Many patients with acute myeloid leukemia (AML) share a mutation in a gene called IDH. A University of Colorado Cancer Center study shows that this IDH mutation may be the first domino in a chain that leads to a more aggressive form of the disease.
‘In fact, it’s not IDH itself that causes the problem,’ says Dan Pollyea, MD, MS, investigator at the CU Cancer Center and assistant professor of haematologic oncology at the University of Colorado School of Medicine. Rather, the mutation in IDH leads to exponentially higher blood levels of a protein called 2-hydroxyglutarate. This protein ‘mucks up,’ as Pollyea says, other genes that in turn promote cancer or fail to inhibit its growth.
The recent study shows that AML patients in remission who retain high levels of 2-hydroxyglutarate – due universally to IDH mutation – are much more likely to relapse than patients without similarly elevated levels.
The chain of causation includes another couple links.
‘2-hydroxyglutarate reduces genes’ ability to regulate themselves,’ says Pollyea. Over time genes accumulate gunk in the form of methylation – these methyl groups attach to silence parts of gene promoters, helping to decide which genes are and are not turned into proteins. Too much methylation is associated with many cancers, including AML. And 2-hydroxyglutarate turns off one of the body’s methylation-regulating genes.
So an IDH mutation leads to high 2-hydroxyglutarate, leads to bad gene regulation, leads to hypermethylation, leads to AML.
Pollyea hopes to stop the first domino from falling by targeting IDH mutations. ‘Imagine screening for patients prospectively and then if they have the mutation, we could use something like an IDH inhibitor,’ Pollyea says. Turn off this mutation and doctors may be able to turn of the disease, or at least its most aggressive characteristics.
But the genetic testing for IDH mutation is currently costly and time consuming. And so Pollyea hopes to identify patients with the IDH mutation by looking downstream – tests for blood-levels of 2-hydroxyglutarate being developed at the CU Cancer Center could determine the patients most likely to benefit from an IDH inhibitor.
Finally, Pollyea and colleagues including molecular biologist James DeGregori, PhD, are exploring novel ways to target the IDH mutation. ‘I think that even beyond the very real promise of IDH inhibitor drugs, this is a potential weak spot for AML that can be targeted in a number of ways,’ Pollyea says. University of Colorado Cancer Center

Researchers at UC have confirmed that fat surrounding the outside of arteries in humans—particularly the left coronary artery—may influence the onset of coronary artery disease, or atherosclerosis, which is the leading cause of death in the U.S.
These findings may help in identifying the molecular culprit, with the goal of creating targeted therapies for atherosclerosis before the disease forms.
Coronary artery disease is a narrowing of the small blood vessels that supply blood and oxygen to the heart.
Tapan Chatterjee, PhD, and researchers in the division of cardiovascular diseases at UC found through global gene expression analysis (measurement of the activity of thousands of genes at once) that this outer fat tissue—known as perivascular fat tissue—is different from subcutaneous (beneath the skin) fat tissues in other parts of the body.
Research has previously shown that perivascular fat tissue in humans with coronary artery diseases is highly inflamed, leading to the belief that dysfunctional perivascular fat is the real culprit in the formation of coronary artery diseases.
Chatterjee’s team was able to replicate this inflammation in animal models.
‘The proximity of the perivascular fat to the artery easily influences the function of the coronary blood vessel wall,’ Chatterjee says. ‘The perivascular fat is very sensitive to high-fat diet induced inflammatory changes in mice. We found that by transplanting perivascular fat from high-fat diet fed obese mice to the carotid artery of lean mice, the tissue was detrimental to the blood vessel wall and promptly caused disease to form there.
‘Our next steps will be to identify various secreted factors, or signals, from perivascular fat tissue of obese mice that could negatively influence the functions of the blood vessel wall,’ he continues. ‘We believe this cross-talk between perivascular fat and the coronary artery is very important in triggering coronary artery diseases. We hope this knowledge helps in targeting the molecules before the onset of coronary artery diseases and treating patients before they ever experience the disease.’ University of Cincinnati Academic Health Center

Even mild head injuries can cause significant abnormalities in brain function that last for several days, which may explain the neurological symptoms experienced by some individuals who have experienced a head injury associated with sports, accidents or combat, according to a study by Virginia Commonwealth University School of Medicine researchers.
These findings advance research in the field of traumatic brain injury (TBI), enabling researchers to better understand what brain structural or functional changes underlie posttraumatic disorders – a question that until now has remained unclear.
Previous research has shown that even a mild case of TBI can result in long-lasting neurological issues that include slowing of cognitive processes, confusion, chronic headache, posttraumatic stress disorder and depression.
The VCU team, led by Kimberle M. Jacobs, Ph.D., associate professor in the Department of Anatomy and Neurobiology, demonstrated for the first time, using sophisticated bioimaging and electrophysiological approaches, that mild injury can cause structural disruption of axons in the brain while also changing the way the neurons fire in areas where they have not been structurally altered. Axons are nerve fibers in the brain responsible for conducting electrical impulses. The team used models of mild traumatic brain injury and followed morphologically identified neurons in live cortical slices.
‘These findings should help move the field forward by providing a unique bioimaging and electrophysiological approach to assess the evolving changes evoked by mild TBI and their potential therapeutic modulation,’ said co-investigator, John T. Povlishock, Ph.D., professor and chair of the VCU School of Medicine’s Department of Anatomy and Neurobiology and director of the Commonwealth Center for the Study of Brain Injury.
According to Povlishock, additional benefit may also derive from the use of this model system with repetitive injuries to determine if repeated insults exacerbate the observed abnormalities. Virginia Commonwealth University

Instrumentation Laboratory (IL) recently announced that their Strategic Alliance Cross-Distribution agreement with Beckman Coulter (BCI) will terminate on June 22, 2012, after more than twenty successful years. From June 23, 2012, IL will initiate direct sales, service, support and marketing to end-user customers in the US and Canada, for their own haemostasis product line, including the HemosIL line of reagents, ACL TOP family of haemostasis testing systems, ACL ELITE/ELITE PRO analysers and other ACL systems.

The transition will allow IL to apply the same direct business model employed in their critical care business, for over fifty years, to their haemostasis product line. Closer proximity to the customer means IL can quickly respond to changing needs, continuously improve the quality of products and services, expedite innovation to haemostasis labs, and reduce complexity of operations. R&D and manufacturing for all of IL’s haemostasis analysers and reagents, along with the company’s world-class haemostasis expertise, reside at their headquarters in Massachusetts and New York, USA.

IL will honour all customer contracts, including end-user and group purchasing organisation agreements. All current pricing, terms and conditions will remain in effect through the term of any existing agreement.

Women 65 or older who have even mild retinopathy, a disease of blood vessels in the retina, are more likely to have cognitive decline and related vascular changes in the brain, according to a multi-institutional study led by scientists at the University of California, San Francisco (UCSF).
The findings suggest that a relatively simple eye screening could serve as a marker for cognitive changes related to vascular disease, allowing for early diagnosis and treatment, potentially reducing the progression of cognitive impairment to dementia.
As retinopathy usually is caused by Type II diabetes or hypertension, a diagnosis could indicate early stages of these diseases, before they are clinically detectable. Early diagnosis could allow for lifestyle or drug interventions when they might be most effective.
‘Lots of people who are pre-diabetic or pre-hypertensive develop retinopathy,’ said the lead author of the study, Mary Haan, DrPH, MPH, UCSF professor of epidemiology and biostatistics. ‘Early intervention might reduce the progression to full onset diabetes or hypertension.’
The results were based on data from the Women’s Health Initiative Memory Study and the Site Examination study, two ancillary studies of the Women’s Health Initiative Clinical Trial of Hormone Therapy.
In the study, the team followed 511 women with an average starting age of 69, for 10 years. Each year, the women took a cognition test focused on short-term memory and thinking processes. In the fourth year, they received an exam to assess eye health. In the eighth year, they received a brain scan.
Of the full group of women, 39 women, or 7.6 percent, were diagnosed with retinopathy. On average, these women scored worse on the cognition test than the other women. They had more difficulty, for instance, recalling a list of several words five minutes after hearing them.
The women with retinopathy also had more damage to the blood vessels of the brain. They had 47 percent more ischemic lesions, or holes, in the vasculature overall and 68 percent more lesions in the parietal lobe. The lesions, associated with vascular disease and sometimes stroke, are believed to be caused by high blood pressure. They also had more thickening of the white matter tracks that transmit signals in the brain, which also appear to be caused by high blood pressure.
Notably, the women did not have more brain atrophy, which is associated with Alzheimer’s disease. This result indicates that retinopathy is a marker of neurovascular disease rather than Alzheimer’s disease, according to Haan. University of California, San Francisco,