Tilting the scales in an ongoing debate, University of Wisconsin-Madison researchers have found new evidence that human cytomegalovirus (HCMV) is associated with glioblastoma multiforme (GBM), the brain cancer that killed Sen. Edward Kennedy.
The findings confirm what only a handful of scientists have found, but in a manner that University of Wisconsin School of Medicine and Public Health researchers believe enhances the scientific rigor of earlier studies.
The study hints for the first time that HCMV may work differently than other cancer-related viruses – possibly by affecting only tumour stem cells, self-renewing cells that keep the tumour growing. The new research may place HCMV in an expanding group of viruses associated with cancer.
‘As many as 15 to 20 percent of all human cancers are caused by viruses, and the number is growing,’ says HCMV expert Dr. Robert Kalejta, associate professor of oncology at the UW School of Medicine and Public Health (SMPH). ‘The viruses may not cause cancer on their own, but they play a critical role in the process.’
Among others, human papilloma virus (HPV) causes cervical cancer, Epstein-Barr virus (EBV) causes lymphoma and hepatitis C virus (HCV) causes liver cancer.
HCMV’s role in GBM has been debated, with many scientists and clinicians remaining skeptical. Oncologist Dr. Charles Cobbs of California Pacific Medical Center has been the main proponent of the theory that HCMV contributes to GBM.
Dr. John Kuo, assistant professor of neurological surgery and human oncology and a cancer stem cell scientist at the School of Medicine and Public Health, was one of the skeptical ones, but he says he’s now convinced that HCMV is associated with human GBM specimens.
Still, the association does not prove a causal relationship between HCMV and the development of GBM, he says.
‘This study may open up a new unexplored area of research for this incurable disease,’ says Kuo, who is director of the Comprehensive Brain Tumor Program at UW Hospital and Clinics. He also co-ordinates clinical trials as chair of the brain tumour group at the Carbone Cancer Center.
Two years ago, Kalejta’s team added support to Cobb’s position when it showed that two HCMV proteins shut down a key protein that restricts tumour growth in general.
‘HCMV can also do every one of the things that are generally considered the 10 hallmarks of cancer,’ says Kalejta, a member of the McArdle Laboratory for Cancer Research, Carbone Cancer Center, Stem Cell and Regenerative Medicine Center and Institute for Molecular Virology at UW-Madison.
The problem with studying HCMV is that the virus is present in a harmless way in almost everyone, so scientists can’t ask if HCMV-positive people are more likely to get cancer than people without HCMV.
Kalejta’s postdoctoral fellow Dr. Padhma Ranganatan used a standard laboratory test, rather than the ultra-sensitive test Cobb has used, to see if HCMV was present in 75 GBM samples. The UW-Madison researchers also looked to see if the entire virus genome – all of its DNA – rather than just a portion of it was present in the tissues. Finally, they wanted to learn if all cells within the tumour or just some of them were infected.
The analysis showed that HCMV is statistically more likely to be present in GBM sample tissues than in other brain tumour and epileptic brain tissues. The whole virus genome, not a portion of it, was present in GBM samples. And the data suggested that a minority of GBM cells were infected with HCMV.
‘We hypothesize that HCMV may be infecting only tumour stem cells, unlike other viruses, which infect every single tumour cell,’ says Kalejta. ‘This leads us to predict that HCMV functions by a unique mechanism that no other virus uses.’ University of Wisconsin-Madison

UT Southwestern Medical Center cardiologists have uncovered how a specific protein’s previously unsuspected role contributes to the deterioration of heart muscle in patients with diabetes. Investigators in the mouse study also have found a way to reverse the damage caused by this protein.
Dr. Joseph HillThe new research was carried out in the laboratory of Dr. Joseph Hill, director of the Harry S. Moss Heart Center at UT Southwestern.
‘If we can protect the heart of diabetic patients, it would be a significant breakthrough,’ said Dr. Hill, the study’s senior author who also serves as chief of cardiology at the medical center. ‘These are fundamental research findings that can be applied to a patient’s bedside.’
Cardiovascular disease is the leading cause of illness and death in patients with diabetes, which affects more than 180 million people around the world, according to the American Heart Association. Diabetes puts additional stress on the heart – above and beyond that provoked by risk factors such as high blood pressure or coronary artery disease, Dr. Hill said.
‘Elevated glucose and the insulin-resistant diabetic state are both toxic to the heart,’ he said.
Dr. Hill and his colleagues in this study were able to maintain heart function in mice exposed to a high fat diet by inactivating a protein called FoxO1. Previous investigations from Dr. Hill’s laboratory demonstrated that FoxO proteins, a class of proteins that govern gene expression and regulate cell size, viability and metabolism, are tightly linked to the development of heart disease in mice with type 2 diabetes.
‘If you eliminate FoxO1, the heart is protected from the stress of diabetes and continues to function normally,’ Dr. Hill said. ‘If we can prevent FoxO1 from being overactive, then there is a chance that we can protect the hearts of patients with diabetes.’ UT Southwestern Medical Center

Atrial fibrillation, or irregular heartbeat, is a very common heart rhythm disturbance that increases the risk of stroke and death. It is usually treated with warfarin, where the dose is calculated by measuring the coagulation of the blood. The dose is increased if coagulation is too quick, and decreased if it is too slow. Patients with unsatisfactory samples are tested more frequently, while satisfactory samples mean that the test interval can be extended.
Researchers at the Sahlgrenska Academy at the University of Gothenburg and Chalmers University of Technology in Sweden have now devised a new method that improves the accuracy of risk assessment. In a study involving 20,000 patients in Sweden, a new measurement method was tested that assesses far more reliably who is at risk of serious complications and admission to hospital. The method takes into account how blood viscosity fluctuates and also takes account of the values’ extremes to establish far more reliably which patients are at risk of a stroke, haemorrhage or death. The new method improves the chances of understanding which patients are at risk of complications, and is therefore an indicator for stepping up checks and probably reducing the risks. It also helps in the decision to discontinue warfarin in favour of other drugs in at-risk patients.

Continuing a series of groundbreaking discoveries begun in 2010 about the genetic causes of the third most common form of inherited muscular dystrophy, an international team of researchers led by a scientist at Fred Hutchinson Cancer Research Center has identified the genes and proteins that damage muscle cells, as well as the mechanisms that can cause the disease.
The discovery could lead to a biomarker-based test for diagnosing facioscapulohumeral muscular dystrophy (FSHD), and the findings have implications for developing future treatments as well as for cancer immunotherapies in general.
The work establishes a viable roadmap for how the expression of the DUX4 gene can cause FSHD. Whether this is the sole cause of FSHD is not known; however, the latest findings ‘are about as strong of evidence as you can get’ of the genetic link, said corresponding author Stephen Tapscott, M.D., Ph.D., a member of the Hutchinson Center’s Human Biology Division.
Tapscott and colleagues sought answers to the questions about what the DUX4 protein does both normally in the body and in the FSHD disease process. In the latest study, they identified that the DUX4 protein regulates many genes that are normally expressed in the male germ line but are abnormally expressed in FSHD muscle. Germ line cells are inherited from parents and passed down to their offspring.
‘This study is a significant step forward by solidifying that the DUX4 transcription factor causes this disease, while offering a number of viable mechanisms for why the muscle is damaged,’ Tapscott said. Transcription factors are tools that cells use to control gene expression. Genes that are ‘turned on’ in the body are ‘transcribed,’ or translated, into proteins.
Now that scientists know that targets for DUX4 are expressed in skeletal muscle, an antibody- or RNA-based test could be developed to diagnose FSHD by examining muscle tissue from a biopsy, Tapscott said. Such biomarker-based tests also could be used to determine how well new treatments are working to suppress FSHD.
The study also discovered that DUX4 regulates cancer/testis antigens. Cancer/testis antigens are encoded by genes that are normally expressed only in the human germ line, but are also abnormally expressed in various tumour types, including melanoma and carcinomas of the bladder, lung and liver.
‘This knowledge now gives us a way to manipulate the expression of cancer/ testis antigens, potentially opening the opportunity to use these antigens in a cancer vaccine,’ Tapscott said. Fred Hutchinson Cancer Research Center

A new genetic mutation that causes familial amyotrophic lateral sclerosis (ALS), a fatal neurological disorder also known as Lou Gehrig’s Disease, has been identified by a team of scientists led by researchers at the University of Massachusetts Medical School (UMMS). Mutations to the profilin (PFN1) gene, which is essential to the growth and development of nerve cell axons, is estimated to account for one to two percent of inherited ALS cases. The finding points to defects in a neuron’s cytoskeleton structure as a potential common feature among diverse ALS genes.
‘This discovery identifies what may possibly be a common biological mechanism involved across familial ALS cases regardless of genetics,’ said John Landers, PhD, associate professor of neurology and senior author of the study. ‘We know of at least three other ALS genes, in addition to PFN1, that adversely impact axon growth. If indeed, this is part of the disease’s mechanism, then it might also be a potential target for therapeutics.’
Robert Brown, MD, DPhil, a co-author on the study and chair of neurology at UMass Medical School, said ‘Dr. Landers has done great work in defining this new pathway for motor neuron death. We are delighted to have identified the defects in families from the U.S., Israel and France that we have been investigating for several years. Our finding is particularly exciting because it may provide new insights into ALS treatment targets.’
ALS is a progressive, neurodegenerative disorder affecting the motor neurons in the central nervous system. As motor neurons die, the brain’s ability to send signals to the body’s muscles is compromised. This leads to loss of voluntary muscle movement, paralysis and eventually respiratory failure. The cause of most cases of ALS is not known. Approximately 10 percent of cases are inherited. Though investigators at UMass Medical School and elsewhere have identified several genes shown to cause inherited or familial ALS, almost 50 percent of these cases have an unknown genetic cause.
The current study details the discovery of the PFN1 gene mutation among two large ALS families. Both families were negative for known ALS-causing mutations and displayed familial relationships that suggested a dominant inheritance mode for the disease. For each family, two affected members with maximum genetic distance were selected for deep DNA sequencing. To identify an ALS-causing mutation, genetic variations between the family members were identified and screened against known databases of human genetic variation, such as the 1000 Genomes Project. This narrowed down the resulting number of candidate, ALS-causing mutations to two within the first family and three within the second. Interestingly, both families contained different mutations within the same gene – PFN1, the likely causative mutation. With additional screening, the team documented that in a total of 274 families sequenced, seven contained a mutation to the PFN1 gene, establishing it as a likely cause for ALS.
While it is not certain how the PFN1 mutation causes ALS, the cellular functions it controls within the motor neurons are responsible for regulation of a number of activities, including the growth and development of the axon, the slender projection through which neurons transmit electrical impulses to neighboring cells, such as muscle. When introduced into motor neuron cells, normal PFN1 protein was found diffused throughout the cytoplasm. Conversely, the mutant PFN1 observed in ALS patients was found to collect in dense aggregates, keeping it from functioning properly. Motor neurons producing mutated PFN1 showed markedly shorter axon outgrowth.
‘The discovery that mutant PFN1 interferes with axon outgrowth was very exciting to us,’ said Claudia Fallini, PhD, a postdoctoral researcher at Emory University School of Medicine who collaborated with the UMass Medical School authors to investigate PFN1’s functions in cultured motor neurons. ‘It suggests that alterations in actin dynamics may be an important mechanism at the basis of motor neuron degeneration.’
‘In healthy neurons, PFN1 acts almost like a railroad tie for fibrous filaments called actin, which make up the axon’ said Landers. ‘PFN1 helps bind these filaments to each other, promoting outgrowth of the axon. Without properly functioning PFN1 these filaments can’t come together. Here we show that mutant PFN1 may contribute to ALS pathogeneses by accumulating in these aggregates and altering the actin dynamics in a way that inhibits axon outgrowth.’ EurekAlert