A class of drug for treating arthritis – all but shelved over fears about side effects – may be given a new lease of life following new research.

The new study, led by Imperial College London, sheds new light on the 10-year-old question of how COX-2 inhibitors – a type of non-steroidal anti-inflammatory drug (NSAID) – can increase the risk of heart attack in some people, and suggests a possible way to identify which patients should avoid using it.

NSAIDs – which include very familiar drugs such as ibuprofen, diclofenac and aspirin – are widely-used treatments for debilitating inflammatory conditions such as arthritis as well as being used for general pain relief worldwide. NSAIDs are also being investigated for their potential to prevent cancer. COX-2 inhibitors, which include Vioxx and Celebrex, were developed in the 1990s to avoid the risk of stomach ulcers caused by some NSAIDs, but after they were linked to an increased risk of heart attacks, they rapidly fell out of favour and some brands, including Vioxx, were withdrawn.

The new study, in mice and human volunteers, was led by Professor Jane Mitchell and Dr James Leiper. Professor Mitchell, from the National Heart and Lung Institute at Imperial, said: “Although the majority of arthritis sufferers could safely use COX-2 inhibitors, the fear of heart attacks has left some patients confused and worried about their medication and GPs nervous about prescribing them. This problem is made worse because we now know that most NSAIDs, not just COX-2 selective drugs, carry a similar risk of heart attacks in some patients.

“If we could identify which people have an increased risk, these patients could be offered more appropriate treatments – and we can start to look at ways of reducing or averting the risk entirely.”

NSAIDs work by preventing the production of prostaglandins – the chemical messengers in tissues and joints that trigger pain and inflammation. Prostaglandins are produced by two different enzymes, known as COX-1 and COX-2, which are found at sites of inflammation as well as in other sites around the body.

The study, funded by the Wellcome Trust, the British Heart Foundation and the Medical Research Council (MRC), looked at where and how removing COX-2 caused changes in gene activity in mice. They found that knocking out COX-2 caused changes in three genes in the kidney which predicted a rise in levels of a molecule linked to cardiovascular disease, called ADMA. In subsequent tests, the researchers found that taking NSAIDs led to a rise in ADMA levels in mice and in 16 human volunteers.

Dr James Leiper, from the MRC Clinical Sciences Centre at Imperial, said: ‘‘ADMA is an independent risk factor for cardiovascular disease. In people increases of ADMA similar to those we found are linked with significant increases in cardiovascular disease and death. Our discovery that COX-2 inhibitors raise ADMA levels provides a plausible mechanism for the increased cardiovascular risk associated with these drugs and provides insights into how this risk might be mitigated’

Professor Mitchell thinks that higher ADMA levels might work as an indicator of which patients are at greater risk of a heart attack.

“If we are right,” said Professor Mitchell, “ADMA could be used as a biomarker in a simple blood test to identify who may be at risk, and regular screening would allow GPs to monitor patients’ ADMA levels to ensure these remain within safe limits whilst taking the drug.”  The team are planning a clinical trial to test their idea. Imperial College London

A study involving scientists from the University of Leicester has established a link between hypoglycaemia and increased risk of cardiovascular events and mortality in patients with diabetes.

Professors Kamlesh Khunti and Melanie Davies, scientists from the University of Leicester’s Diabetes Research Centre, have confirmed an association between hypoglycaemia and an increased risk of cardiovascular events and mortality in insulin-treated patients with diabetes, which could lead to changes in the way some patients’ treatment is managed.

As part of an international collaboration with scientists from Imperial College London, the QIMR Berghofer Medical Research Institute and Novo Nordisk A/S – using data from the UK Clinical Practice Research Datalink database – Professors Khunti and Davies demonstrated that, following hypoglycaemia, insulin-treated patients with diabetes had an ~60% higher risk of cardiovascular events, and were between 2–2.5 times more likely to die over the same period as patients who did not experience hypoglycaemia.

Kamlesh Khunti, Professor of Primary Care Diabetes & Vascular Medicine at the University of Leicester, who led the research, said:  “This is one of the first studies to report the risk of cardiovascular events and mortality in people with both type 1 and type 2 diabetes. The risks are very significant and we need to identify these patients early with a view to implementing strategies to reduce their risk of hypoglycaemia.”

Patients with diabetes are at higher risk of cardiovascular disease due to the formation of atherosclerotic plaques in blood vessels; this is a major cause of early death in these patients. The results of the study show that hypoglycaemia, which occurs when a patient’s blood glucose becomes dangerously low, can trigger potentially fatal cardiovascular events.

Melanie Davies, Professor of Diabetes Medicine at the University of Leicester and Honorary Consultant at Leicester’s Hospitals,  commented: “The data from this important and large piece of research confirms what we already know in people with type 2 diabetes and extends our knowledge in those with type 1 diabetes. It also confirms the significance of hypoglycaemia and the link with an increased risk of cardiovascular events, a risk that persists over a long time period. Going forward we need to focus on management strategies that help patients minimise their risk of having hypoglycaemic events.” University of Leicester

Targeted therapies are a growing and ground-breaking field in cancer care in which drugs or other substances are designed to interfere with genes or molecules that control the growth and survival of cancer cells. Now, scientists at Virginia Commonwealth University Massey Cancer Center and VCU Institute of Molecular Medicine (VIMM) have identified a novel interaction between a microRNA and a gene that could lead to new therapies for the most common and deadly form of brain tumour, malignant glioma.

In a study, a team of scientists led by Luni Emdad, M.B.B.S., Ph.D., and Paul B. Fisher, M.Ph., Ph.D., provided the first evidence of an important link between a specific microRNA, miR-184, and a cancer promoting gene, SND1, in the regulation of malignant glioma. miR-184 is known to suppress tumour development by regulating a variety of genes involved in cancer growth, while SND1 has been shown to play a significant role in the development of breast, colon, prostate and liver cancers. Through a variety of preclinical experiments, the team demonstrated that increasing the expression of miR-184 slows the growth and invasive characteristics of glioma cells through direct regulation of SND1. Additionally, they showed that reduced levels of SND1 led to reduced levels of STAT3, a gene that has been shown to promote the most lethal characteristics of brain cancer.

‘Patients suffering from brain tumours are in desperate need of improved therapies,’ says Fisher, Thelma Newmeyer Corman Endowed Chair in Cancer Research and co-leader of the Cancer Molecular Genetics research program at VCU Massey Cancer Center, chairman of the Department of Human and Molecular Genetics at VCU School of Medicine and director of the VIMM. ‘We’re hopeful that this new understanding of the relationship between miR-184 and SND1 ultimately will lead to the development of new drugs that reduce SND1 expression and improve patient outcomes.’

Prior studies have shown that levels of miR-184 are unusually low in tissue samples from patients with malignant gliomas. Using advanced computer analysis techniques designed to study and process biological data, the researchers identified SND1 among a handful of other genes that miR-184 helps regulate. Knowing SND1 is implicated in a variety of cancers and having previously defined its role in liver cancer, Emdad, Fisher and their colleagues explored this relationship further. They confirmed low levels of miR-184 expression in human glioma tissue samples and cultured cell lines as well as an increase in the expression of SND1 compared to normal brain tissue. Using data from a large public brain tumour database called REMBRANDT, the researchers confirmed that patients with lower levels of SND1 survived longer than those with elevated SND1 expression.

‘We still have a long way to go and many challenges to overcome before we will have therapies that are ready for clinical use, but this is a significant first step in the process,’ says Emdad, member of the Cancer Molecular Genetics research program at Massey, assistant professor in the VCU Department of Human and Molecular Genetics and member of the VIMM. ‘Future studies will aim to explore the relationship between SND1 and STAT3, identify additional microRNAs that may be relevant to malignant glioma and explore the effects of drugs that block SND1 expression in more advanced preclinical models.’ EurekAlert

Integrated DNA Technologies (IDT) and Ubiquitome announced in early December 2014 a partnership to develop the Ubiquitome Freedom4 Real-Time RT-PCR Ebola Virus Assay for easy use in the field. This rapid test is designed to be run on Ubiquitome’s hand-held, battery powered real-time PCR device, the Freedom4. IDT, a market leader in the manufacture of GMP quality products for use in molecular diagnostic tests, is leveraging its PrimeTime qPCR Assay platform to develop an assay that will provide accurate and consistent test results for Ebola virus disease. Fitting in the palm of a hand, Ubiquitome’s Freedom4 instrument operates on battery power alone for up to six hours and delivers gold-standard real-time PCR performance wherever needed. The platform runs using an iPhone or laptop computer, is housed in a rugged aluminum casing and features a solid state design that includes laser-based optical detection, which is widely recognized as offering the highest performance in real-time PCR. Paul Pickering, Ubiquitome CEO, said “The Ubiquitome Freedom4 Real-Time RT-PCR Ebola Virus Assay, run on the Freedom4, will allow rapid, accurate field testing of Ebola virus disease. This is important because regions affected by this disease are often far from an established laboratory.” Stephen Gunstream, Chief Commercial Officer of IDT added, “The sensitivity and specificity of our PrimeTime qPCR Assays are well established. We are excited about how effectively we can combine IDT’s assay design expertise with Ubiquitome’s Freedom4 instrument to provide a field testing service for Ebola virus disease. This test will enable early detection and help control the spread of this devastating disease.” Testing of the Ubiquitome Freedom4 Real-Time RT-PCR Ebola Virus Assay will be conducted by Battelle in Aberdeen, Maryland, USA.

www.idtdna.com          www.ubiquitomebio.com

An analysis of the genomes and epigenomes of lean and obese mice and humans has turned up a wealth of clues about how genes and the environment conspire to trigger diabetes, Johns Hopkins researchers say. Their findings reveal that obesity-induced changes to the epigenome — reversible chemical “tags” on DNA — are surprisingly similar in mice and humans, and might provide a new route to prevention and treatment of the disease, which affects hundreds of millions worldwide.

“It’s well known that most common diseases like diabetes result from a combination of genetic and environmental risk factors. What we haven’t been able to do is figure out how, exactly, the two are connected,” says Andrew Feinberg, M.D., M.P.H., Gilman Scholar and director of the Center for Epigenetics in the Institute for Basic Biomedical Sciences at the Johns Hopkins University School of Medicine. “This study takes a step in that direction.”

Feinberg has long studied the epigenome, which he compares to “software” that runs on DNA’s “hardware.” Epigenetic chemical tags affect whether and how much genes are used without changing the genetic code itself.

Feinberg wondered whether epigenetics might partly explain the skyrocketing worldwide incidence of type 2 diabetes. Obesity is a well-established risk factor for the disease, so Feinberg’s research group teamed with that of a group led by G. William Wong, Ph.D., an associate professor of physiology in the Center for Metabolism and Obesity Research at Johns Hopkins, to study the epigenetics of otherwise identical mice that were fed either normal or high-calorie diets.

Analyzing epigenetic marks at more than 7 million sites in the DNA of the mice’s fat cells, the researchers found clear differences between the normal and obese mice. Some sites that bore chemical tags called methyl groups in the lean mice were missing them in the obese mice, and vice versa. The methyl groups prevent genes from making proteins.

With colleagues at Sweden’s Karolinska Institutet, Feinberg and his team then tested whether the same pattern of differences held in fat cells from lean and obese people, and found, to their surprise, that it did. “Mice and humans are separated by 50 million years of evolution, so it’s interesting that obesity causes similar epigenetic changes to similar genes in both species,” Feinberg says. “It’s likely that when food supplies are highly variable, these epigenetic changes help our bodies adapt to temporary surges in calories. But if the high-calorie diet continues over the long term, the same epigenetic pattern raises the risk for disease.”

The research team also found that some of the epigenetic changes associated with obesity affect genes already known to raise diabetes risk. Others affect genes that had not been conclusively linked to the disease, but that turned out to have roles in how the body breaks down and uses nutrients, a process called metabolism. “This study yielded a list of genes that previously have not been shown to play a role in diabetes,” says Wong. “In further tests, we showed that at least some of these genes indeed regulate insulin action on sugar uptake; they offer insights into new potential targets for treating type 2 diabetes.”

In addition to providing leads for drug development, the results also suggest that an epigenetic test could be developed to identify people much earlier on the path to diabetes, giving more hope for preventing the disease, Feinberg says. John Hopkins Medicine