In a small, preliminary study of regular migraine sufferers, scientists have found that measuring a fat-derived protein called adiponectin (ADP) before and after migraine treatment can accurately reveal which headache victims felt pain relief.

A report on the study of people experiencing two to 12 migraine headaches per month, led by researchers at Johns Hopkins, has been published.

‘This study takes the first steps in identifying a potential biomarker for migraine that predicts treatment response and, we hope, can one day be used as a target for developing new and better migraine therapies,’ says study leader B. Lee Peterlin, D.O., an associate professor of neurology and director of headache research at the Johns Hopkins University School of Medicine. She cautioned that larger, confirmatory studies are needed for that to happen.

Experts estimate that roughly 36 million Americans, or 12 percent of the population, suffer from debilitating migraine headaches that last four hours or longer. Migraines are defined as headaches with at least two of four special characteristics: unilateral or one-side-of-the-head occurrence; moderately to severely painful; aggravated by routine activity and of a pounding or throbbing nature. Sufferers generally also feel nauseated or are sensitive to light and sound. Women are three times as likely to get migraines as men.

Such complicated diagnostic criteria mean that diagnosis is tricky, a fact driving efforts, Peterlin says, to find better diagnostic tools.

For the study, Peterlin and her colleagues collected blood from 20 women who visited three headache clinics between December 2009 and January 2012 during an acute migraine attack. Blood was taken before treatment with either sumatriptan/naproxen sodium (a drug routinely given to people with migraines) or a placebo. The investigators re-drew blood at 30, 60 and 120 minutes after the study drug was given. Eleven women received the drug and nine got the placebo.

The researchers measured blood levels of ADP, a protein hormone secreted from fat tissue and known to modulate several of the pain pathways implicated in migraine. The hormone is also implicated in sugar metabolism, insulin regulation, immunity and inflammation, as well as obesity, which is a risk factor for migraines.

Peterlin and her colleagues looked at total adiponectin levels and two subtypes or fragments of total ADP in circulation in the blood: low molecular weight (LMW)-adiponectin and high molecular weight (HMW)-adiponectin. LMW is comprised of small fragments of ADP and it is known to have anti-inflammatory properties, while HMW is made up of larger fragments of ADP and is known to have pro-inflammatory properties. Inflammatory pathways in blood vessels in the head are at work in migraine headache.

The researchers found that in all 20 participants when levels of LMW increased, the severity of pain decreased. When the ratio of HMW to LMW molecules increased, the pain severity increased.

‘The blood tests could predict response to treatment,’ Peterlin says.

At onset of pain – even before study drug was given – the researchers could identify who would be a responder to treatment and who would not, as there was a greater ratio of HMW to LMW in those who would be responders as compared to those who were not.

After study treatment changes in adiponectin were also seen. Interestingly, in those patients who reported less pain after receiving study drug to treat the migraine – whether they got the active migraine medication or a placebo – researchers were able to see a decrease in total levels of ADP in the blood.

Peterlin says the findings indicate it may be possible to develop a treatment that would reduce levels of ADP or parts of adiponectin such as HMW or LMW adiponectin. She says should ADP prove to be a biomarker for migraine, it could help physicians identify who has migraine and know who is likely to respond to which type of medication. It also may help doctors make better medication choices and try alternate drugs sooner. John Hopkins Medicine

Better diagnosis and treatment of cancer could hinge on the ability to better understand a single cell at its molecular level. New research offers a more comprehensive way of analysing one cell’s unique behaviour, using an array of colours to show patterns that could indicate why a cell will or won’t become cancerous.

A University of Washington team has developed a new method for colour-coding cells that allows them to illuminate 100 biomarkers, a ten-time increase from the current research standard, to help analyse individual cells from cultures or tissue biopsies.
‘Discovering this process is an unprecedented breakthrough for the field,’ said corresponding author Xiaohu Gao, a UW associate professor of bioengineering. ‘This technology opens up exciting opportunities for single-cell analysis and clinical diagnosis.’

The research builds on current methods that use a smaller array of colours to point out a cell’s biomarkers – characteristics that indicate a special, and potentially abnormal or diseased, cell. Ideally, scientists would be able to test for a large number of biomarkers, then rely on the patterns that emerge from those tests to understand a cell’s properties.

The UW research team has created a cycle process that allows scientists to test for up to 100 biomarkers in a single cell. Before, researchers could only test for 10 at a time.

The analysis uses quantum dots, which are fluorescent balls of semiconductor material. Quantum dots are the smaller version of the material found in many electronics, including smartphones and radios. These quantum dots are between 2 and 6 nanometers in diameter, and they vary on the colour they emit depending on their size.

Cyclical testing hasn’t been done before, though many quantum dot papers have tried to expand the number of biomarkers tested for in a single cell. This method essentially reuses the same tissue sample, testing for biomarkers in groups of 10 in each round.
‘Proteins are the building blocks for cell function and cell behaviour, but their makeup in a cell is highly complex,’ Gao said. ‘You need to look at a number of indicators (biomarkers) to know what’s going on.’

The new process works like this: Gao and his team purchase antibodies that are known to bind with the specific biomarkers they want to test for in a cell. They pair quantum dots with the antibodies in a fluid solution, injecting it onto a tissue sample. Then, they use a microscope to look for the presence of fluorescent colours in the cell. If they see particular quantum dot colours in the tissue sample, they know the corresponding biomarker is present in the cell.

After completing one cycle, Gao and co-author Pavel Zrazhevskiy, a UW postdoctoral associate in bioengineering, inject a low-pH fluid into the cell tissue that neutralises the colour fluorescence, essentially wiping the sample clean for the next round. Remarkably, the tissue sample doesn’t degrade at all even after 10 such cycles, Gao said.
For cancer research and treatment, in particular, it’s important to be able to look at a single cell at high resolution to examine its details. For example, if 99 percent of cancer cells in a person’s body respond to a treatment drug, but 1 percent doesn’t, it’s important to analyse and understand the molecular makeup of that 1 percent that responds differently.

‘When you treat with promising drugs, there are still a few cells that usually don’t respond to treatment,’ said Gao. ‘They look the same, but you don’t have a tool to look at their protein building blocks. This will really help us develop new drugs and treatment approaches.’ University of Washington

The Red Cross Blood Transfusion Service of Upper Austria has become the first laboratory in Europe to receive accreditation from the European Federation for Immunogenetics (EFI) for the use of human leukocyte antigen (HLA) tests based on next-generation sequencing with Roche’s GS Junior System. This new method will allow more precise and much more rapid tissue-typing and donor selection for stem cell transplants than has been possible to date. In addition, the HLA testing method previously only used for research will now also be available as a standard routine diagnostic procedure.
“Worldwide, around 50,000 people a year urgently require a stem cell transplant, and the chances of finding an allogeneic stem cell donor are about 1:500,000,” said Thomas Schinecker, Head of Roche Sequencing Solutions. “This accreditation is an example of how the potential of next-generation sequencing can be successfully translated from research into medicine and made widely available to patients in areas of high medical need.”
Underlining the benefits of the new standard method, Dr Christian Gabriel, Medical Director of the Red Cross Blood Transfusion Service of Upper Austria, said: “Standardized laboratory procedures are needed to promote positive therapeutic outcomes for patients. EFI accreditation is an important step, allowing large numbers of patients to benefit from the latest technologies.”

Researchers discover that the extra chromosome inherited in Down syndrome impairs learning and memory because it leads to low levels of SNX27 protein in the brain.

What is it about the extra chromosome inherited in Down syndrome—chromosome 21—that alters brain and body development? Researchers have new evidence that points to a protein called sorting nexin 27, or SNX27. SNX27 production is inhibited by a molecule encoded on chromosome 21. The study shows that SNX27 is reduced in human Down syndrome brains. The extra copy of chromosome 21 means a person with Down syndrome produces less SNX27 protein, which in turn disrupts brain function. What’s more, the researchers showed that restoring SNX27 in Down syndrome mice improves cognitive function and behaviour.

‘In the brain, SNX27 keeps certain receptors on the cell surface—receptors that are necessary for neurons to fire properly,’ said Huaxi Xu, Ph.D., Sanford-Burnham professor and senior author of the study. ‘So, in Down syndrome, we believe lack of SNX27 is at least partly to blame for developmental and cognitive defects.’
Xu and colleagues started out working with mice that lack one copy of the snx27 gene. They noticed that the mice were mostly normal, but showed some significant defects in learning and memory. So the team dug deeper to determine why SNX27 would have that effect. They found that SNX27 helps keep glutamate receptors on the cell surface in neurons. Neurons need glutamate receptors in order to function correctly. With less SNX27, these mice had fewer active glutamate receptors and thus impaired learning and memory.
Then the team got thinking about Down syndrome. The SNX27-deficient mice shared some characteristics with Down syndrome, so they took a look at human brains with the condition. This confirmed the clinical significance of their laboratory findings—humans with Down syndrome have significantly lower levels of SNX27.

Next, Xu and colleagues wondered how Down syndrome and low SNX27 are connected—could the extra chromosome 21 encode something that affects SNX27 levels? They suspected microRNAs, small pieces of genetic material that don’t code for protein, but instead influence the production of other genes. It turns out that chromosome 21 encodes one particular microRNA called miR-155. In human Down syndrome brains, the increase in miR-155 levels correlates almost perfectly with the decrease in SNX27.

Xu and his team concluded that, due to the extra chromosome 21 copy, the brains of people with Down syndrome produce extra miR-155, which by indirect means decreases SNX27 levels, in turn decreasing surface glutamate receptors. Through this mechanism, learning, memory, and behaviour are impaired.

If people with Down syndrome simply have too much miR-155 or not enough SNX27, could that be fixed? The team explored this possibility. They used a non-infectious virus as a delivery vehicle to introduce new human SNX27 in the brains of Down syndrome mice.

‘Everything goes back to normal after SNX27 treatment. It’s amazing—first we see the glutamate receptors come back, then memory deficit is repaired in our Down syndrome mice,’ said Xin Wang, a graduate student in Xu’s lab and first author of the study. ‘Gene therapy of this sort hasn’t really panned out in humans, however. So we’re now screening small molecules to look for some that might increase SNX27 production or function in the brain.’ Sanford-Burnham Institute

The first multi-gene test that can help predict cancer patients’ responses to treatment using the latest DNA sequencing techniques has been launched in the NHS, thanks to a partnership between scientists at the University of Oxford and Oxford University Hospitals NHS Trust.
The test detects mutations across 46 genes in cancer cells, mutations which may be driving the growth of the cancer in patients with solid tumours. The presence of a mutation in a gene can potentially determine which treatment a patient should receive.
The researchers say the number of genes tested marks a step change in introducing next-generation DNA sequencing technology into the NHS, and heralds the arrival of genomic medicine with whole genome sequencing of patients just around the corner.
The new £300 test could save significantly more in drug costs by getting patients on to the right treatments straightaway, reducing harm from side effects as well as the time lost before arriving at an effective treatment.
The many-gene sequencing test has been launched through the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), a collaboration between Oxford University Hospitals NHS Trust and Oxford University.
The BRC Molecular Diagnostics Centre carries out the test. The lab, based at Oxford University Hospitals, covers all cancer patients in the Thames Valley area. But the scientists are looking to scale this up into a truly national NHS service through the course of this year.
‘We are the first to introduce a multi-gene diagnostic test for tumour profiling on the NHS using the latest DNA sequencing technology,’ says Dr Jenny Taylor of the Wellcome Trust Centre for Human Genetics at Oxford University, who is programme director for Genomic Medicine at the NIHR Oxford BRC and was involved in the work. ‘It’s a significant step change in the way we do things. This new 46 gene test moves us away from conventional methods for sequencing of single genes, and marks a huge step towards more comprehensive genome sequencing in both infrastructure and in handling the data produced.’
Dr Anna Schuh, who heads the BRC Molecular Diagnostics Centre and is a consultant haematologist at Oxford University Hospitals, adds: ‘Patients like the idea of a test that can predict and say up front whether they will respond to an otherwise toxic treatment. What the patient sees is no different from present. A biopsy is taken from the patient’s tumour for genetic testing with a consultant talking through the results a few days later. It is part of the normal diagnostic process.’
Cancer is often described as a genetic disease, since the transition a cell goes through in becoming cancerous tends to be driven by changes to the cell’s DNA. And increasingly, new cancer drugs depend on knowing whether a mutation in a single gene is present in a patient’s cancer cells.
For example, a lung cancer patient may have a biopsy taken to check for changes in the EGFR gene. If there is a mutation, the patient may then be treated with a drug that works as an EGFR inhibitor. If there is no mutation, such drugs won’t work and the patient would get a different drug that would be more effective for them. Knowing the presence or absence of mutations in a certain gene can choose the treatment path for that patient.
The NHS can currently test for mutations in 2 or 3 genes – genes called BRAF, EGFR or KRAS – using older sequencing technology that has been around for decades. Efforts are being made to look at increasing the number of cancer genes sequenced to nine as standard.
The Oxford scientists are the first to make such multi-gene tests possible in the NHS using the latest DNA sequencing techniques. The NHS service they have launched looks for mutations in 46 genes, and they are now working towards verifying the use of a test involving 150 genes. University of Oxford