Clinical potential of oligonucleotide-based therapeutics in the respiratory system

The discovery of an ever-expanding plethora of coding and non-coding RNAs with nodal and causal roles in the regulation of lung physiology and disease is reinvigorating interest in the clinical utility of the oligonucleotide therapeutic class. This is strongly supported through recent advances in nucleic acids chemistry, synthetic oligonucleotide delivery and viral gene therapy that have succeeded in bringing to market at least three nucleic acid-based drugs. As a consequence, multiple new candidates such as RNA interference modulators, antisense, and splice switching compounds are now progressing through clinical evaluation. Here, manipulation of RNA for the treatment of lung disease is explored, with emphasis on robust pharmacological evidence aligned to the five pillars of drug development: exposure to the appropriate tissue, binding to the desired molecular target, evidence of the expected mode of action, activity in the relevant patient population and commercially viable value proposition.

Graffiti composition: screenplay

Ongoing collaboration with Christian Marclay. ‘Graffiti Composition’ and ‘Screenplay’ are two related works consisting of live musical improvisation and performance. They are part of an ongoing collaboration with the artist Christian Marclay. 'Graffiti Composition' involved Beresford directing an invited orchestra of improvising musicians. The work focuses on making music from the random compositional acts of strangers. Prior to realization, Marclay fly-posted several hundred sheets of blank manuscript paper, collecting the sheets some days later, after passers-by had written on them – using either traditional music notation or more transgressive interference modes (colour-blocks, torn holes in or abstract graphic symbols on the paper) – and sending photographs of them to Beresford. Beresford’s directorial decisions helped these random graffiti become music via simple formal processes – restricting each musician to a handout of two MS each, or stipulating a mini-concerto for each player. Beresford’s contribution explores the paradox of improvisation stipulated by strangers and controlled, however loosely, by the structuring agency of a musical director. ‘Screenplay’ extended this collaborative process between Marclay and Beresford. Beresford and other musicians responding to a visual track comprising found and public domain moving images manipulated by Marclay – gunfight scenes from a TV Western; running water; racing cars morphing into crying children, and so on, in black-and-white, with single-colour blocks appearing and developing as lines, spots, and other suggestive ‘notation’. The elliptical, surprising, humorous nature of the images at times is hyperexplicated by the improvised music, and at others challenged, ignored or contradicted by the musicians’ interaction. ‘Graffiti Composition’ was performed by the LSO at St. Luke’s, London, March 22, 2005. ‘Screenplay’ premiered in Dundee in 2006, and toured Europe during 2007. Reviewed in the Herald (21 Feb 06) and Times (24 March 07). Beresford’s work as improviser, composer and performer was profiled in The Wire (April 2002, May 2005).

HES1 in immunity and cancer

Hairy and enhancer of split homolog-1 (HES1) is a part of an extensive family of basic helix-loop-helix (bHLH) proteins and plays a crucial role in the control and regulation of cell cycle, proliferation, cell differentiation, survival and apoptosis in neuronal, endocrine, T-lymphocyte progenitors as well as various cancers. HES1 is a transcription factor which is regulated by the NOTCH, Hedgehog and Wnt signalling pathways. Aberrant expression of these pathways is a common feature of cancerous cells. There appears to be a fine and complicated crosstalk at the molecular level between the various signalling pathways and HES1, which contributes to its effects on the immune response and cancers such as leukaemia. Several mechanisms have been proposed, including an enhanced invasiveness and metastasis by inducing epithelial mesenchymal transition (EMT), in addition to its strict requirement for tumour cell survival. In this review, we summarize the current biology and molecular mechanisms as well as its use as a clinical target in cancer therapeutics.

Transmitting Chinese Medicine: Changing Perceptions of Body, Pathology, and Treatment in Late Imperial China

Historians of Chinese medicine acknowledge the plurality of Chinese medicine along both synchronic and diachronic dimensions. Yet, there remains a tendency to think of tradition as being defined by some unchanging features. The Chinese medical body is a case in point. This is assumed to have been formalised by the late Han dynasty around a system of internal organs, conduits, collaterals, and associated body structures. Although criticism was voiced from time to time, this body and the micro/ macrocosmic cosmological resonances that underpin it are seen to persist until the present day. I challenge this view by attending to attempts by physicians in China and Japan in the period from the mid 16th to the late 18th century to reimagine this body. Working within the domain of cold damage therapeutics and combining philological scholarship, empirical observations, and new hermeneutic strategies these physicians worked their way towards a new territorial understanding of the body and of medicine as warfare that required an intimate familiarity with the body’s topography. In late imperial China this new view of the body and medicine was gradually re-absorbed into the mainstream. In Japan, however, it led to a break with this orthodoxy that in the Republican era became influential in China once more. I argue that attending further to the innovations of this period—commonly portrayed as one of decline—from a transnational perspective may help to go beyond the modern insistence to frame East Asian medicines as traditional.