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Next-Gen DNA Sequencing Illuminates Mutations in Lung Cancer

Aided by powerful next-generation DNA sequencing technology, researchers have identified nearly 23,000 mutations in a patient’s small cell lung cancer. The mutations were identified by comparing the entire genetic sequence of the cancer against that of normal DNA from the same patient. In the process, the researchers also identified a new gene (CHD7) associated with lung cancer. The number of mutations found in the study suggests that a person may develop one mutation for every 15 cigarettes smoked, said Dr. John Minna, director of the Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research at the University of Texas Southwestern and one of the authors of the new study. The researchers said the findings illustrate the power of advanced technology to provide important new information about human cancer, including the effect of cancer-causing chemicals on the body and the identification of potential new therapeutic targets. "Cancer is driven by acquired mutations in genes, and we are at a point where it soon will be possible to actually know every mutation in the tumors of each of our patients," Dr. Minna said. "The key will be to use this information to find new ways to help prevent cancers, diagnose them earlier, and to select treatments that might be specific for each patient's tumor. While these findings are the first step, they have lighted our path to clearly point us in the right direction. In addition, they provide the first detailed analysis of a human cance–lung cancer–that is closely linked to smoking." Furthermore, Dr. Minna said, "The data demonstrate the power of whole-genome sequencing to untangle the complex mutational signatures found in cancers induced by cigarette smoke.

New Antifreeze Molecule Found in Alaska Beetle

Scientists have identified a novel antifreeze molecule in a freeze-tolerant Alaska beetle able to survive temperatures below minus 100 degrees Fahrenheit. Unlike all previously described biological antifreezes that contain protein, this new molecule, called xylomannan, has little or no protein. It is composed of a sugar and a fatty acid and may exist in new places within the cells of organisms. "The most exciting part of this discovery is that this molecule is a whole new kind of antifreeze that may work in a different location of the cell and in a different way," said Dr. Brian Barnes, director of the University of Alaska Fairbanks Institute of Arctic Biology and one of five scientists who participated in the Alaska Upis ceramboides beetle project. A possible advantage of this novel molecule comes from it having the same fatty acid that cell membranes do. This similarity, said Dr. Barnes, may allow the molecule to become part of a cell membrane and protect the cell from internal ice crystal formation. Antifreeze molecules made of proteins may not fit into cell membranes. This report was featured as one of the cover articles in the December 1 issue of PNAS. [Press release] [PNAS abstract]

Corn Genome Sequence Is Detailed

A four-year, multi-institutional effort culminated today in publication of a landmark series of papers in the journal Science, revealing in unprecedented detail the DNA sequence of maize (Zea mays). Maize, or corn, as it is commonly called by North American consumers, is one of the world's most important plants and the most valuable agricultural crop grown in the United States, representing $47 billion in annual value. The sequence spans 2.3 billion DNA base-pairs and contains some 32,500 genes, or about one-third more than the human genome, according to the team that assembled it over the last four years. This version of the maize genome--taken from a variant called B73--is important, in part, because it is regarded by the scientific and agricultural communities as a "reference" version. It represents a significant filling-in of gaps in a draft maize sequence announced a year and a half ago, but more importantly, comes with what amounts to a detailed reference manual, a set of comprehensive annotations. "What's important about the maize project," said Dr. W. Richard McCombie, a Cold Spring Harbor Laboratory (CSHL) professor, a co-principal investigator on the maize genome project, and a pioneer in genome sequencing efforts, "is that it provides a reference DNA sequence for the most important agricultural crop in the U.S., making it much easier for people to look at the many variants of different strains or 'accessions' of maize." New sequencing technologies, just now becoming commercially viable, will now be used to "analyze other maize strains by comparing them to this one--albeit at dramatically lower costs and accelerated speeds," Dr. McCombie noted. Another of the co-project leaders from CSHL, Professor Robert Martienssen, put the maize sequencing project into historical perspective.

Stanford Mouse Study Suggests Possible Help for Down Syndrome

New findings from researchers at the Stanford University School of Medicine and Lucile Packard Children's Hospital, and colleagues, shed light on the neural basis of memory defects in Down syndrome and suggest a new strategy for treating the defects with medication. The study, which was conducted in mice, is the first to show that boosting norepinephrine signaling in the brains of mice, which have been genetically engineered to mimic Down syndrome, improves their cognition. Norepinephrine is a neurotransmitter that nerve cells use to communicate. The scientists said that their findings raise the possibility that restoring norepinephrine-mediated neurotransmission could reverse cognitive dysfunction in Down syndrome. "If you intervene early enough, you will be able to help kids with Down syndrome to collect and modulate information," said Dr. Ahmad Salehi, the first author of the study. "Theoretically, that could lead to an improvement in cognitive functions in these kids." The results give "a ray of hope and optimism for the Down syndrome community for the future," said Dr. Melanie Manning, director of the Center for Down Syndrome at Lucile Packard Children's Hospital. Dr. Manning was not a part of the research team. "It's very exciting," she said. "We still have a long way to go, but these are very interesting results." This report was featured as the cover story of the November 18 issue of Science Translational Medicine. [Press release] [Science Translational Medicine abstract]

Female Mountain Goats May Be Conflicted over Mate Choice

Mountain goats are no exception to the general rule among mammals that larger males sire more and healthier offspring. But University of Alberta researcher Dr. David Coltman and colleagues have recently found a genetic quirk that might make female mountain goats think twice about their prospective mates. The larger males pass their physical attributes and mating success to their male heirs. But Dr. Coltman's data shows the daughters of these larger males are routinely smaller and less fit than females produced by physically more modest fathers. Life on the side of a mountain favors bigger, healthier animals, both male and female. Dr. Coltman's research shows that this anomaly could have implications for female mate choice, because a female that mates with a large, dominant male can expect to have larger sons, but smaller and less fit daughters. The research also poses the question of why female offspring sired by the dominant male would be compromised. Another question the study raises is: what if any consideration does the size of their daughters have for would-be mothers? Could this be a factor weighed by a sexually mature female when courted by males that come in a variety of sizes? This study was featured as the cover story of the November 22 issue of the Proceedings of the Royal Society B. [Press release] [PRS abstract]

Nano “Fly Paper” Captures Metastatic Cancer Cells for Testing

Just as fly paper captures insects, an innovative new device with nano-sized features developed by researchers at UCLA is able to capture cancer cells in the blood that have broken off from a tumor. These cells, known as circulating tumor cells, or CTCs, can provide critical information for examining and diagnosing cancer metastasis, determining patient prognosis, and monitoring the effectiveness of therapies. The current gold standard for examining the disease status of tumors is an analysis of metastatic solid biopsy samples, but in the early stages of metastasis, it is often difficult to identify a biopsy site. By capturing CTCs, doctors can essentially perform a "liquid" biopsy, allowing for early detection and diagnosis, as well as improved treatment monitoring. To date, several methods have been developed to track these cells, but the UCLA team's novel "fly paper" approach may be faster and cheaper than others, and it appears to capture far more CTCs. The UCLA team developed a 1-by-2-centimeter silicon chip that is covered with densely packed nanopillars and looks like a shag carpet. To test cell-capture performance, researchers incubated the nanopillar chip in a culture medium with breast cancer cells. As a control, they performed a parallel experiment with a cell-capture method that uses a chip with a flat surface. Both structures were coated with anti-EpCAM, an antibody that can help recognize and capture tumor cells. The researchers found that the cell-capture yields for the UCLA nanopillar chip were significantly higher; the device captured 45 to 65 percent of the cancer cells in the medium, compared with only 4 to 14 percent for the flat device. The time required for CTC detection using CellSearch, a technology currently approved by the U.S.

Evolution of Highly Toxic Box Jellyfish

With thousands of stinging cells that can emit deadly venom from tentacles that can reach ten feet in length, the fifty or so species of box jellyfish have long been of interest to scientists and to the public. Yet little has been known about the evolution of this early branch in the animal tree of life. An international team of researchers has now largely unraveled the evolutionary relationships among the various species of box jellyfish, thereby providing insight into the evolution of their toxicity. “By determining the relationships among the different box jellyfish, some of which are capable of killing a healthy human, this study can help in the future development of antivenoms and treatments for their stings,” said Dr. Allen Collins, a specialist in Cnidaria, the phylum of animals that includes box jellyfish, and senior author of the report. “Researchers will now be able to make more informed choices about organisms for future venom studies, and make predictions on which species are likely to be of public health concern in addition to the known culprits.” Box jellies--also called sea wasps, stingers, or fire jellies--live primarily in warm coastal waters around the world. They are particularly well known in Australia, the Philippines and the rest of Southeast Asia, but they also occur in Hawaii and in waters off the United States Gulf and East Coasts. Their toxicity varies among species and ranges from being completely harmless to humans to causing death within minutes after a sting. Beyond their toxicity, box jellyfish have other interesting characteristics. Some species, for instance, have as many as 24 eyes, capable of sensing light and forming an image of their surroundings.

Mouse Results Suggest Possible Drug Treatment for Huntington’s Disease

Researchers have found that normal synaptic activity in nerve cells (the electrical activity in the brain that allows nerve cells to communicate with one another) protects the brain from the misfolded proteins associated with Huntington's disease. In contrast, excessive extrasynaptic activity (aberrant electrical activity in the brain, usually not associated with communication between nerve cells) enhances the misfolded proteins' deadly effects. In addition, the scientists found that the drug Memantine, which is approved to treat Alzheimer's disease, successfully treated Huntington's disease in a mouse model by preserving normal synaptic electrical activity and suppressing excessive extrasynaptic electrical activity. "Chronic neurodegenerative diseases like Huntington's, Alzheimer's, and Parkinson's are all related to protein misfolding," said Dr. Stuart Lipton of the Burnham Institute for Medical Research, senior author of the report. "We show here, for the first time, that electrical activity controls protein folding, and if you have a drug that can adjust the electrical activity to the correct levels, you can protect against misfolding. Also, this verifies that appropriate electrical activity is protective, supporting the 'use it or lose it theory' of brain activity at the molecular level. For example, this finding may explain why epidemiologists have found that 'using' your brain by performing crossword puzzles and other games can stave off cognitive decline in diseases like Alzheimer's." A small human clinical trial of Memantine for Huntington's disease has recently shown positive effects. Larger, international clinical trials are now being planned. In addition to Dr. Lipton, the article’s authors included Dr. Michael Hayden of the University of British Columbia.

Rasberry Ants on the March

The invasion of a new species of ant (Rasberry ants) has scientists intrigued, businesses concerned, and fire ants running for the hills, said Dr. Jerry Cook, an entomologist at Sam Houston State University. Dr. Cook and other scientists are at a loss to explain the fast and furious spread of the rapacious ant, which is named after exterminator Tom Rasberry, who discovered the ant in 2002. The ant was discovered in Houston in 2002 and has quickly spread as far north as Louisiana and Mississippi within the last year. "This is a species that we do not know much about. Presumably the ant came from the Caribbean through the Port of Houston," Dr. Cook said. "We know the ant is in the Paratrechina genus and is capable of growing a population of billions and they need to eat. They especially like other bugs, like fire ants and honey bees." The population is growing so fast, and so large, that it is potentially an ecosystem disaster, according to Dr. Cook. "If the Rasberry ant can virtually eliminate a pain like the fire ant, what else is it capable of doing?" he asked. "If bees are eliminated, plants will not be pollinated which could result in the lack of crops producing fruits and vegetables. That in turn becomes a major problem for the agriculture community. They could become more than a nuisance, they could become a danger." Dr. Cook emphasized the need for funding for research targeted at better understanding of the Rasberry ant. [Press release]

Absence of LKB1 Gene Increases Insulin Production

Eliminating the LKB1 gene from the beta cells of the pancreas causes the production and secretion of more insulin than from normal beta cells in a mouse model, according to researchers from the Hebrew University of Jerusalem and collaborators. This results in an enhanced response to blood glucose levels. The findings have potentially significant implications for those suffering from diabetes due to insufficient production of insulin in the pancreas. Because it was shown that LKB1 negatively regulates both insulin content and secretion, the way has now been opened to possible development of a novel therapy that would limit the presence of this gene in pancreas beta cells, thus enhancing insulin secretion. This work was reported in the October 7 issue of Cell Metabolism. [Press release] [Cell Metabolism abstract]

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