BreakThrough Digest Medical News |
- University of Alberta breakthrough gives hope for new imaging isotope source
- New stroke treatment could prevent and reduce brain damage
- Long-ignored enzyme turns out to be key to killing infectious bacteria
- Sick from your stomach: Bacterial changes may trigger diseases like rheumatoid arthritis
- Researchers develop a ‘time bomb’ to fight cardiovascular disease
- Brain scans show specific neuronal response to junk food when sleep-restricted
- Positive results from first human clinical trials of a first-generation artificial pancreas system
- Moffitt Cancer Center researchers develop and test new anti-cancer vaccine
- Reach2HD, a Phase II study in Huntington’s disease, launched
- Alzheimer’s vaccine trial a success
- An important breakthrough in immunology by IRCM researchers
- Study reports seizure-freedom in 68 percent of juvenile myoclonic epilepsy patients
- The potential impact of olfactory stem cells as therapy reported in Cell Transplantation
- Study offers hope for more effective treatment of nearsightedness
- Noninvasive genetic test for Down syndrome and Edwards syndrome highly accurate
- Drug combination highly effective for newly diagnosed myeloma patients
- A new multitarget molecule designed with high potential in future treatments for Alzheimer’s disease
- New immune therapy shows promise in kidney cancer
- New hope for migraine sufferers
- Cancer therapy that boosts immune system ready for wider testing
- New target, new drug in breast cancer
- Researchers discover new combination of 2 previously approved FDA drugs to treat lung cancer
- Potential new approach to regenerating skeletal muscle tissue
- New therapy on the horizon for ALK+ non-small cell lung cancer
- ‘Intelligent medicine’ erases side effects
- Researchers determine structure of ‘batteries’ of the biological clock
- Fatty acid found in fish prevents age-related vision loss: U of A medical research
- Researchers say tart cherries have ‘the highest anti-inflammatory content of any food’
- ‘Simple and effective’ injection could offer hope for treatment of autoimmune disease
- Understanding the links between inflammation and chronic disease
- Commonly used painkillers may protect against skin cancer
- Researchers restore neuron function to brains damaged by Huntington’s disease
- Study reveals how the world’s first drug for amyloid disease works
- New drug strategy attacks resistant leukemia and lymphoma
- New stem cell technique promises abundance of key heart cells
- Antiretroviral treatment for preventing HIV infection: an evidence review for physicians
- T cells ‘hunt’ parasites like animal predators seek prey, a Penn Vet-Penn Physics study reveals
- Gene therapy can correct forms of severe combined immunodeficiency
- Key gene found responsible for chronic inflammation, accelerated aging and cancer
- Chronic pain is relieved by cell transplantation in lab study
- From stem cell to brain cell – new technique mimics the brain
- Hazelnuts: New source of key fat for infant formula that’s more like mother’s milk
- Stem-cell-growing surface enables bone repair
- Newly discovered breast milk antibodies help neutralize HIV
- Harvard team cracks code for new drug resistant superbugs
- Folic acid may reduce some childhood cancers
- Research shows some people predisposed for recurrent C. difficile infection
- Treatment of childhood OSA reverses brain abnormalities
- Growth factor in stem cells may spur recovery from MS
- Drug found for parasite that is major cause of death worldwide
| University of Alberta breakthrough gives hope for new imaging isotope source Posted: 10 Jun 2012 09:00 PM PDT A University of Alberta team has made an important breakthrough in the race to find a viable replacement for supply of technetium-99m, an important isotope produced by Canada’s Chalk River reactor. Their research has proven that this important medical isotope, used in nuclear medicine imaging for about 250,000 Alberta patients each year, can be created in a device known as a cyclotron?and is as safe to use and provides as reliable an image as reactor-based isotopes. Their results are a promising first step in responding to an impending global need for an alternative supply.
Sandy McEwan, a researcher with the University of Alberta and medical director with Alberta Health Services’ Cross Cancer Institute in Edmonton, says that the team has produced viable quantities of high-quality technetium-99m using a 19-mega-electron-volt cyclotron, a circular particle accelerator that propels charged particles using a constant magnetic field. McEwan recently presented results from the first human clinical trials at the annual conference of the Society for Nuclear Medicine in Miami. McEwan notes that the clinical trials were performed to Good Clinical Practice (GCP) standards, a set of international quality standards set by the International Conference on Harmonization. The GCP standards serve to protect the human rights of subjects in clinical trials, and ensure the safety and efficacy of the newly developed compounds. He says this is the first time that this type of study has ever been performed to GCP. “We have taken the technetium made on the cyclotron and shown that it behaves exactly the same as the technetium we get from the reactor,” he said. “We’ve shown that the quality of the technetium and the quality of the images is the exactly the same.” This process is a significant step in the search for a viable non-reactor-based solution to replacing the medical isotope stream currently produced by the aging Chalk River facility, where 40 per cent of the world’s medical radioisotope supply is generated. The balance of the world’s supply of these imaging isotopes comes from aging reactors in South Africa, France, Belgium and the Netherlands, installations that will soon need extensive upgrading or replacement. The U of A researchers believe that this is the first time that technetium has been successfully created in commercially viable quantities using a cyclotron. “The reactor supply chain is complex, and these complexities contributed to the difficulties associated with the shutdown of Chalk River. We hope that the local supply model of the cyclotron will avoid these problems of the future.” Currently, technetium-99m is used in 85 per cent of all nuclear medicine procedures globally every year. In the United States, roughly 20 million imaging procedures are performed each year. The procedure is used to diagnose patients with cancer, cardiac illness, neurological diseases and other diseases. It can be critical in identifying the presence or absence of disease, determining best treatment options and identifying recurrence or progression of the disease. “Two million scans are performed in Canada every year with technetium-99m. We believe that we now have the potential to continue supplying patients with the tests they need without constructing new nuclear reactors,” said McEwan. “This means there is now a potentially valid alternative to reactor-produced medical isotopes.” There is also an important financial aspect to this research. McEwan notes that under the current method, production costs would climb because of costly retrofitting or replacement of the reactors around the world. He also cautions that, although this discovery is an important step in replacing the supply chain of medical imaging isotopes through a non-reactor-based process, further testing is still needed to determine the supply cost of technetium. Further testing is also required to confirm that suitable quantities can be produced via cyclotron to serve the population. However, given the results of the clinical trials, he is optimistic that the team’s research is an important first step. “I think that if it’s an 800-metre race, we’ve hit the 300-metre point,” said McEwan. “We’ve established a very clear plan. Following that plan, we have achieved the first two or three goals in that process. We’re confident that the next two goals will be easy.” Contact: Jamie Hanlon |
| New stroke treatment could prevent and reduce brain damage Posted: 10 Jun 2012 09:00 PM PDT
Researchers at the University of Missouri have demonstrated the effectiveness of a potential new therapy for stroke patients in an article published in the journal Molecular Neurodegeneration. Created to target a specific enzyme known to affect important brain functions, the new compound being studied at MU is designed to stop the spread of brain bleeds and protect brain cells from further damage in the crucial hours after a stroke.
Stroke is a leading cause of death in the U.S. with more than 800,000 deaths occurring each year from stroke and other cardiac events. Other than surgery, existing emergency treatments for stroke victims such as the use of a tissue plasminogen activator (tPA) must be administered within hours of the stroke onset because of the risk for brain hemorrhaging. The injectable medication can only be used to treat the most common type of stroke that occurs when blood clots block blood flow to the brain, called ischemic stroke. “For a stroke victim, time is a matter of life and death. While we are still in the research phase for this type of compound, we believe it could be combined with tPA in the future to buy ischemic stroke patients a longer window of time to receive emergency treatment,” said Zezong Gu, MD, PhD, the article’s corresponding author and assistant professor of pathology and anatomical sciences at the MU School of Medicine. The new compound being studied also has potential for use in patients experiencing hemorrhagic stroke, which is a less common type of stroke caused by bleeding within the brain, Gu said. MU researchers collaborated with a team at the University of Notre Dame to study the effects of the new compound, a thiirane class of gelatinase selective inhibitors, on the function of a type of matrix metalloproteinase (MMP) enzyme, particularly MMP-9. MMP-9 is part of a group of more than 20 enzymes or MMPs that are known to contribute to many key pathological events in the brain after stroke, traumatic brain injury and other neurodegenerative events. In 2005, Gu served as a lead author on a research paper published in the Journal of Neuroscience that identified MMP-9 as a promising target for development of therapeutic drugs for stroke patients. Since then, his lab at MU medical school’s Center for Translational Neuroscience has been studying the function of MMP enzymes and how to inhibit the harmful effects of MMP-9. “MMPs play a role in the structure of blood vessels in the brain and are also needed in the interactions between cells during development and tissue remodeling,” Gu said. “Unregulated, the activity of these enzymes contributes to neurological disorders and stroke. With this compound, we’ve now confirmed a potential method to rescue the blood vessels from the damaging effects of MMP-9 and protect neurons at the same time.” MU researchers successfully used a model of ischemic stroke in mice and studied the effects of the MMP-9 inhibitor compound on brain activity after a stroke. “Our lab at the Center for Translational Neuroscience is one of only a few in the United States that has successfully induced a blood clot in the brains of mice,” said Jiankun Cui, MD, the article’s lead author and assistant professor of pathology and anatomical sciences at the MU School of Medicine. “To be able to study the effectiveness of this potential new treatment under these conditions provides us with a highly unique set of data showing this compound can disrupt key harmful pathological events that occur after a stroke.” Contact: Laura Gerding ### |
| Long-ignored enzyme turns out to be key to killing infectious bacteria Posted: 10 Jun 2012 09:00 PM PDT
New research shows that an enzyme that has long been considered relatively useless to the immune response instead has an important role in setting up immune cells to kill infection-causing bacteria.
Ohio State University scientists have determined that this enzyme, called caspase-11 in mice, enables components in immune cells to fuse and degrade the bacteria that cause Legionnaires’ disease, a type of pneumonia. Without that fusion and degradation, these bacteria thrive, grow or replicate and cause illness. Whether the effect is the same in other bacteria remains unknown. The parallel enzyme in humans is a combination of caspases 4 and 5. The researchers determined that Legionella pneumophila bacteria somehow suppress activation of these two enzymes in human cells. But if the enzymes are added back into immune cells, they set off the same fusion events – those also seen in mice – that will kill the bacteria. The findings could lead to the development of non-antibiotic drugs designed to fight certain bacterial infections by activating these caspases. Those most vulnerable to Legionnaires’ disease include the elderly, smokers and people with chronic diseases or compromised immune systems, including patients with cancer and AIDS. “If there were a therapeutic way to express, deliver or induce caspase 4 and 5, humans wouldn’t get Legionella infection. Imagine if you just replenish cells with these caspases, working around Legionella‘s tricky way to suppress them, and then the infection would not happen. That would be huge,” said Amal Amer, assistant professor of microbial infection and immunity and internal medicine at Ohio State and senior author of the study. The research appears online and is scheduled for future print publication in the journal Immunity. Amer said these findings represent a paradigm shift in caspase research. For years, studies have suggested that a different enzyme, caspase-1, was required to set up cells to kill bacteria. Most published research suggested that caspase-11 was necessary only to activate caspase-1. A common way to test an enzyme’s role and effectiveness is to see what happens to cells when the enzyme is not present. A mouse strain genetically altered so it would not have caspase-1 genes served as the basis for many studies that appeared to confirm caspase-1′s importance to the immune response against a range of bacterial, viral and fungal infections. It turns out, however, that those same mice also did not have caspase-11 because the genes responsible for the two enzymes are located very close to each other. So studies that pointed to caspase-1 as the critical enzyme in clearing away pathogens did not take into account any role that caspase-11 might have played. “Scientists should go back and test whether it was really caspase-1 or caspase-11 clearing the bacteria, viruses or fungi,” said Amer, also an investigator in Ohio State’s Center for Microbial Interface Biology and Davis Heart and Lung Research Institute. In fact, Amer is among the scientists who have published studies about caspase-1. She noted that caspase-1 has been considered an attractive drug target because of these many studies. However, driving up activation of caspase-1 to clear bacteria can have a troubling side effect – this enzyme also causes extensive inflammation. Caspase-11 appears to have no such effect, making it a potentially more desirable drug target for pharmaceutical companies, she said. Amer and colleagues demonstrated how caspase-11 helps clear Legionella bacteria in a series of experiments using mouse and human cell cultures and mice genetically altered so they wouldn’t produce caspase-11. As immune cells known as macrophages recognize these bacteria, they consume the bacterial cells and place them inside a compartment called a phagosome. Under normal circumstances, this phagosome will fuse with another cell component called a lysosome. When the two compartments join, the lysosome breaks the unwanted infectious bacteria into pieces. The research showed that caspase-11 in mice, and caspase 4 and 5 together in human cells, made that fusion occur, and did so in an unexpected way. These types of enzymes influence activation of proteins, and typically do so by snipping a compound in a specific way to generate the protein needed by a cell. But caspase-11 instead activates one of its target proteins, called actin, by adding a phosphorous group to it – a process called phosphorylation. “If we put pathogenic bacteria in a normal cell, they may or may not succeed according to the pathogen, but in a cell that doesn’t have casapse-11, the bacteria are going to survive,” Amer said. “Without caspase-11, the phagosome doesn’t fuse with the lysosome, and Legionella survives, replicates and causes infection.” She added that in human cells, the Legionella bacteria somehow suppressed the activation of caspases 4 and 5 – the researchers don’t yet know how the bacteria pull off this stunt. But when they added the two caspases back to immune cell cultures containing Legionella bacteria, the bacteria no longer survived. Amer specializes in Legionella research, but she also tested whether Salmonella bacteria can suppress caspases 4 and 5 in human cells. “Salmonella does not do that. It’s a very peculiar trick for Legionella,” she said. She also noted that caspase-11 is activated only when a pathogenic bacterium enters a cell, and is not needed to clear bacteria that do not cause infection. “That’s exciting, because it means that either caspase-11 can differentiate according to the type of bacteria present, or that two different bacteria, pathogenic and nonpathogenic, enter a cell from completely different pathways – one that engages caspase-11 and another that doesn’t,” Amer said. “We don’t know yet which scenario applies, but that finding provides more evidence that caspase-11 is required to clear certain pathogenic bacteria.” She also noted that caspase-1 can generate the fusion of lysosomes and phagosomes to degrade pathogenic bacteria “to a small degree,” but that her research shows that “caspase-11 is the big player.” ### This work is supported by grants from the National Institutes of Health. Co-authors, all from Ohio State, include Anwari Akhter, Kyle Caution, Arwa Abu Khweek, Mia Tazi, Basant Abdulrahman, Dalia Abdelaziz, Hoda Hassan and Larry Schlesinger of the departments of Microbial Infection and Immunity (MII)/CMIB and Internal Medicine; Abul Azad of MII; Oliver Voss and Andrea Doseff of internal medicine and the Department of Molecular Genetics; and Mark Wewers and Mikhail Gavrilin of internal medicine. All authors also are affiliated with the Davis Heart and Lung Research Institute. Contact: Amal Amer Written by Emily Caldwell, (614) 292-8310; Caldwell.151@osu.edu |
| Sick from your stomach: Bacterial changes may trigger diseases like rheumatoid arthritis Posted: 10 Jun 2012 09:00 PM PDT The billions of bugs in our guts have a newfound role: regulating the immune system and related autoimmune diseases such as rheumatoid arthritis, according to researchers at Mayo Clinic and the University of Illinois at Urbana-Champaign.
Larger-than-normal populations of specific gut bacteria may trigger the development of diseases like rheumatoid arthritis and possibly fuel disease progression in people genetically predisposed to this crippling and confounding condition, say the researchers, who are participating in the Mayo Illinois Alliance for Technology Based Healthcare. The study is published in the April 2012 issue of PloS ONE. “A lot of people suspected that gut flora played a role in rheumatoid arthritis, but no one had been able to prove it because they couldn’t say which came first ? the bacteria or the genes,” says senior author Veena Taneja, Ph.D., a Mayo Clinic immunologist. “Using genomic sequencing technologies, we have been able to show the gut microbiome may be used as a biomarker for predisposition.” The roughly 10 trillion cells that make up the human body have neighbors: mostly bacteria that often help, training the immune system and aiding in digestion, for example. The bacteria in the intestines, in addition to a relatively small number of other microorganisms (the gut microbiome), outnumber human cells 10-to-1. Researchers found that hormones and changes related to aging may further modulate the gut immune system and exacerbate inflammatory conditions in genetically susceptible individuals. Nearly 1 percent of the world’s population has rheumatoid arthritis, a disease in which the immune system attacks tissues, inflaming joints and sometimes leading to deadly complications such as heart disease. Other diseases with suspected gut bacterial ties include type I diabetes and multiple sclerosis. Researchers with the Mayo Illinois Alliance for Technology Based Healthcare say that identifying new biomarkers in intestinal microbial populations and maintaining a balance in gut bacteria could help physicians stop rheumatoid arthritis before it starts. “This study is an important advance in our understanding of the immune system disturbances associated with rheumatoid arthritis. While we do not yet know what the causes of this disease are, this study provides important insights into the immune system and its relationship to bacteria of the gut, and how these factors may affect people with genetic susceptibilities to disease,” says Eric Matteson, M.D., chairman of rheumatology at Mayo Clinic, who was not a study author. Dr. Taneja and her team genetically engineered mice with the human gene HLA-DRB1*0401, a strong indicator of predisposition to rheumatoid arthritis. A set of control mice were engineered with a different variant of the DRB1 gene, known to promote resistance to rheumatoid arthritis. Researchers used these mice to compare their immune responses to different bacteria and the effect on rheumatoid arthritis. “The gut is the largest immune organ in the body,” says co-author Bryan White, Ph.D., director of the University of Illinois’ Microbiome Program in the Division of Biomedical Sciences and a member of the Institute for Genomic Biology. “Because it’s presented with multiple insults daily through the introduction of new bacteria, food sources and foreign antigens, the gut is continually teasing out what’s good and bad.” The gut has several ways to do this, including the mucosal barrier that prevents organisms ? even commensal or “good” bacteria ? from crossing the lumen of the gut into the human body. However, when commensal bacteria breach this barrier, they can trigger autoimmune responses. The body recognizes them as out of place, and in some way this triggers the body to attack itself, he says. These mice mimic human gender trends in rheumatoid arthritis, in that females were about three times as likely to generate autoimmune responses and contract the disease. Researchers believe these “humanized” mice could shed light on why women and other demographic groups are more vulnerable to autoimmune disorders and help guide development of new future therapies. “The next step for us is to show if bugs in the gut can be manipulated to change the course of disease,” Dr. Taneja says. ### The study was funded by the Mayo-Illinois Alliance for Technology Based Healthcare and a grant from the U.S. Department of Defense. Co-authors include Andres Gomez; Carl Yeoman, Ph.D.; and Margret Berg Miller, Ph.D., all of University of Illinois; David Luckey; Eric Marietta, Ph.D.; and Joseph Murray, M.D., all of Mayo Clinic. About Mayo Clinic Mayo Clinic is a nonprofit worldwide leader in medical care, research and education for people from all walks of life. For more information, visit www.mayoclinic.com and www.mayoclinic.org/news. Contact: Sam Smith |
| Researchers develop a ‘time bomb’ to fight cardiovascular disease Posted: 09 Jun 2012 09:00 PM PDT In Switzerland, more than 20,000 people (37% of all deaths) die of cardiovascular disease caused by atherosclerosis each year. Treatment options are currently available to people who suffer from the disease but no drug can target solely the diseased areas, often leading to generalized side effects. Intravenous injection of a vasodilator (a substance that dilates blood vessels), such as nitroglycerin, dilates both the diseased vessels and the rest of our arteries. Blood pressure can thus drop, which would limit the desired increased blood flow generated by vasodilatation of diseased vessels and needed for example during a heart attack.
In order to increase the effectiveness of treatments against atherosclerosis and to reduce side effects, a team of researchers from UNIGE, HUG and the University of Basel have developed nanocontainers having the ability to release their vasodilator content exclusively to diseased areas.
Nanotechnology in medicine
Though no biomarker specific to atherosclerosis has been identified, there is a physical phenomenon inherent to stenosis (the narrowing of blood vessels) known as shear stress. This force results from fluctuations in blood flow induced by the narrowing of the artery and runs parallel to the flow of blood. It is by making use of this phenomenon that the team of researchers has developed a veritable «time bomb», a nanocontainer which, under pressure from the shear stress in stenosed arteries, will release its vasodilator contents. By rearranging the structure of certain molecules (phospholipids) in classic nanocontainers such as liposome, scientists were able to give them a lenticular shape as opposed to the normal spherical shape. In the form of a lens, the nanocontainer then moves through the healthy arteries without breaking. This new nanocontainer is perfectly stable, except when subjected to the shear stress of stenosed arteries. And that’s exactly the intention of this technological advance. The vasodilator content is distributed only to the stenotic arteries, significantly increasing the efficacy of the treatment and reducing side effects. «In brief, we exploited a previously unexplored aspect of an existing technology. This research offers new perspectives in the treatment of patients with cardiovascular disease,» explains Andreas Zumbuehl from the Department of Organic Chemistry at UNIGE. «Nanomedicine is a discipline stemming from general nanoscience but which orients itself towards medical research. The interdisciplinary collaboration between chemistry, physics, basic science and clinical medicine in a highly technical environment could lead to a new era of research,» states Till Saxer of the Cardiology and General Internal Medicine Departments at HUG. «The nano component is present in all disciplines, but the most interesting aspect of nanomedicine is its overview allowing the development of clinical products that integrate this global medical point of view from the earliest onset of research projects,» states Bert Müller, Director of the Biomaterials Science Centre (BMC) at Basel.
When chemistry gets involved
How did scientists manage to change the shape of the nanocontainers so that they resemble a lens? By rearranging the structure of molecules, chemists at UNIGE replaced the ester bond that links the two parts of the phospholipid (head and tail), with an amide bond, an organic compound that promotes interaction among phospholipids. Once modified, the molecules are hydrated then heated to form a liquid sphere which will relax to solidify in the form of a lens upon cooling. The researchers then modelled the cardiovascular system using polymer tubes blocked to varying degrees to represent healthy and stenotic arteries. Next, an artificial extracardiac pump was connected to these arteries in order to reproduce the shear stress induced by the narrowing of the vessels. The nanocontainer was injected into the system and samples were taken from both healthy and stenosed areas. It turns out that the active drug was found in higher concentrations in diseased areas than in non-diseased areas and that the concentrations there were significantly greater than if the drug had been distributed in a homogenous manner. ### Contact: Andreas Zumbuehl |
| Brain scans show specific neuronal response to junk food when sleep-restricted Posted: 09 Jun 2012 09:00 PM PDT The sight of unhealthy food during a period of sleep restriction activated reward centers in the brain that were less active when participants had adequate sleep, according to a new study using brain scans to better understand the link between sleep restriction and obesity.
Researchers from St. Luke’s – Roosevelt Hospital Center and Columbia University in New York performed functional magnetic resonance imaging (fMRI) on 25 men and women of normal weights while they looked at images of healthy and unhealthy foods. The scans were taken after five nights in which sleep was either restricted to four hours or allowed to continue up to nine hours. Results were compared. “The same brain regions activated when unhealthy foods were presented were not involved when we presented healthy foods,” said Marie-Pierre St-Onge, PhD, the study’s principal investigator. “The unhealthy food response was a neuronal pattern specific to restricted sleep. This may suggest greater propensity to succumb to unhealthy foods when one is sleep restricted.” Previous research has shown that restricted sleep leads to increased food consumption in healthy people, and that a self-reported desire for sweet and salty food increases after a period of sleep deprivation. St-Onge said the new study’s results provide additional support for a role of short sleep in appetite-modulation and obesity. “The results suggest that, under restricted sleep, individuals will find unhealthy foods highly salient and rewarding, which may lead to greater consumption of those foods,” St-Onge said. “Indeed, food intake data from this same study showed that participants ate more overall and consumed more fat after a period of sleep restriction compared to regular sleep. The brain imaging data provided the neurocognitive basis for those results.” ### The abstract “Sleep restriction increases the neuronal response to unhealthy food stimuli” is being presented today at SLEEP 2012, the 26th annual meeting of the Associated Professional Sleep Societies (APSS) in Boston. To be placed on the mailing list for SLEEP 2012 press releases or to register for SLEEP 2012 press credentials, contact AASM PR Coordinator Doug Dusik at 630-737-9700 ext. 9364, or at ddusik@aasmnet.org. A joint venture of the American Academy of Sleep Medicine and the Sleep Research Society, the annual SLEEP meeting brings together an international body of more than 5,500 leading clinicians and scientists in the fields of sleep medicine and sleep research. At SLEEP 2012 (www.sleepmeeting.org), more than 1,300 research abstract presentations will showcase new findings that contribute to the understanding of sleep and the effective diagnosis and treatment of sleep disorders such as insomnia, narcolepsy and sleep apnea. Follow @aasmorg on Twitter for live updates and use the official hashtag #SLEEP2012 to see what attendees are saying. “Like” the American Academy of Sleep Medicine on Facebook at Facebook.com/sleepmedicine for photos, videos and more. |
| Positive results from first human clinical trials of a first-generation artificial pancreas system Posted: 09 Jun 2012 09:00 PM PDT Results from the first feasibility study of an advanced first-generation artificial pancreas system were presented today at the 72nd Annual American Diabetes Association Meeting in Philadelphia. Findings from the study indicated that the Hypoglycemia-Hyperglycemia Minimizer (HHM) System was able to automatically predict a rise and fall in blood glucose and correspondingly increase and/or decrease insulin delivery safely. The HHM System included a continuous, subcutaneous insulin pump, a continuous glucose monitor (CGM) and special software used to predict changes in blood glucose. The study was conducted by Animas Corporation in collaboration with JDRF as part of an ongoing partnership to advance the development of a closed-loop artificial pancreas system for patients with Type 1 diabetes.
“The successful completion of this study using the HHM System in a human clinical trial setting is a significant step forward in the development of an advanced first-generation artificial pancreas system,” said Dr. Henry Anhalt, Animas Chief Medical Officer and Medical Director of the Artificial Pancreas Program. “It lays the foundation for subsequent clinical trials, bringing us one step closer to making the dream of an artificial pancreas a reality for millions of people living with Type 1 diabetes.” In June 2011, Animas received Investigational Device Exemption (IDE) approval from the U.S. Food and Drug Administration (FDA) to proceed with human clinical feasibility studies for the development of a closed-loop artificial pancreas system. The company partnered with the JDRF in January 2010 to begin developing such an automated system to help people living with Type 1 diabetes better control their disease. “We are encouraged by the results of the first human trials in this partnership with Animas,” said Aaron Kowalski, Ph.D., Assistant Vice President of Research at JDRF. “An artificial pancreas system that can not only detect, but can predict high and low blood sugar levels and make automatic adjustments to insulin delivery would be a major advance for people with Type 1 diabetes. Such a system could alleviate a huge burden of managing this disease.”
About the Studies
The trial was a non-randomized, uncontrolled feasibility study of 13 participants with Type 1 diabetes at one trial site in the United States. The investigational Hypoglycemia-Hyperglycemia Minimizer (HHM) system was studied for approximately 24 hours for each study participant during periods of open and closed loop control via a model predictive control algorithm with a safety module run from a laptop platform. Insulin and food variables were manipulated throughout the study time period to challenge and assess the system. The primary endpoint was to evaluate the ability of the algorithm to predict a rise and fall in glucose above or below set thresholds and to command the pump to increase, decrease, suspend and/or resume insulin infusion accordingly. The secondary endpoint was to understand the HHM system’s ability to safely keep glucose levels within a target range and to provide guidance for future system development. The study also examined the relationship between CGM trends and the control model’s algorithm for insulin delivery. ###
About Animas Corporation
As part of the Johnson & Johnson Family of Companies, Animas is dedicated to creating a world without limits for people with diabetes through a wide range of products, including the OneTouch® Ping® Glucose Management System and the Animas® 2020 insulin pump. Animas, from the Latin word meaning “true inner self or soul,” has been committed since 1996 to meeting individual patient needs through the development of life-performance technology and customer service 24 hours a day, 7 days a week, 365 days a year. To learn more about Animas, visit http://www.animas.com/. This press release contains “forward-looking statements” as defined in the Private Securities Litigation Reform Act of 1995. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Animas Corporation and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to, general industry conditions and competition; economic factors, such as interest rate and currency exchange rate fluctuations; technological advances and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approvals; domestic and foreign health care reforms and governmental laws and regulations; trends toward health care cost containment; and increased scrutiny of the healthcare industry by government agencies. A further list and description of these risks, uncertainties and other factors can be found in Exhibit 99 of Johnson & Johnson’s Annual Report on Form 10-K for the fiscal year ended January 2, 2011. Copies of this Form 10-K, as well as subsequent filings, are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. Animas Corporation nor Johnson & Johnson undertake to update any forward-looking statements as a result of new information or future events or developments. Contact: Caroline Pavis |
| Moffitt Cancer Center researchers develop and test new anti-cancer vaccine Posted: 07 Jun 2012 09:00 PM PDT Researchers at Moffitt Cancer Center have developed and tested in mice a synthetic vaccine and found it effective in killing human papillomavirus-derived cancer, a virus linked to cervical cancers among others. The research was published in a recent issue of Cancer Immunology, Immunotherapy.
“Vaccines for cancer can be good alternatives to conventional therapies that result in serious side-effects and are rarely effective against advanced disease,” said Esteban Celis, M.D., Ph.D., senior member and professor in Moffitt’s Immunology Program. “The human papillomavirus, or HPV, is known to cause 99 percent of cervical cancers and annually causes more than 250,000 deaths worldwide.” In addition, HPV is the causative agent of a large proportion of head and neck and genital cancers. Although two approved prophylactic vaccines against strains of HPV that cause cervical cancer are now in wide use as a measure to prevent HPV infections, these vaccines cannot be used to treat HPV-induced cancers. Thus, there is a need to develop therapeutic vaccines for HPV-related tumors. In an effort to find an effective HPV-cancer vaccine that would eliminate existing HPV-induced cancer, Celis and Kelly Barrios-Marrugo, Ph.D., of the University of South Florida College of Medicine’s Molecular Medicine program, designed a peptide vaccination strategy called TriVax-HPV. The TriVax vaccine strategy was designed to generate large numbers of cytotoxic T-cells that would seek out the proteins preferentially expressed in the tumors. The HPV16-E6 and E7 proteins function as oncogenic proteins inducing cancer. Thus, according to Celis and Barrios-Marrugo, a vaccine targeting these viral proteins is an “ideal candidate” to create strong immune responses, with the additional benefit of not generating autoimmune-related pathologies. When they tested their vaccine in mice with HPV16-induced tumors, they found that TriVax containing a small synthetic fragment (peptide) of the E7 protein “induced tumor clearance in 100 percent of the treated mice” while the unvaccinated mice with HPV-induced tumors had their tumors grow “at a fast rate.” “Although the magnitude of the T-cell responses achieved with TriVax in mice is impressive,” Barrios-Marrugo said,” we do not know whether similar effects can be accomplished in humans.” Celis and Barrios-Marrugo point out that current therapies for cervical cancer can be devastating, highly toxic and associated with a 10 percent chance of recurrence. Additionally, a significant proportion of women in the Third World will not receive the approved prophylactic vaccine to prevent HPV infection and, thus, will continue at high risk for cervical and other cancers related to HPV. “We believe that these studies may help to launch more effective and less invasive therapeutic vaccines for HPV-caused malignancies,” concluded the authors. ### Their research was supported by National Institutes of Health grants RO1CA136828 and RO1CA157303. About Moffitt Cancer Center Located in Tampa, Moffitt Cancer Center is a National Cancer Institute-designated Comprehensive Cancer Center, which recognizes Moffitt’s excellence in research and contributions to clinical trials, prevention and cancer control. Moffitt is also a member of the National Comprehensive Cancer Network, a prestigious alliance of the country’s leading cancer centers, and is listed in U.S. News & World Report as one of “America’s Best Hospitals” for cancer. Media release by Florida Science Communications Contact: Patty Kim |
| Reach2HD, a Phase II study in Huntington’s disease, launched Posted: 06 Jun 2012 09:00 PM PDT The Huntington Study Group (HSG), under the leadership of Ray Dorsey, M.D. with Johns Hopkins Medical and Diana Rosas, M.D. with Massachusetts General Hospital, is conducting a clinical trial in Huntington’s disease (HD) throughout the United States and Australia, “A randomized, double-blind, placebo-controlled, study to assess the safety and tolerability, and efficacy of PBT2 in patients with early to mid-stage Huntington’s disease” comparing a 100 mg dose or 250 mg dose versus placebo. The HSG is a not-for-profit group of physicians and other clinical researchers who are experienced in the care of HD patients and dedicated to clinical research of the disease. This trial is sponsored by Prana Biotechnology Limited (Melbourne, Australia) and is being managed by the University of Rochester Medical Center.
Huntington’s disease is an inherited neurodegenerative disease which affects over 30,000 people in both the United States and Australia. HD is characterized by brain cell death that usually begins between the ages of 30 to 50, and results in motor, cognitive and behavioral signs and symptoms. While there are medications to help relieve some of the disease symptoms, there is no known treatment to address the cognitive impairment associated with HD. Research has shown that normally occurring metals in the brain play a significant role in diseases such as Alzheimer’s disease and more recently, HD. Researchers at Prana Biotechnology are identifying drugs designed to interrupt interactions between these biological metals and target proteins in the brain, to prevent deterioration of brain cells. One of the chemical compounds, called PBT2, has shown in animal models, and as well as in a small group of patients with Alzheimer’s disease, that it may improve cognition. There is some indication in animal models of HD, that the drug may improve motor function and control, increase life span and reduce the amount of brain cell degeneration. Based on these results, Prana is investigating whether the drug will have similar effects with HD patients. Reach2HD will evaluate how safe and well tolerated PBT2 is at a dose of 100 mg or 250 mg a day compared to a placebo over six months. The trial will also measure whether there is an effect on cognitive abilities as well as other HD symptoms including motor and overall functioning of individuals with HD. “We are excited to work with Prana to investigate the safety and tolerability of an interesting and innovative experimental treatment for Huntington’s disease, PBT2,” said Dorsey. “We have few treatment options for Huntington disease, and none for cognition. We hope this is a step to addressing this large unmet need for patients and their families.” ### There is no cost to participate in Reach2HD. Individuals with early to mid-stage HD who are interested in participating in Reach2HD should visit the HSG website: www.huntington-study-group.org or call toll free: 1(800) 487-7671 (North America) or 1 (800) 794-669 (Australia). Contact: Mark Michaud |
| Alzheimer’s vaccine trial a success Posted: 06 Jun 2012 09:00 PM PDT A study led by Karolinska Institutet in Sweden reports for the first time the positive effects of an active vaccine against Alzheimer’s disease. The new vaccine, CAD106, can prove a breakthrough in the search for a cure for this seriously debilitating dementia disease. The study is published in the distinguished scientific journal Lancet Neurology.
Alzheimer’s disease is a complex neurological dementia disease that is the cause of much human suffering and a great cost to society. According to the World Health Organisation, dementia is the fastest growing global health epidemic of our age. The prevailing hypothesis about its cause involves APP (amyloid precursor protein), a protein that resides in the outer membrane of nerve cells and that, instead of being broken down, form a harmful substance called beta-amyloid, which accumulates as plaques and kills brain cells. There is currently no cure for Alzheimer’s disease, and the medicines in use can only mitigate the symptoms. In the hunt for a cure, scientists are following several avenues of attack, of which vaccination is currently the most popular. The first human vaccination study, which was done almost a decade ago, revealed too many adverse reactions and was discontinued. The vaccine used in that study activated certain white blood cells (T cells), which started to attack the body’s own brain tissue. The new treatment, which is presented in Lancet Neurology, involves active immunisation, using a type of vaccine designed to trigger the body’s immune defence against beta-amyloid. In this second clinical trial on humans, the vaccine was modified to affect only the harmful beta-amyloid. The researchers found that 80 per cent of the patients involved in the trials developed their own protective antibodies against beta-amyloid without suffering any side-effects over the three years of the study. The researchers believe that this suggests that the CAD106 vaccine is a tolerable treatment for patients with mild to moderate Alzheimer’s. Larger trials must now be conducted to confirm the CAD106 vaccine’s efficacy. ### The study was carried out by Professor Bengt Winblad at Karolinska Institutet’s Alzheimer’s Disease Research Centre in Huddinge and leading neurologists in the Swedish Brain Power network: consultant Niels Andreasen from Karolinska University Hospital, Huddinge; Professor Lennart Minthon from the MAS University Hospital, Malmö; and Professor Kaj Blennow from the Sahlgrenska Academy, Gothenburg. The study was financed by Swiss pharmaceutical company Novartis. Publication: “Safety, tolerability, and antibody response of active Aβimmunotherapy with CAD106 in patients with Alzheimer’s disease: randomised, double-blind, placebo-controlled, first-in-human study”, Bengt Winblad, Niels Andreasen, Lennart Minthon, Annette Floesser, Georges Imbert, Thomas Dumortier, R Paul Maguire, Kaj Blennow, Joens Lundmark, Matthias Staufenbiel, Jean-Marc Orgogozo & Ana Graf, Lancet Neurology, online first 6 June 2012, doi:10.1016/S1474-4422(12)70140-0. Read the scientific article: http://goo.gl/Id9uU For further information, please contact: Swedish Brain Power: http://swedishbrainpower.se/en/ Contact the Press Office and download photo: http://ki.se/pressroom Karolinska Institutet – a medical university: http://ki.se/english |
| An important breakthrough in immunology by IRCM researchers Posted: 06 Jun 2012 09:00 PM PDT A team of researchers at the IRCM led by Dr. André Veillette made an important breakthrough in the field of immunology, which will be published online today by the scientific journal Immunity. The scientists explained a poorly understood molecular mechanism associated with a human immune disorder known as XLP disease or Duncan’s syndrome.
“We studied the SAP molecule, which plays a critical role in multiple different types of immune cells,” says Dr. Veillette, Director of the Molecular Oncology research unit at the IRCM. “More specifically, we wanted to understand why SAP is an essential component of natural killer cells’ ability to eliminate abnormal blood cells.” Natural killer (NK) cells are crucial to the immune system, and provide rapid responses against cancer and virus-infected cells, especially blood cells as can be found in leukemia and lymphomas. Patients with XLP are at a high risk of developing lymphomas. “Until now, the way by which SAP enhances NK cells’ response to abnormal blood cells was not well understood,” explains Zhongjun Dong, former researcher in Dr. Veillette’s laboratory and first author of the article. “We discovered that SAP stimulates the function of NK cells through a double mechanism. On one hand, it couples the necessary genes and enzymes to increase NK cell responses, and on the other hand, it prevents genes from inhibiting these responses.” Dr. Dong is now a professor at Tsinghua University, a leading university in China. “The SAP molecule is important in immunity, as it is associated with most cases of XLP disease,” adds Dr. Veillette. “In addition, our findings may have implications on the role of SAP in other diseases such as lupus and arthritis.” According to the XLP Research Trust, X-linked lymphoproliferative disease (XLP), also known as Duncan’s syndrome, is a fatal disease affecting boys worldwide. The cause of the condition was only found in 1998, so many cases may not yet have been properly diagnosed. If untreated, approximately 70% of patients with XLP die by the age of 10. Dr. Veillette’s research is funded by the Canada Research Chairs program and the Canadian Institutes for Health Research (CIHR). “I applaud Dr. Veillette and his team for their research in the field of human immune disorder and their breakthrough discovery in understanding the role of the SAP protein in controlling abnormal blood cells,” said Dr. Marc Ouellette, Scientific Director of the CIHR Institute of Infection and Immunity. “Their work will contribute to a better understanding of our immune system and how to treat human immune diseases for improved health for all Canadians.” ### For more information on this discovery, please refer to the article summary published online by Immunity: http://www.cell.com/immunity/abstract/S1074-7613(12)00231-2.
About Dr. André Veillette
André Veillette obtained his medical degree from the Université Laval. He is Full IRCM Research Professor and Director of the Molecular Oncology research unit. Dr. Veillette is a full researcher-professor in the Department of Medicine (accreditation in molecular biology) at the Université de Montréal. He is also adjunct professor in the Department of Medicine (Division of Experimental Medicine) at McGill University. Dr. Veillette holds the Canada Research Chair in Immune System Signalling. For more information, visit www.ircm.qc.ca/veillette.
About the Institut de recherches cliniques de Montréal (IRCM)
Founded in 1967, the IRCM is currently comprised of 36 research units in various fields, namely immunity and viral infections, cardiovascular and metabolic diseases, cancer, neurobiology and development, systems biology and medicinal chemistry. It also houses three specialized research clinics, seven core facilities and three research platforms with state-of-the-art equipment. The IRCM employs 425 people and is an independent institution affiliated with the Université de Montréal. The IRCM clinic is associated to the Centre hospitalier de l’Université de Montréal (CHUM). The IRCM also maintains a long-standing association with McGill University.
About the Canadian Institutes of Health Research (CIHR)
The Canadian Institutes of Health Research is the Government of Canada’s health research investment agency. CIHR’s mission is to create new scientific knowledge and to enable its translation into improved health, more effective health services and products, and a strengthened Canadian health care system. Composed of 13 Institutes, CIHR provides leadership and support to more than 14,100 health researchers and trainees across Canada. Contact: Julie Langelier |
| Study reports seizure-freedom in 68 percent of juvenile myoclonic epilepsy patients Posted: 05 Jun 2012 09:00 PM PDT A 25-year follow-up study reveals that 68% of patients with juvenile myoclonic epilepsy (JME) became seizure-free, with nearly 30% no longer needing antiepileptic drug (AED) treatment. Findings published today in Epilepsia, a journal of the International League Against Epilepsy (ILAE), report that the occurrence of generalized tonic-clonic seizures preceded by bilateral myoclonic seizures, and AED polytherapy significantly predicted poor long-term seizure outcome.
Patients with JME experience “jerking” of the arms, shoulders, and sometimes the legs. Previous evidence suggests that JME is a common type of epilepsy (in up to 11% of people with epilepsy), occurring more frequently in females than in males, and with onset typically in adolescence.. There is still much debate among experts over the long-term outcome of JME, and about which factors predict seizure outcome. To further investigate JME outcomes and predictive factors, Dr. Felix Schneider and colleagues from the Epilepsy Center at the University of Greifswald in Germany studied data from 12 male and 19 female patients with JME. All participants had a minimum of 25 years follow-up which included review of medical records, and telephone or in-person interviews. Sixty-eight percent of the 31 JME patients became free of seizures, and 28% discontinued AED treatment due to seizure-freedom. Significant predictors of poor long-term seizure outcome included: occurrence of generalized tonic-clonic seizures (GTCS – formerly known as grand mal seizures) that affect the entire brain and which are preceded by bilateral myoclonic seizures (abnormal movements on both sides of the body and a regimen of AED polytherapy. Researchers also determined that remission of GTCS using AED therapy significantly increased the possibility of complete seizure-freedom. However, once AED therapy is discontinued, the occurrence of photoparoxysmal responses (brain discharges in response to brief flashes of light) significantly predicted an increased risk of seizure recurrence. “Our findings confirm the feasibility of personalized treatment of the individual JME patient,” concludes Dr. Schneider. “Life-long AED therapy is not necessarily required in many patients to maintain seizure freedom. Understanding the predictors for successful long-term seizure outcome will aid clinicians in their treatment options for those with JME.” ### This study is published in Epilepsia. Media wishing to receive a PDF of this article may contact healthnews@wiley.com. Full citation:”Predictors for Long-Term Seizure Outcome in Juvenile Myoclonic Epilepsy: 25-63 Years Of Follow-Up.” Julia Geithner, Felix Schneider, Zhong Wang, Julia Berneiser, Rosemarie Herzer, Christof Kessler and Uwe Runge. Epilepsia; Published Online: June 6, 2012 (DOI: 10.1111/j.1528-1167.2012.03526.x). URL upon publication: http://doi.wiley.com/10.1111/j.1528-1167.2012.03526.x Epilepsia is the leading, most authoritative source for current clinical and research results on all aspects of epilepsy. As the journal of the International League Against Epilepsy, subscribers every month will review scientific evidence and clinical methodology in: clinical neurology, neurophysiology, molecular biology, neuroimaging, neurochemistry, neurosurgery, pharmacology, neuroepidemiology, and therapeutic trials. For more information, please visit http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1528-1167. The International League Against Epilepsy (ILAE) is the world’s preeminent association of physicians and health professionals working toward a world where no person’s life is limited by epilepsy. Since 1909 the ILAE has provided educational and research resources that are essential in understanding, diagnosing and treating persons with epilepsy. The ILAE supports health professionals, patients, and their care providers, governments, and the general public worldwide by advancing knowledge of epilepsy. Wiley-Blackwell is the international scientific, technical, medical, and scholarly publishing business of John Wiley & Sons, with strengths in every major academic and professional field and partnerships with many of the world’s leading societies. Wiley-Blackwell publishes nearly 1,500 peer-reviewed journals and 1,500+ new books annually in print and online, as well as databases, major reference works and laboratory protocols. For more information, please visit www.wileyblackwell.com or our new online platform, Wiley Online Library (wileyonlinelibrary.com), one of the world’s most extensive multidisciplinary collections of online resources, covering life, health, social and physical sciences, and humanities. Contact: Dawn Peters |
| The potential impact of olfactory stem cells as therapy reported in Cell Transplantation Posted: 04 Jun 2012 09:00 PM PDT A study characterizing the multipotency and transplantation value of olfactory stem cells, as well as the ease in obtaining them, has been published in a recent issue of Cell Transplantation (20:11/12), now freely available on-line at http://www.ingentaconnect.com/content/cog/ct/.
“There is worldwide enthusiasm for cell transplantation therapy to repair failing organs,” said study lead author Dr. Andrew Wetzig of the King Faisal Specialist Hospital and Research Centre in Riyadh, Saudi Arabia. “The olfactory mucosa of a patient’s nose can provide cells that are potentially significant candidates for human tissue repair.” According to the study authors, olfactory neural stem cells can be derived from a patient’s own cells, they are readily available by a minimally invasive biopsy technique, and they can be expanded in vitro. The cells are plentiful because the olfactory epithelium undergoes neurogenesis and continual replacement of sensory neurons throughout adult life. “Using the rat as our animal model source, we examined the basic aspects of olfactory neural stem cell biology and its potential for self-renewal and phenotypic expression in various circumstances,” said Dr. Wetzig. “Previously, we found that they have performed well in pre-clinical models of disease and transplantation and seem to emulate a wound healing process where the cells acquire the appropriate phenotype in an apparently orderly fashion over time.” The researchers concluded that the olfactory neurospheres contain stem cells whose capacity for differentiation is triggered by signals from the immediate environmental niche. “Stem cell numbers were shown to be enriched by our culture methods,” explained Dr. Wetzig. “We also demonstrated that when adult olfactory stem cells are transplanted into an environmental niche different from that of their origin, they demonstrate multipotency by acquiring the phenotype of the resident cells.” “This study highlights another potential source of stem cells that has shown some degree of promise in a number of studies” said Dr. John Sladek, professor of neurology and pediatrics at the University of Colorado School of Medicine. “Their relatively easy accessibility and multipotent properties are important factors that could rank these cells competitively with other stem cells thus giving them a potential impact as an excellent source for cell therapy”. ### Contact Corresponding Author: Dr. Wayne Murrell, Vilhelm Magnus Center, Institute for Surgical Research, Rikshospital, University of Oslo, Norway 0027. Citation: Wetzig, A.; Mackay-Sim, A,; Murrell, W. Characterization of olfactory stem cells. Cell Transplant. 20 (11/12):1673-1691; 2011. The Coeditor-in-chief’s for Cell Transplantation are at the Diabetes Research Institute, University of Miami Miller School of Medicine and Center for Neuropsychiatry, China Medical University Hospital, TaiChung, Taiwan. Contact, Camillo Ricordi, MD at ricordi@miami.edu or Shinn-Zong Lin, MD, PhD at shinnzong@yahoo.com.tw or David Eve, PhD at celltransplantation@gmail.com |
| Study offers hope for more effective treatment of nearsightedness Posted: 04 Jun 2012 09:00 PM PDT Research by an optometrist at the University of Houston (UH) supports the continued investigation of optical treatments that attempt to slow the progression of nearsightedness in children. Conducted by UH College of Optometry assistant professor David Berntsen and his colleagues from The Ohio State University, the study compared the effects of wearing and then not wearing progressive addition lenses, better known as no-line bifocals, in children who are nearsighted. With funding by a National Institutes of Health National Eye Institute training grant and support from Essilor of America Inc. and the American Optometric Foundation Ezell Fellowship program, the study examined 85 children from 6-11 years old over the course of two years. The results were published in Investigative Ophthalmology and Visual Science, one of the most widely read journals in the field.
Selected according to their eye alignment and accuracy of focusing on near objects, the myopic children were fitted with either normal single-vision lenses or no-line bifocals to correct their nearsightedness. In addition to observing and testing the children, the doctors obtained feedback from parents and guardians of both the children’s outdoor activities and near-work tasks, such as reading and computer use. Previous research suggested that nearsighted children who do not focus accurately when reading books or doing other near work may benefit more from wearing no-line bifocal glasses than nearsighted children who focus more accurately. Berntsen’s study found a small, yet statistically significant, slowing of myopia progression in children wearing the bifocals compared to those who simply wore single-vision lenses. Berntsen asserts, however, that the results do not suggest that children be fitted with no-line bifocal lenses solely for the purpose of slowing the progression of myopia. “While the small effect found in the group of children wearing bifocal spectacles does not warrant a change in clinical practice, we found the beneficial effect was still present for at least one year after children stopped wearing no-line bifocal lenses,” Berntsen said. “This is promising if other optical lens designs can be developed that do an even better job of slowing how fast myopia increases in children.” By understanding why different types of lenses result in the slowing of myopia progression, Berntsen says researchers will be better able to design lenses that may be more effective in slowing the increase of nearsightedness in children. “Single-vision lenses are normally prescribed when a child gets a pair of glasses, but glasses with progressive addition lenses were shown to slightly reduce myopic progression in our study,” Berntsen said. “For any treatment that reduces myopia progression in children to be useful, the effect of the spectacles or contact lenses must persist after children stop wearing them. The fact that the small treatment effect from our study was still present one year after discontinuing the treatment is promising. The results suggest that if newer optical designs currently being investigated do a better job of slowing myopia progression, the effects may be expected to persist and decrease how nearsighted the child ultimately becomes.” An important goal of this study, in particular, was to help them improve their understanding of the mechanism behind myopia progression in children and why no-line bifocals cause this small reduction in its progression. Berntsen says the study results and evidence from other studies suggest that lenses specifically designed to change blur in the eye’s peripheral vision may be able to slow the increase of nearsightedness. “There is support for continuing to investigate new lenses specially designed to change the blur profile on the back of the eye in order to reduce the increase of myopia in children,” Berntsen said. “There is still further research to be done, but our work is an important step in discovering the methods needed to slow the progression of nearsightedness.” ### Berntsen’s collaborators from Ohio State’s College of Optometry were Loraine T. Sinnott, Donald O. Mutti and Karla Zadnik. The study, titled “A randomized trial using progressive addition lenses to evaluate theories of myopia progression in children with a high lag of accommodation,” is available at http://www.iovs.org/content/53/2/640.
About the University of Houston
The University of Houston is a Carnegie-designated Tier One public research university recognized by The Princeton Review as one of the nation’s best colleges for undergraduate education. UH serves the globally competitive Houston and Gulf Coast Region by providing world-class faculty, experiential learning and strategic industry partnerships. Located in the nation’s fourth-largest city, UH serves more than 39,500 students in the most ethnically and culturally diverse region in the country. For more information about UH, visit http://www.uh.edu/news-events/.
About the UH College of Optometry
Since 1952, the University of Houston College of Optometry (UHCO) has educated and trained optometrists to provide the highest quality vision care. One of only 20 optometry schools in the country, UHCO offers a variety of degree programs, including Doctor of Optometry (O.D.), a combined Doctor of Optometry/Doctor of Philosophy (O.D./Ph.D.), Master of Science (M.S.) and Doctor of Philosophy (Ph.D.). UHCO serves an average of 36,000 patients a year through The University Eye Institute and its satellite clinics. Contact: Lisa Merkl |
| Noninvasive genetic test for Down syndrome and Edwards syndrome highly accurate Posted: 04 Jun 2012 09:00 PM PDT Current screening strategies for Down syndrome, caused by fetal trisomy 21 (T21), and Edwards syndrome, caused by fetal trisomy 18 (T18), have false positive rates of 2 to 3%, and false negative rates of 5% or higher. Positive screening results must be confirmed by amniocentesis or chorionic villus sampling, which carry a fetal loss rate of approximately 1 in 300 procedures. Now an international, multicenter cohort study finds that a genetic test to screen for trisomy 21 or 18 from a maternal blood sample is almost 100% accurate. The results of the study are published online in the American Journal of Obstetrics and Gynecology.
The trial evaluated a novel assay known as Digital Analysis of Selected Regions (DANSR) that analyzes fetal cell-free DNA, small DNA fragments which circulate in maternal blood. Unlike similar tests that analyze DNA from the entire genome, DANSR analyzes only the chromosomes under investigation for a more efficient and less expensive process. The results are evaluated with a novel analysis algorithm, the Fetal-fraction Optimized Risk of Trisomy Evaluation (FORTE), which considers age-related risks and the percentage of fetal DNA in the sample to provide an individualized risk score for trisomy detection. A total of 4,002 pregnant women from the United States, the Netherlands, and Sweden were enrolled in the NICE (Non-Invasive Chromosomal Evaluation) study. The mean maternal age was 34.3 years and the cohort was racially and ethnically diverse. Blood samples were taken before the women underwent invasive testing for any indication, and 774 samples were excluded prior to analysis. Of the 3,228 samples that underwent analysis, 57 cases were excluded due to low fetal cfDNA in the sample and 91 samples were excluded due to failure of the assay. The classification of samples as High Risk or Low Risk using the DANSR and FORTE method was compared with the results from amniocentesis and CVS. The DANSR and FORTE method identified 100% of the 81 T21 cases as High Risk, and there was one false positive among the 2,888 normal cases, for a false-positive rate of 0.03%. Of the 38 T18 cases, 37 were classified as High Risk and there were 2 false positives among the 2,888 normal cases, for a sensitivity of 97.4% and a false positive rate of 0.07%. Prior studies of cfDNA have been case-control studies, comparing detection in subjects identified with T21 or T18, to a selected group of those with normal karyotypes. The current study included a large cohort of subjects undergoing invasive prenatal diagnosis. This allowed the researchers to assess the potential impact of other complex and unusual abnormalities on cfDNA test results. Overall, the presence of other chromosomal variants did not interfere with the detection of T21 or T18. While the study included primarily high-risk women, all women undergoing invasive prenatal diagnosis for any indication were eligible, so the cohort represents a broader population than reported in previous studies. “The improvement in sequencing efficiency achieved by the DANSR platform provides a more affordable, scalable approach to cfDNA analysis with high throughput and potential for widespread clinical utility,” says lead investigator Mary E. Norton, MD, director of perinatal research, Lucile Packard Children’s Hospital at Stanford University. “Cell-free DNA offers high accuracy with a single blood test. It is potentially suitable as a replacement for current, relatively inefficient aneuploidy screening.” ### Contact: Francesca Costanzo |
| Drug combination highly effective for newly diagnosed myeloma patients Posted: 03 Jun 2012 09:00 PM PDT A three-drug treatment for the blood cancer multiple myeloma provided rapid, deep and potentially durable responses, researchers report today online in Blood, the Journal of the American Society of Hematology, and yesterday, Sunday, June 3, 2012, at the American Society of Clinical Oncology’s Annual Meeting in Chicago, IL, USA.
The researchers, led by Andrzej J. Jakubowiak, M.D., Ph.D., professor of medicine and director of the multiple myeloma program at the University of Chicago Medical Center, found that combining carfilzomib, a next generation proteasome inhibitor, with two standard drugs – lenalidomide and low-dose dexamethasone compared favorably to other frontline regimens. The longer patients stayed on the therapy, the better their response. After at least eight 28-day cycles of treatment, 61 percent of the 36 patients who remained on the therapy had a stringent complete response, defined as no detectable tumor cells or myeloma protein in the blood or bone marrow; 78 percent had at least a near complete response. More than 90 percent of patients had no progression of their disease at two years. “These rapid and durable response rates are higher than those achieved by the best established regimens for newly diagnosed multiple myeloma,” said Jakubowiak. “We have observed excellent efficacy, the best reported to date, and very good tolerability, including limited peripheral neuropathy that has been problematic with other drug combinations.” The research team enrolled 53 patients in the trial at four centers. Patients, aged 35 to 81, all had newly diagnosed multiple myeloma. Every patient received all three drugs and the carfilzomib dose levels were increased twice for new patients as the study progressed. Most patients responded rapidly to the combination and continued to improve. “Newly diagnosed patients with myeloma are most sensitive to treatment,” Jakubowiak said. “A rapid and sustained response to the initial phase of treatment, as in the case of this study, can typically project longer remission, and, possibly, longer overall survival.” ### Multiple myeloma is a cancer that arises in plasma cells, the bone marrow component that produces antibodies. The American Cancer Society estimates that about 21,700 Americans will be diagnosed with multiple myeloma in 2012 and 10,710 will die from the disease. The Multiple Myeloma Research Consortium, Onyx Pharmaceuticals Inc., Celgene Corp. and the University of Michigan funded the study. Additional authors include Kent Griffith, Tara Anderson, Brian Nordgren, Kristen Detweiler-Short, Daniel Lebovic, Ammar Al-Zoubi, Asra Ahmed, Melissa Mietzel, Daniel Couriel, Terri Jobkar, and Mark Kaminski from the University of Michigan; Dominik Dytfeld from Poznan University of Medical Sciences, Poznan, Poland; David Vesole from Hackensack University Medical Center, Hackensack, NJ; Sundar Jagannath from Mount Sinai Medical Center, New York, NY; Keith Stockerl-Goldstein and Ravi Vij from Washington University, St. Louis, MO; Sandra Wear from the Multiple Myeloma Research Consortium, Norwalk, CT; Mohamad Hussein from Celgene Corporation, Summit, NJ; and Homa Yeganegi from Onyx Pharmaceuticals, South San Francisco, CA. ASCO Presentation: Session: Myeloma, Abstract #8011; Sunday June 3, 8:00 AM to 11:00 AM, Room E354a: Stringent complete response in patients with newly diagnosed multiple myeloma treated with carfilzomib, lenalidomide, and dexamethasone. Contact: John Easton |
| A new multitarget molecule designed with high potential in future treatments for Alzheimer’s disease Posted: 03 Jun 2012 09:00 PM PDT
Researchers at Universitat Autònoma de Barcelona (UAB), the Spanish National Research Council (CSIC) and the University of Barcelona (UB) have developed a multitarget molecule, ASS234, which according to the results of in vitro studies conducted, inhibits the aggregation of the ß-amyloid protein, involved in Alzheimer’s disease. At the same time, ASS234 stimulates the cholinergic and monoaminergic transmission, key factors involved in the cognitive function. In addition, ASS234 is able to cross the blood–brain barrier with an elevated multipotent profile designed on basis of donepezil (Aricept®), one of the few effective drugs in palliative and symptomatic treatments of the disease. In the development of this new molecule, researchers used the strategy of “multipotent drugs”, capable of acting simultaneously on different targets in the brain involved in this neurodegenerative disease, given that the paradigm used in the design of drugs based on the strategy of “one drug, one target” has shown to be unsuitable in offering satisfactory results. ASS234 was developed as a hybrid of two known molecules. One of them, donepezil, is currently used to treat Alzheimer’s disease, and the other, PF9601N compound, is an inhibitor of the monoamino oxidase B (MAO B) enzyme, patented and developed by researchers at UAB and CSIC, with proven neuroprotective effects in different experimental models of Parkinson’s disease. The research was directed by Mercedes Unzeta, researcher of the Department of Biochemistry and Molecular Biology and of the Institute of Neurosciences (INc) at UAB, José Luis Marco Contelles, CSIC researcher at the Institute of General Organic Chemistry (IQOG), and F. Javier Luque, researcher of the Department of Physico-Chemistry at the Faculty of Pharmacy and the Institute of Biomedicine of the UB (IBUB). All three researchers have worked for years on the design, synthesis and biological evaluation of new multipotent molecules capable of stimulating neural transmissions and at the same time having neuroprotective effects. ASS234 acts on both of these processes. The biochemical activity and pharmacological potential of the molecule was exhaustively characterised by Irene Bolea (UAB) and synthesised by Abdelouahid Samadi (CSIC). Previous studies on the interactions of ASS234 with its possible targets were carried out by Jordi Juárez-Jiménez (UB). The ASS234 molecule has been patented by all three institutions. This molecule could be much more efficient than other compounds used to stimulate neural transmission and simultaneously act on different brain targets. To date, in vitro investigations conducted at UAB have demonstrated that ASS234, in addition to being able to inhibit monoamino oxidases A and B, also act on the enzymes acetylcholinesterase and butyrylcholinesterase, thus helping to boost levels of acetylcholine, a neurotransmitter deficient in patients with Alzheimer’s. The latest results obtained indicate that ASS234 also reduces aggregation of the ß-amyloid protein which gives way to the appearance of senile plaques characteristic of the disease. Other recent studies conducted by researchers of the CSIC Cajal Institute and the University of Lodz, Poland, have demonstrated that ASS234 is able to cross the blood-brain barrier and improves memory in mice. All studies conducted to date make clear that ASS234 is a promising multitarget molecule due to its potential therapeutic effects on patients with Alzheimer’s disease. As affirmed by Dr Unzeta and Dr Marco Contelles, ASS234 “a priori appears as a derivative of donepezil, which contains not only its virtues but possesses also a potential multipotent profile drug, which could make it a more efficient drug for the treatment of this disease”. ### The research on ASS234 and results obtained was recently published in the Journal of Medicinal Chemistry.
Contact researcher:
Image:
http://www.uab.es/uabdivulga/img/UAB-INC_Investigadors.jpg Researchers of the Institute of Neurosciences at UAB participating in the biological evaluation of the multitarget molecule to fight against Alzheimer’s disease, the ASS234. From left to right: Laura Fernández, Irene Bolea, Mercedes Unzeta, Gerard Esteban and Montse Solé.
Related articles:
1.- “The multitarget compound ASS234 reduces A? fibrillogenesis and protects SH-SY5Y cells from A? toxicity.” Irene Bolea, Alejandro Gella, Abdelouahid Samadi, Jose Luis Marco and Mercedes Unzeta. (In preparation) 2.- “Multipotent MAO and cholinesterase inhibitors for the treatment of Alzheimer’s disease: Synthesis, pharmacological analysis and molecular modeling of heterocyclic substituted alkyl and cycloalkyl propargyl amine.” Abdelouahid Samadi, Cristóbal de los RÃos, Irene Bolea, Mourad Chioua, Isabel Iriepa, Ignacio Moraleda, Manuela Bartolini, Vincenza Andrisano, Enrique Gálvez, Carolina Valderas, Mercedes Unzeta, José Marco-Contelles. European Journal of Medicinal Chemistry 2012, 52, 251-262 3.- “Synthesis, Biological Evaluation and Molecular Modeling of Donepezil and N-[(5-(Benzyloxy)-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine Hybrids, as New Multipotent Cholinesterase/Monoamine Oxidase Inhibitors for the Treatment of Alzheimer’s Disease.” I. Bolea, J. Juárez-Jiménez, C. de los RÃos, M. Chioua, R. Pouplana, F. J. Luque, M. Unzeta, J. Marco-Contelles, and A. Samadi Journal of Medicinal Chemistry 2011, 54, 8251-8270 4.- “Synthesis, biological assessment and molecular modeling of new multipotent MAO and cholinesterase inhibitors as potential drugs for the treatment of Alzheimer’s disease.” Samadi A, Chioua M, Bolea I, de los RÃos C, Iriepa I, Moraleda I, Bastida A, Esteban E, Unzeta M, Gálvez E and Marco-Contelles J. Eur J Med Chem 46(9):4665-4668 Contact: Maria Jesus Delgado |
| New immune therapy shows promise in kidney cancer Posted: 03 Jun 2012 09:00 PM PDT An antibody that helps a person’s own immune system battle cancer cells shows increasing promise in reducing tumors in patients with advanced kidney cancer, according to researchers at Beth Israel Deaconess Medical Center.
The results of an expanded Phase 1 trial presented at the American Society of Clinical Oncology’s annual conference in Chicago, showed that some patients treated with a fully human monoclonal antibody developed by Bristol Myers Squibb had a positive response to the effort by the agent, BMS-936558, to prolong the immune system’s efforts to fight off renal cell carcinoma without some of the debilitating side effects common to earlier immunotherapies. The presentation by David F. McDermott, MD, Director of Biologic Therapy Program at the Beth Israel Deaconess Medical Center Cancer Center and an Assistant Professor of Medicine at Harvard Medical School, highlights one of two key efforts underway to use the body’s own disease-fighting tools against cancer. Separate work by David Avigan MD, Director of BIDMC’s Blood/Bone Marrow Transplant Program, focuses on developing a personalized vaccine, compromised of the patient’s tumor and immune system agents, to battle kidney cancer. Cancer cells have the ability to trick the immune system, the body’s self-defense mechanism, which is designed to ward off infections. Immune therapy such as antibody treatment and vaccines is designed to reeducate the body to recognized cancer as an invader. “We’ve known for a long time that in certain cases the immune system can be boosted in a way that can create remissions” of hematologic malignancies like leukemia and lymphoma, says McDermott. “We’ve been trying to create the same long term results in solid tumors, which is more difficult.” In this trial, the antibody was designed to block the Programmed Death (PD)-1 inhibitory receptor expressed by activated T cells. PD-1 acts a natural shut off valve for T cells. By blocking its action, these cells can be revived to fight cancer. In the initial portion of the trial, the agent showed “promising” activity in patients with various solid tumors, including metastatic renal cell carcinoma, melanoma and lung cancer. In an expanded trial, patients received up 10 mg/kg of an intravenous treatment twice weekly, followed by 1 mg/kg. Patients received up to 12 cycles of treatment until either progressive disease, unacceptable toxicity or a complete response was detected. “These antibodies were developed based on an understanding of how the immune system is not well designed to fight cancer,” says McDermott. “Your immune system is in place to help fight off infections. So when you have a viral infection, it will turn on in response to that infection and once it’s controlled will shut down. The shut off valves, like PD-1, are actually stronger the pathways that turn on the immune system and this makes cancer difficult to control. The new PD-1 blocking antibody prevents this natural shutoff and allows T-cells to recognize and kill tumors.” McDermott noted that unlike current immunotherapies using interleukin-2, patients do not need to be hospitalized and suffer far less significant side effects such as skin rash or nausea. “We realized that we could this drug at the highest doses without developing many significant or too dangerous side effects,” says McDermott. “Once we realized the drug was relatively safe to give, we expanded into larger numbers of patients who seem to be benefiting early on from this treatment.” McDermott cautions that it is too early in a Phase I trial, designed principally to test side effects and the best dosage and schedule of treatment, to draw sweeping conclusions from the results. “We have seen about 30 percent of the patients with kidney cancer have major responses to this line of treatment. A similar 30 percent of melanoma patients have had major response to treatment and there are much more melanoma patients in this study than kidney cancer patients. And maybe 20 percent or so of patients with lung cancer have had major benefit.” ### In addition to McDermott, authors include Charles G. Drake, Mario Sznol, Toni K. Choueiri, John Powderly, David C. Smith, Jon Wigginton, Dan McDonald, Georgia Kollia, Ashok Kumar Gupta, and Michael B. Atkins with affiliations that include Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD; Yale Cancer Center, New Haven, CT; Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Harvard Medical School, Boston; Carolina Bio-Oncology Institute, Huntersville, NC; University of Michigan, Ann Arbor, MI; Bristol-Myers Squibb, Princeton, NJ. McDermott serves in an advisory role with Bristol Myers Squibb, which provided funding for the study. Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School, and currently ranks third in National Institutes of Health funding among independent hospitals nationwide. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a research partner of Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit www.bidmc.org. Contact: Jerry Berger |
| New hope for migraine sufferers Posted: 02 Jun 2012 09:00 PM PDT New hope has arrived for migraine sufferers following a Griffith University study with the people of Norfolk Island. Led by Professor Lyn Griffiths from the University’s Griffith Health Institute, the team has identified a new region on the X chromosome as playing a role in migraine.
The research provides compelling evidence for a new migraine susceptibility gene involved in migraine. The study also indicated that there may be more than one X chromosomal gene involved and implicated a gene involved in iron regulation in the brain. All females have two X chromosomes whilst males have an X and a Y chromosome. “These results provide more support for the role of the X chromosome in migraine and may explain why so many more females suffer from the disorder,” said Professor Griffiths. Tracking down and identifying the various genes that cause migraine is very important as it provides insights to allow us to develop better means of diagnosis and more targeted treatments. “Currently, 12 per cent of the population suffers from migraine. Even though we have some very good treatments for this very debilitating disease, they certainly don’t work for everyone and can have some adverse side effects. Hence there is a real need to develop new migraine treatments.” This National Health and Medical Research Council funded work involved a unique population study of the remote Norfolk Island where 80 per cent of inhabitants are able to trace their ancestry back to the famous historical event, The Mutiny on the Bounty. “This population was used due to its unusual pedigree structure in which genetic relationships can be traced through genealogical data to the island’s original founders, and also the high incidence of migraine sufferers in this population. It’s very useful for gene mapping purposes because of the reduced genetic and environmental diversity,” said Professor Griffiths. A comprehensive chromosome analysis of around 300 Norfolk participants from a large multigenerational Norfolk family, including many who are affected by migraine, was conducted using DNA samples obtained from the islanders. ### Contact: Louise Durack |
| Cancer therapy that boosts immune system ready for wider testing Posted: 01 Jun 2012 09:00 PM PDT Two clinical trials led by Johns Hopkins Kimmel Cancer Center researchers in collaboration with other medical centers, testing experimental drugs aimed at restoring the immune system’s ability to spot and attack cancer, have shown promising early results in patients with advanced non-small cell lung cancer, melanoma, and kidney cancer. More than 500 patients were treated in the studies of two drugs that target the same immune-suppressive pathway, and the investigators say there is enough evidence to support wider testing in larger groups of patients.
Results of the Phase I clinical trials will be published online June 2 in the New England Journal of Medicine and presented at the 2012 Annual Meeting of the American Society of Clinical Oncology (Abstracts #2509 and #2510). “Based on the positive response rates to these drugs and longevity of many of these responses, we believe that new clinical trials should move forward,” says Suzanne Topalian, M.D., professor of surgery and oncology at Johns Hopkins. Preliminary analysis shows that, among responding patients who were followed for more than one year, responses were maintained for more than one year in two-thirds of those treated on one trial and in half of those in the other trial. The immune-based therapies tested in the two clinical trials, both made by Bristol-Myers Squibb, aim not to kill cancer cells directly, but to block a pathway that shields tumor cells from immune system components able and poised to fight cancer. The pathway includes two proteins called programmed death-1 (PD-1), expressed on the surface of immune cells, and programmed death ligand-1 (PD-L1), expressed on cancer cells. When PD-1 and PD-L1 join together, they form a biochemical “shield” protecting tumor cells from being destroyed by the immune system. Another protein involved in the pathway and also expressed by cells in the immune system, programmed death ligand ð"ƒ€ (PD-L2), was originally discovered by Johns Hopkins investigators. To make cancer cells more vulnerable to attack by the immune system, investigators tested each of two drugs — BMS-936558, which blocks PD-1, and BMS-936559, which blocks PD-L1 — in separate clinical trials conducted at multiple U.S. hospitals. The drugs are given intravenously in an outpatient clinic every two weeks, and patients can remain on the treatment for up to two years. The PD-1 blocking drug was tested in 296 patients with various advanced cancers who had not responded to standard therapies. Of those patients receiving the anti-PD-1 therapy, 240 who started treatment by July 2011 were analyzed for tumor response. Significant tumor shrinkage was seen in 14 of 76 (18 percent) non-small cell lung cancer patients, 26 of 94 (28 percent) melanoma patients and nine of 33 (27 percent) kidney cancer patients. In this trial, some patients experienced stable disease for six months or more, including five of 76 (seven percent) lung cancer patients, six of 94 (six percent) melanoma patients and nine of 33 (27 percent) kidney cancer patients. The investigators say that additional clinical studies will be needed to determine the drug’s potential impact on survival. “This level of response in patients with advanced lung cancer, which is typically not responsive to immune-based therapies, was unexpected and notable,” says Julie Brahmer, M.D., associate professor of oncology at Johns Hopkins. The anti-PD-L1 therapy also showed responses among 207 treated patients. Five of 49 (10 percent) non-small cell lung cancer patients, nine of 52 (17 percent) melanoma patients, and two of 17 (12 percent) kidney cancer patients responded. “The positive results from both drugs give us a good indication that the PD-L1/PD-1 pathway is an important target for cancer therapy,” says Topalian. The anti-PD1 therapy caused serious toxicities in 41 of 296 (14 percent) patients. Many of the toxicities were immune-related, including colon inflammation, thyroid abnormalities and three deaths from pneumonitis (lung inflammation). The investigators say they are working with colleagues across the country to develop better methods for early detection and effective treatment of pneumonitis. Other less severe toxicities included fatigue, itching and rash. The anti-PD-L1 therapy caused nine percent serious toxicities and no deaths. Among patients receiving anti-PD-1, tumor samples collected from 42 study patients before they received the experimental therapy were evaluated at Johns Hopkins Medicine for molecular markers that may correlate with clinical response. The investigators found PD-L1, the partner protein to PD-1, in 25 of the 42 samples. Nine of the 25 patients with PD-L1-positive tumors experienced tumor shrinkage as compared with none of the patients with PD-L1 negative tumors. “These early results indicate that PD-L1 expression in pretreatment tumor biopsies may correlate with clinical response to anti-PD-1 therapy, but more work needs to be done to confirm this, ” says Brahmer. The two therapies targeting the PD-1/PD-L1 pathway are in the same class of so-called “antibody therapies,” which are made of proteins that target and bind to certain molecules on the cell surface. Other antibody therapies include such drugs as Erbitux, Herceptin, and Rituxan. “We have just scratched the surface of laboratory and clinical research on these drugs,” says Topalian. Ultimately, they envision boosting the effectiveness of the therapy by combining it with other anti-cancer agents, including cancer vaccines. ### Funding for the clinical studies was provided by Bristol-Myers Squibb and Ono Pharmaceuticals Co., Ltd. Research support was provided by grants (CA142779 and CA006973) from the National Cancer Institute (NCI) at the National Institutes of Health (NIH) and the Melanoma Research Alliance. In addition to Topalian and Brahmer, other investigators involved in the two studies include Charles G. Drake, M.D., Drew M. Pardoll, M.D., Ph.D., William H. Sharfman, M.D., Robert A. Anders, M.D., Ph.D., Janis M. Taube, M.D., Tracee L. McMiller, M.S., Haiying Xu, B.A., Shuming Chen, Ph.D., and Theresa M. Salay, B.S., from Johns Hopkins; Stephen Hodi, M.D., from the Dana Farber Cancer Center; Scott N. Gettinger, M.D., Lieping Chen, M.D., Ph.D., and Mario Sznol, M.D. from Yale University; David C. Smith, M.D., from the University of Michigan; David F. McDermott, M.D., and Michael B. Atkins, M.D., from Beth Israel Deaconess Medical Center; John D. Powderly, M.D., from the Carolina BioOncology Institute; Richard D. Carvajal, M.D., from Memorial Sloan Kettering Cancer Center; Jeffrey A. Sosman, M.D., and Leora Horn, M.D., from Vanderbilt University; Philip D. Leming, M.D., from Cincinnati Hematology-Oncology Inc.; David R. Spigel, M.D., from the Sara Cannon Research Institute/Tennessee Oncology; Scott J. Antonia, M.D., Ph.D., from the H. Lee Moffitt Cancer Center; Alan J. Korman, Ph.D., Maria Jure-Kunkel, Ph.D., Shruti Agrawal, Ph.D., Dan McDonald, M.B.A., Georgia D. Kollia, Ph.D., Ashok Gupta, M.D., Ph.D., Suresh Alaparthy, Ph.D., Joseph F. Grosso, Ph.D., Susan M. Parker, Ph.D., Stacie M. Goldberg, Ph.D., and Jon M. Wigginton, M.D., from Bristol-Myers Squibb; Scott S. Tykodi, M.D., Ph.D., Laura Q. M. Chow, M.D., Shailender Bhatia, M.D., Renato Martins, M.D., M.P.H., Keith Eaton, M.D., Ph.D., from the University of Washington and Fred Hutchinson Cancer Research Center; Wen-Jen Hwu, M.D., Ph.D., and Patrick Hwu, M.D., from the MD Anderson Cancer Center; Luis H. Camacho, M.D., M.P.H., from the St. Luke’s Episcopal Hospital Cancer Center; John Kauh, M.D., from the Winship Cancer Institute of Emory University; Kunle Odunsi, M.D., Ph.D., from the Roswell Park Cancer Institute; Henry C. Pitot, M.D., from the Mayo Clinic; Omid Hamid, M.D., from the Angeles Clinic. Brahmer, Topalian, Drake and Pardoll have served as consultants to Bristol-Myers Squibb. Topalian is the Chief Scientific Officer of the Melanoma Research Alliance. The terms of these arrangements are being managed by the Johns Hopkins University in accordance with its conflict-of-interest policies. Contact: Vanessa Wasta |
| New target, new drug in breast cancer Posted: 01 Jun 2012 09:00 PM PDT Many breast cancers depend on hormones including estrogen or progesterone for their survival and proliferation. Eight years of lab work at the University of Colorado Cancer Center and elsewhere suggest that the androgen (AR) receptor is an additional hormonal target in many breast cancers. Block AR+ breast cancer’s ability to access androgen and you block the cancer’s ability to survive.
That’s what the drug enzalutamide does, according to a CU Cancer Center study, presented today at the American Society of Clinical Oncology (ASCO) meeting in Chicago. “Preliminary results are promising and show that androgen receptor blockade may indeed be therapeutic,” says Anthony Elias, MD, investigator at the University of Colorado Cancer Center and professor of medical oncology at the University of Colorado School of Medicine. Elias points out that about 88 percent of estrogen-positive breast cancers, 50 percent of HER2+ breast cancers and 25 percent of triple-negative breast cancers are androgen-positive (75 percent of all breast cancers), making androgen receptors a possible first target for many cancers, or a likely second target for cancers that resist other therapies. “Targeting androgen receptors may be especially important for patients whose cancers haven’t responded to existing treatments that target estrogen or progesterone,” Elias says. The Medivation drug enzalutamide blocks the proliferative power of androgen receptors in breast cancer. In breast cancers that were both ER+ and AR+, the effect of enzalutamide against androgen was similar to the effect of the proven drug tamoxifen against estrogen. “This is a possible, new first-line target for breast cancer care,” Elias says. ### Contact: Erika Matich |
| Researchers discover new combination of 2 previously approved FDA drugs to treat lung cancer Posted: 31 May 2012 09:00 PM PDT A team of researchers led by Dr. Goutham Narla at Case Western Reserve University School of Medicine in collaboration with scientists at Mount Sinai School of Medicine in New York, have discovered a previously unrecognized signaling network disrupted in lung cancer that can be turned back on by a novel combination of two previously approved FDA drugs. The drug combination targets a pathway to treat advanced/late stage lung cancer. The work highlights how understanding the basic mechanisms regulating cancer development and progression can lead to new uses for existing FDA approved drugs in the treatment of cancer.
“Because of the financial constraints and length of time it takes to bring new drugs through clinical trials, scientists are moving toward using existing drugs in new ways so that the process of translating the discoveries of today into the treatments of tomorrow can be accelerated,” said Goutham Narla, MD, PhD, assistant professor, Department of Medicine, Institute of Transformative Molecular Medicine, Case Western Reserve University School of Medicine. Dr. Narla is also a medical geneticist at University Hospitals Case Medical Center. “This ‘movement’ in science toward using existing FDA approved drugs for new purposes in the treatment of cancer has expanded our understanding of the pathways that cause the disease and significantly accelerates our ability to treat a greater number of patients. In many instances, every month makes a difference for a patient when dealing with terminal cancer,” said Dr. Narla. Dr. Narla’s laboratory focuses on the identification and characterization of the genes and pathways involved in cancer metastasis. By studying the functional role of the KLF6 tumor suppressor gene, Dr. Narla and his team have identified new signaling pathways regulated by this gene family thus providing new insight into cancer diagnosis and treatment. The team’s research found that KLF6 and FOXO1, both tumor suppressor genes, are turned off as cancer spreads through the body. By using a combination of two existing FDA drugs – Erlotinib, a targeted cancer drug, and Trifluoperazine, a medication used to treat schizophrenia – the team developed an understanding of the properties that turn these critical genes back on, initiating tumor cells to die. Since first discovering the KLF6 gene 13 years ago as a medical student at the Mount Sinai School of Medicine in the laboratory of Dr. Scott Friedman, Dr. Narla has been involved in the identification and characterization of the KLF6 gene and its role in cancer development and the progression of cancer. ### This study appears online in the Journal of Clinical Investigation. Additional support for Dr. Narla’s research comes from the Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Case Western Reserve University Institute for Transformative Molecular Medicine, and the Mount Sinai School of Medicine. Dr. Narla is also supported by an early physician scientist career award from the Howard Hughes Medical Institute (HHMI). Recently, Dr. Narla has also been named the first Harrington Distinguished Scholar. This inaugural award provides physician-scientists who have potential breakthroughs with the ability to tap into grant funding, as well as a peer network of innovators and mentors within the University Hospitals Harrington Discovery Institute’s infrastructure to support their discovery efforts Dr. Narla is the principal investigator leading a multidisciplinary team with investigators at both the Mount Sinai School of Medicine and the Case Western Reserve University School of Medicine that includes Jaya Sangodkar, Neil S. Dhawan, Heather Melville, Varan J. Singh, Eric Yuan, Huma Rana, Sudeh Izadmehr, Caroline Farrington, Sahar Mahzar, Suzanna Katz, Tara Albano, Pearlann Arnovitz, Rachael Okrent, Michael Ohlmeyer, David Burstein, David Zhang, Katerina Politi and Analisa DiFeo.
About Case Western Reserve University School of Medicine
Founded in 1843, Case Western Reserve University School of Medicine is the largest medical research institution in Ohio and is among the nation’s top medical schools for research funding from the National Institutes of Health. The School of Medicine is recognized throughout the international medical community for outstanding achievements in teaching. The School’s innovative and pioneering Western Reserve2 curriculum interweaves four themes–research and scholarship, clinical mastery, leadership, and civic professionalism–to prepare students for the practice of evidence-based medicine in the rapidly changing health care environment of the 21st century. Nine Nobel Laureates have been affiliated with the school of medicine. Annually, the School of Medicine trains more than 800 MD and MD/PhD students and ranks in the top 25 among U.S. research-oriented medical schools as designated by U.S. News & World Report “Guide to Graduate Education.” The School of Medicine’s primary affiliate is University Hospitals Case Medical Center and is additionally affiliated with MetroHealth Medical Center, the Louis Stokes Cleveland Department of Veterans Affairs Medical Center, and the Cleveland Clinic, with which it established the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in 2002. http://casemed.case.edu.
About Case Comprehensive Cancer Center
Case Comprehensive Cancer Center is an NCI-designated Comprehensive Cancer Center located at Case Western Reserve University. The center, now in its 22nd year of funding, integrates the cancer research activities of the largest biomedical research and health care institutions in Ohio – Case Western Reserve, University Hospitals (UH) Case Medical Center, Cleveland Clinic and MetroHealth Medical Center. NCI-designated cancer centers are characterized by scientific excellence and the capability to integrate a diversity of research approaches to focus on the problem of cancer. It is led by Stanton Gerson, MD, Asa and Patricia Shiverick- Jane Shiverick (Tripp) Professor of Hematological Oncology, director of the National Center for Regenerative Medicine, Case Western Reserve, and director of the Seidman Cancer Center at UH Case Medical Center. Contact: Christine Somosi |
| Potential new approach to regenerating skeletal muscle tissue Posted: 31 May 2012 09:00 PM PDT An innovative strategy for regenerating skeletal muscle tissue using cells derived from the amniotic fluid is outlined in new research published by scientists at the UCL Institute of Child Health. The paper shows that damaged muscle tissues can be treated with cells derived from the fluids which surround the fetus during development, leading to satisfactory regeneration and muscle activity. The treatment resulted in longer survival in mice affected by a muscle variant of spinal muscular atrophy. This is the first time that regeneration of diseased muscle tissue has been obtained using cells derived from amniotic fluid.
The research appears in the journal Stem Cells, is authored by Dr Paolo de Coppi (UCL Institute of Child Health and surgeon at Great Ormond Street Hospital) and colleagues in Paris and Padova, and represents an impressive development in the growing field of regenerative medicine. Muscle derived stem cells are presently considered the best source for muscle regeneration. However they cannot be used to treat muscular dystrophies because the stem cells themselves are affected in individuals with these conditions. Due to this challenge, other cell sources have been explored but so far no definitive treatment has been successful. De Coppi’s team has demonstrated that intravenous transplantation of amniotic fluid stem (AFS) cells enhances the muscle strength and improves the survival rate of the affected animals. This is the first study to demonstrate the functional and stable integration of AFS cells into skeletal muscle, highlighting their value as a cell source for the treatment of muscular dystrophies. However, the research is still at a relatively early stage as the work has only been carried out in animal models. Dr Coppi said: “Spinal muscular atrophy is a genetic disease affecting one in 6,000 births. It is currently incurable and in its most severe form children with the condition may not survive long into childhood. Children with a less severe form face the prospect of progressive muscle wasting, loss of mobility and motor function. There is an urgent need for improved treatments. “We are excited by this potential new approach for regenerating skeletal muscle tissue, but much more research is needed. We now need to perform more in-depth studies with human AFS cells in mouse models to see if it is viable to use cells derived from the amniotic fluid to treat diseases affecting skeletal muscle tissue.” ### The study, published in Stem Cells, was funded by Great Ormond Street Hospital Children’s Charity; Hopital Neker, Paris; and Cariparo and Città della Speranza in Italy. For more information about the work carried out in the UCL Centre for Stem Cells and Regenerative Medicine, visit: www.ucl.ac.uk/stemcells The article accepted for publication online can be downloaded from: http://onlinelibrary.wiley.com/doi/10.1002/stem.1134/abstract Contact: David Weston |
| New therapy on the horizon for ALK+ non-small cell lung cancer Posted: 31 May 2012 09:00 PM PDT A new compound that targets anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer is well-tolerated by patients and is already showing early signs of activity, including in patients who no longer respond to crizotinib—the only approved ALK inhibitor. Results of this Novartis-sponsored sudy will be presented by a researcher from Fox Chase Cancer Center during the 2012 Annual Meeting of the American Society of Clinical Oncology on Sunday, June 3.
The compound LDK378, developed by Novartis, targets ALK—a key cancer gene in a subset of lung cancer, lymphoma and the childhood cancer neuroblastoma, and may be associated with other cancers, including breast and colorectal cancer. The study’s authors looked at patients with ALK+ lung cancer, as well as other ALK+ solid tumors. Early data from the phase I study show that the majority of patients treated with active doses of LDK378 responded, including those who had progressed after treatment with crizotinib. “These results are encouraging,” says study author Ranee Mehra, M.D., assistant professor and medical oncologist at Fox Chase. “They offer hope to patients who have tumors with alterations involving ALK, even if they have relapsed from previous treatments. In its first test in people, designed to determine the compound’s safety and optimal dose, 56 people with various types of ALK+ solid tumors (primarily lung cancer) were enrolled, receiving doses between 50 to 750 milligrams per day (mg/day). LDK378 was well-tolerated in most patients up to 750 mg/d, with the most common side effects being nausea, vomiting, and diarrhea. “Whenever you do a trial with a drug, even if it’s just designed to look for safety and dosage, you are interested in whether patients responded,” says Mehra. “These results are definitely encouraging, and mean we can go forward with additional research looking at whether LDK378 is effective in various types of cancers that have alterations involving ALK.” The fact that patients appeared to tolerate LDK378 at doses up to 750 mg/d is also encouraging, she adds, since preclinical research has suggested this dose would have therapeutic effects. In the meantime, Mehra and investigators at other centers around the world are continuing to enroll patients in the trial. The next phase of the study will test the maximum tolerated dose of LDK378 in all patients enrolled. ### This study was sponsored and funded by Novartis. Mehra’s co-authors include: Mehra’s co-authors include: [D. Ross Camidge (University of Colorado, Denver, CO), Sunil Sharma (Huntsman Cancer Center, Salt Lake City, UT), Enriqueta Felip (Vall d’Hebron University Hospital, Barcelona, Spain), Daniel Shao-Weng Tan (National Cancer Centre, Singapore, Singapore), Johan F. Vansteenkiste (University Hospital Gasthuisberg, Leuven, Belgium), Tommaso Martino De Pas (European Institute of Oncology, Milan, Italy), Dong-Wan Kim (Seoul National University Hospital, Seoul, South Korea), Armando Santoro (Humanitas Cancer Center, Rozzano, Italy), Geoffrey Liu (Princess Margaret Hospital, Toronto, ON), Meredith Goldwasser (Novartis Institutes for BioMedical Research, Cambridge, MA), David Dai (Novartis Pharmaceuticals, East Hanover, NJ), Marietta Radona (Novartis Pharmaceuticals, East Hanover, NJ), Anthony Boral (Novartis Institutes for BioMedical Research, Cambridge, MA), Alice Tsang Shaw (Massachusetts General Hospital Cancer Center, Boston, MA). Fox Chase Cancer Center is one of the leading cancer research and treatment centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet status for excellence three consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship, and community outreach. For more information, visit Fox Chase’s Web site at www.foxchase.org or call 1-888-FOX CHASE or (1-888-369-2427). Contact: Diana Quattrone |
| ‘Intelligent medicine’ erases side effects Posted: 30 May 2012 09:00 PM PDT Scientists at Aarhus University, Denmark in collaboration with the biotech company Cytoguide now publish a key to use glucocorticoid steroids in a kind of intelligent medicine that specifically hits the relevant cells. Data are based on rodent studies but if this principle is translated to humans it may greatly improve todays hazardous treatment with this type of potent steroids.
This is the main perspective in the research now published in the recognized research journal Molecular Therapy in the Nature Publishing group.
50-fold higher potency
Synthetic glucocorticoid steroid are used in many acute and chronic inflammatory diseases including many autoimmune diseases such as rheumatoid arthritis. This is the most potent anti-inflammatory medicine, but its use is hampered by serious side effects such as osteoporosis, loss in muscle mass, diabetes and immunosuppression. The new data from the scientists now show that they can target the drugs directly to he ‘macrophage’ immune cells. These cells play a main role in inflammation and their damaging effect on the surrounding tissues is strongly dampened by the glucocorticoid steroids. The new technology is based on the coupling of the steroids to an antibody that specifically binds to a receptor exclusively expressed on the surface of macrophages. The receptors normally take up haemoglobin but they are also able to engulf drug-conjugates binding to the receptors. In the cells, the active steroid is released and it can now execute it effect (gene regulation). In this way the drug only works in the relevant cells and much less is needed to obtain full efficacy.
Perspectives in many diseases
‘Our project may initially have relevance for inflammation disease and our focus is now on the liver inflammation that affects many persons with fatty liver due to obesity or alcohol abuses’ Soren K. Moestrup from Aarhus University says. ‘But this technology may also be applied on completely different types of diseases such as cancer’ he continues. If the scientists get financing and collaboration with the large pharma industry in place they expect to have the first conjugate medicine on the market in about 6 years. ### Read the abstract of the paper: “Targeting the hemoglobin scavenger receptor CD163 in macrophages highly increases the anti-inflammatory potency of dexamethasone”.
Contact: Soeren Kragh Moestrup |
| Researchers determine structure of ‘batteries’ of the biological clock Posted: 30 May 2012 09:00 PM PDT Howard Hughes Medical Institute scientists have determined the three-dimensional structure of two proteins that help keep the body’s clocks in sync. The proteins, CLOCK and BMAL1, bind to each other to regulate the activity of thousands of genes whose expression fluctuates throughout the course of a day. Knowing the structure of the CLOCK:BMAL1 complex will help researchers understand the intricacies of how this regulation is carried out and how mutations in each protein lead the biological clock to go awry.
Every 24 hours, millions of ‘clocks’ inside of our cells reset, helping to tune sleep patterns, blood pressure, and metabolism. When CLOCK and BMAL1 bind to one another inside cells, they initiate the first genetic events that coordinate this 24-hour cycle. “CLOCK and BMAL1 are really the batteries of the biological clock,” says HHMI investigator Joseph S. Takahashi of the University of Texas Southwestern Medical Center, whose findings on the CLOCK:BMAL1 structure are published in the May 31, 2012, online version of the journal Science. “They are the key activators of the whole genomic regulation system.” The Clock gene was the first mammalian gene found to contribute to the body’s circadian rhythms. Takahashi’s team published the initial data on the Clock gene in a series of papers spanning 1994 to 1997. Since then, they’ve uncovered hundreds to thousands of genes under the control of CLOCK that fluctuate in sync with the biological clock in mammals. “What’s amazing is that we’ve now found out that almost every cell in your body has a clock,” says Takahashi. “Over the past five years, the role of those clocks in peripheral tissues has really come to the forefront.” Researchers studying circadian rhythms have used biochemistry and genetics to piece together rough outlines of how each circadian protein interacts with CLOCK. But until now, they’d never been able to visualize the detailed molecular structure of the CLOCK protein. Seeing such a structure would allow them to visualize how different proteins can bind to CLOCK at the same time, or compete for binding spots, and how mutations known to alter circadian rhythms affect this binding. Takahashi notes that CLOCK and BMAL1 are part of a large family of proteins, known as bHLH-PAS proteins (a name that refers to both to the shape of the protein and some better known members of the family), involved in functions ranging from responding to environmental contaminants and low-oxygen levels to the creation of new nerve cells. “It’s not just CLOCK for which we didn’t have a structure,” says Takahashi. “This class of protein had never been solved at the crystallographic level before.” Takahashi explained that researchers had struggled to generate circadian proteins in the crystalline form necessary to determine structure using x-ray crystallography, but by experimenting with different conditions, his team was able to purify CLOCK bound to BMAL1. Rather than use the full-length version of each protein, they created a version consisting of only the pieces known to interact with each other. Having shorter proteins made the process easier. The scientists discovered that CLOCK and BMAL1, when together, are closely intertwined. CLOCK has a groove in the center of its interface that’s key to binding. A single amino acid of BMAL1 fits perfectly into the groove. Other proteins that bind to CLOCK likely take advantage of the same spot. Future research will look into the exact positions in which other circadian rhythm proteins bind to the complex, and how mutations to each protein affect the structure. “Since these are truncated versions of the proteins, what we’d really like to do is to go on to get full-length structures,” says Takahashi. They also want to understand how the Cryptochrome and Period proteins that turn off the activity of CLOCK bind to the CLOCK:BMAL1 complex. But that will take time. ### Contact: Jim Keeley |
| Fatty acid found in fish prevents age-related vision loss: U of A medical research Posted: 29 May 2012 09:00 PM PDT An omega-3 fatty acid found in fish, known as DHA, prevented age-related vision loss in lab tests, demonstrates recently published medical research from the University of Alberta. Faculty of Medicine & Dentistry researcher Yves Sauve and his team discovered lab models fed DHA did not accumulate a toxic molecule at the back of the eyes. The toxin normally builds up in the retina with age and causes vision loss.
“This discovery could result in a very broad therapeutic use,” says Sauve, whose work was recently published in the peer-reviewed journal Investigative Ophthalmology & Visual Science. “In normal aging, this toxin increases two-fold as we age. But in lab tests, there was no increase in this toxin whatsoever. This has never been demonstrated before – that supplementing the diet with DHA could make this kind of difference.” The team recently started another study, looking at people who have age-related macular degeneration (AMD), a condition that results in the loss of central vision and is the main cause of blindness in those over the age of 50. The researchers will look for DNA markers in the blood of study participants. The team wants to determine if participants with certain genetic markers will respond better to increasing amounts of DHA in their diet and if so, why. ### Sauve is a researcher in both the Department of Ophthalmology and the Department of Physiology in the Faculty of Medicine & Dentistry at the U of A. Various organizations funded the research, but the primary funder was the Canadian Institutes of Health Research (CIHR). Contact: Raquel Maurier |
| Researchers say tart cherries have ‘the highest anti-inflammatory content of any food’ Posted: 29 May 2012 09:00 PM PDT Tart cherries may help reduce chronic inflammation, especially for the millions of Americans suffering from debilitating joint pain and arthritis, according to new research from Oregon Health & Science University presented today at the American College of Sports Medicine Conference (ACSM) in San Francisco, Calif.1 In fact, the researchers suggest tart cherries have the “highest anti-inflammatory content of any food” and can help people with osteoarthritis manage their disease.
In a study of twenty women ages 40 to 70 with inflammatory osteoarthritis, the researchers found that drinking tart cherry juice twice daily for three weeks led to significant reductions in important inflammation markers – especially for women who had the highest inflammation levels at the start of the study. “With millions of Americans looking for ways to naturally manage pain, it’s promising that tart cherries can help, without the possible side effects often associated with arthritis medications,” said Kerry Kuehl, M.D, Dr.PH., M.S., Oregon Health & Science University, principal study investigator. “I’m intrigued by the potential for a real food to offer such a powerful anti-inflammatory benefit – especially for active adults.” Often characterized as “wear and tear” arthritis, osteoarthritis is the most common type of arthritis. Athletes are often at a greater risk for developing the condition, given their excessive joint use that can cause a breakdown in cartilage and lead to pain and injury, according to the Arthritis Foundation. The inflammation benefits could be particularly important for athletes, according to Kuehl’s previous research. In a past study he found that people who drank tart cherry juice while training for a long distance run reported significantly less pain after exercise than those who didn’t.2
Go Red Instead to Manage Pain
Along with providing the fruit’s bright red color, the antioxidant compounds in tart cherries – called anthocyanins – have been specifically linked to high antioxidant capacity and reduced inflammation, at levels comparable to some well-known pain medications.3 Previous research on tart cherries and osteoarthritis conducted by researchers at Baylor Research Institute found that a daily dose of tart cherries (as cherry extract) helped reduce osteoarthritis pain by more than 20 percent for the majority of men and women.4 And the same compounds linked to cherries’ arthritis benefits have now shown promise for athletes and sports recovery to help relieve muscle and joint soreness. According to Director of Sports Nutrition at the University of Pennsylvania Medical Center for Sports Medicine, Leslie Bonci, MPH, RD, CSSD, LDN, who has incorporated tart cherries into the training menu of both her professional athletes and active clients as a natural and easy way to manage pain that also tastes great, “Why not eat red when there’s so much science to support the anti-inflammatory benefits of this Super Fruit? And for athletes whose palates prefer the tart-sweet flavor profile of tart cherries, it’s the optimal ingredient.” Available every day of the year in dried, frozen and juice forms, tart cherries are a versatile ingredient to include in any training or inflammation-fighting diet. ### To learn more about the body of research supporting tart cherries’ pain-fighting properties, visit www.choosecherries.com to download The Red Report. There, you can also reference The Red Recovery Routine, a guide to help people train to manage pain with tart cherries. The Cherry Marketing Institute (CMI) is an organization funded by North American tart cherry growers and processors. CMI’s mission is to increase the demand for tart cherries through promotion, market expansion, product development and research. For more information on the science supporting the unique health benefits of cherries and for cherry recipes and menu ideas, visit www.choosecherries.com. Sources: 1. Sleigh, AE, Kuehl KS, Elliot DL . Efficacy of tart cherry juice to reduce inflammation among patients with osteoarthritis. American College of Sports Medicine Annual Meeting. May 30, 2012. 2. Kuehl KS, Perrier ET, Elliot DL, Chestnutt J. Efficacy of tart cherry juice in reducing muscle pain during running: a randomized controlled trial. J Int Soc Sports Nutr 2010;7:17-22. 3. Seeram NP, Momin RA, Nair MG, Bourquin LD. Cyclooxygenase inhibitory and antioxidant cyanidin glycosides in cherries and berries. Phytomedicine 2001;8:362-369. 4. Cush JJ. Baylor Research Institute, pilot study on tart cherry and osteoarthritis of the knees, 2007. Contact: Brian Packer |
| ‘Simple and effective’ injection could offer hope for treatment of autoimmune disease Posted: 29 May 2012 09:00 PM PDT Australian researchers have uncovered a potential new way to regulate the body’s natural immune response, offering hope of a simple and effective new treatment for auto-immune diseases. Auto-immune diseases result from an overactive immune response that causes the body to attack itself.
The new approach involves increasing good regulating cells in the body, unlike most current research which focuses on stopping “bad” or “effector” cells, says lead researcher Dr Suzanne Hodgkinson, from UNSW’s Faculty of Medicine and Liverpool Hospital. The researchers induced the body’s T-cell front-line defences by injecting cell-signalling proteins called cytokines, in particular cytokine Interleukin-5 (II-5 cytokine). When T-regulatory cells are grown in a way to make them specific to a particular protein they develop receptors for the Il-5 cytokine. The Il-5 cytokine boost allows the body’s immune system to better regulate its response to disease without going into overdrive. The team cloned II-5 cytokine and injected it into rats with the neurological condition Guillain–Barré syndrome. These rats recovered much quicker and, if treated as a precaution, did not fall ill. The method has also shown promise in animals with multiple sclerosis, with kidney disease nephritis and trying to overcome organ transplantation rejection. “One of the nice things about this discovery is that it is one of the few treatments in the auto-immune world and in the transplantation world that works not by attacking the effector cells, but by increasing the good regulating cells. So it works in a very different way from almost every other treatment we’ve got available,” Dr Hodgkinson says. Il-5 injections could be more palatable than inoculation by parasitic worms – another approach in regulating auto-immune conditions, the researchers say. International research shows swallowing helminths parasites can regulate the immune system and boost T-cell production to combat illnesses such as celiac disease and multiple sclerosis. The absence of the worms in guts in the developed world has been cited as a possible cause for the sharp rise in auto-immune diseases in Western nations. “The process we’ve developed may be the same process that the helminths kick off. When you get a helminths infestation, one of the changes in your immune response is an increase in cells called eosinophils and these cells make the cytokine Interleukin-5,” Dr Hodgkinson says. “In this new treatment, it’s a matter of injecting the interleukin-5 and the body does the rest. It’s both safe and effective and we think inducing the immune response by injection may be more attractive to people than swallowing parasitic worms.” The next step is to take the treatment to human trials, which could be underway within two to five years, says Dr Hodgkinson, whose paper outlining the study has been published in the journal Blood. ### The research was supported by grants from Bob and Jack Ingham, Liverpool Australia; Multiple Sclerosis Research Australia; the Australian National Health and Medical Research Council; the Juvenile Diabetes Research Foundation; Novatis; and funds from UNSW. Lead researcher was UNSW research fellow Dr Giang Tran. Dr Hodgkinson and co-author Professor Bruce Hall hold US patents related to the treatment. Contact: Dr. Suzanne Hodgkinson |
| Understanding the links between inflammation and chronic disease Posted: 29 May 2012 09:00 PM PDT American parents may want to think again about how much they want to protect their children from everyday germs. A new Northwestern University study done in lowland Ecuador remarkably finds no evidence of chronic low-grade inflammation — associated with diseases of aging like cardiovascular disease, diabetes and dementia.
In contrast, about one-third of adults in the United States have chronically elevated C-reactive protein (CRP). Acute elevations in CRP — a protein in the blood whose levels rise as part of the inflammatory response — are important for protecting us against infectious disease. But when CRP is chronically produced, it is associated with chronic diseases. “In other words, CRP goes up when you need it, but it is almost undetectable when you don’t, after the infection resolves,” said Thomas W. McDade, professor of anthropology at Northwestern and faculty fellow at the university’s Institute for Policy Research. “This is a pretty remarkable finding, and very different from prior research in the U.S., where lots of people tend to have chronically elevated CRP, probably putting them at higher risk for chronic disease.” McDade said the findings build on his previous research in the Philippines, which found that higher levels of microbial exposure in infancy were associated with lower CRP as an adult. Similar exposures during infancy in lowland Ecuador, where rates of infectious disease continue to be high, may have a lasting effect on the pattern of inflammation in adulthood. “In my mind the study underscores the value of an ecological approach to research on the immune system, and it may have significant implications for our understanding of the links between inflammation and chronic disease,” McDade said. “This may be particularly important since nearly three-quarters of all deaths due to cardiovascular disease globally now occur in low- and middle-income nations like the Philippines and Ecuador.” The new research, which was conducted as part of the Shuar Health and Life History Project (http://www.bonesandbehavior.org/shuar/), suggests that higher levels of exposure to infectious microbes early in life may change how we regulate inflammation as adults in ways that prevent chronic inflammation from emerging. Infectious microbes have been part of the human ecology for millennia, and it is only recently that more hygienic environments in affluent industrialized settings have substantially reduced the level and diversity of exposure. A growing body of research has shown that higher levels of chronic inflammation are associated with diseases of aging like cardiovascular disease, diabetes and dementia. But current research is based almost exclusively on people living in affluent industrialized countries like the United States. “We simply do not know what chronic inflammation looks like in places like the Ecuadorian Amazon and other parts of the world where infectious diseases are more common,” McDade said. As a result, McDade, director of the Lab for Human Biology Research and director of Cells to Society (C2S): The Center on Social Disparities and Health, and collaborators at the University of Oregon set out to investigate what factors in the environment and during development influence how people regulate inflammation as adults. The study was conducted in lowland Ecuador – in a group of 52 adults between the ages of 18 and 49. Based on current clinical criteria, McDade and colleagues did not find a single case of chronic low-grade inflammation among adults living in the Ecuadorian Amazon. McDade said people in these places are still dying of diseases such as cardiovascular disease, but probably not through processes that involve inflammation. In terms of population health, McDade said these findings suggest that the association between inflammation and cardiovascular disease frequently reported in the United States may only apply in ecological settings characterized by low levels of exposure to infectious disease. “It builds on research on chronic inflammation and cardiovascular disease in the U.S. and other affluent, industrialized settings and suggests that patterns seen here may not apply globally,” McDade said. “It also suggests that the levels of chronic inflammation we see in the U.S. are not universal, and may be a product of epidemiological transitions that have lowered our level of exposure to infectious microbes.” ### “Analysis of Variability of High Sensitivity C-Reactive Protein in Lowland Ecuador Reveals No Evidence of Chronic Low-Grade Inflammation” is currently available online in the Early View section of the American Journal of Human Biology (http://onlinelibrary.wiley.com/journal/10.1002/%28ISSN%291520-6300/earlyview). The study’s co-authors are Paula S. Tallman, Department of Anthropology, Northwestern University; and Felicia C. Madimenos, Melissa A. Liebert, Tara J. Cepon, Lawrence S. Sugiyama and J. Josh Snodgrass, all with the Department of Anthropology at the University of Oregon and its Institute of Cognitive and Decision Sciences. Sugiyama is also affiliated with the Center for Evolutionary Psychology, University of California, Santa Barbara. Contact: Hilary Hurd Anyaso |
| Commonly used painkillers may protect against skin cancer Posted: 28 May 2012 09:00 PM PDT A new study suggests that aspirin and other similar painkillers may help protect against skin cancer. Published early online in CANCER, a peer-reviewed journal of the American Cancer Society, the findings indicate that skin cancer prevention may be added to the benefits of these commonly used medications.
Previous studies suggest that taking nonsteroidal anti-inflammatory drugs, or NSAIDs, which include aspirin, ibuprofen, and naproxen, as well as a variety of other nonprescription and prescription drugs, can decrease an individual’s risk of developing some types of cancer. Sigrún Alba Jóhannesdóttir, BSc, of Aarhus University Hospital in Denmark, and her colleagues looked to see if the medications might decrease the risk of the three major types of skin cancer: basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. The researchers analyzed medical records from northern Denmark from 1991 through 2009 and identified 1,974 diagnoses of squamous cell carcinoma, 13,316 diagnoses of basal cell carcinoma, and 3,242 diagnoses of malignant melanoma. They compared information, including prescription data, from these patients with information from 178,655 individuals without skin cancer. Individuals who filled more than two prescriptions for NSAIDs had a 15 percent decreased risk for developing squamous cell carcinoma and a 13 percent decreased risk for developing malignant melanoma than those who filled two or fewer prescriptions for the medications, especially when the drugs were taken for seven or more years or taken at high intensity. Individuals who took NSAIDs did not seem to benefit from a reduced risk of developing basal cell carcinoma in general, although they did have a 15 percent and 21 percent reduced risk of developing this type of cancer on less-exposed sites (body areas other than the head and neck) when they took them long term or at high intensity, respectively. “We hope that the potential cancer-protective effect of NSAIDs will inspire more research on skin cancer prevention,” said Ms. Jóhannesdóttir. “Also, this potential cancer-protective effect should be taken into account when discussing benefits and harms of NSAID use.” ### Contact: Amy Molnar |
| Researchers restore neuron function to brains damaged by Huntington’s disease Posted: 28 May 2012 09:00 PM PDT Researchers from South Korea, Sweden, and the United States have collaborated on a project to restore neuron function to parts of the brain damaged by Huntington’s disease (HD) by successfully transplanting HD-induced pluripotent stem cells into animal models.
Induced pluripotent stem cells (iPSCs) can be genetically engineered from human somatic cells such as skin, and can be used to model numerous human diseases. They may also serve as sources of transplantable cells that can be used in novel cell therapies. In the latter case, the patient provides a sample of his or her own skin to the laboratory. In the current study, experimental animals with damage to a deep brain structure called the striatum (an experimental model of HD) exhibited significant behavioral recovery after receiving transplanted iPS cells. The researchers hope that this approach eventually could be tested in patients for the treatment of HD. “The unique features of the iPSC approach means that the transplanted cells will be genetically identical to the patient and therefore no medications that dampen the immune system to prevent graft rejection will be needed,” said Jihwan Song, D.Phil. Associate Professor and Director of Laboratory of Developmental & Stem Cell Biology at CHA Stem Cell Institute, CHA University, Seoul, South Korea and co-author of the study. The study, published online this week in Stem Cells, found that transplanted iPSCs initially formed neurons producing GABA, the chief inhibitory neurotransmitter in the mammalian central nervous system, which plays a critical role in regulating neuronal excitability and acts at inhibitory synapses in the brain. GABAergic neurons, located in the striatum, are the cell type most susceptible to degeneration in HD. Another key point in the study involves the new disease models for HD presented by this method, allowing researchers to study the underlying disease process in detail. Being able to control disease development from such an early stage, using iPS cells, may provide important clues about the very start of disease development in HD. An animal model that closely imitates the real conditions of HD also opens up new and improved opportunities for drug screening. “Having created a model that mimics HD progression from the initial stages of the disease provides us with a unique experimental platform to study Huntington’s disease pathology” said Patrik Brundin, M.D., Ph.D., Director of the Center for Neurodegenerative Science at Van Andel Research Institute (VARI), Head of the Neuronal Survival Unit at Lund University, Sweden, and co-author of the study. Huntington’s disease (HD) is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and psychiatric problems. It typically becomes noticeable in mid-adult life, with symptoms beginning between 35 and 44 years of age. Life expectancy following onset of visual symptoms is about 20 years. The worldwide prevalence of HD is 5-10 cases per 100,000 persons. Key to the disease process is the formation of specific protein aggregates (essentially abnormal clumps) inside some neurons. ### Link to the study abstract: “Neuronal Properties, In Vivo Effects and Pathology of a Huntington’s Disease Patient-Derived Induced Pluripotent Stem Cells”
CHA Stem Cell Institute
Founded by Dr Kwang Yul Cha in 2000, CHA Stem Cell Institute in CHA University is dedicated to understanding of basic mechanisms underlying pluripotency, cell fate control and differentiation of stem cells, as well as translational research for clinical application of basic study to treat currently incurable diseases, including Huntington’s disease, myocardial infarct, and diabetes. Our aim is to provide scientific and clinical evidence for therapeutic application of stem cells. http://en.cha.ac.kr
Neuronal Survival Unit
The research at Neuronal Survival Unit, Lund University, Sweden is focused on pathogenetic mechanisms and pharmacological treatment in cell and animal models of Parkinson’s and Alzheimer’s diseases. We also study cell replacement therapy with stem cells in attempts to repair brains in animal models of Parkinson’s diseases. The group’s mission is to understand neurodegenerative diseases and develop new therapies that are of benefit to patients and their caregivers. http://www.med.lu.se/expmed/neuronal_survival_unit
Van Andel Institute
Established by Jay and Betty Van Andel in 1996, Van Andel Institute is an independent research organization dedicated to preserving, enhancing and expanding the frontiers of medical science, and to achieving excellence in education by probing fundamental issues of education and the learning process. This is accomplished through the work of over 200 researchers in more than 20 on-site laboratories and in collaborative partnerships that span the globe. www.vai.org Contact: Tim Hawkins |
| Study reveals how the world’s first drug for amyloid disease works Posted: 28 May 2012 09:00 PM PDT Scientists from The Scripps Research Institute and Pfizer Inc. have published a new study showing how a new drug called tafamidis (Vyndaqel®) works. Tafamidis, approved for use in Europe and currently under review by the US Food and Drug Administration (FDA), is the first medication approved by a major regulatory agency to treat an amyloid disease, a class of conditions that include Alzheimer’s.
Tafamidis treats a deadly nerve disease caused by transthyretin (TTR) amyloid fibril formation, or the accumulation of abnormal assemblies of the TTR protein. The drug inhibits TTR aggregation, and clinical trials have shown that it delays the typical progression of nerve destruction in polyneuropathy patients. “The details in this new paper, combined with clinical trial data, show for the first time that an amyloid disease can be successfully treated by reducing the rate of amyloid formation,” said Jeffery W. Kelly, chair of the Department of Molecular and Experimental Medicine, the Lita Annenberg Hazen Professor of Chemistry, and member of the Skaggs Institute for Chemical Biology at Scripps Research. Kelly is a senior author of the new paper, which appears in an advance, online Early Edition issue of Proceedings of the National Academy of Sciences on May 29, 2012.
An Array of Progressive Symptoms
While the naturally occurring or “wild type” transthyretin protein is prone to aggregate in older people causing cardiac disease, a variety of destabilizing mutations lead either to a primary cardiomyopathy or to early onset forms of polyneuropathy, known as TTR familial amyloid polyneuropathy, affecting about 10,000 people worldwide. Familial amyloid polyneuropathy compromises the peripheral and autonomic nervous systems, with symptoms including sensory deprivation and pain, muscle weakness and wasting, and alternating constipation and diarrhea. In some familial amyloid polyneuropathy patients, cardiomyopathy can present later in the course of the disease. In transthyretin amyloid diseases that present primarily as a cardiomyopathy, doctors have been able to stave off heart failure with a liver and heart transplant; familial amyloid polyneuropathy patients receiving a liver transplant can benefit, since the liver is the primary source of mutant, disease-associated TTR. For the 90 percent of patients surviving transplantation, this surgical form of gene therapy slows familial amyloid polyneuropathy progression, but does not stop it as the wild type transthyretin protein can continue to form amyloid. Left untreated, the TTR amyloidoses are relentlessly progressive and inevitably fatal, with a course of about a decade from initial symptoms to death.
The Search for Treatments
Kelly began searching for TTR-amyloidogenesis-inhibitors in the mid 1990s, and a few years later began to focus on a family of TTR-binding compounds, the so-called benzoxazoles, whose basic design would further be elaborated into tafamidis using a structure-based drug design paradigm. In 2003, Kelly co-founded a Cambridge, Massachusetts-based biotechnology startup, FoldRx Pharmaceuticals (now a fully owned subsidiary of Pfizer), to develop these compounds and optimize one of them into an orally available drug for the treatment of the TTR amyloidoses. The result was tafamidis meglumine, whose preclinical tests remained unpublished until now. Kelly and his colleagues designed tafamidis to bind to the natural, functional TTR structure (mutant and wild type), in a way that prevents it from deviating from this natural, functional form into the amyloid state. TTR’s natural, functional form is a “tetramer” made from four copies of the protein. Amyloidosis occurs when these tetramers come apart and the individual TTR proteins (“monomers”) undergo shape changes enabling them to misassemble into dysfunctional amyloid aggregates. Included in the TTR aggregate distribution are amyloid fibrils—protein stacks made from millions of TTR monomers—although researchers suspect that smaller, shorter-lived pre-amyloid aggregates do more direct damage to nerve cells and nerve fibers. The early onset TTR amyloidoses are caused by inherited TTR mutations that weaken the tetramers’ ability to stick together, producing monomers more likely to aggregate into amyloids and other aggregate structures. Fortunately, the TTR tetramer, which is the backup carrier of the thyroid hormone thyroxine through the bloodstream, has two unoccupied thyroxine-binding sites along its longest and weakest seam. Kelly and his colleagues designed tafamidis to grab either of these thyroxine-binding sites, in a way that bridges the seam and helps keep the tetramer from coming apart.
A Stabilizing Influence
The newly published molecular and structural data show that tafamidis does indeed stabilize TTR tetramers, under normal physiological conditions in the bloodstream and even under abnormal conditions when they would be much more likely to fall apart and reassemble as amyloids. Tafamidis has this stabilizing effect on tetramers of the normal “wild-type” TTR protein as well as on those made from disease-associated mutant and wild type TTR subunits. “There are more than a hundred TTR mutations that cause amyloidosis, but the vast majority of those TTRs are capable of being bound by tafamidis and held in the natural tetramer state,” said Kelly. Throughout the development of tafamidis-type compounds, Kelly and his colleagues collaborated with the Scripps Research laboratory of Ian A. Wilson, who is Hansen Professor of Structural Biology and a member of the Skaggs Institute at Scripps Research. The Wilson laboratory specializes in the use of X-ray crystallography to determine the atomic structures of interacting proteins. Whenever a small molecule stabilizer of TTR was generated that afforded interesting biochemical stabilization, Wilson’s team analyzed its structure. “By the end, we had determined more than 30 small molecule stabilizer–TTR structures, in an effort to generate tafamidis and identify the molecular interactions that lead to stabilization of the natural TTR tetramer,” said Stephen Connelly, a Wilson laboratory staff scientist who performed these structural studies and who was a co-author the paper. The small molecule benzoxazole, tafamidis, that ultimately entered clinical trials was optimized for several criteria, including its ability to stabilize the TTR tetramer’s weakest seam. “We found that one end of the tafamidis structure fits neatly into the tetramer’s hydrophobic thyroxine-binding pocket, while at the other end it binds to nearby polar amino acids, both types of interactions bridging or stabilizing the two halves of the tetramer,” Connelly said. The drug’s stabilizing force greatly reduces the rate at which these tetramers come apart, and in so doing greatly reduces the rate of amyloid formation. Tafamidis is considered an “orphan” drug because its initial intended treatment population is the relatively small polyneuropathy population. However, even wild-type TTR forms amyloid in 10 to 20 percent of the growing elderly population—leading to cardiomyopathy. Thus, this condition, and drugs such as tafamidis that can treat it, could be of growing interest to the pharmaceutical industry. ### In addition to Kelly, Wilson, and Connelly, co-authors of the paper, “Tafamidis, a Potent and Selective Transthyretin Kinetic Stabilizer That Inhibits the Amyloid Cascade,” are Michael DeVit and Jeff Packman of FoldRx Pharmaceuticals; Lan Wang of Novartis Institutes for Medical Research in Cambridge, Mass.; Charlotte Weigel and James Fleming from Pfizer’s Orphan and Genetic Diseases Research Unit in Cambridge, Mass.; Theodore R. Foss of Life Technologies in Beverly, Mass.; and Evan T. Powers and R. Luke Wiseman of Scripps Research. The studies described in the new paper were funded by FoldRx, the National Institutes of Health, and the Skaggs Institute of Chemical Biology at Scripps Research. Contact: Mika Ono |
| New drug strategy attacks resistant leukemia and lymphoma Posted: 28 May 2012 09:00 PM PDT Scientists at the Dana-Farber/Children’s Hospital Cancer Center have developed an anti-cancer peptide that overcomes the stubborn resistance to chemotherapy and radiation often encountered in certain blood cancers when the disease recurs following initial treatment.
The strategy could pave the way for much needed new therapies to treat relapsed and refractory blood cancers, which are difficult to cure because their cells deploy strong protein “deflector shields” to neutralize the cell death signals that chemotherapy agents used against them initially, say the researchers. The prototype compound, called a “stapled BIM BH3 peptide,” is designed to disable the cancer’s defenses by hitting a family of protein targets that regulate cell death. In proof-of-concept studies in mice with transplanted, drug-resistant leukemia tumors, the compound alone suppressed cancer growth, and when paired with other drugs, showed synergistic anti-cancer activity, say researchers led by Loren Walensky, MD, PhD, of Dana-Farber/Children’s Hospital Cancer Center. Their paper has been posted online by the Journal of Clinical Investigation and will appear in the journal’s June issue. Walensky is the senior author and James LaBelle, MD, PhD, is the first author. A cell’s “fate” – when and whether it lives or dies – depends on a tug-of-war between pro-death and anti-death forces within the cell that serve as a check-and-balance system to maintain orderly growth. The system is regulated by the BCL-2 family of proteins, which contains both pro-death and pro-survival members. When cells are no longer needed or are damaged beyond repair, the body activates pro-death BCL-2 proteins to shut down mitochondria – the power plants of the cell– resulting in an orchestrated cellular destruction known as apoptosis, or programmed cell death. Many cell-killing cancer treatments work by triggering these “executioner proteins” to cause tumor cells to commit suicide in this fashion. But cancer cells can escape their death sentence – and even become immortal – by hyperactivating the survival arm of the family; these proteins intercept the executioner proteins and block their lethal mission. “When cancers recur, they activate not just one type of survival protein, but many,” explains Walensky, whose laboratory has extensively studied the cell-death system and makes compounds to manipulate it for research and therapeutic purposes. “It’s as if relapsed cancers ‘learned’ from their initial exposure to chemotherapy such that when they come back, they put up a variety of formidable barriers to apoptosis,” he adds. “To reactivate cell death in refractory hematologic cancers, we need new pharmacologic strategies that broadly target these obstacles and substantially lower the apoptotic threshold.” When cancers specifically rely on one or two survival proteins, treating them with selective BCL-2 inhibitors can be very effective at eliminating the cancer cells’ survival advantage. But relapsed cancers often evade such agents by deploying a battery of alternate survival proteins, so what’s needed, Walensky says, are “next-generation” compounds that can block a wider range of survival proteins without jeopardizing normal tissues. In the current research, the scientists built a chemically-reinforced peptide containing the death-activating BH3 domain of an especially potent killer protein, BIM, which is able to tightly bind with and neutralize all of the BCL-2 family survival proteins. This ‘stapled’ peptide, which incorporates the natural structure and properties of BIM BH3, not only disables the survival proteins, but also directly activates pro-death BCL-2 family proteins in cancer cells, making them self-destruct. Importantly, non-cancerous cells and tissues were relatively unaffected by the treatment. “The diversity of BCL-2 family survival proteins blunts the anti-tumor activity of essentially all cancer treatments to some degree,” Walensky points out. “By using Nature’s solution to broad targeting of the BCL-2 pathway with a stapled BIM BH3 peptide, our goal is to eliminate cancer’s protective force field and enable the arsenal of cancer treatments to do their job.” ### The research was supported in part by grants from the National Institutes of Health (grants 1K08CA151450, 5P01CA92625 and 5R01CA050239) and the Leukemia and Lymphoma Society. In addition to Walensky and LaBelle, the papers other authors are Samuel Katz, MD, PhD, Brigham and Women’s Hospital; Gregory Bird, PhD, Evripidis Gavathiotis, PhD, and Andrew Kung, MD, PhD, Dana-Farber/Children’s Hospital Cancer Center; Michelle Stewart, Chelsea Lawrence, Jill Fisher, Marina Godes, and Kenneth Pitter, Dana-Farber. Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute. It provides adult cancer care with Brigham and Women’s Hospital as Dana-Farber/Brigham and Women’s Cancer Center and it provides pediatric care with Children’s Hospital Boston as Dana-Farber/Children’s Hospital Cancer Center. Dana-Farber is the top ranked cancer center in New England, according to U.S. News & World Report, and one of the largest recipients among independent hospitals of National Cancer Institute and National Institutes of Health grant funding. Follow Dana-Farber on Twitter: @danafarber or Facebook: facebook.com/danafarbercancerinstitute. Contact: Bill Schaller |
| New stem cell technique promises abundance of key heart cells Posted: 27 May 2012 09:00 PM PDT Cardiomyocytes, the workhorse cells that make up the beating heart, can now be made cheaply and abundantly in the laboratory. Writing this week (May 28, 2012) in the Proceedings of the National Academy of Sciences, a team of Wisconsin scientists describes a way to transform human stem cells — both embryonic and induced pluripotent stem cells — into the critical heart muscle cells by simple manipulation of one key developmental pathway. The technique promises a uniform, inexpensive and far more efficient alternative to the complex bath of serum or growth factors now used to nudge blank slate stem cells to become specialized heart cells.
“Our protocol is more efficient and robust,” explains Sean Palecek, the senior author of the new report and a University of Wisconsin-Madison professor of chemical and biological engineering. “We have been able to reliably generate greater than 80 percent cardiomyocytes in the final population while other methods produce about 30 percent cardiomyocytes with high batch-to-batch variability.” The ability to make the key heart cells in abundance and in a precisely defined way is important because it shows the potential to make the production of large, uniform batches of cardiomyocytes routine, according to Palecek. The cells are in great demand for research, and increasingly for the high throughput screens used by the pharmaceutical industry to test drugs and potential drugs for toxic effects. The capacity to make the heart cells using induced pluripotent stem cells, which can come from adult patients with diseased hearts, means scientists will be able to more readily model those diseases in the laboratory. Such cells contain the genetic profile of the patient, and so can be used to recreate the disease in the lab dish for study. Cardiomyocytes are difficult or impossible to obtain directly from the hearts of patients and, when obtained, survive only briefly in the lab. Scientists also have high hopes that one day healthy lab-grown heart cells can be used to replace the cardiomyocytes that die as a result of heart disease, the leading cause of death in the United States. “Many forms of heart disease are due to the loss or death of functioning cardiomyocytes, so strategies to replace heart cells in the diseased heart continue to be of interest,” notes Timothy Kamp, another senior author of the new PNAS report and a professor of cardiology in the UW School of Medicine and Public Health. “For example, in a large heart attack up to 1 billion cardiomyocytes die. The heart has a limited ability to repair itself, so being able to supply large numbers of potentially patient-matched cardiomyocytes could help.” “These cells will have many applications,” says Xiaojun Lian, a UW-Madison graduate student and the lead author of the new study. The beating cells made using the technique he devised have, so far, been maintained in culture in the lab for six months and remain as viable and stable as the day they were created. Lian and his colleagues found that manipulating a major signaling pathway known as Wnt — turning it on and off at prescribed points in time using just two off-the-shelf small molecule chemicals — is enough to efficiently direct stem cell differentiation to cardiomyocytes. “The fact that turning on and then off one master signaling pathway in the cells can orchestrate the complex developmental dance completely is a remarkable finding as there are many other signaling pathways and molecules involved,” says Kamp. “The biggest advantage of our method is that it uses small molecule chemicals to regulate biological signals,” says Palecek. “It is completely defined, and therefore more reproducible. And the small molecules are much less expensive than protein growth factors.” ### Also contributing to the Wisconsin study, which was supported by the National Institutes of Health and the National Science Foundation, were Cheston Hsiao, Gisela Wilson, Kexian Zhu, Laurie Hazeltine, Samira M. Contact: Sean Palecek |
| Antiretroviral treatment for preventing HIV infection: an evidence review for physicians Posted: 27 May 2012 09:00 PM PDT While immediate postexposure treatment for suspected HIV is critical, pre-exposure preventive treatment is a newer method that may be effective for people in high-risk groups, states a review of evidence published in CMAJ (Canadian Medical Association Journal).
“Although postexposure prophylaxis has a long history of success, newer methods such as pre-exposure prophylaxis and earlier treatment in the course of infection (“treatment as prevention”) are being implemented with some success,” writes Dr. Isaac Bogoch, Harvard Medical School and the Division of Infectious Diseases, Massachusetts General Hospital, Boston, with coauthors. Several recent large randomized controlled trials have added to knowledge about pre-exposure prevention and early initiation of antiretroviral therapy. To provide physicians with current pharmacologic prevention methods, researchers from Massachusetts General Hospital, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts and Sunnybrook Health Sciences, Toronto conducted a review of literature from January 1990 to April 2012. HIV is transmitted mainly through unprotected sex, contaminated needles and from mother to baby, although the latter transmission was not part of the review. After assessing with a detailed history whether a person has been exposed to HIV, postexposure treatment (prophylaxis) should begin as soon as possible or within 72 hours and be continued for 28 days. If the patient is in a low-risk situation but not completely without risk, the physician and patient can decide upon the risks of transmission and whether to treat prophylactically. Current practice recommends a two-drug regimen of tenofovir with emtricitabine and a third drug in people with high-risk exposure. “Evidence for quickly starting prophylaxis and a four-week duration of therapy stem from macaque models of transmission, in which starting prophylaxis later and shorter durations of therapy resulted in higher rates of HIV seroconversion [development of antibodies against HIV],” write the authors. For high-risk populations, such as men who have sex with men, intravenous drug users and women in areas with a high prevalence of HIV, pre-exposure prophylaxis has been shown to prevent HIV infection before being exposed to the virus. For example, one recent trial that involved 900 women from a region with high HIV prevalence showed a 39% reduction in HIV infection rates after application of a topical vaginal microbicide 12 hours before and after sex. “All pre-exposure prophylaxis interventions should be considered one part of a more comprehensive plan for preventing the spread of HIV infection, including standard counselling on safer sexual practices and condom use, testing for and treating other sexually transmitted infections and, in select circumstances, male circumcision and needle exchange programs,” state the authors. “Whereas pre-exposure prophylaxis may be reserved for people with the highest risk of exposure, the trend of treating HIV at higher CD4 T cell counts earlier in infection will likely show the most promise as a pharmacologic strategy for preventing transmission of the virus,” the authors conclude. They note that while pre-exposure prophylaxis is promising, there are unanswered questions, such as which groups would benefit most, the possibility of drug resistance and others. Several large-scale trials are underway to determine effectiveness of early treatment. ### Contact: Kim Barnhardt |
| T cells ‘hunt’ parasites like animal predators seek prey, a Penn Vet-Penn Physics study reveals Posted: 26 May 2012 09:00 PM PDT By pairing an intimate knowledge of immune-system function with a deep understanding of statistical physics, a cross-disciplinary team at the University of Pennsylvania has arrived at a surprising finding: T cells use a movement strategy to track down parasites that is similar to strategies that predators such as monkeys, sharks and blue-fin tuna use to hunt their prey.
With this new insight into immune-cell movement patterns, scientists will be able to create more accurate models of immune-system function, which may, in turn, inform novel approaches to combat diseases from cancer to HIV/AIDS to arthritis. The research involved a unique collaboration between the laboratories of senior authors Christopher Hunter, professor and chair of the Pathobiology Department in Penn’s School of Veterinary Medicine, and Andrea Liu, the Hepburn Professor of Physics in the Department of Physics and Astronomy. Penn Vet postdoctoral researcher Tajie Harris and physics graduate student Edward Banigan also played leading roles in the research. The study, which will be published in the journal Nature, was conducted in mice infected with the parasite Toxoplasma gondii. This single-celled pathogen is a common cause of infection in humans and animals; as much as a third of the world’s population has a dormant form of this infection present in the brain. However, in immunocompromised individuals, such as those with HIV/AIDS or undergoing organ transplantation, this infection can have serious consequences, including brain inflammation and even death. Earlier work had shown that T cells — a key immune-cell type — are central in preventing disease caused by T. gondii. In the new study, the Penn researchers used the infected mice as a natural model system to learn how the movement of T cells in the brain affects the body’s ability to control this infection. Among immunologists, it’s widely believed that the movement of immune cells is governed in part by signaling proteins called chemokines. The Penn-led team demonstrated that a specific chemokine, CXCL10, and its receptor were abundantly produced in the brains of T. gondii-infected mice. When CXCL10 was blocked, mice had fewer T cells, a greater parasite burden and actively reproducing parasites. Next the researchers sought to pinpoint the exact movement patterns of individual T cells in living tissue from T. gondii-infected mice. This was possible with multi-photon imaging, a technique that relies on a refined yet powerful microscope that can display living tissues in three dimensions in real time. Using this approach, the team found that CXCL10 appeared to play a role in the speed at which T cells are able to search for and control infection. To the extent that immunologists had considered T-cell movement patterns at all, many assumed that they moved in a highly directed fashion to find infected cells. But when the researchers analyzed the movement of T cells, they found their data did not match what would be expected: the T cells showed no directed motion. That’s where the statistical physics expertise of Liu and Banigan came in. “We looked at a much more complete way to quantify these tracks and found that the standard model didn’t fit at all,” Liu said. “After some work we managed to find a model that did fit the tracks beautifully.” “The model that finally led us down the right path,” Banigan said, “had a strong signature of something really interesting,” a model known as a Lévy walk. This “walk,” or a mathematically characterized path, tends to have many short “steps” and occasional long “runs.” The model was not fully consistent with the data, however. “Rather, I had to look at variations on the Lévy walk model,” Banigan said, because the researchers also observed that the T cells paused between steps and runs. Like the movements of the cells, the pauses were usually short but occasionally long. Hunter likened the model to a strategy a person might employ to find misplaced keys in the house. “When you lose your keys, how do you go about looking for them? You look in one place for a while, then move to another place and look there,” he said. “What that leads to is a much more efficient way of finding things,” Liu said. And, indeed, when the team modeled the generalized Lévy strategy against other strategies, they confirmed that the Lévy walk was a more efficient technique to find rare targets. That makes sense for T cells, which have to locate sparsely distributed parasites in a sea of mostly normal tissue. Interestingly, T cells are not alone in employing a Lévy-type strategy to find their targets. Several animal predators move in a similar way — with many short-distance movements interspersed with occasional longer-distance moves — to find their prey. The strategy seems particularly common among marine predators, including tuna, sharks, zooplankton, sea turtles and penguins, though terrestrial species like spider monkeys and honeybees may use the same approach to locate rare resources. This parallel with animal predators also makes sense because parasites, like prey species, have evolved to evade detection. “Many pathogens know how to hide, so T cells are not able to move directly to their target,” Hunter said. “The T cell actually needs to go into an area and then see if there’s anything there.” The model is also relevant to cancer and other immune-mediated diseases, Hunter noted. “Instead of looking for a parasite, these T cells could be looking for a cancer cell,” he said. By knowing what controls T cell movement, “you might be able to devise strategies to make the T cells more efficient at finding those cells.” On the physics side, while the Lévy-walk model is not new, the fact that T cells pause in between their steps or runs is something that hadn’t been recognized before when mapping the paths in other contexts. “From a physics point of view, to have runs and pauses is a new model,” Liu said. “Biological phenomena can illustrate what we wouldn’t have thought about otherwise.” The Penn collaborators are working to plot the tracks of other cell types and credit their unique partnership for their discovery. “We’ve said all along that this study could only happen because [our physics colleagues] had such a great expertise and we had our own separate expertise,” Tajie Harris said. “They took a chance working with us, and it turned out to be something really rewarding.” ### Additional Penn contributors to this study included Penn Vet’s David Christian, Christoph Konradt, Elia Tait Wojno and Beena John. The Penn team partnered on the work with Kazumi Norose of Chiba University in Japan; Emma Wilson of the University of California, Riverside; Wolfgang Weninger of the Sydney Medical School; and Andrew Luster of Massachusetts General Hospital. The study was supported by the University of Pennsylvania, National Institutes of Health, National Science Foundation, Commonwealth of Pennsylvania, Japan Society for the Promotion of Science and Ministry of Education, Culture, Sports, Science and Technology of Japan. Contact: Katherine Unger Baillie |
| Gene therapy can correct forms of severe combined immunodeficiency Posted: 23 May 2012 09:00 PM PDT Severe combined immunodeficiency is defect in the immune system that results in a loss of the adaptive immune cells known as B cells and T cells. Mutations in several different genes can lead to the development of severe combined immunodeficiency, including mutation of the adenosine deaminase (ADA) gene. Traditional treatment options, such as enzyme replacement therapy, are of limited efficacy, but bone marrow transplant from a compatible donor leads to a better response. A recent clinical trial indicated that gene therapy to insert the correct ADA gene in the patient’s own bone marrow cells can also lead to a good response.
However, patients were noted to have defects in B cell tolerance, meaning that some B cells that react to antigens from the body fail to be eliminated, leading to an autoimmune response. Dr. Eric Meffre and colleages at Yale University in New Haven, Connecticut and Alessandro Aiuti in Milan, Italy joined together to better understand why patients developed B cell tolerance problems. They found that loss of the ADA gene directly contributes to B cell tolerance problems and that these defects are mostly corrected after gene therapy. Their results point to a previously unknown role for ADA in B cell response and support the use of gene therapy as an effective treatment option for ADA-deficient severe combined immunodeficiency patients. ###
TITLE:
Defective B cell tolerance in adenosine deaminase deficiency is corrected by gene therapy
AUTHOR CONTACT:
Eric Meffre
ACCOMPANYING COMMENTARY
TITLE:
Restoring balance to B cells in ADA deficiency
AUTHOR CONTACT:
Eline Luning Prak Contact: Sarah Jackson |
| Key gene found responsible for chronic inflammation, accelerated aging and cancer Posted: 23 May 2012 09:00 PM PDT Researchers at NYU School of Medicine have, for the first time, identified a single gene that simultaneously controls inflammation, accelerated aging and cancer. “This was certainly an unexpected finding,” said principal investigator Robert J. Schneider, PhD, the Albert Sabin Professor of Molecular Pathogenesis, associate director for translational research and co-director of the Breast Cancer Program at NYU Langone Medical Center. “It is rather uncommon for one gene to have two very different and very significant functions that tie together control of aging and inflammation. The two, if not regulated properly, can eventually lead to cancer development. It’s an exciting scientific find.”
The study, funded by the National Institutes of Health, appears online ahead of print today in Molecular Cell and is scheduled for the July 13 print issue. For decades, the scientific community has known that inflammation, accelerated aging and cancer are somehow intertwined, but the connection between them has remained largely a mystery, Dr. Schneider said. What was known, due in part to past studies by Schneider and his team, was that a gene called AUF1 controls inflammation by turning off the inflammatory response to stop the onset of septic shock. But this finding, while significant, did not explain a connection to accelerated aging and cancer. When the researchers deleted the AUF1 gene, accelerated aging occurred, so they continued to focus their research efforts on the gene. Now, more than a decade in the making, the mystery surrounding the connection between inflammation, advanced aging and cancer is finally being unraveled. The current study reveals that AUF1, a family of four related genes, not only controls the inflammatory response, but also maintains the integrity of chromosomes by activating the enzyme telomerase to repair the ends of chromosomes, thereby simultaneously reducing inflammation, preventing rapid aging and the development of cancer, Dr. Schneider explained. “AUF1 is a medical and scientific trinity,” Dr. Schneider said. “Nature has designed a way to simultaneously turn off harmful inflammation and repair our chromosomes, thereby suppressing aging at the cellular level and in the whole animal.” With this new information, Dr. Schneider and colleagues are examining human populations for specific types of genetic alterations in the AUF1 gene that are associated with the co-development of certain immune diseases, increased rates of aging and higher cancer incidence in individuals to determine exactly how the alterations manifest and present themselves clinically. ###
About NYU School of Medicine:
NYU School of Medicine is one of the nation’s preeminent academic institutions dedicated to achieving world class medical educational excellence. For 170 years, NYU School of Medicine has trained thousands of physicians and scientists who have helped to shape the course of medical history and enrich the lives of countless people. An integral part of NYU Langone Medical Center, the School of Medicine at its core is committed to improving the human condition through medical education, scientific research and direct patient care. The School also maintains academic affiliations with area hospitals, including Bellevue Hospital, one of the nation’s finest municipal hospitals where its students, residents and faculty provide the clinical and emergency care to New York City’s diverse population, which enhances the scope and quality of their medical education and training. Additional information about the NYU School of Medicine is available at http://school.med.nyu.edu/. Contact: Jessica Guenzel |
| Chronic pain is relieved by cell transplantation in lab study Posted: 23 May 2012 09:00 PM PDT Chronic pain, by definition, is difficult to manage, but a new study by UCSF scientists shows how a cell therapy might one day be used not only to quell some common types of persistent and difficult-to-treat pain, but also to cure the conditions that give rise to them.
The researchers, working with mice, focused on treating chronic pain that arises from nerve injury — so-called neuropathic pain. In their study, published in the March 24, 2012 issue of Neuron, the scientists transplanted immature embryonic nerve cells that arise in the brain during development and used them to make up for a loss of function of specific neurons in the spinal cord that normally dampen pain signals. A small fraction of the transplanted cells survived and matured into functioning neurons. The cells integrated into the nerve circuitry of the spinal cord, forming synapses and signaling pathways with neighboring neurons. As a result, pain hypersensitivity associated with nerve injury was almost completely eliminated, the researchers found, without evidence of movement disturbances that are common side effects of the currently favored drug treatment. “Now we are working toward the possibility of potential treatments that might eliminate the source of neuropathic pain, and that may be much more effective than drugs that aim only to treat symptomatically the pain that results from chronic, painful conditions,” said the senior author of the study, Allan Basbaum, PhD, chair of the Department of Anatomy at UCSF. Although pain and hypersensitivity after injury usually resolve, in some cases they outlast the injury, creating the condition of chronic pain. Many types of chronic pain are induced by stimuli that are essentially harmless — such as light touch — but that are perceived as painful, according to Basbaum. Chronic pain due to this type of hypersensitivity is often a debilitating medical condition. Many people suffer from chronic neuropathic pain after a bout of shingles, years or decades after the virus that causes chicken pox has been vanquished. Chronic pain is not merely prolonged acute pain, Basbaum said. Those who suffer from chronic pain often get little relief, even from powerful narcotic painkillers, according to Basbaum. Gabapentin, an anticonvulsant first used to treat epilepsy, now is regarded as the most effective treatment for neuropathic pain. However, it is effective for only roughly 30 percent of patients, and even in those people it only provides about 30 percent relief of the pain, he said. The explanation for neuropathic pain, research shows, is that following injury neurons may be lost, or central nervous system circuitry may change, in ways that are maladaptive, compromising signals that normally help dampen pain. These changes contribute to a state of hyper-excitability, enhancing the transmission of pain messages to the brain and causing normally innocuous stimuli to become painful. The inhibitory neurons that are damaged in the spinal cord to cause pain hypersensitivity release a molecule that normally transmits inhibitory signals — the neurotransmitter GABA. A loss of GABA inhibition also is implicated in epilepsy and may play a role in Parkinson’s disease. Gabapentin does not mimic GABA, but it helps to compensate for the loss of inhibition that GABA normally would provide. Basbaum’s UCSF colleagues, including study co-authors Arturo Alvarez-Buylla, PhD, and Arnold Kriegstein, MD, PhD, along with Scott Baraban, PhD, had already been experimenting with transplanting immature neurons that make GABA, using the transplanted neurons to bolster inhibitory signals in mouse models to prevent epileptic seizures and to combat a Parkinson’s-like disease. However, in those experiments the cells — which originate in a region of the forebrain known as the medial ganglionic eminence — were transplanted within the brain itself, which is their normal home. Upon hearing about the research, Basbaum became interested in transplanting the same cells into the spinal cord as a potential treatment for the loss of GABA-driven inhibition in neuropathic pain. Success was by no means assured, as cells normally do not survive outside their natural environments within such a complex organism. Another co-author of the Neuron study, UCSF researcher John Rubenstein, PhD, has made major progress in identifying molecules that can be manipulated to lead an embryonic stem cell to go through developmental stages that cause it to acquire the properties of GABA neurons that derive from the medial ganglionic eminence. According to Kriegstein, who directs the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF, “This research is at a very early stage, and we’re a long way from thinking about it in human trials, but we do have a method of making cells that are like these inhibitory neurons, starting with human embryonic stem cells.” As a step toward eventual therapies, the UCSF team plans to graft fetal human cells from the medial ganglionic eminence, or cells derived from human embryonic stem cells, into a rodent model of neuropathic pain, to see if the human cells also will alleviate neuropathic chronic pain. “Unlike drugs, the transplanted cells can have very focused effects, depending on where they are transplanted,” Kriegstein said. According to Alvarez-Buylla, a leading scientist among those working to define the potentialities of various cells in the developing brain at different stages, “One of the amazing properties of these cells from the medial ganglionic eminence is their unprecedented migratory capacity, which enables them to navigate through multiple terrains within the central nervous system, and to then become functionally integrated with other cells. Those properties have proved useful in other places where we have transplanted them, and now in the spinal cord.” ### Joao Braz, PhD, an assistant research scientist, and Reza Sharif-Naieni, PhD, a postdoctoral fellow, both working in the Basbaum laboratory, carried out the bulk of the experiments published in Neuron. The authors have a patent pending on the treatment outlined in the study. The study was funded by the National Institutes of Health, the Association for the Study of Pain and the Canadian Institutes of Health Research. UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.
RELATED LINKS:
Pain Control is Focus of Allan Basbaum’s Research Career UCSF Stem-Cell Based Neurological, Liver Therapy Strategies Advanced Novel Parkinson’s Treatment Strategy Involves Cell Transplantation New Period of Brain “Plasticity” Created With Transplanted Embryonic Cells Contact: Jeffrey Norris |
| From stem cell to brain cell – new technique mimics the brain Posted: 23 May 2012 09:00 PM PDT A new technique that converts stem cells into brain cells has been developed by researchers at Lund University. The method is simpler, quicker and safer than previous research has shown and opens the doors to a shorter route to clinical cell transplants.
By adding two different molecules, the researchers have discovered a surprisingly simple way of starting the stem cells’ journey to become finished brain cells. The process mimics the brain’s natural development by releasing signals that are part of the normal development process. Experiments in animal models have shown that the cells quickly adapt in the brain and behave like normal brain cells. “This technique allows us to fine-tune our steering of stem cells to different types of brain cells. Previous studies have not always used the signals that are activated during the brain’s normal development. This has caused the transplanted cells to develop tumours or function poorly in the brain”, says Agnete Kirkeby, one of the authors of the study. Since the method effectively imitates the brain’s own processes, it reduces the risk of tumour formation, one of the most common obstacles in stem cell research. The quick, simple technique makes the cells mature faster, which both makes the transplant safer and helps the cells integrate better into the brain. The results of the study bring stem cell research closer to transplant trials in the human brain. “We have used the new protocol to make dopamine neurons, the type of neuron that is affected by Parkinson’s disease, and for the first time, we are seriously talking about these cells as being good enough to move forward for transplantation in patients. The next step is to test the process on a larger scale and to carry out more pre-clinical safety tests”, explains Malin Parmar, research team leader. ### The research is presented in the report ‘Generation of regionally specified neural progenitors and functional neurons from human embryonic stem cells under defined conditions’ in the journal Cell Reports. The study has been conducted as part of the EU 7th Framework Programme project NeuroStemcell.
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Contact: Malin Parmar |
| Hazelnuts: New source of key fat for infant formula that’s more like mother’s milk Posted: 22 May 2012 09:00 PM PDT Scientists are reporting development of a healthy “designer fat” that, when added to infant formula, provides a key nutrient that premature babies need in high quantities, but isn’t available in large enough amounts in their mothers’ milk. The new nutrient, based on hazelnut oil, also could boost nutrition for babies who are bottle-fed for other reasons. The report appears in ACS’ Journal of Agricultural and Food Chemistry.
Casimir Akoh and colleagues explain that human milk is the “gold standard” for designing infant formulas. Mothers naturally provide the healthful omega-3 fatty acid DHA (docosahexaenoic acid) and omega-6 fatty acid ARA (arachidonic acid) — important for brain development and the development of other organs — to infants during the last three months of pregnancy. These fatty acids (components of fats) are also in human milk. But premature infants don’t get full exposure to DHA and ARA in the uterus because they are born too soon. And their mothers’ milk doesn’t yet contain high enough levels when the infants are born. Some mothers, of course, do not nurse. That’s why infant formulas include proteins, sugars and fats to bring them closer to the standard of human milk. Currently, DHA and ARA (in the form of triacylglycerols) from algae are added to many formulas, but concerns exist about the digestibility of these algae-derived fatty acids, which are not exactly identical to those in human milk. So, Akoh’s team set out to build a new designer fat from hazelnut oil that more closely mimics the DHA and ARA in human milk. The report describes development of fats from hazelnut oil that contain DHA and ARA at the same positions found on fats in human milk. The scientists extensively analyzed these human milk fat mimics and conclude that the new DHA and ARA source is suitable for the supplementation of infant formulas. ### The authors acknowledge funding from the University of Georgia, Çamlica Kültür ve Yardim Vakfi (Turkey) and Istanbul Technical University Scientific Research Projects Department. The American Chemical Society is a nonprofit organization chartered by the U.S. Congress. With more than 164,000 members, ACS is the world’s largest scientific society and a global leader in providing access to chemistry-related research through its multiple databases, peer-reviewed journals and scientific conferences. Its main offices are in Washington, D.C., and Columbus, Ohio. To automatically receive news releases from the American Chemical Society contact newsroom@acs.org. Contact: Michael Bernstein |
| Stem-cell-growing surface enables bone repair Posted: 22 May 2012 09:00 PM PDT —University of Michigan researchers have proven that a special surface, free of biological contaminants, allows adult-derived stem cells to thrive and transform into multiple cell types. Their success brings stem cell therapies another step closer.
To prove the cells’ regenerative powers, bone cells grown on this surface were then transplanted into holes in the skulls of mice, producing four times as much new bone growth as in the mice without the extra bone cells. An embryo’s cells really can be anything they want to be when they grow up: organs, nerves, skin, bone, any type of human cell. Adult-derived “induced” stem cells can do this and better. Because the source cells can come from the patient, they are perfectly compatible for medical treatments. In order to make them, Paul Krebsbach, professor of biological and materials sciences at the U-M School of Dentistry, said, “We turn back the clock, in a way. We’re taking a specialized adult cell and genetically reprogramming it, so it behaves like a more primitive cell.” Specifically, they turn human skin cells into stem cells. Less than five years after the discovery of this method, researchers still don’t know precisely how it works, but the process involves adding proteins that can turn genes on and off to the adult cells. Before stem cells can be used to make repairs in the body, they must be grown and directed into becoming the desired cell type. Researchers typically use surfaces of animal cells and proteins for stem cell habitats, but these gels are expensive to make, and batches vary depending on the individual animal. “You don’t really know what’s in there,” said Joerg Lahann associate professor of chemical engineering and biomedical engineering. For example, he said that human cells are often grown over mouse cells, but they can go a little native, beginning to produce some mouse proteins that may invite an attack by a patient’s immune system. The polymer gel created by Lahann and his colleagues in 2010 avoids these problems because researchers are able to control all of the gel’s ingredients and how they combine. “It’s basically the ease of a plastic dish,” said Lahann. “There is no biological contamination that could potentially influence your human stem cells.” Lahann and colleagues had shown that these surfaces could grow embryonic stem cells. Now, Lahann has teamed up with Krebsbach’s team to show that the polymer surface can also support the growth of the more medically promising induced stem cells, keeping them in their high-potential state. To prove that the cells could transform into different types, the team turned them into fat, cartilage and bone cells. They then tested whether these cells could help the body to make repairs. Specifically, they attempted to repair five-millimeter holes in the skulls of mice. The weak immune systems of the mice didn’t attack the human bone cells, allowing the cells to help fill in the hole. After eight weeks, the mice that had received the bone cells had 4.2 times as much new bone, as well as the beginnings of marrow cavities. The team could prove that the extra bone growth came from the added cells because it was human bone. “The concept is not specific to bone,” said Krebsbach. “If we truly develop ways to grow these cells without mouse or animal products, eventually other scientists around the world could generate their tissue of interest.” In the future, Lahann’s team wants to explore using their gel to grow stem cells and specialized cells in different physical shapes, such as a bone-like structure or a nerve-like microfiber. The paper reporting this work is titled “Derivation of Mesenchymal Stem Cells from Human Induced Pluripotent Stem Cells Cultured on Synthetic Substrates” and it appears in the June edition of the journal Stem Cells. The university is pursuing patent protection for the intellectual property and is seeking commercialization partners to help bring the technology to market. Krebsbach is also the Roy H. Roberts Professor of Dentistry and a professor of biomedical engineering. Lahann is also associate professor of materials sciences and engineering, associate professor of macromolecular sciences and engineering, and the director of the Biointerfaces Institute. ### Paul Krebsbach: www.dent.umich.edu/?q=bms/facultyandstaff/krebsbach Joerg Lahann: www.engin.umich.edu/research/lahann/lahann.htm Full text of paper: http://onlinelibrary.wiley.com/doi/10.1002/stem.1084/abstract New culture dish could advance human embryonic stem cell research (2010): www.ns.umich.edu/new/releases/7730-new-culture-dish-could-advance-human-embryonic-stem-cell-research Contact: Kate McAlpine |
| Newly discovered breast milk antibodies help neutralize HIV Posted: 21 May 2012 09:00 PM PDT Antibodies that help to stop the HIV virus have been found in breast milk. Researchers at Duke University Medical Center isolated the antibodies from immune cells called B cells in the breast milk of infected mothers in Malawi, and showed that the B cells in breast milk can generate neutralizing antibodies that may inhibit the virus that causes AIDS.
HIV-1 can be transmitted from mother to child via breastfeeding, posing a challenge for safe infant feeding practices in areas of high HIV-1 prevalence. But only one in 10 HIV-infected nursing mothers is known to pass the virus to their infants. “That is remarkable, because nursing children are exposed multiple times each day during their first year of life,” said senior author Sallie Permar, M.D., Ph.D., an assistant professor of pediatrics and infectious diseases at Duke. “We are asking if there is an immune response that protects 90 percent of infants, and could we harness that response to develop immune system prophylaxis (protection) during breastfeeding for mothers infected with HIV-1. “Our work helped establish that these B cells in breast milk can produce HIV-neutralizing antibodies, so enhancing the response or getting more mucosal B-cells to produce those helpful antibodies would be useful, and this is a possible route to explore for HIV-1 vaccine development,” Permar said. The study was published on May 18 in PLoS One, an open-access journal published by the Public Library of Science. “This is important work that seeks to understand what a vaccine must do to protect babies from mucosal transmission during breastfeeding,” said Barton Haynes, M.D., co-author and a national leader in AIDS/HIV research, director of the Center for HIV/AIDS Vaccine Immunology (CHAVI), as well as director of the Duke Human Vaccine Institute (DHVI). “The antibodies isolated are the first HIV antibodies isolated from breast milk that react with the HIV-1 envelope, and it important to understand how they work to attack HIV-1.” The findings of two different antibodies with HIV-neutralizing properties isolated from breast milk also may help researchers with new investigations into adult-to-adult transmission, in addition to mother-to-child transmission. Permar said that most HIV-1 transmission occurs at a mucosal site in the body – surfaces lined with epithelial cells, such as the gastrointestinal tract or vaginal tissue. The mucosal compartments all have their own immune system cells. “We’re excited about this finding because the immune cells in mucosal compartments can cross-talk and traffic between compartments,” Permar said. “So the antibodies we found in breast milk indicate that these same antibodies are able to be elicited in other tissues.” Interestingly, the Centers for Disease Control in the U.S. recommend against breastfeeding if a mother has HIV-1, because baby formula is a safe alternative for U.S.-born infants. The World Health Organization, however, encourages HIV-infected nursing mothers in resource-poor regions to breastfeed while the mother and/or infant take antiretroviral drugs to prevent the infection in the infant, because without the nutrients and immune factors in mothers’ milk, many more infants would die from severe diarrhea and respiratory and other diseases. At the DHVI and CHAVI, there are many projects aimed at designing neutralizing responses in vaccinated individuals, and for improved vaccines that display specific targets to the immune system before it gets infected, with the idea of eliciting protective responses that fight against HIV transmission. “Our work will be important in eliminating mother-to-child transmission and getting the types of responses needed for protecting all infants,” Permar said. The study itself wasn’t easy to perform, she noted. The samples came from a group of women in Malawi who were recruited by CHAVI for this study. “Successfully characterizing antibodies from such a fragile medium required global coordination and expertise across multiple fields and is a hopeful testament to the incredible amounts of work and leadership currently under way to fight this devastating disease,” said first author James Friedman, a third-year medical student at Duke University School of Medicine. “To be a part of, and to contribute to such a large-scale and important effort is incredibly exciting.” Because of limited availability of the laboratory instrument needed to isolate single, viable immune cells in the region, the samples were not analyzed there. Instead, samples were frozen and transported for analysis. Keeping the breast milk under the right conditions for later thawing and testing of B cells and for isolating antibodies was a challenge, Permar said. ### Other co-authors from the Duke Human Vaccine Institute were co-senior author Anthony Moody, S. Munir Alam, Xiaoying Shen, Shi-Mao Xia, Shelley Stewart, Kara Anasti, Justin Pollara, Genevieve G. Fouda, Guang Yang, Garnett Kelsoe, Guido Ferrari, Georgia D. Tomaras, and Hua-Xin Liao. The study was funded by the National Institutes of Health (NIH/NIAID/DAIDS) grants: the Center for HIV/AIDS Vaccine Immunology (CHAVI) AI067854, AI07392, and AI087992; and the Doris Duke Foundation Clinical Scientist Development Award. The Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVDVIMC grant 38619) provided additional funding for this work. Contact: Mary Jane Gore |
| Harvard team cracks code for new drug resistant superbugs Posted: 21 May 2012 09:00 PM PDT Summary: National Institutes of Health-funded scientists have determined the genetic sequences of all 12 available strains of Staphylococcus aureus bacteria resistant to vancomycin—an antibiotic of last resort—and have demonstrated that resistance arose independently in each strain after it acquired a specific bit of genetic material called transposon Tn1546. The transposon likely came from vancomycin-resistant Enterococcus bacteria that simultaneously infected the patients. The team also identified shared features among the vancomycin-resistant staph strains that may have helped them acquire Tn1546 and evade human immune defenses. Their findings are reported in the May 22 issue of the journal mBio®.
Boston (May 22, 2012) – Antibiotic-resistant superbugs, including methicillin resistant Staph. aureus (MRSA), have become household words. Antibiotic resistance threatens health and lives. Schools have been closed, athletic facilities have been scrubbed, and assisted living and day care centers have been examined for transmission of these bacteria. Since 2005, MRSA have killed over 18,000 people a year in the United States alone. To make matters worse, in 2002 a new MRSA with resistance to even the last-line drug vancomycin (VRSA) appeared. Since the first case in Michigan, there have been at least 11 other well-documented cases in New York, Pennsylvania, Delaware and more in Michigan. Scientists at the Centers for Disease Control, Harvard University and elsewhere have been working to determine the origin of these VRSA, to understand why they have turned up, and to understand the risk of spread. Most VRSA occurred in foot and limb infections of diabetics who are often in and out of health care facilities. Each of these infections is believed to have had multiple bacteria, an MRSA plus a vancomycin resistant bacterium called Enterococcus (or VRE). VRE has caused vancomycin resistant hospital-acquired infections since the 1980s. But there is hope on the horizon. Scientists have now determined the genome sequence for all available VRSA strains. The Harvard-wide Antibiotic Resistance Program is using this information to develop new ways to prevent and treat infection by MRSA, VRSA and VRE. The team identified several new compounds that stop MRSA by hitting new targets, and is currently subjecting these to further tests. This group works closely with partners at the Broad Institute and Harvard’s Microbial Sciences Initiative. To sequence the genomes, researchers from the National Institutes of Health (NIH)-funded Harvard-wide Antibiotic Resistance Program, headquartered at the Massachusetts Eye and Ear in Boston, assembled an elite international team. Headed by Harvard professor Michael Gilmore, Ph.D., and his associate Veronica Kos, Ph.D., both based at Mass. Eye and Ear, the team included bioinformatics and genomics experts from the Broad Institute of MIT and Harvard, the Institute for Genome Sciences of the University of Maryland, the University of Rochester, and the Wellcome Trust Sanger Center in the UK. They identified features in the genomes that appear to have made it easier for certain MRSA to acquire resistances in mixed infection. Their findings are reported in the May 22 issue of the journal mBio®, the American Society of Microbiology’s first broad-scope, online-only, open access journal. “The genome sequence gave us unprecedented insight into what makes these highly resistant bacteria tick. Several things were remarkable,” says Gilmore. “Vancomycin resistance repeatedly went into just one tribe of MRSA, so the question became ‘what makes that group special — why did they start getting vancomycin resistance?”‘ “What we found was that this group of MRSA has properties that appear to make it more social, so they can live with other bacteria like Enterococcus. This would allow those MRSA to more easily pick up new resistances,” adds Kos. “The good news is that some of these properties weaken the strain’s ability to colonize, and may be limiting their spread.” Gilmore is the Sir William Osler Professor of Ophthalmology, and also serves in the Department of Microbiology and Immunobiology at Harvard Medical School. Kos is a senior research associate in the Gilmore lab. They and colleagues from Harvard’s Microbial Sciences Initiative formed the NIH sponsored Harvard-wide Antibiotic Resistance Program in 2009. ### Authors: Veronica N. Kos, Christopher A. Desjardins, Allison Griggs, Gustavo Cerquiera, Andries Van Tonder, Matthew T.G. Holden, Paul Godfrey, Kelli L. Palmer, Kip Bodi, Emmanuel F. Mongodin, Jennifer Wortman, Michael Felgarden, Trevor Lawley, Steven R. Gill, Brian J. Hass, Bruce Birren and Michael S. Gilmore (list of affiliations available in the PDF) Grant Support: This research was supported in part with Federal funds from the National Institute of Allergy and Infectious Disease (NIAID) including the Harvard-wide Program on Antibiotic Resistance (NIH grant AI083214), Contract No.: HHSN27220090018C to the Broad Institute, Contract HHSN272200700055C for the Network on Antimicrobial Resistance in Staphylococcus aureus Program (NARSA), and National Eye Institute (NEI) grant EY017381 (MSG). Both the NIAID and NEI are parts of the National Institutes of Health.
About Mass. Eye and Ear
The Mass. Eye and Ear/Mass General Department of Ophthalmology is one of the world’s premier centers for excellence in ophthalmic clinical care, research and education. Steadfast dedication to an integrated three-part mission keeps the Department at the forefront of advances in patient care and scientific discovery, while training and advancing generations of leaders through our academic and professional development programs. As the seat of Ophthalmology leadership for Harvard Medical School, the Department builds on the strengths of faculty from such renowned local institutions as Joslin Diabetes Center, Children’s Hospital Boston, the Mass. Eye and Ear-affiliated Schepens Eye Research Institute, Brigham and Women’s Hospital, Beth Israel Deaconess Medical Center and Boston Veteran’s Administration Healthcare System to encourage innovation and remain a global leader in ophthalmology. Founded in 1824, Mass. Eye and Ear is an independent specialty hospital, an international center for treatment and research, and a teaching affiliate of the Harvard Medical School. For more information, call (617) 523-7900 or TDD (617) 523-5498 or visit www.MassEyeAndEar.org. Contact: Mary Leach |
| Folic acid may reduce some childhood cancers Posted: 20 May 2012 09:00 PM PDT Folic acid fortification of foods may reduce the incidence of the most common type of kidney cancer and a type of brain tumors in children, finds a new study by Kimberly J. Johnson, PhD, assistant professor at the Brown School at Washington University in St. Louis, and Amy Linabery, PhD, postdoctoral fellow at the University of Minnesota.
Incidence reductions were found for Wilms’ tumor, a type of kidney cancer, and primitive neuroectodermal tumors (PNET), a type of brain cancer. Since 1998, the U.S. Food and Drug Administration has mandated fortification of foods with folic acid because earlier studies show that prenatal consumption of folic acid significantly reduces the incidence of neural tube defects in babies. “Our study is the largest to date to show that folic acid fortification may also lower the incidence of certain types of childhood cancer in the United States,” Johnson says. The study, published in the current issue of Pediatrics, examined the incidence of childhood cancer pre- and post-mandated folic acid fortification. “We found that Wilms’ tumor rates increased from 1986 to 1997 and decreased thereafter, which is an interesting finding since the downward change in the trend coincides exactly with folic acid fortification,” Johnson says. “PNET rates increased from 1986 to 1993 and decreased thereafter. This change in the trend does not coincide exactly with folic acid fortification, but does coincide nicely with the 1992 recommendation for women of childbearing age to consume 400 micrograms of folic acid daily.” Study authors used the 1986-2008 data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program (SEER), which has collected information on cancer cases in various areas of the U.S. since 1973. The study involved 8,829 children, from birth to age four, diagnosed with cancer. “Declines in Wilms’ tumors and PNETs in children were detected by multiple analyses of the data,” Johnson says. “Importantly, the reduced rates of Wilms’ tumors also were found in a smaller study conducted in Ontario, Canada, that was published in 2011. “More research is needed to confirm these results and to rule out any other explanations.” Julie A. Ross, PhD, professor and director of the Division of Pediatric Epidemiology & Clinical Research in the Department of Pediatrics at the University of Minnesota, was a study co-author. Johnson notes that one concern countries face as they are deciding whether or not to fortify foods to reduce neural tube defects in newborns is the possibility that fortification may cause unintended harm, such as causing new cancers or pre-cancerous lesions. “Here, we are showing that folic acid fortification does not appear to be increasing rates of childhood cancers, which is good news,” she says. ### Contact: Kimberly Johnson |
| Research shows some people predisposed for recurrent C. difficile infection Posted: 20 May 2012 09:00 PM PDT University of Cincinnati (UC) researchers have found that some patients appear to be more predisposed for recurrent infection from the bacterium Clostridium difficile, or C. diff, and that it may advance to a more serious inflammatory condition in those individuals.
These findings are being presented via poster during Digestive Disease Week, Monday, May 21, 2012, in San, Diego. Mary Beth Yacyshyn, PhD, an adjunct assistant professor in division of digestive diseases, says researchers found that the C. diff surface layer proteins (SLP) produced a different set of proteins (cytokines) in samples from individuals with recurrent infection when compared to samples from individuals with an initial onset of the infection, indicating a more chronic inflammatory process, which is also seen in inflammatory bowel disease (IBD). “Surface layer proteins of C. diff play a role in cell adhesion, the pathological process and the host’s inflammatory response,” Yacyshyn explains. “We wanted to see if purified SLP would induce immune responses in the samples from individuals who had their first documented episode of C. difficile and recurrent episodes.” Blood samples were taken from initial, recurrent and healthy patients and the white blood cells (lymphocytes) were isolated and cultured for 48 hours with SLP from C. difficile. Researchers found SLP stimulation produced a wide array of proteins, or cytokines, being secreted in all groups. “However, patients with recurrent C. difficile infection produced a more inflammatory pattern of cytokines than did patients with an initial infection,” she says. “We found that some levels of these cytokines were similar to those found in the comorbid case controls, suggesting that any patient hospitalized for an extended period may be exposed to C. difficile. “Overall, we found that the cytokine response from recurrent patients is more indicative of a chronic inflammatory process, suggesting that the initial immune response may be crucial to clearing the infection. If, due to other underlying disease predispositions, genetics or current medications, a patient does not clear the infection, this may result in a chronic or systemic inflammatory response leading to continuous infection or re-infection.” Yacyshyn says this is the first step in many to target the C. diff infection at the cellular level for the best patient outcome. “In knowing that these cells respond differently in different people, we may be able to tailor treatment and avoid the onset of a chronic condition,” she says. ### These studies have been funded through the Merck-Investigator Initiated studies program. Yacyshyn cites no conflict of interest. Contact: Katie Pence |
| Treatment of childhood OSA reverses brain abnormalities Posted: 19 May 2012 09:00 PM PDT Treatment of obstructive sleep apnea (OSA) in children normalizes disturbances in the neuronal network responsible for attention and executive function, according to a new study. “OSA is known to be associated with deficits in attention, cognition, and executive function,” said lead author Ann Halbower, MD, Associate Professor at the Children’s Hospital Sleep Center and University of Colorado Denver. “Our study is the first to show that treatment of OSA in children can reverse neuronal brain injury, correlated with improvements in attention and verbal memory in these patients.”
The results will be presented at the ATS 2012 International Conference in San Francisco. In the study, children (ages 8-11) with moderate-severe OSA were compared to healthy controls. Brain imaging with magnetic resonance spectroscopy imaging was performed at baseline in 15 OSA patients and seven controls, along with neuropsychological testing. OSA treatment consisted of adenotonsillectomy followed by monitored continuous positive airway pressure (CPAP) or nasal treatments. Brain imaging and neuropsychological testing was performed again in 11 OSA patients and the seven controls six months after treatment. Compared with controls at baseline, children with OSA exhibited significantly decreased N-acetyl aspartate to choline ratios (NAA/Cho) in the left hippocampus and left frontal cortex, along with significant decreases in the executive functions of verbal memory, and attention. Following treatment, both left and right frontal cortex neuronal metabolites normalized, and hippocampal metabolites improved with a medium effect size (0.5). More complete reversal of hippocampal abnormalities was seen in children with milder OSA when apnea-hypopnea index (AHI) improved (although this is very preliminary data). Verbal memory and attention improved with medium to large effect sizes. Improvements in attention and verbal memory were correlated with normalization of NAA/Cho in the right and left frontal cortex (p=0.5). “We have demonstrated for the first time that treatment of OSA in children normalizes brain metabolites in portions of the neuronal network responsible for attention and executive function,” concluded Dr. Halbower. “We speculate that if OSA is treated earlier, there may be a more brisk improvement in the hippocampus, a relay station for executive function, learning, and memory.” “Our results point to the importance of early diagnosis and treatment of OSA in children, as it could potentially have profound effects on their development.” ### “Brain Injury And Cognitive Deficits Reverse With Treatment Of Childhood Obstructive Sleep Apnea” (Session A19, Sunday, May 20, 10:15 a.m., Room 2020-2022, Moscone Center; Abstract 33865) * Please note that numbers in this release may differ slightly from those in the abstract. Many of these investigations are ongoing; the release represents the most up-to-date data available at press time. Abstract 33865
Abstract Body
Introduction : To determine the reversibility of brain neuronal abnormalities with treatment of Pediatric Obstructive Sleep Apnea (OSA), OSA patients were compared to healthy controls (HC) matched by age, gender, race, and SES. We hypothesized that neuronal alterations of the hippocampus and frontal cortex associated with childhood sleep-disordered breathing would reverse with treatment. Methods : OSA patients (N=17) and healthy controls (N=11) age 8-11 years, Tanner stage I-II, underwent neuropsychological tests spanning 7 domains. Magnetic resonance spectroscopy imaging of the brain was performed in 15 OSA and 7 HC. OSA patients underwent Adenotonsillectomy followed by monitored CPAP if AHI>3, or nasal treatments if AHI 2-3. Six months after treatment, 11 OSA patients returned for brain imaging and neuropsychological tests compared to HC. Results : Results: Children were mean age 10 yr, 55% male, 50% Hispanic, 20% AA. Mean OAHI for OSA patients = 13.6, for HC =0.3. Confirming our previous findings, N-acetyl aspartate to choline ratios (NAA/Cho) in the left hippocampus and left frontal cortex were significantly decreased in OSA patients compared to HC (p=0.03 and 0.04 respectively). OSA patients had a significant decrease in the executive function of working memory (p= 0.00), attention (p=0.00) and verbal memory (p=0.02). After treatment, both left and right frontal cortex neuronal metabolites normalized (p= 0.03) while the hippocampal metabolites did not. Verbal memory improved (p=0.04) and improvements in attention were correlated with the normalization of NAA/Cho in the frontal lobes (r=0.67, p=0.05). Conclusion: Conclusion: This is the first study demonstrating that brain metabolites of the neuronal network responsible for attention and executive function, the frontal cortex, normalize with treatment of pediatric OSA. Improvements in attention were correlated with the normalization of metabolites in the frontal lobes. We speculate that earlier diagnosis and treatment of childhood OSA may improve the trajectory of development, thus implying the need to identify these patients and expedite management. Funded by: National Institutes of Health, National Center for Research Resources Contact: Nathaniel Dunford |
| Growth factor in stem cells may spur recovery from MS Posted: 19 May 2012 09:00 PM PDT A substance in human mesenchymal stem cells that promotes growth appears to spur restoration of nerves and their function in rodent models of multiple sclerosis (MS), researchers at Case Western Reserve University School of Medicine have found.
Their study is embargoed until published in the online version of Nature Neuroscience at 1 p.m. U.S. Eastern Standard Time on Sunday, May 20. In animals injected with hepatocyte growth factor, inflammation declined and neural cells grew. Perhaps most important, the myelin sheath, which protects nerves and their ability to gather and send information, regrew, covering lesions caused by the disease. “The importance of this work is we think we’ve identified the driver of the recovery,” said Robert H. Miller, professor of neurosciences at the School of Medicine and vice president for research at Case Western Reserve University. Miller, neurosciences instructor Lianhua Bai and biology professor Arnold I. Caplan, designed the study. They worked with Project Manager Anne DeChant, and research assistants Jordan Hecker, Janet Kranso and Anita Zaremba, from the School of Medicine; and Donald P. Lennon, a research assistant from the university’s Skeletal Research Center. In MS, the immune system attacks myelin, risking injury to exposed nerves’ intricate wiring. When damaged, nerve signals can be interrupted, causing loss of balance and coordination, cognitive ability and other functions. Over time, intermittent losses may become permanent. Miller and Caplan reported in 2009 that when they injected human mesenchymal stem cells into rodent models of MS, the animals recovered from the damage wrought by the disease. Based on their work, a clinical trial is underway in which MS patients are injected with their own stem cells. In this study, the researchers first wanted to test whether the presence of stem cells or something cells produce promotes recovery. They injected mice with the medium in which mesenchymal stem cells, culled from bone marrow, grew. All 11 animals, which have a version of MS, showed a rapid reduction in functional deficits. Analysis showed that the disease remained on course unless the molecules injected were of a certain size; that is, the molecular weight ranged between 50 and 100 kiloDaltons. Research by others and results of their own work indicated hepatocyte growth factor, which is secreted by mesenchymal stem cells, was a likely instigator. The scientists injected animals with 50 or 100 nanograms of the growth factor every other day for five days. The level of signaling molecules that promote inflammation decreased while the level of signaling molecules that counter inflammation increased. Neural cells grew and nerves laid bare by MS were rewrapped with myelin. The 100-nanogram injections appeared to provide slightly better recovery. To test the system further, researchers tied up cell-surface receptors, in this case cMet receptors that are known to work with the growth factor. When they jammed the receptors with a function-blocking cMet antibody, neither the mesenchymal stem cell medium nor the hepatocyte growth factor injections had any effect on the disease. In another test, injections of an anti-hepatocyte growth factor also blocked recovery. The researchers will continue their studies, to determine if they can screen mesenchymal stem cells for those that produce the higher amounts of hepatocyte growth factor needed for effective treatment. That could lead to a more precise cell therapy. “Could we now take away the mesenchymal stem cells and treat only with hepatocyte growth factor?” Miller asked. “We’ve shown we can do that in an animal but it’s not clear if we can do that in a patient.” They also plan to test whether other factors may be used to stimulate the cMet receptors and induce recovery. ### The Myelin Repair Foundation, the E. Virginia and L. David Baldwin Fund, and grant # 5R01NS030800-16 from the National Institute of Neurological Disorders and Stroke at the National Institutes of Health, supported this research. About Case Western Reserve University School of Medicine
Founded in 1843, Case Western Reserve University School of Medicine is the largest medical research institution in Ohio and is among the nation’s top medical schools for research funding from the National Institutes of Health. The School of Medicine is recognized throughout the international medical community for outstanding achievements in teaching. The School’s innovative and pioneering Western Reserve2 curriculum interweaves four themes–research and scholarship, clinical mastery, leadership, and civic professionalism–to prepare students for the practice of evidence-based medicine in the rapidly changing health care environment of the 21st century. Nine Nobel Laureates have been affiliated with the school of medicine. Annually, the School of Medicine trains more than 800 MD and MD/PhD students and ranks in the top 25 among U.S. research-oriented medical schools as designated by U.S. News & World Report “Guide to Graduate Education.” The School of Medicine’s primary affiliate is University Hospitals Case Medical Center and is additionally affiliated with MetroHealth Medical Center, the Louis Stokes Cleveland Department of Veterans Affairs Medical Center, and the Cleveland Clinic, with which it established the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in 2002. http://casemed.case.edu. |
| Drug found for parasite that is major cause of death worldwide Posted: 19 May 2012 09:00 PM PDT Research by a collaborative group of scientists from UC San Diego School of Medicine, UC San Francisco and Wake Forest School of Medicine has led to identification of an existing drug that is effective against Entamoeba histolytica. This parasite causes amebic dysentery and liver abscesses and results in the death of more than 70,000 people worldwide each year.
Using a high-throughput screen for drugs developed by the research team, they discovered that auranofin – a drug approved by the US Food and Drug Administration 25 years ago for rheumatoid arthritis – is very effective in targeting an enzyme that protects amebae from oxygen attack (thus enhancing sensitivity of the amebae to reactive oxygen-mediated killing). The results of the work, led by Sharon L. Reed, MD, professor in the UCSD Departments of Pathology and Medicine and James McKerrow, MD, PhD, professor of Pathology in the UCSF Sandler Center for Drug Discovery, will be published in the May 20, 2012 issue of Nature Medicine. Entamoeba histolytica is a protozoan intestinal parasite that causes human amebiasis, the world’s fourth leading cause of death from protozoan parasites. It is listed by the National Institutes of Health as a category B priority biodefense pathogen. Current treatment relies on metronidazole, which has adverse effects, and potential resistance to the drug is an increasing concern. “Because auranofin has already been approved by the FDA for use in humans, we can save years of expensive development,” said Reed. “In our studies in animal models, auranofin was ten times more potent against this parasite than metronidazole.” In a mouse model of amebic colitis and a hamster model of amebic liver abscess, the drug markedly decreased the number of parasites, damage from inflammation, and size of liver abscesses. “This new use of an old drug represents a promising therapy for a major health threat, and highlights how research funded by the National Institutes of Health can benefit people around the world,” said Reed. The drug has been granted “orphan-drug” status (which identifies a significant, newly developed or recognized treatment for a disease which affects fewer than 200,000 persons in the United States) and UC San Diego hopes to conduct clinical trials in the near future. ### Additional contributors to the study include first author Anjan Debnath, Shamila S. Gunatilleke and James H. McKerrow, UCSF Sandler Center for Drug Discovery; Derek Parsonage and Leslie B. Poole, Wake Forest School of Medicine; Rosa M. Andrade, Chen He, Eduardo R. Cobo and Ken Hirata, UC San Diego School of Medicine; Steven Chen and Michelle R. Arkin, UCSF; Guillermina GarcÃa-Rivera, Esther Orozco and Máximo B. MartÃnez, Instituto Politécnico Nacional, Mexico City; and Amy M. Barrios, University of Utah, Salt Lake City. This work was supported by the Sandler Foundation and US National Institute of Allergy and Infectious Diseases grant 5U01AI077822-02, with additional support from R01 GM050389. Contact: Scott LaFee |
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