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Archive - Apr 2011

April 6th

Engineers Design Protease Probes to Study Disease

Chemical engineers at the University of California at Santa Barbara expect that their new process to create molecular probes may eventually result in the development of new drugs to treat cancer and other illnesses. Their work, reported in the March 25, 2011 issue of Chemistry & Biology, published by Cell Press, describes a new strategy to build molecular probes to visualize, measure, and learn about the activities of enzymes, called proteases, on the surfaces of cancer cells. Dr. Patrick Daugherty, senior author and professor of chemical engineering at UCSB, explained that the probes are effective at understanding proteases involved in tumor metastasis. "Tumor metastasis is widely regarded as the cause of death for cancer patients," said Dr. Daugherty. "It's not usually the primary tumor that causes death. Metastasis is mediated by proteases, like the one we are studying here. These proteases can enable tumor cells to separate and degrade surrounding tissue, and then migrate to sites distant from the primary tumor. The tumor doesn't just fall apart. There are many events that must occur for a tumor to release cancerous cells into the blood stream that can circulate and end up in other tissues such as liver or bone." The probes allowed the researchers, for the first time, to measure directly the activity of a protease involved in metastasis. They did this by adding their probe into a dish of tumor cells. They then measured the activity of this protease that breaks down collagen –– the single most abundant protein (by mass) in the human body. "We have immediate plans to use similar probes to effectively distinguish metastatic HER2 positive tumors, one of the most commonly used biomarkers of breast cancer," said Dr. Daugherty.

Association Between Parkinson’s Disease and Prostate Cancer, Melanoma

University of Utah School of Medicine researchers have found compelling evidence that Parkinson's disease (PD) is associated with an increased risk of prostate cancer and melanoma, and that this increased cancer risk also extends to close and distant relatives of individuals with PD. Although a link between PD and melanoma has been suspected before, this is the first time that an increased risk of prostate cancer has been reported in PD. PD is a progressive neurologic condition that leads to tremors and difficulty with walking, movement, and coordination. Most studies demonstrate that individuals with PD have an overall decreased rate of cancer, with the notable exception of melanoma, the most serious form of skin cancer. Previous research has suggested a possible genetic link between PD and melanoma, but these studies have been limited to first-degree relatives who often share a similar environment, making it difficult to distinguish between genetic and environmental risk factors. "Neurodegenerative disorders such as Parkinson's disease may share common disease-causing mechanisms with some cancers," says Dr. Stefan-M. Pulst, professor and chair of the department of neurology, at the University of Utah, and co-author on this study. "Using the Utah Population Database, we were able to explore the association of PD with different types of cancer by studying cancer risk in individuals with PD, as well as their close and distant relatives." The Utah Population Database (UPDB) includes birth, death, and family relationship data for over 2.2 million individuals, including genealogy data from the original Utah pioneers.

April 5th

Scientist Works on Solution to Nerve Agent Exposure

Dr. Christopher Hadad, professor of chemistry at The Ohio State University (OSU), is leveraging Ohio Supercomputer Center (OSC) resources to help develop a more effective antidote to lethal chemicals called organophosphorus (OP) nerve agents. “This project is a combination of synthetic and computational organic chemistry conducted through OSC at Ohio State, and biochemical studies conducted by colleagues at the U.S. Army Medical Research Institute of Chemical Defense at Aberdeen Proving Ground in Maryland,” said Dr. Hadad. OP nerve agents inhibit the ability of an enzyme called acetylcholinesterase (AChE) to turn off the messages being delivered by acetylcholine (ACh), a neurotransmitter, to activate various muscles, glands and organs throughout the body. After exposure to OP agents, AChE undergoes a series of reactions, culminating in an “aging” process that inactivates AChE from performing its critical biological function. Without the application of an effective antidote, neurosynaptic communication continues unabated, resulting in uncontrolled secretions from the mouth, eyes and nose, as well as severe muscle spasms, which, if untreated, result in death. Conventional antidotes to OP nerve agents block the activity of the nerve agent by introducing oxime compounds, which have been the focus of a number of studies. These compounds attach to the phosphorus atom of the nerve agent, after the OP is bound to AChE, and then split it away from the AChE enzyme, allowing the AChE to engage with receptors and finally relax the tissues. However, in some cases, the combined nerve agent/AChE molecule undergo a process called aging, in which groups of single-bonded carbon and hydrogen atoms called alkyl groups are removed from the molecule and a phosphonate residue is left behind in the AChE active site.

Genetic Clues to a Major Cause of Kidney Failure

For the first time, researchers have found five regions in the human genome that increase susceptibility to immunoglobulin A (IgA) nephropathy, a major cause of kidney failure worldwide. "The study is unique in identifying the biological pathways that mediate IgA nephropathy, mapping the way for further study that may reveal practical targets for diagnosis and treatment," said Dr. Ali Gharavi, Division of Nephrology at Columbia University in New York City, the principal investigator. "The cause and development of IgA nephropathy is poorly understood. Many biological pathways have been suggested, but none has been conclusive until now," he said. The ongoing genome-wide association study is funded by the National Institutes of Health’s Office of the Director, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the National Center for Research Resources, under an NIH Challenge Grant. The project is a part of the $10.4 billion provided to NIH through the Recovery Act. Results were published in the April issue of Nature Genetics. Researchers looked at the genes of 3,144 people of Chinese and European ancestry, all of whom have IgA nephropathy. The disease occurs when abnormal IgA antibodies deposit on the delicate filtering portion of the kidney and form tangles. The immune system tries to get rid of the tangles, but the kidneys are caught in the crossfire, further destroying the delicate filters. Worldwide prevalence of IgA nephropathy appears highest in Asia and southern Europe, and is responsible for most cases of kidney failure in those populations. The U.S. prevalence is much lower — up to 10 percent, although Native Americans from New Mexico have reported rates as high as 38 percent. "IgA nephropathy is most common in Asia, intermediate in prevalence in Europeans and rare in Africans.

Genomic Signature May Explain Why Pregnancy Lowers Risk of Breast Cancer

Women who have children, particularly early in life, have a lower lifetime risk of breast cancer compared with women who do not. Now, Fox Chase Cancer Center researchers have identified a gene expression pattern in breast tissue that differs between post-menopausal women who had children and post-menopausal women who did not. The results will help scientists understand why pregnancy reduces breast cancer risk and may help them develop chemopreventive strategies that can provide similar protection for women who did not have children. Pregnancy triggers differentiation and growth of breast tissue; however breast tissue in post-menopausal women looks similar regardless of childbearing history. That similarity has left researchers wondering why pregnancy is protective throughout a woman's life. This study starts to explain that effect, says Dr. Ricardo López de Cicco, a senior research associate at Fox Chase, who presented the work at the American Association for Cancer Research (AACR) 102nd Annual Meeting 2011 on April 5, 2011. "When a woman has multiple pregnancies beginning at a relatively young age, we see a protective effect against breast cancer," Dr. Lopez says. "In this study, we identified a post-pregnancy genomic signature that can still be seen even after menopause. That is very important because it could begin to help us understand why women who have children early benefit from a reduced risk of breast cancer throughout their lives." By comparing gene expression in breast tissue from 44 post-menopausal women who had children and 21 post-menopausal women who did not, the team identified 208 genes that are differentially expressed. The signature was subsequently validated in an independent cohort of 61 post-menopausal women, 38 who had children and 23 who did not.

April 3rd

New Alzheimer’s Genes Identified

In the largest study of its kind, researchers from a consortium that includes Columbia University Medical Center identified four new genes associated with late-onset Alzheimer's disease. Each of these genes adds to the risk of developing this most common form of the disease, and together they offer a portal into the causes of Alzheimer's. Their identification will help researchers find ways to determine who is at risk of developing the disease, which will be critical as preventive measures become available, and to identify proteins and pathways for drug development. The findings were published online on April 3, 2011, in Nature Genetics. "A significant aspect of our research is that these genes clarify three new pathways," said Dr. Richard Mayeux, one of the lead scientists in the Alzheimer's Disease Genetics Consortium (ADGC) and Chairman of the Department of Neurology of Columbia University Medical Center. "APOE-e4 and the other genes identified earlier are related to the accumulation of amyloid in the brain; these new genes are involved in inflammatory processes, lipid metabolism, and the movement of molecules within cells. Therefore, we may now have four pathways that are critically related to the disease and that could really make a difference in how we study and potentially prevent and treat it."(Dr. Mayeux is also the Gertrude H. Sergievsky Professor of Neurology, Psychiatry and Epidemiology; Director of the Gertrude H. Sergievsky Center, which is devoted to the epidemiological investigation of neurological diseases; and Co-Director of the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at Columbia University Medical Center).

April 2nd

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.