Tumor Cells' Inner Workings Predict Cancer Progression

Using a new assay method to study tumor cells, researchers at the University of California, San Diego School of Medicine and UC San Diego Moores Cancer Center have found evidence of clonal evolution in chronic lymphocytic leukemia (CLL). The assay method distinguishes features of leukemia cells that indicate whether the disease will be aggressive or slow-moving, a key factor in when and how patients are treated.

The findings are published in the July 26, 2012 First Edition online issue of Blood.

The progression of CLL is highly variable, dependent upon the rate and effects of accumulating monoclonal B cells in the blood, marrow, and lymphoid tissues. Some patients are symptom-free for years and do not require treatment, which involves the use of drugs that can cause significant side effects and are not curative. In other patients, however, CLL is relatively aggressive and demands therapeutic intervention soon after diagnosis.

"Our study shows that there may not be a sharp dividing line between the more aggressive and less aggressive forms of CLL," said Thomas J. Kipps, MD, PhD, Evelyn and Edwin Tasch Chair in Cancer Research and senior author of the study. "Instead, it seems that over time the leukemia cells of patients with indolent disease begin to use genes similar to those that are generally used by CLL cells of patients with aggressive disease. In other words, prior to requiring therapy, the patterns of genes expressed by CLL cells appear to converge, regardless of whether or not the patient had aggressive versus indolent disease at diagnosis."

Existing markers for aggressive or indolent disease are mostly fixed and have declining predictive value the longer the patient is from his or her initial diagnosis. When the blood sample is collected, these markers cannot reliably predict whether a CLL patient will need therapy soon, particularly when the patient has had the diagnosis of CLL for many years.

Kipps and colleagues studied thousands of genes, particularly those that code for proteins, in a group of 130 CLL patients with varying risks of disease progression. They identified 38 prognostic subnetworks of interacting genes and proteins that, at the time of sample collection, indicate the relative the aggressiveness of the disease and predict when the patient will require therapy. They confirmed their work using the method on two other, smaller CLL patient cohorts in Germany and Italy.

The subnetworks offer greater predictive value because they are based not on expression levels of individual genes or proteins, but on how they dynamically interact and change over time, influencing the course of the CLL and patient symptoms.

"In a sense, we looked at families rather than individuals," said Kipps. "If you find in an interconnected family where most genes or proteins are expressed at higher levels, it becomes more likely that these genes and proteins have functional significance."

He added that while the subnetworks abound in data, their complexity actually makes them easy to interpret and understand. "It's like when you look out of a window and see the sky, clouds, trees, people, cars. You're getting tremendous amounts of information that individually doesn't tell you much. But when you look at the scene as a whole, you see patterns and networks. This work is similar. We're taking all of the individual gene expression patterns and making sense of them as a whole. We're more able to more clearly see how they control and regulate function."

The findings help define how CLL -- and perhaps other cancers -- evolve over time, becoming more aggressive and deadly. "It's as if each tumor has a clock which determines how frequently it may acquire the chance changes that make it behave more aggressively. Although the rates can vary, it appears that tumors march down similar pathways, which converge over time to a point where they become aggressive enough to require therapy."

The study may alter how scientists think about CLL and how clinicians treat the disease: whether it is better to wait for later stages of the disease when tumor cells are more fragile and easier to kill, or treat early-stage indolent tumor cells aggressively, when they are fewer in number but harder to find and more resistant to therapy.

Journal Reference:

1. Han-Yu Chuang, Laura Rassenti, Michelle Salcedo, Kate Licon, Alexander Kohlmann, Torsten Haferlach, Robin Foà, Trey Ideker, and Thomas J. Kipps. Subnetwork-based analysis of chronic lymphocytic leukemia identifies pathways that associate with disease progression. Blood, July 26, 2012 DOI: 10.1182/blood-2012-03-416461

Courtesy: ScienceDaily

Unique Mechanism Identified in Bacteria as Potential Target for Developing New Antibiotics

Researchers from Florida Atlantic University's Charles E. Schmidt College of Medicine have identified a unique mechanism in bacteria that has the potential to serve as a target for developing new antibiotics for diseases such as AIDS and soft tissue infections including respiratory and urogenital tracts, which are currently difficult to treat. 

The results of these findings were published in an article titled "Novel One-step Mechanism for tRNA 3'-End Maturation by the Exoribonuclease RNase of Mycoplasma gentialium" in the current issue of the Journal of Biological Chemistry.

Co-authors of the article are Ravi K. Alluri, a pre-doctoral student in the department of biomedical science and Dr. Zhongwei Li, Ph.D., associate professor of biomedical science in FAU's Charles E. Schmidt College of Medicine.

Li and Alluri explain that every organism lives on the same principle that genes direct the production of proteins. This process depends on a set of small RNAs called tRNAs that carry the building blocks of proteins. A tRNA is produced from its gene initially as a precursor that contains extra parts at each end (5' and 3' ends) and sometimes in the middle. These extra parts must be removed through RNA processing before tRNA can work during protein production. The processing of tRNA 5' end has been known for quite some time and work on this enzyme has received a Nobel Prize. Processing of the 3' end is much more complicated and has only been revealed in some organisms more recently. Organisms that have nucleus in their cells, including humans, appear to process the 3' end of tRNA in a similar way. A tRNA must be precisely processed before it can carry a building block for proteins.

"Intriguingly, bacteria appear to process the 3' end of tRNA very differently," said Alluri. "And we are still trying to reveal the various enzymes called RNases, which remove the 3' extra parts of tRNA precursors."

Some of the RNases cut the RNA in the middle, while others trim the RNA from the 3' end. Most of the bacterial pathways involve multiple RNases to complete tRNA 3' processing.

"Knowing how tRNA is processed in different types of bacteria is important not only for understanding how bacteria live, but also for developing novel antibiotics that specifically control bacterial pathogens," said Li.

One such pathogen is the bacterium Mycoplasma genitalium, which is the second smallest known free-living organism that is thought to cause infertility. Alluri and Li's current work focuses on this bacterium -- its genome only contains about 10 percent of the genes found in other common bacteria. Surprisingly, this bacterium contains none of the known RNases for tRNA 3' processing and hence it has to use a different RNase to do so.

"What we have discovered with Mycoplasma genitalium is that it uses a completely different RNase called RNase R to process the 3' end of tRNA," said Alluri. "RNase R can trim the 3' extra part of a tRNA precursor to make a 'functional' tRNA. It is even smart enough to recognize some structural features in the tRNA and tell where the trimming has to stop without harming the mature tRNA."

The ability of RNase R to completely remove the 3' extra RNA bases in a single-step trimming reaction represents a novel mechanism of tRNA 3' processing. Other mycoplasmas generally have small genomes and likely process tRNA in the same way. Using only one enzyme for this complicated task saves genetic resources for mycoplasmas.

"Importantly, blocking the function of RNase R in mycoplasmas can stop protein production and kill the bacteria, making RNase R an excellent target of new antibiotics for treatment of mycoplasma infection," said Li.

Story Source:

The above story is reprinted from materials provided by Florida Atlantic University, via Newswise. 

Courtesy: ScienceDaily

Researchers Produce First Complete Computer Model of an Organism

In a breakthrough effort for computational biology, the world's first complete computer model of an organism has been completed, Stanford researchers reported last week in the journal Cell.

A team led by Markus Covert, assistant professor of bioengineering, used data from more than 900 scientific papers to account for every molecular interaction that takes place in the life cycle of Mycoplasma genitalium, the world's smallest free-living bacterium.

By encompassing the entirety of an organism in silico, the paper fulfills a longstanding goal for the field. Not only does the model allow researchers to address questions that aren't practical to examine otherwise, it represents a stepping-stone toward the use of computer-aided design in bioengineering and medicine.

"This achievement demonstrates a transforming approach to answering questions about fundamental biological processes," said James M. Anderson, director of the National Institutes of Health Division of Program Coordination, Planning and Strategic Initiatives. "Comprehensive computer models of entire cells have the potential to advance our understanding of cellular function and, ultimately, to inform new approaches for the diagnosis and treatment of disease."

The research was partially funded by an NIH Director's Pioneer Award from the National Institutes of Health Common Fund.

From information to understanding

Biology over the past two decades has been marked by the rise of high-throughput studies producing enormous troves of cellular information. A lack of experimental data is no longer the primary limiting factor for researchers. Instead, it's how to make sense of what they already know.

Most biological experiments, however, still take a reductionist approach to this vast array of data: knocking out a single gene and seeing what happens.

"Many of the issues we're interested in aren't single-gene problems," said Covert. "They're the complex result of hundreds or thousands of genes interacting."

This situation has resulted in a yawning gap between information and understanding that can only be addressed by "bringing all of that data into one place and seeing how it fits together," according to Stanford bioengineering graduate student and co-first author Jayodita Sanghvi.

Integrative computational models clarify data sets whose sheer size would otherwise place them outside human ken.

"You don't really understand how something works until you can reproduce it yourself," Sanghvi said.

Small is beautiful

Mycoplasma genitalium is a humble parasitic bacterium known mainly for showing up uninvited in human urogenital and respiratory tracts. But the pathogen also has the distinction of containing the smallest genome of any free-living organism -- only 525 genes, as opposed to the 4,288 of E. coli, a more traditional laboratory bacterium.

Despite the difficulty of working with this sexually transmitted parasite, the minimalism of its genome has made it the focus of several recent bioengineering efforts. Notably, these include the J. Craig Venter Institute's 2008 synthesis of the first artificial chromosome.

"The goal hasn't only been to understand M. genitalium better," said co-first author and Stanford biophysics graduate student Jonathan Karr. "It's to understand biology generally."

Even at this small scale, the quantity of data that the Stanford researchers incorporated into the virtual cell's code was enormous. The final model made use of more than 1,900 experimentally determined parameters.

To integrate these disparate data points into a unified machine, the researchers modeled individual biological processes as 28 separate "modules," each governed by its own algorithm. These modules then communicated to each other after every time step, making for a unified whole that closely matched M. genitalium's real-world behavior.

Probing the silicon cell

The purely computational cell opens up procedures that would be difficult to perform in an actual organism, as well as opportunities to reexamine experimental data.

In the paper, the model is used to demonstrate a number of these approaches, including detailed investigations of DNA-binding protein dynamics and the identification of new gene functions.

The program also allowed the researchers to address aspects of cell behavior that emerge from vast numbers of interacting factors.

The researchers had noticed, for instance, that the length of individual stages in the cell cycle varied from cell to cell, while the length of the overall cycle was much more consistent. Consulting the model, the researchers hypothesized that the overall cell cycle's lack of variation was the result of a built-in negative feedback mechanism.

Cells that took longer to begin DNA replication had time to amass a large pool of free nucleotides. The actual replication step, which uses these nucleotides to form new DNA strands, then passed relatively quickly. Cells that went through the initial step quicker, on the other hand, had no nucleotide surplus. Replication ended up slowing to the rate of nucleotide production.

These kinds of findings remain hypotheses until they're confirmed by real-world experiments, but they promise to accelerate the process of scientific inquiry.

"If you use a model to guide your experiments, you're going to discover things faster. We've shown that time and time again," said Covert.

Bio-CAD

Much of the model's future promise lies in more applied fields.

CAD -- computer-aided design -- has revolutionized fields from aeronautics to civil engineering by drastically reducing the trial-and-error involved in design. But our incomplete understanding of even the simplest biological systems has meant that CAD hasn't yet found a place in bioengineering.

Computational models like that of M. genitalium could bring rational design to biology -- allowing not only for computer-guided experimental regimes, but also for the wholesale creation of new microorganisms.

Once similar models have been devised for more experimentally tractable organisms, Karr envisions bacteria or yeast specifically designed to mass-produce pharmaceuticals.

Bio-CAD could also lead to enticing medical advances -- especially in the field of personalized medicine. But these applications are a long way off, the researchers said.

"This is potentially the new Human Genome Project," Karr said. "It's going to take a really large community effort to get close to a human model."

Stanford's Department of Bioengineering is jointly operated by the School of Engineering and the School of Medicine.

Journal Reference:

1. Jonathan R. Karr, Jayodita C. Sanghvi, Derek N. Macklin, Miriam V. Gutschow, Jared M. Jacobs, Benjamin Bolival, Nacyra Assad-Garcia, John I. Glass, Markus W. Covert. A Whole-Cell Computational Model Predicts Phenotype from Genotype. Cell, 2012; 150 (2): 389 DOI: 10.1016/j.cell.2012.05.044

Courtesy: ScienceDaily

Behold, the Artificial Jellyfish: Researchers Create Moving Model, Using Silicone Polymer and Heart Muscle Cells

Using recent advances in marine biomechanics, materials science, and tissue engineering, a team of researchers at Harvard University and the California Institute of Technology (Caltech) have turned inanimate silicone and living cardiac muscle cells into a freely swimming "jellyfish."

The finding serves as a proof of concept for reverse engineering a variety of muscular organs and simple life forms. It also suggests a broader definition of what counts as synthetic life in an emerging field that has primarily focused on replicating life's building blocks.

The researchers' method for building the tissue-engineered jellyfish, dubbed "Medusoid," was published in a Nature Biotechnology paper on July 22.

An expert in cell- and tissue-powered actuators, coauthor Kevin Kit Parker has previously demonstrated bioengineered constructs that can grip, pump, and even walk. The inspiration to raise the bar and mimic a jellyfish came out of his own frustration with the state of the cardiac field.

Similar to the way a human heart moves blood throughout the body, jellyfish propel themselves through the water by pumping. In figuring out how to take apart and then rebuild the primary motor function of a jellyfish, the aim was to gain new insights into how such pumps really worked.

"It occurred to me in 2007 that we might have failed to understand the fundamental laws of muscular pumps," says Parker, Tarr Family Professor of Bioengineering and Applied Physics at the Harvard School of Engineering and Applied Sciences (SEAS) and a Core Faculty Member at the Wyss Institute for Biologically Inspired Engineering at Harvard. "I started looking at marine organisms that pump to survive. Then I saw a jellyfish at the New England Aquarium and I immediately noted both similarities and differences between how the jellyfish and the human heart pump."

To build the Medusoid, Parker collaborated with Janna Nawroth, a doctoral student in biology at Caltech and lead author of the study, who performed the work as a visiting researcher in Parker's lab. They also worked with Nawroth's adviser, John Dabiri, a professor of aeronautics and bioengineering at Caltech, who is an expert in biological propulsion.

"A big goal of our study was to advance tissue engineering," says Nawroth. "In many ways, it is still a very qualitative art, with people trying to copy a tissue or organ just based on what they think is important or what they see as the major components -- without necessarily understanding if those components are relevant to the desired function or without analyzing first how different materials could be used."

It turned out that jellyfish, believed to be the oldest multi-organ animals in the world, were an ideal subject, as they use muscles to pump their way through water, and their basic morphology is similar to that of a beating human heart.

To reverse engineer a medusa jellyfish, the investigators used analysis tools borrowed from the fields of law enforcement biometrics and crystallography to make maps of the alignment of subcellular protein networks within all of the muscle cells within the animal. They then conducted studies to understand the electrophysiological triggering of jellyfish propulsion and the biomechanics of the propulsive stroke itself.

Based on such understanding, it turned out that a sheet of cultured rat heart muscle tissue that would contract when electrically stimulated in a liquid environment was the perfect raw material to create an ersatz jellyfish. The team then incorporated a silicone polymer that fashions the body of the artificial creature into a thin membrane that resembles a small jellyfish, with eight arm-like appendages.

Using the same analysis tools, the investigators were able to quantitatively match the subcellular, cellular, and supracellular architecture of the jellyfish musculature with the rat heart muscle cells.

The artificial construct was placed in container of ocean-like salt water and shocked into swimming with synchronized muscle contractions that mimic those of real jellyfish. (In fact, the muscle cells started to contract a bit on their own even before the electrical current was applied.)

"I was surprised that with relatively few components -- a silicone base and cells that we arranged -- we were able to reproduce some pretty complex swimming and feeding behaviors that you see in biological jellyfish," says Dabiri.

Their design strategy, they say, will be broadly applicable to the reverse engineering of muscular organs in humans.

"As engineers, we are very comfortable with building things out of steel, copper, concrete," says Parker. "I think of cells as another kind of building substrate, but we need rigorous quantitative design specs to move tissue engineering to a reproducible type of engineering. The jellyfish provides a design algorithm for reverse engineering an organ's function and developing quantitative design and performance specifications. We can complete the full exercise of the engineer's design process: design, build, and test."

In addition to advancing the field of tissue engineering, Parker adds that he took on the challenge of building a creature to challenge the traditional view of synthetic biology which is "focused on genetic manipulations of cells." Instead of building just a cell, he sought to "build a beast."

Looking forward, the researchers aim to further evolve the artificial jellyfish, allowing it to turn and move in a particular direction, and even incorporating a simple "brain" so it can respond to its environment and replicate more advanced behaviors like heading toward a light source and seeking energy or food.

Along with Parker, Nawroth, and Dabiri, contributors to the study included Hyungsuk Lee, Adam W. Feinberg, Crystal M. Ripplinger, Megan L. McCain, and Anna Grosberg, all at Harvard.

Journal Reference:

1. Janna C Nawroth, Hyungsuk Lee, Adam W Feinberg, Crystal M Ripplinger, Megan L McCain, Anna Grosberg, John O Dabiri, Kevin Kit Parker. A tissue-engineered jellyfish with biomimetic propulsion. Nature Biotechnology, 2012; DOI: 10.1038/nbt.2269

Courtesy: ScienceDaily

Antibodies Reverse Type 1 Diabetes in New Immunotherapy Animal Study

 T cells (red, green) not detected and insulin (blue) readily observed in pancreatic islets of antibody-treated (Right) versus untreated (Left) diabetic NOD mouse. (Credit: Tisch Lab, UNC)

Scientists at the University of North Carolina School of Medicine have used injections of antibodies to rapidly reverse the onset of Type I diabetes in mice genetically bred to develop the disease. Moreover, just two injections maintained disease remission indefinitely without harming the immune system.

The findings, published online ahead of print (June 29, 2012) in the journal Diabetes, suggest for the first time that using a short course of immunotherapy may someday be of value for reversing the onset of Type I diabetes in recently diagnosed people. This form of diabetes, formerly known as insulin-dependent diabetes mellitus, is an autoimmune disease in which the body's own immune T cells target and destroy insulin-producing beta cells in the pancreas.

The immune system consists of T cells that are required for maintaining immunity against different bacterial and viral pathogens. In people who develop Type 1 diabetes, "autoreactive" T cells that actively destroy beta cells are not kept in check as they are in healthy people.

Senior study author Roland Tisch, PhD, professor of microbiology and immunology at UNC, said a need for effective immunotherapies also exists to treat Type 1 diabetes in people already living with the disease.

"Clinically, there have been some promising results using so-called depleting antibodies in recently diagnosed Type 1 diabetic patients, but the disease process is blocked for only a short period of time," Tisch said. "These antibodies don't discriminate between T cells normally required for maintaining immunity to disease-causing pathogens and the autoreactive T cells. Therefore T cells involved in maintaining normal immune function are also going to be depleted.

"You're getting some efficacy from immunotherapy but its only transient, it doesn't reverse the disease, and there are various complications associated with the use of these depleting antibodies."

Tisch said his UNC lab has been studying the use of certain "non-depleting antibodies." These bind to particular proteins known as CD4 and CD8 expressed by all T cells. Just as the name implies, when these non-depleting antibodies selectively bind to CD4 and CD8 they don't destroy the T cells; the overall numbers of T cells are unaffected.

With this in mind Tisch wanted to determine whether these non-depleting antibodies could have a therapeutic effect in the non-obese diabetic, or NOD mouse, an excellent model for human Type 1 diabetes.

The answer is yes. In some of the recently diagnosed NOD mice, blood sugar levels returned to normal within 48 hours of treatment. Within five days, about 80 percent of the animals had undergone diabetes remission, reversal of clinical diabetes.

"The protective effect is very rapid, and once established, is long-term," he said. "We followed the animals in excess of 400 days after the two antibody treatments, and the majority remained free of diabetes. And although the antibodies are cleared from within the animals in 2-3 weeks after treatment, the protective effect persists." The study showed that beta cells in the NOD mice had been rescued from ongoing autoimmune destruction.

In looking for the mechanism to explain how the therapy worked, the researchers found that the antibodies had a very selective effect on T cells that mediated beta cell destruction. After treatment, "all the T cells that we would normally see in the pancreas or in tissues associated with the pancreas had been purged," said Tisch. This despite the fact that the numbers of T cells found in other tissues and blood were unaffected.

The researchers also found an increase in the numbers of "immune regulatory" T cells. In the healthy individual, these regulatory T cells block autoimmunity, Tisch explained. "They protect us from the autoreactive cells that all of us have. And that's why most of us don't develop autoimmune diseases such as Type 1 diabetes."

"We've demonstrated that the use of non-depleting antibodies is very robust. We're now generating and plan to test antibodies that are specific for the human version of the CD4 and CD8 molecules."

UNC study coauthors with Tisch are first-author, Zuoan Li, (now at the University of Iowa); Ramiro Diz, Aaron Martin, Yves Maurice Morillon, Douglas E. Kline, (now at the University of Chicago); Li Li (now at Harvard Medical School); and Bo Wang.

Support for research came from the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health; and from the Juvenile Diabetes Research Foundation.

Journal Reference:

1. Z. Yi, R. Diz, A. J. Martin, Y. M. Morillon, D. E. Kline, L. Li, B. Wang, R. Tisch. Long-Term Remission of Diabetes in NOD Mice Is Induced by Nondepleting Anti-CD4 and Anti-CD8 Antibodies. Diabetes, 2012; DOI: 10.2337/db12-0098

Courtesy: ScienceDaily

World's Fastest Camera Used to Detect Rogue Cancer Cells

The ability to distinguish and isolate rare cells from among a large population of assorted cells has become increasingly important for the early detection of disease and for monitoring disease treatments.

Circulating cancer tumor cells are a perfect example. Typically, there are only a handful of them among a billion healthy cells, yet they are precursors to metastasis, the spread of cancer that causes about 90 percent of cancer mortalities. Such "rogue" cells are not limited to cancer -- they also include stem cells used for regenerative medicine and other cell types.

Unfortunately, detecting such cells is difficult. Achieving good statistical accuracy requires an automated, high-throughput instrument that can examine millions of cells in a reasonably short time. Microscopes equipped with digital cameras are currently the gold standard for analyzing cells, but they are too slow to be useful for this application.

Now, a new optical microscope developed by UCLA engineers could make the tough task a whole lot easier.

"To catch these elusive cells, the camera must be able to capture and digitally process millions of images continuously at a very high frame rate," said Bahram Jalali, who holds the Northrop Grumman Endowed Opto-Electronic Chair in Electrical Engineering at the UCLA Henry Samueli School of Engineering and Applied Science. "Conventional CCD and CMOS cameras are not fast and sensitive enough. It takes time to read the data from the array of pixels, and they become less sensitive to light at high speed."

The current flow-cytometry method has high throughput, but since it relies on single-point light scattering, as opposed to taking a picture, it is not sensitive enough to detect very rare cell types, such as those present in early-stage or pre-metastasis cancer patients.

To overcome these limitations, an interdisciplinary team of researchers led by Jalali and Dino Di Carlo, a UCLA associate professor of bioengineering, with expertise in optics and high-speed electronics, microfluidics, and biotechnology, has developed a high-throughput flow-through optical microscope with the ability to detect rare cells with sensitivity of one part per million in real time.

This technology builds on the photonic time-stretch camera technology created by Jalali's team in 2009 to produce the world's fastest continuous-running camera.

In the latest issue of the journal Proceedings of the National Academy of Sciences, Jalali, Di Carlo and their colleagues describe how they integrated this camera with advanced microfluidics and real-time image processing in order to classify cells in blood samples. The new blood-screening technology boasts a throughput of 100,000 cells per second, approximately 100 times higher than conventional imaging-based blood analyzers.

"This achievement required the integration of several cutting-edge technologies through collaborations between the departments of bioengineering and electrical engineering and the California NanoSystems Institute and adds to the significant technology infrastructure being developed at UCLA for cell-based diagnostics," Di Carlo said.

Both Jalali and Di Carlo are members of the California NanoSystems Institute at UCLA.

Their research demonstrates real-time identification of rare breast cancer cells in blood with a record low false-positive rate of one cell in a million. Preliminary results indicate that this new technology has the potential to quickly enable the detection of rare circulating tumor cells from a large volume of blood, opening the way for statistically accurate early detection of cancer and for monitoring the efficiency of drug and radiation therapy.

"This technology can significantly reduce errors and costs in medical diagnosis," said lead author Keisuke Goda, a UCLA program manager in electrical engineering and bioengineering.

The results were obtained by mixing cancer cells grown in a laboratory with blood in various proportions to emulate real-life patient blood.

"To further validate the clinical utility of the technology, we are currently performing clinical tests in collaboration with clinicians," said Goda, also a member of the California NanoSystems Institute. "The technology is also potentially useful for urine analysis, water quality monitoring and related applications."

The study was funded by the U.S. Congressionally Directed Medical Research Programs (CDMRP) and by NantWorks LLC and the Burroughs Wellcome Fund.

Journal Reference:

1. K. Goda, A. Ayazi, D. R. Gossett, J. Sadasivam, C. K. Lonappan, E. Sollier, A. M. Fard, S. C. Hur, J. Adam, C. Murray, C. Wang, N. Brackbill, D. Di Carlo, B. Jalali. High-throughput single-microparticle imaging flow analyzer. Proceedings of the National Academy of Sciences, 2012; DOI: 10.1073/pnas.1204718109

Courtesy: ScienceDaily

Keeping the Flu Away: Synthetic Protein Activates Immune System Within Two Hours

San Diego State University researchers at the Donald P. Shiley BioScience Center may have found the secret to helping the immune system fight off the flu before it gets you sick.

A new study published July 6 in the Public Library of Science journal PLoS ONE, finds that EP67, a powerful synthetic protein, is able to activate the innate immune system within just two hours of being administered.

Prior to this study, EP67 had been primarily used as an adjuvant for vaccines, something added to the vaccine to help activate the immune response. But Joy Phillips, Ph.D. a lead author of the study with her colleague Sam Sanderson, Ph.D. at the University of Nebraska Medical Center, saw potential for it to work on its own.

"The flu virus is very sneaky and actively keeps the immune system from detecting it for a few days until you are getting symptoms," Phillips said. "Our research showed that by introducing EP67 into the body within 24 hours of exposure to the flu virus caused the immune system to react almost immediately to the threat, well before your body normally would."

Because EP67 doesn't work on the virus but on the immune system itself, it functions the same no matter the flu strain, unlike the influenza vaccine which has to exactly match the currently circulating strain.

Phillips said while this study focuses on the flu, EP67 has the potential to work on other respiratory diseases and fungal infections and could have huge potential for emergency therapeutics.

"When you find out you've been exposed to the flu, the only treatments available now target the virus directly but they are not reliable and often the virus develops a resistance against them," Phillips said. "EP67 could potentially be a therapeutic that someone would take when they know they've been exposed that would help the body fight off the virus before you get sick."

It could even be used in the event of a new strain of infectious disease, before the actual pathogen has been identified, as in SARS or the 2009 H1N1 influenza outbreak, Phillips said.

Right now, the testing has been done primarily in mice by infecting them with a flu virus. Those that were given a dose of EP67 within 24 hours of the infection didn't get sick (or as sick) as those that were not treated with EP67.

The level of illness in mice is measured by weight loss. Typically, mice lose approximately 20 percent of their weight when they are infected with the flu but mice treated with EP67 lost an average of just six percent. More importantly, mice who were treated a day after being infected with a lethal dose of influenza did not die, Phillips said.

She said there are also huge implications for veterinary applications, since EP67 is active in animals, including birds.

Future research will examine the effect EP67 has in the presence of a number of other pathogens and to look closer at exactly how EP67 functions within different cells in the body.

Journal Reference:

1. Sam D. Sanderson, Marilyn L. Thoman, Kornelia Kis, Elizabeth L. Virts, Edgar B. Herrera, Stephanie Widmann, Homero Sepulveda, Joy A. Phillips. Innate Immune Induction and Influenza Protection Elicited by a Response-Selective Agonist of Human C5a. PLoS ONE, 2012; 7 (7): e40303 DOI: 10.1371/journal.pone.0040303

Courtesy: ScienceDaily

Uncontrollable Anger Prevalent Among U.S. Youth: Almost Two-Thirds Have History of Anger Attacks

Nearly two-thirds of U.S. adolescents have experienced an anger attack that involved threatening violence, destroying property or engaging in violence toward others at some point in their lives. These severe attacks of uncontrollable anger are much more common among adolescents than previously recognized, a new study led by researchers from Harvard Medical School finds.

The study, based on the National Comorbidity Survey Replication Adolescent Supplement, a national face-to-face household survey of 10,148 U.S. adolescents, found that nearly two-thirds of adolescents in the U.S. have a history of anger attacks. It also found that one in 12 young people -- close to six million adolescents -- meet criteria for a diagnosis of Intermittent Explosive Disorder (IED), a syndrome characterized by persistent uncontrollable anger attacks not accounted for by other mental disorders.

The results were published July 2 in Archives of General Psychiatry.

IED has an average onset in late childhood and tends to be quite persistent through the middle years of life. It is associated with the later onset of numerous other problems, including depression and substance abuse, according to senior author Ronald Kessler, McNeil Family Professor of Health Care Policy at HMS and leader of the team that carried out the study. Yet only 6.5 percent of adolescents with IED received professional treatment for their anger attacks.

Study findings indicate that IED is a severe, chronic, commonly occurring disorder among adolescents, one that begins early in life. Yet the study also shows that IED is under-treated: although 37.8 percent of youths with IED obtained treatment for emotional problems in the 12 months prior to the study interview, only 6.5 percent received treatment specifically for anger. The researchers argue for the importance of identifying and treating IED early,perhaps through school-based violence prevention programs.

"If we can detect IED early and intervene with effective treatment right away, we can prevent a substantial amount of future violence perpetration and associated psychopathology," Kessler said.

To be diagnosed with IED, an individual must have had three episodes of impulsive aggressiveness "grossly out of proportion to any precipitating psychosocial stressor," at any time in their life, according to the Diagnostic and Statistical Manual of Mental Disorders. The investigators used an even more stringent definition of IED, requiring that adolescents not meet criteria for other mental disorders associated with aggression, including bipolar disorder, attention-deficit/hyperactivity disorder, oppositional defiant disorder and conduct disorder. As a result, researchers found that 1 in 12 adolescents met criteria for IED.

Collaborators included Katie McLaughlin, an HMS assistant professor of pediatrics and psychology at Boston Children's Hospital, Jennifer Greif Green at Boston University School of Education, Alan Zaslavsky, an HMS professor of health care policy, as well as statistical programmer and data analyst Irving Hwang and Nancy Sampson, a project director at HMS.

This research was funded by the National Institute of Mental Health (U01-MH60220 and R01-MH66627), the National Institute on Drug Abuse, the Substance Abuse and Mental Health Services Administration, the Robert Wood Johnson Foundation and the John W. Alden Trust.

Journal Reference:

1. Jennifer Greif Green. Intermittent Explosive Disorder in the National Comorbidity Survey Replication Adolescent SupplementIntermittent Explosive Disorder in Adolescents. Archives of General Psychiatry, 2012; 1 DOI: 10.1001/archgenpsychiatry.2012.592

Courtesy: ScienceDaily

Autism, Schizophrenia and Bipolar Disorder May Share Common Underlying Factors, Family Histories Suggest

New research led by Patrick F. Sullivan, MD, FRANZCP, a medical geneticist at the University of North Carolina School of Medicine, points to an increased risk of autism spectrum disorders (ASDs) among individuals whose parents or siblings have been diagnosed with schizophrenia or bipolar disorder.

The findings were based on a case-control study using population registers in Sweden and Israel, and the degree to which these three disorders share a basis in causation "has important implications for clinicians, researchers and those affected by the disorders," according to a report of the research published online July 2, 2012 in the Archives of General Psychiatry.

"The results were very consistent in large samples from several different countries and lead us to believe that autism and schizophrenia are more similar than we had thought," said Dr. Sullivan, professor in the department of genetics and director of psychiatric genomics at UNC.

Sullivan and colleagues found that the presence of schizophrenia in parents was associated with an almost three times increased risk for ASD in groups from both Stockholm and all of Sweden.

Schizophrenia in a sibling also was associated with roughly two and a half times the risk for autism in the Swedish national group and a 12 times greater risk in a sample of Israeli military conscripts. The authors speculate that the latter finding from Israel resulted from individuals with earlier onset schizophrenia, "which has a higher sibling recurrence."

Bipolar disorder showed a similar pattern of association but of a lesser magnitude, study results indicate.

"Our findings suggest that ASD, schizophrenia and bipolar disorder share etiologic risk factors," the authors state. "We suggest that future research could usefully attempt to discern risk factors common to these disorders."

Study co-authors with Sullivan are Cecilia Magnusson, MD,PhD, Christina M. Hultman, PhD, Niklas Langstrom, MD, PhD, Paul Lichtenstein, PhD, Marcus Bowman, BS, Christina Dalman, MD, PhD, Anna C. Svensson, PhD and Michael Lundberg, MPH, Karolinska Institute, Stockholm, Sweden; Abraham Reichenberg, PhD, Kings College, London, England; Michael Davidson MD, and Mark Weiser, MD, Sheba Medical Center and Tel Aviv University, Israel; Eyal Fruchter, MD Israeli Defense Force Medical Corp, Ramat Gan, Israel.

The study was funded in part by The Swedish Council for Working Life and Social Research, the Swedish Research Council and the Beatrice and Samuel A. Seaver Foundation.

Journal Reference:

1. Cecilia Magnusson. Family History of Schizophrenia and Bipolar Disorder as Risk Factors for AutismFamily History of Psychosis as Risk Factor for ASD. Archives of General Psychiatry, 2012; : 1 DOI: 10.1001/archgenpsychiatry.2012.730

Courtesy: ScienceDaily

Fast Food Intake Increases Risk of Diabetes and Heart Disease in Singapore

The dangers of fast food are well documented; the portions are often larger and the food is generally high in calories and low in nutrients. Now, University of Minnesota School of Public Health researchers have examined the eating habits of residents in Singapore and found new evidence that a diet heavy in fast food increases the risk of developing Type 2 diabetes and coronary heart disease.

The latest research, published online July 2 by the American Heart Association's journal Circulation, found that people who consume fast food even once a week increase their risk of dying from coronary heart disease by 20 percent in comparison to people who avoid fast food. For people eating fast food two-three times each week, the risk increases by 50 percent, and the risk climbs to nearly 80 percent for people who consume fast food items four or more times each week.

Eating fast food two or more times a week was also found to increase the risk of developing Type 2 diabetes by 27 percent.

According to University of Minnesota researchers, the few existing studies on the association of fast food and metabolic risk have looked almost exclusively at Western-Caucasian populations from the United States.

"We wanted to examine the association of Western-style fast food with cardio-metabolic risk in a Chinese population in Southeast Asia that has become a hotbed for diabetes and heart disease," said the study's lead researcher, University of Minnesota post-doctoral researcher Andrew Odegaard, Ph.D., M.P.H. "What we found was a dramatic public health impact by fast food, a product that is primarily a Western import into a completely new market."

To arrive at their results, School of Public Health researchers worked alongside researchers from the National University of Singapore. Together, they examined results of a study conducted over a period of 16 years beginning in 1993, which looked at the eating habits of 52,000 Chinese residents of Singapore who have experienced a recent and sudden transition from traditional foods to Western-style fast food.

"What's interesting about the results is that study participants who reported eating fast food most frequently were younger, better educated, smoked less and were more likely to be physically active," said Odegaard. "This profile is normally associated with lower cardio-metabolic risk."

According to the study's senior researcher, Mark Pereira, Ph.D., M.P.H., of the School of Public Health's Division of Epidemiology and Community Health, the new research provides an important perspective on global health and the nutrition transfer when cultures developing in different parts of the world start moving away from their traditional diet and mode of exercise.

"The big picture is that this [fast food] aspect of globalization and exportation of U.S. and Western culture might not be the best thing to spread to cultures around the world," he said. "Global public health efforts should focus on maintaining the positive aspects of traditional cultures, while preventing the spread of outside influences thought to be harmful based on the scientific evidence."

Funding for the research was provided by the National Institutes of Health grant nos. NCI RO1 CA055069, R35 CA053890, R01 CA080205, R01 CA098497, and R01 CA144034.

Journal Reference:

1. Andrew O. Odegaard, Woon Puay Koh, Jian-Min Yuan, Myron D. Gross, and Mark A. Pereira. Western-Style Fast Food Intake and Cardio-Metabolic Risk in an Eastern Country. Circulation, July 2 2012 DOI: 10.1161/CIRCULATIONAHA.111.084004

Courtesy: ScienceDaily

Natural Intestinal Flora Strengthen Immune System

Signals from natural intestinal bacteria are necessary for an effective immune response to various viral or bacterial germs. This was the result of experiments by a research team led by Prof. Dr. Andreas Diefenbach and Stephanie Ganal at the Institute of Medical Microbiology and Hygiene of the Freiburg University Medical Center.

The study was published in the current online edition of the Cell Press journal Immunity.

Trillions of bacteria reside in the intestines of healthy humans as well as those of many animals. This natural intestinal flora contributes to digestion and the metabolism of vitamins and is of critical importance for the host organism. Recent research has shown that the intestinal flora also plays an important role in the formation of the immune system in the intestines and that changes to it can increase the risk of food allergies or chronic inflammatory intestinal diseases. "It was previously unclear to what extent the intestinal flora also influences immunological processes outside of the intestines, such as the defense against viral germs like the flu virus, and that was the main question of our work," explain the scientists.

The research team infected two groups of mice with various viral germs. One group had a normal intestinal flora and the other consisted of so-called axenic mice, which do not have any intestinal flora due to having been treated with antibiotics or bred under particularly clean conditions. The immune response in the axenic mice was greatly reduced and led the disease to take a more severe course than in the healthy mice. When the scientists artificially provided the axenic mice with a healthy intestinal flora, their immune response improved.

Diefenbach's group succeeded in localizing the defect in axenic mice on the molecular level. The problem was that these mice were not producing any soluble inflammatory mediators, so-called type I interferons, after viral infections. Dendritic cells, i.e., cells of the innate immune defense, react to an infection by rapidly producing these mediators. If they are not present, the body will not be in the position to develop a sufficient immune defense against the germs. The team succeeded in demonstrating that signals from the intestinal bacteria lead to a conditioning of the dendritic cells. This conditioning takes place on the level of the DNA in the nucleus and enables genes that encode these soluble mediators to be read better. The scientists speak of epigenetic changes. "This is the first time anyone has shown that changes in the natural intestinal flora resulting from antibiotics, hygiene, or lifestyle can have substantial consequences for the entire immune system," says Diefenbach.

Journal Reference:

1. Stephanie C. Ganal, Stephanie L. Sanos, Carsten Kallfass, Karin Oberle, Caroline Johner, Carsten Kirschning, Stefan Lienenklaus, Siegfried Weiss, Peter Staeheli, Peter Aichele, Andreas Diefenbach. Priming of Natural Killer Cells by Nonmucosal Mononuclear Phagocytes Requires Instructive Signals from Commensal Microbiota. Immunity, 2012; DOI: 10.1016/j.immuni.2012.05.020

Courtesy: ScienceDaily