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Their high levels of GM-CSF production are likely the major mediator of immune suppression observed in these patients and are probably responsible for the intratumoral infiltration by MDSCs (36). In fact, peripheral blood lymphocytes (PBLs) from these patients are functionally impaired in their ability to be activated and to proliferate upon stimulation (37). Similar results were also seen in prostate cancer (38) and in nonsmall cell cancer (35). Although this anergic state in solid tumors may be attributable to the ARG1- and/or NOS-dependent suppressive activity of MDSCs, MDSC-mediated immunosuppression has not been previously reported in hematological malignancies. PBMCs from MM patients were stimulated with anti-CD3/CD28 antibody-coated beads in the presence of N-(omega)-hydroxy-nor-L-arginine (NorNOHA; an ARG1-specific inhibitor), NG-monomethyl-L-arginine (L-NMMA; an NOS2 inhibitor), both inhibitors, or neither. 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As seen with purified mouse T cells (Fig. 5 B), sildenafil also failed to enhance the CD3+ T cell proliferation of CD14-depleted PBMCs from cancer patients. Transurethral resection of the prostate - discharge
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