Clues to Pregnancy-Associated Breast Cancer Found

Expression of inflammatory-related genes in breast tissue of women who have previously given birth may explain the aggressiveness and frequency of pregnancy-associated breast cancer, according to new research at the University of Illinois at Chicago.

Pregnancy at a relatively young age reduces the risk of breast cancer over the long term, but epidemiological studies have found that women are at an increased risk for breast cancer during pregnancy and for up to 10 years after giving birth, said Debra Tonetti, associate professor of pharmacology and lead researcher on the study. These pregnancy-associated breast cancers also carry an unusually high risk of spreading to nearby organs and for lethality as compared to breast cancers in women who have never been pregnant, she said.

Tonetti and her research team examined the level of expression of 64 genes in tissue from benign breast biopsies and breast-reduction surgeries at the University of Illinois Medical Center at Chicago. The women, who were between the ages of 18 and 45, were divided into three categories: those who had never been pregnant, those who had been pregnant within the past two years, and those who had been pregnant five to 10 years previously.

The set of examined genes included genes known to be related to immunity and inflammation, extracellular matrix remodeling, angiogenesis (the growth of new blood vessels vital to wound healing) or hormone signaling.

Twenty-two percent of the examined genes showed significant difference in expression in the breast tissue of women who had never given birth compared with those who had. Inflammation-related genes, as a class, were more active in women who had borne a child. Involution -- the process by which the breast returns to normal following lactation -- could be a cause of the inflammation, she said.

"Our results showed an increase in immune/inflammatory activity in the post-pregnant breast," Tonetti said. "Interestingly, this response was not limited to the recently pregnant group, but also characterized more distant pregnancies as well."

A surprising finding was evidence of a protective effect of pregnancy as well, since the expression of many hormone and growth factor signaling genes suggests protection. These findings indicate that a balance between high risk inflammatory and protective hormone signaling gene expression may ultimately determine a woman's individual breast cancer risk, she said.

The researchers were not only interested in determining whether pregnancy and involution are associated with gene expression changes in the normal breast, but whether such changes stay for a short period of time or are permanent, Tonetti said.

The study is among the first to use samples from normal breast tissue to determine whether there is a time-dependent effect on breast cancer risk, she said.

The results will help understand the mechanisms behind pregnancy-associated breast cancer and will indicate potentially effective prevention strategies for women at high risk, such as use of anti-inflammatory agents. In addition, more effective therapeutic approaches may be developed based on the specific molecular pathways involved, Tonetti said.

The findings are published in the March issue of the journal Cancer Prevention Research. The study was funded through a grant from Avon Products Foundation.

Other authors, all from UIC, include Szilard Asztalos and Megan Hayes of the department of biopharmaceutical sciences; Peter Gann, Larisa Nonn and Elizabeth Wiley of the department of pathology; Craig Beam of the department of epidemiology and biostatistics; and Yang Dai of the department of bioengineering.

Cocaine-Related Deaths Rise in Warm Weather, Study Finds

In a study published online in the journal Addiction, researchers in the United States have discovered that accidental overdose deaths involving cocaine rise when the average weekly ambient temperature passes 24 degrees Celsius (75 degrees Fahrenheit).

Using mortality data from New York City's Office of the Chief Medical Examiner for 1990 through 2006, and temperature data from the National Oceanic and Atmospheric Association, researchers found that accidental overdose deaths that were wholly or partly attributable to cocaine use rose significantly as the weekly ambient temperature passed 24 degrees Celsius. The number of cocaine-related overdose deaths continued to rise as temperatures continued to climb.

Cocaine-related overdose deaths increase as the ambient temperature rises because cocaine increases the core body temperature, impairs the cardiovascular system's ability to cool the body, and decreases the sense of heat-related discomfort that ordinarily motivates people to avoid becoming overheated. Cocaine users who become overheated (hyperthermic) can overdose on lower amounts of cocaine because their bodies are under more stress.

The study's findings correct previous research that associated an increase in cocaine-related mortality with much higher temperatures (31.1 degrees Celsius, or 87.9 degrees Fahrenheit). Because cocaine-related overdose fatalities begin to rise at lower ambient temperatures than was previously thought, it is now apparent that cocaine users are at risk for longer periods of each year. Between 1990 and 2006, the average weekly temperature in New York City rose above 24 degrees Celsius for about seven weeks per year.

The study showed no difference in the number of drug overdoses in New York City among those weeks where the average temperature was between -10 and 24 degrees Celsius. Above 24 degrees Celsius, however, there were 0.25 more drug overdoses per 1,000,000 residents per week for every two degrees increase in weekly average temperature. Given that over 8.2 million people live in New York City, the study's findings predict that at least two more people per week will die of a drug overdose in the city for each two degree rise in temperature above 24 degrees Celsius, compared to weeks with average temperatures of 24 degrees and below.

The authors of this study point out the need for public health interventions in warm weather, such as delivering health-related warnings to high-risk groups. Prevention efforts could also include making air conditioning available in locations where cocaine use is common such as urban areas with a known high prevalence of cocaine use, and within those urban areas, particular neighbourhoods with elevated numbers of cocaine-related deaths or arrests. As lead author Dr. Amy Bohnert explains, "Cocaine users are at a high risk for a number of negative health outcomes and need public health attention, particularly when the weather is warm."

Infectious Virus Hidden in Chromosomes Can Be Passed from Parents to Children

Human herpesvirus 6 (HHV-6) infects nearly 100 percent of humans in early childhood, and the infection then lasts for the rest of a person's life. Now, a team led by Peter Medveczky, MD, a professor in the Department of Molecular Medicine at the University of South Florida (USF), has discovered that in some individuals, HHV-6 causes such a permanent infection by inserting or "integrating" its DNA into human chromosomes. From this harbor, the viral DNA cannot be eliminated by the immune system.

The paper describing this research was published online March 8 in Proceedings of the National Academy of Sciences.

The USF team also confirmed preliminary results by other investigators that, a long time ago, the virus inserted its DNA into the DNA of human sperm and egg cells. As a result, some people (about 1 percent of people in the U.S.) are born with the virus's DNA in every cell in their body. Indeed, HHV-6 is the first functional virus of any type reported to be passed through the human germ line.

The team presented clear evidence that the virus can insert its DNA specifically into telomeres -- structures at the ends of each chromosome that play key roles in both aging and cancer.

Finally, the team showed that the chromosomally integrated HHV-6 (CIHHV-6) genomes can be reactivated to an infectious form.

The findings are a surprise, since other human herpesviruses cause permanent infection by a different mechanism. The round up their DNA into a little circle that resides inside the nucleus of the cell: they do not insert their DNA into the chromosomes.

There are many unanswered questions that the USF team hopes to sort out. "We would like to know whether the location of the integration has an impact on pathology," Dr. Medveczky said. "We'd also like to know more about which drugs can provoke reactivation in patients that carry this virus in every cell... It would be important for these patients to avoid drugs that may reactivate the virus."

"This is an exciting and provocative series of observations. The questions raised by this work will keep herpes virologists busy for years," predicted HHV-6 expert Phil Pellett, PhD of Wayne State University.

HHV-6 was discovered in 1986 in the laboratory of Dr. Robert C. Gallo at the National Cancer Institute after Gallo asked his co-workers to look for a herpesvirus in AIDS lymphoma cases that might be triggering cancer. "In my mind these findings also should stimulate further studies on a possible role of HHV-6 in some cancers as suggested by others who have found a possible link to some lymphomas," Dr. Gallo commented. "However, clearly more work will be needed to advance any conclusion in this regard."

HHV-6 causes roseola, a generally benign rash and fever in infants. The virus can reactivate in individuals with suppressed immune systems, sometimes causing serious consequences such as encephalitis, hepatitis, myocarditis, and pneumonia.

Recent research has suggested that HHV-6 may also be associated with diseases in people with apparently healthy immune systems: encephalitis, mesial temporal lobe epilepsy, multiple sclerosis, myocarditis, and idiopathic cardiomyopathy. While there is no proof that the virus plays a causal role in these diseases, the virus has been found more often in the diseased tissue than in healthy tissue.

Previous studies had used a visual technique called fluorescence in situ hybridization (FISH), which showed that the viral DNA was present at the same location (near the telomeres) of the same chromosome in both parent and child. This strongly suggested but did not prove that the virus was inherited through the germ line in these children. By determining the DNA sequence of the ends of the chromosome, the Medveczky team clearly demonstrated that the HHV-6 genome was integrated into telomere DNA. The team also showed that HHV-6 DNA, unlike other human herpesviruses, does not curl into a circle inside the nucleus.

The great majority of people, however, do not inherit HHV-6 DNA from their parents and do not have it in every cell of their body. Yet nearly everyone becomes permanently infected with the virus. So Medveczky and colleagues wondered if the virus might take up permanent residence in the body by integrating its DNA into the chromosomes of just some cells.

To examine this possibility, the investigators took cells that had never been exposed to HHV-6 and infected them with HHV-6 that had been engineered to make infected cells glow bright green. Sure enough, once the infection died down, the green cells contained HHV-6 DNA integrated into the ends of the chromosomes. When the investigators stimulated the cells with chemicals known to activate other herpesviruses, cells with integrated viral DNA began producing infectious virus. It will be important to learn whether a similar process occurs during the form of HHV-6 infection that occurs in most individuals.

For the approximately 1 percent of the population born with viral DNA in every cell in their body, several questions arise. Are such people more prone to diseases because they have a greater risk of viral reactivation? If so, which diseases? If a person is born with viral proteins present from birth, would that person's immune system be "fooled" into thinking that the virus was not foreign and need not be attacked? If so, is that a bad thing or a good thing for a person's health? Finally, the virus inserts itself into the telomeres and could theoretically disrupt the function of the telomeres. Since the telomeres are important in cellular aging and in cancer, could the insertion of viral DNA in the telomeres have any effect on a cell's tendency to age or to turn cancerous?

While unique among known human herpesviruses, the capacity of HHV-6 to integrate into human chromosomes is not unique in nature. A herpesvirus that infects chickens, called Marek's disease virus, appears to behave the same way. Interestingly, although the viruses are not otherwise closely related, the DNA sequence used by Marek's disease virus to integrate into chicken chromosomes is remarkably similar to the DNA sequence used for chromosomal integration by HHV-6.

Doctoral student Jesse Arbuckle and research associate Maria Medveczky, both of the USF Department of Molecular Medicine, were lead authors of the study. Other contributing authors were from Bioworld Consulting Laboratories, the HHV-6 Foundation, University of Minnesota, University of Brussels, Stanford University School of Medicine and Harvard Medical School.

The USF study was funded by the HHV-6 Foundation, a non-profit organization that supports virology research, as well as by a grant from the National Institutes of Health.

Asteroid Killed Off the Dinosaurs, Says International Scientific Panel

The Cretaceous-Tertiary mass extinction, which wiped out the dinosaurs and more than half of species on Earth, was caused by an asteroid colliding with Earth and not massive volcanic activity, according to a comprehensive review of all the available evidence, published in the journal Science.

A panel of 41 international experts, including UK researchers from Imperial College London, the University of Cambridge, University College London and the Open University, reviewed 20 years' worth of research to determine the cause of the Cretaceous-Tertiary (KT) extinction, which happened around 65 million years ago. The extinction wiped out more than half of all species on the planet, including the dinosaurs, bird-like pterosaurs and large marine reptiles, clearing the way for mammals to become the dominant species on Earth.

The new review of the evidence shows that the extinction was caused by a massive asteroid slamming into Earth at Chicxulub (pronounced chick-shoo-loob) in Mexico. The asteroid, which was around 15 kilometres wide, is believed to have hit Earth with a force one billion times more powerful than the atomic bomb at Hiroshima. It would have blasted material at high velocity into the atmosphere, triggering a chain of events that caused a global winter, wiping out much of life on Earth in a matter of days.

Scientists have previously argued about whether the extinction was caused by the asteroid or by volcanic activity in the Deccan Traps in India, where there were a series of super volcanic eruptions that lasted approximately 1.5 million years. These eruptions spewed 1,100,000 km3 of basalt lava across the Deccan Traps, which would have been enough to fill the Black Sea twice, and were thought to have caused a cooling of the atmosphere and acid rain on a global scale.

In the new study, scientists analysed the work of palaeontologists, geochemists, climate modellers, geophysicists and sedimentologists who have been collecting evidence about the KT extinction over the last 20 years. Geological records show that the event that triggered the extinction destroyed marine and land ecosystems rapidly, according to the researchers, who conclude that the Chicxulub asteroid impact is the only plausible explanation for this.

Despite evidence for relatively active volcanism in Deccan Traps at the time, marine and land ecosystems showed only minor changes within the 500,000 years before the time of the KT extinction. Furthermore, computer models and observational data suggest that the release of gases such as sulphur into the atmosphere after each volcanic eruption in the Deccan Traps would have had a short lived effect on the planet. These would not cause enough damage to create a rapid mass extinction of land and marine species.

Dr Joanna Morgan, co-author of the review from the Department of Earth Science and Engineering at Imperial College London, said: "We now have great confidence that an asteroid was the cause of the KT extinction. This triggered large-scale fires, earthquakes measuring more than 10 on the Richter scale, and continental landslides, which created tsunamis. However, the final nail in the coffin for the dinosaurs happened when blasted material was ejected at high velocity into the atmosphere. This shrouded the planet in darkness and caused a global winter, killing off many species that couldn't adapt to this hellish environment."

Dr Gareth Collins, Natural Environment Research Council Fellow and another co-author from the Department of Earth Science and Engineering at Imperial College London, added: "The asteroid was about the size of the Isle of Wight and hit Earth 20 times faster than a speeding bullet. The explosion of hot rock and gas would have looked like a huge ball of fire on the horizon, grilling any living creature in the immediate vicinity that couldn't find shelter. Ironically, while this hellish day signalled the end of the 160 million year reign of the dinosaurs, it turned out to be a great day for mammals, who had lived in the shadow of the dinosaurs prior to this event. The KT extinction was a pivotal moment in Earth's history, which ultimately paved the way for humans to become the dominant species on Earth."

In the review, the panel sifted through past studies to analyse the evidence that linked the asteroid impact and volcanic activity with the KT extinction. One key piece of evidence was the abundance of iridium in geological samples around the world from the time of the extinction. Iridium is very rare in Earth's crust and very common in asteroids. Immediately after the iridium layer, there is a dramatic decline in fossil abundance and species, indicating that the KT extinction followed very soon after the asteroid hit.

Another direct link between the asteroid impact and the extinction is evidence of 'shocked' quartz in geological records. Quartz is shocked when hit very quickly by a massive force and these minerals are only found at nuclear explosion sites and at meteorite impacts sites. The team say that an abundance of shocked quartz in rock layers all around the world at the KT boundary lends further weight to their conclusions that a massive meteorite impact happened at the time of the mass extinction.

The panel was able to discount previous studies that suggested that the Chicxulub impact occurred 300,000 years prior to the KT extinction. The researchers say that these studies had misinterpreted geological data that was gathered close to the Chicxulub impact site. This is because the rocks close to the impact zone underwent complex geological processes after the initial asteroid collision, which made it difficult to interpret the data correctly.

Choking Is a Leading Cause of Injury and Death Among Children

 

Choking is a leading cause of injury and death among children, especially those younger than 4 years of age. The majority of choking-related incidents among children are associated with food, coins and toys. A new policy statement from the American Academy of Pediatrics (AAP), led by a doctor at Nationwide Children’s Hospital and published in the February 22 online issue of Pediatrics, takes a closer look at preventing choking among children.

On average, a child will die every 5 days in the United States from choking on food. However, too little attention is paid by government agencies and food manufacturers to minimizing choking risks. Although some food manufacturers voluntarily place warning labels on high risk products, more work needs to be done to implement safety standards for all high risk foods in regard to choking.

“We have laws and regulations in this country that require warning labels to be placed on toys that pose choking hazards, and we have systems that monitor and recall consumer products that pose a risk,” said the policy’s lead author Gary Smith, MD, DrPH, director of the Center for Injury Research and Policy at Nationwide Children’s Hospital. “However, there are no such regulations on high risk foods - and children are much more likely to put food in their mouths than a toy.”

According to the policy statement, the AAP recommends:

• Warning labels on foods that pose a high choking risk
• A recall of food products that pose a significant choking hazard
• The establishment of a nationwide food-related choking-incident surveillance and reporting system
• A commitment from food manufacturers to design new food and redesign existing food to minimize choking risk, to the extent possible

Parents and caregivers should also be made aware of foods that could be choking hazards. The risk of choking depends on the shape, size and consistency of the item, along with the developmental and behavioral capabilities of the child. Many foods that are thought to be “kid friendly” are actually dangerous. Foods like grapes, popcorn and nuts can easily become lodged in a young child’s throat or lungs. Hot dogs pose the greatest risk, as they cause more choking deaths than any other food.

“If you were to design the perfect plug for a child’s airway, you couldn’t do much better than a hot dog,” said Dr. Smith, also a Professor of Pediatrics at The Ohio State University College of Medicine. “It will wedge itself in tightly and completely block the airway, causing the child to die within minutes because of lack of oxygen.”

In order to reduce the risk of choking, parents and caregivers can do their part by following these safety tips:

• Do not give children younger than 4 any round, firm foods unless they have been cut into very small pieces. Cut hot dogs lengthwise and cut grapes into quarters. This changes the dangerous round shape that can block a young child’s throat.
• Do not give toddlers other high risk foods, such as hard candy, nuts, seeds and raw carrots.
• Never let small children run, play or lie down while eating.
• Keep coins and other small items out of reach of young children at all times.
• Carefully read warning labels on toys before giving them to young children.
• To check if a part of a toy is too small, use a small parts test device, which is available at many toy stores.
• Additionally, parents and caregivers should learn first aid for choking and cardiopulmonary resuscitation (CPR) in the event a choking episode occurs.