To send content items to your account,
please confirm that you agree to abide by our usage policies.
If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account.
Find out more about sending content to .
To send content items to your Kindle, first ensure email@example.com
is added to your Approved Personal Document E-mail List under your Personal Document Settings
on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part
of your Kindle email address below.
Find out more about sending to your Kindle.
Note you can select to send to either the @free.kindle.com or @kindle.com variations.
‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi.
‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.
Medulloblastoma (MB) is the most common malignant pediatric brain tumour, and is categorized into four molecular subgroups, with Group 3 MB having the worst prognosis due to the highest rate of metastatic dissemination and relapse. In this work, we describe the epigenetic regulator Bmi1 as a novel therapeutic target for treatment of recurrent Group 3 MB. Through comparative profiling of primary and recurrent MB, we show that Bmi1 defines a treatment-refractory cell population that is uniquely targetable by a novel class of small molecule inhibitors. We have optimized an in vivo mouse-adapted therapy model that has the advantage of generating recurrent, human, treatment-refractory MBs. Our preliminary studies showed that although chemoradiotherapy administered to mice engrafted with human MB showed reduction in tumour size, Bmi1 expression was enriched in the post-treatment residual tumour. Furthermore, we found that knockdown of Bmi1 in human recurrent MB cells decreases proliferation and self-renewing capacities of MB cells in vitro as well as both tumour size and extent of spinal leptomeningeal metastases in vivo. Oral administration of a potent Bmi1 inhibitor, PTC 028, resulted in a marked reduction in tumour burden and an increased survival in treatment cohort. Bmi1 inhibitors showed high specificity for MB cells and spared normal human neural stem cells, when treated with doses relevant for MB cells. As Group 3 medulloblastoma is often metastatic and uniformly fatal at recurrence, with no current or planned trials of targeted therapy, an efficacious agent such as Bmi1 inhibitor could be rapidly transitioned to clinical trials.
Brain Metastases (BM) represent a leading cause of cancer mortality. While metastatic lesions contain subclones derived from their primary lesion, their functional characterization has been limited by a paucity of preclinical models accurately recapitulating the stages of metastasis. This work describes the isolation of a unique subset of metastatic stem-like cells from primary human patient samples of BM, termed brain metastasis initiating cells (BMICs). Utilizing these BMICs we have established a novel patient-derived xenograft (PDX) model of BM that recapitulates the entire metastatic cascade, from primary tumor initiation to micro-metastasis and macro-metastasis formation in the brain. We then comprehensively interrogated human BM to identify genetic regulators of BMICs using in vitro and in vivo RNA interference screens, and validated hits using both our novel PDX model as well as primary clinical BM specimens. We identified SPOCK1 and TWIST2 as novel BMIC regulators, where in our model SPOCK1 regulated BMIC self-renewal and tumor initiation, and TWIST2 specifically regulated cell migration from lung to brain. A prospective cohort of primary lung cancer specimens was used to establish that SPOCK1 and TWIST2 were only expressed in patients who ultimately developed BM, thus establishing both clinical and functional utility for these gene products. This work offers the first comprehensive preclinical model of human brain metastasis for further characterization of therapeutic targets, identification of predictive biomarkers, and subsequent prophylactic treatment of patients most likely to develop BM. By blocking this process, metastatic lung cancer would effectively become a localized, more manageable disease.
A remarkable blue-grey marble horse with a white marble rider, found in the Basilica at Aphrodisias, has been a focus of recent research. The article describes the archaeology and history of the monument — how it can be reconstructed, with its base and in its precise setting in the Basilica. The group was a daring composition that had already fallen and been restored once in antiquity. What emerges is firstly a new full-size hellenistic-style statue group whose subject can be identified as Troilos and Achilles, and secondly a striking example of the long second lives of classical statues in Late Antiquity. The horse was a great public monument of the early imperial period that was moved to the Basilica probably in the mid-fourth century a.d., where it has a well-documented context. The subject of the group can be identified both from epigraphy and from its iconographic antecedents, and its version of the subject can be related to a particular strand in the rich later literary representations of the story.1
In a previous study, glyphosate-susceptible and -resistant giant ragweed
biotypes grown in sterile field soil survived a higher rate of glyphosate
than those grown in unsterile field soil, and the roots of the susceptible
biotype were colonized by a larger number of soil microorganisms than those
of the resistant biotype when treated with 1.6 kg ae ha−1
glyphosate. Thus, we concluded that soil-borne microbes play a role in
glyphosate activity and now hypothesize that the ability of the resistant
biotype to tolerate glyphosate may involve microbial interactions in the
rhizosphere. The objective of this study was to evaluate differences in the
rhizosphere microbial communities of glyphosate-susceptible and -resistant
giant ragweed biotypes 3 d after a glyphosate treatment. Giant ragweed
biotypes were grown in the greenhouse in unsterile field soil and glyphosate
was applied at either 0 or 1.6 kg ha−1. Rhizosphere soil was
sampled 3 d after the glyphosate treatment, and DNA was extracted, purified,
and sequenced with the use of Illumina Genome Analyzer next-generation
sequencing. The taxonomic distribution of the microbial community,
diversity, genera abundance, and community structure within the rhizosphere
of the two giant ragweed biotypes in response to a glyphosate application
was evaluated by metagenomics analysis. Bacteria comprised approximately 96%
of the total microbial community in both biotypes, and differences in the
distribution of some microbes at the phyla level were observed. Select
soil-borne plant pathogens (Verticillium and
Xanthomonas) and plant-growth–promoting rhizobacteria
(Burkholderia) present in the rhizosphere were
influenced by either biotype or glyphosate application. We did not, however,
observe large differences in the diversity or structure of soil microbial
communities among our treatments. The results of this study indicate that
challenging giant ragweed biotypes with glyphosate causes perturbations in
rhizosphere microbial communities and that the perturbations differ between
the susceptible and resistant biotypes. However, biological relevance of the
rhizosphere microbial community data that we obtained by next-generation
sequencing remains unclear.
When a Master doth a thing a second time, lightly it is for the better.
George Gage to Sir Dudley Carleton, 1 November 1617
This chapter will probe early modern notions of creativity by considering the artistic activities, in and for England, of the most sought-after painter in seventeenth-century Europe – Peter Paul Rubens. The artist's busy workshop helped to satisfy the demand for his works, and as a result Rubens's English patrons, ranging from various dignitaries to Charles I himself, were the recipients of paintings with varying degrees of the master's own participation. An inquiry into Rubens's practice of delegating to studio assistants, and into the value placed by him and his British viewers on autography, will elucidate attitudes towards the manual aspects of creation. A related area of investigation will focus on the phenomenon of self-repetition in the artist's works for his English clients, some of which works were replicas of earlier compositions or reused motifs from previous inventions. Finally, a broader exploration of responses to self-replication, extending at times beyond the shores of England or the confines of painting, will bring to the fore the tensions inherent in early modern attitudes to art.
Replicas and Studio Hands
Although Rubens's stay in England as a diplomatic envoy dates to 1629–30, his relationship with English patrons had begun some thirteen years earlier when Sir Dudley Carleton, the English Ambassador to The Hague, had sought to trade a diamond chain for a hunt scene by the artist.
This book has its origins in an interdisciplinary conference of the same name, held at the University of Manchester in September 2008 as part of a four-year research project entitled ‘Musical Creativity in Restoration England’, which was funded by the Arts and Humanities Research Council in the UK. The conference brought together a group of seventeenth-century specialists including those working in cultural studies, print culture, the history of ideas, and of course historians of art, architecture, theatre, literature and music, to explore how we can seek to understand what it meant to be creative in the early modern period in England. Te symposium revealed the wide variety of approaches to studying creativity being taken by scholars and research students across the humanities, and led to exciting and fruitful cross-fertilization of ideas between its participants, resulting in discussions that in some cases have led to long-lasting research collaborations.
Tis book presents a selection of twelve essays that were developed from the twenty papers given at the conference. In selecting this group, the editors have sought to include a representative sample of the research that was presented, while also aiming to ensure that the collection is accessible to a genuinely interdisciplinary readership. While music examples are used in some of the chapters, these are kept to a minimum, and are supported by audio samples available at www.alc.manchester. ac.uk/subjects/music/research/projects/musicalcreativity.
This essay grows from a concern with the old art-historical problem of how the perception of art, or in this case more specifically architecture, changes over time. It sets out to explore how verbal representations preserve clues about such changes in the way we see the world, while proposing that the dialogue between subject and object is perhaps more palpable in texts than it is in pictures. The protagonist is seventeenth-century diarist John Evelyn, who travelled in Italy between 1644 and 1646. The account of this journey forms part of his seminal Diary, which he compiled mainly retrospectively from the 1660s onwards. One of the main seventeenth-century English sources for historians of all fields and by some even regarded as having changed travel writing, Evelyn is nevertheless well known for having copied generous parts of his text from earlier guidebooks.2 In the following I will try to dismantle sentence by sentence one short passage in which he describes the city of Genoa. Comparing his text to other seventeenth-century guidebooks allows us to see not only what Evelyn copied, but also what he altered, what he added, and, more importantly, what these alterations and additions tell us about contemporary modes of perception and representation. The ensuing analysis raises questions about concepts of creativity and originality in the period while probing the ordering of vision and knowledge in the seventeenth century.
Creation: a making or forming of something, as it were, out of nothing Edward Phillips, The New World of Words
Edward Phillips's attempt to define creation in 1671 highlights a number of issues that are central to developments in thinking about creativity, knowledge and artistic innovation during the seventeenth century. His idea of creating ‘something’ from ‘nothing’ implies, at one level, absolute novelty: a lack of precedence, a complete rupture with and effacement of a past state or experience; something appears where once there was emptiness or blankness. Simultaneously, however, the emphasis on ‘making’ and especially ‘forming’ suggests that there are materials to be moulded: existing matter to be reshaped into something new; Phillips suggests that creation has to be made from something, even as this ‘some-thing’ is described as ‘no-thing’. This ambivalence – the ‘as it were’ in the definition – hints at the multiple concepts and interpretations of creativity that existed in the seventeenth century.
In the early modern period – particularly in the realm of epistemology – creation was understood both in terms of reshaping, translating and reconfiguring that which exists and as the production of fresh entities ‘out of nothing’. Seventeenth-century theories of creativity seem to emanate from precisely this tension between novelty and precedent, between the purity of the new and the foundation of the old.
In the seventeenth century, the concept of creativity was far removed from most of the fundamental ideas about the creative act - notions of human imagination, inspiration, originality and genius - that developed in the eighteenthand nineteenth centuries. Instead, in this period, students learned their crafts by copying and imitating past masters and did not consciously seek to break away from tradition. Most new material was made on the instructions of apatron and had to conform to external expectations; and basic tenets that we tend to take for granted-such as the primacy and individuality of the author-were apparently considered irrelevant in some contexts. This aim of this interdisciplinary collection of essays is to explore what it meant to create buildings and works of art, music and literature in seventeenth-century England and to investigate the processes by which such creations came into existence. Through a series of specific case studies, the book highlights a wide range of ideas, beliefs and approaches to creativity that existed in seventeenth-century England and places them in the context of the prevailing intellectual, social and cultural trends of the period. In so doing, it draws into focus the profound changes that were emerging in the understanding of human creativity in early modern society - transformations that would eventually lead to the development of a more recognisably modern conception of the notion of creativity. The contributors work in and across the fields of literary studies, history, musicology, history of art and history of architecture, and their work collectively explores many of the most fundamental questions about creativity posed by the early modern English 'creative arts'. REBECCA HERISSONE is Head of Music and Senior Lecturer in Musicology at the University of Manchester. ALAN HOWARD is Lecturer in Music at the University of East Anglia.