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In the EU alone, 78,800 men died of prostate cancer last year. While tumors discovered at an early stage can often be completely removed by surgery and radiation therapy, the prospects of successful treatment are reduced if the cancer has further metastasized. At present, physicians cannot predict drug response or therapy resistance in patients.
Three-dimensional structures
The team led by PD Dr. Marianna Kruithof-de Julio at the Urology Research Laboratory at the Department for BioMedical Research (DBMR) of the University of Bern and Inselspital Bern, has developed a new strategy for the generation of prostate cancer organoids that can contribute to assess therapy response, their work is published in the latest issue of Nature Communications. Drs Sofia Karkampouna and Federico La Manna, the two lead co-authors of the paper, spent over one and a half year in optimizing and efficient protocol for the generation of the patient derived organoids and their detailed characterization. Moreover, in collaboration with the NEXUS Personalized Health Technologies, they have meticulously developed a medium-throughput screen for drug testing.
The researchers led by PD Dr. Kruithof-de Julio have demonstrated that patient-derived organoids retain relevant characteristics of the prostate carcinoma from which they have been originated: not only are they characterized by the same genetic mutations, but they also exhibit similar gene activity patterns.
Paving the way for personalized medicine
PD Dr. Kruithof-de Julio and her collaborators first generated a novel early stage, patient derived xenograft that is treatment naïve, then tested 74 different drugs on organoids from this and other experimental tumor models — identifying 13 compounds that reduced prostate cancer cell viability.
The researchers then tested the efficacy of these compounds on organoids from five prostate cancer patients — two with early-stage tumors and three with advanced metastatic tumors. Interestingly, among the hits ponatinib, so far approved for the treatment of leukemia, proved to be particularly effective in reduction of organoid viability and tumor growth in vivo.
However, for PD Dr. Kruithof-de Julio, the significance of these results lies not only in the drug repurposing but more importantly in promoting an approach that the medical community can undertake. “Our results pave the way for personalized medicine. In our study we only analyzed data from five patients retrospectively,” says Kruithof-de Julio. “But we clearly showed that the method would be in principle feasible. Growing the organoids and drug testing can be accomplished in two weeks, a time frame that is compatible with clinical decision making. In collaboration with the Urology Department of the Inselspital, led by Prof Thalmann, we have now already been able to prove this in several cases.”
“In my clinical activity, I am regularly confronted by tumors that do not respond to therapy or for which we do not know which therapy to use,” says Thalmann. “This is a further step in the direction of individualized medicine, where we might be able to tailor the treatment to the tumor during the course of the disease and better understand its biology.” With this approach, the researchers hope to treat patients more efficiently with less side effects and diminished costs.

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Concussion, a form of traumatic brain injury, is a common injury among children and teens. Concussions can have adverse effects on physical, cognitive, emotional and sleep health. Clinical guidelines for managing concussion in children and teens traditionally recommend complete physical and cognitive rest until symptom resolution, followed by a gradual return to activities like school and sports. These guidelines are often disputed and based on expert consensus as opposed to strong evidence. The challenge has been how to quantify the amount of physical and cognitive activity that children and teens should engage in during recovery. A new study by researchers at the Center for Injury Research and Policy, Sports Medicine, and Emergency Medicine at Nationwide Children’s Hospital investigated objectively measured, self-paced physical and cognitive activity across the first week post-concussion.
The study, published today in the Journal of Head Trauma Rehabilitation, found that self-paced physical and cognitive activity during the first week after sustaining a concussion alone neither hastened nor prolonged concussion recovery in children and teens. These findings indicate that children and teens with concussion may have some flexibility to determine their own activity levels during recovery. Physicians may encourage safe, non-contact, light physical activity if it does not make youths’ concussion symptoms worse, while also continuing to emphasize appropriate amounts of necessary rest.
Study participants were 11 to 17 years old, seen within 72 hours of injury in the emergency department or a concussion clinic through Nationwide Children’s Hospital and received a physician-confirmed diagnosis of concussion. They wore two devices — one to measure their physical activity and sleep around the clock, and one to measure their cognitive activity outside of school. Participants rated their daily concussion symptoms by completing the Postconcussion Symptom Scale during the first week post-injury.
Researchers found that while daily physical and cognitive activity increased across the first week post-injury, daily post-concussion symptoms decreased. Increased daily step count was associated with an increased likelihood of early symptom resolution. However, this association was not statistically significant after adjusting for acute post-concussion symptoms and other covariates.
“This study is the first to objectively measure self-paced cognitive activity during the first week post-injury,” said Ginger Yang, PhD, MPH, lead author of the study and principal investigator in the Center for Injury Research and Policy at Nationwide Children’s. “While increased physical and cognitive activity may help reduce post-concussion symptoms, reduced symptoms may also lead to increased physical and cognitive activity levels, highlighting the need for further research to better understand this bi-directional relationship.” Such research will provide evidence of when an individual is ready for physical and cognitive activity after concussion and what level of activity is most appropriate. This information could be used by clinicians to inform treatment decisions, including individualized physical and cognitive activity recommendations post-concussion.
“Concussions behave somewhat like snowflakes in that they are not all the same, and the specific effects of concussion on our young patients varies greatly — one size or treatment does not, necessarily, fit all,” said Thomas Pommering, DO, co-author of the study and division chief of sports medicine at Nationwide Children’s. “The strength of this study is that it appears that children and adolescents with concussions are generally pretty good at self-pacing their physical and cognitive activity so as to not prolong their recovery. With the guidance of physicians, there may be room for personalized treatment plans based on the symptom burden, while still following important guidelines protecting the patient from repeat head injury during the recovery time.”
Data for this study came from youth-parent dyads referred to the study team by their school athletic trainer or recruited at the Nationwide Children’s Hospital emergency department or concussion clinics. Following a physician-confirmed diagnosis of concussion, youth-parent dyads were contacted by research staff and enrolled within 72 hours post-injury after providing written assent and consent. Enrolled dyads were then followed until symptom resolution (defined as being symptom-free or symptoms returned to pre-injury level), or 45 days post-injury, whichever occurred first.

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Several processes in the human body are regulated by biochemical reactions involving hydrogen peroxide (H2O2). Although it can act as a ‘secondary messenger’, relaying or amplifying certain signals between cells, H2O2 is generally toxic because of its oxidant character. The latter means that it converts (oxidizes) biochemical molecules like proteins and DNA. The oxidizing property of H2O2 is of potential therapeutic relevance for cancer, though: deliberately causing tumor cells to increase their H2O2 concentration would be a way to destroy them. In light of this, but also for monitoring pathologies associated with H2O2 overproduction, it is crucial to have a means to reliably quantify hydrogen peroxide concentrations in the extracellular environment. Now, Leonardo Puppulin from Nano Life Science Institute (WPI-NanoLSI), Kanazawa University and colleagues have developed a sensor for measuring concentrations of H2O2 in the vicinity of cell membranes, with nanometer-resolution.
The biosensor consists of a gold nanoparticle with organic molecules attached to it. The whole cluster is designed so that it anchors easily to the outside of a cell’s membrane, which is exactly where the hydrogen peroxide molecules to be detected are. As attachment molecules, the scientists used a compound called 4MPBE, known to have a strong Raman scattering response: when irradiated by a laser, the molecules consume some of the laser light’s energy. By measuring the frequency change of the laser light, and plotting the signal strength as a function of this change, a unique spectrum is obtained — a signature of the 4MPBE molecules. When a 4MPBE molecule reacts with a H2O2 molecule, its Raman spectrum changes. Based on this principle, by comparing Raman spectra, Puppulin and colleagues were able to obtain an estimate of the H2O2 concentration near the biosensor.
After developing a calibration procedure for their nanosensor — relating the H2O2 concentration to a change in Raman spectrum in a quantitative way is not straightforward — the scientists were able to produce a concentration map with a resolution of about 700 nm for lung cancer cell samples. Finally, they also succeeded in extending their technique to obtain measurements of the H2O2 concentration variation across cell membranes.
Puppulin and colleagues conclude that their “novel approach may be useful for the study of actual H2O2 concentrations involved in cell proliferation or death, which are fundamental to fully elucidate physiological processes and to design new therapeutic strategies.”
Surface-enhance Raman spectroscopy
The biosensor developed by Leonardo Puppulin from Kanazawa University and colleagues is based on a method called surface-enhanced Raman spectroscopy (SERS). The principle derives from Raman spectroscopy, in which differences between the incoming and the outcoming frequencies of laser light irradiated onto a sample are analyzed. The spectrum obtained by plotting the signal strength as a function of frequency difference is characteristic for the sample, which can in principle be a single molecule. Typically, however, the signal coming from one molecule is too weak to detect, but the effect can be enhanced when the molecule is absorbed on a rough metal surface. Puppulin and colleagues applied the technique to (indirectly) detect hydrogen peroxide; their Raman-responsive molecule is a compound called 4MPBE, which is modified when exposed to hydrogen peroxide.

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Native to the southeastern United States, a weedy grass has spread northward to Canada and also made its way to Australia and Japan. Andropogon virginicus grows densely packed and up to seven feet tall, disrupting growth patterns of other plants and competing for resources. When burned, it grows back stronger. There is no way to effectively remove the weed once it has invaded. But there might be a way to use it to human advantage.
An international team of researchers has found that A. virginicus extracts appear to be effective against several human diseases, including diabetes and cancer. The results were published on Dec. 31, 2020, in a special issue of Plants, titled “Biological Activities of Plant Extracts.”
“A. virginicus is an invasive weed that seriously threatens agricultural production and economics worldwide,” said paper author Tran Dang Xuan, associate professor in the Transdisciplinary Science and Engineering Program in the Graduate School of Advanced Science and Engineering at Hiroshima University. “However, no solution efficiently utilizing and tackling this plant has been found yet. In this paper, we highlight the potential application of A. virginicus extracts in future medicinal production and therapeutics of chronic diseases such as type 2 diabetes and blood cancer, which can deal with both crop protection and human health concerns.”
Researchers found high levels of flavonoids in the samples they extracted from the weed. These plant chemicals have significant antioxidant and anti-inflammatory properties, according to Xuan. When tested against a variety of cell lines, the extracted plant chemicals bonded to free radicals, preventing damage to the cells. At skin level, this helps prevent age spots by inhibiting a protein called tyrosinase. Among other, deeper healthful actions, this bonding also helps prevent knock-on cellular actions that can lead to type 2 diabetes.
The team also specifically applied the extracted chemicals to a line of chronic myelogenous leukemia, a rare blood cancer. The extract appeared to kill off the cancer cells.
Xuan said the researchers plan to establish a comprehensive process to isolate and purify the compounds responsible for known biological properties, as well as work to identify new uses. They will further test the therapeutical effects of the compounds, with the eventual goal of preparing functional pharmaceuticals for human use.
“Although A. virginicus has been considered a harmful invasive species without economic value, its extracts are promising sources of antioxidant, anti-diabetic, anti-tyrosinase, and antitumor agents,” Xuan said.

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New clues as to why night shift workers are at increased risk of developing certain types of cancer are presented in a new study conducted at Washington State University Health Sciences Spokane.
Published online in the Journal of Pineal Research, the study involved a controlled laboratory experiment that used healthy volunteers who were on simulated night shift or day shift schedules. Findings from the study suggest that night shifts disrupt natural 24-hour rhythms in the activity of certain cancer-related genes, making night shift workers more vulnerable to damage to their DNA while at the same time causing the body’s DNA repair mechanisms to be mistimed to deal with that damage.
Though more research still needs to be done, these discoveries could someday be used to help prevent and treat cancer in night shift workers.
“There has been mounting evidence that cancer is more prevalent in night shift workers, which led the World Health Organization’s International Agency for Research on Cancer to classify night shift work as a probable carcinogenic,” said co-corresponding author Shobhan Gaddameedhi, an associate professor formerly with the WSU College of Pharmacy and Pharmaceutical Sciences and now with North Carolina State University’s Biological Sciences Department and Center for Human Health and the Environment. “However, it has been unclear why night shift work elevates cancer risk, which our study sought to address.”
Studying the rhythms in cancer-related genes
As part of a partnership between the WSU Sleep and Performance Research Center and the U.S. Department of Energy’s Pacific Northwest National Laboratory (PNNL), Gaddameedhi and other WSU scientists worked with bioinformatics experts at PNNL to study the potential involvement of the biological clock, the body’s built-in mechanism that keeps us on a 24-hour night and day cycle. Though there is a central biological clock in the brain, nearly every cell in the body also has its own built-in clock. This cellular clock involves genes known as clock genes that are rhythmic in their expression, meaning their activity levels vary with the time of day or night. The researchers hypothesized that the expression of genes associated with cancer might be rhythmic, too, and that night shift work might disrupt the rhythmicity of these genes.

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To test this, they conducted a simulated shift work experiment that had 14 participants spend seven days inside the sleep laboratory at WSU Health Sciences Spokane. Half of them completed a three-day simulated night shift schedule, while the other half were on a three-day simulated day shift schedule. After completing their simulated shifts, all participants were kept in a constant routine protocol that is used to study humans’ internally generated biological rhythms independent of any external influences. As part of the protocol, they were kept awake for 24 hours in a semi-reclined posture under constant light exposure and room temperature and were given identical snacks every hour. Every three hours a blood sample was drawn.
Analyses of white blood cells taken from the blood samples showed that the rhythms of many of the cancer-related genes were different in the night shift condition compared to the day shift condition. Notably, genes related to DNA repair that showed distinct rhythms in the day shift condition lost their rhythmicity in the night shift condition.
The researchers then looked at what the consequences of the changes in the expression of cancer-related genes might be. They found that white blood cells isolated from the blood of night shift participants showed more evidence of DNA damage than those of day shift participants. What’s more, after the researchers exposed isolated white blood cells to ionizing radiation at two different times of day, cells that were radiated in the evening showed increased DNA damage in the night shift condition as compared to the day shift condition. This meant that white blood cells from night shift participants were more vulnerable to external damage from radiation, a known risk factor for DNA damage and cancer.
“Taken together, these findings suggest that night shift schedules throw off the timing of expression of cancer-related genes in a way that reduces the effectiveness of the body’s DNA repair processes when they are most needed,” said co-corresponding author Jason McDermott, a computational scientist with the Pacific Northwest National Laboratory’s Biological Sciences Division.
Potential for improved prevention, treatment
The researchers’ next step is to conduct the same experiment with real-world shift workers who have been consistently on day or night shifts for many years to determine whether in night workers the unrepaired DNA damage builds up over time, which could ultimately increase the risk of cancer. If what happens in real-world shift workers is consistent with the current findings, this work could eventually be used to develop prevention strategies and drugs that could address the mistiming of DNA repair processes. It could also be the basis for strategies to optimize the timing of cancer therapy so that treatment is administered when effectiveness is greatest and side effects are minimal, a procedure called chronotherapy that would need to be fine-tuned to the internal rhythms of night workers.
“Night shift workers face considerable health disparities, ranging from increased risks of metabolic and cardiovascular disease to mental health disorders and cancer,” said co-senior author Hans Van Dongen, a professor in the WSU Elson S. Floyd College of Medicine and director of the WSU Sleep and Performance Research Center. “It is high time that we find diagnosis and treatment solutions for this underserved group of essential workers so that the medical community can address their unique health challenges.”
In addition to Van Dongen, Gaddameedhi, and McDermott, study authors included Bala Koritala, Kenneth Porter, Osama Arshad, Rajendra Gajula, Hugh Mitchell, Tarana Arman, Mugimane Manjanatha, and Justin Teeguarden.
Funding: National Institutes of Health, Congressionally Directed Medical Research Programs, BRAVE Investment at the Pacific Northwest National Laboratory

Virtual reality avatar-based coaching shows promise to increase access to and extend the reach of nutrition education programs to children at risk for obesity, according to a new study in the Journal of Nutrition Education and Behavior, published by Elsevier.
Researchers introduced 15 adult-child dyads to a virtual avatar-based coaching program that incorporated age-specific information on growth; physical, social, and emotional development; healthy lifestyles; common nutrition concerns; and interview questions around eating behaviors and food resources and counseling.
“We developed a virtual reality avatar computer program as a way to get kids engaged in learning about nutrition education. The goal was to make this a program that could work to prevent childhood obesity,” said lead investigator Jared T. McGuirt, PhD, MPH, Department of Nutrition, University of North Carolina Greensboro, Greensboro, NC, USA. “We were primarily interested in how kids and parents reacted to this program — particularly lower income kids and parents who may not have been able to access this kind of experience in the past.”
A key finding in the study was the avatar’s ability to spark dialogue between the children and adults around dietary habits and behavior. All children and adults reported liking the program and planned to use it in the future, as they found it fun, informational, and motivating. The personalized social aspect of the avatar experience was appealing, as participants thought the avatar would reinforce guidance and provide support while acting as a cue to change health behaviors.
Looking to future implementation of this program in the public health field, Dr. McGuirt noted: “We feel we have a good start. The program was designed so others can build on it, and hopefully advance this technique into community nutrition education programs.

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North Carolina State University engineers continue to improve the efficiency of a flexible device worn on the wrist that harvests heat energy from the human body to monitor health.
In a paper published in npj Flexible Electronics, the NC State researchers report significant enhancements in preventing heat leakage in the flexible body heat harvester they first reported in 2017 and updated in 2020. The harvesters use heat energy from the human body to power wearable technologies — think of smart watches that measure your heart rate, blood oxygen, glucose and other health parameters — that never need to have their batteries recharged. The technology relies on the same principles governing rigid thermoelectric harvesters that convert heat to electrical energy.
Flexible harvesters that conform to the human body are highly desired for use with wearable technologies. Mehmet Ozturk, an NC State professor of electrical and computer engineering and the corresponding author of the paper, mentioned superior skin contact with flexible devices, as well as the ergonomic and comfort considerations to the device wearer, as the core reasons behind building flexible thermoelectric generators, or TEGs.
The performance and efficiency of flexible harvesters, however, historically trail well behind rigid devices, which have been superior in their ability to convert body heat into usable energy.
The NC State proof-of-concept TEG originally reported in 2017 employed semiconductor elements that were connected electrically in series using liquid-metal interconnects made of EGaIn — a non-toxic alloy of gallium and indium. EGaIn provided both metal-like electrical conductivity and stretchability. The entire device was embedded in a stretchable silicone elastomer.
The upgraded device reported in 2020 employed the same architecture but significantly improved the thermal engineering of the previous version, while increasing the density of the semiconductor elements responsible for converting heat into electricity. One of the improvements was a high thermal conductivity silicone elastomer — essentially a type of rubber — that encapsulated the EGaIn interconnects.
The newest iteration adds aerogel flakes to the silicone elastomer to reduce the elastomer’s thermal conductivity. Experimental results showed that this innovation reduced the heat leakage through the elastomer by half.
“The addition of aerogel stops the heat from leaking between the device’s thermoelectric ‘legs,'” Ozturk said. “The higher the heat leakage, the lower the temperature that develops across the device, which translates to lower output power.
“The flexible device reported in this paper is performing an order of magnitude better than the device we reported in 2017 and continues to approach the performance of rigid devices,” Ozturk added.
Ozturk said that one of the strengths of the NC State-patented technology is that it employs the very same semiconductor elements used in rigid devices perfected after decades of research. The approach also provides a low-cost opportunity to existing rigid thermoelectric module manufacturers to enter the flexible thermoelectric market.
He added that his lab will continue to focus on improving the efficiency of these flexible devices.

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Materials provided by North Carolina State University. Original written by Mick Kulikowski. Note: Content may be edited for style and length.

Diphtheria — a relatively easily-preventable infection — is evolving to become resistant to a number of classes of antibiotics and in future could lead to vaccine escape, warn an international team of researchers from the UK and India.
The researchers, led by scientists at the University of Cambridge, say that the impact of COVID-19 on diphtheria vaccination schedules, coupled with a rise in the number of infections, risk the disease once more becoming a major global threat.
Diphtheria is a highly contagious infection that can affect the nose and throat, and sometimes the skin. If left untreated it can prove fatal. In the UK and other high-income countries, babies are vaccinated against infection. However, in low- and middle-income countries, the disease can still cause sporadic infections or outbreaks in unvaccinated and partially-vaccinated communities.
The number of diphtheria cases reported globally has being increasing gradually. In 2018, there were 16,651 reported cases, more than double the yearly average for 1996-2017 (8,105 cases).
Diphtheria is primarily caused by the bacterium Corynebacterium diphtheriae and is mainly spread by coughs and sneezes, or through close contact with someone who is infected. In most cases, the bacteria cause acute infections, driven by the diphtheria toxin — the key target of the vaccine. However, non-toxigenic C. diphtheria can also cause disease, often in the form of systemic infections.
In a study published today in Nature Communications, an international team of researchers from the UK and India used genomics to map infections, including a subset from India, where over half of the globally reported cases occurred in 2018.

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By analysing the genomes of 61 bacteria isolated from patients and combining these with 441 publicly available genomes, the researchers were able to build a phylogenetic tree — a genetic ‘family tree’ — to see how the infections are related and understand how they spread. They also used this information to assess the presence of antimicrobial resistance (AMR) genes and assess toxin variation.
The researchers found clusters to genetically-similar bacteria isolated from multiple continents, most commonly Asia and Europe. This indicates that C. diphtheriae has been established in the human population for at least over a century, spreading across the globe as populations migrated.
The main disease-causing component of C. diphtheriae is the diphtheria toxin, which is encoded by the tox gene. It is this component that is targeted by vaccines. In total, the researchers found 18 different variants of the tox gene, of which several had the potential to change the structure of the toxin.
Professor Gordon Dougan from the Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID) said: “”The diphtheria vaccine is designed to neutralise the toxin, so any genetic variants that change the toxin’s structure could have an impact on how effective the vaccine is. While our data doesn’t suggest the currently used vaccine will be ineffective, the fact that we are seeing an ever-increasing diversity of tox variants suggests that the vaccine, and treatments that target the toxin, need to be appraised on a regular basis.”
Diphtheria infections can usually be treated with a number of classes of antibiotic. While C. diphtheriae resistant to antibiotics have been reported, the extent of such resistance remains largely unknown.

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When the team looked for genes that might confer some degree of resistance to antimicrobials, they found that the average number of AMR genes per genome was increasing each decade. Genomes of bacteria isolated from infections from the most recent decade (2010-19) showed the highest average number of AMR genes per genome, almost four times as many on average than in the next highest decade, the 1990s.
Robert Will, a PhD student at CITIID and the study’s first author, said: “The C. diphtheriae genome is complex and incredibly diverse. It’s acquiring resistance to antibiotics that are not even clinically used in the treatment of diphtheria. There must be other factors at play, such as asymptomatic infection and exposure to a plethora of antibiotics meant for treating other diseases.”
Erythromycin and penicillin are the traditionally recommended antibiotics of choice for treating confirmed cases of early-stage diphtheria, though there are several different classes of antibiotics available to treat the infection. The team identified variants resistant to six of these classes in isolates from the 2010s, higher than in any other decades.
Dr Pankaj Bhatnagar from the World Health Organization country office for India said: “AMR has rarely been considered as a major problem in the treatment of diphtheria, but in some parts of the world, the bacterial genomes are acquiring resistance to numerous classes of antibiotics. There are likely to be a number of reasons to this, including exposure of the bacteria to antibiotics in their environment or in asymptomatic patients being treated against other infections.”
The researchers say that COVID-19 has had a negative impact on childhood vaccination schedules worldwide and comes at a time when reported case numbers are rising, with 2018 showing the highest incidence in 22 years.
Dr Ankur Mutreja from CITIID, who led the study, said: “It’s more important than ever that we understand how diphtheria is evolving and spreading. Genome sequencing gives us a powerful tool for observing this in real time, allowing public health agencies to take action before it’s too late.
“We mustn’t take our eye off the ball with diphtheria, otherwise we risk it becoming a major global threat again, potentially in a modified, better adapted, form.”
The research was funded primarily by the Medical Research Council, with additional support from the NIHR Cambridge Biomedical Research Centre.