Intraclonal heterogeneity and distinct molecular mechanisms characterize the development of t(4;14) and t(11;14) myeloma.

We have used whole exome sequencing to compare a group of presentation t(4;14) with t(11;14) cases of myeloma to define the mutational landscape. Each case was characterized by a median of 24.5 exonic nonsynonymous single-nucleotide variations, and there was a consistently higher number of mutations in the t(4;14) group, but this number did not reach statistical significance. We show that the transition and transversion rates in the 2 subgroups are similar, suggesting that there was no specific mechanism leading to mutation differentiating the 2 groups. Only 3% of mutations were seen in both groups, and recurrently mutated genes include NRAS, KRAS, BRAF, and DIS3 as well as DNAH5, a member of the axonemal dynein family. The pattern of mutation in each group was distinct, with the t(4;14) group being characterized by deregulation of chromatin organization, actin filament, and microfilament movement. Recurrent RAS pathway mutations identified subclonal heterogeneity at a mutational level in both groups, with mutations being present as either dominant or minor subclones. The presence of subclonal diversity was confirmed at a single-cell level using other tumor-acquired mutations. These results are consistent with a distinct molecular pathogenesis underlying each subgroup and have important impacts on targeted treatment strategies. The Medical Research Council Myeloma IX trial is registered under ISRCTN68454111.

Beyond the ‘Tomlinson Trap’: Analysing the Effectiveness of Section 1 of the Compensation Act 2006

One of the intentions underpinning section 1 of the Compensation Act 2006 was to provide reassurance to individual volunteers, and voluntary organisations, involved in what the provision called ‘desirable activities’ and including sport. The perception was that such volunteers, motivated by an apprehension about their increased vulnerability to negligence liability, and as driven by a fear of a wider societal compensation culture, were engaging excessively in risk-averse behaviour to the detriment of such socially desirable activities. Academic commentary on section 1 of the Compensation Act 2006 has largely regarded the provision as unnecessary and doing little more than restating existing common law practice. This article argues otherwise and, on critically reviewing the emerging jurisprudence, posits the alternative view that section 1, in practice, affords an enhanced level of protection and safeguarding for individuals undertaking functions in connection with a desirable activity. Nonetheless, the occasionally idiosyncratic judicial interpretation given to term ‘desirable activity’, potentially compounded by recent enactment of the Social Action, Responsibility and Heroism Act 2015, remains problematic. Two points of interest will be used to inform this debate. First, an analysis of the then House of Lords’ decision in Tomlinson and its celebrated ‘balancing exercise’ when assessing reasonableness in the context of negligence liability. Second, a fuller analysis of the application of section 1 in the specific context of negligence actions relating to the coaching of sport where it is argued that the, albeit limited, jurisprudence might support the practical utility of a heightened evidential threshold of gross negligence.

Perceptions of the common good in planning

There has been plenty of debate in the academic literature about the nature of the common good or public interest in planning. There is a recognition that the idea is one that is extremely difficult to isolate in practical terms; nevertheless, scholars insist that the idea ‘…remains the pivot around which debates about the nature of planning and its purposes turn’ (Campbell & Marshall, 2002, 163–64). At the point of first principles, these debates have broached political theories of the state and even philosophies of science that inform critiques of rationality, social justice and power. In the planning arena specifically, much of the scholarship has tended to focus on theorising the move from a rational comprehensive planning system in the 1960s and 1970s, to one that is now dominated by deliberative democracy in the form of collaborative planning. In theoretical terms, this debate has been framed by a movement from what are perceived as objective and elitist notions of planning practice and decision-making to ones that are considered (by some) to be ‘inter-subjective’ and non-elitist. Yet despite significant conceptual debate, only a small number of empirical studies have tackled the issue by investigating notions of the common good from the perspective of planning practitioners. What do practitioners understand by the idea of the common good in planning? Do they actively consider it when making planning decisions? Do governance/institutional barriers exist to pursuing the common good in planning? In this paper, these sorts of questions are addressed using the case of Ireland. The methodology consists of a series of semi-structured qualitative interviews with 20 urban planners working across four planning authorities within the Greater Dublin Area, Ireland. The findings show that the most frequently cited definition of the common good is balancing different competing interests and avoiding/minimising the negative effects of development. The results show that practitioner views of the common good are far removed from the lofty ideals of planning theory and reflect the ideological shift of planners within an institution that has been heavily neoliberalised since the 1970s.

Angiomatoid fibrous histiocytoma: comparison of fluorescence in situ hybridization and reverse transcription polymerase chain reaction as adjunct diagnostic modalities

Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue neoplasm of intermediate biologic potential and uncertain differentiation, most often arising in the extremities of children and young adults. Although it has characteristic histologic features of a lymphoid cuff surrounding nodules of ovoid cells with blood-filled cystic cavities, diagnosis is often difficult due to its morphologic heterogeneity and lack of specific immunoprofile. Angiomatoid fibrous histiocytoma is associated with recurrent chromosomal translocations, leading to characteristic EWSR1-CREB1, EWSR1-ATF1, and, rarely, FUS-ATF1 gene fusions; fluorescence in situ hybridization (FISH), detecting EWSR1 or FUS rearrangements, and reverse transcription-polymerase chain reaction (RT-PCR) for EWSR1-CREB1 and EWSR1-ATF1 fusion transcripts have become routine ancillary tools. We present a large comparative series of FISH and RT-PCR for AFH. Seventeen neoplasms (from 16 patients) histologically diagnosed as AFH were assessed for EWSR1 rearrangements or EWSR1-CREB1 and EWSR1-ATF1 fusion transcripts. All 17 were positive for either FISH or RT-PCR or both. Of 16, 14 (87.5%) had detectable EWSR1-CREB1 or EWSR1-ATF1 fusion transcripts by RT-PCR, whereas 13 (76.5%) of 17 had positive EWSR1 rearrangement with FISH. All 13 of 13 non-AFH control neoplasms failed to show EWSR1-CREB1 or EWSR1-ATF1 fusion transcripts, whereas EWSR1 rearrangement was present in 2 of these 13 cases (which were histopathologically myoepithelial neoplasms). This study shows that EWSR1-CREB1 or EWSR1-ATF1 fusions predominate in AFH (supporting previous reports that FUS rearrangement is rare in AFH) and that RT-PCR has a comparable detection rate to FISH for AFH. Importantly, cases of AFH can be missed if RT-PCR is not performed in conjunction with FISH, and RT-PCR has the added advantage of specificity, which is crucial, as EWSR1 rearrangements are present in a variety of neoplasms in the histologic differential diagnosis of AFH, that differ in behavior and treatment.

Sister Practices: Non-Normative Experiences of Time and Technology

This chapter summarises some of the learning from a material practice that sits in a sisterly manner next to architecture. Drawing on feminist writing and the experiences of women in professional life more generally, the chapter will examine how mainstream understanding of time and technology limit the engagement of those people in society who do not fit given norms. The chapter argues that when we examine such concepts in more detail and expand them to reflect diverse experiences those very same concepts offer new potentials and innovative openings for the progression of disciplines such as architecture.

Session organiser/chair: The architecture of coal and other energies

Coal ignited the industrial revolution. An organic sedimentary rock that energized the globe, transforming cities, landscapes and societies for generations, the importance of ‘King Coal’ to the development and consolidation of modernity has been well-recognised. And yet, as a critical factor in the production of modern architecture, coal—as well as other forms of energy—has been mostly overlooked.

From Appalachia to Lanarkshire, from the pits of northern France, Belgium and the Ruhr valley, to the monumental opencast excavations of Russia, China, Africa and Australia, mining operations have altered the immediate social and physical landscapes of coal-rich areas. But in contrast to its own underground conditions of production, the winning of coal, especially in the twentieth-century, has produced conspicuously enlightened and humane approaches to architecture and urbanism. In the twentieth century, educational buildings, holiday camps, hospitals, swimming pools, convalescent homes and housing prevailed alongside model collieries in mining settlements and areas connected to them. In 1930s Britain, pit head baths—funded by a levy on each ton produced—were often built in the International Style. Many won praise for architectural merit, appearing in Nicholas Pevsner’s guides to the buildings of England alongside cathedrals, village manors and Masonic halls as testimonies to the public good.

The deep relationships between coal and modernity, and the expressions of architecture it has articulated, in the collieries from which it was hewn, the landscape and towns it shaped, and the power stations and other infrastructure where it was used, offer innumerable opportunities to explore how coal produced architectures which embodied and expressed both social and technological conditions. While proposals on coal are preferred, we also welcome papers that interrogate the complexity, heterogeneity and hybridity of other forms of energy production and how these have also interceded into architectural form at a range of scales.