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Archive - 2012

April 10th

Gene Could Play Key Role in Preventing Pathology in Deadly Pulmonary Fibrosis

An international team of researchers led by Georgia State University (GSU) scientists has found a key component in the pathological process of pulmonary fibrosis, a fatal disease for which there is currently no cure. The scientists found that a key human gene, CLYD, serves as a crucial negative regulator in the development of the disease, halting its progression that leads to death. The research was published online on April 10, 2012 in the journal Nature Communications. "In some patients, CLYD does not function as it should or its protein level is lower than in normal individuals," said Dr. Jian-Dong Li, director of the GSU Center for Inflammation, Immunity, and Infection (CIII) and Georgia Research Alliance (GRA) Eminent Scholar in Inflammation and Immunity. "If this does happen, the human tissue-repairing response can go out of control, leading to the development of fibrosis," added Dr. Li, senior author of the study and professor of biology at GSU. According to the American Lung Association, about 140,000 Americans have been diagnosed with the disease. Patients' breathing symptoms worsen over time, and many patients live only three to five years after diagnosis. There are currently no effective medicines available to health care professionals to cure pulmonary fibrosis. Professionals can treat the symptoms to reduce inflammation using steroids and immunosuppressants, but there are serious side effects over time, including immune system suppression, which makes patients even more susceptible to infections. "The disease often develops after infection or injury. In the case of infections brought on by Streptococcus pneumoniae, a form of pneumonia, the body's immune system responds and tries to repair the damage, but in the case of fibrosis, this repairing process is overactive and causes scarring of the lungs," said Dr.

April 5th

Stem Cell Work Permits Production of Unlimited Quantities of Cystic Fibrosis Lung Tissue for Drug Testing

Harvard stem cell researchers at Massachusetts General Hospital (MGH) have taken a critical step in perhaps making possible the discovery, in the relatively near future, of a drug to control cystic fibrosis (CF), a fatal lung disease that claims about 500 lives each year, with 1,000 new cases diagnosed annually. Beginning with the skin cells of patients with CF, Jayaraj Rajagopal, M.D., and colleagues first created induced pluripotent stem (iPS) cells, and then used those cells to create human disease-specific functioning lung epithelium, the tissue that lines the airways and is the site of the most lethal aspect of CF, where the mutant genes cause irreversible lung disease and inexorable respiratory failure. That tissue, which researchers can now grow in unlimited quantities in the laboratory, contains the delta-508 mutation, the mutation responsible for about 70 percent of all CF cases and 90 percent of the ones in the United States. The tissue also contains the G551D mutation, a mutation that is involved in about 2 percent of CF cases and the one cause of the disease for which there is now a drug. The work is featured on the cover of the April 6, 2012 issue of Cell Stem Cell. Postdoctoral fellow Hongmei Mou, Ph.D., is first author on the paper, and Dr. Rajagopal is the senior author. Dr. Mou credits learning the underlying developmental biology in mice as the key to making tremendous progress in only two years. "I was able to apply these lessons to the iPS cell systems," she said. "I was pleasantly surprised the research went so fast, and it makes me excited to think important things are within reach.

Spontaneous Mutations Linked to Autism Risk with Older Dads

Researchers have turned up a new clue to the workings of a possible environmental factor in autism spectrum disorders (ASDs): fathers were four times more likely than mothers to transmit tiny, spontaneous mutations to their children with the disorders. Moreover, the number of such transmitted genetic changes increased with paternal age. The discovery may help to explain earlier evidence linking autism risk to older fathers. The results are among several from a trio of new studies, supported in part by the National Institutes of Health, finding that such sequence changes in parts of genes that code for proteins play a significant role in ASDs. One of the studies determined that having such mutations boosts a child's risk of developing autism 5 to 20 fold. Taken together, the three studies represent the largest effort of its kind, drawing upon samples from 549 families to maximize statistical power. The results reveal sporadic mutations widely distributed across the genome, sometimes conferring risk and sometimes not. While the changes identified don't account for most cases of illness, they are providing clues to the biology of what are likely multiple syndromes along the autism spectrum. "These results confirm that it's not necessarily the size of a genetic anomaly that confers risk, but its location – specifically in biochemical pathways involved in brain development and neural connections. Ultimately, it's this kind of knowledge that will yield potential targets for new treatments," explained Thomas R. Insel, M.D., director of the NIH's National Institute of Mental Health (NIMH), which funded one of the studies and fostered development of the Autism Sequencing Consortium, of which all three groups are members.

April 3rd

Why Cancer Drug Causes Diabetes-Like Symptoms in Some

Scientists at Dana-Farber Cancer Institute have discovered why diabetes-like symptoms develop in some patients given rapamycin, an immune-suppressant drug that also has shown anti-cancer activity and may even slow ageing. Rapamycin is widely used to prevent organ rejection and is being tested as a cancer treatment in clinical trials. About 15 percent of patients, however, develop insulin resistance and glucose intolerance after taking the drug; until now, scientists had not identified the reason. In a study published in the April 4, 2012 issue of Cell Metabolism, the researchers report that normal mice given rapamycin were more likely to have trouble regulating their blood sugar because of a drop in insulin signaling, which was triggered by activity of a protein called Yin Yang 1, or YY1. But animals in which the YY1 protein was "knocked out" in their muscles had no such response to rapamycin – they were protected against the development of diabetes-like symptoms. This result pinpointed YY1 as the target of rapamycin responsible for the loss of normal insulin function. One of the finding's implications is that physicians should consider giving anti-diabetes drugs along with rapamycin, says Pere Puigserver, Ph.D., senior author of the report. The results also raise a caution flag for researchers and non-scientists who are excited about the potential for rapamycin to extend life, based on recent studies in animals including mammals, he notes. "The possibility of increased diabetes risk needs to be taken into account" in further research on the anti-ageing properties of rapamycin and related compounds, says Dr. Puigserver. Rapamycin is a drug derived from bacteria found on Easter Island, and was approved in 1999 by the FDA as an immunosuppressant in transplant patients.

March 30th

Intestinal Stem Cell Marker Functions As Tumor Suppressor

Tales from the crypt are supposed to be scary, but new research from Vanderbilt University, the HudsonAlpha Institute for Biotechnology and collaborating institutions shows that crypts can be places of renewal too: intestinal crypts, that is. Intestinal crypts are small areas of the intestine where new cells are formed to continuously renew the digestive tract. By focusing on one protein expressed in our intestines called Lrig1, the researchers have identified a special population of intestinal stem cells that respond to damage and help to prevent cancer. The research, published in the March 30, 2012 issue of Cell, also shows that the diversity of stem cells in the intestines is greater than previously thought. "Identification of these cells and the role they likely play in response to injury or damage will help advance discoveries in cancer," said Shawn Levy, Ph.D., faculty investigator at the HudsonAlpha Institute and an author on the study. The intestines and colon are normally lined with a single layer of cells to absorb nutrients from food. There are regular small pockets in the intestines called crypts, where stem cells are gathered. Rapid turnover of the lining cells and replacement by new lining cells made in the crypt, keep the intestines and colon healthy and keep damaged cells from turning into cancerous ones. The new paper demonstrates that, although the makeup of stem cells in the crypt is still controversial, one protein called Lrig1 can distinguish a group of long-lived cells at the base of the crypt. These Lrig1-positive stem cells do not regularly replace lining cells, but instead are only activated when there is damage or injury to the intestine. In addition, the researchers show that the Lrig1 protein functions to prevent cancer as a tumor suppressor molecule.

Dengue Infection Alters Gene Expression in Mosquito Salivary Glands

Mosquitoes infected with dengue virus experience an array of changes in the activity of genes and associated functions of their salivary glands, and these changes may lead to increased virus transmission, according to a recent study led by George Dimopoulos, Ph.D., of the Malaria Research Institute and Bloomberg School of Public Health at Johns Hopkins University. Some of these changes involve the mosquito's immune system and affect its susceptibility to infection with the virus. Others involve factors that enhance the mosquito's capacity to feed on blood, possibly leading to greater transmission of dengue virus to humans, the study authors write. According to the World Health Organization, each year, dengue virus infects about 50 million to 100 million people and causes between 10,000 and 15,000 deaths, most of them in children. Symptoms include high fever and pain in the muscles and joints, and in severe cases can include bleeding under the skin, damage to blood vessels, and death. The disease, which is prevalent in tropical and subtropical regions of the world, has been reported recently in parts of the United States, such as Hawaii, Puerto Rico, and Florida. There is no vaccine or drug treatment for dengue. The only way to prevent infection is to avoid being bitten by Aedes mosquitoes, which can carry the virus in their salivary glands. The Hopkins researchers sought to learn how dengue virus affects the way the glands function during virus transmission. They compared the expression of several thousand genes in Aedes aegypti mosquitoes that either were or were not infected with dengue virus.

Honey Bees Self-Medicate When Infected by Pathogenic Fungus

Research from North Carolina State University shows that honey bees “self-medicate” when their colony is infected with a harmful fungus, bringing in increased amounts of antifungal plant resins to ward off the pathogen. “The colony is willing to expend the energy and effort of its worker bees to collect these resins,” says Dr. Michael Simone-Finstrom, a postdoctoral research scholar in NC State’s Department of Entomology and lead author of a paper describing the research. “So, clearly this behavior has evolved because the benefit to the colony exceeds the cost.” When faced with pathogenic fungi, bees line their hives with more propolis, a waxy, yellow substance. Wild honey bees normally line their hives with propolis, a mixture of plant resins and wax that has antifungal and antibacterial properties. Domesticated honey bees also use propolis, to fill in cracks in their hives. However, researchers found that, when faced with a fungal threat, bees bring in significantly more propolis – 45 percent more, on average. The bees also physically removed infected larvae that had been parasitized by the fungus and were being used to create fungal spores. Researchers know propolis is an effective antifungal agent because they lined some hives with a propolis extract and found that the extract significantly reduced the rate of infection. And apparently bees can sometimes distinguish harmful fungi from harmless ones, because colonies did not bring in increased amounts of propolis when infected with harmless fungal species. Instead, the colonies relied on physically removing the spores. However, the self-medicating behavior does have limits. Honey bee colonies infected with pathogenic bacteria did not bring in significantly more propolis – despite the fact that the propolis also has antibacterial properties.

March 29th

Egg Protein Found Critical to Epigenetic Stability

An international team led by scientists at A*STAR’s Institute of Medical Biology (IMB) has discovered that a protein, called TRIM28, normally present in the mother’s egg, is essential right after fertilization to preserve certain chemical modifications or “epigenetic marks” on a specific set of genes. The study, published in the March 23, 2012 issue of Science, paves the way for more research to explore the role that epigenetics might play in infertility. Previous studies have shown that both nuclear reprogramming as well as “imprinting” are vital for the survival and later development of the embryo. However, the underlying mechanisms governing the intricate interplay of these two processes during the early embryonic phase have not been clear, until now. Immediately after fertilization, the majority of the epigenetic marks on the DNA from the sperm and egg cells are erased. The erasure process, termed nuclear reprogramming, allows the genes from the parents to be reset so that the early embryonic cells can develop into any cell types of the body. On the other hand, certain epigenetic marks on a particular set of genes, some from the mother and some from the father must be preserved. These genes are said to be “imprinted” by their parent of origin and preservation of these marks is critical for the survival of the newly formed embryo. Expression of these imprinted genes at the appropriate levels ensures proper development of the embryo. If the epigenetic marks on the imprinted genes are not protected, severe and multiple developmental defects occur in the embryo. Using genetically identical mice from an inbred mouse strain, Drs. Davor Solter and Barbara Knowles, Senior Principal Investigators at IMB, observed that none of the embryos resulting from the fertilization of eggs lacking TRIM28 survived.

New Breast Cancer Susceptibility Gene Identified Using Exome Sequencing

Rare mutations in a gene called XRCC2 cause increased breast cancer risk, according to a study published online on March 29, 2012 in the American Journal of Human Genetics. The study looked at families that have a history of the disease, but do not have mutations in the currently known breast cancer susceptibility genes. Sean Tavtigian, Ph.D., a Huntsman Cancer Institute (HCI) investigator and associate professor in the Department of Oncological Sciences at the University of Utah (U of U) is one of three co-principal investigators on the study, along with David Goldgar, Ph.D., professor in the Department of Dermatology at the U of U and an HCI investigator, and Melissa Southey, Ph.D., professor in the Department of Pathology at the University of Melbourne, Australia. "We have added to the list of genes that harbor mutations causing breast cancer," said Dr. Tavtigian. "This knowledge will improve breast cancer diagnostics and add years to patients' lives. More important, relatives who have not been affected by the disease, but carry the mutations, will benefit even more. They can find out they are at risk before they have cancer and take action to reduce their risk or catch the cancer early." XRCC2 may also provide a new target for chemotherapy. "A type of drug called a PARP inhibitor appears to kill tumor cells that have gene mutations in a particular DNA repair pathway. XRCC2 is in this pathway, as are BRCA1 and BRCA2. It's reasonably likely that a breast cancer patient who has a mutation in XRCC2 will respond well to treatment with PARP inhibitors," said Dr. Tavtigian. According to Dr. Tavtigian, many breast cancer cases appear in families with a weak history of the disease.

March 27th

New Method May Offer First Viable Approach to Gene Transfer in Sickle Cell Anemia

A team of researchers led by scientists at Weill Cornell Medical College has designed what appears to be a powerful gene therapy strategy that can treat both beta-thalassemia disease and sickle cell anemia. The scientists have also developed a test to predict patient response before treatment. This study's findings, published in online on March 27, 2012 in PLoS ONE, represent a new approach to treating these related, and serious, red blood cell disorders, say the investigators. "This gene therapy technique has the potential to cure many patients, especially if we prescreen them to predict their response using just a few of their cells in a test tube," says the study's lead investigator, Stefano Rivella, Ph.D., an associate professor of genetic medicine at Weill Cornell Medical College. He led a team of 17 researchers in three countries. Dr. Rivella says this is the first time investigators have been able to correlate the outcome of transferring a healthy beta-globin gene into diseased cells with increased production of normal hemoglobin -- which has long been a barrier to effective treatment of these diseases. So far, only one patient, in France, has been treated with gene therapy for beta-thalassemia, and Dr. Rivella and his colleagues believe the new treatment they developed will be a significant improvement. No known patient has received gene therapy yet to treat sickle cell anemia. Beta-thalassemia is an inherited disease caused by defects in the beta-globin gene. This gene produces an essential part of the hemoglobin protein, which, within red blood cells, carries life-sustaining oxygen throughout the body. The new gene transfer technique developed by Dr. Rivella and his colleagues ensures that the beta-globin gene that is delivered will be active, and that it will also provide more curative beta-globin protein.