School of Clinical Medicine Research Directory 2009 - 2011

School of Clinical Medicine Research Directory 2009–2011

Introduction

It is my pleasure to introduce the Research Directory for the School of Clinical Medicine at Cambridge University for 2009–2011.

This Research Directory provides a brief description, department by department of the main areas of our research and lists a small number of our key publications. As a document of record, it is presented on a departmental basis, although of course this belies the reality of how modern medical research takes place: multi-disciplinary teams, thematically, and across departments. Readers interested in a fuller description of our research may wish to consult, in addition to this Directory, our Bi-ennial Review and the research pages on our website www.medschl.cam.ac.uk Regius Professor of Physic Professor Sir Patrick Sissons MD FRCP FRCPath FMedSci

RESEARCH DIRECTORY 2009 –2011

1

Clinical Biochemistry Head of Department and Professor of Clinical Biochemistry and Medicine Professor S O’Rahilly, FRS, FMedSci Tel 01223 336855 Fax 01223 330698 Email so104@medschl.cam.ac.uk

Staff list Professors JP Luzio, FMedSci, Professor of Molecular Membrane Biology IS Farooqi, Professor of Metabolism and Medicine (Wellcome Trust Senior Clinical Fellow) DJ Owen, Professor of Structural and Molecular Biology (Wellcome Trust Principal Fellow) MS Robinson, FMedSci , Professor of Molecular Cell Biology (Wellcome Trust Principal Fellow) D Ron, Professor of Cellular Pathophysiology and Clinical Biochemistry (Wellcome Trust Principal Fellow) K Siddle, Professor of Molecular Endocrinology AJ Vidal-Puig, Professor of Molecular Nutrition and Metabolism Readers FM Gribble, Reader in Endocrine Physiology (Wellcome Trust Senior Clinical Fellow) SE Ozanne, Reader in Developmental Endocrinology (BHF Senior Fellow) University Lecturer AP Coll Senior Research Staff I Barroso (joint appointment with Wellcome Trust Sanger Institute) G Borner N Bright F Buss S Graham H Harding J Hirst B Kelly Peter Murgatroyd H Murphy JS O’Neill A Peden F Reimann (Wellcome Trust Senior Fellow) JJ Rochford DB Savage (Wellcome Trust Senior Clinical Fellow) RK Semple MNJ Seaman (MRC Senior Fellow) JK Sethi S Siniossoglou (MRC Senior Fellow) R Volmer PJ Voshol GS Yeo

2

CLINICAL BIOCHEMISTRY

NHS Consultants (Dept of Clinical Biochemistry and Immunology) J Calvin DS Kumararatne A Sarker D Halsall A Park

Research synopsis Research in the Department is focused on two areas: a) the aetiology and pathogenesis of obesity, diabetes and related metabolic disorders, and b) the molecular cell biology of membrane traffic. Investigators working in metabolic disorders are largely based in the Institute of Metabolic Science (IMS). The Cell Biology group is located entirely in The Cambridge Institute for Medical Research (CIMR). The Department has played a leading role in several recent major initiatives, including the opening of the IMS, the creation of the MRC Centre for Obesity and Related Metabolic Disease (MRC CORD) and the Cambridge Phenomics Centre. Professor Stephen O'Rahilly is Scientific Director of the NIHR Cambridge Biomedical Research Centre, and leads the Metabolic, Endocrine and Bone Theme.

Diabetes, Obesity and Metabolism Group Research themes include the following: molecular mechanisms in human obesity insulin resistance and type 2 diabetes (Barroso, Farooqi, O’Rahilly, Savage, Semple, in collaboration with Prof NJ Wareham and colleagues from the MRC Epidemiology Unit) neurobiology of hunger and satiety (Farooqi, with Prof P Fletcher, Dept of Psychiatry); animal models of obesity and insulin resistance (Coll, Sethi, O’Rahilly, Voshol, Vidal-Puig, Yeo); adipocyte biology (Rochford, Sethi, Vidal-Puig) and how this relates to ‘lipotoxicity’ resulting from inappropriate storage of excess lipids (Vidal-Puig); developmental programming of late-onset metabolic disease (Ozanne); signaling by insulin and insulin-like growth factors (Semple, Siddle); endoplasmic reticulum stress (Ron, Harding, Volmer), entero-endocrine physiology (Gribble, Reimann), non-transcriptional control of circadian rhythms (O’Neill) and improving health outcomes in diabetes. (Murphy) Selected references: Bochukova EG, Huang N, Keogh J, Henning E, Purmann C, Blaszczyk K, Saeed S, Hamilton-Shield J, Clayton-Smith J, O'Rahilly S, Hurles ME, Farooqi IS. (2010) Large, rare chromosomal deletions associated with severe early-onset obesity. Nature 463:666–70.

Dash S, Sano H, Rochford JJ, Semple RK, Yeo G, Hyden CS, Soos MA, Clark J, Rodin A, Langenberg C, Druet C, Fawcett KA, Tung YC, Wareham NJ, Barroso I, Lienhard GE, O’Rahilly S, Savage D. (2009) A truncation mutation in TBC1D4 in a family with acanthosis nigricans and postprandial hyperinsulinemia. Proc Natl Acad Sci (USA) 106, 9350–5

Selected references:

Greenfield JR, Miller JW, Keogh JM, Henning E, Satterwhite JH, Cameron GS, Astruc B, Mayer JP, Brage S, See TC, Lomas DJ, O’Rahilly S, Farooqi IS. (2009) Modulation of blood pressure by central melanocortinergic pathways. N Engl J Med. 360, 44–52

Gordon DE, Mirza M, Sahlender DA, Jakovleska J, Peden AA. (2009) Coiled-coil interactions are required for post-Golgi R-SNARE trafficking.

EMBO Reports 10, 851–856.

Ishii KA, Fumoto T, Iwai K, Takeshita S, Ito M, Shimohata N, Aburatani H, Taketani S, Lelliott CJ, Vidal-Puig A, Ikeda K. (2009) Coordination of PGC-1beta and iron uptake in mitochondrial biogenesis and osteoclast activation. Nat Med. 15:259–66.

Jackson LP, Kelly BT, McCoy AJ, Gaffry T, James LC, Collins BM, Honing S, Evans PR, Owen DJ. (2010) A large-scale conformational change couples membrane recruitment to cargo binding in the AP2 clathrin adaptor complex. Cell 141, 1220–1229.

López M, Varela L, Vázquez MJ, Rodríguez-Cuenca S, González CR, Velagapudi VR, Morgan DA, Schoenmakers E, Agassandian K, Lage R, Martínez de Morentin PB, Tovar S, Nogueiras R, Carling D, Lelliott C, Gallego R, Oresic M, Chatterjee K, Saha AK, Rahmouni K, Diéguez C, Vidal-Puig A. (2010) Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat Med. 16:1001–8.

Karanasios E, Han GS, Xu Z, Carman GM, Siniossoglou S. (2010) A phosphorylation-regulated amphipathic helix controls the membrane translocation and function of the yeast phosphatidate phosphatase.

Proceedings of the National Academy of Sciences of the United States of America 107, 17539–17544.

Murphy HR, Rayman G, Lewis K, Kelly S, Johal B, Duffield K, Fowler D, Campbell PJ, Temple RC. (2008) Effectiveness of continuous glucose monitoring in pregnant women with diabetes: randomised clinical trial. BMJ. 2008 337:a1680.

O’Neill JS, van Ooijen G, Dixon LE, Troein C, Corellou F, Bouget F-Y, Reddy AB, Millar AJ. (2011) Circadian rhythms persist without transcription in a eukaryote. Nature 469, 554–558 O’Neill JS, Reddy AB. (2011) Circadian clocks in human red blood cells.

Nature 469, 498–503 Reimann F, Habib AM, Tolhurst G, Parker HE, Rogers GJ, Gribble FM. (2008) Glucose sensing in L cells: a primary cell study. Cell Metab. 8:532–9.

Tsaytler P, Harding HP, Ron D and Bertolotti A. Selective inhibition of a regulatory subunit of protein phosphatase 1 restores proteostasis.

Science 2011 332:91–94.

Wiseman RL, Zhang Y, Lee KP, Harding HP, Haynes CM, Price J, Sicheri F, Ron D. (2010) Flavonol activation defines an unanticipated ligand-binding site in the kinase-RNase domain of IRE1. Mol Cell 2010 38:291–304.

Intracellular Membrane Trafficking Group Investigators working on the molecular cell biology of intracellular membrane traffic are based in the Cambridge Institute for Medical Research (CIMR). These investigators are: Paul Luzio, working on endocytic pathways and lysosome biogenesis; Margaret Robinson, studying adaptor complexes in coated vesicles; David Owen, studying the structures of proteins involved in membrane traffic; Folma Buss, studying molecular motors and their role in organelle/vesicle movement; Matthew Seaman, studying retrograde traffic between lysosomes/vacuoles and the Golgi complex; Andrew Peden, working on proteins involved in membrane fusion; and Symeon Siniossoglou, studying how lipids regulate the structure and function of membranes and organelles.

Lawrence SP, Bright NA, Luzio JP, Bowers K. (2010) The sodium/proton exchanger NHE8 regulates late endosomal morphology and function.

Molecular Biology of the Cell. 21, 3540–3551.

Puri C, Chibalina MV, Arden SD, Kruppa AJ, Kendrick-Jones J, Buss F. (2010) Overexpression of myosin VI in prostate cancer cells enhances PSA and VEGF secretion, but has no effect on endocytosis.

Oncogene 29, 188–200.

Roberts RC, Peden AA, Buss F, Bright NA, Latouche M, Reilly MM, Kendrick-Jones J, Luzio JP. (2010) Mistargeting of SH3TC2 away from the recycling endosome causes Charcot-Marie-Tooth disease type 4C. Human Molecular Genetics 19, 1009–1018.

Robinson MS, Sahlender DA, Foster SD. (2010) Rapid inactivation of proteins by rapamycin-induced rerouting to mitochondria.

Developmental Cell 18, 324–331.

Seaman MN, Harbour ME, Tattersall D, Read E, Bright N. (2009) Membrane recruitment of the cargo-selective retromer subcomplex is catalysed by the small GTPase Rab7 and inhibited by the Rab-GAP TBC1D5. Journal of Cell Science 122, 2371–2382.

NHS Department of Clinical Biochemistry and Immunology Members of the NHS department run the genomics (Dr Ian McFarlane) and Biochemical Assay (Keith Burling) Core Laboratories of the NIHR Cambridge Biomedical Research Centre. Drs Kumararanatne and Doffinger investigate the molecular basis of the immune deficiencies. Dr Halsall runs specialist endocrine services with important links to genetic research.

CLINICAL BIOCHEMISTRY

3

Clinical Neuroscience Head of Department and Professor of Neurology

and imaging MR science group with the development of realtime MR for brain-computer interface studies of patients with low awareness.

Professor A Compston Tel 01223 217091 Fax 01223 336941 Email alastair.compston@medschl.cam.ac.uk

Marek Czosnyka leads the neurosurgical physics group whose research focuses on cerebral autoregulation following head injury and subarachnoid haemorrhage, and the importance of cerebrovascular and CSF dynamics for hydrocephalus and idiopathic intracranial hypertension. Peter Smielewski has developed software (www.neurosurg.cam.ac.uk/icmplus) required to capture and analyse real-time signals derived from bedside monitoring now introduced into several neuroscience intensive care units worldwide.

Staff list Professors RA Barker, Professor of Clinical Neuroscience JW Fawcett, Professor of Experimental Neurology, Chairman of the Brain Repair Centre K Martin, Professor of Ophthalmology JD Pickard, Professor of Neurosurgery, C hairman of Wolfson Brain Imaging Centre and NHS Divisional Director for the Clinical Neurosciences M-G Spillantini, Professor of Molecular Neurology P St George Hyslop, Professor of Experimental Neuroscience and Wellcome Trust Principal Research Fellow Readers A Carpenter, Reader in Imaging Sciences M Czosnyka, Reader in Brain Physics P Hutchinson, Reader in Neurotrauma JB Rowe, Reader in Cognitive Neurology S J Sawcer, Reader in Neurogenetics University Lecturers AJ Coles S Pluchino P Nestor C Watts Senior Research Staff FI Aigbirhio K Carpenter Z Czosnyka T Fryer

Y Hong S Price A Reddy H Richards

NHS Consultants/Associate Lecturers C Allen R MacFarlane R Laing M Manford

R Roberts P Smielewski G Williams D Williamson P Kirkpatrick E Warburton

Main research themes Traumatic brain injury and stroke The Wolfson Brain Imaging Centre (WBIC) uses positron emission tomography (PET) and magnetic resonance (MR) data to investigate disease mechanisms in traumatic brain injury and neurodegeneration. Adrian Carpenter is establishing the technology for combined PET/MR imaging and elastography.

Franklin Aigbirhio is developing novel radiopharmaceutical probes for molecular imaging using PET. Tim Fryer directs an imaging programme that has introduced experimental microPET and the computing support for experimental and clinical aspects of PET and Cyclotron physics. Guy Williams directs the computing

4

CLINICAL NEUROSCIENCE

John Pickard leads a research group that explores the pathophysiology of traumatic brain injury from initial ictus through intensive care to final outcome using PET, MR and multimodality bedside monitoring. Recent advances include the definition of how early insults after head injury lead to late changes in the brain and cognitive outcome, the effects of cognitive stimulation on brain activation in altered states of consciousness (with David Menon, Department of Medicine), and new insights into parts of the brain affected by hydrocephalus and idiopathic intracranial hypertension including the development of venous stenting (with Nicholas Higgins, Neuroradiology).

Peter Hutchinson has developed care pathways from acute emergency treatment through to neuro-rehabilitation and leads the MRC RESCUEicp (evaluation of Decompressive Craniectomy for raised intracranial pressure following trauma: www.RESCUEicp. com). With Keri Carpenter, he uses intracerebral microdialysis to study changes in metabolic pathways and energy substrates used by the brain to conserve function after traumatic injury; the role of acute inflammation after head injury; and the penetration of neuroprotective agents across the blood brain barrier.

Peter Kirkpatrick leads translational research into neuroprotection, carotid atheroma imaging, and the pathophysiology of cerebrovascular disease. He uses non-invasive assessments of cerebral haemodynamics to improve outcome from cerebrovascular neurosurgical procedures; and leads the STASH (STatins in Aneurysmal Subarachnoid Haemorrhage) trial.

Liz Warburton is studying mechanisms of deterioration and recovery of speech and motor function after stroke. Perfusion and metabolic consequences of acute stroke and the nature of tissue injury are being characterised; and carotid artery plaque imaged and correlated with microembolism and watershed ischaemia.

Plasticity for motor, visual and language functions is being studied in relation to clinical outcome using MRI and PET.

Dementia and neurodegeneration Peter St George Hyslop studies the genetics of Alzheimer’s and related disorders and is using structural biology to develop novel molecules for inhibiting the formation of intracellular protein aggregates that destroy nerve cells.

Peter Nestor works in the Herchel Smith Building for Brain and Mind Sciences on the early features of Alzheimer’s disease, frontotemporal dementia, and related disorders – combining cognitive neuropsychology with structural, metabolic and amyloid brain imaging, and quantitative neuropathology.

Recent work has focused on defining the nature of early neuronal vulnerability in incipient Alzheimer’s disease and the development of structural image analyses as surrogates for the regional molecular pathology.

Maria-Grazia Spillantini has provided molecular classifications for disorders characterised by intracellular aggregates of microtubule-associated proteins (tau and alpha-synuclein) and studies mechanisms of intracellular protein aggregation in human brain tissue and transgenic mice. The focus is on accumulation of alpha-synuclein in the substantia nigra and studies on the microtubule associated protein tau which binds the motor protein dynactin and is abnormally distributed in the brain of patients with MAPT mutations and relevant transgenic mice.

James Rowe provides a bridge between the Department of Clinical Neurosciences, the Herchel Smith Building for Brain and Mind Sciences and the MRC Cognition and Brain Sciences Unit. He investigates behavioural disorders associated with neurodegenerative disease and focal brain injury using structural and functional magnetic resonance imaging and magnetoencephalography. The focus is on restoring function in the brain networks that enable the cognitive control of actions in neurodegeneration, especially Parkinson’s disease, frontotemporal dementia and progressive supranuclear palsy.

Roger Barker conducts clinical work that improves prediction across the spectrum of clinical deficits in Parkinson's and Huntington’s disease using biomarkers for the natural history and heterogeneity of these disorders in epidemiological studies of cohorts studied for clinical and imaging phenotypes, and genomics. He studies abnormalities in adult neural stem cell turnover and differentiation in transgenic models of neurodegeneration, work that has implications for the translation of novel therapies including the use of cell-based therapies for Parkinson’s and Huntington’s disease.

Plasticity and brain repair James Fawcett works on recovery of function through adaptation, plasticity and repair of the injured brain and spinal cord. In axon regeneration the focus is on removing inhibitory chondroitin sulphate proteoglycans produced in scar tissue after damage, and using integrin engineering to enhance the ability of axons to regenerate. In plasticity, the enzyme chondroitinase is being used to degrade the inhibitory proteoglycan structures that normally prevent plasticity in the adult nervous system. The work is seeing applications not only in experimental studies of injury but also in neurodegeneration including Alzheimer’s disease.

Keith Martin studies the mechanisms of visual loss in glaucoma, and is currently investigating the integration of stem cells into the

retina in experimental glaucoma, and studying the role of axonal transport dysfunction associated with glaucomatous retinal ganglion cell death.

Stefano Pluchino works in regenerative neuroscience and studies the physiology of neural stem cells and their application in cell therapies for repair of the central nervous system. He also aims at modeling their role in modulating the fate of inflammatory and degenerative lesions – work that relates to the clinical problems of multiple sclerosis, stroke, spinal cord injury, Parkinson’s disease and glioma.

Multiple sclerosis Stephen Sawcer and Alastair Compston use whole genome screening to study the genetics of multiple sclerosis and Parkinson’s disease as part of national and international consortia.

They have recently identified 57 susceptibility genes, including 34 not previously considered, that demonstrate a genetic basis for the primary role of cell-mediated immune mechanisms in the pathogenesis of multiple sclerosis.

Alasdair Coles and Alastair Compston lead international trials of lemtrada (formerly Campath-1H and alemtuzumab) in early active relapsing-remitting multiple sclerosis; results from the two Phase III trials will be available in 2011 with proposed application for a drug licence in 2012. Their laboratory work focuses on the mechanisms of autoimmunity after alemtuzumab; strategies to avoid the development of anti-idiotypic auto-antibodies; and interactions between inflammatory and neurobiological processes that underlie the sustained recovery of function seen in most patients. A Phase II study in secondary progressive multiple sclerosis using autologous bone marrow-derived mesenchymal stem cells showing preliminary evidence for structural, functional and physiological improvement consistent with neuroprotection has recently been completed.

Other topics Colin Watts has a programme of research in neuro-oncology that combines Phase I/II clinical trials with biomarker-based stratification of participants; development and evaluation of a Brain Tumour Symptom Algorithm for Primary Care (BraTSA: collaboration with the Cambridge University Primary Care Research Unit); and improved treatment for cerebral metastatic disease. Stephen Price is developing a research programme using MR and PET imaging to understand heterogeneity in brain tumours; the main focus is in studying the invasiveness of glioblastomas and understanding the biology of glioma invasion in individual patients (the MALTING Study).

Akhilesh Reddy works in the Institute of Metabolic Science on circadian rhythms in eukaryotic cells and microorganisms.

Rhys Roberts works in the Cambridge Institute for Medical Research on membrane traffic and recirculating endosomes in the context of genetic disorders of peripheral nerve.

CLINICAL NEUROSCIENCE

5

Clinical Neuroscience Selected references Alawneh JA, Jones PS, Mikkelsen IK, Cho TH, Siemonsen S, Mouridsen K, Ribe L, Morris RS, Hjort N, Antoun N, Gillard JH, Fiehler J, Nighoghossian N, Warburton EA, Ostergaard L, Baron JC. Infarction of 'non-core-non-penumbral' tissue after stroke: multivariate modellivvb of clinical impact. Brain 2011; 134: 1765–76 Cimadamore F, Fishwick K, Giusto E, Gnedeva K, Cattarossi G, Miller A, Pluchino S, Brill LM, Bronner-Fraser M, Terskikh AV. Human ESC-Derived Neural Crest Model Reveals a Key Role for SOX2 in Sensory Neurogenesis.

Cell Stem Cell. 2011; 8: 538–51 Coles AJ, Fox E, Vladic A, Gazda SK, Brinar V, Selmaj KW, Bass AD, Wynn DR, Margolin DH, Lake SL, Moran S, Palmer J, Smith MS, Compston DA. Alemtuzumab versus interferon beta-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes. Lancet Neurol 2011; 10: 338–48 Ewbank MP, Lawson RP, Henson RN, Rowe JB, Passamonti L, Calder AJ. Changes in 'top-down' connectivity underlie repetition suppression in the ventral visual pathway. J Neurosci 2011; 31: 5635–42 Garcia-Reitböck P, Anichtchik O, Bellucci A, Iovino M, Ballini C, Fineberg E, Ghetti B, Della Corte L, Spano P, Tofaris GK, Goedert M, Spillantini MG. SNARE protein redistribution and synaptic failure in a transgenic mouse model of Parkinson's disease. Brain 2010; 133: 2032–44 Helmy A, Carpenter KL, Menon DK, Pickard JD, Hutchinson PJ. The cytokine response to human traumatic brain injury: temporal profiles and evidence for cerebral parenchymal production.

J Cereb Blood Flow Metab 2011; 31: 658–70 Hoglinger GU, Melhem NN, Dickson D, et al. Common variants affect risk for the tauopathy Progressive Supranuclear Palsy.

Nature Genetics 2011; 43: 699–705 The International Multiple Sclerosis Genetics Consortium and the Wellcome Trust Case Control Consortium 2. A genetic basis for the role of cell-mediated immunity in the pathogenesis of multiple sclerosis Nature 2011; 476: 214–219 International Parkinsons Disease Genomics Consortium.

Imputation of sequence variants for identification of genetic risks for Parkinson’s disease: a meta-analysis of genome wide association studies. Lancet 2011; 277: 641–649.

Johnson TV, Bull ND, Hunt DP, Marina N, Tomarev SI, Martin KR. Neuroprotective effects of intravitreal mesenchymal stem cell transplantation in experimental glaucoma Invest Ophthalmol Vis Sci 2010 51: 2051–9 Kim SH, Fraser PE, Westaway D, St George-Hyslop PH, Ehrlich ME, Gandy S. Group II metabotropic glutamate receptor stimulation triggers production and release of Alzheimer's amyloid (beta)42 from isolated intact nerve terminals. J Neurosci 2010; 30: 3870–5.

Marina N, Bull ND, Martin KR. A semiautomated targeted sampling method to assess optic nerve axonal loss in a rat model of glaucoma Nature Protocols 2010; 5: 1642–1651 Mion M, Patterson K, Acosta-Cabronero J, Pengas G, Izquierdo-Garcia D, Hong YT, Fryer TD, Williams GB, Hodges JR, Nestor PJ. What the left and right anterior fusiform gyri tell us about semantic memory.

Brain 2010; 133: 3256–68

6

CLINICAL NEUROSCIENCE

Monti MM, Vanhaudenhuyse A, Coleman MR, Boly M, Pickard JD, Tshibanda L, Owen AM, Laureys S. Willful modulation of brain activity in disorders of consciousness N Engl J Med 2010; 362: 579–89 Naj AC, Jun G, Beecham GW, Wang LS et al. Common variants in MS4A4/MS4A6E, CD2AP, CD33, and EPHA1 are associated with late-onset Alzheimer's disease. Nature Genetics 2011; 43: 436–441.

Patani R, Hollins AJ, Wishart TM, Puddifoot CA, Álvarez S, de Lera AR, Wyllie DJA, Compston DAS, Pedersen RA, Gillingwater TH, Hardingham GE, Allen ND, Chandran S. Retinoid-independent generation of motor neurons from human embryonic stem cells reveals a medial columnar ground state. Nature Communications, 2011 Mar, 2: 214.

Somerfield J, Hill-Cawthorne GA, Lin A, Zandi MS, McCarthy C, Jones JL, Willcox M, Shaw D, Thompson SA, Compston AS, Hale G, Waldmann H, Coles AJ. A novel strategy to reduce the immunogenicity of biological therapies. J Immunol 2010; 185: 763–8.

Stacpoole SR, Bilican B, Webber DJ, Luzhynskaya A, He XL, Compston A, Karadottir R, Franklin RJ and Chandran S. Efficient derivation of neural precursor cells, spinal motor neurons and midbrain dopaminergic neurons from human ES cells at 3% oxygen.

Nature Protocols (in press) Timofeev I, Carpenter KL, Nortje J, Al-Rawi PG, O'Connell MT, Czosnyka M, Smielewski P, Pickard JD, Menon DK, Kirkpatrick PJ, Gupta AK, Hutchinson PJ. Cerebral extracellular chemistry and outcome following traumatic brain injury: a microdialysis study of 223 patients Brain 2011; 134: 484–94.

Haematology Head of Department and Professor of Haemato-oncology

Haematopoiesis and leukaemia Haematopoiesis represent the best characterised adult stem cell system and continues to provide important paradigms for understanding other stem cells as well as cancer biology.

The focus of this group continues to be the transcriptional regulation of blood stem cells, and the mechanisms whereby such stem cells are subverted to form leukaemias.

Current research programmes include:

Professor AR Green Telephone 01223 336820 Fax 01223 7622670 Email arg1000@cam.ac.uk

Staff list Professors B Göttgens, Professor of Molecular Haematology JA Huntington, Professor of Molecular Haemostasis WH Ouwehand, Professor of Experimental Haematology RJ Read, Professor of Protein Crystallography AJ Warren, Professor of Haematology Director of Research H Lee

3 The pathogenesis of bone marrow failure syndromes and leukaemia (Professor Warren).

4 The biology of leukaemia stem cells (Dr Huntly).

Structural medicine and thrombosis P Smethurst C Wisniewski A Zhou

NHS Consultants/Associate Lecturers/Affiliated Lecturers TP Baglin C Crawley M Scott M Besser Dr G Follows A Sureda M Bradbury D Foukaneli M Van't Veer PJ Campbell M Gattens G Vassiliou JIO Craig D Perry Voluntary Research Agreement J-P Allain Clinical Lecturers N Bolli

2 Transcriptional networks regulating blood stem cells (Professor Göttgens).

5 The developmental origin of haematopoietic stem cells (Dr Ottersbach).

University Senior Lecturers C Ghevaert BJP Huntly Senior Research Associates J Deane Corzo J Li M Dineva W Li B Goyenenchea K Ottersbach

1 Myeloproliferative neoplasms, JAK/STAT signalling and stem cell subversion (Professor Green).

CC Wong

Structural biology gives an unparalleled insight into the molecular details of biological mechanisms, an insight that has the potential to lead to rationally-designed therapies.

This is illustrated by some recent studies. Professor Huntington is studying the details of the delicate control of coagulation by members of the serpin family of serine protease inhibitors; over the past year, new insights have been gained into the control by serpins of factor IXa and thrombin. Dr Zhou is studying members of the serpin family adapted for non-inhibitory roles, with a series of structures of angiotensinogen and its complex with renin revealing a new mechanism by which oxidative stress modulates the control of blood pressure. The determination of such structures is heavily driven by computer methods, an area to which Professor Read’s group is making significant contributions.

Research synopsis

Transfusion medicine

Research in the department falls into three main areas with major relevance for human disease. The Haematopoiesis and Leukaemia Group are based in the Cambridge Institute for Medical Research (Professor Green, Professor Göttgens, Dr Huntly, Dr Ottersbach) and the MRC Laboratory of Molecular Biology (Professor Warren). The Structural Medicine and Thrombosis Group (Professor Read, Professor Huntington) are based in the CIMR, and the Transfusion Medicine Group (Professor Allain, Dr Lee, Professor Ouwehand, Dr Ghevaert) are based in the NHS Blood and Transplant Building.

Recent research initiatives include the establishment of a $6.0m Specialist Centre for Research, funded by the US Leukemia and Lymphoma Society, the only one in Europe. The department has also played a leading role in establishing a £5.8m European Bloodomics programme.

The focus of transfusion medicine research is in blood borne viruses, diagnostics and transfusion in resource poor areas, biology and genomics of megakaryocytes and platelets.

Particular highlights include: 1 Global studies of the molecular epidemiology of Hepatitis B virus in collaboration with major blood centres around the world. The genomes of HBsAg- and HBsAg+ strains have been sequenced and analysed. (Professor J-P Allain).

2 A Genome-Wide Association Study meta-analysis which identified 15 genetic loci that regulate the volume and count of platelets and the discovery of novel genetic loci that regulate platelet function (Professor H Ouwehand).

3 A rapid low cost diagnostic test for Chlamydia trachomatis has been developed and is now widely available. A test for HBsAg is being submitted for licensing (Dr H Lee).

HAEMATOLOGY

7

Haematology Selected references Yamasaki M, Li W, Johnson DJD and Huntington JA. Crystal structure of a stable dimer reveals the molecular basis of serpin polymerization.

Nature, 455(7217): 1255–1258, 2008.

Zhao R, Follows GA, Beer PA, Scott LM, Huntly BJP, Green AR*, Alexander DR* (*joint senior authors). Inhibition of the Bcl-xL deamidation pathway in myeloproliferative disorders. N. Engl J Med, 359(26): 2778–2789, 2008.

Ghevaert C, Wilcox DA, Fang J, Armour KL, Clark MR, Ouwehand WH, Williamson LM. Developing recombinant HPA-1a-specific antibodies with abrogated Fcgamma receptor binding for the treatment of fetomaternal alloimmune thrombocytopenia. J Clin Invest, 118(8): 2929–2938, 2008.

Dawson MA†, Bannister AJ†, Gottgens B, Foster SD, Bartke T, Green AR*, Kouzarides T* (†joint first authors; *joint senior authors).

JAK2 phosphorylates histone H3Y41 and excludes HP1a from chromatin.

Nature, 461(7265): 819–822, 2009.

Kantorovitz MR, Kazemian M, Kinston S, Miranda-Saavedra D, Zhu Q, Robinson GE, Göttgens B*, Halfon MS*, Sinha S* (*joint senior authors). Motif-blind, genome-wide discovery of cis-regulatory modules in Drosophila and mouse. Developmental Cell 17: 568–579, 2009.

Wilson NK, Miranda-Saavedra D, Kinston SJ, Bonadies N, Foster SD, Calero-Nieto F, Dawson MA, Donaldson IJ, Dumon S, Frampton J, Janky R, Sun X-H, Teichmann SA, Bannister AJ, Göttgens B. The transcriptional program controlled by the stem cell leukaemia gene Scl/Tal1 during early embryonic hematopoietic development.

Blood, 113(22): 5456–5465, 2009.

Mascarenhas M., Parker A, Dzierzak E & Ottersbach K. Identification of novel regulators of hematopoietic stem cell development through refinement of stem cell localization and expression profiling.

Blood, 114: 4645–4653, 2009.

Read RJ and Kleywegt GJ. Case-controlled structure validation.

Acta Cryst. D65: 140–147, 2009.

Soranzo N, Spector TD, Mangino M, … … Greinacher A, Deloukas P*, Ouwehand WH* and Gieger C* (shared first authors; *equal senior authors). A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium.

Nat Genet, 41, 1182–1190, 2009.

O'Connor MN, Salles I, Cvejic A, Watkins NA, Walker A, Garner SF, Jones CI, Macaulay IC, Steward M, Zwaginga JJ, Bray SL, Dudbridge F, de Bono B, Goodall AH, Deckmyn H, Stemple DL and Ouwehand WH. Functional genomics in zebrafish permits rapid characterization of novel platelet membrane proteins. Blood, 113: 4754–4762, 2009.

Beer PA, Delhommeau F, LeCouédic JP, Dawson MA, Chen E, Bareford D, Kušec R, McMullin MF, Harrison CN, Vannucchi AM, Vainchenker W, Green AR. Two routes to leukemic transformation after a JAK2 mutation-positive myeloproliferative neoplasm.

Blood, 115(14): 2891–2900, 2010.

Chen E, Beer PA, Godfrey AL, Ortmann CA, Li J, Costa-Pereira AP, Ingle CE, Dermitzakis ET, Campbell PJ, and Green AR. Distinct clinical phenotypes associated with JAK2V617F reflect differential STAT1 signaling. Cancer Cell, 18(5): 524–535, 2010.

Johnson DJD, Langdown J and Huntington JA. Molecular basis of factor IXa recognition by heparin-activated antithrombin revealed by a 1.7Å structure of the ternary complex. Proc. Natl. Acad. Sci. USA, 107(2): 645–650, 2010.

8

haematology

Lechtenberg B, Johnson DJD, Freund S and Huntington JA. NMR resonance assignments of thrombin reveal the conformational and dynamic effects of ligation. Proc. Natl. Acad. Sci. USA, 107 (32): 14087–14092, 2010.

Wilson NK, Foster SD, Wang, Knezevic K, Schütte J, Kaimakis P, Chilarska P, Kinston S, Ouwehand WH, Dzierzak E, Pimanda JE, de Bruijn MF. Göttgens B. Combinatorial Transcriptional Control in Blood Stem/Progenitor Cells: Genome-wide Analysis of 10 major Transcriptional Regulators. Cell Stem Cell 7(4): 532–544, 2010.

Vezzoli A, Bonadies N, Allen MD, Freund SM, Santiveri CM, Kvinlaug BT, Huntly BJ, Göttgens B, Bycroft M. Molecular basis of histone H3K36me3 recognition by the PWWP domain of Brpf1. Nat Struct Mol Biol, 17(5): 617–619, 2010.

Li J, Spensberger D, Ahn JS, Anand S, Beer PA, Ghevaert C, Forrai A, Chen E, Ferreira R, Campbell P, Watson S. Bradly A, Liu P, Erber W, Huntly BJP, Ottersbach K and Green AR. JAK2 V617F impairs hematopoietic stem cell function in a conditional knock-in mouse model of JAK2 V617F-positive essential thrombocythaemia.

Blood, 116: 1528–1538, 2010.

Zhou A, Carrell RW, Murphy MP, Wei Z, Yan Y, Stanley PL, Stein PE, Broughton Pipkin F and Read RJ. A redox switch in angiotensinogen modulates angiotensin release. Nature, 468: 108–111, 2010.

Goodall AH, Burns P, Salles I, Macaulay IC, Jones CI, Ardissino D, de Bono B, Bray SL, Deckmyn H, Dudbridge F, Fitzgerald DJ, Garner SF, Gusnanto A, Koch K, Langford C, O'Connor MN, Rice CM, Stemple D, Stephens J, Trip MD, Zwaginga JJ, Samani NJ, Watkins NA, Maguire PB and Ouwehand WH. Transcription profiling in human platelets reveals LRRFIP1 as a novel protein regulating platelet function.

Blood, 116: 4646–4656,

Histopathology Head of Division and Professor of Histopathology and Morbid Anatomy Professor VP Collins Tel 01223 336072 Fax 01223 586670 Email vpc20@cam.ac.uk

Selected references Madden L, Rosebeck S, Jin X, Appert A, Hamoudi R, Gu S, Noels H, Baens M, Du MQ, Lucas PC, McAllister-Lucas LM. Oncogenic noncanonical NF-OB activation via API2-MALT1 fusion protein mediated cleavage and stabilization of NIK. Science (in press)

Staff list

Vogazianou AP, Chan R, Backlund LM, Pearson DM, Liu L, Langford CF, Gregory SG, Collins VP, and Ichimura K. (2010) Distinct patterns of 1p and 19q alterations identify subtypes of human gliomas that have different prognoses. Neuro Oncol. E-pub 2010

Professors M-Q Du, Professor of Oncological Pathology N Coleman, Professor of Molecular Pathology Reader M Arends, Reader in Histopathology

Liu H, Brais R, Lavergne-Slove A, Zeng Q, Payne K, Ye H, Liu Z, Carreras J, Huang Y, Bacon CM, Save V, Venkatraman L, Isaacson PG, Woodward J, Du MQ. Continual Monitoring of Intraepithelial Lymphocyte Immunophenotype and Clonality Is More Important Than Snapshot Analysis in the Surveillance of Refractory Coeliac Disease. Gut 2010; 59(4):452–60.

Senior University Lecturer J Xuereb Clinician Scientist Fellow A Ibrahim Research Fellow S Turner NHS Consultants/Associate Lecturers V Bardsley FA Jessop R Brais M Jimenez-Linan A Cluroe A Marker S Davies R Moseley AF Dean DG O'Donovan J Grant M O'Donovan M Griffiths A Patterson

The Cambridge Brain Bank, a division of the Tissue Bank is also located in the Division and underpins a number of major projects on aging and degenerative neurological disease.

V Phillips S Pursglove E Rytina A Warren A Whitehead P Wright

Research synopsis The Division combines research, teaching and diagnostic histopathology. The research focuses on analysing the molecular and cell biology of disease and applying advances in this area to clinical histopathology, and where relevant, therapy.

The Division takes part in the teaching and examining of Pathological Sciences in Pt. Ib and Pt. II tripos as well as being responsible for the clinical pathology course at Addenbrooke's and the Final MB Part I Examination. The Division has a number of major projects, studying in particular neoplastic disease.

These include the study of human tumours of the central nervous system, tumours of the lower intestinal tract, lymphomas, breast and ovarian tumours. Many of the projects are in collaboration with other research groups within Addenbrooke's or the University of Cambridge. The Division has an established tissue bank, and through this can provide researchers with wellcharacterised human tissue, subject to project approval

by NHS R&D and NRES.

Poulogiannis G, McIntyre R, Dimitriadi M, Apps JR, Wilson C, Ichimura K, Luo F, Cantley LC, Wyllie AH, Adams DJ, Arends MJ. PARK2 deletions occur frequently in sporadic colorectal cancer and accelerate adenoma development in Apc mutant mice. Proc Natl Acad Sci U. S. A. (2010); 107(34):15145–15150. PMID: 20696900 Hodges JR, Mitchell J, Dawson K, Spillantini MG, Xuereb JH, McMonagle P, Nestor PJ, Patterson K. Semantic dementia: demography, familial factors and survival in a consecutive series of 100 cases. Brain. 2010 Jan;133 (Pt 1):300–6.

Gray E, Pett MR, Ward D, Winder DM, Stanley MA, Roberts I, Scarpini CG, Coleman N. (2010) HPV16 episome-associated cervical neoplastic progression in vitro demonstrates fundamental similarities to integrant-associated carcinogenesis. Cancer Research 70:4081–91 Palmer RD, Murray MJ, Saini HK, van Dongen S, Abreu-Goodger C, Muralidhar B, Pett MR, Thornton CM, Nicholson JC, Enright AJ, Coleman N. (2010) Malignant germ cell tumors display common micro RNA profiles resulting in global changes in expression of mRNA targets. Cancer Research 70:2911–23 Ibrahim AE, Arends MJ, Silva AL, Wyllie AH, Greger L, Ito Y, Vowler SL, Huang TH, Tavaré S, Murrell A, Brenton JD. Gut. 2010 Nov 10. Sequential DNA methylation changes are associated with DNMT3B overexpression in colorectal neoplastic progression. [Epub ahead of print] Merkel O, Hamacher F, Laimer D, Scheideler M, Trajanoski Z, Egger G, Turner SD, Greil R and Kenner L (2010) Diacritic and functionally active microRNAs in both ALK+ and ALK- ALCL. PNAS 107(37):16228–33.

Jones DT, Kocialkowski S, Liu L, Pearson DM, Ichimura K, Collin VP. (2009) Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549: BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma. Oncogene 28, 2119–2123 Cui Y, Kerby A, McDuff FKE, Turner SD. (2009) NPM-ALK modulates the p53 tumour suppressor pathway in a JNK and PI 3-Kinase dependent manner: MDM-2 is a potential therapeutic target for the treatment of ALK-expressing malignancies. Blood.113(21):5217–5227.

HISTOPATHOLOGY

9

Medical Genetics Head of Department and Professor of Medical Genetics Professor J Todd (Acting until March 2012) Telephone 01223 762101 Fax 01223 746777 Email john.todd@cimr.cam.ac.uk

Staff list Professors DG Clayton, Professor of Biostatistics FE Karet, Professor of Nephrology DC Rubinsztein, Professor of Molecular Neurogenetics LS Wicker, Professor of Immunogenetics GC Woods, Professor of Human Genetics Readers FL Raymond, Reader in Neurogenetics RN Sandford, Reader in Renal Genetics University Lecturer M Tischkowitz Senior Research Staff K Baker J Carmichael E Reid, Wellcome Trust Senior Clinical Fellow in Clinical Science A-L Tavares NHS Consultants/Associate Lecturers: H Firth Affiliated Lecturers: J Whittaker

Research synopsis The Department’s research examines mechanisms responsible for important single gene and polygenic disorders. The major areas under study include: type 1 diabetes; neurological diseases such as Huntington’s disease; hereditary spastic paraplegias; renal disorders such as renal tubular acidosis and polycystic kidney disease; X-linked intellectual disability disorders; prenatal brain growth and genetics disorders of pain sensing.

The Department currently has particular strengths in three major areas: 1 Large scale gene mapping, expression, functional, statistical and bioinformatic technologies, being applied to developing strategies for the primary prevention of type 1 diabetes in the Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory; and to X-linked intellectual disabilities.

10

medical genetics

2 Experimental analysis of the molecular cell biology of genetic disease, with novel disease mechanisms identified over the last two years for a number of different kidney, renal and neurological disorders.

3 Development of therapeutic strategies for brain and muscle diseases associated with intracellular aggregate formation and autophagy.

The expectation is that this research into genetic cause and mechanism will lead, in the long term, to treatments for genetic diseases.

Medical Genetics is also a major participant and contributor to the National Institute for Health Research Cambridge Biomedical Research Centre, which focuses on translational experimental medicine studies in neurodegeneration, clinical genetics, renal disease and type 1 diabetes. The Department is actively involved in two cross-cutting activities, the Eastern Sequence and Informatics Hub and the Cambridge BioResource, providing key resources for the Biomedical Research Centre.

Whilst most research is carried out in the Cambridge Institute for Medical Research the Academic Laboratory of Medical Genetics is located alongside the Clinical Department on level 6 of the Addenbrooke’s Treatment Centre. The medically qualified members of the Department also have clinical duties, and there is close interaction and joint projects between the University and NHS departments.

Selected references Connell JW, Lindon C, Luzio JP, Reid E. (2009) Spastin couples microtubule severing to membrane traffic in completion of cytokinesis and secretion. Traffic, 10:42–56 Ravikumar B, Moreau K, Jahreiss L, Puri C and Rubinsztein DC. (2010) Plasma membrane contributes to the formation of pre-autophagosomal structures. Nature Cell Biology 12:747–757 Nicholas AK, Khurshid M, Désir J, Carvalho OP, Cox JJ, Thornton G, Kausar R, Ansar M, Ahmad W, Verloes A, Passemard S, Misson JP, Lindsay S, Gergely F, Dobyns WB, Roberts E, Abramowicz M, Woods CG. (2010) WDR62 is associated with the spindle pole and is mutated in human microcephaly. Nat Genet. 42:1010–4 Dendrou CA, Plagnol V, Fung E, Yang JHM, Downes K, Cooper JD, Nutland S, Coleman G, Himsworth M, Hardy M, Burren O, Healy B, Walker NM, Koch K, Ouwehand WH, Bradley JR, Wareham NJ, Todd JA, and Wicker LS. (2009) Cell-specific protein phenotypes for the autoimmune locus IL2RA using a genotype-selectable human bioresource. Nature Genetics 41:1011–1015 Heinig M, Petretto E, Wallace C, Bottolo L, Rotival M, Lu H, Li Y, Sarwar R, Langley SR, Bauerfeind A, Hummel O, Lee Y-A, Paskas S, Rintisch C, Saar K, Cooper J, Buchan R, Gray EE, Cyster JG, Cardiogenics Consortium, Erdmann J, Hengstenberg C, Maouche S, Ouwehand WH, Rice CM, et al. (2010) A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk. Nature 467: 460–464

Medicine Head of Department and Professor of Medicine Professor KGC Smith Tel 01223 336848 Fax 01223 336846 Email hodmed@medschl.cam.ac.uk

Staff list Professors MR Bennett, Professor of Cardiovascular Sciences MJ Brown, Professor of Clinical Pharmacology Sir L Borysiewicz, Professor of Medicine and Vice-Chancellor VKK Chatterjee, Professor of Endocrinology ER Chilvers, Professor of Respiratory Medicine JE Compston, Professor of Bone Medicine TM Cox, Professor of Medicine (1962) AW Cuthbert, Emeritus Shield Professor of Pharmacology DT Fearon, Emeritus Sheila Joan Smith Professor of Immunology JSH Gaston, Professor of Rheumatology G Griffiths, Professor of Immunology and Cell Biology A Kaser, Professor of Gastroenterology PJ Lehner, Professor of Immunology and Medicine AML Lever, Professor of Infectious Diseases DA Lomas, Professor of Respiratory Biology Z Mallat, BHF Professor of Cardiovascular Medicine DK Menon, Professor of Anaesthesia N Morrell, BHF Professor of Cardiopulmonary Medicine S Peacock, Professor of Clinical Microbiology JH Sinclair, Professor of Molecular Virology JGP Sissons, Regius Professor of Physic Readers AP Davenport, Reader in Cardiovascular Pharmacology IB Wilkinson, Reader in Clinical Pharmacology and Therapeutics University Senior Lecturers KM O'Shaughnessy JC Sterling University Lecturers MR Clatworthy JP Coles AM Condliffe DP Dutka

ML Evans M Gurnell FC Hall T Krieg

H Parfrey JHF Rudd KES Poole DW Wheeler

Senior Research Staff C Berzuini R Busch MB Cachon-Gonzalez AN Chaudhry AS Cowburn U Desselberger RA Floto R Foo J Garland JC Goodall

I Gorenne DJ Grainger H Jorgensen T Littlewood NJ Loveridge PA Lyons C McEniery J Maguire S Marciniak J Murphy

M Murthy S Nejentsev KJ Patel A Rana J Reeve S Sinha P Upton L Wei MR Wills Y Yasmin

NHS Consultants/Associate Lecturers A Adler J Gass GJ Alexander AES Gimson S Aliyu WJH Griffiths MED Allison CW Glazebrook P Barry S Gunda M Belham KE Gunning R Biram A Gupta JR Bradley T Ha NP Burrows DRW Jayne T Burton JR Jenner E Cameron A Johnston GA Campbell PM Jones AJ Carmichael Y-M Lee CA Carne MS Lillicrap S Chan R Mahadeva A Chaudhry BF Matta J Cheriyan SJ Middleton M Chua F Mir M Cranston S Mulroy AJ Crisp S Nasser PB Deegan C Nicholl E Gkrania-Klotsas PG Norris PW Ewan E O’Brien JD Firth S Ojha N Flanagan AJK Ostor PD Flynn M O’Sullivan DR Forsyth M Parkes J Fuld J Preller Clinical Lecturers R Beale B Challis H Durrington A Ercole B Gooptu J Herre

S Hoole A Marshall A McGeoch EF McKinney M Mahmoudi C Summers

P Pugh NR Pritchard R Rusk C Sander PM Schofield LM Shapiro N Shenker L Sibal JM Shneerson B Silverman S Sinha P Sivasothy H Smith IE Smith C Sonnex C Speed S Stinchcombe PM Todd E Torok NR Torpey M Vindlacheruvu E Warburton P Weissberg L Willcocks J Wilson RJ Winter J Woodward

L Tomlinson M Toshner M Weekes DW Wheeler

Research synopsis The Department of Medicine is one of the largest in the Clinical School comprising 11 Divisions and over 400 members of staff, including 22 professors, and holding current grants in excess of £38m. The Department has an active research programme whose broad aim is to understand disease processes at the molecular level and apply this knowledge to clinical management. The thematic focus of the Department of Medicine is in the broad area of immunity, inflammation and infection, and a number of new posts are currently being appointed to increase the Department’s strength in these areas. The Department is also home to the NIHR Biomedical Research Centre Cell Phenotyping Hub, which provides state of the art flow cytometry facilities for unscreened human samples. medicine

11

Medicine Anaesthesia The research in the Division has three main strands: The first involves physiological imaging in traumatic brain injury (TBI), at all stages, from ictus to late outcome. Positron emission tomography (PET) and magnetic resonance imaging (MRI) in the acute phase currently addresses novel mechanisms of energy failure, including diffusion hypoxia and mitochondrial dysfunction. Allied studies have addressed the mechanisms of action of novel interventions such as hyperoxia. Our late studies with 11C-flumazenil PET have shown selective neuronal loss and late diffusion weighted imaging has been used to map the extent and severity of white matter loss. Both of these subtle sequelae of TBI are missed by conventional MR imaging, and may account for the mismatch between structural lesions and cognitive outcomes.

A second strand focuses on the neuro-anatomical basis of coma and consciousness, both in pathological states, and in the controlled situation of sedation induced by anaesthetic agents.

Finally, the Division has a growing program in pain research that involves functional imaging, pain phenotyping and pain genetics.

Selected references Newcombe VF, Outtrim JG, Chatfield DA, Manktelow A, Hutchinson PJ, Coles JP, Williams GB, Sahakian BJ, Menon DK. Parcellating the neuroanatomical basis of impaired decision-making in traumatic brain injury. Brain 2011; 134:759–68.

Stamatakis EA, Adapa RM, Absalom AR, Menon DK. Changes in resting neural connectivity during propofol sedation. PLoS One 2010; 5:e14224.

Janowitz T, Menon DK. Exploring new routes for neuroprotective drug development in traumatic brain injury. Sci Transl Med 2010; 2:27rv1.

Wheeler DW, Thompson AJ, Corletto F, Reckless J, Loke JC, Lapaque N, Grant AJ, Mastroeni P, Grainger DJ, Padgett CL, O'Brien JA, Miller NG, Trowsdale J, Lummis SC, Menon DK, Beech JS. Anaesthetic impairment of immune function is mediated via GABA(A) receptors. PLoS One 2011; 6:e17152.

Cardiovascular Medicine The Division has assembled a collaborative group of cardiovascular investigators who collectively provide expertise in basic, translational and clinical cardiovascular research and who employ genomics, epigenetics, high throughput sequencing, biomarker identification and validation, through to novel imaging, diagnostics and experimental medicine studies to improve patient outcomes. Atherosclerosis leading to myocardial infarction (MI) and stroke is the commonest cause of death in the UK. Inflammation, cell death (apoptosis), and cell senescence in atherosclerotic plaques are major contributors to plaque rupture and MI, and cardiomyocyte apoptosis underlies heart failure.

Our research examines the causes and regulation of these processes in atherosclerosis, with a particular focus on DNA damage, and more recently the role of epigenetics in human heart failure. Professor Ziad Mallat has recently joined the Division, with a major interest in immune regulation of atherosclerosis and aneurysm formation, and Dr Helle Jørgensen as a University Lecturer interested in epigenetic regulation of stem cell differentiation, to support the MRC-funded Cambridge 12

Medicine

Cardiovascular Consortium, a network of researchers focused on cardiovascular stem cells and development.

The Division’s major clinical research interests include the diagnosis of heart failure, assessment of viability in dysfunctional myocardium, and the utility of transient ischaemia or novel therapeutics to protect the heart from further insults.

We have developed metabolic cardioprotection during PCI (both primary emergency and elective intervention), examined the effect of new agents to treat diabetes on cardiac performance in type 2 diabetes, and determined the optimum use of cardiac resynchronisation therapy based on the underlying pathophysiology. As part of our unstable atherosclerosis and aneurysm programme, we have developed novel methods and ligands for imaging of unstable plaques, particularly using PET, CT and VH-IVUS, to utilise imaging for risk stratification and to monitor drug therapy. We are determining (a) whether inflammation, hypoxia and neovascularisation detected by PET/CT and MRI at baseline predict future aortic aneurysm expansion over a 3-year period: (b) the mechanism of increased cardiovascular death in patients with rheumatoid arthritis, using PET/CT to detect changes in arterial inflammation after antiTNFalpha therapy: (c) whether a novel anti-atherosclerosis drug could reduce vascular inflammation. This was the world’s first multi-centre PET/CT vascular imaging study, conducted in collaboration with GSK. Selected references Rudd JH, Myers KS, Bansilal S, Machac J, Woodward M, Fuster V, Farkouh ME, Fayad ZA. Relationships among regional arterial inflammation, calcification, risk factors, and biomarkers: a prospective fluorodeoxyglucose positron-emission tomography/computed tomography imaging study. Circ Cardiovasc Imaging 2009; 2:107–115.

Mercer J, Cheng KK, Figg N, Gorenne I, Mahmoudi M, Griffin J, Vidal-Puig A, Logan A, Murphy MP, Bennett MR. DNA damage links mitochondrial dysfunction to atherosclerosis and the metabolic syndrome. Circ Res 2010; 107:1021–1031.

Hoole SP, Heck PM, White PA, Read PA, Khan SN, West NEJ, O’Sullivan M, Dutka DP. Stunning and cumulative left ventricular dysfunction occurs late after coronary balloon occlusion in humans: Insights from simultaneous coronary and left ventricular hemodynamic assessment.

J Am Coll Cardiol Intv 2010 3:412–8.

Ait-Oufella H.; Herbin O.; Bouaziz JD, Binder CJ, Uyttenhove C, Laurans L, Taleb S, Van Vre E, Esposito B, Vilar J, Sirvent J, Van Snick J, Tedgui A, Tedder TF, Mallat Z. B-Cell depletion reduces the development of atherosclerosis in mice. J Exp Med 2010; 207:1579–1587.

Jørgensen HF, Terry A, Beretta C, Pereira CF, Leleu M, Chen ZF, Kelly C, Merkenschlager M, Fisher AG. REST selectively represses a subset of RE1containing neuronal genes in mouse embryonic stem cells. Development 2009; 136:715–721.

Clinical Pharmacology This Division hosts the £5.5m Wellcome Trust/GSK interdisciplinary training programme in Translational Medicine and Therapeutics, which includes a full- or part-time MPhil in Translational Medicine, and annual competitions for posts as MBPhD,

ACF, PhD Fellowship, and Clinical Lectureships. The programme enables trainees in almost any branch of Medicine to acquire skills that bridge the bench-to-bedside divide. The division’s internal research interests are: 1 Professor Morris Brown investigates genetic and non-genetic approaches to relating pathogenesis of hypertension to finding the best treatment or cure in individual patients.

Clinically, he leads the BHF’s multicentre programme of trials, PATHWAY, which will lead to the routine use of plasma renin analysis, and has validated use of 11C-metomidate for PET-CT scanning of Conn’s adenomas of the adrenal. Laboratory discoveries include the finding of somatic mutation of a K+ channel in 50% of 50 Conn’s adenomas, and the role of an orphan G-protein coupled receptor (GPCR), GPR61, in regulating aldosterone secretion.

2 Dr Anthony Davenport studies apelin and other novel G-protein couple receptors that are emerging as drug targets.

He has identified apelin peptides as transmitters in the human cardiovascular system with potent inotropic and vascular actions. In collaboration with the Department of Chemistry selective agonists and the first apelin antagonists have been discovered.

3 Dr Ian Wilkinson studies large artery function and endothelial function. He holds a BHF Senior Clinical Fellowship, which centres on dissecting out the mechanisms responsible for arteriosclerosis or arterial stiffening, which underlies systolic hypertension. Thus far inflammation and calcification have been identified as important drivers of stiffness. He was recently awarded a £3m TSB grant to identify cardiovascular biomarkers in patients with COPD and test the effectiveness of two novel GSK compounds.

4 Dr Thomas Krieg investigates pathways of myocardial protection following ischaemic injury.

Selected references Brown MJ, McInnes GM, Papst CC, Zhang J, MacDonald TM. Aliskiren and the calcium channel blocker amlodipine combination as an initial treatment strategy for hypertension control (ACCELERATE): a randomised, parallel-group trial. Lancet 2011; 377:312–320.

Burton TJ, Cope G, Wang J, Sim JC, Azizan EA, O'Shaughnessy KM, et al. Expression of the epithelial Na(+) channel and other components of an aldosterone response pathway in human adrenocortical cells.

Eur J Pharmacol 2009; 613:176–81.

Cheriyan J, Webb AJ, Sarov-Blat L, Elkhawad M, Wallace SM, Maki-Petaja KM, Collier DJ, Morgan J, Fang Z, Willette RN, Lepore JJ, Cockcroft JR, Sprecher DL, Wilkinson IB. Inhibition of p38 MAPK improves nitric oxide-mediated vasodilatation and reduces inflammation in hypercholesterolemia. Circulation 2011; 123:515–523.

Maguire JJ, Kleinz MJ, Pitkin SL, Davenport AP. [Pyr1]apelin-13 identified as the predominant apelin isoform in human heart: vasoactive mechanisms and inotropic action in disease. Hypertension 2009; 54:598–604.

Pitkin SL, Maguire JJ, Kuc RE, Davenport AP. Modulation of the apelin/APJ system in heart failure and atherosclerosis in man.

Br J Pharmacol 2010; 160:1785–95.

McEniery CM, Yasmin, Maki-Petaja KM, McDonnell BJ, Munnery M, Hickson SS, Franklin SS, Cockcroft JR, Wilkinson IB and Investigators A-CCT. The impact of cardiovascular risk factors on aortic stiffness and wave reflections depends on age: the Anglo-Cardiff Collaborative Trial (ACCT III). Hypertension 2010; 56:591–597.

Diabetes & Endocrinology This Division has three main areas of research: 1 Dr Evans is interested in (1) how the brain detects changes in blood glucose and how this glucose-sensing interacts with peripheral metabolism, (2) how defences against hypoglycaemia may become abnormal in diabetes, (3) the effects of hypoglycaemia on the brain, and (4) improving the ability of patients with type 1 diabetes to manage their own diabetes through structured education and judicious use of new and innovative technology for monitoring and managing diabetes, including in collaboration with Dr Roman Hovorka (Department of Paediatrics) and colleagues, the closed loop insulin pump systems (the 'artificial pancreas').

2 Dr Gurnell’s research interests include (i) the role of nuclear hormone receptors in human disease, and genetic disorders of the hypothalamic-pituitary-thyroid axis, (ii) functional imaging in endocrine neoplasia, (iii) novel approaches to sparing hypothalamic-pituitary function in patients with sellar/parasellar tumours, and (iv) the endocrine and neural basis of financial decision making.

3 Professor Chatterjee’s research interests relate to disorders of nuclear hormone synthesis and action. He is studying several human cohorts: congenital hypothyroidism (CH) that is familial, syndromic or on a consanguineous background; Resistance to Thyroid Hormone (RTH); and lipodystrophic insulin resistance associated with PPARγ gene defects.

Candidate gene and whole exome approaches are used to identify novel genetic aetiologies mediating thyroid dysgenesis or hormonogenesis and defective hormone action.

These approaches are supported by human phenotypic studies, studies in multisystem selenoprotein deficiency disorders and translation through our national diagnostic laboratory service to develop biomarkers of hormone action and therapies applicable to commoner thyroid disorders.

Selected references Hovorka RH, Kumareswaran K, Harris J, Allen JM, Elleri DE, Xing D, Collman C, Nodale M, Murphy H, Dunger DB, Amiel SA, Heller SR, Wilinska ME, Evans ML. Overnight closed loop insulin delivery in adults with type 1 diabetes; a randomised crossover study.

Brit Med J 2011; in press.

Osundiji MA, Hurst P, Moore SP, Markkula SP, Yueh C-Y, Swamy A, Hoashi S, Shaw JS, Riches CH, Heisler LK, Evans ML. Recurrent hypoglycemia increases hypothalamic glucose phosphorylation activity in rats. Metabolism 2011; 60:550–556.

Annamalai AK, Gayton EL, Webb A, Halsall DJ, Rice C, Ibram F, Virgo G, Chaudhry AN, Simpson HL, Berman L, Gurnell M. Increased prevalence of gallbladder polyps in acromegaly. J Clin Endocrinol Metab 2011; in press.

medicine

13

Medicine Coates JM, Gurnell M, Rustichini A. Second to fourth digit ratio predicts success among high-frequency financial traders. Proc Natl Acad Sci USA 2009; 106:623–628.

Castanet M, Mallya U, Agostini M, Schoenmakers E, Mitchell CS, Demuth S, Raymond L, Schwabe JWR, Gurnell M, Chatterjee VKK. Maternal isodisomy for chromosome 9 causing homozygosity for a novel FOXE1 mutation in syndromic congenital hypothyroidism.

J Clin Endocrinol Metab 2010; 95:4031–6.

Schoenmakers E, Agostini M, Mitchell C, Schoenmakers N, Papp L, Rajanayagam O, Padidela R, Ceron-Gutierrez L, Doffinger R, Prevosto C, Luan J, Montano S, Lu J, Castanet M, Clemons N, Groeneveld M, Castets P, Karbaschi M, Aitken S, Dixon A, Williams J, Campi I, Blount M, Burton H, Muntoni F, O’Donovan D, Dean A, Warren A, Brierley C, Baguley D, Guicheney P, Fitzgerald R, Coles A, Gaston H, Todd P, Holmgren A, Khanna K, Cooke M, Semple R, Halsall D, Wareham N, Schwabe J, Grasso L, Beck-Peccoz P, Ogunko A, Dattani M, Gurnell M, Chatterjee K. Mutations in the selenocysteine insertion sequence-binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans. J Clin Invest 2010; 120:4220–4235.

Gastoenterology and Hepatology Research in this Division focuses on immunity and inflammation and its consequences, and the genetic underpinning of gastrointestinal diseases.

1 Professor Kaser’s group has a research focus on inflammation at mucosal body surfaces and inflammatory bowel disease (IBD). Specifically his group investigates the role of the intestinal epithelium at the interface between the intestinal microbiota and the sterile host environment, with a particular interest in the epithelium’s endoplasmic reticulum stress response.

2 Dr Parkes investigates the genetic basis of IBD through genome-wide association studies (GWAS) performed in collaboration with the Wellcome Trust Sanger Centre.

He has also been leading the International IBD Genetics consortium’s GWAS meta-analysis, which revealed almost 100 distinct genetic loci associated with IBD. 3 Dr Fitzgerald (based in the MRC Cancer Cell Unit) investigates the molecular pathogenesis and progression of Barrett’s disease and oesophageal cancer to provide tools for early diagnosis, accurate prognostication and therapy which can be applied to clinical practice.

4 Further research topics covered in the Division are on chronic liver disease (Dr Alexander), liver transplantation (Dr Gimson), small bowel transplantation (Dr Middleton and Dr Woodward), non-alcoholic fatty liver disease (Dr Allison) and inherited liver disease (Dr Griffiths). In translational research, multi-centre trials of novel biological therapies for IBD, which target specific immune functions, are pursued within the Division.

14

Medicine

Selected references Kaser A, Zeissig S, Blumberg RS. Inflammatory Bowel Disease.

Annu Rev Immunol 2010; 28: 573–621.

Kaser A, Lee AH, Franke A, Glickman JN, Zeissig S, Tilg H, Nieuwenhuis EE, Higgins DE, Schreiber S, Glimcher LH, Blumberg RS. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 2008; 134:743–56.

Franke A, McGovern DP, Barrett JC, Wang K, Radford-Smith GL, Ahmad T, Lees CW, Balschun T, Lee J, Roberts R, Anderson CA, Bis JC, Bumpstead S, Ellinghaus D, Festen EM, Georges M, Green T, Haritunians T, Jostins L, Latiano A, Mathew CG, Montgomery GW, Prescott NJ, Raychaudhuri S, Rotter JI, Schumm P, Sharma Y, Simms LA, Taylor KD, Whiteman D, Wijmenga C, Baldassano RN, Barclay M, Bayless TM, Brand S, Büning C, Cohen A, Colombel JF, Cottone M, Stronati L, Denson T, De Vos M, D'Inca R, Dubinsky M, Edwards C, Florin T, Franchimont D, Gearry R, Glas J, Van Gossum A, Guthery SL, Halfvarson J, Verspaget HW, Hugot JP, Karban A, Laukens D, Lawrance I, Lemann M, Levine A, Libioulle C, Louis E, Mowat C, Newman W, Panés J, Phillips A, Proctor DD, Regueiro M, Russell R, Rutgeerts P, Sanderson J, Sans M, Seibold F, Steinhart AH, Stokkers PC, Torkvist L, Kullak-Ublick G, Wilson D, Walters T, Targan SR, Brant SR, Rioux JD, D'Amato M, Weersma RK, Kugathasan S, Griffiths AM, Mansfield JC, Vermeire S, Duerr RH, Silverberg MS, Satsangi J, Schreiber S, Cho JH, Annese V, Hakonarson H, Daly MJ, Parkes M. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet. 2010; 42:1118–25.

Anderson CA, Massey DC, Barrett JC, Prescott NJ, Tremelling M, Fisher SA, Gwilliam R, Jacob J, Nimmo ER, Drummond H, Lees CW, Onnie CM, Hanson C, Blaszczyk K, Ravindrarajah R, Hunt S, Varma D, Hammond N, Lewis G, Attlesey H, Watkins N, Ouwehand W, Strachan D, McArdle W, Lewis CM; Wellcome Trust Case Control Consortium, Lobo A, Sanderson J, Jewell DP, Deloukas P, Mansfield JC, Mathew CG, Satsangi J, Parkes M. Investigation of Crohn's disease risk loci in ulcerative colitis further defines their molecular relationship. Gastroenterology 2009; 136:523–9.

Saadi A, Shannon NB, Lao-Sirieix P, O'Donovan M, Walker E, Clemons NJ, Hardwick JS, Zhang C, Das M, Save V, Novelli M, Balkwill F, Fitzgerald RC. Stromal genes discriminate preinvasive from invasive disease, predict outcome, and highlight inflammatory pathways in digestive cancers. Proc Natl Acad Sci USA 2010; 107:2177–82.

Bird-Lieberman EL, Neves AA, Lao-Sirieix P, O'Donovan M, Novelli M, Lovat L, Mahal DLK, Eng WS, Brindle KM, Fitzgerald RC. Molecular imaging via novel application of fluorescent lectins permits rapid endoscopic identification of dysplasia in Barrett's esophagus.

Nat Med 2011 in press.

Immunology Work in the Division of Immunology covers three mains areas: 1 The Fearon lab has shifted its interest from the memory CD8+ T cell to tumor immunology. The immune system should be able to control the growth of many tumors because cancer cells with genomic instability generate neoantigens, which serve to make them appear as 'foreign' to the immune system. However, this obviously does not occur. One problem appears to be that the tumor microenvironment is immune suppressive, so that the systemic T cell responses to tumor antigens that can be demonstrated are prevented from

attacking the cancer cells. Our lab has recently shown that one type of tumor stromal cell (ie. a cell in tumors other than the cancer cell), the FAP+ cell, mediates local immune suppression, and its elimination allows immune control of tumor growth.

We have also found that the FAP+ cell resides in normal tissues where it has unexpected functions, such as the prevention of cachexia, the muscle wasting syndrome often associated with cancer. We wonder whether the biological role of the FAP+ cell is related to tissue maintenance and repair, accounting for its regrettable presence in tumors? We are trying to discover how to interrupt the immune suppressive function of the FAP+ stromal cell.

2 The Griffths lab studies cytotoxic T lymphocytes (CTL) and Natural Killer (NK) cells, which use polarised secretion to destroy virally infected and tumorigenic target cells.

Specialised secretory lysosomes, containing the pore forming protein perforin and a series of serine proteases, termed granzymes deliver the lethal hit in a specialised domain of the immunological synapse. The research is focused on understanding the molecular basis of polarised secretion from CTLs and has used a series of rare genetic diseases including Hermansky-Pudlak and Haemophagocytic syndromes to identify the roles of proteins involved in secretion from CTL and NK cells.

3 The Lehner lab studies mechanisms used by viruses to evade immune recognition, with a particular interest in the role of ubiquitin in receptor regulation. While initially focusing on viral evasion of MHC class I molecules, they recently developed a quantitative proteomics technique termed ‘plasma membrane profiling’ which takes an unbiased approach to analyze how viruses alter expression of any cell surface receptor to enable their replication. This powerful approach has identified novel immune as well as metabolic receptors, such as transporters downregulated by latent human cytomegalovirus infection (collaboration with Prof John Sinclair), and is now being used to interrogate cell surface receptor regulation by several different intracellular pathogens.

Selected references Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, Gopinathan A, Tuveson DA, Fearon DT. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science 2010; 330:827–830.

Bannard O, Kraman M, Fearon DT. Secondary replicative function of CD8+ T cells that had developed an effector phenotype. Science 2009; 323:505–509.

Jenkins MR, Tsun A, Stinchcombe JC, Griffiths GM. The strength of T cell receptor signal controls the polarization of cytotoxic machinery to the immunological synapse. Immunity 2009; 31:621–631.

Stagg HR, Thomas M, Van den Boomen D, Wiertz EH, Drabkin HA, Gemmill RM, Lehner PJ. The TRC8 E3 Ligase ubiquitinates MHC class I molecules before dislocation from the ER. J Cell Biol 2009; 186:685–92.

Randow F, Lehner PJ. Viral avoidance and exploitation of the ubiquitin system. Nature Cell Biol 2009; 11:527–34.

Infectious Diseases Infectious diseases research encompasses basic studies on viruses, bacteria and host immune responses.

1 Professor John Sinclair’s group studies how human cytomegalovirus (HCMV) persists in healthy individuals studying cellular factors which control virus latency and reactivation. In collaboration with Professor Sinclair, Professor Sissons and Dr Wills’ group study the control of HCMV infection by the immune system. They have shown dendritic cells to be a major site of HCMV carriage. More recently the group has defined novel viral immune evasion molecules.

2 Professor Lever’s group studies retroviruses, including structural and molecular studies of RNA and RNA:protein interactions involved in genome encapsidation and the development of gene vectors. He and Dr Desselberger are investigating rotavirus RNA structures involved in encapsidating the viral genome and which host cell proteins or organelles may interact with the virus and be involved in viral assembly.

3 Dr Nejentsev’s group investigates the genetic basis of susceptibility to mycobacterial infection and tuberculosis (TB).

Discovery of such genes will help to understand mechanisms of resistance to infection and may point to new targets for therapeutic intervention. The group is part of the TB-EUROGEN consortium. In collaboration with the Wellcome Trust Sanger Institute they are performing a genome-wide association study aiming to discover genomic regions associated with TB. 4 Professor Sharon Peacock’s group aims to introduce highthroughput whole genome sequencing technologies into diagnostic and public health microbiology collaborating with the Wellcome Trust Sanger Institute and the Health Protection Agency. Proof of principle will be achieved by developing a system to track transmission of, methicillin resistant Staphylococcus aureus (MRSA) in real-time. This technology will subsequently be extended to other important human pathogens.

Selected references Nejentsev S, Walker N, Riches D, Egholm M, Todd JA. Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 2009; 324:387–389.

Bennett, NJ, Ashiru O, Morgan FJ, Pang Y, Okecha G, Eagle RA, Trowsdale J, Sissons JG, Wills MR. Intracellular sequestration of the NKG2D ligand ULBP3 by human cytomegalovirus. J Immunol 2010; 185:1093–1102.

Reeves M, Woodhall D, Compton T, Sinclair J. Human cytomegalovirus IE72 protein interacts with the transcriptional repressor hDaxx to regulate LUNA gene expression during lytic infection. J Virol, 2010; 84:7185–7194.

Cheung W, Gill M, Esposito A, Kaminski CF, Courousse N, Chwetzoff S, Trugnan G, Keshavan N, Lever A, Desselberger U. Rotaviruses associate with cellular lipid droplet components to replicate in viroplasms, and compounds disrupting or blocking lipid droplets inhibit viroplasm formation and viral replication. J Virol 2010; 4:6782–6798.

medicine

15

Medicine Kenyon JC, Tanner SJ, Legiewicz M, Phillip PS, Rizvi TA, Le Grice SFJ, Lever AM. SHAPE analysis of the FIV leader RNA reveals a structural switch potentially controlling viral packaging and genome dimerization. Nucleic Acids Res. 2011; in press.

Griffiths WJH, Mayr R, McFarlane I, Hermann H, Halsall DJ, Zoller H, Cox TM. Clinical presentation and molecular pathophysiology of autosomal dominant hemochromatosis caused by a novel ferroportin mutation. Hepatology 2010; 51:788–95.

Harris SR, Feil EJ, Holden MT, Quail MA, Nickerson EK, Chantratita N, Gardete S, Tavares A, Day N, Lindsay JA, Edgeworth JD, de Lencastre H, Parkhill J, Peacotyttck SJ, Bentley SD. Evolution of MRSA during hospital transmission and intercontinental spread. Science 2010; 327:469–474.

Cox TM. Eliglustat tartrate, an orally active glucocerebroside synthase inhibitor for the potential treatment of Gaucher disease and other lysosomal storage diseases. Curr Opin Invest Drugs 2010; 11:1169–81.

Metabolic Medicine Professor Cox’s group studies the molecular pathogenesis of lysosomal diseases with particular emphasis on the development of effective treatments – he gave the inaugural lecture at the first Gordon Conference on Lysosomal Diseases in 2011.

With Dr Deegan, Clinical Director of the National Centre for the Treatment and Diagnosis of Lysosomal diseases, several clinical trials of substrate reducing drugs, pharmacological chaperones and innovative enzyme therapies are underway, particularly for Gaucher’s disease and Fabry disease. Dr Stein, in collaboration with Professor Read, has been analysing the 3-dimensional structure of mutant and therapeutic-lysosomal proteins to understand the consequences of the disease-related changes and their susceptibility to therapeutic molecular manipulation – pharmacological chaperones. Dr Marchesan conducts studies of the molecular targeting and delivery of lysosomal proteins to their sites of action. With Dr Pavlova, there are studies to investigate the predictive role of cytokine biomarkers for the development of the much-feared bone complications in Gaucher disease; in a crosssectional collaborative in more than 100 patients with Gaucher disease, we have found that those with a history of sporadic infarction events have higher serum cytokine biomarkers, which respond to enzymatic therapy. With other investigators in a European Framework Package 7 (FP7) award 'EUCLYD' Dr Pavlova is investigating novel inhibitors of sphingolipid in a tissue–specific and inducible experimental model of Gaucher disease. These studies should reveal much about the molecular pathogenesis of the osseous complications and further define the relationship between defined cytokines and disease manifestations. Dr Cachón-González and Dr Sargeant study the molecular pathogenesis of the emblematic neurodegenerative storage disorder, Tay-Sachs disease. Overall the group has been central to the formation of an International Tay-Sachs disease Gene Therapy Consortium to translate successful gene therapy conducted in murine models into a viable therapeutic agent for use in man. These studies can be applied clinically and offer the opportunity for a unique understanding of the molecular pathogenesis of disorders affecting the metabolism of complex glycosphingolipids.

Selected references Jeyakumar M, Williams I, Smith DA, Cox TM, Platt FM. Critical role of iron in the pathogenesis of the murine gangliosidoses. Neurobiol Dis 2009; 34:406–16.

16

medicine

Roos HI, Roos JCP, Cox TM. Orphan drug pricing may merit a competition law investigation. Brit Med J 2010; 341:1084–6.

Pavlova EV, Deegan, PB, Tindall J, McFarlane I, Mehta A, Hughes D, Wraith JE, Cox TM. Potential Biomarkers of Osteonecrosis in Gaucher Disease. Blood Cells Mol and Dis 2011; 46:27–33.

Deegan PB, Pavlova EV, Tindall J, Stein P, Bearcroft P, Mehta A, Hughes D, Wraith JE, Cox TM. Osseous Manifestations of Adult Gaucher Disease in the Era of Enzyme Replacement Therapy. Medicine (Baltimore) 2011; 90:52–60.

Renal Medicine 1 Professor Smith’s group is based in the CIMR, and works on immune regulation and autoimmune and inflammatory disease. This has focused on how naturally occurring variants in immune molecules such as FcγRIIB alter immune function and predispose to autoimmunity. The accumulation of these risk variants in the population has been shown to be, at least in part, due to their ability to protect against infections such as malaria. With Dr Lyons and in collaboration with Addenbrooke’s Vasculitis & SLE Clinic and the Division of Gastroenterology, Smith runs a translational programme studying the pathogenesis of human disease at the same time as looking for biomarkers. A CD8T cell transcriptional signature has been found which predicts prognosis in autoimmune disease. The European Vasculitis Genetics Consortium is also led from the laboratory.

2 Dr Clatworthy studies immunological mechanisms of renal injury, in particular in areas of acute tubular necrosis and transplantation, using cutting-edge imaging technology.

3 Dr Jayne runs the Vasculitis & Lupus clinic, and coordinates multi-centre trials in vasculitis and SLE. These are focused on the evaluation of new agents and the optimization of conventional therapies. His group recently coordinated a study contributing to the DFA approval of Rituximab for use in the therapy of vasculitis. He coordinates the European Vasculitis Study Group which forms clinical trials and long term evaluation of vasculitis patients.

4 Dr Bradley’s group has been studying the pathways involved in signaling by TNF-alpha family members in endothelial cells and their relevance to renal inflammation and transplant rejection. He coordinates the Yale-Cambridge Cardiovascular Research Initiative, and is the Director of the NIHR Cambridge Biomedical Research Centre.

Selected references Al-Lamki RS, Sadler TJ, Wang J, Reid MJ, Warren AY, Movassagh M, Lu W, Mills IG, Neal DE, Burge J, Vandenebeele P, Pober JS, Bradley JR. Tumor necrosis factor receptor expression and signaling in renal cell carcinoma. Am J Pathol 2010; 177:943–54.

Jones RB, Tervaert JW, Hauser T, Luqmani R, Morgan MD, Peh CA, Savage CO, Segelmark M, Tesar V, van Paassen P, Walsh D, Walsh M, Westman K, Jayne DRW. European Vasculitis Study Group. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis.

N Engl J Med 2010; 363:211–20.

Linterman MA, Pierson W, Lee SK, Kallies A, Kawamoto S, Rayner TF, Srivastava M, Divekar DP, Beaton L, Hogan JJ, Fagarasan S, Liston A, Smith KGC*, Vinuesa CG* (equal senior authors). Foxp3(+) follicular regulatory T cells control the germinal center response. Nature Med. 2011;17:975–82.

McKinney EF, Lyons PA, Carr EJ, Hollis JL, Jayne DRW, Willcocks LC, Koukoulaki M, Brazma A, Jovanovic V, Kemeny DM, Pollard AJ, Macary PA, Chaudhry AN, Smith KGC. A CD8+ T cell transcription signature predicts prognosis in autoimmune disease. Nature Med 2010; 16:586–591.

Willcocks LC, Carr EJ, Niederer HA, Rayner TF, Williams TN, Yang W, Scott JA, Urban BC, Peshu N, Vyse TJ, Lau YL, Lyons PA, Smith KG. A defunctioning polymorphism in FCGR2B is associated with protection against malaria but susceptibility to systemic lupus erythematosus.

Proc Natl Acad Sci USA 2010; 107:7881–5.

Clatworthy MR, Watson CJ, Plotnek G, Bardsley V, Chaudhry AN, Bradley JA, Smith KGC. B-cell-depleting induction therapy and acute cellular rejection. N Engl J Med 2009; 360:2683–5.

Respiratory Medicine The Respiratory Medicine Division has six main areas of research: granulocyte cell biology and trafficking, the structure and function of alpha1-antitrypsin and related serpins, the genetic and molecular basis of pulmonary hypertension, the immunopathology of allergic diseases, the control of antigen processing by dendritic cells and the molecular mechanisms of ER stress.

1 Professor Chilvers’, Dr Condliffe’s and Dr Parfrey’s interests relate to granulocyte cell biology, in particular, mechanisms underlying neutrophil priming, activation and apoptosis.

The group also has an interest in TNFα and hypoxia signaling and neutrophil and eosinophil trafficking in vivo.

2 Professor Lomas’ group works on the pathobiology of alpha-1-antitrypsin deficiency and the serpinopathies.

They are also interested in the identification of genetic factors and protein biomarkers that relate to components of the COPD phenotype.

3 Professor Morrell’s group is studying the molecular mechanisms leading to the development of idiopathic pulmonary arterial hypertension (PAH). In particular, his laboratory has elucidated the ways in which mutations in the bone morphogenetic protein type II receptor (BMPR-II), which underlie the majority of cases of familial PAH, disrupt intracellular signaling and proliferation of pulmonary vascular cells.

4 Dr Ewan’s, Dr Clark’s and Dr Nasser’s research interests are in the clinical and immunological aspects of food allergy, anaphylaxis and asthma and novel approaches to desensitization with particular reference to nut allergy.

5 Dr Floto’s group works on the molecular basis of antigen processing by dendritic cells and macrophages and how this influences the host responses to bacterial and mycobacterial infection.

6 Dr Marciniak’s group studies the role of endoplasmic reticulum stress in human disease, including malignant mesothelioma, using both tissue culture and Drosophila model systems.

Selected references McGovern NN, Cowburn AS, Walmsley SR, Thompson R, Summers C, Willcocks LC, Whyte MKB, Condliffe AM, Chilvers ER. Hypoxia inhibits respiratory burst activity and killing of staphylococcus aureus in human neutrophils. J Immunol 2011; in press.

Walmsley SR, Chilvers ER, Vaughan K, Marriott H, Thompson R, McGrath E, Shaw G, Pugh CW, Ratcliffe PJ, Taylor C, Sabroe I, Dockrell D, Johnson RS, Maxwell PH, Carmeliet P, Whyte M. Prolyl hydroxylase PHD3 is essential for hypoxic regulation of neutrophilic inflammation.

J Clin Invest 2011; in press.

Miranda E, Pérez J, Ekeowa UI, Hadzic D, Kalsheker N, Gooptu B, Portmann B, Belorgey D, Hill M, Chambers S, Teckman J, Alexander GJ, Marciniak SJ, Lomas DA. A novel monoclonal antibody to characterize pathogenic polymers in liver disease associated with a1-antitrypsin deficiency. Hepatology 2010; 52:1078–88.

Ekeowa UI, Freeke J, Miranda E, Gooptu B, Bush MF, Pérez J, Teckman J, Robinson CV, Lomas DA. Defining the mechanism of polymerization in the serpinopathies. Proc Natl Acad Sci 2010; 107:17146–51.

Yang J, Li X, Al-Lamki RS, Southwood M, Zhao J, Lever AM, Grimminger F, Schermuly RT, Morrell NW. Smad-dependent and smad-independent induction of id1 by prostacyclin analogues inhibits proliferation of pulmonary artery smooth muscle cells in vitro and in vivo. Circ Res 2010; 107:252–62.

Durrington HJ, Upton PD, Hoer S, Boname J, Dunmore BJ, Yang J, Crilley TK, Butler LM, Blackbourn DJ, Nash GB, Lehner PJ, Morrell NW. Identification of a lysosomal pathway regulating degradation of the bone morphogenetic protein receptor type II. J Biol Chem 2010; 285:37641–9.

Clark AT, Islam S, King Y, Deighton J, Anagnostou K, Ewan PW. Successful oral tolerance induction in severe peanut allergy. Allergy 2009; 64:1218–20.

Renna M, Schaffner C, Winslow AR, Menzies FM, Peden AA, Floto RA, Rubinsztein DC. Autophagic substrate clearance requires activity of the syntaxin-5 SNARE complex. J Cell Sci 2011; 124:469–82.

Renna M, Schaffner C, Brown K, Shang S, Henao Tamayo M, Hegyi K, Grimsey N, Cusens D, Coulter S, Cooper J, Bowden A R, Newton S, Kampmannm B, Helm J, Jones A, Haworth H, Basaraba, RJ, DeGroote M, Ordway DJ, Rubinsztein DC, Floto RA. Azithromycin blocks autophagy and may predispose to mycobacterial infection. J Clin Invest 2011 in press.

Hopkins TG, Maher E, Reid E, Marciniak SJ. Recurrent pneumothorax.

Lancet 2011; in press.

Malzer E, Daly ML, Moloney A, Sendall TJ, Thomas SL, Ryder E, Ryoo HD, Crowther DC, Lomas DA, Marciniak SJ. Impaired tissue growth is mediated by checkpoint kinase 1 (CHK1) in the integrated stress response. J Cell Sci 2010; 123:2892–900.

Medicine

17

Medicine Rheumatology Research in this division covers the basic mechanisms underlying inflammatory arthritis and metabolic bone disease, together with development and validation of novel biomarkers which can be used to predict clinical outcomes.

1 Prof Gaston and Dr Goodall study the immunologic basis of inflammatory arthritis, and the factors which influence differentiation of pro-inflammatory T lymphocytes, particularly the role of dendritic cells in integrating signals from pathogens and cellular stress to alter cytokine production.

2 Dr Hall is investigating biomarkers in connective tissue diseases, including lymphocyte phenotype, novel measures of hand ischaemia, and assessment of the micro-circulation using haemoglobin video microscopy.

3 Dr Busch’s group studies the biochemical mechanisms that link genetic variants of antigen-presenting MHC molecules to autoimmune pathogenesis, focusing on the characterisation of allelic differences in MHC protein turnover, their mechanistic basis and immunological consequences.

4 Prof Compston’s laboratory combines clinical and laboratory studies in osteoporosis. Recent work includes bone histomorphometric study of age-related changes, the relationship between regional skeletal blood flow and osteoblast activity in postmenopausal osteoporosis or renal bone disease, and study of the incidence, skeletal location and underlying risk factors for fragility fracture in the obese population.

5 Dr Poole's group applies novel imaging techniques to investigate human bone diseases. With the Engineering for Clinical Practice team of Graham Treece and Andrew Gee, they have studied focal thinning as a cause of femoral neck fracture and have discovered that bone building drugs have targeted effects at key sites within the osteoporotic femur.

18

medicine

Selected references Shen H, Goodall J, Gaston JSH. Frequency and phenotype of peripheral blood Th17 cells in ankylosing spondylitis and rheumatoid arthritis.

Arthritis Rheum 2009; 60:1647–56.

Goodall JC, Wu C, Zhang Y, Ellis L, O’Brien L, Saudek V, Gaston JSH. ER stress signals are integrated by dendritic cells to enhance IL-23 responses to Toll-like receptor. Proc Natl Acad Sci USA 2010; 107:17698–703.

De Riva A, Deery MJ, McDonald S, Lund T, Busch R. Measurement of protein synthesis using heavy water labeling and peptide MS: discrimination between MHC allotypes.

Anal Biochem 2010; 403:1–12.

Poole KES, Treece GM, Ridgway GR, Mayhew PM, Borggrefe J, Gee AH. Targeted Regeneration of Bone in the Osteoporotic Human Femur.

PLoS ONE 2011; 6:e1619.

Poole KES, Mayhew PM, Rose CM, Brown JK, Bearcroft PJ, Loveridge N, Reeve J. Changing structure of the femoral neck across the adult female lifespan. J Bone Miner Res 2010; 25:482–91.

Vedi S, Kaptoge S, Compston JE. Age-related changes in iliac crest cortical width and porosity: a histomorphometric study. J Anat 2011; 218:510–6.

Premaor MO, Pilbrow L, Tonkin C, Parker RA, Compston JE. Obesity and fractures in postmenopausal women. J Bone Miner Res 2010; 25:292–7.

Obstetrics and Gynaecology Head of Department and Professor of Obstetrics and Gynaecology Professor GCS Smith Tel 01223 336871 Fax 01223 215327 Email gcss2@cam.ac.uk

Staff list University Readers DS Charnock-Jones, Reader in Reproductive Biology F Colucci, Reader in Immunology University Lecturers M Constancia A Prentice NHS Consultants/Associate Lecturers P Baldwin R Kearney P Bose J Latimer J Brocklesby C Lees RAF Crawford J MacDougall GA Hackett R Mathur F Hoveyda H Missfelder-Lobos

C Patient C Prasannan-Nair M Shafi M Slack A Wilson

Research synopsis The Department of Obstetrics and Gynaecology has programmes of basic, translational and clinical research addressing the determinants of pregnancy complications. Dr Charnock-Jones, Dr Constancia and Dr Colucci use transgenic mouse models to identify key genes involved in murine placentation with the aim of better understanding normal reproductive function.

Dr Charnock-Jones studies the effect of oxygen on endothelial cells and trophoblast in the placenta.

Dr Constancia has a major interest in placental epigenetics, in particular genomic imprinting (ie. selective epigenetic silencing of genes according to parent of origin). Dr Colucci aims at understanding how immune cells impact on reproduction, cancer and transplantation.

Other basic work in the department addresses preparative changes in gene expression in the fetus for post-natal life.

The major focus of translational research in the Department is a prospective cohort study of women in their first pregnancy, which will have recruited 3500–4000 women by the end of 2011

and is funded by the NIHR Cambridge Comprehensive Biomedical Research Centre. The project has created a central resource of data, blood samples taken throughout pregnancy, and samples of placenta obtained at birth. The resource will be used to understand better the role of the placenta in determining adverse pregnancy outcome and, it is hoped, to identify novel biomarkers which may be clinically useful. A major focus of this research will involve the application of next generation sequencing to these samples, with a particular focus on the epigenetic regulation (methylation, histone modification and non-coding RNA) of placental gene expression. These studies involve close collaboration with the University’s Centre for Trophoblast Research (www.trophoblast.cam.ac.uk).

Finally, clinical research in the Department uses secondary analysis of diverse data sources to study determinants and predictors pregnancy outcome.

Selected references Smith GCS. First trimester determination of complications of late pregnancy. JAMA 2010;303:561–562.

Pasupathy D, Wood AM, Pell JP, Fleming M, Smith GCS. Rates of and factors associated with delivery-related perinatal death among term infants in Scotland. JAMA 2009;302:660–668.

Dilworth MR, Kusinski LC, Cowley E, Ward BS, Husain SM, Constancia M, Sibley CF, Glazier JD. Placental-specific Igf2 knock-out mice exhibit hypocalcemia and adaptive changes in placental calcium transport. Proc Natl Acad Sci USA 2010;107:3894–3899 Li P, Burke S, Wang J, Chen X, Ortiz M, Lee S, Lu D, Campos L, Goulding D, Ling Ng B, Dougan G, Huntly B, Gottgens B, Jenkins NA, Copeland NG, Colucci F, Liu P. Reprogramming of T Cells to Natural Killer–like Cells upon Bcl11b Deletion. Science 2010;329(5987):85–9.

Colucci F, Cilio CM. Taming killer cells may halt diabetes progression.

Nat Immunol 2010;11:111–2 Lakshmikanth T, Burke S, Ali TH, Kimpfler S, Ursini F, Ruggeri L, Capanni M, Umansky V, Paschen A, Sucker A, Pende D, Groh V, Biassoni R, Höglund P, Kato M, Shibuya K, Schadendorf D, Anichini A, Ferrone S, Velardi A, Kärre K, Shibuya A, Carbone E, Colucci F. NCRs and DNAM-1 mediate NK cell recognition and lysis of human and mouse melanoma cell lines in vitro and in vivo. J Clin Invest 2009;119:1251–63 Saudemont A, Garçon F, Yadi H, Roche-Molina M, Segonds-Pichon A, Martín-Fontecha A, Okkenhaug K, Colucci F. The p110gamma and p110delta isoforms of phosphoinositide 3-kinase differentially regulate natural killer cell migration in health and disease. PNAS 2009;106:5795–800 Mokhtar NM, Cheng CW, Cook E, Bielby H, Smith SK, Charnock-Jones DS. Progestin regulates chemokine (C-X-C motif ) ligand 14 transcript level in human endometrium. Mol Hum Reprod 2010; 16: 170–177.

Obstetrics and Gynaecology

19

Oncology Head of Department and Li Ka Shing Professor of Oncology and Director of Cancer Research UK Cambridge Research Institute Professor Sir Bruce Ponder, FRCP, FRCPath, FMedSci, FRS Tel 01223 404124 Fax 01223 404128 Email bruce.ponder@cancer.org.uk

Staff list Professors C Caldas, Professor of Clinical Oncology T Eisen, Professor of Medical Oncology J Griffiths, Professor of Molecular Imaging D Jodrell, Professor of Cancer Therapeutics G Murphy, Professor of Cancer Cell Biology D Neal, Professor of Surgical Oncology S TavarĂŠ, Professor of Bioinformatics AR Venkitaraman, Ursula Zoellner Professor of Cancer Research University Readers NG Burnet, Reader in Radiation Oncology HM Earl, Reader in Clinical Cancer Medicine P Pharoah, Reader in Cancer Epidemiology A Philpott, Reader in Cancer and Developmental Biology Senior Research staff J Brenton A M Dunning R Fitzgerald V Gnanapragasam

F Gergely E Gherardi H Hatcher R Jena

NHS Consultants/Associate Lecturers A Ahmed D Gilligan R Benson S Harden S Booth G Horan R Bulusu SJ Jefferies C Coles CR Jepthcott PG Corrie D Mazhar MM Daly KF McAdam K Fife AM Moody H Ford H Patterson Clinical Lecturer C Parkinson

K Jensen A Murrell

C Palmer S Russell LT Tan RJ Thomas D Traue K Waite MV Williams C Wilson C Woodward

F Skoulidis

Research synopsis Since 1998, we have developed a new Centre for cancer research in Cambridge. Our aim is to provide a nucleus of clinical and laboratory research that can interface with research across the University and science parks, and bring the combined expertise of Cambridge to practical application within the hospital. The Cancer Centre is a virtual organisation which provides a framework (and pump priming funds) to encourage cancer-related collaborations across disciplines, especially between biology, medicine and the physical sciences.

20

Oncology

It is based on the University Department of Oncology, whose activities are reported here, but contains other substantial components: (1) the Cancer Research UK Cambridge Research Institute, opened in 2007, which when complete will contain over 30 research groups; (2) the MRC Cancer Cell Unit opened in 2001, which shares the Hutchison/MRC Research Centre building with the Department of Oncology; (3) the Strangeways Research Laboratories for Genetic Epidemiology, which involve close collaboration between Oncology and Public Health in studies of cancer susceptibility; (4) a new Clinical Trials Centre within the hospital.

Our aim is to create an environment in which individual research ideas can flourish, supported by the necessary clinical infrastructure. Nevertheless, to build the Centre, we have had to specify some focus. Within Oncology, we have set up programmes around selected cancer sites, that will span from basic biology to clinical application and which will act as a framework with which science across the Clinical School and University can interact. Currently, these cancer sites are breast, prostate, pancreas and ovary, with additional programmes under development in lung cancer. Infrastructure and interactions are shared with established programmes in haematological cancers (within the Cambridge Institute for Medical Research) and in oesophageal cancer (within the MRC Cancer Cell Unit). Laboratory research themes include epithelial cell biology, gene regulation, DNA repair and checkpoint function, and there are strong programmes in molecular imaging, genomics, computational biology, drug discovery, and animal models of cancer. These biological and technological resources underpin a further major clinical programme in experimental cancer therapeutics.

In the past two years research in the Department of Oncology and the CRUK Cambridge Research Institute has contributed significantly in several fields. For example, in breast cancer we have identified proteins that are required for the oestrogen receptor to bind the DNA and induce transcription. One such protein is FoxA1; inhibitors of FoxA1 binding may provide a therapeutic approach to breast cancer which is resistant to endocrine deprivation. In a separate collaborative study of 1000 women from whom we have frozen breast tumour material and clinical data with a median 10 year follow-up, we have completed a genome-wide analysis of copy number variation and of gene expression, which has provided a far more detailed molecular subclassification of breast cancer than was previously available, with new insights into personalised approaches to treatment. In pancreatic cancer, we have shown using transgenic mouse models that resistance to the commonly used drug gemcitabine may result from poor penetration of the drug into the tumour because of the dense surrounding stroma. Experimental data suggest that combined use of a drug targeted at the stroma may improve treatment outcome: an idea that is now being tested in the clinic. In prostate cancer, our 100,000-strong cohort of men who have had PSA testing as part of a study of the management of the early disease, has provided low-PSA controls for successful genome-wide association studies, which have identified a majority of the prostate

cancer susceptibility loci so far identified. Further investigation of one of these loci has yielded a protein biomarker, MSMB, which may provide a better, and urine-based, marker for detection of significant early disease than PSA. Details of these and of many other research studies can be found at www.cambridgecancer.org.uk, www.cancer.cam.ac.uk, www.oncology.cam.ac.uk.

Selected references Ahmed AA, Etemadmoghadam D, Temple J, Lynch AG, Riad M, Sharma R, Stewart C, Fereday S, Caldas C, Defazio A, Bowtell D, Brenton JD. Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovary. J Pathol. 2010 May;221(1):49– 56. PMID: 20229506 Barnett GC, Wilkinson JS, Moody AM, Wilson CB, Twyman N, Wishart GC, Burnet NG, Coles CE. Randomized Controlled Trial of Forward-Planned Intensity-Modulated Radiotherapy for Early Breast Cancer: Interim Results at 2 Years. Int J Radiat Oncol Biol Phys. 2011 Feb [Epub ahead of print] PMID: 21345620 Holland DG, Burleigh A, Git A, Goldgraben MA, Perez-Mancera PA, Chin SF, Hurtado A, Bruna A, Ali HR, Greenwood W, Dunning MJ, Samarajiwa S, Menon S, Rueda OM, Lynch AG, McKinney S, Ellis IO, Eaves CJ, Carroll JS, Curtis C, Aparicio S, Caldas C. ZNF703 is a common Luminal B breast cancer oncogene that differentially regulates luminal and basal progenitors in human mammary epithelium. EMBO Mol Med. 2011 Mar;3(3):167–80. doi: 10.1002/emmm.201100122. Epub 2011 Feb 18.

PMID: 21337521 Fitzgerald RC, Hardwick R, Huntsman D, Carneiro F, Guilford P, Blair V, Chung DC, Norton J, Ragunath K, Van Krieken JH, Dwerryhouse S, Caldas C; Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. International Gastric Cancer Linkage Consortium. J Med Genet.

2010 Jul;47(7):436–44. Erratum in: J Med Genet. 2011 Mar;48(3):216. Van Krieken, Nicola [corrected to Van Grieken, Nicola C]. PMID: 20591882 Blows FM, Driver KE, Schmidt MK, Broeks A, van Leeuwen FE, Wesseling J, Cheang MC, Gelmon K, Nielsen TO, Blomqvist C, Heikkilä P, Heikkinen T, Nevanlinna H, Akslen LA, Bégin LR, Foulkes WD, Couch FJ, Wang X, Cafourek V, Olson JE, Baglietto L, Giles GG, Severi G, McLean CA, Southey MC, Rakha E, Green AR, Ellis IO, Sherman ME, Lissowska J, Anderson WF, Cox A, Cross SS, Reed MW, Provenzano E, Dawson SJ, Dunning AM, Humphreys M, Easton DF, García-Closas M, Caldas C, Pharoah PD, Huntsman D. Subtyping of breast cancer by immunohistochemistry to investigate a relationship between subtype and short and long term survival: a collaborative analysis of data for 10,159 cases from 12 studies. PLoS Med. 2010 May 25;7(5):e1000279.PMID: 20520800 Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, Friedlander M, Arun B, Loman N, Schmutzler RK, Wardley A, Mitchell G, Earl H, Wickens M, Carmichael J. Lancet. Oral poly (ADPribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial.

2010 Jul 24;376(9737):235–44. Epub 2010 Jul 6. PMID: 20609467 Bartlett JM, Munro AF, Dunn JA, McConkey C, Jordan S, Twelves CJ, Cameron DA, Thomas J, Campbell FM, Rea DW, Provenzano E, Caldas C, Pharoah P, Hiller L, Earl H, Poole CJ. Predictive markers of anthracycline benefit: a prospectively planned analysis of the UK National Epirubicin Adjuvant Trial (NEAT/BR9601). Lancet Oncol. 2010 Mar;11(3):266–74.

Epub 2010 Jan 13.PMID: 20079691

Kadri SR, Lao-Sirieix P, O'Donovan M, Debiram I, Das M, Blazeby JM, Emery J, Boussioutas A, Morris H, Walter FM, Pharoah P, Hardwick RH, Fitzgerald RC. Acceptability and accuracy of a non-endoscopic screening test for Barrett's oesophagus in primary care: cohort study. BMJ. 2010 Sep 10;341:c4372. doi: 10.1136/bmj.c4372. PMID: 20833740 Bapiro TE, Richards FM, Goldgraben MA, Olive KP, Madhu B, Frese KK, Cook N, Jacobetz MA, Smith DM, Tuveson DA, Griffiths JR, Jodrell DI. A novel method for quantification of gemcitabine and its metabolites 2',2'-difluorodeoxyuridine and gemcitabine triphosphate in tumour tissue by LC-MS/MS: comparison with (19)F NMR spectroscopy.

Cancer Chemother Pharmacol. 2011 Mar 23. [Epub ahead of print] Massie CE, Lynch A, Ramos-Montoya A, Boren J, Stark R, Fazli L, Warren AY, Scott H, Madhu B, Sharma N, Bon H, Zecchini V, Smith DM, DeNicola GM, Mathews N, Osborne M, Hadfield J, MacArthur S, Adryan B, Lyons SK, Brindle KM, Griffiths J, Gleave ME, Rennie PS, Neal DE* and Mills IG*. * These authors contributed equally to the research.

The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis. EMBO J. 2011. In press.

Gudmundsson J, Besenbacher S, Sulem P, Gudbjartsson DF, Olafsson I, et al. Genetic correction of PSA values using sequence variants associated with PSA levels. Sci Transl Med. 2010 Dec 15;2(62):62ra92. PMID: 21160077 Gudmundsson J, Besenbacher S, Sulem P, Gudbjartsson DF, Olafsson I, Arinbjarnarson S, Agnarsson BA, Benediktsdottir KR, Isaksson HJ, Kostic JP, Gudjonsson SA, Stacey SN, Gylfason A, Sigurdsson A, Holm H, Bjornsdottir US, Eyjolfsson GI, Navarrete S, Fuertes F, Garcia-Prats MD, Polo E, Checherita IA, Jinga M, Badea P, Aben KK, Schalken JA, van Oort IM, Sweep FC, Helfand BT, Davis M, Donovan JL, Hamdy FC, Kristjansson K, Gulcher JR, Masson G, Kong A, Catalona WJ, Mayordomo JI, Geirsson G, Einarsson GV, Barkardottir RB, Jonsson E, Jinga V, Mates D, Kiemeney LA, Neal DE, Thorsteinsdottir U, Rafnar T, Stefansson K. Goode EL, Chenevix-Trench G, Song H, Ramus SJ, Notaridou M, et al.

A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24. Nat. Genet. 2010;42(10):874-879.

Goode EL, Chenevix-Trench G, Song H, Ramus SJ, Notaridou M, Lawrenson K, Widschwendter M, Vierkant RA, Larson MC, Kjaer SK, Birrer MJ, Berchuck A, Schildkraut J, Tomlinson I, Kiemeney LA, Cook LS, Gronwald J, Garcia-Closas M, Gore ME, Campbell I, Whittemore AS, Sutphen R, Phelan C, Anton-Culver H, Pearce CL, Lambrechts D, Rossing MA, Chang-Claude J, Moysich KB, Goodman MT, Dork T, Nevanlinna H, Ness RB, Rafnar T, Hogdall C, Hogdall E, Fridley BL, Cunningham JM, Sieh W, McGuire V, Godwin AK, Cramer DW, Hernandez D, Levine D, Lu K, Iversen ES, Palmieri RT, Houlston R, van Altena AM, Aben KK, Massuger LF, Brooks-Wilson A, Kelemen LE, Le ND, Jakubowska A, Lubinski J, Medrek K, Stafford A, Easton DF, Tyrer J, Bolton KL, Harrington P, Eccles D, Chen A, Molina AN, Davila BN, Arango H, Tsai YY, Chen Z, Risch HA, McLaughlin J, Narod SA, Ziogas A, Brewster W, Gentry-Maharaj A, Menon U, Wu AH, Stram DO, Pike MC, Beesley J, Webb PM, Chen X, Ekici AB, Thiel FC, Beckmann MW, Yang H, Wentzensen N, Lissowska J, Fasching PA, Despierre E, Amant F, Vergote I, Doherty J, Hein R, Wang-Gohrke S, Lurie G, Carney ME, Thompson PJ, Runnebaum I, Hillemanns P, Durst M, Antonenkova N, Bogdanova N, Leminen A, Butzow R, Heikkinen T, Stefansson K, Sulem P, Besenbacher S, Sellers TA, Gayther SA, Pharoah PD.

Oncology

21

Oncology Ahmed S, Thomas G, Ghoussaini M, Healey CS, Humphreys MK, et al.

Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2.

Nat Genet. 2009 May;41(5):585–90. Epub 2009 Mar 29. PMID: 19330027 Ahmed S, Thomas G, Ghoussaini M, Healey CS, Humphreys MK, Platte R, Morrison J, Maranian M, Pooley KA, Luben R, Eccles D, Evans DG, Fletcher O, Johnson N, dos Santos Silva I, Peto J, Stratton MR, Rahman N, Jacobs K, Prentice R, Anderson GL, Rajkovic A, Curb JD, Ziegler RG, Berg CD, Buys SS, McCarty CA, Feigelson HS, Calle EE, Thun MJ, Diver WR, Bojesen S, Nordestgaard BG, Flyger H, Dörk T, Schürmann P, Hillemanns P, Karstens JH, Bogdanova NV, Antonenkova NN, Zalutsky IV, Bermisheva M, Fedorova S, Khusnutdinova E; SEARCH, Kang D, Yoo KY, Noh DY, Ahn SH, Devilee P, van Asperen CJ, Tollenaar RA, Seynaeve C, Garcia-Closas M, Lissowska J, Brinton L, Peplonska B, Nevanlinna H, Heikkinen T, Aittomäki K, Blomqvist C, Hopper JL, Southey MC, Smith L, Spurdle AB, Schmidt MK, Broeks A, van Hien RR, Cornelissen S, Milne RL, Ribas G, González-Neira A, Benitez J, Schmutzler RK, Burwinkel B, Bartram CR, Meindl A, Brauch H, Justenhoven C, Hamann U; GENICA Consortium, Chang-Claude J, Hein R, Wang-Gohrke S, Lindblom A, Margolin S, Mannermaa A, Kosma VM, Kataja V, Olson JE, Wang X, Fredericksen Z, Giles GG, Severi G, Baglietto L, English DR, Hankinson SE, Cox DG, Kraft P, Vatten LJ, Hveem K, Kumle M, Sigurdson A, Doody M, Bhatti P, Alexander BH, Hooning MJ, van den Ouweland AM, Oldenburg RA, Schutte M, Hall P, Czene K, Liu J, Li Y, Cox A, Elliott G, Brock I, Reed MW, Shen CY, Yu JC, Hsu GC, Chen ST, Anton-Culver H, Ziogas A, Andrulis IL, Knight JA; kConFab; Australian Ovarian Cancer Study Group, Beesley J, Goode EL, Couch F, Chenevix-Trench G, Hoover RN, Ponder BA, Hunter DJ, Pharoah PD, Dunning AM, Chanock SJ, Easton DF. Narita M, Young AR, Arakawa S, Samarajiwa SA, Nakashima T, Yoshida S, Hong S, Berry LS, Reichelt S, Ferreira M, Tavaré S, Inoki K, Shimizu S, Narita M. Spatial Coupling of mTOR and Autophagy Augments Secretory Phenotypes. Science. 2011 Apr 21. [Epub ahead of print] PMID: 21512002 Barbosa-Morais NL, Dunning MJ, Samarajiwa SA, Darot JF, Ritchie ME, Lynch AG, Tavaré S. A re-annotation pipeline for Illumina BeadArrays: improving the interpretation of gene expression data. Nucleic Acids Res. 2010 Jan;38(3):e17. Epub 2009 Nov 18. PMID: 19923232 Garnett MJ, Mansfeld J, Godwin C, Matsusaka T, Wu J, Russell P, Pines J, Venkitaraman AR. UBE2S elongates ubiquitin chains on APC/C substrates to promote mitotic exit. Nat Cell Biol. 2009 Nov;11(11):1363–9. Epub 2009 Oct 11. PMID: 19820702 Carreira A, Hilario J, Amitani I, Baskin RJ, Shivji MK, Venkitaraman AR, Kowalczykowski SC. The BRC repeats of BRCA2 modulate the DNAbinding selectivity of RAD51. Cell. 2009 Mar 20;136(6):1032–43.

PMID: 19303847 Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, Gopinathan A, Tuveson DA, Fearon DT. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science. 2010 Nov 5;330(6005):827–30. PMID: t21051638

22

Oncology

Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, Madhu B, Goldgraben MA, Caldwell ME, Allard D, Frese KK, Denicola G, Feig C, Combs C, Winter SP, Ireland-Zecchini H, Reichelt S, Howat WJ, Chang A, Dhara M, Wang L, Rückert F, Grützmann R, Pilarsky C, Izeradjene K, Hingorani SR, Huang P, Davies SE, Plunkett W, Egorin M, Hruban RH, Whitebread N, McGovern K, Adams J, IacobuzioDonahue C, Griffiths J, Tuveson DA. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009 Jun 12;324(5933):1457–61. Epub 2009 May 21.

PMID: 19460966 Karreth FA, DeNicola GM, Winter SP, Tuveson DA. C-Raf inhibits MAPK activation and transformation by B-Raf(V600E). Mol Cell. 2009 Nov 13;36(3):477–86. PMID: 19917255

Paediatrics Head of Department and Professor of Paediatrics Professor D Dunger (Acting until October, 2012) Tel 01223 336886 Fax 01223 336996 Email dbd25@cam.ac.uk

Staff list Professor IA Hughes, Foundation Chair University Senior Lecturer C Acerini University Lecturer K Beardsall Principal Research Associate R Hovorka Senior Research Staff C Petry Clinical Lecturers R Williams

M Zilbauer

Affiliated Lecturer K Ong Associate Lecturers/NHS Consultants N Abdullah P Heinz J Ahluwalia R Heuschkel A Aslam R Iles T Austin C Jackson J Brain F Janjua S Broster W Kelsall A Burke A Khan D Carroll D Krishnakumar A Clarke E Lewis D Conlan D McShane A Curley S Morley D D'Amore J Nicholson K Farrer D O'Donnell M Gattens A Ogilvy-Stuart

A Parker L Preston U Ramaswami A Rehm R Ross-Russell C Salvestrini A Sansome F Torrente C Verity D Vickers D Williams M Williams

Research synopsis The Department's research is in four main areas: genetic and hormonal control of human sex development; genetics and pathophysiology of diabetes; the determinants of birth size and infant growth; critical illness endocrine physiology.

Studies on mammalian sex development are applied to the management of infants with disorders of sex development (DSD), including the effects of environmental chemicals, which may

disrupt endocrine control of fetal development. Polymorphic variants in genes controlling androgen production and action appear to affect normal development, including growth at puberty. Much of this research is underpinned by the Cambridge Baby Growth Study (CGGS) established by Professor Hughes in 2001 and now celebrating its 10th Anniversary, with over 2000 families recruited. A major component of CBGS studies, directed

by Dr Ken Ong at the MRC Epidemiology Unit, is now focusing on nutrition and how early feeding practices influence risks of obesity and age of onset of puberty. This unique resource is spawning collaborative studies across several specialties in the Cambridge Biomedical Campus. In 2008 Professor Dunger and his team launched the first international study of the use of ACE inhibitors and statins in adolescents with Type 1 diabetes (T1D).

Ongoing studies on T1D include the role of the growth hormone – IGF1 axis in insulin resistance, and the place of growth hormone inhibitors in preventing diabetic complications.

Clinical testing of closed-loop insulin delivery in T1D developed

by Dr Hovorka is showing promising results. Under supervised conditions, overnight closed-loop reduced the risk of nocturnal hypoglycaemia and improved glucose control. First ever home testing will adopt an in-house prototype system which has received regulatory approval. The physiology of survival and late morbidity as a consequence of acute life-threatening or critical illness is being studied by examining the effects of stress endocrinology and hyperglycaemia. The successful Neonatal Insulin Replacement Therapy in Europe (NIRTURE) study is being extended to early childhood to determine the role of insulin and glucose control on long term risk of glucose intolerance in later life.

Selected references Miles HL, Gidlöf S, Nordenström A, Ong KK, Hughes IA. (2010) The role of androgens in fetal growth: observational study in two genetic models of disordered androgen signalling.

Arch Dis Child Fetal Neonatal Ed 2010; 95:F435–438.

Ong KK, Elks CE, Li S, Zhao JH et al. Genetic variation in LIN28B is associated with the timing of puberty. Nat Genet 2009; 41:729–733.

Acerini CL, Miles HL, Dunger DB, Ong KK, Hughes IA. The descriptive epidemiology of congenital and acquired cryptorchidism in a UK infant cohort. Dis Child. 2009;94:868–72.

Hovorka R, Allen JM, Elleri D, Chassin LJ et al. Manual closed-loop insulin delivery in children and adolescents with type 1 diabetes: a phase 2 randomised crossover trial. Lancet 2010; 375:743–51.

Regan FM, Williams RM, McDonald A, Umpleby AM et al.

Treatment with Recombinant Human Insulin-like Growth Factor (rhIGF)-1/ rhIGF Binding Protein-3 Complex Improves Metabolic Control in Subjects with Severe Insulin Resistance. J Clin Endocrinol Metab 2010;95:2113–22.

Beardsall K, Vanhaesebrouck S, Ogilvy-Stuart AL, et al. Prevalence and determinants of hyperglycaemia in very low birth weight infants: cohort analyses of the NIRTURE study. J Pediatr 2010; 157: 715–9.

Paediatrics

23

Psychiatry Head of Department and Professor of Psychiatry

Research synopsis The Department boasts the highest quality psychiatry research in the UK, with 80% of research rated as being 4* or 3* (world-leading or internationally excellent) in the Research Assessment Exercise 2008.

Professor PB Jones Tel 01223 336961 Fax 02223 336581 Email pbj21@cam.ac.uk

Staff list Professors S Baron-Cohen, Developmental Psychopathology GE Berrios, Epistemology of Psychiatry (Emeritus) ET Bullmore, Psychiatry S Gathercole, Cognitive Psychology (faculty board appointment) IM Goodyer, Child & Adolescent Psychiatry AJ Holland, Learning Disability (Healthcare Foundation Professorship) FA Huppert, Psychology ES Paykel, Psychiatry (Emeritus) B Sahakian, Cognitive Neuropsychology P Fletcher, Health Neuroscience (Bernard Wolfe Professorship) University Senior Lecturer T Croudace University Lecturers B Lennox U Muller

HA Ring P Wilkinson

Director of Research J Suckling Senior Research Associates K Ersche J Murray E Fernandez-Egea M Redley G Murray

Research in the Department is focused on major disease areas using a range of investigative techniques. Developmental paradigms are central in much of the Department's work from the point of view of pathological states, life course models of adult health and the application of novel statistical techniques.

Contemporary neurobiological techniques such as structural and functional MRI, neuro-endocrinology, cognitive psychology and molecular genetics are used to characterize large, epidemiologically principled or longitudinal samples as well as to elucidate drug models of disorders and their treatments in smaller scale, more mechanistic studies. There are cognate methodological strengths in many of these techniques, especially epidemiology neuroimaging, cognitive psychology and psychopharmacology.

The full gamut of translational clinical research is an increasing focus. Research activity in the Department benefits from a wide range of national and international collaborations including leadership roles in the MRC/Wellcome Trust Behavioural & Clinical Neurosciences Institute, the NIHR Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for Cambridgeshire and Peterborough, a Wellcome Trust Strategic Award for Neurosciences and Mental Health and the GSK Clinical Unit.

Selected references

M Spencer V Voon

Bassett DS, Greenfield DL, Meyer-Lindenberg A, Weinberger DR, Moore SW, Bullmore ET (2010). Efficient physical embedding of topologically complex information processing networks in brains and computer circuits. PLoS Computational Biology. 6(4):e1000748.

Clinical Lecturer R Cardinal J Deakin

V Dobler R Dudas

Chen CH, Suckling J, Ooi C, Jacob R, Lupson V, Bullmore ET, Lennox BR (2010). A longitudinal fMRI study of the manic and euthymic states of bipolar disorder. Bipolar Disorders. 12: 344–347.

Affiliated Lecturers A Bateman ICH Clare

P Emson A Humphrey

Colman I, Murray J, Abbott RA, Maughan B, Kuh D, Croudace TJ, Jones PB (2009). Outcomes of conduct problems in adolescence: 40 year follow-up of national cohort. BMJ; 338:a2981.

Visiting Research Staff M Aguis E Fernandez-Egea J Akiste N Fineberg J Barnett M Kar-Ray A Blackwell N Martin S Chamberlain M O’Riordan F Chen J Perez Sancho-Toledo G Gomez de la Curesta W Riedel J Eccles NHS Consultants/Associate Lecturers R Chipperfield AJ Jaffa T Denning CA Lawton FMC Denman A Michael DM Girling J Perez E Hegazi R Ramana NJ Hunt S Robling 24

psychiatry

J Semple A Stringaris D Tantam G Todd R Zaman S Zaman J Zimbron

J Shapleske M Stefan E Vithayathil C Walsh (Clinical sub-Dean)

Fairchild G, Stobbe Y, van Goozen SH, Calder AJ, Goodyer IM (2010).

Facial expression recognition, fear conditioning, and startle modulation in female subjects with conduct disorder. Biological Psychiatry; 68(3):272–9.

Fletcher PC, Napolitano A, Skeggs A, Miller SR, Delafont B, Cambridge VC, de Wit S, Nathan PJ, Brooke A, O'Rahilly S, Farooqi IS, Bullmore ET (2010).

Distinct modulatory effects of satiety and sibutramine on brain responses to food images in humans: a double dissociation across hypothalamus, amygdala, and ventral striatum. Journal of Neuroscience; 30(43):14346–55.

Lai MC, Lombardo MV, Chakrabarti B, Sadek SA, Pasco G, Wheelwright SJ, Bullmore ET, Baron-Cohen S, Suckling J (2010). A Shift to Randomness of Brain Oscillations in People with Autism. Biological Psychiatry. 68: 1092–1099.

The Oxford Handbook of Neuroethics. Eds. J Illes & BJ Sahakian (Oxford University Press, 2011).

Scoriels L, Barnett JH, Murray GK, Cherukuru S, Fielding M, Cheng F, Lennox BR, Sahakian BJ, Jones PB (2011) Effects of modafinil on emotional processing in first episode psychosis. Biological Psychiatry; 69(5): 457–464.

Public Health and Primary Care Head of Department and Professor of Epidemiology and Medicine Professor JN Danesh Tel 01223 741302 Fax 01223 741339 Email john.danesh@phpc.cam.ac.uk

Professors C Brayne, Professor of Public Health Medicine (Director, Institute of Public Health) DF Easton, Professor of Genetic Epidemiology KT Khaw, Professor of Clinical Gerontology AL Kinmonth, Professor of General Practice JW Mant, Professor of Primary Care Research T Marteau, Professor of Health Psychology (KCL) (Director, Policy Research Unit) M Roland, Professor of Heath Services Research SR Sutton, Professor of Behavioural Science SG Thompson, Professor and Director of Research in Biostatistics NJ Wareham, Honorary Professor of Epidemiology (Director, MRC Epidemiology Unit) Reader P Pharoah, Reader in Cancer Epidemiology JW Powles

University Lecturers E Di Angelantonio D Saleheen (unestablished) MS Sandhu AM Wood Clinical Lecturers O Franco N Mavaddat

R Payne FM Walter

J Yip

Affiliated Lecturers P Badrinath R Fordham

A Hibble MH Reacher

P Treasure

Senior Research Staff AC Antoniou SIG Barclay M Farquhar W Hardeman S Kaptoge

T Minett HC Morris R Mullis D Nunn C Paddison

CR Palmer B Stephan N Wainwright M Walker KM Williams

Senior Visiting Fellows P Cosford C Jagger N Day M Kelly J Emery T Ling J Grant E Nolte V Gudnason DC Pencheon R Himsworth TC Prevost Clinical Research Fellows/Associates JP Graffy G Lyratzopoulos V Keevil J Usher-Smith

R O’Donnell J Sargent J Schram RL Zimmern

Research synopsis

Staff list

University Senior Lecturers JA Benson S Cohn P Monsivais

NHS Consultants/Associate Lecturers TS Alderson E Fistein LK Atkinson S Forrest RG Davies SJ Gillam J Ferdinand RJ Morris

P Surtees H Thomas I White D Williams

The Department of Public Health and Primary Care at the University of Cambridge is one of the UK's leading university departments of population health sciences, top-ranked in Epidemiology and Public Health in the Research Assessment Exercise 2008.

The department has been led since 2001 by Professor John Danesh and consists of over 330 staff and postgraduate students.

The overall research mission is to generate scientific evidence that will inform the prevention of premature death and disability, particularly in relation to common chronic conditions such as cardiovascular disease, common cancers, dementia, diseases of ageing, osteoporosis, and metabolic diseases. The goal is to translate this evidence into the development and evaluation of preventative interventions.

Key strategies involve investigations of the separate and combined influences of genetic and environmental factors in chronic diseases by studies of several in-house epidemiological collections and of large-scale collections established through national and international collaborations. In several of these studies, aetiological investigations and patho-physiological natural history studies are integrated with molecular biology and clinical medicine. Understanding of the determinants of disease and behaviour change are then utilised in the development and evaluation of interventions at individual and population levels. There is also research into methods of study design, development of interventions and biostatistical analyses.

The Department has recently made senior appointments, including Professor Theresa Marteau (Director, Policy Research Unit, 2010) and Professor Simon Thompson (Director of Research in Biostatistics, 2011). Further examples of major developments in recent years include: 1 establishment of major research initiatives in developing countries, especially in South Asia, such as the Pakistan Risk of Myocardial Infarction Study and partnership in the Public Health Foundation of India-UK Consortium from 2008 2 establishment of the MPhil course in Public Health in 2006, and co-direction of a new four-year inter-disciplinary PhD programme in cardiovascular research supported by the British Heart Foundation from 2009 3 establishment of a new Department of Health funded Policy Research Unit in 2010 4 leadership of international customised gene array consortia in cancer ('iCOGs') and in vascular disease ('metabochip+').

public health and primary care

25

Public Health and Primary Care Selected examples of population collections (Study name/sample size/major focus of study) 1 EPIC-Norfolk / 30,000 / nutrition and cancer 2 Emerging Risk Factor Collaboration / 1,800,000 / evaluation of novel coronary biomarkers 3 EPIC-CVD / 25,000 incident CVD cases, 520,000 participants / gene-lifestyle interplay 4 Breast Cancer Association Consortium / >90,000 / genetics of breast cancer 5 Cognitive Function and Ageing / 18,000 / cognitive decline 6 SEARCH / >20,000 / genetics of breast, ovarian, and other cancers 7 Ely / 2,000 / determinants of metabolic disease 8 Pakistan Risk of Myocardial Infarction Study / >30,000 / genetics of MI and stroke

Teaching and training The Department continues to train and provide teaching to a wide range of constituencies. These main areas are teaching within the medical student curriculum, training for public health careers, and research training (as a recognised MRC training location in epidemiology and public health and NIHR training centre for ACFs and Clinical Lectureships). Key events and achievements are noted below:

Postgraduate

Selected references N Engl J Med. The Emerging Risk Factors Collaboration. Diabetes mellitus, fasting glucose, and risk of cause-specific death. 2011;364:829–841.

The Emerging Risk Factors Collaboration. Separate and combined associations of body-mass index and abdominal adiposity with cardiovascular disease: collaborative analysis of 58 prospective studies. Lancet 2011;377:1085–95.

Spurdle AB, Thompson DJ, Ahmed S, Ferguson K, Healey CS, O'Mara T et al. Genome-wide association study identifies a common variant associated with risk of endometrial cancer. Nat Genet 2011; 43:451–454.

The Emerging Risk Factors Collaboration. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 2010;375:2215–2222.

The Triglyceride Coronary Disease Genetics Consortium and The Emerging Risk Factors Collaboration. Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies.

Lancet 2010;375:1634–9.

McManus RJ, Mant J, Bray EP, Holder R, Jones MI, Greenfield S et al.

Telemonitoring and self-management in the control of hypertension (TASMINH2): a randomised controlled trial. Lancet 2010;375:163–72.

Turnbull C, Rapley EA, Seal S, Pernet D, Renwick A, Hughes D et al.

Variants near DMRT1, TERT and ATF7IP are associated with testicular germ cell cancer. Nat Genet 2010;42:604–607.

Turnbull C, Ahmed S, Morrison J, Pernet D, Renwick A, Maranian M et al. Genome-wide association study identifies five new breast cancer susceptibility loci. Nat Genet 2010;42:504–7.

1 Appointment of University Lecturer, Dr Emanuele Di Angelantonio (UL in Medical Screening, 2010) and Clinical Lecturers Dr Oscar Franco (Clinical Lecturer in Public Health, 2010), Dr Rupert Payne (NIHR Clinical Lecturer in General Practice, 2010) and Dr Jennifer Yip (Clinical Lecturer in Public Health, 2011).

Rodondi N, den Elzen WP, Bauer DC, Cappola AR, Razvi S, Walsh JP et al. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA 2010;304:1365–74.

2 The MPhil in Epidemiology is a one-year full-time course, which in 2009/10 had 18 students and has been running for 19 years. The course has had over 200 students graduate to date. The Nick Day Prize in Epidemiology for the top student was established in 2006.

Savva GM, Wharton SB, Ince PG, Forster G, Matthews F, Brayne C. Age, neuropathology, and dementia. N Engl J Med 2009;360:2302–2309.

3 The MPhil in Public Health is a one-year full-time course, which in 2009/10 had 16 students and has been running for 6 years. The course has had about 50 students graduate to date. The Tom Davies Prize in Public Health for the top student was established in 2007.

Paddison CAM, Eborall H, Sutton S, French DO, Vasconcelos J, Prevost AT et al. Are people with negative screening tests for diabetes falsely reassured? A parallel group cohort study embedded in the ADDITION (Cambridge) randomised controlled trial. BMJ 2009;339: b4535. (Acting) Head of Department and Professor of Clinical MRI

4 Together, the MPhil programmes are supported by a total of five annual studentships from the MRC. There are about 44 doctoral students studying a range of topics.

5 Academic supervision has been provided to around 40 public health trainees.

6 Postgraduate students and honorary fellows are supported by a range of competitive awards including MRC studentships and fellowships from the BHF, Cancer Research UK, Wellcome Trust, NIHR, ESRC and Macmillan Cancer Support.

26

public health and primary care

Eeles RA, Kote-Jarai J, Al Olama AA, Giles GG, Guy M, Severi G et al.

Identification of seven new prostate cancer susceptibility loci through a genome-wide association study. Nat Genet 2009;41:1116–1121.

Campbell SM, Reeves D, Kontopantelis E, Sibbald B, Roland M. Effects of pay-for-performance on the quality of primary care in England.

N Engl J Med 2009;361:368–78.

Radiology Head of Department and Professor of Radiology Professor F Gilbert Tel 01223 336890 Fax 01223 330915 Email: fjg28@cam.ac.uk

Staff list Professors AK Dixon, Emeritus Professor of Radiology DJ Lomas, Professor of Clinical MRI JH Gillard, Professor of Neuroradiology JR Griffiths, Hon Prof in Magnetic Resonance applied to Cancer University Lecturers LH Berman TF Massoud

E Sala

Senior Research Staff F Gallagher NHS Consultants/Associate Lecturers N Antoun J Cross J Babar J Dutton A Balan A Freeman K Balan S Freeman S Barter M Gaskarth P Bearcroft A Gomez A Booth D Gopalan P Britton B Khoo J Buscombe N Higgins N Carroll M Hopper HK Cheow J Hughes C Cousins D Scoffings Clinical Lecturers O Arthurs

N Screaton T See P Set A Shaw R Sinnatamby A Tasker S Uppon M Wallis S Whitley A Winterbottom

O Thomas

Affiliated Lecturer MJ Graves

Research synopsis The research activity of the department spans a wide range from molecular imaging developments at a 'bench' level, through novel imaging technique development to clinical studies of new imaging applications. These activities involve numerous multidisciplinary collaborations across the Campus and the wider University, including links with Engineering, Physics, Medical Physics, the CRUK Cambridge Research Institute and the major themes of the NIHR Cambridge Biomedical Research Centre of which Imaging forms a key cross-cutting theme.

The department benefits from access to an extensive portfolio of modern imaging equipment including advanced colour

Doppler Ultrasound, 1.5T and 3T MRI and MRS, 16, 64 and 128 detector and dual energy CT as well as PET-CT and advanced radiochemistry. There are close research links with the Neurosciences utilising CT, MR and PET techniques in studies involving stroke and carotid disease in particular. Multiple new clinical trials in Oncology have been established, investigating both new imaging based biomarkers and the evaluation of new therapeutic agents in early phase 1 trials. A particular focus of current and future work has been molecular imaging with the development of gene reporter techniques as well as hyperpolarised 13C agents and related imaging applications in collaboration with the CRI and Biochemistry.

Individual groups have undertaken research in the identification and characterization of vulnerable plaque, the improved definition and characterization of brain tumours, the development of new interactive real-time techniques for paediatric and neonatal MRI, the development of non-contrast enhanced 3D vascular imaging techniques, the clinical applications of ultrasound and MR based elastography for malignant lymph node detection and focal liver lesion characterisation. Our previous work on the impact of imaging techniques on clinical decision making continues to be cited in national guidelines, notably involving breast cancer and chest disease management.

High spatial resolution 3D arteriograms of the lower legs generated using a novel non-invasive MR technique that removes the need for any injected contrast medium.

Selected references 1 Barrett T, Bowden DJ, Greenberg DC, Brown CH, Wishart GC, Britton PD. 2009. Radiological staging in breast cancer: which asymptomatic patients to image and how. Br J Cancer, 101(9), Nov 3, 1522–8.

2 Sadat U, Weerakkody RA, Bowden DJ, Young VE, Graves MJ, Li ZY, Tang TY, Gaunt ME, Hayes PD, Gillard JH. 2009. Utility of high resolution MR imaging to assess carotid plaque morphology: a comparison of acute symptomatic, recently symptomatic and asymptomatic patients with carotid artery disease. Atherosclerosis, 207(2), Dec, 434–9.

3 Graves MJ, Black RT, Lomas DJ. 2009. Constrained surface controllers for three-dimensional image data reformatting. Radiology, 252(1), Jul, 218–24.

4 Gallagher FA, Kettunen MI, Hu DE, Jensen PR, Zandt RI, Karlsson M, Gisselsson A, Nelson SK, Witney TH, Bohndiek SE, Hansson G, Peitersen T, Lerche MH, Brindle KM. 2009. Production of hyperpolarized [1,4-13C2] malate from [1,4-13C2] fumarate is a marker of cell necrosis and treatment response in tumors.

Proc Natl Acad Sci U S A, 106(47), Nov 24, 19801–06.

5 Massoud TF, Paulmurugan R, Gambhir SS. 2010. A molecularly engineered split reporter for imaging protein-protein interactions with positron emission tomography. Nat Med. Aug;16(8):921–6.

6 Priest AN, Gill AB, Kataoka M, McLean MA, Joubert I, Graves MJ, Griffiths JR, Crawford RA, Earl H, Brenton JD, Lomas DJ, Sala E. Dynamic contrast-enhanced MRI in ovarian cancer: Initial experience at 3 tesla in primary and metastatic disease. Magn Reson Med, 2010.

63(4): p. 1044–9.

Radiology

27

Surgery Head of Department and Professor of Surgery Professor JA Bradley Tel 01223 336976 Fax 01223 762523 Email jab52@cam.ac.uk

Staff list Professors DE Neal, Professor of Surgical Oncology RAL Pedersen, Professor of Regenerative Medicine N Rushton, Professor of Orthopaedic Surgery J Wallwork, Honorary Professor of Cardiothoracic Surgery CJE Watson, Professor of Transplantation University Senior Lecturer P Gibbs University Lecturers A Butler VJ Gnanapragasam

GJ Pettigrew

Assistant Director of Research EM Bolton Senior Research Staff RA Brooks L Vallier (Principal Research Associate) Clinical Lecturers CJ Callaghan S Harper MRV Kosmoliaptsis

SS Liau K Saeb-Parsy

NHS Consultants/AssociateLecturers DM Adlam PH Gillespie TF Aho I Grant T Ahmed RF Gray A Aslam NR Hall P Axon PN Hall AM Baxter RH Hardwick JR Benson PD Hayes SL Benyon E Huguet D Bister J Hopkinson-Woolley A Boyle MS Irwin JR Boyle C Jackson AJL Brain A Jah JA Bavisha NV Jamieson MG Cameron P Jani D Carroll D Jenkins C Collins P Johnstone DP Conlon AR Kahn GC Cormack C Kastner RJ Davies V Khanduja A Doble GS Keene N Donnolly RJ Kendall AJ Durrani MG Kerr-Muir DJ Edwards SR Large NS Fearnhead CM Malata BM Fish K Madavan P Forouhi DJ McAuley ME Gaunt DC McKiernan

28

surgery

G Shaw MGB Tran

Research synopsis The Department of Surgery has a strong clinical emphasis and the overall research strategy is to improve the surgical management of disease through developments in both basic and translational research.

There is a major focus on applied clinical research and a key feature of the department is the close integration of University and NHS surgeons. University surgeons in parallel with directing programmes of research play an important role in the development and delivery of specialist surgical services. Similarly, many NHS surgeons are, in addition to their clinical responsibilities, undertaking high quality clinical research supported through close collaboration with University colleagues.

In contrast with the trend in many other UK universities, academic surgery in Cambridge is flourishing and the department continues to expand. The principal research interests are transplantation, stem cell medicine, surgical oncology and orthopaedic surgery. In addition, clinical research of international importance is being led by NHS surgical colleagues across a range of surgical disciplines, including ear, nose and throat surgery, ophthalmic surgery, gastrointestinal surgery and vascular surgery.

Transplantation

R Miller DA Moffat CN Morrison AM Nashef A Norrish PJ Owen M Pereira R Praseedom RD Price A Rehm J Rimes AHN Robinson SM Robinson PM Safranek NC Shah NP Smith N Thiruchelvam MK Thomson S Tsui WH Turner G Tytherleigh-Strong L Van-Rensburg K Varty AS Vince FC Wells MPL Williams OJ Wiseman

The Division of Transplantation, directed by Professor Bradley, has been at the international forefront of clinical developments in organ transplantation for many years and the world-renowned clinical programmes in abdominal organ transplantation based at Addenbrooke’s, and thoracic organ transplantation based at Papworth Hospital NHS Foundation Trust, are each underpinned by well-established multidisciplinary research programmes.

Research ranges from basic molecular and cellular immunology to translational research and evaluation of new technologies.

The Division includes the Transplantation and Regenerative Medicine Theme of the NIHR Biomedical Research Centre.

There are strong programmes of basic research into the molecular basis of allograft rejection, with a particular focus on the role of B cells and alloantibody in acute and chronic rejection, interactions between endothelial and immune cells in allograft vasculopathy, molecular mechanisms underlying the induction and maintenance of immunological tolerance, and analysis of physicochemical properties determining the immunogenicity of HLA molecules. The division is undertaking, a number of investigator led single and multi-centre clinical research programmes aimed at evaluating novel immunosuppressive agents, extending donor organ use and minimising organ injury prior to transplantation. Senior investigators in the department are also working closely with scientists and statisticians in the Division of Organ Donation and Transplantation at NHS Blood and Transplant to maximise the outcome of organ transplantation in the UK.

Selected references Reid AW, Harper S, Jackson CH, Wells AC, Summers DM, Gjorgjimajkoska O, Sharples LD, Bradley JA, Pettigrew GJ. Expansion of the kidney donor pool by using cardiac death donors with prolonged time to cardiorespiratory arrest. Am J Transplant. 2011; 11: 995–1005.

Kosmoliaptsis V, Sharples LD, Chaudhry AN, Halsall DJ, Bradley JA, Taylor CJ. Predicting HLA class II alloantigen immunogenicity from the number and physiochemical properties of amino acid polymorphisms.

Transplantation. 2011; 91: 183–90.

Watson CJ, Wells AC, Roberts RJ, Akoh JA, Friend PJ, Akyol M, Calder FR, Allen JE, Jones MN, Collett D, Bradley JA. Cold machine perfusion versus static cold storage of kidneys donated after cardiac death: a UK multicenter randomized controlled trial. Am J Transplant. 2010; 10: 1991–9.

Summers DM, Johnson RJ, Allen J, Fuggle SV, Collett D, Watson CJ, Bradley JA. Analysis of factors that affect outcome after transplantation of kidneys donated after cardiac death in the UK: a cohort study.

Lancet. 2010; 376: 1303–11.

Kosmoliaptsis V, Chaudhry AN, Sharples LD, Halsall DJ, Dafforn TR, Bradley JA, Taylor CJ. Predicting HLA class I alloantigen immunogenicity from the number and physiochemical properties of amino acid polymorphisms. Transplantation. 2009; 88: 791–8.

Win TS, Rehakova S, Negus MC, Saeb-Parsy K, Goddard M, Conlon TM, Bolton EM, Bradley JA, Pettigrew GJ. Donor CD4 T cells contribute to cardiac allograft vasculopathy by providing help for autoantibody production. Circ Heart Fail. 2009; 2: 361–9.

Stem Cell Medicine Prof Roger Pedersen’s and Dr Ludovic Vallier’s groups are conducting research into the early stages of embryonic stem cell differentiation and the genetic mechanisms responsible for these processes. Both mouse and human embryonic stem (hES) cells are being studied, and interfering (si)RNAs are being used to modify gene function and examine the role of specific genes, with the aim of ultimately controlling differentiation into specialised cell types for potential therapeutic use. Research is also being undertaken into the mechanisms responsible for the maintenance of pluripotency in hES cells and the formation of mesodermal and endodermal cell lineages, as well as the epigenetic stability of pluripotent stem cell lines. Both groups interact extensively with other leading investigators within and outwith the University; both are key contributors to the Cambridge Stem Cell Initiative, which aims at biomedical translation of stem cell and regenerative medicine research.

Both Prof Pedersen and Dr. Vallier are founding members of the School of Clinical Medicine’s Anne McLaren Laboratory for Regenerative Medicine (LRM). The LRM has played a key role in the Cambridge Stem Cell Initiative by serving as the Clinical School host for the MRC Centre Centre for Stem Cell Biology and Regenerative Medicine, which together with the Wellcome Trust Centre for Stem Cell Research on Tennis Court Road constitute the hubs of the Cambridge Stem Cell Initiative. In 2009, Dr Vallier established the human induced pluripotent stem cell Core Resource, with support from the National Institute for Health Research Cambridge University Hospitals NHS Trust Biomedical Research Centre. During the past two years, the hIPSC Core Facility has derived more the 400 hIPSC lines from 60 patients suffering from neurodegenerative diseases, cardiovascular syndromes,

metabolic and blood disorders. In parallel, the hIPSC Core Facility has become a major training centre by accommodating more than 20 visiting scientists and by supporting the development of similar platforms in several European countries.

Selected references Yusa K*, Rashid ST*, Strick-Marchand H, Varela I, Liu PQ, Paschon DE, Miranda E, Ordóñez A, Hannan N, Rouhani FJ, Darche S, Alexander G, Marciniak SJ, Fusaki N, Hasegawa M, Holmes MC, Di Santo JP, Lomas DA*, Bradley A* and Vallier L* (2011). Targeted gene correction of α1-antitrypsin deficiency in induced pluripotent stem cells.

Nature, 12;478(7368):191–5 (*joint authorship).

Teo AKK, Arnold SJ, Trotter MWB, Brown S, Ang LT, Chng, Z, Robertson EJ, Dunn NR, Vallier L (2011). Pluripotency factors regulate definitive endoderm specification through eomesodermin. Genes & Development, 25: 238–250.

Brown S, Teo A, Pauklin S, Hannan N, Cho CH-H, Lim B, Vardy L, Dunn NR, Trotter M, Pedersen R, Vallier L. (2011). Activin/Nodal Signalling Controls Divergent Transcriptional Networks in Human Embryonic Stem Cells and in Endoderm Progenitors. Stem Cells 29:1176–85.

Bernardo AS, Faial T, Gardner L, Niakan KK, Ortmann D, Senner CE, Callery EM, et al. (2011). BRACHYURY and CDX2 Mediate BMP-Induced Differentiation of Human and Mouse Pluripotent Stem Cells into Embryonic and Extraembryonic Lineages. Cell Stem Cell, 9(2), 144–55.

Patani R, Hollins AJ, Wishart TM, Puddifoot CA, Álvarez S, de Lera AR, Wyllie DJA, Compston DAS, Pedersen RA, Gillingwater TH, Hardingham GE, Allen ND and Chandran S. Retinoid independent generation of motor neurons from human embryonic stem cells reveals a medial columnar ground state. In press, Nature Communications.

Rashid ST, Corbineau S, Hannan N, Marciniak SJ, Miranda E, Alexander G, Huang-Doran I, Ahrlund-Richter L, Skepper J, Griffin J, Semple R, Weber A, Lomas DA, Vallier L. (2010) Modelling inherited metabolic disorders of the liver with human induced pluripotent stem cells. Journal of Clinical Investigations. J Clin Invest. 2010 Sep 1;120(9):3127–36.

Touboul T, Hannan N, Corbineau S, Martinez A, Martinet C, Branchereau S, Mainot S, Strick-Marchand H, Pedersen R, Di Santo J, Weber A and Vallier L. (2010). Generation of functional hepatocytes from human embryonic stem cells under chemically defined conditions which recapitulate liver development. Hepatology. 51(5):1754–65.

Chng ZZ, Teo A, Pedersen R*, Vallier L*(2010) SIP1 mediates cell fate decisions between neuroectoderm and mesendoderm in human embryonic pluripotent stem cells. Cell Stem Cell. 6(1). 59–70 * joint authorship.

Vallier L, Touboul T, Brown, Cho C, Bilican B, Alexander M, Cedervall J, Chandran S, Ährlund-Richter L, Weber A, Pedersen RA. (2009). Signalling pathways controlling pluripotency and early cell fate decisions of human induced pluripotent stem cells. Stem Cells. 27(11):2655–2666.

Vallier L, Touboul T, Chng Z, Brimpari M, Hannan N, Millan E, Smithers LE, Trotter M, Rugg-Gunn P, Weber A, Pedersen RA (2009).

Early cell fate decisions of human embryonic stem cells and mouse epiblast stem cells are controlled by the same signalling pathways.

Plos One. June 30;4(6):e6082.

Vallier L, Mendjan S, Brown S, Chng Z, Teo A, Smithers LE, Trotter MW, Cho CH, Martinez A, Rugg-Gunn P, Brons G, Pedersen RA. (2009) Activin/ Nodal signalling maintains pluripotency by controlling Nanog expression Development. Apr;136(8):1339–49.

surgery

29

Surgery Orthopaedics (Department of Surgery)

Surgical Oncology

The Orthopaedic Research Unit, directed by Professor Neil Rushton, has a novel programme of fundamental and translational research in bone and joint repair using in vitro and in vivo approaches.

The uro-oncology division, directed by Professor Neal, is closely associated with the Departments of Oncology and Surgery.

Cambridge has the largest robotic prostatectomy programme within the NHS and this, together with other clinical trials has allowed the development of a well-annotated bio-repository.

Neal is one of the three PIs on a major NIHR funded trial (ProtecT) to determine the best treatment for men with early prostate cancer and is the largest ever surgical trial in prostate cancer.

Collaborative genetic research continues with Strangeways and the ICR in London.

The basic science programme is designed to elucidate the developmental cascade of the osteoblast and chondrocyte lineages, both from known precursors and novel sources, and to understand their interaction with normal and newly developed matrices. Understanding how local niches impinge on the developmental cascade is a new theme. In addition to investigations on the developmental cascade there is an ongoing programme investigating the damage /repair response of the osteochondral unit.

In collaboration with the Departments of Materials Science and Engineering we are evaluating the interactions of human cells and in particular mesenchymal stem cells with collagenbased materials for the regeneration of cartilage, meniscus and tendon. With the Department of Chemistry we are using nuclear magnetic resonance spectroscopy to investigate chemical signatures within bone matrix and between the matrix and mineral phases of bone.

Translational research has resulted in the CE marking and first in man trials of an osteochondral repair product following development work carried out in the Unit. The clinical use of bone substitute materials in impaction grafting has been supported by research on the mechanical properties of mixtures of bioactive ceramic and bone.

Selected references Enea D, Henson F, Kew S, Wardale J, Getgood A, Brooks R, Rushton N. Extruded collagen fibres for tissue engineering applications: effect of crosslinking method on mechanical and biological properties.

J. Mater. Sci: Mater Med. 2011; 22(6):1569–78.

Getgood A, Henson F, Brooks R, Fortier LA, Rushton N. Platelet-rich plasma activation in combination with biphasic osteochondral scaffoldsconditions for maximal growth factor production. Knee Surg Sports Traumatol Arthrosc. 2011; 19 (11):1942–7.

Kew SJ, Gwynne JH, Enea D, Abu-Rub M, Pandit A, Zeugolis D, Brooks RA, Rushton N, Best SM, Cameron RE. Regeneration and repair of tendon and ligament tissue using collagen fibre biomaterials. Acta Biomaterialia 7 (9): 3237–3247 Cristofolini L, Juszczyk M, Taddei F, Field R, Rushton N, Viceconti M. Assessment of femoral neck fracture risk for a novel proximal epiphyseal hip prosthesis. Clinical Biomechanics 2011; 26 (6): 585–91.

Mullen LM, Best SM, Brooks RA, Ghose S, Gwynne JH, Wardale J, Rushton N, Cameron RE. Binding and Release Characteristics of InsulinLike Growth Factor-1 from a Collagen-Glycosaminoglycan Scaffold.

Tissue Engineering Part C. 2010; 16 (6):1439–48.

Brooks RA, Field RE, Jones E, Sood A, Rushton N. A histological study of retrieved Cambridge acetabular components. Hip Int. 2010; 20 (1):56–63.

Spence G, Patel N, Brooks R, Bonfield W, Rushton N. Osteoclastogenesis on hydroxyapatite ceramics: the effect of carbonate substitution. J Biomed Mater Res A. 2010; 92(4): 1292–300.

30

Surgery

There is a large translational research programme involving Gnanapragasam and experimental medicine studies including imaging led from the Cambridge Research Institute where Neal is group leader. Following studies of SNPs in prostate cancer, novel biomarkers have been developed. The majority of the work in the CRI is focused on androgen receptor signalling where we have discovered novel binding sites and functionally important therapeutic targets.

Selected references Al Olama AA, Kote-Jarai Z, Giles GG, Guy M, Morrison J, Severi G, et al. Multiple loci on 8q24 associated with prostate cancer susceptibility.

Nat Genet. 2009 Oct;41(10):1058–60.

Eeles RA, Kote-Jarai Z, Al Olama AA, Giles GG, Guy M, Severi G, et al.

Identification of seven new prostate cancer susceptibility loci through a genome-wide association study. Nat Genet. 2009 Oct;41(10):1116–21.

Murphy T, Darby S, Mathers ME, Gnanapragasam VJ. Evidence for distinct alterations in the FGF axis in prostate cancer progression to an aggressive clinical phenotype. J Pathol. 2010 Mar;220(4):452–60.

McLean MA, Barrett T, Gnanapragasam VJ, Priest AN, Joubert I, Lomas DJ, et al. Prostate cancer metabolite quantification relative to water in (1)H-MRSI in vivo at 3 Tesla. Magn Reson Med. 2010 Nov 16.

Whitaker HC, Kote-Jarai Z, Ross-Adams H, Warren AY, Burge J, George A, et al. The rs10993994 Risk Allele for Prostate Cancer Results in Clinically Relevant Changes in Microseminoprotein-Beta Expression in Tissue and Urine. PLoS One. 2010;5(10).

Massie CE, Lynch A, Ramos–Montoya A, Boren J, Stark R, Fazlil et al.

The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthsis EMBRO J 2011; 30(13): 2719–33

Design and production: Media Studio, Cambridge University Hospitals NHS Foundation Trust Front cover photograph: Media Studio, Cambridge University Hospitals NHS Foundation Trust © University of Cambridge School of Clinical Medicine 2012 • MS111481 • 02/2012