Tumor necrosis factor-α-mediated threonine 435 phosphorylation of p65 nuclear factor-κB subunit in endothelial cells induces vasogenic edema and neutrophil infiltration in the rat piriform cortex following status epilepticus

<p>Abstract</p> <p>Background</p> <p>Status epilepticus (SE) induces severe vasogenic edema in the piriform cortex (PC) accompanied by neuronal and astroglial damages. To elucidate the mechanism of SE-induced vasogenic edema, we investigated the roles of tumor necrosis factor (TNF)-α in blood-brain barrier (BBB) disruption during vasogenic edema and its related events in rat epilepsy models provoked by pilocarpine-induced SE.</p> <p>Methods</p> <p>SE was induced by pilocarpine in rats that were intracerebroventricularly infused with saline-, and soluble TNF p55 receptor (sTNFp55R) prior to SE induction. Thereafter, we performed Fluoro-Jade B staining and immunohistochemical studies for TNF-α and NF-κB subunits.</p> <p>Results</p> <p>Following SE, most activated microglia showed strong TNF-α immunoreactivity. In addition, TNF p75 receptor expression was detected in endothelial cells as well as astrocytes. In addition, only p65-Thr435 phosphorylation was increased in endothelial cells accompanied by SMI-71 expression (an endothelial barrier antigen). Neutralization of TNF-α by soluble TNF p55 receptor (sTNFp55R) infusion attenuated SE-induced vasogenic edema and neuronal damages via inhibition of p65-Thr435 phosphorylation in endothelial cells. Furthermore, sTNFp55R infusion reduced SE-induced neutrophil infiltration in the PC.</p> <p>Conclusion</p> <p>These findings suggest that impairments of endothelial cell functions via TNF-α-mediated p65-Thr 485 NF-κB phosphorylation may be involved in SE-induced vasogenic edema. Subsequently, vasogenic edema results in extensive neutrophil infiltration and neuronal-astroglial loss.</p

Cyr61/CCN1 Displays High-Affinity Binding to the Somatomedin B 1–44 Domain of Vitronectin

OV) family of extracellular-associated (matricellular) proteins that present four distinct functional modules, namely insulin-like growth factor binding protein (IGFBP), von Willebrand factor type C (vWF), thrombospondin type 1 (TSP), and C-terminal growth factor cysteine knot (CT) domain. While heparin sulphate proteoglycans reportedly mediate the interaction of Cyr61 with the matrix and cell surface, the role of other extracellular associated proteins has not been revealed. at high concentrations attenuate Cyr61 binding to immobilized VTNC, while monomeric VTNC was ineffective. Therefore, immobilization of VTNC exposes cryptic epitopes that recognize Cyr61 with high affinity, as reported for a number of antibodies, β-endorphin, and other molecules. domain suggests that VTNC represent a point of anchorage for CCN family members to the matrix. Results are discussed in the context of the role of CCN and VTNC in matrix biology and angiogenesis

Extraction of artefactual MRS patterns from a large database using non-negative matrix factorization

Despite the success of automated pattern recognition methods in problems of human brain tumor diagnostic classification, limited attention has been paid to the issue of automated data quality assessment in the field of MRS for neuro-oncology. Beyond some early attempts to address this issue, the current standard in practice is MRS quality control through human (expert-based) assessment. One aspect of automatic quality control is the problem of detecting artefacts in MRS data. Artefacts, whose variety has already been reviewed in some detail and some of which may even escape human quality control, have a negative influence in pattern recognition methods attempting to assist tumor characterization. The automatic detection of MRS artefacts should be beneficial for radiology as it guarantees more reliable tumor characterizations, as well as the development of more robust pattern recognition-based tumor classifiers and more trustable MRS data processing and analysis pipelines. Feature extraction methods have previously been used to help distinguishing between good and bad quality spectra to apply subsequent supervised pattern recognition techniques. In this study, we apply feature extraction differently and use a variant of a method for blind source separation, namely Convex Non-Negative Matrix Factorization, to unveil MRS signal sources in a completely unsupervised way. We hypothesize that, while most sources will correspond to the different tumor patterns, some of them will reflect signal artefacts. The experimental work reported in this paper, analyzing a combined short and long echo time 1H-MRS database of more than 2000 spectra acquired at 1.5T and corresponding to different tumor types and other anomalous masses, provides a first proof of concept that points to the possible validity of this approach.Peer ReviewedPostprint (author's final draft

Use of ER/PR/HER2 subtypes in conjunction with the 2007 St Gallen Consensus Statement for early breast cancer

<p>Abstract</p> <p>Background</p> <p>The 2007 St Gallen international expert consensus statement describes three risk categories and provides recommendations for treatment of early breast cancer. The set of recommendations on how to best treat primary breast cancer is recognized and used by clinicians worldwide. We now examine the variability of five-year survival of the 2007 St Gallen Risk Classifications utilizing the ER/PR/HER2 subtypes.</p> <p>Methods</p> <p>Using the population-based California Cancer Registry, 114,786 incident cases of Stages 1-3 invasive breast cancer diagnosed between 2000 and 2006 were identified. Cases were assigned to Low, Intermediate, or High Risk categories. Five-year-relative survival was computed for the three St Gallen risk categories and for the ER/PR/HER2 subtypes for further differentiation.</p> <p>Results and Discussion</p> <p>There were 9,124 (13%) cases classified as Low Risk, 44,234 (65%) cases as Intermediate Risk, and 14,340 (21%) as High Risk. Within the Intermediate Risk group, 33,735 (76%) were node-negative (Intermediate Risk 2) and 10,499 (24%) were node-positive (Intermediate Risk 3). For the High Risk group, 6,149 (43%) had 1 to 3 positive axillary lymph nodes (High Risk 4) and 8,191 (57%) had four or more positive lymph nodes (High Risk 5).</p> <p>Using five-year relative survival as the principal criterion, we found the following: a) There was very little difference between the Low Risk and Intermediate Risk categories; b) Use of the ER/PR/HER2 subtypes within the Intermediate and High Risk categories separated each into a group with better five-year survival (ER-positive) and a group with worse survival (ER-negative), irrespective of HER2-status; c) The heterogeneity of the High Risk category was most evident when one examined the ER/PR/HER2 subtypes with four or more positive axillary lymph nodes; (d) HER2-positivity did not always translate to worse survival, as noted when one compared the triple positive subtype (ER+/PR+/HER2+) to the triple negative subtype (ER-/PR-/HER2-); and (e) ER-negativity appeared to be a stronger predictor of poor survival than HER2-positivity.</p> <p>Conclusion</p> <p>The use of ER/PR/HER2 subtype highlights the marked heterogeneity of the Intermediate and High Risk categories of the 2007 St Gallen statements. The use of ER/PR/HER2 subtypes and correlation with molecular classification of breast cancer is recommended.</p

Dopamine Regulates Mobilization of Mesenchymal Stem Cells during Wound Angiogenesis

Angiogenesis is an important step in the complex biological and molecular events leading to successful healing of dermal wounds. Among the different cellular effectors of wound angiogenesis, the role of mesenchymal stem cells (MSCs) is of current interest due to their transdifferentiation and proangiogenic potentials. Skin is richly innervated by sympathetic nerves which secrete dopamine (DA) and we have recently shown that concentration of DA present in synaptic cleft can significantly inhibit wound tissue neovascularization. As recent reports indicate that MSCs by mobilizing into wound bed play an important role in promoting wound angiogenesis, we therefore investigated the effect of DA on the migration of MSCs in wound tissues. DA acted through its D2 receptors present in the MSCs to inhibit their mobilization to the wound beds by suppressing Akt phosphorylation and actin polymerization. In contrast, this inhibitory effect of DA was reversed after treatment with specific DA D2 receptor antagonist. Increased mobilization of MSCs was demonstrated in the wound site following blockade of DA D2 receptor mediated actions, and this in turn was associated with significantly more angiogenesis in wound tissues. This study is of translational value and indicates use of DA D2 receptor antagonists to stimulate mobilization of these stem cells for faster regeneration of damaged tissues

Checkerboard Patterns, Interspecific Competition, and Extinction: Lessons from Distribution Patterns of Tarsiers (Tarsius) and Slow Lorises (Nycticebus) in Insular Southeast Asia

Tarsiers (Tarsius) and slow lorises (Nycticebus) are the only extant nocturnal primates occurring in Southeast Asia. Harcourt (1999) hypothesized that in insular Southeast Asia, slow lorises and tarsiers showed a checkerboard distribution on 12 small (<12,000 km2) islands, i.e., only one or the other occurs, and attributed this to extreme levels of competition between these 2 largely faunivorous primates. Further, he predicted slow lorises were able to persist on smaller islands than tarsiers. We re-evaluated these findings using an expanded dataset including 49 islands where tarsiers or slow lorises occur. Tarsiers and slow lorises live on islands of similar size (median size of ca. 300–900 km2), and both taxa inhabit an equal proportion of small, medium, and large islands. On small islands within their area of sympatry tarsiers occur on 1 island, slow lorises on 8, both genera on 3, and we can assume they have become extinct from 11 small islands since the Last Glacial Maximum. Sizes of islands where tarsiers or slow lorises have become extinct do not differ from islands where they are still extant. We show that slow lorises occur on more islands in insular Southeast Asia than perhaps previously assumed, but these islands are not smaller on average than islands where tarsiers occur. A checkerboard distribution between these taxa is not evident. More studies are needed at the macroecological level to assess the importance of biogeographic history in explaining their present-day distribution patterns