High-density lipoprotein cholesterol (HDL-C) is known as “good” cholesterol, because HDL particles removes excess cholesterol from arterial walls and transport them back to the liver. A research group has developed a practical test for the ability of HDL to accept cholesterol. This method could help to prevent and monitor cardiovascular disease, and it is simple enough to be used in everyday clinical situations.
The group members include Senior Researcher HARADA Amane (Central Research Laboratories, Sysmex Corporation), Project Associate Professor TOH Ryuji (Kobe University Graduate School of Medicine, Division of Evidence-Based Laboratory Medicine) in collaboration with a research team led by Professor HIRATA Ken-ichi (Kobe University Graduate School of Medicine, Division of Cardiovascular Medicine).
Standard health checks measure HDL-C, the amount of cholesterol collected by HDL – they do not look at HDL’s capacity to accept cholesterol. However, HDL’s ability to extract and accept excess cholesterol that has accumulated in cells is a more effective marker in preventing and monitoring cardiovascular disease.
In order to measure HDL’s ability to extract cholesterol (efflux capacity), standard methods use cultured cells that contain cholesterol marked by radioisotopes. This procedure is complicated and takes several days, so it cannot be used in everyday clinical situations. In this study, researchers invented a simpler and faster way to measure HDL capacity.
The team marked cholesterol with fluorescent dye instead of radioactive isotopes and added it to blood serum samples from test subjects. They supplemented the HDL in the blood serum and evaluated the amount of cholesterol accepted by HDL by measuring the strength of the fluorescence . The team called the marker for this method cholesterol “uptake capacity”, as opposed to the conventional method that measures cholesterol “extraction” (efflux) capacity.
The research team is currently using this marker on a larger population to confirm the effect of decreased HDL capacity on the prevention and control of cardiovascular disease. The results of this study could help in creating strong core technology to develop drugs that improve HDL’s function.

Kobe University
www.kobe-u.ac.jp/research_at_kobe_en/NEWS/news/2017_07_10_01.html

A research team has revealed the intrinsic gene expression patterns of glioblastoma (GBM) tumours, insights that could drive more effective treatments for GBM, the most common and deadly malignant primary brain tumours in adults.
Jackson Laboratory (JAX) Professor Roel Verhaak, Ph.D., is the senior author of a paper showing tumour gene expression patterns distinct from those of the surrounding immune cells, and characterizing the effects of chemotherapy and radiation treatments.
Verhaak was the first author of a 2010 paper that established four subclasses of GBM — proneural, mesenchymal, neural and classical — based on molecular markers found in patient tumours. That paper was widely influential in the glioblastoma research field, observes Verhaak. “However, these four subtypes have not translated into differential treatment strategies. Every glioblastoma patient receives essentially the same treatment. We hope that our latest work will improve understanding of how to optimally stratify patients, another step towards precision medicine and more targeted, effective treatments.”
The cells that surround a tumour are known as its microenvironment, usually consisting of immune cells, supporting cells and other normal cells. Tumours donated to tissue banks consist of a mixture of microenvironment cells and cancer cells.
In the new paper, the research team isolated the intrinsic gene expression of 364 GBM tumours and observed the impact of the standard cancer treatment regimens of temozolomide and radiation on that expression after subtracting out the effects of therapy on the tumour-associated non-cancer cells.
“By separating out the contributions of the microenvironment, we developed a much clearer picture of the ‘ecosystem’ of hundreds of tumours,” Verhaak says. “We determined what types of cells are in the microenvironment and what their contributions are, and also assessed how treatment affects the microenvironment as well as the tumour cells themselves.”
Through this approach, the researchers found that the molecular markers defining the neural subtype of GBM was actually ascribed by the presence of normal neural tissue in the tumour margin, thus not representing a true tumour subtype.
By studying gene expression patterns in glioblastomas after treatment, their analysis also revealed that the presence of macrophages correlates with poorer outcomes for GBM patients receiving radiation therapy, and that tumours with a relatively high number of point mutations have an increased number of positive T cells, indicating they could respond to a kind of immunotherapy known as checkpoint inhibitors.
The resulting gene expression datasets, which are publicly available to researchers, provide comprehensive profiles of glioblastoma characteristics to more accurately guide immunotherapy trials.

Jackson Laboratory
www.jax.org/news-and-insights/2017/july/glioblastoma-ecosystem-redefined

Researchers led by Arizona State University (ASU) and the Translational Genomics Research Institute (TGen) have identified altered expression of a gene called ANK1, which only recently has been associated with memory robbing Alzheimer’s disease, in specific cells in the brain.
Using an extremely precise method of isolating cells called "laser capture microdissection," researchers looked at three specific cell types – microglia, astrocytes and neurons – in the brain tissue of individuals with a pathological diagnosis of Alzheimer’s disease, and compared them to brain samples from healthy individuals and those with Parkinson’s disease.
Following sequencing of each of these cell types, the ASU-TGen led team found that altered ANK1 expression originates in microglia, a type of immune cell found in the brain and central nervous system.
"Although previous genetic and epigenetic-wide association studies had shown a significant association between ANK1 and AD, they were unable to identify the class of cells that may be responsible for such association because of the use of brain homogenates. Here, we provide evidence that microglia are the source of the previously observed differential expression patterns in the ANK1 gene in Alzheimer’s disease," said Dr. Diego Mastroeni, an Assistant Research Professor at Biodesign’s ASU-Banner Neurodegenerative Disease Research Center, and the study’s lead author.
All three of the cell types in this study were derived from the hippocampus, a small looping structure shaped like a seahorse (its name derives from the Greek words for horse and sea monster).  The hippocampus resides deep inside the human brain and plays important roles in the consolidation of both short-term and long-term memory, and in the spatial memory that enables the body to navigate.
In Alzheimer’s disease – and other forms of dementia – the hippocampus is one of the first regions of the brain to suffer damage, resulting in short-term memory loss and disorientation. Individuals with extensive damage to the hippocampus are unable to form and retain new memories.
"Using our unique data set, we show that in the hippocampus, ANK1 is significantly increased four-fold in Alzheimer’s disease microglia, but not in neurons or astrocytes from the same individuals," said Dr. Winnie Liang, an Assistant Professor, Director of TGen Scientific Operations and Director of TGen’s Collaborative Sequencing Center, and one of the study’s authors. "These findings emphasize that expression analysis of defined classes of cells is required to understand what genes and pathways are dysregulated in Alzheimer’s."
Alzheimer’s features many signs of chronic inflammation, and microglia are key regulators of the inflammatory cascade, proposed as an early event in the development of Alzheimer’s, the study said.
Because the study found that ANK1 also was increased two-fold in Parkinson’s disease, "these data suggest that alterations in ANK1, at lease in microglia, may not be disease specific, but rather a response, or phenotype associated with neurodegeneration … more specifically, neuroinflammation."

Translational Genomics Research Institute
tgen.org/home/news/2017-media-releases/asu-tgen-find-source-of-alzheimers-gene.aspx#.WWqRu_-GP5Y

Scientists investigating the genetic causes and altered functioning of nerve cells in motor neurone disease (MND) have discovered a new mechanism that could lead to fresh treatment approaches for one of the most common forms of the disease.
The team, based in the Sheffield Institute for Translational Neuroscience (SITraN), investigated a mutation in one particular gene, which causes sections of DNA to replicate themselves inexplicably within cells. They found a way to prevent RNA, carrying these replicated sequences, from leaving the cell’s nucleus and travelling into the surrounding cytoplasm where they cause cell death.
Patients with MND suffer progressive paralysis as the nerves supplying muscles degenerate. Although there are several different types of MND, this mutation, in a gene called C9ORF72, is responsible for the most common type of MND, called Amyotrophic Lateral Sclerosis (ALS). This accounts for about 40-50 per cent of inherited cases and 10 per cent of all MND cases. The mutations or environmental factors causing the vast majority of MND cases remain unknown.
DNA is produced in the cell’s nucleus and contains the instructions which cells use to carry out their functions. Messenger RNA, called mRNA, transcribes this information and carries it out of the cell to ‘protein factories’ in the cytoplasm surrounding the nucleus. It is quite common for some sections of repeated DNA stretches to replicate themselves for reasons that are poorly understood. These repetitions are ‘non-coding’ sections that are not responsible for building proteins and are edited out before they leave the nucleus to serve as templates for the production of proteins.
In this particular type of motor neurone disease, however, the RNA not only contains the unnecessary replicated sequences, it is able to take them out of nucleus and into the cell’s cytoplasm. Once in the cytoplasm, the RNA is used to make up repeated proteins that clump together and block the normal function of the cell, causing it to die.
In an early stage study the researchers have been able to pinpoint why the repeated RNA sequences are able to leave the cell’s nucleus to cause cell death. The team identified a particular protein called SRSF1 which binds to the pathological repeated RNA molecules and transports them out of the cell centre, effectively overriding the gatekeeping machinery within the nucleus by opening a back door.
Working in partnership with researchers at the MRC Mitochondrial Biology Unit at the University of Cambridge, the team have shown that by targeting the SRSF1 protein, it is possible to reduce the amount of rogue RNA escaping into the cell’s cytoplasm.
“This is a completely new approach to tackling the most common type of motor neurone disease. No one has yet attempted to prevent these repeated sequences of RNA from leaving the cell’s nucleus and it opens up new areas of investigation for gene therapy,” explains University of Sheffield’s Dr Guillaume Hautbergue, who conceived the study and led the research jointly with Dr Alexander Whitworth, of the University of Cambridge, and SITraN Director, Professor Dame Pamela Shaw.

The University of Sheffield
www.sheffield.ac.uk/news/nr/motor-neurone-disease-1.716303

Boxers and mixed martial arts fighters may have markers of long-term brain injury in their blood, according to a study.
“This study is part of a larger study to detect not just individual concussions but permanent brain injury overall at its earliest stages and to determine which fighters are at greatest risk of long-term complications,” said study author Charles Bernick, MD, of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas and member of the American Academy of Neurology. “Our study looked at data over a five-year period and found elevated levels of two brain injury markers in the blood; now the question is whether they may signify permanent traumatic brain injury with long-term consequences.”
Researchers measured two biological markers of brain injury. One is a brain protein called neurofilament light chain, the other is called tau. Both are components of nerve fibres that can be detected in the blood when the fibres are injured.
For the study, researchers took blood samples from 291 active professional fighters with an average age of 30, 44 retired fighters with an average age of 45 and 103 non-fighters with an average age of 30. The blood samples were then tested for levels of both proteins.
Researchers found that active professional fighters had higher levels of both proteins compared to retired fighters or non-fighters. For example, they found that levels of neurofilament light chain were 40 percent higher in active boxers than in non-fighters. They also found that the more a fighter sparred in the two weeks before the blood samples were taken, the higher the levels of neurofilament light chain in their blood.
Neither age, ethnicity nor number of professional fights in active fighters were linked to levels of either protein.
Bernick said while neurofilament light chain protein was higher in active fighters at the start of the study, levels did not increase significantly during the study period. On the other hand, there was a group of fighters who showed increasing levels of tau over time.
When the researchers looked at brain size, they found that for fighters who had increasing levels of tau over time, there was a 7 percent decline in the volume of their thalamus, which is located in the centre of the brain and regulates sleep, consciousness, alertness, cognitive function and language while also sending sensory and movement signals to other portions of the brain.
Finally, the study found that fighters with higher levels of neurofilament light chain protein did not do as well on computerized tests that measure the brain’s processing speed as the retired fighters and non-fighters.
“Our study found that higher levels of both proteins may be associated with repetitive head trauma,” said Bernick. “However, neurofilament light may be more sensitive to acute traumatic brain injury whereas tau may be a better measurement of cumulative damage over time. More research needs to be done to see how these may be used to monitor traumatic brain injury and the neurological consequences over time.”
A limitation of the study was the difference in the average age of active and retired fighters.

The American Academy of Neurology
www.aan.com/PressRoom/Home/PressRelease/1568