Chondrosarcoma is a unique type of bone cancer in that it does not respond to chemotherapy or radiation therapy, and therefore many affected patients die from metastatic disease. Metastasis has been correlated with the upregulation of the matrix metalloproteinase (MMP) family of proteases, which can degrade extracellular components. ETV5 is a transcription factor which has shown to be overexpressed in various types of invasive tumors. We hypothesized that ETV5 regulates MMP2 in human chondrosarcoma with the protease acting as a downstream effector. Gene knock-down of ETV5 in human chondrosarcoma cells reduces MMP2 mRNA expression as well as decreased protein production and significantly decreased MMP2 activity. With plasmid transfected ETV5 upregulation, MMP2 expression is similarly upregulated at the gene expression and protein levels. Data from our bone resorption studies revealed that when a matrix metalloproteinase-2 inhibitor is added to the growth media of chondrosarcoma cells, collagen released from bone chips incubated with the cells decreased by 27%. This data suggests that ETV5 has a significant role in regulating MMP2 expression and therefore matrix resorption in human chondrosarcoma, and thus may be a targetable upstream effector of the metastatic cascade in this cancer. Keywords: bone resorption; transcription factor; gelatinase; metastasis; collagen Chondrosarcoma is a type of bone cancer originating from cartilaginous tissue, and accounts for 25-30% of all cancers originating from the skeletal system. [1][2][3] Chondrosarcoma is a unique type of bone cancer, as it is nonresponsive to chemotherapy or radiation therapy. 2,4-7 Most chondrosarcomas (80-90%) are conventional (primary) chondrosarcomas, 7 which occur in the medullar cavity or at the bone surface. 8 Chondrosarcoma appears most often in the long bones 1,2 but has also been found in the ribs, spine 9 as well as the pelvis and scapula. 1 The current method of treatment is resection of the affected bone, which is not always possible depending on numerous factors including patient comorbidities and the anatomic extent of the tumor within the skeleton and surrounding soft-tissue. 2,5 Metastasis of chondrosarcoma occurs most commonly to the lungs leading to a 50% overall 5-year survival rate 3 and a 30% 10-year survival rate. 4,6 Metastasis is, at least in part, results from the upregulation of proteases within the tumor, which degrade the surrounding tissue and cause dissemination of cancer cells into the bloodstream. 10 Of these proteases, the matrix metalloproteinase (MMP) family can degrade extracellular components including many types of gelatin, elastin, and collagen 10,11 and is commonly associated with more metastatic types of cancers. 12 Specifically, matrix metalloproteinase 2 (MMP2) has been noted to be highly expressed in pancreatic cancer, 13 which lead to poor prognoses. This is partly due to the fact that MMP2 is capable of degrading type-I collagen fragments 10,14 which is abundant in the ECM as well as at the bone surf...

In humans, 5-HT1D serotonin receptors represent terminal autoreceptors, and there is some evidence that 5-HT1D ligands may be useful in the treatment of migraine. The most widely used 5-HT1D agonist is sumatriptan; however, this agent reportedly displays little selectivity for 5-HT1D versus 5-HT1A receptors. To identify novel serotonergic agents with enhanced 5-HT1D versus 5-HT1A selectivity, we attempted to take advantage of possible differences in the regions of bulk tolerance associated with the 5-position of the 5-HT binding sites for these two populations of receptors. Examination of a series of 5-(alkyloxy)tryptamine derivatives demonstrated that compounds with unbranched alkyl groups of up to eight carbon atoms bind with high affinity at human 5-HT1D beta receptors (Ki < 5 nM) but demonstrate less than 50-fold selectivity relative to 5-HT1A receptors. Alkyl groups longer than eight carbon atoms impart reduced affinity for 5-HT1A receptors whereas groups longer than nine carbon atoms lead to compounds with reduced affinity at 5-HT1D beta receptors. 5-(Nonyloxy)tryptamine (10) represents a compound with optimal 5-HT1D beta affinity (Ki = 1 nM) and selectivity (> 300-fold). Branching of the alkyl chain, to 5-[(7,7-dimethylheptyl)oxy]tryptamine (15), results in an agent with somewhat lower affinity (5-HT1D beta Ki = 2.3 nM) but with greater (i.e, 400-fold) 5-HT1D versus 5-HT1A selectivity. Replacement of the oxygen atom of 10 with a methylene group (i.e., 20), replacement of the O-proximate methylene with a carbonyl group (i.e., ester 26), or cyclization of the aminoethyl moiety to a carbazole (e.g., 34, 36) or beta-carboline (i.e., 37), result in reduced affinity and/or selectivity. None of the compounds examined displayed significant selectivity for 5-HT1D beta versus 5-HT1D alpha sites; nevertheless, compounds 10 (recently shown to have as a 5-HT1D agonist) and 15 represent the most 5-HT1D versus 5-HT1A selective agents reported to date.

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Objectives: Covert stroke is a complication of coronary artery bypass graft surgery that is increasingly recognized as a serious problem. In noncardiac surgery settings, covert stroke is associated with the development of delirium, long-term cognitive decline, and future clinical stroke. Therefore, we sought to determine the feasibility of conducting a large, prospective cohort study of the influence of covert stroke on neurocognitive outcomes in patients undergoing coronary artery bypass graft surgery.Methods: NeuroVISION Cardiac pilot was a prospective cohort study enrolling patients aged !21 years undergoing isolated coronary artery bypass graft surgery to receive diffusion-weighted magnetic resonance imaging of the brain after surgery to identify patients with covert stroke. Patients were screened for postoperative delirium in-hospital and were administered questionnaires of cognitive and global function (once before and twice after surgery). Regional cerebral oxygen saturation was recorded during surgery using near-infrared spectroscopy.