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Gene for Autism and Epilepsy Identified

Researchers from the CHUM Research Centre (CRCHUM) in Montreal, Canada, and colleagues have identified a gene that, when mutated, predisposes people to both autism and epilepsy. Led by the neurologist Dr. Patrick Cossette, the research team found a severe mutation of the synapsin gene (SYN1) in all members of a large French-Canadian family suffering from epilepsy, including individuals also suffering from autism. This study also includes an analysis of two cohorts of individuals from Quebec, which made it possible to identify other mutations in the SYN1 gene among 1% and 3.5% of those suffering respectively from autism and epilepsy, while several carriers of the SYN1 mutation displayed symptoms of both disorders. "The results show for the first time the role of the SYN1 gene in autism, in addition to epilepsy, and strengthen the hypothesis that a deregulation of the function of synapse because of this mutation is the cause of both diseases," notes Dr. Cossette, who is also a professor with the Faculty of Medicine at the Université de Montréal. He adds that "until now, no other genetic study of humans has made this demonstration." The different forms of autism are often genetic in origin and nearly a third of people with autism also suffer from epilepsy. The reason for this comorbidity is unknown. The synapsin gene plays a crucial role in the development of the membrane surrounding neurotransmitters, also referred to as synaptic vesicles. These neurotransmitters ensure communication between neurons. Although mutations in other genes involved in the development of synapses (the functional junction between two neurons) have previously been identified, this mechanism has never been proved in epilepsy in humans until the present study.

Soy Increases Radiation’s Ability to Kill Lung Cancer

Components in soybeans increase radiation's ability to kill lung cancer cells, according to a Wayne State University study published in the April 2011 issue of the Journal of Thoracic Oncology, the official monthly journal of the International Association for the Study of Lung Cancer. "To improve radiotherapy for lung cancer, we are studying the potential of natural non-toxic components of soybeans, called soy isoflavones, to augment the effect of radiation against the tumor cells and at the same time protect normal lung cells against radiation injury," said Dr. Gilda Hillman, associate professor in the Department of Radiation Oncology at Wayne State University's School of Medicine and the Karmanos Cancer Institute, who led the team of researchers. "These natural soy isoflavones can sensitize cancer cells to the effects of radiotherapy by inhibiting the survival mechanisms that cancer cells activate to protect themselves," Dr. Hillman said. "At the same time, soy isoflavones can also act as antioxidants, which protect normal tissues against unintended damage from the radiotherapy." Dr. Hillman and her team demonstrated that soy isoflavones increase killing of cancer cells by radiation via blocking DNA repair mechanisms, which are turned on by the cancer cells to survive the damage caused by radiation. Human A549 non-small cell lung cancer (NSCLC) cells that were treated with soy isoflavones before radiation showed more DNA damage and less repair activity than cells that received only radiation. Researchers used a formulation consisting of the three main isoflavones found in soybeans, including genistein, daidzein and glycitein.

Two Metastasis-Promoting Molecules Are Identified

For many types of cancer, the original tumor itself is usually not deadly. Instead, it's the spread of a tiny subpopulation of cells from the primary tumor to other parts of the body—the process known as metastasis—that all too often kills the patient. Now, researchers at Albert Einstein College of Medicine of Yeshiva University have identified two molecules that enable cancer to spread inside the body. These findings could eventually lead to therapies that prevent metastasis by inactivating the molecules. The regulatory molecules are involved in forming invadopodia, the protrusions that enable tumor cells to turn metastatic – by becoming motile, degrading extracellular material, penetrating blood vessels and, ultimately, seeding themselves in other parts of the body. The research appears online on April 7, 2011 in Current Biology. The study's senior author is Dr. John Condeelis, co-chair and professor of anatomy and structural biology, co-director of the Gruss Lipper Biophotonics Center and holder of the Judith and Burton P. Resnick Chair in Translational Research at Einstein. Dr. Condeelis and his team identified two molecules (p190RhoGEF and p190RhoGAP) that regulate the activity of RhoC, an enzyme that plays a crucial role during tumor metastasis and that has been identified as a biomarker for invasive breast cancer. "In vitro as well as in vivo studies have shown that RhoC's activity is positively correlated with increased invasion and motility of tumor cells," said corresponding author Dr. Jose Javier Bravo-Cordero, Ph.D., a postdoctoral fellow in the labs of Dr. Condeelis and assistant professor Louis Hodgson, Ph.D., in the Gruss Lipper Biophotonics Center and the department of anatomy and structural biology.

Vision Loss Slowed in Severe Form of Macular Degeneration

A phase 2 clinical trial for the treatment of a severe form of age-related macular degeneration (AMD) called geographic atrophy (GA) has become the first study to show the benefit of a therapy to slow the progression of vision loss for this disease. The results highlight the benefit of the use of a neurotrophic factor to treat GA and provide hope to nearly one million Americans suffering from GA. The multi-center research team, including Dr. Kang Zhang, of the University of California, San Diego, Shiley Eye Center, the lead author of the paper and one of the leading investigators in the study, found that long-term delivery of ciliary neurotrophic factor (CNTF) served to re-nourish the retina and stop or slow the loss of visual acuity caused by the disorder. The results were published online on March 28, 2011, in PNAS. According to Dr. Zhang -- professor of ophthalmology and human genetics at the UCSD School of Medicine and director of UCSD's Institute of Genomic Medicine – there is currently no effective treatment for dry AMD or GA, though there is a very big need. "This could open the door to long-term treatment of dry AMD, using a simple surgical procedure." AMD is a leading cause of vision loss in Americans age 60 and older. It is a disease that causes cells in the macula – the part of the eye that allows us to see in fine detail – to die. There are two forms of the disorder, wet and dry AMD. GA is considered the end stage of dry AMD, where central vision is lost. According to the National Eye Institute, wet AMD occurs when abnormal blood vessels behind the retina start to grow under the macula. These new blood vessels tend to be very fragile and often leak blood and fluid. The blood and fluid raise the macula from its normal place at the back of the eye, resulting in rapid loss of central version.

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.

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.

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).

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