Latest Science Updates

Obedience rates essentially unchanged in more than 40 years; No differences between men and women

WASHINGTON – Nearly 50 years after one of the most controversial behavioral experiments in history, a social psychologist has found that people are still just as willing to administer what they believe are painful electric shocks to others when urged on by an authority figure.

Jerry M. Burger, PhD, replicated one of the famous obedience experiments of the late Stanley Milgram, PhD, and found that compliance rates in the replication were only slightly lower than those found by Milgram. And, like Milgram, he found no difference in the rates of obedience between men and women.

Burger's findings are reported in the January issue of American Psychologist, the flagship journal of the American Psychological Association. The issue includes a special section reflecting on Milgram's work 24 years after his death on Dec. 20, 1984, and analyzing Burger's study.

"People learning about Milgram's work often wonder whether results would be any different today," said Burger, a professor at Santa Clara University. "Many point to the lessons of the Holocaust and argue that there is greater societal awareness of the dangers of blind obedience. But what I found is the same situational factors that affected obedience in Milgram's experiments still operate today."

Stanley Milgram was an assistant professor at Yale University in 1961 when he conducted the first in a series of experiments in which subjects – thinking they were testing the effect of punishment on learning – administered what they believed were increasingly powerful electric shocks to another person in a separate room. An authority figure conducting the experiment prodded the first person, who was assigned the role of "teacher" to continue shocking the other person, who was playing the role of "learner." In reality, both the authority figure and the learner were in on the real intent of the experiment, and the imposing-looking shock generator machine was a fake.

Milgram found that, after hearing the learner's first cries of pain at 150 volts, 82.5 percent of participants continued administering shocks; of those, 79 percent continued to the shock generator's end, at 450 volts. In Burger's replication, 70 percent of the participants had to be stopped as they continued past 150 volts – a difference that was not statistically significant.

"Nearly four out of five of Milgram's participants who continued after 150 volts went all the way to the end of the shock generator," Burger said. "Because of this pattern, knowing how participants react at the 150-volt juncture allows us to make a reasonable guess about what they would have done if we had continued with the complete procedure."

Milgram's techniques have been debated ever since his research was first published. As a result, there is now an ethics codes for psychologists and other controls have been placed on experimental research that have effectively prevented any precise replications of Milgram's work. "No study using procedures similar to Milgram's has been published in more than three decades," according to Burger.

Burger implemented a number of safeguards that enabled him to win approval for the work from his university's institutional review board. First, he determined that while Milgram allowed his subjects to administer "shocks" of up to 450 volts in 15-volt increments, 150 volts appeared to be the critical point where nearly every participant paused and indicated reluctance to continue. Thus, 150 volts was the top range in Burger's study.

In addition, Burger screened out any potential subjects who had taken more than two psychology courses in college or who indicated familiarity with Milgram's research. A clinical psychologist also interviewed potential subjects and eliminated anyone who might have a negative reaction to the study procedure.

In Burger's study, participants were told at least three times that they could withdraw from the study at any time and still receive the $50 payment. Also, these participants were given a lower-voltage sample shock to show the generator was real – 15 volts, as compared to 45 volts administered by Milgram.

Several of the psychologists writing in the same issue of American Psychologist questioned whether Burger's study is truly comparable to Milgram's, although they acknowledge its usefulness.

"…there are simply too many differences between this study and the earlier obedience research to permit conceptually precise and useful comparisons," wrote Arthur G. Miller, PhD, of Miami University in Oxford, Ohio.

"Though direct comparisons of absolute levels of obedience cannot be made between the 150-volt maximum of Burger's research design and Milgram's 450-volt maximum, Burger's 'obedience lite' procedures can be used to explore further some of the situational variables studied by Milgram, as well as look at additional variables," wrote Alan C. Elms, PhD, of the University of California, Davis. Elms assisted Milgram in the summer of 1961.

source-www.eurekalert.org

Earth's location in the Universe is utterly unremarkable, despite recent theories that propose toppling a foundation of modern cosmology, according to a team of University of British Columbia researchers.

Polish astronomer Nicolaus Copernicus's 1543 book, On the Revolutions of the Heavenly Spheres, moved Earth from being the centre of the Universe to just another planet orbiting the Sun. Since then, astronomers have extended the idea and formed the Copernican Principle, which says that our place in the Universe as a whole is completely ordinary. Although the Copernican Principle has become a pillar of modern cosmology, finding conclusive evidence that our neighbourhood of the Universe really isn't special has proven difficult.

In 1998, studies of distant explosions called "type Ia supernovae" indicated that the expansion of the Universe is accelerating, an observation attributed to the repulsive force of a mysterious "dark energy." However, some scientists put forward an alternate theory: They proposed that the Earth was near the centre of a giant "bubble," or "void," mostly empty of matter, and strongly violating the Copernican Principle. If this were the case, gravity would create the illusion of acceleration, mimicking the effect of dark energy on the supernova observations.

Now some advanced analysis and modeling performed by UBC post-doctoral fellows Jim Zibin and Adam Moss and Astronomy Prof. Douglas Scott is showing that this alternate "void theory" just doesn't add up. Their findings are published today in the journal Physical Review Letters.

The researchers used data from the Wilkinson Microwave Anisotropy Probe satellite, which includes members from UBC on its international team, as well as data from various ground-based instruments and surveys.

"We tested void models against the latest data, including subtle features in the cosmic microwave background radiation – the afterglow of the Big Bang – and ripples in the large-scale distribution of matter," says Zibin. "We found that void models do a very poor job of explaining the combination of these data."

The team's calculations instead solidify the conventional view that an enigmatic dark energy fills the cosmos and is responsible for the acceleration of the Universe. "Recent advances in data collection have brought us to the era of precision cosmology," says Zibin. "Void models are terrible at explaining the new data, but the standard dark energy model works very well.

"Since we can only observe the Universe from Earth, it's really hard to determine if we're in a 'special place,'" says Zibin. "But we've now learned that our location is much more ordinary than the strange dark energy that fills the Universe."

source-www.eurekalert.org

Scientists have found that genetic variation at the hexokinase-1 gene is linked to variation in the blood concentration of glycated hemoglobin, an index of long-term blood glucose concentration widely used in the follow-up of diabetes patients. The study, conducted by researchers from the Brigham and Women's Hospital in Boston, USA, is published December 19 in the open-access journal PLoS Genetics.

Diabetes is a leading cause of morbidity and mortality in both the developed and developing world. Because the main metabolic characteristic of diabetes is increased blood glucose concentration, the researchers sought to uncover the genetic determinants of glycated hemoglobin. Lead author Guillaume Paré and his team analyzed glycated hemoglobin concentration in a subset of 14,618 women from the Women's Genome Health Study, a large-scale study seeking to identify patterns of genetic variations that predict future disease states in otherwise healthy American women.

Using new technologies to study genetic variation on a whole genome basis, the group found that variations at the hexokinase-1 gene are an important determinant of glycated hemoglobin concentrations. Hexokinase-1 encodes the enzyme hexokinase, responsible for the first metabolic step in glucose utilization and a likely candidate for the control of glucose metabolism.

While further work will be needed to fully understand the metabolic role of these genetic variants, it is hoped that this discovery could lead to a better understanding of the mechanisms underlying diabetes and its complications.

source-www.eurekalert.org

'Now researchers can focus on more promising therapies'

Kingston, ON – A commonly-prescribed drug for men suffering from a painful pelvic condition failed to significantly reduce patients' symptoms in an international study led by Queen's University professor and urologist at Kingston General Hospital, Curtis Nickel.

The drug, called Alfuzosin, is regularly prescribed by more than half of family doctors to treat chronic prostititis/chronic pelvic pain syndrome. This affliction is estimated to affect from six to 12 per cent of the population.

Sponsored by the U.S. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health, the study is published today in the prestigious New England Journal of Medicine.

"The results of our study will inform not only future clinical trials of alpha-blockers, but also other potential therapies," says Dr. Nickel, who is Canada Research Chair in Urologic Pain and Inflammation.

"Although the evidence for using alpha-blockers to treat new cases of chronic prostatitis/chronic pelvic pain syndrome is weak, some physicians have advocated use of this class of drug in men with this condition," he adds. "Our findings do not support this recommendation and should prompt reconsideration of use of an alpha-blocker as the first drug of choice for these patients."

Prostatitis is a common and costly medical condition, with chronic prostatitis/chronic pelvic pain syndrome the most frequent type seen by physicians. Men with this condition experience pain in the genital and urinary tract area and also report lower urinary tract symptoms and sexual problems that negatively affect their quality of life.

In the Queen's-led study, 233 men diagnosed with chronic prostatitis/chronic pelvic pain syndrome were randomly assigned to either alfuzosin or an identical-looking placebo. None of the men had received prior treatment with a beta-blocker.

Over the 12-week trial, participants were asked to rate improvements in pain perception, problems with urination, and their quality of life. The rates of response in both groups were the same.

"In medical research, it is as important to find out which treatments are effective, as well as those which are not beneficial," notes NIDDK Director Griffin Rodgers. "Now researchers can focus their efforts on more promising therapies."

source-www.eurekalert.org

Researchers advocate including imaging technology as diagnostic test

Tampa, FL (Dec. 18, 2008) -- MRI scans that detect shrinkage in specific regions of the mid-brain attacked by Alzheimer's disease accurately diagnose the neurodegenerative disease, even before symptoms interfere with daily function, a study by the Florida Alzheimer's Disease Research Center (ADRC) in Miami and Tampa found.

The study, reported earlier this month in the journal Neurology, adds to a growing body of evidence indicating MRI brain scans provide valuable diagnostic information about Alzheimer's disease. The findings are important in light of many new disease-modifying drugs in trials -- treatments that may prevent mild memory loss from advancing to full-blown dementia if administered early enough.

"We advocate, based on these findings, that the criteria for the diagnosis of Alzheimer's disease should include MRI scans," said the study's lead author Ranjan Duara, MD, medical director of the Wien Center for Alzheimer's Disease and Memory Disorders at Mount Sinai Medical Center who is affiliated with the University of Miami Miller School of Medicine and University of South Florida College of Medicine. "By incorporating MRIs into the assessment of patients with memory problems, early diagnosis can be standardized and done far more accurately."

"This study demonstrates that MRI brain scans are accurate enough to be clinically useful, both in diagnosing Alzheimer's disease itself at an early stage and in identifying people at risk of developing Alzheimer's," said Florida ADRC Center Director Huntington Potter, PhD, a neuroscientist at the Byrd Alzheimer's Center and Research Institute, University of South Florida.

Alzheimer's disease, the most common cause of dementia, is characterized by memory loss, disorientation, difficulty with reasoning and the decline of language and thinking skills. Alzheimer's is diagnosed by a process of elimination since many other diseases and related disorders can mimic its symptoms, and autopsy is currently the only definitive way a diagnosis can be confirmed. The diagnosis often includes a medical history, mental status tests, neurological evaluations and blood tests. Physicians typically use brain scans only to exclude conditions that can also cause memory deficits, such as strokes and brain tumors.

The Florida researchers used a new visual rating system to evaluate the severity of shrinkage, or atrophy, in the brain's medial temporal lobe – specifically in three structures essential for the conscious memory of facts and events. They compared the MRI brain scans of 260 people -- a group with probable Alzheimer's disease, two groups with varying degrees of mild cognitive impairment (mild memory problems), and a control group of normal elderly with no discernable memory loss. They found that scores generated by this MRI-facilitated test accurately distinguished each group from the other and correlated with the types of memory problems most frequently caused by Alzheimer's disease. The more extensive the brain atrophy, the more advanced the clinical stage of Alzheimer's disease.

The researchers even found brain atrophy in some people without memory complaints at the study's onset who demonstrated memory decline when assessed a year or two later. This suggests MRIs could predict who will get the disease well before signs of dementia become apparent by other diagnostic methods as well as rule out an Alzheimer's diagnosis in people experiencing memory problems, Dr. Duara said. "If you don't have changes in these three particular areas of the brain, then you don't have Alzheimer's."

Researchers at centers like Miami's Wien Center and USF's Byrd Institute are developing new Alzheimer's drugs that attack mechanisms leading to the death of nerve cells and their connections. The emergence of these disease-modifying treatments has made an earlier diagnosis of Alzheimer's increasingly important, Dr. Duara said. "Having an accurate diagnosis will allow us to start using drugs earlier. The earlier treatment begins, the more likely you are to stop disease progression and benefit the patient."

Most participants in the MRI study were enrolled in the clinical arm of the Florida ADRC, which is supported by a grant from the National Institute on Aging.

The Florida ADRC, the first statewide, multi-center ADRC in the United States, was critical for the successful implementation of the study, said Dr. Potter, the study's senior author. "To validate any new diagnostic test or treatment, you need a large number of diverse volunteers for good comparisons. Alzheimer's research is a partnership between the scientific community and study volunteers; we need both to solve the complexities of Alzheimer's disease."

source-/www.eurekalert.org

Smoking during the first trimester of pregnancy is clearly linked with an increased risk of cleft lip in newborns. Genes that play a role in detoxification of cigarette smoke do not appear to be involved. This is shown in a new study published in the journal Epidemiology.

Oral clefts are one of the most common birth defects. Closure of the lip occurs about 5 weeks into pregnancy, followed by closure of the palate at week 9. If this does not happen, a cleft lip and/or cleft palate are the result, requiring surgery. The researchers wanted to see if smoking or exposure to passive smoking play a role in these defects and whether genes influence the oral cleft risk through the way toxic chemicals in cigarette smoke are processed.

The study is based on an extensive Norwegian case-control study on oral clefts with collaborating researchers from the Norwegian Institute of Public Health, University of Bergen, Rikshospital, Haukeland University Hospital and the National Institutes of Health in USA. Between 1996 and 2001, 676 babies born with oral clefts were referred for cleft surgery, and of these, 573 took part in the study. 763 babies born during the same period in Norway were randomly selected as controls.

DNA and questionnaires

Blood samples were taken from the children referred for surgery and their PKU test samples, routinely taken at birth, were also retrieved. Their mothers and fathers donated cheek swabs and blood samples. From the control group, cheek swabs were obtained from the mother, father (after November 1998) and child, plus the PKU test sample taken at birth. DNA was extracted from the samples.

Four weeks after birth, the mothers in both groups completed a questionnaire about medical conditions and environmental exposure. They were specifically asked about their smoking habits and exposure to passive smoking before pregnancy and during the first trimester. 42 % of case mothers and 32 % of control mothers said that they smoked in the first trimester.

There was little evidence of an effect of smoking on the risk of cleft palate alone. However, for cleft lip (with or without cleft palate), there was an increased risk, almost two-fold when the mother smoked over 10 cigarettes per day and a 1.6 fold risk from passive smoking (defined as being within 2 metres of a smoker for 2 hours a day). The researchers estimate that 19 % of cases of cleft lip in Norway may be due to maternal smoking in the first trimester.

Genetic Analysis

Using the DNA extracted from the babies and their parents, the researchers looked at the genes related to detoxification of chemicals in cigarette smoke (NAT1, NAT2, CYP1A1, GSTP1, GSTT1, GSTM1). These genes did not appear to affect the incidence of cleft lip, although there was an inconclusive link with NAT2 and cleft lip risk which was independent of smoking. The mechanism by which maternal smoking increases the risk of cleft lip remains unknown.

source-www.eurekalert.org

The German Cancer Society has worked out new guidelines for the diagnosis and treatment of malignant melanoma—a disease with unfavorable prognosis. Malignant melanoma is responsible for 90% of deaths from skin cancer. The incidence has increased 5-fold within the last 30 years and UV radiation is thought to be an important cause. Caucasian populations are most affected.

Claus Garbe of Tübingen University and his coauthors present the therapy of melanoma in the current edition of Deutsches Ärzteblatt International (Dtsch Arztebl Int 2008; 105[49]: 845-51). Physicians should confirm the diagnosis by histopathology after complete surgical removal of the tumor. The German Cancer Society recommends specific treatments or therapeutic combinations, depending on the thickness of the tumor and its stage. For example, if the tumor has more than a specific thickness, it is recommended that the primary tumor should be surgically removed, together with the sentinel lymph nodes and in combination with immunotherapy. If surgical removal is not possible, radiotherapy is indicated. If there are distant metastases, physicians should perform monochemotherapy.

source-www.eurekalert.org

Earth's magnetic field, which shields our planet from particles streaming outward from the Sun, often develops two holes that allow the largest leaks, according to researchers sponsored by NASA and the National Science Foundation.

"The discovery overturns a long-standing belief about how and when most of the solar particles penetrate Earth's magnetic field, and could be used to predict when solar storms will be severe. Based on these results, we expect more severe storms during the upcoming solar cycle," said Vassilis Angelopoulos of the University of California, Los Angeles, Principal Investigator for NASA's THEMIS mission (Time History of Events and Macroscale Interactions during Substorms). THEMIS was used to discover the size of the leak.

Earth's magnetic field acts as a shield against the bombardment of particles continuously streaming from the sun. Because the solar particles (ions and electrons) are electrically charged, they feel magnetic forces and most are deflected by our planet's magnetic field. However, our magnetic field is a leaky shield and the number of particles breaching this shield depends on the orientation of the sun's magnetic field. It had been thought that when the sun's magnetic field is aligned with that of the Earth, the door is shut and that few if any solar particles enter Earth's magnetic shield. The door was thought to open up when the solar magnetic field direction points opposite to Earth's field, leading to more solar particles inside the shield.

Surprisingly, recent observations by the THEMIS spacecraft fleet demonstrate that the opposite is true. "Twenty times more solar particles cross the Earth's leaky magnetic shield when the sun's magnetic field is aligned with that of the Earth compared to when the two magnetic fields are oppositely directed," said Marit Oieroset of the University of California, Berkeley, lead author of one of two papers on this research, published May 2008 in Geophysical Research Letters.

Researchers have long suspected that this "closed door" entry mechanism might exist, but didn't know how important it was. "It's as if people knew there was a crack in a levy, but they did not know how much flooding it caused," said Oieroset.

Previous spacecraft could only sample a small part of this enormous layer of solar particles inside the Earth's magnetic shield, but the five spacecraft in the THEMIS fleet spanned the entire rapidly-growing layer to give definitive measurements.

While the THEMIS researchers discovered the size of the leak, they didn't know its location(s). This was discovered by Wenhui Li of the University of New Hampshire, Durham, N.H., and his team. They used a computer simulation to discover where two holes frequently develop in Earth's magnetic field, one at high latitude over the Northern hemisphere, and one at high latitude over the Southern hemisphere. The holes form over the daylit side of Earth, on the side of the magnetic shield facing the sun.

The simulation also showed how the leaks develop. As solar particles flow out from the sun, they carry solar magnetic fields past our planet. Li's team realized that the solar magnetic field drapes against Earth's field as it passes by. Even though the two fields point in the same direction at equatorial latitudes, they point in opposite directions at high latitudes, When compression forces the opposite fields together, they link up with each other in a process called magnetic reconnection.

This process tears the two holes in Earth's magnetic field and appends the section of the solar field between the two holes to Earth's field, carrying the solar particles on this section into the magnetosphere, according to Li's team. "We've found if the door is closed, the sun tears down a wall. The crack is huge – about four times wider than Earth and more then seven Earth diameters long," said Li, whose paper will be published in an upcoming article of the Journal of Geophysical Research.

Solar particles by themselves don't cause severe space weather, but they get energized when the solar magnetic field becomes oppositely-directed to Earth's and reconnects in a different way. The energized particles then cause magnetic storms that can overload power lines with excess current, causing widespread blackouts. The particles also can cause radiation storms that present hazards to spacecraft in high orbits and astronauts passing through the storms on the way to the moon or other destinations in the solar system.

"The more particles, the more severe the storm," said Joachim "Jimmy" Raeder of the University of New Hampshire, a co-author of Li's paper. "If the solar field has been aligned with the Earth's for a while, we now know Earth's field is heavily loaded with solar particles and primed for a strong storm. This discovery gives us a basic predictive capability for the severity of solar storms, similar to a hurricane forecaster's realization that warmer oceans set the stage for more intense hurricanes. In fact, we expect stronger storms in the upcoming solar cycle. The sun's magnetic field changes direction every cycle, and due to its new orientation in the upcoming cycle, we expect the clouds of particles ejected from the sun will have a field which is at first aligned with Earth, then becomes opposite as the cloud passes by."

source-www.sciencedaily.com

Researchers at Northwestern University have discovered a critical new way a man can transmit the HIV virus to a woman.

Scientists had long believed that the normal lining of the female vaginal tract was an effective barrier to invasion of the HIV virus during sexual intercourse. They thought the large HIV virus couldn't penetrate the tissue.

But new research from Northwestern University's Feinberg School of Medicine has shown for the first time that the HIV virus does indeed penetrate a woman's normal, healthy genital tissue to a depth were it can gain access to its immune cell targets.

"This is an unexpected and important result," said Thomas Hope, principle investigator and professor of cell and molecular biology at the Feinberg School. "We have a new understanding of how HIV can invade the female vaginal tract."

"Until now, science has really had no idea about the details of how sexual transmission of HIV actually works," Hope added. "The mechanism was all very murky."

Hope, his Northwestern colleagues, and collaborators at Tulane University discovered that interior vaginal skin is vulnerable to HIV invasion at the level where it naturally sheds and replaces skin cells, a point where the cells are not as tightly bound together. He will present his findings December 16 at the American Society for Cell Biology 48th annual meeting in San Francisco.

Women and female adolescents now account for 26 percent of all new HIV cases in the U.S., according to the Centers for Disease Control. Based on its most recent analysis of 2005 data, the CDC estimated that there were 56,300 new HIV infections that year and traced 31 percent of the total to high-risk heterosexual contact. More than half of the new cases of HIV infection worldwide are in women.

Hope said he hopes his findings, if confirmed by future studies, will provide information to help develop microbicides and vaccines to protect against HIV.

"We urgently need new prevention strategies or therapeutics to block the entry of HIV through a woman's genital skin," Hope said. While condoms are 100% effective in blocking the virus, "people don't always use them for cultural and other reasons," he noted.

By labeling the HIV viruses with photo-activated fluorescent tags, Northwestern researchers were able to view the virus as it penetrated the outermost lining of the female genital tract, called the squamous epithelium, in female human tissue obtained from a hysterectomy and in animal models.

Researchers found that HIV penetrated the genital skin barrier primarily by moving quickly -- in just four hours -- between skin cells to reach 50 microns beneath the skin, a depth similar to the width of a human hair. This is the depth at which some of the immune cells targeted by HIV are located.

HIV penetration was more common in the outermost superficial layers of skin and likely occurred during the normal turnover and shedding of skin cells. In the shedding process, the skin cells are no longer as tightly bound together so water -- and HIV -- can easily enter.

"As pieces of the skin flake off, that's the loose point in the system where the virus can get in," Hope said.

Previously, scientists thought that the HIV virus invaded a woman's immune system through the single layer of skin cells that line her cervical canal. "That was always thought to be the weak point in the system," Hope said.

However, a previous trial in Africa in which women used a diaphragm to block the cervix did not reduce transmission. Nor are women who have had hysterectomies less vulnerable to contracting HIV through sex.

Hope said researchers had also believed the only way HIV could enter the vaginal tract was if a woman had an open lesion on her skin, for example caused by the herpes virus. When breaks are present in the skin it should be easier for HIV to enter the skin and bind to and infect immune cells. But in studies where women were given anti-herpes drugs to decrease their lesions, there was no decrease in transmission. In light of the new results, it is possible that HIV can enter the vaginal tissue and initiate infection without any physical breaks.

"A big mistake in this field is the idea that transmission only takes place one way," Hope said. "Our perspective is the viruses can infect people in more than one way. We say one of those ways that needs to be in the equation is that the virus can be transmitted directly through the skin."

The next step will be to prove that the virus actually infects the immune cells in the vaginal tract. "A key experiment in the future is to identify the first cells to get infected in the epithelium, which is not necessarily where people would have looked for them before," Hope said.

source-www.sciencedaily.com

Scientists have shown that tiny crystals found inside bacteria provide a magnetic compass to help them navigate through sediment to find the best food, in research out today

Scientists have shown that tiny crystals found inside bacteria provide a magnetic compass to help them navigate through sediment to find the best food, in research out today.

Researchers say their study, published in the Journal of the Royal Society Interface, could provide fresh clues to explain biomagnetism – a phenomenon in which some birds, insects and marine life navigate using the magnetic field that encompasses the Earth.

The study focuses on magnetotactic bacteria, which contain chains of magnetic crystals, called magnetosomes. They exist all over the globe, living in lake and pond sediments and in ocean coastal regions.

Since the discovery of magnetotactic bacteria in the 1970s, it has not been clear exactly what magnetosomes were for. Previous research suggested that some magnetosome chains would not be useful for navigation because their crystal sizes did not possess the right magnetic qualities.

However, researchers at Imperial College London and the University of Edinburgh have now shown that previous modelling methods were inaccurate. New calculations prove that all known magnetosomes do posses the right magnetic qualities needed to facilitate navigation. Study leader, Dr Adrian Muxworthy, from Imperial's Department of Earth Science and Engineering, explains:

"Magnetosomes align with one another to form a chain inside the bacteria and work like a magnetic compass. We are still not sure how, but this compass interacts with the Earth's magnetic field, helping the bacteria to navigate through sediment to the best feeding grounds."

Dr Muxworthy says the study is a nice example of evolution which demonstrates how a relatively simple organism can develop a highly optimised navigational capability. He says it may provide fresh insights into the evolutionary processes that have helped other animals and aquatic species to become skilled navigators.

source-www.eurekalert.org

Surgery to treat obesity could be avoided if GPs and healthcare trusts put more time and money into early stage weight management programmes, a senior clinical researcher will say today (Wednesday, 17 December, 2008).

And he will say that patients suffering from obesity face a "post code lottery" when seeking access to specialist care.

Speaking at the British Pharmacological Society's Winter Meeting in Brighton today, Dr Nick Finer, Clinical Director, Wellcome Clinical Research Facility at Addenbrooke's Hospital in Cambridge, will call for anti-obesity drugs to be more widely used.

Dr Finer will say that these drugs are cost-effective interventions and do work if correctly used.

But he will add that in some patients early potential for drug treatment to prevent the later need for surgery is being missed - due to the reluctance of primary care doctors to treat obesity.

In his presentation, entitled 'Clinical challenges: can current drugs compete with surgery?', Dr Finer will be discussing the place of drug treatment in the management of obesity.

Dr Finer said: "About one third of people taking the two drugs currently licensed for obesity management, in conjunction with a diet and lifestyle programme, will achieve a 10 per cent weight loss and around half a five per cent loss. Weight loss is well maintained if drug treatment is continued.

"Drug treatment has also been shown to delay or prevent the development of type 2 diabetes, reduce cardiovascular risk factors and improve well-being.

"These results clearly do not match surgery but could be more generally adopted in clinical care.

"Despite NICE (National Institute for Health and Clinical Excellence) guidelines, there is a reluctance of primary care doctors to treat obesity, with or without drugs, and thus the early potential for drug treatment to prevent the later need for surgery in some people is missed.

"There remains a strong antipathy from many doctors, primary care trusts and specialist commissioning groups to invest in obesity management.

"NICE guidelines - and even more seriously previous Health Technology Assessments - remain to be implemented. There is a complete post code lottery for patients to access specialist care.

"Until the QOF (Quality and Outcomes Framework) system remunerates GPs for undertaking weight management there will be little stimulus for adoption of current evidence-based treatment guidelines."

Dr Finer is just one of the presenters at a special symposium on Obesity at the BPS Winter Meeting, which also includes a presentation on the regulatory challenges for new anti-obesity drugs. For the full programme please see below.

source-www.eurekalert.org

A map of natural hazard mortality in the United States has been produced. The map, featured in BioMed Central's open access International Journal of Health Geographics, gives a county-level representation of the likelihood of dying as the result of natural events such as floods, earthquakes or extreme weather.

Susan Cutter and Kevin Borden, from the University of South Carolina, Columbia, used nationwide data going back to 1970 to create their map. According to Cutter, "This work will enable research and emergency management practitioners to examine hazard deaths through a geographic lens. Using this as a tool to identify areas with higher than average hazard deaths can justify allocation of resources to these areas with the goal of reducing loss of life".

Hazard mortality is most prominent in the South, where most people were killed by various severe weather hazards and tornadoes. Other areas of elevated risk are the northern Great Plains Region where heat and drought were the biggest killers and in the mountain west with winter weather and flooding deaths. The south central US is also a dangerous area, with floods and tornadoes posing the greatest threat.

Heat/drought ranked highest among the hazard categories, causing 19.6% of total deaths, closely followed by severe summer weather (18.8%) and winter weather (18.1%). Geophysical events (such as earthquakes), wildfires, and hurricanes were responsible for less than 5% of total hazard deaths combined. Cutter said, "What is noteworthy here is that over time, highly destructive, highly publicized, often catastrophic singular events such as hurricanes and earthquakes are responsible for relatively few deaths when compared to the more frequent, less catastrophic events such as heat waves and severe weather (summer or winter)".

The authors conclude, "The spatial patterns revealed in our results may be unsurprising – greater risk of death along the hurricane coasts, in the interior west, and in the South – all areas prone to natural hazards as well as significant population growth and expansion throughout the study period. However, using this analysis as a blueprint for hazard mortality 'hot spots' supports justification for a more in-depth study of hazard- induced deaths in specific regions or communities. It is at this local scale where defining the deadliest hazard becomes important and emergency management officials can take action to try to reduce the number of future deaths".

spurce-www.eurekalert.org

DURHAM, N.C.—Neuroscientists from Duke University Medical Center have discovered that older people use their brains differently than younger people when it comes to storing memories, particularly those associated with negative emotions.

The study, appearing online in the January issue of Psychological Science, is a novel look at how brain connections change with age.

Older adults, average age 70, and younger adults, average age 24, were shown a series of 30 photographs while their brains were imaged in a functional MRI (fMRI) machine. Some of the photos were neutral in nature and others had strong negative content such as attacking snakes, mutilated bodies and violent acts. While in the fMRI machine, the subjects looked at the photos and ranked them on a pleasantness scale. Then they completed an unexpected recall task following the fMRI scan to determine whether the brain activity that occurred while looking at the pictures could predict later memory. The results were sorted according to the numbers of negative and neutral pictures that were remembered or missed by each group.

The scientists found that older adults have less connectivity between an area of the brain that generates emotions and a region involved in memory and learning. But they also found that the older adults have stronger connections with the frontal cortex, the higher thinking area of the brain that controls these lower-order parts of the brain.

Young adults used more of the brain regions typically involved in emotion and recalling memories.

"The younger adults were able to recall more of the negative photos," said Roberto Cabeza, Ph.D., senior author and Duke professor in the Center for Cognitive Neuroscience. If the older adults are using more thinking than feeling, "that may be one reason why older adults showed a reduction in memory for pictures with a more negative emotional content."

"It wasn't surprising that older people showed a reduction in memory for negative pictures, but it was surprising that the older subjects were using a different system to help them to better encode those pictures they could remember," said lead author Peggy St. Jacques, a graduate student in the Cabeza laboratory.

The emotional centers of the older subjects were as active as those of younger subjects -- it was the brain connections that differed.

"If using the frontal regions to perform a memory task was always beneficial, then the young people would use that strategy, too," Cabeza said. "Each way of doing a task has some trade-offs. Older people have learned to be less affected by negative information in order to maintain their well being and emotional state – they may have sacrificed more accurate memory for a negative stimulus, so that they won't be so affected by it."

"Perhaps at different stages of life, there are different brain strategies," Cabeza speculated. "Younger adults might need to keep an accurate memory for both positive and negative information in the world. Older people dwell in a world with a lot of negatives, so perhaps they have learned to reduce the impact of negative information and remember in a different way." According to Cabeza, the results of the study are consistent with a theory about emotional processes in older adults proposed by Dr. Laura Carstensen at Stanford University, an expert in cognitive processing in old age.

"One thing we might do in the future is to ask subjects to try to actively regulate their emotions as they look at the pictures," St. Jacques said. "Would there be a shift in the neural networks for processing the negative pictures when we asked younger people to regulate their emotional responses? How would that affect their later recall of the negative pictures?"

source-www.eurekalert.org

8,900 Danish schoolchildren behind new research findings

New knowledge: Girls have a better sense of taste than boys. Every third child of school age prefers soft drinks which are not sweet. Children and young people love fish and do not think of themselves as being fussy eaters. Boys have a sweeter tooth than girls. And teenagers taste differently. The findings of the world's largest study so far on the ability of children and young people to taste and what they like have now been published. The study was conducted jointly by Danish Science Communication, food scientists from The Faculty of Life Sciences (LIFE) at University of Copenhagen and 8,900 Danish schoolchildren.

In September, 8,900 schoolchildren from all over Denmark took part in a large-scale experiment conducted by Danish Science Communication and The Faculty of Life Sciences (LIFE) at University of Copenhagen. It is the first time that such a large-scale study has been done on the sense of taste of children and young people and what they like to eat.

Danish schoolchildren help scientists

One of the reasons why it was possible to include so many children and young people in the study was that the experiment itself was conducted in quite an unorthodox way: It was planned as a 'mass experiment' in conjunction with this year's natural science festival at Danish primary and secondary schools. All the participating groups of children were sent a complete kit of taster samples and very detailed instructions, and then conducted the experiment as part of their natural science classes. The various tests were designed to quantify the ability of children and young people to discover and recognise sweet and sour tastes at varying intensities, to establish which sourness or sweetness they prefer, how many taste buds they have and, finally, the children answered a number of questions on their eating habits and fussiness over food. And both pupils and teachers have taken the experiment very seriously: "What is most surprising is that the results are so clear and of such a high quality," says Bodil Allesen-Holm, MSc in Food Science and Technology, who is the scientific head of the project and head of the Sensory Laboratory at the Department of Food Science at LIFE. "The trends are very clear in all the answers from the many primary and secondary schools: the pupils and teachers have been very thorough and accurate."

Industry must do better, and parents could experiment more

According to Bodil Allesen-Holm, the results provide food for thought for both the food industry – and for parents: "It is quite clear that children and young people are very good tasters, and that there are bigger variations between them than most people would expect. There is, for example, a marked difference between boys and girls, and the ability of children to recognise tastes changes with age. So one could easily develop more varied food products and snacks for children and young people. For example, it is quite clear that children do not necessarily prefer sweet things. According to the findings, healthy snacks could easily be developed for boys with slightly extreme and sour flavours."

"This experiment has focused on taste alone, while future studies will include more sensory aspects such as smells and appearance to provide a more all-round understanding of Danish children's preferences," says Wender Bredie, Professor of Sensory Science at the Department of Food Science at LIFE.

New facts about what children can taste – and what they like:

• Girls are better at recognising tastes than boys

  One of the many findings shows that girls are generally better at recognising tastes than boys. They are better at recognising all concentrations of both sweet and sour tastes. The difference is not dramatic, but it is quite clear. It is also a known fact that women generally have a finer sense of taste than men. "We also asked the pupils to count 'taste buds' or organs of taste on the tongue. However, the experiment showed that boys and girls have largely the same number of taste buds. So it would appear that what makes the difference is the way in which boys and girls process taste impressions," says Michael Bom Frøst, Associate Professor at the Department of Food Science at LIFE. According to the figures, boys need an average of approximately 10 per cent more sourness and approximately 20 per cent more sweetness to recognise the taste.

• Every third schoolchild would prefer not to eat sweet things

  Another sensational finding is that every third schoolchild would prefer non-sugary soft drinks. All the pupils did a blind test in which they were instructed to give scores to ten different variants of the same soft drink – with varying sweetness and sourness. Surprisingly, as many as 30 per cent of the pupils preferred the variant which contained no sugar at all or very little. "This is new. In other words, soft drinks for children and young people do not always have to contain a lot of sugar," says Bodil Allesen-Holm. On the other hand, 48 per cent of the pupils just couldn't get enough: They gave top marks to the sweetest of the variants. "It may be because many pupils are quite used to drinking a lot of soft drinks and eating a lot of sweets," says Bodil Allesen-Holm.

• Boys like it wild, girls prefer more muted flavours

  Funnily enough, girls generally prefer flavours which are not too strong. Boys, on the other hand, tend to like the more extreme flavours. Boys also have a sweeter tooth than girls – most of the boys preferred the super sweet soft drink variety. And most boys also gave top marks to the sourest samples.

• Yes, I like fish!

  The study shows that when you ask the children about their likes and dislikes, they actually like fish. As many as 70 per cent of the pupils said they like fish. And you can safely give them exciting foods. As many as 59 per cent of pupils do not consider themselves to be fussy eaters, and this applies to both girls and boys.

• The world becomes more sour and exciting for teenagers

  It would appear that you can safely notch up a gear when it comes to food, drinks and snacks for teenagers. The study showed that their sense of taste changes noticeably: The ability to recognise tastes increases gradually with age, and the greatest shift is seen at 13-14 years when children become markedly more sensitive to sour tastes. At exactly the same time, their love of very sweet flavours starts waning. And it is here too that many more declare they are not fussy eaters. Past studies have shown that children who like sour things tend not to be nearly as fussy as children who are not mad about sour foods. Those who prefer sour flavours are also more open to tasting new foods.

source-www.eurekalert.org

Human and veterinary medicine could receive a big boost through use of larger animals, especially pigs and dogs, in research, with Europe at the forefront. There is the prospect of bringing drugs to the market more quickly at less cost, as well as accelerating progress in other forms of therapy, notably the use of stem cells in regenerative medicine. The potential in this new field was discussed at a recent workshop organised by the European Science Foundation (ESF), which called for a European pig clinic to facilitate generation and characterisation of models of human disease that would be funded within the EU's Seventh Framework programme, the main source of EU funding for research projects.

The immediate goal in the field is to establish a common standardised way of using animals with clearly defined characteristics (phenotypes), so that results can be compared across Europe. "The workshop showed that there is excellent expertise in individual labs, but the phenotypic tests need to be harmonised and standardised to facilitate comparison of results obtained in different labs," said Angelika Schnieke, one of the workshop's convenors, who holds the chair of Livestock Biotechnology at the Centre of Life Science in Weihenstephan, Germany.

Such standardisation has already been achieved for rodents, particularly the mouse, which is the most widely used animal model at present for human disease research. The extension of such a framework to pigs and dogs will bring great rewards not just for human medicine, but also for treatment of animal diseases. "Large animals offer a link between the classical rodent models and application in the clinic," said Schnieke.

"In view of the close genetic, anatomical and physiological similarities between dog and pig on the one side and human on the other, large animal models are likely to catalyse drug development." As Schnieke added, large animals would also help pursue other therapeutic avenues beyond drug development, including new medical technologies, devices and interventions. Large animals could also be used for research in a number of disease categories, including cancer, metabolic disorders such as obesity, and regenerative therapies, such as use of stem cells to replace damaged heart muscle.

The workshop focused particularly on pigs and dogs because these two animals are quite similar in scale and anatomy to humans, while serving quite complementary functions. Dogs could be used as models for studying the immediate consequences of infectious disease, while pigs could be genetically engineered to mimic certain human conditions, such as deficiencies in the immune system. In such cases pigs would be used like mice are at present to model certain aspects of human immunity or metabolic disorder, but with the advantage of being closer to us in many respects.

"A possible idea is the generation of pigs with a humanised immune system," said Schnieke. "The proof of principle has been shown in the mouse. Immune-deficient mice can be reconstituted with human immune cells and can be used to study immune reactions, for example against tissue xenografts (transplantation of tissue between species, such as pig to human). In theory this could also be possible in pigs. Therefore the generation of immune-deficient pigs is an important goal."

But further funding is required to develop suitable pig models, possibly within a European pig clinic. The workshop also discussed setting up smaller collaborative projects focussed on specific disease areas, with a view to obtaining funding from the ESF. A task force was established to pursue these goals.

source-www.eurekalert.org

Washington, D.C. – Researchers at Georgetown University Medical Center have found a gene they say is inactivated in two aggressive cancers – malignant melanoma, a form of skin cancer, and glioblastoma multiforme, a lethal brain tumor. They add that because this gene, known as PTPRD, has recently been found to be inactivated in several other cancers as well, their discovery suggests that PTPRD may play a tumor suppressor role in a wide variety of different cancers.

The findings are published in the December 15 issue of Cancer Research.

"Over the past decade several dozen tumor suppressor genes have been identified, but only a minority of them is important in causing many different tumor types. PTPRD seems to be one of these broad spectrum tumor suppressor genes," says the study's lead investigator, Todd Waldman, MD, PhD, an associate professor of oncology at Georgetown's Lombardi Comprehensive Cancer Center.

If the hypothesis is true – and Waldman and his team are now investigating loss of PTPRD in a number of additional cancers – then it may be possible to design a therapy that has wide applicability in oncology, he says.

"Most targeted cancer drugs today work by inhibiting gene products that are overactive in cancer cells. In this case, it is loss of the PTPRD gene that leads to cancer," Waldman says. "Therefore, we are trying to discover the molecules that PTPRD's protein controls, and then we plan to target these downstream molecules with a novel agent."

Waldman found that when the researchers restored production of the gene's protein in cancer cells that harbored PTPRD deletions or mutations, these tumors stopped growing and initiated a program of cell suicide.

The researchers also discovered PTPRD mutations in both the blood and in tumors of a patient with multiple different kinds of cancers. "This suggests that the gene could be responsible for an inherited predisposition to cancer," Waldman says

PTPRD produces a receptor protein tyrosine phosphatase that bisects the outer membrane of a cell. The part that protrudes outside the cell body is thought to be involved in helping cells stick to each other to form a tissue as well as in cell-to-cell communication. The part that juts into the cell is an enzyme that removes phosphates from other proteins – in other words, it changes the activity of proteins either by activating or deactivating them, Waldman says.

"In the absence of PTPRD, there are as yet unknown proteins floating around inside the cell with more phosphate residues than they should have, and it is a well known fact that the presence of these residues activates cellular growth pathways," he says. But it is not yet known which specific proteins PTPRD regulates, Waldman says.

Deletions of PTPRD in human cancer cells were first discovered in 2005, and since then, deletions or mutations of the gene have been discovered in several cancer types, including those of the colon and lung.

In this study, Waldman and his research team, which includes investigators from the National Cancer Institute, the University of Iowa and Duke University, used a laboratory technique known as copy number analysis to look for PTPRD in melanoma cell lines and in samples of human glioblastoma multiforme, the deadliest of brain cancers.

This technique uses a gene microarray that contains millions of probes that can stick to different regions of the human genome. The researchers purified DNA from tumors and then used the microarray chip to quantify genomic copy number. They found that PTPRD was deleted or mutated in 12 percent of melanoma tumors and in 14 percent of glioblastoma tumors examined. "That makes PTPRD one of the most commonly mutated genes discovered yet in melanoma," Waldman says.

"Before this study, no single tyrosine phosphatase was thought to play a generally important role as a tumor suppressor gene n multiple tumor types," Waldman says. "Now we have provided the first functional evidence that PTPRD is a tumor suppressor gene, and potentially an important one at that."

source-www.eurekalert.org

Metastasis is the ability of cancer cells to spread from a primary site, to form tumours at distant sites. It is a complex process in which cell motility and invasion play a fundamental role. Essential to our understanding of how metastasis develops is identification of the molecules, and characterisation of the mechanisms that regulate cell motility. Hitherto, these mechanisms have been poorly understood. Now, a team of researchers lead by Professor Marco Falasca at Barts and The London School of Medicine and Dentistry has shown not only that the enzyme phospholipase Cγ1 (PLCγ1) plays a crucial role in metastasis formation, but that down regulation of PLCγ1 expression is able to revert metastasis progression.

The team investigated the role of PLCγ1 in cell invasion and metastasis using different approaches to modulate its expression in highly invasive cancer cell lines. Their results showed that PLCγ1 is required for breast cancer cell invasion and activation of the protein Rac1. They revealed a functional link between PLCγ1 and Rac1 that provides insight into processes regulating cell invasion.

Professor Falasca explained: "Consistent with these data we detected an increase in PLC1 expression in metastases compared to primary tumours in breast cancer patients. Therefore PLCγ1 is critical for metastasis formation, and development and inhibition of this enzyme has a therapeutic potential in the treatment of metastasis dissemination."

"This is an exciting discovery. He has shown that turning off this molecule prevents metastasis. The simple fact is that if you stop metastasis, you stop cancer from killing people. We now need to focus on developing drugs that can block PLCγ1."

source-www.eurekalert.org

M. D. Anderson study finds improved breast cancer detection by alternating screening tests every six months

SAN ANTONIO - Magnetic resonance imaging (MRI) alternated with mammography at six-month intervals can detect breast cancers not identified by mammography alone, a research team from The University of Texas M. D. Anderson Cancer Center will report at the 31st at the CRTC-AACR San Antonio Breast Cancer Symposium.

MRI is known to be more sensitive in detecting breast cancers than mammography, with a 71 - 100 percent accuracy compared to a 16 - 40 percent accuracy for mammography. As a result, annual breast cancer screening for high-risk women now typically includes MRI along with mammography and a clinical breast exam.

"In the high-risk population, the recent standard of practice is to perform mammography and MRI every year," said Huong Le-Petross, M.D., assistant professor of diagnostic radiology at M. D. Anderson and the study's first author. "What we started to do at M. D. Anderson was to see if we could do mammography and then six months later do a breast MRI exam, followed six months later with a mammogram exam, and then six months after that with a breast MRI. That way the women would receive an imaging modality screening every six months."

In the pilot study, to be presented at a poster session on Dec. 13, the researchers performed a retrospective chart review of 334 women who had participated in a high-risk breast cancer-screening program at M. D. Anderson from Jan. 1997 to Dec. 2007. The women had undergone between one and four MRI screening cycles and were considered to be at high risk if they had hereditary breast and ovarian cancer syndrome, a personal history of breast cancer, a biopsy indicating atypia or lobular carcinoma in situ (LCIS), or a 20 percent or higher lifetime risk of developing breast cancer, as estimated by the Gail model.

In the all-M. D. Anderson study, 86 of the 334 high-risk women (26 percent) underwent this alternating approach. Among this group, 46 percent completed the first round of MRI screening, 28 percent completed the second round, 13 percent completed the third round, and 4 percent completed the fourth round. The other 248 women underwent prophylactic mastectomy or were started on chemoprevention agents. All study participants were given a clinical breast exam every six months. The median follow-up time was 2 years, with a range of one to four years).

The alternating MRI and mammography screening program detected nine cancers among the 86 women-five invasive ductal carcinomas, three invasive lobular carcinoma, and two ductal carcinomas in situ. Five (55 percent) of these cancers were identified by MRI but not by mammography, three (33 percent) were found by both MRI and mammography, and one (11 percent) cancer, a tumor one millimeter in size, was overlooked by both screening techniques. No cancer was detected by mammography alone.

"We found that MRI picked up the majority of cancers, while mammography picked up only three out of the nine," Le-Petross noted. With five of the eight cancers detected by MRI, the mammogram from six months earlier was either normal or suggested benign findings.

"The global picture is that MRI can pick up cancers that mammography cannot," Le-Petross said. "This would suggest that in this population it is more beneficial for the patient to have screening MRI so that we can pick up small lesions before a mammogram can detect them."

One important unanswered question is whether an alternating MRI and mammography screening program will save lives. "That is going to take a 5- to 10-year follow-up to determine," Le-Petross added. "It is an exciting question because mammography has always been the standard, and now we are challenging that gold standard examination."

source-www.eurekalert.org

San Antonio – An interim analysis of a breast cancer prevention study using exemestane (Aromasin®) finds an "acceptable" level of bone loss.

The ongoing phase II study details reported today, by Jennifer Eng-Wong, MD, a breast cancer specialist at Georgetown's Lombardi Comprehensive Cancer Center at the San Antonio Breast Cancer Symposium, examines the use of exemestane in postmenopausal women who are at an increased risk of developing breast cancer based on commonly used risk assessment measures. In addition to exemestane, all the study participants received calcium carbonate and vitamin D.

Wong's report represents findings from a planned interim safety analysis in 18 women who completed one year of exemestane.

"We found a drop in bone mineral density in these women similar to what we've seen in women taking exemestane in the adjuvant treatment setting." Eng-Wong reports. "Like aromatase inhibitors in the adjuvant setting there is a small amount of bone loss in the spine and hip. The long term clinical impact of the small decrease is not known."

The exemestane study continues with endpoints including bone density measurements and change in breast density over two years of treatment. Dense breasts as observed on a mammogram are associated with an increase in a woman's risk of developing breast cancer.

source-www.eurekalert.org

SAN ANTONIO - A type of benign breast disease (BBD) known as atypical hyperplasia substantially increases a young woman's risk of developing breast cancer, even if there is no history of breast cancer in her family, say researchers at Mayo Clinic.

The investigators, who presented their findings at the Cancer Therapy & Research Center-American Association for Cancer Research (CTRC-AACR) San Antonio Breast Cancer Symposium, say the women they studied with this kind of benign breast disease had a relative risk of developing breast cancer that was almost six times greater than women with no evidence of the disease.

Young women diagnosed with two other forms of benign breast disease were at much less risk than patients with atypical hyperplasia, the researchers say. Those with non-proliferative disease were only slightly at increased risk (1.2 times, or .2 percent higher than normal) and women with proliferative disease without atypia had a risk that was doubled. A family history of breast cancer increased risk in these two groups of patients, but only slightly, the researchers say.

"Breast cancer is the leading cause of cancer death in women age 25 to 49, and these young patients also have worse overall survival and increased risk of cancer coming back compared to older women, so it is important that we try to understand how the cancer develops and the measures that help prevent it," says the study's lead investigator, Karthik Ghosh, M.D.

The average age of benign breast disease diagnosis in the 4,460 women included in this study was 39 years old. Within that group, 326 women eventually - sometimes decades later - developed breast cancer.

The study is the latest set of findings in Mayo Clinic's effort to precisely define a woman's risk for developing breast cancer in order to tailor screening and risk-reduction measures to the individual. With support from a $5.8 million Department of Defense Congressionally Directed Medical Research Program, Mayo researchers have been studying benign breast disease in 9,376 women whose lesions were biopsied at Mayo Clinic between 1967 and 1991. The scientists continue to follow the progress of these women.

Their research has led to a number of findings, published in such journals as The New England Journal of Medicine, that are helping researchers predict which benign lesions will become cancerous. For example, they have found that in the entire benign breast disease cohort, women with atypical hyperplasia were more than three times more likely to develop breast cancer. They also found that risk decreases in women diagnosed with benign breast disease when the milk-producing lobular ductal glands - where cancer usually develops - shut down, a process known as lobular regression or involution.

In atyical hyperplasia, an increased number of cells line the milk duct or lobule, than is typical and the cells do not look normal under a microscope, but they are not cancerous, according to Dr. Ghosh. In proliferative disease without atypia, an increased number of cells line the milk duct but they look normal. Women with non-proliferative disease have fibrocystic changes but no increase in cell number.

This study was designed to look specifically at younger women in the group, because the earlier findings suggested these women were at increased risk of developing breast cancer, especially if they were diagnosed with atypical hyperplasia. Among the group of 4,460 women less than 50 years old in the study, 2 percent had been diagnosed with atypical hyperplasia, 72 percent had non-proliferative disease and 26 percent had been diagnosed with proliferative disease without atypia.

Researchers found that after a median follow-up of 20 years, 326 of the women included in this study developed breast cancer. That meant the relative risk of developing the cancer was 1.5 times greater than women not diagnosed with BBD.

They further found that a strong family history of breast cancer was associated with a 2.2 times greater relative risk of cancer development in women with non-proliferative disease or proliferative disease without atypia.

They also found that the 5 percent of women who had complete lobular involution had a reduced relative risk (.68 times less) for developing breast cancer. "The impact of lobular involution on risk, even in young women with benign breast disease, is an interesting finding," Dr. Ghosh says. "It suggests that future research could potentially think about ways of promoting lobular involution as a means to reduce breast cancer risk."

source-www.eurekalert.org

SAN ANTONIO - Findings from a new study have prompted Mayo Clinic researchers to recommend CYP2D6 gene testing for postmenopausal women about to begin tamoxifen therapy. This data confirms that women with an inherited deficiency in the CYP2D6 gene, which is important for the metabolism of tamoxifen, have a nearly fourfold higher risk of early breast cancer recurrence compared to women who have not inherited the deficiency. The research findings, announced jointly by investigators from Mayo Clinic and the Austrian Breast and Colorectal Cancer Study Group (ABCSG) confirmed results from a previous study conducted by Mayo Clinic.

VIDEO ALERT: Additional audio and video resources, including excerpts from an interview with Dr. Goetz describing the research, are available on the Mayo Clinic News Blog http://newsblog.mayoclinic.org/2008/12/11/gene-testing-may-be-key-for-treating-some-women-with-breast-cancer/, with password: sabcs08g.

The latest findings will be presented today at the Cancer Therapy & Research Center-American Association for Cancer Research (CTRC-AACR) 31st annual San Antonio Breast Cancer Symposium.

Tamoxifen, approved by the Food and Drug Administration (FDA) to both prevent development of estrogen-receptor-positive (ER+) breast cancer and as a therapy to stop ER+ breast cancer from coming back, is a "pro-drug"; it must be metabolized in the liver to become active. Mayo researchers had previously discovered that the drug is less effective in postmenopausal breast cancer patients who had a deficiency in the CYP2D6 gene, which is key for activating tamoxifen and many other drugs. However, until now, testing for the gene has not been done routinely at most medical centers.

"These new results validate our earlier findings," says the study's lead investigator, Matthew Goetz, M.D., an assistant professor of oncology and pharmacology at Mayo Clinic, "and strongly suggest that going forward, postmenopausal patients being considered for tamoxifen therapy should be tested for CYP2D6 before beginning therapy."

The research teams examined DNA from a subset of postmenopausal women treated in the ABCSG-8 study, which previously randomized nearly 3,900 women whose ER+ breast cancer had been surgically treated. One group was randomized to five years of tamoxifen therapy, and the other randomized to tamoxifen for two years followed by three years of anastrozole, an aromatase inhibitor. The initial results of ABCSG-8, reported in 2005, concluded that women who switched to anastrozole had a 40 percent reduced risk of breast cancer recurrence compared to staying on tamoxifen.

The aim of the new study was to determine whether CYP2D6 genetic variation would identify a subgroup of patients at higher risk of recurrence within the context of the ABCSG-8 trial. "Among the patients randomized to tamoxifen, poor metabolizers had a 3.8-fold increase in risk of developing breast cancer recurrence than extensive metabolizers across the five-year span," said Michael Gnant, M.D., professor of Surgery at the Medical University of Vienna, Austria, and president of ABCSG. "That is the key message coming out of this great collaboration between the Mayo Clinic team and the Austrian Breast and Colorectal Cancer Study Group."

However, the researchers also demonstrated that among patients who switched to anastrozole, there was no increased risk of breast cancer recurrence for CYP2D6 poor metabolizers in years three to five. The benefit of switching to anastrozole, says Dr. Goetz, may be most pronounced in the group of patients with deficient CYP2D6 metabolism. "Poor metabolizers who were fortunate to not develop breast cancer recurrence in the first two years of tamoxifen appear to be rescued by anastrozole," he says.

The findings reported by Mayo and ABCSG highlight the emerging science of pharmacogenomics. Researchers in this field are studying whether genetic differences in how patients metabolize or process drugs can be used to individualize therapy.

Additionally, in collaboration with bioTheranostics (a molecular diagnostics testing firm), the researchers examined whether a tumor-based test, HOXB13: IL17BR gene expression ratio, and a 5-gene molecular grade index were prognostic markers of distant breast cancer recurrence. Dr. Goetz and his colleagues confirmed that high expression of both HOXB13:IL17BR and molecular grade index, found in 25 percent of the tumors, led to a nearly threefold higher risk of recurrence elsewhere in the body compared to patients whose tumors were considered to be low risk according to these gene markers.

These findings suggest that the combined index will identify patients with early stage breast cancer who haveith a higher risk of distant metastases when treated only with hormonal therapy, the researchers say.

source-www.eurekalert.org

SAN ANTONIO - Having dense breasts - areas that show up light on a mammogram - is strongly associated with increased breast cancer risk, but "why" remains to be answered. Now, by examining dense and non-dense tissue taken from the breasts of healthy volunteers, researchers from Mayo Clinic have found several potential links.

In two studies being presented simultaneously in poster form at the Cancer Therapy & Research Center-American Association for Cancer Research (CTRC-AACR) San Antonio Breast Cancer Symposium, the researchers report that dense breast tissue contains more cells believed to give rise to breast cancer, compared to non-dense tissue. "We found a dramatic difference in tissue composition between dense and non-dense tissue in the breast," says Karthik Ghosh, M.D., a Mayo Clinic breast cancer researcher and physician who led one study.

In a second study, researchers also found that dense breast tissue has more aromatase enzyme than non-dense tissue. This is significant because aromatase helps convert androgen hormones into estrogen, and estrogen is important in breast cancer development, says that study's lead investigator, Celine Vachon, Ph.D.

"If aromatase is differentially expressed in dense and non-dense breast tissue, this could provide one mechanism by which density may increase breast cancer risk," Dr. Vachon says.

The researchers say these findings are unique because these studies are the first to examine areas of both dense and non-dense tissue taken from the same breast in healthy volunteers. Examination of healthy women is important, Dr. Ghosh says, because most prior studies of breast density have looked at tissue taken from women with known breast disease.

Sixty women, age 40 to 85, allowed Mayo Clinic researchers to take eight core-needle biopsies from their breasts; none had a history of breast cancer.

Dr. Ghosh and her team examined the biopsies to determine the percentage of epithelium tissue, stroma, and fat content in each. The epithelium is primarily composed of milk glands and ductal cells, and stroma is the connective tissue that supports epithelial cells. Dr. Vachon and her colleagues looked at aromatase expression within cells in both dense and non-dense tissue.

Results are now available from more than half of the participants who donated biopsy tissue. Dr. Ghosh found that areas of density contained much more epithelium (6 percent) and stroma (64 percent) and much less fat (30 percent), compared to non-dense tissue that contained less than 1 percent epithelium, about 20 percent stroma, and almost 80 percent fat. "This shows us that both the epithelium and stroma contribute to density, and suggests that the large difference in stroma content in dense breast tissue may play a significant role in breast cancer risk," Dr. Ghosh says.

She also looked at lobular involution, a decrease in the size and number of milk ducts that has been associated with decreased breast cancer risk, and found that 85 percent of non-dense tissue had complete involution compared to 35 percent of dense tissue.

Dr. Vachon and her team examined expression of aromatase in the biopsy samples and found that the stromal cells in dense breast tissue had more aromatase and intensity of expression in dense tissue, compared to non-dense. They say these findings may help explain why women with greater proportion of dense breast tissue are at greater risk for breast cancer than women with little or no density.

"These are initial findings from one of the first attempts to study breast density at the level of healthy tissue. It doesn't explain everything yet, but is providing really valuable insights," says Dr. Ghosh, who established the patient resource for both studies.

Drs. Ghosh and Vachon are finishing their analysis of the initial 60 volunteers, and they are also enrolling more participants in order to validate and expand their findings. "No one knows why density increases breast cancer risk, but we are attempting to connect the dots," Dr. Vachon says.

source-www.eurekalert.org

Scientists funded by the Biotechnology and Biological Sciences Research Council (BBSRC) have identified a potential new avenue for altering lung development in the embryo which may help to improve the outcome for very premature babies. The researchers at Cardiff University, in collaboration with those at the Saban Research Institute at Los Angeles Children's Hospital, have discovered a key player in early lung development which is a potential drug target for treating very premature babies with small, immature lungs. The research is published today (12th December 2008) in The Journal of Physiology. The work was carried out in the laboratories of Dr Daniela Riccardi and Professor Paul Kemp (School of Biosciences, Cardiff University, UK) in collaboration with Professor David Warburton (Saban Research Institute, Childrens Hospital Los Angeles, USA).

Dr. Riccardi said: "Within minutes of birth, a baby relies solely on its lungs to get the oxygen it needs. One of the reasons that the lives of very premature babies are in such dire jeopardy is that the final stages of lung development happen very late in pregnancy and so premature babies are born with immature lungs that struggle to take in enough oxygen. Under-developed lungs don't absorb enough oxygen and premature babies with respiratory problems often develop chronic lung disease that may extend into adulthood. Through our research we have gained a better understanding of how lungs develop normally and so we can now begin to work out what happens when things go wrong, such as when a baby is born much too early. From the work we have published today, we now have a real possibility for fast-tracking new drugs for helping these very premature babies."

Along with their research associates Dr Brenda Finney and Dr William Wilkinson, Dr Riccardi and Professor Kemp have discovered that a molecule called CaR (calcium receptor) is a crucial factor in the control of lung development in the womb. CaR co-ordinates messages from within the growing fetus that instruct the lungs to develop thousands of channels and tiny air pockets. This complicated structure is what will ultimately allow oxygen to move from the air into the baby's blood stream.

Professor Kemp said: "The really exciting thing about CaR is that there are already drugs available that can alter its function and, therefore, could modulate lung development. We know that CaR works by sensing calcium and we also know that there are already drugs available that are designed to regulate how calcium is used in the body. If we can show that one of these drugs can modulate the action of CaR in the lung, it could be used to mature the lungs of a very premature baby as it grows. Better still, an existing drug could potentially be approved much more quickly than a new one."

Professor Janet Allen, BBSRC Director of Research said: "It is exciting to see that BBSRC-funded research has the potential to improve the lives of thousands of very premature babies. These scientists have shown that by first asking questions about a fundamental biological process, the possibilities for understanding and treating devastating human disease can then be thrown wide open. This demonstrates the value of basic research in biology for delivering real life impact."

source-www.eurekalert.org

SAN ANTONIO - Breast cancer is a multifaceted disease requiring creative solutions for diagnosis, quality of life management and adjuvant therapies. Data presented at the CTRC-AACR San Antonio Breast Cancer Symposium explore these areas.

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Hormone Supplements Reduce Death from Breast Cancer
Abstract #65, Sarah Marshall, M.A.

Although hormone supplements have been implicated in increased rates of breast cancer, they appear to mitigate the mortality risk of breast cancers that do develop. Compared with women who did not use hormone therapy, women who took estrogen-progestin were 63 percent less likely to die from breast cancer while those who took estrogen alone were 30 percent less likely.

Full release available/Complete data to be presented at the meeting.

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Tamoxifen Tops Anastrazole for Quality of Life, but not Survival
Abstract #1136, Shozo Ohsumi, M.D., Ph.D.
Embargo: 5:30 p.m. CST, December 11, 2008

After one to four years of tamoxifen, switching to anastrozole improves disease-free survival by about 31 percent, but patients pay a price in quality of life measures. The difference in quality of life is significant enough that scientists say it should be considered, and may even be the deciding factor, when making a clinical decision about therapeutic strategy.

Full release available/Complete data to be presented at the meeting.

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Letrozole following breast cancer surgery may provide survival benefit
Abstract #13, Alan Coates, M.D.
Embargo: 9:45 a.m. CST, December 11, 2008

Letrozole may improve overall survival in patients with primary breast cancer. A four-arm comparison study of letrozole and tamoxifen shows letrozole not only reduces recurrence, but may provide a 13 percent reduction in risk of death. Additionally, the study finds that using a sequence of tamoxifen and letrozole is not superior to letrozole alone. The sequence of letrozole followed by tamoxifen was closely similar to letrozole alone implying that patients can safely switch to tamoxifen after initial letrozole if required.

Complete data to be presented at the meeting.

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Use of Written Forms Doubles Breast Cancer Detection Rate
Abstract #5012, William Goodson, M.D.

When clinicians used simple written forms to focus attention during clinical breast exams, the rate of breast mass detection from the previous year doubled without retraining clinicians, thus affirming the importance of clinician attentiveness. This finding, researchers say, can be applied to all aspects of medicine and undermines the need for intensive training, complicated techniques, and medical reimbursement codes to improve this simple, yet valuable procedure.

Complete data to be presented at the meeting.

source-www.eurekalert.org

MANHATTAN -- A Kansas State University graduate student has found a correlation between childhood obesity and asthma.

Sara Rosenkranz, doctoral student in human nutrition, Manhattan, conducted research that found that healthy children with higher levels of body fat and lower levels of physical activity had greater amounts of airway narrowing after exercise.

"Kids who are overweight and inactive are having -- even at the age of 8 to 10 years old -- a negative response to exercise challenge tests, which might be contributing to the increase that we've been seeing over the past several decades in asthma prevalence as well as obesity prevalence," Rosenkranz said.

Rosenkranz worked with other K-State faculty and students to recruit 40 children in the 8- to 10-year-old age range to participate in exercise studies. All of the children were healthy, meaning none of took medication or had a diagnoses or history of acute or chronic disease, including asthma.

For Rosenkranz's project, the children completed pulmonary function tests, an exercise test that doctors often conduct to determine if children have asthma, and body composition tests.

The children also took questionnaires to determine if they were active or inactive compared to the standards of their age, gender and ethnicity.

After the exercise challenge, the researchers measured the children's FEV-1, which determines if the individual's airwaves narrow post-exercise. The researchers found that the higher the body fat and the lower the level of activity of the child, the more likely they were to have asthma-like symptoms following exercise. In fact, these specific children had FEV-1 measures that many consider to be classified as exercise-induced asthma.

"It was pretty interesting. There's that whole idea that it's possible to be fit and fat in adults, but that really hasn't been looked at closely in kids," Rosenkranz said. "That's what spurred the idea for this research."

At the completion of the project, a follow-up letter was sent to the parents that showed their child's pulmonary test results and body fat percentage, which also had the corresponding fat group based on the child's age, gender and ethnicity.

"It's important for parents to know what's going on with their children at a young age so that they can help do something to maybe stop a downward cycle," Rosenkranz said. "It's especially important for those kids who already are overweight and are very physically inactive."

For many of the students that had higher levels of body fat and lower levels of activity, Rosenkranz said it is possible that they had the early stages of asthma and they didn't know it.

"They might not know it because they might not be doing anything that could ever trigger it," she said.

When an asthma diagnosis is made, Rosenkranz said it is important that the child remain active to prevent airway problems.

Before the study, little was known about the role body composition and physical activity have in airway health in children, Rosenkranz said. When considering childhood obesity, pulmonary function wasn't often considered, she said.

"At K-State, we just started working with the childhood population," she said. "We've been working more with college-age students because that's a handy group to have access to, but with kids, it's a whole new world and there's not much information out there."

source-www.eurekalert.org

Findings presented at San Antonio Breast Cancer Symposium; Vaccine trial to follow

CLEVELAND: Research out of the Ireland Cancer Center of University Hospitals Case Medical Center has found that the vast majority of triple negative breast cancers express the MUC-1 target. This first-of-its-kind finding, presented today at the San Antonio Breast Cancer Symposium, has paved the way for an upcoming vaccine trial for patients with early stage triple negative breast cancer that could potentially prevent recurrence of this aggressive type of breast cancer.

Joseph Baar, MD, PhD, Director of Breast Cancer Research at the Ireland Cancer Center, and colleagues analyzed 53 tumors and determined that 92 percent of them expressed MUC-1. These findings support their theory that this MUC-1 protein on breast cancer cells could be a target for a novel vaccine using the patient's immune system to target and kill cancer cells.

Dr. Baar has received a prestigious grant from the National Cancer Institute and the Avon Foundation to begin the vaccine trial in January 2009 for women with early stage triple negative breast cancer to see if this vaccine can raise their immune response against MUC-1. If it does, then a later study would be undertaken to determine whether the generation of such an immune response leads to an increase in patients' relapse-free survival rates, thereby preventing recurrence. The vaccine will be administered following standard therapy of surgery, radiation and chemotherapy.

"This vaccine trial has the potential to rev up patients' immune response to the MUC-1 protein and shut down the tumor's ability to grow," says Dr. Baar. "Women with this aggressive triple negative breast cancer have an increased risk of recurrence and we are hoping to provide them with protection against the return of this deadly disease. Our findings that have been presented at the San Antonio Breast Symposium provide us a strong basis for this trial."

Triple negative breast cancer is a highly aggressive form which comprises 10-15 percent of newly diagnosed early stage breast cancer. Most triple negative tumors are high grade and have a high incidence of recurrence and metastases (spreading to other organs). Unlike other types of breast cancer, there is no standard follow-up treatment for triple negative breast cancer to prevent recurrence.

"This is an important study because there has traditionally been nothing to offer women with triple negative breast cancer beyond standard therapy," says Stanton Gerson, MD, Director of the Ireland Cancer Center. "This vaccine trial has the potential to lay the groundwork for a new standard of care for women with this aggressive form of breast cancer."

source-www.eurekalert.org

HIV is so deadly largely because it evolves so rapidly. With a single virus as the origin of an infection, most patients will quickly come to harbor thousands of different versions of HIV, all a little bit different and all competing with one another to most efficiently infect that person's cells. Its rapid and unique evolution in every patient is what allows HIV to evade the body's defenses and gives the virus great skill at developing resistance to a pantheon of antiviral drugs.

"A huge amount of HIV diversity accumulates in the body of a patient with HIV, and it's a big reason why HIV is such a powerful virus," said Ha Youn Lee, Ph.D., assistant professor of Biostatistics and Computational Biology at the University of Rochester and corresponding author of the study.

Lee and colleagues have settled a longstanding question about just how HIV morphs in the body. In a paper published Dec. 12 in PLoS Computational Biology, scientists show that HIV evolution in the body does not occur at a constant rate. Rather, the virus's rate of change suddenly slows when the level of crucial immune cells known as CD4+ T-cells falls in a patient.

The team suggests several possible reasons for why HIV slows its evolution later in the disease process. One is that there are simply fewer immune cells left for the virus to infect. Another possibility is that since the immune system is no longer as effective targeting the virus, the virus no longer feels the "selective pressure" of the immune system, and the virus slows its evolution in response.

Picture a criminal on the lam. When the police are out in force, the criminal must change his disguise more and more to survive, but when fewer police are present, the criminal can change his disguise less often. In the case of HIV, the virus actually eliminates the "police officers" – CD4+ T-cells patrolling the body. As time goes on and fewer immune cells are present to flag HIV, the virus no longer has the need to evolve as rapidly as it did when the cells were out in force.

"In a person with a strong immune system, the virus is constantly on the run – it has to change to survive," said co-author Thomas Leitner, Ph.D., of Los Alamos National Laboratory, who studies viral and bacterial evolution. "But even in a person who has lived with HIV for a decade or more, in most cases, at some point, the immune system weakens. The virus notices and evolves accordingly. It's a very dynamic process."

While the research shows that the virus is creating fewer new versions of itself late in the disease process, the researchers say the clinical implications of the research are unclear. Since the virus's ability to evolve is at the heart of the drug-resistance capability that makes HIV so deadly, the work could help scientists who are trying to figure out new ways to stop the virus.

"It's possible that this work would have some implications for our understanding of drug resistance late in the disease process," said Lisa Demeter, M.D., a University of Rochester virologist not involved in the study. "When HIV is evolving more slowly in a patient, that patient is less likely to develop resistance to treatment so quickly," said Demeter, an expert on how HIV develops resistance and professor of Medicine in the Infectious Diseases Division.

Scientists have debated the pace of change of HIV in the body. Some studies have suggested that the virus evolves slowly in people who live many years with HIV before developing AIDS, while other studies showed that the virus evolves quickly in those patients.

To address the issue, the team developed a mathematical and computational model of how HIV evolves in the body. They tested the model by analyzing the blood from 15 HIV patients whose blood was sampled every few months for anywhere from three to 12 years. The data came from the HIV Sequence Database at Los Alamos National Laboratory, which holds more than 250,000 genetic sequences of HIV from patients around the globe.

The team found that the when the immune system is relatively healthy, the HIV virus evolves at a constant and rapid rate, but when a patient's CD4+ cells decrease, HIV's rate of evolution slows. The shift occurs long before a patient is considered to have AIDS, which is indicated when the CD4+ level drops to 200 cells per microliter of blood. The finding was true of 13 of 15 of the patients.

The team focused its attention on 600 nucleotides of the RNA that make up HIV's env gene, which codes for the protein's outer envelope that the virus uses to bind onto the cells of the host. In the team's study, on average, slightly less than one mutation per month occurred per patient in this swath of the HIV genome during the time when CD4+ levels were relatively high and the rate of change was constant.

That's a very rapid rate of change for one small portion of a virus, especially one so prolific: Every day, the HIV virus population in an infected person – up to 10 billion viral particles – copies itself and recreates 95 percent of its particles. With all that reproducing, and without a high regard for accuracy, one change leads to another, and the results are astounding: Most patients have literally many thousands of different types of HIV virus in their bodies.

"Every single person on Earth who is infected with HIV has his or her own unique HIV population," said Leitner.

As the virus mutates, giving birth to viral offspring called quasispecies, it presents an ever-changing face to the immune system, which is continually adapting itself to keep up with the onslaught. The immune system does a remarkable job fending off the assault, killing most of the viral particles every day. Even so, some of the virus is able to elude the body's defenses and ultimately devastates the immune system in most patients.

source-www.eurekalert.org

The human immune system is in a perpetual state of self-experimentation. It expertly mutates and shuffles the DNA of its own cells to evolve new defenses against the vast array of microbes that try to invade our bodies. But when the genetic experiment goes awry, the result can be a deadly cancer.

Now, Rockefeller University scientists have discovered that the same enzyme that enables the immune system's defensive creativity is also responsible for a particular genetic malfunction — a translocation of one piece of DNA to the wrong chromosome — that causes Burkitt's lymphoma. The findings, to be published in the December 12 edition of Cell, suggest the enzyme, called activation-induced deaminase (AID), is probably involved in a broader range of cancers as well.

"We strongly suspect that many or all of the translocations of human lymphomas in mature B cells are the product of this enzyme," says Michel C. Nussenzweig, Sherman Fairchild Professor and head of the Laboratory of Molecular Immunology. "And there's more and more data to show that it may be involved in other cancers as well. It's been identified in stomach cancers, for instance."

A very specific translocation causes Burkitt's lymphoma, a cancer that plagues children in equatorial Africa. It involves a DNA break in an immune system antibody gene and the much more rare break in a cancer-promoting gene called c-myc. Previous work had shown that AID was responsible for breaking antibody genes but not c-myc. In fact, scientists thought a host of other factors might be involved in the c-myc break, but AID had been all but ruled out.

Despite the prior studies, Davide Robbiani, a research associate in Nussenzweig's lab and a Leukemia and Lymphoma Society Fellow, believed AID was the culprit. To prove it, he and his colleagues started by deleting the promoter region of the c-myc oncogene, rendering the gene inactive, in a mutant line of mice. By looking for — and not finding — the specific translocation in these mice, he showed that c-myc had to be active in order for its DNA break to take place.

He then inserted a DNA tag into the mouse genome that allowed him to induce a break at the c-myc gene, which occurs only very rarely if left to its own devices. He found that his artificially created breaks were comparable in most every way to the breaks caused by AID, but when he looked for the translocation in mice that didn't produce this enzyme, they were nowhere to be found.

"This is a definitive study," says Nussenzweig, who is also a Howard Hughes Medical Institute investigator. "We now know AID is causing damage in other parts of the genome, not just in antibody genes."

Because AID normally enables the genetic experimentation that's critical to an effective immune response, shutting it down even to fight cancer is perilous. "As a general rule, you wouldn't want to give an AID inhibitor to everyone because immune systems would not be working so well," Nussenzweig says. Still, a pharmaceutical AID inhibitor, if developed, might prove useful in treating certain tumors that are expressions of this powerful gene mutator.

The next step is to figure out exactly how AID works and identify other genetic sites where AID is active. "We are now developing the tools to do exactly that," Robbiani says.

source-www.eurekalert.org