Diagnostica Stago S.A.S, a privately held company that provides reference tests and instrumentation in hemostasis, announced that the company has entered a joint research agreement with Bristol-Myers Squibb Company (BMY) to develop an assay for measuring the circulating blood concentration of the oral Factor Xa inhibitor ELIQUIS (apixaban). No commercial assay is presently available to specifically measure apixaban plasma concentration. Terms of the agreement were not disclosed.

“Stago is pleased to have the opportunity to develop this test”, said Tristan Herve, Director of Pharmaceutical Development, “These oral Factor Xa inhibitors address an important unmet need for patients requiring anticoagulant therapy”.

Stago has already completed prototype development and will be applying for health authority approvals of the assay worldwide. Diagnostica Stago retains 100 percent global development and commercialization rights for the assay.

Chlamydia trachomatis is a human pathogen that is the leading cause of bacterial sexually transmitted disease worldwide with more than 90 million new cases of genital infections occurring each year. About 70 percent of women infected with Chlamydia remain asymptomatic and these bacteria can establish chronic infections for months, or even years. Even when it causes no symptoms, Chlamydia can damage a woman’s reproductive organs. In addition, standard antibacterial drugs are proving increasingly ineffective in complete eradication, as Chlamydia goes in to persistent mode, leading to asymptomatic chronic infection. Researchers at the Max Planck Institute for Infection Biology in Berlin (MPIIB) now show that Chlamydia infections can cause mutations in the host DNA by overriding the normal mechanisms by which their host prevents unregulated growth of genetically damaged cells that pave the way for the development of cancer.
Owing to their intracellular lifestyle Chlamydia depend on various host cell functions for their survival. Chlamydia manipulates the host cell mechanism to favour its growth, however the consequences of such alterations on the fate of host cells remains enigmatic. Even more worrying is mounting epidemiological evidence which links Chlamydia infections with the development of cervical and ovarian cancer. Cindrilla Chumduri, Rajendra Kumar Gurumurthy and Thomas F. Meyer, researchers at the Max Planck Institute for Infection Biology in Berlin, have now discovered that Chlamydia induces long-lasting effects on the genome and epi-genome of their host cells. Such changes are increasingly implicated in the development of a range of cancers.

The team found increased levels of DNA breaks in Chlamydia-infected cells. In normal cells, depending on the extent of damage, cells either ‘commit suicide’ or activate repair by special protein complexes in a process called the DNA Damage Response, which reseals the broken strands of DNA and makes sure the sequence of the genetic code has not been changed. Crucially, in Chlamydia-infected cells the DNA Damage Response was impaired, leading to an error-prone repair of the DNA breaks- a potential cause of mutations. Strikingly, despite the presence of extensive DNA damage, Chlamydia infected cells continued to proliferate, facilitated by additional pro-survival signals activated in the host cells by Chlamydia. The flip-side of this forced survival of damaged cells is an increased tendency to evade the normal mechanisms that eliminate cells carrying mutations that could lead to cancer. The team believe that this could be the first step on the path to carcinogenesis of the infected cells, due to uncontrolled cell growth in the presence of accumulating DNA damage – the hallmark of cancer.

The identification of infections as the origin of human cancers is important since it would allow early prevention of cancerogenesis by means of vaccination or antibiotic treatment. Such preventive strategies are currently successfully pursued against the cancer-inducing agents Human Papiloma Virus (HPV) and Helicobacter pylori, the etiological agents of cervical and gastric cancer, respectively. However, many infection-based cancer etiologies have not been firmly established and therefore cancer treatment is usually restricted to patients at an advanced stage and with an established cancer diagnosis. The department of Professor Meyer at MPIIB therefore vigorously pursues several lines of research to unequivocally assess the linkage between bacterial infections and cancer, apart from the well-known carcinogenic role of H. pylori. The current paper by Chumduri et al. constitutes one important mosaic piece, corroborating a potential link between female ascending Chlamydia infections and ovarian cancer in particular. Max Planck Society

The search for the cause of multiple sclerosis, a debilitating disease that affects up to a half million people in the United States, has confounded researchers and medical professionals for generations. But Steven Schutzer, a physician and scientist at Rutgers New Jersey Medical School, has now found an important clue why progress has been slow – it appears that most research on the origins of MS has focused on the wrong part of the brain.

Look more to the gray matter and less to the white. That change of approach could give physicians effective tools to treat MS far earlier than ever before.

Until recently, most MS research has focused on the brain’s white matter, which contains the nerve fibres. And for good reason: Symptoms of the disease, which include muscle weakness and vision loss, occur when there is deterioration of a fatty substance called myelin, which coats nerves contained in the white matter and acts as insulation for them. When myelin in the brain is degraded, apparently by the body’s own immune system, and the nerve fibre is exposed, transmission of nerve impulses can be slowed or interrupted. So when patients’ symptoms flare up, the white matter is where the action in the brain appears to be.
Fluid drawn from the central nervous system contained proteins whose discovery may change the focus of multiple sclerosis research and lead to earlier diagnosis and treatment of the disease.
But Schutzer attacked the problem from a different direction. He is one of the first scientists to analyse patients’ cerebrospinal fluid (CSF) by taking full advantage of a combination of technologies called proteomics and high-resolution mass spectrometry. ‘Proteins present in the clear liquid that bathes the central nervous system can be a window to physical changes that accompany neurological disease,’ says Schutzer, ‘and the latest mass spectrometry techniques allow us to see them as never before.’ In this study, he used that novel approach to compare the cerebrospinal fluid of newly diagnosed MS patients with that of longer term patients, as well as fluid taken from people with no signs of neurological disease.

What Schutzer found startled one of his co-investigators, Patricia K. Coyle of Stony Brook University in New York, one of the leading MS clinicians and researchers in the country. The proteins in the CSF of the new MS patients suggested physiological disruptions not only in the white matter of the brain where the myelin damage eventually shows up. They also pointed to substantial disruptions in the gray matter, a different part of the brain that contains the axons and dendrites and synapses that transfer signals between nerves.

Several scientists had in fact hypothesised that there might be gray matter involvement in early MS, but the technology needed to test their theories did not yet exist. Schutzer’s analysis, which Coyle calls ‘exquisitely sensitive,’ provides the solid physical evidence for the very first time. It includes a finding that nine specific proteins associated with gray matter were far more abundant in patients who had just suffered their first attack than in longer term MS patients or in the healthy controls. ‘This evidence indicates gray matter may be the critical initial target in MS rather than white matter,’ says Coyle. ‘We may have been looking in the wrong area.’

According to Coyle, that realisation presents exciting possibilities. One, she says, is that patients who suffer attacks that appear related to MS could have their cerebrospinal fluid tested quickly. If proteins that point to early MS are found, helpful therapy could begin at once, before the disease can progress further.

Coyle says Schutzer’s findings may also lead one day to more effective treatments for MS with far fewer side effects. Without specific knowledge of what causes multiple sclerosis, patients now need to take medications that can broadly weaken their immune systems. These drugs slow the body’s destruction of myelin in the brain, but also degrade the immune system’s ability to keep the body healthy in other ways. By suggesting an exciting new direction for MS research, Schutzer and his team may have set the stage for more targeted treatments that attack MS while preserving other important immune functions.

Schutzer sees an even broader future for the work he is now doing. He also has used advanced analysis of cerebrospinal fluid to identify physical markers for neurological ailments that include Lyme disease, in which he has been a world leader in research for many years, as well as chronic fatigue syndrome. He says, ‘When techniques are refined, more medical conditions are examined, and costs per patient come down, one day there could be a broad panel of tests through which patients and their doctors can get early evidence of a variety of disorders, and use that knowledge to treat them both more quickly and far more effectively than is possible now. Rutgers University

Researchers at King’s College London and King’s College Hospital, part of King’s Health Partners Academic Health Sciences Centre, have developed a new, non-invasive blood test that can reliably detect whether or not an unborn baby has Down’s syndrome. The test can be given earlier in pregnancy and is more accurate than current checks.
Down’s syndrome, also referred to as trisomy 21, is a genetic disorder caused by the presence of all or part of an extra copy of chromosome 21 in a person’s DNA. Current screening for Down’s syndrome and other trisomy conditions includes a combined test done between the 11th and 13th weeks of pregnancy, which involves an ultrasound screen and a hormonal analysis of the pregnant woman’s blood. Methods such as chorionic villus sampling (CVS), which involves taking cell samples from the placenta, and amniocentesis (using a sample of amniotic fluid), are also used to detect abnormalities but they are both invasive and carry a risk of miscarriage.
Several studies have shown that non-invasive prenatal diagnosis for trisomy syndromes using foetal cell free (cf) DNA from a pregnant woman’s blood is highly sensitive and specific, making it a potentially reliable alternative that can be done earlier in pregnancy.
Kypros Nicolaides, Professor of Fetal Medicine at King’s College London and Head of the Harris Birthright Research Centre for Fetal Medicine at King’s College Hospital, and colleagues have now demonstrated the feasibility of routine screening for trisomies 21, 18, and 13 by cfDNA testing. Testing done in 1005 pregnancies at 10 weeks had a lower false positive rate and higher sensitivity for foetal trisomy than the combined test done at 12 weeks. Both cfDNA and combined testing detected all trisomies, but the estimated false-positive rates were 0.1 percent and 3.4 percent, respectively.
‘This study has shown that the main advantage of cfDNA testing, compared with the combined test, is the substantial reduction in false positive rate. Another major advantage of cfDNA testing is the reporting of results as very high or very low risk, which makes it easier for parents to decide in favour of or against invasive testing,’ said Professor Nicolaides.
A second Ultrasound in Obstetrics & Gynecology study by the group, which included pregnancies undergoing screening at three UK hospitals between March 2006 and May 2012, found that effective first-trimester screening for Down’s syndrome could be achieved by cfDNA testing contingent on the results of the combined test done at 11 to 13 weeks. The strategy detected 98 percent of cases, and invasive testing was needed for confirmation in less than 0.5 percent of cases.
The authors conclude that screening for trisomy 21 by cfDNA testing contingent on the results of an expanded combined test would retain the advantages of the current method of screening, but with a simultaneous major increase in detection rate and decrease in the rate of invasive testing. Kings College London

Problems with a key group of enzymes called topoisomerases can have profound effects on the genetic machinery behind brain development and potentially lead to autism spectrum disorder (ASD), according to research. Scientists at the University of North Carolina School of Medicine have described a finding that represents a significant advance in the hunt for environmental factors behind autism and lends new insights into the disorder’s genetic causes.

‘Our study shows the magnitude of what can happen if topoisomerases are impaired,’ said senior study author Mark Zylka, PhD, associate professor in the Neuroscience Center and the Department of Cell Biology and Physiology at UNC. ‘Inhibiting these enzymes has the potential to profoundly affect neurodevelopment — perhaps even more so than having a mutation in any one of the genes that have been linked to autism.’

The study could have important implications for ASD detection and prevention.

‘This could point to an environmental component to autism,’ said Zylka. ‘A temporary exposure to a topoisomerase inhibitor in utero has the potential to have a long-lasting effect on the brain, by affecting critical periods of brain development. ‘

This study could also explain why some people with mutations in topoisomerases develop autism and other neurodevelopmental disorders.

Topiosomerases are enzymes found in all human cells. Their main function is to untangle DNA when it becomes overwound, a common occurrence that can interfere with key biological processes.

Most of the known topoisomerase-inhibiting chemicals are used as chemotherapy drugs. Zylka said his team is searching for other compounds that have similar effects in nerve cells. ‘If there are additional compounds like this in the environment, then it becomes important to identify them,’ said Zylka. ‘That’s really motivating us to move quickly to identify other drugs or environmental compounds that have similar effects — so that pregnant women can avoid being exposed to these compounds.’

Zylka and his colleagues stumbled upon the discovery quite by accident while studying topotecan, a topoisomerase-inhibiting drug that is used in chemotherapy. Investigating the drug’s effects in mouse and human-derived nerve cells, they noticed that the drug tended to interfere with the proper functioning of genes that were exceptionally long — composed of many DNA base pairs. The group then made the serendipitous connection that many autism-linked genes are extremely long.

‘That’s when we had the ‘Eureka moment,’’ said Zylka. ‘We realised that a lot of the genes that were suppressed were incredibly long autism genes.’

Of the more than 300 genes that are linked to autism, nearly 50 were suppressed by topotecan. Suppressing that many genes across the board — even to a small extent — means a person who is exposed to a topoisomerase inhibitor during brain development could experience neurological effects equivalent to those seen in a person who gets ASD because of a single faulty gene.

The study’s findings could also help lead to a unified theory of how autism-linked genes work. About 20 percent of such genes are connected to synapses — the connections between brain cells. Another 20 percent are related to gene transcription — the process of translating genetic information into biological functions. Zylka said this study bridges those two groups, because it shows that having problems transcribing long synapse genes could impair a person’s ability to construct synapses.

‘Our discovery has the potential to unite these two classes of genes — synaptic genes and transcriptional regulators,’ said Zylka. ‘It could ultimately explain the biological mechanisms behind a large number of autism cases.’ University of North Carolina School of Medicine