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Edgbaston, United Kingdom

O'Donnell V.B.,University of Cardiff | Murphy R.C.,University of Colorado at Denver | Watson S.P.,Institute of Biomedical Research
Circulation Research | Year: 2014

Lipids are diverse families of biomolecules that perform essential structural and signaling roles in platelets. Their formation and metabolism are tightly controlled by enzymes and signal transduction pathways, and their dysregulation leads to significant defects in platelet function and disease. Platelet activation is associated with significant changes to membrane lipids, and formation of diverse bioactive lipids plays essential roles in hemostasis. In recent years, new generation mass spectrometry analysis of lipids (termed lipidomics) has begun to alter our understanding of how these molecules participate in key cellular processes. Although the application of lipidomics to platelet biology is still in its infancy, seminal earlier studies have shaped our knowledge of how lipids regulate key aspects of platelet biology, including aggregation, shape change, coagulation, and degranulation, as well as how lipids generated by platelets influence other cells, such as leukocytes and the vascular wall, and thus how they regulate hemostasis, vascular integrity, and inflammation, as well as contribute to pathologies, including arterial/deep vein thrombosis and atherosclerosis. This review will provide a brief historical perspective on the characterization of lipids in platelets, then an overview of the new generation lipidomic approaches, their recent application to platelet biology, and future perspectives for research in this area. The major platelet-regulatory lipid families, their formation, metabolism, and their role in health and disease, will be summarized. Source

Koyasu S.,Kyoto University | Koyasu S.,Kobe City Medical Center | Nakamoto Y.,Kyoto University | Kikuchi M.,Kobe City Medical Center | And 4 more authors.
American Journal of Roentgenology | Year: 2014

OBJECTIVE. The purpose of this study was to determine whether pretreatment quantitative and visual parameters seen on PET/CT using 18F-FDG add prognostic information for clinical staging in patients with head and neck cancer. MATERIALS AND METHODS. We enrolled 108 patients with histologically proven oral, oropharyngeal, hypopharyngeal, and laryngeal squamous cell carcinomas who underwent FDG PET/CT before treatment and, later, definitive therapy in our study. PET/CT parameters - maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and uptake pattern (sphere-shaped or ring-shaped) - were recorded. The prognostic value of these parameters was evaluated using univariate and multivariate Cox regression analyses. RESULTS. In the univariate analysis, all of the FDG PET/CT parameters - SUVmax (> 10 g/mL) of the primary tumor, MTV (> 20 cm3), TLG (> 70 g), and uptake pattern (ring-shaped) - were significantly associated with negative effects on disease-specific survival (DSS) and disease-free survival (DFS). In the multivariate analysis, the MTV and uptake pattern remained associated with DSS after corrections for the Union for International Cancer Control (UICC) stage and definitive therapy (p = 0.023 and < 0.001, respectively). Another multivariate model that included MTV as a continuous variable, uptake pattern, and UICC stage showed that the uptake pattern remained significantly associated with DSS, whereas the association between DSS and MTV was not significant (p < 0.001 and = 0.332, respectively). CONCLUSION. Our data indicate that the pretreatment PET/CT parameters had prognostic value. In particular, a qualitative factor, uptake pattern, provided better prognostic information to the clinical staging of head and neck squamous cell carcinomas than the other PET/CT parameters. © American Roentgen Ray Society. Source

Ignjatovic N.L.,Serbian Academy of Science and Arts | Ajdukovic Z.R.,University of Sfax | Savic V.P.,Institute of Biomedical Research | Uskokovic D.P.,Serbian Academy of Science and Arts
Journal of Biomedical Materials Research - Part B Applied Biomaterials | Year: 2010

In this article, synthesis and application of calcium phosphate/poly-DL- lactide-co-glycolide (CP/PLGA) composite biomaterial in particulate form, in which each CP granule/particle is coated with PLGA, are described. Two types of the particulate material having different particle sizes were synthesized: one with an average particle diameter between 150 and 250 μm (micron-sized particles, MPs) and the other with an average particle diameter smaller than 50 nm (nanoparticles, NPs). A comparative in vivo analysis was done by reconstructing defects in osteoporotic alveolar bones using both composites. The material, CP granules/particles covered with polymer, was characterized using X-ray structural analysis, scanning electron microscopy, and atomic force microscopy. Changes in reparatory functions of tissues affected by osteoporosis were examined in mice in vivo, using these two kinds of composite materials, with and without autologous plasma. Having defined the target segment, histomorphometric parameters - bone area fraction, area, and mean density - were determined. The best results in the regeneration and recuperation of alveolar bone damaged by osteoporosis were achieved with the implantation of a mixture of nanoparticulate CP/PLGA composite and autologous plasma. After the implantation of microparticulate CP/PLGA, in the form of granules, mixed with autologous plasma, into an artificial defect in alveolar bone, new bone formation was also observed, although its formation rate was slower. © 2010 Wiley Periodicals, Inc. Source

Moh C.,Case Western Reserve University | Kubiak J.Z.,University of Rennes 1 | Bajic V.P.,Institute of Biomedical Research | Zhu X.,Case Western Reserve University | And 2 more authors.
Results and Problems in Cell Differentiation | Year: 2011

The cell cycle consists of four main phases: G1, S, G 2, and M. Most cells undergo these cycles up to 40-60 times in their life. However, neurons remain in a nondividing, nonreplicating phase, G 0. Neurons initiate but do not complete cell division, eventually entering apoptosis. Research has suggested that like cancer, Alzheimer's disease (AD) involves dysfunction in neuronal cell cycle reentry, leading to the development of the two-hit hypothesis of AD. The first hit is abnormal cell cycle reentry, which typically results in neuronal apoptosis and prevention of AD. However, with the second hit of chronic oxidative damage preventing apoptosis, neurons gain "immortality" analogous to tumor cells. Once both of these hits are activated, AD can develop and produce senile plaques and neurofibrillary tangles throughout brain tissue. In this review, we propose a mechanism for neuronal cell cycle reentry and the development of AD. © 2011 Springer-Verlag Berlin Heidelberg. Source

Mejias M.,Institute of Biomedical Research | Garcia-Pras E.,Institute of Biomedical Research | Gallego J.,Institute of Biomedical Research | Mendez R.,University Pompeu Fabra | And 2 more authors.
Journal of Hepatology | Year: 2010

Background & Aims: Splenomegaly is a frequent hallmark of portal hypertension that, in some cases, can be very prominent and cause symptoms like abdominal pain, splenic infarction, and cytopenia. This study characterizes the pathogenetic mechanisms leading to spleen enlargement in portal hypertensive rats and focuses on mTOR pathway as a potential modulator of splenomegaly in portal hypertension. Methods: Characterization of splenomegaly was performed by histological, hematological, immunohistochemical and Western blot analyses in rats with portal hypertension induced by portal vein ligation, and compared with sham-operated animals. The contribution of the mTOR signaling pathway to splenomegaly was determined in rats with fully developed portal hypertension and control rats by treatment with rapamycin or vehicle. Results: Our results illustrate that splenomegaly in portal hypertensive rats arises as a consequence of the interplay of several factors, including not only spleen congestion, as traditionally thought, but also enlargement and hyperactivation of the splenic lymphoid tissue, as well as increased angiogenesis and fibrogenesis. Since mTOR signaling plays a central role in immunological processes, angiogenesis and fibrogenesis, we next determined the involvement of mTOR in splenomegaly. Interestingly, mTOR signaling was overactivated in the spleen of portal hypertensive rats, and mTOR blockade by rapamycin profoundly ameliorated splenomegaly, causing a 44% decrease in spleen size. This effect was most likely accounted for the inhibitory action of rapamycin on lymphocyte proliferation, neovascularization and fibrosis. Conclusions: These findings shed light on the pathogenesis of splenomegaly in portal hypertension, and identify mTOR signaling as a potential target for therapeutic intervention in this disease. © 2010 European Association for the Study of the Liver. Source

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