Simple Injection Could Limit Damage from Heart Attacks and Stroke

New research offers promise of a simple injection that could be developed to limit the devastating consequences of heart attacks and strokes.

Described by the lead researcher as 'a fascinating new achievement', work has already begun to translate the research into novel clinical therapies.

The University of Leicester led an international team whose research has been published in the Early Online Edition of the Proceedings of the National Academy of Sciences (PNAS).

Professor Wilhelm Schwaeble of the Department of Infection, Immunity and Inflammation at the University of Leicester, initiated and co-ordinated research collaborations with King's College London, the Medical University of Fukushima, Japan and the State University of New York, to achieve the present breakthrough findings, which were published in PNAS.

Professor Schwaeble and collaborators identified an enzyme, Mannan Binding Lectin-Associated Serine Protease-2 (MASP-2), that is found in blood and is a key component of the lectin pathway of complement activation, a component of the innate immune system.

The lectin pathway is responsible for the potentially devastating inflammatory tissue response that can occur when any bodily tissue or organ is reconnected to blood supply following ischaemia -- a temporary loss of that blood supply and the oxygen that it carries. This excessive inflammatory response is, in part, responsible for the morbidity and mortality associated with myocardial infarction (heart attack) and cerebrovascular accidents (CVAs or strokes). Moreover, the work succeeded in finding a way to neutralise this enzyme by raising a therapeutic antibody against it. A single antibody injection in animals has been shown to be sufficient to disrupt the molecular process that leads to tissue and organ destruction following ischaemic events, resulting in significantly less damage and markedly improved outcomes.

"This is a fascinating new achievement in the search for novel treatments to significantly reduce the tissue damage and impaired organ function that occur following ischaemia in widespread and serious conditions such as heart attacks and strokes," said Professor Schwaeble. "This new potential therapy was also shown in animals to significantly improve outcomes of transplant surgery and may be applicable to any surgical procedure where tissue viability is at risk due to temporary interruption of blood flow.

"The main focus of our work was to identify a key molecular mechanism responsible for the overshooting inflammatory response that can cause substantial destruction to tissues and organs following their temporary loss of blood supply, a pathophysiological phenomenon called ischaemia/reperfusion injury," added Professor Schwaeble. "Limiting this inflammatory response in oxygen-deprived tissues could dramatically improve outcomes and survival in patients suffering heart attacks or strokes."

For more than seven years, the University of Leicester team has been working closely with a commercial partner, Omeros Corporation in Seattle (USA), to develop therapeutic antibodies for research and clinical applications. Omeros holds exclusive worldwide intellectual property rights to the MASP-2 protein, all therapeutic antibodies targeting MASP-2 and all methods for treating complement-mediated disorders by inhibiting MASP-2. The company has already begun manufacturing scale-up of an antibody for use in human clinical trials.

Professor Schwaeble's team and Omeros are also working with Professor Nilesh Samani, the British Heart Foundation Professor of Cardiology and Head of the Department of Cardiovascular Sciences at the University of Leicester. It is anticipated that the first clinical trials evaluating Omeros' human antibody in myocardial infarction patients will be conducted in the Leicester Biomedical Research Unit , at Glenfield Hospital, Leicester.

The development of this new technology was made possible through substantial and long-term grant support of the Wellcome Trust and the Medical Research Council, as well as through funding provided to Omeros Corporation by the U.S. National Institutes of Health.

Journal Reference:

1. W. J. Schwaeble, N. J. Lynch, J. E. Clark, M. Marber, N. J. Samani, Y. M. Ali, T. Dudler, B. Parent, K. Lhotta, R. Wallis, C. A. Farrar, S. Sacks, H. Lee, M. Zhang, D. Iwaki, M. Takahashi, T. Fujita, C. E. Tedford, C. M. Stover. Targeting of mannan-binding lectin-associated serine protease-2 (Masp2) confers a significant degree of protection from myocardial and gastrointestinal ischemia/reperfusion injury. Proceedings of the National Academy of Sciences, 2011; DOI: 10.1073/pnas.1101748108

Courtesy: ScienceDaily

Alzheimer's Diagnostic Guidelines Updated for First Time in Decades

For the first time in 27 years, clinical diagnostic criteria for Alzheimer's disease dementia have been revised, and research guidelines for earlier stages of the disease have been characterized to reflect a deeper understanding of the disorder. The National Institute on Aging/Alzheimer's Association Diagnostic Guidelines for Alzheimer's Disease outline some new approaches for clinicians and provides scientists with more advanced guidelines for moving forward with research on diagnosis and treatments. They mark a major change in how experts think about and study Alzheimer's disease. Development of the new guidelines was led by the National Institutes of Health and the Alzheimer's Association.

The original criteria were the first to address the disease and described only later stages, when symptoms of dementia are already evident. The updated guidelines just announced cover the full spectrum of the disease as it gradually changes over many years. They describe the earliest preclinical stages of the disease, mild cognitive impairment, and dementia due to Alzheimer's pathology. Importantly, the guidelines now address the use of imaging and biomarkers in blood and spinal fluid that may help determine whether changes in the brain and those in body fluids are due to Alzheimer's disease. Biomarkers are increasingly employed in the research setting to detect onset of the disease and to track progression, but cannot yet be used routinely in clinical diagnosis without further testing and validation.

"Alzheimer's research has greatly evolved over the past quarter of a century. Bringing the diagnostic guidelines up to speed with those advances is both a necessary and rewarding effort that will benefit patients and accelerate the pace of research," said National Institute on Aging Director Richard J. Hodes, M.D.

"We believe that the publication of these articles is a major milestone for the field," said William Thies, Ph.D., chief medical and scientific officer at the Alzheimer's Association. "Our vision is that this process will result in improved diagnosis and treatment of Alzheimer's, and will drive research that ultimately will enable us to detect and treat the disease earlier and more effectively. This would allow more people to live full, rich lives without -- or with a minimum of -- Alzheimer's symptoms."

The new guidelines appear online April 19, 2011 in Alzheimer's & Dementia: The Journal of the Alzheimer's Association. They were developed by expert panels convened last year by the National Institute on Aging (NIA), part of the NIH, and the Alzheimer's Association. Preliminary recommendations were announced at the Association's International Conference on Alzheimer's Disease in July 2010, followed by a comment period.

Guy M. McKhann, M.D., Johns Hopkins University School of Medicine, Baltimore, and David S. Knopman, M.D., Mayo Clinic, Rochester, Minn., co-chaired the panel that revised the 1984 clinical Alzheimer's dementia criteria. Marilyn Albert, Ph.D., Johns Hopkins University School of Medicine, headed the panel refining the MCI criteria. Reisa A. Sperling, M.D, Brigham and Women's Hospital, Harvard Medical School, Boston, led the panel tasked with defining the preclinical stage. The journal also includes a paper by Clifford Jack, M.D., Mayo Clinic, Rochester, Minn., as senior author, on the need for and concept behind the new guidelines.

The original 1984 clinical criteria for Alzheimer's disease, reflecting the limited knowledge of the day, defined Alzheimer's as having a single stage, dementia, and based diagnosis solely on clinical symptoms. It assumed that people free of dementia symptoms were disease-free. Diagnosis was confirmed only at autopsy, when the hallmarks of the disease, abnormal amounts of amyloid proteins forming plaques and tau proteins forming tangles, were found in the brain.

Since then, research has determined that Alzheimer's may cause changes in the brain a decade or more before symptoms appear and that symptoms do not always directly relate to abnormal changes in the brain caused by Alzheimer's. For example, some older people are found to have abnormal levels of amyloid plaques in the brain at autopsy yet never showed signs of dementia during life. It also appears that amyloid deposits begin early in the disease process but that tangle formation and loss of neurons occur later and may accelerate just before clinical symptoms appear.

To reflect what has been learned, the National Institute on Aging/Alzheimer's Association Diagnostic Guidelines for Alzheimer's Disease cover three distinct stages of Alzheimer's disease:

• Preclinical -- The preclinical stage, for which the guidelines only apply in a research setting, describes a phase in which brain changes, including amyloid buildup and other early nerve cell changes, may already be in process. At this point, significant clinical symptoms are not yet evident. In some people, amyloid buildup can be detected with positron emission tomography (PET) scans and cerebrospinal fluid (CSF) analysis, but it is unknown what the risk for progression to Alzheimer's dementia is for these individuals. However, use of these imaging and biomarker tests at this stage are recommended only for research. These biomarkers are still being developed and standardized and are not ready for use by clinicians in general practice.
• Mild Cognitive Impairment (MCI) -- The guidelines for the MCI stage are also largely for research, although they clarify existing guidelines for MCI for use in a clinical setting. The MCI stage is marked by symptoms of memory problems, enough to be noticed and measured, but not compromising a person's independence. People with MCI may or may not progress to Alzheimer's dementia. Researchers will particularly focus on standardizing biomarkers for amyloid and for other possible signs of injury to the brain. Currently, biomarkers include elevated levels of tau or decreased levels of beta-amyloid in the CSF, reduced glucose uptake in the brain as determined by PET, and atrophy of certain areas of the brain as seen with structural magnetic resonance imaging (MRI). These tests will be used primarily by researchers, but may be applied in specialized clinical settings to supplement standard clinical tests to help determine possible causes of MCI symptoms.
• Alzheimer's Dementia -- These criteria apply to the final stage of the disease, and are most relevant for doctors and patients. They outline ways clinicians should approach evaluating causes and progression of cognitive decline. The guidelines also expand the concept of Alzheimer's dementia beyond memory loss as its most central characteristic. A decline in other aspects of cognition, such as word-finding, vision/spatial issues, and impaired reasoning or judgment may be the first symptom to be noticed. At this stage, biomarker test results may be used in some cases to increase or decrease the level of certainty about a diagnosis of Alzheimer's dementia and to distinguish Alzheimer's dementia from other dementias, even as the validity of such tests is still under study for application and value in everyday clinical practice.

The panels purposefully left the guidelines flexible to allow for changes that could come from emerging technologies and advances in understanding of biomarkers and the disease process itself.

"The guidelines discuss biomarkers currently known, and mention others that may have future applications," said Creighton H. Phelps, Ph.D., of the NIA Alzheimer's Disease Centers Program. "With researchers worldwide striving to develop, validate and standardize the application of biomarkers at every stage of Alzheimer's disease, we devised a framework flexible enough to incorporate new findings."

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by NIH/National Institute on Aging, via EurekAlert!, a service of AAAS.

Courtesy: ScienceDaily

Successful Strategy Developed to Regenerate Blood Vessels

Researchers at The University of Western Ontario have discovered a strategy for stimulating the formation of highly functional new blood vessels in tissues that are starved of oxygen. Dr. Geoffrey Pickering and Matthew Frontini at the Schulich School of Medicine & Dentistry developed a strategy in which a biological factor, called fibroblast growth factor 9 (FGF9), is delivered at the same time that the body is making its own effort at forming new blood vessels in vulnerable or damaged tissue. The result is that an otherwise unsuccessful attempt at regenerating a blood supply becomes a successful one.

Their findings are published online in Nature Biotechnology.

"Heart attacks and strokes are leading causes of death and disability .... Coronary bypass surgery and stenting are important treatments but are not suitable for many individuals," explains Dr. Pickering, a professor of Medicine (Cardiology), Biochemistry, and Medical Biophysics, and a scientist at the Robarts Research Institute. "Because of this, there has been considerable interest in recent years in developing biological strategies that promote the regeneration of a patient's own blood vessels."

This potential treatment has been termed 'therapeutic angiogenesis'. "Unfortunately and despite considerable investigation, therapeutic angiogenesis has not as yet been found to be beneficial to patients with coronary artery disease. It appears that new blood vessels that form using approaches to date do not last long, and may not have the ability to control the flow of blood into the areas starved of oxygen."

The work of Dr. Pickering and collaborators provides a method to overcome these limitations. This strategy is based on paying more attention to the "supporting" cells of the vessel wall, rather than the endothelial or lining cells of the artery wall. The research team found that by activating the supporting cells, new blood vessel sprouts in adult mice did not shrivel up and disappear but instead lasted for over a year. Furthermore, these regenerating blood vessels were now enveloped by smooth muscle cells that gave them the ability to constrict and relax, a critical process that ensures the right amount of blood and oxygen gets to the tissues.

"FGF9 seemed to 'awaken' the supporting cells and stimulated their wrapping around the otherwise fragile blood vessel wall" said Frontini, the first author of the manuscript. "The idea of promoting the supporting cellular actors rather than the leading actors opens new ways of thinking about vascular regeneration and new possibilities for treating patients with vascular disease."

Funding for the research was provided by the Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario, and Lawson Health Research Institute.

Journal Reference:

1. Matthew J Frontini, Zengxuan Nong, Robert Gros, Maria Drangova, Caroline O'Neil, Mona N Rahman, Oula Akawi, Hao Yin, Christopher G Ellis, J Geoffrey Pickering. Fibroblast growth factor 9 delivery during angiogenesis produces durable, vasoresponsive microvessels wrapped by smooth muscle cells. Nature Biotechnology, 2011; DOI: 10.1038/nbt.1845

Courtesy: ScienceDaily

Nanofiber Spheres Carrying Cells Injected Into Wounds to Grow Tissue

For the first time, scientists have made star-shaped, biodegradable polymers that can self-assemble into hollow, nanofiber spheres, and when the spheres are injected with cells into wounds, these spheres biodegrade, but the cells live on to form new tissue.

Developing this nanofiber sphere as a cell carrier that simulates the natural growing environment of the cell is a very significant advance in tissue repair, says Peter Ma, professor at the University of Michigan School of Dentistry and lead author of a paper about the research scheduled for advanced online publication in Nature Materials. Co-authors are Xiaohua Liu and Xiaobing Jin.

Repairing tissue is very difficult and success is extremely limited by a shortage of donor tissue, says Ma, who also has an appointment at the U-M College of Engineering. The procedure gives hope to people with certain types of cartilage injuries for which there aren't good treatments now. It also provides a better alternative to ACI, which is a clinical method of treating cartilage injuries where the patient's own cells are directly injected into the patient's body. The quality of the tissue repair by the ACI technique isn't good because the cells are injected loosely and are not supported by a carrier that simulates the natural environment for the cells, Ma says.

To repair complex or oddly shaped tissue defects, an injectable cell carrier is desirable to achieve accurate fit and to minimize surgery, he says. Ma's lab has been working on a biomimetic strategy to design a cell matrix -- a system that copies biology and supports the cells as they grow and form tissue -- using biodegradable nanofibers.

Ma says the nanofibrous hollow microspheres are highly porous, which allows nutrients to enter easily, and they mimic the functions of cellular matrix in the body. Additionally, the nanofibers in these hollow microspheres do not generate much degradation byproducts that could hurt the cells, he says.

The nanofibrous hollow spheres are combined with cells and then injected into the wound. When the nanofiber spheres, which are slightly bigger than the cells they carry, degrade at the wound site, the cells they are carrying have already gotten a good start growing because the nanofiber spheres provide an environment in which the cells naturally thrive.

This approach has been more successful than the traditional cell matrix currently used in tissue growth, he says. Until now, there has been no way to make such a matrix injectable so it's not been used to deliver cells to complex-shaped wounds.

During testing, the nanofiber repair group grew as much as three to four times more tissue than the control group, Ma says. The next step is to see how the new cell carrier works in larger animals and eventually in people to repair cartilage and other tissue types.

Journal Reference:

1. Xiaohua Liu, Xiaobing Jin & Peter X. Ma. Nanofibrous hollow microspheres self-assembled from star-shaped polymers as injectable cell carriers for knee repair. Nature Materials, 17 April 2011 DOI: 10.1038/nmat2999

Courtesy: ScienceDaily

'Good Cholesterol' Nanoparticles Seek and Destroy Cancer Cells

High-density lipoprotein's hauls excess cholesterol to the liver for disposal, but new research suggests "good cholesterol" can also act as a special delivery vehicle of destruction for cancer.

Synthetic HDL nanoparticles loaded with small interfering RNA to silence cancer-promoting genes selectively shrunk or destroyed ovarian cancer tumors in mice, a research team led by scientists from The University of Texas MD Anderson Cancer Center and the University of North Texas Health Science Center reports in the April edition of Neoplasia.

"RNA interference has great therapeutic potential but delivering it to cancer cells has been problematic," said Anil Sood, M.D., the study's senior author and MD Anderson's director of Ovarian Cancer Research and co-director of the Center for RNA Interference and Non-Coding RNA at MD Anderson. "Combining siRNA with HDL provides an efficient way to get these molecules to their targets. This study has several important implications in the ability to fight certain cancers."

Sood and Andras Lacko, Ph.D., professor of Molecular Biology and Immunology at UNT Health Science Center, jointly developed the nanoparticles, which build on Lacko's original insight about HDL's potential for cancer drug delivery.

The next step is to prepare for human clinical trials, the two scientists said. "If we can knock out 70, 80 or 90 percent of tumors without drug accumulation in normal tissues in mice, it is likely that many cancer patients could benefit from this new type of treatment in the long run," Lacko said.

Only cancer and liver cells express HDL receptor

Previous studies have shown that cancer cells attract and scavenge HDL by producing high levels of its receptor, SR-B1. As cancer cells take in HDL, they grow and proliferate. The only other site in the body that makes SR-B1 receptor is the liver. This selectivity for cancer cells protects normal, healthy cells from side effects.

Previous attempts to deliver siRNA by lipsomes and other nanoparticles have been hampered by toxicity and other concerns. The tiny bits of RNA, which regulate genes in a highly targeted fashion, can't simply be injected, for example.

"If siRNA is not in a nanoparticle, it gets broken down and excreted before it can be effective," Sood said. "HDL is completely biocompatible and is a safety improvement over other types of nanoparticles."

The team developed a synthetic version of HDL, called rHDL, because it's more stable than the natural version.

Fewer and smaller tumors, less toxicity

Using rHDL as a delivery method has other advantages as well. rHDL has not shown to cause immunologic responses, helping to minimize potential side effects, Lacko said, and it exhibits longer time in circulation than other drug formulations or lipoproteins. Also, because SR-B1 is found only in the liver, an rHDL vehicle will help block and treat metastasis to that organ.

Researchers first confirmed the distribution of SR-B1 and the uptake of rHDL nanoparticles in mice injected with cancer cells. They found that siRNA was distributed evenly in about 80 percent of a treated tumor. As expected, the nanoparticles accumulated in the liver with minimal or no delivery to the brain, heart, lung, kidney or spleen. Safety studies showed uptake in the liver did not cause adverse effects.

Using siRNA tailored to the individual gene, the researchers separately shut down the genes STAT3 and FAK in various types of treatment-resistant ovarian cancer tumors. STAT3 and FAK are important to cancer growth, progression and metastasis; however, they also play important roles in normal tissue so targeting precision is vital.

The siRNA/rHDL formulation alone reduced the size and number of tumors by 60 to 80 percent. Combinations with chemotherapy caused reductions above 90 percent.

Conventional approaches to target STAT3 have met limited success, Sood said. FAK, which is over expressed in colorectal, breast, ovarian, thyroid and prostate cancers, is particularly aggressive in ovarian cancer and one reason for its poor survival rate. While previous attempts have targeted FAK with liposomal nanoparticles or small molecule inhibitors, these methods are not tumor-specific and are more likely to harm normal cells, the scientists noted.

Next Step: Clinical Studies

"In order to help expedite the study's progress to a clinical setting, we have identified 12 genes as biomarkers for response to STAT3-targeted therapy," Sood said. "Next, we'll work with the National Cancer Institute Nanoparticle Characterization Lab to develop a formulation of the HDL/siRNA nanoparticle for human use."

MD Anderson and UNT have applied for a patent for the nanoparticle delivery method. These arrangements are managed by MD Anderson and the University of North Texas HSC in accordance with institutional conflict of interest policies.

This research was supported by grants from GCF Molly-Cade, National Institutes of Health, U.S. Department of Defense, Ovarian Cancer Research Fund, Inc., Zarrow Foundation, The Marcus Foundation, the University of Texas MD Anderson Cancer Center SPORE in Ovarian Cancer, the Betty Ann Asche Murray Distinguished Professorship, Deborah Gonzalez Women's Health Fellowship Award, the Puerto Rico Comprehensive Cancer Center, Cowtown Cruisin' for the Cure and a HER grant from the University of North Texas Health Science Center.

Journal Reference:

1. Mian M.K. Shahzad, Lingegowda S. Mangala, Hee D. Han, Chunhua Lu, Justin Bottsford-Miller, Edna M. Mora, Jeong W. Lee, Rebecca L. Stone, Duangmani Thanapprapasr, Ju-Won Roh, Puja Gaur, Maya P. Nair, Yun Y. Park, Nirupama Sabnis, Michael T. Deavers, Ju-Seog Lee, Lee M. Ellis, Gabriel Lopez-Berestein, Walter J. McConathy, Laszlo Prokai, Andras G. Lacko and Anil K Sood. Targeted Delivery of Small Interfering RNA Using rHDL Nanoparticles. Neoplasia, Year 2011, Volume 13, Issue 4 [link]

Courtesy: ScienceDaily

Scientists Develop 'Universal' Virus-Free Method to Turn Blood Cells Into 'Beating' Heart Cells

Johns Hopkins scientists have developed a simplified, cheaper, all-purpose method they say can be used by scientists around the globe to more safely turn blood cells into heart cells. The method is virus-free and produces heart cells that beat with nearly 100 percent efficiency, they claim.

"We took the recipe for this process from a complex minestrone to a simple miso soup," says Elias Zambidis, M.D., Ph.D., assistant professor of oncology and pediatrics at the Johns Hopkins Institute for Cell Engineering and the Kimmel Cancer Center.

Zambidis says, "many scientists previously thought that a nonviral method of inducing blood cells to turn into highly functioning cardiac cells was not within reach, but "we've found a way to do it very efficiently and we want other scientists to test the method in their own labs." However, he cautions that the cells are not yet ready for human testing.

To get stem cells taken from one source (such as blood) and develop them into a cell of another type (such as heart), scientists generally use viruses to deliver a package of genes into cells to, first, get them to turn into stem cells. However, viruses can mutate genes and initiate cancers in newly transformed cells. To insert the genes without using a virus, Zambidis' team turned to plasmids, rings of DNA that replicate briefly inside cells and eventually degrade.

Adding to the complexity of coaxing stem cells into other cell types is the expensive and varied recipe of growth factors, nutrients and conditions that bathe stem cells during their transformation. The recipe of this "broth" differs from lab to lab and cell line to cell line.

Reporting in the April 8 issue of Public Library of Science ONE (PLoS ONE), Zambidis' team described what he called a "painstaking, two-year process" to simplify the recipe and environmental conditions that house cells undergoing transformation into heart cells. They found that their recipe worked consistently for at least 11 different stem cell lines tested and worked equally well for the more controversial embryonic stem cells, as well as stem cell lines generated from adult blood stem cells, their main focus.

The process began with Johns Hopkins postdoctoral scientist Paul Burridge, Ph.D., who studied some 30 papers on techniques to create cardiac cells. He drew charts of 48 different variables used to create heart cells, including buffers, enzymes, growth factors, timing, and the size of compartments in cell culture plates. After testing hundreds of combinations of these variables, Burridge narrowed the choices down to between four to nine essential ingredients at each of three stages of cardiac development.

Beyond simplification, an added benefit is reduced cost. Burridge used a cheaper growth media that is one-tenth the price of standard media for these cells at $250 per bottle lasting about one week.

Zambidis says that he wants other scientists to test the method on their stem cell lines, but also notes that the growth "soup" is still a work in progress. "We have recently optimized the conditions for complete removal of the fetal bovine serum from one brief step of the procedure -- it's made from an animal product and could introduce unwanted viruses," he says.

In their experiments with the new growth medium, the Hopkins team began with cord blood stem cells and a plasmid to transfer seven genes into the stem cells. They delivered an electric pulse to the cells, making tiny holes in the surface through which plasmids can slip inside. Once inside, the plasmids trigger the cells to revert to a more primitive cell state that can be coaxed into various cell types. At this stage, the cells are called induced pluripotent stem cells (iPSC).

Burridge then bathed the newly formed iPSCs in the now simplified recipe of growth media, which they named "universal cardiac differentiation system." The growth media recipe is specific to creating cardiac cells from any iPSC line.

Finally, they incubated the cells in containers that removed oxygen down to a quarter of ordinary atmospheric levels. "The idea is to recreate conditions experienced by an embryo when these primitive cells are developing into different cell types," says Burridge. They also added a chemical called PVA, which works like glue to make cells stick together.

Nine days later, the nonviral iPSCs turned into functional, beating cardiac cells, each the size of a needlepoint.

Burridge manually counted how often iPSCs formed into cardiac cells in petri dishes by peering into a microscope and identifying each beating cluster of cells. In each of 11 cell lines tested, each plate of cells had an average of 94.5 percent beating heart cells. "Most scientists get 10 percent efficiency for IPSC lines if they're lucky," says Zambidis.

Zambidis and Burridge also worked with Johns Hopkins University bioengineering experts to apply a miniversion of an electrocardiograph to the cells, which tests how cardiac cells use calcium and transmit a voltage. The resulting rhythm showed characteristic pulses seen in a normal human heart.

Virus-free, iPSC-derived cardiac cells could be used in laboratories to test drugs that treat arrhythmia and other conditions. Eventually, bioengineers could develop grafts of the cells that are implanted into patients who suffered heart attacks.

Zambidis' team has recently developed similar techniques for turning these blood-derived iPSC lines into retinal, neural and vascular cells.

The research was funded by the Maryland Stem Cell Research Fund and the National Institutes of Health.

Research participants include Susan Thompson, Michal Millrod, Seth Weinberg, Xuan Yuan, Ann Peters, Vasiliki Mahairaki, Vassilis E. Koliatsos, and Leslie Tung at Johns Hopkins.

Journal Reference:

1. Paul W. Burridge, Susan Thompson, Michal A. Millrod, Seth Weinberg, Xuan Yuan, Ann Peters, Vasiliki Mahairaki, Vassilis E. Koliatsos, Leslie Tung, Elias T. Zambidis. A Universal System for Highly Efficient Cardiac Differentiation of Human Induced Pluripotent Stem Cells That Eliminates Interline Variability. PLoS ONE, 2011; 6 (4): e18293 DOI: 10.1371/journal.pone.0018293

Courtesy: ScienceDaily

Aspirin May Lower the Risk of Pancreatic Cancer

The use of aspirin at least once per month is associated with a significant decrease in pancreatic cancer risk, according to results of a large case-control study presented at the AACR 102nd Annual Meeting 2011, held in Orlando, Florida, April 2-6.

Xiang-Lin Tan, Ph.D., M.D., a research fellow at Mayo Clinic in Rochester, Minn., said the findings from this large collaborative study are preliminary and do not encourage widespread use of aspirin for this purpose.

"The results are not meant to suggest everyone should start taking aspirin once monthly to reduce their risk of pancreatic cancer," said Tan. "Individuals should discuss use of aspirin with their physicians because the drug carries some side effects."

For the current study, Tan and colleagues enrolled 904 patients who had documented pancreatic cancer and compared them with 1,224 healthy patients. All patients were at least 55 years old and reported their use of aspirin, NSAIDs and acetaminophen by questionnaire.

Results showed that people who took aspirin at least one day during a month had a 26 percent decreased risk of pancreatic cancer compared to those who did not take aspirin regularly. The effect was also found for those who took low-dose aspirin for heart disease prevention at 35 percent lower risk, according to Tan.

The researchers did not see a benefit from non-aspirin NSAIDs or acetaminophen. "This provides additional evidence that aspirin may have chemoprevention activity against pancreatic cancer," said Tan. He added that more data must be gathered before we can prove a real benefit.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by American Association for Cancer Research.

Courtesy: ScienceDaily

How Brain's Memory Center Repairs Damage from Head Injury

Researchers from UT Southwestern Medical Center have described for the first time how the brain's memory center repairs itself following severe trauma -- a process that may explain why it is harder to bounce back after multiple head injuries.

The study, published in The Journal of Neuroscience, reports significant learning and memory problems in mice who were unable to create new nerve cells in the brain's memory area, the hippocampus, following brain trauma. The study's senior author, Dr. Steven G. Kernie, associate professor of pediatrics and developmental biology at UT Southwestern, said the hippocampus contains a well of neural stem cells that become neurons in response to injury; those stem cells must grow into functioning nerve cells to mend the damage.

"Traumatic brain injury (TBI) has received a lot of attention recently because of the recognition that both military personnel and football players suffer from debilitating brain injuries," Dr. Kernie said, adding that memory and learning problems are common after repeated severe head injuries.

"We have discovered that neural stem cells in the brain's memory area become activated by injury and remodel the area with newly generated nerve cells," Dr. Kernie said. "We also found that the activation of these stem cells is required for recovery."

The scientists developed unique transgenic mice that were unable to create hippocampal neurons when exposed to a usually harmless chemical called ganciclovir soon after brain injury. Four groups of these transgenic mice received either sham surgery or a controlled cortical injury (CCI) to mimic the diffuse damage of a moderate to severe head injury, and two of the groups were exposed to ganciclovir, Dr. Kernie said.

After a month -- the time earlier experiments indicated it takes for neural stem cells to mature and integrate as neurons into the hippocampus -- the researchers gave the mice a learning task called the Morris water maze in which the mice had to find a white platform hidden in a white pool of water. On the first day of learning the task, there were no group-noteworthy differences in swim speed, indicating no motor impairment in the test mice. During the next 10 days, however, the test group spent more time swimming along the edges of the tank, and they traveled longer distances to reach the platform.

"This suggests that injured mice who lack new nerve cells fail to progress to a more efficient spatial strategy to find the hidden platform. We interpret this result as a mild but statistically significant learning deficit," he said.

The UT Southwestern scientists then let the mice rest a day, removed the platform and retested them to see how well they remembered where the platform's location.

Compared to controls, CCI mice showed no preference for the platform's previous location or even for the target quadrant of the pool where the platform had been, Dr. Kernie said.

In comparison, CCI mice with intact nerve cell generation had an intermediate response to the water maze and non-CCI mice with intact nerve cell generation had the best response. Dr. Kernie said those findings suggest that neurogenesis is necessary for learning after TBI, and they raise the question of whether the neural stem cell pool is limited.

"The ability to self-repair may be limited," he said.

Since there are already Food and Drug Administration-approved medications available to increase neurogenesis, the next steps are to determine if these can be used to improve outcomes after traumatic brain injuries. In addition, Dr. Kernie and colleagues are determining what molecules direct this process and how the stem cell pool might be preserved in order to enhance the ability to recover from recurrent injury.

Other UT Southwestern researchers involved in the study were lead author Dr. Cory Blaiss, a former postdoctoral researcher who now is an assistant research scientist at the Ernest Gallo Clinic and Research Center at the University of California, San Francisco; Dr. Tzong-Shiue Yu, former graduate student who now is a postdoctoral researcher at Toronto Hospital for Sick Children; Gui Zhang, research assistant in pediatrics; Georgi Dimchev, former graduate student presently enrolled at Manchester Metropolitan University in England; Dr. Luis Parada, chairman of developmental biology; and Dr. Craig Powell, assistant professor of neurology and neurotherapeutics and psychiatry.

The research was funded by the National Institutes of Health, the Seay Endowed Fund for Research on Brain and Spinal Cord Injuries in Children, the National Institutes of Mental Health, the National Institute of Child Health and Human Development, and the Hartwell Foundation.

Journal Reference:

1. C. A. Blaiss, T.-S. Yu, G. Zhang, J. Chen, G. Dimchev, L. F. Parada, C. M. Powell, S. G. Kernie. Temporally Specified Genetic Ablation of Neurogenesis Impairs Cognitive Recovery after Traumatic Brain Injury. Journal of Neuroscience, 2011; 31 (13): 4906 DOI: 10.1523/JNEUROSCI.5265-10.2011

Courtesy: ScienceDaily

Older and Stronger: Progressive Resistance Training Can Build Muscle, Increase Strength as We Age

Getting older doesn't mean giving up muscle strength. Not only can adults fight the battle of strength and muscle loss that comes with age, but the Golden Years can be a time to get stronger, say experts at the University of Michigan Health System.

"Resistance exercise is a great way to increase lean muscle tissue and strength capacity so that people can function more readily in daily life," says Mark Peterson, Ph.D., a research fellow in the U-M Physical Activity and Exercise Intervention Research Laboratory, at the Department of Physical Medicine and Rehabilitation.

Through resistance training adults can improve their ability to stand up out of a chair walk across the floor, climb a flight of stairs -- anything that requires manipulating their own body mass through a full range of motions.

Normally, adults who are sedentary beyond age 50 can expect muscle loss of up to 0.4 pounds a year.

"That only worsens as people age. But even earlier in adulthood -- the 30s, 40s and 50s -- you can begin to see declines if you do not engage in any strengthening activities," Peterson says.

"Our analyses of current research show that the most important factor in somebody's function is their strength capacity. No matter what age an individual is, they can experience significant strength improvement with progressive resistance exercise even into the eighth and ninth decades of life," he says.

Progressive resistance training means that the amount of weight used, and the frequency and duration of training sessions is altered over time to accommodate an individual's improvements.

A review article by U-M researchers, published in The American Journal of Medicine, shows that after an average of 18-20 weeks of progressive resistance training, an adult can add 2.42 pounds of lean muscle to their body mass and increases their overall strength by 25-30 percent.

Recommendations for those over age 50

Peterson says that anyone over age 50 should strongly consider participating in resistance exercise.

A good way for people to start on a resistance training program, especially for people who are relatively sedentary -- and after getting permission from their doctor to do so -- is to use their body mass as a load for various exercises.

Exercises you can do using your own body weight include squats, standing up out of a chair, modified push-ups, lying hip bridges, as well as non-traditional exercises that progress through a full range of motion, such as Thai Chi or Pilates and Yoga.

Transition to the gym

After getting accustomed to these activities, older adults can move on to more advanced resistance training in an exercise and fitness facility. A certified trainer or fitness professional that has experience with special populations can help with the transition.

Peterson says you should feel comfortable asking a trainer whether they have experience working with aging adults before you begin any fitness routine.

"Working out at age 20 is not the same as at age 70. A fitness professional who understands those differences is important for your safety. In addition, current recommendations suggest that an older individual participate in strengthening exercise two days per week," Peterson says. "Based on the results of our studies, I would suggest that be thought of as the minimum."

Don't forget to progress

As resistance training progresses and weights and machines are introduced, Peterson recommends incorporating full body exercises and exercises that use more than one joint and muscle group at a time, such as the leg press, chest press, and rows. These are safer and more effective in building muscle mass.

"You should also keep in mind the need for increased resistance and intensity of your training to continue building muscle mass and strength," he says.

A good fitness professional can help plan an appropriate training regimen, and make adjustments based on how you respond as you progress.

"We firmly believe based on this research that progressive resistance training should be encouraged among healthy older adults to help minimize the loss of muscle mass and strength as they age," Peterson says.

Journal Reference:

1. Mark D. Peterson, Paul M. Gordon. Resistance Exercise for the Aging Adult: Clinical Implications and Prescription Guidelines. The American Journal of Medicine, 2011; 124 (3): 194 DOI: 10.1016/j.amjmed.2010.08.020

Courtesy: ScienceDaily

How Do Neurons in the Retina Encode What We 'See'?

The moment we open our eyes, we perceive the world with apparent ease. But the question of how neurons in the retina encode what we "see" has been a tricky one. A key obstacle to understanding how our brain functions is that its components -- neurons -- respond in highly nonlinear ways to complex stimuli, making stimulus-response relationships extremely difficult to discern.

Now a team of physicists at the Salk Institute for Biological Studies has developed a general mathematical framework that makes optimal use of limited measurements, bringing them a step closer to deciphering the "language of the brain." The approach, described in the current issue of the Public Library of Science, Computational Biology, reveals for the first time that only information about pairs of temporal stimulus patterns is relayed to the brain.

"We were surprised to find that higher-order stimulus combinations were not encoded, because they are so prevalent in our natural environment," says the study's leader Tatyana Sharpee, Ph.D., an assistant professor in the Computational Neurobiology Laboratory and holder of the Helen McLorraine Developmental Chair in Neurobiology. "Humans are quite sensitive to changes in higher-order combinations of spatial patterns. We found it not to be the case for temporal patterns. This highlights a fundamental difference in the spatial and temporal aspects of visual encoding."

The human face is a perfect example of a higher-order combination of spatial patterns. All components -- eyes, nose, mouth -- have very specific spatial relationships with each other, and not even Picasso, in his Cubist period, could throw the rules completely overboard.

Our eyes take in the visual environment and transmit information about individual components, such as color, position, shape, motion and brightness to the brain. Individual neurons in the retina get excited by certain features and respond with an electrical signal, or spike, that is passed on to visual centers in the brain, where information sent by neurons with different preferences is assembled and processed.

For simple sensory events -- like turning on a light, for example -- the brightness correlates well with the spike probability in a luminance-sensitive cell in the retina. "However, over the last decade or so, it has become apparent that neurons actually encode information about several features at the same time," says graduate student and first author Jeffrey D. Fitzgerald.

"Up to this point, most of the work has been focused on identifying the features the cell responds to," he says. "The question of what kind of information about these features the cell is encoding had been ignored. The direct measurements of stimulus-response relationships often yielded weird shapes, and people didn't have a mathematical framework for analyzing it."

To overcome those limitations, Fitzgerald and colleagues developed a so-called minimal model of the nonlinear relationships of information processing systems by maximizing a quantity that is referred to as noise entropy. The latter describes the uncertainty about a neuron's probability to spike in response to a stimulus.

When Fitzgerald applied this approach to recordings of visual neurons probed with flickering movies, which co-author Lawrence Sincich and Jonathan Horton at the University of California, San Francisco, had made, he discovered that on average, first-order correlations accounted for 78 percent of the encoded information, while second-order correlations accounted for more than 92 percent. Thus, the brain received very little information about correlations that were higher than second order.

"Biological systems across all scales, from molecules to ecosystems, can all be considered information processors that detect important events in their environment and transform them into actionable information," says Sharpee. "We therefore hope that this way of 'focusing' the data by identifying maximally informative, critical stimulus-response relationships will be useful in other areas of systems biology."

The work was funded in part by the National Institutes of Health, the Searle Scholar Program, The Alfred P. Sloan Fellowship, the W.M. Keck Research Excellence Award and the Ray Thomas Edwards Career Development Award in Biomedical Sciences.

Journal Reference:

1. Jeffrey D. Fitzgerald, Lawrence C. Sincich, Tatyana O. Sharpee. Minimal Models of Multidimensional Computations. PLoS Computational Biology, 2011; 7 (3): e1001111 DOI: 10.1371/journal.pcbi.1001111

Courtesy: ScienceDaily

DNA of 50 Breast Cancer Patients Decoded

In the single largest cancer genomics investigation reported to date, scientists have sequenced the whole genomes of tumors from 50 breast cancer patients and compared them to the matched DNA of the same patients' healthy cells. This comparison allowed researchers to find mutations that only occurred in the cancer cells.

They uncovered incredible complexity in the cancer genomes, but also got a glimpse of new routes toward personalized medicine. The work was presented at the American Association for Cancer Research 102nd Annual Meeting 2011.

In all, the tumors had more than 1,700 mutations, most of which were unique to the individual, says Matthew J. Ellis, MD, PhD, professor of medicine at Washington University School of Medicine in St. Louis and a lead investigator on the project.

"Cancer genomes are extraordinarily complicated," Ellis says. "This explains our difficulty in predicting outcomes and finding new treatments."

To undertake the massive task, Washington University oncologists and pathologists at the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine collaborated with the university's Genome Institute to sequence more than 10 trillion chemical bases of DNA -- repeating the sequencing of each patient's tumor and healthy DNA about 30 times to ensure accurate data.

"The computing facilities required to analyze this amount of data are similar in scale to those of the Large Hadron Collider, used to understand the workings of sub-atomic particles," Ellis says.

The DNA samples came from patients enrolled in a clinical trial that Ellis is leading for the American College of Surgeons Oncology Group. All patients in the trial had what is called estrogen-receptor-positive breast cancer. These cancer cells have receptors that bind to the hormone estrogen and help the tumors grow.

To slow tumor growth and make the tumors easier to remove, patients received estrogen-lowering drugs before surgery. But, for unknown reasons, this treatment does not always work. Twenty-four of the 50 tumor samples came from patients whose tumors were resistant to this treatment, and 26 came from patients whose tumors responded. Comparing the two groups might help explain why some estrogen-receptor-positive breast cancer patients do well with estrogen-lowering drugs and others poorly.

Confirming previous work, Ellis and colleagues found that two mutations were relatively common in many of the patients' cancers. One called PIK3CA is present in about 40 percent of breast cancers that express receptors for estrogen. Another called TP53 is present in about 20 percent.

Adding to this short list of common mutations, Ellis and colleagues found a third, MAP3K1, that controls programmed cell death and is disabled in about 10 percent of estrogen-receptor-positive breast cancers. The mutated gene allows cells that should die to continue living. Only two other genes, ATR and MYST3, harbored mutations that recurred at a similar frequency as MAP3K1 and were statistically significant.

"To get through this experiment and find only three additional gene mutations at the 10 percent recurrence level was a bit of a shock," Ellis says.

In addition, they found 21 genes that were also significantly mutated, but at much lower rates -- never appearing in more than two or three patients. Despite the relative rarity of these mutations, Ellis stresses their importance.

"Breast cancer is so common that mutations that recur at a 5 percent frequency level still involve many thousands of women," he says.

Ellis points out that some mutations that are rare in breast cancer may be common in other cancers and already have drugs designed to treat them.

"You may find the rare breast cancer patient whose tumor has a mutation that's more commonly found in leukemia, for example. So you might give that breast cancer patient a leukemia drug," Ellis says.

But such treatment is only possible when the cancer's genetics are known in advance. Ideally, Ellis says, the goal is to design treatments by sequencing the tumor genome when the cancer is first diagnosed.

"We get good therapeutic ideas from the genomic information," he says. "The near-term goal is to use information on whole genome sequencing to guide a personalized approach to the patient's treatment."

This work builds on previous collaborations between Washington University oncologists and the Genome Institute. In a study published last year in Nature, they reported the complete tumor and normal DNA sequences of a woman with "triple-negative" breast cancer, a particularly aggressive type that is difficult to treat and more common in younger women and African-Americans.

While many mutations are rare or even unique to one patient, Ellis says quite a few can be classified on the basis of common biological effects and therefore could be considered together for a particular therapeutic approach.

Ellis looks to future work to help make sense of breast cancer's complexity. But these highly detailed genome maps are an important first step.

"At least we're reaching the limits of the complexity of the problem," he says. "It's not like looking into a telescope and wondering how far the universe goes. Ultimately, the universe of breast cancer is restricted by the size of the human genome."

Reference: Ellis et al. Breast cancer genome. Presented April 2, 2011, at the 102nd Annual Meeting of the American Association for Cancer Research in Orlando, Fla.

Ding L, Ellis MJ, Weinstock GM, Aft R, Watson M, Ley TJ, Wilson RK, Mardis ER et al. Cancer remodeling in a basal-like breast cancer metastasis and xenograft. Nature. April 15, 2010.

This work was supported by grants from the National Human Genome Research Institute, the Breast Cancer Research Foundation, the National Cancer Institute, Susan G. Komen for the Cure and Washington University School of Medicine.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Washington University School of Medicine. The original article was written by Julia Evangelou Strait.

Courtesy: ScienceDaily

Four New Genes for Alzheimer's Disease Risk Identified

In the largest study of its kind, researchers from a consortium of 44 universities and research institutions in the United States, including Rush University Medical Center, identified four new genes linked to Alzheimer's disease. Each gene individually adds to the risk of having this common form of dementia later in life.

The findings, published in the April issue of Nature Genetics, offer new insight into the underlying causes of Alzheimer's disease.

"This is a major advance in the field thanks to many scientists across the country working together over several years," said Dr. David Bennett, director of the Rush Alzheimer's Disease Center. "These findings add key information needed to understand the causes of Alzheimer's disease and should help in discovering approaches to its treatment and prevention."

In the study, the Alzheimer's Disease Genetics Consortium conducted a genetic analysis of more than 11,000 people with Alzheimer's disease and nearly the same number of elderly people who have no symptoms of dementia.

The Rush Alzheimer's Disease Center contributed clinical and genomic data from more than 1,500 participants in two of its premier cohort studies, the Rush Religious Orders Study and the Rush Memory and Aging Project.

Three other consortia contributed confirming data from additional people, bringing the total number of people analyzed to over 54,000. The consortium also contributed to the identification of a fifth gene reported by other groups of investigators from the United States, the United Kingdom, France, and other European countries.

Until recently, only four genes associated with late-onset Alzheimer's have been confirmed. The gene for apolipoprotein E-e4, APOE-e4, identified over 15 years ago, has the largest effect on risk. Over the past two years, three additional genes have been identified, including CR1, CLU, and BIN1. The present study adds another four -- MS4A, CD2AP, CD33, and EPHA1 -- and contributes to identifying and confirming two other genes, BIN1 and ABCA7, thereby doubling the number of genes known to play a role in Alzheimer's disease.

The identification of new genes associated with Alzheimer's provides major clues about the causes of the disease, information that is critical for drug discovery. Currently available treatments are only marginally effective.

In addition, genetic studies can help researchers understand the pathogenic mechanisms that begin in the brain long before symptoms appear, eventually destroying large parts of the brain and causing the complete loss of cognitive abilities. One primary goal of genetic studies is to help identify who is likely to develop the disease, which will be important when preventive measures become available.

Currently, Alzheimer's genetics researchers are collaborating on an even larger, similar study. The Alzheimer's Association in the U.S. and the Foundation Plan Alzheimer in France have funded the formation of the International Genomics of Alzheimer's Project, whose members met for the first time in November 2010 in Paris.

The present study was supported by the National Institute on Aging (NIA), part of the National Institutes of Health, which includes 29 Alzheimer's Disease Centers, the National Alzheimer's Coordinating Center, the NIA Genetics of Alzheimer's Disease Data Storage Site, the NIA Late Onset Alzheimer's Disease Family Study and the National Cell Repository for Alzheimer's Disease.

Journal Reference:

1. Naj et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nature Genetics, 2011; DOI: 10.1038/ng.801

Courtesy: ScienceDaily

How Well Do You Know Your Friends?

How does your best friend feel when people act needy? Or, about people being dishonest? What do they think when others seem uncomfortable in social situations? According to an upcoming study in Psychological Science, a journal of the Association for Psychological Science, if you don't know - your relationship may pay a price.

There are lots of ways to know someone's personality. You can say "she's an extrovert" or "she's usually happy." You may also know how he or she reacts to different situations and other people's behavior. "It's a more detailed way of understanding personality," says Charity A. Friesen, a graduate student at Wilfrid Laurier University, who co-wrote the new paper with Lara K. Kammrath. "You might know the person is extroverted when they're out with their friends but more introverted when they're in a new situation." When a person is faced with one of a list of situations, then how does he or she behave? Friesen identifies this as an "if-then profile."

Friesen and Kammrath recruited university students to take part in the study. Each student was asked to get a friend to participate in the study with them. Then each of the participants individually filled out an online survey. This included a list of "triggers" -- descriptions of behaviors that someone might find annoying. One example was the word "skepticism" which was described as when someone is overly disbelieving of information that he/she receives, when he/she questions things that are generally accepted, or when he/she is very hard to convince of something. The list also included gullibility, social timidity, social boldness, perfectionism, obliviousness and several dozen other possible triggers. For each behavior, each respondent answered a question about how much this triggers them and how much it triggers their friend.

Some people knew their friends' triggers well; others had almost no idea what set their friends off. And that made a difference to the friendship. People who had more knowledge of their friend's if-then profile of triggers had better relationships. They had less conflict with the friend and less frustration with the relationship. Other research has shown that it's not that hard to come up with a list of traits that describe someone; casual acquaintances can do it. "But, if I'm close to someone, I can really start to learn the if-then profiles, and that's what's going to pay off in my relationship," Friesen says.

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Association for Psychological Science.

Courtesy: ScienceDaily