of proteins and lipids in their vicinity. These newly generated neoepitopes represent a unique set of damage-associated molecular patterns (DAMPs) associated with oxidative stress termed oxidation-specific epitopes (OSEs). OSEs are enriched on oxidized lipoproteins, microvesicles, and dying cells, and can trigger sterile inflammation. Therefore, prompt recognition and removal of OSEs is required to maintain the homeostatic balance. This is partially achieved by various humoral components of the innate immune system, such as natural IgM antibodies, pentraxins and complement components that not only bind OSEs but in some cases modulate their pro-inflammatory potential. Natural IgM antibodies are potent complement activators, and 30% of them recognize OSEs such as oxidized phosphocholine (OxPC-), 4-HNE-, and MDA-epitopes. Furthermore, OxPC-epitopes can bind the complement-activating pentraxin C-reactive protein, while MDA-epitopes are bound by C1q, C3a, complement factor H (CFH), and complement factor H-related proteins 1, 3, 5 (FHR-1, FHR-3, FHR-5). In addition, CFH and FHR-3 are recruited to 2-(ω-carboxyethyl)pyrrole (CEP), and full-length CFH also possesses the ability to attenuate 4-HNE-induced oxidative stress. Consequently, alterations in the innate humoral defense against OSEs predispose to the development of diseases associated with oxidative stress, as shown for the prototypical OSE, MDA-epitopes. In this mini-review, we focus on the mechanisms of the accumulation of OSEs, the pathophysiological consequences, and the interactions between different OSEs and complement components. Additionally, we will discuss the clinical potential of genetic variants in OSE-recognizing complement proteins – the OSE complotype - in the risk estimation of diseases associated with oxidative stress.

• C-Reactive Protein
• Complement C1q
• Complement Factor H
• Epitopes
• Humans
• Immunoglobulin M
• Immunologic Factors
• Inflammation
• Lipids
• Malondialdehyde
• Phosphorylcholine

• MHC class I presented peptide
• T-cell epitope
• T-cell receptor mimic antibody
• T-cell receptor-like antibody
• cancer immunotherapy
• intrabody
• intracellular antibody
• therapeutic antibody

• Aging
• Irradiation
• Neonatal
• Neural stem cell
• Stroke

Pancreatic cancer (PC) is a leading cause of cancer-related death worldwide. Clinical symptoms typically present late when treatment options are limited and survival expectancy is very short. Metastatic mutations are heterogeneous and can accumulate up to twenty years before PC diagnosis. Given such genetic diversity, detecting and managing the complex states of disease progression may be limited to imaging modalities and markers present in circulation. Recent developments in digital pathology imaging show potential for early PC detection, making a differential diagnosis, and predicting treatment sensitivity leading to long-term survival in advanced stage patients. Despite large research efforts, the only serum marker currently approved for clinical use is CA 19-9. Utility of CA 19-9 has been shown to improve when it is used in combination with PC-specific markers. Efforts are being made to develop early-screening assays that can detect tumor-derived material, present in circulation, before metastasis takes a significant course. Detection of markers that identify circulating tumor cells and tumor-derived extracellular vesicles (EVs) in biofluid samples offers a promising non-invasive method for this purpose. Circulating tumor cells exhibit varying expression of epithelial and mesenchymal markers depending on the state of tumor differentiation. This offers a possibility for monitoring disease progression using minimally invasive procedures. EVs also offer the benefit of detecting molecular cargo of tumor origin and add the potential to detect circulating vesicle markers from tumors that lack invasive properties. This review integrates recent genetic insights of PC progression with developments in digital pathology and early detection of tumor-derived circulating material.

• Circulating tumor cells
• Digital pathology
• Early detection
• Exosomes
• Pancreatic cancer