Comparison of high-specific-activity ultratrace 123/131I-MIBG and carrier-added 123/131I-MIBG on efficacy, pharmacokinetics, and tissue distribution

Metaiodobenzylguanidine (MIBG) is an enzymatically stable synthetic analog of norepinephrine that when radiolabled with diagnostic ((123)I) or therapeutic ((131)I) isotopes has been shown to concentrate highly in sympathetically innervated tissues such as the heart and neuroendocrine tumors that possesses high levels of norepinephrine transporter (NET). As the transport of MIBG by NET is a saturable event, the specific activity of the preparation may have dramatic effects on both the efficacy and safety of the radiodiagnostic/radiotherapeutic. Using a solid labeling approach (Ultratrace), noncarrier-added radiolabeled MIBG can be efficiently produced. In this study, specific activities of >1200 mCi/micromol for (123)I and >1600 mCi/micromol for (131)I have been achieved. A series of studies were performed to assess the impact of cold carrier MIBG on the tissue distribution of (123/131)I-MIBG in the conscious rat and on cardiovascular parameters in the conscious instrumented dog. The present series of studies demonstrated that the carrier-free Ultratrace MIBG radiolabeled with either (123)I or (131)I exhibited similar tissue distribution to the carrier-added radiolabeled MIBG in all nontarget tissues. In tissues that express NETs, the higher the specific activity of the preparation the greater will be the radiopharmaceutical uptake. This was reflected by greater efficacy in the mouse neuroblastoma SK-N-BE(2c) xenograft model and less appreciable cardiovascular side-effects in dogs when the high-specific-activity radiopharmaceutical was used. The increased uptake and retention of Ultratrace (123/131)I-MIBG may translate into a superior diagnostic and therapeutic potential. Lastly, care must be taken when administering therapeutic doses of the current carrier-added (131)I-MIBG because of its potential to cause adverse cardiovascular side-effects, nausea, and vomiting

Analysis of dynamic wireless power transfer systems based on behavioral modeling of mutual inductance

This paper proposes a system-level approach suitable to analyze the performance of a dynamic Wireless Power Transfer System (WPTS) for electric vehicles, accounting for the uncertainty in the vehicle trajectory. The key-point of the approach is the use of an analytical behavioral model that relates mutual inductance between the coil pair to their relative positions along the actual vehicle trajectory. The behavioral model is derived from a limited training data set of simulations, by using a multi-objective genetic programming algorithm, and is validated against experimental data, taken from a real dynamic WPTS. This approach avoids the massive use of computationally expensive 3D finite element simulations, that would be required if this analysis were performed by means of look-up tables. This analytical model is here embedded into a system-level circuital model of the entire WPTS, thus allowing a fast and accurate analysis of the sensitivity of the performance as the actual vehicle trajectory deviates from the nominal one. The system-level analysis is eventually performed to assess the sensitivity of the power and efficiency of the WPTS to the vehicle misalignment from the nominal trajectory during the dynamic charging process

Gene expression profile and genomic alterations in colonic tumours induced by 1,2-dimethylhydrazine (DMH) in rats

<p>Abstract</p> <p>Background</p> <p>Azoxymethane (AOM) or 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in rats shares many phenotypical similarities with human sporadic colon cancer and is a reliable model for identifying chemopreventive agents. Genetic mutations relevant to human colon cancer have been described in this model, but comprehensive gene expression and genomic analysis have not been reported so far. Therefore, we applied genome-wide technologies to study variations in gene expression and genomic alterations in DMH-induced colon cancer in F344 rats.</p> <p>Methods</p> <p>For gene expression analysis, 9 tumours (TUM) and their paired normal mucosa (NM) were hybridized on 4 × 44K Whole rat arrays (Agilent) and selected genes were validated by semi-quantitative RT-PCR. Functional analysis on microarray data was performed by GenMAPP/MappFinder analysis. Array-comparative genomic hybridization (a-CGH) was performed on 10 paired TUM-NM samples hybridized on Rat genome arrays 2 × 105K (Agilent) and the results were analyzed by CGH Analytics (Agilent).</p> <p>Results</p> <p>Microarray gene expression analysis showed that <it>Defcr4</it>, <it>Igfbp5</it>, <it>Mmp7, Nos2, S100A8 </it>and <it>S100A9 </it>were among the most up-regulated genes in tumours (Fold Change (FC) compared with NM: 183, 48, 39, 38, 36 and 32, respectively), while <it>Slc26a3</it>, <it>Mptx</it>, <it>Retlna </it>and <it>Muc2 </it>were strongly down-regulated (FC: -500; -376, -167, -79, respectively). Functional analysis showed that pathways controlling cell cycle, protein synthesis, matrix metalloproteinases, TNFα/NFkB, and inflammatory responses were up-regulated in tumours, while Krebs cycle, the electron transport chain, and fatty acid beta oxidation were down-regulated. a-CGH analysis showed that four TUM out of ten had one or two chromosomal aberrations. Importantly, one sample showed a deletion on chromosome 18 including <it>Apc</it>.</p> <p>Conclusion</p> <p>The results showed complex gene expression alterations in adenocarcinomas encompassing many altered pathways. While a-CGH analysis showed a low degree of genomic imbalance, it is interesting to note that one of the alterations concerned <it>Apc</it>, a key gene in colorectal carcinogenesis. The fact that many of the molecular alterations described in this study are documented in human colon tumours confirms the relevance of DMH-induced cancers as a powerful tool for the study of colon carcinogenesis and chemoprevention.</p

A classification prognostic score to predict OS in stage IV well-differentiated neuroendocrine tumors

No validated prognostic tool is available for predicting overall survival (OS) of patients with well-differentiated neuroendocrine tumors (WDNETs). This study, conducted in three independent cohorts of patients from five different European countries, aimed to develop and validate a classification prognostic score for OS in patients with stage IV WDNETs. We retrospectively collected data on 1387 patients: (i) patients treated at the Istituto Nazionale Tumori (Milan, Italy; n = 515); (ii) European cohort of rare NET patients included in the European RARECAREnet database (n = 457); (iii) Italian multicentric cohort of pancreatic NET (pNETs) patients treated at 24 Italian institutions (n = 415). The score was developed using data from patients included in cohort (i) (training set); external validation was performed by applying the score to the data of the two independent cohorts (ii) and (iii) evaluating both calibration and discriminative ability (Harrell C statistic). We used data on age, primary tumor site, metastasis (synchronous vs metachronous), Ki-67, functional status and primary surgery to build the score, which was developed for classifying patients into three groups with differential 10-year OS: (I) favorable risk group: 10-year OS &gt;= 70%; (II) intermediate risk group: 30% &lt;= 10-year OS &lt; 70%; (III) poor risk group: 10-year OS &lt; 30%. The Harrell C statistic was 0.661 in the training set, and 0.626 and 0.601 in the RARECAREnet and Italian multicentric validation sets, respectively. In conclusion, based on the analysis of three 'field-practice' cohorts collected in different settings, we defined and validated a prognostic score to classify patients into three groups with different long-term prognoses

Turning collegial governance on its head : symbolic violence, hegemony and the academic board

This article draws on Bourdieu&rsquo;s theorisation of domination and Gramsci&rsquo;s notions of hegemony within the context of a larger empirical study of Australian university academic governance, and of academic boards (also known as academic senates or faculty senates) in particular. Reporting data that suggest a continued but radically altered form of collegial governance in which hegemony is exercised by management rather than by the professor, it theorises the domination of academic boards within western democratic universities. However, traditional collegial governance is also dependent upon a community of scholars, a role historically played by the academic board. In view of the suggested transition in collegial governance and the resultant convergence of academic work and management, the article concludes with questions about whether academic boards can continue to serve as communities of scholars in future

Creating the cultures of the future: cultural strategy, policy and institutions in Gramsci. Part one: Gramsci and cultural policy studies: some methodological reflections

Gramsci’s writings have rarely been discussed and used systematically by scholars in cultural policy studies, despite the fact that in cultural studies, from which the field emerged, Gramsci has been a major source of theoretical concepts. Cultural policy studies were, in fact, theorised as an anti-Gramscian project between the late 1980s and the early 1990s, when a group of scholars based in Australia advocated a major political and theoretical reorientation of cultural studies away from hegemony theory and radical politicisation, and towards reformist-technocratic engagement with the policy concerns of contemporary government and business. Their criticism of the ‘Gramscian tradition’ as inadequate for the study of cultural policy and institutions has remained largely unexamined in any detail for almost twenty years and seems to have had a significant role in the subsequent neglect of Gramsci’s contribution in this area of study. This essay, consisting of three parts, is an attempt to challenge such criticism and to provide an analysis of Gramsci’s writings, with the aim of proposing a more systematic contribution of his work to the theoretical development of cultural policy studies. In Part One, I question the use of the notion of ‘Gramscian tradition’ made by its critics and challenge the claim that it was inadequate for the study of cultural policy and institutions. In parts Two and Three, I consider Gramsci’s specific writings on questions of cultural strategy, policy and institutions, which have so far been overlooked by scholars, arguing that they provide further analytical insights to those offered by his more general concepts. More specifically, in Part Two, I consider Gramsci’s pre-prison writings and political practice in relation to questions of cultural strategy and institutions. I argue that the analysis of these early texts, which were written in the years in which Gramsci was active in party organisation and leadership, is fundamental not only for understanding the nature of Gramsci’s early and continued involvement with questions of cultural strategy and institutions, but also as a key for deciphering and interpreting cultural policy themes that he later developed in the prison notebooks, and which originated in earlier debates. Finally, in Part Three, I carry out a detailed analysis of Gramsci’s prison notes on questions of cultural strategy, policy and institutions, which enrich the theoretical underpinnings for critical frameworks of analysis as well as for radical practices of cultural strategy, cultural policy-making and cultural organisation. I then answer the question of whether Gramsci’s insights amount to a theory of cultural policy