Impaired Fibrinolysis in the Antiphospholipid Syndrome

The pathogenesis of the antiphospholipid syndrome (APS) is complex and involves the persistent presence of antiphospholipid antibodies (aPL) in the bloodstream causing a prothrombotic condition. aPL induce excessive activation of the endothelium, monocytes, and platelets in consort with aberrations in hemostasis/clotting, fibrinolytic system, and complement activation. Impaired fibrinolysis has been found in APS patients with thrombotic as well as obstetric manifestations. Increased levels of plasminogen activator inhibitor-1 and thrombin-activatable fibrinolysis inhibitor, together with the presence of aPL against annexin-2, tissue-type plasminogen activator, and plasminogen contribute to the compromised fibrinolytic activity in these patients. Furthermore, unfavorably altered fibrin morphology, less amenable to fibrinolysis, has been proposed as a novel prothrombotic mechanism in APS. This review aims to summarize the present knowledge of the mechanisms involved in impaired fibrinolysis in APS patients. We also present a case from clinical practice as an illustration of fibrinolysis impairment in APS patients from a real-life setting.

HO-1 Interactors Involved in the Colonization of the Bone Niche: Role of ANXA2 in Prostate Cancer Progression

Background: Prostate cancer (PCa) dissemination shows a tendency to develop in the bone, where heme oxygenase 1 (HO-1) plays a critical role in bone remodeling. Previously by LC/ESI-MSMS, we screened for HO-1 interacting proteins and identified annexin 2 (ANXA2). The aim of this study was to analyze the relevance of ANXA2/HO-1 in PCa and bone metastasis. Methods: We assessed ANXA2 levels using a co-culture transwell system of PC3 cells (pre-treated or not with hemin, an HO-1 specific inducer) and the pre-osteoclastic Raw264.7 cell line. Results: Under co-culture conditions, ANXA2 mRNA levels were significantly modulated in both cell lines. Immunofluorescence analysis unveiled a clear ANXA2 reduction in cell membrane immunostaining for Raw264.7 under the same conditions. This effect was supported by the detection of a decrease in Ca2+ concentration in the conditioned medium. HO-1 induction in tumor cells prevented both, the ANXA2 intracellular relocation and the decrease in Ca2+ concentration. Further, secretome analysis revealed urokinase (uPA) as a key player in the communication between osteoclast progenitors and PC3 cells. To assess the clinical significance of ANXA2/HO-1, we performed a bioinformatics analysis and identified that low expression of each gene strongly associated with poor prognosis in PCa regardless of the clinico-pathological parameters assessed. Further, these genes appear to behave in a dependent manner. Conclusions: ANXA2/HO-1 rises as a critical axis in PCa.

Chlorotoxin—A Multimodal Imaging Platform for Targeting Glioma Tumors

Chlorotoxin (CTX) is a 36-amino-acid disulfide-containing peptide derived from the venom of the scorpion Leiurus quinquestriatus. CTX alters physiology in numerous ways. It interacts with voltage gated chloride channels, Annexin-2, and matrix metalloproteinase-2 (MMP-2). CTX-based bioconjugates have been widely subjected to phase I/II clinical trials and have shown substantial promise. Many studies have demonstrated that CTX preferentially binds to neuroectodermal tumors, such as glioblastoma, without cross-reactivity to normal brain cells. With its ability to penetrate the blood-brain-barrier (BBB) and its tyrosine residue allows covalent conjugation with functional moieties, CTX is an attractive platform to explore development of diagnostic and therapeutic agents for gliomas. In this review, we outline CTX structure and its molecular targets, summarize molecular variations of CTX developed for glioma imaging, and discuss future trends and perspectives for CTX conjugates as a theranostic agent.