Monocytes express various receptors, which monitor and sense environmental changes. Monocytes are highly plastic and heterogeneous, and change their functional phenotype in response to environmental stimulation. Evidence from murine and human studies has suggested that monocytosis can be an indicator of various inflammatory diseases. Monocytes can differentiate into inflammatory or anti-inflammatory subsets. Upon tissue damage or infection, monocytes are rapidly recruited to the tissue, where they can differentiate into tissue macrophages or dendritic cells. Given the rapid progress in monocyte research from broad spectrum of inflammatory diseases, there is a need to summarize our knowledge in monocyte heterogeneity and its impact in human disease. In this review, we describe the current understanding of heterogeneity of human and murine monocytes, the function of distinct subsets of monocytes, and a potential mechanism for monocyte differentiation. We emphasize that inflammatory monocyte subsets are valuable biomarkers for inflammatory diseases, including cardiovascular diseases.

Because of the high risk of recurrence in high-grade serous ovarian carcinoma (HGS-OvCa), the development of outcome predictors could be valuable for patient stratification. Using the catalog of The Cancer Genome Atlas (TCGA), we developed subtype and survival gene expression signatures, which, when combined, provide a prognostic model of HGS-OvCa classification, named "Classification of Ovarian Cancer" (CLOVAR). We validated CLOVAR on an independent dataset consisting of 879 HGS-OvCa expression profiles. The worst outcome group, accounting for 23% of all cases, was associated with a median survival of 23 months and a platinum resistance rate of 63%, versus a median survival of 46 months and platinum resistance rate of 23% in other cases. Associating the outcome prediction model with BRCA1/BRCA2 mutation status, residual disease after surgery, and disease stage further optimized outcome classification. Ovarian cancer is a disease in urgent need of more effective therapies. The spectrum of outcomes observed here and their association with CLOVAR signatures suggests variations in underlying tumor biology. Prospective validation of the CLOVAR model in the context of additional prognostic variables may provide a rationale for optimal combination of patient and treatment regimens. IntroductionHigh-grade serous ovarian carcinoma (HGS-OvCa) accounts for 60%-80% of the approximately 26,000 women diagnosed with epithelial ovarian carcinoma in the US annually (1, 2). Known risk determinants for the development of ovarian carcinoma include BRCA1/BRCA2 mutations, family history, nulliparity, oral contraceptive use, tubal ligation, pregnancy, and lactation (1, 3). A common treatment regimen consists of tumor debulking, followed by administration of platinum and taxane-based chemotherapy (4). The advanced stage at which most patients present, combined

Healthy vascular function is primarily regulated by several factors including EDRF (endothelium-dependent relaxing factor), EDCF (endothelium-dependent contracting factor) and EDHF (endothelium-dependent hyperpolarizing factor). Vascular dysfunction or injury induced by aging, smoking, inflammation, trauma, hyperlipidaemia and hyperglycaemia are among a myriad of risk factors that may contribute to the pathogenesis of many cardiovascular diseases, such as hypertension, diabetes and atherosclerosis. However, the exact mechanisms underlying the impaired vascular activity remain unresolved and there is no current scientific consensus. Accumulating evidence suggests that the inflammatory cytokine TNF (tumour necrosis factor)-α plays a pivotal role in the disruption of macrovascular and microvascular circulation both in vivo and in vitro. AGEs (advanced glycation end-products)/RAGE (receptor for AGEs), LOX-1 [lectin-like oxidized low-density lipoprotein receptor-1) and NF-κB (nuclear factor κB) signalling play key roles in TNF-α expression through an increase in circulating and/or local vascular TNF-α production. The increase in TNF-α expression induces the production of ROS (reactive oxygen species), resulting in endothelial dysfunction in many pathophysiological conditions. Lipid metabolism, dietary supplements and physical activity affect TNF-α expression. The interaction between TNF-α and stem cells is also important in terms of vascular repair or regeneration. Careful scrutiny of these factors may help elucidate the mechanisms that induce vascular dysfunction. The focus of the present review is to summarize recent evidence showing the role of TNF-α in vascular dysfunction in cardiovascular disease. We believe these findings may prompt new directions for targeting inflammation in future therapies.

Rationale Chronic kidney disease (CKD) patients develop hyperhomocysteinemia (HHcy) and have a higher cardiovascular mortality than those without HHcy by 10-fold. Objective We investigated monocyte (MC) differentiation in human CKD and cardiovascular disease (CVD). Methods and Results We identified CD40 as a CKD-related MC activation gene using CKD-MC-mRNA array analysis and classified CD40 MC (CD40+CD14+) as a stronger inflammatory subset than the intermediate MC (CD14++CD16+) subset. We recruited 27 CVD/CKD patients and 14 healthy subjects and found that CD40/CD40 classical/CD40 intermediate MC (CD40+CD14+/CD40+CD14++CD16−/CD40+CD14++CD16+), plasma homocysteine (Hcy), S-adenosylhomocysteine (SAH) and S-adenosylmethionine (SAM) levels were higher in CVD and further elevated in CVD+CKD. CD40 and CD40 intermediate subsets were positively correlated with plasma/cellular Hcy levels and SAH and SAM but negatively correlated with estimated glomerular filtration rate (eGFR). HHcy was established as a likely mediator for CKD-induced CD40 intermediate MC, and reduced SAH/SAM was established for CKD-induced CD40/CD40 intermediate MC. Soluble CD40 ligand (sCD40L), TNFα/IL-6/IFNγ levels were elevated in CVD/CKD. CKD serum/Hcy/CD40L/TNFα/IL-6/IFNγ-induced CD40/CD40 intermediate MC in PBMC. Hcy and CKD serum-induced CD40 MC were prevented by neutralizing antibodies against CD40L/TNFα/IL-6. DNA hypomethylation was found on NFκB consensus element in CD40 promoter in WBC from CKD patients with lower SAM/SAH ratios. Finally, Hcy inhibited DNA methyltransferase-1 activity and promoted CD40 intermediate MC differentiation which was reversed by folic acid in PBMC. Conclusion CD40 MC is a novel inflammatory MC subset that appears to be a biomarker for CKD severity. HHcy mediates CD40 MC differentiation via sCD40L induction and CD40 DNA hypomethylation in CKD.

. Feed-forward signaling of TNF-␣ and NF-B via IKK-␤ pathway contributes to insulin resistance and coronary arteriolar dysfunction in type 2 diabetic mice.