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Massive study identifies potential new targets for brain cancer treatments

Fri, 05 Sep 2008 10:10:00 -0400

American researchers have identified some new genetic changes that may be targets for future therapies to treat brain cancer.

The breakthrough results from the efforts made by scientists from Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard, as well as their collaborating investigators from 18 institutions and organizations.

The researchers say that the large-scale combing of the brain cancer genome, part of the 100million dollar pilot project of The Cancer Genome Atlas (TCGA), has also enabled them to confirm the key roles that some of the previously known mutated genes play in glioblastoma multiforme (GBM), the most aggressive type of primary brain tumour.

"The findings of significant mutations in genes that have implications for therapeutic development illustrate precisely how unbiased and systematic cancer genome analyses can lead to paradigm-shifting discoveries," Nature magazine quoted Dr. Lynda Chin, who chairs the GBM disease working group within TCGA, as saying.

"These data show that this approach, of looking at large numbers of tumours and a large number of genetic factors, can be done and the results are really valuable. We have made significant novel findings, and the reproducibility of the data is high," added Dr. Matthew Meyerson, who co-led the writing effort for the first summary of data from the pilot project.

The research collaborators analysed the complete sets of DNA of tumour samples donated by 206 patients with GBM.

They looked for several categories of flaws—"typos" in the DNA code of a gene that alters its function; too many or too few copies of a given gene; damage to chromosomes causing loss or dislocation of pieces; gene activity that is higher or lower than normal; and changes in DNA methylation—by turning genes on or off without affecting their structure.

The team also had access to information on how the patients who donated the samples had fared, including how they responded to certain drugs.

While five major gene mutations have previously been identified in glioblastoma cells, the new sequencing effort revealed three that hadn''t been discovered.

The researchers say that one mutation affects the NF1 gene that causes neurofibromatosis, a second mutation is in the ERBB2 gene known to be involved in breast cancer, and the third affects a gene in the PIK3 signaling pathway that is abnormally activated in a number of cancers.

They, however, add that a particular gene called PIK3R1 had been only rarely implicated in any cancer.

"Each of these mutated genes defines a new target for glioblastoma treatment," said Meyerson.

The researchers also found that three signalling pathways, networks of genes and proteins that act together to carry out a cellular function, were disrupted in more than three-quarters of the GBM tumours.

They revealed their identity as the cyclin-dependent kinase/retinoblastoma pathway that regulates cell division, the p53 tumour suppressor pathway that is involved in response to DNA damage and cell death, and the receptor tyrosine kinase pathway that carries signals that control cell growth.

Chin said that the most exciting finding was that the multipronged study design also enabled the scientists to make a potentially important connection between a methylation change in the glioblastoma cells and which drugs should be used for treatment.

Brain tumours that contain a silenced form of a gene known as MGMT are known to be more susceptible to cancer drug temozolomide (Temodar), and thus it is routinely given along with radiation to patients with MGMT methylation.

However, the study suggests that when patients treated with Temodar subsequently have a recurrence of the tumour, it is very likely to become resistant to treatment because of "hypermutation", an increased rate of gene changes that led to the tumour''s ability to evade the drugs.

"This could have immediate clinical applications," said Chin.

The authors of the study say that these findings are only the tip of an expected iceberg, and that the "most powerful impact" is expected to come from further research studies.

"These impressive results from TCGA provide the most comprehensive view to date of the complicated genomic landscape of this deadly cancer. The more we learn about the molecular basis of glioblastoma multiforme, the more swiftly we can develop better ways of helping patients with this terrible disease. Clearly, we should move ahead and apply the power of large-scale, genomic research to many other types of cancer," said NIH Director Dr. Elias A. Zerhouni. (ANI)

Scientists identify gene that may hold key to neutralize HIV

Fri, 05 Sep 2008 04:47:00 -0400

A team of researchers at the Gladstone Institute of Virology and Immunology (GIVI) and the National Institutes of Allergy and Infectious Diseases (NIAID) has discovered a new gene that may influence the production of antibodies that neutralize HIV.

According to the researhcers, the new finding will likely spur a new approach for making an HIV vaccine that elicits neutralizing antibodies.

In 1978, researchers at the National Institutes of Health (NIH) studying a similar retrovirus in mice discovered a gene called Rfv3 that influenced the production of neutralizing antibodies that allowed the animals to recover.

By 1999, they had narrowed the location of Rfv3 to a relatively small region on mouse chromosome 15, but that region contained more than 60 genes.

The laboratory of GIVI Director Warner C. Greene and a team of scientists from NIAID now demonstrate that Rfv3 is Apobec3, an innate immunity gene with antiretroviral activity.

"This newfound link between Apobec3 and the production of neutralizing antibodies came as a complete surprise," said Dr. Greene, senior author of the study.

HIV uses one of its genes, Vif, to specifically disable human Apobec3 proteins and HIV-infected patients rarely make broadly neutralizing antibodies against this virus.

This new study raises the possibility that drugs or vaccines that interfere with Vif might allow humans to naturally make better neutralizing antibody responses against HIV.

Gladstone scientist Mario Santiago, PhD, said: "We now have a host factor needed for the production of neutralizing antibodies that HIV targets and destroys. This offers a fresh perspective on how to strengthen this arm of the immune response against HIV, with direct implications for immunotherapy and vaccine development."

The researhcers conducted a series of genetic experiments by mating mice with different Rfv3 and Apobec3 profiles.

The researchers demonstrated that Apobec3, like Rfv3, contributes to the early control of retroviral infection in mice, and also influences specific retroviral antibody responses.

Also, they discovered that Rfv3 susceptible mouse strains that fail to make antibody responses have a natural defect in Apobec3. These results provide convincing evidence that Rfv3 and Apobec3 are the same gene.

"We set out to solve a 30-year old mystery in retrovirus biology and in the process made a discovery that might impact future development of HIV vaccines," said Dr. Greene.

The study is published in the September 5 issue of Science. (ANI)

Women who binge drink indulge more in unsafe sexual practices

Fri, 05 Sep 2008 04:45:00 -0400

Women, who binge drink are more likely to indulge in unsafe sexual practices, and so are at an increased risk of having sexually transmitted diseases (STDs), according to a new study.

The researchers found that women, who drink more than five alcoholic beverages at one time, are likely to unsafe sexual practices – such as multiple partners and anal sex.

"Binge drinking results in a decreased ability to make clear decisions and can enable individuals to engage in behaviours that they would not if sober,” said Geetanjali Chander, assistant professor of medicine in the division of general internal medicine at Johns Hopkins University School of Medicine.

“Initially, some individuals may drink with the expectation of decreasing inhibitions, or some may drink because they are anxious, or depressed, and they expect alcohol to alleviate their symptoms.

“Regardless of why they choose to drink, many people do not perceive the potential risk or harm that may result from binge drinking," she added.

During the study, between July 2000 and August 2001, researchers approached 795 STD-clinic patients being evaluated or treated for STDs.

Of those approached, 671, 322 males, 349 females agreed to answer questions about their recent alcohol/drug use and risky sexual behaviours using audio computer-assisted-self interview technology.

"We found that binge drinking among women STD-clinic patients is associated with certain risky sexual behaviours," said Heidi E. Hutton, assistant professor of psychiatry and behavioural sciences at Johns Hopkins University School of Medicine as well as corresponding author for the study.

"Across gender, women binge drinkers are more likely to have anal sex than men binge drinkers. Within gender, women binge drinkers are three times as likely to have anal sex, and twice as likely to have multiple sex partners compared to women who do not drink alcohol.

“Compared to non-drinking women, women binge drinkers are also five times as likely to have gonorrhea," she added.

Hutton said that both binge drinking and risky sexual behaviours are more hazardous to women than men.

"Gonorrhea is a sexually transmitted disease which reflects unsafe sexual practices," Chander said.

"This association between binge drinking and high-risk sexual behaviours is especially important as risky behaviours are associated with HIV acquisition and transmission,” she added.

The study is published in the November issue of Alcoholism: Clinical & Experimental Research. (ANI)

‘Antibiotic cycling’ lowers MRSA infections in hospital ICUs

Fri, 05 Sep 2008 04:42:00 -0400

Doctors at the University of Virginia Health System have successfully used a method called antibiotic cycling, wherein medications are rotated at regular intervals, to significantly reduce MRSA infections among surgical intensive care patients.

The researchers said that the MRSA infection rate decreased from 1.9 to 1.4 patients per 100 admissions in the surgical ICU when they switched between two antibiotics, linezolid and vancomycin, every three months.

In their study report, published in the journal Surgical Infections, the researchers have also revealed that in-hospital mortality from surgical ICU-acquired MRSA infections fell from 3.8 patients per year to none.

The report suggests that study data spanned six years, including the period before cycling began (1997 to 2001) and the period after it was instituted (2002 to 2003).

It also reveals that the study’s key focus was resistant gram-positive cocci, a subgroup defined as MRSA (methicillin-resistant Staphylococcus aureus) and VRE (vancomycin-resistant Enterococcus).

"Before we began cycling, 67 percent of the Staphylococcus aureus infections in our surgical ICU were caused by MRSA. Cycling reduced MRSA cases to 36 percent of that total," says the lead author of the study, Dr. Robert Sawyer, a professor of surgery and co-director of UVA''s Surgical Trauma Intensive Care Unit.

The researchers claim that their study is the first to assess the impact of antibiotic cycling on a group of bacteria known as gram-positive cocci.

Dr. Sawyer says that though the findings are important, they need to be confirmed by similar studies in other ICU''s.

"If cycling proves effective at other centers, we might be able to turn the tide on antibiotic resistance, at least for MRSA. In the long run, reducing MRSA should decrease the number of deaths among critically ill patients. However, the problem is very complex and will almost certainly need a variety of interventions to achieve the best outcomes," he says.

While MRSA infection rates fell during cycling, the prevalence of VRE remained virtually unaltered.

According to the researchers, VRE infection rates rose slightly, from .76 to .98 patients per 100 admissions. In-hospital mortality from VRE dropped from 2.8 to 2.5 patients per year.

Cycling reduced the surgical ICU''s overall gram-positive infection rate from 19.6 to 11.8 patients per 100 admissions, and lowered the rate of infections from resistant gram-positive cocci from 4.6 to 1.7 patients per 100 admissions. (ANI)

Roman conquered area people more prone to AIDS

Fri, 05 Sep 2008 04:41:00 -0400

People living in countries that were once conquered by the Roman army may be more vulnerable to AIDS as compared to others, according to a study.

Researchers at Provence University in France have discovered that a gene that reduces susceptibility to HIV occurs in greater frequency in areas of Europe that the Roman Empire did not stretch to.

The researchers have revealed that the gene lacks certain DNA elements due to which HIV cannot bind to it easily, and thus the virus’ ability to infect cells diminishes.

According to them, people possessing the mutation have some resistance to HIV infection, and also take longer to develop AIDS.

Studying about 19,000 DNA samples from across Europe, the researchers found that the gene variant seemed to dwindle in regions conquered by the Romans.

The gene, which generally only people in Europe and western Asia carry, seemed to become much less frequent as the researchers moved south.

In their study report, the researchers have revealed that over 15 per cent of people in some areas of northern Europe carried the gene, compared with fewer than four per cent of Greeks.

Study leader Dr Eric Faure rules out the possiblitity that the Romans spread the regular version of the gene into their colonies by breeding with indigenous people.

"Gene flow between the two was extremely low," the Telegraph quoted him as telling New Scientist.

The researcher instead believes that the Romans introduced a disease to which people carrying the gene variant were particularly susceptible.

According to him, as the Romans moved north, the disease killed off people with the variant gene that now protects against HIV.

The findings of the study have been published in the journal Infection, Genetics and Evolution. (ANI)