In autoimmune diseases, the immune system wrongly identifies its "enemy", and produces antibodies that attack the patient’s own cells. One of these diseases, the anti-phospholipid antibody syndrome (APS), is still poorly understood, even though it can have serious consequences. APS is caused by antibodies circulating in the blood plasma that are directed against a protein, which increase the blood’s tendency to form clots. This can lead to a range of vascular accidents, such as venous thromboses, strokes or repeated miscarriages. Although the prevalence of APS is very difficult to assess, it is likely to affect around 0.5% of the general population. Diagnosing the disease is a complicated affair: the test currently used has a number of problems in terms of variability, specificity and sensitivity. This situation, however, is set to change: researchers at the University of Geneva (UNIGE), Switzerland, and the Geneva University Hospitals (HUG) have succeeded in identifying the exact spot where the anti-phospholipid antibodies attach themselves. This means a more accurate and standardized diagnostic test can now be devised– an undeniable improvement for patients.
In people suffering from APS, antibodies called "anti-Β2GP1" attach themselves to elements found on the surface of certain cells, particularly those of the blood vessels and placenta. They bind themselves to receptors located on the cell membrane, generating a signal that produces the pro-inflammatory and pro-thrombotic factors that cause vascular accidents. By identifying the exact location where these antibodies bind, the research team at UNIGE and HUG have been able to clarify how they function. Karim Brandt, a researcher at the UNIGE Faculty of medicine, explains the importance of this discovery: "The current diagnostic tests use the entire protein, which reduces its specificity and leads to standardization issues.
Consequently, two tests are required at an interval of 12 weeks after a thrombotic episode or following one or more miscarriages. Our new test specifically targets this pathogenic antibody, with rapid and more accurate results."

An antibody with a rather special behaviour
The researchers managed to isolate a "motif", which is a small part of the membrane protein. Motifs are recognized by the antibody, which then binds to it, like a key in a lock. In this instance, the key can open several locks, which correspond to the proteins found on the surface of the cells and induce the pathogenic effects. And if the target protein was identified as such, it is because it is the only protein in all the human proteome to have five of these motifs; it has therefore as many potential binding points for the pathogenic antibody.
APS is usually treated with oral anticoagulants such as low-molecular-weight heparin and aspirin, long-term treatments that are not without side effects, and that must be used with caution by pregnant women. Moreover, treatment becomes very burdensome in patients suffering from the most severe form of the disease, called "catastrophic APS". As Karim Brandt is keen to stress, the researchers are also focusing their working in this direction: "Our breakthrough could also give rise to a targeted treatment that would neutralize specific pathogenic antibodies, reducing not just their actions but also the side effects associated with the current treatment. It would involve injecting the protein motif we have identified into a patient’s circulatory system so that it explicitly binds itself to the pathogenic antibody and prevents it from causing harm."
For the time being, the diagnostic test needs to be optimized for prototypes to be developed. To ensure its validity, the researchers will reanalyze hundreds of samples already tested with the old method and compare results.

EurekAlert
www.eurekalert.org/pub_releases/2017-06/udg-ant061417.php

Cancer cells obtained from a blood test may be able to predict how early-stage lung cancer patients will fare, a team from the University of Michigan has shown.
This information could be used to determine which patients are most likely to benefit from additional therapies to head off the spread of the cancer to other areas of the body.
With a new single cell analysis service in U-M’s Comprehensive Cancer Center, the researchers are making the necessary technology more widely available in the university system. They hope these "liquid biopsies" will be offered to patients within the next five years.
Circulating tumour cells, representing only about one in a billion cells in the bloodstream, are largely untapped sources of information about tumours, but new methods are bringing their diagnostic value ever closer to patient care.
Sunitha Nagrath, U-M professor of chemical engineering who designs devices that can capture these rare cells, led a team including oncologists and surgeons to explore how cancer cells escape tumours and travel through the body in the bloodstream. This is how metastases, or satellite tumours elsewhere in the body, are thought to form.
"The tumours were constantly shedding cells even when they were small — that’s one thing we learned," Nagrath said. "Although we define the tumours as early stage, already they are disseminating cells in the body."
Early-stage lung cancer patients, whose tumours may only measure a few millimetres in diameter, are typically treated with surgical removal of the tumour, but the study results suggest that this may not be enough. A handful of patients had tumours that were shedding hundreds or thousands of tumour cells into the lung.
"Even though you removed the tumour, you left behind these hundreds and hundreds of cells," Nagrath said. "If you know this patient walking out of the clinic is going to relapse after less than a year because of these cells, why don’t we treat them now?"
With a relatively small sample of 36 patients, the team can’t definitively say that an actively shedding tumour will lead to metastasis within a year, but Nagrath is exploring the predictive power of cancer cells drawn from the blood. In particular, the study showed that clusters of two or more tumour cells indicated shorter survival times. Six of the nine patients whose cancer returned during the two to 26 months of follow-up had circulating tumour cells appearing in clusters.
"Ultimately, this method will help us look for and find potential markers for either metastatic spread or cancer detection," said Rishindra Reddy, U-M associate professor of surgery who coordinated the blood samples and designed the study with Nagrath and Nithya Ramnath, an associate professor of medical oncology at the U-M Medical School.

University of Michigan
www.mcancer.org/news/archive/blood-test-can-predict-early-lung-cancer-prognosis
 

Reporting results, researchers seek ways to develop regenerative therapies for muscle disorders by getting stem cells to fuse and form functioning skeletal muscle tissues.
A detour on the road to regenerative medicine for people with muscular disorders is figuring out how to coax muscle stem cells to fuse together and form functioning skeletal muscle tissues. A study published reports scientists identify a new gene essential to this process, shedding new light on possible new therapeutic strategies.
Led by researchers at the Cincinnati Children’s Hospital Medical Center Heart Institute, the study demonstrates the gene Gm7325 and its protein – which the scientists named “myomerger” – prompt muscle stem cells to fuse and develop skeletal muscles the body needs to move and survive. They also show that myomerger works with another gene, Tmem8c, and its associated protein “myomaker” to fuse cells that normally would not.
In laboratory tests on embryonic mice engineered to not express myomerger in skeletal muscle, the animals did not develop enough muscle fibre to live.
"These findings stimulate new avenues for cell therapy approaches for regenerative medicine,” said Douglas Millay, PhD, study senior investigator and a scientist in the Division of Molecular Cardiovascular Biology at Cincinnati Children’s. “This includes the potential for cells expressing myomaker and myomerger to be loaded with therapeutic material and then fused to diseased tissue. An example would be muscular dystrophy, which is a devastating genetic muscle disease. The fusion technology possibly could be harnessed to provide muscle cells with a normal copy of the missing gene.”
One of the molecular mysteries hindering development of regenerative therapy for muscles is uncovering the precise genetic and molecular processes that cause skeletal muscle stem cells (called myoblasts) to fuse and form the striated muscle fibres that allow movement. Millay and his colleagues are identifying, deconstructing and analysing these processes to search for new therapeutic clues.
Genetic degenerative disorders of the muscle number in the dozens, but are rare in the overall population, according to the National Institutes of Health. The major categories of these devastating wasting diseases include: muscular dystrophy, congenital myopathy and metabolic myopathy. Muscular dystrophies are a group of more than 30 genetic diseases characterized by progressive weakness and degeneration of the skeletal muscles that control movement. The most common form is Duchenne MD.
A previous study authored by Millay in 2014 identified myomaker and its gene through bioinformatic analysis. Myomaker is also required for myoblast stem cells to fuse. However, it was clear from that work that myomaker did not work alone and needed a partner to drive the fusion process. The current study indicates that myomerger is the missing link for fusion, and that both genes are absolutely required for fusion to occur, according to the researchers.
To find additional genes that regulate fusion, Millay’s team screened for those activated by expression of a protein called MyoD, which is the primary initiator of the all the genes that make muscle. The team focused on the top 100 genes induced by MyoD (including GM7325/myomerger) and designed a screen to test the factors that could function within and across cell membranes. They also looked for genes not previously studied for having a role in fusing muscle stem cells. These analyses eventually pointed to a previously uncharacterized gene listed in the database – Gm7325.
The researchers are building on their current findings, which they say establishes a system for reconstituting cell fusion in mammalian cells, a feat not yet achieved by biomedical science.

Cincinnati Children’s Hospital
www.cincinnatichildrens.org/news/release/2017/regenerative-therapy

An extensive exercise to map genetic variation in Sweden has found 33 million genetic variants, 10 million of which were previously unknown. Large-scale DNA sequencing methods were used to analyse the whole genome of 1,000 individuals from different parts of the country. The study was led by researchers at Uppsala University.
“This resource will benefit many national research projects investigating the association between genetic variants and diseases,” says Professor Ulf Gyllensten, Uppsala University and SciLifeLab, who has led the project.
The data will also be of immediate use in clinical diagnostics to determine whether a genetic variation in a patient is a cause of disease, or if it is also present among healthy individuals in the population.
“Our study shows the presence of millions of previously unidentified genetic variants in Sweden, the majority of which occur at low frequency in the population. It is crucial to identify these low frequency variants to facilitate the diagnosis of genetic diseases,” says Adam Ameur, bioinformatician at Uppsala University and SciLifeLab, who has been responsible for the data analyses.
Several groups at SciLifeLab have been involved in the sequencing of the 1,000 DNA samples and in the development of data analysis methods. Very large amounts of data have been generated, over 100 terabytes for the entire project. Integrity and data security have been a high priority since the DNA sequences contain sensitive and personal information about the individuals.
“The resource is freely available, which enables researchers to quickly investigate genetic variant frequencies among the 1,000 Swedish individuals. However, a special request must be approved for access to data on individuals, and all processing must be performed within a custom-built computer system with extra high security,” says Gyllensten.
This work is part of SciLifeLab’s national project initiative in genomics, which has been made possible by grants from the Knut and Alice Wallenberg Foundation.
The variant frequency data is available from swefreq.nbis.se.

Uppsala University
www.uu.se/en/media/news/article/?id=9160&area=2,4,10,16,24&typ=artikel&lang=en

Mologic Ltd, which develops personalized diagnostics, recently announced it has received CE-mark approval for BVPro^®, a rapid point-of-care test for patients presenting with symptoms of vaginosis. The company also announced the commercial launch of the test, and that it has signed a 3-year distribution agreement with Hitado GmbH, a leading diagnostic supplier specializing in point-of-care products, and subsidiary of Sysmex, to enable distribution of BVPro throughout Germany.
Bacterial vaginosis (BV) is an abnormal vaginal condition that is characterized by vaginal discharge and results from an overgrowth of atypical bacteria in the vagina. Although not critical in its own right, BV is associated with serious medical complications such as post-operative infections, a greater susceptibility of contracting sexually transmitted infections (STIs) such as genital herpes and HIV, and also a higher risk of preterm birth in pregnant women.
BVPro is a simple, 15-minute, point-of-care diagnostic for professional use with patients presenting with symptoms of vaginosis. It detects sialidase enzyme activity from a vaginal swab sample which is a well-established clinical marker of bacterial vaginosis. The CE-marked diagnostic has been designed in the familiar lateral flow format (typical of pregnancy tests) so that the visual result is easy to interpret and enables a rapid, alternative to current methods, such as wet mount microscopic analysis and test tube-based colour-change assays, which often provide ambiguous results and are time consuming.
Mark Davis, co-founder and CEO at Mologic commented: “BVPro is another in Mologic’s pipeline of diagnostic tests to receive CE-mark approval. We are very pleased to be making such progress in bringing point-of-care tests to patients and by doing so, enabling the earlier treatment of a range of diseases, including sepsis, urinary tract infections and chronic obstructive pulmonary disease (COPD). Appointing Hitado to distribute our products in Germany represents a significant milestone for our company; we look forward to working with them as our first formal distributor and also others as we bring them on board in different geographies. www.mologic.co.uk/bvpro