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

Today, heterosexuals in Europe are at particular risk of carrying HIV for so long that they remain undiagnosed until their immune system starts to fail and they become ill.
An international study under the leadership of the HIV in Europe initiative has now revealed that a number of diseases, including herpes zoster and certain forms of cancer, should be on the list of indicators for having HIV – and thus serve to prompt health care professionals to suggest an HIV-test to their patients.
The new results and guidelines are to be debated at a major international HIV conference in Copenhagen on 19th-20th March.
‘At the HIV in Europe conference we will be discussing how to disseminate knowledge of the new HIV indicator diseases to non-HIV doctors and health care professionals across Europe,’ says Jens Lundgren, Co-chair of the HIV in Europe initiative.
He’s also a Professor of Viral Diseases at Rigshospitalet and the Faculty of Health and Medical Sciences at the University of Copenhagen, where he heads the Copenhagen HIV Programme, one of the leading HIV/AIDS centres in the world.
Half of all people living with HIV are diagnosed very late in the course of their chronic HIV infection. People infected through heterosexual transmission now comprise 42 per cent of these late presenters, as a study of 90,000 Europeans tested HIV positive since 2.000 shows.
UNAIDS has estimated that 2,5 million Europeans carry an HIV infection, and as many as 900 000 of these, are still unaware of this. Inside EU the numbers are 800.000 infected with 250.000 undiagnosed.
Ton Coenen, co-chair of the HIV in Europe initiative, Director of Aids Funds and Soa AIDS Nederland suggests that since the HIV/AIDS issue is no longer high on the agenda in many European countries, and since people have to actively choose to be HIV-tested, many perhaps no longer consider going for a test if they have had unsafe sex.
However, the sooner HIV-infected individuals receive a diagnosis and start therapy, the greater are their chances of survival and their quality of life. And new research also shows therapy lowers the risk of passing the infection on to someone else.
‘The currently situation shows that we need more effective testing strategies and guidelines,’ Ton Coenen continues. ‘More than 300 doctors, health care professionals, NGOs and health politicians from 40 European countries will be discussing this need at the conference on 19th and 20th of March, so we have the ideal forum for it.’
‘We already have a list of Aids defining diseases, the vast majority of which indicate a weak immune system. This is a symptom of HIV and should lead to an immediate HIV test,’ Professor Lundgren explains. ‘We nned to find people living with HIV sooner than is currently the case, but to do so requires that doctors and other health care professionals offer tests to people presenting with diseases indicative of a hidden and undiagnosed HIV infection earlier in the course of the disease.’
The HIV in Europe initiative took up this challenge in 2009 and started the HIDES study (HIV Indicator Diseases Across Europe), which investigated eight new diseases and how often they proved to be signs of an undiagnosed HIV infection among the 3588 patients in the study.
‘We could see that if an adult had a sexually transmitted infection, malignant lymphoma, cervical or anal cancer/dysplasia, herpes zoster, hepatitis B or C, ongoing mononucleosis-like illness, inexplicable, persistent decline in the number of circulating white blood cells, or seborrheic dermatitis/exanthema, the risk of HIV infection was so high that it would be cost-effectiveness for society to routinely offer them a test,’ Professor Lundgren says. He also emphasises that the new indicator diseases do not necessarily mean that the patient has HIV.
‘But the incidence of HIV is greater for these eight indicator diseases and they should encourage health care professionals to offer the patient an HIV test. Draft guidelines on how to ensure this throughout Europe are one of the topics we need to debate and decide on, before they can be implemented.’ University of Copenhagen