Clinical trial designs for rare diseases: Studies developed and discussed by the International Rare Cancers Initiative

BACKGROUND: The past three decades have seen rapid improvements in the diagnosis and treatment of most cancers and the most important contributor has been research. Progress in rare cancers has been slower, not least because of the challenges of undertaking research.

SETTINGS: The International Rare Cancers Initiative (IRCI) is a partnership which aims to stimulate and facilitate the development of international clinical trials for patients with rare cancers. It is focused on interventional--usually randomized--clinical trials with the clear goal of improving outcomes for patients. The key challenges are organisational and methodological. A multi-disciplinary workshop to review the methods used in ICRI portfolio trials was held in Amsterdam in September 2013. Other as-yet unrealised methods were also discussed.

RESULTS: The IRCI trials are each presented to exemplify possible approaches to designing credible trials in rare cancers. Researchers may consider these for use in future trials and understand the choices made for each design.

INTERPRETATION: Trials can be designed using a wide array of possibilities. There is no 'one size fits all' solution. In order to make progress in the rare diseases, decisions to change practice will have to be based on less direct evidence from clinical trials than in more common diseases.

Romance Sociolinguistics

This is a commissioned book that will be co-edited by Ayres-Bennett (Cambridge) and Carruthers (Queen's). The editors will co-write the introduction and a chapter each. There will be 27 chapters in all from scholars around the world.

Representing Irishness in Belfast’s Gaeltacht Quarter

This paper examines a place-making project in post-conflict Belfast, analyzing efforts to transform an area which has often been used as a byword for militant Irish nationalism and social deprivation into an inclusive, vibrant tourist destination and cultural hub themed around the Irish language (called the "Gaeltacht Quarter‟). The antagonistic and territorial assumptions about place that characterize divided cities now co-exist with global trends towards the commodification of difference as recreation or spectacle, and longstanding struggles over the representation of contested identities are intertwined with the struggle to compete for international tourism and investment. The proliferation of officially themed quarters in many cities across the world reflects the enthusiasm with which planning authorities have embraced the vision of difference as a benign resource for the creation of tourist revenue. Yet, analysis of „quartering‟ processes reveals that such commodification does not neutralise or evade the political potency of naming, representing and delimiting cultural difference. Indeed, this paper argues that such projects offer a valuable insight into the inseparable roles of physical and representational space as both loci and catalysts of contestation in urban conflicts. Bringing together a wide range of public and private interest groups, projects redefining parts of Belfast as distinctive quarters have been explicitly linked with efforts to deterritorialize the city. The creation of bounded, themed spaces as an attempt to leave behind the ethno-sectarian geographical segregation that parts of Belfast still experience has its particular ironies, but is in many ways typical of contemporary trends in urban planning. The Gaeltacht Quarter exemplifies both the importance and the challenge of representation within cities where culturally distinguishing features have acted as markers of violent division, and where negotiations about how to successfully encompass difference necessarily address multiple local and international audiences simultaneously.

Molecular Medicine and Molecular Pathology for Hematologists:II. Lets go Techno; Principles of the Molecular Technologies and their Applications in Haematology

Molecular techniques have a key role to play in laboratory and clinical haematology. Restriction enzymes allow nucleic acids to be reduced in size for subsequent analysis. In addition they allow selection of specific DNA or RNA sequences for cloning into bacterial plasmids. These plasmids are naturally occuring DNA molecules which reside in bacterial cells. They can be manipulated to act as vehicles or carriers for biologically and medically important genes, allowing the production of large amounts of cloned material for research purposes or to aid in the production of medically important recombinant molecules such as insulin. As acquired or inherited genetic changes are implicated in a wide range of haematological diseases, it is necessary to have highly specific and sensitive assays to detect these mutations. Most of these techniques rely on nucleic acid hybridisation, benefitting from the ability of DNA or RNA to bind tighly to complimentary bases in the nucleic acid structure. Production of artificial DNA molecules called probes permits nucleic acid hybridiation assays to be performed, using the techniques of southern blotting or dot blot analysis. In addition the base composition of any gene or region of DNA can be determined using DNA sequencing technology. The advent of the polymerase chain reaction (PCR) has revolutionised all aspects of medicine, but has particular relevance in haematology where easy access to biopsy material provides a wealth of material for analysis. PCR permits quick and reliable manipulation of sample material and its ability to be automated makes it an ideal tool for use in the haematology laboratory.

Molecular Medicine and Molecular Pathology for Haematologists:I. Gene Speak made Easy: An Overview of Genes and Gene Expression

Molecular Medicine and Molecular Pathology are integral parts of Haematology as we enter the new millennium. Their origins can be linked to fundamental developments in the basic sciences, particularly genetics, chemistry and biochemistry. The structure of DNA and the genetic code that it encrypts are the critical starting points to our understanding of these new disciplines. The genetic alphabet is a simple one, consisting of just 4 letters, buts its influence is crucial to human development and differentiation. The concept of a gene is not a new one but the Human Genome Project (a joint world-wide effort to characterise our entire genetic make-up) is providing an invaluable understanding of how genes function in normal cellular processes and pinpointing how disruption of these processes can lead to disease. Transcription and translation are the key events by which our genotype is converted to our phenotype (via a messenger RNA intermediate), producing the myriad proteins and enzymes which populate the cellular factory of our body. Unlike the bacterial or prokaryotic genome, the human genome contains a large amount of non coding DNA (less than 1% of our genome codes for proteins), and our genes are interrupted, with the coding regions or exons separated by non coding introns. Precise removal of the intronic material after transcription (though a process called splicing) is critical for efficient translation to occur. Incorrect splicing can lead to the generation of mutant proteins, which can have a dilaterious effect on the phenotype of the individual. Thus the 100,000-200,000 genes which are present in each cell in our body have a defined control mechanism permitting efficient and appropriate expression of proteins and enzymes and yet a single base change in just one of those genes can lead to diseases such as haemophilia or fanconis anaemia.

Revisiting Iris Marion Young on Normalisation, Inclusion and Democracy

Vieten's edited collection brings together papers that were given at the I M Young Memorial Symposium 'Inclusion and Democracy Revisited', held in Amsterdam in 2012. The different chapters presented explore in-depth, Young's models of a 'politics of cultural difference', and a 'politics of positional difference' read in combination with her critique of normalisation. Young regards the latter as decisive to any change for the better when reaching out politically to a fairer and more just democratic society.
With the current political, economic and socio-cultural crisis in mind, the contemporary world of global speed and transformed societies in and beyond Europe needs a refinement of what we understand 'normalisation' and 'difference' to be. How can we connect to each other, and in what ways can Young's 'structural inequality model' be applied to develop alternative outlooks on how to enhance inclusion and democracy in different nation states?