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Sequencing Shows CREBBP Mutations in Relapsing Leukemia

Despite dramatically improved survival rates for childhood acute lymphoblastic leukemia (ALL), relapse remains a leading cause of death from the disease. Work led by St. Jude Children's Research Hospital investigators identified mutations in a gene named CREBBP that may help the cancer resist steroid treatment and fuel ALL's return. CREBBP plays an important role in normal blood cell development, helping to switch other genes on and off. In this study, researchers found that 18.3 percent of the 71 relapsed-ALL patients carried alterations in the DNA sequence of CREBBP. In contrast, the gene's sequence was changed in just one of the 270 young leukemia patients whose cancer did not return. Investigators say the gene is a potential indicator of relapse risk because of the high frequency of CREBBP mutations in relapsed patients and evidence the changes persisted from diagnosis or emerged at relapse from subpopulations of leukemia cells present from the beginning. Researchers also found evidence the changes occur in important regulatory regions of the gene and affect cell function, including how cancer cells respond to the steroids that play an important role in cancer treatment. The work appears in the March 10 issue of Nature. "This study gives us further evidence that detailed genomic studies can identify important mutations that influence tumor response to treatment," said Dr. Charles Mullighan, assistant member of the St. Jude Department of Pathology. Dr. Mullighan and Dr. Jinghui Zhang, an associate member of the St. Jude Department of Computational Biology, are co-first authors of the ALL article. Dr. Mullighan is also the corresponding and senior author. ALL is the most common childhood cancer. While ALL cure rates have climbed to 90 percent, the disease is often deadly if it returns.

Calcium Channel Defect Causes Deafness, Irregular Heartbeat

Ten years ago, scientists seeking to understand how a certain type of cell feature called an L-type calcium channel worked created a knockout mouse missing both copies of the CACNA1D gene. The CACNA1D gene makes a protein that lets calcium flow into a cell, transmitting important instructions from other cells. The knockout mice lived a normal life span, but their hearts beat slowly and arrhythmically. They were also completely deaf. On March 9, 2011, at the 55th Annual Biophysical Society Meeting in Baltimore, an international team lead by Dr. Hanno Bolz of the University of Cologne in Germany reported identification of a mutation on the CACNA1D gene affecting two families in Pakistan. The altered gene adds one extra amino acid to the middle of the protein, which is more than 2,000 amino acids in length. The result is that family members with two copies of the mutated gene are not only deaf, but also have an irregular heartbeat. "Their heart beats slowly, dropping below 30 beats a minute during sleep," said Dr. Joerg Striessnig, professor at the University of Innsbruck in Austria and one of the study’s senior authors. The researchers analyzed the family's mutation and determined that it does not destroy the protein, said Dr. Striessnig. "Normally, part of the protein acts like a hinge to open the calcium channel once the cell gets stimulated. The mutated protein still sits in the cell's surface membrane where it should be, but the hinge does not open the channel," he said. "It's not only interesting for medicine but also for understanding how these channels work as molecular machines." [Press release]

How Scientists Identified Anthrax Strain in 2001 Letter Attacks

It took nearly a decade before University of Maryland researchers were allowed to talk about their work identifying the anthrax strain used in the 2001 deadly letter attacks. But now, they and the other key members of the high-powered science team have published the first account of the pioneering work, which launched the new field of "microbial forensics" and gave bioterrorism investigators a way to "fingerprint" bacteria. An article published online on March 7, 2011, in PNAS details the multi-institutional research that the FBI ultimately used to track anthrax-laden letters back to test tube number RMR-1029 at a lab in Fort Detrick, Maryland. University of Maryland bioinformatics experts co-authored the article and conducted the computational analysis that detected four genetic mutations that together comprised a unique signature of a particular colony of anthrax bacteria. The FBI subsequently determined this colony was found only in that Ft. Detrick test tube. The Maryland researchers have since developed their work into a genetic 'fingerprinting' tool that is available online to law enforcement seeking to track down other microbial suspects. "We found unique bio-markers to help investigators track down the source of the anthrax," said Dr. Steven Salzberg, director of the University of Maryland Center for Bioinformatics and Computational Biology (CBCB). "At first the tiny mutations were elusive. We thought we'd pieced together the 'jigsaw puzzle' of data very neatly, until we ended up with a few oddball bits left over. When we looked more closely, we found an extra copy of a critical gene." "Fortunately, anthrax bacteria mutate relatively slowly, so the material in this colony developed these small distinctive mutations that resulted in physically distinct characteristics," explained Dr. Mihai Pop, Dr.

Drug Halts Progression of Parkinson’s Disease in Mice

In a major breakthrough in the battle against Parkinson's disease, a research team at the University of Colorado School of Medicine has discovered a drug (phenylbutyrate) that stops the progression of the degenerative illness in mice and is now being tested in humans. "Drugs currently used to treat Parkinson's disease just treat symptoms; they do not stop the disease from getting worse," said senior author Dr. Curt Freed, who heads the division of Clinical Pharmacology and Toxicology at the CU School of Medicine. "We've now discovered that we can prevent the progression of the disease by turning on a protective gene in the brain." The results were published online on March 3, 2011, in the Journal of Biological Chemistry. Lead author Dr. Wenbo Zhou, Assistant Professor of Medicine, and Dr. Freed, a national pioneer in Parkinson's research, and colleagues have found that the drug phenylbutyrate turns on a gene that can protect dopamine neurons in Parkinson's disease. The gene, called DJ-1, can increase production of antioxidants like glutathione to reduce the debilitating effects of excess oxygen in brain cells. In addition, activating DJ-1 helps cells eliminate abnormal proteins that otherwise accumulate and kill brain cells. Dopamine neurons are particularly susceptible to too much oxygen and abnormal protein deposits. Parkinson's disease is caused by dying midbrain dopamine neurons. Dr. Zhou and Dr. Freed have studied the DJ-1 gene since 2003 when a European group discovered that mutations in DJ-1 could cause Parkinson's disease. The Colorado scientists immediately started work to see why the gene was so important and have published a series of papers on the subject since 2005. But to convert their findings into a practical treatment for Parkinson's disease, they needed to find a drug to turn on the DJ-1 gene.

Animal Model Suggests Blood-Brain Barrier Damaged in Sanfilippo Syndrome

A study into the effects of Sanfilippo Syndrome type B (MPS III B) has found that the barrier responsible for protecting the brain from the entry of harmful blood-borne substances is structurally and functionally damaged by the devastating disease. University of South Florida researchers identified damage in specific brain structures involved in the pathology of MPS III B, one of four Sanfilippo syndromes, all of which are inherited diseases of metabolism. The study, using a mouse model of MPS III B, was published online on March 7, 2011, in the journal PLoS ONE. Before this study, little was known about the integrity of the blood-brain barrier in this disease. "These new findings about blood-brain barrier structural and functional impairment in MPS III B mice, even at early disease stage, may have implications for disease pathogenesis and should be considered in the development of treatments for MPS III B," said study lead author Dr. Svitlana Garbuzova-Davis, an assistant professor in the Department of Neurosurgery and Brain Repair at the University of South Florida. Sanfilippo syndrome type B is caused by a deficiency in the Naglu gene, the gene responsible for producing an enzyme needed to degrade heparan sulfate. Naglu-deficient mice show progressive deterioration of movement, vision, and hearing. Neurons in various parts of the brain – including the olfactory bulb, cortex, thalamus, amygdala, and other areas – are affected by the disease. Consequently, patients with MPS III B experience a variety of pathological brain changes. "Among our findings was that endothelial cells and other cells comprising the blood-brain barrier are damaged, resulting in vascular leakage," said Dr. Garbuzova-Davis. "This compromise may lead to destruction of the fragile central nervous system equilibrium." Dr.

Kinase Inhibitors Target Proliferative Mechanism of Malaria Parasite

A group of researchers from the Ecole Polytechnique Federale de Lausanne’s (EPFL) Global Health Institute (GHI) and Inserm (Institut National de la Santé et de la Recherche Médicale, the French government agency for biomedical research) has discovered that a class of chemotherapy drugs originally designed to inhibit key signaling pathways in cancer cells also kills the parasite that causes malaria. The discovery could quickly open up a whole new strategy for combating this deadly disease. The research, published online on March 4, 2011, in the journal Cellular Microbiology, shows that the malaria parasite depends upon a signaling pathway present in the host – initially in liver cells, and then in red blood cells – in order to proliferate. The enzymes active in the signaling pathway are not encoded by the parasite, but rather hijacked by the parasite to serve its own purposes. These same pathways are targeted by a new class of molecules developed for cancer chemotherapy known as kinase inhibitors. When the GHI/Inserm team treated red blood cells infected with malaria with the chemotherapy drug, the parasite was stopped in its tracks. Professor Christian Doerig and his colleagues tested red blood cells infected with Plasmodium falciparum parasites and showed that the specific PAK-MEK signaling pathway was more highly activated in infected cells than in uninfected cells. When they disabled the pathway pharmacologically, the parasite was unable to proliferate and died. Applied in vitro, the chemotherapy drug also killed a rodent version of malaria (P. berghei), in both liver cells and red blood cells.

Nobelist’s New Work Shows Compound Rids Animal Cells of Alzheimer Protein Debris

If you can't stop the beta-amyloid protein plaques from forming in Alzheimer's disease patients, then maybe you can help the body rid itself of them instead. At least that's what scientists from New York were hoping for when they found a drug candidate to do just that. Their work appears in a research report online on March 2, 2011, in The FASEB Journal, and shows that a new compound, called "SMER28" stimulated autophagy in rat and mice cells. Autophagy is a process cells use to "clean out" the debris from their interior, including unwanted materials such as the protein aggregates that are hallmarks of Alzheimer's disease. In mice and rat cells, SMER28 effectively slowed down the accumulation of beta-amyloid. "Our work demonstrates that small molecules can be developed as therapies, by activating a cellular function called autophagy, to prevent Alzheimer's disease," said senior author Dr. Paul Greengard, Nobel laureate and director of the Laboratory of Molecular and Cellular Neuroscience at The Rockefeller University in New York, NY. "By increasing our understanding of autophagy, it might be possible to stimulate it pharmacologically or naturally to improve the quality of life for aging people." Using mouse and rat cells, scientists tested various compounds for their ability to reduce the buildup of beta-amyloid by exposing cultured cells to compounds known to activate autophagy. The effects of these compounds were then compared by removing growth factors from the culture medium. Researchers then focused on the most effective compound, which was SMER28, to characterize the cellular components involved in this phenomenon. For that purpose, the effect of SMER28 on beta-amyloid formation was compared using normal cells or cells where the expression of genes known to be involved in autophagy was reduced or abolished.

Psoriasis Medication May Be Useful in Treating Multiple Sclerosis

Fumaric acid salts have been in use against severe psoriasis for a long time. About ten years ago, researchers in Bochum, Germany, speculated that they may also have a favorable effect on multiple sclerosis (MS) as a result of their Th2 polarizing mechanisms. In parallel to phase III studies, researchers have been actively searching for the precise effective mechanisms. This has now been achieved by a neuroimmunological group at Bochum: fumaric acid salts detoxify radicals released during the inflammation process. In this way, they protect nerve and glial cells. Neurologists at the Ruhr University Hospital, St. Josef Hospital, working with Professor Ralf Gold, report these findings in the March 3 issue of the leading neurology journal BRAIN. As MS, psoriasis is an auto-immune disease, in which the immune system attacks the body's own cells. In MS, the insulating myelin layer of the axons is destroyed in this way. About ten years ago, the Ruhr University Bochum dermatologist Professor Peter Altmeyer informed his colleague, the neurologist Professor Horst Przuntek, that the mixture of fumaric acid salts registered for treatment of psoriasis under the trade name FUMADERM could possibly exert favorable effects in MS as well. In turn, the Swiss manufacturer Fumapharm sponsored a small study in Bochum. Ten patients were examined for a period of 48 weeks (Schimrigk et al European Journal of Neurology 2006, 13: 604). In parallel to this, Fumapharm supported basic research which Professor Gold then performed at his MS Institute in Göttingen (Schilling et al. Clin. Exp. Immunology 2006; 145: 101-107). After that, the scenario moved rapidly: the US pharmaceutical company BiogenIdec with its focus in MS research took over Fumapharm AG and initiated a successful Phase II study (Kappos, Gold, Lancet 2008; 372: 1463).

Putrescine Protects Brain from Epileptic Seizures in Tadpole Studies

For years, brain scientists have puzzled over the shadowy role played by the molecule putrescine, which always seems to be present in the brain following an epileptic seizure, but without a clear indication whether it was there to exacerbate brain damage that follows a seizure or protect the brain from it. A new Brown University study unmasks the molecule as squarely on the side of good: It seems to protect against seizures hours later. Putrescine is a foul-smelling organic chemical compound (1,4-diaminobutane or butanediamine) that is related to cadaverine; both are produced by the breakdown of amino acids in living and dead organisms and both are toxic in large doses. The two compounds are largely responsible for the foul odor of putrefying flesh. Putrescine is one in a family of molecules called "polyamines" that are present throughout the body to mediate crucial functions such as cell division. Why they surge in the brain after seizures isn't understood. In a lengthy set of experiments, Brown neuroscientists meticulously traced their activity in the brains of seizure-laden tadpoles. What they found is that putrescine ultimately is converted into the neurotransmitter GABA, which is known to calm brain activity. When the researchers caused a seizure in the tadpoles, they found that the putrescine produced in a first wave of seizures helped tadpoles hold out longer against a second wave of induced seizures. Dr. Carlos Aizenman, assistant professor of neuroscience and senior author of the study published online on March 6, 2011, in the journal Nature Neuroscience, said further research could ultimately produce a drug that targets the process, potentially helping young children with epilepsy. Tadpoles and toddlers aren't much alike, but this basic aspect of their brain chemistry is.

Clinical Observation Yields Molecular Insight into Lung Cancer

A discovery at University of Colorado Cancer Center shows testing lung cancer on a molecular level may produce new insights into this deadly disease. Cancer Center member Dr. D. Ross Camidge, director of the thoracic oncology clinical program at University of Colorado Hospital (UCH), turned a chance clinical observation into a new field of discovery in lung cancer. In October 2010, Dr. Camidge and colleagues published a study in the New England Journal of Medicine showing more than half of patients with a specific kind of lung cancer respond positively to a treatment that targets the gene that drives their cancer. Fifty-seven percent of patients with anaplastic lymphoma kinase (ALK) positive advanced non-small cell lung cancer responded to a tablet called crizotinib, an investigational ALK inhibitor. Camidge's latest study, published in the Journal of Thoracic Oncology, shows people with ALK-positive lung cancer also have much better outcomes with an established chemotherapy drug called pemetrexed (trade name: alimta). "We had been running a home-grown clinical trial with pemetrexed in lung cancer when I noticed that some patients were doing astonishingly well on this chemotherapy," said Dr. Camidge, associate professor of medical oncology at the University of Colorado School of Medicine. "Pemetrexed is not like most other chemotherapies. It can be given for long periods of time, often with little in the way of side-effects. However, when someone is given pemetrexed, on average it only takes three to four months before their cancer starts to grow again. But certain people in this trial were responding to the treatment for a year or more. When we started to test their cancers at the molecular level, almost all of those 'super-survivors' turned out to be ALK-positive.

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