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Archive - Feb 2013

Date

February 3rd

Scientists Capture Key Moments in Cell Death

Scientists at the Walter and Eliza Hall Institute have for the first time visualized the molecular changes in a critical cell death protein that force cells to die. The finding provides important insights into how cell death occurs, and could lead to new classes of medicines that control whether diseased cells live or die. Controlled cell death, called apoptosis, is important for controlling the number of cells in the body. Defects in cell death have been linked to the development of diseases such as cancer and neurodegenerative conditions. Insufficient cell death can cause cancer by allowing cells to become immortal while excessive cell death of neurons may be a cause of neurodegenerative conditions. Dr. Peter Czabotar, Professor Peter Colman, and colleagues in the institute's Structural Biology division, together with Dr. Dana Westphal from the institute's Molecular Genetics of Cancer division, made the discovery which is published in the January 31, 2013 edition of the journal Cell. Dr. Czabotar said activation of the protein Bax had long been known to be an important event leading to apoptosis, but until now it was not known how this activation occurred. "One of the key steps in cell death is that holes are punched into a membrane in the cell, the mitochondrial membrane," Dr Czabotar said. "Once this happens the cell is going to go on and die. Bax is responsible for punching the holes in the mitochondrial membrane and visualizing its activation brings us a step closer to understanding the mechanics of cell death." Using the Australian Synchrotron, Dr. Czabotar and colleagues were able to obtain detailed three-dimensional images of Bax changing shape as it moved from its inactive to active form. The active form ruptures mitochondrial membranes, removing the cell's energy supply and causing cell death.

February 1st

Researchers Develop Automated Breast Density Test Linked To Cancer Risk

Researchers at the Moffitt Cancer Center in Tampa, Florida, and colleagues at the Mayo Clinic in Rochester, Minnesota, have developed a novel computer algorithm to easily quantify a major risk factor for breast cancer based on analysis of a screening mammogram. Increased levels of mammographic breast density have been shown in multiple studies to be correlated with elevated risk of breast cancer, but the approach to quantifying this parameter has been limited to the laboratory setting where measurement requires highly skilled technicians. This new discovery opens the door for translation to the clinic where the algorithm can be used to identify high-risk women for tailored treatment. “We recently developed an automated method to estimate mammographic breast density that assesses the variation in grayscale values in mammograms,” explained study lead author John J. Heine, Ph.D., associate member of the Cancer Epidemiology Program and Cancer Imaging and Metabolism Department at Moffitt. According to the authors, mammographic breast density, or the proportion of fibroglandular tissue pictured on the mammogram, is an established risk factor for breast cancer. Women with high mammographic breast density have a greater risk of developing breast cancer. However, mammographic breast density has not been used in clinical settings for risk assessments due in large part to the lack of an automated and standardized measurement. Using their new method, the researchers compared the accuracy and reliability of their measurements of variation in breast density with the performance of tests that use the degree of dense breast tissue in a mammogram to assess breast cancer risk. A study describing their novel method and its utility was first published online on July 3, 2012 in the Journal of the National Cancer Institute.

New Methods for Quantifying Antisense Drug Delivery to Target Cells and Tissues

Powerful antisense drugs that target disease-associated genes to block their expression can be used to treat a broad range of diseases. Though antisense therapy has been proven effective, challenges remain in ensuring that the drugs reach their intended targets. Two new methods for detecting and measuring the levels of antisense drugs in cells that could accelerate the development of improved antisense drugs are described in a fast-track 2013 article in BioResearch Open Access, a bimonthly peer-reviewed journal. In the article, Drs. Frederick Schnell, Stacy Crumley, Dan Mourich, and P.L. Iversen, from Sarepta Therapeutics and Oregon State University (Corvallis, OR), describe two fast and sensitive methods for detecting a promising type of antisense therapeutic called a phosphorodiamidate morpholine oligomer, or PMO. Using these novel methods the scientists were able to detect PMO delivery to individual cells and quantify how much PMO resides in a particular tissue in the body, such as the lung. For example, the authors describe the measurement of intranasally delivered PMO in lung tissue and, more specifically, in different cell types in the lung. They were able to measure the clearance kinetics of the PMO and determine if it stayed in the lung tissue. "The development of novel, rapid PMO detection techniques such as these will advance the field of PMO research in a significant way, providing valid alternatives to the current time-consuming and labor-intensive methods," says BioResearch Open Access Editor-in-Chief Jane Taylor, Ph.D., MRC Centre for Regenerative Medicine, University of Edinburgh, Scotland. [Press release] [BioResearch Open Access article]

Cats and Humans Suffer from Similar Forms of Epilepsy

Epilepsy arises when the brain is temporarily swamped by uncoordinated signals from nerve cells. Research at the Vetmeduni Vienna has now uncovered a cause of a particular type of epilepsy in cats. Surprisingly, an incorrectly channelled immune response seems to be responsible for the condition, which closely resembles a form of epilepsy in humans. The work is published in the January/February 2013 issue of the Journal of Veterinary Internal Medicine. There is something sinister about epilepsy: the disease affects the very core of our being, our brain. Epileptic attacks can lead to seizures throughout the body or in parts of it. Clouding of consciousness or memory lapses are also possible. The causes are still only partially understood, but in some cases brain tumors, infections, inflammations of the brain, or metabolic diseases have been implicated. Epilepsy is not confined to humans and many animals also suffer from it. Together with partners in Oxford and Budapest, Dr. Akos Pakozdy and his colleagues at the University of Veterinary Medicine, Vienna, have managed to identify the cause of a certain form of epilepsy in cats, in which the cat’s own immune system attacks particular proteins in the cell membranes of nerve cells. The symptoms include twitching facial muscles, a fixed stare, chewing motions, and heavy dribbling. Based on their clinical experience, the researchers believe that this form of epilepsy is fairly widespread in cats. Interestingly, a highly similar type of epilepsy occurs in humans: an inflammation in the brain, known as limbic encephalitis, leads to epileptic seizures that generally manifest themselves in the arm and the facial muscles on only one side of the body. Dr.

Genetically Modified Tobacco Plants Produce Economic Antibodies to Treat Rabies

Smoking tobacco might be bad for your health, but a genetically altered version of the plant might provide a relatively inexpensive cure for infection with the deadly rabies virus. In a new research report appearing online on January 31, 2013 in The FASEB Journal, scientists produced a monoclonal antibody in transgenic tobacco plants that was shown to neutralize the rabies virus. This new antibody works by preventing the virus from attaching to nerve endings around the bite site and keeps the virus from traveling to the brain. "Rabies continues to kill many thousands of people throughout the developing world every year and can also affect international travelers," said Leonard Both, M.Sc., a researcher involved in the work from the Hotung Molecular Immunology Unit at St. George's, University of London, in the United Kingdom. "An untreated rabies infection is nearly 100 percent fatal and is usually seen as a death sentence. Producing an inexpensive antibody in transgenic plants opens the prospect of adequate rabies prevention for low-income families in developing countries." To make this advance, Both and colleagues "humanized" the sequences for the antibody so people could tolerate it. Then, the antibody was produced using transgenic tobacco plants as an inexpensive production platform. The antibody was purified from the plant leaves and characterized with regards to its protein and sugar composition. The antibody was also shown to be active in neutralizing a broad panel of rabies viruses, and the exact antibody docking site on the viral envelope was identified using certain chimeric rabies viruses. "Although treatable by antibodies if caught in time, rabies is bad news," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal.