Proceedings of the National Academy of Sciences of the United States of America
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Proc. Natl. Acad. Sci. U.S.A. · Feb 2005
CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids.
CB(2) cannabinoid receptor-selective agonists are promising candidates for the treatment of pain. CB(2) receptor activation inhibits acute, inflammatory, and neuropathic pain responses but does not cause central nervous system (CNS) effects, consistent with the lack of CB(2) receptors in the normal CNS. To date, there has been virtually no information regarding the mechanism of CB(2) receptor-mediated inhibition of pain responses. ⋯ These data suggest that CB(2) receptor activation stimulates release from keratinocytes of beta-endorphin, which acts at local neuronal mu-opioid receptors to inhibit nociception. Supporting this possibility, CB(2) immunolabeling was detected on beta-endorphin-containing keratinocytes in stratum granulosum throughout the epidermis of the hindpaw. This mechanism allows for the local release of beta-endorphin, where CB(2) receptors are present, leading to anatomical specificity of opioid effects.
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Proc. Natl. Acad. Sci. U.S.A. · Feb 2005
A non-ATP-competitive inhibitor of BCR-ABL overrides imatinib resistance.
Imatinib, which is an inhibitor of the BCR-ABL tyrosine kinase, has been a remarkable success for the treatment of Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemias (CMLs). However, a significant proportion of patients chronically treated with imatinib develop resistance because of the acquisition of mutations in the kinase domain of BCR-ABL. Mutations occur at residues directly implicated in imatinib binding or, more commonly, at residues important for the ability of the kinase to adopt the specific closed (inactive) conformation to which imatinib binds. ⋯ Kinetic studies demonstrate that this compound is not ATP-competitive but is substrate-competitive and works synergistically with imatinib in wild-type BCR-ABL inhibition. More importantly, ON012380 was found to induce apoptosis of all of the known imatinib-resistant mutants at concentrations of <10 nM concentration in vitro and cause regression of leukemias induced by i.v. injection of 32Dcl3 cells expressing the imatinib-resistant BCR-ABL isoform T315I. Daily i.v. dosing for up to 3 weeks with a >100 mg/kg concentration of this agent is well tolerated in rodents, without any hematotoxicity.
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Proc. Natl. Acad. Sci. U.S.A. · Feb 2005
Brain correlates of subjective reality of physically and psychologically induced pain.
Meaningful behavior requires successful differentiation of events surfacing from one's mind from those arising from the external world. Such judgements may be especially demanding during pain because of the strong contribution from psychological factors to this experience. It is unknown how the subjective reality of pain (SRP) is constructed in the human brain, and neuronal mechanisms of the subjective reality are poorly understood in general. ⋯ These findings support the view that information about sensory-discriminative characteristics of pain contributes to the SRP. Differences in such information between physically and psychologically induced pain, however, could be quantitative rather than qualitative and therefore insufficient for judging the reality of pain without knowledge about the source of this information. The medial prefrontal cortex is a likely area to contribute to such source monitoring.
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Proc. Natl. Acad. Sci. U.S.A. · Dec 2004
Molecular and genetic analysis of disseminated neoplastic cells in lymphangioleiomyomatosis.
Lymphangioleiomyomatosis (LAM) is a multisystem disorder of women, characterized by cystic degeneration of the lungs, renal angiomyolipomas (AML), and lymphatic abnormalities. LAM lesions result from the proliferation of benign-appearing, smooth muscle-like LAM cells, which are characterized by loss of heterozygosity (LOH) of one of the tuberous sclerosis complex (TSC) genes. LAM cells are believed to migrate among the involved organs. ⋯ Identification of LAM cells with TSC2 LOH in body fluids was not correlated with severity of lung disease or extrapulmonary involvement and was found in one patient after double lung transplantation. These studies are compatible with a multisite origin for LAM cells. They establish the existence of disseminated, potentially metastatic LAM cells through a relatively simple, noninvasive procedure that should be valuable for molecular and genetic studies of somatic mutations in LAM and perhaps other metastatic diseases.
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Proc. Natl. Acad. Sci. U.S.A. · Oct 2004
Randomized Controlled Trial Clinical TrialAspirin triggers antiinflammatory 15-epi-lipoxin A4 and inhibits thromboxane in a randomized human trial.
There is increasing evidence that aspirin initiates biosynthesis of novel antiinflammatory mediators by means of interactions between endothelial cells and leukocytes. These mediators are classified as aspirin-triggered 15-epi-lipoxins. Such compounds may account at least in part for aspirin's clinical benefits, which are distinct from the well appreciated action of aspirin as a platelet inhibitor. ⋯ These results demonstrated that low-dose aspirin (81 mg daily) initiates production of antiinflammatory ATL opposite to the inhibition of TX. Monitoring ATL may represent a simple clinical parameter to verify an individual's vascular leukocyte antiinflammatory response with low-dose aspirin treatment. These results also emphasize the importance of cell-cell interactions in the modulation of hemostatic, thrombotic, and inflammatory processes.