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Improving cytocompatibility of Co28Cr6Mo by TiO2 coating: gene expression study in human endothelial cells.
Tsaryk, R, Peters, K, Unger, RE, Feldmann, M, Hoffmann, B, Heidenau, F, Kirkpatrick, CJ
Journal of the Royal Society, Interface. 2013;(86):20130428
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Abstract
Cobalt-based materials are widely used for coronary stents, as well as bone and joint implants. However, their use is associated with high corrosion incidence. Titanium alloys, by contrast, are more biocompatible owing to the formation of a relatively inactive titanium oxide (TiO2) layer on their surface. This study was aimed at improving Co28Cr6Mo alloy cytocompatibility via sol-gel TiO2 coating to reduce metal corrosion and metal ion release. Owing to their role in inflammation and tissue remodelling around an implant, endothelial cells present a suitable in vitro model for testing the biological response to metallic materials. Primary human endothelial cells seeded on Co28Cr6Mo showed a stress phenotype with numerous F-actin fibres absent on TiO2-coated material. To investigate this effect at the gene expression level, cDNA microarray analysis of in total 1301 genes was performed. Compared with control cells, 247 genes were expressed differentially in the cells grown on Co28Cr6Mo, among them genes involved in proliferation, oxidative stress response and inflammation. TiO2 coating reduced the effects of Co28Cr6Mo on gene expression in endothelial cells, with only 34 genes being differentially expressed. Quantitative real-time polymerase chain reaction and protein analysis confirmed microarray data for selected genes. The effect of TiO2 coating can be, in part, attributed to the reduced release of Co(2+), because addition of CoCl2 resulted in similar cellular responses. TiO2 coating of cobalt-based materials, therefore, could be used in the production of cobalt-based devices for cardiovascular and skeletal applications to reduce the adverse effects of metal corrosion products and to improve the response of endothelial and other cell types.
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PGH1, the precursor for the anti-inflammatory prostaglandins of the 1-series, is a potent activator of the pro-inflammatory receptor CRTH2/DP2.
Schröder, R, Xue, L, Konya, V, Martini, L, Kampitsch, N, Whistler, JL, Ulven, T, Heinemann, A, Pettipher, R, Kostenis, E
PloS one. 2012;(3):e33329
Abstract
Prostaglandin H(1) (PGH(1)) is the cyclo-oxygenase metabolite of dihomo-γ-linolenic acid (DGLA) and the precursor for the 1-series of prostaglandins which are often viewed as "anti-inflammatory". Herein we present evidence that PGH(1) is a potent activator of the pro-inflammatory PGD(2) receptor CRTH2, an attractive therapeutic target to treat allergic diseases such as asthma and atopic dermatitis. Non-invasive, real time dynamic mass redistribution analysis of living human CRTH2 transfectants and Ca(2+) flux studies reveal that PGH(1) activates CRTH2 as PGH(2), PGD(2) or PGD(1) do. The PGH(1) precursor DGLA and the other PGH(1) metabolites did not display such effect. PGH(1) specifically internalizes CRTH2 in stable CRTH2 transfectants as assessed by antibody feeding assays. Physiological relevance of CRTH2 ligation by PGH(1) is demonstrated in several primary human hematopoietic lineages, which endogenously express CRTH2: PGH(1) mediates migration of and Ca(2+) flux in Th2 lymphocytes, shape change of eosinophils, and their adhesion to human pulmonary microvascular endothelial cells under physiological flow conditions. All these effects are abrogated in the presence of the CRTH2 specific antagonist TM30089. Together, our results identify PGH(1) as an important lipid intermediate and novel CRTH2 agonist which may trigger CRTH2 activation in vivo in the absence of functional prostaglandin D synthase.
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Clinical value of circulating endothelial cell levels in metastatic colorectal cancer patients treated with first-line chemotherapy and bevacizumab.
Malka, D, Boige, V, Jacques, N, Vimond, N, Adenis, A, Boucher, E, Pierga, JY, Conroy, T, Chauffert, B, François, E, et al
Annals of oncology : official journal of the European Society for Medical Oncology. 2012;(4):919-27
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Abstract
BACKGROUND We investigated whether circulating endothelial cells (CECs) predict clinical outcome of first-line chemotherapy and bevacizumab in metastatic colorectal cancer (mCRC) patients. PATIENTS AND METHODS In a substudy of the randomized phase II FNCLCC ACCORD 13/0503 trial, CECs (CD45- CD31+ CD146+ 7-amino-actinomycin- cells) were enumerated in 99 patients by four-color flow cytometry at baseline and after one cycle of treatment. We correlated CEC levels with objective response rate (ORR), 6-month progression-free survival (PFS) rate (primary end point of the trial), PFS, and overall survival (OS). Multivariate analyses of potential prognostic factors, including CEC counts and Köhne score, were carried out. RESULTS By multivariate analysis, high baseline CEC levels were the only independent prognostic factor for 6-month PFS rate (P < 0.01) and were independently associated with worse PFS (P = 0.02). High CEC levels after one cycle were the only independent prognostic factor for ORR (P = 0.03). High CEC levels at both time points independently predicted worse ORR (P = 0.025), 6-month PFS rate (P = 0.007), and PFS (P = 0.02). Köhne score was the only variable associated with OS. CONCLUSION CEC levels at baseline and after one treatment cycle may independently predict ORR and PFS in mCRC patients starting first-line bevacizumab and chemotherapy.
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A potent oral P-selectin blocking agent improves microcirculatory blood flow and a marker of endothelial cell injury in patients with sickle cell disease.
Kutlar, A, Ataga, KI, McMahon, L, Howard, J, Galacteros, F, Hagar, W, Vichinsky, E, Cheung, AT, Matsui, N, Embury, SH
American journal of hematology. 2012;(5):536-9
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Abstract
Abnormal blood flow accounts for most of the clinical morbidity of sickle cell disease (SCD) [1,2]. Most notably, occlusion of flow in the microvasculature causes the acute pain crises [3] that are the commonest cause for patients with SCD to seek medical attention [4] and major determinants of their quality of life [5]. Based on evidence that endothelial P-selectin is central to the abnormal blood flow in SCD we provide results from four of our studies that are germane to microvascular blood flow in SCD. A proof-of-principle study established that doses of heparin lower than what are used for anticoagulation but sufficient to block P-selectin improved microvascular blood flow inpatients with SCD. An in vitro study showed that Pentosan Polysulfate Sodium (PPS) had greater P-selectin blocking activity than heparin. A Phase I clinical study demonstrated that a single oral dose of PPS increased microvascular blood flow in patients with SCD. A Phase II clinical study that was not completed documented that daily oral doses of PPS administered for 8 weeks lowered plasma levels of sVCAM-1 and tended to improve microvascular blood flow in patients with SCD. These data support the concept that P-selectin on the microvascular endothelium is critical to both acute vascular occlusion and chronically impaired microvascular blood flow in SCD. They also demonstrate that oral PPS is beneficial to microvascular sickle cell blood flow and has potential as an efficacious agent for long-term prophylactic therapy of SCD.
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Exchanging saturated fatty acids for (n-6) polyunsaturated fatty acids in a mixed meal may decrease postprandial lipemia and markers of inflammation and endothelial activity in overweight men.
Masson, CJ, Mensink, RP
The Journal of nutrition. 2011;(5):816-21
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Abstract
Postprandial lipemia, low-grade systemic inflammation, and endothelial activity are related to metabolic disorders. It is well known that dietary fatty acid composition modulates postprandial lipemia, but information on the other metabolic risk markers is limited. We therefore studied the acute effects of a meal rich in SFA compared with those of a meal rich in (n-6) PUFA on postprandial responses in overweight men who are at an increased risk to develop the metabolic syndrome and its comorbidities. In a crossover design, the effects of 50 g butter (rich in SFA) on lipemia and markers for inflammation and endothelial activity were compared with those of 50 g sunflower oil [rich in (n-6) PUFA] during an 8-h postprandial mixed meal tolerance test in 13 overweight men. Postprandial changes in serum TG were comparable between the meals (P = 0.38), except for a reduction in the incremental area under the curve (P = 0.046) in the late postprandial phase after (n-6) PUFA (125 ± 96 mmol⋅min⋅L(-1)) compared with SFA (148 ± 98 mmol⋅min⋅L(-1)). Compared with the SFA meal, the (n-6) PUFA meal decreased plasma IL-6 (P = 0.003), TNFα (P = 0.005), soluble TNF receptors I and II (sTNFr; P = 0.024 and P < 0.001, respectively), and soluble vascular cell adhesion molecule-1 (sVCAM-1; P = 0.030) concentrations. These results indicate that exchanging SFA from butterfat for (n-6) PUFA in a mixed meal may decrease postprandial lipemia and concentrations of IL-6, TNFα, sTNFr-I and -II, and sVCAM-1 in overweight men.