The latest list of publications from the Cambridge Biomedical Research Centre with a brief summary.
Jason M. Ali, Margaret C. Negus, Thomas M. Conlon, Ines G. Harper, M. Saeed Qureshi, Reza Motallebzadeh, Richard Willis, Kourosh Saeb-Parsy, Eleanor M. Bolton, J. Andrew Bradley, Gavin J. Pettigrew
9 February 2016
MHC alloantigen is recognized by two pathways: “directly,” intact on donor cells, or “indirectly,” as self-restricted allopeptide. The duration of each pathway, and its relative contribution to allograft vasculopathy, remain unclear. Using a murine model of chronic allograft rejection, we report that direct-pathway CD4 T cell alloresponses, as well as indirect-pathway responses against MHC class II alloantigen, are curtailed by rapid elimination of donor hematopoietic antigen-presenting cells. In contrast, persistent presentation of epitope resulted in continual division and less-profound contraction of the class I allopeptide-specific CD4 T cell population, with approximately 10,000-fold more cells persisting than following acute allograft rejection. This expanded population nevertheless displayed sub-optimal anamnestic responses and was unable to provide co-stimulation-independent help for generating alloantibody. Indirect-pathway CD4 T cell responses are heterogeneous. Appreciation that responses against particular alloantigens dominate at late time points will likely inform development of strategies aimed at improving transplant outcomes.View publication
Publication: Frontiers in Behavioural Neuroscience
George Savulich, Emily Thorp, Thomas Piercy, Katie A Peterson, John D Pickard, Barbara J Sahakian.
21 Jan 2019
A new ‘brain training’ game designed by researchers at the University of Cambridge improves users’ concentration, according to new research published today. The scientists behind the venture say this could provide a welcome antidote to the daily distractions that we face in a busy world.
A team from the Behavioural and Clinical Neuroscience Institute at the University of Cambridge, has developed and tested ‘Decoder’, a new game that is aimed at helping users improve their attention and concentration. The game is based on the team’s own research and has been evaluated scientifically.
In a study published in the journal Frontiers in Behavioural Neuroscience Professor Sahakian and colleague Dr George Savulich have demonstrated that playing Decoder on an iPad for eight hours over one month improves attention and concentration. This form of attention activates a frontal-parietal network in the brain. Read the full story hereView publication
Publication: Oxford Academic
Lisa Pennells, Stephen Kaptoge, AngelaWood, Mike Sweeting , Xiaohui Zhao, Ian White, Stephen Burgess, Peter Willeit, Thomas Bolton, Karel G.M. Moons, Yvonne T. van der Schouw, Randi Selmer, Kay-Tee Khaw, Vilmundur Gudnason, Gerd Assmann, Philippe Amouyel, Veikko Salomaa, Mika Kivimaki, Børge G. Nordestgaard, Michael J. Blaha, Lewis H. Kuller, Hermann Brenner, Richard F. Gillum, Christa Meisinger, Ian Ford, MatthewW. Knuiman, Annika Rosengren, Debbie A. Lawlor, Henry Vo¨ lzke, Cyrus Cooper, Alejandro Marı´n Iba~nez, Edoardo Casiglia, Jussi Kauhanen, Jackie A. Cooper, Beatriz Rodriguez, Johan Sundstro¨m, Elizabeth Barrett-Connor, Rachel Dankner, Paul J. Nietert, KarinaW. Davidson, Robert B.Wallace, Dan G. Blazer, Cecilia Bjo¨ rkelund, Chiara Donfrancesco, Harlan M. Krumholz, Aulikki Nissinen, Barry R. Davis, Sean Coady, Peter H.Whincup, Torben Jørgensen, Pierre Ducimetiere, Maurizio Trevisan, Gunnar Engstro¨m, Carlos J. Crespo, TomW. Meade, Marjolein Visser, Daan Kromhout, Stefan Kiechl, Makoto Daimon, Jackie F. Price, Agustin Go´mez de la Ca´mara, JWouter Jukema, Benoıˆt Lamarche, Altan Onat, Leon A. Simons, Maryam Kavousi, Yoav Ben-Shlomo, John Gallacher, Jacqueline M. Dekker, Hisatomi Arima, Nawar Shara, RobertW. Tipping, Ronan Roussel, Eric J Brunner, Wolfgang Koenig, Masaru Sakurai, Jelena Pavlovic, Ron T. Gansevoort, Dorothea Nagel, Uri Goldbourt, Elizabeth L.M. Barr, Luigi Palmieri, Inger Njølstad, Shinichi Sato,W.M. Monique Verschuren, Cherian V. Varghese, Ian Graham, Oyere Onuma, Philip Greenland, MarkWoodward, Majid Ezzati, Bruce M. Psaty, Naveed Sattar, Rod Jackson, Paul M. Ridker, Nancy R. Cook, Ralph B. D’Agostino,View publication
Loes CA Rutten-Jacobs, Susanna C Larsson,, Rainer Malik,, Kristiina Rannikmäe, MEGASTROKE consortium, International Stroke Genetics Consortium, Cathie L Sudlow, Martin Dichgans, Hugh S Markus, professor2, Matthew Traylor
Researchers investigated whether a genetic risk score for stroke is associated with actual (“incident”) stroke in a large population of British adults.
They developed a genetic risk score based on 90 gene variants known to be associated with stroke from 306,473 white men and women in the UK Biobank – a database of biological information from half a million British adults.
Participants were aged between 40 and 73 years and had no history of stroke or heart attack. Adherence to a healthy lifestyle was based on four factors: non-smoker, diet rich in fruit, vegetables and fish, not overweight or obese (body mass index less than 30), and regular physical exercise.
A high genetic risk combined with an unfavourable lifestyle profile was associated with a more than twofold increased risk of stroke compared with a low genetic risk and a favourable lifestyle. Full story hereView publication
Baland Jalal, Annette Brühl, Claire O’Callaghan, Thomas Piercy, Rudolf N. Cardinal, Vilayanur S. Ramachandran and Barbara J. Sahakian
A ‘brain training’ app could help people who suffer from obsessive compulsive disorder (OCD) manage their symptoms, which may typically include excessive handwashing and contamination fears.
One of the most common types of OCD, affecting up to 46% of OCD patients, is characterised by severe contamination fears and excessive washing behaviour. Excessive washing can be harmful as sometimes OCD patients use spirits, surface cleansers or even bleach to clean their hands. The behaviours can have a serious impact on people’s lives, their mental health, their relationships and their ability to hold down jobs.
Cambridge researchers developed a new treatment to help people with contamination fears and excessive washing. The intervention, which can be delivered through a smartphone app, involves patients watching videos of themselves washing their hands or touching fake contaminated surfaces. Read the full story here
Publication: Journal of the American College of Cardiology
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Genetic factors have long been known to be major contributors of someone’s risk of developing coronary heart disease – the leading cause of heart attacks. Currently to identify those at risk doctors use scores based on lifestyle and clinical conditions associated with coronary heart disease such as cholesterol level, blood pressure, diabetes and smoking. But these scores are imprecise, age-dependent and miss a large proportion of people who appear ‘healthy’, but will still develop the disease.
The ‘big-data’ GRS technique takes into account 1.7 million genetic variants in a person’s DNA to calculate their underlying genetic risk for coronary heart disease.
The team analysed genomic data of nearly half a million people from the UK Biobank research project aged between 40-69 years. This included over 22,000 people who had coronary heart disease.
The GRS was better at predicting someone’s risk of developing heart disease than each of the classic risk factors for coronary heart disease alone. The ability of the GRS to predict coronary heart disease was also largely independent of these known risk factors. This showed that the genes which increase the risk of coronary heart disease don’t simply work by elevating blood pressure or cholesterol, for example.
People with a genomic risk score in the top 20 per cent of the population were over four-times more likely to develop coronary heart disease than someone with a genomic risk score in the bottom 20 per cent. Read the full press releaseView publication
Publication: Nature Genetics
Geoff Macintyre, Teodora E. Goranova, Dilrini De Silva, Darren Ennis, Anna M. Piskorz, Matthew Eldridge, Daoud Sie, Liz-Anne Lewsley, Aishah Hanif, Cheryl Wilson, Suzanne Dowson, Rosalind M. Glasspool, Michelle Lockley, Elly Brockbank, Ana Montes, Axel Walther, Sudha Sundar, Richard Edmondson, Geoff D. Hall, Andrew Clamp, Charlie Gourley, Marcia Hall, Christina Fotopoulou, Hani Gabra, James Paul, Anna Supernat, David Millan, Aoisha Hoyle, Gareth Bryson, Craig Nourse, Laura Mincarelli, Luis Navarro Sanchez, Bauke Ylstra, Mercedes Jimenez-Linan, Luiza Moore, Oliver Hofmann, Florian Markowetz, Iain A. McNeish and James D. Brenton
Researchers have found distinct patterns of DNA rearrangement that are linked to patient outcomes.
In this study of ovarian cancer samples from over 500 women, the research team harnessed big data processing techniques to look for broad patterns in the genetic readouts from ovarian cancer cells.
Rather than focusing on the detail of each individual mistake in the DNA, they designed powerful computer algorithms to scan the genetic data, finding seven distinct patterns.
They showed that each pattern, or “signature”, represented a different mechanism of DNA mutation. Taken together, these signatures were able to make sense of the chaos seen in ovarian cancer genomes. Read the full story hereView publication
Publication: The Lancet
Michael J Sweeting, Katya L Masconi, PhD, Edmund Jones, PhD, Pinar Ulug, PhD, Matthew J Glover, MSc, Prof Jonathan A Michaels, MChir, Prof Matthew J Bown, MD, Prof Janet T Powell, MD, Prof Simon G Thompson, DSc
The NHS introduced ultrasound screening in men aged 65 and over in 2009 to detect and treat the condition – which arises when the main blood vessel swells in the abdomen, and is symptomless until the point of rupture. Since the launch, the programme has been successfully screening and identifying men at risk of an AAA.
Researchers wanted to see if UK women – who are less likely to have AAAs – could also benefit from a similar screening programme. Read the full press release here
Publication: The Lancet
Gemma D Banham, MRCP(UK), Shaun M Flint, FRACP, Nicholas Torpey, FRCP, Paul A Lyons, PhD, Don N Shanahan, MSc, Adele Gibson, BSc, Prof Christopher J E Watson, FRCS, Ann-Marie O’Sullivan, MRes, Joseph A Chadwick, Katie E Foster, PhD, Rachel B Jones, FRCP, Luke R Devey, MRCSEd, Anna Richards, MRCP(UK), Prof Lars-Peter Erwig, MD, Prof Caroline O Savage,FMedSci, Prof Kenneth G C Smith, FMedSci, Robert B Henderson, PhD, Menna R Clatworthy, FRCP†,
Transplantation is the best form of treatment for most patients with end-stage renal failure, but long-term graft survival is limited by the development of antibodies against the graft. There is therefore a major unmet need to find immunosuppressants that target humoral alloimmunity.
Researchers investigated the use of Belimumab, a monoclonal antibody that binds the B cell pro-survival cytokine BAFF, in kidney transplant recipients.
The study found that the use of belimumab was not associated with any excess risk of infection, and led to a reduction in antibody-producing plasmablasts, activated memory B cells, new IgG antibody formation and in non-HLA IgG antibodies associated with poor graft outcomes. Remarkably, belimumab treatment spared regulatory B cells – a cell type associated with transplant tolerance, with an increase in IL10-producing B cells observed.View publication
Publication: The Lancet
Angela M Wood PhD, P, Stephen Kaptoge, PhD, Adam S Butterworth, PhD, Peter Willeit, MD, Samantha Warnakula, PhD, Thomas Bolton, MMath, Ellie Paige, PhD, Dirk S Paul, PhD, Michael Sweeting, PhD, Stephen Burgess, PhD, Steven Bell, PhD, William Astle, PhD, David Stevens, MSc, Albert Koulman, PhD, Randi M Selmer, PhD, Prof W M Monique Verschuren, PhD, Prof Shinichi Sato, MD, Prof Inger Njølstad, MD, Prof Mark Woodward, PhD, Prof Veikko Salomaa, MD, Prof Børge G Nordestgaard, MD, Prof Bu B Yeap, MBBS, Prof Astrid Fletcher, PhD, Prof Olle Melander, MD, Prof Lewis H Kuller, MD, Beverley Balkau, PhD, Prof Michael Marmot, FMedSci, Prof Wolfgang Koenig, MD, Prof Edoardo Casiglia, MD, Prof Cyrus Cooper, FMedSci, Volker Arndt, MD, Prof Oscar H Franco, MD, Patrik Wennberg, MD, Prof John Gallacher, PhD, Agustín Gómez de la Cámara, MD, Prof Henry Völzke, MD, Christina C Dahm, PhD, Caroline E Dale, PhD, Manuela M Bergmann, PhD, Carlos J Crespo, PhD, Prof Yvonne T van der Schouw, PhD, Prof Rudolf Kaaks, MD, Leon A Simons, MD, Pagona Lagiou, MD, Josje D Schoufour, PhD, Jolanda M A Boer, PhD, Prof Timothy J Key, DPhil, Beatriz Rodriguez, MD, Conchi Moreno-Iribas, PhD, Karina W Davidson, PhD, James O Taylor, MD, Carlotta Sacerdote, PhD, Prof Robert B Wallace, MD, J Ramon Quiros, MD, Prof Rosario Tumino, MD, Dan G Blazer II, MD, Prof Allan Linneberg, MD, Makoto Daimon, MD, Salvatore Panico, MD, Barbara Howard, PhD, Guri Skeie, PhD, Prof Timo Strandberg, MD, Prof Elisabete Weiderpass, PhD, Prof Paul J Nietert, PhD, Prof Bruce M Psaty, MD, Prof Daan Kromhout, PhD, Elena Salamanca-Fernandez, MSc, Prof Stefan Kiechl, MD, Prof Harlan M Krumholz, MD, Sara Grioni, BSc, Domenico Palli, MD, José M Huerta, PhD, Prof Jackie Price, MD, Prof Johan Sundström, MD, Larraitz Arriola, MD, Prof Hisatomi Arima, MD, Ruth C Travis, DPhil, Prof Demosthenes B Panagiotakos, PhD, Anna Karakatsani, MD, Prof Antonia Trichopoulou, MD, Tilman Kühn, PhD, Prof Diederick E Grobbee, MD, Elizabeth Barrett-Connor, MD, Natasja van Schoor, MD, Prof Heiner Boeing, PhD, Prof Kim Overvad, MD, Prof Jussi Kauhanen, MD, Prof Nick Wareham, MD, Claudia Langenberg, MD, Prof Nita Forouhi, PhD, Maria Wennberg, PhD, Prof Jean-Pierre Després, DPhil, Prof Mary Cushman, MD, Jackie A Cooper, MSc, Prof Carlos J Rodriguez, MD, Masaru Sakurai, MD, Jonathan E Shaw, PhD, Prof Matthew Knuiman, PhD, Trudy Voortman, PhD, Prof Christa Meisinger, MD, Anne Tjønneland, MD, Prof Hermann Brenner, MD, Luigi Palmieri, PhD, Jean Dallongeville, MD, Prof Eric J Brunner, PhD, Prof Gerd Assmann, MD, Maurizio Trevisan, MD, Richard F Gillum, MD, Prof Ian Ford, PhD, Prof Naveed Sattar, FMedSci, Mariana Lazo, MD, Prof Simon G Thompson, FMedSci, Pietro Ferrari, PhD, Prof David A Leon, PhD, Prof George Davey Smith, MD, Prof Richard Peto, FRS, Prof Rod Jackson, PhD, Prof Emily Banks, PhD, Emanuele Di Angelantonio, MD, Prof John Danesh,
Regularly drinking more than the recommended UK guidelines for alcohol could take years off your life, according to new research from the University of Cambridge. The study shows that drinking more alcohol is associated with a higher risk of stroke, fatal aneurysm, heart failure and death.
The authors say their findings challenge the widely held belief that moderate drinking is beneficial to cardiovascular health, and support the UK’s recently lowered guidelines. The study compared the health and drinking habits of over 600,000 people in 19 countries worldwide and controlled for age, smoking, history of diabetes, level of education and occupation.
Publication: Nature Communications
Stefan Gräf, Matthias Haimel, Marta Bleda, Charaka Hadinnapola, Laura Southgate, Wei Li, Joshua Hodgson, Bin Liu, Richard M. Salmon, Mark Southwood, Rajiv D. Machado, Jennifer M. Martin, Carmen M. Treacy, Katherine Yates, Louise C. Daugherty, Olga Shamardina, Deborah Whitehorn, Simon Holden, Micheala Aldred, Harm J. Bogaard, Colin Church, Gerry Coghlan, Robin Condliffe, Paul A. Corris, Cesare Danesino, Mélanie Eyries, Henning Gall, Stefano Ghio, Hossein-Ardeschir Ghofrani, J. Simon R. Gibbs, Barbara Girerd, Arjan C. Houweling, Luke Howard, Marc Humbert, David G. Kiely, Gabor Kovacs, Robert V. MacKenzie Ross, Shahin Moledina, David Montani, Michael Newnham, Andrea Olschewski, Horst Olschewski, Andrew J. Peacock, Joanna Pepke-Zaba, Inga Prokopenko, Christopher J. Rhodes, Laura Scelsi, Werner Seeger, Florent Soubrier, Dan F. Stein, Jay Suntharalingam, Emilia M. Swietlik, Mark R. Toshner, David A. van Heel, Anton Vonk Noordegraaf, Quinten Waisfisz, John Wharton, Stephen J. Wort, Willem H. Ouwehand, Nicole Soranzo, Allan Lawrie, Paul D. Upton, Martin R. Wilkins, Richard C. Trembath & Nicholas W. Morrell
Pulmonary Arterial Hypertension (PAH) is a fatal lung disease and causes the walls of the arteries become thick and stiff, narrowing the space for blood to pass through and increasing blood pressure then leading to heart failure.
The disease kills 50% of those affected within five years, but little was known about what caused the condition in some people. Now experts say they have discovered five genes that cause the illness and could pave the way for more treatments.
Scientists carried out the largest ever genetic study of the disease by analysing the genomes – the unique sequence of a person’s DNA – of more than 1,000 PAH patients for whom the cause of the illness was unknown.
They found that mutations in five genes were responsible for causing the illness in these people, including in four genes that were not previously known to be involved in the disease. In people with the condition these genes fail to effectively produce the proteins that are required for the structure, function and regulation of the body’s tissues, researchers found.View publication
Linda M. O’Keeffe, PhD; Anna Ramond, DPharm; Clare Oliver-Williams, PhD; Peter Willeit, MD; Ellie Paige, PhD; Patrick Trotter, MBChB; Jonathan Evans, MBChB; Jonas Wadström, MD; Michael Nicholson, MD; Dave Collett, PhD; Emanuele Di Angelantonio, MD
Living kidney donors are not at increased risk for some health outcomes previously of concern, but do seem at risk for worse blood pressure and kidney function than nondonors. In addition, female donors seem to be at increased risk for preeclampsia.
A team lead by researchers reviewed 52 published studies comprising more than 100,000 living kidney donors and more than 110,000 nondonors to assess the mid- and long-term health risks associated with living kidney donation in adults.
The data showed that kidney donors had higher diastolic blood pressure, poorer renal function, and higher risk for ESRD than nondonors. Female donors had an almost two-fold higher risk than nondonors for pregnancy-related complications, such as preeclampsia.
There was no evidence that living kidney donors had higher risk for mortality, cardiovascular disease, or type 2 diabetes, or reduced quality of life.View publication