Development of a Tumour Growth Inhibition Model to Elucidate the Effects of Ritonavir on Intratumoural Metabolism and Anti-tumour Effect of Docetaxel in a Mouse Model for Hereditary Breast Cancer

In a mouse tumour model for hereditary breast cancer, we previously explored the anti-cancer effects of docetaxel, ritonavir and the combination of both and studied the effect of ritonavir on the intratumoural concentration of docetaxel. The objective of the current study was to apply pharmacokinetic (PK)-pharmacodynamic (PD) modelling on this previous study to further elucidate and quantify the effects of docetaxel when co-administered with ritonavir. PK models of docetaxel and ritonavir in plasma and in tumour were developed. The effect of ritonavir on docetaxel concentration in the systemic circulation of Cyp3a knock-out mice and in the implanted tumour (with inherent Cyp3a expression) was studied, respectively. Subsequently, we designed a tumour growth inhibition model that included the inhibitory effects of both docetaxel and ritonavir. Ritonavir decreased docetaxel systemic clearance with 8% (relative standard error 0.4%) in the co-treated group compared to that in the docetaxel only-treated group. The docetaxel concentration in tumour tissues was significantly increased by ritonavir with mean area under the concentration-time curve 2.5-fold higher when combined with ritonavir. Observed tumour volume profiles in mice could be properly described by the PK/PD model. In the co-treated group, the enhanced anti-tumour effect was mainly due to increased docetaxel tumour concentration; however, we demonstrated a small but significant anti-tumour effect of ritonavir addition (p value <0.001). In conclusion, we showed that the increased anti-tumour effect observed when docetaxel is combined with ritonavir is mainly caused by enhanced docetaxel tumour concentration and to a minor extent by a direct anti-tumour effect of ritonavir.

Development and characterization of chemical cochleostomy in the Guinea pig

OBJECTIVES Creation of an atraumatic, hearing-preservation cochleostomy is integral to the future of minimally invasive inner ear surgery. The goal of this study was to develop and characterize a novel chemical approach to cochleostomy. STUDY DESIGN Prospective animal study. SETTING Laboratory. METHODS Experimental animal study in which phosphoric acid gel (PAG) was used to decalcify the otic capsule in 25 Hartley guinea pigs. Five animals in each of 5 surgical groups were studied: (1) mechanically opening the auditory bulla alone, (2) PAG thinning of the basal turn otic capsule, leaving endosteum covered by a layer of bone, (3) micro-pick manual cochleostomy, (4) PAG chemical cochleostomy, exposing the endosteum, and (5) combined PAG/micro-pick cochleostomy, with initial chemical thinning and subsequent manual removal of the last osseous layer. Preoperative and postoperative auditory brainstem responses and otoacoustic emissions were obtained at 2, 6, 10, and 16 kHz. Hematoxylin and eosin-stained paraffin sections were compared. RESULTS Surgical and histologic findings confirmed that application of PAG provided reproducible local bone removal, and cochlear access was enabled. Statistically significant auditory threshold shifts were observed at 10 kHz (P = .048) and 16 kHz (P = .0013) following cochleostomy using PAG alone (group 4) and at 16 kHz using manual cochleostomy (group 3) (P = .028). No statistically significant, postoperative auditory threshold shifts were observed in the other groups, including PAG thinning with manual completion cochleostomy (group 5). CONCLUSION Hearing preservation cochleostomy can be performed in an animal model using a novel technique of thinning cochlear bone with PAG and manually completing cochleostomy.

Development and voluntarism in football clubs

Volunteers are still the most important resource for amateur football clubs. However, stable voluntary engagement can no longer be granted. This difficulty is confirmed by existing research across various European countries. From a club management point of view, a detailed understanding of how to attract volunteers and retain them is becoming a high priority. The purpose of this study is (1) to analyse the influence of individual characteristics and corresponding organisational conditions on volunteering and (2) to examine the decision-making processes in relation to implement effective strategies for recruiting volunteers. To answer these questions, the current state of research is summarised and then a multi-level-framework is developed which is based on the structural-individualistic social theory. The individual and context factors for volunteering are estimated in different multi-level models based on a sample of n=1,434 sport club members from 36 sport clubs in Switzerland. Results indicate that volunteering is not just an outcome of individual characteristics such as lower workloads, higher income, children belonging to the sport club, longer club membership, or a strong commitment to the club. It is also influenced by club-specific structural conditions. Concerning decision-making processes an in-depth analysis of recruitment practices for volunteers was conducted in selected clubs (case study design). based on the garbage can model. The results show that systematically designed decision-making processes with a clear regulation of responsibilities seem to solve personnel problems more purposefully and more quickly. Based on the findings some recommendations for volunteer management in football clubs are worked out.

Development of Drugs Targeting the PI3K Signalling Pathway in Leukaemias and Lymphomas

The phosphoinositide 3-kinase (PI3K) family of signalling enzymes play a key role in the transduction of signals from activated cell surface receptors controlling cell growth and proliferation, survival, metabolism, and migration. The intracellular signalling pathway from activated receptors to PI3K and its downstream targets v-akt murine thymoma viral oncogene homolog (Akt) and mechanistic target of rapamycin (mTOR) is very frequently deregulated by genetic and epigenetic mechanisms in human cancer, including leukaemia and lymphoma. In the past decade, an arsenal of small molecule inhibitors of key enzymes in this pathway has been developed and evaluated in pre-clinical studies and clinical trials in cancer patients. These include pharmacological inhibitors of Akt, mTOR, and PI3K, some of which are approved for the treatment of leukaemia and lymphoma. The PI3K family comprises eight different catalytic isoforms in humans, which have been subdivided into three classes. Class I PI3K isoforms have been extensively studied in the context of human cancer, and the isoforms p110α and p110δ are validated drug targets. The recent approval of a p110δ-specific PI3K inhibitor (idelalisib/Zydelig®) for the treatment of selected B cell malignancies represents the first success in developing these molecules into anti-cancer drugs. In addition to PI3K inhibitors, mTOR inhibitors are intensively studied in leukaemia and lymphoma, and temsirolimus (Torisel®) is approved for the treatment of a type of lymphoma. Based on these promising results it is hoped that additional novel PI3K pathway inhibitors will in the near future be further developed into new drugs for leukaemia and lymphoma.

Development and characterization of novel microsatellite markers for Arion slug species

Seventeen polymorphic microsatellite markers were isolated and characterized in Arion vulgaris/lusitanicus, which belongs to the worst European slug pests with serious economic and ecological impact. These markers were tested on 23 individuals collected in a population in Switzerland. Numbers of alleles ranged from 2 to 14 per locus, observed and expected heterozygosities ranged from 0.174 to 0.87, and from 0.162 to 0.903, respectively. These loci were also successfully amplified and were polymorphic in the closely related species A. rufus and A. ater. These loci represent the first highly polymorphic nuclear markers described for A. vulgaris and pave the way for population genetics and molecular ecology research of the important Arion pest slugs.

Development of a questionnaire measuring Attitudes towards Psychological Online Interventions–the APOI

BACKGROUND: Only a minority of people suffering from depression receive adequate treatment. Psychological Online Interventions (POIs) could help bridge existing treatment gaps and augment the effectiveness of current treatments. Apart from effectiveness, user acceptance of POIs must be achieved if such interventions are to be broadly implemented in existing health-care. Valid measurement tools examining attitudes towards POIs are lacking. Therefore, we examined the dimensionality of attitudes towards POIs, developed a novel questionnaire, the Attitudes towards Psychological Online Interventions Questionnaire (APOI), and gathered data to examine its reliability. METHODS: We recruited a sample of 1004 adults with mild to moderate depressive symptoms from a range of sources. We constructed a set of 35 items based on literature review as well as expert and patient queries. The initial items were subjected to an exploratory factor analysis (EFA) in a randomly selected subsample. A final set of 16 items was subjected to a confirmatory factor analysis (CFA) to cross-validate the factor structure in a separate subsample. RESULTS: The EFA revealed four dimensions: "Scepticism and Perception of Risks", "Confidence in Effectiveness", "Technologization Threat" and "Anonymity Benefits". The model fit in the CFA was excellent relating to all applied indices (χ(2)=105.816, p=.651; SRMR=.042; RMSEA=.013; CFI=.994) and the APOI total scale showed acceptable to good internal consistency. CONCLUSIONS: Further research with the APOI might facilitate the development and dissemination of POIs and, ultimately, help improve the quality of care for people experiencing depressive symptoms.

Development of the gas chromatograph – mass spectrometer to investigate volatile species in the lunar soil for the Luna-Resurs mission

Since the analysis of the lunar rocks and soil samples, brought to Earth by the Apollo missions, it is believed that the Moon has a waterless nature and also other volatile species are strongly depleted. Advancement in analysis techniques helped to identify water and other volatile species in lunar volcanic glasses. Additionally, recent lunar space missions detected water and volatile organic compounds in the region of the lunar poles where permanently shadowed craters are existing. All known lunar soil samples available on Earth come from the lunar near side, close to the equator. To verify the most recent measurement results and to enhance the knowledge of the geological history of the Moon it is of high interest to perform in situ measurements on the lunar poles. For this reason the Russian space agency, Roskosmos, developed aprogram for the scientific exploration of the lunar poles. The Gas Analysis Package (GAP) is part of the selected scientific payload aboard the Luna-Resurs Lander. This instrument uses pyrolytic cells and will apply laser spectroscopy, gas chromatography and mass spectrometry to detect and analyze volatile components trapped in the lunar soil. An existing ion optical design of a compact reflectron type time-of-flight mass spectrometer, originally built for the MEAP/P-BACE balloon mission, was chosen as a part of the GAP instrument. The scope of this thesis is the development of the interface between gas chromatography (GC) and this Neutral Gas Mass Spectrometer (NGMS) to perform coupled GC-MS measurements. In the first part of this thesis the interfacing concept was developed and verified by coupling the NGMS prototype to gas chromatography. The second part of this thesis is devoted to the development of the NGMS flight version.

GATS and the Regulation of Trade in Services

This collection of essays takes stock of the key challenges that have arisen since the entry into force of the General Agreement on Trade in Services in the mid-1990s and situates them in the context of the WTO's Doha Development Agenda and the proliferation of preferential agreements addressing services today. The multidisciplinary approach provides an opportunity for many of the world's leading experts and a number of new analytical voices to exchange ideas on the future of services trade and regulation. Cosmopolitan approaches to the treatment of labour mobility, the shape of services trade disciplines in the digital age and pro-competitive regulation in air transport are explored with a view to helping readers gain a better understanding of the forces shaping the changes. An essential read for all those concerned with the evolution of the rules-based trading system and its impact on the service economy.

Persistent Deadlock in Multilateral Trade Negotiations: The Case of Doha

The history of the General Agreement on Tariffs and Trade negotiations is full of anecdotes on missed deadlines, failed ministerial conferences, and brinkmanship situations. Tactics such as walking away from the table or sleep-depriving night sessions are legendary in the context of attempting to overcome impasse in negotiations. This article traces and explains the recurrent deadlock in the Doha Round negotiations. It identifies four structural/contextual factors – ideas, institutions, interests, and information – as necessary for understanding and anticipating potential deadlocks. The article also offers a definition of deadlock, and discusses a set of factors highlighted in the international relations literature that explain the existence and persistence of deadlock. With the help of game theory, it then illustrates the challenges faced by actors during trade negotiations. The article concludes by outlining two general scenarios for the Doha Development Agenda and discusses their implications for the World Trade Organization.

Towards a plurilateral Trade in Services Agreement (TISA): Challenges and prospects

This paper addresses a number of policy challenges arising from ongoing attempts to negotiate a plurilateral Trade in Services Agreement (TISA), a recently launched plurilateral negotiating initiative coexisting uneasily alongside the World Trade Organisation’s General Agreement on Trade in Services (GATS), particularly in the context of the ongoing Doha Development Agenda. While the TISA offers scope for imparting much needed forward movement to a policy area of central economy-wide and trade importance, such progress, even if realized within the narrower confines of a preferential trade agreement made possible under the GATS, poses a number of systemic risks to the multilateral order extending beyond services trade.