How MicroRNAs Drive Tumor Progression

UCSF researchers have identified collections of tiny molecules known as microRNAs that affect distinct processes critical for the progression of cancer. The findings, they say, expand researchers' understanding of the important regulatory function of microRNAs in tumor biology and point to new directions for future study and potential treatments.

The researchers refer to these microRNA collections as signatures, and their study results are reported in the September 15 issue of Genes & Development. The study, available online at http://genesdev.cshlp.org/, was led by the laboratory of Douglas Hanahan, PhD, an American Cancer Society Research Professor in the Department of Biochemistry and Biophysics at UCSF.

Approximately five percent of all known human genes encode, or produce, microRNAs, yet scientists are only now - nearly a decade after their discovery - beginning to unlock the mystery of their functions.

MicroRNAs are snippets of single-stranded RNAs that prevent a gene's code from being translated from messenger RNA into proteins, which are essential for cell growth and development. Produced in the nucleus and released into the cytoplasm, they home in on messenger RNAs that possess a stretch that is complementary to their genetic sequence. When they locate them, they latch on, preventing the messenger RNA from being processed by the protein-making machines known as ribosomes. As such, microRNAs are able to ratchet down a cell's production of a given protein.

Over the last several years, several groups have identified hundreds of microRNAs that are deregulated between normal tissue and tumors, however researchers only understand what a handful of these powerful regulators are doing to drive tumor formation.

"Virtually all cancers acquire approximately six distinct capabilities en route to tumor formation," said lead author Peter Olson, PhD, a postdoctoral fellow in the Diabetes Center and Helen Diller Family Comprehensive Cancer Center at UCSF. "When a cancer researcher observes a gene or microRNA go awry, it can be challenging to understand how that microRNA impacts tumorigenesis."

To home in on the question, the authors turned to a mouse model of pancreatic neuroendocrine tumors in which lesions go through discrete stages before culminating in invasive and metastatic carcinomas. In the three-year microRNA study, they found that cells in the mouse model developed and functioned normally but started to replicate uncontrollably at five weeks. Several weeks later, some pancreatic islets had become angiogenic (forming new blood vessels) - a step in the journey from a dormant state to a malignant state - though had not yet formed a tumor. By 10 weeks, a subset of angiogenic lesions had progressed to the tumor stage, and by week 16, a small percentage of mice had developed liver metastasis.

"This represents the spectrum of stages that we think are important for all tumors, including human disease," said Olson.

By measuring the expression level of all known microRNA in pre-tumor stages, tumors and metastases, the authors were able to associate deregulated microRNAs with processes such as hyperproliferation, angiogenesis and metastasis.

Focusing on the metastatic signature, researchers found - in one of the most striking observations of the project - that tumors bore a startlingly divergent microRNA expression pattern compared to primary tumors. Moreover, a subset of primary tumors showed more similarity to metastases than to other primary tumors.

"If you can identify tumors that have an increased propensity to metastasize, then it would have a very important clinical application," said Olson. "A lively debate in metastatic research has centered around whether primary tumor cells must suffer an additional mutation that endows that cell with a metastatic capability, or whether certain mutational combinations that are responsible for primary tumor formation also significantly increase the propensity of that cell to metastasize. These data provide evidence for the latter.''

Olson conducted the research in the Hanahan laboratory. Hanahan is a member of the UCSF Helen Diller Family Comprehensive Cancer Center. He also is a professor at the UCSF Diabetes Center.

Also collaborating on the project were Anny Shai and Matthew G. Chun of the UCSF Diabetes Center and the UCSF Helen Diller Family Comprehensive Cancer Center, and Yucheng Wang and Eric K. Nakakura of the UCSF Helen Diller Family Comprehensive Cancer Center. Other co-authors include Jun Lu, Hao Zhang, and Todd R. Golub of the Broad Institute of MIT and Harvard, and Steven K. Libutti who is with the Tumor Angiogenesis Section, Surgery Branch, of the National Cancer Institute.

The research was supported in part by the National Cancer Institute, the American Cancer Society and the National Science Foundation.

Source:
Elizabeth Fernandez
University of California - San Francisco

New Way Deadly Food-borne Bacteria Spread Discovered By University Of Central Florida Professor

University of Central Florida Microbiology Professor Keith Ireton has uncovered a previously unknown mechanism that plays an important role in the spread of a deadly food-borne bacterium.

Listeria monocytogenes is a bacterium that can cause pregnant women to lose their fetuses and trigger fatal cases of meningitis in the elderly or people with compromised immune systems. The bacterium has been linked to outbreaks traced to food processing plants in the U.S. and Canada.

In 2002, a multi-state outbreak of listeriosis - the serious disease caused by Listeria - resulted in 46 confirmed cases, seven deaths and three stillbirths or miscarriages. Those cases in eight states were linked to people eating contaminated sliced turkey deli meat. From January to August 1985, there was another outbreak with 142 cases of listeriosis.

Scientists have long known that Listeria spreads from one human cell to another. Bacteria growing in one cell move fast enough to create a finger-like structure that protrudes from the cell and pushes into an adjacent cell. The bacteria then infect the adjacent cell.

Ireton and his team have discovered a previously unknown second process that aids in the spread of bacteria to healthy cells. The process, which gradually overwhelms the second cell's ability to defend itself from infection, is featured in this week's edition of the science journal Nature Cell Biology.

The plasma membrane, or outer layer, of healthy human cells normally exhibits tension. Such tension might be expected to prevent Listeria from spreading to adjacent uninfected cells. However, Ireton's lab found that a Listeria protein called InlC appears to relieve tension at the plasma membrane in infected cells, making it easier for moving bacteria to deform the membrane and then spread into adjacent, healthy cells.

Ireton's laboratory also reports that the way InlC relieves tension is by blocking the function of a human protein called Tuba. The normal role of Tuba in uninfected human cells appears to be to help generate tension at the plasma membrane. The Listeria protein InlC inactivates Tuba, reducing that tension and enabling bacteria to spread to nearby cells.

"The idea that a pathogenic bacterium can spread by controlling membrane tension in the human cell has not been previously described in the scientific literature," Ireton said. "Our discovery could have relevance for bacterial pathogens that cause Shigellosis or Rocky Mountain spotted fever, as these bacteria resemble Listeria in their ability to move inside the host cell and spread."

More research is needed, but Ireton says that discovering this mechanism could aid in future therapies and perhaps open a window into understanding how certain bacterial pathogens cause disease.

Others who worked on Ireton's team include Tina Rajabian and Scott D. Gray-Owen at the University of Toronto, Balramakrishna Gavicherla at UCF and Martin Heisig, Stefanie Müller-Altrock and Werner Goebel at the University of Würzburg in Germany.

Ireton joined UCF's Burnett School of Biomedical Sciences, housed in the College of Medicine, in 2006. He earned his Ph.D. at the Massachusetts Institute of Technology and completed post-doctoral work at the Pasteur Institute in France, a private institute dedicated to the treatment of diseases through biomedical research, education and public health. He conducted research and taught at the University of Toronto for several years before arriving at UCF.

Source:
Zenaida Gonzalez Kotala
University of Central Florida

Scientists Make First Step Towards Growing Human Lungs For Transplant

Scientists have successfully converted human embryonic stem cells into lung cells, taking a first step towards building human lungs for transplantation.

According to research to be published in the journal Tissue Engineering, the team from Imperial College London, took human embryonic stem cells and 'directed' them to convert into the type of cells needed for gas exchange in the lung, known as mature small airway epithelium.

Dame Professor Julia Polak, from Imperial College London, who led the research team, says: "This is a very exciting development, and could be a huge step towards being able to build human lungs for transplantation or to repair lungs severely damaged by incurable diseases such as cancer."

The research involved taking human embryonic stem cells and growing them in Petri dishes in the laboratory in a specialized system that encouraged them to change into the cells that line the part of the lung where oxygen is absorbed and carbon dioxide excreted. Although this was done in the first instance on embryonic stem cells, the system will be tested further on stem cells from other sources, including umbilical cord blood and bone marrow.

Dr Anne Bishop, from Imperial College London and based at Chelsea and Westminster Hospital, and senior author of the paper, adds: "Although it will be some years before we are able to build actual human lungs for transplantation, this is a major step towards deriving cells that could be used to repair damaged lungs."

Following further laboratory tests, the researchers plan to use their findings to treat problems such as acute respiratory distress syndrome (ARDS), a condition which causes the lining of the cells to fall off, and which currently kills many intensive care patients. By injecting stem cells that will become lung cells, they hope to be able to repopulate the lung lining.

Two-way Communication Between Common Biological Pathways And Body's Daily Clock

While scientists have known for several years that our body's internal clock helps regulate many biological processes, researchers have found that the reverse is also true: Many common biological processes – including insulin metabolism – regulate the clock, according to a new study by investigators at the University of Pennsylvania School of Medicine, the Genomics Institute of the Novartis Research Foundation, and the University of California at San Diego.

The new data, published online in Cell this week, suggest that someday physicians may be able to use small molecules that inhibit or stimulate these biological processes in order to influence a person's clock when it gets out of sync due to jetlag or shift work, and to devise new ways to treat metabolic disorders that are intimately tied to the body's daily cycles.

Using a genome-wide screen, the investigators found that reducing expression of any one of hundreds of genes could substantially alter the length of the circadian cycle, which controls the 24-hour sleep/wake cycle. The clock-influencing genes are involved in a large number of biological processes, but the researchers found that components of insulin metabolism, folate metabolism, and the cell cycle were overrepresented in the gene screen, suggesting that these pathways are closely linked to the clock.

"Clock biologists all appreciated that the communication went one direction – from the clock to biological processes – but I don't think anyone anticipated that there would be this level of integration with cell metabolism and the cell cycle, or all these other pathways impinging on clock function," says John Hogenesch, PhD, Associate Professor of Pharmacology in the Institute for Translational Medicine and Therapeutics at Penn. Hogenesch is a co-senior author on the paper with Steve Kay, Dean of the Division of Biological Sciences at UCSD. "There were some hints this might occur for some genes, but not to this extent."

The idea that biological processes might have feedback systems with the circadian clock makes some sense to Hogenesch. For example, he points to the influence of insulin metabolism, saying "If your energy requirements aren't being met, instead of spending a lot of energy on a cell division, a cell might necessarily delay it. It is the same strategy we use when we are not ready to do something, we delay. Maybe procrastination is an evolutionary cellular strategy enabled by the clock to confront situations where resources are limited."

While biologists regularly draw molecular pathways as if they are distinct from one another, they know the reality is much different. "This is a good example showing how dozens of pathways are functionally interconnected with clock function and vice versa," Hogenesch says. "It is important to remember that when you start to change function with a drug, for example, that the perturbation can have unanticipated consequence. Sometimes these consequences are good, but sometimes not."

Hogenesch stresses that while the new experiments show a feedback loop between biological processes and the clock in individual cells in culture, it is not yet clear how feedback systems work in the whole organism. Currently the team is working on biochemical and genetic experiments to answer that question.

In addition to publishing the data in the journal, the investigators have displayed the data on the BioGPS open-access searchable database (http://biogps.gnf.org). The circadian genome-wide screen data can be found at http://biogps.gnf.org/circadian/ and are linked to expression data from Penn, gene function data at Wikipedia and the National Center for Biotechnology Information (NCBI), as well as gene structure information from the University of California at Santa Cruz.

Hogenesch, who helped develop the website when he worked at the Genomics Institute of the Novartis Research Foundation in San Diego, said the site relies on web 2.0 technology and is very simple to use and customize. He and his colleagues built the site because many researchers want to do large database searches but are not computer scientists or informatics specialists. "Andy Su [of Novartis] and I decided to develop a site that even my mom could use, and pitched at the 90% of biologists who want to use something but don't have the skill sets. We decided to build something that would allow them to take advantage of large datasets such as this one."

Co-first authors on the paper are Eric E. Zhang and Tsuyoshi Hirota of the Genomics Institute of the Novartis Research Foundation, and UCSD, and Andrew C. Liu, of the Genomics Institute of the Novartis Research Foundation and the University of Memphis, Tenn. Other authors on the paper include Loren J. Miraglia, Genevieve Welch, Xianzhong Liu, Jon W. Huss III, Jeff Janes, and Andrew I. Su of the Genomics Institute of the Novartis Research Foundation, and Pagkapol Y. Pongsawakul, Ann Atwood, and Steve A. Kay of UCSD.

This research was funded by Silvio O. Conte Center and the National Institute of Mental Health.

Courtesy: ScienceDaily

Star-shaped Cells In Brain Help With Learning

Every movement and every thought requires the passing of specific information between networks of nerve cells. To improve a skill or to learn something new entails more efficient or a greater number of cell contacts. Scientists at the Max Planck Institute of Neurobiology in Martinsried can now show, together with an international team of researchers, that certain cells in the brain, the astrocytes, actively influence this information exchange.

Until now, astrocytes were thought to have their main role in the development and nutrition of the brain's nerve cells. The new findings improve our comprehension of how the brain learns and remembers. They could also aid in the basic research of diseases such as epilepsy and the amyotrophic lateral sclerosis (ALS).

To live is to learn: Even fruit flies can learn to avoid detrimental odors and also in humans, most abilities are based on what we learn through practice and experience. Thus we are able to perform both fundamental processes such as walking and speaking and also master complex tasks such as logical reasoning and social interactions.

Learning at the cellular level

In order to learn something, i.e. to process new information, nerve cells grow new connections or strengthen existing contact points. At such contact points, the synapses, information is passed from one cell to the next. Once a synapse is created, new information has a means to be passed on and the information is learned. Enhancing an acquired skill through practice is then accomplished by strengthening the synapses involved. Incoming information elicits a much stronger response in the downstream nerve cell when passing through a strengthened synapse, as compared to a "normal" synapse.

At the cellular level, this can be envisioned as follows: At a synapse, the two communicating nerve cells do not come in direct contact but are separated by a small gap. When incoming information reaches the synapse, glutamate is released into the gap. These transmitter molecules cross the gap and bind to special receptors in the downstream nerve cell. This in turn prompts the downstream cell to pass on the information. In a strengthened synapse, the informing cell releases more glutamate into the synaptic gap and/or the informed cell is more efficient at binding the glutamate. As a result, information transmission is significantly enhanced.

Not just passive aid

In the brain, parts of nerve cells and single synapses are often enclosed by star-shaped cells, the astrocytes. So far, astrocytes were mainly thought to aid nerve cells - for example by supporting them or by promoting the maturation of synapses. Scientists of the Max Planck Institute of Neurobiology and an international team of researchers have now shown that astrocytes also have another, much more active role in the brain: They affect the synapses' ability to strengthen, and thus help to facilitate the learning process.

By removing the glutamate transmitter from the synaptic gap via so-called transporters, astrocytes regulate the availability of glutamate. "These transporters are somewhat like small vacuum cleaners", says Ruediger Klein, the supervisor of the study. "They suck surplus glutamate from the gap, which prevents, for example, glutamate spilling over from one synapse to the next." The existence of this "glutamate vacuum cleaner" was already known to science. So far unheard of, and now shown by the scientists, was that the astrocyte and downstream nerve cell communicate with each other and thus regulate the number of glutamate-eliminating transporters.

Signaling pathway with extensive consequences

This communication was found while the neurobiologists were examining the signaling molecule ephrinA3 and its binding partner EphA4 in mice. Ephrins and Eph-receptors are regularly involved when cells recognize or influence each other. Astrocytes, for example, promote synapse maturation via ephrinA3/EphA4 interaction. "Yet it came as a surprise to find an effect working also in the other direction", Ruediger Klein remembers. The scientists found that if a nerve cell is lacking the EphA4-receptor, the neighboring astrocyte increases its transporter numbers. The resulting superabundant transporters eliminate so much glutamate from the synapse that its strengthening becomes impossible, a sure disadvantage for the ability to learn.

The importance of the ephrinA3/EphA4 signaling pathway was further emphasized by the control studies. If the signaling molecule ephrinA3 was absent in an astrocyte, a synaptic strengthening was impaired due to the lack of glutamate - just what happened when EphA4 was missing. In contrast, if ephrinA3 was experimentally increased, the number of astrocyte-transporters decreased. As a result glutamate accumulated in the synaptic gap which in turn quickly led to cell damages and malfunctions of the affected synapses.

Next steps

"We are currently investigating the mechanisms through which ephrinA3/EphA4 affect the transporter production", explains Ruediger Klein. The scientists' aim is to better understand the transporters' function. An important task, as malfunctioning of the astrocyte transporters is known to play a role in neurological and neurodegenerative diseases such as epilepsy and the amyotrophic lateral sclerosis (ALS).

Journal reference:

1. Alessandro Filosa, Sónia Paixão, Silke D. Honsek, Maria A. Carmona, Lore Becker, Berend Feddersen, Louise Gaitanos, York Rudhard, Ralf Schoepfer, Thomas Klopstock, Klas Kullander, Christine R. Rose, Elena B. Pasquale, Rüdiger Klein. Neuron-glia communication via EphA4/ephrin-A3 modulates LTP through glial glutamate transport. Nature Neuroscience, 2009; DOI: 10.1038/nn.2394

Second-hand Smoking Results In Liver Disease, Study Finds

A team of scientists at the University of California, Riverside has found that even second-hand tobacco smoke exposure can result in nonalcoholic fatty liver disease (NAFLD), a common disease and rising cause of chronic liver injury in which fat accumulates in the liver of people who drink little or no alcohol.

The researchers found fat accumulated in liver cells of mice exposed to second-hand cigarette smoke for a year in the lab. Such fat buildup is a sign of NAFLD, leading eventually to liver dysfunction.

In their study, the researchers focused on two key regulators of lipid (fat) metabolism that are found in many human cells as well: SREBP (sterol regulatory element-binding protein) that stimulates synthesis of fatty acids in the liver, and AMPK (adenosine monophosphate kinase) that turns SREBP on and off.

They found that second-hand smoke exposure inhibits AMPK activity, which, in turn, causes an increase in activity of SREBP. When SREBP is more active, more fatty acids get synthesized. The result is NAFLD induced by second-hand smoke.

"Our study provides compelling experimental evidence in support of tobacco smoke exposure playing a major role in NAFLD development," said Manuela Martins-Green, a professor of cell biology, who led the study. "Our work points to SREBP and AMPK as new molecular targets for drug therapy that can reverse NAFLD development resulting from second-hand smoke. Drugs could now be developed that stimulate AMPK activity, and thereby inhibit SREBP, leading to reduced fatty acid production in the liver."

Results of the study appear in the September issue of the Journal of Hepatology.

The study emphasizes that discouraging cigarette smoking helps prevent not only cardiovascular disease, pulmonary disease and cancer, but now also liver disease.

Second-hand smoke is the combination of smoke exhaled by a smoker and smoke given off by the burning end of a tobacco product. Lingering in the air long after tobacco products have been extinguished, it is involuntarily inhaled by nonsmokers in the vicinity.

Second-hand smoke is a major toxicant that affects children, the elderly and nonsmokers living in the household of adults who smoke. Many state and local governments have passed laws prohibiting smoking in public facilities. Diseases associated with second-hand smoking include cancer, heart disease, atherosclerosis, pneumonia, bronchitis and severe asthma.

Despite the large body of scientific evidence documenting the effects of passive or active smoking on the heart and lungs, reports investigating how smoking causes liver injury are scant.

"Until our study, second-hand smoking had not been linked to NAFLD development," Martins-Green said.

She was joined in the study by her graduate student Hongwei Yuan (first author of the research paper and now a postdoctoral researcher in her lab) and UC Riverside's John Shyy, a professor of biomedical sciences. Next, the team plans to investigate the clinical relevance of their findings. A grant to Martins-Green from Philip Morris USA, Inc., supported the research.

Courtesy: science daily

Cancer Drug May Improve Memory In Alzheimer's Patients

A drug now used to treat cancer may also be able to restore memory deficits in patients with Alzheimer's disease, according to a new study conducted by scientists at Columbia University Medical Center, which appeared in the September issue of The Journal of Alzheimer's Disease.

The loss of short, day-to-day memories is often the first sign of Alzheimer's -- a disease that is expected, by the year 2050, to afflict 120 million people worldwide.

"People often joke that they must have Alzheimer's because they can't remember where they put their keys, but for a person with the disease, this type of short-term memory loss is extremely debilitating," says the study's lead author, Ottavio Arancio, Ph.D., associate professor of pathology and cell biology in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at Columbia University Medical Center.

Dr. Arancio says that the cancer drug targets a previously unknown defect in the brains of mice with Alzheimer's.

The reason why the drug improves memory lies in the way the brain records new memories. To create new memories, the neurons in the brain must manufacture new proteins. The first step is to open up and read the DNA, which contains instructions for making the proteins.

To read the DNA, the neuron attaches a chemical reactive group to the spool around which DNA is tightly wound. "These groups, called acetyls, unwind the DNA to make it more accessible," says co-author Yitshak Francis, Ph.D., a postdoctoral research scientist at Columbia. "It's like unwinding knitting wool from its spool."

This unwrapping step, the researchers found, is impaired in mice with a form of Alzheimer's disease. The mice with Alzheimer's attached about half as many acetyls to DNA as normal mice and had poorer memory.

The researchers then discovered that they could improve memory in the Alzheimer's-afflicted mice with a cancer drug from a family of compounds, called HDAC inhibitors, which increase the DNA's spool acetylation and gene transcription. The drug improved memory performance to the level found in normal mice.

"Because this type of drug has already been approved for some cancer patients," says co-author Mauro Fà, Ph.D., associate research scientist in Columbia's Taub Institute, "we hope that clinical trials for Alzheimer's disease can start in about three to four years."

"For making memories, you need transcription and protein synthesis at the cellular level. If you don't have that, you don't have memory," said Dr. Francis.

This work was supported in part by Alzheimer Disease Research Zenith Award ZEN-07-58977, National Institutes of Health Grant R01 NS049442 (to O.A.) and by United Kingdom Alzheimer's Research Trust Pilot Grant, The International Sephardic Educational Foundation (ISEF) Scholarship, The Lewis Family Trust Scholarship, The Sidney & Elizabeth Corob Charitable Trust Scholarship, the Charlotte and Yule Bogue Research Fellowships (to Y.I.F).

Journal reference:

1. Yitshak I Francis, Mauro Fà, Haider Ashraf, Hong Zhang, Agnieszka Staniszewski, David S. Latchman, Ottavio Arancio. Dysregulation of Histone Acetylation in the APP/PS1 Mouse Model of Alzheimer%u2019s Disease. Journal of Alzheimer's Disease, 18:1 (September 2009)

Human Brain Could Be Replicated In 10 Years, Researcher Predicts

A model that replicates the functions of the human brain is feasible in 10 years according to neuroscientist Professor Henry Markram of the Brain Mind Institute in Switzerland. "I absolutely believe it is technically and biologically possible. The only uncertainty is financial. It is an extremely expensive project and not all is yet secured."

The apparent complexity of the human mind is not a barrier to building a 'replica' brain claims Professor Markram. "The brain is of course extremely complex because it has trillions of synapses, billions of neurons, millions of proteins, and thousands of genes. But they are still finite in number. Today's technology is already highly sophisticated and it allows us to reverse engineer the brain rapidly." An example of the capability already in place is that today's robots can do screenings and mappings tens of thousands of times faster than human scientists and technicians.

Another hurdle on the path to a model human brain is that 100 years of neuroscience discovery has led to millions of fragments of data and knowledge that have never been brought together and exploited fully. "Actually no one even knows what we already understand about the brain," says Professor Markram. "A model would serve to bring this all together and then allow anyone to test whatever theory you want about the brain. The biggest challenge is to understand how electrical-magnetic-chemical patterns in the brain convert into our perception of reality. We think we see with our eyes, but in fact most of what we 'see' is generated as a projection by your brain. So what are we actually looking at when we look at something 'outside' of us?"

For Professor Markram, the most exciting part of his research is putting together the hundreds of thousands of small pieces of data that his lab has collected over the past 15 years, and seeing what a microcircuit of the brain looks like. "When we first switched it on it already started to display some interesting emergent properties. But this is just the beginning because we know now that it is possible to build it. As we progress we are learning about design secrets of our brains which were unimaginable before. In fact the brain uses some simple rules to solve highly complex problems and extracting each of these rules one by one is very exciting. For example we have been surprised at finding simple design principles that allow billions of neurons to connect to each other. I think we will understand how the brain is designed and works before we have finished building it."

The opportunities for this neuroscience research challenge are immense explains Professor Markram: "A brain model will sit on a massive supercomputer and serve as a kind of educational and diagnostic service to society. As the industrial revolution in science progresses we will generate more data than anyone can track or any computer can store, so models that can absorb it are simply unavoidable. It is also essential to build models when it comes to treating brain diseases affecting around two billion people. At present, there is no brain disease for which we really understand what has gone wrong in the processing, in the circuits, neurons or synapses. It is also important if we are to replace the need for the millions of animal experiments each year for brain research."

Courtesy: ScienceDaily

Discovery Leads To Rapid Mouse 'Personalized Trials' In Breast Cancer

One person's breast cancer is not the same as another person's, because the gene mutations differ in each tumor. That makes it difficult to match the best therapy with the individual patient.

Using a finding that the genetic complexity of tumors in mice parallels that in humans, researchers at the Duke University Institute for Genome Sciences and Policy and Duke University Medical Center are starting trial studies in mice, just like human clinical trials, to evaluate whether understanding tumor diversity can improve cancer treatment.

"Giving everyone the same few current treatments doesn't take the very different types of tumors into account," said Joseph Nevins, Ph.D., Barbara Levine University Professor of Breast Cancer Genomics at Duke, who directs the Center for Applied Genomics & Technology at Duke. "It's like trying to treat a virus infection without recognizing that it may be HIV, influenza or cold virus."

For a study appearing recently in the Proceedings of the National Academy of Sciences, Nevins and colleagues painstakingly examined a large number of mouse breast tumors and performed genomic analyses to differentiate the tumors.

"The genetic pathways in the tumors determine the sensitivity to drugs," Nevins said. "We still have so much to learn about this."

All of the mice were bred to have a Myc gene variant that gave them tumors; however, additional gene mutations are acquired that contribute to the development of the tumor, including mutations in the Ras gene and others. The spectrum of tumor variation at the genetic level mimicked the complexity of human cancers.

"If we are going to successfully treat a tumor, we must recognize the extensive heterogeneity of what we call breast cancer and match drugs carefully to the characteristics of that particular tumor," Nevins said. "Today breast tumors may be sorted by whether they are estrogen-sensitive or HER-2 sensitive, but that is about the extent of it. We are performing human trials to look at the underlying biological pathways and examine how best to match therapies with the individual patient. But, these are lengthy studies. Now we can develop new strategies to match a therapy with a mouse tumor subtype and have results in a much shorter period of time."

Nevins and colleagues plan to conduct trials in the mice just as they would in humans: find the tumor, perform a needle biopsy, learn all they can about the tumor, and match it to a drug based on scientific data. The mouse studies don't replace human trials, but they can be an important component of advancing a strategy, Nevins said.

"This work highlights the importance of both biological and computational model systems to unravel the complexities and heterogeneity of human cancer," said Daniel Gallahan, Ph.D., program director for the Integrative Cancer Biology Program at the National Cancer Institute. "This type of analysis can be exploited to better align a therapeutic strategy with an individual's specific cancer."

Running parallel to human trials, the mouse trials will show what works well and what doesn't in the trial methods, data collection, analysis and other aspects of the trials. Researchers can then translate these findings immediately to keep the human clinical trials advancing as effectively as possible.

With so much mouse model research happening around the globe, why weren't these mouse tumor differences noted before? The gene expression analyses performed on mouse tumors simply haven't been large enough, Nevins said.

"We examined a large number, up to 80 samples of mouse tumors. And in the same way that a picture gets clearer when you add more pixels, the information about the tumors became clearer as we examined more samples," he said. "In effect, we went to a higher resolution and could begin to see patterns more clearly."

The study was funded by the National Institutes of Health and the V Foundation for Cancer Research, named in honor of the late North Carolina State basketball coach Jim Valvano.

Other authors include Eran R. Andrechek, Jeffrey T. Chang, Michael L. Gatza, Chaitanya R. Acharya, and Anil Potti of the Duke Institute for Genome Sciences and Policy, and Robert D. Cardiff of the Center for Comparative Medicine at the University of California at Davis.

Courtesy: ScienceDaily

Hormone important in recognizing familiar faces

Oxytocin, a hormone involved in child-birth and breast-feeding, helps people recognize familiar faces, according to new research in the January 7 issue of The Journal of Neuroscience. Study participants who had one dose of an oxytocin nasal spray showed improved recognition memory for faces, but not for inanimate objects.

“This is the first paper showing that a single dose of oxytocin specifically improves recognition memory for social, but not for nonsocial, stimuli,” said Ernst Fehr, PhD, an economist at the University of Zurich who has studied oxytocin’s effect on trust and is unaffiliated with the new study. “The results suggest an immediate, selective effect of the hormone: strengthening neuronal systems of social memory,” Fehr said.

In mice, oxytocin has been shown to be important in social recognition — remembering that another mouse is familiar. Unlike humans, who use visual cues, mice use smell to recognize and distinguish other mice.

In humans, oxytocin increases social behaviors like trust, but its role in social memory has been unclear. “Recognizing a familiar face is a crucial feature of successful social interaction in humans,” said Peter Klaver, PhD, at the University of Zurich, the senior author of the new study, which was led by Ulrike Rimmele, PhD, at New York University. “In this study, we investigated for the first time the systematic effect of oxytocin on social memory in humans,” Klaver said.

Klaver and colleagues had study participants use a nasal spray containing either oxytocin or a placebo and then showed them images of faces and inanimate objects, including houses, sculptures, and landscapes. Participants were given a surprise test when they returned the next day — they were shown some of the images they had seen the day before as well as some new ones and were asked to distinguish between images that were “new,” images that they specifically “remembered” being presented, and images they recognized (”knew”) as familiar but could not recall the presentation context.

Volunteers who used the oxytocin spray more accurately recognized the faces they had seen before than did those in the placebo group. However, the two groups did not differ in recognizing the other, nonsocial images, suggesting that oxytocin specifically improved social memory and that different mechanisms exist for social and nonsocial memory. Further analysis showed that oxytocin selectively improved the discrimination of new and familiar faces — participants with oxytocin were less likely to mistakenly characterize unfamiliar faces as familiar. “Together, our data indicate that oxytocin in humans immediately strengthens the capability to correctly recognize and discriminate faces,” Klaver said.

“The study highlights the parallels in social information processing in mice and man, and adds further support to the notion that oxytocin plays a critical role,” said Larry Young, PhD, at Emory University, an expert on oxytocin who is unaffiliated with the current study. “This has important implications for disorders such as autism, where social information processing is clearly impaired,” Young said.

Source : http://www.sfn.org/

Scientists discover an ancient odor-detecting mechanism in insects

In 1913 Theodore Roosevelt added cartographer to his resume when he and his crew ventured up an unspeakably dangerous and uncharted tributary named the River of Doubt. Now, on a charting expedition of their own, Rockefeller University scientists have completed a journey that has also defied expectation. In work to be published in the January 9 issue of Cell, the team reports the discovery of a new family of receptors in the fly nose, a finding that not only fills in a missing piece in the organizational logic of the insect olfactory system but also unearths one of the most ancient mechanisms that organisms have evolved to smell.

Vosshall, head of the Laboratory of Neurogenetics and Behavior, revamps traditional ideas regarding the roles of ionotropic glutamate receptors, proteins that reside deep in the brain at the synapses. There, they grab glutamate molecules and quickly relay messages from one nerve cell to the next, helping animals learn, move and remember. But Vosshall’s group now shows that insects do not relegate these receptors to the depths of the brain. They also put them to use elsewhere: in the nose.

“On the surface it’s a completely absurd idea,” says Vosshall, who is also a Howard Hughes Medical Institute investigator. “We know what these proteins do; they sit at the synapse and mediate fast neuronal communication. So the idea that the fly has massively expanded the number of these receptors and positioned them to interact with small molecules in the air seems very strange. But if you think about it, it makes sense. The process is the same, but rather than grabbing small molecules at the synapse, they’re grabbing small molecules from the air.”

The project began two years ago, when Vosshall and Richard Benton, then a postdoc in her lab, noticed a group of six ionotropic glutamate receptor genes while sifting through the fly genome. Although this group was recognized 10 years ago, ever since the genome was sequenced, the genes did not have a known function, in part because it was assumed they must be similar to any other ionotropic glutamate receptor deep in the fly brain. But to Vosshall and Benton, who is now at the Center for Integrative Genomics in Lausanne, Switzerland, that didn’t matter.

Vosshall and her team wondered whether these receptors could in fact represent the “missing” receptors thought to exist in the fly’s “nose” — its two antennae. Each antenna is divided into three types of smell neurons. Scientists have characterized the receptors that detect odors in two of these types but those receptors were mysteriously absent in the third, a swath of territory known as the coeloconic sensilla. “It has been shown that cells in the coeloconic sensilla detect odors,” Vosshall says. “It’s just that we didn’t know how they did it.”

The team showed that these receptors, which the Vosshall lab named ionotropic receptors, do in fact explain how cells in coeloconic sensilla detect odors. First, they showed that they are expressed in complex combinatorial patterns at the sensory end of olfactory neurons where they have access to and can scan the outside world for odors. They then showed that when these receptors are expressed in the cells in the coeloconic sensilla, the cells respond to odors. Finally, the researchers showed that when they plucked a receptor — say one that detects an odor that resembles a mix of grass and honey — out of its native cell and genetically embedded it in a different cell, the new cell would now detect that odor.

Although it is still unclear why insects have developed two sets of chemosensory receptors — olfactory receptors and ionotropic receptors — the work raises questions regarding their evolutionary origin. Ten years ago, researchers at New York University revealed that plants, which detect soil nutrients and chemicals in the air, also express glutamate receptors, suggesting that the ancestral origin of glutamate receptors may have been to detect small molecules in the air, rather than small molecules in the brain.

“In a way, these receptors were very well hidden because everyone assumed that they were extra glutamate receptors that were unlikely to be of interest,” explains Vosshall. “All we did to find them was searched for a gene family of unknown function — and left our preconceived notions aside.”

Source : http://www.rockefeller.edu/

Chemist Shows How RNA Can Be the Starting Point for Life

By NICHOLAS WADE

An English chemist has found the hidden gateway to the RNA world, the chemical milieu from which the first forms of life are thought to have emerged on earth some 3.8 billion years ago.

He has solved a problem that for 20 years has thwarted researchers trying to understand the origin of life — how the building blocks of RNA, called nucleotides, could have spontaneously assembled themselves in the conditions of the primitive earth. The discovery, if correct, should set researchers on the right track to solving many other mysteries about the origin of life. It will also mean that for the first time a plausible explanation exists for how an information-carrying biological molecule could have emerged through natural processes from chemicals on the primitive earth.

The author, John D. Sutherland, a chemist at the University of Manchester, likened his work to a crossword puzzle in which doing the first clues makes the others easier. “Whether we’ve done one across is an open question,” he said. “Our worry is that it may not be right.”

Other researchers say they believe he has made a major advance in prebiotic chemistry, the study of the natural chemical reactions that preceded the first living cells. “It is precisely because this work opens up so many new directions for research that it will stand for years as one of the great advances in prebiotic chemistry,” Jack Szostak of the Massachusetts General Hospital wrote in a commentary in Nature, where the work is being published on Thursday.

Scientists have long suspected that the first forms of life carried their biological information not in DNA but in RNA, its close chemical cousin. Though DNA is better known because of its storage of genetic information, RNA performs many of the trickiest operations in living cells. RNA seems to have delegated the chore of data storage to the chemically more stable DNA eons ago. If the first forms of life were based on RNA, then the issue is to explain how the first RNA molecules were formed.

For more than 20 years researchers have been working on this problem. The building blocks of RNA, known as nucleotides, each consist of a chemical base, a sugar molecule called ribose and a phosphate group. Chemists quickly found plausible natural ways for each of these constituents to form from natural chemicals. But there was no natural way for them all to join together.

The spontaneous appearance of such nucleotides on the primitive earth “would have been a near miracle,” two leading researchers, Gerald Joyce and Leslie Orgel, wrote in 1999. Others were so despairing that they believed some other molecule must have preceded RNA and started looking for a pre-RNA world.

The miracle seems now to have been explained. In the article in Nature, Dr. Sutherland and his colleagues Matthew W. Powner and Béatrice Gerland report that they have taken the same starting chemicals used by others but have caused them to react in a different order and in different combinations than in previous experiments. they discovered their recipe, which is far from intuitive, after 10 years of working through every possible combination of starting chemicals.

Instead of making the starting chemicals form a sugar and a base, they mixed them in a different order, in which the chemicals naturally formed a compound that is half-sugar and half-base. When another half-sugar and half-base are added, the RNA nucleotide called ribocytidine phosphate emerges.

A second nucleotide is created if ultraviolet light is shined on the mixture. Dr. Sutherland said he had not yet found natural ways to generate the other two types of nucleotides found in RNA molecules, but synthesis of the first two was thought to be harder to achieve.

If all four nucleotides formed naturally, they would zip together easily to form an RNA molecule with a backbone of alternating sugar and phosphate groups. The bases attached to the sugar constitute a four-letter alphabet in which biological information can be represented.

“My assumption is that we are here on this planet as a fundamental consequence of organic chemistry,” Dr. Sutherland said. “So it must be chemistry that wants to work.”

The reactions he has described look convincing to most other chemists. “The chemistry is very robust — all the yields are good and the chemistry is simple,” said Dr. Joyce, an expert on the chemical origin of life at the Scripps Research Institute in La Jolla, Calif.

New Find in the Pacific: Worms With Glow Sticks

By HENRY FOUNTAIN

Scientists have discovered seven new species of deep-sea worms in the Pacific. The worms, members of a new genus, Swima, are up to about four inches long, eyeless and have paddlelike bristles that move rapidly, allowing them to swim forward or backward.

That’s all very interesting, but what makes the worms truly spectacular are the little green glow sticks that are found on five of the species. Attached to segments near the head, these tiny organs — more blobs than sticks, actually — can be released from the body, instantly producing a bright green bioluminescence that lasts for many seconds as the worms swim away. The researchers refer to the worms colloquially as green bombers and say the phenomenon may help them distract potential predators.

Using remotely operated submersibles, Karen J. Osborn of the Scripps Institution of Oceanography and colleagues from the Monterey Bay Aquarium Research Institute and other organizations found the worms at depths of about 6,000 to 12,500 feet off Mexico, California and Oregon and near the Philippines. Their report is published in the journal Science.

The researchers say the new species are more closely related to worms that live in seafloor sediments than to other swimming worms, so they represent an evolutionary adaptation as bottom-dwellers moved into the water column.

The worms seem to be fairly common at those great depths; a video camera on a submersible recorded five of one species, S. bombiviridis, swimming together at about 7,000 feet. The submersibles did not record a bomb release in the wild, but the researchers were able to stimulate the release of bombs in the laboratory by touching the worms. They suggest that predators, presumably fish, that similarly try to disturb the worms would be left with the small glowing blobs instead of the tasty meal they were hoping for.

Researchers Identify New, Cancer-causing Role For Protein

The mainstay immune system protein TRAF6 plays an unexpected, key role activating a cell signaling molecule that in mutant form is associated with cancer growth, researchers at The University of Texas M. D. Anderson Cancer Center report in the Aug. 28 edition of Science.

"The mechanism that we discovered activates Akt and also contributes to hyperactivation of a mutant form of Akt found in breast, colon and other cancers," said senior author Hui-Kuan Lin, Ph.D., assistant professor in M. D. Anderson's Department of Molecular and Cellular Oncology.

Akt is a signaling protein that plays a central role in numerous biological functions, including cell growth and programmed cell death, or apoptosis, Lin said. Deregulated Akt expression has been found to contribute to cancer development.

"Our novel findings are that Akt undergoes ubiquitination to be activated, and that TRAF6 regulates that process. We've found that TRAF6 is not just involved in the innate immune response, but plays a role in cell growth and carcinogenesis," Lin said.

Ubiquitins are regulatory proteins that work by binding to other proteins. While ubiquitins are best known for marking a defective protein for death by the cell's proteasome complex, Lin said, ubiquitination of Akt is not tied to the proteasome. Ubiquitins are transferred to target proteins by another set of proteins called ligases.

Akt resides in the cell's cytoplasm and must be recruited to the cell membrane in order to be activated by attachment of phosphate groups to specific locations on the protein, Lin explained. The mechanism that gets Akt to the membrane had not been understood.

Because one type of ubiquitination involves protein movement, Lin's team launched a series of cell line experiments that showed Akt is ubiquitinated, and in a way not involving the proteasome.

Screening a different class of ubiquitin ligases showed that overexpression of TRAF6 E3 ligase promotes Akt ubiquitination. Subsequent experiments showed that Akt ubiquitination is required to move Akt to the cell membrane, and leads to Akt's phosphorylation and activation.

Next, the researchers analyzed a mutant form of Akt implicated in human breast cancer, finding that increased Akt ubiquitination contributes to the hyperactivation of Akt in the mutant cells. "We discovered this oncogenic Akt mutant is hyperubiquitinated," Lin said. "If you disrupt its ubiquitination, you deactivate the mutant."

The team found depleting TRAF6 in prostate cancer cells reduced Akt activation. And mice with TRAF6 knocked down developed smaller prostate cancer tumors than those with active TRAF6. "We believe that TRAF6 is a previously unrecognized oncogene and is a new potential target for treating human cancers," Lin said.

Having discovered this Akt activation pathway, Lin and colleagues are now trying to identify the enzyme that normally turns it off.

Research for this paper was funded by an M. D. Anderson Trust Scholar Fund award to Lin.

Co-authors are first author Wei-Lei Yang, Jing Wang, Ph.D., Chia-Hsin Chan, Ph.D., Szu-Wei Lee, Brian C. Grabiner, and Xin Lin, Ph.D., all of the department of Molecular and Cellular Oncology; Yang, Lee, and Grabiner are all students in The University of Texas Graduate School of Biomedical Sciences at Houston, a joint operation of M. D. Anderson and The University of Texas Health Science Center at Houston, and Xin Lin is on the GSBS faculty; and Alejandro Campos, Betty Lamothe, Ph.D., Lana Hur, and Bryant Darnay, Ph.D., all of M. D. Anderson's Department of Experimental Therapeutics.

Discovery Of Natural Odors Could Help Develop Mosquito Repellents

The image depicts scanning electron micrographs of the heads of a Culex quinquefasciatus mosquito (foreground) and Drosophila melanogaster (fruit fly; background). Representative traces of a CO2-sensitive neuron activated by CO2 (top trace) and inhibited by addition of odor 2,3-butanedione (bottom trace). The structures of CO2 and 2,3-butanedione are also shown. (Credit: S. Turner, UC Riverside)

Entomologists at the University of California, Riverside working on fruit flies in the lab have discovered a novel class of compounds that could pave the way for developing inexpensive and safe mosquito repellents for combating West Nile virus and other deadly tropical diseases.

When fruit flies undergo stress, they emit carbon dioxide (CO₂) that serves as a warning to other fruit flies that danger or predators could be nearby. The fruit flies are able to detect the CO₂ and escape because their antennae are equipped with specialized neurons that are sensitive to the gas.

But fruits and other important food sources for fruit flies also emit CO₂ as a by-product of respiration and ripening. If the innate response of the fruit fly is to avoid CO₂, how then does it find its way to these foods?

Anandasankar Ray, an assistant professor in the Department of Entomology, and Stephanie Turner, his graduate student, now provide an answer to the paradox.

They have identified a new class of odorants – chemical compounds with smells – present in ripening fruit that prevent the CO₂-sensitive neurons in the antennae from functioning. In particular two odors, hexanol and 2,3- butanedione, are strong inhibitors of the CO₂-sensitive neurons in the fruit fly.

The research has strong implications for control of deadly diseases transmitted by Culex mosquitoes such as West Nile virus disease and filariasis, an infectious tropical disease affecting the lymphatic system. Since 1999, nearly 29,000 people in the United States have been reported with West Nile virus disease. Lymphatic filariasis has affected more than 120 million people in the world.

"CO₂ emitted in human breath is the main attractant for the Culex mosquito to find people, aiding the transmission of these deadly diseases," Ray said. "In our experiments we identified hexanol, and a related odor, butanal, as strong inhibitors of CO₂-sensitive neurons in Culex mosquitoes. These compounds can now be used to guide research in developing novel repellents and masking agents that are economical and environmentally safe methods to block mosquitoes' ability to detect CO₂ in our breath, thereby dramatically reducing mosquito-human contact."

Study results appear Aug. 26 in the advance online publication of Nature.

"This is a beautiful study that breaks new ground in the field of olfaction," said John Carlson, the Eugene Higgins Professor of Molecular, Cellular and Developmental Biology at Yale University, who was not involved in the research. "It shows that certain odorants can strongly inhibit the response of receptors that detect CO₂. The results suggest some very interesting new strategies for the control of certain insect pests."

Besides showing that inhibitory odors can play an important role in modifying insect behavior, the research paper also illustrates how some of these odors have a long-term effect. Ray and Turner found, for example, that some odors silenced the CO₂ neuron in the fruit fly well beyond the period of application.

"To our surprise, we found that exposure to a long-term CO₂ response inhibitor can exert a profound and specific effect on the behavior of the insect, even after the inhibitor is no longer in the environment," Ray said. "This means this odorant could potentially be used to keep mosquitoes at bay for longer periods of time, benefiting people in areas where mosquito-transmitted diseases are prevalent."

Ray received his doctoral degree in molecular, cellular and developmental biology from Yale University in 2005. He joined UC Riverside in 2007.

Originally from India, Ray contracted malaria during childhood. When his wife caught dengue fever on a trip to India a few years ago, he decided to intensify his research on mosquito-borne diseases.

Stephanie Turner, the first author of the research paper, received her bachelor's degree in biochemistry from UC Santa Cruz, where she performed research as an undergraduate. She worked for two years in biotechnology before joining the Cell, Molecular and Developmental Biology Graduate Program at UCR.

The research related to this project was conceived, initiated and carried out at UCR over the past one year, and was supported by UCR startup funds. Ray has plans to launch a startup company in the near future to take his basic science research on the odorants from the lab to applications that directly benefit people.

Ray and Turner already have begun work in the lab on mosquitoes that cause malaria and dengue fever. They also are setting up collaborations with a number of scientists from around the globe to do research on various mosquito species and tsetse flies.

The UCR Office of Technology Commercialization has filed a patent application on the discovery.

Courtesy: Science Daily