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Next-Gen Sequencing Reveals Single Genetic Change in Some Ovarian Cancers

Using powerful “next-generation” sequencing technology, researchers in Canada have sequenced the entire genome of a rare and often untreatable form of ovarian cancer (granulosa cell tumors) from four individuals and shown that the tumors share a single base change in the gene FOXL2. This gene encodes a transcription factor known to be critical for granulosa cell development. The research team further validated its work by examining a large number of additional tumor samples from across Canada and around the world, and the team is satisfied it has been able to validate that this mutation is present in almost all granulosa cell tumors and not in unrelated cancers. Most types of cancers, including most ovarian cancers, have a broad range of genetic abnormalities. The current finding shows that granulosa cell tumors have a characteristic single DNA spelling mistake that can serve as an easy-to-read identity tag for this cancer type. "This is really a two-fold discovery," said Dr. David Hunstman, senior author of the research report. "It clearly shows the power of the new generation of DNA sequencing technologies to impact clinical medicine, and for those of us in the area of ovarian cancer research and care, by identifying the singular mutation that causes granulosa cell tumours, we can now more easily identify them and develop news ways to treat them." For this effort, the research team used next-generation sequencing machines that are able to decode billions of nucleotides at rapid speed, together with new computer techniques to quickly assemble the data. "This task would have been unfathomable in terms of both cost and complexity even two years ago," said Dr. Marco Marra, also an author of the report. This work was published in the June 11 issue of the New England Journal of Medicine.

Four New Targets (LPA Pathway) for Breast Cancer Therapies

Researchers at the M.D. Anderson Cancer Center have identified four related new potential targets for breast cancer therapies. These potential targets are three lysophosphatidic acid (LPA) receptors (LPA1, LPA2, and LPA3) and the LPA-producing enzyme, autotoxin (ATX). "Lysophosphatidic acid is the single most potent known cellular survival factor," said senior author Dr. Gordon Mills. It binds to a series of G protein-coupled receptors to spark normal cell proliferation, viability, production of growth factors, and survival. The current research shows that this powerful network is hijacked to initiate breast cancer and fuel tumor growth, invasion, and metastasis. The authors show that breast cancer-resistant mice, when engineered to overexpress any one of the four molecules, develop invasive and metastatic mammary cancers. “We've compiled lots of evidence that they (LPA1, LPA2, LPA3, and ATX) are associated with cancer; what's been missing is proof that they could cause cancer. There are no questions left; they should be targeted." A number of drugs that target the receptors and ATX are currently in preclinical development, Dr. Mills said. "Now we have transgenic mouse models to test drugs to go forward against these targets." The current research was published in the June edition of Cancer Cell. [Press release] [Cancer Cell abstract]

Beetle Shell May Be Clue to Whiter, Lighter Paper

The brilliant white shell of an obscure beetle (Cyphochilus) has provided scientists with insights as to how to produce a brighter coating for white paper. The novel coating would also be thinner and lighter than current coatings and this would translate into reduced transportation costs, while simultaneously reducing the economic and environmental costs of manufacture. Cyphochilus is native to south-east Asia, and it is believed that its whiteness evolved to mimic local white fungi as a form of camouflage. In 2007, research conducted at the University of Exeter and Imerys Minerals Ltd., and published in Science, revealed how the beetle produces its brilliant whiteness using a unique surface structure of long, flat, ultrathin scales with highly random internal 3-D structures--ideal for creating whiteness, which results from the scattering of all colors simultaneously. In the new work, members of the same research team showed how some of the beetle’s shell structure can be mimicked to produce thinner, whiter coatings for white paper. "It is interesting to consider that clues found in a small, obscure beetle could find application in large-scale industry,” one of the researchers noted. “Taking this concept forward is an interesting challenge, but we have good ideas about our next steps and, if successful, feel that such developments might have profound implications for future commercial white coatings.” The current research was published in the June 10 issue of Applied Optics. [Press release] [Applied Optics abstract]

Termite Results Suggest Non-Toxic Approach to $30 Billion Pest Problem

Scientists at MIT and collaborating institutions have shown that a naturally occurring, non-toxic glucose derivative, GLD, can be used to compromise the immunity of termites and make them more vulnerable to lethal microbial infections. Insect pests such as termites cause damage to crops and man-made structures estimated at over $30 billion per year, imposing a global challenge on the human economy, the authors noted. They said that the use of GLD may lead to the development of non-toxic, sustainable pest control methods. Termites normally secrete a form of an antimicrobial protein into their nests to prevent pathogenic infections. The authors reported a technique to block this protein’s effects with GDL. They found that adding GDL to termite nests caused the termites to die more quickly at the hands of fungi that normally infect termites, as well as at the hands of opportunistic bacteria. The authors suggested that GDL, which is also biodegradable, and other similar molecules could be developed for food processing and storage and for use in building materials to protect against insect attacks. Plants could be engineered to produce GDL at high amounts in specific locations to increase their immunity, the authors suggested. This work was published online on June 8 in PNAS. [PNAS abstract]

New Angiogenesis Target Discovered

A new angiogenesis-promoting growth factor has been identified by researchers at the University of North Carolina and collaborating institutions. The newly identified growth factor protein, SFRP2, was found in the blood vessels of numerous tumor sites, including breast, prostate, lung, pancreas, ovarian, colon, kidney, and angiosarcomas. “The discovery that SFRP2 stimulates angiogenesis and is present in blood vessels of a wide variety of tumors provides us with a new target for drug design,” said Dr Nancy Klauber-DeMore, the senior author of the study. One growth factor that causes angiogenesis has been previously identified--vascular endothelial growth factor or VEGF--and drugs to inhibit VEGF are already in use. But not all tumors respond to the therapy initially or over the long term. Thus, new growth factors need to be identified to aid in developing the next generation of angiogenesis inhibitors. The current work was reported online in Cancer Research. [Press release]

Primary Insomnia Linked to Neurochemical Abnormality

For the first time, researchers have identified a specific neurochemical abnormality in adults with primary insomnia. Primary insomnia is difficulty getting to sleep or staying asleep, or having non-refreshing sleep, for at least one month without any known physical or mental condition. The current study results indicate that gamma-aminobutyric acid (GABA), the most common inhibitory transmitter in the brain, is reduced by nearly 30 percent in individuals who suffer from primary insomnia for more than six months. These findings suggest that primary insomnia is a manifestation of a neurobiological state of hyperarousal, which is present during both waking and sleep at physiological and cognitive levels. "Recognition that insomnia has manifestations in the brain may increase the legitimacy of those who have insomnia and report substantial daytime consequences," said Dr. John Winkelman, of Brigham and Women’s Hospital at Harvard Medical School, the principal investigator on the study. "Insomnia is not just a phenomenon observed at night, but has daytime consequences for energy, concentration, and mood." This work was reported June 9 at SLEEP 2000, the 23rd Annual Meeting of the Associated Professional Sleep Societies. [Press release]

Active Microenvironment May Provide Treatment Targets for Prostate Cancer

In a study of the response of prostate stroma (the surrounding structural framework of the prostate gland) to prostate cancer, researchers at the Baylor College of Medicine have identified 1,141 genes whose expression is altered in this response. Among the gene expression changes are ones that induce the formation of new structures such as blood vessels, nerves, and parts of nerves. These changes may explain why men with reactive stroma face a more aggressive disease, said Dr. Michael Ittmann, a senior author of the report. "Often in prostate cancer, you don't see much change in the stromal cells," said Dr. Ittmann. "However, in this subgroup of patients (in which the stroma become visibly reactive), you see a histologically recognizable change in the appearance of the stroma. Dr. (Gustavo) Ayala (another senior author of the report) has shown previously that this correlates with a bad prognosis. We know the stroma are doing something to promote bad behavior in cancer cells." "These findings are very important as this is the first step in discovering pathways and mechanisms in the tumor microenvironment that could be targeted as a novel therapeutic approach to treat prostate cancer by treating the cancer microenvironment niche,” said Dr. David Rowley, another author of the report, which was published in Clinical Cancer Research. [Press release]

Genetic Roots of Animal Tameness Discovered in Rats

In breeding studies conducted in rats, an international team of researchers has identified genomic regions associated with tameness. The discovery could help animal breeders, farmers, zoologists, and anyone else who handles and raises animals to more fully understand what makes some animals interact with humans better than do others. It may also lead to more precise breeding strategies designed to pass specific genes from one generation to the next as a way to produce tame animals. “I hope our study will ultimately lead to a detailed understanding of the genetics and biology of tameness," said Dr. Frank Albert, the lead author of the research report. "Maybe we'll then be able to domesticate a few of those species where humans have historically not been successful, like the wild African Buffalo." For this study, two groups of rats, one bred for tameness toward humans and the other bred for aggressiveness toward humans, were mated with each other and genomic regions associated with tameness and with aggressiveness were identified. The senior author of this study was Dr. Svante Paabo. The research was published in the June issue of Genetics. [Press release] [Genetics abstract]

New Class of Alkaloids Found in Amazonian Poison Frogs

Scientists have identified a new class of alkaloids in some Amazonian poison frogs (family Dendrobatidae). The class of alkaloids, N-methyldecahydroquinolines, has not been previously identified in the frogs or, it is believed, in nature. Senior author Dr. H. Martin Garraffo and colleagues noted that there are more than 500 alkaloids, potentially toxic substances, known to exist in the skin of poison frogs of the family Dendrobatidae. The frogs use the alkaloids as a chemical defense to discourage predators from biting and eating them. Western Colombian natives have used skin extracts from another group of frogs, unrelated to those in the new study, to coat blow-darts for hunting. The frogs obtain nearly all of the alkaloids from their diet--removing the chemicals from ants, mites, small beetles, millipedes, and possibly other small arthropods; concentrating them with incredible efficiency; and storing them in their skin. Although the researchers speculate that the frogs could get the new alkaloids from ants, they are, in fact, not certain about the origin of the chemicals, which could also be produced in the frogs' own bodies. Feeding experiments with alkaloids fed to captive frogs are planned, which might settle this point. This work was published online ahead-of-print in the American Chemical Society’s Journal of Natural Products and is scheduled for publication in the June 26 issue of the journal. [Journal of Natural Products article]

Lifespan-Extending Mutations Activate Germ Cell Pathways in Somatic Cells

Scientists at Massachusetts General Hospital and Harvard Medical School have shown that mutations extending lifespan in the experimental roundworm C. elegans induce expression of germline genes and pathways in somatic cells. "C. elegans mutants with extreme longevity accomplish this feat, in part, by adopting genetic programs, normally restricted to the germline, into somatic cells," said Dr. Sean Curran, the study's lead author. "We know that germline cells are more stable than somatic cells--they live longer and are more resistant to stresses that damage other cells--and understanding the molecular pathways involved in that stability may someday allow us to devise therapies protective against age-related decline in other tissues." Earlier, senior author Dr. Gary Ruvkun and other researchers had discovered that simple mutations in genetic pathways conserved throughout evolution can double or triple the lifespan of C. elegans, and that similar mutations in the corresponding pathways also dramatically extend mammalian lifespan. "The idea that somatic cells can reacquire genetic pathways usually restricted to germline cells is fascinating, and since germline protection is seen across species, the activity of these genes may play a role in controlling mammalian lifespan," said Dr. Ruvkun. "Understanding the mechanisms involved in this transformation could help us develop new ways to repair and even regenerate key cells and tissues." Dr. Ruvkun was a co-recipient of the 2008 Lasker Award for Basic Medical Research for his role in discovering that tiny molecules of RNA can control the activity of critical genes. The current research was published online in Nature on June 7.

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