Monthly Archives: October 2016
The findings, reported in the journal Science Advances, are a first step toward developing more effective bone marrow treatments for diseases like leukemia and lymphoma.
Blood cells flow throughout the body delivering life-supporting oxygen and nutrients. As these cells are used and recycled they are regenerated by bone marrow, the soft tissue inside the body’s long and hollow bones.
Certain regions of bone marrow contain hematopoietic stem cells, the precursors of all blood and immune cells, said University of Illinois chemical and biomolecular engineering professor Brendan Harley, who led the research with postdoctoral researcher Ji Sun Choi.
“The tissue environment that surrounds these cells in the bone marrow provides a wealth of signals that can alter how these precursor cells behave. This paper looked at the signals provided by the tissue matrix itself,” said Harley, who also is affiliated with the Carl R. Woese Institute for Genomic Biology at the U. of I.
One of the major tools that oncologists use to treat leukemia and lymphoma involves transplanting HSCs. The donor stem cells must locate marrow cavities and start producing blood and immune cells. However, there is a limited quantity of available donor HSCs and the success rate of transplantation is low.
“We’re interested in this problem from an engineering standpoint,” Harley said. “The goal is to create better tools to both expand the number of donor HSCs and improve their capacity to repopulate the bone marrow after transplantation.”
Like cells throughout the body, HSCs are contained in a three-dimensional tissue environment known as the extracellular matrix. Harley and Choi gathered samples of HSCs from mice and then grew them in the laboratory using biomaterials engineered to mimic some of the extracellular matrix properties of the native bone marrow. Their goal was to examine how these engineered systems could alter the HSCs’ capacity to proliferate and differentiate to become blood cells.
The researchers examined two main elements of the matrix that regularly interact with HSCs: collagen and fibronectin. They found that the HSCs that were exposed to collagen proliferated more rapidly but that they had differentiated, meaning they were no longer stem cells. When exposed to fibronectin, the stem cells proliferated less rapidly, but were able to maintain their stem cell-like nature.
“With the collagen substrates, we got more cells but not useful cells,” Harley said. “With the right combination of stiffness in the matrix and the presence of fibronectin, we identified a class of biomaterials that show promise for being able to maintain and eventually expand these stem cells outside of the body. An engineered bone marrow will be of enormous value for treating hematopoietic cancers such as leukemia, but also for understanding the process of bone marrow failure and other hematopoietic diseases.”
This project is only the first step in controlling the signals from the matrix that influence HSCs, Harley said. He and other researchers in his lab are currently investigating other features of the matrix that can be manipulated to increase the number of stem cells and make them more effective in transplantation.
“We believe that ours is the first study to demonstrate a beneficial effect of lung-directed resveratrol treatments on aging lung function,” said Driscoll.
Resveratrol (RSL), a chemical found in red wine, is an antimicrobial chemical substance produced by plants to protect against infection and stress-related changes. It has previously been shown to support muscle metabolism when delivered orally.
RSL prophylaxis by inhalation was a novel measure taken by the research team as a potential approach for slowing age-related deterioration of lung function and structure by preserving alveolar epithelial type 2 cells (AEC2) which line alveoli (the tiny air sacs in the lungs through which the exchange of oxygen and carbon dioxide takes place) and produce surfactant which is vital for efficient breathing.
In healthy young adults, breathing is an essential, efficient process, but natural aging of the lung occurs at a steady and irreversible rate, as measured by a decline in lung function. This natural deterioration leads to a significantly reduced quality of life, over a time frame dependent on genetic and environmental factors. Although some available therapies can ameliorate symptoms, aging-related lung failure is generally irreversible and is accompanied by high rates of morbidity and mortality due to increased disease risk, including development of COPD, with accompanying emphysema and chronic bronchitis.
Using a rapidly aging mouse model, the research team investigated whether the accumulation of age-related degenerative changes in the lung could be slowed by inhaled RSL. Treatment cohorts received either RSL or vehicle by intratracheal (IT) instillation monthly for three months. One month following the final treatment, whole lung function and injury-related gene expression in AEC2 were assessed.
The research team found that inhaled, prophylactic resveratrol treatments can slow the rate of lung function decline, alveolar enlargement and alveolar epithelial type 2 cell DNA damage that occurs in the early stages of lung aging. They concluded that administration of resveratrol directly to the lungs may be an effective intervention for lung aging, which is a significant risk factor for development of chronic lung disease.
“While the natural deterioration of the human lung generally occurs over decades, the injury to lung cells is analogous to the lung cell damage that occurs in premature infants who experience respiratory distress before their lungs have fully developed,” added Driscoll. “Identifying a way to protect and strengthen young lungs before significant damage occurs is the goal of our research.”
Researchers report that brain scans can help predict how people will perform a challenging mental task, a discovery that could lead to a better understanding of how the mind learns new things.
The researchers found that what they once thought was “noise” in the brain, like static from a television, actually plays a major role and “is very important for understanding how the brain does things,” said study author Dr. Maurizio Corbetta, a professor of neurology at Washington University at St. Louis.
This means a brain scan has the potential to act as a kind of crystal ball, he said: “One of the most exciting things we could do is look at the brain activity and do more to try to predict what the brain is going to do next.”
The study authors scanned the brains of 14 people — seven men and seven women — using functional MRI to measure bursts of activity in the brain. The researchers tracked the brains of the volunteers as they learned how to better use their peripheral vision through a computer game.
In the game, participants learned to detect the presence or absence of a tilted letter “T” in the lower left side of a screen while they were distracted by other “T”s. It took about a week for the participants to figure out how to get to the level where their responses were correct 80 percent of the time. This is in contrast to the level of about 10 percent to 20 percent, where some participants began, Corbetta said.
The game is similar to day-to-day life in the way that you have to figure out what to pay attention to as you navigate the world. “It’s always a balance as to what you see and what you pay attention to,” he said.
The researchers found that the level of connectivity in the visual-oriented part of the brain predicted which people would do better on the test and learn more quickly, Corbetta said. “If you have a visual system that is strongly connected, then you are more likely to perform the task well.”
The research is important because scientists still need to better understand how the brain learns, he said. While people can train themselves to be better at specific tasks, skills don’t always translate to other tasks, he said.
“This is a big problem when we do rehab with patients,” he said. “We can retrain them on one task, but that doesn’t always translate to real life.”
Dr. Gary Small, a brain researcher and director of the University of California at Los Angeles Center on Aging, said the finding is interesting but doesn’t have practical implications at the moment. The idea of predicting what the brain will do next — potentially a form of mind reading — is still far in the future, he said.
“That’s the next step, to measure perceptions and ideas,” he said. “I think that’s in the realm of science, but we’re not quite there yet.”
An investigational drug called pridopidine seems an effective and safe treatment for people with the progressive movement disorder Huntington’s disease, researchers report.
Huntington’s patients have an imbalance in the signaling chemical dopamine. The new drug stabilizes dopamine signaling in areas of the brain that control movement and coordination.
According to the study authors, this is the first drug shown to improve patients’ loss of ability to move their muscles voluntarily. The only drug currently approved for Huntington’s is tetrabenazine, which treats only involuntary movements and can cause serious side effects.
The results of the phase 3 clinical trial, conducted by Spanish researchers led by Dr. Justo Garcia de Yebenes, of the department of neurology, Hospital Ramon y Cajal in Madrid, appear in the Nov. 7 online edition of The Lancet Neurology.
The study included 437 Huntington’s disease patients from eight European countries. The participants took either pridopidine (45 milligrams once daily or 45 mg twice daily) or a placebo for 26 weeks.
After six months of treatment, patients taking the higher dose of pridopidine showed improvements in motor function — specifically in eye and hand movements, involuntary muscle contractions (dystonia), and gait and balance — compared with patients taking the placebo.
More than 70 percent of the patients taking the higher dose of the drug showed a significant benefit, according to the researchers. Side effects among patients taking the drug were similar to the placebo group.
“Pridopidine has the potential to complement available treatments by improving a different range of motor deficits. Its lack of severe side-effects . . . suggests that pridopidine might be useful even for those patients who are treated at sites that are not centers of excellence for Huntington’s disease,” the researchers concluded.
One U.S. neurologist agreed that the drug seems promising against a disease with few treatment options.
“There has been a great deal of attention for this drug, as it is one of the few molecules that in preliminary studies was found to have some efficacy in Huntington’s disease,” said Dr. Alessandro Di Rocco, professor in the department of neurology and chief of the division of movement disorders at NYU Langone Medical Center in New York City.
“However, this is the first large study to show evidence of a positive result in treating the motor symptoms of this devastating disease. And, though the compound is apparently well tolerated without significant side effects, the benefit is modest and limited to the motor symptoms of the disease and it is unknown how long the improvement observed could last,” he added.
Still, pridopidine does not get at the underlying cause of Huntington’s disease, Di Rocco said.
“Unfortunately, Huntington’s is a progressive disease and this drug is not a treatment of the disease itself but only improves some of its symptoms,” he explained. “Nevertheless, it is a welcome addition because there is very little else yet available to treat the symptoms. The challenge for scientists and clinicians is to discover therapies that actually slows or halts the progression of the disease.”
Another expert agreed that new treatment options for patients are sorely needed.
“A well-tolerated drug that produces even small benefits for patients with Huntington’s disease would be a very welcome addition to the currently available treatments for this debilitating disorder,” Andrew Feigin, from The Feinstein Institute for Medical Research in New York City, wrote in an accompanying commentary.