Human epididymis protein 4 antigen-autoantibody complexes complement cancer antigen 125 for detecting early-stage ovarian cancer

Background: Early detection of ovarian cancer could significantly improve patient outcomes. Cancer antigen 125 (CA 125) is elevated in sera from approximately 60% of patients with early‐stage (I/II) disease. Sensitivity might be improved through the combination of CA 125 with other biomarkers. Among potential biomarkers, antigen‐autoantibody (Ag‐AAb) complexes have received relatively little attention. / Methods: Luminex‐based immunoassays were used to measure human epididymis protein 4 (HE4), anti‐HE4 autoantibody, and HE4 Ag‐AAb complexes in sera from patients with early‐ (n = 73) and late‐stage ovarian cancers (n = 49) at the time of diagnosis and from asymptomatic women with (n = 15) or without ovarian cancer (n = 212) enrolled in the Normal Risk Ovarian Cancer Screening Study. / Results: At 98% specificity for healthy, asymptomatic women, 7% of patients with early‐stage (I/II) ovarian cancer and 4% of patients with late‐stage (III/IV) disease had elevated levels of HE4 autoantibody, whereas elevated levels of HE4 Ag‐AAb complexes were detected in sera from 38% of early‐stage cases and 31% of late‐stage cases. Complementarity was observed in receiver operating characteristic (ROC) curves between HE4 Ag‐AAb complexes and CA 125 levels in early‐stage ovarian cancer (P < .001). CA 125 detected 63% of cases, and a combination of CA 125 and HE4 Ag‐AAb complexes detected 81%. Complementarity was also observed in ROC curves for an independent validation set with 69 early‐stage patients (P = .039). HE4 Ag‐AAb complexes were detected in serial preclinical serum samples from women destined to develop ovarian cancer: they correlated with CA 125 but did not provide a lead time. / Conclusions: HE4 Ag‐AAb complexes could complement CA 125 in detecting a higher fraction of early‐stage ovarian cancers

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference