HDAC 3-selective inhibitor RGFP966 demonstrates anti-inflammatory properties in RAW 264.7 macrophages and mouse precision-cut lung slices by attenuating NF-κB p65 transcriptional activity

AbstractThe increasing number of patients suffering from chronic obstructive pulmonary disease (COPD) represents a major and increasing health problem. Therefore, novel therapeutic approaches are needed. Class I HDACs 1, 2 and 3 play key roles in the regulation of inflammatory gene expression with a particular pro-inflammatory role for HDAC 3. HDAC 3 has been reported to be an important player in inflammation by deacetylating NF-κB p65, which has been implicated in the pathology of COPD. Here, we applied the pharmacological HDAC 3-selective inhibitor RGFP966, which attenuated pro-inflammatory gene expression in models for inflammatory lung diseases. Consistent with this, a robust decrease of the transcriptional activity of NF-κB p65 was observed. HDAC 3 inhibition affected neither the acetylation status of NF-κB p65 nor histone H3 or histone H4. This indicates that HDAC 3 inhibition does not inhibit NF-κB p65 transcriptional activity by affecting its deacetylation but rather by inhibiting enzymatic activity of HDAC 3. Taken together, our findings indicate that pharmacological HDAC 3-selective inhibition by inhibitors such as RGFP966 may provide a novel and effective approach toward development of therapeutics for inflammatory lung diseases

HDAC1-3 inhibitor MS-275 enhances IL10 expression in RAW264.7 macrophages and reduces cigarette smoke-induced airway inflammation in mice

Chronic obstructive pulmonary disease (COPD) constitutes a major health burden. Studying underlying molecular mechanisms could lead to new therapeutic targets. Macrophages are orchestrators of COPD, by releasing pro-inflammatory cytokines. This process relies on transcription factors such as NF-κB, among others. NF-κB is regulated by lysine acetylation; a post-translational modification installed by histone acetyltransferases and removed by histone deacetylases (HDACs). We hypothesized that small molecule HDAC inhibitors (HDACi) targeting class I HDACs members that can regulate NF-κB could attenuate inflammatory responses in COPD via modulation of the NF-κB signaling output. MS-275 is an isoform-selective inhibitor of HDAC1-3. In precision-cut lung slices and RAW264.7 macrophages, MS-275 upregulated the expression of both pro- and anti-inflammatory genes, implying mixed effects. Interestingly, anti-inflammatory IL10 expression was upregulated in these model systems. In the macrophages, this was associated with increased NF-κB activity, acetylation, nuclear translocation, and binding to the IL10 promoter. Importantly, in an in vivo model of cigarette smoke-exposed C57Bl/6 mice, MS-275 robustly attenuated inflammatory expression of KC and neutrophil influx in the lungs. This study highlights for the first time the potential of isoform-selective HDACi for the treatment of inflammatory lung diseases like COPD

Bringing Nuance into the Globalization Debate: Changes in US, Japanese, and German Management, with Special Reference to the Impact of International Finance

Defence date: 11 February 2008Examining board: Prof. Colin Crouch, University of Warwick (EUI Supervisor) ; Prof. Geoffrey Hodgson, University of Hertfordshire ; Prof. David Marsden, London School of Economics ; Prof. Peter Wagner, University of TrentoThis study presents the results of an application of an extended version of grounded theory to bring nuance into the globalization debate by looking at changes in US, Japanese, and German management, with special reference to the impact of international finance. It starts out by presenting the core of the preconceptions with which I started my research, represented by reconstructions of three perspectives that were highly popular and influential in the financial globalization debate at the end of the 1980s and during the 1990s. Next, well-substantiated, systematized, and synthesized empirical and theoretical material from many different sources is presented with which the three perspectives are compared. On the basis of the findings, the study concludes that the three perspectives cannot reasonably be upheld. More generally, the study indicates different sources of causality that more or less contradict each other and that lead to some kind of transformation. The main channels through which financial globalization is hypothesized to impact on management practices are the possibility of offshore outsourcing, financial deregulation, foreign shareholdings, the way attempts to improve global competitiveness have been affected by international finance, and management practices of MNCs. The pressures resulting from financial globalization are interpreted to be to some extent resisted by domestic power constellations, while for many changes the relation to financial globalization is unclear. In all three countries, a number of ‘neo-liberal’ practices has become more common. But some cultural adaptation appears to have occurred, while certain practices may already have been common in Japan and Germany. In addition, elements of Japanese management have been introduced in the US and Germany while universal banking has been introduced in the US and Japan. For management practices of MNCs, a mixture of home- and host-country practices is found together with some cultural adaptation. A case study of management practices in Japanese MNCs in the US also finds a mixture of home- and host-country practices

Trends in PACS architecture

Radiological Picture Archiving and Communication Systems (PACS) have only relatively recently become abundant. Many hospitals have made the transition to PACS about a decade ago. During that decade requirements and available technology have changed considerably. In this paper we look at factors that influence the design of tomorrow's systems, especially those in larger multidisciplinary hospitals. We discuss their impact on PACS architecture (a technological perspective) as well as their impact on radiology (a management perspective).status: publishe