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Archive - 2012

November 13th

Sequencing ID’s Abnormal Gene That Launches Rare Childhood Leukemia

Research led by the St. Jude Children's Research Hospital – Washington University Pediatric Cancer Genome Project has identified a fusion gene responsible for almost 30 percent of a rare subtype of childhood leukemia with an extremely poor prognosis. The finding offers the first evidence of a mistake that gives rise to a significant percentage of acute megakaryoblastic leukemia (AMKL) cases in children. AMKL accounts for about 10 percent of pediatric acute myeloid leukemia (AML). The discovery paves the way for desperately needed treatment advances. Investigators traced the genetic misstep to the rearrangement of chromosome 16, which brings together pieces of two genes and sets the stage for production of an abnormal protein. The fusion protein features the front end of CBFA2T3, a blood protein, and the back of GLIS2, a protein that is normally produced only in the kidney. Work that appears in the November 13, 2012 edition of the journal Cancer Cell reports that in a variety of laboratory models the CBFA2T3-GLIS2 protein switched on genes that drive immature blood cells to keep dividing long after normal cells had died. This alteration directly contributes to leukemia. AMKL patients with the fusion gene were also found to be at high risk of failing therapy. Researchers checked long-term survival of 40 AMKL patients treated at multiple medical centers around the world and found about 28 percent of patients with the fusion gene became long-term survivors, compared to 42 percent for patients without CBFA2T3-GLIS2. Overall long-term survival for pediatric AML patients in the U.S. is now 71 percent.

New Cause of Thyroid Hormone Deficiency Discovered

International researchers, including a team at McGill University, have discovered a new cause for thyroid hormone deficiency, or hypothyroidism. This common endocrine disorder is typically caused by problems of the thyroid gland, and more rarely, by defects in the brain or the pituitary gland (hypophysis). However, a new cause of the disease has been discovered from an unsuspected source and was reported online on November 11, 2012 in the journal Nature Genetics. The scientists, led by McGill Professor Daniel Bernard, Department of Pharmacology and Therapeutics in the Faculty of Medicine, identified a new hereditary form of hypothyroidism that is more prevalent in males than in females. This sex bias shone a light on where to look for the underlying cause. "Our collaborators in the Netherlands had been following a family in which two cousins had an unusual syndrome of hypothyroidisim and enlarged testicles," said Professor Bernard. "Using state-of-the-art DNA sequencing technologies, we identified a mutation in a gene called immunoglobulin superfamily, member 1 (IGSF1), in both boys and their maternal grandfather. As one of few labs in the world studying this gene, we initiated a collaboration to determine whether the observed mutation might cause the disorder. At the time, the IGSF1 gene was known to be active in the pituitary gland, but its function was a mystery.

November 12th

Cilia Guide Neuronal Migration in Developing Brain

A new study demonstrates the dynamic role cilia play in guiding the migration of neurons in the embryonic brain. Cilia are tiny hair-like structures on the surfaces of cells, but here they are acting more like radio antennae. In developing mouse embryos, researchers were able to see cilia extending and retracting as neurons migrate. The cilia appear to be receiving signals needed for neurons to find their places. Genetic mutations that cause the neurodevelopmental disorder Joubert syndrome interfere with these migratory functions of cilia, the researchers show. The finding suggests that problems with neuron migration may explain some aspects of Joubert syndrome patients' symptoms. The results were published November 13, 2012 in the journal Developmental Cell. "The most surprising thing was how dynamic the cilia are," says Tamara Caspary, Ph.D., assistant professor of human genetics at Emory University School of Medicine. "As interneurons migrate into the developing cerebral cortex, they move in steps. When they pause, we could see the cilia extending, as if the interneurons are trying to figure out where to go next." The paper is the result of a collaboration between Dr. Caspary's laboratory and that of Eva Anton, Ph.D., professor of cell and molecular physiology at the University of North Carolina School of Medicine. First author Dr. Holden Higginbotham, formerly a postdoc in Anton's laboratory, is now a faculty member at Brigham Young University in Idaho. Readers may be familiar with motile cilia, which can be found on a paramecium or in our trachea or reproductive organs. In contrast, primary (non-motile) cilia can be found on almost every cell in the human body, each cell having just one. Ciliopathies are a class of genetic disorders involving defects in cilia, and include kidney and eye diseases, as well as Joubert syndrome.

November 11th

Schizophrenia Genetic Networks Identified; Connection to Autism Found

Although schizophrenia is highly genetic in origin, the genes involved in the disorder have been difficult to identify. In the past few years, researchers have implicated several genes, but it is unclear how they act to produce the disorder. A new study by researchers at Columbia University Medical Center identifies affected gene networks and provides insight into the molecular causes of the disease. The paper was published November 11, 2012 in the online edition of the journal Nature Neuroscience. Using an unbiased collection of hundreds of mutations associated with schizophrenia, the Columbia researchers applied a sophisticated computational approach to uncover hidden relationships among seemingly unrelated genes. The analysis revealed that many of the genes mutated in schizophrenia are organized into two main networks, which take part in a few key processes, including axon guidance, synapse function, neuron mobility, and chromosomal modification. The study also uncovered an intriguing connection between schizophrenia and autism. "If we hadn't known that these were two different diseases, and had put all the mutations into a single analysis, it would have come up with very similar networks," said the study's senior author, Dennis Vitkup, Ph.D., associate professor in the Department of Biomedical Informatics, the Center for Computational Biology and Bioinformatics, and the Columbia Initiative in Systems Biology at Columbia University Medical Center. "It shows how closely the autism and schizophrenia genetic networks are intertwined," he added. Although it will take time to translate the findings into practical treatments, the study provides insight into the molecular causes of schizophrenia.

Mutations in Genes That Modify DNA Packaging Result in Facioscapulohumeral Muscular Dystrophy (FSHD)

A recent finding by medical geneticists sheds new light on how facioscapulohumeral muscular dystrophy develops and how it might be treated. More commonly known as FSHD, the devastating disease affects both men and women. FSHD is usually an inherited genetic disorder, yet sometimes appears spontaneously via new mutations in individuals with no family history of the condition. "People with the condition experience progressive muscle weakness and about 1 in 5 require wheelchair assistance by age 40," said Dr. Daniel G. Miller, University of Washington (UW) associate professor of pediatrics in the Division of Genetic Medicine. Dr. Miller and his worldwide collaborators study the molecular events leading to symptoms of FSHD in the hopes of designing therapies to prevent the emergence of symptoms or reduce their severity. In the November 11, 2012 online issue of Nature Genetics, Dr. Miller and Dr. Silvere M. van der Maarel of Leiden University in The Netherlands, along with an international team, report their latest findings on the role of epigenetic modifications in causing the disease. In Seattle, Dr. Stephen Tapscott of the Fred Hutchinson Cancer Research Center was also a major contributor to the project. He is a UW professor of neurology and a researcher at the UW Center for Human Development and Disability. Epigenetics refers to mechanisms that influence how the genome is regulated and how, where, and when genes act -- all without altering the underlying DNA sequence. The flexibility of DNA packaging – its wrapping, which can be tightened and loosened, and its chemical tags – is one of the epigenetic forces on the genome. This packaging is called the chromatin structure and is one way specialized cells such as those in our muscles allow groups of genes to be shut off, or be available for expression.

Age-Related Wet Macular Degeneration Treatment Effective Even with Macular Traction Problems

The primary treatment for wet macular degeneration, a chronic eye condition that causes vision loss, is effective even if patients have macular traction problems, a Mayo Clinic study shows. The findings were presented November 11, 2012 at the annual meeting of the American Academy of Ophthalmology in Chicago. Due to the aging population, an increasing number of patients are being treated for age-related macular degeneration (AMD), an eye condition in which abnormal blood vessels develop and leak into the eye. When patients develop wet AMD, they receive injections of anti-vascular endothelial growth factor medication (VEGF). VEGF prompts growth of new blood vessels in the body. In the case of AMD, however, such new growth is unwanted and may cause bleeding in the retina. It has not been clear whether this treatment would also serve patients experiencing other symptoms, such as vitreomacular interface disease (VMID), in which there is traction or contact between the retina and the vitreous matter in the eye. Mayo researchers retrospectively studied 178 patients, of whom 18 percent had VMID over an average of 2.5 years. Findings showed that while eyes with some kind of macular traction required more injections, they still showed improvement (best corrected visual acuity) to similar eyes without VMID. "This finding is significant," says senior author Sophie J. Bakri, M.D., "because it showed that patients with VMID are not necessarily treatment resistant for AMD." She also says it may help physicians not give up on treating such patients, and understand the need for more doses of medication for those with VMID. Researchers say more study is needed, including a prospective clinical trial. Co-authors include Amy Green-Simms, M.D., and Blake Fechtel and Zubin Agarwal, M.P.H., all of the Mayo Clinic.

Texas Cotton Getting a Genetic “Tune-Up”

Can you imagine trying to build a competitive race car with old parts? Chances are, the entry would not fare well at the Indy 500. Very much the same thing might be said about today's crops, according to a Texas A&M AgriLife Research scientist. "Contemporary crops such as Texas cotton are like finely tuned racing machines — they need high quality parts to perform optimally," said Dr. David Stelly, AgriLife Research cotton geneticist in College Station. "And they constantly need new ones to replace ones that are no longer functional, as well as those that are still effective, but no longer at the cutting edge of competition." Dr. Stelly said his role in the AgriLife Research cotton breeding program is to infuse new genes and gene combinations into the genetics and breeding research arena, "so that we can utilize natural genetic resources to help meet the many challenges breeding programs face." Transferring genes into a cultivated crop from a wild species “is like swimming upstream, one is fighting all sorts of biological and genetic barriers," he said. For years, he and his long-time research assistant, Dwaine Raska, have been transferring the alien genes by a special breeding process called "chromosome substitution." "Using chromosome substitution, we can target one pair of cultivated cotton chromosomes at a time, and replace it with the corresponding pair of chromosomes from a wild species chosen as the donor. On average, each substitution replaces about 2,000 cotton genes with donor genes," Dr. Stelly said. Having already developed chromosome substitution lines for many chromosomes from three donor species, Dr. Stelly is working in collaboration with a former graduate student, Dr. Sukumar Saha, now with the U.S.

Scent Markings May Be Used to Stop Endangered African Wild Dogs from Wandering into Extinction

Throughout history, and all over the world, people have killed wild carnivores to protect their livestock. Now, a relentless expansion of human activities that brings people and their livestock into ever larger areas of former wildlife habitat is rapidly escalating both the threats to carnivore populations and the impact of carnivores on rural people’s liveliehoods. In southern Africa a radically new way to reduce conflict between people and wild carnivores is being developed by the BioBoundary Project of the Botswana Predator Conservation Trust (BPCT, http://www.bpctrust.org/). With funding from the Paul G. Allen Family Foundation, the BioBoundary Project is using the protection of endangered African wild dogs as a test case of whether wild carnivores can be kept away from livestock by artifical scent-mark boundaries between protected wildlife areas and livestock areas. African wild dogs (Lycaon pictus) are intensely social super-predators. They live in packs with huge home ranges that extend beyond the boundaries of even the largest of protected areas. When wild dogs cross these boundaries into landscapes that are dominated by humans and livestock they run a gauntlet of shooting, snaring, and poisoning; in most wild dog populations, more dogs are killed by people than by anything else. African wild dogs used to range across 39 sub-Saharan countries but now their numbers have dwindled to fewer than 6,000 and only two populations are large enough to be self-sustaining in the long term. Each African wild dog pack stakes out its territory by soaking patches of soil with the urine of the pack’s alpha pair.

November 10th

Ancient Genetic Building Block Discovered in Cyanobacteria

Scientists believe that prior to the advent of DNA as the earth’s primary genetic material, early forms of life used RNA to encode genetic instructions. What sort of genetic molecules did life rely on before RNA? The answer may be AEG, a small molecule that when linked into chains forms a hypothetical backbone for peptide nucleic acids (PNA), which have been hypothesized as the first genetic molecules. Synthetic AEG has been studied by the pharmaceutical industry as a possible gene silencer to stop or slow certain genetic diseases. The only problem with the theory is that up to now, AEG has been unknown in nature. A team of scientists from the USA and Sweden announced that they have discovered AEG within cyanobacteria which are believed to be some of the most primitive organisms on earth. Cyanobacteria sometimes appear as mats or scums on the surface of reservoirs and lakes during hot summer months. Their tolerance for extreme habitats is remarkable, ranging from the hot springs of Yellowstone to the tundra of the Arctic. “Our discovery of AEG in cyanobacteria was unexpected,” explains Dr. Paul Alan Cox, co-author of the paper that appeared November 7, 2012 in the journal PLoS ONE. The American team is based at the Institute for Ethnomedicine in Jackson Hole, Wyoming, and serves as adjunct faculty at Weber State University in Ogden, Utah. “While we were writing our manuscript,” Dr. Cox says, “we learned that our colleagues at the Stockholm University Department of Analytical Chemistry had made a similar discovery, so we asked them to join us on the paper.” To determine how widespread AEG production is among cyanobacteria, the scientists analyzed pristine cyanobacterial cultures from the Pasteur Culture Collection of Paris, France.

Resveratrol Could Be Key to Fighting Prostate Cancer

Resveratrol, a compound found commonly in grape skins and red wine, has been shown to have several beneficial effects on human health, including cardiovascular health and stroke prevention. Now, a University of Missouri (MU) researcher has discovered that the compound can make prostate tumor cells more susceptible to radiation treatment, increasing the chances of a full recovery from all types of prostate cancer, including aggressive tumors. "Other studies have noted that resveratrol made tumor cells more susceptible to chemotherapy, and we wanted to see if it had the same effect for radiation therapy," said Dr. Michael Nicholl, an assistant professor of surgical oncology in the MU School of Medicine. "We found that when exposed to the compound, the tumor cells were more susceptible to radiation treatment, but that the effect was greater than just treating with both compounds separately." Prostate tumor cells contain very low levels of two proteins, perforin and granzyme B, which can function together to kill cells. However, both proteins need to be highly "expressed" to kill tumor cells. In his study, when Dr. Nicholl introduced resveratrol into the prostate tumor cells, the activity of the two proteins increased greatly. Following radiation treatment, Nicholl found that up to 97 percent of the tumor cells died, which is a much higher percentage than treatment with radiation alone. "It is critical that both proteins, perforin and granzyme B, are present in order to kill the tumor cells, and we found that the resveratrol helped to increase their activity in prostate tumor cells," Dr. Nicholl said. "Following the resveratrol-radiation treatment, we realized that we were able to kill many more tumor cells when compared with treating the tumor with radiation alone.