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Interferon (IFN)-a is one of the most commonly used agents in immunotherapy for patients with advanced stage renal cell carcinoma. However, because of the drug resistance to IFN-a, its benefits are limited. In this study, we examined whether repression of suppressor of cytokine signaling (SOCS) proteins, which are involved in the IFN-induced signaling pathway, can overcome the IFN resistance of renal cell carcinoma. The effect of IFN-a on SOCS3 expression and cell proliferation was examined using IFN-resistant 786-O and IFN-sensitive ACHN cell lines. The effects of SOCS3-targeted siRNA on 786-O xenografts were determined by SOCS3 expression, morphological observation, and tumor volume. The Although over half of renal cancers are found incidentally due to improved radiological evaluation, a quarter of the patients present with advanced disease, including locally advanced or metastatic RCC.As a therapeutic strategy against RCC, surgery is the standard treatment for localized disease. However, its role in the presence of distant metastases is limited. Furthermore, the role of radiotherapy is also limited to palliation of symptoms, and hormonal treatment and chemotherapy are ineffective. Recently, novel targeted agents have been used for the treatment of advanced RCC.(2,3) Randomized phase III trials of the targeted agents versus interferon (IFN) in patients with metastatic RCC have shown benefits associated with the use of these targeted agents. (2,4,5) In the era of molecular targeted agents, immunotherapy seems to have a minimal role in the management of advanced RCC. However, the combination of immunotherapy with molecular targeted agents is of great interest as a potential first-line therapy. Moreover, IFN-a is still one of the options as a subsequent therapy for progressive disease in the National Comprehensive Cancer Network practice guidelines (http://www.nccn.org/ index.asp). It is possible that improving the sensitivity of RCC against IFN-a would contribute to an improvement in the therapeutic effect against advanced RCC.Interferon-a is one of the most frequently used agents in immunotherapy against metastatic or recurrent RCC. Many reports have indicated that IFN-a therapy improved the survival of RCC patients.(6,7) Although this agent can lead to a complete response, (6,7) and can be used as an alternative in non-responders to targeted therapy, its benefits are limited due to drug resistance. Interferon-a can exert a direct antiproliferative response by modulating the expression of proteins that control cell cycle entry and exit, and cell cycle progression, and can also mediate apoptosis by regulating tumor necrosis factor-induced signaling events.(8) Among the IFN-a signalings, the Janus kinase ⁄ signal transducer and activator of transcription (JAK ⁄ STAT) pathway is one of the most important signal transduction cascades. In this pathway, the suppressor of cytokine signaling (SOCS) protein family is known to act as negative regulators of IFN-a signaling by inhibiting the JAK ⁄ STAT pathway.(9) Eight SO...

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This paper proposes a model that determines optimal capital and debt structure when a firm uses two types of debt; a bank debt and a bond. Their difference lies in whether a firm can renegotiate with a creditor or not. Renegotiation with bondholders seems to be hard because bonds are dispersively held by many bondholders. So we assume that interest payments to the bank debt can be reduced by the renegotiation when the firm goes worse but those to the bondholders cannot. Benefit of the renegotiation makes the bank debt more favorable. However, since the bank debt accompanies its additional costs, taking account of these trade-off, the firm decides optimal composition of equity, a bank debt, and a bond.