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Archive - Mar 2011

March 19th

Llama Antibodies Provide Clues to Novel Treatment of Virulent Hospital Infection

Clostridium difficile is a health problem that affects hundreds of thousands of patients and costs $10 billion to $20 billion every year in North America. Researchers from the University of Calgary and the National Research Council of Canada and colleagues say they are gaining a deeper understanding of this disease and are closer to developing a novel treatment using antibodies from llamas. "We have found that relatively simple antibodies can interfere with the disease-causing toxins from C. difficile," said paper co-author Dr. Kenneth Ng, an associate professor of biological sciences at the University of Calgary and principal investigator of the Alberta Ingenuity Centre for Carbohydrate Science. "This discovery moves us a step closer to understanding how to neutralize the toxins and to create novel treatments for the disease." His research is part of a paper published in the March 18, 2011 issue of the Journal of Biological Chemistry. Approximately two percent of all patients admitted to hospital may be infected by C. difficile, which thrives when healthy bacteria in the gut are weakened by antibiotics, thus allowing spores from Clostridium to germinate and colonize the large intestine. "This research is significant because C. difficile is an increasing heath care problem and many people may experience multiple infections," said Dr. Glen Armstrong, head of the Department of Microbiology, Immunology, and Infectious Diseases in the Faculty of Medicine at the University of Calgary. "The current treatments are becoming less effective and C. difficile is developing resistance to conventional antibiotics. This research promises to provide a much-needed alternate treatment option that will overcome the failings of conventional antibiotics." C.

March 18th

Protein Is Promising Candidate for New TB Vaccine

Scientists have discovered a protein secreted by tuberculosis (TB) bacteria that could be a promising new vaccine candidate, they report online on March 18, 2011, in PNAS. The protein could also be used to improve diagnosis of TB. TB is caused by the bacterium Mycobacterium tuberculosis (MTB), which infects the lungs and spreads through the air as a result of coughing. There are 9 million new cases of TB each year, killing 4,700 people a day worldwide. BCG, an attenuated mycobacterial strain, is the only available vaccine but it is of limited effectiveness in protecting against TB. BCG derives from the Mycobacterium bovis bacterium, which infects cattle and is closely related to MTB. Vaccines work by stimulating the immune system to retain a memory of particular molecules from a microbe that will trigger a rapid immune response if the microbe is encountered later. The best candidates for vaccines are those that trigger the strongest response from the immune system. In the new study, scientists identified a protein, called EspC, that triggers a stronger immune response in people infected with the TB bacterium than any other known molecule. This protein is secreted by the TB bacterium but not by the BCG vaccine. As a result, the BCG vaccine does not induce an immune response to this protein, so deploying it as a new TB vaccine would provide additive immunity over and above that provided by BCG. The protein could also be useful as a diagnostic tool, because an immune response to it is seen in TB-infected people, but not in non-infected people who have had a BCG vaccine. Detecting immune responses to it would distinguish BCG-vaccinated people from TB-infected people, which the currently-used tuberculin skin prick test (the Mantoux test) is unable to do.

Scientists Show Enzyme Family Plays Key Role in Cell Motility

Researchers at Albert Einstein College of Medicine of Yeshiva University and colleagues have discovered that members of an enzyme family found in humans and throughout the plant and animal kingdoms play a crucial role in regulating cell motility. Their findings suggest an entirely new strategy for treating conditions ranging from diabetic ulcers to metastatic cancer. Dr. David Sharp, associate professor of physiology & biophysics, was the senior author of the study, which was published online on March 6, 2011, in Nature Cell Biology. "Cells in our bodies are in constant motion, migrating from their birth sites to distant targets," said Dr. Sharp. "Cellular movement builds our tissues and organs and underlies key functions such as the immune response and wound healing. But uncontrolled cell migration can lead to devastating problems including mental retardation, vascular disease, and metastatic cancer." Dr. Sharp and his colleagues found that certain members of an enzyme family known as katanins concentrate at the outer edge of non-dividing cells where they break up microtubules – dynamic intracellular polymers that regulate cell movement by controlling the formation of protrusions called lamellipodia. When Dr. Sharp's team treated motile cells of the fruit fly Drosophila with a drug that inhibited katanin production, the treated cells moved significantly faster than control cells and with a striking increase in high-velocity movements, indicating that katanin prevents cells from moving too rapidly or in an uncontrolled manner. The researchers observed similar effects with katanin when they examined human cells. "Our study opens up a new avenue for developing therapeutic agents for treating wounds – burns and diabetic ulcers, for example – as well as metastatic disease," added Dr. Sharp.

March 17th

New Research Tool Targets MicroRNA Expression

A new research tool for studying microRNA expression in zebrafish will help researchers analyze the effects of microRNA (miRNA) on the early development of this model organism and better understand developmental and disease mechanisms in humans, as described in Zebrafish, a peer-reviewed journal published by Mary Ann Liebert, Inc. The article is available free online ahead of print. Researchers from University of Oregon (Eugene) have developed a novel, cost-effective method for measuring the expression of miRNAs in specific tissues in developing zebrafish embryos. miRNAs play an important role in regulating embryonic development. They are difficult to detect because they are very short strands of oligonucleotide and are often present in cells at low levels. Drs. Xinjun He, Yi-Lin Yan, April DeLaurier, and John Postlethwait describe the efficient technique they devised using digoxigenin-labeled riboprobes (oligonucleotide-based probe sequences capable of binding to a complementary miRNA sequence) in in situ hybridization (ISH) experiments. "This is a terrific new addition to the zebrafish toolbox, opening the door to an array of new experiments focused on the biology of non-coding RNAs using this superb model system," said Dr. Stephen Ekker, Editor-in-Chief of Zebrafish and Professor of Medicine at the Mayo Clinic, Rochester, Minnesota. [Press release] [Zebrafish abstract]

New Clinical Guidelines on Diagnosis and Management of Idiopathic Pulmonary Fibrosis

The American Thoracic Society has released new official clinical guidelines on the diagnosis and management of idiopathic pulmonary fibrosis (IPF). The statement replaces ATS guidelines published in 2000, and reviews current knowledge in the epidemiology, etiology, diagnosis and management of IPF, as well as available treatment options, including pharmacologic and non-pharmacologic therapies and palliative care. The statement appears in the March 15, 2011 issue of American Journal of Respiratory and Critical Care Medicine. IPF is a chronic, progressive, fatal form of fibrotic lung disease, characterized by shortness of breath during exertion, which occurs primarily in relatively older adults. The etiology of IPF is unclear. The disease occurs when injury to the lungs is triggered by an unknown cause, resulting in the formation of scar tissue that causes the lungs to become thickened and stiff. IPF may progress slowly over several years and may be punctuated by episodes of acute respiratory decline. Lung transplantation is a feasible treatment option in highly selected patients. A subgroup of patients with IPF has a genetic predisposition to the disease. "In the decade since the publication of the previous statement on IPF, studies have used the criteria for the diagnosis of IPF and recommendations published in the previous consensus-based statement to further our understanding of the clinical manifestations and course of IPF, and there has been an increasing body of evidence pertinent to its clinical management," said Dr. Ganesh Raghu, director of the Interstitial Lung Disease/Sarcoid/Pulmonary Fibrosis Program at the University of Washington Medical Center in Seattle and chair of the collaborative committee that drafted the statement.

Bacteria More Likely to Adopt “Loner” Genes

A new study of more than three dozen bacteria species — including the microbes responsible for pneumonia, meningitis, stomach ulcers and plague — settles a longstanding debate about why bacteria are more likely to steal some genes than others. While most organisms get their genes from their parents just as people do, bacteria and other single-celled creatures also regularly pick up genes from more distant relatives. This ability to 'steal' snippets of DNA from other species — known as lateral gene transfer — is responsible for the rapid spread of drug resistance among disease-causing bacteria. "By understanding why some genes are more likely to spread from one species to the next, we can better understand how new virulent bacterial strains emerge," said co-author Dr. Tal Pupko, a visiting scientist at the National Evolutionary Synthesis Center in Durham, North Carolina. Scientists have proposed several theories to explain why some bacterial genes are more likely to jump into other genomes. One theory, Dr. Pupko explained, is that it depends on what the gene does in the cell. Genes involved in core functions, like converting RNA into protein, are much less likely to make the leap. "If a species already has the basic molecular machinery for transcription and translation, there's no advantage to taking in another set of genes that do the same thing," Pupko said. Other studies suggest it's not what the gene does that matters, but how many proteins it interacts with – a network researchers have dubbed the 'interactome.' Genes involved in transcription and translation, for example, must work in concert with many partners to do their job.

March 16th

Using Light to Move Molecules in Living Cells

Using a light-triggered chemical tool, Johns Hopkins scientists report that they have refined a means of moving individual molecules around inside living cells and sending them to exact locations at precise times. This new tool, they say, gives scientists greater command than ever in manipulating single molecules, allowing them to see how molecules in certain cell locations can influence cell behavior and to determine whether cells will grow, die, move or divide. A report on the work was published in the January 12, 2011 issue of the Journal of the American Chemical Society. Studying how just one signaling molecule communicates in various parts of a living cell has posed a challenge for scientists investigating how different interactions influence cell behavior, such as the decision to move, change shape or divide. "By using one magical chemical set off by light, we modified our previous technique for moving molecules around and gained much more control," said Dr. Takanari Inoue, assistant professor of cell biology and member of the Center for Cell Dynamics in the Institute for Basic Biomedical Sciences. "The advantage of using light is that it is very controllable, and by confining the light, we can manipulate communication of molecules in only a tiny region of the cell," he said. Specifically, the Hopkins team designed a way to initiate and spatially restrict the molecular interactions to a small portion of the cell by attaching a light-triggered chemical to a bulky molecule, the bond between which would break when researchers shined a defined beam of ultraviolet light on it. This enabled the chemical to enter the cell and force two different and specific proteins in that cell to mingle when they otherwise wouldn't.

Nanopolymer Used to Screen for Kinase Inhibitors

A Purdue University scientist's nanopolymer would make it easier and cheaper for drug developers to test the effectiveness of a widely used class of cancer inhibitors (kinase inhibitors). Dr. W. Andy Tao, an associate professor of biochemistry analytical chemistry and a member of the Purdue Center for Cancer Research team, created the Purdue-patented pIMAGO nanopolymer that can be used to determine whether cancer drugs have been effective against biochemical processes that can lead to cancer cell formation. The nanopolymers would attach themselves to target proteins that would later be detected by a relatively simple laboratory procedure called chemiluminescence. Tymora Analytical, a company Tao started in the Purdue Research Park, will manufacture the pIMAGO nanopolymers. The 'p' stands for phosphor, and the IMAGO comes from the Greek word for image. Tao's pIMAGO nanopolymers are coated in titanium ions and would attract and bond with phosphorylated proteins, ones in which a phosphate group has been added to a protein activating an enzyme called kinase. Kinase, when overactive, is known to cause cancer cell formation, and many cancer drugs are aimed at inhibiting kinase activity. “It is universal. You can detect any kind of phosphorylation in a protein," said Tao, whose findings were reported online on March 11, 2011, in the journal Analytical Chemistry. "It is also cheaper and would be more widely available." The nanopolymers would be added to a solution of proteins, a chemical agent to start phosphorylation and a drug to inhibit kinase activity. Phosphorylated proteins would only be present if the drug is ineffective. Avidin-HRP - the protein Avidin bound with the enzyme horseradish peroxidase - would be added. Avidin would bind with a vitamin B acid called biotin that is also on the nanopolymers' surfaces.

Some Blind “See” with Their Ears

Dr. Olivier Collignon of the University of Montreal's Saint-Justine Hospital Research Centre compared the brain activity of people who can see and people who were born blind, and discovered that the part of the brain that normally works with our eyes to process vision and space perception can actually rewire itself to process sound information instead. The research was undertaken in collaboration with Dr Franco Lepore of the Centre for Research in Neuropsychology and Cognition and was published in the March 15, 2011 issue of PNAS. The research builds on other studies which show that the blind have a heightened ability to process sounds as part of their space perception. "Although several studies have shown occipital regions of people who were born blind to be involved in nonvisual processing, whether the functional organization of the visual cortex observed in sighted individuals is maintained in the rewired occipital regions of the blind has only been recently investigated," Dr. Collignon said. The visual cortex is responsible for processing sight. The right and left hemisphere of the brain have one each. They are located at the back of the brain, which is called the occipital lobe. "Our study reveals that some regions of the right dorsal occipital stream do not require visual experience to develop a specialization for the processing of spatial information and are functionally integrated in the preexisting brain network dedicated to this ability." The researchers worked with 11 individuals who were born blind and 11 who were not. Their brain activity was analyzed via MRI scanning while they were subjected to a series of tones. "The results demonstrate the brain's amazing plasticity," Dr. Collignon said.

March 14th

Jagged2 Binding Drives Metastasis in Lung Cancer Study

Researchers have discovered a new, key component in the spread of lung cancer as well as a likely way to block it with drugs now in clinical trial. The study was published on March 14, 2011, in the Journal of Clinical Investigation. A team led by scientists at The University of Texas MD Anderson Cancer Center found a way to identify metastasis-prone lung cancer cells and then uncovered a mechanism that shifts primary tumor cells into a more deadly type of cell with the capacity to move elsewhere in the body. "We think tumors have to learn how to metastasize because they can't do it initially," said paper senior author Dr. Jonathan Kurie, professor in MD Anderson's Department of Thoracic/Head and Neck Medical Oncology. "Cells change in response to cues from their external environment." About 90 percent of all cancer deaths are caused by metastasis - the spread to, and invasion of, other organs. Lung cancer is the leading cause of cancer-related death in the United States, accounting for more than 157,000 deaths annually. The median five-year survival rate is 3.5%. The researchers found that when a protein called Jagged2 binds externally to Notch, a membrane protein that sticks out through the surface of a cell, it suppresses a microRNA that thwarts metastasis inside the cell. "Jagged2 suppresses miR-200 and drives metastasis as a consequence." Dr. Kurie said. "It's been known for some time that Notch is involved in cancer, but no one really knew how." Two Notch inhibitors are in clinical trial at MD Anderson. "These drugs might suppress the ability of primary tumors to metastasize," Dr. Kurie said. "One question is who is supposed to get these drugs," Dr. Kurie said.