MECHANISMS OF THROMBOSIS IN SYSTEMIC LUPUS ERYTHEMATOSUS.

Thrombotic events are highly prevalent in systemic lupus erythematosus (SLE). Antiphospholipid antibodies play an essential role in promoting thrombosis by activating several intracellular signaling pathways (TLR4, p38MAPK, NFkB) in platelets, monocytes and endothelial cells. New therapeutic opportunities might be offered by addressing these molecular targets. Chronic inflammatory status, the degree of disease activity and accelerated atherosclerosis are also responsible for the thrombotic phenotype in patients with SLE. The aim of this review is to highlight thrombosis mechanisms and to look for possible connection between SLE, antiphospholipid antibodies and cancer, especially myeloproliferative neoplasms.

Matrix metalloproteinase-9 expression in the nuclear compartment of neurons and glial cells in aging and stroke.

Matrix metalloproteinases (MMPs) are well-recognized denominators for extracellular matrix remodeling in the pathology of both ischemic and hemorrhagic strokes. Recent data on non-nervous system tissue showed intracellular and even intranuclear localizations for different MMPs, and together with this, a plethora of new functions have been proposed for these intracellular active enzymes, but are mostly related to apoptosis induction and malign transformation. In neurons and glial cells, on human tissue, animal models and cell cultures, different active MMPs have been also proven to be located in the intra-cytoplasmic or intra-nuclear compartments, with no clear-cut function. In the present study we show for the first time on human tissue the nuclear expression of MMP-9, mainly in neurons and to a lesser extent in astrocytes. We have studied ischemic and hemorrhagic stroke patients, as well as aged control patients. Age and ischemic suffering seemed to be the best predictors for an elevated MMP-9 nuclear expression, and there was no evidence of a clear-cut extracellular proteolytic activity for this compartment, as revealed by intact vascular basement membranes and assessment of vascular densities. More, the majority of the cells expressing MMP-9 in the nuclear compartment also co-expressed activated-caspase 3, indicating a possible link between nuclear MMP-9 localization and apoptosis in neuronal and glial cells following an ischemic or hemorrhagic event. These results, besides showing for the first time the nuclear localization of MMP-9 on a large series of human stroke and aged brain tissues, raise new questions regarding the unknown spectrum of the functions MMPs in human CNS pathology.

On the Dual Role of Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 (CEACAM1) in Human Malignancies.

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a glycoprotein belonging to the carcinoembryonic antigen (CEA) family that is expressed on a wide variety of cells and holds a complex role in inflammation through its alternate splicing and generation of various isoforms, mediating intricate mechanisms of modulation and dysregulation. Initially regarded as a tumor suppressor as its expression shows considerable downregulation within the epithelia in the early phases of many solid cancers, CEACAM1 has been linked lately to the progression of malignancy and metastatic spread as various papers point to its role in tumor progression, angiogenesis, and invasion. We reviewed the literature and discussed the various expression patterns of CEACAM1 in different types of tumors, describing its structure and general biologic functions and emphasizing the most significant findings that link this molecule to poor prognosis. The importance of understanding the role of CEACAM1 in cell transformation stands not only in this adhesion molecule's value as a prognostic factor but also in its promising premise as a potential new molecular target that could be exploited as a specific cancer therapy.

Variations in the expression of TIMP1, TIMP2 and TIMP3 in cutaneous melanoma with regression and their possible function as prognostic predictors.

Regression in melanoma is a frequent biological event of uncertain prognostic value as the lesion exhibits heterogeneous phenotypical features, both at the morphological and immunohistochemical level. In the present study, we examined the expression of tissue inhibitors of metalloproteinases (TIMP1, TIMP2 and TIMP3) in melanoma with regression. We specifically examined the expression levels of these TIMPs in regressed components (RC) and non-regressed components (NRC) of the tumor and compared their expression levels with those in non-regressed melanomas. We found that TIMP1 was overexpressed in the NRC of melanomas with partial regression (PR) compared with the NRC in melanomas with segmental regression (SR) (P=0.011). TIMP2 was overexpressed in the NRC of melanomas with PR compared with the NRC in melanomas with SR (PR/SR, P=0.009); or compared with the NRC in melanomas with simultaneous SR-PR (P=0.002); or compared with melanomas without regression (absence of regression) (P=0.037). Moreover, TIMP3 was overexpressed in the NRC of all melanomas with SR as compared to the RC component (P=0.007). Our findings on the differential expression of TIMP1, TIMP2 and TIMP3 in melanomas with regression support the hypothesis that the morphological differences identified in the melanoma regression spectrum may have a correlation with prognosis. This may explain the controversial findings within the literature concerning the biological and prognostic role of regression in melanoma.

Different dynamics of aquaporin 4 and glutamate transporter-1 distribution in the perineuronal and perivascular compartments during ischemic stroke.

Aquaporin-4 (AQP4) and glutamate transporter-1 (GLT-1) represent the major water and glutamate astrocyte buffering gateways in the brain. Utilizing perilesional ischemic human cortices, we have performed here for the first time an integrative assessment on both AQP4 and GLT-1, and on their proximity to blood vessels and neurons. Counting the relative number of AQP4±/GLT-1±/glial fibrillary acidic protein± cells showed that double-positive variants were overall most frequent, and their number tended to decrease from organized and recent perilesional cortices to controls. AQP4/GLT-1 colocalization showed higher coefficients for the perilesional cortices compared with controls, suggesting an increased water/glutamate-buffering capability. Distance frequency analysis of AQP4/GLT-1 in relationship to neurons showed that both markers were concentrated at 20-40 µm around the perikarya; with AQP4 being more abundant in close proximity, these differences were not being driven by changes in neuropil density alone. Our study suggests a dual, simultaneous astrocytic function depending on the relative distance to neurons and vessels, with increased water and glutamate-buffering capability in the mid perineuronal space, and an increased water-buffering capability in the immediate perineuronal space, even higher than around vessels. Thus, adding specific AQP4/GLT-1 modulator agents selectively depending on the acute/chronic phase of stroke might increase the efficacy of existing treatments.