A Phase I and Pharmacokinetic Study of OSI-7904L, a Liposomal Thymidylate Synthase Inhibitor in Combination with Oxaliplatin in Patients with Advanced Colorectal Cancer.

OSI-7904L is a liposomal formulation of a potent thymidylate synthase (TS) inhibitor. This phase I study evaluated the safety, tolerability and pharmacokinetics (PK) of OSI-7904L administered in combination with oxaliplatin every 21 days in patients with advanced colorectal carcinoma. METHOD: A 3+3 study design was utilized at predefined dose levels. Polymorphisms in the TS enhancer region and XPD enzyme were investigated as potential predictors of efficacy and toxicity. RESULTS: Fourteen patients received 76 cycles of treatment. At the highest dose level (OSI-7904L 9 mg/m(2), oxaliplatin 130 mg/m(2)) investigated, one of nine patients experienced dose-limiting toxicity of grade 3 oral mucositis with cycle 1 and five further patients required dose reductions. The toxicity profile of stomatitis, diarrhea, nausea, fatigue, sensory neuropathy and skin rash was consistent with that expected for a TS inhibitor/oxaliplatin combination regimen. PK analysis showed high interpatient variability with no detectable interaction between OSI-7904L and oxaliplatin. Partial radiological responses were documented in two patients. CONCLUSIONS: The recommended regimen for further investigation is OSI-7904L 9 mg/m(2) and oxaliplatin 130 mg/m(2).

Breast cancer genetics: Unsolved questions and open perspectives in an expanding clinical practice

Breast cancer is the most common cause of cancer death in the United Kingdom, with a lifetime risk of one in nine in women. Only 5-10% of all cancers is thought to be due to strongly penetrant inherited predisposing genes, such as BRCA1 and BRCA2. However, other less penetrant genes, including some autosomal recessive genes, are likely to be of etiological importance in other families. This review addresses the current knowledge of breast cancer susceptibility genes and explores the possibilities for future developments. Features of tumor pathology, prognosis, and the scope for targeted treatments in mutation carriers are discussed, and the management of known carriers and those at increased risk for developing breast cancer are evaluated. Genetic testing for cancer susceptibility may become widely available in the future, and has important ethical and management implications. (C) 2004 Wiley-Liss, Inc.

Ser6 in the maize actin-depolymerizing factor, ZmADF3, is phosphorylated by a calcium-stimulated protein kinase and is essential for the control of functional activity

Maize actin-depolymerizing factor, ZmADF, binds both G- and F-actin and enhances in vitro actin dynamics. Evidence from studies on vertebrate ADF/cofilin supports the view that this class of protein responds to intracellular and extracellular signals and causes actin reorganization. As a test to determine whether such signal-responsive pathways existed in plants, this study addressed the ability of maize ADF to be phosphorylated and the likely effects of such phosphorylation on its capacity to modulate actin dynamics. It is shown that maize ADF3 (ZmADF3) can be phosphorylated by a calcium-stimulated protein kinase present in a 40-70% ammonium sulphate fraction of a plant cell extract. Phosphorylation is shown to be on Ser6, which is only one of nine amino acids that are fully conserved among the ADF/cofilin proteins across distantly related species. In addition, an analogue of phosphorylated ZmADF3 created by mutating Ser6 to Asp6 (zmadf3-4) does not bind G- or F-actin and has little effect on the enhancement of actin dynamics. These results are discussed in context of the previously observed actin reorganization in root hair cells.

Mapping cosmopolis: moral topographies of the medieval city

Cosmopolis is a concept that has a long history in many cultures around the globe. It is a mirroring of the 'social' and 'natural' worlds, such that in one is seen the order and the structures of the other -- a mutual 'mapping'. In this paper I examine how the presence of cosmopolis -- a Christianised cosmopolis of the European Middle Ages -- was made evident in the representation and formation of cities at that time. I reveal a dualism between the social and spatial ordering of both city and cosmos which defined and reinforced social and spatial boundaries in urban landscapes, evident for example in the 11th and 12th centuries. Recently, Toulmin (1992) has taken the idea of cosmopolis to argue that it has been a persistent presence in Western - Enlightenment science, philosophy, and religion -- a 'hidden agenda of modernity'. I contend that, as an idea, cosmopolis has a much earlier circulation in European thinking, not least in the Middle Ages. Locating cosmopolis in the medieval and the modern periods then begs a question of what is it that really makes the two distinct and separate? All too often human geographers have emphasised discontinuities between the 'medieval' and 'modern' age, locating the 'rise of modernity' some time in the Enlightenment period. However, what 'mapping' cosmopolis reveals are continuities, binding time and space together, which when looked at begin to help query the modernity concept itself.

The death blow to unlimited liability in Victorian Britain: The City of Glasgow failure

In 1878, one of Britain's largest banks, the City of Glasgow Bank, collapsed, leaving a huge deficit between its assets and liabilities. As this bank, similar to many other contemporary British banks, had unlimited liability, its failure was accompanied by the bankruptcy of the vast majority of its stockholders. It is generally believed that the collapse of this depository institution revealed the extent to which ownership in large joint-stock banks had been diffused to investors of very modest means. It is also believed that the failure resulted in bank shareholders dumping their shares unto the market. Our evidence, garnered from ownership records, trading data, and stock prices, offers no support for these widely held beliefs. © 2007 Elsevier Inc. All rights reserved.

‘”Like an Old Cathedral City”: Belfast Welcomes Queen Victoria, August 1849’,

Belfast, with its history of communal violence, is normally seen as lying outside the mainstream of nineteenth-century British urban development. The visit of Queen Victoria in 1849 suggests a more complex, less linear picture. What emerges is an urban identity in transition, in which aspirations to conform to an ideal of civic harmony temporarily overrode acute sectarian and political divisions, where pride in recent economic achievement sat uneasily alongside an awareness of the town’s newcomer status, and where an emerging sense of regional difference competed with a continuing assumption of Irish identity.

Bio-port Free Energy City

In an age of depleting oil reserves and increasing energy demand, humanity faces a stalemate between environmentalism and politics, where crude oil is traded at record highs yet the spotlight on being ‘green’ and sustainable is stronger than ever. A key theme on today’s political agenda is energy independence from foreign nations, and the United Kingdom is bracing itself for nuclear renaissance which is hoped will feed the rapacious centralised system that the UK is structured upon. But what if this centralised system was dissembled, and in its place stood dozens of cities which grow and monopolise from their own energy? Rather than one dominant network, would a series of autonomous city-based energy systems not offer a mutually profitable alternative? Bio-Port is a utopian vision of a ‘Free Energy City’ set in Liverpool, where the old dockyards, redundant space, and the Mersey Estuary have been transformed into bio-productive algae farms. Bio-Port Free Energy City is a utopian ideal, where energy is superfluous; in fact so abundant that meters are obsolete. The city functions as an energy generator and thrives from its own product with minimal impact upon the planet it inhabits. Algaculture is the fundamental energy source, where a matrix of algae reactors swamp the abandoned dockyards; which themselves have been further expanded and reclaimed from the River Mersey. Each year, the algae farm is capable of producing over 200 million gallons of bio-fuel, which in-turn can produce enough electricity to power almost 2 million homes. The metabolism of Free-Energy City is circular and holistic, where the waste products of one process are simply the inputs of a new one. Livestock farming – once traditionally a high-carbon countryside exercise has become urbanised. Cattle are located alongside the algae matrix, and waste gases emitted by farmyards and livestock are largely sequestered by algal blooms or anaerobically converted to natural gas. Bio-Port Free Energy City mitigates the imbalances between ecology and urbanity, and exemplifies an environment where nature and the human machine can function productively and in harmony with one another. According to James Lovelock, our population has grown in number to the point where our presence is perceptibly disabling the planet, but in order to reverse the effects of our humanist flaws, it is vital that new eco-urban utopias are realised.

Exhibiting Maritime Histories: Titanic Belfast in the Post-Conflict City

The sinking of the RMS Titanic in 1912 represents one of the most infamous maritime disasters in the history of shipping. Yet despite it entering the public imagination in the decades after its sinking, until recently it has all but been erased from the collective memory of the people of Belfast, the city in which it was built. In a post-conflict context, however, Belfast has begun to re-imagine the role of the ship in the city’s history, most particularly in the re-development of the docklands area and its designation as the Titanic Quarter, and through its landmark project the Titanic Belfast museum. This paper will trace the economic, social and political context from which the Titanic was built, and the role that this played in silencing any very public commemoration of its sinking until after the signing of the Belfast Agreement. The ‘story’ told in the new museum will be analysed from this perspective and will illustrate how the wounds of the Troubles continue to inform the interpretation of the city’s divided past.

From Beijing with love: The global dimension of Bertolucci’s The Last Emperor

Famous for being the first foreign feature film that obtained permission to shoot in the Forbidden City, The Last Emperor (1987) is also one of the most ambitious and expensive independent productions of its time, awarded four Golden Globes and nine Academy Awards, including Best Picture. In addition, The Last Emperor can be considered as one of the first attempts of cinematic collaboration between West and East, in a period of cultural and economic transformations witnessed by China. This article aims to offer an overview of the production history of The Last Emperor, focusing on the co-production collaborations and the outcomes of a western auteur’s gaze on Chinese history. Questions of Orientalism, travel narrative and critical reception are taken into account in order to engage with the transnational implications of Bertolucci’s film and the western fascination with China.

City Profile: Erbil

Erbil (Hawler in Kurdish), is the capital and the largest city of Iraqi Kurdistan. Having been continuously inhabited for about 6000 years, the city has recently been regarded by UNESCO World Heritage as one of the world’s oldest urban settlements. The city is witnessing remarkable urban growth and rapid spatial expansion compounded by a dramatic increase in population due to emigration from the countryside and rural areas over the last three decades. Following the changing geopolitical landscape of post-war Iraq, urban changes and socio-political transformation are largely driven by Erbil’s growing autonomous status as the capital of northern region of Kurdistan since 2003. This paper explores the layers of historical, spatial and social developments of the contemporary urban context of Kurdistan in general and of Erbil in particular as a reflection of the changing status of the city, as well as the polarization of Iraq and the emergence of neoliberal urbanism. The tension between the global and modern from one side and traditional and authentic from another is ever present and evident in everyday challenges in the planning of the city. In large part, Erbil’s built fabric embodies the dichotomy of identity and contests between its past and future, in which the present remains a transition between two disconnected realities.

PatchCity: Procedural City Generation using Texture Synthesis

PatchCity is a new approach to the procedural generation of city models. The algorithm uses texture synthesis to create a city layout in the visual style of one or more input examples. Data is provided in vector graphic form from either real or synthetic city definitions. The paper describes the PatchCity algorithm, illustrates its use, and identifies its strengths and limitations. The technique provides a greater range of features and styles of city layout than existing generative methods, thereby achieving results that are more realistic. An open source implementation of the algorithm is available.

In the Shadows of the Old Town: Thomas Anna and 19th-century Glasgow

In 1858, a volume entitled Midnight Scenes and Social Photographs – being sketches of life in the streets, wynds and dens of the city of Glasgow was published under the pseudonym of ‘Shadow’ by Alexander Brown, a Glaswegian flâneur and reformer. Its frontispiece is an etching which depicts a theatre-like proscenium arch whose curtains have been withdrawn to reveal to the audience all the poverty, destitution and disorder that one was likely to find after dark in the insalubrious quarters of the city. At the extreme left-hand side, partly obscured by the curtain a silhouetted figure stands behind an unwieldy camera perched on a tripod. Distinctly unaffected by the mêlée, an arm is calmly raised and a finger precisely arched in the moment before the shutter is clicked and the scene committed to record. The volume, however, relies exclusively on textual descriptions to evoke the underside of the city and contains no photographs at all. Instead, the use of the word photograph in the title can be understood as a metaphor for detached scientific objectivity, a quality much celebrated by nineteenth-century reformers and investigators of social ills. As it happened, a decade after Shadow disappeared into the labyrinthine back-lands of Old Town Glasgow, he was followed there by a real photographer. In 1868, Thomas Annan was commissioned by the City Improvements Trust to take photographs of the Old Town in its last moments of existence before it was pulled down under a series of legislative acts. But perhaps paradoxically, given Shadow’s faith in the analytical properties of photography, Annan’s work seems to refute much of the material contained in Midnight Scenes and other similar tracts. Instead of the dens, shebeens, labyrinths and rowdy crowds described by Shadow, Annan’s depictions of the Old Town convey a static, calm environment, one which is often sparsely inhabited by a curious but apparently orderly population.

Taking account of the sensational tendencies of many reformists’ texts, this paper investigates the discrepancies between the two representations, focussing in particular on the constraints which operated on Annan during his commission. It argues that Annan’s compositions – which became very influential on other 19th century photographers of everyday life such as John Thomson or Jacob Riis – far from being dispassionate analytical works, emerged as a result of a matrix of factors which included: photographic and artistic precedents; Annan’s own predilections as a photographer; technological limitations; the nature of the commission from the City Improvements Trust and political climate in which it was given; the medieval urban fabric in which he had to operate; and, perhaps, most importantly, the identity of the Old Towns inhabitants themselves.

Old Town Glasgow: Squalor, Agitation and City Improvements

In 1862, Glasgow Corporation initiated the first of a series of three legislative acts which would become known collectively as the City Improvements Acts. Despite having some influence on the nature of the built fabric on the expanding city as a whole, the most extensive consequences of these acts was reserved for one specific area of the city, the remnants of the medieval Old Town. As the city had expanded towards all points of the compass in a regular, grid-iron structure throughout the nineteenth century, the Old Town remained singularly as a densely wrought fabric of medieval wynds, vennels, oblique passageways and accelerated tenementalisation. Here, as the rest of the city began to assume the form of an ordered entity, visible and classifiable, one could still find and addresses such as ‘Bridgegate, No. 29, backland, stair first left, three up, right lobby, door facing’ (quoted in Pacione, 1995).

Unsurprisingly, this place, where proximity to the midden (dung-heap) was considered an enviable position, was seen by the authorities as a major health hazard and a source not only of cholera, but also of the more alarming typhoid epidemic of 1842. Accordingly, the demolitions which occurred in the backlands of the Old Town under the first of the acts, the Glasgow Police Act of 1862, were justified on health and medical grounds. But disease was not the only social problem thought to issue from this district. Reports from social reformers including Fredrick Engels suggested that the decay of the area’s physical fabric could be extended to the moral profile of its inhabitants. This was in such a state of degeneracy that there were calls for a nearby military barracks to be relocated to more salubrious climes because troops were routinely coming into contact ‘with the most dissolute and profligate portion of the population’ (Peter Clonston, Lord Provost, June 1861). Perhaps more worrying for the city fathers, however, was that the barracks’ arsenal was seen as a potential source of arms for the militant and often illegal cotton workers’ unions and organisations who inhabited the Old Town as well as the districts to the east. In fact, the Old Town and East End had been the site of numerous working class actions and riots since 1787, including a strike of 60,000 workers in 1820, 100,000 in 1838, and the so-called Bread Riots of 1848 where shouts of ‘Vive La Revolution’ were reported in the Gallowgate.

The events in Paris in 1848 precipitated Baron Hausmann’s interventions into that city. The boulevards were in turn visited by members of Glasgow Corporation and ultimately, it can be argued, provided an example for Old Town Glasgow. This paper suggests that the city improvement acts carried a similarly complex and pervasive agenda, one which embodied not only health, class conflict and sexual morality but also the more local condition of sectarianism. And, like in Paris, these were played out spatially in a extensive reconfiguration of the urban fabric of the Old Town which, through the creation of new streets and a railway yard, not only made it more amenable to large scale military manoeuvres but also, opened up the area to capitalist accumulation. By the end of the works, the medieval heritage of the Old Town had been almost completely razed, the working class and Catholic East End had, through the insertion of the railway yard, been isolated from the city centre and approximately 70,000 people had been made homeless.