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May 5th, 2013

Epileptic Seizures Halted in Mouse Model

University of California San Francisco (UCSF) cell therapy raises hope for severe human forms of epilepsy. UCSF scientists controlled seizures in epileptic mice with a one-time transplantation of medial ganglionic eminence (MGE) cells, which inhibit signaling in overactive nerve circuits, into the hippocampus, a brain region associated with seizures, as well as with learning and memory. Other researchers had previously used different cell types in rodent cell transplantation experiments and failed to stop seizures. Cell therapy has become an active focus of epilepsy research, in part because current medications, even when effective, only control symptoms and not underlying causes of the disease, according to Scott C. Baraban, Ph.D., who holds the William K. Bowes Jr. Endowed Chair in Neuroscience Research at UCSF and led the new study. In many types of epilepsy, he said, current drugs have no therapeutic value at all. "Our results are an encouraging step toward using inhibitory neurons for cell transplantation in adults with severe forms of epilepsy," Dr. Baraban said. "This procedure offers the possibility of controlling seizures and rescuing cognitive deficits in these patients." The findings, which are the first ever to report stopping seizures in mouse models of adult human epilepsy, were published online on May 5, 2013 in Nature Neuroscience. During epileptic seizures, extreme muscle contractions and, often, a loss of consciousness can cause seizure sufferers to lose control, fall, and sometimes be seriously injured. The unseen malfunction behind these effects is the abnormal firing of many excitatory nerve cells in the brain at the same time.

May 4th

New Marker Identified for Sleep Loss

For years, Paul Shaw, Ph .D., a researcher at Washington University School of Medicine in St. Louis, has used what he learns in fruit flies to look for markers of sleep loss in humans. Dr. Shaw reverses the process in a new paper, taking what he finds in humans back to the flies and gaining new insight into humans as a result: identification of a human gene that is more active after sleep deprivation. “I’m calling the approach cross-translational research,” says Dr. Shaw, associate professor of neurobiology. “Normally we go from model to human, but there’s no reason why we can’t take our studies from human to model and back again.” Dr. Shaw and his colleagues plan to use the information they are gaining to create a panel of tests for sleep loss. The tests may one day help assess a person’s risk of falling asleep at the wheel of a car or in other dangerous contexts. PLOS ONE published the results online on April 24, 2013. Scientists have known for years that sleep disorders and disruption raise blood serum levels of interleukin 6, an inflammatory immune compound. Dr. Shaw showed that this change is also detectable in saliva samples from sleep-deprived rats and humans. Based on this link, Shaw tested the activity of other immune proteins in humans to see if any changed after sleep loss. The scientists took saliva samples from research participants after they had a normal night’s sleep and after they stayed awake for 30 hours. They found two immune genes whose activity levels rose during sleep deprivation. “Normally we would do additional human experiments to verify these links,” Dr. Shaw says.

November 30th, 2011

Research Suggests Way to Improve Efficiency and Safety of Gene Therapy

A combination of two techniques promises to improve the efficiency and effectiveness of experimental gene therapies, while also reducing potential side effects, says a new research report published in the December 2011 issue of the FASEB Journal. The report describes how scientists from Germany combined two techniques involving the use of site-specific recombinases, or enzymes that facilitate the exchange of genetic material between DNA strands, to help guide exactly where new genetic material is inserted into a cell's DNA. This experimental approach to gene therapy represents an important advance, as successful gene therapy has the potential to correct the root cause of numerous illnesses and health conditions. "The central outcome of these and related techniques is the predictability and safety of a therapeutic regimen," said Dr. Juergen Bode, a researcher involved in the work from the Institute of Experimental Hematology at Hanover Medical School in Hanover, Germany. "These novel strategies will obviate the majority of animal experiments that are presently needed; it will enhance the effectiveness and shorten the timeline." To make this discovery, Bode and colleagues identified two types of site-specific recombinases (SSR), one from yeast (Flp recombinase) and one from phages (PhiC31 recombinase), which are capable of tagging and targeting specific areas in a DNA strand. Specifically, the tagging process involves mounting a distinct address within a genome, whereas the targeting process covers the delivery of genetic material to this address. PhiC31was identified as an ideal enzyme for tagging because it recognizes just a limited number of pre-existent genomic addresses with well-known and mostly beneficial characteristics, allows for only a one-way transfer of genetic material, and is basically irreversible.

November 26th

Monarch Butterfly Genome May Reveal Secrets of Epic Migration

Each fall millions of monarch butterflies from across the eastern United States use a time-compensated sun compass to direct their navigation south, traveling up to 2,000 miles to an overwintering site in a specific grove of fir trees in central Mexico. Scientists have long been fascinated by the biological mechanisms that allow successive generations of these delicate creatures to traverse such long distances to a small region roughly 300 square miles in size. To unlock the genetic and regulatory elements important for this remarkable journey, neurobiologists at the University of Massachusetts Medical School (UMMS) are the first to sequence and analyze the monarch butterfly genome. "Migratory monarchs are at least two generations removed from those that made the journey the previous fall," said Dr. Steven M. Reppert, professor and chair of neurobiology and senior author of the study. "They have never been to the overwintering sites before, and have no relatives to follow on their way. There must be a genetic program underlying the butterflies' migratory behavior. We want to know what that program is, and how it works." In a paper featured as the cover article of the November 23, 2011 issue of Cell, Dr. Reppert and UMMS colleagues Dr. Shuai Zhan, and Dr. Christine Merlin, along with collaborator Dr. Jeffrey L. Boore, CEO of Genome Project Solutions in Hercules, California, describe how next-generation sequencing technology was used to generate a draft 273 Mb genome of the migratory monarch. Analysis of the combined genetic assembly revealed an estimated set of 16,866 protein-coding genes, comprising several gene families likely involved in major aspects of the monarch's seasonal migration. The novel insights gained by Dr.

November 15th

Gene Variant Impedes Recovery from Alcoholism

People who are alcohol-dependent and who also carry a particular variant of a gene run an increased risk of premature death. This is a recent finding from the interdisciplinary research at the Department of Psychology and the Sahlgrenska Academy at the University of Gothenburg, Sweden. Researchers in the longitudinal project Göteborg Alcohol Research Project (GARP) have been investigating the dopamine D2 receptor gene and found that a variant of this gene is overrepresented in people with severe alcohol dependency, and that it is linked to a number of different negative consequences that can be of vital significance to the person affected. "Our research shows that alcohol-dependent individuals, who are also carriers of this gene variant, run 10 times the risk of dying prematurely, compared with the average population," says Dr. Claudia Fahlke, a representative from the research team. In a study published recently in the journal Alcohol and Alcoholism (issue 46), the research team shows that this gene variant also appears to be associated with a higher tendency among these individuals to suffer a relapse, even if they have undergone treatment for their alcohol dependency. This may provide one explanation as to the higher mortality rate in people suffering from alcohol dependency, who are carriers of this gene variant. "This knowledge emphasises the importance of developing methods for early identifying individuals who are also carriers of this gene variant, since the consequences can be so serious," says Dr. Jan Balldin at the Sahlgrenska Academy, University of Gothenburg. [Press release] [Alcohol and Alcoholism journal]

July 22nd

Scientists Complete First Genome-Wide Mapping of 5hmC in Human Embryonic Stem Cells

Stem cell researchers at UCLA have generated the first genome-wide mapping of a DNA modification called 5-hydroxymethylcytosine (5hmC) in embryonic stem cells, and discovered that it is predominantly found in genes that are turned on, or active. The finding by researchers with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA may prove to be important in controlling diseases like cancer, where the regulation of certain genes plays a role in disease development. "Any way you can control genes will be hugely important for human disease and cancer," said Dr. Steven E. Jacobsen, a professor of molecular, cell and developmental biology in the Life Sciences and a Howard Hughes Medical Institute investigator. "Cancer is generally a problem of genes being inappropriately turned off or mutated, like tumor suppressors genes, or genes that should be off getting switched on." The study appears in the July issue of the journal Genome Biology. 5hmC is formed from the DNA base cytosine by adding a methyl group and then a hydroxy group. The molecule is important in epigenetics - the study of changes in gene expression caused by mechanisms other than changes in the DNA sequence - because the newly formed hydroxymethyl group on the cytosine can potentially switch a gene on and off, Dr. Jacobsen said. The molecule 5hmC was only recently discovered, and its function has not been clearly understood, Dr. Jacobsen said. Until now, researchers didn't know where 5hmC was located within the genome. "That is important to know because it helps you to understand how it is functioning and what it's being used for," said Dr. Jacobsen, who also is a researcher with UCLA's Jonsson Comprehensive Cancer Center.

April 20th

Nutlin-3a Activates p53, Stimulates Apoptosis in Glioblastoma Cells

Researchers of Apoptosis and Cancer Group of the Bellvitge Biomedical Research Institute (IDIBELL) have found that a small molecule, Nutlin-3a, an antagonist of MDM2 protein, stimulates the signaling pathway of another protein, p53. In this way, it induces cell death and senescence (loss of proliferative capacity) in brain cancer, a fact that slows the cancer’s growth. These results open the door for MDM2 agonists as new treatments for glioblastomas. The study was published online on April 5, 2011, in the journal PLOS One. Glioblastoma multiforme is the most common brain tumor in adults and the most aggressive. Despite efforts on new treatments and technological innovation in neurosurgery, radiation therapy, and clinical trials of new therapeutic agents, most patients die two years after diagnosis. Dr. Avelina Tortosa, IDIBELL and University of Barcelona (UB) researcher, coordinator of the study, explained that one objective of her group is "to find substances that sensitize tumor cells to radiotherapy for more efficient treatments.” There is evidence that several genetic alterations promote the growth, invasion, and resistance to stimuli that induce programmed cell death (apoptosis). Along these lines, the pilot project TCGA (The Cancer Genome Atlas) has sequenced the genome of up to 25 glioblastomas noting that 14% of patients have an increased expression of MDM2 and 35% had alterations in p53 expression (apoptosis-inducing). That's why research is now focused on the development of new therapeutic strategies that target the apoptosis in gliomas. The aim of this study was to investigate the antitumor activity of Nutlin-3a in cell lines and primary cultures of glioblastoma.

April 7th

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.

April 4th

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.