Chronic inflammation is a secondary reaction of Duchenne muscular dystrophy and may contribute to disease progression. To examine whether immunosuppressant therapies could benefit dystrophic patients, we analyzed the effects of cyclosporine A (CsA) on a dystrophic mouse model. Mdx mice were treated with 10 mg/kg of CsA for 4 to 8 weeks throughout a period of exercise on treadmill, a protocol that worsens the dystrophic condition. The CsA treatment fully prevented the 60% drop of forelimb strength induced by exercise. A significant amelioration (P < 0.05) was observed in histological profile of CsA-treated gastrocnemius muscle with reductions of nonmuscle area (20%), centronucleated fibers (12%), and degenerating area (50%) compared to untreated exercised mdx mice. Consequently, the percentage of normal fibers increased from 26 to 35% in CsA-treated mice. Decreases in creatine kinase and markers of fibrosis were also observed. By electrophysiological recordings ex vivo, we found that CsA counteracted the decrease in chloride conductance (gCl), a functional index of degeneration in diaphragm and extensor digitorum longus muscle fibers. However, electrophysiology and fura-2 calcium imaging did not show any amelioration of calcium homeostasis in extensor digitorum longus muscle fibers. No significant effect Duchenne muscular dystrophy (DMD) is a fatal genetic disorder for which no definitive cure is available. The X-linked mutation of the dystrophin gene leads to the absence of dystrophin in skeletal muscle fibers, a biochemical defect also observed in the mdx mouse, the murine phenotype of DMD. 1 Dystrophin is a subsarcolemmal protein involved in the link between the contractile machinery and the extracellular matrix. It is generally accepted that the absence of dystrophin weakens the sarcolemma and impairs the transduction of the mechanical signal imposed by the contraction. This leads to a complex and still not fully understood network of interconnected pathogenic events responsible for progressive muscle degeneration; these events involve the increased entrance of calcium, the activation of proteases, and the occurrence of a functional ischemic state. [1][2][3][4] Recent evidence suggests that a chronic inflammatory state is a secondary reaction that strongly contributes to the progression of the pathology. A significant overexpression of inflammatory and immune response genes has been described by microarray in muscle of dystrophic subjects. 5,6 Also, activated helper and cytotoxic T cells have been found to be present in higher number in muscles of dystrophic mdx mice and to promote pathology in this phenotype. 7 According to this view, immunoSupported by Telethon-Italy (to project no. 1150) and the Association Franç ais Contre les Myopathies (as part of postdoctoral fellowships to

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Inhibition of multiple myeloma (MM) plasma cells in their permissive bone marrow microenvironment represents an attractive strategy for blocking the tumor/ vessel growth associated with the disease progression. However, target speci-ficity is an essential aim of this approach. Here, we identified platelet-derived growth factor (PDGF)-receptor beta (PDGFR) and pp60c-Src as shared constitutively activated tyrosine-kinases (TKs) in plasma cells and endothelial cells (ECs) isolated from MM patients (MMECs). Our cellular and molecular dissection showed that the PDGF-BB/PDGFR kinase axis promoted MM tumor growth and vessel sprouting by activating ERK1/2, AKT, and the transcription of MMEC-released proangio-genic factors, such as vascular endothe-lial growth factor (VEGF) and interleukin-8 (IL-8). Interestingly, pp60c-Src TK-activity was selectively induced by VEGF in MM tumor and ECs, and the use of small-interfering (si)RNAs validated pp60c-Src as a key signaling effector of VEGF loop required for MMEC survival, migration, and angiogenesis. We also assessed the antitumor/vessel activity of dasatinib, a novel orally bioactive PDGFR/Src TK-inhibitor that significantly delayed MM tumor growth and angiogenesis in vivo, showing a synergistic cytotoxicity with conventional and novel antimyeloma drugs (ie, melphalan, prednisone, bor-tezomib, and thalidomide). Overall data highlight the biologic and therapeutic relevance of the combined targeting of PDGFR/c-Src TKs in MM, providing a framework for future clinical trials. (Blood. 2008;112:1346-1356) Introduction Multiple myeloma (MM) is characterized by a clonal proliferation of immunoglobulin-secreting plasma cells in the bone marrow (BM), with clinical manifestations including lytic bone lesions, anemia, renal failure, immunodeficiency, and hypercalcemia. 1 For patients treated with conventional and high-dose chemotherapies, the median survival time from diagnosis is 3 to 4 years. 2 Approximately one-half of patients with newly diagnosed MM achieve remission from these therapies, but options are more limited for primary resistant or relapsing disease. Partial remission occurs in only 20% of resistant patients and in 45% of relapsing patients. Survival time improves in approximately 50% of those younger than 60 who are able to undergo high-dose chemotherapy followed by autologous stem cell transplantation, but approximately 30% of them are late in the graft intake or even develop myelodysplasia that prevents additional chemotherapy while relapse or resistant disease occurs. Induction of MM plasma cells is thought to involve genetic lesions (ie, translocations between immunoglobulin enhancers and oncogenes) and secondary events underlying the activation of bidirectional MM tumor-microenvironment interactions. 3-5 Indeed, homing and survival of MM plasma cells are sustained by overangiogenic sprouting of microvascular endothelial cells (ECs), 6,7 as well as by osteoclasts, fibroblasts, monocytes, macrophages, and mast cells, 4,8,9 thus resulting in a multiplicity of autocrine/...

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