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.

The Complete Works of John Milton: Volume III: The Shorter Poems (826pp.)

Stephen B. Dobranski, Milton Quarterly 49.3 (October, 2015), 181-4:

'By addressing classical and neo-Latin works with which Milton's poems appear to engage, Haan has pursued something unattempted yet. Her erudite and engaging commentary on the Poemata is the most extensive and impressive that I have encountered in any edition ... Haan's discussion of Milton's Poemata - including the Testimonia, the one Italian and four Latin encomia by the poet's acquaintances published in 1645 and 1673 - is remarkably detailed and well-researched. In these sections, readers learn, for example, how Milton's Epitaphium Damonis borrows from both classical writers (Theocritus, Moschus) and contemporary models (Castiglione, Zanchi) while transcending all of them through a pattern of resurrection motifs. Or, readers can discover affinities between Milton's lament on the death of the Bishop of Ely and a poem by the Italian humanist Hieronymo Aleander, Jr., or learn about the connections between Milton's Elegia Quinta and George Buchanan's Maiae Calendae ... The Shorter Poems is a scholarly achievement of the highest order.'

Noam Reisner, Review of English Studies 65 (2014), 744-5:
‘Haan shines with her Neo-Latinist expertise by offering a vivid separate introduction to the Latin poems, which sets up Milton’s poemata specifically within the Neo-Latin contexts of the seventeenth century, thereby dispelling any remaining view of these poems as juvenilia (a view which results from reading the poems chronologically). … The present volume will instantly establish itself as the definitive resource for any reader interested in Milton’s shorter poems, and it is scarcely imaginable that it will ever be eclipsed or be in need of replacing. Its contribution is important in all areas, especially in providing for the first time in a single volume truly valuable documents which can teach us a lot more about Milton’s poetic development than simply reading the poems in chronological sequence. But perhaps, this edition’s greatest achievement is the way in which it succeeds in giving Milton’s Latin poems the pride of place they have long deserved as fully integral to Milton’s complete poetic imagination. Haan’s specific achievement in this regard is less in updating the translations than in providing a different context through which to look at the Latin poems themselves. Haan’s detailed commentaries set the Latin poems in a completely fresh light which looks beyond the obvious classical references and allusions, noted by Carey and many other editors, to Milton’s complex engagement with the Neo-Latin literary culture of his time. It is this aspect of the volume, more than anything else, which vindicates its essentialness.'

Chapter Three – Host–Parasite Interactions and the Evolution of Immune Defense

Parasites and pathogens are ubiquitous and act as an important selection pressure on animals. Here, drawing primarily on our own research, mostly on insects, we illustrate how host-parasite interactions have played a role in the evolution of a range of phenomena, including animal coloration, social behavior, foraging ecology, sexual selection, and life-history tradeoffs, as well as how variation in host behavior and ecology can drive variation in parasitism risk and host allocation of resources to immunity and other antiparasite defenses. We conclude by identifying key areas for future study.

John Birks: Pioneer in quantitative palaeoecology

We describe the career of John Birks as a pioneering scientist who has, over a career spanning five decades, transformed palaeoecology from a largely descriptive to a rigorous quantitative science relevant to contemporary questions in ecology and environmental change. We review his influence on students and colleagues not only at Cambridge and Bergen Universities, his places of primary employment, but also on individuals and research groups in Europe and North America. We also introduce the collection of papers that we have assembled in his honour. The papers are written by his former students and close colleagues and span many of the areas of palaeoecology to which John himself has made major contributions. These include the relationship between ecology and palaeoecology, late-glacial and Holocene palaeoecology, ecological succession, climate change and vegetation history, the role of palaeoecological techniques in reconstructing and understanding the impact of human activity on terrestrial and freshwater ecosystems and numerical analysis of multivariate palaeoecological data.

John Punch, Scotist Holy War, and the Irish Catholic Revolutionary Tradition in the Seventeenth Century

During the 1640s, the Irish Franciscan theologian John Punch taught his theology students in Rome that war against Protestants was made just by their religion alone. Jesuits like Luis de Molina identified the holy war tradition in which Punch stood as a Scotist one, and insisted that the Scotists had confused the natural and supernatural spheres. Among Irishmen, Punch was unusual. The main Irish Catholic revolutionary tradition employed Jesuit and Thomist theory. They argued that the Stuarts had lost the right to rule Ireland for natural reasons, not supernatural ones; because the Stuarts were tyrants, not because they were Protestants.

John Maxwell

Biography of General Sir John Maxwell

The androgen receptor controls expression of the cancer-associated sTn antigen and cell adhesion through induction of ST6GalNAc1 in prostate cancer

Patterns of glycosylation are important in cancer, but the molecular mechanisms that drive changes are often poorly understood. The androgen receptor drives prostate cancer (PCa) development and progression to lethal metastatic castration-resistant disease. Here we used RNA-Seq coupled with bioinformatic analyses of androgen-receptor (AR) binding sites and clinical PCa expression array data to identify ST6GalNAc1 as a direct and rapidly activated target gene of the AR in PCa cells. ST6GalNAc1 encodes a sialytransferase that catalyses formation of the cancer-associated sialyl-Tn antigen (sTn), which we find is also induced by androgen exposure. Androgens induce expression of a novel splice variant of the ST6GalNAc1 protein in PCa cells. This splice variant encodes a shorter protein isoform that is still fully functional as a sialyltransferase and able to induce expression of the sTn-antigen. Surprisingly, given its high expression in tumours, stable expression of ST6GalNAc1 in PCa cells reduced formation of stable tumours in mice, reduced cell adhesion and induced a switch towards a more mesenchymal-like cell phenotype in vitro. ST6GalNAc1 has a dynamic expression pattern in clinical datasets, beingsignificantly up-regulated in primary prostate carcinoma but relatively down-regulated in established metastatic tissue. ST6GalNAc1 is frequently upregulated concurrently with another important glycosylation enzyme GCNT1 previously associated with prostate cancer progression and implicated in Sialyl Lewis X antigen synthesis. Together our data establishes an androgen-dependent mechanism for sTn antigen expression in PCa, and are consistent with a general role for the androgen receptor in driving important coordinate changes to the glycoproteome during PCa progression.

John Thompson: Seeing through China

In 1848, Karl Marx predicted that a flow of cheap commodities would be the heavy artillery which would batter down all Chinese walls and open up the country to the west (Marx, 1978, p. 477). The Scottish photographer John Thomson (1837-1921) was both chronicler of and participant in the early moments of this process. Thomson was a commercial photographer who first arrived in the Far East in 1862. He earned the moniker of 'China' in a decade-long stay during which he photographed what he considered to be the key aspects of its culture and landscape. In this body of work, Illustrations of China and its People (first published in 1874) is perhaps the most comprehensive. It explores, through two hundred photographs and accompanying texts, a series of phenomena from the macro-scale of landscape, infrastructure and industry to the smaller scales of streetscapes, domestic spaces, individual portraits, and other details of everyday life. Despite his own description of the volumes as encyclopedic, Illustrations is geographically quite limited. Thomson's explorations into the hinterland proceed up the country’s principal rivers from those coastal ports which had already been wrested into western hands during the Opium Wars (of the 1840s) and subsequently opened up to trade. This is perhaps one of the reasons why Illustrations has been described as an explicitly colonial text, a guide-book for the prospective settler whose content offered the strategic knowledge of land, culture and natural resources necessary if the territorial advantages of the coastal periphery were to extended to the interior (Jeffrey, 1981, p. 64). It can also be argued, however, that Thomson’s volume offered justification for a potential colonial presence. Faced with a civilization whose history was as sophisticated as the west, it depicts a culture that is static and moribund, its addiction to traditional values an impediment to progress. While this is perhaps most explicit in the texts of Illustrations of China, it can also be seen in the images whose uniform chemical rendering also serves to make an essentially diverse culture seem homogenous. Yet it is these images that distinguish Illustrations from previous attempts to collate China’s culture and landscape. Here, the mechanical precision of his camera captures a reality that often subverts the colonial narrative, confounding stereotypes as Thomson’s mass-produced images allow another China to emerge.