Macrophage Scavenger Receptor a Promotes Tumor Progression in Murine Models of Ovarian and Pancreatic Cancer.

Macrophage Scavenger Receptor A Promotes Tumor Progression in Murine Models of Ovarian and Pancreatic Cancer.

J Immunol. 2013 Feb 27;
Neyen C, Plüddemann A, Mukhopadhyay S, Maniati E, Bossard M, Gordon S, Hagemann T

Alternatively activated macrophages express the pattern recognition receptor scavenger receptor A (SR-A). We demonstrated previously that coculture of macrophages with tumor cells upregulates macrophage SR-A expression. We show in this study that macrophage SR-A deficiency inhibits tumor cell migration in a coculture assay. We further demonstrate that coculture of tumor-associated macrophages and tumor cells induces secretion of factors that are recognized by SR-A on tumor-associated macrophages. We tentatively identified several potential ligands for the SR-A receptor in tumor cell-macrophage cocultures by mass spectrometry. Competing with the coculture-induced ligand in our invasion assay recapitulates SR-A deficiency and leads to similar inhibition of tumor cell invasion. In line with our in vitro findings, tumor progression and metastasis are inhibited in SR-A-/- mice in two in vivo models of ovarian and pancreatic cancer. Finally, treatment of tumor-bearing mice with 4F, a small peptide SR-A ligand able to compete with physiological SR-A ligands in vitro, recapitulates the inhibition of tumor progression and metastasis observed in SR-A-/- mice. Our observations suggest that SR-A may be a potential drug target in the prevention of metastatic cancer progression. HubMed – drug


Can molecular methods detect 1% isoniazid resistance in Mycobacterium tuberculosis?

J Clin Microbiol. 2013 Feb 27;
Folkvardsen DB, Svensson E, Thomsen VO, Rasmussen EM, Bang D, Werngren J, Hoffner S, Hillemann D, Rigouts L

Patients may harbour both drug susceptible and resistant bacteria, i.e. heteroresistance. We studied mixtures of isoniazid resistant and susceptible Mycobacterium tuberculosis strains. Conventional drug susceptibility testing was the most sensitive whereas the line probe assay and sequencing were not able to detect the clinically relevant 1% proportion of resistant bacteria. HubMed – drug


Increased Agonist Affinity at the ?-Opioid Receptor Induced by Prolonged Agonist Exposure.

J Neurosci. 2013 Feb 27; 33(9): 4118-27
Birdsong WT, Arttamangkul S, Clark MJ, Cheng K, Rice KC, Traynor JR, Williams JT

Prolonged exposure to high-efficacy agonists results in desensitization of the ?-opioid receptor (MOR). Desensitized receptors are thought to be unable to couple to G-proteins, preventing downstream signaling; however, the changes to the receptor itself are not well characterized. In the current study, confocal imaging was used to determine whether desensitizing conditions cause a change in agonist-receptor interactions. Using rapid solution exchange, the binding kinetics of fluorescently labeled opioid agonist, dermorphin Alexa594 (derm A594), to MORs was measured in live cells. The affinity of derm A594 binding increased after prolonged treatment of cells with multiple agonists that are known to cause receptor desensitization. In contrast, binding of a fluorescent antagonist, naltrexamine Alexa594, was unaffected by similar agonist pretreatment. The increased affinity of derm A594 for the receptor was long-lived and partially reversed after a 45 min wash. Treatment of the cells with pertussis toxin did not alter the increase in affinity of the derm A594 for MOR. Likewise, the affinity of derm A594 for MORs expressed in mouse embryonic fibroblasts derived from arrestin 1 and 2 knock-out animals increased after treatment of the cells with the desensitization protocol. Thus, opioid receptors were “imprinted” with a memory of prior agonist exposure that was independent of G-protein activation or arrestin binding that altered subsequent agonist-receptor interactions. The increased affinity suggests that acute desensitization results in a long-lasting but reversible conformational change in the receptor. HubMed – drug