Bev was well tolerated at this dose and prolonged disease stabilization was achieved in one-quarter of metastatic melanoma patients. Low-dose IFN-alpha2b did not augment the activity of Bev.
Contractile processes in non-muscle cells mimic those occurring in smooth muscle tissues, indicating the value of using non-muscle cells to investigate the biochemical pathways that regulate contraction (4 -8). Phosphorylation of myosin light chains (MLC) in non-muscle cells causes the formation of myosin-containing stress fibers, which are contractile bundles of actin filaments associated with myosin II (4 -8). Phosphorylation of MLC similarly increases actin-myosin interactions in smooth muscle cells, resulting in smooth muscle contraction (reviewed in Refs. 9 -12). In addition to smooth muscle contraction, many fundamental cellular processes such as adhesion, migration, and division depend upon the interaction of myosin with actin in contractile filaments (reviewed in Ref. 12). Activation of mAChR may affect these fundamental processes by altering myosin activity in non-muscle cells as it does in smooth muscle. Although mAChR activation induces MLC phosphorylation and subsequent contraction in smooth muscle cells (13)(14)(15)(16)(17), the ability of mAChR to regulate MLC phosphorylation and myosin organization in non-muscle cells has not been reported.We investigated the ability of transfected human mAChR subtypes to regulate myosin organization in Chinese hamster ovary (CHO) cells. Activation of transfected M 3 mAChR induces MLC phosphorylation and causes myosin-containing stress fibers to form in CHO cells. The involvement of PKC in these events is indicated by our findings that 1) direct activation of PKC with phorbol esters induces MLC phosphorylation and myosin reorganization in CHO cells, 2) specific PKC antagonists inhibit M 3 mAChR-mediated myosin reorganization, and 3) activation of transfected M 1 but not M 2 mAChR subtypes also induces the formation of myosin-containing stress fibers, demonstrating that only mAChR subtypes that stimulate PKC activity induce myosin reorganization. The participation of myosin light chain kinase (MLCK) and RhoA in mAChRmediated myosin reorganization was also investigated, since these proteins regulate contractile processes in other systems
Background-We previously reported that cancer-related psychological stress is associated with reduced natural killer (NK) cell lysis. We hypothesized that reduced NK cell cytotoxicity in patients with increased levels of stress would correlate with alterations in the expression of inhibitory NK cell receptors (killer immunoglobulin-like receptors, or KIRs). The specific aim of this study was to examine KIR expression in patients with high or low levels of psychologic stress and correlate alterations in KIR expression with NK cell function.
Metastatic melanoma lesions often are unresectable due to their size and/or location near critical structures. These lesions represent a significant challenge for the oncologist, because radiation therapy and chemotherapy are infrequently successful in halting tumor growth. Of primary concern is the fact that these lesions are usually painful and present a cosmetic dilemma. We hypothesized that the development of a silicon-based nano-device capable of delivering antitumor compounds (e.g. immune modulators), locally, at a constant rate, to the tumor microenvironment could avoid the toxicity of systemic administration and the inconvenience of frequent clinic visits for local injections. Because of its diminutive size, such a device could be implanted using a minimally invasive procedure in close proximity to unresectable melanoma lesions. The current report uses interferon alpha-2b (IFN-alpha) as a model antitumor agent, since it is commonly used in the treatment of malignant melanoma and metastatic renal cell carcinoma. In this system, IFN-alpha is delivered directly to the tumor microenvironment by a novel nanochannel delivery system (nDS) that is capable of zero order release of small molecules. We have demonstrated that the IFN-alpha released from the nDS is functionally active on both host immune cells and a human melanoma cell line in vitro. This drug delivery platform could be used to develop alternative strategies for the treatment of unresectable tumors.
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