18F-RB390: innovative ligand for imaging the T877A androgen receptor mutant in prostate cancer via positron emission tomography (PET).

BACKGROUND Detecting prostate cancer before spreading or predicting a favorable therapy are challenging issues for impacting patient's survival. Presently, 2-[(18) F]-fluoro-2-deoxy-D-glucose ((18) F-FDG) and/or (18) F-fluorocholine ((18) F-FCH) are the generally used PET-tracers in oncology yet do not emphasize the T877A androgen receptor (AR) mutation being exclusively present in cancerous tissue and escaping androgen deprivation treatment. METHODS We designed and synthesized fluorinated 5α-dihydrotestosterone (DHT) derivatives to target T877A-AR. We performed binding assays to select suitable candidates using COS-7 cells transfected with wild-type or T877A AR (WT-AR, T877A-AR) expressing plasmids and investigated cellular uptake of candidate (18) F-RB390. Stability, biodistribution analyses and PET-Imaging were assessed by injecting (18) F-RB390 (10MBq), with and without co-injection of an excess of unlabeled DHT in C4-2 and PC-3 tumor bearing male SCID mice (n = 12). RESULTS RB390 presented a higher relative binding affinity (RBA) (28.1%, IC50  = 32 nM) for T877A-AR than for WT-AR (1.7%, IC50  = 357 nM) related to DHT (RBA = 100%). A small fraction of (18) F-RB390 was metabolized when incubated with murine liver homogenate or human blood for 3 hr. The metabolite of RB390, 3-hydroxysteroid RB448, presented similar binding characteristics as RB390. (18) F-RB390 but not (18) F-FDG or (18) F-FCH accumulated 2.5× more in COS-7 cells transfected with pSG5AR-T877A than with control plasmid. Accumulation was reduced with an excess of DHT. PET/CT imaging and biodistribution studies revealed a significantly higher uptake of (18) F-RB390 in T877A mutation positive xenografts compared to PC-3 control tumors. This effect was blunted with DHT. CONCLUSION Given the differential binding capacity and the favorable radioactivity pattern, (18) F-RB390 represents the portrayal of the first imaging ligand with predictive potential for mutant T877A-AR in prostate cancer for guiding therapy. Prostate 75:348-359, 2015. © 2014 Wiley Periodicals, Inc.

Reglucosylation of the Benzoxazinoid DIMBOA with Inversion of Stereochemical Configuration is a Detoxification Strategy in Lepidopteran Herbivores

Benzoxazinoids are chemical defenses against herbivores and are produced by many members of the grass family. These compounds are stored as stable glucosides in plant cells and require the activity of glucosidases to release the corresponding toxic aglucones. In maize leaves, the most abundant benzoxazinoid is (2R)-DIMBOA-Glc, which is converted into the toxic DIMBOA upon herbivory. The ways in which three Spodoptera species metabolize this toxin were investigated. (2S)-DIMBOA-Glc, an epimer of the initial plant compound, was observed in the insect frass, and the associated glucosyltransferase activity was detected in the insect gut tissue. The epimeric glucoside produced by the insect was found to be no longer reactive towards plant glucosidases and thus cannot be converted into a toxin. Stereoselective reglucosylation thus represents a detoxification strategy in Spodoptera species that might help to explain their success as agricultural pests on benzoxazinoid-containing crops.

Tumour border configuration in colorectal cancer: proposal for an alternative scoring system based on the percentage of infiltrating margin.

AIMS Information on tumour border configuration (TBC) in colorectal cancer (CRC) is currently not included in most pathology reports, owing to lack of reproducibility and/or established evaluation systems. The aim of this study was to investigate whether an alternative scoring system based on the percentage of the infiltrating component may represent a reliable method for assessing TBC. METHODS AND RESULTS Two hundred and fifteen CRCs with complete clinicopathological data were evaluated by two independent observers, both 'traditionally' by assigning the tumours into pushing/infiltrating/mixed categories, and alternatively by scoring the percentage of infiltrating margin. With the pushing/infiltrating/mixed pattern method, interobserver agreement (IOA) was moderate (κ = 0.58), whereas with the percentage of infiltrating margins method, IOA was excellent (intraclass correlation coefficient of 0.86). A higher percentage of infiltrating margin correlated with adverse features such as higher grade (P = 0.0025), higher pT (P = 0.0007), pN (P = 0.0001) and pM classification (P = 0.0063), high-grade tumour budding (P < 0.0001), lymphatic invasion (P < 0.0001), vascular invasion (P = 0.0032), and shorter survival (P = 0.0008), and was significantly associated with an increased probability of lymph node metastasis (P < 0.001). CONCLUSIONS Information on TBC gives additional prognostic value to pathology reports on CRC. The novel proposed scoring system, by using the percentage of infiltrating margin, outperforms the 'traditional' way of reporting TBC. Additionally, it is reproducible and simple to apply, and can therefore be easily integrated into daily diagnostic practice.

Desertification and Global Change: Innovative Management of Scarce Resources in Semi-Arid Areas. Experiences from development and research: Challenges for a better future

While most events related to the International Year of Deserts and Desertification 2006 took mainly a problem-oriented perspective and approach, the Bern Symposium held in May 2006 tried to adopt a more positive attitude by attempting to take stock of experience as well as best and worst practices in the past, both in development practice and in research. Through this deliberate focus on potentials, positive experiences, solutions and pathways, predominant passive and reactive attitudes and hopelessness might be better overcome. The Symposium was organized by CDE, NCCR North-South and Forum SLM.

Innovative Agricultural Approaches of Promoting Food Security in Eritrea: Trends, Challenges and Opportunities for Growth: Proceedings of the Workshop of the Association of Eritreans in Agricultural Sciences (AEAS)

Eritrea is a Sahel country in terms of climate, and rainfall is low and highly variable. Shortage of food is thus a recurrent problem, and food security one of the key issues in development. The present publication presents the results of a nationwide workshop organised in 2006 in Asmara, Eritrea, by the Association of Eritreans in Agricultural Sciences (AEAS). The workshop was attended by over 200 participants from government administration, academia, development circles including NGOs and UN organisations. Specifically, the present publication deals with themes such as biotechnology, non-wood forest products, spate irrigation, the role of women relating to food security, and institutional and organisational aspects of food security. It also contains a chapter with policy recommendations, as well as an extensive summary of the main findings (paper abstracts) in Tigrinya.

Best practices and innovative capacity development approaches in ARD programmes of ERA-ARD consortium members: Draft compilation of National Contribution

In the framework of the European Research Area for Agricultural Research for Development (ERA-ARD) project, a survey of innovative approaches in capacity development (CD) was undertaken. All Consortium members were asked to describe innovative approaches and best practices of CD mechanisms within their ARD programmes. A tabular overview of all the programmes or mechanisms can be found on page 4. Abstracts of the programmes or mechanisms are compiled in alphabetic order of the consortium members in this document. The intention of this catalogue of mechanisms is to give an overview of different approaches and practices and not to provide a comprehensive mapping of all the ongoing CD activities of the Consortium members. Thus, the programmes described represent only a fraction of all the ongoing CD programmes on the national level.

Innovative capacity development approaches for the ERA-ARD project

The aim of the present paper is: 1. To provide definitions and outline trends in capacity development in Agricultural Research for Development (ARD) 2. to summarize the findings and recommendations of recent documents on planning and conducting capacity development activities in ARD 3. to present a summary and a compilation of best practices and innovative capacity development approaches among ERA-ARD consortium members 4. to derive basic principles for capacity development in ARD and to define entry points for joint and/or transnational activities to strengthen capacity development in ARD.

Combinations of dexmedetomidine and alfaxalone with butorphanol in cats: application of an innovative stepwise optimisation method to identify optimal clinical doses for intramuscular anaesthesia

OBJECTIVES The aim of this study was to optimise dexmedetomidine and alfaxalone dosing, for intramuscular administration with butorphanol, to perform minor surgeries in cats. METHODS Initially, cats were assigned to one of five groups, each composed of six animals and receiving, in addition to 0.3 mg/kg butorphanol intramuscularly, one of the following: (A) 0.005 mg/kg dexmedetomidine, 2 mg/kg alfaxalone; (B) 0.008 mg/kg dexmedetomidine, 1.5 mg/kg alfaxalone; (C) 0.012 mg/kg dexmedetomidine, 1 mg/kg alfaxalone; (D) 0.005 mg/kg dexmedetomidine, 1 mg/kg alfaxalone; and (E) 0.012 mg/kg dexmedetomidine, 2 mg/kg alfaxalone. Thereafter, a modified 'direct search' method, conducted in a stepwise manner, was used to optimise drug dosing. The quality of anaesthesia was evaluated on the basis of composite scores (one for anaesthesia and one for recovery), visual analogue scales and the propofol requirement to suppress spontaneous movements. The medians or means of these variables were used to rank the treatments; 'unsatisfactory' and 'promising' combinations were identified to calculate, through the equation first described by Berenbaum in 1990, new dexmedetomidine and alfaxalone doses to be tested in the next step. At each step, five combinations (one new plus the best previous four) were tested. RESULTS None of the tested combinations resulted in adverse effects. Four steps and 120 animals were necessary to identify the optimal drug combination (0.014 mg/kg dexmedetomidine, 2.5 mg/kg alfaxalone and 0.3 mg/kg butorphanol). CONCLUSIONS AND RELEVANCE The investigated drug mixture, at the doses found with the optimisation method, is suitable for cats undergoing minor clinical procedures.

Reactive, Slow and...Innovative? Decision-making Structures and Policy Outputs

Consensus democracies like Switzerland are generally known to have a low innovation capacity (Lijphart 1999). This is due to the high number of veto points such as perfect bicameralism or the popular referendum. These institutions provide actors opposing a policy with several opportunities to block potential policy change (Immergut 1990; Tsebelis 2002). In order to avoid a failure of a process because opposing actors activate veto points, decision-making processes in Switzerland tend to integrate a large number of actors with different - and often diverging - preferences (Kriesi and Trechsel 2008). Including a variety of actors in a decision-making process and taking into account their preferences implies important trade-offs. Integrating a large number of actors and accommodating their preferences takes time and carries the risk of resulting in lowest common denominator solutions. On the contrary, major innovative reforms usually fail or come only as a result of strong external pressures from either the international environment, economic turmoil or the public (Kriesi 1980: 635f.; Kriesi and Trechsel 2008; Sciarini 1994). Standard decision-making processes are therefore characterized as reactive, slow and capable of only marginal adjustments (Kriesi 1980; Kriesi and Trechsel 2008; Linder 2009; Sciarini 2006). This, in turn, may be at odds with the rapid developments of international politics, the flexibility of the private sector, or the speed of technological development.