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.

OBJECTIVE We investigated the prevalence of sarcopenic obesity (SO) and its relationship with metabolic syndrome in a community-based elderly cohort in Korea. RESEARCH DESIGN AND METHODS In this study, 287 men and 278 women aged 65 or older were recruited. Sarcopenia was defined as the appendicular skeletal muscle mass (ASM) divided by height squared (Ht²) (kg/m²) or by weight (Wt) (%) of <1 SD below the sex-specific mean for young adults. Obesity was defined as a visceral fat area ≥100 cm². RESULTS The prevalence of SO was 16.7% in men and 5.7% in women with sarcopenia defined by ASM/Ht²; however, it was 35.1% in men and 48.1% in women by ASM/Wt. Using ASM/Wt, the homeostasis model assessment of insulin resistance of subjects with SO was higher and they were at higher risk for metabolic syndrome (odds ratio [OR] 8.28 [95% CI 4.45–15.40]) than the obese (5.51 [2.81–10.80]) or sarcopenic group (2.64 [1.08–6.44]). CONCLUSIONS SO defined by ASM/Wt was more closely associated with metabolic syndrome than either sarcopenia or obesity alone.

BACKGROUND: The effects of the BRAF^V600E mutation on prognostic factors and poor clinical outcomes in papillary thyroid cancer (PTC) have not been fully quantified. The authors performed comprehensive meta‐analysis to assess the strength of associations between these conditions and the BRAF^V600E mutation.METHODS: The authors identified the clinical studies that examined the association of the BRAF^V600E mutation in surgical specimens with clinicopathologic outcomes between January 2003 and October 2010 using the Medline database. One hundred thirty‐one relevant studies were hand‐searched. The authors selected 27 studies that included 5655 PTC patients. They calculated the pooled odds ratios (ORs) or risk ratios with 95% confidence intervals (CIs) for each study using a random effect model.RESULTS: The average prevalence rate of the BRAF^V600E mutation was 49.4%. In 26 studies, compared with the patients who had the wild‐type BRAF genes, the PTC patients with the BRAF^V600E mutation had increased ORs of an extrathyroidal invasion (OR, 2.14; 95% CI, 1.68‐2.73), a lymph node metastasis (OR, 1.54; 95% CI, 1.21‐1.97), and an advanced TNM stage (OR, 2.00; 95% CI, 1.61‐2.49). In 8 studies, patients with the mutation had 2.14‐fold increased risk of recurrent and persistent disease (95% CI, 1.67‐2.74). The associations were generally consistent across the different study populations.CONCLUSIONS: This meta‐analysis demonstrates that the BRAF^V600E mutation is closely related to the high‐risk clinicopathological factors and poorer outcome of PTC. The results obtained here suggest that the BRAF^V600E mutation should be considered as a poor prognostic marker in PTC and may lead to better management for individual patients. Cancer 2012;. © 2011 American Cancer Society.

Follicular thyroid carcinoma (FTC) and benign follicular adenoma (FA) are indistinguishable by preoperative diagnosis due to their similar histological features. Here we report the first RNA sequencing study of these tumors, with data for 30 minimally invasive FTCs (miFTCs) and 25 FAs. We also compared 77 classical papillary thyroid carcinomas (cPTCs) and 48 follicular variant of PTCs (FVPTCs) to observe the differences in their molecular properties. Mutations in H/K/NRAS, DICER1, EIF1AX, IDH1, PTEN, SOS1, and SPOP were identified in miFTC or FA. We identified a low frequency of fusion genes in miFTC (only one, PAX8–PPARG), but a high frequency of that in PTC (17.60%). The frequencies of BRAF^V600E and H/K/NRAS mutations were substantially different in miFTC and cPTC, and those of FVPTC were intermediate between miFTC and cPTC. Gene expression analysis demonstrated three molecular subtypes regardless of their histological features, including Non–BRAF–Non–RAS (NBNR), as well as BRAF–like and RAS–like. The novel molecular subtype, NBNR, was associated with DICER1, EIF1AX, IDH1, PTEN, SOS1, SPOP, and PAX8–PPARG. The transcriptome of miFTC or encapsulated FVPTC was indistinguishable from that of FA, providing a molecular explanation for the similarly indolent behavior of these tumors. We identified upregulation of genes that are related to mitochondrial biogenesis including ESRRA and PPARGC1A in oncocytic follicular thyroid neoplasm. Arm-level copy number variations were correlated to histological and molecular characteristics. These results expanded the current molecular understanding of thyroid cancer and may lead to new diagnostic and therapeutic approaches to the disease. Recently, The Cancer Genome Atlas proposed an improved classification of the subtypes of papillary thyroid carcinoma (PTC) based on gene expression profiles, which better represents cell signaling and differentiation. However, a molecular characterization of follicular thyroid carcinoma (FTC), which has a greater tendency for hematogenous spread to lung and bone is not yet fully elucidated. In this study, we describe the first RNA sequencing data of minimally invasive FTC (miFTC) and benign follicular adenoma (FA), which cause diagnostic difficulties due to their similar histological features. Additionally, classical PTC and follicular variant of PTC (FVPTC) were sequenced to compare their transcriptional and mutational landscape. BRAF, H/K/NRAS, fusion genes, and copy number variations were associated with tumor histology. Based on gene expression profiles, thyroid tumors were classified as three molecular subtypes regardless of histological subtypes, BRAF–like, RAS–like, and Non–BRAF–Non–RAS. In particular, we found identical gene expression profiles between miFTC, FA, and encapsulated FVPTC. Oncocytic follicular thyroid tumors have gene expression signatures related to mitochondrial biogenesis including ESRRA and PPARGC1A. These results expanded the current molecular understanding of thyroid cancer to its follicular types.

Anaplastic thyroid cancer (ATC) and advanced differentiated thyroid cancers (DTCs) show fatal outcomes, unlike DTCs. Here, we demonstrate mutational landscape of 27 ATCs and 86 advanced DTCs by massively-parallel DNA sequencing, and transcriptome of 13 ATCs and 12 advanced DTCs were profiled by RNA sequencing.TERT,AKT1,PIK3CA, andEIF1AXwere frequently co-mutated with driver genes (BRAF^V600EandRAS) in advanced DTCs as well as ATC, but tumor suppressors (e.g.,TP53andCDKN2A) were predominantly altered in ATC.CDKN2Aloss was significantly associated with poor disease-specific survival in patients with ATC or advanced DTCs, and up-regulation ofCD274(PD-L1) andPDCD1LG2(PD-L2). Transcriptome analysis revealed a fourth molecular subtype of thyroid cancer (TC), ATC-like, which hardly reflects the molecular signatures in DTC. Furthermore, the activation of JAK-STAT signaling pathway could be a potential druggable target inRAS-positive ATC. Our findings provide insights for precision medicine in patients with advanced TCs.

Macrophages are a component of a tumor's microenvironment and have various roles in tumor progression and metastasis. This study evaluated the relationships between tumor-associated macrophage (TAM) density and clinical outcomes in 14 different types of human cancers. We investigated TAM density in human tissue microarray sections from 14 different types of human cancers (n = 266) and normal thyroid, lung, and breast tissues (n = 22). The five-year survival rates of each cancer were obtained from the 2011 Korea Central Cancer Registry. Among 13 human cancers, excluding thyroid cancer, pancreas, lung, and gallbladder cancers had the highest density of CD163-positive macrophages (7.0±3.5%, 6.9±7.4%, and 6.9 ± 5.5%, respectively). The five-year relative survival rates of these cancers (pancreas, 8.7%; lung, 20.7%; gallbladder, 27.5%) were lower than those of other cancers. The histological subtypes in thyroid cancer exhibited significantly different CD163-positive macrophages densities (papillary, 1.8 ± 1.6% vs anaplastic, 22.9 ± 17.1%; p < .001), but no significant difference between histological subtypes was detected in lung and breast cancers. Moreover, there was no significant difference in CD163-positive macrophages densities among the TNM stages in lung, breast, and thyroid cancers. Cancers with higher TAM densities (pancreas, lung, anaplastic thyroid, and gallbladder) were associated with poor survival rate.