Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protease-activated receptor-2 (PAR2), a cell surface receptor for trypsin-like proteases, plays a key role in a number of acute and chronic inflammatory diseases of the joints, lungs, brain, gastrointestinal tract, and vascular systems. Despite considerable effort by the pharmaceutical industry, PAR2 has proven recalcitrant to targeting by small molecule inhibitors, which have been unable to effectively prevent the interaction of the protease-generated tethered ligand with the body of the receptor. Here, we report the development of first-in-class cell-penetrating lipopeptide "pepducin" antagonists of PAR2. The design of the third intracellular (i3) loop pepducins were based on a structural model of a PAR2 dimer and by mutating key pharmacophores in the receptor intracellular loops and analogous pepducins. Individual pharmacophores were identified, which controlled constitutive, agonist, and antagonist activities. This approach culminated in the identification of the P2pal-18S pepducin which completely suppressed trypsin and mast cell tryptase signaling through PAR2 in neutrophils and colon cancer cells. The PAR2 pepducin was highly efficacious in blocking PAR2-dependent inflammatory responses in mouse models. These effects were lost in PAR2-deficient and mast-cell-deficient mice, thereby validating the specificity of the pepducin in vivo. These data provide proof of concept that PAR2 pepducin antagonists may afford effective treatments of potentially debilitating inflammatory diseases and serve as a blueprint for developing highly potent and specific i3-loop-based pepducins for other G protein-coupled receptors (GPCRs).
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PMID:Interdicting protease-activated receptor-2-driven inflammation with cell-penetrating pepducins. 2153 78

The prognostic value of mast cells (MCs) in patients with liver metastases is a relatively new topic. The present study comparatively assessed tryptase-positive (MCT(+)) and CD117(+) MCs in liver metastases from various sites and correlated their expression with clinicopathological prognostic factors and survival. Our data pointed to differences in MCT and CD117 expression in liver metastases that seem to be related to the origin of the primary tumor. For colon cancer metastases, intra-tumor MCT(+) MCs were significantly correlated with tumor grade and nodal status, while peritumoral MCT(+) MCs and peritumoral CD117(+) MCs were significantly correlated with overall survival. No significant correlations between MCT(+) and CD117(+) MC number and clinicopathological parameters or survival were found for gastric cancer metastases. To the best of our knowledge, this is the first report regarding MC involvement in liver metastases from different malignant tumors correlated with clinicopathological parameters and overall survival. Different mast cell phenotype together with their specific correlation with tumor grade, nodal status and survival suggest their involvement in the metastatic process in a specific manner related to tumor origin. Mast cells from liver metastases remain a questionable issue regarding their origin, pathogenic role and their ability to be potential targets for adjuvant therapy.
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PMID:Tryptase-positive and CD117 Positive Mast Cells Correlate with Survival in Patients with Liver Metastasis. 2640 93