Week Ending FRIDAY May 8, 2009---------------------------News Archive
Pregnancy Study Suggests Probiotics May Help Limit Obesity
One year after giving birth, women were less likely to have the most dangerous kind of obesity if they had been given probiotics from the first trimester of pregnancy, found new research that suggests manipulating the balance of bacteria in the gut may help fight obesity
Probiotics are bacteria that help maintain a healthy bacterial balance in the digestive tract by reducing the growth of harmful bacteria. They are part of the normal digestive system and play a role in controlling inflammation. Researchers have for many years been studying the potential of using probiotic supplementation to address a number of intestinal diseases. More recently, obesity researchers have started to investigate whether the balance of bacteria in the gut might play a role in making people fat and whether adjusting that balance could help.
"The results of our study, the first to demonstrate the impact of probiotics-supplemented dietary counselling on adiposity, were encouraging," said Kirsi Laitinen, a nutritionist and senior lecturer at the University of Turku in Finland who presented her findings on Thursday at the European Congress on Obesity. "The women who got the probiotics fared best. One year after childbirth, they had the lowest levels of central obesity as well as the lowest body fat percentage."
"Central obesity, where overall obesity is combined with a particularly fat belly, is considered especially unhealthy," Laitinen said. "We found it in 25% of the women who had received the probiotics along with dietary counselling, compared with 43% in the women who received diet advice alone."
In the study, 256 women were randomly divided into three groups during the first trimester of pregnancy. Two of the groups received dietary counselling consistent with what's recommended during pregnancy for healthy weight gain and optimal foetal development. They were also given food such as spreads and salad dressings with monounsaturated and polyunsaturated fatty acids, as well as fibre-enriched pasta and breakfast cereal to take home. One of those groups also received daily capsules of probiotics containing Lactobacillus and Bifidobacterium, which are the most commonly used probiotics. The other group received dummy capsules. A third group received dummy capsules and no dietary counselling. The capsules were continued until the women stopped exclusive breastfeeding, up to 6 months.
The researchers weighed the women at the start of the study. At the end of the study they weighed them again and measured their waist circumference and skin fold thickness. The results were adjusted for weight at the start of the study.
Central obesity - defined as a body mass index (BMI) of 30 or more or a waist circumference over 80 centimetres - was found in 25% of the women who had been given the probiotics as well as diet advice. That compared with 43% of the women who got dietary counselling alone and 40% of the women who got neither diet advice nor probiotics. The average body fat percentage in the probiotics group was 28%, compared with 29% in the diet advice only group and 30% in the third group.
Laitinen said further research is needed to confirm the potential role of probiotics in fighting obesity. One of the limitations of the study was that it did not control for the mothers' weight before pregnancy, which may influence how fat they later become.
She said she and her colleagues will continue to follow the women and their babies to see whether giving probiotics during pregnancy has any influence on health outcomes in the children.
"The advantage of studying pregnant women to investigate the potential link between probiotics and obesity is that it allows us to see the effects not only in the women, but also in their children," she said. "Particularly during pregnancy, the impacts of obesity can be immense, with the effects seen both in the mother and the child. Bacteria are passed from mother to child through the birth canal, as well as through breast milk and research indicates that early nutrition may influence the risk of obesity later in life. There is growing evidence that this approach might open a new angle on the fight against obesity, either through prevention or treatment."
New Drugs that Help DNA Unwind May Improve Memory
New research suggests that brain cells prepare to store new memories by first unwinding a little. Howard Hughes Medical Institute scientists have identified a protein that hampers learning and memory by keeping DNA inside neurons tightly coiled and unable to “relax,” according to a new study published in the May 7, 2009, issue of Nature
Compounds that block the activity of this newly identified protein appear to enhance memory in mice. The drugs boost memory by permitting DNA inside neurons to relax, thereby giving enzymes access to genes that must be turned on to enable learning. Some of those drugs are already being evaluated as potential anti-cancer therapies. They may also help treat memory loss associated with Alzheimer’s disease and other neurodegenerative diseases, said HHMI investigator Li-Huei Tsai at the Massachusetts Institute of Technology.
When people learn, connections between their brain cells - synapses - reshuffle and strengthen. Some ephemeral learning takes place within seconds or minutes of, say, looking up a phone number or navigating a new route to the store. That information is stored for a short time and usually disappears soon after the task is completed. To make memories stick, a certain cadre of genes must be activated in the brain. And to activate the genes needed for learning and memory, the DNA inside neurons and the protein spools around which it is wrapped - the histones - must unwind.
Histones are covered with chemical tags called acetyl groups, which mark specific segments of DNA that need to be relaxed so enzymes can gain access and turn those genes on. Previous studies suggested that adding or removing acetyl groups influences learning and memory by encouraging the growth of neurons. For instance, Tsai had previously shown that inhibiting histone deacetylase (HDAC) proteins, the enzymes that remove acetyl groups, improved memory in mice with gene mutations that cause a disease similar to Alzheimer’s disease. “All you need to do is increase histone acetylation and you can rescue the memory deficits,” says Tsai.
Tsai began to wonder whether inhibiting such enzymes could help slow memory loss in patients with neurodegenerative disorders. Her earlier studies were done with general HDAC inhibitors, which do not discriminate between the 11 subtly different HDAC proteins in the cells of humans and mice. To reduce the risk of side effects, Tsai wanted to target only those HDAC proteins relevant to learning and memory. But she first needed to design experiments to find them. “If you want to have a more selective drug, you need to have some idea of which of the 11 HDACSs are involved in learning and memory,” she says.
To home in on the particular HDACs involved, Tsai and her colleagues tested several different drugs that inhibit HDAC activity in mice. They found that only those compounds that targeted HDAC1 or HDAC2 improved memory in the mice. Earlier studies by a group of researchers led by HHMI investigator Eric Kandel showed that one of those drugs, SAHA, improved memory in a mouse model of Rubinstein-Taybi syndrome, a condition characterized by short stature and moderate to severe learning difficulties.
To dig deeper, they studied lines of mice that produced unusually large amounts of HDAC1 or HDAC2. Using several memory tests, they found that mice with extra HDAC1 learned just as well as normal animals, but mice with boosted HDAC2 were slow learners. That suggested that HDAC2, but not HDAC1, was responsible for impaired learning. Further studies confirmed that animals lacking HDAC2 performed better than normal in the memory tests.
The researchers then examined the brain tissue of animals with and without the HDAC2 protein. Neurons lacking HDAC2 formed a greater than normal number of synapses with neighboring cells, whereas cells with a greater quantity of HDAC2 made few synapses. Moreover, genes involved in learning and memory were more active in mice without HDAC2; those genes were quieter in animals with extra HDAC2.
Tsai’s team also found that SAHA enhanced learning in animals with boosted HDAC2. But SAHA had no effect on learning in animals that did not have HDAC2, suggesting that SAHA improves memory by blocking HDAC2. “This is a mechanism that can serve as a master switch that can coordinately regulate a whole set of genes involved in learning and memory,” says Tsai.
Tsai acknowledges that testing HDAC2-blockers on humans is not likely to happen anytime soon. “Now that we’ve identified a major target, the next question is whether we or someone else can come up with very selective small molecules,” says Tsai. If researchers can zero in on this kind of molecule, she is optimistic that they'll help people with a variety of learning-related problems. “I suspect they’ll be beneficial in Alzheimer’s disease, other types of dementia, and mental retardation,” she says.
She also wants to investigate whether drugs that encourage DNA to relax could help other conditions. For instance, Tsai wants to test HDAC2 blockers in mouse models of autism. The social and communication problems typical of autism seem to result from faulty wiring in the brain, and making learning easier could help the brain rewire correctly. Encouraging acetylation could even help schizophrenia, which also results from wiring problems. Although cancer researchers have explored HDAC inhibitors for many years, Tsai says they are new to the field of neuroscience. “People are very excited,” she says. Unraveling the puzzle of how unwinding DNA helps learning and memory could mean new hope for people with a variety of learning disorders.
Babies Brainier Than Many Imagine
A new study from Northwestern University shows what many mothers already know: their babies are a lot smarter than others may realize
Though only five months old, the study’s cuties indicated through their curious stares that they could differentiate water in a glass from solid blue material that looked very much like water in a similar glass.
The finding that infants can distinguish between solids and liquids at such an early age builds upon a growing body of research that strongly suggests that babies are not blank slates who primarily depend on others for acquiring knowledge. That’s a common assumption of researchers in the not too distant past.
“Rather, our research shows that babies are amazing little experimenters with innate knowledge,” Susan Hespos said. “They’re collecting data all the time.”
Hespos, an assistant professor of psychology in the Weinberg College of Arts and Sciences at Northwestern, is lead author of the study, which will appear in the May 2009 issue of Psychological Science, a journal of the Association for Psychological Science.
In a test with one group of infants in the study, a researcher tilted a glass filled with blue water back and forth to emphasize the physical characteristics of the substance inside. Another group of babies looked at a glass filled with a blue solid resembling water, which also was moved back and forth to demonstrate its physical properties.
Next all the infants were presented with test trials that alternated between the liquid or solid being transferred between two glasses.
According to the well-established looking-time test, babies, like adults, look significantly longer at something that is new, unexpected or unpredictable.
The infants who in their first trials observed the blue water in the glass looked significantly longer at the blue solid, compared to the liquid test trials. The longer stares indicated the babies were having an “Aha!” moment, noticing the solid substance’s difference from the liquid. The infants who in their first trials observed the blue solid in the glass showed the opposite pattern. They looked longer at the liquid, compared to the solid test trials.
“As capricious as it may sound, how long a baby looks at something is a strong indicator of what they know,” Hespos said. “They are looking longer because they detect a change and want to know what is going on.”
The five-month-old infants were able to discriminate a solid from a similar-looking liquid based on movement cues, or on how the substances poured or tumbled out of upended glasses.
In a second experiment, the babies also first saw either liquid or a similar-looking solid in a glass that was tipped back and forth. This time, both groups of infants next witnessed test trials in which a cylindrical pipe was lowered into either the liquid-filled glass or the solid-containing glass.
The outcomes were similar to those of the previous experiment. Infants who first observed the glass with the liquid looked longer in the subsequent test when the pipe was lowered onto the solid. Likewise, the infants who looked at the solid in their first trials stared longer when later the pipe was lowered into the liquid.
The motion cues led to distinct expectations about whether an object would pass through or remain on top of the liquid or solid, the Northwestern researchers noted.
“Together these experiments provide the earliest evidence that infants have expectations about the physical properties of liquids,” the researchers concluded in the Psychological Science study.
Hespos primarily is interested in how the brain works, and, to that end, her research on babies’ brand new, relatively uncomplicated brains provides invaluable insights. She also is doing optical imaging of babies’ brains, in which the biological measures confirm behavioral findings.
“Our research on babies strongly suggests that right from the beginning babies are active learners,” Hespos said. “It shows that we perceive the world in pretty much the same way from infancy throughout life, making fine adjustments along the way.”
In addition to Hespos, the co-investigators of the Psychological Science study, “Five-Month-Old Infants Have Different Expectations for Solids and Liquids,” are Alissa Ferry, a graduate student, and Lance Rips, professor of psychology, at Northwestern.
Glucose to Glycerol Conversion in Yeast Nets Anti-Aging Effect
Cell biologists have found a more filling substitute for caloric restriction in extending the life span of simple organisms
In a study published May 8 in the open-access journal PLoS Genetics, researchers from the University of Southern California Andrus Gerontology Center show that yeast cells maintained on a glycerol diet live twice as long as normal - as long as yeast cells on a severe caloric-restriction diet. They are also more resistant to cell damage.
Many studies have shown that caloric restriction can extend the life span of a variety of laboratory animals. Caloric restriction is also known to cause major improvements in a number of markers for cardiovascular diseases in humans. This study is the first to propose that "dietary substitution" can replace "dietary restriction" in a living species.
"If you add glycerol, or restrict caloric intake, you obtain the same effect," said senior author Valter Longo. "It's as good as calorie restriction, yet cells can take it up and utilize it to generate energy or for the synthesis of cellular components."
Longo and colleagues Min Wei and Paola Fabrizio introduced a glycerol diet after discovering that genetically engineered long-lived yeast cells that survive up to 5-fold longer than normal have increased levels of the genes that produce glycerol. In fact, they convert virtually all the glucose and ethanol into glycerol. Notably, these cells have a reduced activity in the TOR1/SCH9 pathway, which is also believed to extend life span in organisms ranging from worms to mice.
When the researchers blocked the genes that produce glycerol, the cells lost most of their life span advantage. However, Longo and colleagues believe that the "glucose to glycerol" switch represents only a component of the protective systems required for the extended survival. The current study indicates that glycerol biosynthesis is an important process in the metabolic switch that allows this simple organism to activate its protective systems and live longer.
"This is a fundamental observation in a very simple system," Longo said, "that at least introduces the possibility that you don't have to be calorie-restricted to achieve some of the remarkable protective effects of the hypocaloric diet observed in many organisms, including humans. It may be sufficient to substitute the carbon source and possibly other macronutrients with nutrients that do not promote the "pro-aging" changes induced by sugars."
New Tag Could Lead to More Detailed Structural Studies of Mammalian Proteins
To say our genes are resourceful is a gross understatement. Through ingenious combinations of a paltry 20 amino acids, the basic building blocks of life, genes engineer all of the tissues and organs that are the marvel of our working bodies
Now scientists are adding to the parsimonious genetic repertoire to good effect: With careful targeting using genetic engineering, so-called unnatural amino acids can effectively tag proteins that scientists want to study, because, like a lighthouse beacon in a soupy fog, they stand out from the ones the body already produces.
In work published last month in Nature Chemical Biology, new research at The Rockefeller University reveals a method that could theoretically be adapted to place a fluorescent probe at any position in any protein in a mammalian cell. The new technology could enable single-molecule fluorescent studies in live cells, says Thomas P. Sakmar, head of the Laboratory of Molecular Biology and Biochemistry. “It’s a new tool to study membrane protein dynamics that should be of general use. We’re building technologies to move the science forward.”
Sakmar, research associate Thomas Huber and postdoctoral associate Shixin Ye, working with a colleague in Germany, Reiner Vogel, combined a variety of genetic engineering techniques to introduce an amino acid, azidoF, a relative of phenylalanine, into three points on rhodopsin, the light-sensitive cell receptor that is crucial to vision. The three-nitrogen-atom azido is an especially good probe for three reasons: In contrast to other tags, azido does not exist naturally in mammals, which makes it easier to “see;” it is small enough to not interfere with a protein’s normal functioning; and it has chemical properties that make it a good handle on which to hang other molecules, like fluorescent probes, says Huber.
Similar approaches have been successfully used in bacteria, but this is the first time it has been applied to mammalian cells with such specificity and efficiency, the scientists say. Extensive genetic screening allowed the team to target the azido probes efficiently. They then confirmed the presence of azido with fourier transform infrared (FTIR) difference spectroscopy, which measures stretching frequencies of the atoms in the amino acids that make up a protein. Because azido has a unique vibration frequency that is sensitive to its surroundings, the team was able to use the spectroscopic data to confirm structural changes rhodopsin undergoes in light versus dark. “What you want is a probe that doesn’t perturb the protein and one that can tell you something about its structure,” Sakmar says. “That’s what we have here, and in principle, you can put it at any position of any protein of interest in a mammalian cell, which will allow us to study all of the interesting proteins that can’t be expressed in bacteria.”
THURSDAY May 7, 2009---------------------------News Archive
Treatment For Extreme Nausea & Vomiting During Pregnancy
Nausea and vomiting are telltale indicators of pregnancy, affecting more than 80 percent of future mothers. For a few moms-to-be, symptoms can become so severe that hospitalization is required.
Yet a new medication protocol, introduced by the Sainte-Justine University Hospital Center, appears effective in improving symptoms more quickly and provides a safer option than those previously available. The findings, which are good news for moms and babies, are published in a recent edition of the European Journal of Obstetrics and Gynecology and Reproductive Biology.
“In 2002, we had to quickly change the medication protocol to treat hyperemisis gravidarum (HG), or severe nausea and vomiting of pregnancy, due to a FDA and Health Canada warnings,” says senior researcher Anick Bérard, a professor at the Université de Montréal's Faculty of Pharmacy and director of the Research Unit on Medications and Pregnancy of the Sainte-Justine University Hospital Center.
“The warning found that a previously used anti-vomiting medication might cause adverse cardiovascular effects in mothers. We had to quickly choose another treatment, which was safer. The current study looks back at the data to evaluate the effectiveness of this treatment.”
Dr. Bérard and her team, which included researchers from the Université de Bourgogne, evaluated 229 pregnant women who were admitted to hospital and treated for HG. The scientists compared use of the standard drug droperidol versus the administration of a newer medication called metoclopramide.
They found that metoclopramide worked faster to quell symptoms of nausea and vomiting than droperidol. Importantly, they found no evidence that either of these medications increased the birth defect rate compared to women who received no medication. As expected, metoclopramide was not associated with other serious side effects.
“This study validates our protocol,” says Dr. Bérard. “Clinical trials are not conducted on pregnant women, so we had to rely on data from prospective and retrospective studies in this case. We anticipate that other institutions will now be comfortable adopting this new treatment regime.
About hyperemis gravidarum
Hyperemis gravidarum, or severe nausea and vomiting of pregnancy, affects about one percent of pregnant women. If left untreated, it can result in severe weight loss, dehydration, or death. Symptoms to look out for include severe vomiting and nausea; incapacity to keep food down for two to three days; lack of energy.
According to Dr. Bérard, women should not wait too long before seeking medical help. “The longer the symptoms continue, the longer the hospital stay,” she says, adding most women with HG leave the hospital within three days and many are required to take medication throughout their pregnancy.
Infants' Immunization Pain Varies With Which Vaccine Is First
Infants who receive the pneumococcal conjugate vaccine (PCV) following the combination vaccine for diphtheria, polio, tetanus, pertussis and Haemophilus influenzae type b (DPTaP-Hib vaccine) appear to experience less pain than those who are immunized in the opposite order, according to a report in the May issue of Archives of Pediatrics & Adolescent Medicine, a theme issue on vaccines
Injections are the most painful common medical procedure conducted in childhood, according to background information in the article. "Multiple injections are routinely administered during a single visit to a physician," the authors write. "Because some vaccines cause more pain than others, the order in which they are given may affect the overall pain experience." In a recent study of U.S. pediatricians, more than 90 percent reported at least one parent in their practice had refused to have a child vaccinated in the previous year, most commonly due to the pain caused by multiple vaccines. Therefore, reducing the pain associated with vaccines could increase immunization rates and prevent a resurgence of infectious diseases.
Moshe Ipp, M.B.B.Ch., of The Hospital for Sick Children, Toronto, Ontario, Canada, and colleagues studied 120 healthy infants age 2 to 6 months undergoing routine immunization at an outpatient pediatric clinic in 2006 or 2007. Sixty infants received the PCV before the DPTaP-Hib vaccine, while 60 received the DPTaP-Hib vaccine first. The procedure was videotaped and pain was assessed on a scale that considered the infant's facial expression, crying and body movements after vaccination. Parents were also asked to rate their children's pain levels on a scale of zero to 10.
"Infant pain response during routine intramuscular vaccine injection was affected by the order of administration of the vaccine," the authors write. "Infants given the less painful DPTaP-Hib vaccine first followed by the more painful PCV experienced less pain overall when compared with those given the vaccines in the reverse order. In addition, pain increased from the first to the second injection, regardless of the order of vaccine injection."
These data suggest that when two immunizations are given, the least painful vaccine should be administered first, the authors note. Giving the more painful injection first may focus the infant's attention on the procedure and activate pain processing centers in the brain, resulting in a more intense pain signal in response to any shots given afterward.
"Steps to minimize vaccine-related pain reduces the pain experienced by the child and improves the immunization experience of parents and health care workers," the authors conclude. "Varying the order of vaccine administration to reduce pain is a strategy that is simple and effective, cost-free and easily incorporated into clinical practice. In considering methods of reducing pain with vaccination, vaccine manufacturers must play a more integral role in attempting to produce vaccine formulations that are less painful."
(Arch Pediatr Adoles Med. 2009;163469-472. Available to the media pre-embargo at www.jamamedia.org).
Neutralizing Tumor Growth in Embryonic Stem Cell Therapy
TResearchers at the Hebrew University of Jerusalem have discovered a method to potentially eliminate the tumor-risk factor in utilizing human embryonic stem cells. Their work paves the way for further progress in the promising field of stem cell therapy
Human embryonic stem cells are theoretically capable of differentiation to all cells of the mature human body (and are hence defined as "pluripotent"). This ability, along with the ability to remain undifferentiated indefinitely in culture, make regenerative medicine using human embryonic stem cells a potentially unprecedented tool for the treatment of various diseases, including diabetes, Parkinson's disease and heart failure.
A major drawback to the use of stem cells, however, remains the demonstrated tendency of such cells to grow into a specific kind of tumor, called teratoma, when they are implanted in laboratory experiments into mice. It is assumed that this tumorigenic feature will be manifested upon transplantation to human patients as well. The development of tumors from embryonic stem cells is especially puzzling given that these cells start out as completely normal cells.
A team of researchers at the Stem Cell Unit in the Department of Genetics at the Silberman Institute of Life Sciences at the Hebrew University has been working on various approaches to deal with this problem.
In their latest project, the researchers analyzed the genetic basis of tumor formation from human embryonic stem cells and identified a key gene that is involved in this unique tumorigenicity. This gene, called survivin, is expressed in most cancers and in early stage embryos, but it is almost completely absent from mature normal tissues.
The survivin gene is especially highly expressed in undifferentiated human embryonic stem cells and in their derived tumors. By neutralizing the activity of survivin in the undifferentiated cells as well as in the tumors, the researchers were able to initiate programmed cell death (apoptosis) in those cells.
This inhibition of this gene just before or after transplantation of the cells could minimize the chances of tumor formation, but the researchers caution that a combination of strategies may be needed to address the major safety concerns regarding tumor formation by human embryonic stem cells.
Youthful Infertility Balanced by Late-Blooming Ovaries
Young women with fertility problems caused by polycystic ovary syndrome may have reason to take heart. Over a lifetime their chances of having children appear just as good as other women's, perhaps because egg production increases as they grow older
About 7 per cent of reproductive-age women have PCOS, which features irregular periods, high levels of male hormones and greater numbers of developing follicles, or cysts, on the surface of their ovaries. In a normal ovary, a few follicles appear each month, one or two of which mature and release an egg; the rest die off. Women with PCOS ovulate less often because their extra follicles interfere with normal hormonal activity and stop follicles maturing past a certain stage. This is how PCOS lowers fertility.
Now it looks like that is not the end of the story. Miriam Hudecova and colleagues at Uppsala University in Sweden interviewed 91 women who were 35 or older and had been diagnosed with PCOS when younger. They found the women had undergone just as many pregnancies and borne as many babies, on average, as PCOS-free women of the same age. Some of the women with PCOS had been treated for infertility, but more than two-thirds had become pregnant without such help.
Hudecova also examined most of the women and found that the ovaries of the older women with PCOS showed signs of being more active, with better hormone levels and more eggs available, than those of control women of the same age (Human Reproduction, DOI: 10.1093/humrep/den482). "As they get older, the chance of getting pregnant may actually be higher," says Hudecova.
As women with polycystic ovarian syndrome get older the chance of getting pregnant may be higher
There may be an explanation for this. As women age, fewer follicles are produced each month, and in most this reduces fertility. With PCOS, however, fewer follicles may have the opposite effect: it may stop the hormonal interference and cause follicles to release eggs normally.
The hypothesis is backed up by other studies that have shown that the menstrual cycles of women with PCOS tend to become more regular as they age (Human Reproduction, vol 15, p 24). Marcelle Cedars, a reproductive endocrinologist at the University of California, San Francisco, points out that it also chimes with a recent finding that hormone treatments can coax immature follicles to produce eggs.
"They might hit their reproductive peak a little bit later than other women," says Richard Legro, a gynaecologist at Penn State Milton S. Hershey Medical Center in Hershey, Pennsylvania. "When we see more data to that effect we'll revise what we tell them."
Genes that Drive Breast Cancer’s Spread to the Brain
Researchers have uncovered the first genetic clues that suggest how invasive breast cancer cells pry their way into the tightly protected interior of the brain, where they can grow into new and lethal tumors
Howard Hughes Medical Institute researcher Joan Massagué and colleagues at Memorial Sloan-Kettering Cancer Center have identified three genes that work together to fuel the spread of breast cancer to the brain. Their studies indicate that those renegade cancer cells use some of the same strategies that other breast cancer cells rely on to invade the lungs but also need more specialized molecular tools to infiltrate the brain. The study is reported in an advance online publication on May 6, 2009, in the journal Nature.
“This is the first paper of its kind that opens up a window into what it takes for cancer cells to attack the brain,” Massagué said. “It shows that is possible to start deconstructing this problem. Until now we knew almost nothing about it.”
Metastasis occurs when cells from a primary tumor break off and invade another organ. It is the deadliest transformation that a cancer can undergo, and is the cause of 90 percent of all cancer deaths. Metastases to the brain usually from breast or lung cancers -- can be particularly devastating. Even with treatment, patients usually survive only six to 10 months after diagnosis. Despite its clinical impact, Massagué says, metastasis is poorly understood.
“Metastasis is what we fight with post-operative therapies, such as chemotherapy and radiation therapy, yet very little is known about the mechanisms that drive it,” he said. “That inspired me and others to isolate metastatic cells from patients, and ask what these cells have - above and beyond just being tumor cells - that allows them to infiltrate and survive in distant organs.”
Some cancerous cells, such as lung cancer cells, seem well equipped to invade multiple tissues soon after a tumor develops. But for breast cancer cells, metastasis takes time. When breast cancer spreads to distant organs, new tumors may not appear until years or even decades -- after the original tumor has been removed from the breast. Massagué says this indicates that breast cancer cells do not become fully metastatic until they accumulate the genetic alterations that allow them to infiltrate new tissues and survive in that environment. “If metastasis occurs, the primary tumor must have released cells that were competent to be released and to hide away,” he said. “However, when they were released, they evidently did not yet have everything that it takes to grow in the bones, or the lungs, or the brain. It may take years to acquire that capacity.”
Breast cancer metastases to the brain develop even more slowly than metastases to other organs. Massagué says this suggests that cells need a particularly specialized set of tools to enter and grow in the brain. This should not come as a surprise, he says, because the brain is well protected by a tightly woven, double-layered network of cells called the blood-brain barrier.
Massagué’s lab had already demonstrated that metastatic breast cancer cells acquire certain genetic characteristics that permit them to invade and survive in different organs, such as bone or lung. He likens cancer cells’ adaptation to these tissues to the evolution of different species of finches in the Galápagos Islands. Like the birds, whose beaks are shaped to best exploit the food source on individual islands, metastatic breast cancer cells acquire the specific properties they need to survive in a particular environment, Massagué says.
To find out which genetic adaptations are associated with brain metastases, the group implanted tumor cells from a patient with advanced breast cancer into mice. They later isolated cells that generated tumors in the brains of the mice. The scientists measured gene activity in the metastatic cells and found 243 genes whose expression appeared abnormal. They next measured the activity of those 243 genes in clinical tumor samples and narrowed their focus to 17 genes associated with brain metastases. “Cells that have these genes activated are better ready to invade the brain of a mouse,” Massagué explained. “We also found that patients whose primary tumors have these genes activated have a higher rate of brain metastases.”
“These results show that for entry into the brain tissue, breast cancer cells use some of the genes that they use to penetrate into the lung, but then some more. They are also using genes that are more specialized for the blood-brain barrier,” he said.
The next step, he says, is to see if they can determine the biological roles of these genes in cancer cells. His team has already done these kinds of studies for three of the candidate genes identified in their study. When they reduced the activity of any of the three genes in cells grown in the laboratory, those cells were not as effective at infiltrating a cellular model of the blood-brain barrier. Two of the genes, COX2 and HBEGF, also help breast cancer invade the lungs. The third gene, ST6GALNAC5, appears to specifically enable metastasis to the brain. ST6GALNAC produces a protein that normally modifies the surface of cells in the brain. The cancer cells appear to use it to insinuate themselves into the brain “like a wolf in sheep’s clothing,” Massagué says.
Further characterization of the other genes Massagué’s group identified could provide new ideas for cancer therapy, or new markers to predict which cancers are most likely to spread to the brain, Massagué says. But importantly, their findings are already providing a new glimpse into the mechanisms that control metastasis to the brain.
WEDNESDAY May 6, 2009---------------------------News Archive
Safety of Midwife-Attended Home Births Questioned
The risk of newborns dying is higher when delivery is at home attended by a certified nurse midwife than when babies are born in hospitals with a certified nurse midwife in attendance, according to data released here at the meeting of the Pediatric Academic Societies
"Currently, the only Western country with a substantial number of home births is the Netherlands, where 30 percent of births are in the home," Dr. Michael H. Malloy pointed out. "In the U.S., less than 1 percent of births are in the home, and the American College of Obstetrics and Gynecology 'does not support programs that advocate for, or individuals who provide, home births'."
Malloy, at the University of Texas Medical Branch in Galveston, compared outcomes in newborn babies by type of delivery attendant and by place of delivery in the U.S. over a recent 5-year period.
His analysis was limited to term babies delivered in the normal way. "I decided to restrict the analysis to this low-risk population because they would be the best candidates for home delivery," Malloy explained.
During the study period, there were almost 12 million such births. The great majority, 88.5 percent, were in hospitals with a physician attending. The next most common arrangement, 10.6 percent, was hospital delivery with a certified nurse midwife attending.
Far behind in popularity were hospital births with other nurse midwives (0.2 percent) births; home births with a certified nurse midwife on hand (0.1 percent); home delivery with other nurse midwives (0.4 percent); and birth-center delivery with a certified nurse midwife attending (0.2 percent).
While there were only 14 newborn deaths among babies delivered at home by a certified nurse midwife, this rate was more than two-fold higher than for hospital deliveries attended by a certified nurse midwife.
Furthermore, the rate was four-fold higher for home deliveries by other midwives.
Overall, the results demonstrate that the safest setting for a delivery is in hospital attended by a certified nurse midwife. Women who decide to deliver in the home "need to recognize the greater risk associated with that choice," Malloy said.
As for why in-hospital deliveries by certified nurse midwives had a lower risk of mortality in his study than in-hospital physician deliveries, Malloy said he assumes it's because physicians are delivering babies at higher risk.
Does New Swine Flu Virus Kill by Causing 'Cytokine storm'?
The swine flu outbreak that began in Mexico and continues to spread around the globe may be particularly dangerous for young, otherwise healthy adults because it contains genetic components of the H5N1 avian influenza virus, which can induce a "cytokine storm," in which a patient's hyper-activated immune system causes potentially fatal damage to the lungs
Research studies and review articles exploring the regulation of cytokine responses in the lung and how infection-related dysregulation can cause a cytokine storm have been published in Viral Immunology, a peer-reviewed journal published by Mary Ann Liebert, Inc. (www.liebertpub.com/vim).
A cytokine storm occurs when the body's immune system over-reacts to an intruder, such as a virus, by producing high levels of cytokines, which are signaling chemicals that help mobilize immune cells capable of removing infectious agents from the body. When too many cytokines are produced, they can stimulate an inflammatory response in which the accumulation of immune cells and fluid at the site of infection may prevent affected tissues and organs such as the lungs from functioning properly and may even cause death.
H5N1 avian influenza virusparts of which are present in the Mexican H1N1 swine flu virus causing the current outbreaktend to cause an unusually high proportion of deaths among healthy young adults with well-functioning immune systems who become infected, most likely due to this cytokine storm phenomenon. The Spanish influenza pandemic of 1918, for example, was particularly deadly for young healthy adults.
David L. Woodland, PhD, Editor-in Chief of Viral Immunology, and President and Director of the Trudeau Institute, Inc. (Saranac Lake, NY), emphasizes that much is still not known about the current influenza outbreak and the human/avian combination virus causing it. "We do not know how long ago this virus emerged, how deadly it is, whether it has pandemic potential, how the severity of infection relates to patient age, and why some infected patients diewhether a cytokine storm is responsible for these deaths," says Woodland.
What we do know, he adds, is that some H1N1 viruses have pandemic potential and that historical evidence supports the possibility that young healthy adults may be especially susceptible to more severe infection and poor outcomes due to the ability of a strong immune system to initiate a cytokine storm.
Gene May 'Bypass' Disease-Linked Mitochondrial Defects
By lending them a gene normally reserved for other classes of animals, researchers have shown they can rescue flies from their Parkinson's-like symptoms, including movement defects and excess free radicals produced in power-generating cellular components called mitochondria
The gene swap also protects healthy flies' mitochondria, and to a large extent the flies themselves, from the damaging effects of cyanide and other toxins, the team reports in the May issue of Cell Metabolism, a Cell Press publication.
The key gene (single-subunit alternative oxidase or AOX) in essence acts as a bypass for blockages in the so-called oxidative phosphorylation (OXPHOS) cytochrome chain in mitochondria. Howard Jacobs, who led the study at the University of Tampere in Finland, likens that chain to a series of waterfalls in a hydroelectric power station. Only, in the case of mitochondria, it is electrons that flow to release energy that is captured in molecular form.
"This is the first whole organism test for the idea that you can take a gene that encodes a single polypeptide and bypass OXPHOS where it is blocked," said Jacobs, emphasizing that OXPHOS includes dozens of components and hundreds of proteins. "You may lose power from one [molecular] 'turbine,' but power from the others can be restored. With a single peptide, you can bypass two-thirds of the system. That's the beauty of the idea."
Defects in mitochondrial OXPHOS are associated with diverse and mostly intractable human disorders, the researchers said. Therefore, there's a chance that the strategy might also prove beneficial in mammals, including humans, which like arthropods have also lost the AOX gene over the course of evolution. (Arthropods are represented by insects, spiders, and crabs.)
On the other hand, most plants, animals, and fungi do possess an alternative mitochondrial respiratory chain, which can bypass the OXPHOS system under specific physiological conditions. In plants, AOX is thought to be essential for maintaining energy balance under daylight conditions. In fungi, AOX has been implicated in the control of longevity and resistance to oxidative stress. In many animals, too, including annelid worms, mollusks, and urochordatesan underwater filter-feeding sister group to vertebrates AOX is present and is believed to provide resistance to oxidative stress.
In a previous study, Jacobs and his colleagues tested the idea that AOX might bypass the consequences of OXPHOS inhibition in human cells. They introduced the gene into human cells by inserting DNA taken from the urochordate Ciona intestinalis. Those studies found that the protein encoded by the Ciona AOX gene made its way to mitochondria, where it conferred cyanide-resistant respiration and protected against metabolic acidosis, oxidative stress, and cell death when cells were treated with OXPHOS inhibitors such as antimycin or cyanide.
Now, they've shown that the same holds true in a living animal. Importantly, ubiquitous Ciona AOX activity had no apparent ill effects for the flies. Quite the contrary, mitochondria taken from AOX-expressing flies showed significant resistance to cyanide, and the flies partially resisted both cyanide and antimycin. AOX also rescued the movement defect and excess production of reactive oxygen species by mitochondria in flies with a mutant version of a gene known as dj-1b, which is the fly equivalent to the human Parkinson's disease gene DJ1.
The findings led the researchers to conclude that "AOX appears to offer promise as a wide-spectrum therapeutic tool in OXPHOS disorders." The next step is to test whether the findings in flies will also hold true in mammals, Jacobs said. His hope is that the AOX gene might someday be delivered to humans via a suitable gene therapy, although he admits that goal assumes many things will fall into place.
"OXPHOS dysfunction is not just a problem in some rare genetic disorders or in degenerative diseases," he said. It's an issue in a very large number of pathologiesand a major cause of tissue damage after heart attack and stroke.
So, why don't we have this gene in the first place, one might ask?
Jacobs said he isn't entirely sure, but he suspects the gene renders energy production by mitochondria less efficient under normal circumstances, which isn't ideal for running fast to catch prey or avoid predators. But in today's world, he said, as people live longer and longer, it might be better to avoid the consequences of a stroke than to run a marathon.
Snippet of RNA Helps Make Individuals Remarkably Alike
"No two people are alike." Yet when we consider the thousands of genes with frequent differences in genetic composition among different people, it is remarkable how much alike we are.
Uniformity, or singleness of form, is not unique to humans but a general property of life. Biologists have long pondered how this feature is produced in the face of such great variation in genetics as well as environmental conditions.
Northwestern University researchers now have identified a type of molecule that plays a specific role in maintaining uniformity: a little snippet of RNA called a microRNA. They found that a microRNA called miR-7 is critical to the robustness of the molecular network that helps regulate uniformity.
The findings are published online by the journal Cell and also are featured in a Cell podcast: http://www.cell.com/. This knowledge could lead to a better understanding of the workings of cancer cells, which do not act in controllable, uniform ways.
The Northwestern research builds on an idea that originated in the 1940's: Molecules within cells of the body work together in networks, each molecule interconnected with others.
"When something is changed, say the genetic sequence of a molecule or the temperature of the organism, the network responds to compensate for the change and keep things intact," said Richard W. Carthew, Owen L. Coon Professor of Molecular Biology in the Weinberg College of Arts and Sciences at Northwestern. Carthew led the research. "This design is similar to the principle that engineers use to design safety features into products."
There are hundreds of different types of microRNAs in animals. Their function is to dampen or shut down the production of proteins in the body. The Carthew group found one of these microRNAs, miR-7, dampens production of proteins that work in the same networks as miR-7.
In a study of Drosophila, when the researchers eliminated miR-7, the networks remained intact but only under uniform environmental conditions. When the researchers perturbed the environment by modulating the temperature, the networks failed to keep things intact, and animals suffered from developmental defects. If the microRNA was present, however, the networks resisted the temperature fluctuation, and animals were normal and healthy.
MicroRNAs, found in all plants and animals, may have evolved as tiny buffers within multicellular organisms to allow the remarkable unity of form in a constantly changing environment.
"This idea has health implications as well," said Carthew. "Cancer cells are notoriously heterogeneous and do not act in controllable ways. Interestingly, microRNAs are among the most frequently mutated targets in cancers, leading some to speculate that their absence is linked to cancer's heterogeneous behavior."
Prostate Cancer A Single Rogue Cell?
One cell…one initial set of genetic changes that’s all it takes to begin a series of events that lead to metastatic cancer. Now, Johns Hopkins experts have tracked how the cancer process began in 33 men with prostate cancer who died of the disease. Culling information from autopsies, their study points to a set of genetic defects in a single cell that are different for each person’s cancer
“These were not your average autopsies,” says pathologist G. Steven Bova, M.D., assistant professor of pathology at Johns Hopkins. “We dissected every bit of tumor in the primary and metastatic sites and recorded exactly where each piece of tissue came from, analyzed it, and databased the findings.” In total, Bova estimates that he and his colleagues examined 150,000 slides and 30,000 blocks of tissue.
The study took 14 years to complete, and part of the challenge was in finding men living with prostate cancer who would agree to have their body autopsied immediately after they died. “Many of the men were motivated to join the study in hopes of leaving some legacy that might lead to cures for this cancer,” says Bova, who holds secondary appointments in the departments of pathology, genetic medicine, health sciences informatics, oncology, and urology at Johns Hopkins.
“Much is unclear and appears chaotic about how cancer spreads, but analyzing genetic markers allows us to trace its roots backward, somewhat like ancestry,” says Bova. Findings from the study were published online April 12 in Nature Medicine.
Clues to finding the genetic culprit for cancer spread are hidden in the changes that occur in a cell’s DNA, the alphabetical code made up of chemicals that guide the everyday life of a cell. Cancers are caused by alterations in DNA code that occur in a variety of ways: making errors in the nucleotide alphabet through mutations, changing the balance of chemicals attached to the on/off switches of genes, and altering the number of gene copies in a cell. When the number of gene copies is disrupted in a cell beyond the customary two copies inherited from each parent, a gene’s function can be damaged. This process, called copy number variation, can set the stage for unchecked cell growth and spread, a hallmark of cancer.
For this study, the investigators scanned genes spanning the whole genome in the autopsy samples looking for areas of copy number variation. They did this by attaching the DNA to special silicon chips, and then photographed them with a computer program that produces a report with varying colors representing the amount of DNA in the sample.
The scientists compared the patterns of gains and losses in tissue samples from multiple metastatic sites in 29 of the men. Unique copy number changes were identified, as well as ones that were shared between multiple metastatic sites in each man and with other men in the study.
For example, in several men, the investigators found cells in different areas of metastasis that contained missing chunks of DNA in one common region of the genome. The exact location of the DNA loss was different for each man, but all occurred in the same DNA region. “Each person has a different set of defects that contributes to the cancer,” explains Bova.
Metastatic sites develop from cancer cells that break off of the primary cancer. If cancer cells at more than one metastatic site carry a common set of nonrandom genetic defects, it is likely that these cells are derived from a single parent cell, says Bova. Tissue samples from 14 of the 33 men were studied at the highest available resolution, and all showed common genetic patterns across metastatic sites, suggesting a single cell source for their cancer.
Bova says that future studies will help determine whether the common set of changes shared by the various metastatic sites arose in a single “big bang” in the prostate or if the changes accumulated more slowly over time.
Bova says that such autopsy studies of metastatic cancer can provide a molecular catalogue of cellular defects specific to individuals and general groups. The findings, he says, could help narrow the focus of research and guide personalized cancer therapy.
TUESDAY May 5, 2009---------------------------News Archive
Evidence Grows That Maternal Immune Response During Pregnancy A Key Factor In Some Autism
New studies in pregnant mice using antibodies against fetal brains made by the mothers of autistic children show that immune cells can cross the placenta and trigger neurobehavioral changes similar to autism in the mouse pups
A report on the research from investigators at the Johns Hopkins Children’s Center published online in the Journal of Neuroimmunology expands on a 2008 report from the same team showing that mothers of autistic children tested positive for fetal brain antibodies. Antibodies are proteins the body naturally makes to attack foreign tissues, viruses or bacteria. Because a growing fetus is not “rejected” by the mother’s immune system even though some of its DNA is “foreign” (from the father), scientists have long suspected that some combination of maternal and fetal biological protection is at work. The new research from Hopkins, however, suggests that the protective system is not perfect and that antibodies are not only made but are re-circulated back to the fetus through the placenta, possibly triggering inflammation in the brain and leading to a cascade of neurological changes resulting in neurodevelopmental disorders, such as autism.
Despite this new evidence, the researchers warn against over-interpreting the results, saying prenatal exposure to maternal antibodies is likely only one of several factors implicated in autism.
“Autism is a complex disorder and it would be naïve to assume there’s a single mechanism that can cause it,” says Harvey Singer, M.D., director of pediatric neurology at Hopkins Children’s. “It’s most likely the cumulative result of several factors, including genes, metabolism and environment. We believe we have identified one of these factors.”
For the new study, Singer and colleagues injected antibodies from mothers of autistic children into pregnant mice and used several standard neurobehavioral tests to identify neurobehavioral changes in the pups. As control groups, they used offspring of mice injected with antibodies from mothers of nonautistic children and the offspring of mice who received no injections.
“Comparing mice to humans is tricky, and we should be cautious anytime we do so, but our findings strongly suggest that the behaviors we observed in the offspring of mice injected with fetal brain antibodies from human mothers did behave in a manner that mimics some behaviors seen in people with autism,” Singer says.
Following the mice throughout adolescence (four to six weeks) and adulthood (four to six months), the Hopkins team measured novelty-seeking (or willingness to explore unfamiliar open spaces), response to loud noise, sociability and anxiety-like behavior.
Overall, mice exposed prenatally to antibodies from mothers of autistic children behaved more anxiously, spent less time in open spaces when placed in an elevated maze, and were overall more hyperactive, fretting back and forth between open and closed spaces in the maze and in an open field environment, both behaviors that in humans would equal abnormal activity.
Again, compared to control mice, the mice exposed to antibodies from mothers of autistic children were also more easily startled by loud noises and were less social, choosing to spend more time visiting an empty cage rather than one with a live mouse in it.
The differences among groups were less pronounced in the adolescent mice, but as the mice aged, researchers observed an increase in autism-like symptoms, a finding consistent with neurodevelopmental disorders in humans, who tend to develop new or more pronounced symptoms over time, investigators point out.
Comparing brain tissues from all groups of mice, researchers observed markedly more activation of microglia - immune cells in the central nervous system activated during inflammation in the brain tissues of the group injected prenatally with antibodies from mothers of autistic children.
In further studies, the Hopkins scientists hope to identify which specific brain proteins the antibodies affect and to correlate changes in brain anatomy and function to changes in behavior.
Ultimately, researchers hope to develop ways to detect and analyze culprit antibodies in pregnant women and prevent them from binding to fetal brain proteins.
The causes of autism, a disorder manifesting itself with a range of brain problems, impaired social interactions, communication disorders and repetitive behaviors, remain unknown for an estimated 90 percent of children diagnosed with it. Genetic, metabolic and environmental factors have been implicated in various studies of autism, which affects an estimated 1 in 150 U.S. children, according to the Centers for Disease Control and Prevention.
White Blood Cells Move like Millipedes
How do white blood cells immune system ‘soldiers’ get to the site of infection or injury?
To do so, they must crawl swiftly along the lining of the blood vessel gripping it tightly to avoid being swept away in the blood flow all the while searching for temporary ‘road signs’ made of special adhesion molecules that let them know where to cross the blood vessel barrier so they can get to the damaged tissue.
In research recently published in the journal Immunity, Prof. Ronen Alon and his research student Ziv Shulman of the Weizmann Institute’s Immunology Department show how white blood cells advance along the length of the endothelial cells lining the blood vessels. Current opinion maintains that immune cells advance like inchworms, but Alon’s new findings show that the rapid movement of the white blood cells is more like that of millipedes.
Rather than sticking front and back, folding and extending to push itself forward, the cell creates numerous tiny ‘legs’ no more than a micron in length adhesion points, rich in adhesion molecules (named LFA-1) that bind to partner adhesion molecules present on the surface of the blood vessels. Tens of these legs attach and detach in sequence within seconds allowing them to move rapidly while keeping a good grip on the vessels’ sides.
Next, the scientists turned to the Institute’s Electron Microscopy Unit. Images produced by scanning and transmission electron microscopes, taken by Drs. Eugenia Klein and Vera Shinder, showed that upon attaching to the blood vessel wall, the white blood cell legs ‘dig’ themselves into the endothelium, pressing down on its surface. The fact that these legs which had been thought to appear only when the cells leave the blood vessels are used in crawling the vessel lining suggests that they may serve as probes to sense exit signals.
The researchers found that the shear force created by the blood flow was necessary for the legs to embed themselves. Without the thrust of the rushing blood, the white blood cells couldn’t sense the exit signals or get to the site of the injury. These results explain Alon’s previous findings that the blood’s shear force is essential for the white blood cells to exit the blood vessel wall. The present study suggests that shear forces cause their adhesion molecules to enter highly active states. The scientists believe that the tiny legs are trifunctional: Used for gripping, moving and sensing distress signals from the damaged tissue.
In future studies, the scientists plan to check whether it is possible to regulate aggressive immune reactions (such as in autoimmune diseases) by interrupting the ‘digging’ of immune cell legs into the endothelium. They also plan to investigate whether cancerous blood cells metastasize through the blood stream using similar mechanisms in order to exit the blood vessels and enter different tissues.
Cigarette Smoke May Rob Children of Needed Antioxidants
Children exposed to cigarette smoke have lower levels of antioxidants, which help the body defend itself against many biological stresses.
A University of Rochester Medical Center study looked at the levels of antioxidants versus the amount of smoke exposure in more than 2,000 6 and 18 years old in the 2003-2004 National Health and Nutrition Examination Survey (NHANES). The study, which was presented at the Pediatric Academic Society Meeting in Baltimore, shows that secondhand smoke exposure is associated with lower levels of antioxidants in children.
"We don't know enough yet to say that this group of children need supplements to make up for the antioxidants they're losing, but it's always wise to feed children an abundance of fruits and vegetables high in antioxidants and other healthy nutrients," said Karen Wilson, M.D., M.P.H., a senior instructor of Pediatrics at the University of Rochester Medical Center and the study's author.
Antioxidants are believed to play an important role in protecting the body's cells against free radicals, which can damage cells. Free radicals are produced during many body processes including when we use oxygen and respond to infections. It is not completely understood how antioxidants work together to neutralize free radicals, but scientists continue to discover more antioxidant compounds, including those examined in the study vitamins E and C, folate and beta-carotene.
Children's exposure to tobacco smoke was determined by the level of cotinine in their blood (cotinine is a byproduct of metabolizing tobacco smoke). The higher the level of cotinine in a child's blood, the lower the antioxidant level, after controlling for diet and supplements. The study also looked at vitamins that were not antioxidants and found that these compounds did not seem to be reduced with smoke exposure.
Enzymatic Activity of Factors Involved in Childhood Leukemia
The Stowers Institute’s Shilatifard Lab and colleagues have provided new insight into the molecular basis for H3K4 methylation, an activity associated with the MLL protein found in chromosomal translocation-based aggressive infant acute leukemias
Studies describing these collaborative studies were published online by Molecular and Cellular Biology and Cell this week.
Many hematological malignancies are associated with a genetic error in which a portion of one chromosome has broken and fused with another chromosome. This inappropriate fusion of chromosomal DNA is referred to as chromosomal translocation. A large proportion of infant leukemias are the result of chromosomal translocations in the Mixed Lineage Leukemia (MLL) gene. Children suffering from these chromosomal translocations have low survival rates and face treatment options that have devastating side effects.
The Stowers Institute’s Shilatifard Lab studies chromosomal translocations related to the MLL gene. Several years ago, they identified a molecular complex COMPASS containing the yeast homologue of the human MLL. COMPASS was the first H3K4 methylase to be identified, and human MLL is also found in COMPASS-like complexes capable of methylating H3K4, a posttranslational modification marking chromosomes for transcription.
“We observed that the addition of three methyl groups (a process known as trimethylation) on the fourth lysine of H3K4 is regulated by the active site of the yeast equivalent of the MLL protein complex, COMPASS,” said Yoh-hei Takahashi, Ph.D., Postdoctoral Research Associate and first author on the publication in Molecular and Cellular Biology. “We also demonstrated that a single residue (Tyr1052) functions with a known subunit of COMPASS (Cps40) to regulate the trimethylation of H3K4.”
“These are exciting findings because each of these are significant steps that lead to unraveling how translocations cause leukemia and how we can develop treatments that better target and cure leukemia,” said Ali Shilatifard, Ph.D., Investigator and senior author on the publication.
Additional contributing authors to the study published in Molecular and Cellular Biology from the Stowers Institute include Jung Shin Lee, Ph.D., Postdoctoral Research Associate; Selene Swanson, Research Specialist II; Anita Saraf, M.D., Ph.D., Senior Proteomics Scientist; Laurence Florens, Ph.D., Managing Director of Proteomics; and Michael Washburn, Ph.D., Director of Proteomics Center. Raymond Trievel, Ph.D., of the University of Michigan also contributed.
The Shilatifard Lab also has collaborated with Robert Roeder and colleagues at The Rockefeller University on a publication in Cell that sheds new light on the process of communication between histones known as histone crosstalk. This process has been a topic of interest to the Shilatifard Lab for many years, and they have made a number of important contributions to its understanding.
Through a series of laborious biochemical and genetic screens in yeast and over five years of work, the Shilatifard Lab identified the molecular machinery required for proper H3K4 methylation by COMPASS. This includes the modification of histone H2B by attaching a single ubiquitin a regulatory protein that is very similar from species to species by the Rad6/Bre1 complex in a process called histone crosstalk. In the Cell publication, the team demonstrated that human Rad6/Bre1 also functions in histone crosstalk as it does in yeast.
“This study demonstrates the awesome power of simple genetic and biochemical model systems such as yeast in deciphering molecular machinery involved in chromatin biology and how yeast can play a role as a template in identifying the human counterparts of these proteins,” said Dr. Shilatifard. “Indeed, as reported this week in Cell, human Rad6 can functionally replace yeast Rad6, and H2B monoubiquitination in humans functions by the same histone crosstalk mechanism as it does in yeast, demonstrating the conservation in this system from yeast to humans.”
MONDAY May 4, 2009---------------------------News Archive
Women Live Longer, Not Better, Largely Because of Obesity and Arthritis
Obesity and arthritis that take root during early and middle age significantly contribute to women's decreased quality of life during their senior years, according to researchers at Duke University Medical Center
In a study that included 5,888 people over 65, women suffered up to two and a half times more disabilities than men of the same age.
Higher rates of obesity and arthritis among these women explained up to 48 percent of the gender gap in disability - above all other common chronic health conditions.
"While women tend to live longer than men, this study shows that they are at greater risk of living with disability and much of the excess disability is attributable to higher rates of obesity and arthritis," said Heather Whitson, MD, assistant professor of medicine and lead investigator of the study presented today at the Annual Scientific Meeting of the American Geriatrics Society.
"This is important because it suggests that women's tendency to pack on extra pounds in their child-bearing and peri-menopausal years translates into loss of independence in their old age."
Researchers said the study is the first to isolate the impact of specific chronic health conditions on the difference in disability rates between older men and women. While many people are studying how chronic conditions affect mortality, the investigators were surprised to see the extent to which these conditions explained the gender difference in disability.
"The reason for this discrepancy in disability has not been well understood but we found that chronic health conditions that women experience in greater numbers than men may explain part of that gap," said Harvey Jay Cohen, MD, the study's senior author, chair of the Department of Medicine and director of Duke's Center for the Study of Aging and Human Development.
"Women have a natural tendency to gain more weight than men over the lifespan, but may be more motivated to maintain a healthy weight if they realize that those extra pounds make it more likely that they will be disabled in later years - potentially becoming a burden to their children or requiring a nursing home," Whitson said.
The current study is an analysis of the Cardiovascular Health Study which asked participants about their ability to conduct common activities of daily living, such as grooming, eating, getting dressed, managing money and upper and lower body movement, including reaching, grasping, walking and climbing stairs.
The Duke team said the study also draws attention to two concerning health trends that could worsen the average quality of life for women in the future. First, as the rate of obesity continues to rise, the rates of disability in older adults are expected to increase. To the extent that women are more likely than men to develop obesity, the obesity epidemic will have its greatest impact on older women's quality of life.
Second, the investigators note that women are gaining equality with men on cardiovascular disease, stroke and emphysema, which had previously been less common among women.
Rates of cardiovascular disease are not improving as quickly among women as they are among men and smoking-related disease is becoming more common in women. If the occurrence of these conditions becomes more comparable between men and women, the result would be an even wider gap in disability rates.
"The findings of our study are more troubling when you consider the increasing rates of obesity among women and the higher rates of other conditions that are currently over-represented among men," Cohen said. "We need to help women make better decisions earlier in life."
In addition to obesity and arthritis, the study found the women were more likely than men to experience fractures, vision problems and bronchitis. Men were more likely to have emphysema, coronary heart disease, congestive heart failure, stroke, diabetes and hearing problems.
Researchers say that the next step is to determine whether older women who have been disabled by obesity or arthritis regain function if they undergo treatment to help them achieve a healthy weight or to control their arthritis pain. If not, then it becomes even more important to focus efforts on preventing obesity and arthritis in younger populations.
When Cells Reach Out and Touch
MicroRNAs are single-stranded snippets that, not long ago, were given short shrift as genetic junk
Now that studies have shown they regulate genes involved in normal functioning as well as diseases such as cancer, everyone wants to know: What regulates microRNAs?
Scientists at Johns Hopkins were surprised to find an elegantly simple answer: touch. In a new study, published online April 9 in the Proceedings of the National Academy of Sciences, the researchers discovered that cell-to-cell contact revs up the manufacture of these small but mighty molecules.
“This study documents one of the very few clear examples of a stimulus that directly influences the global efficiency of microRNA production,” says Josh Mendell, M.D., Ph.D., an assistant professor in the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine. “No one anticipated, including us, that the production of microRNAs is linked to how densely cells are packed together.”
In what Mendell describes as an “accidental discovery,” the team was studying contact inhibition: a phenomenon in which non-cancerous cells growing in a dish stop multiplying when they touch each other. Cancer cells, on the other hand, lose contact inhibition and continue to proliferate even when they’re touching. The researchers suspected that microRNAs might play a role in contact inhibition because whenever they studied these enigmatic bits - only about 20 or so genetic building blocks comprise a microRNA - they always saw more in the tissues of animals, where cells are packed together, relative to the amount they found in isolated cells growing in culture.
To investigate, the team grew cancer cells and non-cancer cells to increasing densities in culture and, using a tool developed in the Mendell laboratory, measured the abundance of hundreds of microRNAs simultaneously. This analysis revealed that the more densely the cells were packed together, the more microRNA was produced in each cell.
The scientists then examined microRNA production in five additional commonly studied human and mouse cell lines, including human breast cancer cells, human colorectal cancer cells and human pancreatic cancer cells. They also tested fruit fly cells to determine whether or not the phenomenon is restricted to mammals.
In all tested cell lines, including the fruit fly cells, scientists observed a dramatic increase in microRNA abundance with increasing cell density.
“All evidence points to the fact that physical contact -- when cells actually touch each other -- is the critical factor that revs up the production of microRNAs,” Mendell says. “Through additional experiments, we were able to identify the specific molecular steps at which microRNA production is affected. We expect that this phenomenon will profoundly influence how cells behave in normal development and disease.”
The team’s finding has practical importance for researchers who are investigating a range of biological processes that are most conveniently studied in cells growing in culture, Mendell says: “Little did we know the manufacture of microRNAs was so potently influenced simply by growing cells to different densities. We now recognize that this is a critical parameter that must be closely monitored when performing experiments with microRNAs in tissue culture.”
A better understanding of how microRNA production is regulated is important because a reduction in the abundance of these molecules has been linked to the development of certain cancers. To date, one barrier to understanding how microRNAs are regulated in normal development and in disease states has been the lack of a simple system by which scientists could turn on and off a molecular pathway that controls microRNA production. Now, it seems, they may be able to toggle that pathway using cell-to-cell contact.
“If we can identify the mechanisms through which microRNA production is regulated in normal settings, such as under conditions of extensive cell-cell contact, we can then ask whether the same mechanisms block microRNA manufacture in diseases such as cancer,” Mendell says. “This might allow the development of small molecules or other methods to turn microRNA production back on for therapeutic benefit.”
The research was supported by the National Institutes of Health and the Sol Goldman Center for Pancreatic Cancer Research."
ISU Researcher Identifies Key Function in Protein, Cell Transcription
When cells decide to make proteins, key building blocks of all organisms, they need to know where to start reading the instructions for assembling them
An Iowa State University researcher has figured out a mechanism involved in marking where these instructions are located in a cell's DNA.
In the current edition of The Journal of Biological Chemistry, Michael Shogren-Knaak, assistant professor in biochemistry, biophysics and molecular biology, along with Shanshan Li, a graduate student in his lab, show how a protein, Gcn5, is involved in this process.
When a portion of the Gcn5 protein recognizes chemically modified proteins associated with DNA, called histones, this recognition facilitates further chemical modification of the histones.
This allows the information contained in that DNA, or genes, to be read more efficiently.
"This is very important in normal cell development from single cell organisms to us (humans)," said Shogren-Knaak.
Understanding how DNA is read should shed light on diseases where DNA is often inappropriately read.
"This is very likely to be significant for diseases like cancer," said Shogren-Knaak.
"Cancer is distinguished by containing a lots of genes that should be turned off but aren't, and by proteins that should be made but aren't," he said. "That leads to cells that grow in an uncontrolled and undesirable manner."
Folic Acid May Also Help Treat Allergies, Asthma
Folic acid, or vitamin B9, essential for red blood cell health and long known to reduce the risk of spinal birth defects, may also suppress allergic reactions and lessen the severity of allergy and asthma symptoms, according to new research from the Johns Hopkins Children's Center
In what is believed to be the first study in humans examining the link between blood levels of folate -- the naturally occurring form of folic acid -- and allergies, the scientists say results add to mounting evidence that folate can help regulate inflammation. Recent studies, including research from Johns Hopkins, have found a link between folate levels and inflammation-mediated diseases, including heart disease. A report on the Johns Hopkins Children's findings appears online ahead of print in the Journal of Allergy & Clinical Immunology.
Cautioning that it's far too soon to recommend folic acid supplements to prevent or treat people with asthma and allergies, the researchers emphasize that more research needs to be done to confirm their results, and to establish safe doses and risks.
Reviewing the medical records of more than 8,000 people ages 2 to 85 the investigators tracked the effect of folate levels on respiratory and allergic symptoms and on levels of IgE antibodies, immune system markers that rise in response to an allergen. People with higher blood levels of folate had fewer IgE antibodies, fewer reported allergies, less wheezing and lower likelihood of asthma, researchers report.
"Our findings are a clear indication that folic acid may indeed help regulate immune response to allergens, and may reduce allergy and asthma symptoms," says lead investigator Elizabeth Matsui, M.D., M.H.S., pediatric allergist at Johns Hopkins Children's. "But we still need to figure out the exact mechanism behind it, and to do so we need studies that follow people receiving treatment with folic acid, before we even consider supplementation with folic acid to treat or prevent allergies and asthma."
The current recommendation for daily dietary intake of folic acid is 400 micrograms for healthy men and non-pregnant women. Many cereals and grain products are already fortified with folate, and folate is found naturally in green, leafy vegetables, beans and nuts.
Other findings of the study:
• People with the lowest folate levels (below 8 nanograms per milliliter) had 40 percent higher risk of wheezing than people with the highest folate levels (above 18 ng/ml).
• People with the lowest folate levels had a 30 percent higher risk than those with the highest folate levels of having elevated IgE antibodies, markers of allergy predisposition.
• Those with the lowest folate levels had 31 percent higher risk of atopy (allergic symptoms) than people with the highest folate levels.
• Those with lowest folate levels had 16 percent higher risk of having asthma than people with the highest folate levels.
Blacks and Hispanics had lower blood folate levels - 12 and 12.5 nanograms per milliliter, respectively - than whites (15 ng/ml), but the differences were not due to income and socio-economic status.
The Johns Hopkins team is planning a study comparing the effects of folic acid and placebo in people with allergies and asthma.
Asthma affects more than 7 percent of adults and children in the United States, and is the most common chronic condition among children, according to the Centers for Disease Control and Prevention. Environmental allergies are estimated to affect 25 million Americans, according to the CDC.
Late Motherhood Boosts Family Lifespan
Women who have babies naturally in their 40s or 50s tend to live longer than other women. Now, a new study shows their brothers also live longer, but the brothers' wives do not, suggesting the same genes prolong lifespan and female fertility, and may be more important than social and environmental factors
"If women in your family give birth at older ages, you may well have a chance of living longer than you would otherwise," says the study's lead author, demographer Ken R. Smith, a professor of family and consumer studies at the University of Utah. "If you have a female relative who had children after age 45, then there may be some genetic benefit in your family that will enhance your longevity."
For descendants of the Utah and Quebec pioneers studied, "you may be able to look at the ages when your female ancestors gave birth - rather than just their longevity - in estimating how long you may live," says Smith, whose study will be published online May 4 and in the June 10 print issue of the Journal of Gerontology: Biological Sciences.
The researchers examined high-quality genealogical records from the Utah Population Database at the University of Utah with its records of 1.6 million Utah Mormon pioneers and their descendants. They also used the University of Montreal's Program on Demographic History Research, which has records on 400,000 people who lived in heavily Catholic Quebec between 1608 and 1850.
Specifically, the study involved the records of 11,604 Utah men who were born between 1800 and 1869 and who had at least one sister who lived at least to age 50; and the records of 6,206 Quebec men who lived between 1670 and 1750, and had at least one sister who lived to 50 or older. The key findings:
Women who had "late fertility" - a birth at age 45 or older - were 14 percent to 17 percent less likely to die during any year after age 50 than women who did not deliver a child after age 40. That confirmed earlier studies. But those studies did not determine if the women gave birth later and lived longer because of genes or because of social and environmental factors such as good nutrition or healthy living.
Brothers who had at least three sisters, including at least one sister who gave birth at age 45 or later, were 20 percent to 22 percent less likely to die during any year after age 50 than brothers who had no "late fertile" sisters. That indicates what earlier studies did not, namely, the same genes may influence the lifespan of both sexes and women's ability to give birth at older ages.
The brothers' wives didn't have longer lives, suggesting any environmental or social factors that influence lifespan had only a weak influence, and that genes may explain why brothers lived longer when they had a sister who gave birth in her 40s.
The study didn't address how much longevity is due to genetics, but Smith says scientists believe genes account for up to 25 percent of differences in longevity.