TAK-242 (resatorvid), a small-molecule-specific inhibitor of Toll-like receptor (TLR) 4 signaling, inhibits the production of lipopolysaccharide-induced inflammatory mediators by binding to the intracellular domain of TLR4. Cys747 in TLR4 has been identified previously as the binding site of TAK-242. However, the mechanism by which TAK-242 inhibits TLR4 signaling after binding to TLR4 remains unknown. The present study demonstrated, using coimmunoprecipitation, that TAK-242 interferes with protein-protein interactions between TLR4 and its adaptor molecules. Among 10 different human TLRs, TAK-242 selectively bound to TLR4. The time course of the inhibitory effect of TAK-242 on inflammatory mediator production corresponded to that of the binding of TAK-242 to TLR4. TAK-242 inhibited the association of TLR4 with Toll/interleukin-1 receptor domain-containing adaptor protein (TIRAP) or Toll/interleukin-1 receptor domain-containing adaptor protein inducing interferon-␤-related adaptor molecule (TRAM) in human embryonic kidney (HEK) 293 cells overexpressing TLR4, MD-2, and TIRAP or TRAM, respectively. TAK-242 inhibited the TIRAPmediated activation of nuclear factor B (NF-B) and the TRAM-mediated activation of NF-B and interferon-sensitive response element in HEK293 cells stably expressing TLR4, MD-2, and CD14. The activation of endogenous interleukin-1 receptor-associated kinase in RAW264.7 cells was also inhibited by TAK-242 treatment. These findings suggest that TAK-242 binds selectively to TLR4 and subsequently disrupts the interaction of TLR4 with adaptor molecules, thereby inhibiting TLR4 signal transduction and its downstream signaling events. This work proposes a novel paradigm of a small molecule capable of disrupting protein-protein interactions.

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In human CRC cells, loss of SMAD4 leads to up-regulation of CCL15 expression. Human liver metastases that express CCL15 contain higher numbers CCR1(+) cells; patients with these metastases have shorter times of disease-free survival. Reagents designed to block CCL15 recruitment of CCR1(+) cells could prevent metastasis of CRC to liver.

Dendritic cells (DCs) are a heterogeneous population playing a pivotal role in immune responses and tolerance. DCs promote immune tolerance by participating in the negative selection of autoreactive T cells in the thymus. Furthermore, to eliminate autoreactive T cells that have escaped thymic deletion, DCs also induce immune tolerance in the periphery through various mechanisms. Breakdown of these functions leads to autoimmune diseases. Moreover, DCs play a critical role in maintenance of homeostasis in body organs, especially the skin and intestine. In this review, we focus on recent developments in our understanding of the mechanisms of tolerance induction by DCs in the body.

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Background: Sarcopenia has been proposed as a prognostic factor for various diseases. Patients with critical limb ischemia (CLI) have a very poor prognosis, but sarcopenia has not been reported as a prognostic factor for CLI patients. If sarcopenia is associated with the prognosis of CLI patients, it could help select the treatment plan. Therefore, we examined whether sarcopenia is a prognostic factor for CLI patients. Methods: We performed a retrospective study of CLI patients diagnosed with Fontaine III or IV peripheral artery disease who underwent preoperative computed tomography imaging and revascularization between January 2002 and December 2009. The presence of sarcopenia was defined as skeletal muscle area of <114.0 cm 2 for men or <89.8 cm 2 for women using transverse computed tomography scans at the third lumbar vertebra. We compared the 5-year survival rate and clinical characteristics between patients with or without sarcopenia. We also screened possible prognostic factors for overall survival using hazard ratios (HRs) with 95% confidence intervals (CIs). Results: Of 64 eligible patients, 28 patients had sarcopenia and 36 did not. There were significant differences in age, skeletal muscle area, body mass index, and the presence of smoking, cerebrovascular disease, and hemodialysis between patients with and without sarcopenia (all P < .05). The 5-year survival rate was significantly lower in patients with sarcopenia (23.5% vs 77.5%, P [ .001). Prognostic factors for overall survival were the presence of sarcopenia (HR, 3.22; 95% CI, 1.24-9.11; P [ .02), requirement for hemodialysis (HR, 4.30; 95% CI, 1.60-12.2; P [ .004), and postoperative complications (HR, 5.02; 95% CI, 1.90-13.7; P [ .001). Conclusions: Our results suggest that sarcopenia is a prognostic factor for CLI patients. Exercise and nutritional interventions focusing on improving sarcopenia might be useful treatment options for CLI patients.

Purpose: Positron emission tomography (PET) with 18 F-fluorodeoxyglucose (FDG) has been widely used in the management of colorectal cancer (CRC). However, the relationship between FDG accumulation and KRAS/BRAF mutations has not yet been investigated. The purpose of this study was to investigate whether KRAS/BRAF mutations affect FDG accumulation in CRC.Experimental Design: Retrospective analysis was conducted in 51 patients with CRC who underwent FDG-PET/computed tomographic (CT) scans for staging before primary tumor resection. The maximum standardized uptake value (SUV max ) for the primary tumor and the tumor-to-liver ratio (TLR) were calculated from FDG accumulation and compared between KRAS/BRAF mutated and wild-type groups. Expression levels of glucose transporter-1 (GLUT1) and hexokinase type-II (HXK-II) were assessed by immunohistochemical analysis.Results: Both SUV max and TLR were significantly higher in the KRAS/BRAF-mutated group compared with the wild-type group (P ¼ 0.006 and 0.001, respectively). Multivariate analysis indicated that SUV max and TLR remained significantly associated with KRAS/BRAF mutations (P ¼ 0.016 and 0.01, respectively). KRAS/BRAF status could be predicted with an accuracy of 75% when a SUV max cutoff value of 13 or 14 was used. GLUT1 expression in cancer cells was positively correlated with FDG accumulation and KRAS/BRAF status whereas HXK-II expression was not.Conclusion: FDG accumulation was higher in CRC with KRAS/BRAF mutations. FDG-PET/CT scans may be useful for predicting the KRAS/BRAF status of patients with CRC and thus aid in determination of therapeutic strategies for patients with CRC.