Publications

The latest list of publications from the Cambridge Biomedical Research Centre with a brief summary. 

If you are publishing research which has had funding and / or support from the NIHR Cambridge Biomedical Research Centre, please complete the attached form

Publication: Nature Microbiology

Francesca Gaccioli, Susanne Lager, Marcus C. de Goffau, Ulla Sovio, Justyna Dopierala, Sungsam Gong, Emma Cook, Andrew Sharkey, Ashley Moffett, Wai Kwong Lee, Christian Delles, Cristina Venturini, Judith Breuer, Julian Parkhill, Sharon J. Peacock, D. Stephen Charnock-Jones & Gordon C. S. Smith

4 May 2020


Summary: 

The placenta is the interface between the mum and the fetus and supports the growth of the baby in the womb. Abnormal function of the placenta is associated with poor pregnancy outcome, including maternal and infant diseases and deaths. In turn, placental dysfunction could be due to viral infections, which are known to cause organ failure. We investigated whether viral infection of the placenta is associated with diseases of human pregnancy related to poor placental function, such as pre-eclampsia (hypertensive disorder in the mother) and fetal growth restriction (impaired growth of the fetus during pregnancy).

Using samples from more than 5,000 pregnancies and data available in the literature, we demonstrated that the presence of inherited human herpesvirus 6 (HHV-6) DNA in the feto-placental unit is associated with an increased risk of the mother to develop pre-eclampsia. The virus can be passed to the fetus and the placenta from both the mother and the father. Importantly, our study did not identify any other viral associations with the 2 studied conditions. HHV-6 was the only clear viral signal observed in a large number of placental samples from pathological and normal pregnancies.

Pre-eclampsia is a condition characterized by high maternal blood pressure and protein levels in the urine in the second half of pregnancy. It represents a major determinant of the global burden of disease. Although pre-eclamspia is known to be associated with poor development and function of the placenta, the causes of placental insufficiency are not fully understood. Identifying those will help us to understand and treat this condition, which affects 5-8% of all pregnant women and is responsible for over 75,000 maternal deaths and 500,000 fetal deaths worldwide every year. Our work demonstates that viral infection of the placenta is not a major cause of pre-eclampsia and that a small proportion of cases is likely to be due to the presence of HHV-6 in the feto-placental unit.

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Publication: Nature

Luiza Moore, Daniel Leongamornlert, Tim H. H. Coorens, Mathijs A. Sanders, Peter Ellis, Stefan Dentro, Kevin Dawson, Tim Butler, Raheleh Rahbari, Thomas J Mitchell, Francesco Maura, Jyoti Nangalia, Patrick S. Tarpey, Simon F. Brunner, Henry Lee-Six, Yvette Hooks, Sarah Moody, Krishnaa Mahbubani, Mercedes Jimenez-Linan, Jan J. Brosens, Christine A. Iacobuzio-Donahue, Inigo Martincorena, Kourosh Saeb-Parsy, Peter J. Campbell, Michael R. Stratton

22 April 2020


Summary: 

This paper looks at somatic mutation (changes in the DNA) in healthy human tissue in the endometrium (womb lining) and provides insights into the earliest stages of uterine cancer development, which is the fourth most common cancer in women in the UK.

Many cells in the inner lining of the uterus carry ‘cancer-driving’ mutations that frequently arise early in life. Using whole-genome sequencing to better understand the genetic changes in healthy endometrial tissue, the researchers found that a high proportion of cells carry driver mutations, even though they appear completely normal under the microscope. Furthermore the team found that many of these driver mutations appear to have arisen early in life, in many cases during childhood.

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Publication: BMC Medicine

Lois Kim, Nicholas Boxall, Anne George, Keith Burling, Pete Acher, Jonathan Aning, Stuart McCracken, Toby Page and Vincent J. Gnanapragasam

17 April 2020


Summary: 

At the moment if a man is referred for suspected prostate cancer he has to undergo an MRI scan and perhaps a prostate biopsy to find out if he has the disease. This costs a lot of money and means many hospital visits and potentially dangerous side effects (bleeding or infections from the biopsy). In this study researchers wanted to test if using a new biomarker blood test called PHI (Prostate Health Index) could reduce the number of unnecessary investigations for suspected prostate cancer. To do this they measured the PHI levels in over 500 men from 5 hospitals and tested how effective it was at selecting men for further investigations.

They found that if the PHI test was used to decide who should go onto have MRI and biopsies, doctors would reduce the number of scans needed by 25% and the number of biopsies needed by 40%, but still find the same number of prostate cancers. Moreover, using this test and pathway would save the NHS a lot of money as it is much cheaper than the current pathway.

Hospital visits and appointments could also be drastically reduced, which is particularly important in these days of shielding and social distancing to help with the COVID crisis.

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Publication: Scientific Reports

T. D. Turmezei, G. M. Treece, A. H. Gee, S. Sigurdsson, H. Jonsson, T. Aspelund, V. Gudnason & K. E. S. Poole

March 2020


Summary

Hip osteoarthritis is a very common condition that will affect up to 25% of the population in their lifetime. There is no cure for this painful and debilitating disease, with the mainstay of treatment currently being surgical replacement of the joint once it has become too stiff or painful to use. Research trials trying to find effective therapies for osteoarthritis currently rely on x-ray radiograph imaging to test if there have been any meaningful changes in the structure of the joint for a new therapy, but this method suffers from being unable to detect small changes reliably and from only being able to see the joint in 2D.

We developed the joint space mapping (JSM) technique in a collaboration between the Departments of Medicine and Engineering at the University of Cambridge and have since taken it to test on patient data from the widely regarded AGES-Reykjavik patient cohort of healthy older Icelandic adults.

Our research showed that JSM can identify structurally relevant disease features related to the important outcome of joint replacement in hip osteoarthritis better than the current clinical trial 2D imaging gold standards. This means that JSM could be a significantly better way of identifying who might be at high risk from getting hip osteoarthritis, those in whom the disease might be progressing rapidly, and whether any new therapy is effective at stopping the joint destruction that ultimately leads to joint failure. These results have been achieved by using an existing and readily available clinical imaging technique to look at the hip joint in 3D.

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Publication: European Heart Journal

Tammy Y N Tong, Paul N Appleby, Timothy J Key, Christina C Dahm, Kim Overvad, Anja Olsen, Anne Tjønneland, Verena Katzke, Tilman Kühn, Heiner Boeing, Anna Karakatsani, Eleni Peppa, Antonia Trichopoulou, Elisabete Weiderpass, Giovanna Masala, Sara Grioni, Salvatore Panico, Rosario Tumino, Jolanda M A Boer, W M Monique Verschuren, J Ramón Quirós, Antonio Agudo, Miguel Rodríguez-Barranco, Liher Imaz, María-Dolores Chirlaque, Conchi Moreno-Iribas, Gunnar Engström, Emily Sonestedt, Marcus Lind, Julia Otten, Kay-Tee Khaw, Dagfinn Aune, Elio Riboli, Nicholas J Wareham, Fumiaki Imamura, Nita G Forouhi, Emanuele di Angelantonio, Angela M Wood, Adam S Butterworth, Aurora Perez-Cornago

24 February 2020


Summary: 

This research looked at more than 418,000 people in nine European countries who were recruited to the European Prospective Investigation into Cancer and Nutrition (EPIC) study between 1992 and 2000. Researchers found that while higher intakes of fruit, vegetables, fibre, milk, cheese or yoghurt were each linked to a lower risk of ischaemic stroke, there was no significant association with a lower risk of haemorrhagic stroke.

As the study is observational, it cannot show that the foods studied cause an increase or decrease in risk of ischaemic or haemorrhagic stroke, only that they are associated with different risks.

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Publication: Clinical Transplantation

John O. O. Ayorinde, Mazin Hamed, Mingzheng Aaron Goh, Dominic M. Summers, Anna Dare, Yining Chen, Kourosh Saeb‐Parsy

20 January 2020


Summary:

This research recorded donor and recipient data of kidney transplants and matched them with clinical outcomes, helping to build the Cambridge Kidney Assessment Tool (CKAT).

CKAT will assist surgeons to define macroscopic features of donor kidneys to help them better predict clinical outcome and help reduce unecessary discarding of donor kidneys offered for transplantion.

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Publication: Science

Jong-Eun Park, Rachel A. Botting, Cecilia Domínguez Conde, Dorin-Mirel Popescu, Marieke Lavaert, Daniel J. Kunz, Issac Goh, Emily Stephenson, Roberta Ragazzini, Elizabeth Tuck, Anna Wilbrey-Clark, Kenny Roberts, Veronika R. Kedlian, John R. Ferdinand, Xiaoling He, Simone Webb, Daniel Maunder, Niels Vandamme, Krishnaa T. Mahbubani, Krzysztof Polanski, Lira Mamanova, Liam Bolt, David Crossland, Fabrizio de Rita, Andrew Fuller, Andrew Filby, Gary Reynolds, David Dixon, Kourosh Saeb-Parsy, Steven Lisgo, Deborah Henderson, Roser Vento-Tormo, Omer A. Bayraktar, Roger A. Barker, Kerstin B. Meyer, Yvan Saeys, Paola Bonfanti, Sam Behjati, Menna R. Clatworthy, Tom Taghon, Muzlifah Haniffa, Sarah A. Teichmann

21 February 2020


Summary:

Human thymus tissue makes T-cells for adaptive immunity and this research made a comprehensive cell atlas of thymus tissue over the course of human life, from embryo to adult thus gaining new insights into human T-cell development.

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Publication: Genome Biology

E. Madissoon, A. Wilbrey-Clark, R. J. Miragaia, K. Saeb-Parsy, K. T. Mahbubani, N. Georgakopoulos, P. Harding, K. Polanski, N. Huang, K. Nowicki-Osuch, R. C. Fitzgerald, K. W. Loudon, J. R. Ferdinand, M. R. Clatworthy, A. Tsingene, S. van Dongen, M. Dabrowska, M. Patel, M. J. T. Stubbington, S. A. Teichmann, O. Stegle & K. B. Meyer

31 December 2019


Summary: 

The Human Cell Atlas, which is an international collaboration to map all the cell types in the human body.

However, delays between fresh sample collection and processing may lead to poor data and difficulties in experimental design.

This study looked at the effect of cold storage on fresh healthy spleen, esophagus, and lung from donors and concluded that cold storage of tissue works well and increases the time frame for processing samples; however robust protocols are needed for tissue preservation that can be used by all the research teams involved.

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Publication: Nature

Anthony P. Coll, Michael Chen, Stephen O’Rahilly et al

25 December 2019


Cambridge scientists have discovered that metformin causes the cells of the intestine to make large amounts of a hormone, called GDF15, and secrete it into the bloodstream.

The high blood levels of GDF15 are sensed by a highly specific area of the brain where they suppress hunger and reduce food intake. When GDF15 is blocked, metformin has no effect on body weight.

The work was undertaken in the MRC Metabolic Diseases Unit at the University of Cambridge with collaborators at NGM Biopharmaceuticals, the University of Glasgow and elsewhere.

Dr Tony Coll, a lead author, said “We usually think that drugs have to pass through the intestine to have their effects in the body. In this case, though, the cells of the intestine themselves respond to the drug to create a hormonal signal which does the work.”

Metformin has been used to treat Type 2 diabetes for over 60 years and is the world’s most commonly prescribed anti-diabetic drug. It can also prevent the onset of diabetes in those at risk, doing so by helping people to lose and keep off weight. However, how metformin reduces body weight has been a mystery.

Professor Stephen O’Rahilly said: “How metformin keeps body weight down has been a mystery. This work shows that all of this effect is down to GDF15 acting on a tiny number of cells in the brain.”

These findings are supported  by an independent study from McMaster University published in Nature Metabolism  and should stimulate research into the use of GDF15 itself as an anti-obesity agent.

 

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Publication: J Clin Endocrinol Metab.

David Church, Luís Cardoso, Richard G Kay, Claire L Williams, Bernard Freudenthal, Catriona Clarke, Julie Harris, Myuri Moorthy, Efthmia Karra, Fiona M Gribble, Frank Reimann, Keith Burling, Alistair J K Williams, Alia Munir, T Hugh Jones, Dagmar Führer, Lars C Moeller, Mark Cohen, Bernard Khoo, David Halsall, Robert K Semple

31 July 2018


Insulin and c-peptide levels are routinely measured to monitor glucose-competence in patients, however, ocassionally the standard assays give readings well ouside the normal range. Very high readings could indicate an insulin producing tumor or exogenous insulin overdosing or in rare patients can be a result of insulin-auto antibodies.

LC-MS/MS can be a highly selective method to detect insulin and distinguishes between natural insulin and insulin drugs, making it valuable add-on to “standard” immunoassays when these give unexpected readings. It can also measure multiple analytes in a single extraction, reducing the volume of blood needed for analysis.

The superior performance of LC-MS/MS in analysing blood from insulin autoimmune syndrome patients should enable clearer diagnosis and the initiation of immunomodulatory therapy.

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Publication: Nature Medicine

Ulla Sovio, Neil Goulding, Nancy McBride, Emma Cook, Francesca Gaccioli, D. Stephen Charnock-Jones, Debbie A. Lawlor & Gordon C. S. Smith

11 March 2020


Summary: 

Fetal growth restriction (FGR) means that the fetus fails to grow according to its growth potential. The condition is a major cause of stillbirth, neonatal illness and death. Maternal risk factors and ultrasound measurements alone are not effective in screening for fetal growth restriction. Biomarkers in the pregnant woman’s blood could possibly improve screening for FGR.

Using serial maternal serum samples from the Pregnancy Outcome Prediction (POP) study, the research team identified metabolites that were predictive of FGR at term. These were used to calculate a ratio that clearly improves the prediction of FGR over currently known risk factors. They successfully validated the finding in plasma samples from a demographically different Born in Bradford (BiB) study.

Together with ultrasound measurements, the metabolite ratio could possibly be used to improve late pregnancy screening for fetal growth restriction. Screen-positive women could be offered enhanced monitoring and targeted induction of labour to prevent adverse effects associated with FGR.

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Publication: Immunity

Tomas Castro-Dopico, Thomas W. Dennison, John R. Ferdinand, Simon Clare, Miles Parkes, Menna R. Clatworthy et al

12 March 2019


Summary: 

Inflammatory bowel disease (IBD) is due to aberrant responses of the gut mucosa to the resident microbiome.

This research looked at Crohn’s and Ulcerative Colitis (both types of IBD) to identify which immune cells are involved in IBD, and to help identify novel therapeutic targets.

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