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The immunoreceptor tyrosine-based activation motif (ITAM)-related factors are increased in synovial tissue and vasculature of rheumatoid arthritic joints

Sat, 31 Dec 2011 13:30:00 GMT

Title: The immunoreceptor tyrosine-based activation motif (ITAM)-related factors are increased in synovial tissue and vasculature of rheumatoid arthritic joints Author: Crotti, Tania Narelle; Dharmapatni, Kencana; Alias, Ekram; Zannettino, Andrew Christopher William; Smith, Malcolm D.; Haynes, David Robert Abstract: Introduction: The immunoreceptor tyrosine-based activation motif (ITAM) pathway provides osteoclast co-stimulatory signals and regulates proliferation, survival and differentiation of effector immune cells. In the osteoclast, the receptors Triggering Receptor Expressed on Myeloid cells 2 (TREM2) and Osteoclast Associated Receptor (OSCAR) and their respective adaptor proteins, DAP12 and FcRγ mediate ITAM signals and induce calcium signaling and the crucial transcription factor, NFATc1. In rheumatoid arthritis (RA), OSCAR expression by monocytes is inversely correlated with disease activity. Additionally, serum levels of OSCAR are reduced in RA patients versus healthy controls suggesting that expression and secretion or cleavage of soluble (s) OSCAR is immune modulated. Recent data suggest that endothelial cells may also be a source of OSCAR. Methods: ITAM receptors, their adaptor proteins, and NFATc1 and cathepsin K were detected in human synovial tissues by immunohistochemistry. Synovial tissues from patients with active RA were compared with tissue from patients in remission, osteoarthritis (OA) patients and healthy individuals. OSCAR was measured by immunoassay in synovial fluids recovered from active RA and OA patients. Endothelial cells were cultured with or without 5 ng/mL TNF-α or IL-1β over 72 hours. Temporal expression of OSCAR mRNA was assessed by qRT PCR and OSCAR protein in the supernatant was measured by ELISA. Results: Significantly higher (P < 0.05) NFATc1-positive inflammatory cell aggregates were found in active RA tissues than in healthy synovial tissue. Similarly, the percentage of OSCAR, FcRγ, DAP12 and TREM2 positive cells was significantly higher in active RA tissues compared to the healthy synovial tissue. Notably, OSCAR was strongly expressed in the microvasculature of the active RA tissues (9/9), inactive RA (8/9) weakly in OA (4/9) but only in the lumen of healthy synovial tissue (0/8). OSCAR levels were detected in synovial fluids from both RA (47 to 152 ng/mL) and OA (112 to 145 ng/mL) patients. Moreover, OSCAR mRNA expression and soluble OSCAR release was stimulated by TNF-α and IL1-β in cultured endothelial cells. Conclusions: Increased levels of ITAM related factors were present in synovial tissue from active RA joints compared to OA and healthy joints. OSCAR was strongly expressed by the vasculature of active RA patients and membrane bound and soluble OSCAR was stimulated by inflammatory mediators in endothelial cells in vitro. Description: Extent: 13p.

Micro-CT examination of human bone: from biopsies towards the entire organ

Sat, 31 Dec 2011 13:30:00 GMT

Title: Micro-CT examination of human bone: from biopsies towards the entire organ Author: Perilli, Egon; Parkinson, Ian Henry; Reynolds, Karen J. Abstract: Micro-CT systems are available that facilitate ex vivo examinations of human specimens as big as entire vertebrae, with spatial resolutions in the 10-micrometer range. This opens a new way for looking at entire bones in 3D. Accurate description of the internal microarchitecture of the entire organ can be obtained, at spatial resolutions previously achievable only on excised biopsies. These high resolution scans produce large datasets and come with costs and benefits, which have to be considered in the successful planning of an experiment. The aim of this paper is to present examples of human vertebrae scanned at high resolution (17 μm/pixel), allowing the visualization and quantification of the microarchitecture, and to discuss some aspects of using high resolution scans of such large specimens. The datasets were down-sampled to 34 μm and 68 μm pixel size, and their morphometric parameters compared to those obtained at 17 μm pixel size, in relation to data size and calculation time.

Temporal changes in bone composition, architecture, and strength following estrogen deficiency in osteoporosis

Sat, 31 Dec 2011 13:30:00 GMT

Title: Temporal changes in bone composition, architecture, and strength following estrogen deficiency in osteoporosis Author: Brennan, Orlaith; Kuliwaba, Julia Suzanne; Lee, T. Clive; Parkinson, Ian Henry; Fazzalari, Nicola L.; McNamara, Laoise M.; O'Brien, Fergal J.

Gastric HER2 Testing Study (GaTHER): An Evaluation of Gastric/Gastroesophageal Junction Cancer Testing Accuracy in Australia

Sat, 31 Dec 2011 13:30:00 GMT

Title: Gastric HER2 Testing Study (GaTHER): An Evaluation of Gastric/Gastroesophageal Junction Cancer Testing Accuracy in Australia Author: Fox, Stephen; Kumarasinghe, Marian Priyanthi; Armes, Jane E.; Bilous, Michael; Cummings, Margaret; Farshid, Gelareh; Fitzpatrick, Nicole; Francis, Glenn; McCloud, Philip I.; Raymond, Wendy Ann; Morey, Adrienne Abstract: rastuzumab provides a survival benefit in patients with human epidermal growth factor receptor 2 (HER2)-amplified/overexpressed advanced gastric and gastroesophageal junction cancers (GC/GJCs). However, the optimal method for testing is unclear. The aim of this study was to assess interlaboratory agreement on HER2 scoring in GC/GJC to aid the development of a robust testing algorithm for diagnostic practice in Australia. Nine laboratories assessed the HER2 status of 100 GC/GJC tissue samples by immunohistochemistry (IHC) and in situ hybridization (ISH) [chromogenic (CISH) or silver (SISH)] using both HER2 copy number and HER2:chr17 (chromosome 17) ratio. Results were compared with reference fluorescence ISH (FISH). Interlaboratory agreement on IHC3+ scoring was good ([kappa]=0.76), and there was good/very good agreement between IHC (positivity defined as IHC3+) and ISH when HER2 copy number was used ([kappa]=0.72 to 0.87). Agreement on CISH/SISH scoring was good/very good when HER2 copy number was used ([kappa]=0.68 to 0.86), and agreement between CISH/SISH and FISH using HER2 copy number was very good ([kappa]=0.88 to 0.91). Agreement was reduced when HER2:chr17 ratio was used. The good agreement for HER2 copy number determined by bright-field ISH suggests that this is the optimal method for testing in GC/GJC cases. An IHC3+ score was strongly predictive of a positive ISH result, although agreement for all IHC scores was only moderate, suggesting that IHC triage before ISH testing would be the most cost-effective strategy. However, because of the unique features of GC/GJC samples and the difficulty of ensuring consistent HER2 staining in the community setting, it is recommended that HER2 status in advanced GC/GJC be determined by both IHC and ISH in the same laboratory.