A change in inflammatory foot print precedes plaque instability: A systematic evaluation of cellular aspects of the adaptive immune response in human atherosclerosis

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Local and distant recurrences in rectal cancer patients are predicted by the nonspecific immune response; specific immune response has only a systemic effect - a histopathological and immunohistochemical study

BACKGROUND: Invasion and metastasis is a complex process governed by the interaction of genetically altered tumor cells and the immunological and inflammatory host reponse. Specific T-cells directed against tumor cells and the nonspecific inflammatory reaction due to tissue damage, cooperate against invasive tumor cells in order to prevent recurrences. Data concerning involvement of individual cell types are readily available but little is known about the coordinate interactions between both forms of immune response. PATIENTS AND METHODS: The presence of inflammatory infiltrate and eosinophils was determined in 1530 patients with rectal adenocarcinoma from a multicenter trial. We selected 160 patients to analyze this inflammatory infiltrate in more detail using immunohistochemistry. The association with the development of local and distant relapses was determined using univariate and multivariate log rank testing. RESULTS: Patients with an extensive inflammatory infiltrate around the tumor had lower recurrence rates (3.4% versus 6.9%, p = 0.03), showing the importance of host response against tumor cells. In particular, peritumoral mast cells prevent local and distant recurrence (44% versus 15%, p = 0.007 and 86% versus 21%, p < 0.0001, respectively), with improved survival as a consequence. The presence of intratumoral T-cells had independent prognostic value for the occurrence of distant metastases (32% versus 76%, p < 0.0001). CONCLUSIONS: We showed that next to properties of tumor cells, the amount and type of inflammation is also relevant in the control of rectal cancer. Knowledge of the factors involved may lead to new approaches in the management of rectal cancer

Visualizing TGF-beta and BMP signaling in human atherosclerosis: a histological evaluation based on Smad activation

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Effects of IL-2 on MMP Expression in Freshly Isolated Human NK Cells and the IL-2-independent NK Cell Line YT

Interleukin-2 is an important activation factor for natural killer (NK) cells but its effect on NK cell matrix metalloproteinases (MMP) production and matrix degradation is less well investigated. We have used freshly isolated human NK cells and the IL-2-independent NK cell line, YT, to investigate the effects of IL-2 stimulation on NK cell invasion of Matrigel and on MMP expression and production. In YT cells, we found opposing early and late effects of IL-2 stimulation with an early (2 h) increase in MMP-9 protein level and enhanced migration in the Matrigel invasion assay and by 30 hours a decreased mRNA expression of MMP-2, MMP-9, MMP-13, MT3-MMP, and MT6-MMP. We also found a preculture period of 48 hours with IL-2 to negatively affect YT cell migration. We furthermore found that freshly isolated human NK cells Matrigel invasion was MMP-dependent and it increased in response to IL-2. Importantly, in freshly isolated human NK cells we did not see a downregulation of MMPs after 24 hours IL-2 stimulation, but instead a significant upregulation of MT6-MMP mRNA. Because of the cellular localisation of MT6-MMP, which ensures a focalized proteolytic activity, and its high expression compared with the other MMPs in freshly isolated human NK cells makes it of interest to study further.Surgical oncolog

Visualizing TGF-ß and BMP signaling in human atherosclerosis: a histological evaluation based on Smad activation

Background: The TGF-ß superfamily members Transforming Growth Factor-ß (TGF-ß/Activin) and Bone Morphogenetic Proteins (BMP) have been implicated in the pathogenesis of atherosclerosis. However, their role in human disease remains controversial. In this study we used Smad phosphorylation as a read out for TGF-ß and BMP signaling during the initiation, progression and (de)stabilization of human atherosclerotic disease. Material and methods: A systematic analysis was performed in 114 peri-renal aortic patches (stained with Movat Pentachrome, H&E, pSmad2, pSmad1,5,8 and PAI-1) covering the entire atherosclerotic spectrum (van Dijk, 2010). Immunostaining against T-cells (CD3) and monocytes and macrophages (CD68) was used to explore a putative association between TGF-ß and BMP signaling and vascular inflammation. Results: Smad phosphorylation was present within the normal arterial wall in approximately 10% of the endothelial cells and intimal smooth muscle cells. A significant increase in pSmad2 and pSmad1,5,8 positivity was found in non-progressive lesions (>50% positivity). No further increase or decrease was found in the progressive atherosclerotic lesions, vulnerable and stabilized lesions. No association was found between TGF-ß and BMP signaling and CD3 and CD68 expression, nor cap thickness. Conclusion: Activation of the TGF-ß and BMP pathways is an early event in atherosclerotic lesion formation. No significant relationships were found between Smad phosphorylation and vessel wall inflammation or plaque vulnerability

Autoantibodies and histogenesis of celiac disease

OBJECTIVE: Autoantibodies are used as markers for celiac disease (CD) identifying patients with mucosal lesions. The purpose of this study was to evaluate the sensitivity and role of the autoantibodies such as IgA antiendomysium (EMA), IgA antigliadin (AGA) and the IgA antitissue transglutaminase (tTGA) in histogenesis of celiac disease. METHODS: Seventy-nine cases including 30 untreated celiacs, 5 celiacs on gluten-free diet (GFD), 41 first degree relatives and 3 non-relatives suspected for CD were investigated. Three untreated celiacs with IgA deficiency were excluded from this study group. IgA antibodies to tTGA were determined by ELISA, as described before. Twelve of 41 relatives and 2 cases of non relatives suspected with positive serology underwent a small intestinal biopsy. Results were correlated with the degrees of abnormality of the intestinal mucosa in patients with CD. Intestinal biopsies obtained from study population were evaluated for histological quantification. RESULTS: Celiacs and suspected cases with positive EMA/AGA and or tTGA showed shorter villi (p < 0.007) and/or a higher number of intraepithelial lymphocytes (IEL) (p < 0.035). The sensitivity of serology (EMA, AGA, tTGA) in patients with Marsh IIIc was 100%. However, in patients with Marsh IIIa the sensitivity for EMA, AGA, and tTGA was 40%, 50% and 20% respectively. CONCLUSIONS: The appearance of antibodies is related to the degree of mucosal infiltration by IELs. Although tTGA, like EMA provide a highly sensitive parameter for the detection of celiacs with severe mucosal damage, it appears to be less sensitive (even less than AGA) in celiac patients with milder histopathological abnormalities. However, it should be recognized that the substantial part of the celiac population present with these milder forms of mucosal abnormalities. Using tTGA as a single test in screening may result in missing up to 60-70% of celiacs with mild mucosal abnormalities. Combination with other screening tests (at least with AGA) is essential and strongly recommende

SLUG Is Expressed in Endothelial Cells Lacking Primary Cilia to Promote Cellular Calcification

Therapeutic cell differentiatio