A generalization of normal spaces

summary:A new class of spaces which contains the class of all normal spaces is defined and its characterization and properties are discussed

Large Conductance, Calcium Activated Potassium (BK) Channels as New Therapeutic Target for Glioma

Gliomas are the most common malignant primary brain tumors that arise within the central nervous sys-tem in adults and they account for more than 80% of all brain tumors (Central Brain Tumor Registry of the United States [CBTRUS] http://www.cbtrus.org/). These tumors remain difficult to treat because of the infiltrative growth of the tumor cells, and their resist-ance to standard therapy. Glioblastoma Multiforme (WHO grade IV) is the most aggressive of the gliomas, accounts for nearly 60-70% of malignant gliomas. A common approach for the treatment of GBM involves surgery, radiation therapy, and various chemotherapeu-tic regimens [1,2]. Despite advance standard therapy, including surgical resection followed by radiation and chemotherapy, the prognosis for patients with GBM remains poor. Even patients who are optimally treated with combined multimodal treatments have a median survival of only 12 months. This is possibly because of the poor drug delivery and the correspondingly lim-ited therapeutic response caused by partly intact blood brain barrier (BBB) and blood-tumor barrier (BTB)

Novel 5-arylthio-5H-chromenopyridines as a new class of anti-fibrotic agents

Liver fibrosis is a critical wound healing response to chronic liver injury such as hepatitis C virus (HCV) infection. If persistent, liver fibrosis can lead to cirrhosis and hepatocellular carcinoma (HCC). The development of new therapies for preventing liver fibrosis and its progression to cancer associated with HCV infection remains a critical challenge. Identification of novel anti-fibrotic compounds will provide opportunities for innovative therapeutic intervention of HCV-mediated liver fibrosis. We designed and synthesized a focused set of 5-arylthio-5H-chromenopyridines as a new class of anti-fibrotic agents. Liver fibrosis assays demonstrated that the compounds 3a and 3c show inhibitory activity towards human hepatic stellate cells (LX2) activation at 10 μM. The HCV NS3 and NS5A proteins in HCV subgenome-expressing cells were also significantly reduced in cells treated with 3a and 3c, suggesting the possible inhibitory role of the compounds in HCV translation/replication activities. We have also examined the reactivity of these compounds with medicinally-relevant metal compounds such as platinum and gold. The reactivity of these complexes with metals and during Mass Spectrometry suggests that CS bond cleavage is relatively facile

Novel 5-arylthio-5H-chromenopyridines as a new class of anti-fibrotic agents

Liver fibrosis is a critical wound healing response to chronic liver injury such as hepatitis C virus (HCV) infection. If persistent, liver fibrosis can lead to cirrhosis and hepatocellular carcinoma (HCC). The development of new therapies for preventing liver fibrosis and its progression to cancer associated with HCV infection remains a critical challenge. Identification of novel anti-fibrotic compounds will provide opportunities for innovative therapeutic intervention of HCV-mediated liver fibrosis. We designed and synthesized a focused set of 5-arylthio-5H-chromenopyridines as a new class of anti-fibrotic agents. Liver fibrosis assays demonstrated that the compounds 3a and 3c show inhibitory activity towards human hepatic stellate cells (LX2) activation at 10 μM. The HCV NS3 and NS5A proteins in HCV subgenome-expressing cells were also significantly reduced in cells treated with 3a and 3c, suggesting the possible inhibitory role of the compounds in HCV translation/replication activities. We have also examined the reactivity of these compounds with medicinally-relevant metal compounds such as platinum and gold. The reactivity of these complexes with metals and during Mass Spectrometry suggests that CS bond cleavage is relatively facile

Machine Learning Based Annotating Search Results from Web Databases

ABSTRACT: Deep web is a database based, i.e., for many search engines, data encoded in the returned result pages come from the underlying structured databases. Such type of search engines is often referred as Web databases (WDB). A typical result page returned from a WDB has multiple search result records (SRRs). Unfortunately, the semantic labels of data units are often not provided in result pages. Having semantic labels for data units is not only important for the above record linkage task, but also for storing collected SRRs into a database table. Early applications require tremendous human efforts to annotate data units manually, which severely limit their scalability. In this paper, we consider how to automatically assign labels to the data units within the SRRs returned from WDBs improve the results with new kernel function for improving the accuracy of the Support Vector Machines (SVMs) classification. The proposed kernel function is stated in general form and is called Gaussian Radial Basis Polynomials Function (GRPF) that combines both Gaussian Radial Basis Function (RBF) and Polynomial (POLY) kernels. We implement the proposed kernel with a number of parameters associated with the use of the SVM algorithm that can impact the results

Hits of a high-throughput screen identify the hydrophobic pocket of autotaxin/lysophospholipase D as an inhibitory surface

Autotaxin (ATX), a lysophospholipase D, plays an important role in cancer invasion, metastasis, tumor progression, tumorigenesis, neuropathic pain, fibrotic diseases, cholestatic pruritus, lymphocyte homing, and thrombotic diseases by producing the lipid mediator lysophosphatidic acid (LPA). A high-throughput screen of ATX inhibition using the lysophosphatidylcholine-like substrate fluorogenic substrate 3 (FS-3) and ~10,000 compounds from the University of Cincinnati Drug Discovery Center identified several small-molecule inhibitors with IC50 vales ranging from nanomolar to low micromolar. The pharmacology of the three most potent compounds: 918013 (1; 2,4-dichloro-N-(3-fluorophenyl)-5-(4- morpholinylsulfonyl) benzamide), 931126 (2; 4-oxo-4-{2-[(5- phenoxy-1H-indol-2-yl)carbonyl]hydrazino}-N-(4-phenylbutan- 2-yl)butanamide), and 966791 (3; N-(2,6-dimethylphenyl)-2-[N- (2-furylmethyl)(4-(1,2,3,4-tetraazolyl)phenyl)carbonylamino]-2- (4-hydroxy-3-methoxyphenyl) acetamide), were further characterized in enzyme, cellular, and whole animal models. Compounds 1 and 2 were competitive inhibitors of ATX-mediated hydrolysis of the lysophospholipase substrate FS-3. In contrast, compound 3 was a competitive inhibitor of both FS-3 and the phosphodiesterase substrate p-nitrophenyl thymidine 59-monophosphate. Computational docking and mutagenesis suggested that compounds 1 and 2 target the hydrophobic pocket, thereby blocking access to the active site of ATX. The potencies of compounds 1-3 were comparable to each other in each of the assays. All of these compounds significantly reduced invasion of A2058 human melanoma cells in vitro and the colonization of lung metastases by B16-F10 murine melanoma cells in C57BL/6 mice. The compounds had no agonist or antagonist effects on select LPA or sphingosine 1-phosphate receptors, nor did they inhibit nucleotide pyrophosphatase/phosphodiesterase (NPP) enzymes NPP6 and NPP7. These results identify the molecular surface of the hydrophobic pocket of ATX as a targetbinding site for inhibitors of enzymatic activity. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics