Alex Travis, associate professor at the Baker Institute for Animal Health, co-authored the study that led to the development of a new stroke diagnosis tool.
Minutes count when treating stroke, but current diagnostics take as long as three hours, careful lab work and skilled technicians to arrive at a conclusive diagnosis. Scientists at Cornell’s Baker Institute for Animal Health have developed a device that helps diagnose stroke in less than 10 minutes using a drop of blood barely big enough to moisten your fingertip.

Having demonstrated proof of principle, the technology eventually could be expanded and used in point-of-care testing devices to diagnose other conditions in humans and animals, including traumatic brain injury (concussion), some forms of dementia, and even some types of cancer and heart disease.

The study’s lead author, Roy Cohen, a research scientist at the Baker Institute, says the technology represents the successful pairing of two big goals in medical diagnostics – small size and simplicity, a combination that means testing could be carried out at a patient’s bedside.

“Three-quarters of stroke patients suffer from ischemic stroke – a blockage of a blood vessel in the brain. In those cases, time is of the essence, because there is a good drug available, but for a successful outcome it has to be given within three or four hours after the onset of symptoms,” says Cohen. “By the time someone identifies the symptoms, gets to the hospital and sits in the emergency room, you don’t have much time to obtain the full benefit of this drug.” Enhancing the speed of diagnosis could save many people from suffering lasting effects of ischemic stroke, he says.

To diagnose stroke, a condition in which blood flow to an area of the brain is limited or cut off, the technology will one day detect several bloodborne biomarkers, molecules that appear in the blood when the stroke occurs. The technology uses enzymes attached to nanoparticles to detect the biomarker molecules and convert that detection into light.

To demonstrate the effectiveness of this new approach, the researchers focused on the biomarker neuron-specific enolase (NSE), a substance found in higher concentrations in the blood of victims of stroke and other conditions. By measuring the amount of light produced from various samples, Cohen and his colleagues can determine the concentration of NSE in the sample. At each step of the way, the signal from the NSE is amplified, so even minute quantities give off enough light for detection.

The idea to tether the enzymes, says co-author Alex Travis, associate professor of reproductive biology at the Baker Institute for Animal Health, came from the hardworking enzymes tethered to the shafts of sperm tails. These sperm enzymes efficiently turn sugars into energy that powers the flagellum and moves the sperm along. The fact that they’re attached to the sperm tail instead of floating around in solution enables the enzymes to efficiently pass the substrate along from point to point and get the most “bang for the buck” from a sugar molecule, according to Travis.

Going forward, Travis and his team will collaborate with a private company to develop the stroke-detecting technique for clinical testing and eventually make it available for use in hospitals. But he’s also excited to expand the system to diagnose other conditions.

“This system could be tailored to detect multiple biomarkers,” says Travis. “That’s the strength of the technique. You could assemble a microfluidic card based on this technology that could detect 10 biomarkers in different wells, and the readout would be the same for each one: light.” Using the same detection system for multiple different biomarkers would make for a simple system in a relatively small package, he says. Cornell University

Stress induced cardiomyopathy after cerebral haemorrhage has been shown to increase the risk of further brain damage. These patients can now be identified by a simple blood test, and a possible treatment for stress induced cardiomyopathy has been discovered – a different kind of anaesthesia than that currently being used.

Stress induced cardiomyopathy is a relatively recently discovered disease where part of the heart muscle ceases to function and results in the heart having reduced pumping capacity. Approximately 90 percent of those affected are upper middle-aged women. The onset is similar to a heart attack, with chest pain and difficulty breathing, but stress induced cardiomyopathy follows a different course.

With stress induced heart failure, the heart spontaneously recovers within a few weeks and thus the prognosis has been seen as good; but, new findings show the prognosis to be approximately the same as for acute ischemic heart disease.

In a new thesis from Sahlgrenska Academy, all patients from the region that suffered a specific type of cerebral haemorrhage (subarachnoid haemorrhage) were followed for two years. In conjunction with the haemorrhage, patients experience a strong stress component. Stress induced cardiomyopathy is therefore relatively common (10-20 percent of the patients) following this type of cerebral haemorrhage, which can cause significant brain damage.
“We saw that patients with stress induced cardiomyopathy had an increased risk of further brain damage in the aftermath of a cerebral haemorrhage and had a worse long-term prognosis, even after we made adjustments for other risk factors,” says Jonatan Oras, PhD Student at Sahlgrenska Academy.

In the thesis, two biomarkers were identified that can be used to identify patients who suffer from stress induced heart failure.
“With a blood test, we are now able to quickly identify patients with stress induced heart failure and apply the right measures sooner,” says Jonatan Oras.

In the experimental part of the thesis, an animal model was used with rats to find a possible treatment for stress induced heart failure. It was found that if the animals were anesthetized with a particular anaesthetic (isoflurane), they did not develop heart failure and the heart muscle retained its elasticity and pumping capacity.

“When we used other anaesthetics, including those currently in use in healthcare, we saw no cardioprotective effect. This is the first potential cardioprotective treatment for stress induced cardiomyopathy to be presented,” says Jonatan Oras.

Further studies of this possible treatment for stress induced cardiomyopathy on patients at risk of developing stress induced cardiomyopathy should be conducted,” Jonatan Oras points out. Sahlgrenska Academy

A particular location in DNA, called the Dlk1-Gtl2 locus, plays a critical role in protecting hematopoietic, or blood-forming, stem cells–a discovery revealing a critical role of metabolic control in adult stem cells, and providing insight for potentially diagnosing and treating cancer, according to researchers from the Stowers Institute for Medical Research.

In their study, Stowers Investigator Linheng Li, Ph.D., and first author Pengxu Qian, Ph.D., along with other collaborators, reveal how the mammalian imprinted Gtl2, located on mouse chromosome 12qF1, protects adult hematopoietic stem cells by restricting metabolic activity in the cells’ mitochondria.

The research focused on imprinted genes–genes ‘stamped’ according to whether they are inherited from the mother or father. With imprinted genes, one working copy, or allele, is inherited instead of two. Either the copy from the mother or father is inactivated or ‘silenced.’ Typically, the paternally inherited allele’s expression promotes growth, while the maternally inherited allele’s expression suppresses it.

The researchers found that when the Gtl2 locus is expressed from the maternally inherited allele, it produces non-coding RNAs to curb metabolic activity. Mechanistically, Gtl2’s ‘megacluster’ of microRNA, the largest cluster of microRNA in the mammalian genome, suppresses the mTOR signaling pathway and downstream mitochondrial biogenesis and metabolism, thus blocking mitochondrial-associated byproducts called reactive oxygen species (ROS) that can damage adult stem cells.

‘Reactive oxygen species are like the potentially harmful by-products that come from industrial manufacturing,’ says Li. ‘ROS are unavoidable derivatives of the mitochondrial metabolic process and need to be managed by the cell,’ he explains.

Hematopoietic stems cells renew themselves and differentiate into other cells, including white blood cells, red blood cells, and platelets, constantly renewing the body’s blood supply in a process called hematopoiesis. Because of their extraordinary transformative qualities, the transplantation or transfusion of isolated human hematopoietic stem cells has been used in the treatment of anemia, immune deficiencies, and other diseases, including cancer.

While hematopoietic stem cells have gained attention in research, it remains largely unknown how cell metabolic states are controlled. The new findings shed light on the delicate metabolic control required to balance hematopoietic stem cell maintenance and action and the associated healthy hematopoiesis.

An upset in that balance can cause cells to grow abnormally and lead to disease. Abnormalities in the Gtl2 locus on human chromosome 14q32.2 are associated with uniparental disomy in which an individual receives two copies of a chromosome from one parent and no copy from the other parent. Uniparental disomy may cause delayed development, mental retardation, or other medical problems. Differences in gene expression at the Gtl2 locus have also been linked to fetal alcohol exposure disorder.

But when working properly, the Gtl2 locus acts as a great protector of cells.

‘Most of the non-coding RNAs at the Gtl2 locus have been documented to function as tumor suppressors to maintain normal cell function,’ Qian says.

Li’s team zeroed in on Gtl2 by studying hematopoietic stem cells in mice with support from Stowers core centers including cytometry, bioinformatics, histology and electron microscopy, molecular biology, and tissue culture. Other collaborators included researchers from the University of Kansas; the University of Kansas Medical Center; Tianjin Medical University, China; Christian Medical College, Vellore, India; Tokyo University of Agriculture, Japan; and University of Cambridge, United Kingdom.

Over the three-year study, investigators used transcriptome profiling to analyze 17 hematopoietic cell types and found that non-coding RNAs expressed from the Gtl2 locus are predominantly located in a subset of the cell types, including adult ‘long-term’ hematopoietic stem cells which have long-term self-renewal capacity. In subsequent experiments, deleting the locus from the maternally inherited allele in hematopoietic stem cells increased mitochondrial biogenesis and subsequent metabolic activity as well as increased ROS levels, with the latter inducing cell death.

The finding opens the possibility for Gtl2 to be used as a biomarker because it could help label dormant (or reserve) stem cells in normal or potentially cancerous stem cell populations, Li says. The addition of a fluorescent tag to the Gtl2 locus could allow researchers to mark other adult stem cells in the gut, hair follicle, muscle, and neural systems. EurekAlert

Variations in genes involved in normal bone development are associated with an 8- to 15-fold increased risk for osteonecrosis in young patients with acute lymphoblastic leukaemia (ALL), according to research led by St. Jude Children’s Research Hospital and Children’s Oncology Group investigators.

Osteonecrosis is a major side effect of ALL treatment with chemotherapy. About 15 percent of ALL patients develop the complication, which is caused by reduced blood flow to bones in the hips and other joints and leads bone to break down faster than it is replaced. For patients, the results may include stiffness, pain, disability and joint-replacement surgery. ALL patients aged 10 to 20 years old are at particularly high risk for osteonecrosis.

This study is the first to focus on genetic risk factors for osteonecrosis in ALL patients less than 10 years old, an age group that accounts for about 75 percent of newly identified ALL patients and about half of ALL patients who develop osteonecrosis. Researchers used genome-wide association studies to check the DNA of 1,186 ALL patients less than 10 years old for single changes in the 3.2 billion “letters” or chemical bases that make up the human genetic code.

Researchers checked for genetic variations that were more common in 82 young ALL patients who developed osteonecrosis than in 287 who did not. The screening was then repeated with an additional 817 ALL patients younger than 10 years old. The patients were treated in clinical trials of the Children’s Oncology Group, an international clinical trials group focused exclusively on paediatric cancer.

Patients with osteonecrosis were eight to 15 times more likely to have genetic variations located near BMP7, a gene important for normal bone development.

“The goal of this and earlier studies is to identify and understand genetic and other risk factors for osteonecrosis so we can identify patients at high risk for the side effect and develop interventions to prevent the disease,” said first author Seth Karol, M.D., a St. Jude Physician Scientist Training Program fellow. Karol works with the study’s senior author Mary Relling, Pharm.D., chair of the St. Jude Department of Pharmaceutical Sciences.

A variation in the glutamate receptor gene GRID2 was also associated with a greater likelihood of osteonecrosis in ALL patients younger than 10. GRID2 belongs to a family of genes that carries instructions for assembling receptor proteins on the cell membrane that cells rely on to respond to the chemical messenger glutamate. The finding confirms previous research that reported variations in other glutamate receptor genes were associated with an elevated risk of osteonecrosis, with the prior study primarily identifying the risk in patients aged 10 and older.

“The finding that the genetic variations that affect osteonecrosis risk differ by age was unexpected,” Karol said. “The results suggest that as children age, particularly when bone growth is accelerated during adolescence, certain gene variants may become more or less important.”

Additional research is planned to expand the search for osteonecrosis genetic risk factors to include additional ALL treatment regimens and subtypes of the disease. Working in laboratory models, researchers also plan to study how gene variants affect osteonecrosis risk in order to help lay the groundwork for intervention to prevent the disease. St. Jude Children’s Research Hospital

In the first study to run a genome-wide analysis of Short Tandem Repeats (STRs) in gene expression, a large team of computational geneticists led by investigators from Columbia Engineering and the New York Genome Center have shown that STRs, thought to be just neutral, or ‘junk,’ actually play an important role in regulating gene expression.

“Our work expands the repertoire of functional genetic elements,” says the study’s leader Yaniv Erlich, who is an assistant professor of computer science at Columbia Engineering, a member of Columbia’s Data Science Institute, and a core member of the New York Genome Center. “We expect our findings will lead to a better understanding of disease mechanisms and perhaps eventually help to identify new drug targets.”

Genomic variants are what makes our DNA different from each other, and come,
Erlich explains, “like spelling errors in different flavours.” The most common
variants are SNPs (single nucleotide polymorphisms). Computational geneticists
have been focused mostly on SNPs that look like a single letter typo—mother vs.
muther—and their effect on complex human traits.

Erlich’s study looked at Short Tandem Repeats (STRs), variants that create what
look like typos: stutter vs. stututututututter. Most researchers, assuming that
STRs were neutral, dismissed them as not important. In addition, these variants
are extremely hard to study. “They look so different to analysis algorithms,” Erlich notes, “that they just usually classify them as noise and skip these positions.”

Erlich used a multitude of statistical genetic and integrative genomics analyses to
reveal that STRs have a function: they act like springs or knobs that can expand
and contract, and fine-tune the nearby gene expression. Different lengths
correspond to different tensions of the spring and can control gene expression and disease traits. He is calling these variants eSTRs, or expression STRs, to note that they regulate gene expression. He and his team also discovered that these eSTRs can be associated with a range of conditions including Crohn’s diseases, high blood pressure, and a range of metabolites. These eSTRs explain on average 10 to 15% the genetic differences of gene expression between individuals.
“We’ve known that STRs are known to play a role in these diseases, but no one has ever conducted a genome-wide scan to find their effect on complex traits,” Erlich adds. “If we want to do personalized medicine, we really need to understand every part of the genome, including repeat elements—there’s a lot of exciting biologyahead.” New York Genome Centre