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April 2nd, 2011

50 Breast Cancer Genomes Sequenced

In one of the largest cancer genomics investigation reported to date, scientists have sequenced the whole genomes of tumors from 50 breast cancer patients and compared them to the matched DNA of the same patients' healthy cells. This comparison allowed researchers to find mutations that only occurred in the cancer cells. The scientists uncovered incredible complexity in the cancer genomes, but also got a glimpse of new routes toward personalized medicine. The work was presented at the American Association for Cancer Research 102nd Annual Meeting 2011. In all, the tumors had more than 1,700 mutations, most of which were unique to the individual, says Dr. Matthew J. Ellis, professor of medicine at Washington University School of Medicine in St. Louis and a lead investigator on the project. "Cancer genomes are extraordinarily complicated," Dr. Ellis says. "This explains our difficulty in predicting outcomes and finding new treatments." To undertake the massive task, Washington University oncologists and pathologists at the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine collaborated with the university's Genome Institute to sequence more than 10 trillion chemical bases of DNA — repeating the sequencing of each patient's tumor and healthy DNA about 30 times to ensure accurate data. "The computing facilities required to analyze this amount of data are similar in scale to those of the Large Hadron Collider, used to understand the workings of sub-atomic particles," Dr. Ellis says. The DNA samples came from patients enrolled in a clinical trial that Dr. Ellis is leading for the American College of Surgeons Oncology Group. All patients in the trial had what is called estrogen-receptor-positive breast cancer.

April 1st

MicroRNA Marker for Lung Cancer Metastasis to Brain

Conducting genetic profiles using microRNA can help doctors predict which lung cancer patients are likely to also develop brain metastasis (BM), according to a study published by Scottsdale Healthcare and the Translational Genomics Research Institute (TGen) and collaborating institutions. The study identified microRNA-328 as a potential therapeutic target because of its association with the spread of cancer to the brain in patients with non-small cell lung cancer (NSCLC). NSCLC makes up 88 percent of the 222,000 annual U.S. cases of lung cancer, which is by far the most common of all cancers among Americans. "This is one of the first studies using microRNA to identify lung cancer patients at risk for developing or likely to have brain metastasis," said Dr. Glen Weiss, the paper's senior author and Director of Thoracic Oncology at TGen Clinical Research Services (TCRS) at Scottsdale Healthcare. TCRS is a partnership between TGen and Scottsdale Healthcare that helps bring new therapies quickly to patients at the Virginia G. Piper Cancer Center in Scottsdale. The paper was published online on March 29, 2011, in the International Journal of Cancer. MicroRNAs are single-stranded RNA molecules that regulate how genes and proteins control cellular development. Because microRNAs are so resilient, they are relatively easy to detect in tumor tissue and blood, which is often a limitation for other biomarkers. In addition, one microRNA can regulate hundreds of genes. "Previous efforts to characterize patients that will develop brain metastasis have been fairly disappointing," said Dr. Weiss. BM can cause neurologic, cognitive, and emotional difficulties.

Studies Focus on Invasive Ladybug

A University of Georgia researcher studying invasive ladybugs has developed new models that help explain how these insects have spread so quickly and their potential impacts on native species. In recent years, some people have noticed swarms of ladybugs massing in the fall, even infesting their homes. These are Asian lady beetles, insects native to eastern Asia, introduced to the U.S. as a biocontrol for aphids and they have since spread throughout the country and into Canada. When he found the beetles in his own home, Assistant Research Scientist Dr. Richard Hall, of the UGA Odum School of Ecology, was motivated to learn more about them. Dr. Hall knew that the Asian lady beetle had only recently, in 2004, arrived in his native England, and is already found all over the U.K. Data collected as part of a citizen science effort based at Cambridge University shows it to be one of the fastest documented invasions ever by an insect. He also knew that in the U.S., the Asian lady beetle has excluded many indigenous ladybugs from parts of their original range. “I wanted to know how this insect could have invaded the U.K. so quickly,” Dr. Hall said. “And I also wanted to know what the impacts on native species are likely to be.” He has just published two new papers that explore these questions in the journals Biology Letters and Ecology. “What makes this insect a good biocontrol also makes it a good invader,” Dr. Hall said. “It has multiple generations per year, compared to just one for native British ladybugs. It tolerates a wide range of environmental conditions. And it has a generalist diet—it likes aphids, but it will also eat other ladybugs. In other words, it eats its own competition.” Dr.

March 31st

Supposedly Inactive Protein Proves Key to Parasitic Disease

Researchers from the University of Pittsburgh and Stanford University have discovered that a supposedly inactive protein actually plays a crucial role in the ability of one the world’s most prolific pathogens to cause disease, findings that suggest the possible role of similar proteins in other diseases. The team reported online on March 21, 2011, in PNAS that Toxoplasma gondii—the parasitic protozoan responsible for toxoplasmosis—attacks healthy cells by first injecting them with pseudokinases, which are enzymes that have abandoned their original function of transferring phosphates. When the researchers engineered strains of T. gondii without a particular pseudokinase gene cluster called ROP5, the pathogen was subsequently unable to cause disease in mice—a notable loss of potency in an organism that can infect nearly any warm-blooded animal. These results are among the first to implicate pseudokinases as indispensible actors in pathogen-based disease, said senior author Dr. Jon Boyle, a professor in the Department of Biological Sciences in Pitt’s School of Arts and Sciences. Dr. Boyle co-authored the paper with Dr. John Boothroyd, a professor of microbiology and immunology in the Stanford School of Medicine. Drs. Boyle and Boothroyd worked with Dr. Michael Reese, a postdoctoral researcher in Dr. Boothroyd’s lab, as well as Drs. Gusti Zeiner and Jeroen Saeij, former postdoctoral researchers under Dr. Boothroyd. The Pitt-Stanford project suggests that the significance of these “functionless” enzymes to T. gondii could apply to pseudokinases in other pathogens, Dr. Boyle said, including the parasite’s close relative Plasmodium, which causes malaria. “Our work shows that just because these proteins have lost their original function does not mean they don’t do anything,” Dr. Boyle said. “T.

Odor May Be Used to Combat Bed Bugs

Bed bugs are an increasingly common pest that necessitates extensive decontamination of homes. However, researchers from Lund and Sundsvall in Sweden have now discovered that young bed bugs produce an odor that repels other bed bugs. It is hoped that these findings could contribute to more effective control of the blood-sucking insects. In recent years, bed bug infestations have become increasingly common in Swedish homes. There are two different species of bed bug that suck blood from humans – the common bed bug and the tropical bed bug. Increased foreign travel has meant that tropical bed bugs frequently accompany travellers to Sweden. A team of researchers from Lund University and Mid Sweden University in Sundsvall has now identified and quantified a type of odor that bed bugs produce using alarm pheromones. The researchers have studied the odors in both adult bed bugs and nymphs (immature bed bugs). The research team observed that the odors given off by the two stages of insect are surprisingly similar. Moreover, nymphs give off a different odor from adult bed bugs. Behavioral tests show that the nymphs’ odor is repulsive to both adult individuals and other nymphs. The researchers believe that this repellent effect could be used in control systems where alarm pheromones make the bed bugs more mobile and therefore increase the effectiveness of drying agents to kill them. However, this type of possible environmentally friendly control method requires greater understanding of how bed bugs’ pheromone system works. The research results were published online on March 30, 2011, in the journal PloS ONE. [Press release] [PLoS ONE abstract]

Rare Genetic Variants Most Likely to Cause Disease, New Study Suggests

New genomic analyses suggest that the most common genetic variants in the human genome aren't the ones most likely causing disease. Rare genetic variants, the type found most often in functional areas of human DNA, are more often linked to disease, genetic experts at Duke University Medical Center report. The study was published online in the American Journal of Human Genetics on March 31, 2011. "The more common a variant is, the less likely it is to be found in a functional region of the genome," said senior author Dr. David Goldstein, director of the Duke Center for Human Genome Variation. "Scientists have reported this observation before, but this study is the most comprehensive effort to date using annotations of the functional regions of the human genome and fully sequenced genomes." Dr. Goldstein said that "the magnitude of the effect is dramatic and is consistent across all frequencies of variants we looked at." He also said he was surprised by the notable consistency of the finding. "It's not just that the most rare variants are different from the most common, it's that at every increase in frequency, a variant is less and less likely to be found in a functional region of the DNA," Dr. Goldstein said. "This analysis is consistent with what appears to be a growing consensus that common variants are less important in common diseases than many had originally thought." The researchers established simple criteria to learn which genetic variants were functional, based on their locations. They looked at the regions in genes that make proteins and also functional regions that influence the expression of proteins. The scientists sequenced the complete genomes of 29 people (of European origin) to assess the relationship between the functional properties of the variants and their population allele frequencies.

Obese Mice Produce Excess Micro-RNA That Blocks Effect of Insulin

Body weight influences the risk of developing diabetes: between 80 and 90 percent of patients with type 2 diabetes are overweight or obese. According to scientists at the Max Planck Institute for Neurological Research in Cologne and the Cologne Cluster of Excellence in Cellular Stress Responses in Aging-associated Diseases (CECAD), short ribonucleic acid molecules, known as micro-RNAs, appear to play an important role in this mechanism. The researchers discovered that obese mice form increased levels of the regulatory RNA molecule miRNA-143. miRNA-143 inhibits the insulin-stimulated activation of the enzyme AKT. Without active AKT, insulin cannot unfold its blood-sugar-reducing effect and the blood sugar level is thrown out of kilter. This newly discovered mechanism could provide the starting point for the development of new drugs for the treatment of diabetes. The hormone insulin plays a key role in the regulation of blood sugar levels. If there is too much glucose in the blood, insulin opens the glucose transport channels in the cell membrane of muscles and fat cells. Glucose then reaches the body's cells and the blood's sugar content drops. Additionally, the insulin inhibits the production of new sugar in the liver. Many Type 2 diabetics are able to produce sufficient volumes of insulin; however, their cells are resistant to it - and the hormone is unable to fulfill its task. If untreated, this disease damages the blood vessels due to the raised blood sugar levels, which can lead to a heart attack or stroke. The molecular processes in the body's cells responsible for the connection between body weight and diabetes are largely unknown. However, in all tissues that respond to insulin, micro-RNAs can be found. The Cologne-based scientists working with Dr.

Tet1 Protein’s Two-Pronged Approach to Stem Cell Maintenance

Last year, a research team at the University of North Carolina at Chapel Hill discovered one way the protein Tet 1 helps stem cells keep their pluripotency—the unique ability to become any cell type in the body. In two new studies, the team and collaborators take a broad look at the protein's location in the mouse genome, revealing a surprising dual function and offering the first genome-wide location of the protein and its product, 5-hydroxymethylcytosine—dubbed the "sixth base" of DNA. UNC biochemist Dr. Yi Zhang, whose team conducted the studies, called the findings an important step in understanding the molecular mechanisms behind cell differentiation and the development of cancer. The findings appear in two recent papers, published March 30, 2011 online in Nature and in the April 1, 2011 issue of Genes & Development. "There is no doubt that Tet proteins are relevant to cancer," said Dr. Zhang, Kenan distinguished professor of biochemistry and biophysics. Zhang is also an investigator of the Howard Hughes Medical Institute and a member of the UNC Lineberger Comprehensive Cancer Center. Tet proteins were initially discovered in leukemia as fusion proteins, which are commonly found in cancer cells, where they may function as oncoproteins. In addition, Zhang said, "Tet is likely to be one of the important players for stem cell reprogramming." Learning to "reprogram" cells in the adult body to make them behave like stem cells has long been a goal for stem cell researchers; understanding how Tet proteins operate could help advance stem-cell based treatments. Tet proteins are known to help stem cells stay pluripotent. Zhang's team analyzed Tet1's occupancy across the entire mouse embryonic stem cell genome.

Insight into Lignin Biosynthesis

Lignin is the durable biopolymer that gives carrots their fiber and crunch. Acting as the glue that holds the plant cell wall together, lignin imparts tremendous mechanical strength to the plant. Present in all land plants except mosses, lignin performs three important functions: it allows plants to grow upright as they compete for sunlight, it facilitates the upward movement of water and minerals through the plant's vascular tissue, and it protects plants from pathogens and foraging animals. Lignin also sequesters atmospheric carbon and thereby plays an important role in the carbon cycle. Approximately 30% of non-fossil organic carbon is stored in lignin, and, after cellulose, lignin is the most abundant biological polymer on Earth. Lignin consists of three phenylpropanoid subunits, G (guaiacyl), S (syringyl), and H (p-hydroxyphenyl). The precursors of these subunits are generated inside the cell and transported to the cell wall, where they are oxidized by enzymes and then join together to form lignin's highly complex and heterogeneous three-dimensional structure. Biologists have long wondered how this process of lignification is regulated. Two families of enzymes, the peroxidases and laccases, occur in plant cell walls and have been proposed to catalyze the oxidation of lignin precursors. Whereas the involvement of peroxidases in lignification has been confirmed, that of laccases had not. Now, a team of researchers at the Institut Jean Pierre Bourgin INRA, France, provide compelling evidence that laccases do indeed contribute to lignification in the model plant Arabidopsis (a member of the mustard and cabbage family). The work was published online in The Plant Cell on March 29, 2011. Seventeen laccase genes are present in Arabidopsis.

March 30th

Drug Helps Cure Chronic Hepatitis C Infections

The drug boceprevir helps cure hard-to-treat hepatitis C infections, says Saint Louis University investigator Dr. Bruce R. Bacon, an author of the March 31 New England Journal of Medicine article detailing study findings. The results, which were first reported at the 61st annual meeting of the American Association for the Study of Liver Disease's last November, offer a brighter outlook for patients who have not responded to standard treatment. Dr. Bacon, who is professor of internal medicine at Saint Louis University School of Medicine and co-principal investigator of the HCV RESPOND-2 study, studied the protease inhibitor boceprevir and found that it significantly increased the number of patients whose blood had undetectable levels of the virus. "These findings are especially significant for patients who don't respond to initial treatment," said Dr. Bacon. "When the hepatitis C virus is not eliminated, debilitating fatigue and more serious problems can follow." Hepatitis C is caused by a virus that is transmitted by contact with blood. The infection may initially be asymptomatic, but for patients who develop chronic hepatitis C infection, inflammation of the liver may develop, leading to fibrosis and cirrhosis (scarring of the liver), as well as other complications including liver cancer and death. The prognosis varies for patients with chronic hepatitis C. With the current standard therapy, about half fully recover after an initial course of peginterferon and ribavirin anti-viral therapy that may last from six months to a year. The remaining patients, known as non-responders, may improve with initial treatment but the virus is not eliminated, or may not respond to treatment at all.