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Week Ending FRIDAY January 28, 2011---------News Archive

Bacteria Possible Cause Of Preterm Births

The type of bacteria that colonize the placenta during pregnancy could be associated with preterm birth and other developmental problems in newborns.

"The fetal inflammatory response appears to contribute to the onset of preterm labor, fetal injury and complications, underlying lifetime health challenges facing these children," say the researchers from Harvard Medical School, Brigham and Women's Hospital and Children's Hospital of Boston.

"Our data suggest that placental colonization by specific groups of organisms can increase or decrease the risk of a systemic inflammatory condition."

Preterm birth occurs in nearly a half million pregnancies in the United States alone. Despite improved care, preterm and especially extremely low-gestational-age newborns continue to be at a considerably higher risk of morbidity, mortality and developmental problems. Much of this risk is attributable to imbalanced inflammatory responses of the fetus and newborn.

The systemic fetal inflammatory response to intrauterine exposures, especially infections, is regarded as an important contributor to the onset and often lifelong consequences of preterm labor, fetal injury and early organ damage.

Approximately half of all placentas delivered before the second trimester and 41% of those delivered by Caesarean section harbor microorganisms detectable by culture techniques.

In order to better understand what role, these microorganisms could play in the extremely preterm inflammatory response the researchers analyzed protein biomarkers in dry blood spots obtained from 527 newborns delivered by Caesarean section and cultured and identified the bacteria from their respective placentas.

Placentas colonized by microorganisms commonly associated with bacterial vaginosis (BV) were found to be associated with elevated levels of proinflammatory protein in newborns.

In contrast, colonization by Lactobacillus species of bacteria (often found in decreased concentrations during BV) were associated with lower levels of proinflammatory proteins.

"Our study supports the concept that the placental colonization with vaginal microorganisms can induce a systemic inflammatory response in the fetus and newborn and that the dominating molecular feature of this response can be dependent on the type of bacteria," says Andrew Onderdonk of Harvard Medical School and Brigham and Women's Hospital, one of the authors of the study.

"Our data suggest that the targeting of placental colonization by specific drugs or probiotics during early pregnancy may hold promise for preventing not only preterm birth but also the devastating and far-reaching inflammatory consequences in premature newborns."

mBio® is a new open access online journal published by the American Society for Microbiology to make microbiology research broadly accessible. The focus of the journal is on rapid publication of cutting-edge research spanning the entire spectrum of microbiology and related fields.

The research data is published in the current issue of the online journal mBio®.


Secondhand Smoke Law Reduces Ear Infections

Harvard School of Public Health (HSPH) researchers and colleagues from Research Institute for a Tobacco Free Society have found that a reduction in secondhand smoking in American homes was associated with fewer cases of otitis media, the scientific name for middle ear infection.

"Our study is the first to demonstrate the public health benefits to children of the increase in smoke-free homes across the nation. It also is the first study to quantify over the past 13 years a reversal in what had been a long-term increasing trend in middle ear infections among children," said lead author Hillel Alpert, research scientist in HSPH's Department of Society, Human Development, and Health. "If parents avoid smoking at home, they can protect their children from the disease that is the most common cause of visits to physicians and hospitals for medical care," he said.

Secondhand smoke (smoke from a burning cigarette combined with smoke exhaled by a smoker) has been shown to increase the level of unhealthy particles in the air, including nicotine and other toxins. In 2006 the U.S. Surgeon General stated that enough evidence existed to suggest a link between parents' smoking and children's ear infections.

Otitis media is the leading reason for visits to medical practices and hospitals among U.S. children, with an annual estimated economic burden of $3 billion to $5 billion.

Children's visits for otitis media increased steadily from 9.9 million in 1975 to 24.5 million visits in 1990. However, the researchers found the average annual number of outpatient visits for otitis media in children aged 6 years and younger dropped 5%, and hospital discharges fell by 10% per year from 1993 to 2006. (The researchers note that other factors may have contributed to the decline, including a pneumonia vaccine that was introduced in 2000.)

To determine the number of smoke-free households, the researchers used data from the National Cancer Institute's Tobacco Use Supplement to the Current Population Survey. They found voluntary no-smoking rules in households nearly doubled from 45% in 1993 to 86% in 2006, most likely due to increased awareness of secondhand smoke hazards and a reduction in the number of people smoking in homes.

"Smoke-free rules in homes are extremely important to protect children, given the many adverse effects that secondhand tobacco smoke exposure has on child health," Alpert said.

The study appears on January 26, 2011, as an online first article on the website of the journal Tobacco Control.

The study was funded by the Flight Attendant Medical Research Institute. "Smoke-free Households with Children and Decreasing Rates of Paediatric Clinical Encounters for Otitis Media in the United States," Hillel R. Alpert, Ilan Behm, Gregory N. Connolly, Zubair Kabir. Tobacco Control (2010). doi:10.1136/tc.2010.038711. Online January 26, 2011.

Infants Determine Who Is Boss Through Size

We may be born with some grasp of social hierarchy and how it relates to physical size

Psychologists at Harvard University have found that infants less than one year old understand social dominance and use relative size to predict who will prevail when two individuals' goals conflict. The finding is presented this week in the journal Science.

Lead author Lotte Thomsen says the work suggests we may be born with -- or develop at a very early age -- some understanding of social dominance and how it relates to relative size, a correlation ubiquitous across human cultures and the animal kingdom. This potentially innate knowledge may help infants face the formidable challenge of learning the structure of their social environment, specifying ways of recognizing who is socially dominant in their particular culture.

"Traditional kings and chieftains sit on large, elevated thrones and wear elaborate crowns or robes that make them look bigger than they really are, and subordinates often bow or kneel to show respect to superior humans and gods," says Thomsen, a research fellow in Harvard's Department of Psychology and assistant professor of psychology at the University of Copenhagen. "Many animals, like birds and cats, will puff themselves up to look physically larger to an adversary, and prostrate themselves to demonstrate submission, like dogs do. Our work suggests that even with limited socialization, preverbal human infants may understand such displays."

Thomsen and colleagues at Harvard and the University of California, Los Angeles, studied the reactions of infants ranging from 8 to 16 months old as they watched videos of interactions between cartoon figures of various sizes.

"Since preverbal infants can't be interviewed, their experiences and expectations must be assessed by their behavior," Thomsen says. "Infants tend to watch longer when something surprises them. So we can test hypotheses about what they expect by measuring how long they look at scenarios that either violate or confirm their expectations."

The researchers showed infants videos depicting a large and a small block with eyes and mouth bouncing across a stage in opposite directions. Next, infants watched the two blocks meet in the middle, impeding one another's progress. They then saw either the large or the small block bow and step aside, deferring to the other.

"As predicted by our theory, the infants watched much longer when a large agent yielded to a smaller one," Thomsen says. On average, the babies watched this unexpected outcome for 20 seconds, compared to just 12 seconds when a smaller character made way for a larger one.

In a follow-up experiment, Thomsen and her co-authors found that eight-month-old infants failed to grasp the significance of the larger block deferring to the smaller one. But those who were 10 to 16 months old consistently demonstrated surprise at depictions of a larger individual yielding to a smaller one, suggesting that this conceptual understanding develops between 8 and 10 months of age.

Two other follow-ups showed that infants' reactions were not simply caused by the expectation that smaller individuals tend to fall over in general, including in situations that do not involve conflicting goals.

"Understanding what makes humans' rich conceptual repertoire possible is one of the formidable challenges of cognitive science," says co-author Susan Carey, the Henry A. Morss, Jr. and Elisabeth W. Morss Professor of Psychology at Harvard. "Part of meeting this challenge is specifying the initial state: What representational resources are infants born with that enable further learning? Our work shows that apparently, infants come prepared to understand abstract aspects of their social world."

In recent decades, scientists have learned that the infant mind creates abstract representations of intuitive physics, psychology, and mathematics. It has also been shown that young infants represent aspects of the social world, such as tracking whether other agents help or hinder third parties. These representations constitute part of what babies need in order to understand collaboration and cooperation in the world.

"The studies we report here are the first to show that young infants also understand events where agents have conflicting goals, and have ways of predicting which of two agents will prevail," Carey says.

Thomsen and Carey's co-authors on the Science paper are Willem E. Frankenhuis at UCLA and McCaila Ingold-Smith at Harvard. Their work was sponsored by Harvard, the National Institutes of Health, the Winkler Foundation, and the National Danish Science Foundation.


THURSDAY January 27, 2011---------News Archive

Improved Fertility Through Reversal of Aging

For the first time a dramatic reversal of many aspects of age-related degeneration in mice has been engineered.

Harvard scientists at Dana-Farber Cancer Institute say they have for the first time partially reversed age-related degeneration in mice, resulting in new growth of the brain and testes, improved fertility, and the return of a lost cognitive function.

In a report posted online by the journal Nature in advance of print publication, research led by Ronald A. DePinho, a Harvard Medical School (HMS) professor of genetics, has achieved the milestone in aging science with a controllable telomerase gene. Telomerase is an enzyme that maintains the protective caps called telomeres shielding the ends of chromosomes.

As humans age, low levels of telomerase are associated with progressive erosion of telomeres which may then contribute to tissue degeneration and functional decline. By creating mice with a telomerase switch, the researchers were able to generate prematurely aged mice. The switch allowed the scientists to find out whether reactivating telomerase in the animals would restore telomeres.

Their work showed a dramatic reversal of many aspects of aging, including reversal of brain disease and infertility.

While human application remains in the future, the technique might one day be used to treat conditions such as Progeria, a rare genetic premature aging syndrome in which shortened telomeres play an important role. “Whether this would impact on normal aging is a more difficult question,” he added. “But it is notable that telomere loss is associated with age-associated disorders and thus restoration of telomeres could alleviate such decline.” said DePinho, senior author of the report and the director of Dana-Farber’sBelfer Institute for Applied Cancer Science.

Importantly, the mice showed no signs of developing cancer. This remains a concern as cancer cells turn on telomerase to make themselves virtually immortal. DePinho said the risk can be minimized by switching on telomerase only for a matter of days or weeks - which may be brief enough to avoid fueling hidden cancers or causing new ones to develop. Still, he observed, it is an important issue for further study.

In addition, DePinho said these results may provide new avenues for regenerative medicine, because they suggest that quiescent adult stem cells in severely aged tissues remain viable and can be reactivated to repair tissue damage.

“If you can remove the underlying damage and stresses that drive the aging process and cause stem cells to go into growth arrest, you may be able to recruit them back into a regenerative response to rejuvenate tissues and maintain health in the aged,” he said. Those stresses include the shortening of telomeres over time causing cells and tissues to fail.

The experiments used mice that had been engineered to develop severe DNA and tissue damage as a result of abnormal, premature aging. These animals had short, dysfunctional telomeres and suffered a variety of age-related afflictions that progressed into successive generations. Among the conditions were testes reduced in size and depleted of sperm, atrophied spleens, damaged intestines, shrinkage of the brain along with an inability to grow new brain cells.

“We wanted to know: If you could flip the telomerase switch on and restore telomeres in animals with entrenched age-related disease, what would happen?” explained DePinho. “Would it slow down aging, stabilize it, or even reverse it?”

Rather than supply the rodents with supplemental telomerase, the scientists devised a way to switch on the animals’ own dormant telomerase gene, known as TERT. They engineered the TERT gene to encode a fusion protein. This protein only becomes activated with a special form of estrogen. Scientists could then give the mice an estrogen-like drug at any time to stimulate the estrogen receptor protein and restore TERT to actively maintain telomeres.

The researchers administered the estrogen drug to some of the mice via a time-release pellet inserted under their skin. Control mice were given a pellet containing no active drug.

After four weeks, the scientists observed remarkable signs of rejuvenation in the treated mice.

Overall, the mice exhibited biological changes indicative of cells returning to a growth state with reversal of tissue degeneration, and increase in size of the spleen, testes, and brain. “It was akin to a Ponce de León effect,” noted DePinho, referring to the Spanish explorer who sought the mythical Fountain of Youth.

“When we flipped the telomerase switch on and looked a month later, the brains had largely returned to normal,” said DePinho. More newborn nerve cells were observed, and the fatty myelin sheaths around nerve cells - which had become thinned in the aged animals - increased in diameter. In addition, the increase in telomerase revitalized slumbering brain stem cells so they could produce new neurons.

To show functional improvement, the scientists tested the mice’s ability to avoid unpleasant odors associated with danger, such as scents of predators or rotten food. Previous to treatment, the mice had lost that survival skill as their olfactory nerve cells were atrophied. After the telomerase boost, those nerves regenerated and the mice regained their crucial sense of smell.

“One of the most amazing changes was in the animals’ testes, which were essentially barren as aging caused the death and elimination of sperm cells,” recounted DePinho. “When we restored telomerase, the testes produced new sperm cells, and the animals’ fecundity was improved - their mates gave birth to larger litters.”

The telomerase boost also lengthened the rodents’ life spans compared to the untreated controls - but they did not live longer than normal mice.

The authors concluded, “This unprecedented reversal of age-related decline in the central nervous system and other organs vital to adult mammalian health justifies exploration of telomere rejuvenation strategies for age-associated diseases.”

The first author on the paper is Mariela Jaskelioff, a research fellow in medicine in DePinho’s laboratory. Other authors include members of the DePinho research group and Eleftheria Maratos-Flier, an HMS professor of medicine at Beth Israel Deaconess Medical Center.

The research was supported by grants from the National Institutes of Health and the Belfer Foundation.

While Pregnant, Avoid Soft Cheese

Researchers have found that particular strains of a food-borne bacteria are able to invade the heart of vulnerable populations - such as pregnant women and the developing fetus, leading to serious and difficult-to-treat heart infections.

Eating soft cheese during pregnancy is NOT safe
Scientists at the University of Illinois (UIC) Chicago College of Medicine have found that the bacteria Listeria monocytogenes is commonly in soft cheeses and chilled ready-to-eat products.

For healthy individuals, listeria infections are usually mild, but for susceptible individuals, infection can result in serious illness usually associated with the central nervous system, the placenta and the developing fetus, and the elderly.

About 10 percent of serious listeria infections involve a cardiac infection, according to Nancy Freitag, associate professor of microbiology and immunology and principle investigator on the study. These infections are difficult to treat, more than one-third proving fatal, but have not been widely studied and are poorly understood.

Freitag and her colleagues obtained a strain of listeria that had been isolated from a patient with endocarditis - infection of the heart. “This looked to be an unusual strain, and the infection itself was unusual,” she said. Usually with endocarditis there is bacterial growth on heart valves, but in this case the infection had invaded the cardiac muscle.

The researchers were interested in determining whether patient predisposition led to heart infection or whether something different about the cardiac strain itself caused it to target the heart.

When they infected mice with either the cardiac isolate or a lab strain, they found 10 times as much bacteria in the hearts of mice infected with the cardiac strain. In both groups of mice, the spleen and liver - organs commonly targeted by listeria - displayed equal levels of bacteria.

Further, while the lab-strain-infected group often had no heart infection, 90 percent of the mice infected with the cardiac strain did have heart infections. Researchers obtained more strains of listeria, repeating the experiment, but observed only one other strain to also target the heart.

“They [listeria bacteria] infected the heart of more animals and were always infecting heart muscle and always in greater number,” Freitag said. “Some strains seem to have this enhanced ability to target the heart for infection.”

Freitag’s team used molecular genetics and cardiac cell cultures to explore what was different about these two strains.

“These strains seem to have a better ability to invade cardiac cells,” she said. The results suggest that these cardiac-associated strains display modified proteins on their surface that enable the bacteria to more easily enter cardiac cells, targeting the heart and leading to bacterial infection.

“Listeria is actually pretty common in foods,” said Freitag. “And because it can grow at refrigerated temperatures, as foods are being produced with a longer and longer shelf life, listeria infection may become more common. In combination with aging and vulnerable populations that are more susceptible to serious infection, it’s important that we learn all we can about these deadly infections.”

The study is available online in the Journal of Medical Microbiology.

The study was supported by a Public Health Service Grant; by Public Health Service post-doctoral training fellowships; and an American Heart Association Predoctoral Fellowship.

UIC graduate student Francis Alonzo III was first author of the study. Linda Bobo of Washington University School of Medicine in St. Louis and Daniel Skiest of Baystate Medical Center-Tufts University School of Medicine in Springfield, Mass., also contributed to the study.

For more information visit UIC


WEDNESDAY January 26, 2011---------News Archive

Evolution of Cancer Follows Complexity of Life

Cancer is a product of evolution, and understanding how cancer evolves may be a key to more successful treatment strategies.

A billion years ago the world was cancer-free. That’s because Earth was home to only one-celled organisms – bacteria, for instance. Deadly tumors are a scourge that emerged as life on Earth became increasingly complex.

The trouble starts with multi-cellular life forms. Animals with many cells – mice, whales and humans – develop in complex ways. From embryo to adult, cells divide and move. But cancer is like development gone wild.

“The problem of building a multi-cellular organism is really the problem of suppressing cancer,” says UCSF’s Carlo Maley, PhD, an expert in both evolutionary biology and bioinformatics. “How do you get cells to stop proliferating and to devote their resources to the good of the larger organism?”

The short answer is that during the evolution of higher life forms cells have learned to listen to and obey molecular signals from other cells and from their surroundings. During development cells morph and become specialized – all at the proper time and in the appropriate place, in a precisely orchestrated way. Eventually cells that make up our 200-or-so types of tissues stop expanding their ranks and settle down where they belong.

The seed of cancer is a cell that ignores the directives of the orchestra conductor and that instead follows an offbeat drummer. Tumors emerge when cells that break the rules are not rehabilitated or eliminated. Over time, a succession of changes in a cell’s genetic program – encoded by DNA — sometimes allows a cell not only to behave abnormally, but also to go unpunished. Self-serving, out-of-control growth is the result.

For an individual cell, a DNA mutation is an uncommon event. But there are 3 billion DNA building-block nucleotides in each cell nucleus. And let’s not forget that humans have trillions of cells. Throw in the fact that we live for several decades, and it becomes clear that normal physiological and biochemical wear-and-tear should result in a multitude of instances of harmful and even cancer-causing DNA damage. Cancer should be even more devastating than it is – perhaps even a threat to the survival of the species.

The reason many more do not experience cancer is that we have in fact evolved natural defenses to protect against such out-of-control cell growth, Maley says. But these defenses are imperfect.

Some species fare better than others in suppressing cancer. For instance, elephants do not get more cancers than mice, even though an elephant has about a million times more cells than a mouse, Maley says.

Not all the defense mechanisms against cancer are known, but several are. Humans and other animals have biochemical tool kits for repairing DNA. If repair fails, the offending cell normally is programmed to commit suicide. And even without the constraints imposed by the neighboring community of cells, a cell can divide only a limited number of times.

The immune system often is capable of attacking cells displaying molecular markers that point to abnormal growth. Even so, the immune response may be insufficient to stop the formation of a tumor.

The cells that become cancerous are the ones that mutate and change in ways that allow them to get around these gatekeepers.

Although multi-cellular organisms have evolved ways to fight cancer, each individual tumor also is capable of evolving. The evolution of tumors is lightning-fast in comparison to the evolution of species. While medical science works a bit faster than human evolution, cancers also morph to elude the grasp of oncologists who would vanquish them with the latest drugs.

But the same concepts that are used to study the evolution of sexually reproducing, multi-cellular organisms can be applied to tumors to come up with new and possibly more effective treatment strategies, Maley says. The key is to not treat the tumor as something that is uniform and unchanging.

Survival of the fittest – what scientists call “selection” – is at play during cancer treatment. Whack that tumor with some nasty chemotherapy and it may disappear, only to grow back years later. Cancer’s resilience is a result of genetic diversity.

Scientists and physicians who treat cancer have come to appreciate more and more that tumors differ genetically from patient to patient — even among individuals with the same diagnosis, and even when the tumors look the same to a pathologist. But in recent years researchers also have learned that within a single tumor there is great genetic diversity and variation among clusters of cells.

Cancer starts as a mob of cells, all clones derived from one lone evildoer. As the cells in the clone colony breach normal constraints and continue to grow and divide, every so often they give rise to cells with new genetic mutations. This is the source of genetic diversity within the tumor.

Treatment represents a change in the tumor’s environment to which tumor cells must adapt to in order to survive. The tumor cells that endure and keep growing despite treatment are genetically different and have different capabilities than those that dominated before treatment. They are the product of natural selection in action, Maley explains.

“Natural selection happens anytime in any system in which you have three conditions. There must be variability in the population. Variation must be heritable. And variation has to affect fitness.”

“There is no cancer therapy known that does not select for resistance,” he says. “A more diverse cancer-cell population is more likely to have a resistant clone, and in the environment of the therapy, it will tend to out-compete the other cancer cells.”

Maley has shown that a better understanding of evolution within tumors can help better predict how quickly or slowly cancers are likely to arise from pre-malignant, abnormal generations of cells. Similar explorations of cancer evolution can shed light on treatment resistance and how to overcome it – the key to greatly improving patients’ chances for survival.

In essence, the goal is to slow down the evolution of cancer within the patient. “If you measure someone’s pre-malignant tumor and how fast it evolves, then you should be able to predict how long it’s going to be before they get cancer,” Maley says. “You could do the same in someone who already has cancer to predict how long it may be until they relapse after therapy.”

In a study of a pre-cancerous condition called Barrett’s esophagus, Maley and colleagues are developing methods to measure the factors that influence how quickly abnormally growing clusters of cells evolve through a succession of clones on the way to becoming full-blown cancers.

One factor is mutation rate – either the mutation rate of all DNA, or of just the DNA that encodes proteins. Another is a measure of the number of evolving cells in a tumor. But for this measure, the only cells that count are those that are capable of dividing continually, Maley says. A third factor is how quickly cells divide. And yet another is the relative advantage a cell gains over a competitor due to a specific mutation.

So far, Maley has determined that the amount of genetic diversity within Barrett’s esophagus is a good marker of tumor evolution. In his study it was significantly associated with the development of cancer.

Of course the larger goal is to come up with new treatment approaches to keep tumors from morphing into forms that are ever more life threatening. “We want to intervene to slow down evolution in the cells of our bodies,” Maley says.

In some cases current drugs may even speed the evolution of cancers, according to Maley. Many chemotherapy drugs are what Maley calls “cytotoxic.” This means they aim to kill cells, usually by interfering with a cell’s production of new DNA as it prepares to divide. “With chemotherapy you try to kill all the cancer cells,” Maley says. “That’s a very strong selective pressure, and it offers a huge advantage to any cells that are resistant to the treatment. Resistant cells can run wild after cytotoxic drugs clear out all the competitors.”

New approaches may be able to hold death-by-cancer at bay until the clock runs out. For instance, a drug – or a combination of drugs – that slows cell division could reduce selective pressure for resistance and delay the onset of cancer past the natural lifespan of humans.

“We tend to judge the immediate effects of treatment on tumor size, but what’s really important is patient survival,” Maley says. “A drug might not quickly shrink a tumor measurably, but that would not matter down the road if the patient never relapses.”

Cancer is primarily a disease associated with aging. The median age of diagnosis for most cancers is in the mid-sixties.

“We think the process from first mutation to malignant tumor takes from 20 to 50 years. If we increase the generation time of cancer by factor of two, most people would die from another cause,” Maley says.

A much more in-depth presentation of cancer evolution can be found a Wikipedia site that Maley curates, called “Somatic Evolution in Cancer.”

Hot Flashes Reduce Risk of Breast Cancer

The more frequent and severe the hot flashes, the lower the cancer risk

Women who have experienced hot flashes and other symptoms of menopause may have a 50 percent lower risk of developing the most common forms of breast cancer than postmenopausal women who have never had such symptoms, according to a recent study by researchers at Fred Hutchinson Cancer Research Center.

The results of the first study to examine the relationship between menopausal symptoms and breast cancer risk are available online ahead of the February print issue of Cancer Epidemiology Biomarkers and Prevention.

The protective effect appeared to increase along with the number and severity of menopausal symptoms, according to senior author Christopher I. Li, M.D., Ph.D., a breast cancer epidemiologist in the Hutchinson Center’s Public Health Sciences Division.

“In particular we found that women who experienced more intense hot flashes – the kind that woke them up at night – had a particularly low risk of breast cancer,” he said.

Li and colleagues suspected a link between menopause misery and decreased breast cancer risk because hormones such as estrogen and progesterone play an important role in the development of most breast cancers, and reductions in these hormones caused by gradual cessation of ovarian function can impact the frequency and severity of menopausal symptoms.

“Since menopausal symptoms occur as hormone levels fluctuate and drop, we hypothesized that women who experienced symptoms such as hot flashes and night sweats – particularly frequent and severe symptoms – might have a lower risk of breast cancer due to decreased estrogen levels,” he said.

Indeed, the researchers found a 40 percent to 60 percent reduction in the risk of invasive ductal and invasive lobular carcinoma – the two most common types of breast cancer – among women who experienced hot flashes and other symptoms. The association between such symptoms and decreased cancer risk did not change even after the researchers accounted for other factors known to boost breast cancer risk, such as obesity and use of hormone replacement therapy.

For the study, which was funded by the National Cancer Institute, Li and colleagues interviewed 1,437 postmenopausal Seattle-area women, 988 of whom had been previously diagnosed with breast cancer and 449 of whom had not, who served as a comparison group. The women were surveyed about perimenopausal and menopausal symptoms ranging from hot flushes, night sweats and insomnia to vaginal dryness, irregular or heavy menstrual bleeding, depression and anxiety.

“While menopausal symptoms can certainly have a negative impact on quality of life, our study suggests that there may be a silver lining if the reduction in breast cancer risk is confirmed in future studies,” Li said. “If these findings are confirmed, they have the potential to improve our understanding of the causes of breast cancer and improve approaches to preventing this disease.”

At Fred Hutchinson Cancer Research Center, our interdisciplinary teams of world-renowned scientists and humanitarians work together to prevent, diagnose and treat cancer, HIV/AIDS and other diseases. Our researchers, including three Nobel laureates, bring a relentless pursuit and passion for health, knowledge and hope to their work and to the world. For more information, please visit www.fhcrc.org.


TUESDAY January 25, 2011---------News Archive

'Breast On A Chip' Model for Breast Cancer

Purdue researchers' new model for breast cancer research, called "breast on-a-chip," mimicing the branching mammary duct system.

New model for breast cancer research, called "breast on-a-chip," mimics the branching mammary duct system. (Purdue University/Lelièvre laboratory)
Purdue University researchers have reproduced portions of the female breast in a tiny slide-sized model dubbed "breast on-a-chip" that will be used to test nanomedical approaches for the detection and treatment of breast cancer.

The model mimics the branching mammary duct system, where most breast cancers begin, and will serve as an "engineered organ" to study the use of nanoparticles to detect and target tumor cells within the ducts.

Sophie Lelièvre, associate professor of basic medical sciences in the School of Veterinary Medicine, and James Leary, SVM Professor of Nanomedicine and professor of basic medical sciences in the School of Veterinary Medicine and professor of biomedical engineering in the Weldon School of Biomedical Engineering, led the team.

"Breast cancer is the most common cancer in women in most countries, and in the U.S. alone nearly 40,000 women lost their lives to it this past year," said Lelièvre, who is associate director of discovery groups in the Purdue Center for Cancer Research and a leader of the international breast cancer and nutrition project in the Oncological Sciences Center. "We've known that the best way to detect this cancer early and treat it effectively would be to get inside the mammary ducts to evaluate and treat the cells directly, and this is the first step in that direction."

Lelièvre and Leary hope eventually to be able to introduce magnetic nanoparticles through openings in the nipple, use a magnetic field to guide them through the ducts where they would attach to cancer cells and then reverse the magnetic field to retract any excess nanoparticles. The nanoparticles could carry contrast agents to improve mammography, fluorescent markers to guide surgeons or anticancer agents to treat the cancer, Leary said.

"Nanoparticles can be designed to latch on to cancer cells and illuminate them, decreasing the size of a tumor that can be detected through mammography from 5 millimeters to 2 millimeters, which translates into finding the cancer 10 times earlier in its evolution," Leary said. "There also is great potential for nanoparticles to deliver anticancer agents directly to the cancer cells, eliminating the need for standard chemotherapy that circulates through the entire body causing harmful side effects."

Physicians have tried to access the mammary ducts through the nipple in the past, injecting fluid solutions to try to wash out cells that could be examined and used for a diagnosis of cancer. However, this approach could only reach the first third of the breast due to fluid pressure from the ducts, which branch and become smaller and smaller as they approach the glands that produce milk, Leary said.

"The idea is that nanoparticles with a magnetic core can float through the naturally occurring fluid in the ducts and be pulled by a magnet as opposed to being pushed with pressure," he said. "We think they could reach all the way to the back of the ducts, where it is believed most breast cancers originate. Of course, we are only at the earliest stages and many tests need to be done."

3-D rendering of one of the channels lined with cells (Purdue University/Lelièvre laboratory)
Such tests could not be done using standard models that grow cells across a flat surface in a plastic dish, so the team created the artificial organlike model in which living cells line a three-dimensional replica of the smallest portions of the mammary ducts.

Leary is internationally known for his nanofabrication work using photolithography to build tiny, precise structures on thin pieces of silicon to create high-speed cell sorting and analysis tools. The channels are about 5 millimeters long of various diameters from 20 microns to 100 microns, roughly the diameter of a human hair, that match what is found near the end of the mammary duct system.

Lelièvre, whose group is one of the few in the world able to successfully grow the complicated cells that line the mammary ducts, coaxed the cells to grow within the mold and behave as they would within a real human breast.

"The cells within the breast ductal system have a very specific organization that has proven difficult to obtain in a laboratory," Lelièvre said. "The cells have different sides, and one side must face the wall of the duct and the other must face the inner channel. Reproducing this behavior is very challenging, and it had never been achieved on an artificial structure before."

The team has demonstrated that nanoparticles can be moved within the bare channels of the mold filled with fluid, but has not yet moved nanoparticles through the finished model lined with living cells, Lelièvre said.

The team next plans to create and test nanoparticles with a slippery surface that will prevent them from sticking to the cells as they travel through the channels and coatings that contain antibodies to target and attach to specific types of cancerous and precancerous cells, she said.

"Although we are at the very beginning stages of this work, we are hopeful that this nanomedical approach will one day save lives and provide patients with an easier road to recovery," Lelièvre said. "The successful creation of this model is an important milestone in this work and it is a testament to what can be accomplished through multidisciplinary research."

A paper detailing the team's work, which was funded by the U.S. Department of Defense, is published in the current issue of Integrative Biology. In addition to Lelièvre and Leary, co-authors include graduate student Meggie Grafton, research associate Lei Wang and postdoctoral researcher Pierre-Alexandre Vidi.

Lelièvre and Leary are both members of the Purdue Center for Cancer Research and the Oncological Sciences Center. Leary also is a member of the Birck Nanotechnology Center and Bindley Bioscience Center at Purdue's Discovery Park.

What We Learn From Pregnant Horses

Like humans, horses are prone to miscarriage. In fact, about one in ten pregnancies results in miscarriage at a very early stage.

Some horses have a history of early miscarriages and it has become customary to treat them with a type of progestin hormone known as altrenogest - although there have not been any studies to assess whether this actually improves the chances that the pregnancy will run to term.

The group of Christine Aurich at the University of Veterinary Medicine, Vienna has now investigated the effect of altrenogest treatment on the development of the foetus and on the horses’ hormone levels.

Surprisingly, the researchers found that the foetus developed significantly more slowly in older mares compared with younger animals. The difference disappeared in horses treated with altrenogest, showing for the first time that the progestin has a positive effect on foetal development. The results are published in the 75th issue of the journal Theriogenology.

Most miscarriages in horses results at very early stages of pregnancy (within about three weeks) and it is generally believed that the primary cause is that the foetus grows or develops too slowly: smaller than normal embryos have a higher chance of being lost then normally sized ones. It is not clear whether low concentrations of progesterone lead to slower embryonic development but nevertheless the progestin altrenogest is routinely used to treat mares that frequently suffer miscarriages.

Aurich’s group has now found that altrenogest treatment has no effect on the levels of luteinizing hormone (LH) or progesterone, hormones that are known to be important in maintaining pregnancy. Furthermore, treatment does not influence the ease with which the mares became pregnant, nor does it affect the size of the vesicles housing the embryos, at least for the first 22 days after conception.

However, the researchers did notice that at 20 days after conception the embryonic vesicles are smaller if the mares are older. They also found that the foetuses of older mares grow significantly more slowly after this period, although if the mares are treated with altrenogest their foetuses grow at the normal rate.

The smaller size of the foetuses in older mares provides an explanation for the higher rate of pregnancy losses as horses grow older.

Smaller foetuses in these animals may result from a reduced quality of the eggs as the horses age, making the mares more susceptible to miscarriage.

Encouragingly, treatment with altrenogest appeared to enable the smaller foetuses to recover and to grow at a normal rate during the second crucial period in the animals’ development, when the embryonic organs are formed and the mare’s placenta is generated (from 35 to 45 days after conception).

It seems conceivable that altrenogest encourages the formation of the placenta.

The results show that altrenogest treatment does have an effect in reducing the risk of miscarriage in horses, although not the one that might have been expected. It does not seem able to prevent miscarriages in early pregnancy but instead to compensate for later problems in foetal development that are more frequently encountered as mares grow older.

As Aurich says, “We are now well used to the idea of a hormonal therapy in humans to prevent osteoporosis. Perhaps horses could also benefit from the same type of treatment to help them avoid miscarriages.”

The paper title is: "Effect of age and altrenogest treatment on conceptus development and secretion of LH, progesterone and eCG in early-pregnant mares" by Conrad Willmann, Gerhard Schuler, Bernd Hoffmann, Nahid Parvizi and Christine Aurich is published in the 75th issue of the journal Theriogenology (2011, Vol. 75(3), 421-428).

The work was performed at the Graf Lehndorff Institute for Equine Science in Neusdadt (Dosse), Germany in collaboration with groups from Giessen and Mariensee.About the University of Veterinary Medicine, ViennaThe University of Veterinary Medicine, Vienna is the only academic and research institution in Austria that focuses on the veterinary sciences. The Graf Lehndorff Institute for Equine Science in Neusdadt (Dosse), Germany belongs to the University.

About the University of Veterinary Medicine, Vienna
The University of Veterinary Medicine, Vienna is the only academic and research institution in Austria that focuses on the veterinary sciences. About 1000 employees and 2300 students work on the campus in the north of Vienna, which also houses the animal hospital and various spin-off-companies. The Graf Lehndorff Institute for Equine Science in Neusdadt (Dosse), Germany belongs to the University.


MONDAY January 24, 2011---------News Archive

Effects of Diet On Childhood Asthma

Asthma is one of the world's most common chronic diseases, affecting as many as 300 million people. It is estimated that by 2025 there could be an additional 100 million people with the disease. This rapid increase in asthma is most likely due to changing environmental or lifestyle factors, and over the last 15 years, changing diet has emerged as a promising contributor.

Two studies published in the in the February 2011 issue of the Journal of the American Dietetic Association explore the possible relationship between nutrition and asthma. Researchers review the rationale for investigating associations between diet and asthma, discuss the potential for dietary intervention to complement conventional asthma treatment, and summarize the recent data suggesting that diet may influence the development of asthma.

Investigators from the University of Aberdeen, UK, review three dietary factors that have been hypothesized to explain the increase in asthma – a changing antioxidant intake, an increasing ratio of n-6 to n-3 polyunsaturated fatty acid (PUFA) consumption and changing vitamin D status.

Although there is insufficient clinical evidence for the use of nutritional supplements to complement conventional asthma treatments, the authors note that ongoing studies may change this picture. They also review a small number of studies of maternal diet during pregnancy that suggest that dietary modification during pregnancy might reduce the incidence of childhood asthma.

According to Graham Devereux, MD, PhD, "The generally weak observational and very limited intervention data suggest that whilst there are associations between diet and asthma, the nature of the associations (with PUFA, antioxidants, nutrients, food), the timing (antenatal, infancy, childhood, adulthood), and the therapeutic potential of the associations are far from clear."

He continues, "Future studies should consider the use of dietary intervention to increase the intake of nutrients highlighted by birth cohorts (vitamin E, PUFA, vitamin D, zinc) in order to capture the complexity of dietary nutrient intake. If shown to be efficacious, such a dietary intervention could be the basis for a low cost, safe public health intervention to rapidly reduce the prevalence of asthma in children and ultimately adults, with obvious beneficial consequences for the wellbeing of individuals and society as a whole. Until the results of ongoing and planned trials are available, the practical consequences of research linking diet with asthma are minimal, and based on the available evidence, people with asthma, pregnant women, parents, and children should not be advised to change or supplement their diet in order to treat or reduce the risk of developing asthma."

In a study published in the same issue a multi-institutional team of researchers in Greece examined associations between salty snack consumption and TV or video game viewing and asthma symptoms in young adolescents. While noting that although both factors have been implicated in asthma development, results have been conflicting. In their cross-sectional study of 700 children 10-12 years old, living in and around Athens, Greece, they found that there was a 4.8 times higher risk of having asthma symptoms when salty snacks were consumed more than 3 times per week. This association was even more prominent in children who watch TV or play video games more than 2 hours per day.

The authors also found that children who consumed a "Mediterranean diet" were less likely to have asthma symptoms, consistent with previous studies evaluating the association between the Mediterranean diet and asthma in children. The Mediterranean diet has a high content of vegetables, fresh fruits, cereals and olive oil, with a high intake of beta-carotene, vitamins C and E and various important protective substances like selenium, flavonoids and polyphenols with marked antioxidant activity.

Lead investigators Demosthenes Panagiotakos, PhD, Associate Professor, Department of Nutrition – Dietetics, Harokopio University, and Kostas Priftis, MD, PhD, Assistant Professor, School of Medicine, University of Athens, Greece, conclude, "Since the prevalence of asthma is quite high in industrialized populations, and has continued to increase during the past years, future interventions and public health messages should be focused on changing these behaviors from the early stages of life, by informing parents, guardians, teachers and any other person that could teach children a healthier lifestyle."

"Diet and asthma: Nutritional implications from prevention to treatment" by Keith Allan, MSc, and Graham Devereux, MD, PhD
"Salty-snack eating, television or video-game viewing, and asthma symptoms among 10- to 12-year- old children: The PANACEA study" by Fotini Arvaniti, RD, MSc, Kostas N. Priftis, MD, PhD, Anastasios Papadimitriou, MD, PhD, Panagiotis Yiallouros, MD, Maria Kapsokefalou, PhD, Michael B. Anthracopoulos, MD, PhD, and Demosthenes B. Panagiotakos, MD, PhD

Both appear in the Journal of the American Dietetic Association, Volume 111 Issue 2 (February 2011) published by Elsevier.

Effects of Diet On Childhood Asthma

Asthma is one of the world's most common chronic diseases, affecting as many as 300 million people. It is estimated that by 2025 there could be an additional 100 million people with the disease. This rapid increase in asthma is most likely due to changing environmental or lifestyle factors, and over the last 15 years, changing diet has emerged as a promising contributor.

Two studies published in the in the February 2011 issue of the Journal of the American Dietetic Association explore the possible relationship between nutrition and asthma. Researchers review the rationale for investigating associations between diet and asthma, discuss the potential for dietary intervention to complement conventional asthma treatment, and summarize the recent data suggesting that diet may influence the development of asthma.

Investigators from the University of Aberdeen, UK, review three dietary factors that have been hypothesized to explain the increase in asthma – a changing antioxidant intake, an increasing ratio of n-6 to n-3 polyunsaturated fatty acid (PUFA) consumption and changing vitamin D status.

Although there is insufficient clinical evidence for the use of nutritional supplements to complement conventional asthma treatments, the authors note that ongoing studies may change this picture. They also review a small number of studies of maternal diet during pregnancy that suggest that dietary modification during pregnancy might reduce the incidence of childhood asthma.

According to Graham Devereux, MD, PhD, "The generally weak observational and very limited intervention data suggest that whilst there are associations between diet and asthma, the nature of the associations (with PUFA, antioxidants, nutrients, food), the timing (antenatal, infancy, childhood, adulthood), and the therapeutic potential of the associations are far from clear."

He continues, "Future studies should consider the use of dietary intervention to increase the intake of nutrients highlighted by birth cohorts (vitamin E, PUFA, vitamin D, zinc) in order to capture the complexity of dietary nutrient intake. If shown to be efficacious, such a dietary intervention could be the basis for a low cost, safe public health intervention to rapidly reduce the prevalence of asthma in children and ultimately adults, with obvious beneficial consequences for the wellbeing of individuals and society as a whole. Until the results of ongoing and planned trials are available, the practical consequences of research linking diet with asthma are minimal, and based on the available evidence, people with asthma, pregnant women, parents, and children should not be advised to change or supplement their diet in order to treat or reduce the risk of developing asthma."

In a study published in the same issue a multi-institutional team of researchers in Greece examined associations between salty snack consumption and TV or video game viewing and asthma symptoms in young adolescents. While noting that although both factors have been implicated in asthma development, results have been conflicting. In their cross-sectional study of 700 children 10-12 years old, living in and around Athens, Greece, they found that there was a 4.8 times higher risk of having asthma symptoms when salty snacks were consumed more than 3 times per week. This association was even more prominent in children who watch TV or play video games more than 2 hours per day.

The authors also found that children who consumed a "Mediterranean diet" were less likely to have asthma symptoms, consistent with previous studies evaluating the association between the Mediterranean diet and asthma in children. The Mediterranean diet has a high content of vegetables, fresh fruits, cereals and olive oil, with a high intake of beta-carotene, vitamins C and E and various important protective substances like selenium, flavonoids and polyphenols with marked antioxidant activity.

Lead investigators Demosthenes Panagiotakos, PhD, Associate Professor, Department of Nutrition – Dietetics, Harokopio University, and Kostas Priftis, MD, PhD, Assistant Professor, School of Medicine, University of Athens, Greece, conclude, "Since the prevalence of asthma is quite high in industrialized populations, and has continued to increase during the past years, future interventions and public health messages should be focused on changing these behaviors from the early stages of life, by informing parents, guardians, teachers and any other person that could teach children a healthier lifestyle."

"Diet and asthma: Nutritional implications from prevention to treatment" by Keith Allan, MSc, and Graham Devereux, MD, PhD
"Salty-snack eating, television or video-game viewing, and asthma symptoms among 10- to 12-year- old children: The PANACEA study" by Fotini Arvaniti, RD, MSc, Kostas N. Priftis, MD, PhD, Anastasios Papadimitriou, MD, PhD, Panagiotis Yiallouros, MD, Maria Kapsokefalou, PhD, Michael B. Anthracopoulos, MD, PhD, and Demosthenes B. Panagiotakos, MD, PhD

Both appear in the Journal of the American Dietetic Association, Volume 111 Issue 2 (February 2011) published by Elsevier.

Norway Reduces Contaminants In Breast Milk

The levels of environmental contaminants in a mother's body decrease during breast-feeding.

After a year of lactation, the levels of a number of environmental contaminants in breast milk drop by 15 – 94 per cent, according to a recent study from the Norwegian Institute of Public Health. There has been little study into this topic previously.

Breast milk is nutritionally the best food for infants and contains all the substances a child needs for optimal growth and development. However, breast milk contains low but measurable concentrations of environmental contaminants, health-harming chemicals from industry and manufacturing products that are widely spread in the environment.

Environmental contaminants enter the body through food and are partly excreted in breast milk. The contaminant levels in breast milk reflect those in the mother's body and are therefore ideal for monitoring exposure levels.

Norwegian women are among the mothers in the world who breast-feed their children longest; about 80 per cent of babies receive breast milk when they are six months old, and it is not unusual to breast-feed until the child is more than eighteen months old. This makes it especially important to study which contaminants infants are exposed to through breast milk in Norway.

The Department of Analytical Chemistry at the Norwegian Institute of Public Health has recently investigated how the content of environmental contaminants in breast milk changes during the lactation period for each mother. Over 30 compounds of known contaminants such as brominated flame retardants, PCBs, and perfluorinated compounds were studied.

The study shows that the levels of almost all compounds in milk decrease with time, and are reduced by 15-94 per cent within a year of lactation. This must be considered when evaluating the benefits and possible risks of breast-feeding.

From previous studies we know that the levels of known environmental contaminants in breast milk and blood have fallen sharply in recent decades. The exceptions are brominated flame retardants and perfluorinated compounds, which first began to decline around the turn of the century.

The decline shows that measures taken by industry and by authorities to reduce the spread of these substances into the environment has meant that the population does not ingest as many environmental contaminants as before.

C. Thomsen, LS Haug, H. Stigum, M. Frøshaug, SL Broadwell, G. Becher. "Changes in concentrations of perfluorinated compounds, polybrominated diphenyl ethers and polychlorinated biphenyls in breast milk during twelve months of lactation." Environmental Science and Technology, 44 (2010) 9550-9556















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