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Archive - Nov 2011

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November 8th

Scientists Investigate “Second Hit” Model in Burkitt’s Lymphoma

Although Burkitt’s lymphoma is thankfully fairly rare in the general population, it is the most common form of malignancy in children in Equatorial Africa and is very frequent in immunocompromised persons, such as those suffering from AIDS. It is invariably accompanied by an increase in the expression of a particular gene, the so-called c-myc gene. An increased level of c-myc is not usually enough to cause cancer and most patients also have alterations to another gene. The groups of Dr. Veronika Sexl at the University of Veterinary Medicine, Vienna (Vetmeduni Vienna), and Dr. Dagmar Stoiber at the Ludwig Boltzmann Institute for Cancer Research, Vienna, have recently provided important new information on how the nature of the additional alterations shapes the course and onset of disease. The results are published in the October 27, 2011 issue of the journal Blood and are of immediate relevance to lymphoma treatment. The human c-myc gene encodes a transcription factor (MYC) involved in the regulation of a vast number of other genes – it has been estimated that the transcription of about one in six genes is somehow under the control of MYC. Perhaps because of MYC’s wide range of targets, mutations of the c-myc gene are frequently associated with a variety of tumors, not only with Burkitt’s lymphoma. Mutations that lead to excessive amounts of the MYC protein are particularly threatening. It has long been known that Burkitt’s lymphoma only develops when MYC is mutated or overexpressed, although experiments in mice have shown that some animals live quite happily and healthily with higher levels of the MYC protein. This observation is consistent with the “second hit” model for the origin of cancer: as well as a change to c-myc, a second gene must also be disturbed before disease is initiated.

November 7th

Findings Suggest Personalized Brain Tumor Therapy with Src Inhibitors

The embryonic enzyme pyruvate kinase M2 (PKM2) has a well-established role in metabolism and is highly expressed in human cancers. Now, a team led by researchers at the University of Texas MD Anderson Cancer Center reports online on November 6, 2011 in the journal Nature that PKM2 has important non-metabolic functions in cancer formation. "Our research shows that although PKM2 plays an important role in cancer metabolism, this enzyme also has an unexpected pivotal function – it regulates cell proliferation directly," said senior author Dr. Zhimin Lu, associate professor in the Department of Neuro-Oncology at MD Anderson. "Basically, PKM2 contributes directly to gene transcription for cell growth – a finding that was very surprising." The researchers demonstrated that PKM2 is essential for epidermal growth factor receptor (EGFR)–promoted beta-catenin activation, which leads to gene expression, cell growth, and tumor formation. They also discovered that levels of beta-catenin phosphorylation and PKM2 in the cell nucleus are correlated with brain tumor malignancy and prognosis and might serve as biomarkers for customized treatment with Src inhibitors. In response to epidermal growth factor (EGF), the team found, PKM2 moves into the cell nucleus and binds to beta-catenin that has had a phosphate atom and three oxygen atoms attached at a specific spot called Y333 by the protein c-Src. This binding is essential for beta-catenin activation and expression of downstream gene cyclin D1. This newly discovered way to regulate beta-catenin is independent of the Wnt signaling pathway previously known to activate beta-catenin. In metabolism, PKM2 enhances oxygen-driven processing of sugar known as aerobic glycolysis or the Warburg effect found in tumor cells.

How Brain Cells Degrade Dangerous Protein Aggregates

Researchers at the RIKEN Brain Science Institute (BSI) in Japan have discovered a key mechanism responsible for selectively degrading aggregates of ubiquitinated proteins from the cell. Their findings indicate that the capture and removal of such aggregates is mediated by the phosphorylation of a protein called p62, opening the door to new avenues for treating neurodegenerative diseases such as Huntington's disease and Alzheimer's disease. One of the most important activities of a cell is the production of proteins, which play essential functions in everything from oxygen transport, to immune defense, to food digestion. Equally important to the cell's survival is how it deals with these proteins when they pass their expiration date: damaged or misfolded proteins have been associated with a range of debilitating conditions, including neurodegenerative diseases such as Alzheimer's disease. In eukaryotic cells, the recycling of damaged or misformed proteins is governed by a small regulatory protein called ubiquitin in a process called "ubiquitination." By attaching itself to a protein, a ubiquitin molecule can tag the protein for destruction by proteasomes, large protein complexes that degrade and recycle unneeded proteins in the cell. This recycling of proteins by proteasomes is crucial to the maintenance of cellular homeostasis. With their research, the BSI research group sought to shed light on one area where proteasome-based recycling falls short: protein complexes or aggregates, which proteasomes have trouble degrading. The group shows that this weakness is made up for by the phosphorylation of a protein called p62 at the serine 403 (S403) loci of its ubiquitin-associated (UBA) domain, which triggers a catabolic process called selective autophagy that degrades protein aggregates.

November 6th

Pigeonpea Genome Sequenced; Should Speed Development of High-Yield Varieties

Once referred to as an "orphan crop" grown mainly by poor farmers, pigeonpea is now joining the world's league of major food crops with the completion of its genome sequence. The completed genome sequence of pigeonpea is featured as an advance online publication on November 6, 2011 on the website of the journal Nature Biotechnology. The paper provides an overview of the structure and function of the genes that define the pigeonpea plant. It also reveals clues on how the genomic sequence can be useful to crop improvement for sustainable food production particularly in the marginal environments of Asia and sub-Saharan Africa. Years of genome analysis by a global research partnership led by the International Crops Research Institute for the Semi-Arid Tropics (ICRISAT) based in Hyderabad, India have resulted in the identification of 48,680 pigeonpea genes. A couple of hundreds of these genes were found unique to the crop in terms of drought tolerance, an important trait that can be transferred to other similar crops like soybean, cowpea, or common bean that belong to the same family. In the fight against poverty and hunger amid the threat of climate change, highly nutritious, drought-tolerant crops are the best bets for smallholder farmers in marginal environments to survive and improve their livelihoods. Pigeonpea, grown on about 5 million hectares in Asia, sub-Saharan Africa, and South-Central America, is a very important food legume for millions of the poor in the semi-arid regions of the world. Known as the "poor people's meat" because of its high protein content, it provides a well-balanced diet when accompanied with cereals. "The mapping of the pigeonpea genome is a breakthrough that could not have come at a better time.

November 5th

Common Bacterial Pathogen Contributes to Some Colon Tumors

Working with lab cultures and mice, Johns Hopkins scientists have found that a strain of the common gut pathogen Bacteroides fragilis causes colon inflammation and increases activity of a gene called spermine oxidase (SMO) in the intestine. The effect is to expose the gut to hydrogen peroxide – the caustic, germ-fighting substance found in many medicine cabinets -- and cause DNA damage, contributing to the formation of colon tumors, say the scientists. "Our data suggest that the SMO gene and its products may be one of the few good targets we have discovered for chemoprevention," says Dr. Robert Casero, professor of oncology at the Johns Hopkins Kimmel Cancer Center. In a study, Casero and his colleagues introduced B. fragilis to two colon cell lines and measured SMO gene activity. In both cell lines, SMO gene activity increased two to four times higher than in cells not exposed to the bacteria. The scientists also observed similar increases in enzymes produced by the SMO gene. The scientists successfully prevented DNA damage in these cells by blocking SMO enzyme activity with a compound called MDL 72527. The Johns Hopkins team also tested their observations in a mouse model, created by Hopkins infectious disease specialist Dr. Cynthia Sears to develop colon tumors. Mice exposed to the bacteria had similar increases in SMO. Mice treated with MDL 72527 had far fewer tumors and lower levels of colon inflammation than untreated mice. Results of the experiments were published on September 13, 2011 in the Proceedings of the National Academy of Sciences. Dr. Casero says hydrogen peroxide can freely distribute through and into other cells. "It roams around, and can damage the DNA in cells," he says. Rising levels of hydrogen peroxide and DNA damage in the colon are clear steps to tumor development, says Dr.

N-Terminal Acetylation Promotes Some Protein Interactions; Cancer Drug Implications

Research led by St. Jude Children's Research Hospital scientists has identified an unexpected mechanism facilitating some protein interactions that are the workhorses of cells and, in the process, identified a potential new cancer drug development target. The discovery involves a chemical known as an acetyl group. An estimated 85 percent of human proteins have this chemical added to the amino acid at one end of the protein. The addition comes in a process known as N-terminal acetylation. N-terminal acetylation occurs shortly after proteins are assembled. Although it has long been known that proteins are N-terminally acetylated, until now it was unknown how such acetylation could serve specific functions. The findings came from scientists studying a system cells use to regulate the fate and function of proteins. The researchers showed that much like a key must fit precisely to work a lock, the acetylated end of one enzyme fits perfectly into a deep pocket on the surface of another protein. The connection helps accelerate the activity of a protein complex that is involved in regulating cell division and that has been linked to cancer. The research appears in the November 4, 2011 issue of the journal Science. The findings have potential implications for drug discovery and for understanding basic mechanisms governing the interaction of possibly thousands of proteins, said the study's senior author, Dr. Brenda Schulman, a member of the St. Jude Department of Structural Biology and a Howard Hughes Medical Institute investigator. "The work presents a major new concept in protein-protein interactions," she said.

Blocking Key Enzyme May Protect Against Kidney Disease in Diabetes

The enzyme arginase-2 plays a major role in kidney failure, and blocking the action of this enzyme might lead to protection against renal disease in diabetes, according to researchers. "We believe these arginase inhibitors may be one of the new targets that can slow down the progression of, or even prevent the development of, end-stage renal disease," said Dr. Alaa S. Awad, assistant professor of nephrology, Penn State College of Medicine. In the United States, diabetes is the leading cause of end-stage renal disease -- kidney failure -- causing nearly 45 percent of all cases. Currently the treatment for diabetic patients likely to develop end-stage renal disease includes blood pressure and glucose control therapy and life-style changes. The researchers tested two different sets of diabetic mice to try to prevent kidney failure. They gave one set of mice -- genetically diabetic -- a potent arginase inhibitor; the other set of mice -- induced to be diabetic -- were genetically unable to produce arginase-2. Both sets of mice showed no signs of kidney failure during the test period. The body naturally produces varieties of arginase. The liver produces arginase-1, while the kidneys produce arginase-2, which leads to kidney failure. The researchers did not detect arginase-1 in the kidneys of the mice, and they have not yet developed an arginase inhibitor that can differentiate between the two forms of the enzyme. "These findings indicate that arginase-2 plays a major role in induction of diabetic renal injury and that blocking arginase-2 activity or expression could be a novel therapeutic approach for treatment of diabetic nephropathy," the researchers report in the November 2011 issue of Diabetes. One of the symptoms of diabetic nephropathy is albuminuria -- losing protein in the urine.

November 4th

Protein Protects Against Cerebral Palsy-Like Brain Damage in Mice

Scientists at Washington University School of Medicine in St. Louis have shown that a particular protein may help prevent the kind of brain damage that occurs in babies with cerebral palsy. Using a mouse model that mimics the devastating condition in newborns, the researchers found that high levels of the protective protein, Nmnat1 (NAD-synthesizing enzyme nicotinamide mononucleotide adenylyl transferase 1), substantially reduce damage that develops when the brain is deprived of oxygen and blood flow. The finding offers a potential new strategy for treating cerebral palsy as well as strokes, and perhaps Alzheimer's, Parkinson's, and other neurodegenerative diseases. The research was reported online on November 4, 2011 in the Proceedings of the National Academy of Sciences. "Under normal circumstances, the brain can handle a temporary disruption of either oxygen or blood flow during birth, but when they occur together and for long enough, long-term disability and death can result," says senior author Dr. David M. Holtzman, the Andrew and Gretchen Jones Professor and head of the Department of Neurology. "If we can use drugs to trigger the same protective pathway as Nmnat1, it may be possible to prevent brain damage that occurs from these conditions as well as from neurodegenerative diseases." The researchers aren't exactly sure how Nmnat1 protects brain cells, but they suspect that it blocks the effects of the powerful neurotransmitter glutamate. Brain cells that are damaged or oxygen-starved release glutamate, which can overstimulate and kill neighboring nerve cells. The protective effects of Nmnat1 were first identified five years ago by Dr. Jeff Milbrandt, the James S.

Research Reveals Exit Strategy of Measles Virus

Measles virus is perhaps the most contagious virus in the world, affecting 10 million children worldwide each year and accounting for 120,000 deaths. An article published online on November 2, 2011 in Nature explains why this virus spreads so rapidly. The discovery by Dr. Roberto Cattaneo, at the Mayo Clinic in Rochester, Minnesota, in collaboration with Dr. Veronika von Messling, at the Centre INRS–Institut Armand-Frappier and research teams at several other universities opens up promising new avenues in cancer treatment. Measles virus spreads from host to host primarily by respiratory secretions. This mode of transmission explains why the virus spreads so quickly and how it resists worldwide vaccination programs to eradicate it. The study in Nature shows for the first time how the measles virus "exits" its host via nectin-4, which is found in the trachea. While viruses generally use cellular receptors to trigger and spread infection in the body, measles virus uses one host protein to enter the host and another protein expressed at a strategic site to get out. Nectin-4 is a biomarker for certain types of cancer, such as breast, ovarian, and lung cancers. Clinical trials are currently under way using a modified measles virus. Because measles virus actively targets nectin-4, measles-based cancer therapy may be more successful in patients whose cancers express nectin-4. Such therapy could be less toxic than chemotherapy or radiation. [Press release] [Nature abstract]

Chemical Breakthrough May Revolutionize PET Scans

A new chemical process developed by a team of Harvard researchers, and collaborators at Massachusetts General Hospital, greatly increases the utility of positron emission tomography (PET) in creating real-time 3-D images of chemical process occurring inside the human body. The work is described in the November 4, 2011 issue of Science. This new work by Dr. Tobias Ritter, Associate Professor of Chemistry and Chemical Biology, and colleagues holds out the tantalizing possibility of using PET scans to peer into any number of functions inside the bodies of living patients by simplifying the process of creating "tracer" molecules used to create the 3-D images. For example, imagine a pharmaceutical company developing new treatments by studying the way "micro-doses" of drugs behave in the bodies of living humans. Imagine researchers using non-invasive tests to study the efficacy of drugs aimed at combatting disorders such as Alzheimer's disease, and to identify the physiological differences in the brains of patients suffering from schizophrenia and bipolar disorder. The process is a never-before-achieved way of chemically transforming fluoride into an intermediate reagent, which can then be used to bind a fluorine isotope to organic molecules, creating the PET tracers. Often used in combination with CT scans, PET imaging works by detecting radiation emitted by tracer atoms, which can be incorporated into compounds used in the body or attached to other molecules. "It's extremely exciting," Dr. Ritter said, of the breakthrough. "A lot of people said we would never achieve this, but this allows us to now make tracers that would have been very challenging using conventional chemistry." The new process builds on Dr.