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OBJECTIVES/GOALS: Neuroblastoma (NB) is an embryonal cancer of the sympathetic nervous system that affects mostly infants and young children. The complex genetic background present across NB patients results in diverse clinical response and difficulty in individualizing therapy. Currently, NB patients undergo a regimen of genotoxic chemotherapeutics, radiation therapy, and new immunotherapy that, while effective, has significant side effects, including excruciating pain. One promising avenue for targeted therapy in neuroblastoma focuses on anaplastic lymphoma kinase (ALK), a cell surface neural receptor tyrosine kinase. We previously identified activating point mutations within the tyrosine kinase domain of ALK as the primary cause of hereditary NB, and we and others subsequently showed that these same alterations are the most common somatic single-nucleotide mutations in the sporadic forms of the disease. Crizotinib, a first-generation small molecule ATP-competitive inhibitor of the ALK tyrosine kinase, showed limited anti-tumor activity in patients with relapsed NB harboring ALK F1174 and F1245 mutations. We have demonstrated that lorlatinib, a novel ATP-competitive ALK inhibitor, overcomes this de novo resistance in preclinical models of ALK-driven NB. Recent clinical trials with lorlatinib in patients with non-small cell lung cancer harboring an ALK fusion, and in patients with NB harboring ALK mutations show the emergence of multiple or compound ALK mutations as a mechanism of resistance. We postulate that these compound mutations disrupt the interaction between and ALK and cause resistance. In this study, we employ a computational approach to model mutated ALK in complex with lorlatinib as well as ATP to understand whether the new mutations alter the affinity or mode of lorlatinib/ATP binding to ALK, and thus cause suboptimal ALK inhibition. METHODS/STUDY POPULATION: We employ methods in computational structural biology and drug design, primarily based on molecular modeling, molecular dynamics (MD), and molecular docking. Based on existing crystal structures of wildtype ALK, we model the mutations and perform MD simulations in order to characterize the activation state of the protein as well as perform ensemble docking calculations to assess the binding affinities and modes in ALK-lorlatinib and ALK-ATP complexes. RESULTS/ANTICIPATED RESULTS: We expect that the compound mutations cause resistance to lorlatinib either by lowering protein affinity for the drug or increasing the affinity for ATP. Alternatively, the compound mutations may disrupt the protein activation state, in which case ALK may no longer be active, and another protein/pathway could be driving the resistance. DISCUSSION/SIGNIFICANCE OF IMPACT: The results of this study will enable the understanding of the mechanism of resistance to lorlatinib and facilitate the design of new ALK inhibitors, or help develop more optimal and mechanism-guided therapies aimed to overcome the resistance.
Caste has always generated political and scholarly controversy, but the forms that this takes today newly combine anti-caste activism with counter-claims that caste is irrelevant or non-existent, or claims to castelessness. Claims to castelessness are, in turn, viewed by some as a new disguise for caste power and privilege, while castlessness is also an aspiration for people subject to caste-based discrimination. This article looks at elite claims to “enclose” caste within religion, specifically Hinduism, and the Indian nation so as to restrict the field of social policy that caste applies to, to exempt caste-based discrimination from the law, and to limit the social politics of caste. It does so through a comparative analysis of two cases. The first is the exclusion of Christian and Muslim Dalits—members of castes subordinated as “untouchable”—from provisions and protections as Scheduled Castes in India. The other case is that of responses to the introduction of caste into anti-discrimination law in the UK. While Hindu organizations in the UK reject “caste” as a colonial and racist term and deploy postcolonial scholarship to deny caste discrimination, Dalit organizations, representing its potential victims, turn to scholarly discourse on caste, race, or human rights to support their cause. These are epistemological disputes about categories of description and how “the social” is made available for public debate, and especially for law. Such disputes engage with anthropology, whose analytical terms animate and change the social world that is their subject.
What place does the caste system have in modern India with its globally integrating market economy? The most influential anthropological approaches to caste have tended to emphasize caste as India's traditional religious and ritual order, or (treating such order as a product of the colonial encounter) as shaped politically, especially today by the dynamics of caste-based electoral politics. Less attention has been paid to caste effects in the economy. This article argues that the scholarly framing of caste mirrors a public-policy ‘enclosure’ of caste in the non-modern realm of religion and ‘caste politics’, while aligning modernity to the caste-erasing market economy. Village-level fieldwork in South India finds a parallel public narrative of caste either as ritual rank eroded by market relations or as identity politics deflected from everyday economic life. But, locally and nationally, the effects of caste are found to be pervasive in labour markets and the business economy. In the age of the market, caste is a resource, sometimes in the form of a network, its opportunity-hoarding advantages discriminating against others. Dalits are not discriminated by caste as a set of relations separate from economy, but by the very economic and market processes through which they often seek liberation. The caste processes, enclosures, and evasions in post-liberalization India suggest the need to rethink the modernity of caste beyond orientalist and post-colonial frameworks, and consider the presuppositions that shape understanding of an institution, the nature and experience of which are determined by the inequalities and subject positions it produces.
We employ Pan-STARRS photometry, Gaia trigonometric parallaxes, modern stellar evolution and atmosphere models, and our Bayesian fitting approach to determine cooling and total ages for 159,238 white dwarfs. In many cases we are able to derive precise ages (better than 5%) for individual white dwarfs. These results are meant for broad use within the white dwarf and stellar astrophysics communities and we plan to make available on-line the posterior distributions for cooling age, total age, initial stellar mass, and other parameters.
Limited data exist for management of hyperuricemia in non-oncologic patients, particularly in paediatric cardiac patients. Hyperuricemia is a risk factor for acute kidney injury and may prompt treatment in critically ill patients. The primary objective was to determine if rasburicase use was associated with greater probability normalisation of serum uric acid compared to allopurinol. Secondary outcomes included percent reduction in uric acid, changes in serum creatinine, and cost of therapy.
A single-centre retrospective chart review.
A 20-bed quaternary cardiovascular ICU in a university-based paediatric hospital in California.
Patients admitted to cardiovascular ICU who received rasburicase or intravenous allopurinol between 2015 and 2016.
Measurements and main results:
Data from a cohort of 14 patients receiving rasburicase were compared to 7 patients receiving IV allopurinol. Patients who were administered rasburicase for hyperuricemia were more likely to have a post-treatment uric acid level less than 8 mg/dl as compared to IV allopurinol (100 versus 43%; p = 0.0058). Patients who received rasburicase had a greater absolute reduction in post-treatment day 1 uric acid (−9 mg/dl versus −1.9 mg/dl; p = 0.002). There were no differences in post-treatment day 3 or day 7 serum creatinine or time to normalisation of serum creatinine. The cost of therapy normalised to a 20 kg patient was greater in the allopurinol group ($18,720 versus $1928; p = 0.001).
In a limited paediatric cardiac cohort, the use of rasburicase was associated with a greater reduction in uric acid levels and associated with a lower cost compared to IV allopurinol.
Organismal metabolic rates reflect the interaction of environmental and physiological factors. Thus, calcifying organisms that record growth history can provide insight into both the ancient environments in which they lived and their own physiology and life history. However, interpreting them requires understanding which environmental factors have the greatest influence on growth rate and the extent to which evolutionary history constrains growth rates across lineages. We integrated satellite measurements of sea-surface temperature and chlorophyll-a concentration with a database of growth coefficients, body sizes, and life spans for 692 populations of living marine bivalves in 195 species, set within the context of a new maximum-likelihood phylogeny of bivalves. We find that environmental predictors overall explain only a small proportion of variation in growth coefficient across all species; temperature is a better predictor of growth coefficient than food supply, and growth coefficient is somewhat more variable at higher summer temperatures. Growth coefficients exhibit moderate phylogenetic signal, and taxonomic membership is a stronger predictor of growth coefficient than any environmental predictor, but phylogenetic inertia cannot fully explain the disjunction between our findings and the extensive body of work demonstrating strong environmental control on growth rates within taxa. Accounting for evolutionary history is critical when considering shells as historical archives. The weak relationship between variation in food supply and variation in growth coefficient in our data set is inconsistent with the hypothesis that the increase in mean body size through the Phanerozoic was driven by increasing productivity enabling faster growth rates.
It is all too tempting for those of us who live in Europe or one of the Anglophone countries to take a Eurocentric view of archives. The conventional narrative of archives is that they grew up in the 19th century and were associated with the ‘scientific’ or ‘German’ school of history pioneered by Ranke in Germany and Acton in England. In this narrative, the growth of archives meant that historians were able to write a history which was based on records rather than on repeating what had been said in earlier books. The scientific historians drove the antiquarians out of the temple.
Although in the West archives are part of the beginning of modernity, elsewhere they were closely connected with the experience of colonialism. In Malawi and India they have played a dual role, both the record of the European settlers, traders and governments and, at the same time, a tool for recording an oral culture and developing national identity. In Japan they have followed a quite different path. There is a long tradition of writing official histories (of companies and organizations and even the nation itself) in that country, and of accumulating a collection of archives to facilitate the writing of history. Unlike in the West, where history followed the archive, in Japan the archive followed the history.
The situation in Hong Kong is similar but different to that in Japan. For most of its history as a British colony, Hong Kong was dominated by large British companies which developed the habit of collecting archives in order to produce corporate histories and anniversary books. Some of their records are now deposited overseas and, sadly, most of Hong Kong's public records were destroyed in World War 2. Most Chinese-owned companies were small or medium sized and family owned, and it was not until the 1970s that they began to take an interest in their own culture and heritage and began collecting archives and undertaking research. What seems to be fairly universally true is the ability of archives to right wrongs done by governments to their citizens. In Malawi, the archives were used to secure compensation for people damaged by the regime of Dr Banda; in Australia they were of significant value in the restitution of ancestral human remains and the compensation of children mistreated in children's homes.
The title of this book, The Politics of Swidden Farming: Environment and Development in Eastern India, hardly conveys the ethnographic depth and historical reach of the study. This scope becomes apparent as the reader comes to discover the significance of swidden or shifting cultivation, not just as a relationship of communities to land and ecology, but as a critical mediator of relationships with the colonial and postcolonial state and its civilizing or development projects over the past century. The study is located in a region and among people who become, through their social lives and livelihoods (including their swidden cultivation), as Anna Tsing puts it, ‘icons of the archaic disorder that represents the limit and test of state order and development’ (Tsing 1993: 28). The remote Naga villages that are the ethnographic focus of this book are in this sense represented simultaneously as a political–administrative border, an agricultural margin and a moral frontier. The kinds of colonial and postcolonial projects that have sought to regulate and control such borderland communities, whether irrigation projects, roads, settlement schemes or plantations, are well known, but what is rarer is the kind of longitudinal account offered here of the interplay of state power, Christian mission and local communities, examined also through the complex relationships between and within these Nagaland villages themselves. With regard to this latter theme of the role and agency of local communities in their own transformation, it becomes evident not only that colonial administrative power was asserted through harnessing inter-group antagonisms, but also that transformations brought to the cultivated landscape, to social institutions and cultural practices through Christian missions, came by way of neighbouring social groups, who modelled new ways of worshipping and working the land, expanding cash-crop or rice cultivation (an established archetype of settled civility).
Violence is a thread that runs through the account of the political and moral relationships of this frontier zone. Debojyoti Das offers the reader his own experience of being caught up in a violent episode involving a kidnap, interrupting the decade-long ceasefire between the army and Naga militants, as a route into ethical and methodological reflection.
This book will explore ways of establishing and measuring value in the archives and special collections.There is a vast literature about ways of measuring value for cultural heritage assets as a whole, particularly museums and visitor attractions, but archives and special collections in libraries have largely been overlooked. They have been very poor at garnering statistical data and devising ways of measuring the impact of what they do, unlike museums and visitor attractions with their much heavier footfall.Do Archives Have Value? discusses the various valuation methods available, including contingent valuation, willingness to pay and value chain, and assesses their suitability for use by archives and special collections. The book also assesses the impact of the transition to the digital in archival holdings, which will transform their character and will almost certainly cost more. The discussion will be set in the context of changing societal expectations of the archive in the wake of child abuse and other scandals where records to address grievances must be kept irrespective of cost.Value is explored in a range of different cultural and organizational contexts with case studies from a range of countries, including Australia, China, Japan, Malawi, Kenya, Russia and Thailand. There are contributions from Nancy Bell, Head of Conservation at The National Archives, Louise Craven, one of the leading UK archival scholars, Paul Lihoma, National Archivist of Malawi, Helen Morgan from the University of Melbourne, Pak Te Lee of the University of Hong Kong and Richard Wato from the National Archives of Kenya.
This chapter discusses the economic impact which the move towards commercial family history websites has had on archival institutions. It describes how the ability to license copies of archive records and to make them available online has spawned a multi-billion-dollar industry. The major family history companies provide online access to billions of records and have transformed family history research and academic investigation of biographical material. This new industry has leveraged millions of dollars of investment into digital archival resources and has generated some income for archives, but arguably not nearly enough. As we will discover, it has had some downside for the sociability of the family history community.
Since 2002, archives have largely contracted out their online public service offerings to family history companies. In most cases it is possible to access the records in archive buildings (in a variety of formats), but for those wishing to access them without travelling long distances, or who want access to the indexes which the family history companies provide, then there is little alternative but to sign up to Ancestry, Findmypast, MyHeritage or other suppliers and buy services from them.
Very little has been published on the economics of archives, except to bemoan the collapse in user numbers without asking why or considering if the current business model is any longer sustainable. Most of the literature focuses on the cognate, but different, fields of museums and libraries. One pioneering work undertaken in the USA by Yakel et al. (2012) looked at a range of ways of measuring the economic impact of archives. These included contingent measures which attempt to discover how much a user would be willing to pay to use an existing service or how much a user would have to pay to buy that service on the market. Yakel and colleagues also discussed direct measures which looked at the financial impact of cultural services – how much money in terms of staff salaries, construction expenditure, revenues from sales taxes etc. went to the local economy from cultural institutions.
However, the approach favoured by Yakel et al. was to focus on the indirect economic benefits of archives, calculating how much users spent during their visits. Their conclusions were that the economic benefits of archives were real, but modest.
In his essay ‘The Strange Death of Municipal England’, Tom Crewe presents some sobering facts. Between 2008 and 2018, local authority spending in the UK has been squeezed by 37%, and a further substantial reduction is scheduled up to 2023. For many local councils this will mean the loss of more than 60% of income by 2020 (Crewe, 2016). Further retrenchment of already pinched resources will inevitably focus resources on essential front-line services. Crewe presents a carefully argued narrative based on compelling evidence. The experience in the UK is replicated in many other countries that have large budget deficits in the wake of the 2008 financial crisis.
The consequences of increasing digital access
Financial retrenchment in the public sector is just one factor impacting on the sector, which is witnessing a decline in staffing and supposed ‘efficiencies’ to be gained through mergers with other cultural heritage services, such as libraries and museums. The sector has to compete for the ‘leisure pound’ and the increasingly vast amount of heritage assets available on the web, which will continue radically to change how collections are accessed and used by a diverse community of users. In the wake of the digital abundance, new forms of content are added daily, from a variety of sources (Zephoria Digital Marketing, 2019); for example, five new Facebook profiles are added every second, creating new pipelines of content for researchers and immersive experiences hitherto unimaginable. In the analogue world historical newspapers were rarely used, but now that they have been digitised and are fully searchable, they are heavily exploited and provide an increasingly alternative channel to the use of archives, at least in the modern period. While this evolving digital offer is to be applauded for giving greater access to collections, there are inevitably unintended consequences. Worryingly, there has been a decline of 3%, over the period 2015–2017 in numbers of on-site visitors to archives, largely from the 65–74 year age group. Although a good deal of the most commonly used digitised content is sheltered behind the paywalls of third-party providers, a similar reduction in online access to collections through archive and library websites has been reported by the Department for Digital, Culture, Media and Sport (2017).
In the Chinese philosopher Zhuangzi's famous parable, Zhuang Zhou dreams he is a butterfly, only to awake to discover that he was a man, but he is left with the nagging doubt as to whether he was Zhuang Zhou who had dreamed he was a butterfly or if he was a butterfly dreaming he was a man (Giles, 1926, 47). Brewster Kahle dreamed he could archive the internet, but in this chapter we will argue that he will wake up one day to find that the internet has archived him. Far from being an object that is archived, we will argue that the internet is itself an archive, but one which does not conform to the rules of archiving as we know them. The chapter will further go on to dem - onstrate that, like the world in which men can wake up to find they are butterflies, the internet as archive has a unique ability to change the past as well as the present. Those of us who work in the field of memory institutions need to confront this new world in which the internet is not archived but is the archive, not by claiming that it is not but by exploring its properties and possibilities.
In 2011, the Cinque Port Scribes mounted The Last Word exhibition that toured five of the churches on Romney Marsh: ‘using redundant books and calligraphy developed as part of a discussion of digital books and their impact on the printed book market and whether this may lead to printed books becoming as precious as the hand-written manuscripts they originally represented’. Perhaps surprisingly it was not a lament but a paean of wonder at the potential of this new form of communication.
One piece made from beautifully scripted strips of paper was ‘Els’ Chrysalis’ by Els Van Den Steen with the legend: ‘Metamorphosis – to be reborn anew to live again’ Beside it the artist had written poignantly: ‘The metamorphosis of the printed book is taking place right now! And just like before, the written word is evolving into a new form … To achieve the decomposing effect of the printed book, I used a rifle and a shotgun … Will the new ebook be a beautiful butterfly?’